KR20010020590A - Glucagon antagonists/inverse agonists - Google Patents

Glucagon antagonists/inverse agonists Download PDF

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KR20010020590A
KR20010020590A KR1019997012562A KR19997012562A KR20010020590A KR 20010020590 A KR20010020590 A KR 20010020590A KR 1019997012562 A KR1019997012562 A KR 1019997012562A KR 19997012562 A KR19997012562 A KR 19997012562A KR 20010020590 A KR20010020590 A KR 20010020590A
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lower alkyl
aryl
hydrogen
compound
nmr
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KR1019997012562A
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Korean (ko)
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안소니 링
블라드 그레거
자비어 곤잘레스
여펭 홍
단 키엘
아츠오 쿠키
솅후아 쉬
라르스 나에름
페테르 매드센
크리스티안 샘스
제스페르 라우
미카엘 브루노 플레베
준 펭
민 텡
마이클 데이비드 존슨
킴벌리 앤 테스톤
울라 그로베 시델만
롯테 브제레 크누드센
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한센 핀 베네드, 안네 제헤르, 웨이콥 마리안느
노보 노르디스크 에이/에스
개리 이. 프라이드만
아구론 파마슈티컬스, 인크.
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Publication of KR20010020590A publication Critical patent/KR20010020590A/en

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Abstract

중심의 히드라지드 모티브로 이루어지는 비펩티드계 화합물 및 그것의 합성방법. 이 화합물은 글루카곤 펩티드 호르몬의 작용을 길항하는 것으로 작용한다.A non-peptide compound composed of a central hydrazide motif and a method for synthesizing it. This compound acts to antagonize the action of glucagon peptide hormone.

Description

글루카곤 길항제/역 효현제{GLUCAGON ANTAGONISTS/INVERSE AGONISTS}Glucagon antagonist / inverse agonist {GLUCAGON ANTAGONISTS / INVERSE AGONISTS}

글루카곤은 인슐린과 협력하여 혈중 글루코오스 양의 항상적 조절을 매개하는 핵심 호르몬 작용제이다. 글루카곤은 기본적으로 혈중 글루코오스 레벨이 떨어질 때, 특정 세포(대부분 간세포)를 자극시켜 글루코오스를 유리시킴으로써 작용한다. 글루카곤의 작용은, 혈중 글루코오스 레벨이 오를 때 세포가 글루코오스를 흡수하여 저장하도록 자극시키는 인슐린에 반대된다. 글루카곤 및 인슐린 둘다 펩티드 호르몬이다.Glucagon is a key hormonal agent that, in cooperation with insulin, mediates the homeostatic regulation of glucose levels in the blood. Glucagon basically works by stimulating certain cells (mostly hepatocytes) to release glucose when blood glucose levels drop. Glucagon's action is opposed to insulin, which stimulates cells to absorb and store glucose when blood glucose levels rise. Both glucagon and insulin are peptide hormones.

글루카곤은 췌장의 알파 소도세포(islet cell)에서 생산되고, 인슐린은 췌장의 베타 소도세포에서 생산된다. 글루코오스 대사의 흔한 장애인 당뇨병은 고혈당으로 특징되고 특성상 인슐린 의존성인 타입 I 또는 비인슐린 의존성인 타입 II로서 나타낼 수 있다. 타입 I 당뇨병을 가진 환자는 고혈당 및 저인슐린혈증의 상태에 있고, 이 형태의 질병에 대한 종래의 치료는 인슐린을 제공하는 것이다. 그러나 타입 I 또는 II 당뇨병을 가진 몇몇 환자에서는, 절대적 또는 상대적으로 상승된 글루카곤 레벨이 고혈당 상태에 기여하는 것으로 밝혀졌다. 타입 I 및 II의 동물모델 뿐만 아니라 건강한 동물 둘다에서, 선택적이고 특이적 항체로 순환하는 글루카곤를 제거하는 것이 혈당 레벨의 감소를 초래하였다(Brand et al. Diabetologia 37, 985(1994); Diabetes 43, [suppl 1], 172A (1994); Am J Physiol 269, E469-E477 (1995); Diabetes 44[suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). 이들 연구는 글루카곤의 억제 또는 글루카곤에 대한 길항작용이 당뇨병에 대한 종래의 항고혈당 치료의 보조에 유용할 수 있는 것을 제안한다. 글루카곤의 작용은 글루카곤에 의해 유도되는 반응을 억제하거나 예방하는 물질인 길항제 또는 역 효현제를 제공함으로써 억제시킬 수 있다. 길항제는 사실상 펩티트계이거나 비펩티드계가 될 수 있다. 원래 글루카곤은 다음 서열을 가지는 29개의 아미노산으로 이루어지는 펩티드이다.Glucagon is produced in the pancreatic alpha islet cells, and insulin is produced in the pancreatic beta islet cells. Common disorders of glucose metabolism Diabetes is characterized by hyperglycemia and may be characterized as type I which is insulin dependent or type II which is non-insulin dependent. Patients with type I diabetes are in a state of hyperglycemia and hypoinsulinemia, and conventional treatment for this type of disease is to provide insulin. However, in some patients with type I or II diabetes, absolute or relatively elevated glucagon levels have been found to contribute to hyperglycemic conditions. In both healthy and animal models of type I and II, eliminating glucagon circulating with selective and specific antibodies resulted in a decrease in blood glucose levels (Brand et al. Diabetologia 37, 985 (1994); Diabetes 43, [ suppl 1], 172A (1994); Am J Physiol 269, E469-E477 (1995); Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that inhibition of glucagon or antagonism against glucagon may be useful in assisting conventional antihyperglycemic treatment for diabetes. The action of glucagon can be inhibited by providing antagonists or inverse agonists that are substances that inhibit or prevent the reaction induced by glucagon. Antagonists can be either peptide based or non-peptide based. Glucagon is originally a peptide consisting of 29 amino acids with the following sequence:

His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH2.His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp- Leu-Met-Asn-Thr-NH 2 .

글루카곤은 7-막통과 G-단백질에 결합된 수용체 집합체의 글루카곤-세크레틴부분의 일부인 그것의 수용체에 결합하고 활성화시킴으로써 그 작용을 수행한다(Jelinek et al. Science 259, 1614, (1993)). 수용제는 아데닐 사이클라제 2차 전령계를 활성화시킴으로써 기능하고 그 결과로 cAMP 레벨이 증가한다.Glucagon performs its action by binding to and activating its receptor, which is part of the glucagon-secretin portion of the receptor aggregate bound to 7-membrane and G-protein (Jelinek et al. Science 259, 1614, (1993)). Receptors function by activating the adenyl cyclase secondary messenger system, resulting in increased cAMP levels.

몇몇 공보는 펩티드계 길항제를 개시한다. 아마도, 가장 완전히 특성이 규명된 길항제는 DesHis1[Glu9]-글루카곤 아미드(Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993))이다. 다른 길항제는 예컨대 DesHis1,Phe6[Glu9]-글루카곤 아미드(Azizh et al., Bioorganic & Medicinal Chem. Lett. 16, 1849 (1995)) 또는 NLeu9,Ala11,16-글루카곤 아미드(Unson et al., J. Biol. Chem. 269(17), 12548 (1994))이다.Some publications disclose peptide based antagonists. Perhaps the most fully characterized antagonist DesHis 1 [Glu 9 ] -glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662). (1993). Other antagonists such as DesHis 1 , Phe 6 [Glu 9 ] -glucagon amide (Azizh et al., Bioorganic & Medicinal Chem. Lett. 16, 1849 (1995)) or NLeu 9 , Ala 11,16 -glucagon amide (Unson et al., J. Biol. Chem. 269 (17), 12548 (1994)).

펩티드 호르몬의 펩티드계 길항제는 자주 매우 강력하다; 그러나, 이들은 생리적 효소에 의한 분해 및 불량한 생분포로 인해 약물로서는 결점을 가진다. 그러므로 펩티드 호르몬의 비펩티드계 길항제가 바람직하다. 비펩티드계 글루카곤 길항제중, 퀴녹살린 유도체, 즉 (2-스티릴-3-[3-(디메틸아미노)프로필메틸아미노]-6,7-디클로로퀴녹살린이 래트의 간 수용체로부터 글루카곤을 치환하는 것으로 밝혀졌다(Collins, J.L. et al. (1992) Bioorganic and Medicinal Chemistry Letters 2(9):915-918). West R.R. 등(1994), WO 94/14426은 글루카곤 길항제로서 한 쌍의 연결된 9,10-안트라세네디온기와 그것의 합성 유사체로 이루어지는 천연 생성물 스키린(skyrin)의 사용을 개시한다. Anderson, P.L., 미국특허번호 4,359,474는 1-페닐 피라졸 유도체의 글루카곤 길항제 성질을 개시한다. Barcza, S., 미국특허번호 4,374,130은 글루카곤 길항제로서 치환 디실라시클로헥산을 개시한다. WO 98/04528(Bayer Corporation)은 글루카곤 길항제로서 치환 피리딘 및 비페닐을 개시한다. 게다가, WO 97/16442(Merck & Co., Inc.)는 글루카곤 길항제로서 치환 피리딜 피롤을 개시하고 WO 98/21957(Merck & Co., Inc.)은 글루카곤 길항제로서 2,4-디아릴-5-피리딜이미다졸을 개시한다. 이들 글루카곤 길항제는 구조적으로 본 발명의 화합물과 다르다.Peptide antagonists of peptide hormones are often very potent; However, they have drawbacks as drugs due to degradation by physiological enzymes and poor biodistribution. Therefore, nonpeptide antagonists of peptide hormones are preferred. Among non-peptide-based glucagon antagonists, quinoxaline derivatives, namely (2-styryl-3- [3- (dimethylamino) propylmethylamino] -6,7-dichloroquinoxaline, are substituted for glucagon from rat liver receptors. (Collins, JL et al. (1992) Bioorganic and Medicinal Chemistry Letters 2 (9): 915-918) .West RR et al. (1994), WO 94/14426, are a pair of linked 9,10- as glucagon antagonists. The use of the natural product skirin, consisting of anthracenedione groups and synthetic analogs thereof, discloses Anderson, PL, US Pat. No. 4,359,474, which discloses the glucagon antagonist properties of 1-phenyl pyrazole derivatives. US Pat. No. 4,374,130 discloses substituted disilacyclohexane as a glucagon antagonist, WO 98/04528 (Bayer Corporation) discloses substituted pyridine and biphenyl as glucagon antagonists, as well as WO 97/16442 (Merck & Co. , Inc.) as a glucagon antagonist Discloses ring pyridyl pyrroles and WO 98/21957 (Merck & Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists These glucagon antagonists are structurally present invention It is different from compound.

본 발명은 글루카곤 펩티드 호르몬의 작용을 길항하는 작용제에 관한 것이다. 본 발명은 특히 비펩티드계 글루카곤 길항제 또는 역 효현제에 관한 것이다.The present invention relates to agents that antagonize the action of glucagon peptide hormone. The present invention relates in particular to non-peptide based glucagon antagonists or inverse agonists.

정의Justice

다음은 본 발명의 화합물을 설명하는 데 사용되는 용어의 상세한 정의이다.The following is a detailed definition of the terms used to describe the compounds of the present invention.

"할로겐"은 F, Cl, Br 또는 I로 구성되는 군으로부터 선택된 원자를 나타낸다."Halogen" refers to an atom selected from the group consisting of F, Cl, Br or I.

본 문맥에서 용어 "알킬"은 1 내지 10개의 탄소원자의 치환 또는 비치환 탄화수소 사슬 또는 고리를 가리키는 데 선형 또는 분지형 또는 고리형의 형태를 가질 수 있다. 따라서 알킬은 예컨대, n-옥틸, 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, tert-부틸, 알릴, 프로파르길, 2-헥신일, 시클로프로필, 시클로프로필메틸, 시클로펜틸, 시클로헥실, 시클로옥틸, 4-시클로헥실부틸 등을 포함한다.The term "alkyl" in this context may refer to a substituted or unsubstituted hydrocarbon chain or ring of 1 to 10 carbon atoms and may have a linear or branched or cyclic form. Thus alkyl is for example n-octyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, propargyl, 2-hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl , Cyclooctyl, 4-cyclohexylbutyl, and the like.

추가의 제한없는 예로서는, sec-부틸, n-펜틸, 이소펜틸, 네오펜틸, tert-펜틸, n-헥실, 이소헥실, n-헵틸, n-노닐, n-데실, 비닐, 1-프로펜일, 1-부텐일, 2-부텐일, 3-부텐일, 2-메틸-1-프로펜일, 1-펜텐일, 2-펜텐일, 3-펜텐일, 4-펜텐일, 3-메틸-2-부텐일, 1-헥센일, 3-헥센일, 2,4-헥사디에닐, 5-헥센일, 1-헵텐일, 2,4-헵타디에닐, 1-옥텐일, 2,4-옥타디에닐, 에틴일, 1-프로핀일, 1-부틴일, 2-부틴일, 3-부틴일, 1-펜틴일, 2-펜틴일, 3-펜틴일, 4-펜틴일, 1-헥신일, 3-헥신일, 2,4-헥사딘일, 5-헥신일, 1-헤핀일, 1-옥틴일, 2-데신일, 시클로부틸, 시클로펜틸, 1-시클로펜텐일, 2-시클로펜텐일, 3-시클로펜텐일, 1-시클로헥센일, 2-시클로헥센일, 3-시클로헥센일, 2-시클로프로필에틸, 시클로부틸메틸, 2-시클로부틸에틸, 시클로헥센일메틸, 4-시클로헥실-2-부텐일, 4-(1-시클로헥센일)-비닐 등을 들 수 있다.Further non-limiting examples include sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohhexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2- Butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4-octadiee Neyl, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentinyl, 2-pentinyl, 3-pentinyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadinyl, 5-hexynyl, 1-hepinyl, 1-octinyl, 2-decynyl, cyclobutyl, cyclopentyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclohexenylmethyl, 4-cyclohexyl- 2-butenyl, 4- (1-cyclohexenyl) -vinyl, etc. are mentioned. Can be.

용어 "저급 알킬"은 1 내지 6개의 탄소 원자의 상기 특정된 탄화수소부분을 가리킨다.The term "lower alkyl" refers to the hydrocarbon moiety specified above of 1 to 6 carbon atoms.

"아릴"은 방향족 고리부분, 예컨대; 페닐, 나프틸, 푸릴, 티엔일, 피롤일, 피리딜, 피리미딘일, 피라졸릴, 이미다졸릴, 피라진일, 피리다진일, 1,2,3-트리아진일, 1,2,4-트리아진일, 옥사졸릴, 이속사졸릴, 1,2,3-옥사디아졸릴, 1,2,4-옥사디아졸릴, 1,3,4-옥사디아졸릴, 1,2,3-티아디아졸릴, 1,2,4-티아디아졸릴, 1,3,4-티아디아졸릴, 티아졸릴, 이소티아졸릴, 테트라졸릴, 1-H-테트라졸-5-일, 인돌일, 퀴놀릴, 퀴나졸리닐, 벤조푸릴, 벤조티오페닐(티아나프텐일) 등을 의미한다."Aryl" refers to an aromatic ring moiety, such as; Phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-tria True, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1 , 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, 1-H-tetrazol-5-yl, indolyl, quinolyl, quinazolinyl, Benzofuryl, benzothiophenyl (thianaphthenyl) and the like.

추가의 제한없는 예로서는 비페닐, 안트라센일, 펜안트렌일, 플루오렌일, 인데닐, 1,2,3,4-테트라히드로나프틸, 2,3-디히드로벤조푸릴, 트리아졸릴, 피란일, 티아디아진일, 이소인돌릴, 인다졸릴, 1,2,5-옥사디아졸릴, 1,2,5-티아디아졸릴, 벤조티에닐, 벤즈이미다졸릴, 벤즈티아졸릴, 벤즈이소티아졸릴, 벤족사졸릴, 벤즈이속사졸릴, 푸린일, 퀴놀리진일, 이소퀴놀릴, 퀴녹살린일, 나프티리딘일, 프테리딘일, 카르바졸릴, 아크리딘일, 피롤린일, 피라졸린일, 인돌린일, 피롤리딘일, 피페리딘일 등을 들 수 있다.Further non-limiting examples include biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyl, pyranyl, Thiadizinyl, isoindolyl, indazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, ben Joxazolyl, benzisoxazolyl, purinyl, quinolizyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pterridylyl, carbazolyl, acridinyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrroli Dinyl, piperidinyl, etc. are mentioned.

아릴 부분은 예컨대 F, Cl, I 및 Br; 저급 알킬; 포르밀, 아세틸, 프로피오닐, 부티릴, 발레릴, 헥산오일 등의 저급 알칸오일; -OH; -NO2; -CN; -CO2H; -O-저급 알킬; 아릴; 아릴-저급 알킬; -CO2CH3; -CONH2; -OCH2CONH2; -NH2; -N(CH3)2; -SO2NH2; -OCHF2; -CF3; -OCF3등으로 구성되는 군에서 선택된 1개 이상의 치환기로 선택적으로 치환된다. 추가의 제한없는 예는 -NH-(C=S)-NH2이다.The aryl moiety is for example F, Cl, I and Br; Lower alkyl; Lower alkan oils such as formyl, acetyl, propionyl, butyryl, valeryl, hexane oil and the like; -OH; -NO 2 ; -CN; -CO 2 H; -O-lower alkyl; Aryl; Aryl-lower alkyl; -CO 2 CH 3 ; -CONH 2 ; -OCH 2 CONH 2 ; -NH 2 ; -N (CH 3 ) 2 ; -SO 2 NH 2 ; -OCHF 2 ; -CF 3 ; -Is optionally substituted with one or more substituents selected from the group consisting of -OCF 3 and the like. A further non-limiting example is -NH- (C = S) -NH 2 .

이러한 아릴 부부은 예컨대 -OCH2O-와 같은 다리를 형성하는 2개의 치환기로 치환될 수 있다.Such aryl couples may be substituted with two substituents that form a bridge, such as, for example, -OCH 2 O-.

"아릴-저급 알킬"은 아릴로 치환된, 상기 정의된 바와 같은 저급 알킬을 의미한다. 예:"Aryl-lower alkyl" means lower alkyl as defined above substituted with aryl. Yes:

아릴기는 상기 정의된 바와 같이 선택적으로 치환된다.Aryl groups are optionally substituted as defined above.

발명의 설명Description of the invention

본 발명은 하기 개시된 선택된 질소함유 중심 모티브와 일반적인 구조적 특징을 가진 화합물이 글루카곤의 작용을 길항하는 예상치 못한 관찰에 근거한 것이다.The present invention is based on the unexpected observation that selected nitrogen-containing central motifs and compounds with general structural features disclosed below antagonize the action of glucagon.

따라서, 본 발명은 다음 화학식 I의 화합물과 그것의 모든 광학이성체 또는 기하이성체 또는 이들의 혼합물을 포함하는 호변체 형태 또는 그것의 약학적으로 허용되는 염에 관한 것이다.Accordingly, the present invention relates to tautomeric forms or pharmaceutically acceptable salts thereof comprising the compounds of formula (I) and all of the optical isomers or geometric isomers or mixtures thereof.

상기 식에서:Where:

R1및 R2는 독립적으로 수소 또는 저급 알킬이거나, 또는 함께 원자가 결합을 형성하고;R 1 and R 2 are independently hydrogen or lower alkyl, or together form a valent bond;

R3및 R4는 독립적으로 수소 또는 저급 알킬이고,R 3 and R 4 are independently hydrogen or lower alkyl,

n은 0, 1, 2 또는 3이고;n is 0, 1, 2 or 3;

m은 0 또는 1이고;m is 0 or 1;

X는 >C=O, >C=S, >C=NR5또는 >SO2이고;X is> C = O,> C = S,> C = NR 5 or> SO 2 ;

상기 식에서, R5는 수소, 저급 알킬, 아릴-저급 알킬 또는 -OR6이고;In which R 5 is hydrogen, lower alkyl, aryl-lower alkyl or —OR 6 ;

상기 식에서 R6는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이다;R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

A는A is

이고: 상기 식에서,And: wherein

R7은 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SO2NR11R12, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -OCH2CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13또는 -OSO2CF3이며;R 7 is hydrogen, halogen, -CN, -CF 3, -OCF 3 , -OCH 2 CF 3, -NO 2, -OR 11, -NR 11 R 12, lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SO 2 NR 11 R 12 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -OCH 2 CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 ;

R8및 R9는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13또는 -OSO2CF3이거나, 또는 R8및 R9는 함께 다리 -OCH2O- 또는 -OCH2CH2O-를 형성하고;R 8 and R 9 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 , or R 8 and R 9 together form a bridge —OCH 2 O— or —OCH 2 CH 2 O—;

상기 식에서, R11및 R12는 독립적으로 수소, -COR13, -SO2R13, 저급 알킬 또는 아릴이고;Wherein R 11 and R 12 are independently hydrogen, —COR 13 , —SO 2 R 13 , lower alkyl or aryl;

상기 식에서, R13은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;In which R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;

R10은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;

B는B is

이고, 또는 원자가 결합이며:Or a valence bond:

상기 식에서, R14및 R15는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -O(CH2)lCF3, -NO2, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)lCONR16R17, -O(CH2)lCONR16R17, -(CH2)lCOR16, -(CH2)lCOR16, -(CH2)lOR16, -(CH2)lOR16, -(CH2)lNR16R17, -O(CH2)lNR16R17, -OCOR16, -CO2R18또는 -O(CH2)lCO2R18, -O(CH2)lCN, -O(CH2)lCl, 또는 R14및 R15는 함께 다리 -O(CH2)lO- 또는 -(CH2)l-를 형성하고;Wherein R 14 and R 15 are independently hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —O (CH 2 ) 1 CF 3 , —NO 2 , —OR 16 , —NR 16 R 17 , Lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 ,-(CH 2 ) l CONR 16 R 17 , -O (CH 2 ) l CONR 16 R 17 ,-(CH 2 ) l COR 16 ,-(CH 2 ) l COR 16 ,-(CH 2 ) l OR 16 ,-(CH 2 ) l OR 16 ,-(CH 2 ) l NR 16 R 17 , -O (CH 2 ) l NR 16 R 17 , -OCOR 16 , -CO 2 R 18 or -O (CH 2 ) l CO 2 R 18 , -O (CH 2 ) 1 CN, —O (CH 2 ) 1 Cl, or R 14 and R 15 together form a bridge —O (CH 2 ) 1 O— or — (CH 2 ) 1 —;

상기 식에서 l은 1, 2, 3 또는 4이고;Wherein l is 1, 2, 3 or 4;

R16및 R17은 독립적으로 수소, -COR18, -SO2R18, 저급 알킬, 아릴이거나, 또는 R16및 R17이 함께 2 내지 7개의 탄소원자를 포함하는 고리형 알킬 다리를 형성하고;R 16 and R 17 are independently hydrogen, —COR 18 , —SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing 2 to 7 carbon atoms;

상기 식에서 R18은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

W는 -N= 또는 -CR19=이고;W is -N = or -CR 19 =;

Y는 -N= 또는 -CR20=이고;Y is -N = or -CR 20 =;

Z는 -N= 또는 -CR21=이고;Z is -N = or -CR 21 =;

V는 -N= 또는 -CR22=이고;V is -N = or -CR 22 =;

Q는 -NR23-, -O- 또는 -S-이고;Q is -NR 23- , -O- or -S-;

상기 식에서, R19, R20, R21및 R22는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24또는 -CO2R24이거나, 또는 R19및 R20, R20및 R21, 또는 R21및 R22는 함께 다리 -OCH2O-를 형성하고;Wherein R 19 , R 20 , R 21 and R 22 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 24 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 , Or R 21 and R 22 together form a bridge -OCH 2 O-;

상기 식에서, R24및 R25는 독립적으로 수소, -COR26, -SO2R26, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;Wherein R 24 and R 25 are independently hydrogen, —COR 26 , —SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl;

상기 식에서, R26은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R23은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

K는K is

이고: 상기 식에서, R3a, R3b, R4a및 R4b는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a또는 -CO2R24a이고;Wherein: R 3a , R 3b , R 4a and R 4b are independently hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —NO 2 , —OR 24a , —NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 25a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ;

상기 식에서, R24a및 R25b는 독립적으로 수소, -COR26a, -SO2R26a, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;Wherein R 24a and R 25b are independently hydrogen, —COR 26a , —SO 2 R 26a , lower alkyl, aryl or aryl-lower alkyl;

상기 식에서, R26a는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

또는 R3a및 R3b, R4a및 R4b, 또는 R3a및 R4b는 함께 다리 -(CH2)i-를 형성하고;Or R 3a and R 3b , R 4a and R 4b , or R 3a and R 4b together form a bridge — (CH 2 ) i —;

상기 식에서, i는 1, 2, 3 또는 4이고;Wherein i is 1, 2, 3 or 4;

a, b, c 및 d는 독립적으로 0, 1, 2, 3 또는 4이고;a, b, c and d are independently 0, 1, 2, 3 or 4;

e, f 및 p는 독립적으로 0 또는 1이고;e, f and p are independently 0 or 1;

q는 0, 1 또는 2이고;q is 0, 1 or 2;

L 및 M은 독립적으로 -O-, -S-, -CH=CH-, -C≡C-, -NR5a, -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5aSO2-, -NR5aCONR5b-, -CONR5aNR5b-, -NR5aCSNR5b-, -OCONR5b-, -CH2CONR5b, -OCH2CONR5b-, -P(O)(OR5a)O-, -NR5aC(O)O- 또는L and M are independently selected from -O-, -S-, -CH = CH-, -C≡C-, -NR 5a, -CH 2 NR 5a -, -CO-, -OCO-, -COO-, - CONR 5a -, -CONR 5b -, -NR 5a CO-, -SO-, -SO 2 -, -OSO 2 -, -SO 2 NR 5a -, -NR 5a SO 2 -, -NR 5a CONR 5b -, -CONR 5a NR 5b -, -NR 5a CSNR 5b -, -OCONR 5b -, -CH 2 CONR 5b, -OCH 2 CONR 5b -, -P (O) (OR 5a) O-, -NR 5a C (O O- or

이고;ego;

상기 식에서, R5a및 R5b는 독립적으로 수소, 저급 알킬, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6aR6b, 아릴, 아릴-저급 알킬, -(CH2)g-COOR43또는 -(CH2)g-CF3이고;Wherein R 5a and R 5b are independently hydrogen, lower alkyl, -OH,-(CH 2 ) k -OR 6a , -COR 6a ,-(CH 2 ) k -CH (OR 6a ) 2 ,-(CH 2 ) k -CN,-(CH 2 ) k -NR 6a R 6b , aryl, aryl-lower alkyl,-(CH 2 ) g -COOR 43 or-(CH 2 ) g -CF 3 ;

상기 식에서, k는 1, 2, 3 또는 4이고;Wherein k is 1, 2, 3 or 4;

R6a및 R6b는 독립적으로 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 6a and R 6b are independently hydrogen, lower alkyl, aryl or aryl-lower alkyl;

g는 0, 1, 2, 3 또는 4이고;g is 0, 1, 2, 3 or 4;

R43은 수소 또는 저급 알킬이고;R 43 is hydrogen or lower alkyl;

G"는 -OCH2CO-, -CH2CO-, -CO- 또는 원자가 결합이고;G ″ is —OCH 2 CO—, —CH 2 CO—, —CO— or a valence bond;

E"는 -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- 또는 -CH2CH2NH-이고;E ″ is —CH 2 —, —CH 2 CH 2 —, —CH═CH—, —CH 2 NH— or —CH 2 CH 2 NH—;

D는 수소,D is hydrogen,

이고: 상기 식에서, r은 O 또는 1이고;Wherein: r is 0 or 1;

s는 0, 1, 2 또는 3이고;s is 0, 1, 2 or 3;

E, E', F, G 및 G'는 독립적으로 -CHR38-, >C=O, >NR39, -O- 또는 -S-이고;E, E ', F, G and G' are independently -CHR 38 -,> C = O,> NR 39 , -O- or -S-;

F'는 >CR38또는 >N-이고;F 'is> CR 38 or>N-;

Y'는 -N= 또는 -CR32=이고;Y 'is -N = or -CR 32 =;

Z'는 -N= 또는 -CR33=이고;Z 'is -N = or -CR 33 =;

V'는 -N= 또는 -CR34=이고;V 'is -N = or -CR 34 =;

W'는 -N= 또는 -CR35=; 및W 'is -N = or -CR 35 =; And

Q'는 -NR36-, -O- 또는 -S-이고;Q 'is -NR 36- , -O- or -S-;

상기 식에서, R27, R28, R32, R33, R34및 R35는 수소, 할로겐, -CN, -CF3, -O(CH2)yCF3, -(CH2)yNHCOCF3, -NO2, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -COR29또는 -CO2R29이거나;Wherein R 27 , R 28 , R 32 , R 33 , R 34 and R 35 are hydrogen, halogen, -CN, -CF 3 , -O (CH 2 ) y CF 3 ,-(CH 2 ) y NHCOCF 3 , -NO 2 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 ,- (CH 2 ) y CONR 29 R 30 , -O (CH 2 ) y CONR 29 R 30 ,-(CH 2 ) y OR 29 ,-(CH 2 ) y NR 29 R 30 , -OCOR 29 , -COR 29 or -CO 2 R 29 ;

R27및 R28, R32및 R33, R33및 R34, 또는 R34및 R35는 함께 -0(CH2)yO-를 형성하고;R 27 and R 28 , R 32 and R 33 , R 33 and R 34 , or R 34 and R 35 together form —0 (CH 2 ) y O—;

상기 식에서, y는 0, 1, 2, 3 또는 4이고;Wherein y is 0, 1, 2, 3 or 4;

R29및 R30은 독립적으로 수소, -COR31, -CO2R31, -SO2R31, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 29 and R 30 are independently hydrogen, —COR 31 , —CO 2 R 31 , —SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl;

상기 식에서, R31은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R36및 R39는 독립적으로 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 36 and R 39 are independently hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R38은 수소, -OR40, -NR40R41, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)xCONR40R41, -(CH2)xOR40, -(CH2)xNR40R41, -OCOR40또는 -CO2R40이고;R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 ,-(CH 2 ) x CONR 40 R 41 , -O (CH 2 ) x CONR 40 R 41 ,-(CH 2 ) x OR 40 ,-(CH 2 ) x NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ;

상기 식에서 x는 1, 2, 3 또는 4이고;In which x is 1, 2, 3 or 4;

R40및 R41은 독립적으로 수소, -COR42, -SO2R42, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 40 and R 41 are independently hydrogen, —COR 42 , —SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;

상기 식에서 R42는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이다.In which R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

B의 화학식이 존재한다면, R19, R20, R21, R22및 R23은 각각 R14, R15에 의해 치환될 수 있다. 이러한 경우, 예컨대 W는 -N=, -CR19- 및 -CR14-로부터 선택될 수 있다.If the formula of B is present, R 19 , R 20 , R 21 , R 22 and R 23 may be substituted by R 14 , R 15 , respectively. In this case, for example, W may be selected from -N =, -CR 19- , and -CR 14- .

유사하게, D의 화학식이 존재한다면, R32, R33, R34, R35, R36, R38및 R39는 대안적으로 R27또는 R28에 의해 치환될 수 있다. 이러한 경우, 예컨대 E는 -CHR38-, >C=O, >NR39, -O-, -S-, -CHR27- 및 >NR27로부터 선택될 수 있다.Similarly, if the formula of D is present, R 32 , R 33 , R 34 , R 35 , R 36 , R 38 and R 39 may alternatively be substituted by R 27 or R 28 . In this case, for example, E can be selected from -CHR 38 -,> C = O,> NR 39 , -O-, -S-, -CHR 27 -and> NR 27 .

바람직한 구체예에서, 본 발명은 다음 화학식 II의 화합물에 관한 것이다.In a preferred embodiment, the invention relates to compounds of the formula

상기 식에서, A, B, K, D, R3, R4, n 및 m은 화학식 I에서 정의된 바와 같다.Wherein A, B, K, D, R 3 , R 4 , n and m are as defined in formula (I).

또 다른 바람직한 구체예에서, 본 발명은 다음 화학식 III의 화합물에 관한 것이다.In another preferred embodiment, the invention relates to compounds of formula III

상기 식에서, A, B, K, D, R3, R4, n 및 m은 화학식 I에서 정의된 바와 같다.Wherein A, B, K, D, R 3 , R 4 , n and m are as defined in formula (I).

또 다른 바람직한 구체예에서, 본 발명은 다음 화학식 IV의 화합물에 관한 것이다.In another preferred embodiment, the invention relates to compounds of formula

상기 식에서, A, B, K, D, R3, R4, n 및 m은 화학식 I에서 정의된 바와 같다.Wherein A, B, K, D, R 3 , R 4 , n and m are as defined in formula (I).

상기 화학식 I 내지 IV의 화합물에서, 다음의 치환기가 바람직하다:In the compounds of the above formulas (I) to (IV), the following substituents are preferred:

R3은 바람직하게는 수소이다.R 3 is preferably hydrogen.

R4은 바람직하게는 수소이다.R 4 is preferably hydrogen.

A는 바람직하게는 다음으로 구성되는 군으로부터 선택된다:A is preferably selected from the group consisting of:

상기 식에서, R7, R8, R9및 R10은 화학식 I에서 정의된 바와 같다.Wherein R 7 , R 8 , R 9 and R 10 are as defined in formula (I).

A는 보다 바람직하게A is more preferably

이다. 상기 식에서 R7, R8및 R9은 화학식 I에서 정의된 바와 같다.to be. Wherein R 7 , R 8 and R 9 are as defined in formula (I).

A의 상기 구체예에서, R7은 바람직하게는 수소, 할로겐, 저급 알킬, -OH, -NO2, -CN, -CO2H, -O-저급 알킬, 아릴, 아릴-저급 알킬, -CO2CH3, -CONH2, -OCH2CONH2, -NH2, -N(CH3)2, -SO2NH2, -OCHF2, -CF3또는 -OCF3이며;In this embodiment of A, R 7 is preferably hydrogen, halogen, lower alkyl, -OH, -NO 2 , -CN, -CO 2 H, -O-lower alkyl, aryl, aryl-lower alkyl, -CO 2 CH 3 , -CONH 2 , -OCH 2 CONH 2 , -NH 2 , -N (CH 3 ) 2 , -SO 2 NH 2 , -OCHF 2 , -CF 3 or -OCF 3 ;

바람직하게는, R8및 R9는 독립적으로 수소, 할로겐, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, 메톡시 및 에톡시와 같은 O-저급 알킬, 메틸 및 에틸과 같은 저급 알킬, 또는 페닐이고, R10은 수소, 저급 알킬 또는 페닐이다.Preferably, R 8 and R 9 are independently hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 , -SCF 3 , -CF 3 , -OCH 2 CF 3 , methoxy And O-lower alkyl such as ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R 10 is hydrogen, lower alkyl or phenyl.

보다 바람직하게, R8및 R9는 수소, -F 및 -Cl과 같은 할로겐, 메톡시 및 에톡시와 같은 -O-저급 알킬, -NH2, -CN 또는 -NO2로부터 독립적으로 선택되고, R10은 수소이다.More preferably, R 8 and R 9 are independently selected from hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH 2 , -CN or -NO 2 , R 10 is hydrogen.

특히 바람직한 구체예에서, A는In a particularly preferred embodiment, A is

상기 식에서, R8및 R9는 독립적으로 수소, 할로겐, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, 메톡시 및 에톡시와 같은 O-저급 알킬, 메틸 및 에틸 과 같은 저급 알킬, 또는 페닐이고, 바람직하게는 수소, -F 및 -Cl과 같은 할로겐, 메톡시 및 에톡시와 같은 -O-저급 알킬, -NH2, -CN 또는 -NO2이다.Wherein R 8 and R 9 are independently hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 , -SCF 3 , -CF 3 , -OCH 2 CF 3 , methoxy and O-lower alkyl such as ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH 2 , -CN or -NO 2 .

이다.to be.

더 특히 바람직한 구체예에서, A는In a more particularly preferred embodiment, A is

이다. 상기 식에서, R8은 수소, -F 및 -Cl과 같은 할로겐, -OCH3또는 -OC2H5등의 -O-저급 알킬, -NH2, -CN 또는 -NO2이고; R9는 수소 또는 -F 및 -Cl과 같은 할로겐이다.to be. Wherein R 8 is hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as -OCH 3 or -OC 2 H 5 , -NH 2 , -CN or -NO 2 ; R 9 is hydrogen or halogen such as -F and -Cl.

바람직한 구체예에서, R8은 수소이고; R9는 수소이다.In a preferred embodiment, R 8 is hydrogen; R 9 is hydrogen.

보다 바람직한 구체예에서, 본 발명은 다음 화학식 V의 화합물에 관한 것이다.In a more preferred embodiment, the invention relates to compounds of formula

상기 식에서, R4, B, K, D 및 m은 화학식 I에서 정의된 바와 같고, R8및 R9는 화학식 I에서 정의된 바와 같고, 바람직하게는 상기 A의 바람직한 구체예에서 정의된 바와 같다.Wherein R 4 , B, K, D and m are as defined in formula I, R 8 and R 9 are as defined in formula I, preferably as defined in the preferred embodiment of A above .

B는 바람직하게는:B is preferably:

이고, 상기 식에서, V, W, Z, Y 및 Q는 화학식 I에서 정의된 바와 같고;Wherein V, W, Z, Y and Q are as defined in formula (I);

R14및 R15는 독립적으로 수소, 할로겐, -CF3, -OCF3, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16또는 -CO2R18; 또는 R14및 R15는 함께 다리 -OCH2O- 또는 -(CH2)l-를 형성하고;R 14 and R 15 are independently hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; Or R 14 and R 15 together form a bridge —OCH 2 O— or — (CH 2 ) 1 —;

상기 식에서, l, R16, R17및 R18은 화학식 I에서 정의된 바와 같다.Wherein R, R 16 , R 17 and R 18 are as defined in formula (I).

Q는 바람직하게 -O- 또는 -NH-이다.Q is preferably -O- or -NH-.

특히 바람직한 화합물은 B가Particularly preferred compounds are those

인 화합물이고, 상기 식에서, V, W, Z, Y 및 Q는 화학식 I에서 정의된 바와 같고;Phosphorus compound, wherein V, W, Z, Y and Q are as defined in formula (I);

R14및 R15는 독립적으로 수소, 할로겐, -CF3, -OCF3, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16또는 -CO2R18; 또는 R14및 R15는 함께 다리 -OCH2O- 또는 -(CH2)l-를 형성하고;R 14 and R 15 are independently hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; Or R 14 and R 15 together form a bridge —OCH 2 O— or — (CH 2 ) 1 —;

상기 식에서, l, R16, R17및 R18은 화학식 I에서 정의된 바와 같다.Wherein R, R 16 , R 17 and R 18 are as defined in formula (I).

보다 더 바람직하게는 다음 화학식 VI의 화합물이다.Even more preferred are compounds of formula VI.

다음 화학식 VII의 화합물도 바람직하다.Also preferred are compounds of formula (VII).

다음 화학식 VIIIa 또는 VIIIb의 화합물도 바람직하다.Also preferred are compounds of formula VIIIa or VIIIb.

또는or

R14및 R15는 독립적으로 수소, 할로겐, -CF3, -OCF3, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16또는 -CO2R18; 또는 R14및 R15는 함께 다리 -OCH2O- 또는 -(CH2)l-를 형성하고;R 14 and R 15 are independently hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; Or R 14 and R 15 together form a bridge —OCH 2 O— or — (CH 2 ) 1 —;

상기 식에서, l, R16, R17및 R18은 화학식 I에서 정의된 바와 같다.Wherein R, R 16 , R 17 and R 18 are as defined in formula (I).

K, D 및 m은 화학식 I에서 정의된 바와 같고,K, D and m are as defined in formula (I),

R8및 R9는 화학식 I에서 정의된 바와 같고, 바람직하게는 상기 A의 바람직한 구체예에서 정의된 바와 같다.R 8 and R 9 are as defined in formula (I), preferably as defined in preferred embodiments of A above.

상기 화학식 VI, VII 및 VIII에서, R14및 R15는 바람직하게 독립적으로 수소, 할로겐, 저급 알킬, 페닐과 같은 아릴, 또는 메톡시와 같은 -O-저급 알킬이다.In the above formulas VI, VII and VIII, R 14 and R 15 are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl or —O-lower alkyl such as methoxy.

상기 화학식 VI 및 VII에서, K는 바람직하게는 파라위치에 결합되고, 상기 화학식 VIIIa 및 VIIIb에서, K는 인돌기의 질소위치에 결합된다.In Formulas VI and VII, K is preferably bonded at the para position, and in Formulas VIIIa and VIIIb, K is bonded at the nitrogen position of the indole group.

K는 바람직하게 다음으로 구성되는 군으로부터 선택된다:K is preferably selected from the group consisting of:

상기 식에서, R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p 및 q는 화학식 I에서 정의된 바와 같다.Wherein R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined in formula (I).

보다 바람직하게는, K는 다음으로 구성되는 군으로부터 선택된다.More preferably, K is selected from the group consisting of:

상기 식에서, R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p 및 q는 화학식 I에서 정의된 바와 같다.Wherein R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined in formula (I).

보다 바람직한 구체예에서, K는 다음으로 구성되는 군으로부터 선택된다.In a more preferred embodiment, K is selected from the group consisting of

상기 식에서, R3a, R3b, R4a, R4b, R5a, R5b, b, c, d, p 및 q는 화학식 I에서 정의된 바와 같다.Wherein R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , b, c, d, p and q are as defined in formula (I).

K의 바람직한 구체예에서, R5a및 R5b는 바람직하게는 독립적으로 수소, 저급 알킬, -OH, -(CH2)kOR6a, 아릴, 아릴-저급 알킬, -CH2CF3, -(CH2)g-COOR43, -COOR43, -(CH2)k-CN 또는 -(CH2)k-NR6aR6b이고, 상기 식에서, g, k, R43, R6a및 R6b는 화학식 I에서 정의된 바와 같다.In a preferred embodiment of K, R 5a and R 5b are preferably independently hydrogen, lower alkyl, -OH,-(CH 2 ) k OR 6a , aryl, aryl-lower alkyl, -CH 2 CF 3 ,-( CH 2 ) g -COOR 43 , -COOR 43 ,-(CH 2 ) k -CN or-(CH 2 ) k -NR 6a R 6b , wherein g, k, R 43 , R 6a and R 6b are As defined in Formula (I).

바람직하게는, g 및 k는 독립적으로, 1, 2 또는 3이고, R6a및 R6b는 독립적으로 수소, 메틸 또는 에틸과 같은 저급 알킬, 페닐과 같은 아릴이다.Preferably, g and k are independently 1, 2 or 3 and R 6a and R 6b are independently hydrogen, lower alkyl such as methyl or ethyl, aryl such as phenyl.

K의 상기 구체예에서, R3a및 R3b는 바람직하게는 독립적으로 수소, 할로겐, -OH, -O-저급 알킬, -COO-저급 알킬, 저급 알킬 또는 아릴-저급 알킬이다.In this embodiment of K, R 3a and R 3b are preferably independently hydrogen, halogen, —OH, —O-lower alkyl, —COO-lower alkyl, lower alkyl or aryl-lower alkyl.

K의 상기 구체예에서, R4a및 R4b는 바람직하게는 독립적으로, 수소, -CN, -CONH2, -(CH2)-N(CH3)2, -O-저급 알킬, -CH2OH, -CH2O-아릴, -N(CH3)2, -OH, -CO2-저급 알킬 또는 저급 알킬이다.In this embodiment of K, R 4a and R 4b are preferably independently hydrogen, —CN, —CONH 2 , — (CH 2 ) —N (CH 3 ) 2 , —O-lower alkyl, —CH 2 OH, -CH 2 O-aryl, -N (CH 3 ) 2 , -OH, -CO 2 -lower alkyl or lower alkyl.

D는 바람직하게 수소,D is preferably hydrogen,

이고, 상기 식에서, s, r, R27, R28, V', Y', Q', Z', W', E, E', F, F', G 및 G'는 화학식 I에서 정의된 바와 같다.Wherein, s, r, R 27 , R 28 , V ', Y', Q ', Z', W ', E, E', F, F ', G and G' are defined in Formula (I) As shown.

보다 더 바람직한 구체예에서, D는 수소,In even more preferred embodiments, D is hydrogen,

이고, 상기 식에서, s, r, R27, R28, V', Y', Q', Z', W', E, E', F, F', G 및 G'는 화학식 I에서 정의된 바와 같다.Wherein, s, r, R 27 , R 28 , V ', Y', Q ', Z', W ', E, E', F, F ', G and G' are defined in Formula (I) As shown.

D는 보다 바람직하게는 수소,D is more preferably hydrogen,

이고, 상기 식에서, E 및 E'는 독립적으로 >CHR38, >NR39, -O-이고; F, G 및 G'는 독립적으로 >CHR38, >C=O, 또는 -NR39; F'는 >CR38- 또는 >N-이고; s, r, R27, R28, R38, R39, V', Y', Z', Q' 및 W'는 화학식 I에서 정의된 바와 같다.Wherein E and E 'are independently> CHR 38 ,> NR 39 , -O-; F, G and G 'are independently> CHR 38 ,> C = O, or -NR 39 ; F 'is> CR 38 -or>N-; s, r, R 27 , R 28 , R 38 , R 39 , V ', Y', Z ', Q' and W 'are as defined in formula (I).

R27및 R28은 수소; -Cl, -Br 또는 -F와 같은 할로겐; -CF3; -OCF3, -OCHF2; -OCH2CF3; -(CH2)yNHCOCF3; -NHCOCF3; -CN; -NO2; -COR29, -COOR29, -(CH2)yOR29또는 OR29이고, 상기 식에서, R29는 수소, 아릴 또는 저급 알킬이고, y는 1, 2, 3 또는 4이고; 메틸, 에틸, 2-프로펜일, 이소프로필, tert-부틸 또는 시클로헥실과 같은 저급 알킬; 저급 알킬티오; -SCF3; 페닐과 같은 아릴; -(CH2)yNR29R30또는 -NR29R30(상기 식에서, R27및 R28은 독립적으로 수소, -COO-저급 알킬 또는 저급 알킬이고, y는 1, 2, 3 또는 4이다); 또는 -CONH2; 또는 R27및 R28은 함께 다리 -OCH2O-를 형성하고; R38은 수소; -OCHF2; -OR40(상기 식에서, R40은 수소 또는 저급 알킬이다); 메틸, 이소프로필 또는 tert-부틸과 같은 저급 알킬; 저급 알킬티오; -SCF3; -CH2OH; -COO-저급 알킬 또는 -CONH2; 및 R39는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이다.R 27 and R 28 are hydrogen; Halogen, such as -Cl, -Br or -F; -CF 3 ; -OCF 3 , -OCHF 2 ; -OCH 2 CF 3 ; -(CH 2 ) y NHCOCF 3 ; -NHCOCF 3 ; -CN; -NO 2 ; -COR 29 , -COOR 29 ,-(CH 2 ) y OR 29 or OR 29 , wherein R 29 is hydrogen, aryl or lower alkyl, y is 1, 2, 3 or 4; Lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; Lower alkylthio; -SCF 3 ; Aryl such as phenyl; — (CH 2 ) y NR 29 R 30 or —NR 29 R 30 (wherein R 27 and R 28 are independently hydrogen, —COO-lower alkyl or lower alkyl, y is 1, 2, 3 or 4 ); Or -CONH 2 ; Or R 27 and R 28 together form a bridge —OCH 2 O—; R 38 is hydrogen; -OCHF 2 ; -OR 40 , wherein R 40 is hydrogen or lower alkyl; Lower alkyl such as methyl, isopropyl or tert-butyl; Lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl or -CONH 2 ; And R 39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

보다 바람직한 구체예에서, 본 발명은 다음의 화학식 I의 화합물에 관한 것이다.In a more preferred embodiment, the invention relates to compounds of formula (I)

상기 식에서, R1및 R2는 독립적으로 수소 또는 저급 알킬이거나, 또는 함께 원자가 결합을 형성하고;Wherein R 1 and R 2 are independently hydrogen or lower alkyl, or together form a valent bond;

R3및 R4는 독립적으로 수소 또는 저급 알킬이고,R 3 and R 4 are independently hydrogen or lower alkyl,

X는 >C=O, >C=S, >C=NR5또는 >SO2이고;X is> C = O,> C = S,> C = NR 5 or> SO 2 ;

n은 0, 1, 2 또는 3이고;n is 0, 1, 2 or 3;

m은 0 또는 1이고;m is 0 or 1;

R5는 수소, 저급 알킬, 아릴-저급 알킬 또는 -OR6이고;R 5 is hydrogen, lower alkyl, aryl-lower alkyl or —OR 6 ;

상기 식에서 R6는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이다;R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

A는A is

이고: R7은 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -OCH2OR11, -CH2NR11R12, -OCOR11, -CO2R13, -OSO2CF3이며;Is: R 7 is hydrogen, halogen, -CN, -CF 3, -OCF 3 , -OCH 2 CF 3, -NO 2, -OR 11, -NR 11 R 12, lower alkyl, aryl, -SCF 3, - SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -OCH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 , -OSO 2 CF 3 ;

R8및 R9는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13, -OSO2CF3이거나, 또는 R8및 R9는 함께 다리 -OCH2O-를 형성하고;R 8 and R 9 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 , -OSO 2 CF 3 or R 8 and R 9 together form a bridge —OCH 2 O—;

R11및 R12는 독립적으로 수소, -COR13, -SO2R13, 저급 알킬 또는 아릴이고;R 11 and R 12 are independently hydrogen, —COR 13 , —SO 2 R 13 , lower alkyl or aryl;

R13은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;

R10은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;

B는B is

또는 원자가 결합이며: 바람직하게Or a valence bond: preferably

이고, R14및 R15는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -O(CH2)lCF3, -NO2, -OR16, -NR16R17, 저급 알킬, 아릴, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)lCONR16R17, -O(CH2)lCONR16R17, -(CH2)lCOR16, -O(CH2)lCOR16, -(CH2)lOR16, -O(CH2)lOR16, -(CH2)lNR16R17, -O(CH2)lNR16R17, -OCOR16, -CO2R18, -O(CH2)lCN, -O(CH2)lCl이거나 또는 R14및 R15는 함께 다리 -O-CH2-O-를 형성하고;R 14 and R 15 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O (CH 2 ) l CF 3 , -NO 2 , -OR 16 , -NR 16 R 17 , lower Alkyl, aryl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 ,-(CH 2 ) l CONR 16 R 17 ,- O (CH 2 ) l CONR 16 R 17 ,-(CH 2 ) l COR 16 , -O (CH 2 ) l COR 16 ,-(CH 2 ) l OR 16 , -O (CH 2 ) l OR 16 ,- (CH 2 ) l NR 16 R 17 , -O (CH 2 ) l NR 16 R 17 , -OCOR 16 , -CO 2 R 18 , -O (CH 2 ) l CN, -O (CH 2 ) l Cl Or R 14 and R 15 together form a bridge —O—CH 2 —O—;

R14및 R15는 바람직하게 독립적으로 수소, 할로겐, -CF3, -OCF3, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16또는 -CO2R18를 나타내거나 또는 함께 다리 -OCH2O-를 형성하고;R14And R15Is preferably independently hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, Lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16Or -CO2R18To -OCH indicating or leg together2Forms O-;

l은 1, 2, 3 또는 4이고;l is 1, 2, 3 or 4;

R16및 R17은 독립적으로 수소, -COR18, -SO2R18, 저급 알킬, 아릴이거나, 또는 R16및 R17이 함께 2 내지 7개의 탄소원자를 포함하는 고리형 알킬 다리를 형성하고;R 16 and R 17 are independently hydrogen, —COR 18 , —SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing 2 to 7 carbon atoms;

R18은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

W는 -N= 또는 -CR19=이고;W is -N = or -CR 19 =;

Y는 -N= 또는 -CR20=이고;Y is -N = or -CR 20 =;

Z는 -N= 또는 -CR21=이고;Z is -N = or -CR 21 =;

V는 -N= 또는 -CR22=이고;V is -N = or -CR 22 =;

Q는 -NR23-, -O- 또는 -S-이고;Q is -NR 23- , -O- or -S-;

상기 식에서, R19, R20, R21및 R22는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, 저급 알킬, 아릴, 아릴-저급 알킬, SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24또는 -CO2R24이거나, 또는 R19및 R20, R20및 R21, 또는 R21및 R22는 함께 다리 -OCH2O-를 형성하고;Wherein R 19 , R 20 , R 21 and R 22 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 24 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 , or R 21 and R 22 together form a bridge —OCH 2 O—;

R24및 R25는 독립적으로 수소, -COR26, -SO2R26, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 24 and R 25 are independently hydrogen, —COR 26 , —SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl;

R26은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R23은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

K는K is

이고: 상기 식에서, R3a, R3b, R4a및 R4b는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a또는 -CO2R24a이고; 상기 식에서, R24a및 R25a는 독립적으로 수소, -COR26a, -SO2R26a, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;Wherein: R 3a , R 3b , R 4a and R 4b are independently hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —NO 2 , —OR 24a , —NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 25a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ; Wherein R 24a and R 25a are independently hydrogen, —COR 26a , —SO 2 R 26a , lower alkyl, aryl or aryl-lower alkyl;

R26a는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고; 또는R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or

R3a및 R3b, R4a및 R4b, 또는 R3a및 R4b는 함께 다리 -(CH2)i-를 형성하고;R 3a and R 3b , R 4a and R 4b , or R 3a and R 4b together form a bridge — (CH 2 ) i —;

i는 1, 2, 3 또는 4이고;i is 1, 2, 3 or 4;

a, b, c 및 d는 독립적으로 0, 1, 2, 3 또는 4이고;a, b, c and d are independently 0, 1, 2, 3 or 4;

e, f, p 및 q는 독립적으로 0 또는 1이고;e, f, p and q are independently 0 or 1;

L 및 M은 독립적으로 -O-, -S-, -CH=CH-, -C≡C-, -NR5a-, -COO-, -CONR5a-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5aSO2-, -NR5aCONR5b-, -NR5aCSNR5b-, -OCONR5b- 또는 -NR5aC(O)O-이고;L and M are independently selected from -O-, -S-, -CH = CH-, -C≡C-, -NR 5a -, -COO-, -CONR 5a -, -NR 5a CO-, -SO-, -SO 2 -, -OSO 2 -, -SO 2 NR 5a -, -NR 5a SO 2 -, -NR 5a CONR 5b -, -NR 5a CSNR 5b -, -OCONR 5b - or -NR 5a C (O) O-;

R5a및 R5b는 독립적으로 수소, 저급 알킬, -(CH2)k-OH, -(CH2)k-NR6aR6a, 아릴 또는 아릴-저급 알킬이고;R 5a and R 5b are independently hydrogen, lower alkyl, — (CH 2 ) k —OH, — (CH 2 ) k —NR 6a R 6a , aryl or aryl-lower alkyl;

상기 식에서 k는 2, 3, 또는 4이고;In which k is 2, 3, or 4;

R6a및 R6b는 독립적으로 수소, 저급 알킬 또는 아릴-저급 알킬이고;R 6a and R 6b are independently hydrogen, lower alkyl or aryl-lower alkyl;

k는 바람직하게k is preferably

를 나타내고;Represents;

D는 수소 또는D is hydrogen or

를 나타내고, 바람직하게는 수소,, Preferably hydrogen,

를 나타내고: 상기 식에서 r 및 s는 독립적으로 1 또는 2이고;In which r and s are independently 1 or 2;

E, F 및 G는 독립적으로 -CHR38-, >C=O, >NR39, -O- 또는 -S-이고;E, F and G are independently —CHR 38 —,>C═O,> NR 39 , —O— or —S—;

Y'는 -N= 또는 -CR32=이고;Y 'is -N = or -CR 32 =;

Z'는 -N= 또는 -CR33=이고;Z 'is -N = or -CR 33 =;

V'는 -N= 또는 -CR34=이고;V 'is -N = or -CR 34 =;

W'는 -N= 또는 -CR35=; 및W 'is -N = or -CR 35 =; And

Q'는 -NR36-, -O- 또는 -S-이고;Q 'is -NR 36- , -O- or -S-;

상기 식에서, R27, R28, R32, R33, R34및 R35는 수소, 할로겐, -CN, -CF3, -OCF3, -O(CH2)yCF3, -NO2, -OR29, -NR29R30, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -CONR29R30, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -CO2R29이거나; R27및 R28, R32및 R33, R33및 R34, 또는 R34및 R35는 함께 다리 -0CH2O-를 형성하고;Wherein R 27 , R 28 , R 32 , R 33 , R 34 and R 35 are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O (CH 2 ) y CF 3 , -NO 2 , -OR 29 , -NR 29 R 30 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 , -CONR 29 R 30 ,-(CH 2 ) y CONR 29 R 30 , -O (CH 2 ) y CONR 29 R 30 ,-(CH 2 ) y OR 29 ,-(CH 2 ) y NR 29 R 30 , -OCOR 29 , -CO 2 R 29 ; R 27 and R 28 , R 32 and R 33 , R 33 and R 34 , or R 34 and R 35 together form a bridge —0CH 2 O—;

R29및 R30은 바람직하게는 독립적으로 수소, 할로겐, -CF3, -OCF3, -OCH2CF3, OR29, 저급 알킬, 아릴 또는 아릴-저급 알킬이거나, 또는 함께 다리 -0CH2O-를 형성하고;R 29 and R 30 are preferably independently selected from hydrogen, halogen, -CF 3, -OCF 3, -OCH 2 CF 3, OR 29, lower alkyl, aryl or aryl-lower alkyl, or a bridge -0CH 2 O with To form-;

y는 1, 2, 3 또는 4이고;y is 1, 2, 3 or 4;

R29및 R30은 독립적으로 수소, -COR31, -SO2R31, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 29 and R 30 are independently hydrogen, —COR 31 , —SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl;

R31은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R36및 R39는 독립적으로 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 36 and R 39 are independently hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R38은 수소, -OR40, -NR40R41, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)xCONR40R41, -(CH2)xOR40, -(CH2)xNR40R41, -OCOR40또는 -CO2R40이고;R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 ,-(CH 2 ) x CONR 40 R 41 , -O (CH 2 ) x CONR 40 R 41 ,-(CH 2 ) x OR 40 ,-(CH 2 ) x NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ;

x는 1, 2, 3 또는 4이고;x is 1, 2, 3 or 4;

R40및 R41은 독립적으로 수소, -COR42, -SO2R42, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 40 and R 41 are independently hydrogen, —COR 42 , —SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;

R42는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이다.R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

그 이상의 구체예에서, 본 발명은 다음의 화학식 I의 화합물에 관한 것이다.In further embodiments, the present invention relates to compounds of formula (I)

R1및 R2는 독립적으로 수소 또는 저급 알킬이거나, 또는 함께 원자가 결합을 형성하고;R 1 and R 2 are independently hydrogen or lower alkyl, or together form a valent bond;

R3및 R4는 독립적으로 수소 또는 저급 알킬이고,R 3 and R 4 are independently hydrogen or lower alkyl,

n은 0, 1, 2 또는 3이고;n is 0, 1, 2 or 3;

m은 0 또는 1이고;m is 0 or 1;

X는 >C=O, >C=S, >C=NR5또는 >SO2이고;X is> C = O,> C = S,> C = NR 5 or> SO 2 ;

상기 식에서, R5는 수소, 저급 알킬, 아릴-저급 알킬 또는 -OR6이고;In which R 5 is hydrogen, lower alkyl, aryl-lower alkyl or —OR 6 ;

상기 식에서 R6는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

A는A is

이고: 상기 식에서, R7은 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13또는 -OSO2CF3이며;Wherein: R 7 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 ;

R8및 R9는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13또는 -OSO2CF3이거나, 또는 R8및 R9는 함께 다리 -OCH2O- 또는 -OCH2CH2O-를 형성하고;R 8 and R 9 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 , or R 8 and R 9 together form a bridge —OCH 2 O— or —OCH 2 CH 2 O—;

상기 식에서, R11및 R12는 독립적으로 수소, -COR13, -SO2R13, 저급 알킬 또는 아릴이고;Wherein R 11 and R 12 are independently hydrogen, —COR 13 , —SO 2 R 13 , lower alkyl or aryl;

상기 식에서, R13은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;In which R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;

R10은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;

B는B is

이거나, 또는 원자가 결합이며; 바람직하게Or a valence bond; Preferably

이고: 상기 식에서, R14및 R15는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -O(CH2)lCF3, -NO2, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)lCONR16R17, -O(CH2)lCONR16R17, -(CH2)lCOR16, -(CH2)lCOR16, -(CH2)lOR16, -O(CH2)lOR16, -(CH2)lNR16R17, -O(CH2)lNR16R17, -OCOR16, -CO2R18, -O(CH2)lCO2R18, -O(CH2)lCN, -O(CH2)lCl, 또는 R14및 R15는 함께 다리 -OCH2O-를 형성하고;Wherein: R 14 and R 15 are independently hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —O (CH 2 ) 1 CF 3 , —NO 2 , —OR 16 , —NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 ,-(CH 2 ) l CONR 16 R 17 , -O (CH 2 ) l CONR 16 R 17 ,-(CH 2 ) l COR 16 ,-(CH 2 ) l COR 16 ,-(CH 2 ) l OR 16 , -O (CH 2 ) l OR 16 ,-(CH 2 ) l NR 16 R 17 , -O (CH 2 ) l NR 16 R 17 , -OCOR 16 , -CO 2 R 18 , -O (CH 2 ) l CO 2 R 18 , —O (CH 2 ) 1 CN, —O (CH 2 ) 1 Cl, or R 14 and R 15 together form a bridge —OCH 2 O—;

R14및 R15는 바람직하게는 독립적으로 수소, 할로겐, -CF3, -OCF3, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16또는 -CO2R18이거나, 또는 함께 다리 -OCH2O-를 형성하고;R 14 and R 15 are preferably independently hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 ,- CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 , or together form a bridge -OCH 2 O-;

상기 식에서, l은 1, 2, 3 또는 4이고;Wherein l is 1, 2, 3 or 4;

R16및 R17은 독립적으로 수소, -COR18, -SO2R18, 저급 알킬, 아릴이거나, 또는 R16및 R17이 함께 2 내지 7개의 탄소원자를 포함하는 고리형 알킬 다리를 형성하고;R 16 and R 17 are independently hydrogen, —COR 18 , —SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing 2 to 7 carbon atoms;

상기 식에서 R18은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

W는 -N= 또는 -CR19=이고;W is -N = or -CR 19 =;

Y는 -N= 또는 -CR20=이고;Y is -N = or -CR 20 =;

Z는 -N= 또는 -CR21=이고;Z is -N = or -CR 21 =;

V는 -N= 또는 -CR22=이고;V is -N = or -CR 22 =;

Q는 -NR23-, -O- 또는 -S-이고;Q is -NR 23- , -O- or -S-;

상기 식에서, R19, R20, R21및 R22는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, 저급 알킬, 아릴, 아릴-저급 알킬, SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24또는 CO2R24이거나, 또는 R19및 R20, R20및 R21, 또는 R21및 R22는 함께 다리 -OCH2O-를 형성하고;Wherein R 19 , R 20 , R 21 and R 22 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 24 R 25 , -OCOR 24 or CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 , or R 21 and R 22 together form a bridge —OCH 2 O—;

상기 식에서, R24및 R25는 독립적으로 수소, -COR26, -SO2R26, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;Wherein R 24 and R 25 are independently hydrogen, —COR 26 , —SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl;

상기 식에서, R26은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R23은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

K는K is

이고: 상기 식에서, R3a, R3b, R4a및 R4b는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, 저급 알킬, 아릴, 아릴-저급 알킬, SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a또는 -CO2R24a이고;Wherein: R 3a , R 3b , R 4a and R 4b are independently hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —NO 2 , —OR 24a , —NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 25a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ;

상기 식에서, R24a및 R25a는 독립적으로 수소, -COR26a, -SO2R26a, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;Wherein R 24a and R 25a are independently hydrogen, —COR 26a , —SO 2 R 26a , lower alkyl, aryl or aryl-lower alkyl;

상기 식에서, R26a는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

또는 R3a및 R3b, R4a및 R4b, 또는 R3a및 R4b는 함께 다리 -(CH2)i-를 형성하고;Or R 3a and R 3b , R 4a and R 4b , or R 3a and R 4b together form a bridge — (CH 2 ) i —;

상기 식에서, i는 1, 2, 3 또는 4이고;Wherein i is 1, 2, 3 or 4;

a, b, c 및 d는 독립적으로 0, 1, 2, 3 또는 4이고;a, b, c and d are independently 0, 1, 2, 3 or 4;

e, f 및 p는 독립적으로 0 또는 1이고;e, f and p are independently 0 or 1;

q는 0, 1 또는 2이고;q is 0, 1 or 2;

L 및 M은 독립적으로 -O-, -S-, -CH=CH-, -C≡C-, -NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2-NR5a-, -NR5aSO2-, -NR5aCONR5b-, -NR5aCSNR5b-, -OCONR5b- 또는 -NR5aC(O)O-이고;L and M are independently selected from -O-, -S-, -CH = CH-, -C≡C-, -NR 5a -, -CO-, -OCO-, -COO-, -CONR 5a -, -NR 5a CO-, -SO-, -SO 2 - , -OSO 2 -, -SO 2 -NR 5a -, -NR 5a SO 2 -, -NR 5a CONR 5b -, -NR 5a CSNR 5b -, -OCONR 5b Or -NR 5a C (O) O-;

상기 식에서, R5a및 R5b는 독립적으로 수소, 저급 알킬, -(CH2)k-OㅗH, -(CH2)k-NR6aR6b, 아릴, 아릴-저급 알킬이고;Wherein R 5a and R 5b are independently hydrogen, lower alkyl, — (CH 2 ) k —O ㅗ H, — (CH 2 ) k —NR 6a R 6b , aryl, aryl-lower alkyl;

상기 식에서, k는 1, 2, 3 또는 4이고;Wherein k is 1, 2, 3 or 4;

R6a및 R6b는 독립적으로 수소, 저급 알킬 또는 아릴-저급 알킬이고;R 6a and R 6b are independently hydrogen, lower alkyl or aryl-lower alkyl;

k는 바람직하게는k is preferably

를 나타내고,Indicates,

D는 수소,D is hydrogen,

이고: 바람직하게는 수소,Is preferably hydrogen,

상기 식에서, r 및 s는 독립적으로 O, 1 또는 2이고;Wherein r and s are independently O, 1 or 2;

E, F 및 G는 독립적으로 -CHR38-, >C=O, >NR39, -O- 또는 -S-이고;E, F and G are independently —CHR 38 —,>C═O,> NR 39 , —O— or —S—;

F'는 >CR38또는 >N-이고;F 'is> CR 38 or>N-;

Y'는 -N= 또는 -CR32=이고;Y 'is -N = or -CR 32 =;

Z'는 -N= 또는 -CR33=이고;Z 'is -N = or -CR 33 =;

V'는 -N= 또는 -CR34=이고;V 'is -N = or -CR 34 =;

W'는 -N= 또는 -CR35=이고;W 'is -N = or -CR 35 =;

Q'는 -NR36-, -O- 또는 -S-이고;Q 'is -NR 36- , -O- or -S-;

상기 식에서, R27, R28, R32, R33, R34및 R35는 수소, 할로겐, -CN, -CF3, -OCF3, -O(CH2)yCF3, -NO2, OR29, -NR29R30, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -CONR29R30, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29또는 -CO2R29이거나; 또는Wherein R 27 , R 28 , R 32 , R 33 , R 34 and R 35 are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O (CH 2 ) y CF 3 , -NO 2 , OR 29 , -NR 29 R 30 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 , -CONR 29 R 30 ,-(CH 2 ) y CONR 29 R 30 , -O (CH 2 ) y CONR 29 R 30 ,-(CH 2 ) y OR 29 ,-(CH 2 ) y NR 29 R 30 , -OCOR 29 or -CO 2 R 29 ; or

R27및 R28, R32및 R33, R33및 R34, 또는 R34및 R35는 함께 -0CH2O-를 형성하고;R 27 and R 28 , R 32 and R 33 , R 33 and R 34 , or R 34 and R 35 together form —0CH 2 O—;

R27및 R28은 바람직하게 독립적으로 수소; -Cl 또는 -F와 같은 할로겐; -CF3; -OCF3; -OCHF2; -OCH2CF3; OR29(상기 식에서, R29는 수소 또는 저급 알킬이다); 메틸, 이소프로필 또는 tert-부틸과 같은 저급 알킬; 저급 알킬티오; -SCF3; -CH2OH; -COO-저급 알킬; 아릴; 아릴 또는 -CONH2; 또는 함께 다리 -OCH2O-를 형성하고;R 27 and R 28 are preferably independently hydrogen; Halogen, such as -Cl or -F; -CF 3 ; -OCF 3 ; -OCHF 2 ; -OCH 2 CF 3 ; OR 29 (wherein R 29 is hydrogen or lower alkyl); Lower alkyl such as methyl, isopropyl or tert-butyl; Lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl; Aryl; Aryl or -CONH 2 ; Or together form a bridge -OCH 2 O-;

상기 식에서, y는 1, 2, 3 또는 4이고;Wherein y is 1, 2, 3 or 4;

R29및 R30은 독립적으로 수소, -COR31, -SO2R31, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 29 and R 30 are independently hydrogen, —COR 31 , —SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl;

R31은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R36및 R39는 독립적으로 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 36 and R 39 are independently hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R38은 수소, -OR40, -NR40R41, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)xCONR40R41, -(CH2)xOR40, -(CH2)xNR40R41, -OCOR40또는 -CO2R40이고;R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 ,-(CH 2 ) x CONR 40 R 41 , -O (CH 2 ) x CONR 40 R 41 ,-(CH 2 ) x OR 40 ,-(CH 2 ) x NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ;

상기 식에서 x는 1, 2, 3 또는 4이고;In which x is 1, 2, 3 or 4;

R40및 R41은 독립적으로 수소, -COR42, -SO2R42, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 40 and R 41 are independently hydrogen, —COR 42 , —SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;

상기 식에서 R42는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이다.In which R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

상기 화학식 V로 표시되는 구체적인 화합물의 예는 다음과 같다:Examples of the specific compound represented by Formula V are as follows:

상기 화학식 III으로 표시되는 가장 바람직한 구체적인 화합물은 다음과 같다:Most preferred specific compounds represented by the formula (III) are as follows:

상기 화학식 IV로 표시되는 가장 바람직한 구체적인 화합물은 다음과 같다:Most preferred specific compounds represented by the above formula IV are as follows:

화학식 VI 및 VII으로 표시되는 바람직한 구체적인 화합물은 다음과 같다:Preferred specific compounds represented by formulas (VI) and (VII) are as follows:

A가 헤테로고리 및/또는 2환 부분인 화학식 I의 가장 바람직한 구체적인 화합물은 다음과 같다:Most preferred specific compounds of formula I, wherein A is a heterocyclic and / or bicyclic moiety, are as follows:

다음의 화합물이 사람의 글루카곤 수용체에 특히 높은 친화성을 나타내고, 본 발명에 따라 특히 바람직하다.The following compounds show particularly high affinity for the human glucagon receptor and are particularly preferred according to the invention.

본 발명의 화합물은 1개 이상의 비대칭 중심을 가질 수 있고, 모든 광학이성체, 분리된다면, 순수 또는 부분적으로 정제된 광학이성체 또는 그것의 라세미 혼합물은 본 발명의 범위에 포함된다.Compounds of the present invention may have one or more asymmetric centers, and all optical isomers, if separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present invention.

더욱이, 1개 이상의 탄소-탄소 또는 탄소-질소 이중결합이 화합물에 존재할 수 있고, 그것은 기하이성체를 발생시킨다. 모든 기하이성체, 분리된다면, 순수 또는 부분적으로 정제된 기하이성체 또는 그것의 혼합물은 본 발명의 범위에 포함된다.Moreover, more than one carbon-carbon or carbon-nitrogen double bond may be present in the compound, which gives rise to geometric isomers. All geometric isomers, if separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the present invention.

더욱이, 본 발명의 화합물은 예컨대, 하기의 호변체 형태와 같이 서로 다른 호변체의 형태로 존재할 수 있다.Furthermore, the compounds of the present invention may exist in different tautomeric forms, for example, as follows.

화합물이 형성할 수 있는 모든 호변체 형태는 본 발명의 범위에 포함된다.All tautomeric forms that compounds can form are included in the scope of the present invention.

글루카곤 수용체를 길항하는 본 화합물의 효능으로 인하여, 본 화합물은 모든 글루카곤이 매개된 증상 및 질환의 예방 및/또는 치료에 적합하다.Due to the efficacy of the compounds antagonizing the glucagon receptor, the compounds are suitable for the prophylaxis and / or treatment of all glucagon mediated symptoms and diseases.

따라서, 본 발명의 화합물은 어떤 원인으로 인한 당뇨와 관련된 저혈당증 또는 예컨대, 손상된 글루코오스 내성, 인슐린저항증, 신드롬 X, 타입 I 당뇨병, 타입 II 당뇨병, 고지혈증, 이상지혈증, 과중성 지방혈증, 글루카곤종, 급성 췌장염, 심혈관계 질환, 심장 과운동증, 위장관계 장애, 비만으로 인한 당뇨 등의 다른 질환 및 증상에 관련된 고혈당증의 치료에 응용가능할 수 있다. 게다가, 본 화합물은 글루카곤 수용체에 어떤 결점을 가지는 환자를 식별하는 진단시약으로서, 위산 분비를 증가시키기 위한 치료제로서, 글루카곤 투여로 인한 장관 저운동성을 반전시키기 위해, 타입 I과 타입 II 당뇨, 절식, AIDS, 암, 식욕부진, 노화 및 다른 증상의 모든 원인을 포함하여 이화작용, 음성 질소균형의 상태에서 질소손실 및 단백질 소모를 반전시키기 위해, 수술후 또는 수술중의 상기 증상 또는 질환의 치료를 위해, 포만을 감소시키고 에너지 축척을 증가시키기 위해 응용가능하다. 따라서, 그 이상의 양태에서, 본 발명은 활성 성분으로서 약학적으로 허용되는 담체 또는 부형제와 함께 본 발명에 따르는 적어도 1개의 화합물로 이루어지는 약학적 조성물에 관한 것이다.Accordingly, the compounds of the present invention may be useful for treating hypoglycemia associated with diabetes due to any cause or for example impaired glucose tolerance, insulin resistance, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagon, It may be applicable to the treatment of hyperglycemia associated with other diseases and symptoms such as acute pancreatitis, cardiovascular disease, cardiac hyperkinesia, gastrointestinal disorders, diabetes due to obesity. In addition, the present compounds are diagnostic reagents for identifying patients with certain defects in glucagon receptor, therapeutic agents for increasing gastric acid secretion, and to reverse type I and type II diabetes, fasting, To reverse nitrogen loss and protein consumption in the state of catabolism, negative nitrogen balance, including all causes of AIDS, cancer, anorexia, aging and other symptoms, for the treatment of such symptoms or diseases after or during surgery, It is applicable to reduce satiety and increase energy accumulation. Thus, in further embodiments, the present invention relates to a pharmaceutical composition consisting of at least one compound according to the invention with a pharmaceutically acceptable carrier or excipient as the active ingredient.

본 발명은 게다가, 타입 I 또는 타입 II 당뇨병 또는 저혈당증의 치료방법으로서, 본 발명에 따르는 화합물의 유효량을 그러한 치료가 필요한 환자에게 투여하는 것으로 이루어지는 방법에 관한 것이다.The present invention furthermore relates to a method for the treatment of type I or type II diabetes or hypoglycemia comprising the administration of an effective amount of a compound according to the invention to a patient in need of such treatment.

더욱이, 본 발명은 포유동물에서 혈중 글루코오스를 낮추는 방법으로서, 상기 포유동물에게 본 발명에 따르는 화합물의 유효량을 투여하는 것으로 이루어지는 방법에 관한 것이다.Moreover, the present invention relates to a method for lowering blood glucose in a mammal, the method comprising administering to said mammal an effective amount of a compound according to the invention.

본 발명은 또한 타입 I 또는 타입 II 당뇨병 또는 저혈당증을 치료하기 위한, 포유동물에서 혈중 글루코오스를 낮추기 위한 약제의 제조에 본 발명에 따르는 화합물의 사용에 관련된다.The invention also relates to the use of a compound according to the invention in the manufacture of a medicament for lowering blood glucose in a mammal for treating type I or type II diabetes or hypoglycemia.

약학적 제형 및 투여방법Pharmaceutical Formulations and Methods of Administration

본 발명에 따르는 화합물은 또한 활성 성분으로서 나타낼 수 있고, 경구, 직장, 경비, 폐, 국소(박칼 및 설하 포함), 경피, 질 및 장관외(피하, 근육내, 정맥내 및 내피)를 포함하는 어떤 적당한 경로에 의해 치료용으로 투여될 수 있고 경구투여가 바람직하다. 바람직한 경로는 환자의 증상과 나이, 치료되는 증상의 성질, 및 선택된 활성성분에 따라 다양할 것임이 인식될 것이다.The compounds according to the invention can also be represented as active ingredients and include oral, rectal, nasal, pulmonary, topical (including thin and sublingual), transdermal, vaginal and extraoral (subcutaneous, intramuscular, intravenous and endothelial). Administration can be by any suitable route and oral administration is preferred. It will be appreciated that the preferred route will vary depending upon the condition and age of the patient, the nature of the condition being treated, and the active ingredient selected.

본 발명의 화합물은 광범위한 용량의 범위에서 유효하다. 전형적인 용량은 1일당 1회 내지 3회와 같이, 1일당 1회 이상의 투여용으로 약 0.5mg 내지 약 250mgr과 같이, 0.05 내지 약 1000mg의 범위내이고, 바람직하게 약 0.1 내지 약 500mg의 범위내이다. 정확한 용량은 당업자에게 명백한 다른 요인 뿐만 아니라 투여회수 및 투여모드, 성별, 연령, 체중 및 치료되는 환자의 일반적인 증상, 치료되는 증상의 성질 및 심각성, 그리고 치료되는 병존질환에도 좌우될 것이다.Compounds of the invention are effective in a wide range of doses. Typical doses are in the range of 0.05 to about 1000 mg, preferably in the range of about 0.1 to about 500 mg, such as about 0.5 mg to about 250 mgr, for one or more administrations per day, such as once to three times per day. . The exact dosage will depend on the frequency and mode of administration, gender, age, weight and general symptoms of the patient being treated, the nature and severity of the condition being treated, and the coexisting disease being treated, as well as other factors apparent to those skilled in the art.

제형은 편리하게 당기술에 공지된 방법에 의해 단위 제형으로 제공될 수 있다.The formulations may conveniently be presented in unit dosage form by methods known in the art.

정맥내, 수막강내, 근육내 및 유사한 투여방법 등의 장관외 투여용으로, 전형적으로 용량은 경구투여용으로 사용된 용량의 약 1/2의 오더가 된다.For extra-intestinal administration, such as intravenous, intramedullary, intramuscular and similar methods of administration, typically the dose will be about half the order of the dose used for oral administration.

본 발명의 화합물은 일반적으로 유리된 형태의 물질 또는 그것의 약학적으로 허용되는 염으로서 사용된다. 하나의 예로서는 유리 염기로 사용되는 화합물의 산부가염이다. 화학식 I의 화합물이 유리 염기를 포함할 때, 그러한 염은 화학식 I의 유리 염기의 용액 또는 현탁액을 화학적 등량의 약학적으로 허용되는 산, 예를 들면, 무기산 및 유기산, 에컨대: 말레산, 푸마르산, 벤조산, 아스코르브산, 파모산, 숙신산, 비스-메틸렌 살리실산, 메탄술폰산, 에탄디술폰산, 아세트산, 옥살산, 프로피온산, 타르타르산, 살리실산, 시트르산, 피루브산, 글루콘산, 락트산, 말산, 만델산, 신남산, 시트라콘산, 아스파트산, 스테아르산, 팔미트산, EDTA, 글리콜산, p-아미노벤조산, 글루탐산, 벤젠술폰산, p-톨루엔술폰산, 염산, 브롬산, 황산, 인산 또는 질산으로 처리함으로써 종래의 방법으로 제조된다. 히드록시기를 가진 화합물의 생리학적으로 허용되는 염은 나트륨 또는 암모늄 이온 등의 적당한 양이온과 결합한 상기 화합물의 음이온을 포함한다.The compounds of the present invention are generally used as substances in free form or as pharmaceutically acceptable salts thereof. One example is acid addition salts of compounds used as free bases. When the compound of formula (I) comprises a free base, such salts may contain a solution or suspension of the free base of formula (I) in chemically equivalent amounts of pharmaceutically acceptable acids, such as inorganic and organic acids, such as maleic acid and fumaric acid. , Benzoic acid, ascorbic acid, pamo acid, succinic acid, bis-methylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, pyruvic acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, Conventional treatment by treatment with citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid or nitric acid Prepared by the method. Physiologically acceptable salts of compounds with hydroxy groups include the anions of these compounds in combination with suitable cations such as sodium or ammonium ions.

본 발명의 화합물은 단일용량 또는 복수의 용량으로, 단독으로 또는 약학적으로 허용되는 담체와 함께 투여될 수 있다.The compounds of the present invention may be administered in a single dose or in multiple doses, alone or in combination with a pharmaceutically acceptable carrier.

장관외투여용으로서, 무균의 수성 용액, 수성 프로필렌글리콜 또는 참기름 또는 낙화생유중의 화학식 I의 신규한 화합물의 용액이 사용될 수 있다. 이러한 수성 용액은 필요하다면 완충될 수 있고, 수성의 희석 용액을 먼저 충분한 염 도는 글루코오스로 등장으로 만들어야 한다. 수성 용액은 특히 정맥, 근육내, 피하 및 복강투여용으로 적합하다. 사용되는 무균의 수성 매질은 모두 당기술에 공지된 표준 기술에 의해 모두 용이하게 이용할 수 있다. 적당한 약학적 담체는 불활성 고체 희석제 또는 충전재, 무균의 수성 용매 및 다양한 유기 용매를 포함한다. 고체 담체의 예로서는 유당, 테라 알바(terra alba), 수크로오스, 시클로덱스트린, 탈크, 젤라틴, 아가, 펙틴, 아카시아, 마그네슘스테아레이트, 스테아르산 또는 셀룰로오스의 저급 알킬에테르를 들 수 있다. 액체 담체의 예로서는 시럽, 낙화생유, 올리브유, 인지질, 지방산, 지방산아민, 폴리옥시에틸렌 또는 물을 들 수 있다. 유사하게, 담체 또는 희석제는 글리세릴 모노스테아레이트 또는 글리세릴 디스테아레이트 등의 당기술에 공지된 서방형 물질을 단독으로 또는 왁스와 혼합하여 포함할 수 있다. 그런 다음, 신규한 화학식 I의 화합물과 약학적으로 허용되는 담체를 결합함으로써 형성된 약학적 조성물은 개시된 투여경로에 적합한 다양한 제형으로 쉽게 투여될 수 있다. 제형은 편리하게 약학분야의 공지된 방법에 의해 단위 제형으로 제공될 수 있다.As for intestinal administration, a solution of a novel compound of formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame oil or peanut oil can be used. This aqueous solution can be buffered if necessary and the aqueous dilution solution must first be isotonic with sufficient salt. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All of the sterile aqueous media used are readily available by standard techniques known in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solvents and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of the liquid carrier include syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may comprise a sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula I with pharmaceutically acceptable carriers can then be easily administered in a variety of formulations suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

경구 투여에 적합한 본 발명의 제형은 각 활성 성분의 지정된 양을 함유하는 캅셀 또는 정제 등의 별개의 단위로서 제공될 수 있고 적당한 부형제를 함유할 수 있다. 이들 제형은 파우더 또는 과립의 형태, 수성 또는 비수성 액체중 용액 또는 현탁액, 또는 수성중 유성 또는 유성중 수성 유제의 형태일 수 있다.Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets containing the indicated amounts of each active ingredient and may contain suitable excipients. These formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or in the form of oil-in-water or oil-in-water emulsions.

고체 담체가 경구투여용으로 사용된다면, 조제품은 정제화될 수 있고 파우더 또는 펠릿의 형태로 경질 젤라틴 캅셀에 충전될 수 있고, 트로키 또는 약용 드롭스의 형태가 될 수 있다. 고체 담체의 양은 광범위하게 다양할 것이나, 통상 약 25mg 내지 약 1g의 범위가 될 것이다.If a solid carrier is used for oral administration, the preparation can be tableted and filled into hard gelatin capsules in the form of powder or pellets, and can be in the form of troches or medicinal drops. The amount of solid carrier will vary widely but will usually range from about 25 mg to about 1 g.

액체 담체가 사용된다면, 조제품은 시럽, 유제, 연질 젤라틴 캅셀 또는 수성 또는 비수성 액체 현탁액 또는 용액 등의 무균의 주사용 액체의 형태가 될 수 있을 것이다.If a liquid carrier is used, the preparation may be in the form of sterile injectable liquids, such as syrups, emulsions, soft gelatin capsules or aqueous or non-aqueous liquid suspensions or solutions.

종래의 타정기술에 의해 제조될 수 있는 전형적인 정제는 다음을 포함할 수 있다.Typical tablets that may be prepared by conventional tableting techniques may include the following.

코어:core:

활성 성분(유리 화합물 또는 그것의 염으로서) 100mg100 mg of active ingredient (as a free compound or salt thereof)

콜로이드 2산화규소(Aerosil) 1.5mgColloidal Silicon Dioxide (Aerosil) 1.5mg

셀룰로오스, 미세결정(Avicel) 70mgCellulose, Microcrystalline 70mg

변성 셀룰로오스 검(Ac-Di-Sol) 7.5mg7.5mg of modified cellulose gum (Ac-Di-Sol)

마그네슘스테아레이트Magnesium stearate

코팅:coating:

HPMC 대략 9mgHPMC approximately 9mg

*Mywacett 9-40 T 대략 0.9mg * Mywacett 9-40 T approximately 0.9mg

*필름코팅용의 가소제로서 사용된 아실화 모노글리세리드 * Acylated monoglycerides used as plasticizers for film coating

경비투여용으로서, 조제품은 액체 담체, 특히 수성 담체에 용해되거나 현탁된 화학식 I의 화합물을 에어로졸용으로 포함할 수 있다. 담체는 프로필렌글리콜 등의 가용화제, 계면활성제, 레시틴(포스파티딜콜린) 또는 시클로덱스트린 등의 흡수증진제, 파라벤 등의 보존제 등의 첨가제를 포함할 수 있다.For non-administration, the preparation may comprise for the aerosol a compound of formula (I) dissolved or suspended in a liquid carrier, especially an aqueous carrier. The carrier may include additives such as solubilizers such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, and preservatives such as parabens.

선택적으로, 본 발명의 약학적 조성물은 인슐린 저항성 및 인슐린 내성이 병리생리학적 기전인 질병의 치료 및 예방을 위한 화합물을 포함하는 항당뇨병제 또는 다른 약물학적 활성물질 등의 1개 이상의 다른 약물학적 활성 화합물과 결합하여 화학식 I의 화합물을 포함할 수 있다. 적당한 항당뇨병제로서는 글리벤클라미드 및 글리피지드 등의 설포닐우레아; 메트포민 등의 바이구아나이드; 레파글리니드등의 벤조산 유도체; 및 트로글리타존 및 시글리타존 등의 티아졸리딘디온과 PPAR 및 RXR 효현제 뿐만 아니라 인슐린, 참고자료로서 여기에 삽입된 WO 98/08871(Novo Nordisk A/S)개시된 것과 같은 GLP-1 유도체를 포함한다.Optionally, the pharmaceutical composition of the present invention may comprise one or more other pharmacological activities, such as antidiabetic agents or other pharmacologically active substances, including compounds for the treatment and prevention of diseases in which insulin resistance and insulin resistance are pathophysiological mechanisms. It may include a compound of formula (I) in combination with a compound. Suitable antidiabetic agents include sulfonylureas such as glybenclamide and glyphide; Biguanides such as metformin; Benzoic acid derivatives such as repaglinide; And thiazolidinediones such as troglitazone and cyglitazone, as well as PPAR and RXR agonists, as well as insulin, GLP-1 derivatives such as those disclosed by WO 98/08871 (Novo Nordisk A / S), incorporated herein by reference.

실험Experiment

글루카곤 결합:Glucagon Bonding:

하기의 절에서, 본 발명의 화합물의 효능을 평가하는 데 유용한 기능의 효력시험과 결합의 효력시험을 기재한다.In the sections that follow, the potency test and the potency test of binding functions useful for evaluating the efficacy of the compounds of the invention are described.

글루카곤 결합의 효력시험(I)Efficacy test of glucagon binding (I)

글루카곤 수용체에 대한 화합물의 결합은 클로닝된 사람의 글루카곤 수용체를 사용하는 경쟁적 결합의 효력시험으로 측정하였다.Binding of compounds to glucagon receptors was determined by potency testing of competitive binding using cloned human glucagon receptors.

스크리닝 구성에서, 길항작용은 화합물이 5nM 글루카곤의 존재하에서 형성된 cAMP의 양을 저해하는 능력으로서 측정하였다.In the screening construct, antagonism was measured as the ability of the compound to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.

완전한 특성규명을 위해, 길항작용은 기능적 효력시험으로서 결정하였고, 글루카곤의 용량-반응 곡선을 우측이동시키는 화합물의 능력으로서 측정하였다. 적어도 3개의 서로 다른 길항제의 농도를 사용하여, Ki는 Schild 플로팅으로 계산하였다. 수용체 결합은 클로닝된 사람의 수용체(Lok 등, Gene 140, 203-209 (1994))를 사용하여 시험하였다. EcoRI/SSt1 제한위치(Lok 등)를 사용하여 pLJ6' 발현벡터에 삽입된 수용체는 갓난 햄스터 신장 세포계(A3 BHK 570-25)에서 발현시켰다. 클론은 0.5mg/ml G-418의 존재하에서 선택하였고, 40 계대이상에 적합한 것으로 나타났다. Kd는 0.1nM인 것으로 밝혀졌다.For complete characterization, antagonism was determined as a functional potency test and measured as the compound's ability to right shift the dose-response curves of glucagon. Using concentrations of at least three different antagonists, K i was calculated by Schild plotting. Receptor binding was tested using cloned human receptors (Lok et al., Gene 140, 203-209 (1994)). Receptors inserted into the pLJ6 'expression vector using EcoRI / SSt1 restriction sites (Lok et al.) Were expressed in the newborn hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg / ml G-418 and appeared to be suitable for passage 40 or above. K d was found to be 0.1 nM.

원형질막을 세포가 집합할 때까지 성장시키고, 세포들을 표면에서 분리하고, 세포를 30mM NaCl, 1mM 디티오트레이톨, 5mg/l 류펩틴(Sigma), 5mg/l 펩스타틴(Sigma), 100mg/l 박시트라신(Sigma) 및 15mg/l 재조합 아프로티닌(Novo Nordisk)를 포함하는 pH 7.4의 냉완충액(10mM tris/HCl)에 재현탁시키고, Polytron PT 10-35 균질기(Kinematica)를 사용하여 10초간 파열을 2회 실시하여 균질화하고, 95.000*g에서 75분간 한층의 41w/v% 수크로오스상에서 원심분리시켜 제조하였다. 2층 사이에 위치한 백색 밴드를 완충액에서 희석시키고 40.000*g에서 45분간 원심분리시켰다. 원형질막을 포함하는 침전물을 완충액에 현탁시키고 필요할 때까지 -80℃에서 저장하였다.The plasma membrane is grown until the cells aggregate, the cells are separated from the surface, and the cells are 30 mM NaCl, 1 mM dithiothreitol, 5 mg / l leupetin (Sigma), 5 mg / l pepstatin (Sigma), 100 mg / l Resuspend in cold buffer (10 mM tris / HCl) at pH 7.4 containing baccitracin (Sigma) and 15 mg / l recombinant aprotinin (Novo Nordisk), and using a Polytron PT 10-35 homogenizer (Kinematica) Two times of rupture was performed to homogenize and prepared by centrifugation at 95.000 * g for 75 minutes on a further 41w / v% sucrose. The white band located between the two layers was diluted in buffer and centrifuged at 40.000 * g for 45 minutes. Precipitates containing plasma membranes were suspended in buffer and stored at -80 ° C until needed.

글루카곤은 클로라민 T 법(Hunter and Greenwood, Nature, 194, 495 (1962))에 따라 요오드화시켰고, 음이온 교환크로마토그래피(Jrgensen et al, Hormone and Metab. Res. 4, 223-224 (1972))를 사용하여 정제하였다. 특이적 활성은 요오드화시킨 당일 460μCi/㎍이었다. 추적자를 분취량으로 -18℃에서 보관하였고 해동후 즉시 사용하였다.Glucagon was iodinated according to the Chloramine T method (Hunter and Greenwood, Nature, 194, 495 (1962)) and anion exchange chromatography (J rgensen et al, Hormone and Metab. Res. 4, 223-224 (1972)). Specific activity was 460 μCi / μg on the day of iodinated. Tracers were stored in aliquots at -18 ° C and used immediately after thawing.

결합 시험은 필터 마이크로타이터 플레이트(MADV N65, Millipore)에서 3중으로 수행하였다. 본 시험에서 사용된 완충액은 0.1% 사람의 혈청 알부민(Sigma, grade V)를 포함하는 25mM HEPES pH 7.4였다. 글루카곤은 HSA를 동량(w/w) 가한 0.05M HCl에 용해시키고, 동결건조시켰다. 사용하는 당일, 물에 용해시키고 완충액에 원하는 농도까지 희석하였다.Binding tests were performed in triplicate on filter microtiter plates (MADV N65, Millipore). The buffer used in this test was 25 mM HEPES pH 7.4 containing 0.1% human serum albumin (Sigma, grade V). Glucagon was dissolved in 0.05 M HCl to which HSA was added (w / w) and lyophilized. On the day of use, it was dissolved in water and diluted to the desired concentration in buffer.

샘플 175㎕(글루카곤 또는 시험 화합물)를 각 웰에 가하였다. 추적자(50.000cpm)를 완충액에 희석시키고, 15㎕를 각 웰에 가하였다. 0.5㎍의 새롭게 해동시킨 원형질막 단백질을 완충액에 희석시키고 각 웰에 15㎕씩 가하였다. 플레이트를 25℃에서 2시간동안 인큐베이션하였다. 비특이적 결합은 10-6M 글루카곤으로 측정하였다. 그런 다음 결합 및 비결합 추적자를 진공여과(Millipore vacuum manifold)에 의해 분리하였다. 플레이트를 150㎕ 완충액/웰로 1회 세척하였다. 플레이트를 두세시간동안 공기건조하고, 그 후, 필터를 Millipore Puncher를 사용하여 플레이트로부터 분리하였다. 필터를 γ카운터에서 측정하였다.175 μL of sample (glucagon or test compound) was added to each well. Tracer (50.000 cpm) was diluted in buffer and 15 μl was added to each well. 0.5 μg of freshly thawed plasma membrane protein was diluted in buffer and 15 μl was added to each well. Plates were incubated at 25 ° C. for 2 hours. Nonspecific binding was measured by 10-6 M glucagon. The bound and unbound tracers were then separated by Millipore vacuum manifold. Plates were washed once with 150 μl buffer / well. The plate was air dried for two to three hours and then the filter was separated from the plate using a Millipore Puncher. The filter was measured on the γ counter.

기능 시험(I)Functional test (I)

기능 시험을 96웰 마이크로타이터 플레이트(조직배양플레이트, Nunc)에서 수행하였다. 시험에서 그 결과의 완충액의 농도는 50mM tris/HCl, 1mM EGTA, 1.5mM MgSO4, 1.7mM ATP, 20μM GTP, 2mM IBMX, 0.02% 트윈-20 및 0.1% HSA였다. pH는 7.4였다. 글루카곤과 제시된 길항제를 50mM tris/HCl, 1mM EGTA, 1.85mM MgSO4, 0.0222% 트윈-20 및 0.111% HSA, pH 7.4중에 희석시킨 35㎕에 가하였다. 50mM tris/HCl, 1mM EGTA, 1.5mM MgSO4, 11.8mM ATP, 0.14mM GTP, 14mM 이소-부틸-메틸-크산틴(IBMX) 및 0.1% HSA, pH7.4중 20㎕를 가하였다. GTP를 시험전 즉시 용해시켰다.Functional tests were performed in 96-well microtiter plates (tissue culture plates, Nunc). The concentrations of the resulting buffer in the tests were 50 mM tris / HCl, 1 mM EGTA, 1.5 mM MgSO 4 , 1.7 mM ATP, 20 μM GTP, 2 mM IBMX, 0.02% Tween-20 and 0.1% HSA. pH was 7.4. Glucagon and the indicated antagonist were added to 35 μl diluted in 50 mM tris / HCl, 1 mM EGTA, 1.85 mM MgSO 4 , 0.0222% Tween-20 and 0.111% HSA, pH 7.4. 20 μl of 50 mM tris / HCl, 1 mM EGTA, 1.5 mM MgSO 4 , 11.8 mM ATP, 0.14 mM GTP, 14 mM iso-butyl-methyl-xanthine (IBMX) and 0.1% HSA, pH 7.4 were added. GTP was dissolved immediately before testing.

5㎍의 원형질막을 포함하는 50㎕를 tris/HCl, EGTA, MgSO4, HSA 완충액에 가하였다(실제 농도는 저장된 원형질막중 단백질의 농도에 좌우되었다).50 μl containing 5 μg plasma membrane was added to tris / HCl, EGTA, MgSO 4 , HSA buffer (actual concentrations depended on the concentration of protein in stored plasma membrane).

총 시험부피는 140㎕였다. 시험물은 계속적으로 진동시키면서 37℃에서 2시간동안 인큐베이션하였다. 반응을 0.5N HCl 25㎕를 가해 중지시켰다. cAMP는 신틸레이션 근접 키트(Amersham)을 사용하여 측정하였다.Total test volume was 140 μl. The test specimens were incubated at 37 ° C. for 2 hours with continuous vibration. The reaction was stopped by adding 25 μl 0.5N HCl. cAMP was measured using the scintillation proximity kit (Amersham).

글루카곤 결합 시험(II)Glucagon Bond Test (II)

수용체 결합을 클로닝된 사람의 수용체를 사용하여 시험하였다(Lok 등, Gene 140, 203-209 (1994)). EcoRI/SSt1 제한위치(Lok 등)를 사용하여 pLJ6' 발현벡터에 삽입된 수용체를 갓난 햄스터 신장 세포계(A3 BHK 570-25)에서 발현시켰다. 클론은 0.5mg/ml G-418의 존재하에서 선택하였고, 40 계대 이상에 적합한 것으로 나타났다. Kd는 0.1nM인 것으로 밝혀졌다.Receptor binding was tested using cloned human receptors (Lok et al., Gene 140, 203-209 (1994)). Receptors inserted into the pLJ6 'expression vector were expressed in a newborn hamster kidney cell line (A3 BHK 570-25) using EcoRI / SSt1 restriction sites (Lok et al.). Clones were selected in the presence of 0.5 mg / ml G-418 and appeared to be suitable for 40 passages or more. K d was found to be 0.1 nM.

원형질막을 세포가 집합할 때까지 성장시키고, 세포들을 표면에서 분리하고, 세포를 30mM NaCl, 1mM 디티오트레이톨, 5mg/l 류펩틴(Sigma), 5mg/l 펩스타틴(Sigma), 100mg/l 박시트라신(Sigma) 및 15mg/l 재조합 아프로티닌(Novo Nordisk)를 포함하는 pH 7.4의 냉완충액(10mM tris/HCl)에 재현탁시키고, Polytron PT 10-35 균질기(Kinematica)를 사용하여 10초간 파열을 2회 실시하여 균질화하고, 원심분리시켜 제조하였다. 균질물을 재현탁시키고 다시 원심분리시켰다. 원형질막을 포함하는 침전물을 완충액에 현탁시키고 필요할 때까지 -80℃에서 저장하였다.The plasma membrane is grown until the cells aggregate, the cells are separated from the surface, and the cells are 30 mM NaCl, 1 mM dithiothreitol, 5 mg / l leupetin (Sigma), 5 mg / l pepstatin (Sigma), 100 mg / l Resuspend in cold buffer (10 mM tris / HCl) at pH 7.4 containing baccitracin (Sigma) and 15 mg / l recombinant aprotinin (Novo Nordisk), and using a Polytron PT 10-35 homogenizer (Kinematica) The second burst was performed twice, homogenized and prepared by centrifugation. Homogenates were resuspended and centrifuged again. Precipitates containing plasma membranes were suspended in buffer and stored at -80 ° C until needed.

결합 시험은 폴리프로필렌 튜브 또는 마이크로타이터 플레이트에서 2중으로 실험하였다. 이 시험에서 사용된 완충액은 0.1% 소혈청 알부민(Sigma, fraction V)을 포함하는 25mM HEPES pH 7.4였다. 샘플(글루카곤(Bachem CA) 또는 시험 화합물)은 각 튜브 또는 웰에 첨가하였다. 추적자(~25000cpm)를 완충액에 희석시키고 각 튜브 또는 웰에 첨가하였다. 새롭게 해동시킨 원형질막 0.5㎍을 완충액에 희석시킨 다음 각 튜브 또는 웰에 분취량을 가하였다. 튜브 또는 플레이트를 37℃에서 1시간동안 인큐베이션하였다. 비특이적 결합은 10-7M 글루카곤으로 측정하였다. 그런 다음 결합 및 비결합 추적자를 진공여과(Brandel)에 의해 분리하였다. 튜브 또는 웰을 완충액으로 2회 세척하였다. 필터 또는 플레이트를 감마 카운터에서 측정하였다.Bonding tests were conducted in duplicate in polypropylene tubes or microtiter plates. The buffer used in this test was 25 mM HEPES pH 7.4 containing 0.1% bovine serum albumin (Sigma, fraction V). Samples (glucagon (Bachem CA) or test compound) were added to each tube or well. Tracer (˜25000 cpm) was diluted in buffer and added to each tube or well. 0.5 μg of freshly thawed plasma membrane was diluted in buffer and aliquots were added to each tube or well. The tube or plate was incubated at 37 ° C. for 1 hour. Nonspecific binding was measured by 10 -7 M glucagon. The bound and unbound tracers were then separated by vacuum filtration (Brandel). Tubes or wells were washed twice with buffer. Filters or plates were measured on a gamma counter.

기능 시험(II)Functional test (II)

기능시험은 글루카곤으로 자극된 cAMP의 형성을 길항하는 화합물의 능력을 전세포 시험으로 측정하였다. 시험은 보로실리케이트 글래스 12 x 75 튜브에서 수행하였다. 시험에서 완충액의 농도를 10mM HEPES, 1mM EGTA, 1.4mM MgCl2, 0.1mM IBMX, 30mM NaCl, 4.7mM KCl, 2.5mM NaH2PO4, 3mM 글루코오스 및 0.2% BSA였다. pH는 7.4였다. 느슨한 전세포(0.5ml, 106/ml)를 화합물의 다양한 농도에서 37℃에서 10분간 전처리한 후, 글루카곤으로 20분간 처리하였다. 세포의 몇몇 분취량(500㎕)을 효현제 활성을 시험하기 위해 시험화합물(50uL) 단독으로 처리하였다. 반응은 원심분리에 의해 종료시키고, 이어서 0.1% HCl 500㎕를 가하여 세포 용해시켰다. 세포의 잔해를 펠릿화하고 cAMP를 함유하는 상층액을 건조한 상태가 될 때까지 증발시켰다. cAMP를 RIA 키트(NEN, NEK-033)을 사용하여 측정하였다. 몇몇 시험은 NEN으로부터 아데닐레이트 사이클라제 FlashPlate 시스템을 사용하여 수행하였다.The functional test measured the ability of a compound to antagonize the formation of glucagon stimulated cAMP in a whole cell test. The test was carried out in borosilicate glass 12 × 75 tubes. The concentration of buffer in the test was 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCl 2 , 0.1 mM IBMX, 30 mM NaCl, 4.7 mM KCl, 2.5 mM NaH 2 PO 4 , 3 mM glucose and 0.2% BSA. pH was 7.4. Loose whole cells (0.5 ml, 10 6 / ml) were pretreated at 37 ° C. for 10 minutes at various concentrations of the compound and then treated with glucagon for 20 minutes. Several aliquots of cells (500 μl) were treated with test compound (50 uL) alone to test agonist activity. The reaction was terminated by centrifugation followed by cell lysis with 500 μl of 0.1% HCl. The debris of the cells was pelleted and the supernatant containing cAMP was evaporated to dryness. cAMP was measured using the RIA kit (NEN, NEK-033). Several tests were performed using the adenylate cyclase FlashPlate system from NEN.

합성방법Synthesis method

다음의 합성 프로토콜은 명세서와 합성반응식에서 확인되는 중간체 화합물과 최종 생성물을 가리킨다. 본 발명의 화합물의 제법은 하기 실시예에서 상세히 설명되나 설명되는 화학반응은 본 발명의 글루카곤 길항제의 제조를 위해 일반적인 응용성의 관점에서 개시된다. 때때로, 반응은 본 발명에 개시된 범위내에 포함된 각 화합물에 대하여 기재된 바대로 응용가능하지 않을 수 있다. 이러한 화합물은 당업자에 의해 용이하게 인식될 것이다. 그러한 모든 경우에서, 반응은 당업제에게 공지된 종래의 변경으로, 즉 방해기의 적절한 보호, 다른 종래의 시약으로의 변화, 또는 반응 조건의 관례적 변경에 의해 성공적으로 수행할 수 있다. 다른 방법으로, 여기에 개시되거나 또는 그렇지 않은 종래의 다른 반응은 본 발명의 상응하는 화합물의 제조에 응용가능할 것이다. 모든 제조방법에서, 모든 출발물질은 공지되어 있거나 공지된 출발물질로부터 쉽게 제조가능하다. 모든 온도는 섭씨온도로 나타내고, 다르게 지시되지 않는다면, 수율을 가리킬 때, 모든 부 및 백분율은 중량부이고, 용매 또는 용리액을 가리킬 때 모든 부는 용량부이다.The following synthesis protocols refer to intermediate compounds and end products identified in the specification and the scheme. The preparation of the compounds of the invention is described in detail in the Examples below, but the chemical reactions described are disclosed in terms of general applicability for the preparation of the glucagon antagonists of the invention. At times, the reaction may not be applicable as described for each compound included within the scope disclosed herein. Such compounds will be readily appreciated by those skilled in the art. In all such cases, the reaction can be carried out successfully by conventional modifications known to those skilled in the art, ie by appropriate protection of the interferers, changes to other conventional reagents, or customary changes of reaction conditions. Alternatively, other conventional reactions disclosed or otherwise herein will be applicable to the preparation of the corresponding compounds of the present invention. In all preparation methods, all starting materials are known or can be readily prepared from known starting materials. All temperatures are expressed in degrees Celsius and unless otherwise indicated, all parts and percentages are parts by weight when referring to yield, and all parts are parts by volume when referring to solvent or eluent.

알킬리덴 히드라지드의 제조를 위한 일반적인 방법General method for the preparation of alkylidene hydrazide

화학식 I의 화합물은 본 발명의 하나의 구체예, 즉 화학식 II의 알킬리덴 히드라지드에 따라서, 반응식 I에 나타낸 바와 같이, 즉 카르복실산, 예컨대 방향족 산의 에스테르를 히드라지드 유도체로 변환시키고, 그 생성 화합물을 치환 알데히드 또는 케톤과 더 반응시켜 치환 알킬리덴 히드라지드를 얻음으로써 제조할 수 있다.According to one embodiment of the invention, i.e., the alkylidene hydrazide of formula (II), the compound of formula (I) converts an ester of a carboxylic acid, such as an aromatic acid, into a hydrazide derivative, The resulting compound can be prepared by further reacting with a substituted aldehyde or ketone to obtain a substituted alkylidene hydrazide.

상기 식에서, A, B, K, D, m, n 및 R4는 화학식 I에서 정의된 바와 같고, Ra은 저급 알킬이다.Wherein A, B, K, D, m, n and R 4 are as defined in formula (I) and R a is lower alkyl.

전구체 히드라지드 A-(C=O)-NHNH2의 합성을 위한 일반적인 제법:General preparations for the synthesis of precursor hydrazide A- (C = O) -NHNH 2 :

반응은 공지되어 있고(Org. Syn., Coll. Vol. II, A.H. Blatt, ed., John Wiley & Sons, New York, 1943, p. 85; Org. Syn., Coll. Vol. IV, N. Rabjohn, ed., John Wiley & Sons, New York, 1963, p. 819), 해당하는 에스테르(메틸, 에틸 또는 기타 저급 알킬에스테르)를 2-10 몰의 과량의 히드라진과, 에틸알콜, 메틸알콜, 이소프로필 또는 tert-부틸알콜 또는 테트라히드로푸란, 디옥산, DMSO, 에틸렌글리콜, 에틸렌글리콜디메틸에스테르, 벤젠, 톨루엔 또는 상기 용매의 혼합물의 존재하, 또는 과량의 히드라진이 용매로서 작용하는 경우 용매없이 교반시킴으로써 일반적으로 수행할 수 있다. 반응은 0℃ 내지 130℃사이에서 수행되고, 바람직하게 20℃ 내지 100℃, 가장 바람직하게 용매의 환류온도에서 또는 그 근처에서 수행된다. 반응은 바람직하게 N2또는 Ar 등의 불활성 분위기에서 수행된다. 반응이 TLC 또는 HPLC에 의해 출발 에스테르가 사라진 것으로 판단하여 완결되면, 용매를 대기 또는 감압하에서 농축하여 제거할 수 있다.The reaction is known (Org. Syn., Coll. Vol. II, AH Blatt, ed., John Wiley & Sons, New York, 1943, p. 85; Org. Syn., Coll. Vol. IV, N. Rabjohn, ed., John Wiley & Sons, New York, 1963, p. 819), corresponding esters (methyl, ethyl or other lower alkyl esters) in excess of 2-10 moles of hydrazine, ethyl alcohol, methyl alcohol, Stir without solvent in the presence of isopropyl or tert-butyl alcohol or tetrahydrofuran, dioxane, DMSO, ethylene glycol, ethylene glycol dimethyl ester, benzene, toluene or mixtures of these solvents, or when excess hydrazine acts as solvent It can be generally carried out by the. The reaction is carried out between 0 ° C. and 130 ° C., preferably at 20 ° C. to 100 ° C., most preferably at or near the reflux temperature of the solvent. The reaction is preferably carried out in an inert atmosphere such as N 2 or Ar. Once the reaction is complete as determined by TLC or HPLC that the starting ester has disappeared, the solvent can be removed by concentration under atmospheric or reduced pressure.

생성물은 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물 또는 상기중 2 이상의 혼합물 등의 용매로부터 재결정시킴으로써 더 정제할 수 있다. 다른 방법으로, 생성물은 용리액으로 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로서 사용하여 컬럼크로마토그래피에 의해 정제할 수 있다. 해당하는 분획을 대기압에서 또는 진공에서 농축시킴으로써 순수한 아로일히드라지드를 얻는다.The product can be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of them. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent as eluent. Pure aroylhydrazide is obtained by concentrating the corresponding fractions at atmospheric pressure or in vacuo.

방향족 산 히드라지드의 제법:Preparation of Aromatic Acid Hydrazide:

해당하는 방향족 산, 예컨대 치환 벤조산 에스테르 등의 메틸 또는 에틸 에스테르를 에탄올에 용해시키고, 히드라진(5eq)을 가한다. 반응물은 질소하에서 하룻밤동안 환류한다. 냉각시키는 동안, 치환 히드라지드 유도체는 통상 침전한다. 여과후, 생성물을 통상 뜨거운 메탄올, 에탄올 또는 이소프로필알콜로부터 재결정시킨다. 히드라지드가 침전되지 않을 경우, 반응물을 진공하에서 농축시키고, 용리액으로서 디클로로메탄/메탄올을 사용하여 실리카겔상에서 크로마토그래피한다. 방향족 히드라지드의 제조를 예시하는 구체적인 예는 하기에서 제공된다.Corresponding aromatic acids such as methyl or ethyl esters, such as substituted benzoic acid esters, are dissolved in ethanol and hydrazine (5eq) is added. The reaction is refluxed under nitrogen overnight. During cooling, substituted hydrazide derivatives usually precipitate. After filtration, the product is usually recrystallized from hot methanol, ethanol or isopropyl alcohol. If hydrazide does not precipitate, the reaction is concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol as eluent. Specific examples illustrating the preparation of aromatic hydrazides are provided below.

5-히드록시인돌-2-카르복실산 히드라지드의 제법:Preparation of 5-hydroxyindole-2-carboxylic acid hydrazide:

히드라진(4mL, 121mmol)을 에탄올에 용해시킨 에틸 5-히드록시인돌-2-카르복실레이트(5g, 24mmol)의 샘플에 가하였다. 반응물을 질소하에서 하룻밤동안 환류시켰다. 반응용기를 냉각시키는 동안, 원하는 생성물을 결정화하였다. 백색고체를 여과시켜 분리하였다. 뜨거운 에탄올에서 재결정하여, 5-히드록시인돌-3-카르복실산 히드라지드를 85%의 수율로 얻었다.Hydrazine (4 mL, 121 mmol) was added to a sample of ethyl 5-hydroxyindole-2-carboxylate (5 g, 24 mmol) dissolved in ethanol. The reaction was refluxed under nitrogen overnight. While cooling the reaction vessel, the desired product was crystallized. The white solid was isolated by filtration. Recrystallization from hot ethanol gave 5-hydroxyindole-3-carboxylic acid hydrazide in a yield of 85%.

1H NMR (DMSO-d6): δ 4.38(s, 2H); 6.62(dd, 1H); 6.76(dd, 2H); 7.13(d, 1H); 8.70(s, 1H); 9.57(s, 1H); 11.21(s, 1H); MS(FAB):m/z 192(M+H)+ 1 H NMR (DMSO-d 6 ): δ 4.38 (s, 2H); 6.62 (dd, 1 H); 6.76 (dd, 2 H); 7.13 (d, 1 H); 8.70 (s, 1 H); 9.57 (s, 1 H); 11.21 (s, 1 H); MS (FAB): m / z 192 (M + H) +

3-클로로-4-히드록시벤조산 히드라지드의 제법:Preparation of 3-chloro-4-hydroxybenzoic acid hydrazide:

히드라진(1.8mL)를 에탄올(50mL)에 용해시킨 메틸 3-클로로-4-히드록시벤조에이트(2g)의 샘플에 가하였다. 반응물을 질소하에서 하룻밤동안 환류시켰다. 반응용기를 냉각시키는 동안, 원하는 생성물을 용액으로부터 결정화하였다. 백색고체를 여과시켜 분리하였다. 뜨거운 에탄올에서 재결정하여, 3-클로로-4-히드록시벤조산 히드라지드를 60%의 수율로 얻었다.Hydrazine (1.8 mL) was added to a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL). The reaction was refluxed under nitrogen overnight. While cooling the reaction vessel, the desired product was crystallized from the solution. The white solid was isolated by filtration. Recrystallization from hot ethanol gave 3-chloro-4-hydroxybenzoic acid hydrazide in 60% yield.

1H NMR (DMSO-d6): δ 4.49 (broad s, 2H), 7.05 (dd, 1H), 7.71 (dd, 1H), 7.89 (d, 1H), 9.669 (s, 1H), 10.72 (broad s, 1H). 1 H NMR (DMSO-d 6 ): δ 4.49 (broad s, 2H), 7.05 (dd, 1H), 7.71 (dd, 1H), 7.89 (d, 1H), 9.669 (s, 1H), 10.72 (broad s, 1 H).

상기 방법을 사용하여, 본 발명의 화합물을 제조하는 데 중간체로서 유용한 다른 히드라지드를 제조한다. 예:Using this method, other hydrazides are useful which are useful as intermediates for the preparation of the compounds of the invention. Yes:

3-브로모-4-히드록시벤조산 히드라지드3-bromo-4-hydroxybenzoic acid hydrazide

1H NMR (DMSO-d6): δ 9.95 (s, 1H), 9.65 (d, 1H), 9.61 (broad s, 1H), 6.95 (d, 1H), 4.40 (broad s, 2H); MS m/z 233.1. 1 H NMR (DMSO-d 6 ): δ 9.95 (s, 1H), 9.65 (d, 1H), 9.61 (broad s, 1H), 6.95 (d, 1H), 4.40 (broad s, 2H); MS m / z 233.1.

3-니트로-4-히드록시벤조산 히드라지드3-nitro-4-hydroxybenzoic acid hydrazide

1H NMR (DMSO-d6): δ 9.28 (broad s,1H), 8.28 (s, 1H), 7.52 (d, 1H), 6.41 (d, 1H). MS m/z 198. 1 H NMR (DMSO-d 6 ): δ 9.28 (broad s, 1H), 8.28 (s, 1H), 7.52 (d, 1H), 6.41 (d, 1H). MS m / z 198.

3-플루오로-4-히드록시벤조산 히드라지드3-fluoro-4-hydroxybenzoic acid hydrazide

1H NMR (DMSO-d6): δ 9.45 (broad s, 1H), 7.5 (d, 1H), 7.43 (d, 1H), 6.85 (t, 1H), 5.55 (broad s, 3H). 1 H NMR (DMSO-d 6 ): δ 9.45 (broad s, 1H), 7.5 (d, 1H), 7.43 (d, 1H), 6.85 (t, 1H), 5.55 (broad s, 3H).

2-클로로-4-히드록시벤조산 히드라지드, 2,3-디클로로-4-히드록시벤조산 히드라지드 및 2,5-디클로로-4-히드록시벤조산 히드라지드의 제법Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide, 2,3-dichloro-4-hydroxybenzoic acid hydrazide and 2,5-dichloro-4-hydroxybenzoic acid hydrazide

2-클로로-4-히드록시벤조산 히드라지드의 제법:Preparation of 2-Chloro-4-hydroxybenzoic acid hydrazide:

단계 A:Step A:

4-아미노-2-클로로벤조산(10g, 58mmol)을 H2SO4(12N, 120mL)에 가열하면서 용해시켰다. 얼음욕에서 용액을 냉각한 후, 수성 NaNO2(2.5M, 25mL)를 적가하여 내부 온도를 5℃로 유지하였다. 우레아를 혼합물에 가하고 15분간 교반하여 과량의 NaNO2를 파괴시켰다(전분 요오드 시험으로 모니터함). CuSO4(100-200mg)를 가하고 혼합물을 가스의 분출이 멈출 때까지 90℃로 가열시켰다. 냉각 후, 혼합물을 에틸에테르(3x)로 추출하였다. 합한 유기분획을 3N NaOH(3x)로 추출하였다. 합한 수층을 농 HCl로 산성화하였고, 생성물을 에틸에테르(3x)로 추출하였다. 유기 분획을 물, 함수로 세척하였고 MgSO4에서 건조시켰다. 미정제 생성물을 실리카겔 컬럼에 도입하고, 에틸아세테이트/헥산(1:1)로 용리하여 2-클로로-4-히드록시벤조산을 얻었다.4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H 2 SO 4 (12N, 120 mL) while heating. After cooling the solution in an ice bath, aqueous NaNO 2 (2.5M, 25 mL) was added dropwise to maintain the internal temperature at 5 ° C. Urea was added to the mixture and stirred for 15 minutes to destroy excess NaNO 2 (monitored by starch iodine test). CuSO 4 (100-200 mg) was added and the mixture was heated to 90 ° C. until gas evolution ceased. After cooling, the mixture was extracted with ethyl ether (3 ×). The combined organic fractions were extracted with 3N NaOH (3 ×). The combined aqueous layers were acidified with concentrated HCl and the product was extracted with ethyl ether (3 ×). The organic fractions were washed with water, brine and dried over MgSO 4 . The crude product was introduced into a silica gel column and eluted with ethyl acetate / hexanes (1: 1) to afford 2-chloro-4-hydroxybenzoic acid.

1H NMR (DMSO-D6):δ6.97(dd, 1H), 7.05(d, 1H), 7.95(d, 1H), 10.90(brd s, 1H). 1 H NMR (DMSO-D6): δ 6.97 (dd, 1H), 7.05 (d, 1H), 7.95 (d, 1H), 10.90 (brd s, 1H).

단계 B:Step B:

염화티오닐(1.5eq)을 무수 메탄올중 2-클로로-4-히드록시벤조산 용액에 가하였다. 용액을 실온에서 16시간동안 교반한 후, 용매를 증발시켰다. 잔여물을 에틸아세테이트에 흡수시키고, 포화 수성 중탄산나트륨, 물, 함수로 세척하였고, MgSO4에서 건조시키고 진공에서 농축시켜 메틸 2-클로로-4-히드록시벤조에이트를 얻었다.Thionyl chloride (1.5eq) was added to a 2-chloro-4-hydroxybenzoic acid solution in anhydrous methanol. The solution was stirred at rt for 16 h before the solvent was evaporated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water, brine, dried over MgSO 4 and concentrated in vacuo to afford methyl 2-chloro-4-hydroxybenzoate.

단계 C:Step C:

N-클로로숙신이미드(9.8g, 73.7mmol)을 아세트산(300mL)중 메틸 2-클로로-4-히드록시벤조에이트(13.6g, 73.1mmol)의 용액에 가하였다. 용액을 24시간동안 환류시키고, 용매를 진공하에서 증발시켰다. 잔여물을 클로로포름에 흡수시키고, 물, 함수로 세척하고, 황산마그네슘에서 건조시키고, 여과, 농축시켰다. 메틸 2,3-디틀로로-4-히드록시벤조에이트를 에틸아세테이트로부터 침전시켰다. 에틸아세테이트/헥산(1/9에서 3/7)을 사용하여 잔여물을 크로마토그래피하여 메틸 2,5-디클로로-4-히드록시벤조에이트(1.4g, 60%)와 추가의 배치의 메틸 2,3-디클로로-4-히드록시벤조에이트 이성체(총 8.4g, 10%)를 얻었다.N-chlorosuccinimide (9.8 g, 73.7 mmol) was added to a solution of methyl 2-chloro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 mL). The solution was refluxed for 24 hours and the solvent was evaporated in vacuo. The residue was taken up in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Methyl 2,3-difluoro-4-hydroxybenzoate was precipitated from ethyl acetate. Chromatography of the residue with ethyl acetate / hexanes (1/9 to 3/7) gave methyl 2,5-dichloro-4-hydroxybenzoate (1.4 g, 60%) and an additional batch of methyl 2, 3-dichloro-4-hydroxybenzoate isomer (8.4 g in total, 10%) was obtained.

메틸 2,3-디클로로-4-히드록시벤조에이트:Methyl 2,3-dichloro-4-hydroxybenzoate:

1H NMR (DMSO-D6):δ3.81(s, 3H), 7.02(d, 1H), 7.70(d, 1H), 11.52(s, 1H);MS (APCl):221,223. 1 H NMR (DMSO-D6): δ3.81 (s, 3H), 7.02 (d, 1H), 7.70 (d, 1H), 11.52 (s, 1H); MS (APCl): 221,223.

메틸 2,5-디클로로-4-히드록시벤조에이트:Methyl 2,5-dichloro-4-hydroxybenzoate:

1H NMR (CDCl3):δ3.90(s, 3H), 6.00(s, 1H), 7.14(s, 1H), 7.27(s, 1H), 7.96(s,1H);MS (APCl):221,9. 1 H NMR (CDCl 3 ): δ 3.90 (s, 3H), 6.00 (s, 1H), 7.14 (s, 1H), 7.27 (s, 1H), 7.96 (s, 1H); MS (APCl): 221,9.

단계 D:Step D:

표제의 화합물을 전구체 히드라지드 A-(C=O)-NHNH2의 합성을 위한 일반적인 방법에 따라 제조하였다.The title compound was prepared according to the general method for the synthesis of precursor hydrazide A- (C = 0) -NHNH 2 .

1H NMR (DMSO-D6):δ6.82(dd, 1H), 6.90(d, 1H), 7.79(d, 1H), 10.68(brd s, 1H). 1 H NMR (DMSO-D6): δ 6.82 (dd, 1H), 6.90 (d, 1H), 7.79 (d, 1H), 10.68 (brd s, 1H).

2,3-디클로로-4-히드록시벤조산 히드라지드 및 2,5-디클로로-4-히드록시벤조산 히드라지드의 제법(단계 D):Preparation of 2,3-dichloro-4-hydroxybenzoic acid hydrazide and 2,5-dichloro-4-hydroxybenzoic acid hydrazide (step D):

2,3-디클로로-4-히드록시벤조산 히드라지드를 펜탄올을 최상의 용매로 하는 것을 제외하고 전구체 히드라지드 A-(C=O)-NHNH2의 합성을 위한 일반적인 방법에 따라 상기 메틸 2,3-디클로로-4-히드록시벤조에이트로부터 제조하였다. 생성물을 CH2Cl2/MeOH(95/5에서 80/20)를 사용하여 실리카겔 크로마토그래피를 통해 정제하였다. 수율=50%Methyl 2,3 according to the general method for the synthesis of precursor hydrazide A- (C = O) -NHNH 2 except that 2,3-dichloro-4-hydroxybenzoic acid hydrazide is the best solvent for pentanol Prepared from dichloro-4-hydroxybenzoate. The product was purified by silica gel chromatography using CH 2 Cl 2 / MeOH (95/5 to 80/20). Yield = 50%

2,5-디클로로-4-히드록시벤조산 히드라지드를 2,5-디클로로-4-히드록시벤조에이트로부터 출발하여 유사한 방법으로 제조하였다.2,5-dichloro-4-hydroxybenzoic acid hydrazide was prepared in a similar manner starting from 2,5-dichloro-4-hydroxybenzoate.

2,5-디클로로-4-히드록시벤조산 히드라지드:2,5-dichloro-4-hydroxybenzoic acid hydrazide:

1H NMR (DMSO-D6)δ4.41(brd s, 2H), 6.99(1, 1H), 7.37(s, 1H), 9.46(s, 1H), 11.04(s, 1H). 1 H NMR (DMSO-D6) δ4.41 (brd s, 2H), 6.99 (1, 1H), 7.37 (s, 1H), 9.46 (s, 1H), 11.04 (s, 1H).

2,5-디클로로-4-히드록시벤조산 히드라지드:2,5-dichloro-4-hydroxybenzoic acid hydrazide:

1H NMR (DMSO-D6)δ4.48(brd s, 3H), 6.92(d, 2H), 7.18(d, 2H), 9.45(brd s, 1H). 1 H NMR (DMSO-D6) δ 4.48 (brd s, 3H), 6.92 (d, 2H), 7.18 (d, 2H), 9.45 (brd s, 1H).

2,3-디플루오로-4-히드록시벤조산 히드라지드의 제법:Preparation of 2,3-difluoro-4-hydroxybenzoic acid hydrazide:

단계 A:Step A:

물(8mL)중 2,3-디플루오로-4-시아노페놀(1g, 6.45mmol), H2SO4(8mL) 및 아세트산(8mL)의 혼합물을 48시간동안 환류시켰다. 용매를 회전식 증발기로 제거하여 슬러리를 얻고 그것을 얼음에 부었다. 생성물을 용액으로부터 침전시키고 여과시켰다. 고체를 물로 세척하고 건조시켜 2,3-디플루오로-4-히드록시벤조산(800mg, 71%)를 얻었다.A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol), H 2 SO 4 (8 mL) and acetic acid (8 mL) in water (8 mL) was refluxed for 48 h. The solvent was removed with a rotary evaporator to obtain a slurry which was poured on ice. The product precipitated out of solution and filtered. The solid was washed with water and dried to give 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 71%).

1H NMR (DMSO-D6):δ6.87(t, 1H), 7.60(t, 1H), 11.28(s, 1H), 12.53(brd s, 1H). 1 H NMR (DMSO-D 6 ): δ6.87 (t, 1H), 7.60 (t, 1H), 11.28 (s, 1H), 12.53 (brd s, 1H).

단계 B:Step B:

염화티오닐(50mL)을 무수 메탄올(50mL)에 용해시킨 2,3-디플루오로-4-히드록시벤조산(800mg, 5.1mmol)에 가하였다. 용액을 실온에서 16시간동안 교반한 후, 용매를 증발시켰다. 잔여물을 에틸아세테이트에 흡수시키고 포화 수성 중탄산나트륨, 물, 함수로 세척하고 MgSO4로 건조시켜 메틸 2,3-디플루오로-4-히드록시벤조에이트 (540mg, 62%)를 얻었다.Thionyl chloride (50 mL) was added to 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol (50 mL). The solution was stirred at rt for 16 h before the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine and dried over MgSO 4 to afford methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).

1H NMR (CDCl3):δ3.92(s, 3H), 6.34(brd s, 1H), 6.82(dt, 1H), 7.68(dt, 1H). 1 H NMR (CDCl 3 ): δ 3.92 (s, 3H), 6.34 (brd s, 1H), 6.82 (dt, 1H), 7.68 (dt, 1H).

단계 C:Step C:

2,3-디플루오로-4-히드록시벤조산 히드라지드를 전구체 히드라지드 A-(C=O)-NHNhH2의 합성을 위한 일반적인 방법에 따라 상기 메틸 2,3-디플루오로-4-히드록시벤조에이트로부터 제조하였다. 생성물을 CH2Cl2/MeOH(95/5에서 80/20)를 사용하여 실리카겔 컬럼크로마토그래피를 통해 정제하여 표제의 화합물을 얻었다.Methyl 2,3-difluoro-4-hydride according to a general method for the synthesis of 2,3-difluoro-4-hydroxybenzoic acid hydrazide for precursor hydrazide A- (C = O) -NHNhH 2 Prepared from oxybenzoate. The product was purified via silica gel column chromatography using CH 2 Cl 2 / MeOH (95/5 to 80/20) to afford the title compound.

1H NMR (DMSO-D6):δ4.48(s, 2H), 6.80(m, 1H), 7.22(m, 1H), 9.36(s, 1H), 10.89(s, 1H); MS(APCl):189. 1 H NMR (DMSO-D 6 ): δ 4.48 (s, 2H), 6.80 (m, 1H), 7.22 (m, 1H), 9.36 (s, 1H), 10.89 (s, 1H); MS (APCl): 189.

3-시아노-4-히드록시벤조산 히드라지드, 트리플루오로아세테이트의 제법:Preparation of 3-cyano-4-hydroxybenzoic acid hydrazide, trifluoroacetate:

단계 A:Step A:

메틸-4-히드록시벤조에이트(35.5g, 0.233mol)을 따뜻한(65℃) 아세트산(200mL)에 용해시켰다. 메틸-4-히드록시벤조에이트 용액에 아세트산 50mL 중 1염화요오드(37.8g, 0.233mol)의 용액을 65℃의 온도를 유지하고 격렬히 교반하면서 천천히(40분) 가하였다. 실온에서 냉각하는 동안, 생성물을 용액으로부터 결정화하고 하룻밤동안 방치하였다. 결정을 필터상에 모으고 물로 세척한 후, 진공하에서 건조하였다. 메틸-4-히드록시-3-요오도벤조에이트(28.6g, 44%)를 백색의 결정으로 얻었다.Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in warm (65 ° C) acetic acid (200 mL). To a methyl-4-hydroxybenzoate solution was added a solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid slowly (40 minutes) while maintaining a temperature of 65 ° C. with vigorous stirring. While cooling at room temperature, the product crystallized out of solution and left overnight. The crystals were collected on a filter, washed with water and dried in vacuo. Methyl-4-hydroxy-3-iodobenzoate (28.6 g, 44%) was obtained as white crystals.

1H NMR (DMSO-D6):δ3.79(s, 3H), 6.95(d, J=8.3, 1H), 7.81(dd, J=8.3, 2.2, 1H), 8.22(d, J=2.2, 1H);13C NMR (DMSO-D6):δ52.8, 85.2, 115.5, 123.0, 132.0, 141.0, 161.9, 165.6.; MS(APCl, neg):277. 1 H NMR (DMSO-D 6 ): δ3.79 (s, 3H), 6.95 (d, J = 8.3, 1H), 7.81 (dd, J = 8.3, 2.2, 1H), 8.22 (d, J = 2.2 , 1H); 13 C NMR (DMSO-D 6 ): δ 52.8, 85.2, 115.5, 123.0, 132.0, 141.0, 161.9, 165.6 .; MS (APCl, neg): 277.

단계 B:Step B:

메틸-4-히드록시-3-요오도벤조에이트(2.00g, 7.2mmol)을 건조 DMF 5ml에서 용해시켰다. 시안화구리(I)(0.72g, 8.0mmol)과 시안화나트륨의 작은 결정을 가하였다. 혼합물에 질소로 흘러내렸고, 오일 가열욕(100-110℃)에 두고 하룻밤동안 교반하였다. TLC는 거의 완결된 반응을 나타내었다. 그 혼합물을 냉각시키고, 고체르 여과하여 제거하였다. 고체를 DMF(3mL)로 추출하였다. 여과물과 세척물을 에틸아세테이트 100mL에 흡수시킨 후, 포화 염화나트륨 용액 3부로 세척하였다. 고체 및 수성 세척물을 모으고, 에틸아세테이트 50mL와 염화제2철 용액(농염산 7mL중 수화 염화제2철 4g)의 혼합물과 흔들어 교반하였다. 에틸아세테이트 층을 모으고, 메타비술피트를 함유하는 함수로 세척하고, 황산나트륨으로 건조, 여과하고, 용매를 진공에서 제거하였다. 그 결과의 고체를 실리카겔상의 플래시 크로마토그래피(20% 에틸아세테이트/헥산)로 정제하여 메틸-3-시아노-4-히드록시벤조에이트 0.93g(73%)을 얻었다.Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved in 5 ml of dry DMF. Small crystals of copper cyanide (I) (0.72 g, 8.0 mmol) and sodium cyanide were added. The mixture was run down with nitrogen and placed in an oil heating bath (100-110 ° C.) and stirred overnight. TLC showed almost complete reaction. The mixture was cooled down and removed by solid filtration. The solid was extracted with DMF (3 mL). The filtrate and washings were absorbed in 100 mL of ethyl acetate and washed with 3 parts of saturated sodium chloride solution. The solid and aqueous washes were combined and stirred with a mixture of 50 mL of ethyl acetate and ferric chloride solution (4 g of hydrated ferric chloride in 7 mL concentrated hydrochloric acid). The ethyl acetate layer was combined, washed with brine containing metabisulfite, dried over sodium sulfate, filtered and the solvent removed in vacuo. The resulting solid was purified by flash chromatography on silica gel (20% ethyl acetate / hexane) to give 0.93 g (73%) of methyl-3-cyano-4-hydroxybenzoate.

1H NMR (DMSO-D6):δ3.79(s, 3H), 7.07(d, J=8.7, 1H), 8.02(dd, J=8.7, 1.9, 1H), 8.10(d, J=1.9, 1H). 1 H NMR (DMSO-D 6 ): δ 3.79 (s, 3H), 7.07 (d, J = 8.7, 1H), 8.02 (dd, J = 8.7, 1.9, 1H), 8.10 (d, J = 1.9 , 1H).

단계 C:Step C:

메틸-3-시아노-4-히드록시벤조에이트(2.71g, 15.3mmol)을 THF 50ml중에 용해시켰다. 용액을 얼음욕에서 냉각시키고, 2.0M 수산화칼륨(17mL, 34mmol)을 적가하였다. 그 결과의 혼합물을 실온에서 하룻밤동안 교반하였다. TLC로 반응의 완결을 확인하였다. THF를 회전식 증발기에 의해 제거하였다. 수성 잔여물을 수성 트리플루오로아세트산으로 산성화하고, 역상 HPLC(C-18, 물과 아세토니트릴중 0.1% TFA)로 정제하였다. 3-시아노-4-히드록시벤조산(2.1g, 84%)을 동결건조후 백색 파우더로 얻었다.Methyl-3-cyano-4-hydroxybenzoate (2.71 g, 15.3 mmol) was dissolved in 50 ml of THF. The solution was cooled in an ice bath and 2.0 M potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at rt overnight. TLC confirmed the completion of the reaction. THF was removed by rotary evaporator. The aqueous residue was acidified with aqueous trifluoroacetic acid and purified by reverse phase HPLC (C-18, 0.1% TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid (2.1 g, 84%) was obtained as a white powder after lyophilization.

1H NMR (DMSO-D6):δ7.09(d, J=9.0, 1H), 8.00(dd, J=9.0, 2.3, 1H), 8.07(d, J=2.3, 1H) 12.5(br s, 2H); MS(APCl, neg):162. IR:2252cm-1, CN. 1 H NMR (DMSO-D 6 ): δ7.09 (d, J = 9.0, 1H), 8.00 (dd, J = 9.0, 2.3, 1H), 8.07 (d, J = 2.3, 1H) 12.5 (br s , 2H); MS (APCl, neg): 162. IR: 2252 cm -1 , CN.

단계 DStep D

3-시아노-4-히드록시벤조산(1.88g, 11.5mmol)을 염화메틸렌/DMF (1/1) 20mL에 용해시키고 얼음욕에서 냉각시켰다. 디이소프로필에틸아민(12mL, 69mmol), t-부틸카르바제이트(1.76g, 13.3mmol), 및 PyBroP(브로모-트리스-피롤리디노-포스포늄 헥사플루오로포스페이트, 6g, 12.9mmol)를 가하고, 이 혼합물을 교반하여 맑은 용액을 형성하였다. 용액을 냉장고에 하룻밤동안 두었다. TLC로 반응이 완결되지 않았음을 확인하여 추가의 디이소프로필에틸아민(22mL, 127mmol), t-부틸카바제이트(1.85g, 6.4mmol), 및 PyBroP(3.0g, 6.4mmol)를 가하였다. 0℃에서 추가의 8시간 후, 반응을 다음과 같이 워크업하였다. 용액을 회전식 증발기로 감소시켰다. 잔여 DMF 용액을 에틸아세테이트 100mL로 희석시키고, 0.1M HCl 두세부로 세척하였다(세척액이 리트머스 종이를 산성으로 남을 때까지). 에틸아세테이트 층을 함수 3부로 더 세척하고, 황산마그네슘에서 건조시키고, 여과하고, 진공에서 감소되어 오일이 되었다. 이 오일을 실리카겔 상의 크로마토그래피(헥산:에틸아세테이트 6:4)로 정제하여 tert-부틸옥시카르보닐(3-시아노-4-히드록시)벤조산 히드라지드(1.8g, 56%)를 백색의 고체의 형태로 얻었다.3-Cyano-4-hydroxybenzoic acid (1.88 g, 11.5 mmol) was dissolved in 20 mL of methylene chloride / DMF (1/1) and cooled in an ice bath. Diisopropylethylamine (12 mL, 69 mmol), t-butylcarbazate (1.76 g, 13.3 mmol), and PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 6 g, 12.9 mmol) Was added and the mixture was stirred to form a clear solution. The solution was placed in the refrigerator overnight. Additional diisopropylethylamine (22 mL, 127 mmol), t-butylcarbazate (1.85 g, 6.4 mmol), and PyBroP (3.0 g, 6.4 mmol) were added, confirming that the reaction was not complete by TLC. . After an additional 8 hours at 0 ° C., the reaction was worked up as follows. The solution was reduced with a rotary evaporator. The remaining DMF solution was diluted with 100 mL of ethyl acetate and washed with 0.1 M HCl headwash (until the wash left acidic litmus paper). The ethyl acetate layer was further washed with three portions of brine, dried over magnesium sulfate, filtered and reduced in vacuo to an oil. The oil was purified by chromatography on silica gel (hexane: ethyl acetate 6: 4) to give tert-butyloxycarbonyl (3-cyano-4-hydroxy) benzoic acid hydrazide (1.8 g, 56%) as a white solid. Obtained in the form of.

1H NMR (DMSO- D6): δ 1.42 (s, 9H), 7.09 (d, J = 8.7, 1H), 7.98 (m, 1H), 8.11 (br s, 1H), 8.92 (s, 1H), 10.15 (s, 1H), 11.73 (br s, 1H); MS (APCI, neg): 276; IR: 2232 cm-1, CN. 1 H NMR (DMSO-D 6 ): δ 1.42 (s, 9H), 7.09 (d, J = 8.7, 1H), 7.98 (m, 1H), 8.11 (br s, 1H), 8.92 (s, 1H) , 10.15 (s, 1 H), 11.73 (br s, 1 H); MS (APCI, neg): 276; IR: 2232 cm -1 , CN.

단계 E:Step E:

Boc-히드라지드(1.8g, 6.5mmol)를 클로로포름 50mL에 희석시키고, 얼음욕에서 냉각시켰다. 트리플루오로아세트산을 교반하면서 가하고, 그 결과의 용액을 0℃에서 4시간동안 두었다. TCL로 반응의 완결을 확인하였다. 용매 및 과량의 TFA를 회전식 증발기로 제거하였다. 잔여 오일을 역상 액체크로마토그래피(Aquasil C-18컬럼, 물/아세토니트릴/0.1% TFA)로 정제하였다. 표제의 화합물(0.24g, 13%)을 백색의 고체 형태로 얻었다.Boc-hydrazide (1.8 g, 6.5 mmol) was diluted in 50 mL of chloroform and cooled in an ice bath. Trifluoroacetic acid was added with stirring, and the resulting solution was kept at 0 ° C. for 4 hours. TCL confirmed the completion of the reaction. Solvent and excess TFA were removed by rotary evaporator. The residual oil was purified by reversed phase liquid chromatography (Aquasil C-18 column, water / acetonitrile / 0.1% TFA). The title compound (0.24 g, 13%) was obtained in the form of a white solid.

1H NMR (DMSO- D6): δ 7.16 (d, J = 9.0, 1H), 8.00 (dd, J = 1.5, 9.0, 1H), 8.14 (d, J = 1.5, 1H), 10.47 (br s, 5H); MS (APCI, neg): 176. 1 H NMR (DMSO-D 6 ): δ 7.16 (d, J = 9.0, 1H), 8.00 (dd, J = 1.5, 9.0, 1H), 8.14 (d, J = 1.5, 1H), 10.47 (br s , 5H); MS (APCI, neg): 176.

4-히드록시나프토산 히드라지드의 제조:Preparation of 4-hydroxynaphthoic acid hydrazide:

단계 A:Step A:

질산은(17g, 0.1mol)을 물(10mL)에 용해시키고, 1N NaOH(300mL, 0.3mol)로 처리하였다. 형성된 갈색의 침전물을 30분동안 교반하였고, 그 상층액을 가만히 따라냈다. 갈색의 산화은을 추가의 물(3X)로 세척하였다. 상기 산화은에 1N NaOH(150mL) 및 4-히드록시나프트알데히드(1g, 6mmol)을 가하였다. 혼합물을 70℃까지 10분간 가열한 후, 추가량의 4-히드록시나프트알데히드(5.5g, 32mmol)를 몇부 가하였다. 혼합물을 80℃에서 16시간동안 유지하였다. TLC분석으로 불완전한 변환을 확인하였다. 추가의 산화은을 상기와 같이 제조하여 반응혼합물에 가하였다. 혼합물을 6시간동안 더 가열한 후, 혼합물을 냉각시키고 1N HCl로 산성화하였다. 수층을 에틸아세테이트(3X)로 추출하고 농축하면서 4-히드록시나프토산(3.7g, 60%)을 용액에서 침전시켰다.Silver nitrate (17 g, 0.1 mol) was dissolved in water (10 mL) and treated with 1N NaOH (300 mL, 0.3 mol). The brown precipitate formed was stirred for 30 minutes and the supernatant was left to decant. Brown silver oxide was washed with additional water (3 ×). To the silver oxide was added 1N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol). The mixture was heated to 70 ° C. for 10 minutes and then additional portions of additional 4-hydroxynaphthaldehyde (5.5 g, 32 mmol) were added. The mixture was kept at 80 ° C. for 16 hours. TLC analysis confirmed incomplete conversion. Additional silver oxide was prepared as above and added to the reaction mixture. The mixture was further heated for 6 hours before the mixture was cooled and acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (3X) and concentrated to 4-hydroxynaphthoic acid (3.7 g, 60%) in solution.

1H NMR (DMSO-D6): δ 6.69 (d, 1H), 7.28 (t, 1H), 7.39 (t, 1H), 7.93 (d, 1H), 8.03 (d, 1H), 8.82 (d, 1H), 10.82 (s, 1H), 12.29 (s, 1H). 1 H NMR (DMSO-D6): δ 6.69 (d, 1H), 7.28 (t, 1H), 7.39 (t, 1H), 7.93 (d, 1H), 8.03 (d, 1H), 8.82 (d, 1H ), 10.82 (s, 1 H), 12.29 (s, 1 H).

단계 B:Step B:

무수메탄올중 4-히드록시나프토산 용액에 0℃에서 염화티오닐(1.5eq)을 가하였다. 용액을 실온에서 16시간동안 교반한 후, 용매를 증발시켰다. 잔여물을 에틸아세테이트에 흡수시키고 포화 수성 중탄산나트륨, 물, 함수로 세척하고, MgSO4로 건조시켜 메틸 4-히드록시나프토에이트를 얻었다.To a 4-hydroxynaphthoic acid solution in anhydrous methanol was added thionyl chloride (1.5eq) at 0 ° C. The solution was stirred at rt for 16 h before the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine and dried over MgSO 4 to afford methyl 4-hydroxynaphthoate.

1H NMR (DMSO-D6): δ 3.87 (s, 3H), 6.92 (d, 1H), 7.53 (t, 1H), 7.65 (t, 1H), 8.13 (d, 1H), 8.26 (d, 1H), 8.93 (d, 1H), 11.16 (s, 1H). 1 H NMR (DMSO-D6): δ 3.87 (s, 3H), 6.92 (d, 1H), 7.53 (t, 1H), 7.65 (t, 1H), 8.13 (d, 1H), 8.26 (d, 1H ), 8.93 (d, 1 H), 11.16 (s, 1 H).

단계 C:Step C:

표제의 화합물을 전구체 히드라지드 A-(C=O)-NHNH2의 합성에서의 방법에 따라 메틸 4-히드록시나프토에이트로부터 제조하였다.The title compound was prepared from methyl 4-hydroxynaphthoate according to the method in the synthesis of precursor hydrazide A- (C = 0) -NHNH 2 .

1H NMR (DMSO-D6): δ 6.60 (d, 1H), 7.28 (m, 3H), 7.95 (d, 1H), 8.07 (d, 1H), 9.25 (brd s, 1H). 1 H NMR (DMSO-D6): δ 6.60 (d, 1H), 7.28 (m, 3H), 7.95 (d, 1H), 8.07 (d, 1H), 9.25 (brd s, 1H).

게다가, 상기 방법을 사용하여, 본 발명의 화합물을 제조하는 데 중간체로서 유용한 다음의 히드라지드를 제조할 수 있다:In addition, the above methods can be used to prepare the following hydrazides which are useful as intermediates in the preparation of the compounds of the present invention:

에테르로 치환된 아릴-알데히드의 합성을 위한 일반적인 방법:General methods for the synthesis of aryl-aldehydes substituted with ethers:

에테르가 결합된 알데히드는 상응하는 페놀성 화합물을 일반적으로 Williamson 에테르 합성으로 알려진 반응에서 상기 정의된 바와 같은 -(K)m-D 부분을 도입하는 여러가지 친전자성 알킬화제를 사용하여 O-알킬화시킴으로써 제조될 수 있다(H. Feuer, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p. 446-460).Ether bound aldehydes are prepared by O-alkylation of the corresponding phenolic compounds with various electrophilic alkylating agents which introduce a-(K) m -D moiety as defined above in a reaction generally known as Williamson ether synthesis. (H. Feuer, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p. 446-460).

상기 식에서, Lx는 -Cl, -Br, -I, -OSO2CㅗH3, -OSO2p-톨릴 또는 -OSO2CF3과 같은 이탈기이고; R3a, R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R14and R15는 화학식 I에서 정의된 바와 같다.Wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO 2 C ㅗ H 3 , -OSO 2 p-tolyl or -OSO 2 CF 3 ; R 3a , R 3b , R 4a , R 4b , a, b, c, d, f, p, q, D, M, R 14 and R 15 are as defined in formula (I).

반응식 II에 따라서, 에테르로 치환된 아릴-알데히드는 아세톤, 메틸에틸케톤, 디메틸포름아미드, 디옥산, 테트라푸란, 톨루엔, 에틸렌글리콜디메틸에테르, 술폴란, 디에틸에테르, 물 또는 상기 용매중 상용성인 2이상의 혼합물과 같은 유기 용매중에서, 히드록시벤즈알데히드 또는 히드록시나프트알데히드를 등몰량의 알킬할라이드 또는 아릴-저급알킬할라이드와 함께, 1 내지 15당량(바람직하게 1 내지 5당량)의 수소화나트륨, 수소화칼륨, 메톡시화, 에톡시화 또는 tert-부톡시화, 나트륨 또는 칼륨, 탄산 나트륨, 칼륨 또는 세슘, 플루오로화 칼륨 또는 세슘, 수산화 나트륨 또는 칼륨 등의 염기, 또는 디이소프로필에틸아민, 2,4,6-콜리딘 또는 메톡시화 또는 수산화 벤질디메틸-암모늄 등의 유기 염기의 존재하에서 교반시킴으로써 제조할 수 있다. 반응은 0℃ 내지 150℃, 바람직하게 20℃ 내지 100℃에서, 바람직하게 N2또는 Ar의 불활성 분위기에서 수행될 수 있다. 반응이 완결되면, 혼합물을 여과하고, 진공에서 농축하고, 그 결과의 생성물을 선택적으로 에틸아세테이트/헥산을 용리액으로 하는 실리카겔상의 크로마토그래피로 정제하였다. 화합물은 또한(적당하다면) 에틸알콜, 에틸아세테이트, 이소프로필알콜, 물, 헥산, 톨루엔 또는 상용성인 이들의 혼합물과 같은 적당한 용매로부터 재결정함으로써 정제할 수 있다. 에테르로 치환된 아릴-알데히드의 제조를 예시하는 구체적인 예가 이하 제공된다.According to Scheme II, the aryl-aldehyde substituted by ether is acetone, methyl ethyl ketone, dimethylformamide, dioxane, tetrafuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethyl ether, water or compatible in the above solvents. In an organic solvent such as a mixture of two or more, 1 to 15 equivalents (preferably 1 to 5 equivalents) of sodium hydride, hydrogenation of hydroxybenzaldehyde or hydroxynaphthaldehyde with an equimolar amount of alkyl halide or aryl-lower alkyl halide Potassium, methoxylated, ethoxylated or tert-butoxylated, sodium or potassium, sodium carbonate, potassium or cesium, potassium fluoride or cesium, bases such as sodium hydroxide or potassium, or diisopropylethylamine, 2,4, It can be prepared by stirring in the presence of an organic base such as 6-collidine or methoxylated or benzyldimethyl-ammonium hydroxide. The reaction can be carried out at 0 ° C. to 150 ° C., preferably at 20 ° C. to 100 ° C., preferably in an inert atmosphere of N 2 or Ar. Upon completion of the reaction, the mixture was filtered, concentrated in vacuo and the resulting product was purified by chromatography on silica gel, optionally with ethyl acetate / hexane as eluent. The compounds may also be purified by recrystallization from suitable solvents, such as, if appropriate, ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or mixtures thereof. Specific examples are provided below to illustrate the preparation of aryl-aldehydes substituted with ethers.

4-(2-테트라히드로피라닐메톡시)-1-나프트알데히드의 제조:Preparation of 4- (2-tetrahydropyranylmethoxy) -1-naphthaldehyde:

디메틸 포름아미드중 4-히드록시나프트알데히드(1g, 5.8mmol), 2-브로모메틸 테트라히드로푸란(1 g, 5.8 mmol) 및 파우더 K2CO3(1.2 g, 8.7 mmol)의 혼합물을 60℃에서 하룻밤동안 교반하였다. 혼합물을 물과 에틸아세테이트에 흡수시켰다. 유기층을 분리하고 물, 함수로 세척하고, MgSO4에서 건조시키고, 여과하고 농축시켰다. 생성물을 에틸아세테이트/헥산을 사용하여 실리카겔 컬럼크로마토그래피로 정제하였다.A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydrofuran (1 g, 5.8 mmol) and powder K 2 CO 3 (1.2 g, 8.7 mmol) in dimethyl formamide was added to 60 Stir overnight at ° C. The mixture was taken up in water and ethyl acetate. The organic layer was separated and washed with water, brine, dried over MgSO 4 , filtered and concentrated. The product was purified by silica gel column chromatography using ethyl acetate / hexanes.

1H NMR (DMSO-d6): δ 1.48 (m, 4H), 1.74 (d, 1H), 1.84 (m, 1H), 3.44 (m, 1H), 3.78 (m, 1H), 3.92 (d, 1H), 4.23 (m, 2H), 7.17 (d, 1H), 7.64 (t, 1H), 7.74 (t, 1H), 8.11 (d, 1H), 8.27 (d, 1H), 9.22 (d, 1H), 10.17 (s,1H). 1 H NMR (DMSO-d 6 ): δ 1.48 (m, 4H), 1.74 (d, 1H), 1.84 (m, 1H), 3.44 (m, 1H), 3.78 (m, 1H), 3.92 (d, 1H), 4.23 (m, 2H), 7.17 (d, 1H), 7.64 (t, 1H), 7.74 (t, 1H), 8.11 (d, 1H), 8.27 (d, 1H), 9.22 (d, 1H ), 10.17 (s, 1 H).

4-[(3,5-비스-트리플루오로메틸)벤질옥시]-1-나프트알데히드의 제조:Preparation of 4-[(3,5-bis-trifluoromethyl) benzyloxy] -1-naphthaldehyde:

4-히드록시나프트알데히드(1 g, 5.8 mmol), 3,5-비스-트리플루오로메틸벤즈브로마이드(1.8 g, 5.8 mmol), 및 파우더 K2CO3(1.2 g, 8.7 mmol)의 혼합물을 하룻밤동안 아세톤(40mL)중에서 교반하였다. 혼합물을 얼음조각 200 mL에 붓고 얼음이 녹을 때까지 교반하였다. 황색의 침전물, 4-((3,5-비스-트리플루오로메틸)벤질옥시)-1-나프트알데히드를 수집하고 건조시켰다.Mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 3,5-bis-trifluoromethylbenzbromide (1.8 g, 5.8 mmol), and powder K 2 CO 3 (1.2 g, 8.7 mmol) Was stirred in acetone (40 mL) overnight. The mixture was poured into 200 mL of ice cubes and stirred until the ice melted. A yellow precipitate, 4-((3,5-bis-trifluoromethyl) benzyloxy) -1-naphthaldehyde, was collected and dried.

1H NMR (DMSO-d6): δ 5.58 (s, 2H), 7.07 (d, 1H), 7.22 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.79 (d, 1H), 7.86 (d, 1H), 7.99 (s, 1H), 8.14 (s, 1H), 8.30 (s, 3H), 8.94 (s, 1H), 8.97 (d, 1H), 11.0 (broad s, 1H), 11.69 (s,1H); MS (ESI) m/z 675.2 (M+H)+. 1 H NMR (DMSO-d 6 ): δ 5.58 (s, 2H), 7.07 (d, 1H), 7.22 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.79 (d, 1H), 7.86 (d, 1H), 7.99 (s, 1H), 8.14 (s, 1H), 8.30 (s, 3H), 8.94 (s, 1H), 8.97 (d, 1H), 11.0 (broad s, 1H), 11.69 (s, 1H); MS (ESI) m / z 675.2 (M + H) + .

4-(2-클로로에톡시)-1-나프트알데히드의 제조:Preparation of 4- (2-chloroethoxy) -1-naphthaldehyde:

N,N-디메틸포름아미드(DMF)(40mL)중 4-히드록시-1-나프트알데히드(8.6g, 50mmol)과 탄산칼륨(13.8g, 100mmol)의 용액에 1-브로모-2-클로로에탄(7.4g, 50mmoles)을 가하였다. 혼합물을 하룻밤동안 60℃에서 가열시켰다. 용액을 에틸아세테이트(500mL)로 희석시키고, 물과 함수로 추출하였다. 유기층을 황산마그네슘에서 건조시키고 용매를 증발시켜 생성물 12.1g을 얻었다(수율 52%).1-Bromo-2-chloro in a solution of 4-hydroxy-1-naphthaldehyde (8.6 g, 50 mmol) and potassium carbonate (13.8 g, 100 mmol) in N, N-dimethylformamide (DMF) (40 mL). Ethane (7.4 g, 50 mmoles) was added. The mixture was heated at 60 ° C. overnight. The solution was diluted with ethyl acetate (500 mL) and extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to give 12.1 g of product (yield 52%).

MS (CI): 403, 405, 407.1H NMR (CDCl3): δ 10.2 (s, 1H), 9.3 (d, 1H) 8.35 (d, 1H), 7.85 (d, 1H), 7.65 (m, 1H), 7.5 (m, 1H), 7.1 (d, 1H), 4.35 (t, 2H), 4.15 (t, 2H).MS (CI): 403, 405 , 407. 1 H NMR (CDCl 3): δ 10.2 (s, 1H), 9.3 (d, 1H) 8.35 (d, 1H), 7.85 (d, 1H), 7.65 (m , 1H), 7.5 (m, 1H), 7.1 (d, 1H), 4.35 (t, 2H), 4.15 (t, 2H).

생성물을 그 자체로 추가의 변형에서 사용하였다.The product itself was used in further variations.

상기 방법을 응용하여 다음의 치환된 알데히드 중간체를 합성하였다:The method was applied to synthesize the following substituted aldehyde intermediates:

4-(3,5-디플루오로벤질옥시)-1-나프트알데히드4- (3,5-difluorobenzyloxy) -1-naphthaldehyde

융점. 100-101℃Melting point. 100-101 ℃

3-알릴-4-히드록시-5-메톡시-벤즈알데히드의 제조:Preparation of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde:

아세톤(30mL)중 바닐린(1.0g, 6.57mmol)의 용액을 탄산나트륨(4.50g, 32.8mmol) 및 브롬화알릴(0.62mL, 7.3mmol)에 가하였다. 혼합물을 6시간동안 환류하에서 가열하였다. TLC로 새로운 스팟이 나타났음을 확인하였다. 칼륨염을 여과하여 제거하고 여과물을 시럽으로 농축시켰다. 작은 샘플을 헥산/에틸아세테이트 7:3을 전개용매로 사용하는 제조용 TLC를 사용하여 정제하였다.1H NMR (CDCl3) δ = 3.94 (s, 3H), 4.67 - 4.83 (m, 2H), 5.30 - 5.55 (m, 2H), 6.01 - 6.21 (m, 1H), 6.98 (d, J = 9 Hz, 1H), 7.40 - 7.56 (m, 2H), 9.85 (s, 1H); MS (APCI): 193.6A solution of vanillin (1.0 g, 6.57 mmol) in acetone (30 mL) was added to sodium carbonate (4.50 g, 32.8 mmol) and allyl bromide (0.62 mL, 7.3 mmol). The mixture was heated at reflux for 6 hours. TLC confirmed that new spots appeared. The potassium salt was filtered off and the filtrate was concentrated to syrup. Small samples were purified using preparative TLC using hexane / ethylacetate 7: 3 as the developing solvent. 1 H NMR (CDCl 3 ) δ = 3.94 (s, 3H), 4.67-4.83 (m, 2H), 5.30-5.55 (m, 2H), 6.01-6.21 (m, 1H), 6.98 (d, J = 9 Hz, 1H), 7.40-7.56 (m, 2H), 9.85 (s, 1H); MS (APCI): 193.6

미정제 시럽을 6시간동안 200℃의 오일욕에서 그 자체로 가열하였다. 미정제 물질을 클로로포름에 용해시키고 1팩의 실리카겔을 통해 여과시켰다. 미정제 생성물(수율 72%)을 다음 단계인 O-알킬화에서 사용하였다. 작은 부분을 조제용-TLC를 사용하여 정제하여 3-알릴-4-히드록시-5-메톡시-벤즈알데히드의 순수한 샘플을 얻었다.1H NMR (CDCl3) δ = 3.46 (d, J = 6 Hz, 2 H), 3.96 (s, 3H), 5.02 - 5.22 (m, 2H), 5.94 - 6.11 (m, 1H), 6.30 (s, 1H), 7.45 (s, 2H), 9.80 (s, 1 H); MS (APCI): 193.3.The crude syrup was heated by itself in an oil bath at 200 ° C. for 6 hours. The crude material was dissolved in chloroform and filtered through one pack of silica gel. The crude product (yield 72%) was used in the next step O-alkylation. A small portion was purified using prep-TLC to obtain a pure sample of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde. 1 H NMR (CDCl 3 ) δ = 3.46 (d, J = 6 Hz, 2 H), 3.96 (s, 3H), 5.02-5.22 (m, 2H), 5.94-6.11 (m, 1H), 6.30 (s , 1H), 7.45 (s, 2H), 9.80 (s, 1H); MS (APCI): 193.3.

3-알릴-4-(4-이소프로필벤질옥시)-5-메톡시벤즈알데히드의 제법:Preparation of 3-allyl-4- (4-isopropylbenzyloxy) -5-methoxybenzaldehyde:

미정제 3-알릴-4-히드록시-5-메톡시-벤즈알데히드를 아세톤에 흡수시키고 염화 4-이소프로필벤질로 탄산칼륨의 존재하에서 처리하여 원하는 생성물을 얻었다.Crude 3-allyl-4-hydroxy-5-methoxy-benzaldehyde was absorbed into acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to afford the desired product.

1H NMR (CDCl3) δ = 1.26 (d, J = 7 Hz, 6 H), 2.92 (m, 1H), 3.38 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 4.98 - 5.12 (m, 4H), 5.93 - 5.75 (m, 1H), 7.20 - 7.43 (m, 6H), 9.87 (s, 1H). 1 H NMR (CDCl 3 ) δ = 1.26 (d, J = 7 Hz, 6 H), 2.92 (m, 1H), 3.38 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 4.98- 5.12 (m, 4H), 5.93-5.75 (m, 1H), 7.20-7.43 (m, 6H), 9.87 (s, 1H).

화학식 IXa 및 IXb의 화합물의 합성을 위한 일반적인 방법:General Methods for the Synthesis of Compounds of Formulas IXa and IXb:

상기 식에서, B, D, R8및 R9는 화학식 I에서 정의된 것과 동일한 의미를 가진다.In the above formula, B, D, R8And R9Has the same meaning as defined in formula (I).

단계 A:Step A:

THF중 아닐린(또는 아닐린유도체)(1eq.) 용액에 염화클로로아세틸(1.2eq.)을 적가하였다. 실온에서 하룻밤동안 교반한 후, 물 100mL를 가하고, 그 혼합물을 에틸아세테이드로 추출하였다. 유기상을 희염산으로 2회, 물로 2회 세척하고, MgSO4에서 건조시킨 다음 농축시켜 순수한 생성물을 얻었다.To a solution of aniline (or aniline derivative) (1 eq.) In THF was added dropwise chloroacetyl (1.2 eq.). After stirring at room temperature overnight, 100 mL of water was added and the mixture was extracted with ethyl acetate. The organic phase was washed twice with dilute hydrochloric acid and twice with water, dried over MgS0 4 and concentrated to afford pure product.

단계 B:Step B:

DMSO중 클로로아세트아닐리드(또는 이들의 유도체)(1.2eq.) 및 2-메톡시-4-히드록시 벤즈알데히드(또는 히드록시기로 치환된 다른 방향족 알데히드)(1eq.)의 용액에 탄산칼륨(1.5eq.)을 가하였다. 실온에서 하룻밤동안 교반한 후, 물 100mL를 가하였다. 그 혼합물을 에틸아세테이드로 추출하고, 유기상을 포화 중탄산나트륨 용액으로 2회, 물로 2회 세척하고, MgSO4에서 건조시켰다. 진공에서 농축시켜 생성물을 얻었다.Potassium carbonate (1.5 eq.) In a solution of chloroacetanilide (or derivative thereof) (1.2 eq.) And 2-methoxy-4-hydroxy benzaldehyde (or other aromatic aldehyde substituted with hydroxy group) (1 eq.) In DMSO. ) Was added. After stirring at room temperature overnight, 100 mL of water was added. The mixture was extracted with ethyl acetate and the organic phase was washed twice with saturated sodium bicarbonate solution and twice with water and dried over MgSO 4 . Concentration in vacuo gave the product.

하기 2개의 알데히드는 이 방법을 사용하여 제조될 수 있는 화합물의 예로서 제조되었다.The following two aldehydes have been prepared as examples of compounds that can be prepared using this method.

N-(4-클로로페닐)-2-(4-포르밀-3-메톡시페녹시)아세트아미드:N- (4-chlorophenyl) -2- (4-formyl-3-methoxyphenoxy) acetamide:

1H NMR (CDCl3): δ 4.28 (s, 3H), 5.01 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.97 ( dd, J = 8.6, 2.1 Hz, 1H), 7.67 ( d, J = 8.9Hz , 2H), 7.89 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.6Hz, 1H), 8.51 (s, 1H), 10.66 ( s, 1H); MS ( APCI ): 319.9 . 1 H NMR (CDCl 3 ): δ 4.28 (s, 3H), 5.01 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.6, 2.1 Hz, 1H), 7.67 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.6 Hz, 1H), 8.51 (s, 1H), 10.66 (s, 1H); MS (APCI): 319.9.

N-(4-이소프로필페닐)-2-(4-포르밀-3-메톡시페녹시)아세트아미드:N- (4-isopropylphenyl) -2- (4-formyl-3-methoxyphenoxy) acetamide:

1H NMR ( DMSO-D6): δ 2.07 (d, J = 6.9 Hz , 6H), 2.70 (m, J = 6.9 Hz, 1H), 3.77 (s, 3H), 4.68 (s, 2H), 6.56 (dd, J = 8.7, 2.1 Hz, 1H), 6.66 ( d, J = 2.1Hz, 1H), 7.06 (d, J = 8.5Hz, 2H), 7.39 ( d, J = 8.50 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 9.93 (s, 1H), 10.05 (s, 1H); MS (APCI ): 328. 1 H NMR (DMSO-D6): δ 2.07 (d, J = 6.9 Hz, 6H), 2.70 (m, J = 6.9 Hz, 1H), 3.77 (s, 3H), 4.68 (s, 2H), 6.56 ( dd, J = 8.7, 2.1 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.50 Hz, 2H), 7.55 ( d, J = 8.7 Hz, 1 H), 9.93 (s, 1 H), 10.05 (s, 1 H); MS (APCI): 328.

이 유형의 알데히드는 단계 D에 기재된 방법을 사용하여 히드라지드에 결합시켜 화학식 IXa의 화합물을 얻을 수 있다. 다른 방법으로, 이들 화합물은 하기(단계 C)에 기재된 염기로 처리하여 전위된 후, 히드라지드(단계 D)에 결합되어 화학식 IXb의 화합물을 얻을 수 있다.This type of aldehyde can be bound to hydrazide using the method described in step D to give a compound of formula IXa. Alternatively, these compounds can be inverted by treatment with a base described below (step C) and then bound to hydrazide (step D) to afford the compound of formula IXb.

단계 C:Step C:

아세토니트릴중 알데히드(1eq.) 및 탄산칼륨(1.5eq.)의 혼합물을 환류하였다. 반응물을 TLC(헥산:에틸아세테이트=2:1)로 모니터하였다. TLC가 거의완전한 변환을 나타냈을 때(약 48h), 물 100mL를 가하였다. 그 혼합물을 에틸아세테이드로 추출하고, 유기상을 MgSO4로 건조시키고 농축시켜 컬럼크로마토그래피로 더 정제하거나 다음 단계에서 직접 사용할 수 있는 원하는 생성물을 얻었다.A mixture of aldehyde (1 eq.) And potassium carbonate (1.5 eq.) In acetonitrile was refluxed. The reaction was monitored by TLC (hexane: ethyl acetate = 2: 1). When TLC showed nearly complete conversion (about 48 h), 100 mL of water was added. The mixture was extracted with ethyl acetate and the organic phase was dried over MgSO 4 and concentrated to give the desired product which could be further purified by column chromatography or used directly in the next step.

하기 2개의 알데히드는 이 방법을 사용하여 제조될 수 있는 화합물의 예로서 제조되었다.The following two aldehydes have been prepared as examples of compounds that can be prepared using this method.

4-(4-클로로페닐아미노)-2-메톡시벤즈알데히드:4- (4-chlorophenylamino) -2-methoxybenzaldehyde:

상기 단계 C에 기재된 방법을 사용하여 N-(4-클로로페닐)-2-(4-포르밀-3-메톡시페녹시)아세트아미드로부터 제조됨.Prepared from N- (4-chlorophenyl) -2- (4-formyl-3-methoxyphenoxy) acetamide using the method described in step C above.

1H NMR (CDCl3): δ 3.84 (s, 3 H), 6.14 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.54 ( dd, J = 8.4, 1.8Hz, 1H), 7.14 (d, J = 8.7Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.5Hz, 1H), 10.22 (s, 1H); MS (APCI ): 261.9. 1 H NMR (CDCl 3 ): δ 3.84 (s, 3H), 6.14 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 8.4, 1.8 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.5 Hz, 1H), 10.22 (s, 1H); MS (APCI): 261.9.

4-(4-이소프로필페닐아미노)-2-메톡시벤즈알데히드:4- (4-isopropylphenylamino) -2-methoxybenzaldehyde:

상기 단계 C에 기재된 방법을 사용하여 N-(4-이소프로필페닐)-2-(4-포르밀-3-메톡시페녹시)아세트아미드로부터 제조됨.Prepared from N- (4-isopropylphenyl) -2- (4-formyl-3-methoxyphenoxy) acetamide using the method described in step C above.

1H NMR (CDCl3) δ 1.26 (d, J = 6.9Hz, 6H), 2.88 (m, J = 6.9Hz, 1H), 3.84 (s, 3H), 6.50 (d, J = 1.9Hz, 1H), 6.55 (dd, J = 8.6, 1.8Hz, 1H), 6.96 (s, 1H), 7.15 (d, 2H, J = 8.5Hz, 2H), 7.22 (d, J = 8.5Hz, 2H), 7.69 (d, J = 8.5Hz, 1H), 10.18 (s, 1H); MS (APCI ): 269. 1 H NMR (CDCl 3 ) δ 1.26 (d, J = 6.9 Hz, 6H), 2.88 (m, J = 6.9 Hz, 1H), 3.84 (s, 3H), 6.50 (d, J = 1.9 Hz, 1H) , 6.55 (dd, J = 8.6, 1.8 Hz, 1H), 6.96 (s, 1H), 7.15 (d, 2H, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.69 ( d, J = 8.5 Hz, 1H), 10.18 (s, 1H); MS (APCI): 269.

단계 D:Step D:

그 결과의 카르보닐화합물을 용매중에서 상응하는 아실히드라지드로 처리하였다. 용매는 다음중 하나일 수 있다: 에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, 아세트산, 물 또는 상기 용매중 상용성인 2 이상의 혼합물. 아세트산 등의 촉매가 첨가될 수 있다. 트리에틸오르토포르메이트 등의 탈수제가 또한 반응혼합물에 첨가될 수 있다. 반응은 바람직하게 N2또는 Ar의 불활성 분위기하에서 0℃ 내지 140℃, 바람직하게 10℃ 내지 80℃의 온도에서 반응혼합물을 교반함으로써 수행된다. 많은 경우, 생성물은 반응이 완결되면 간편하게 결정석출되고 흡입여과에 의해 분리한다. 필요하다면, 상기 기재된 반응용매와 같은 용매로부터 더 재결정될 수 있다. 생성물은 진공에서 반응혼합물을 농축시키고, 이어서 클로로포름/메탄올 또는 디클로로메탄/메탄올 또는 클로로포름/에틸아세테이트 등의 용매계를 사용하여 실리카겔상의 컬럼크로마토그래피로 분리시켜 화학식 IXb의 화합물을 얻을 수 있다.The resulting carbonyl compound was treated with the corresponding acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, Two or more mixtures compatible with water or the solvent. Catalysts such as acetic acid can be added. Dehydrating agents such as triethylorthoformate may also be added to the reaction mixture. The reaction is preferably carried out by stirring the reaction mixture at a temperature of 0 ° C. to 140 ° C., preferably 10 ° C. to 80 ° C., under an inert atmosphere of N 2 or Ar. In many cases, the product readily crystallizes upon completion of the reaction and is separated by suction filtration. If necessary, it may be further recrystallized from a solvent such as the reaction solvent described above. The product can be concentrated in vacuo and then separated by column chromatography on silica gel using a solvent system such as chloroform / methanol or dichloromethane / methanol or chloroform / ethylacetate to afford the compound of formula IXb.

다음의 본 발명에 따르는 화학식 IXa 또는 IXb의 화합물은 이 방법으로 제조될 수 있는 화합물의 예로서 제조되었다:The following compounds of formula (IXa) or (IXb) according to the invention have been prepared as examples of compounds which can be prepared by this method:

실시예 1:Example 1:

3-클로로-4-히드록시벤조산[4-(4-클로로페닐아미노)-2-메톡시벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [4- (4-chlorophenylamino) -2-methoxybenzylidene] hydrazide

1H NMR ( DMSO-D6 ): δ 3.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J = 8.5Hz, 1H), 7.17 ( d, J = 8.7Hz, 2H) 7.31 (d, J = 8.7Hz, 2H), 7.77- 7.70 (m, 2H), 7.96 (d, J = 1.6Hz, 1H), 8.65 (s, 1H), 8.70 (s, 1H), 10.87 (s, 1H), 11.51 (s, 1H); MS (APCI ): 430. 1 H NMR (DMSO-D6): δ 3.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H) 7.31 (d, J = 8.7 Hz, 2H), 7.77-7.70 (m, 2H), 7.96 (d, J = 1.6 Hz, 1H), 8.65 (s, 1H), 8.70 (s, 1H), 10.87 (s, 1H), 11.51 (s, 1 H); MS (APCI): 430.

실시예 2:Example 2:

3-클로로-4-히드록시벤조산[4-(4-이소프로필페닐아미노)-2-메톡시벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [4- (4-isopropylphenylamino) -2-methoxybenzylidene] hydrazide

1H NMR (DMSO-D6): δ 1.18 (2s, 6H), 2.86 (m, 1H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1H), 7.75 (dd, 1H), 7.97 (s, 1H), 8.49 (s, 1H), 8.64 (s, 1H), 10.88 (s, 1H), 11.48 (s, 1H); MS (FAB): 438.16. 1 H NMR (DMSO-D 6 ): δ 1.18 (2s, 6H), 2.86 (m, 1H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1H), 7.75 (dd, 1H), 7.97 (s, 1H), 8.49 (s, 1H), 8.64 (s, 1H), 10.88 (s, 1H ), 11.48 (s, 1 H); MS (FAB): 438.16.

실시예 3:Example 3:

2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페녹시}-N-(4-클로로페닐)아세트아미드2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenoxy} -N- (4-chlorophenyl) acetamide

1H NMR (DMSO-D6): δ 3.66 (s, 3H), 4.57 (s, 2H), 6.48 (d, 1H), 6.55 (s, 1H), 6.83 (d, 1H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 8.48 (s, 1H), 10.05 (s, 1H), 10.72 (brd s, 1H), 11.40 (s, 1H); MS (APCI): 487.8. 1 H NMR (DMSO-D 6 ): δ 3.66 (s, 3H), 4.57 (s, 2H), 6.48 (d, 1H), 6.55 (s, 1H), 6.83 (d, 1H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 8.48 (s, 1H), 10.05 (s, 1H), 10.72 (brd s, 1H), 11.40 (s, 1 H); MS (APCI): 487.8.

실시예 4:Example 4:

2-{4-[3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페녹시}-N-(4-이소프로필페닐)아세트아미드2- {4- [3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenoxy} -N- (4-isopropylphenyl) acetamide

1H NMR (DMSO-D6): δ 1.17 (2 s, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1H), 6.76 (d, 1H), 7.05 (d, 1H), 7.20 (d, 2H), 7.55 (d, 2H), 7.77 (dd, 1H), 7.80 (d, 1H), 7.98 (s, 1H), 8.70 (s, 1H), 10.03 (s, 1H), 10.92 (s, 1H), 11.62 (s, 1H); MS (FAB): 496.16. 1 H NMR (DMSO-D 6 ): δ 1.17 (2 s, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1H), 6.76 (d , 1H), 7.05 (d, 1H), 7.20 (d, 2H), 7.55 (d, 2H), 7.77 (dd, 1H), 7.80 (d, 1H), 7.98 (s, 1H), 8.70 (s, 1H), 10.03 (s, 1H), 10.92 (s, 1H), 11.62 (s, 1H); MS (FAB): 496.16.

실시예 5:Example 5:

2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페녹시}-N-(3,5-디클로로페닐)아세트아미드2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenoxy} -N- (3,5-dichlorophenyl) acetamide

1H NMR (DMSO-D6): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.8 (d, 1H), 6.88 (s, 1H), 7.20 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 524.8. 1 H NMR (DMSO-D 6 ): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.8 (d, 1H), 6.88 (s, 1H), 7.20 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 524.8.

본 발명에 따르는 화학식 II의 알킬리덴히드라지드의 합성을 위한 일반적인 방법:General method for the synthesis of alkylidenehydrazide of formula II according to the present invention:

아실히드라지드를 알데히드 또는 케톤 등의 상응하는 카르보닐과 용매중에서처리한다. 용매는 다음중 하나가 될 수 있다:에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, 아세트산, 물 또는 상기 용매중 상용성인 2 이상의 혼합물. 반응은 바람직하게 N2또는 Ar의 불활성 분위기하에서 0℃ 내지 140℃, 바람직하게 10℃ 내지 80℃의 온도에서 반응혼합물을 교반함으로써 수행된다. 많은 경우, 생성물은 반응이 완결되면 간편하게 결정석출되고 흡입여과에 의해 분리한다. 필요하다면, 상기 기재된 반응용매와 같은 용매로부터 더 재결정될 수 있다. 생성물은 진공에서 반응혼합물을 농축시키고, 이어서 클로로포름/메탄올 또는 디클로로메탄/메탄올 또는 클로로포름/에틸아세테이트 등의 용매계를 사용하여 실리카겔상의 컬럼크로마토그래피로 분리시킬 수 있다. 생성물을 적절한 분획을 진공하에서 농축시켜 분리한다. 본 발명에 따르는 화합물의 제조를 예시하는 구체적인 실시예가 하기 제공된다.Acylhydrazide is treated in a solvent with the corresponding carbonyl, such as aldehyde or ketone. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid Two or more mixtures which are compatible in water or in said solvent. The reaction is preferably carried out by stirring the reaction mixture at a temperature of 0 ° C. to 140 ° C., preferably 10 ° C. to 80 ° C., under an inert atmosphere of N 2 or Ar. In many cases, the product readily crystallizes upon completion of the reaction and is separated by suction filtration. If necessary, it may be further recrystallized from a solvent such as the reaction solvent described above. The product can be concentrated in vacuo and then separated by column chromatography on silica gel using a solvent system such as chloroform / methanol or dichloromethane / methanol or chloroform / ethylacetate. The product is separated by concentrating the appropriate fractions in vacuo. Specific examples are provided below to illustrate the preparation of the compounds according to the invention.

실시예 6:Example 6:

3-클로로-4-히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

DMSO(2ml)중 3-클로로-4-히드록시벤조산 히드라지드(200mg, 1.1mmol)의 용액에 4-히드록시나프트알데히드와 촉매량의 냉 아세트산(5방울)을 가하였다. 반응물을 하룻밤동안 질소하에서 교반하고 에틸아세테이트로 희석시켰다. 용액을 포화 중탄산나트륨, 물, 함수로 세척하고, MgSO4에서 건조시켰다. 유기 부피를 진공하에서 농축시켜 미정제 생성물을 얻었다. 생성물을 이동상으로서 CH2Cl2/MeOH를 사용하는 실리카겔 컬럼크로마토그래피로 정제하였다.To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 ml) was added 4-hydroxynaphthaldehyde and a catalytic amount of cold acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine and dried over MgSO 4 . The organic volume was concentrated in vacuo to afford crude product. The product was purified by silica gel column chromatography using CH 2 Cl 2 / MeOH as the mobile phase.

1H NMR (DMSO-d6): δ 6.89 (d, 2H), 7.02 (d, 1H), 7.47 (t, 1H), 7.58 (t, 1H), 7.66 (d, 1H), 7.73 (d, 1H), 7.93 (s, 1H), 8.17 (d, 1H), 8.84 (s, 1H), 8.88 (d, 1H), 10.73 (s, 1H), 10.88 (s, 1H), 11.54 (s, 1H); MS (ESI): m/z 341.04 (M+H)+. 1 H NMR (DMSO-d 6 ): δ 6.89 (d, 2H), 7.02 (d, 1H), 7.47 (t, 1H), 7.58 (t, 1H), 7.66 (d, 1H), 7.73 (d, 1H), 7.93 (s, 1H), 8.17 (d, 1H), 8.84 (s, 1H), 8.88 (d, 1H), 10.73 (s, 1H), 10.88 (s, 1H), 11.54 (s, 1H ); MS (ESI): m / z 341.04 (M + H) + .

실시예 7:Example 7:

3-클로로-4-히드록시벤조산[4-(3,5-비스-트리플루오로메틸벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (3,5-bis-trifluoromethylbenzyloxy) -1-naphthylmethylene] hydrazide

DMSO(2ml)중 3-클로로-4-히드록시벤조산 히드라지드(200mg, 1.1mmol)의 용액에 4-(3,5-비스-트리플루오로메틸벤질옥시)-1-나프트알데히드(440mg, 1.1mmol)과 촉매량의 냉 아세트산(5방울)을 가하였다. 반응물을 하룻밤동안 질소하에서 교반하고 에틸아세테이트로 희석시켰다. 용액을 포화 중탄산나트륨, 물, 함수로 세척하고, MgSO4에서 건조시켰다. 유기 부피를 진공하에서 농축시켜 미정제 생성물을 얻었다. 생성물을 이동상으로서 CH2Cl2/MeOH를 사용하는 실리카겔 컬럼크로마토그래피로 정제하였다.To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 mL) 4- (3,5-bis-trifluoromethylbenzyloxy) -1-naphthaldehyde (440 mg, 1.1 mmol) and a catalytic amount of cold acetic acid (5 drops) were added. The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine and dried over MgSO 4 . The organic volume was concentrated in vacuo to afford crude product. The product was purified by silica gel column chromatography using CH 2 Cl 2 / MeOH as the mobile phase.

1H NMR (DMSO-d6): δ 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1H), 7.30 (d, 2H), 7.52 (d, 2H), 7.68 (m, 1H), 7.89 (s, 1H), 8.29 (s, 1H), 10.90 (broad s, 1H), 11.69 (s, 1H); MS (ESI): m/z 525.37 (M+H)+. 1 H NMR (DMSO-d 6 ): δ 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1H), 7.30 (d, 2H), 7.52 (d, 2H), 7.68 (m, 1H), 7.89 (s, 1H), 8.29 (s, 1H), 10.90 (broad s, 1H), 11.69 (s, 1H); MS (ESI): m / z 525.37 (M + H) + .

실시예 8:Example 8:

3-클로로-4-히드록시벤조산[4-(2-클로로에톡시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (2-chloroethoxy) -1-naphthylmethylene] hydrazide

1-(4-클로로에톡시)나프트알데히드(2.35g, 10mmol), 3-클로로-4-히드록시벤조산 히드라지드(1.87g, 10mmol), 냉 아세트산(0.2mL) 및 디메틸술폭시드(DMSO) (15mL)의 용액을 실온에서 하룻밤동안 교반하였다. 에틸아세테이트(100mL)를 가하였다. 용액을 물과 함수로 추출하여 침전을 유도하였다. 생성물(3.1g, 수율 77%)를 흡입여과로 얻었다. 생성물을 에틸아세테이트로부터 재결정하여 정제하였다.1- (4-chloroethoxy) naphthaldehyde (2.35 g, 10 mmol), 3-chloro-4-hydroxybenzoic acid hydrazide (1.87 g, 10 mmol), cold acetic acid (0.2 mL) and dimethyl sulfoxide (DMSO) (15 mL) of the solution was stirred overnight at room temperature. Ethyl acetate (100 mL) was added. The solution was extracted with water and brine to induce precipitation. The product (3.1 g, yield 77%) was obtained by suction filtration. The product was purified by recrystallization from ethyl acetate.

MS (CI): 235.1H NMR (DMSO-d6): δ 11.5 (s, 1H), 10.7 (s, 1H), 8.7 (bs, 2H), 8.1 (m, 1H), 7.8 (s, 1H), 7.6-7.3 (m, 2H), 7.0 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H).MS (CI): 235. 1 H NMR (DMSO-d 6 ): δ 11.5 (s, 1H), 10.7 (s, 1H), 8.7 (bs, 2H), 8.1 (m, 1H), 7.8 (s, 1H), 7.6-7.3 (m, 2H), 7.0 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H).

상기 방법을 응용하여, 다음의 본 발명의 화합물을 하기 일반적인 방법을 사용하여 합성한다:Using the above method, the following compounds of the present invention are synthesized using the following general method:

무수 DMSO 2mL중 아릴카르복실산 히드라지드 용액 1mmol에 카르보닐화합물(알데히드 또는 케톤) 1mmol을 가하고, 이어서 촉매량의 냉 아세트산을 가하였다. 반응물을 하룻밤동안 질소하에서 교반하고 에틸아세테이트로 희석시켰다. 유기층을 포화 중탄산나트륨, 물, 함수로 세척하고, MgSO4에서 건조시켰다. 진공하에서 용매를 부분적으로 농축시켜 알킬렌 히드라지드를 통상적으로 침전시켰다. 알킬렌 히드라지드를 열 에탄올 또는 에틸아세테이트로부터 재결정하거나 용리액으로서 CH2Cl2/MeOH를 사용하는 크로마토그래피로 더 정제하였다.To 1 mmol of the arylcarboxylic acid hydrazide solution in 2 mL of anhydrous DMSO was added 1 mmol of a carbonyl compound (aldehyde or ketone), followed by addition of a catalytic amount of cold acetic acid. The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine and dried over MgSO 4 . The solvent was partially concentrated in vacuo to normally precipitate the alkylene hydrazide. Alkylene hydrazide was recrystallized from thermal ethanol or ethyl acetate or further purified by chromatography using CH 2 Cl 2 / MeOH as eluent.

실시예 9:Example 9:

4-히드록시-3-메톡시벤조산(2-나프틸메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (2-naphthylmethylene) hydrazide

1H NMR (DMSO-d6) δ 3.66 (s, 3 H), 6.67 (d, J = 8.2 Hz, 1 H), 7.32 - 7.47 (m, 5 H), 7.74 (d, J = 7.2 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 2 H), 8.60 (d, J = 8.2 Hz, 1 H), 9.11 (s, 1 H), 11.80 (s, 1 H). 1 H NMR (DMSO-d 6 ) δ 3.66 (s, 3H), 6.67 (d, J = 8.2 Hz, 1 H), 7.32-7.47 (m, 5H), 7.74 (d, J = 7.2 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 2 H), 8.60 (d, J = 8.2 Hz, 1 H), 9.11 (s, 1 H), 11.80 (s, 1 H).

APCI m/z: 321APCI m / z: 321

실시예 10:Example 10:

4-히드록시-3-메톡시벤조산(4-메톡시-1-나프틸메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (4-methoxy-1-naphthylmethylene) hydrazide

1H NMR (CDCl3): δ 4.80 (s, 3 H), 3.86 (s, 3 H), 6.00 (s, 1 H), 6.59 (d, 1 H), 6.83 (d, 1 H), 7.39 (m, 3 H), 7.52 (s, 1 H), 7.73 (s, 1 H), 8.18 (d, 1 H), 8.58 (d, 1 H), 8.88 (s, 1 H), 9.95 (s,1 H). MS (APCI): 351. 1 H NMR (CDCl 3 ): δ 4.80 (s, 3 H), 3.86 (s, 3 H), 6.00 (s, 1 H), 6.59 (d, 1 H), 6.83 (d, 1 H), 7.39 (m, 3H), 7.52 (s, 1H), 7.73 (s, 1H), 8.18 (d, 1H), 8.58 (d, 1H), 8.88 (s, 1H), 9.95 (s , 1 H). MS (APCI): 351.

실시예 11:Example 11:

4-히드록시-3-메톡시벤조산(4-tert-부틸벤질리덴)히드라지드4-hydroxy-3-methoxybenzoic acid (4-tert-butylbenzylidene) hydrazide

1H NMR (CDCl3): δ 1.30 (s, 9 H), 3.91 (s, 3 H), 6.16 (s, 1 H), 6.88 (d, 1 H), 7.23 - 7.78 (m, 6 H), 8.28 (s, 1 H), 9.58 (s, 1 H). MS (APCI): 327. 1 H NMR (CDCl 3 ): δ 1.30 (s, 9 H), 3.91 (s, 3 H), 6.16 (s, 1 H), 6.88 (d, 1 H), 7.23-7.78 (m, 6 H) , 8.28 (s, 1 H), 9.58 (s, 1 H). MS (APCI): 327.

실시예 12:Example 12:

4-히드록시-3-메톡시벤조산(4-이소프로필벤질리덴)히드라지드4-hydroxy-3-methoxybenzoic acid (4-isopropylbenzylidene) hydrazide

1H NMR (CDCl3) δ 1.29 (d, 6 H), 2.94 (q, 1 H), 3.98 (s, 3 H), 6.13 (s, 1 H), 6.97 (d, 1 H), 7.20 - 7.80 (m, 6 H), 8.29 (s, 1 H), 9.38 (s, 1 H). MS (APCI): 313 1 H NMR (CDCl 3 ) δ 1.29 (d, 6 H), 2.94 (q, 1 H), 3.98 (s, 3 H), 6.13 (s, 1 H), 6.97 (d, 1 H), 7.20- 7.80 (m, 6H), 8.29 (s, 1H), 9.38 (s, 1H). MS (APCI): 313

실시예 13:Example 13:

4-히드록시-3-메톡시벤조산(4-트리플루오로메톡시벤질리덴)히드라지드4-hydroxy-3-methoxybenzoic acid (4-trifluoromethoxybenzylidene) hydrazide

1H NMR (DMSO-d6): δ 4.01 (s, 3 H), 7.04 (d, J = 8.1 Hz, 1 H), 7.60 - 7.65 (m, 4 H), 8.01 (d, J = 8.4 Hz, 2 H), 8.63 (s, 1 H), 9.92 (s, 1 H), 11.89 (s, 1 H). MS (APCI): 355, 313, 222, 205. 1 H NMR (DMSO-d 6 ): δ 4.01 (s, 3H), 7.04 (d, J = 8.1 Hz, 1 H), 7.60-7.65 (m, 4H), 8.01 (d, J = 8.4 Hz , 2H), 8.63 (s, 1H), 9.92 (s, 1H), 11.89 (s, 1H). MS (APCI): 355, 313, 222, 205.

실시예 14:Example 14:

4-히드록시-3-메톡시벤조산(1H-인돌-3-일메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (1H-indol-3-ylmethylene) hydrazide

1H NMR (DMSO-d6) δ 3.79 (s, 3 H), 6.80 (d, J = 8.2 Hz, 1 H), 7.11 (m, 2 H), 7.38 (m, 3 H), 7.73 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 7.5 Hz, 1 H), 8.53 (s, 1 H), 9.58 (s, 1 H), 11.23 (s, 1 H), 11.49 (s, 1 H). MS (APCI): 310. 1 H NMR (DMSO-d 6 ) δ 3.79 (s, 3 H), 6.80 (d, J = 8.2 Hz, 1 H), 7.11 (m, 2 H), 7.38 (m, 3 H), 7.73 (d , J = 2.0 Hz, 1 H), 8.53 (d, J = 7.5 Hz, 1 H), 8.53 (s, 1 H), 9.58 (s, 1 H), 11.23 (s, 1 H), 11.49 (s , 1 H). MS (APCI): 310.

실시예 15:Example 15:

4-히드록시-3-메톡시벤조산(4-디메톡시아미노-1-나프틸메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (4-dimethoxyamino-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 3.05 (s, 6 H), 4.03 (s, 3 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.63 - 7.80 (m, 4 H), 7.97 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 7.9 Hz, 1 H), 9.10 (d, J = 8.4 Hz, 1 H), 9.15 (s, 1 H), 9.90 (s, 1 H), 11.73 (s, 1 H). MS (APCI): 364. 1 H NMR (DMSO-d 6 ): δ 3.05 (s, 6 H), 4.03 (s, 3 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.63-7.80 (m, 4H), 7.97 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 7.9 Hz, 1 H), 9.10 (d, J = 8.4 Hz, 1 H ), 9.15 (s, 1 H), 9.90 (s, 1 H), 11.73 (s, 1 H). MS (APCI): 364.

실시예 16:Example 16:

4-히드록시-3-메톡시벤조산(4-페닐벤질리덴)히드라지드4-hydroxy-3-methoxybenzoic acid (4-phenylbenzylidene) hydrazide

1H NMR (DMSO-d6): δ 4.02 (s, 3 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.63 - 7.68 (m, 5 H), 7.88 - 7.96 (m, 6 H), 8.64 (s, 1 H), 9.91 (s, 1 H), 11.83 (s, 1 H). MS (APCI): 347. 1 H NMR (DMSO-d 6 ): δ 4.02 (s, 3H), 7.04 (d, J = 8.2 Hz, 1H), 7.63-7.68 (m, 5H), 7.88-7.96 (m, 6H ), 8.64 (s, 1 H), 9.91 (s, 1 H), 11.83 (s, 1 H). MS (APCI): 347.

실시예 17:Example 17:

4-히드록시벤조산(1-나프틸메틸렌)히드라지드4-hydroxybenzoic acid (1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.82 (d, J = 8.2 Hz, 2 H), 7.48 - 7.68 (m, 3 H), 7.72 - 7.88 (m, 3 H), 7.95 (d, J = 8.2 Hz, 2 H), 8.80 (d, 1 H), 9.04 (s, 1 H), 10.14 (s, 1 H). MS (APCI): 291. 1 H NMR (DMSO-d 6 ): δ 6.82 (d, J = 8.2 Hz, 2H), 7.48-7.68 (m, 3H), 7.72-7.88 (m, 3H), 7.95 (d, J = 8.2 Hz, 2 H), 8.80 (d, 1 H), 9.04 (s, 1 H), 10.14 (s, 1 H). MS (APCI): 291.

실시예 18:Example 18:

4-히드록시벤조산(4-메톡시-1-나프틸메틸렌)히드라지드4-hydroxybenzoic acid (4-methoxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 3.97 (s, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.52 (dd, J = 7.3, 7.7 Hz, 1 H), 7.62 (dd, J = 6.8, 7.7 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 3 H), 8.19 (d, J = 8.2 Hz, 1 H), 8.89 (m, 2 H), 10.06 (s, 1 H). MS (APCI): 321. 1 H NMR (DMSO-d 6 ): δ 3.97 (s, 3H), 6.82 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 7.52 (dd, J = 7.3, 7.7 Hz, 1 H), 7.62 (dd, J = 6.8, 7.7 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 3 H), 8.19 (d, J = 8.2 Hz, 1 H) , 8.89 (m, 2H), 10.06 (s, 1H). MS (APCI): 321.

실시예 19:Example 19:

3,4-디히드록시벤조산(1-나프틸메틸렌)히드라지드3,4-dihydroxybenzoic acid (1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.64 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.36 - 7.42 (m, 3 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 2 H), 8.65 (d, J = 8.2 Hz, 1 H), 8.88 (s, 1 H), 9.07 (s, 1 H), 9.46 (s, 1H), 11.45 (s, 1 H). MS (APCI): 307. 1 H NMR (DMSO-d 6 ): δ 6.64 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.36-7.42 (m, 3H), 7.68 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 8.65 (d, J = 8.2 Hz, 1H), 8.88 (s, 1 H), 9.07 (s, 1 H), 9.46 (s, 1 H), 11.45 (s, 1 H). MS (APCI): 307.

실시예 20:Example 20:

4-히드록시-3-메톡시벤조산(1-나프틸메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6) δ 3.94 (s, 3H), 6.74 (d, 1H), 7.37-7.52 (m, 6H), 7.77 (d, 1H), 7.89 (d, 2H), 8.67 (d, 1H), 9.93 (s, 1H), 10.90 (s, 1H). MS (APCI): 321. 1 H NMR (DMSO-d 6 ) δ 3.94 (s, 3H), 6.74 (d, 1H), 7.37-7.52 (m, 6H), 7.77 (d, 1H), 7.89 (d, 2H), 8.67 (d , 1H), 9.93 (s, 1H), 10.90 (s, 1H). MS (APCI): 321.

실시예 21:Example 21:

4-히드록시-3-메톡시벤조산[3-(3-트리플루오로메틸페녹시)벤질리덴]히드라지드4-hydroxy-3-methoxybenzoic acid [3- (3-trifluoromethylphenoxy) benzylidene] hydrazide

1H NMR (DMSO-d6) δ 3.83 (s, 3H), 6.85 (d, 1H), 7.16 (dd, 1H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1H), 8.43 (s, 1H), 1.75 (s, 1H), 11.69 (s, 1H). MS (APCI): 431. 1 H NMR (DMSO-d 6 ) δ 3.83 (s, 3H), 6.85 (d, 1H), 7.16 (dd, 1H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1H ), 8.43 (s, 1 H), 1.75 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431.

실시예 22:Example 22:

4-히드록시-3-메톡시벤조산(4-퀴놀린일메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (4-quinolinylmethylene) hydrazide

1H NMR (DMSO-d6): δ 3.58 (s, 3 H), 6.52 (d, J = 8.0 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.47 (dd, J = J' = 8.1 Hz, 1 H), 7.59 (m, 2 H), 7.86 (d, J = 8.4 Hz, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 8.73 (d, J = 4.5 Hz, 1 H), 8.94 (s, 1 H). MS (APCI): 322. 1 H NMR (DMSO-d 6 ): δ 3.58 (s, 3H), 6.52 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.47 (dd, J = J '= 8.1 Hz, 1 H), 7.59 (m, 2 H), 7.86 (d, J = 8.4 Hz, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 8.73 (d, J = 4.5 Hz, 1 H), 8.94 (s, 1 H). MS (APCI): 322.

실시예 23:Example 23:

4-히드록시벤조산[3-(1,1,2,2-테트라플루오로에톡시)벤질리덴]히드라지드4-hydroxybenzoic acid [3- (1,1,2,2-tetrafluoroethoxy) benzylidene] hydrazide

1H NMR (DMSO-d6) δ 6.49-6.78 (m, 3H), 7.10 (d, 1H), 7.32 (t, 1H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s, 1H), 10.01 (s, 1H), 11.59 (s, 1H). MS (APCI): 357. 1 H NMR (DMSO-d 6 ) δ 6.49-6.78 (m, 3H), 7.10 (d, 1H), 7.32 (t, 1H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s , 1H), 10.01 (s, 1H), 11.59 (s, 1H). MS (APCI): 357.

실시예 24:Example 24:

4-히드록시벤조산[3-(4-tert-부틸페닐)부트-2-엔일리덴]히드라지드4-hydroxybenzoic acid [3- (4-tert-butylphenyl) but-2-enylidene] hydrazide

1H NMR (DMSO-d6) δ 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H), 8.06 (s, 1H), 9.98 (s, 1H), 11.36 (s, 1H). MS (APCI): 337. 1 H NMR (DMSO-d 6 ) δ 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H ), 8.06 (s, 1 H), 9.98 (s, 1 H), 11.36 (s, 1 H). MS (APCI): 337.

실시예 25:Example 25:

4-히드록시-3-메톡시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 3.90 (s, 3 H), 6.89 (d, 1 H), 6.99 (d, 1 H), 7.19 (d, 1 H), 7.45 - 7.80 (m, 5 H), 8.22 (d, 1 H), 8.90 (s, 2 H), 9.62 (s, 1 H), 10.68 (s, 1 H). MS (APCI): 337. 1 H NMR (DMSO-d 6 ): δ 3.90 (s, 3 H), 6.89 (d, 1 H), 6.99 (d, 1 H), 7.19 (d, 1 H), 7.45-7.80 (m, 5 H), 8.22 (d, 1 H), 8.90 (s, 2 H), 9.62 (s, 1 H), 10.68 (s, 1 H). MS (APCI): 337.

실시예 26:Example 26:

4-히드록시벤조산(벤질리덴)히드라지드4-hydroxybenzoic acid (benzylidene) hydrazide

1H NMR (DMSO-d6): δ 6.86 (d, 2 H), 7.41 - 7.52 (m, 3 H), 7.72 (m, 2 H), 7.82 (d, 2 H), 8.41 (s, 1 H), 10.14 (s, 1 H). MS (APCI): 241. 1 H NMR (DMSO-d 6 ): δ 6.86 (d, 2 H), 7.41-7.52 (m, 3 H), 7.72 (m, 2 H), 7.82 (d, 2 H), 8.41 (s, 1 H), 10.14 (s, 1 H). MS (APCI): 241.

실시예 27:Example 27:

3-아미노-4-히드록시벤조산(1-나프틸메틸렌)히드라지드3-Amino-4-hydroxybenzoic acid (1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 4.71 (bs, 2 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.01 (dd, J = 2.0, 8.2 Hz, 1 H), 7.17 (d, J = 2.0 Hz, 1 H), 7.51 - 7.62 (m, 3 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 8.75 (d, J = 7.6 Hz, 1 H), 9.01 (s, 1 H), 9.70 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 306. 1 H NMR (DMSO-d 6 ): δ 4.71 (bs, 2 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.01 (dd, J = 2.0, 8.2 Hz, 1 H), 7.17 (d , J = 2.0 Hz, 1 H), 7.51-7.62 (m, 3 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 8.75 (d, J = 7.6 Hz, 1 H), 9.01 (s, 1 H), 9.70 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 306.

실시예 28:Example 28:

3-아미노-4-히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드3-Amino-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 4.68 (bs, 2 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.91 (d, J = 7.3 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 7.15 (s, 1 H), 7.43 - 7.65 (m, 3 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.83 (m, 2 H), 10.71 (s, 1 H), 11.34 (s, 1 H). MS (APCI): 322. 1 H NMR (DMSO-d 6 ): δ 4.68 (bs, 2 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.91 (d, J = 7.3 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 7.15 (s, 1 H), 7.43-7.65 (m, 3 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.83 (m, 2 H), 10.71 (s , 1 H), 11.34 (s, 1 H). MS (APCI): 322.

실시예 29:Example 29:

4-히드록시벤조산[3-(3-트리플루오로메틸벤질옥시)벤질리덴]히드라지드4-hydroxybenzoic acid [3- (3-trifluoromethylbenzyloxy) benzylidene] hydrazide

1H NMR (DMSO-d6): δ 5.28 (s, 2 H), 6.88 (d, 2 H), 7.12 (m, 1 H), 7.24 - 7.50 (m, 3 H), 7.55 - 7.92 (m, 6 H), 8.41 (s, 1 H), 10.16 (s, 1 H), 10.86 (s, 1 H). MS (APCI): 415. 1 H NMR (DMSO-d 6 ): δ 5.28 (s, 2H), 6.88 (d, 2H), 7.12 (m, 1H), 7.24-7.50 (m, 3H), 7.55-7.92 (m , 6 H), 8.41 (s, 1 H), 10.16 (s, 1 H), 10.86 (s, 1 H). MS (APCI): 415.

실시예 30:Example 30:

3-클로로-4-히드록시벤조산(1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 7.03 (d, J = 8.2 Hz, 1 H), 7.52 - 7.62 (m, 3 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.86 (d, J =7.0 Hz, 1 H), 7.96 (m, 3 H), 8.79 (d, J = 8.2 Hz, 1 H), 9.01 (s, 1 H), 10.94 (s, 1 H), 11.76 (s, 1 H). MS (APCI): 325. 1 H NMR (DMSO-d 6 ): δ 7.03 (d, J = 8.2 Hz, 1 H), 7.52-7.62 (m, 3H), 7.74 (d, J = 8.2 Hz, 1H), 7.86 (d , J = 7.0 Hz, 1 H), 7.96 (m, 3 H), 8.79 (d, J = 8.2 Hz, 1 H), 9.01 (s, 1 H), 10.94 (s, 1 H), 11.76 (s , 1 H). MS (APCI): 325.

실시예 31:Example 31:

3-클로로-4-히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.50 (dd, J = J' = 7.8 Hz, 1 H), 7.58 (dd, J = 7.1, 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.93 (s, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J =8.5 Hz, 1 H), 10.73 (s, 1 H), 10.88 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 343, 341. 1 H NMR (DMSO-d 6 ): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.50 (dd, J = J '= 7.8 Hz, 1 H), 7.58 (dd, J = 7.1, 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.93 (s, 1 H ), 8.17 (d, J = 8.2 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J = 8.5 Hz, 1 H), 10.73 (s, 1 H), 10.88 (s, 1 H ), 11.54 (s, 1 H). MS (APCI): 343, 341.

실시예 32:Example 32:

4-히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.88 (d, 2 H), 6.98 (d, 1 H), 7.55 (dd, 1 H), 7.64 (dd, 1 H), 7.71 (d, 1 H), 7.82 (d, 2 H), 8.22 (d, 1 H), 8.94 (m, 2 H), 10.11 (s, 1 H), 10.77 (s, 1 H). MS (APCI): 307. 1 H NMR (DMSO-d 6 ): δ 6.88 (d, 2 H), 6.98 (d, 1 H), 7.55 (dd, 1 H), 7.64 (dd, 1 H), 7.71 (d, 1 H) , 7.82 (d, 2H), 8.22 (d, 1H), 8.94 (m, 2H), 10.11 (s, 1H), 10.77 (s, 1H). MS (APCI): 307.

실시예 33:Example 33:

4-히드록시벤조산[4-(3-트리플루오로메틸페녹시)벤질리덴]히드라지드4-hydroxybenzoic acid [4- (3-trifluoromethylphenoxy) benzylidene] hydrazide

1H NMR (DMSO-d6): δ 6.81(d, 2 H), 6.98 (d, 1 H), 7.13 (dd, 1 H), 7.30 - 7.48 (m, 3 H), 7.48 - 7.60 (m, 3 H), 7.68 (dd, 1 H), 7.81 (d, 2 H), 8.41 (s, 1 H). MS (APCI): 401. 1 H NMR (DMSO-d 6 ): δ 6.81 (d, 2 H), 6.98 (d, 1 H), 7.13 (dd, 1 H), 7.30-7.48 (m, 3 H), 7.48-7.60 (m , 3H), 7.68 (dd, 1H), 7.81 (d, 2H), 8.41 (s, 1H). MS (APCI): 401.

실시예 34:Example 34:

4-히드록시벤조산(5-페닐-3-피라졸릴메틸렌)히드라지드4-hydroxybenzoic acid (5-phenyl-3-pyrazolylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.81 (d, 2 H), 7.40 - 7.62 (m, 5 H), 7.78 (d, 2 H), 8.09 (s, 1 H), 8.50 (s, 1 H). MS (APCI): 307. 1 H NMR (DMSO-d 6 ): δ 6.81 (d, 2 H), 7.40-7.62 (m, 5 H), 7.78 (d, 2 H), 8.09 (s, 1 H), 8.50 (s, 1 H). MS (APCI): 307.

실시예 35:Example 35:

2,4-디히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드2,4-dihydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): 6.35 (s, 1 H), 6.39 (d, 1 H), 6.99 (d, 1 H), 7.51 (dd, 1 H), 7.65 (dd, 1H), 7.73 (d, 1H), 7.82 (d, 1 H), 8.26 (d, 1 H), 8.88 (s, 1 H), 8.98 (d, 1 H), 10.0 - 11.0 (m, 4 H). MS (APCI): 323. 1 H NMR (DMSO-d 6 ): 6.35 (s, 1 H), 6.39 (d, 1 H), 6.99 (d, 1 H), 7.51 (dd, 1 H), 7.65 (dd, 1H), 7.73 (d, 1H), 7.82 (d, 1H), 8.26 (d, 1H), 8.88 (s, 1H), 8.98 (d, 1H), 10.0-11.0 (m, 4H). MS (APCI): 323.

실시예 36:Example 36:

4-히드록시-3-니트로벤조산(1-나프틸메틸렌)히드라지드4-hydroxy-3-nitrobenzoic acid (1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.15 (d, J = 9.3 Hz, 1 H), 7.37 - 7.48 (m, 4 H), 6.70 (d, J = 7.1 Hz, 1 H), 7.78 - 7.82 (m, 2 H), 8.29 (s, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.85 (s, 1 H). 1 H NMR (DMSO-d 6 ): δ 6.15 (d, J = 9.3 Hz, 1 H), 7.37-7.48 (m, 4H), 6.70 (d, J = 7.1 Hz, 1H), 7.78-7.82 (m, 2H), 8.29 (s, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.85 (s, 1H).

실시예 37:Example 37:

4-히드록시-3-니트로벤조산(4-히드록시-1-나프틸메틸렌)히드라지드4-hydroxy-3-nitrobenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.24 (d, J = 9.3 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 7.37 -7.52 (m, 3 H), 7.57 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.34 (s, 1 H), 8.76 (s, 1 H), 8.79 (s, 1 H), 10.57 (s, 1 H), 11.17 (m, 1 H). 1 H NMR (DMSO-d 6 ): δ 6.24 (d, J = 9.3 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 7.37 -7.52 (m, 3H), 7.57 (d , J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.34 (s, 1 H), 8.76 (s, 1 H), 8.79 (s, 1 H), 10.57 (s , 1 H), 11.17 (m, 1H).

실시예 38:Example 38:

3,4-디히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드3,4-dihydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.86 (d, 1 H), 6.98 (d, 1 H), 7.32 (d, 1 H), 7.42 (s, 1H), 7.56 (dd, 1 H), 7.63 (dd, 1 H), 7.71 (d, 1 H), 8.24 (d, 1 H), 8.88 (s, 1 H), 8.92 (m, 2 H), 9.26 (s, 1 H), 9.54 (s, 1 H), 10.75 (s, 1 H). MS (APCI): 323. 1 H NMR (DMSO-d 6 ): δ 6.86 (d, 1 H), 6.98 (d, 1 H), 7.32 (d, 1 H), 7.42 (s, 1H), 7.56 (dd, 1 H), 7.63 (dd, 1 H), 7.71 (d, 1 H), 8.24 (d, 1 H), 8.88 (s, 1 H), 8.92 (m, 2 H), 9.26 (s, 1 H), 9.54 ( s, 1 H), 10.75 (s, 1 H). MS (APCI): 323.

실시예 39:Example 39:

4-히드록시벤조산(6-메톡시-2-나프틸메틸렌)히드라지드4-hydroxybenzoic acid (6-methoxy-2-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 3.89 (s, 3 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.22 (dd, J = 2.3, 8.9 Hz, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.80 - 7.93 (m, 6 H), 8.04 (s, 1 H), 8.53 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 321. 1 H NMR (DMSO-d 6 ): δ 3.89 (s, 3H), 6.86 (d, J = 8.6 Hz, 2H), 7.22 (dd, J = 2.3, 8.9 Hz, 1H), 7.37 (d , J = 2.3 Hz, 1 H), 7.80-7.93 (m, 6 H), 8.04 (s, 1 H), 8.53 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 321.

실시예 40:Example 40:

3,5-디클로로-4-히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드3,5-dichloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.98 (d, 1 H), 7.58 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (d, 1 H), 8.02 (s, 2 H), 8.27 (d, 1 H), 8.90 (s, 1 H), 8.96 (d, 1 H), 10.81 (s, 1 H), 10.98 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 375, 377. 1 H NMR (DMSO-d 6 ): δ 6.98 (d, 1 H), 7.58 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (d, 1 H), 8.02 (s, 2 H) , 8.27 (d, 1 H), 8.90 (s, 1 H), 8.96 (d, 1 H), 10.81 (s, 1 H), 10.98 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 375, 377.

실시예 41:Example 41:

6-히드록시-2-나프토산(4-히드록시-1-나프틸메틸렌)히드라지드6-hydroxy-2-naphthoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.04 (d, 2 H), 6.33 (m, 1 H), 6.62 (dd, 2 H), 6.79 (dd, 2 H), 7.06 (d, 2 H), 7.44 (d, 2 H), 8.27 (d, 2 H), 8.39 (s, 2 H). 1 H NMR (DMSO-d 6 ): δ 6.04 (d, 2 H), 6.33 (m, 1 H), 6.62 (dd, 2 H), 6.79 (dd, 2 H), 7.06 (d, 2 H) , 7.44 (d, 2H), 8.27 (d, 2H), 8.39 (s, 2H).

실시예 42:Example 42:

4-히드록시-3-메톡시벤조산(9-에틸-9H-3-카르바졸릴메틸렌)히드라지드4-hydroxy-3-methoxybenzoic acid (9-ethyl-9H-3-carbazolylmethylene) hydrazide

1H NMR (DMSO-d6) δ 1.34 (t, J = 7.0 Hz, 3 H), 3.88 (s, 3 H), 4.47 (q, J = 7.0 Hz, 2 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.47 - 7.54 (m, 3 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 7.7 Hz, 1 H), 8.45 (s, 1 H), 8.62 (s, 1 H) 9.62 (s, 1 H), 11.51 (s, 1H). MS (APCI): 388. 1 H NMR (DMSO-d 6 ) δ 1.34 (t, J = 7.0 Hz, 3H), 3.88 (s, 3H), 4.47 (q, J = 7.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.47-7.54 (m, 3 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 7.7 Hz, 1 H), 8.45 (s, 1 H), 8.62 (s, 1 H) 9.62 (s , 1 H), 11.51 (s, 1 H). MS (APCI): 388.

실시예 43:Example 43:

4-히드록시-3-메톡시벤조산[5-(3-클로로페닐)-2-푸란일메틸렌]히드라지드4-hydroxy-3-methoxybenzoic acid [5- (3-chlorophenyl) -2-furanylmethylene] hydrazide

1H NMR (DMSO-d6): δ 3.93 (s, 3 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 3.5 Hz, 1 H), 7.37 (d, J = 3.5 Hz, 1 H), 7.48 - 7.63 (m, 4 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 8.47 (s, 1 H), 9.85 (s, 1 H), 11.75 (s, 1 H). MS (APCI): 371. 1 H NMR (DMSO-d 6 ): δ 3.93 (s, 3 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 3.5 Hz, 1 H), 7.37 (d, J = 3.5 Hz, 1 H), 7.48-7.63 (m, 4 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 8.47 (s, 1 H), 9.85 (s , 1 H), 11.75 (s, 1 H). MS (APCI): 371.

실시예 44:Example 44:

3-클로로-4-히드록시벤조산(3-페닐알릴리덴)히드라지드3-Chloro-4-hydroxybenzoic acid (3-phenylallylidene) hydrazide

1H NMR (DMSO-d6): δ 7.00 (m, 3 H), 7.22 - 7.40 (m, 3 H), 7.57 (d, 2 H), 7.69 (d, 1 H), 7.89 (s, 1 H), 8.12 (d, 1 H), 11.0 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 301. 1 H NMR (DMSO-d 6 ): δ 7.00 (m, 3 H), 7.22-7.40 (m, 3 H), 7.57 (d, 2 H), 7.69 (d, 1 H), 7.89 (s, 1 H), 8.12 (d, 1 H), 11.0 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 301.

실시예 45:Example 45:

3-클로로-4-히드록시벤조산(4-알릴옥시-1-나프틸메틸렌)히드라지드3-chloro-4-hydroxybenzoic acid (4-allyloxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 4.68 (m, 2 H), 5.21 (d, 1 H), 5.38 (d, 1 H), 5.90 -6.10 (m, 1 H), 6.86 (dd, 2 H), 7.42 (dd, 1 H), 7.53 (dd, 1 H), 7.67 (dd, 2 H), 7.86 (s, 1 H), 8.18 (d, 1 H), 8.78 (s, 1 H), 8.82 (d, 1 H), 10.9 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 381. 1 H NMR (DMSO-d 6 ): δ 4.68 (m, 2 H), 5.21 (d, 1 H), 5.38 (d, 1 H), 5.90 -6.10 (m, 1 H), 6.86 (dd, 2 H), 7.42 (dd, 1 H), 7.53 (dd, 1 H), 7.67 (dd, 2 H), 7.86 (s, 1 H), 8.18 (d, 1 H), 8.78 (s, 1 H) , 8.82 (d, 1 H), 10.9 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 381.

실시예 46:Example 46:

3-클로로-4-히드록시벤조산(4-에틴일메톡시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-ethynylmethoxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 3.60 (s, 1 H), 5.06 (s, 2 H), 6.99 (d, 1 H), 7.12 (d, 1 H), 7.55 (t, 1 H), 7.66 (t, 1 H), 7.73 (t, 1 H), 7.93 (s, 1 H), 8.02 (d, 1 H), 8.16 (t, 1 H), 8.86 (d, 1 H), 9.27 (d, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 378. 1 H NMR (DMSO-d 6 ): δ 3.60 (s, 1 H), 5.06 (s, 2 H), 6.99 (d, 1 H), 7.12 (d, 1 H), 7.55 (t, 1 H) , 7.66 (t, 1 H), 7.73 (t, 1 H), 7.93 (s, 1 H), 8.02 (d, 1 H), 8.16 (t, 1 H), 8.86 (d, 1 H), 9.27 (d, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 378.

실시예 47:Example 47:

3-클로로-4-히드록시벤조산(4-벤질옥시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 5.40 (s, 2 H), 7.08 (d, 1 H), 7.08 (s, 1 H), 7.39 (d, 1 H), 7.43 (m, 3 H), 7.70 (m, 5 H), 8.00 (s, 1 H), 8.01 (d, 1 H), 8.33 (t, 1 H), 8.94 (d, 1 H), 9.35 (d, 1 H), 10.98 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431, 433. 1 H NMR (DMSO-d 6 ): δ 5.40 (s, 2 H), 7.08 (d, 1 H), 7.08 (s, 1 H), 7.39 (d, 1 H), 7.43 (m, 3 H) , 7.70 (m, 5H), 8.00 (s, 1H), 8.01 (d, 1H), 8.33 (t, 1H), 8.94 (d, 1H), 9.35 (d, 1H), 10.98 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431, 433.

실시예 48:Example 48:

2-(4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-1-나프틸옥시)아세트아미드2- (4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -1-naphthyloxy) acetamide

1H NMR (DMSO-d6): δ 4.68 (d, 2 H), 6.94 (d, 1 H), 6.98 (dd, 1H), 7.40 - 7.86 (m, 5 H), 8.00 (m, 1 H), 8.48 (dd, 1 H), 8.93 (m, 1 H), 9.38 (m, 1 H). MS (APCI): 398. 1 H NMR (DMSO-d 6 ): δ 4.68 (d, 2 H), 6.94 (d, 1 H), 6.98 (dd, 1H), 7.40-7.86 (m, 5 H), 8.00 (m, 1 H ), 8.48 (dd, 1 H), 8.93 (m, 1 H), 9.38 (m, 1 H). MS (APCI): 398.

실시예 49:Example 49:

3-클로로-4-히드록시벤조산(4-메틸-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-methyl-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 2.70 (s, 3 H), 7.10 (d, 1 H), 7.49 (d, 1 H), 7.67 (m, 2 H), 7.81 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, 1 H), 8.88 (d, 1 H), 9.07 (s, 1H), 11.0 (s, 1 H). MS (APCI): 339, 341. 1 H NMR (DMSO-d 6 ): δ 2.70 (s, 3 H), 7.10 (d, 1 H), 7.49 (d, 1 H), 7.67 (m, 2 H), 7.81 (m, 2 H) , 8.00 (s, 1H), 8.11 (d, 1H), 8.88 (d, 1H), 9.07 (s, 1H), 11.0 (s, 1H). MS (APCI): 339, 341.

실시예 50:Example 50:

3-클로로-4-히드록시벤조산(2-히드록시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.98 (d, 1 H), 7.98 (d, 1 H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.69 (d, 1 H), 7.78 (dd, 2 H), 7.90 (s, 1 H), 8.06 (d, 1 H), 9.32 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 341. 1 H NMR (DMSO-d 6 ): δ 6.98 (d, 1 H), 7.98 (d, 1 H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.69 (d, 1 H) , 7.78 (dd, 2H), 7.90 (s, 1H), 8.06 (d, 1H), 9.32 (s, 1H), 11.00 (s, 1H). MS (APCI): 341.

실시예 51:Example 51:

3-클로로-4-히드록시벤조산(4-메톡시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-methoxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 4.05 (s, 3 H), 7.06 (m, 2 H), 7.59 (dd, 1 H), 7.70 (dd, 1 H), 7.81 (d, 1 H), 7.86 (d, 1 H), 8.00 (s, 1 H), 8.27 (d, 1 H), 8.93 (s, 1 H), 8.99 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 341, 339. 1 H NMR (DMSO-d 6 ): δ 4.05 (s, 3H), 7.06 (m, 2H), 7.59 (dd, 1H), 7.70 (dd, 1H), 7.81 (d, 1H) , 7.86 (d, 1 H), 8.00 (s, 1 H), 8.27 (d, 1 H), 8.93 (s, 1 H), 8.99 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 341, 339.

실시예 52:Example 52:

N-(2-[(3-클로로-4-히드록시벤조일)히드라조노]에틸)-2,2-디페닐아세트아미드N- (2-[(3-chloro-4-hydroxybenzoyl) hydrazono] ethyl) -2,2-diphenylacetamide

1H NMR (DMSO-d6) δ 3.85 (t, 2 H), 4.93 (s, 2 H), 7.16 - 7.25 (m, 10 H), 7.26 (m, 1 H), 7.62 (d, 1 H), 7.82 (s, 1 H), 8.69 (t, 1 H), 10.85 (s, 1 H), 11.39 (s, 1 H). MS (APCI): 422 1 H NMR (DMSO-d 6 ) δ 3.85 (t, 2 H), 4.93 (s, 2 H), 7.16-7.25 (m, 10 H), 7.26 (m, 1 H), 7.62 (d, 1 H ), 7.82 (s, 1 H), 8.69 (t, 1 H), 10.85 (s, 1 H), 11.39 (s, 1 H). MS (APCI): 422

실시예 53:Example 53:

3-클로로-4-히드록시벤조산(1-히드록시-2-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (1-hydroxy-2-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.99 (d, 1 H), 7.22 (d, 1 H), 7.37 -7.56 (m, 4 H), 7.68 (dd, 1 H), 7.77 (d, 1 H), 7.90 (s, 1 H), 8.19 (d, 1 H), 8.58 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 341. 1 H NMR (DMSO-d 6 ): δ 6.99 (d, 1 H), 7.22 (d, 1 H), 7.37 -7.56 (m, 4 H), 7.68 (dd, 1 H), 7.77 (d, 1 H), 7.90 (s, 1 H), 8.19 (d, 1 H), 8.58 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 341.

실시예 54:Example 54:

3-클로로-4-히드록시벤조산(2,2-디페닐에틸리덴)히드라지드3-chloro-4-hydroxybenzoic acid (2,2-diphenylethylidene) hydrazide

1H NMR (DMSO-d6): δ 4.94 (d, 1 H), 6.98 (d, 1 H), 7.11 - 7.22 (m, 5 H), 7.22 -7.34 (m, 4 H), 7.68 (d, 1 H), 7.82 (s, 1 H), 8.19 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 365, 367. 1 H NMR (DMSO-d 6 ): δ 4.94 (d, 1 H), 6.98 (d, 1 H), 7.11-7.22 (m, 5 H), 7.22 -7.34 (m, 4 H), 7.68 (d , 1 H), 7.82 (s, 1 H), 8.19 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 365, 367.

실시예 55:Example 55:

3-클로로-4-히드록시벤조산(4-벤질옥시-3,5-디메톡시벤질리덴)히드라지드3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-3,5-dimethoxybenzylidene) hydrazide

1H NMR (DMSO-d6): δ 3.86 (s, 6 H), 4.98 (s, 2 H), 7.03 (s, 2 H), 7.09 (d, 1 H), 7.25 - 7.33 (m, 3 H), 7.48 (m, 2 H), 7.89 (dd, 1 H), 7.99 (s, 1 H), 8.32 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 441. 1 H NMR (DMSO-d 6 ): δ 3.86 (s, 6 H), 4.98 (s, 2 H), 7.03 (s, 2 H), 7.09 (d, 1 H), 7.25-7.33 (m, 3 H), 7.48 (m, 2H), 7.89 (dd, 1H), 7.99 (s, 1H), 8.32 (s, 1H), 11.00 (s, 1H). MS (APCI): 441.

실시예 56:Example 56:

3-클로로-4-히드록시벤조산[3-(4-tert-부틸페녹시)벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [3- (4-tert-butylphenoxy) benzylidene] hydrazide

1H NMR (DMSO-d6): δ 1.05 (s, 9 H), 6.90 (m, 3 H), 7.09 (d, 1 H), 7.30 (t, 1 H), 7.40 (m, 3 H), 7.69 (m, 2 H), 7.88 (s, 1 H), 8.44 (s, 1 H), 10.60 (s, 1 H), 11.55 (s, 1 H). MS (APCI): 423. 1 H NMR (DMSO-d 6 ): δ 1.05 (s, 9 H), 6.90 (m, 3 H), 7.09 (d, 1 H), 7.30 (t, 1 H), 7.40 (m, 3 H) , 7.69 (m, 2H), 7.88 (s, 1H), 8.44 (s, 1H), 10.60 (s, 1H), 11.55 (s, 1H). MS (APCI): 423.

실시예 57:Example 57:

3-클로로-4-히드록시벤조산(4-메틸-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-methyl-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 2.64 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 7.4 Hz, 1 H), 7.58 (m, 2 H), 7.78 (m, 2 H), 7.95 (d, J = 2.0 Hz, 1 H), 8.06 (dd, J = 2.0, 8.0 Hz, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 9.07 (s, 1 H), 10.93 (s, 1 H), 11.71 (s, 1 H). MS (APCI): 337. 339. 1 H NMR (DMSO-d 6 ): δ 2.64 (s, 3H), 7.03 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 7.4 Hz, 1 H), 7.58 (m, 2 H), 7.78 (m, 2H), 7.95 (d, J = 2.0 Hz, 1 H), 8.06 (dd, J = 2.0, 8.0 Hz, 1 H), 8.82 (d, J = 8.0 Hz, 1 H ), 9.07 (s, 1 H), 10.93 (s, 1 H), 11.71 (s, 1 H). MS (APCI): 337. 339.

실시예 58:Example 58:

3-클로로-4-히드록시벤조산(3-브로모-4-히드록시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (3-bromo-4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (CDCl3): δ 7.02 (d, J = 8.5 Hz, 1 H), 7.51 - 7.62 (m, 4 H), 7.80 (dd, J = 2.0, 8.5 Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 8.21 (s, 1 H), 8.59 (d, J = 8.5 Hz, 1 H), 8.91 (s, 1 H). MS (APCI): 421, 423. 1 H NMR (CDCl 3 ): δ 7.02 (d, J = 8.5 Hz, 1 H), 7.51-7.62 (m, 4 H), 7.80 (dd, J = 2.0, 8.5 Hz, 1 H), 8.00 (d , J = 2.0 Hz, 1 H), 8.21 (s, 1 H), 8.59 (d, J = 8.5 Hz, 1 H), 8.91 (s, 1 H). MS (APCI): 421, 423.

실시예 59:Example 59:

아세트산 4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-1-나프틸 에스테르Acetic acid 4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -1-naphthyl ester

1H NMR (DMSO-d6): δ 2.63 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.60 (dd, J = 7.0, 7.5 Hz, 1 H), 7.68 (dd, J = 7.0, 8.0 Hz, 1 H), 7.75 (dd, J = 1.4, 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 8.85 (d, J = 8.5 Hz, 1 H), 9.08 (s, 1 H), 11.0 (s, 1 H), 11.78 (s, 1 H). MS (APCI): 383. 1 H NMR (DMSO-d 6 ): δ 2.63 (s, 3H), 7.03 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 7.0, 7.5 Hz, 1 H), 7.68 (dd, J = 7.0, 8.0 Hz, 1 H), 7.75 (dd, J = 1.4, 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 8.85 (d, J = 8.5 Hz, 1 H), 9.08 (s, 1 H), 11.0 (s, 1 H), 11.78 (s, 1 H). MS (APCI): 383.

실시예 60:Example 60:

3-클로로-4-히드록시벤조산(4-시아노메톡시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-cyanomethoxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 5.40 (s, 2 H), 7.00 (d, 1 H), 7.21 (d, 1 H), 7.58 - 7.80 (m, 3 H), 7.82 (d, 1 H), 7.96 (s, 1 H), 8.18 (d, 1 H), 8.90 (s, 2 H), 9.28 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 380, 382. 1 H NMR (DMSO-d 6 ): δ 5.40 (s, 2 H), 7.00 (d, 1 H), 7.21 (d, 1 H), 7.58-7.80 (m, 3 H), 7.82 (d, 1 H), 7.96 (s, 1 H), 8.18 (d, 1 H), 8.90 (s, 2 H), 9.28 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 380, 382.

실시예 61:Example 61:

3-클로로-4-히드록시벤조산(2-히드록시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 7.18 (d, 1 H), 7.30 (d, 1 H), 7.50 (dd, 1H), 7.68 (dd, 1 H), 7.88 (d, 1 H), 7.95 (m, 2 H), 8.08 (s, 1 H), 8.29 (d, 1 H), 9.51 (s, 1 H), 11.12 (s, 1 H), 12.12 (s, 1 H). MS (APCI): 341, 343. 1 H NMR (DMSO-d 6 ): δ 7.18 (d, 1 H), 7.30 (d, 1 H), 7.50 (dd, 1H), 7.68 (dd, 1 H), 7.88 (d, 1 H), 7.95 (m, 2H), 8.08 (s, 1H), 8.29 (d, 1H), 9.51 (s, 1H), 11.12 (s, 1H), 12.12 (s, 1H). MS (APCI): 341, 343.

실시예 62:Example 62:

3-클로로-4-히드록시벤조산 (2,3-메틸렌디옥시벤질리덴)히드라지드3-Chloro-4-hydroxybenzoic acid (2,3-methylenedioxybenzylidene) hydrazide

1H NMR (DMSO-d6): δ 6.06 (s, 2 H), 6.86 (dd, 1 H), 6.90 (dd, 1H), 7.01 (d, 1 H), 7.25 (d, 1 H), 7.71 (dd, 1 H), 7.92 (s, 1 H), 8.49 (s, 1 H), 10.93 (s, 1 H), 11.70 (s, 1 H). MS (APCI): 319, 321. 1 H NMR (DMSO-d 6 ): δ 6.06 (s, 2 H), 6.86 (dd, 1 H), 6.90 (dd, 1H), 7.01 (d, 1 H), 7.25 (d, 1 H), 7.71 (dd, 1 H), 7.92 (s, 1 H), 8.49 (s, 1 H), 10.93 (s, 1 H), 11.70 (s, 1 H). MS (APCI): 319, 321.

실시예 63:Example 63:

3-클로로-4-히드록시벤조산[3-(4-메톡시페녹시)벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [3- (4-methoxyphenoxy) benzylidene] hydrazide

1H NMR (DMSO-d6): δ 3.98 (s, 3 H), 7.38 (m, 6 H), 7.48 (s, 1 H), 7.72 (m, 2 H), 7.97 (d, 1 H), 8.19 (s, 1 H), 8.64 (s, 1 H), 11.93 (s, 1 H). MS (APCI): 397, 399. 1 H NMR (DMSO-d 6 ): δ 3.98 (s, 3 H), 7.38 (m, 6 H), 7.48 (s, 1 H), 7.72 (m, 2 H), 7.97 (d, 1 H) , 8.19 (s, 1 H), 8.64 (s, 1 H), 11.93 (s, 1 H). MS (APCI): 397, 399.

실시예 64:Example 64:

3-클로로-4-히드록시벤조산(9-펜안트렌일메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (9-phenanthrenylmethylene) hydrazide

1H NMR (DMSO-d6): δ 7.02 (d, 1 H), 7.52 - 7.83 (m, 5 H), 7.99 (d, 1 H), 8.08 (d, 1 H), 8.21 (s, 1 H), 8.82 (d, 1 H), 8.89 (dd, 1 H), 8.96 (dd, 1 H), 9.06 (s, 1 H), 10.96 (s, 1 H), 11.82 (s, 1 H). MS (APCI): 375, 377. 1 H NMR (DMSO-d 6 ): δ 7.02 (d, 1 H), 7.52-7.83 (m, 5 H), 7.99 (d, 1 H), 8.08 (d, 1 H), 8.21 (s, 1 H), 8.82 (d, 1 H), 8.89 (dd, 1 H), 8.96 (dd, 1 H), 9.06 (s, 1 H), 10.96 (s, 1 H), 11.82 (s, 1 H) . MS (APCI): 375, 377.

실시예 65:Example 65:

3-클로로-4-히드록시벤조산[4-(2-히드록시에톡시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (2-hydroxyethoxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 3.81 (t, J = 4.8 Hz, 2 H), 4.16 (t, J = 4.8 Hz, 2 H), 6.46 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 7.51 - 7.61 (m, 3 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 2.1 Hz, 1 H), 8.30 (d, J = 8.2 Hz, 1 H), 8.85 (s, 1 H), 8.87 (d, J = 8.5 Hz, 1 H), 11.38 (s, 1 H). MS (APCI): 385, 387. 1 H NMR (DMSO-d 6 ): δ 3.81 (t, J = 4.8 Hz, 2H), 4.16 (t, J = 4.8 Hz, 2H), 6.46 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1 H), 7.51-7.61 (m, 3 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 2.1 Hz, 1 H), 8.30 (d, J = 8.2 Hz, 1 H), 8.85 (s, 1 H), 8.87 (d, J = 8.5 Hz, 1 H), 11.38 (s, 1 H). MS (APCI): 385, 387.

실시예 66:Example 66:

3-브로모-4-히드록시벤조산 (4-히드록시-1-나프틸메틸렌)히드라지드3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = J' = 8.0 Hz, 1 H), 7.58 (dd, J = J " = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 2.0, 8.0 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J = 8.0 Hz, 1 H), 10.73 (s, 1 H), 11.53 (s, 1 H). MS (APCI): 385, 387. 1 H NMR (DMSO-d 6 ): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = J '= 8.0 Hz, 1 H), 7.58 (dd, J = J "= 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 2.0, 8.0 Hz, 1 H), 8.08 (d , J = 2.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J = 8.0 Hz, 1 H), 10.73 (s, 1 H ), 11.53 (s, 1H) .MS (APCI): 385, 387.

실시예 67:Example 67:

니코틴산 4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-1-나프틸 에스테르Nicotinic Acid 4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -1-naphthyl ester

1H NMR (DMSO-d6): δ 7.04 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.64 - 7.69 (m, 4 H), 7.74 - 8.02 (m, 3 H), 8.56 (dd, J = 2.0, 8.0 Hz, 1 H), 8.91 (m, 2 H), 9.05 (s, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 10.96 (s, 1 H), 11.84 (s, 1 H). MS (APCI): 446, 448. 1 H NMR (DMSO-d 6 ): δ 7.04 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.64-7.69 (m, 4H), 7.74-8.02 (m, 3H), 8.56 (dd, J = 2.0, 8.0 Hz, 1H), 8.91 (m, 2H), 9.05 (s, 1H), 8.35 (d, J = 1.8 Hz, 1H) , 10.96 (s, 1 H), 11.84 (s, 1 H). MS (APCI): 446, 448.

실시예 68:Example 68:

3-클로로-4-히드록시벤조산[4-(1,3-디옥소-1,3-디히드로이소인돌-2-일메톡시)-1-나프틸메틸렌]-히드라지드3-Chloro-4-hydroxybenzoic acid [4- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethoxy) -1-naphthylmethylene] -hydrazide

1H NMR (DMSO-d6): δ 5.78 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.48 (m, 1 H), 7.61 (m, 1 H), 7.73 - 7.81 (m, 8 H), 8.90 (m, 2 H), 10.91 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 500, 502. 1 H NMR (DMSO-d 6 ): δ 5.78 (s, 2H), 7.03 (d, J = 8.5 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.48 (m, 1 H), 7.61 (m, 1H), 7.73-7.81 (m, 8H), 8.90 (m, 2H), 10.91 (s, 1H), 11.67 (s, 1H). MS (APCI): 500, 502.

실시예 69:Example 69:

3-클로로-4-히드록시벤조산[4-(시클로헥실메톡시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (cyclohexylmethoxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 1.08 - 1.19 (m, 4 H), 1.66 - 1.72 (m, 3 H), 1.83 - 1.92 (m, 3 H), 3.21 (m, 1 H), 3.95 (m, 2 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.53 (dd, J = J' = 7.4 Hz, 1 H), 7.62 (dd, J = J ' = 7.5 Hz, 1 H), 7.72 -7.93 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.94 (s, 1 H), 11.60 (s, 1 H). MS (APCI): 437, 439. 1 H NMR (DMSO-d 6 ): δ 1.08-1.19 (m, 4 H), 1.66-1.72 (m, 3 H), 1.83-1.92 (m, 3 H), 3.21 (m, 1 H), 3.95 (m, 2H), 6.99 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.53 (dd, J = J '= 7.4 Hz, 1H), 7.62 (dd, J = J '= 7.5 Hz, 1 H), 7.72 -7.93 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H) , 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.94 (s, 1 H), 11.60 (s, 1 H). MS (APCI): 437, 439.

실시예 70:Example 70:

3-클로로-4-히드록시벤조산[4-(테트라히드로-2-피란일메톡시)-1-나프틸메틸렌]-히드라지드3-Chloro-4-hydroxybenzoic acid [4- (tetrahydro-2-pyranylmethoxy) -1-naphthylmethylene] -hydrazide

1H NMR (DMSO-d6): δ 1.35 (m, 3 H), 1.60 - 1.71 (m, 2 H), 3.15 - 3.38 (m, 2 H), 3.64 (m, 1 H), 3.78 (m, 1 H), 4.02 (m, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 7.46 (dd, J = J' = 7.4 Hz, 1 H), 7.54 (dd, J = J ' = 8.2 Hz, 1 H), 7.66 (m, 2 H), 7.86 (d, J = 2.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.78 (s, 1 H), 8.83 (d, J = 8.5 Hz, 1 H), 10.83 (s, 1 H), 11.52 (s, 1 H). MS (APCI): 439, 441. 1 H NMR (DMSO-d 6 ): δ 1.35 (m, 3 H), 1.60-1.71 (m, 2 H), 3.15-3.38 (m, 2 H), 3.64 (m, 1 H), 3.78 (m , 1 H), 4.02 (m, 2H), 6.94 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = J '= 7.4 Hz, 1H), 7.54 (dd, J = J' = 8.2 Hz, 1 H), 7.66 (m, 2 H), 7.86 (d, J = 2.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.78 (s, 1 H), 8.83 (d, J = 8.5 Hz, 1 H), 10.83 (s, 1 H), 11.52 (s, 1 H). MS (APCI): 439, 441.

실시예 71:Example 71:

3-클로로-4-히드록시벤조산[4-(3-피리딜메톡시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (3-pyridylmethoxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 5.28 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.34 (dd, J = 4.8, 7.8 Hz, 1 H), 7.45 (dd, J = J' = 7.6 Hz, 1 H), 7.54 (dd, J = J ' = 7.5 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.86 (m, 2 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.45 (dd, J =1.5, 4.8 Hz, 1 H), 8.65 (s, 1 H), 8.81 (m, 2 H), 10.90 (s, 1 H), 11.56 (s, 1 H). MS (APCI): 432, 434. 1 H NMR (DMSO-d 6 ): δ 5.28 (m, 2H), 6.94 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 4.8, 7.8 Hz, 1 H), 7.45 (dd, J = J '= 7.6 Hz, 1 H), 7.54 (dd, J = J' = 7.5 Hz, 1 H), 7.66 (d, J = 8.5 Hz , 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.86 (m, 2 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.45 (dd, J = 1.5, 4.8 Hz, 1 H), 8.65 (s, 1 H), 8.81 (m, 2 H), 10.90 (s, 1 H), 11.56 (s, 1 H). MS (APCI): 432, 434.

실시예 72:Example 72:

4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-1-나프틸옥시)아세트산 에틸에스테르4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -1-naphthyloxy) acetic acid ethyl ester

1H NMR (DMSO-d6): δ 1.25 (t, J = 7.0 Hz, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 5.11 (s, 2 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.64 -7.70 (m, 2 H), 7.76 (d, J = 8.2 Hz, 2 H), 8.04 (d, J = 2.1 Hz, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.97 (s, 1 H), 9.02 (d, J = 8.5 Hz, 1 H), 11.01 (s, 1 H), 11.74 (s, 1 H). MS (APCI): 427, 429. 1 H NMR (DMSO-d 6 ): δ 1.25 (t, J = 7.0 Hz, 3H), 4.25 (q, J = 7.0 Hz, 2H), 5.11 (s, 2H), 7.06 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.64 -7.70 (m, 2H), 7.76 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 2.1 Hz, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.97 (s, 1 H), 9.02 (d, J = 8.5 Hz, 1 H), 11.01 (s, 1 H), 11.74 (s, 1 H). MS (APCI): 427, 429.

실시예 73:Example 73:

3-클로로-4-히드록시벤조산(3-니트로벤질리덴)히드라지드3-Chloro-4-hydroxybenzoic acid (3-nitrobenzylidene) hydrazide

1H NMR (DMSO-d6): δ 7.13 (d, J = 8.5 Hz, 1 H), 7.79 -7.86 (m, 2 H), 8.03 (d, J = 2.1 Hz, 1 H), 8.18 (d, J = 7.5 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.58 (s, 2 H), 11.08 (s, 1 H), 12.05 (s, 1 H). MS (APCI): 320, 322. 1 H NMR (DMSO-d 6 ): δ 7.13 (d, J = 8.5 Hz, 1 H), 7.79 -7.86 (m, 2H), 8.03 (d, J = 2.1 Hz, 1 H), 8.18 (d , J = 7.5 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.58 (s, 2 H), 11.08 (s, 1 H), 12.05 (s, 1 H). MS (APCI): 320, 322.

실시예 74:Example 74:

3-클로로-4-히드록시벤조산(2,4-디클로로벤질리덴)히드라지드3-Chloro-4-hydroxybenzoic acid (2,4-dichlorobenzylidene) hydrazide

1H NMR (DMSO-d6): δ 7.02 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.66 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.95 (m, 2 H), 8.71 (s, 1 H), 11.97 (s, 1 H), 11.94 (s, 1 H). MS (APCI): 345. 1 H NMR (DMSO-d 6 ): δ 7.02 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.66 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.95 (m, 2H), 8.71 (s, 1H), 11.97 (s, 1H), 11.94 (s, 1H). MS (APCI): 345.

실시예 75:Example 75:

3-클로로-4-히드록시벤조산(4-플루오로-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4-fluoro-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 7.00 (d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 8.2, 10.3 Hz, 1 H), 7.62 - 7.72 (m, 3 H), 7.82 (m, 1 H), 7.91 (d, J = 1.9 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 8.09 (m, 1 H), 8.91 (s, 1 H), 10.81 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 343. 1 H NMR (DMSO-d 6 ): δ 7.00 (d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 8.2, 10.3 Hz, 1 H), 7.62-7.72 (m, 3H), 7.82 (m, 1H), 7.91 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 8.09 (m, 1H), 8.91 (s, 1H), 10.81 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 343.

실시예 76:Example 76:

3-플루오로-4-히드록시벤조산(4-히드록시-1-나프틸메틸렌)히드라지드3-fluoro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (t, J = 8.6 Hz, 1 H), 7.44 - 7.72 (m, 6 H), 8.17 (d, J = 8.6 Hz, 1 H), 8.84 (s, 1 H), 8.89 (d, J = 8.5 Hz, 1 H), 10.60 (s, 1 H), 11.50 (s, 1 H). MS (APCI): 325. 1 H NMR (DMSO-d 6 ): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (t, J = 8.6 Hz, 1 H), 7.44-7.72 (m, 6H), 8.17 (d , J = 8.6 Hz, 1 H), 8.84 (s, 1 H), 8.89 (d, J = 8.5 Hz, 1 H), 10.60 (s, 1 H), 11.50 (s, 1 H). MS (APCI): 325.

실시예 77:Example 77:

3-클로로-4-히드록시벤조산[4-(2,4-디플루오로벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (2,4-difluorobenzyloxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 5.33 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (m, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.31 (m, 1 H), 7.52 (m, 1 H), 7.54 (m, 1H), 7.69 - 7.80 (m, 3 H), 7.94 (s, 1 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.90 (m, 2 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 467, 469. 1 H NMR (DMSO-d 6 ): δ 5.33 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (m, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.31 (m, 1H), 7.52 (m, 1H), 7.54 (m, 1H), 7.69-7.80 (m, 3H), 7.94 (s, 1H), 8.16 (d, J = 8.2 Hz, 1 H), 8.90 (m, 2H), 10.91 (s, 1H), 11.63 (s, 1H). MS (APCI): 467, 469.

실시예 78:Example 78:

3-플루오로-4-히드록시벤조산(1-나프틸메틸렌)히드라지드3-fluoro-4-hydroxybenzoic acid (1-naphthylmethylene) hydrazide

MS (APCI): 309.MS (APCI): 309.

실시예 79:Example 79:

3-클로로-4-히드록시벤조산[4-(3-메톡시벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (3-methoxybenzyloxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 3.71 (s, 3 H), 5.29 (s, 2 H), 6.87 (d, J = 8.5 Hz, 1 H), 7.00 - 7.14 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.55 (m, 1 H), 7.68 (m, 1 H), 7.75 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 11.00 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461. 1 H NMR (DMSO-d 6 ): δ 3.71 (s, 3 H), 5.29 (s, 2 H), 6.87 (d, J = 8.5 Hz, 1 H), 7.00-7.14 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.55 (m, 1 H), 7.68 (m, 1 H), 7.75 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 11.00 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461.

실시예 80:Example 80:

3-클로로-4-히드록시벤조산[4-(4-플루오로벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (4-fluorobenzyloxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 5.30 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.13 - 7.25 (m, 3 H), 7.53 - 7.60 (m, 4 H), 7.79 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 449, 451. 1 H NMR (DMSO-d 6 ): δ 5.30 (s, 2H), 7.02 (d, J = 8.5 Hz, 1H), 7.13-7.25 (m, 3H), 7.53-7.60 (m, 4H ), 7.79 (m, 2H), 7.94 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.88 (s, 1H), 8.92 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 449, 451.

실시예 81:Example 81:

3-클로로-4-히드록시벤조산[4-(2-테트라히드로푸란일메톡시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (2-tetrahydrofuranylmethoxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 1.77 - 2.04 (m, 4 H), 3.68 (m, 1 H), 3.78 (m, 1 H), 4.12 - 4.16 (m, 2 H), 4.26 (m, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.53 (m, 1 H), 7.62 (m, 1 H), 7.74 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.61 (s, 1 H). MS (APCI): 425, 427. 1 H NMR (DMSO-d 6 ): δ 1.77-2.04 (m, 4 H), 3.68 (m, 1 H), 3.78 (m, 1 H), 4.12-4.16 (m, 2 H), 4.26 (m , 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.53 (m, 1 H), 7.62 (m, 1 H), 7.74 (m , 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H ), 10.93 (s, 1 H), 11.61 (s, 1 H). MS (APCI): 425, 427.

실시예 82:Example 82:

3-클로로-4-히드록시벤조산(3-브로모-4-메톡시-1-나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (3-bromo-4-methoxy-1-naphthylmethylene) hydrazide

1H NMR (DMSO-d6): δ 3.91 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.65 - 7.76 (m, 3 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.02 (s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.71 (d, J = 8.0 Hz, 1 H), 8.95 (s, 1 H), 10.96 (s, 1 H), 11.85 (s, 1 H). MS (APCI): 433, 435. 1 H NMR (DMSO-d 6 ): δ 3.91 (s, 3H), 7.03 (d, J = 8.5 Hz, 1 H), 7.65-7.76 (m, 3H), 7.94 (d, J = 2.0 Hz , 1 H), 8.02 (s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.71 (d, J = 8.0 Hz, 1 H), 8.95 (s, 1 H), 10.96 (s , 1 H), 11.85 (s, 1 H). MS (APCI): 433, 435.

실시예 83:Example 83:

3-클로로-4-히드록시벤조산[4-(3-테트라히드로푸란일메톡시)-1-나프틸메틸렌]-히드라지드3-Chloro-4-hydroxybenzoic acid [4- (3-tetrahydrofuranylmethoxy) -1-naphthylmethylene] -hydrazide

1H NMR (DMSO-d6): δ 1.92 (m, 1 H), 2.10 (m, 1 H), 2.77 (m, 1 H), 3.28 - 3.88 (m, 4 H), 4.12 (m, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.55 (m, 1 H), 7.62 (m, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 425, 427. 1 H NMR (DMSO-d 6 ): δ 1.92 (m, 1 H), 2.10 (m, 1 H), 2.77 (m, 1 H), 3.28-3.88 (m, 4 H), 4.12 (m, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.55 (m, 1 H), 7.62 (m, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.88 (s , 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 425, 427.

실시예 84:Example 84:

4-(4-[3-클로로-4-히드록시벤조일)히드라조노메틸]-1-나프틸옥시메틸)벤조산 메틸에스테르4- (4- [3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -1-naphthyloxymethyl) benzoic acid methyl ester

1H NMR (DMSO-d6): δ 3.80 (s, 3 H), 5.43 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.54 (m, 1 H), 7.57 (d, J = 8.0 Hz, 4 H), 7.93 - 7.99 (m, 3 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 489, 491. 1 H NMR (DMSO-d 6 ): δ 3.80 (s, 3 H), 5.43 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.54 (m, 1H), 7.57 (d, J = 8.0 Hz, 4H), 7.93-7.99 (m, 3H), 8.30 (d, J = 8.0 Hz, 1H), 8.87 (s , 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 489, 491.

실시예 85:Example 85:

3-클로로-4-히드록시벤조산[3,5-디메톡시-4-(4-트리플루오로메톡시벤질옥시)벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4- (4-trifluoromethoxybenzyloxy) benzylidene] hydrazide

1H NMR (DMSO-d6): δ 3.76 (s, 6 H), 4.91 (s, 2 H), 6.95 - 7.00 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 2.0, 8.5 Hz, 1 H), 7.88 (s, 1 H), 8.29 (s, 1 H), 10.91 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 525, 527. 1 H NMR (DMSO-d 6 ): δ 3.76 (s, 6 H), 4.91 (s, 2 H), 6.95-7.00 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 2.0, 8.5 Hz, 1 H), 7.88 (s, 1 H), 8.29 (s, 1 H), 10.91 (s, 1 H ), 11.69 (s, 1H). MS (APCI): 525, 527.

실시예 86:Example 86:

3-클로로-4-히드록시벤조산[4-(4-트리플루오로메톡시벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (4-trifluoromethoxybenzyloxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 5.36 (s, 2 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.56 (m, 1 H), 7.62 (m, 3 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 515, 517. 1 H NMR (DMSO-d 6 ): δ 5.36 (s, 2 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.56 (m, 1 H), 7.62 (m, 3 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 515, 517.

실시예 87:Example 87:

3-클로로-4-히드록시벤조산[4-(2-메톡시벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (2-methoxybenzyloxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 3.79 (s, 3 H), 5.27 (s, 2 H), 6.95 (m, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.31 (m, 1 H), 7.46 - 7.53 (m, 2 H), 7.61 (m, 1 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.22 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461, 463. 1 H NMR (DMSO-d 6 ): δ 3.79 (s, 3 H), 5.27 (s, 2 H), 6.95 (m, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 ( d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.31 (m, 1 H), 7.46-7.53 (m, 2 H), 7.61 (m, 1 H), 7.76 (m, 2H), 7.94 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.88 (s, 1H), 8.92 (d, J = 8.5 Hz , 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461, 463.

실시예 88:Example 88:

3-클로로-4-히드록시벤조산[4-(2-플루오로벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (2-fluorobenzyloxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 5.36 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.19 - 7.28 (m, 3 H), 7.39 (m, 1 H), 7.53 (m, 1 H), 7.63 (m, 2 H), 7.72 - 7.80 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.19 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.64 (s, 1 H). MS (APCI): 449, 451. 1 H NMR (DMSO-d 6 ): δ 5.36 (s, 2H), 7.03 (d, J = 8.5 Hz, 1H), 7.19-7.28 (m, 3H), 7.39 (m, 1H), 7.53 (m, 1 H), 7.63 (m, 2 H), 7.72-7.80 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.19 (d, J = 8.3 Hz, 1 H ), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.64 (s, 1 H). MS (APCI): 449, 451.

실시예 89:Example 89:

3-클로로-4-히드록시벤조산[4-(2,6-디플루오로벤질옥시)-1-나프틸메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (2,6-difluorobenzyloxy) -1-naphthylmethylene] hydrazide

1H NMR (DMSO-d6): δ 5.34 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.16 (d, J = 8.2 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.51 (m, 2 H), 7.72 (m, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 8.89 (s, 1 H), 8.91 (d, J = 8.5 Hz, 1 H), 10.97 (s, 1 H), 11.65 (s, 1 H). MS (APCI): 467, 469. 1 H NMR (DMSO-d 6 ): δ 5.34 (s, 2H), 7.03 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.51 (m, 2 H), 7.72 (m, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 8.89 (s, 1 H), 8.91 (d , J = 8.5 Hz, 1 H), 10.97 (s, 1 H), 11.65 (s, 1 H). MS (APCI): 467, 469.

실시예 90:Example 90:

4-히드록시-3-메톡시벤조산[3,5-디메톡시-4-(5,5,8,8-테트라메틸-5,6,7,8-테트라히드로나프트-1-일메톡시)벤질리덴]히드라지드4-hydroxy-3-methoxybenzoic acid [3,5-dimethoxy-4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-1-ylmethoxy) Benzylidene] hydrazide

1H NMR (DMSO-d6): δ 1.2 (s, 12H), 1.63 (s, 4H), 3.82 (s, 6H), 3.85 (s, 3H), 4.90 (s, 2H), 6.88 (d, 1H), 7.01 (s, 2H), 7.18 (d, 1H), 7.29 (d, 1H), 7.38 (s, 1H), 7.44 (d, 1H), 7.48 (s, 1H), 8.40 (brδ s, 1H), 11.62 (s 1H); MS (APCI): 547.1. 1 H NMR (DMSO-d 6 ): δ 1.2 (s, 12H), 1.63 (s, 4H), 3.82 (s, 6H), 3.85 (s, 3H), 4.90 (s, 2H), 6.88 (d, 1H), 7.01 (s, 2H), 7.18 (d, 1H), 7.29 (d, 1H), 7.38 (s, 1H), 7.44 (d, 1H), 7.48 (s, 1H), 8.40 (brδ s, 1H), 11.62 (s 1H); MS (APCI): 547.1.

실시예 91:Example 91:

3-플루오로-4-히드록시벤조산[4-(4-이소프로필벤질옥시)-3,5-디메톡시벤질리덴]히드라지드3-fluoro-4-hydroxybenzoic acid [4- (4-isopropylbenzyloxy) -3,5-dimethoxybenzylidene] hydrazide

1H NMR (DMSO-d6): δ 1.05 (d, 6H), 2.67 (m, 1H), 3.61 (s, 6H), 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1H), 7.01 (d, 2H), 7.24 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 8.10 (brd s, 1H), 10.32 (s, 1H), 11.41 (s, 1H); MS (APCI): 467.19. 1 H NMR (DMSO-d 6 ): δ 1.05 (d, 6H), 2.67 (m, 1H), 3.61 (s, 6H), 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1H), 7.01 (d, 2H), 7.24 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 8.10 (brd s, 1H), 10.32 (s, 1H), 11.41 (s, 1H); MS (APCI): 467.19.

실시예 92:Example 92:

3-클로로-4-히드록시벤조산 [4-(4-tert-부틸벤질옥시)-3,5-디메틸벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [4- (4-tert-butylbenzyloxy) -3,5-dimethylbenzylidene] hydrazide

1H NMR (DMSO-d6): δ 1.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H), 6.83 (d, 1H), 7.19 (s, 6H), 7.52 (d, 1H), 7.73 (s, 1H), 8.09 (s, 1H), 10.74 (brd s, 1H), 11.44 (s, 1H); MS (FAB): 465.6. 1 H NMR (DMSO-d 6 ): δ 1.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H), 6.83 (d, 1H), 7.19 (s, 6H), 7.52 (d, 1H), 7.73 (s, 1H), 8.09 (s, 1H), 10.74 (brd s, 1H), 11.44 (s, 1H); MS (FAB): 465.6.

실시예 93:Example 93:

3-클로로-4-히드록시벤조산[3-브로모-5-메톡시-4-(4-트리플루오로메톡시벤질옥시)벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [3-bromo-5-methoxy-4- (4-trifluoromethoxybenzyloxy) benzylidene] hydrazide

1H NMR (DMSO-d6): δ 3.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1H), 7.40 (m, 3H), 7.52 (s, 1H), 7.63 (d, 2H), 7.77 (dd, 1H), 7.97 (d, 1H), 8.35 (s, 1H), 11.00 (brd s, 1H), 11.86 (s, 1H); MS (FAB): 575.0 1 H NMR (DMSO-d 6 ): δ 3.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1H), 7.40 (m, 3H), 7.52 (s, 1H), 7.63 (d, 2H), 7.77 (dd, 1H), 7.97 (d, 1H), 8.35 (s, 1H), 11.00 (brd s, 1H), 11.86 (s, 1H); MS (FAB): 575.0

실시예 94:Example 94:

4-히드록시벤조산[4-(4-이소프로필벤질옥시)-3,5-디메톡시벤질리덴]히드라지드4-hydroxybenzoic acid [4- (4-isopropylbenzyloxy) -3,5-dimethoxybenzylidene] hydrazide

1H NMR (DMSO-d6): δ 1.05 (d, 6H), 2.71 (m, 1H), 3.67 (s, 6H), 4.75 (s, 2H), 6.70 (d, 2H), 6.85 (s, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.64 (d, 2H), 8.21 (brd s, 1H), 9.97 (brd s, 1H), 11.47 (s, 1H); MS (APCI): 448.9. 1 H NMR (DMSO-d 6 ): δ 1.05 (d, 6H), 2.71 (m, 1H), 3.67 (s, 6H), 4.75 (s, 2H), 6.70 (d, 2H), 6.85 (s, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.64 (d, 2H), 8.21 (brd s, 1H), 9.97 (brd s, 1H), 11.47 (s, 1H); MS (APCI): 448.9.

실시예 95:Example 95:

2-클로로-4-히드록시벤조산[4-(4-이소프로필벤질옥시)-3,5-디메톡시벤질리덴]히드라지드:2-Chloro-4-hydroxybenzoic acid [4- (4-isopropylbenzyloxy) -3,5-dimethoxybenzylidene] hydrazide:

1H NMR (DMSO-D6): δ 1.18 (d, 6H), 2.87 (septet, 1H), [3.68 (s, 1H) + 3.81 (s, 5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.01 (s, 1.5 H), 2H], [6.80 (dd, 1H) + 6.88 (d, 1H), 2H], 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1H), [7.91 (s, 0.3H) + 8.18 (s, 0.7H), 2H], 10.17 (s, 0.7H) + 11.73 (s, 0.3H), 1H]; MS (APCI): 483.0. 1 H NMR (DMSO-D 6 ): δ 1.18 (d, 6H), 2.87 (septet, 1H), [3.68 (s, 1H) + 3.81 (s, 5H), 6H], [4.83 (s, 0.5H) ) + 4.90 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.01 (s, 1.5H), 2H], [6.80 (dd, 1H) + 6.88 (d, 1H), 2H] , 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1H), [7.91 (s, 0.3H) + 8.18 (s, 0.7H), 2H], 10.17 (s, 0.7H) + 11.73 (s, 0.3H), 1 H]; MS (APCI): 483.0.

실시예 96:Example 96:

3-클로로-4-히드록시벤조산[3-(4-이소프로필벤질옥시)-4,5-디메톡시벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [3- (4-isopropylbenzyloxy) -4,5-dimethoxybenzylidene] hydrazide

1H NMR (DMSO-d6): δ 1.05 (d, 6H), 2.70 (m, 1H), 3.54 (s, 3H), 3.66 (s, 3H), 4.94 (s, 2H), 6.87 (m, 3H), 7.08 (d, 2H), 7.20 (d, 2H), 7.56 (dd, 1H), 7.77 (s, 1H), 8.15 (s, 1H), 10.76 (s, 1H), 11.52 (s, 1H); MS (APCI): 483.7. 1 H NMR (DMSO-d 6 ): δ 1.05 (d, 6H), 2.70 (m, 1H), 3.54 (s, 3H), 3.66 (s, 3H), 4.94 (s, 2H), 6.87 (m, 3H), 7.08 (d, 2H), 7.20 (d, 2H), 7.56 (dd, 1H), 7.77 (s, 1H), 8.15 (s, 1H), 10.76 (s, 1H), 11.52 (s, 1H ); MS (APCI): 483.7.

실시예 97:Example 97:

3-클로로-4-히드록시벤조산[3-(4-이소프로필벤질옥시)-2,4-디메톡시벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [3- (4-isopropylbenzyloxy) -2,4-dimethoxybenzylidene] hydrazide

1H NMR (DMSO-d6): δ 1.20 (d, 6H), 2.89 (m, 1H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1H), 7.78 (dd, 1H), 7.97 (d, 1H), 8.62 (s, 1H), 11.68 (s, 1H); MS (APCI): 483.8. 1 H NMR (DMSO-d 6 ): δ 1.20 (d, 6H), 2.89 (m, 1H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1H), 7.78 (dd, 1H), 7.97 (d, 1H), 8.62 (s, 1H), 11.68 (s, 1H ); MS (APCI): 483.8.

실시예 98:Example 98:

3-클로로-4-히드록시벤조산[4-(3-트리플루오로메톡시벤질옥시)나프트-1-일메틸렌]히드라지드3-chloro-4-hydroxybenzoic acid [4- (3-trifluoromethoxybenzyloxy) naphth-1-ylmethylene] hydrazide

1H NMR (DMSO-d6): δ 5.46 (s, 2H), 7.10 (d, 1H), 7.20 (d, 1H), 7.37 (d, 1H), 7.65 (m, 5H), 7.82 (m, 2H), 8.01 (s, 1H), 8.32 (d, 1H), 8.97 (m, 2H), 11.70 (s, 1H); MS (APCI): 514.8 1 H NMR (DMSO-d 6 ): δ 5.46 (s, 2H), 7.10 (d, 1H), 7.20 (d, 1H), 7.37 (d, 1H), 7.65 (m, 5H), 7.82 (m, 2H), 8.01 (s, 1H), 8.32 (d, 1H), 8.97 (m, 2H), 11.70 (s, 1H); MS (APCI): 514.8

실시예 99:Example 99:

3-클로로-4-히드록시-벤조산[4-(4-이소프로필벤질옥시)-8-메톡시나프탈렌-1-일메틸렌]히드라지드3-Chloro-4-hydroxy-benzoic acid [4- (4-isopropylbenzyloxy) -8-methoxynaphthalen-1-ylmethylene] hydrazide

4-히드록시-8-메톡시나프탈렌-1-카르발데히드(2g, 9.9mmol)을 DMF(25mL)중에 용해시켰다. 이 혼합물에 탄산칼륨(6.8g, 50mmol) 및 염화 4-이소프로필벤질(1.8g, 10.4mmol)을 가하고, 그 결과의 혼합물을 실온에서 16시간동안 교반하였다. 물(100mL)을 가하고 그 결과의 혼합물을 디에틸에테르(3x100mL)로 추출하였다. 합한 유기 추출물을 포화 염화나트륨(100mL)으로 세척하고, 건조(MgSO4)시키고 진공에서 증발시켜 미정제 생성물 3.0g을 얻었다. 이것을 에틸아세테이트와 헵탄(1:4)의 혼합물을 용리시키는 실리카겔 상(300mL)의 컬럼크로마토그래피를 사용하여 정제하였다. 이렇게 하여 4-이소프로필벤질옥시-8-메톡시나프탈렌-1-카르발데히드 2.57g (81%)을 얻었다.4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (2 g, 9.9 mmol) was dissolved in DMF (25 mL). Potassium carbonate (6.8 g, 50 mmol) and 4-isopropylbenzyl chloride (1.8 g, 10.4 mmol) were added to the mixture, and the resulting mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the resulting mixture was extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO 4 ) and evaporated in vacuo to afford 3.0 g of crude product. This was purified using column chromatography on silica gel (300 mL) eluting a mixture of ethyl acetate and heptane (1: 4). This gave 2.57 g (81%) of 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde.

C22H22O3의 계산치:C, 79.02%; H, 6.63%. 실측치:C, 79.10%, H, 6.69%, C, 79.17%, H, 6.69%.Calcd for C 22 H 22 0 3 : C, 79.02%; H, 6.63%. Found: C, 79.10%, H, 6.69%, C, 79.17%, H, 6.69%.

3-클로로-4-히드록시벤조산 히드라지드(205mg, 1.1mmol)을 DMSO(2mL)에 용해시키고 상기 4-이소프로필벤질옥시-8-메톡시나프탈렌-1-카르발데히드(365mg, 1.1mmol) 및 냉 아세트산(5방울)을 가하고 그 결과의 혼합물을 실온에서 20분간 교반하였다. DMSO(2mL)를 더 가하고 혼합물을 16시간동안 실온에서 교반하였다. 고체를 여과하여 수집하고 DMSO와 에틸아세테이트로 연속적으로 세척하여 표제의 화합물 330mg(66%)를 얻었다.3-chloro-4-hydroxybenzoic acid hydrazide (205 mg, 1.1 mmol) was dissolved in DMSO (2 mL) and the 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde (365 mg, 1.1 mmol) And cold acetic acid (5 drops) were added and the resulting mixture was stirred at room temperature for 20 minutes. More DMSO (2 mL) was added and the mixture was stirred at rt for 16 h. The solid was collected by filtration and washed successively with DMSO and ethyl acetate to give 330 mg (66%) of the title compound.

융점:>250℃.Melting Point:> 250 ° C.

실시예 100:Example 100:

1H NMR ( DMSO-d6) δ 1.13 (d, 6H), 2.82 (sept, 1H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1H), 7.18 (s, 2H), 7.30 (d, 2H), 8.00 (dd, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 11.84 (s, 1H);. MS (APCI): 494.0 1 H NMR (DMSO-d 6 ) δ 1.13 (d, 6H), 2.82 (sept, 1H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1H), 7.18 (s, 2H ), 7.30 (d, 2H), 8.00 (dd, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 11.84 (s, 1H); MS (APCI): 494.0

실시예 101:Example 101:

1H NMR ( DMSO-d6) δ 5.38 (s, 2H), 6.95 (d, 1H), 7.06 (d, 1H), 7.49 (t, 1H), 7.56 (t, 1H), 7.65-7.71 (m, 6H), 7.87 (d, 1H), 8.22 (d, 1H), 8.80 (s, 1H), 8.86 (d, 1H), 10.82 (s, 1H), 11.55 (s, 1H); MS (FAB): 499 1 H NMR (DMSO-d 6 ) δ 5.38 (s, 2H), 6.95 (d, 1H), 7.06 (d, 1H), 7.49 (t, 1H), 7.56 (t, 1H), 7.65-7.71 (m , 6H), 7.87 (d, 1H), 8.22 (d, 1H), 8.80 (s, 1H), 8.86 (d, 1H), 10.82 (s, 1H), 11.55 (s, 1H); MS (FAB): 499

실시예 102:Example 102:

1H NMR ( DMSO-d6) δ 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1H), 8.16 (d, 2H), 8.33 (d, 1H), 8.90 (s, 1H), 893 (s, 1H), 10.90 (brd s, 1H), 11.63 (s, 1H); MS (FAB): 543 1 H NMR (DMSO-d 6 ) δ 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1H), 8.16 (d , 2H), 8.33 (d, 1H), 8.90 (s, 1H), 893 (s, 1H), 10.90 (brd s, 1H), 11.63 (s, 1H); MS (FAB): 543

실시예 103:Example 103:

3-클로로-4-히드록시벤조산{4-[2-(4-브로모페녹시)에톡시]-3,5-디메톡시벤질리덴}히드라지드3-Chloro-4-hydroxybenzoic acid {4- [2- (4-bromophenoxy) ethoxy] -3,5-dimethoxybenzylidene} hydrazide

1H NMR (DMSO-d6): δ 3.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H), 7.05 (d, 1H), 7.44 (d, 2H), 7.75 (dd, 1H), 7.96 (s, 1H), 8.36 (s, 1H), 10.95 (brd s, 1H), 11.66 (s, 1H); MS(APCI): 548.8. 1 H NMR (DMSO-d 6 ): δ 3.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H), 7.05 (d, 1H), 7.44 (d, 2H), 7.75 (dd, 1H), 7.96 (s, 1H), 8.36 (s, 1H), 10.95 (brd s, 1H), 11.66 (s, 1H); MS (APCI): 548.8.

실시예 104:Example 104:

3-클로로-4-히드록시벤조산[4-(3-메톡시-3-(4-메틸페닐)-프로필옥시)나프트-1-일메틸렌]히드라지드3-Chloro-4-hydroxybenzoic acid [4- (3-methoxy-3- (4-methylphenyl) -propyloxy) naphth-1-ylmethylene] hydrazide

MS (APCI): 502.9MS (APCI): 502.9

실시예 105:Example 105:

(2-에틸페닐)카르밤산 2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-나프트-1-일옥시}에틸에스테르(2-ethylphenyl) carbamic acid 2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -naphth-1-yloxy} ethyl ester

1H NMR (CDCl3): δ 1.12 (t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1H), 6.57 (t, 1H), 6.74 (d, 1H), 6.97 (d, 1H), 7.08 (m, 3H), 7.57 (t, 1H), 7.67 (t, 1H), 7.81 (t, 2H), 8.01 (s, 1H), 8.35 (d, 1H), 8.95 (m, 2H), 11.67 (s, 1H). 1 H NMR (CDCl 3 ): δ 1.12 (t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1H), 6.57 (t, 1H) , 6.74 (d, 1H), 6.97 (d, 1H), 7.08 (m, 3H), 7.57 (t, 1H), 7.67 (t, 1H), 7.81 (t, 2H), 8.01 (s, 1H), 8.35 (d, 1 H), 8.95 (m, 2 H), 11.67 (s, 1 H).

실시예 106:Example 106:

3-클로로-4-히드록시벤조산[3-알릴-4-(4-이소프로필벤질옥시)-5-메톡시벤질리덴]히드라지드3-Chloro-4-hydroxybenzoic acid [3-allyl-4- (4-isopropylbenzyloxy) -5-methoxybenzylidene] hydrazide

1H NMR (DMSO-d6) : δ 1.13 (d, 6H), 2.80 (m, 1H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1H), 6.96 (s, 1H), 7.05 (s, 1H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1H), 7.89 (s, 1H), 8.28 (s, 1H), 10.80 (brδ s, 1H), 11.61 (s, 1H); MS (APCI): 493.1. 1 H NMR (DMSO-d 6 ): δ 1.13 (d, 6H), 2.80 (m, 1H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1H), 6.96 (s, 1H), 7.05 (s, 1H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1H), 7.89 (s, 1H ), 8.28 (s, 1 H), 10.80 (brδ s, 1 H), 11.61 (s, 1 H); MS (APCI): 493.1.

유사하게, 다음 화합물을 제조하였다.Similarly, the following compounds were prepared.

실시예 107:Example 107:

1H NMR (DMSO-D6): δ 0.99 (d, 6H), 2.68 (septet, 1H), 4.89 (s, 2H), 6.84 (d, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.55 (d, 1H), 7.75 (s, 1H), 8.18 (s, 1H), 10.75 (s, 1H), 11.52 (s, 1H); MS (APCI): 423.7, 425.6. 1 H NMR (DMSO-D 6 ): δ 0.99 (d, 6H), 2.68 (septet, 1H), 4.89 (s, 2H), 6.84 (d, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.55 (d, 1H), 7.75 (s, 1H), 8.18 (s, 1H), 10.75 (s, 1H), 11.52 (s, 1H); MS (APCI): 423.7, 425.6.

실시예 108:Example 108:

1H NMR (DMSO-D6): δ 1.18 (d, 1H), 2.88 (septet, 1H), 5.20 (s, 2H), 7.04 (d, 1H), 7.28 (t, 2H), 7.30 (s, 1H), 7.38 (d, 2H), 7.62 (d, 1H), 7.73 (dd, 1H), 7.79 (s, 1H), 7.94 (d, 1H), 8.32 (s, 1H), 11.94 (s, 1H), 11.72 (s, 1H); MS (APCI): 457.4, 459.1. 1 H NMR (DMSO-D 6 ): δ 1.18 (d, 1H), 2.88 (septet, 1H), 5.20 (s, 2H), 7.04 (d, 1H), 7.28 (t, 2H), 7.30 (s, 1H), 7.38 (d, 2H), 7.62 (d, 1H), 7.73 (dd, 1H), 7.79 (s, 1H), 7.94 (d, 1H), 8.32 (s, 1H), 11.94 (s, 1H ), 11.72 (s, 1 H); MS (APCI): 457.4, 459.1.

실시예 109:Example 109:

1H NMR (DMSO-D6): δ 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1H), 7.9 (s, 1H), 8.2 (s, 1H), 10.9 (s, 1H), 11.6 (s, 1H); MS (APCI): 451.6, 453.3. 1 H NMR (DMSO-D 6 ): δ 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1H), 7.9 (s, 1H), 8.2 (s, 1H), 10.9 (s, 1H), 11.6 (s, 1H); MS (APCI): 451.6, 453.3.

실시예 110:Example 110:

1H NMR (DMSO-D6): δ 1.1 (d, 6H), 2.8 (septet, 1H), 3.3 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.2 (s, 2H), 5.9 (m, 1H), 7.0 (d, 1H), 7.1 (d, 1H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1H), 7.5 (s, 1H), 7.7 (dd, 1H), 7.9 (d, 1H), 8.3 (s, 1H), 10.9 (brd s, 1H), 11.5 (s, 1H); MS (APCI): 463.5, 465.1. 1 H NMR (DMSO-D 6 ): δ 1.1 (d, 6H), 2.8 (septet, 1H), 3.3 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.2 (s, 2H), 5.9 (m, 1H), 7.0 (d, 1H), 7.1 (d, 1H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1H), 7.5 (s, 1H ), 7.7 (dd, 1H), 7.9 (d, 1H), 8.3 (s, 1H), 10.9 (brd s, 1H), 11.5 (s, 1H); MS (APCI): 463.5, 465.1.

실시예 111:Example 111:

1H NMR (DMSO-D6): δ 4.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1H), 7.14 (d, 1H), 7.45 (d, 2H), 7.53 (t, 1H), 7.27 (d, 1H), 7.79 (m, 2H), 7.96 (d, 1H), 8.17 (d, 1H), 8.91 (s, 1H), 8.94 (d, 1H), 10.92 (s, 1H), 11.64 (s, 1H), MS (APCI): 539.3, 541.1, 543.1. 1 H NMR (DMSO-D 6 ): δ 4.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1H), 7.14 (d, 1H), 7.45 (d, 2H), 7.53 (t, 1H), 7.27 (d, 1H), 7.79 (m, 2H), 7.96 (d, 1H), 8.17 (d, 1H), 8.91 (s, 1H), 8.94 (d, 1H ), 10.92 (s, 1 H), 11.64 (s, 1 H), MS (APCI): 539.3, 541.1, 543.1.

실시예 112:Example 112:

1H NMR (DMSO-D6): δ 1.18 (d, 6H), 2.87 (septet, 1H), [3.67 (s, 1.5H) + 3.81 (s, 4.5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], 6.73 (s, 0.5H) + [7.02 (m, 2.5H), + 7.27 (m, 2.5H) + 7.37 (m, 2.5H), 8H], [7.92 (s, 0.3H) + 8.17 (s, 0.7H), 1H], [10.96 (s, 0.3H) + 11.12 (s, 0.7H), 1H], [11.82 (s, 0.7H) + 11.95 (s, 0.3H), 1H]; MS (APCI): 517.6, 519.2. 1 H NMR (DMSO-D 6 ): δ 1.18 (d, 6H), 2.87 (septet, 1H), [3.67 (s, 1.5H) + 3.81 (s, 4.5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], 6.73 (s, 0.5H) + [7.02 (m, 2.5H), + 7.27 (m, 2.5H) + 7.37 (m, 2.5H), 8H ], [7.92 (s, 0.3H) + 8.17 (s, 0.7H), 1H], [10.96 (s, 0.3H) + 11.12 (s, 0.7H), 1H], [11.82 (s, 0.7H) + 11.95 (s, 0.3H), 1 H]; MS (APCI): 517.6, 519.2.

실시예 113:Example 113:

1H NMR (DMSO-D6): δ 1.19 (d, 6H), 2.89 (septet, 1H), [3.68 (s, 1.5H) + 3.82 (s, 4.5H), 6H], [4.84 (s, 0.5H) + 4.89 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.02 (m, 2.5H), 3H], 7.20 (m, 2H), 7.34 (m, 2H), [7.50 (s, 0.3H) + 7.62 (s, 0.7H), 1H], 7.92 (s, 0.3H) + 8.18 (s, 0.7H), 1H], 11.17 (brd s, 1H), 11.81 (s, 0.7H) + 11.96 (s, 0.3H), 1H]; MS (APCI): 517.7, 519.2. 1 H NMR (DMSO-D 6 ): δ 1.19 (d, 6H), 2.89 (septet, 1H), [3.68 (s, 1.5H) + 3.82 (s, 4.5H), 6H], [4.84 (s, 0.5H) + 4.89 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.02 (m, 2.5H), 3H], 7.20 (m, 2H), 7.34 (m, 2H), [ 7.50 (s, 0.3H) + 7.62 (s, 0.7H), 1H], 7.92 (s, 0.3H) + 8.18 (s, 0.7H), 1H], 11.17 (brd s, 1H), 11.81 (s, 0.7H) + 11.96 (s, 0.3H), 1H]; MS (APCI): 517.7, 519.2.

실시예 114:Example 114:

1H NMR (DMSO-D6): δ 1.20 (d, 6H), 2.87 (septet, 1H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1H), 9.8 (brd s, 1H), 11.50 (s, 1H); MS (APCI): 464.7. 1 H NMR (DMSO-D 6 ): δ 1.20 (d, 6H), 2.87 (septet, 1H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1H), 9.8 (brd s, 1H), 11.50 (s, 1H); MS (APCI): 464.7.

실시예 115:Example 115:

1H NMR (DMSO-D6): δ 1.19 (d, 6H), 2.30 (septet, 1H), [3.71 (s) + 3.82 (s), 6H], 4.90 (s, 2H), [6.81 (m, 1.5H) + 6.88 (s, 1.5H), 3H], [7.24 (s, 0.2H) + 8.24 (s, 0.8H), 1H], 11.05 (brd, 1H), 11.69 (s, 0.75H) + 11.94 (s, 0.25H), 1H]; MS (APCI): 485.5, 486.3. 1 H NMR (DMSO-D 6 ): δ 1.19 (d, 6H), 2.30 (septet, 1H), [3.71 (s) + 3.82 (s), 6H], 4.90 (s, 2H), [6.81 (m , 1.5H) + 6.88 (s, 1.5H), 3H], [7.24 (s, 0.2H) + 8.24 (s, 0.8H), 1H], 11.05 (brd, 1H), 11.69 (s, 0.75H) + 11.94 (s, 0.25 H), 1 H]; MS (APCI): 485.5, 486.3.

실시예 116:Example 116:

1H NMR (DMSO-D6): δ 1.19 (d, 6H), 2.88 (septet, 1H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1H), 11.82 (s, 1H); MS (APCI): 499.8. 1 H NMR (DMSO-D 6 ): δ 1.19 (d, 6H), 2.88 (septet, 1H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1H), 11.82 (s, 1H); MS (APCI): 499.8.

실시예 117:Example 117:

1H NMR (DMSO-D6): δ 1.20 (d, J = 6.9, 6H), 2.89 (sept, J = 6.9, 1H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J = 8.8, 1H), 7.23 (d, J = 8.0, 2H), 7.37 (d, J = 8.0, 2H), 8.04 (dd, J = 2.2, 8.8, 1H), 8.21 (br s, 1H), 8.35 (br s, 1H), 11.78 (s, 1H), 11.89 (br s, 1H); MS (APCI, neg): 472. 1 H NMR (DMSO-D 6 ): δ 1.20 (d, J = 6.9, 6H), 2.89 (sept, J = 6.9, 1H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J = 8.8, 1H), 7.23 (d, J = 8.0, 2H), 7.37 (d, J = 8.0, 2H), 8.04 (dd, J = 2.2, 8.8, 1H) , 8.21 (br s, 1 H), 8.35 (br s, 1 H), 11.78 (s, 1 H), 11.89 (br s, 1 H); MS (APCI, neg): 472.

4-(2-히드록시에틸)-1-나프트알데히드의 아실-히드라존의 제조:Preparation of Acyl-Hydrazone of 4- (2-hydroxyethyl) -1-naphthaldehyde:

화학식 X의 화합물을 합성하기 위한 일반적인 방법:General Methods for Synthesizing Compounds of Formula X:

상기 식에서, b는 1, 2, 3 또는 4이다.Wherein b is 1, 2, 3 or 4.

4-(2-히드록시에틸)-1-나프트알데히드의 제조:Preparation of 4- (2-hydroxyethyl) -1-naphthaldehyde:

1-브로모-4-(2-히드록시에틸)나프트알데히드:1-Bromo-4- (2-hydroxyethyl) naphthaldehyde:

무수 THF(15mL)중 메틸 4-브로모 나프탈렌 아세테이트(2.0g, 7.16mmol)의 용액에 THF(4mL)중 1M 수소화리튬알루미늄을 0℃에서 적가하였다. 혼합물을 실온에서 16시간동안 교반하고, 물(5mL)로 희석하고, 농 염산으로 산성화하고 에틸아세테이트(3x20mL)로 추출하였다. 합한 유기 추출물을 건조(MgSO4)하고, 농축시켜 무색의 오일 1.71g(95%)를 얻었다. 유사한 합성의 참고자료는 A. A. Kiprianov, A. A. Shulezhko. Zh. Org. Khim. 2 (1966), 1852, English translation: J. Org. Chem. (USSR) 2 (1966) 1820]에 기재되어 있다.To a solution of methyl 4-bromo naphthalene acetate (2.0 g, 7.16 mmol) in dry THF (15 mL) was added dropwise 1 M lithium aluminum hydride in THF (4 mL) at 0 ° C. The mixture was stirred at rt for 16 h, diluted with water (5 mL), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated to give 1.71 g (95%) of a colorless oil. References for similar synthesis can be found in AA Kiprianov, AA Shulezhko. Zh. Org. Khim. 2 (1966), 1852, English translation: J. Org. Chem. (USSR) 2 (1966) 1820.

1H NMR (CDCl3) δ = 2.36 (s, 1H), 3.33 (t, J = 6.7 Hz, 2H), 3.99 (t, J = 6.7 Hz, 2H), 7.24 (d, J = 7.3 Hz, 1H), 7.58 - 7.63 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (m, 1H), 8.31 (dd, J = 1.1, 8.0 Hz, 1H). GCMS (pos.) 250, 252. 1 H NMR (CDCl 3 ) δ = 2.36 (s, 1H), 3.33 (t, J = 6.7 Hz, 2H), 3.99 (t, J = 6.7 Hz, 2H), 7.24 (d, J = 7.3 Hz, 1H ), 7.58-7.63 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (m, 1H), 8.31 (dd, J = 1.1, 8.0 Hz, 1H). GCMS (pos.) 250, 252.

1-브로모-4-(2-테트라히드로피란일옥시에틸)나프탈렌:1-bromo-4- (2-tetrahydropyranyloxyethyl) naphthalene:

디클로로메탄(20mL)중 1-브로모-4-(2-히드록시에틸)나프탈렌(1.71g, 6.8mmol)의 용액에 3,4-디히드로-2H-피란(1mL, 0.92g, 11.0mmol) 및 p-톨루엔 술폰산(80mg)을 가하였다. 혼합물을 실온에서 90분간 교반하고 디클로로메탄(20mL)로 희석하고, 포화 NaHCO3의 용액(20mL)로 세척하고, 건조(MgSO4)하고, 농축시켰다. 헥산/에틸아세테이트 9:1을 용리액으로서 사용하는 플래시 크로마토그래피하여 무색의 오일 1.69g(75%)을 얻었다.3,4-dihydro-2H-pyran (1 mL, 0.92 g, 11.0 mmol) in a solution of 1-bromo-4- (2-hydroxyethyl) naphthalene (1.71 g, 6.8 mmol) in dichloromethane (20 mL) And p-toluene sulfonic acid (80 mg) were added. The mixture was stirred at rt for 90 min and diluted with dichloromethane (20 mL), washed with a solution of saturated NaHCO 3 (20 mL), dried (MgSO 4 ) and concentrated. Flash chromatography using hexane / ethyl acetate 9: 1 as the eluent gave 1.69 g (75%) of a colorless oil.

1H NMR (CDCl3) δ = 1.51 -1.60 m (6H), 3.37 (t , J = 7.2 Hz, 2H), 3.39 - 3.47 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 4.08 (dd, J = 2.4, 7.5 Hz, 1H), 4.60 (m, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.56 - 7.61 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 8.09 - 8.12 (m, 1H), 8.29 (dd, J = 2.5, 7.1 Hz, 1H). GCMS (pos), 334, 336. 1 H NMR (CDCl 3 ) δ = 1.51 -1.60 m (6H), 3.37 (t, J = 7.2 Hz, 2H), 3.39-3.47 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 4.08 (dd, J = 2.4, 7.5 Hz, 1H), 4.60 (m, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.56-7.61 (m, 2H), 7.72 (d, J = 7.6 Hz , 1H), 8.09-8.12 (m, 1H), 8.29 (dd, J = 2.5, 7.1 Hz, 1H). GCMS (pos), 334, 336.

1-포르밀-4-(2-테트라히드로피란일옥시에틸)나프탈렌:1-formyl-4- (2-tetrahydropyranyloxyethyl) naphthalene:

무수 THF(15mL)중 1-브로모-4-(2-테트라히드로피란일옥시에틸)나프탈렌의 용액을 질소하에서 -78℃까지 냉각시켰다. n-부틸리튬(헥산중 2.5M 용액, 1.4mL)을 시린지를 통해 가하고, 혼합물을 동일한 온도에서 30분동안 교반하였다. DMF(1.1mL)를 가하고, 혼합물을 실온에 도달할 때까지 두었다. 포화 NH4Cl 용액(10mL)로 희석하고, 에테르(3x10mL)로 추출하고, 건조(MgSO4)하고 농축시켰다. 헥산/에틸아세테이트 5:1을 용리액으로서 사용하는 플래시 크로마토그래피하여 무색의 오일 408mg(54%)을 얻었다.A solution of 1-bromo-4- (2-tetrahydropyranyloxyethyl) naphthalene in anhydrous THF (15 mL) was cooled to -78 ° C under nitrogen. n-butyllithium (2.5M solution in hexane, 1.4 mL) was added via syringe and the mixture was stirred at the same temperature for 30 minutes. DMF (1.1 mL) was added and the mixture was left until room temperature was reached. Diluted with saturated NH 4 Cl solution (10 mL), extracted with ether (3 × 10 mL), dried (MgSO 4 ) and concentrated. Flash chromatography using hexane / ethyl acetate 5: 1 as the eluent gave 408 mg (54%) of a colorless oil.

1H NMR (CDCl3) δ = 1.48 -1.69 m (6H), 3.45 - 3.50 (m, 3H), 3.69 - 3.85 (m, 2H), 4.07 - 4.17 (m, 1H), 4.61 (m, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.62 -7.73 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 8.20 (d, J = 1.0, 8.1 Hz, 1H), 10.36 (s, 1H). GCMS: 284 1 H NMR (CDCl 3 ) δ = 1.48 -1.69 m (6H), 3.45-3.50 (m, 3H), 3.69-3.85 (m, 2H), 4.07-4.17 (m, 1H), 4.61 (m, 1H) , 7.58 (d, J = 7.3 Hz, 1H), 7.62 -7.73 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 8.20 (d, J = 1.0, 8.1 Hz, 1H), 10.36 ( s, 1 H). GCMS: 284

1-포르밀-4-(2-히드록시에틸)나프탈렌:1-formyl-4- (2-hydroxyethyl) naphthalene:

1-포르밀-4-(2-테트라히드로피란일옥시에틸)나프탈렌(400mg, 1.40mmol)을 메탄올(15mL)에 용해시키고, p-톨루엔 술폰산(45mg)을 가하였다. 혼합물을 실온에서 16시간동안 교반하고 농축시켰다. 잔여물을 에틸아세테이트(3x10mL)에 용해시키고, 포화 NaHCO3(20mL)로 세척하고, 건조(MgSO4)하고 농축시켰다. 헥산/에틸아세테이트 3:1을 용리액으로서 사용하는 플래시 크로마토그래피에 의해 정제하여 무색의 오일 182mg(65%)을 얻었다.1-formyl-4- (2-tetrahydropyranyloxyethyl) naphthalene (400 mg, 1.40 mmol) was dissolved in methanol (15 mL) and p-toluene sulfonic acid (45 mg) was added. The mixture was stirred at rt for 16 h and concentrated. The residue was dissolved in ethyl acetate (3 × 10 mL), washed with saturated NaHCO 3 (20 mL), dried (MgSO 4 ) and concentrated. Purification by flash chromatography using hexane / ethyl acetate 3: 1 as the eluent gave 182 mg (65%) of a colorless oil.

1H NMR (CDCl3) δ = 2.09 (s, 1H), 3.40 (t, J = 6.6 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.61- 7.71 (m, 2H), 7.88 (d, J =7.3 Hz, 1H), 8.13 (dd, J = 1.3, 8.0 Hz, 1H), 9.29 (dd, J = 1.3, 8.0 Hz, 1H), 10.28 (s, 1H). GCMS: 200 1 H NMR (CDCl 3 ) δ = 2.09 (s, 1H), 3.40 (t, J = 6.6 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H ), 7.61-7.71 (m, 2H), 7.88 (d, J = 7.3 Hz, 1H), 8.13 (dd, J = 1.3, 8.0 Hz, 1H), 9.29 (dd, J = 1.3, 8.0 Hz, 1H) , 10.28 (s, 1 H). GCMS: 200

하기 화합물은 1-포르밀-4-(2-히드록시에틸)나프탈렌(단계 D로부터)와 4-히드록시벤조산 히드라지드를 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.The following compounds were prepared according to the general method of condensing 1-formyl-4- (2-hydroxyethyl) naphthalene (from Step D) with 4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazones.

실시예 118:Example 118:

1H NMR (DMSO-D6) δ = 3.25 (t, J = 6.5 Hz, 2H), 3.73 (dt, J =J'6.5 Hz, 2H), 4.84 (t, J = 6.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.60 - 7.68 (m, 2H), 7.80 (dd, J = 1.8, 7.4 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 6.7 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H); MS (APCI, pos.): 369.4, 371.2. 1 H NMR (DMSO-D 6 ) δ = 3.25 (t, J = 6.5 Hz, 2H), 3.73 (dt, J = J'6.5 Hz, 2H), 4.84 (t, J = 6.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.60-7.68 (m, 2H), 7.80 (dd, J = 1.8, 7.4 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 6.7 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H) , 10.98 (s, 1 H), 11.76 (s, 1 H); MS (APCI, pos.): 369.4, 371.2.

실시예 119:Example 119:

1H NMR (DMSO-D6) δ = 3.18 (t, J = 7.0 Hz, 1H), 3.25 (t, J = 7.0 Hz, 1H), 3.65 (dd, J = 7.0 Hz, 1H), 3.74 (dd, J = 5.3, 7.0 Hz, 1H), 4.74 (t, J = 5.3 Hz, 0.5H), 4.79 (t, J = 5.3 Hz, 0.5H), 7.04 (d, J = 8.3 Hz, 0.5H), 7.05 (d, J = 8.3 Hz, 0.5H), 7.25 (d, J = 8.3 Hz, 0.5H), 7.28 (d, J = 8.3 Hz, 0.5H), 7.38 (d, J = 7.4 Hz, 0.5H), 7.43 (d, J = 8.4 Hz, 0.5H), 7.47 - 7.57 (m, 1.5H), 7.61-7.72 (m, 1H), 7.82 (d, J = 7.2 Hz, 0.5H), 8.10 (d, J = 8.6 Hz, 0.5H), 8.19 (dd, J = 2.2, 7.2 Hz, 0.5H), 8.45 (d, J = 8.6 Hz, 0.5H), 8.48 (s, 0.5H), 8.85 (s, 0.5H), 8.87 (dd, J = 2.2, 6.5 Hz, 0.5H), 11.00 (s, 0.5H), 11.15 (s, 0.5H), 11.86 (s, 0.5H), 11.92 (s, 0.5H); MS (APCI, pos.): 403.4, 405.2, 406.1. 1 H NMR (DMSO-D6) δ = 3.18 (t, J = 7.0 Hz, 1H), 3.25 (t, J = 7.0 Hz, 1H), 3.65 (dd, J = 7.0 Hz, 1H), 3.74 (dd, J = 5.3, 7.0 Hz, 1H), 4.74 (t, J = 5.3 Hz, 0.5H), 4.79 (t, J = 5.3 Hz, 0.5H), 7.04 (d, J = 8.3 Hz, 0.5H), 7.05 (d, J = 8.3 Hz, 0.5H), 7.25 (d, J = 8.3 Hz, 0.5H), 7.28 (d, J = 8.3 Hz, 0.5H), 7.38 (d, J = 7.4 Hz, 0.5H) , 7.43 (d, J = 8.4 Hz, 0.5H), 7.47-7.57 (m, 1.5H), 7.61-7.72 (m, 1H), 7.82 (d, J = 7.2 Hz, 0.5H), 8.10 (d, J = 8.6 Hz, 0.5H), 8.19 (dd, J = 2.2, 7.2 Hz, 0.5H), 8.45 (d, J = 8.6 Hz, 0.5H), 8.48 (s, 0.5H), 8.85 (s, 0.5 H), 8.87 (dd, J = 2.2, 6.5 Hz, 0.5H), 11.00 (s, 0.5H), 11.15 (s, 0.5H), 11.86 (s, 0.5H), 11.92 (s, 0.5H); MS (APCI, pos.): 403.4, 405.2, 406.1.

4-히드록시메틸나프트알데히드의 아실히드라존의 제조:Preparation of Acylhydrazone of 4-hydroxymethylnaphthaldehyde:

단계 A:Step A:

1,4-나프탈렌디카르복실산(25g, 116mmol)을 무수 THF 600mL중 수소화리튬알루미늄(15g, 395mmol)의 혼합물에 적가하고, 2일동안 환류시켰다. 혼합물을 얼음욕에서 냉각시키고 과량의 LAH를 메틸렌, 얼음조각을 차례로 천천히 가하여 분해시켰다. THF를 진공하에서 제거하고 잔여물을 1N HCl로 산성화시켰다. 생성물을 에틸아세테이트(3x)로 추출하고, 수성 중탄산나트륨(3x), 물, 함수로 세척하고, 황산마그네슘에서 건조시켰다. 용매를 증발시킨 후 1,4-비스히드록시메틸나프탈렌(70%)을 고체로서 얻었고 이것은 추가의 정제없이 이후의 산화단계에서 사용될 수 있다. 이 물질의 일부분을 특성규명의 목적으로 헥산/에틸아세테이트(80/20에서 75/25)를 사용하는 컬럼크로마토그래피로 정제하였다.1,4-naphthalenedicarboxylic acid (25 g, 116 mmol) was added dropwise to a mixture of lithium aluminum hydride (15 g, 395 mmol) in 600 mL of dry THF and refluxed for 2 days. The mixture was cooled in an ice bath and excess LAH was decomposed by the slow addition of methylene and ice cubes in turn. THF was removed in vacuo and the residue acidified with 1N HCl. The product was extracted with ethyl acetate (3x), washed with aqueous sodium bicarbonate (3x), water, brine and dried over magnesium sulfate. After evaporation of the solvent 1,4-bishydroxymethylnaphthalene (70%) was obtained as a solid which can be used in subsequent oxidation steps without further purification. A portion of this material was purified by column chromatography using hexanes / ethyl acetate (80/20 to 75/25) for characterization purposes.

1H NMR (DMSO-D6): δ 5.19 (s, 4H), 7.77 (m, 4H), 8.32 (m, 2H). 1 H NMR (DMSO-D6): δ 5.19 (s, 4H), 7.77 (m, 4H), 8.32 (m, 2H).

단계 B:Step B:

에틸아세테이트(300mL)중 1,4-비스히드록시메틸나프탈렌(12g, 65mmol)의 용액에 2산화망간(28g, 325mmol)을 가하였다. 45분동안 교반한 후, 대부분의 출발물질이 사라졌고 2개의 새로운 스팟(모노알데히드 및 디알데히드)가 TLC상에 나타났다. 상부 스팟은 디알데히드에 해당하였다. 혼합물을 셀라이트의 베드를 통과시켰고 추가의 에틸아세테이트의 부피로 용리시켰다. 용매를 증발시키고 4-히드록시메틸나프트알데히드를 헥산/에틸아세테이트(80/20에서 75/25)를 사용하는 컬럼크로마토그래피로 정제하여 50% 수율을 얻었다.Manganese dioxide (28 g, 325 mmol) was added to a solution of 1,4-bishydroxymethylnaphthalene (12 g, 65 mmol) in ethyl acetate (300 mL). After stirring for 45 minutes, most of the starting material disappeared and two new spots (monoaldehyde and dialdehyde) appeared on the TLC. The upper spot corresponded to dialdehyde. The mixture was passed through a bed of celite and eluted with a further volume of ethyl acetate. The solvent was evaporated and 4-hydroxymethylnaphthaldehyde was purified by column chromatography using hexanes / ethyl acetate (80/20 to 75/25) to give 50% yield.

H NMR (DMSO-D6): δ 5.19 (s, 2H), 5.71 (brd s, 1H), 7.73 (t, 1H), 7.78 (t, 1H), 7.95 (d, 1H), 8.26 (m, 2H), 9.34 (d, 1H), 10.46 (s, 1H).H NMR (DMSO-D6): δ 5.19 (s, 2H), 5.71 (brd s, 1H), 7.73 (t, 1H), 7.78 (t, 1H), 7.95 (d, 1H), 8.26 (m, 2H ), 9.34 (d, 1 H), 10.46 (s, 1 H).

상기 알데히드를 사용한 생성물의 예:Examples of products using such aldehydes:

실시예 120:Example 120:

상기 화합물을 상기 알데히드를 3-시아노-4-히드록시벤조산 히드라지드와 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.The compound was prepared according to the general method of condensing the aldehyde with 3-cyano-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazone.

1H NMR (DMSO-D6): δ 5.02 (s, 2H), 5.44 (s, 1H), 7.14 (d, 1H), 7.69 (m, 3H), 7.91 (d, 1H), 8.10 (d, 1H), 8.14 (d, 1H), 8.27 (s, 1H), 8.87 (d, 1H), 9.06 (s, 1H), 11.84 (brd s, 2H); MS (ACPI): 346.3, 347.2. 1 H NMR (DMSO-D 6 ): δ 5.02 (s, 2H), 5.44 (s, 1H), 7.14 (d, 1H), 7.69 (m, 3H), 7.91 (d, 1H), 8.10 (d, 1H), 8.14 (d, 1H), 8.27 (s, 1H), 8.87 (d, 1H), 9.06 (s, 1H), 11.84 (brd s, 2H); MS (ACPI): 346.3, 347.2.

실시예 121:Example 121:

상기 화합물을 상기 알데히드를 3-클로로-4-히드록시벤조산 히드라지드와 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.The compound was prepared according to the general method of condensing the aldehyde with 3-chloro-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazone.

1H NMR (DMSO-D6): δ 5.02 (s, 2H), 5.43 (t, 1H), 7.10 (d, 1H), 7.66 (m, 3H), 7.80 (d, 1H), 7.90 (d, 1H), 8.02 (s, 1H), 8.15 (d, 1H), 8.87 (d, 1H), 9.08 (s, 1H), 10.98 (s, 1H), 11. 79 (s, 1H); MS (APCI): 355.5 1 H NMR (DMSO-D 6 ): δ 5.02 (s, 2H), 5.43 (t, 1H), 7.10 (d, 1H), 7.66 (m, 3H), 7.80 (d, 1H), 7.90 (d, 1H), 8.02 (s, 1H), 8.15 (d, 1H), 8.87 (d, 1H), 9.08 (s, 1H), 10.98 (s, 1H), 11. 79 (s, 1H); MS (APCI): 355.5

실시예 122:Example 122:

상기 화합물을 상기 알데히드를 3-플루오로-4-히드록시벤조산 히드라지드와 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.The compound was prepared according to the general method of condensing the aldehyde with 3-fluoro-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazone.

1H NMR (DMSO-D6): d4.84 (s, 2H), 6.91 (t, 1H), 7.43-7.53 (m, 4H), 7.62 (d, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8.68 (d, 1H), 8.98 (s, 1H), 11.71 (brd s, 1H); MS (APCI): 339.4, 340.3. 1 H NMR (DMSO-D 6 ): d4.84 (s, 2H), 6.91 (t, 1H), 7.43-7.53 (m, 4H), 7.62 (d, 1H), 7.72 (d, 1H), 7.96 (d, 1 H), 8.68 (d, 1 H), 8.98 (s, 1 H), 11.71 (brd s, 1 H); MS (APCI): 339.4, 340.3.

화학식 II의 화합물은 상기 언급된 프로토콜을 사용하는 병렬적 합성에 의해 조합적 방법으로 제조될 수 있다. 따라서 화학식 II의 수천가지의 화합물은 반자동 또는 완전 자동화될 수 있는 이 조합적 방법에 의해 제조될 수 있다. 이 프로토콜의 자동화는 예컨대 96웰 장치에서 자동화 합성장치를 사용하는 용액상 조합화학을사용하여 수행할 수 있다. 합성의 제 1 단계에서, 알데히드 또는 케톤은 선택된 수의 알데히드 또는 케톤과 선택된 수의 알킬화제를 결합함으로써 반응식 II에 따라서 제조될 수 있다. 제 2 단계에서, 생성된 알데히드/케톤은 선택된 수의 히드라지드와 결합되어 이로서 지정된 수많은 수의 화합물을 단일체로서 생성시킬 수 있다.Compounds of formula (II) can be prepared in a combinatorial manner by parallel synthesis using the above mentioned protocol. Thus thousands of compounds of formula II can be prepared by this combination method which can be semi-automated or fully automated. Automation of this protocol can be performed using, for example, solution phase combinatorial chemistry using an automated synthesizer in a 96 well device. In the first step of the synthesis, the aldehyde or ketone can be prepared according to Scheme II by combining the selected number of aldehydes or ketones with the selected number of alkylating agents. In a second step, the resulting aldehyde / ketone can be combined with a selected number of hydrazides to produce a specified number of compounds as a single entity.

상기 언급한 합성된 화합물은 이 조합방법을 사용하여 제조될 수 있는 화합물의 예이다.The above-mentioned synthesized compounds are examples of compounds that can be prepared using this combination method.

상기 방법을 응용하여, 다음의 화합물이 합성될 수 있다:By applying this method, the following compounds can be synthesized:

더 유도된 화학식 II의 히드라지드를 합성하기 위한 일반적인 방법:General methods for synthesizing more derived hydrazide of formula II:

화학식 I의 화합물은 본 발명의 하나의 구체예, 화학식 II의 알킬리덴 히드라지드에 따라서, 반응식 III에 나타낸 바와 같이, 즉, 알킬리덴 히드라지드(반응식 I 및 더 자세하게 실시예 8에 나타낸 일반적 방법에 따라 제조됨)를 더 유도된 알킬리덴 히드라지드로 변환시킴으로써 제조될 수 있다. 따라서, 아민을 이탈기 XL(반응식 III)을 포함하는 알킬리덴 히드라지드와 반응시킴으로써 화학식 II의 K기에 아민을 포함하는 새로운 알킬리덴 히드라지드를 형성할 수 있다.According to one embodiment of the invention, the alkylidene hydrazide of formula (II), the compound of formula (I), as shown in Scheme III, i.e. alkylidene hydrazide (Scheme I and the general method shown in Example 8 in more detail Prepared according to the present invention). Thus, the amine can be reacted with an alkylidene hydrazide containing leaving group X L (Scheme III) to form a new alkylidene hydrazide comprising an amine in the K group of formula (II).

상기 식에서, A, B, D, n, R4, R3a, a, b 및 d는 화학식 I에서 정의된 바와 같고, R5a는 저급알킬이다. 화학식 II의 더 유도된 히드라지드의 제조를 예시하는 구체적인 실시예가 이하 제공된다:Wherein A, B, D, n, R 4 , R 3a , a, b and d are as defined in formula (I) and R 5a is lower alkyl. Specific examples are provided below illustrating the preparation of further derived hydrazide of Formula II:

실시예 143:Example 143:

3-클로로-4-히드록시벤조산{4-[2-[N'-(2-N,N-디에틸아미노에틸)-N'-(4-트리플루오로메톡시벤질아미노)]]에톡시-1-나프틸메틸렌}히드라지드3-Chloro-4-hydroxybenzoic acid {4- [2- [N '-(2-N, N-diethylaminoethyl) -N'-(4-trifluoromethoxybenzylamino)]] ethoxy- 1-naphthylmethylene} hydrazide

N,N-디에틸-N'-(4-트리플루오로메톡시벤질)에틸렌디아민:N, N-diethyl-N '-(4-trifluoromethoxybenzyl) ethylenediamine:

건조 100mL 둥근바닥 플라스크내 메탄올(10mL)중 (4-트리플루오로메톡시)벤즈알데히드(1.9g, 10mmol), N,N-디에틸에틸렌디아민(1.16g, 10mmol), 염화아연(1.36g, 10mmol) 및 시아노보로히드리드나트륨(1.26g, 20mmol)의 용액을 실온에서 8시간동안 교반하였다. 그런 다음, 물(20mL)을 가하고, 대부분의 메탄올을 진공에서 제거하였다. 잔여물을 에틸아세테이트와 1N HCl사이에 분배하였다. 산성의 수층을 과량의 수산화나트륨으로 염기성화하였다. 미정제 N,N-디에틸-N'-(4-트리플루오로메톡시벤질)에틸렌디아민을 얻었다. 미정제 생성물을 추가의 정제없이 이후의 반응에서 사용하였다.(4-trifluoromethoxy) benzaldehyde (1.9 g, 10 mmol), N, N-diethylethylenediamine (1.16 g, 10 mmol), zinc chloride (1.36 g, 10 mmol) in methanol (10 mL) in a dry 100 mL round bottom flask And a solution of sodium cyanoborohydride (1.26 g, 20 mmol) was stirred at room temperature for 8 hours. Water (20 mL) was then added and most of the methanol was removed in vacuo. The residue was partitioned between ethyl acetate and 1N HCl. The acidic aqueous layer was basified with excess sodium hydroxide. Crude N, N-diethyl-N '-(4-trifluoromethoxybenzyl) ethylenediamine was obtained. The crude product was used in the subsequent reaction without further purification.

MS (CI): 291.1H NMR (CDCl3): δ 7.4 (m, 2H), 7.2 (m, 2H), 3.9 (bs, 2H), 3.1-2.6 (m, 9H), 1.4-1.1 (t, 6H).MS (CI): 291. 1 H NMR (CDCl 3 ): δ 7.4 (m, 2H), 7.2 (m, 2H), 3.9 (bs, 2H), 3.1-2.6 (m, 9H), 1.4-1.1 ( t, 6H).

DMF(5mL)중 N,N-디에틸-N'-(4-트리플루오로메톡시벤질)에틸렌디아민(0.29g, 1mmol)을 함유하는 플라스크에 [1-(4-클로로에톡시)나프틸](3-클로로-4-히드록시)벤조산 히드라지드(0.41g, 1mmol) 및 트리에틸아민(0.1g, 1mmol)을 가하였다. 그 결과의 용액을 80℃에서 하룻밤동안 가열시켰다. 대부분의 용매를 진공에서 제거하고 실리카겔상의 플래시 크로마토그래피(10:1 CHCl3/MeOH)하여 갈색의 고체로서 표제의 화합물을 얻었다.[1- (4-Chloroethoxy) naphthyl] in a flask containing N, N-diethyl-N '-(4-trifluoromethoxybenzyl) ethylenediamine (0.29 g, 1 mmol) in DMF (5 mL). (3-Chloro-4-hydroxy) benzoic acid hydrazide (0.41 g, 1 mmol) and triethylamine (0.1 g, 1 mmol) were added. The resulting solution was heated at 80 ° C. overnight. Most of the solvent was removed in vacuo and flash chromatography on silica gel (10: 1 CHCl 3 / MeOH) gave the title compound as a brown solid.

1HNMR (DMSO-d6): δ 11.7 (1H), 9.0 bs, 2H), 8.4-7.0 (m, 12 H), 4.75 (bs, 1H), 4.65 (bs, 1H), 4.55 (t, 1H), 4.35 (t, 1H), 4.15 (t, 1H), 3.9 (bs, 1H), 3.5 (q, 4H), 3.05 (t, 1H), 1.3 (t, 3H), 0.95 (t, 3H). M.p.: 134-136oC. MS (CI): 657, 659. 1 HNMR (DMSO-d 6 ): δ 11.7 (1H), 9.0 bs, 2H, 8.4-7.0 (m, 12H), 4.75 (bs, 1H), 4.65 (bs, 1H), 4.55 (t, 1H ), 4.35 (t, 1H), 4.15 (t, 1H), 3.9 (bs, 1H), 3.5 (q, 4H), 3.05 (t, 1H), 1.3 (t, 3H), 0.95 (t, 3H) . Mp: 134-136 o C. MS (CI): 657, 659.

실시예 144:Example 144:

3-클로로-4-히드록시벤조산{4-[2-(4-트리플루오로메톡시)벤질아미노에톡시]-1-나프틸메틸렌}히드라지드3-chloro-4-hydroxybenzoic acid {4- [2- (4-trifluoromethoxy) benzylaminoethoxy] -1-naphthylmethylene} hydrazide

DMF(5mL)중 4-트리플루오로메톡시벤질아민(0.29g, 1mmol)을 함유하는 플라스크에 3-클로로-4-히드록시벤조산[4-(2-클로로에톡시)-1-나프틸메틸렌]히드라지드 (0.403g, 1mmol) 및 트리에틸아민(0.1g, 1mmol)을 가하였다. 그 결과의 용액을 80℃에서 16시간동안 가열시켰다. 대부분의 용매를 진공에서 제거하고 실리카겔상의 플래시 크로마토그래피(10:1 CHCl3/MeOH)하여 갈색의 고체로서 표제의 화합물을 얻었다.3-chloro-4-hydroxybenzoic acid [4- (2-chloroethoxy) -1-naphthylmethylene] in a flask containing 4-trifluoromethoxybenzylamine (0.29 g, 1 mmol) in DMF (5 mL). Hydrazide (0.403 g, 1 mmol) and triethylamine (0.1 g, 1 mmol) were added. The resulting solution was heated at 80 ° C. for 16 hours. Most of the solvent was removed in vacuo and flash chromatography on silica gel (10: 1 CHCl 3 / MeOH) gave the title compound as a brown solid.

1HNMR (DMSO-d6): δ 11.6 (s, 1H), 9.0 (m 2H), 8.3 (m 1H), 8.0 (m,1H), 7.8 (s, 2H), 7.7 (m,1H), 7.6 (m, 1H), 7.5 (m, 3H), 7.3 (m, 2H), 7.1 (m, 2H), 4.3 (t, 2H), 3.9 (s, 2H), 3.0 (t, 2H). MS (CI): 557, 559. 1 HNMR (DMSO-d 6 ): δ 11.6 (s, 1H), 9.0 (m 2H), 8.3 (m 1H), 8.0 (m, 1H), 7.8 (s, 2H), 7.7 (m, 1H), 7.6 (m, 1H), 7.5 (m, 3H), 7.3 (m, 2H), 7.1 (m, 2H), 4.3 (t, 2H), 3.9 (s, 2H), 3.0 (t, 2H). MS (CI): 557, 559.

상기 방법을 응용하여 다음의 본 발명의 화합물을 합성하였다:The above method was applied to synthesize the following compounds of the invention:

실시예 145:Example 145:

3-클로로-4-히드록시벤조산{3,5-디메톡시-4-[2-(4-트리플루오로메톡시벤질아민)에톡시]벤질리덴}히드라지드3-chloro-4-hydroxybenzoic acid {3,5-dimethoxy-4- [2- (4-trifluoromethoxybenzylamine) ethoxy] benzylidene} hydrazide

1H NMR (CD3OD): δ 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 1H), 7.10 (s, 2H), 7.20 (d, 2H), 7.43 (d, 2H), 7.65 (m, 1H), 7.82 (m, 1H), 8.11 (brd s, 1H); MS (APCI): 567.9. 1 H NMR (CD 3 OD): δ 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 1H), 7.10 (s , 2H), 7.20 (d, 2H), 7.43 (d, 2H), 7.65 (m, 1H), 7.82 (m, 1H), 8.11 (brd s, 1H); MS (APCI): 567.9.

실시예 146:Example 146:

3-클로로-4-히드록시벤조산{4-[2-(2-피페리딘-1-일-에틸아미노)에톡시]나프트-1-일메틸렌}히드라지드3-Chloro-4-hydroxybenzoic acid {4- [2- (2-piperidin-1-yl-ethylamino) ethoxy] naphth-1-ylmethylene} hydrazide

1H NMR (DMSO-d6): δ 1.53 (m, 2H), 1.74 (m, 4H), 3.12 (m, 2H), 3.40 (m, 2H), 3.54 (m, 2H), 3.63 (m, 4H), 4.52 (s, 2H), 7.10 (d,1H), 7.14 (d, 1H), 7.60 (t, 1H), 7.71 (m,1H), 7.80 (dd, 1H), 7.83 (d, 1H), 8.00 (d,1H), 8.51 (d, 1H), 8.95 (d, 1H), 8.98 (s, 1H), 11.69 (s,1H); MS (APCI): 495.0 1 H NMR (DMSO-d 6 ): δ 1.53 (m, 2H), 1.74 (m, 4H), 3.12 (m, 2H), 3.40 (m, 2H), 3.54 (m, 2H), 3.63 (m, 4H), 4.52 (s, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.60 (t, 1H), 7.71 (m, 1H), 7.80 (dd, 1H), 7.83 (d, 1H ), 8.00 (d, 1H), 8.51 (d, 1H), 8.95 (d, 1H), 8.98 (s, 1H), 11.69 (s, 1H); MS (APCI): 495.0

실시예 147:Example 147:

3-클로로-4-히드록시벤조산{4-[2-(3-디에틸아미노프로필아미노)에톡시]나프트-1-일메틸렌}히드라지드3-chloro-4-hydroxybenzoic acid {4- [2- (3-diethylaminopropylamino) ethoxy] naphth-1-ylmethylene} hydrazide

1H NMR (DMSO-d6): δ 1.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.73 (m, 1H), 7.80 (dd, 1H), 7.84 (d, 1H), 8.00 (d, 1H), 8.46 (d,1H), 8.93 (s,1H), 8.98 (m, 1H), 9.20 (m, 2H), 9.69 (m, 1H), 11.00 (s, 1H), 11.69 (s, 1H); MS (APCI): 497.0. 1 H NMR (DMSO-d 6 ): δ 1.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.73 (m, 1H), 7.80 (dd, 1H), 7.84 (d, 1H), 8.00 (d, 1H), 8.46 (d, 1H), 8.93 (s, 1H ), 8.98 (m, 1H), 9.20 (m, 2H), 9.69 (m, 1H), 11.00 (s, 1H), 11.69 (s, 1H); MS (APCI): 497.0.

실시예 148:Example 148:

1-(2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}에틸)-4-페닐아미노피페리딘-4-카르복실산 아미드1- (2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} ethyl) -4-phenylaminopiperidine-4-carboxylic acid amide

1H NMR (DMSO-d6): δ 1.16 (m, 2 H), 1.88 (m, 2H), 2.03 (m, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 4.37 (m, 2 H), 4.40 (brd s, 2H), 4.44 (s, 1 H), 6.55 - 6.62 (m, 3 H), 6.96 (s,1 H), 7.03-7.16 (m, 5H), 7.61(dd, 1H), 7.68 (dd,1 H), 8.00 (d, 1H), 8.27 (d, 1H), 8.94 (s,1 H), 8.97 (s, 1H), 11.63 (s, 1H); MS (APCI): 586.4 1 H NMR (DMSO-d 6 ): δ 1.16 (m, 2 H), 1.88 (m, 2H), 2.03 (m, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 4.37 (m , 2H), 4.40 (brd s, 2H), 4.44 (s, 1H), 6.55-6.62 (m, 3H), 6.96 (s, 1H), 7.03-7.16 (m, 5H), 7.61 ( dd, 1H), 7.68 (dd, 1H), 8.00 (d, 1H), 8.27 (d, 1H), 8.94 (s, 1H), 8.97 (s, 1H), 11.63 (s, 1H); MS (APCI): 586.4

실시예 149:Example 149:

4-(2-{4-[3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}에틸아미노)피페리딘-1-카르복실산 에틸에스테르4- (2- {4- [3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} ethylamino) piperidine-1-carboxylic acid ethyl ester

1H NMR (DMSO-d6): δ 1,10 (t, 3H), 1.15 - 1.23 (m, 2H), 1.86 (m, 2H), 2.79 (m, 3H), 3.30 (m, 2H), 3.87 (m, 2H), 3.94 (q, 2H), 4.28 (m, 2H), 7.03 (d,1H), 7.05 (m, 1H), 7.51 - 7.63 (m, 3H), 7.13 (d, 1H), 7.75 (m,1 H), 7.93 (d, 1H), 8.29 (d,1 H), 8.87 (m,2 H), 11.55 (s, 1H); MS (APCI): 539.1, 541.0. 1 H NMR (DMSO-d 6 ): δ 1,10 (t, 3H), 1.15-1.23 (m, 2H), 1.86 (m, 2H), 2.79 (m, 3H), 3.30 (m, 2H), 3.87 (m, 2H), 3.94 (q, 2H), 4.28 (m, 2H), 7.03 (d, 1H), 7.05 (m, 1H), 7.51-7.63 (m, 3H), 7.13 (d, 1H) , 7.75 (m, 1H), 7.93 (d, 1H), 8.29 (d, 1H), 8.87 (m, 2H), 11.55 (s, 1H); MS (APCI): 539.1, 541.0.

실시예 150:Example 150:

3-클로로-4-히드록시벤조산{4-[2-(1,2,3,4-테트라히드로나프트-1-일아미노)에톡시]-나프트-1-일메틸렌}히드라지드3-Chloro-4-hydroxybenzoic acid {4- [2- (1,2,3,4-tetrahydronaphth-1-ylamino) ethoxy] -naphth-1-ylmethylene} hydrazide

1H NMR (DMSO-d6): δ 1.76 (m, 1H), 2.04 (m, 1H), 2.17 (m, 2H), 2.75 - 2.94 (m, 2H), 3.61 (m, 2H), 4.55 (m,2H), 4.71(s, 1H), 7.11 (d, 1H), 7.13 (d, 1H), 7.23 - 7.35 (m, 3H), 7.61 (d, 1H), 7.67 (d,1H), 7.71 (dd, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.01(d, 1H), 8.48 (d, 1H), 8.94 (m, 1H), 8.99 (m, 1H), 9.22 (m, 2H), 11.00 (s,1 H), 11.64 (s,1H); MS (APCI): 514.0, 516.0 1 H NMR (DMSO-d 6 ): δ 1.76 (m, 1H), 2.04 (m, 1H), 2.17 (m, 2H), 2.75-2.94 (m, 2H), 3.61 (m, 2H), 4.55 ( m, 2H), 4.71 (s, 1H), 7.11 (d, 1H), 7.13 (d, 1H), 7.23-7.35 (m, 3H), 7.61 (d, 1H), 7.67 (d, 1H), 7.71 (dd, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.01 (d, 1H), 8.48 (d, 1H), 8.94 (m, 1H), 8.99 (m, 1H), 9.22 ( m, 2H), 11.00 (s, 1H), 11.64 (s, 1H); MS (APCI): 514.0, 516.0

실시예 151:Example 151:

1-(2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}에틸)피페리딘-4-카르복실산 아미드1- (2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} ethyl) piperidine-4-carboxylic acid amide

MS(APCl): 495.0MS (APCl): 495.0

실시예 152:Example 152:

3-클로로-4-히드록시벤조산{4-[2-(2-트리플루오로메톡시벤질아미노)-에톡시]-1-나프틸메틸렌}히드라지드3-Chloro-4-hydroxybenzoic acid {4- [2- (2-trifluoromethoxybenzylamino) -ethoxy] -1-naphthylmethylene} hydrazide

실시예 153:Example 153:

3-클로로-4-히드록시벤조산{4-[2-(4-모르폴린일에틸아미노)에톡시]-1-나프틸메틸렌}히드라지드3-chloro-4-hydroxybenzoic acid {4- [2- (4-morpholinylethylamino) ethoxy] -1-naphthylmethylene} hydrazide

상기 방법을 응용하여 다음 화합물을 또한 합성할 수 있다:The method can also be applied to synthesize the following compounds:

실시예 154:Example 154:

본 발명에 따라서 알킬리덴 아릴술포닐 히드라지드의 제조를 위한 일반적인 방법General process for the preparation of alkylidene arylsulfonyl hydrazides according to the invention

화학식 I의 화합물은 본 발명의 하나의 구체예, 즉 화학식 III의 알킬리덴 아릴술포닐 히드라지드에 따라서, 아릴술포닐 할라이드, 예컨대 염화 또는 브롬화를 상응하는 히드라지드 유도체로 변환시키고 생성물 아리술포닐 히드라지드 화합물을 치환 알데히드 또는 케톤과 더 반응시킴으로써 반응식 IV에 예시된 바와 같은 알킬리덴 아릴술포닐 히드라지드 유도체를 얻는다.According to one embodiment of the present invention, i.e., the alkylidene arylsulfonyl hydrazide of formula III, the arylsulfonyl halides such as chloride or bromination are converted into the corresponding hydrazide derivatives and the product arsulfonyl hydra Further reaction of the zide compound with a substituted aldehyde or ketone yields an alkylidene arylsulfonyl hydrazide derivative as illustrated in Scheme IV.

상기 식에서, A, B, K, D, m, n 및 R4는 화학식 I에서 정의된 바와 같다.Wherein A, B, K, D, m, n and R 4 are as defined in formula (I).

아릴술포닐히드라지드 전구체의 합성은 일반적인 방법, 예컨대 Friedman, L.; Litle, R.L; Reichle, W.R. in Org. Synth. Coll. Vol. V, 1973, 1055-1057에 기재된 바와 같이, 그 자체로 또는 테트라히드로푸란, 디메틸에테르, 디옥산 또는 디에틸에테르 등의 불활성 용매를 가한 용액중의 염화아릴술포닐을 그 자체인 또는 상기 용매중 하나 또는 이들의 혼합물을 가한 용매중의 과량의 히드라진에 -20℃ 내지 100℃에서, 바람직하게 0℃ 내지 60℃에서 천천히 가함으로써 수행된다. 반응이 완결된 것으로 판단되면, 과량의 용매와 휘발성 시약을 대기압 또는 진공에서 증류제거한다. 잔여 생성물을 메틸알콜, 에틸알콜, 이소프로필알콜, 물, 톨루엔, 아세트산, 디옥산, 테트라히드로푸란 또는 상기 용매중 상용성인 2이상의 혼합물 등의 용매로부터 재결정시킴으로써 더 정제할 수 있다.Synthesis of arylsulfonylhydrazide precursors can be carried out by conventional methods such as Friedman, L .; Litle, R. L; Reichle, W. R. in Org. Synth. Coll. Vol. As described in V, 1973, 1055-1057, arylsulfonyl chloride in itself or in a solution to which an inert solvent such as tetrahydrofuran, dimethylether, dioxane or diethylether is added One or a mixture of these is carried out by slow addition of excess hydrazine in the solvent added at -20 ° C to 100 ° C, preferably at 0 ° C to 60 ° C. Once the reaction is determined to be complete, excess solvent and volatile reagents are distilled off at atmospheric pressure or vacuum. The residual product can be further purified by recrystallization from a solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, water, toluene, acetic acid, dioxane, tetrahydrofuran or a mixture of two or more compatible in the above solvents.

다른 방법으로, 생성물은 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로서 사용하는 컬럼크로마토그래피에 의해 정제할 수 있다. 해당하는 분획을 대기압 또는 진공에서 농축하여 순수한 아릴술포닐 히드라지드를 얻는다.Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated at atmospheric pressure or in vacuo to give pure arylsulfonyl hydrazide.

상기 방법을 사용하여, 다음의 화합물을 제조할 수 있다:Using this method, the following compounds can be prepared:

실시예 161:Example 161:

3-클로로-4-히드록시벤젠술폰산(벤질리덴)히드라지드3-chloro-4-hydroxybenzenesulfonic acid (benzylidene) hydrazide

3-클로로-4-히드록시벤젠술포닐 히드라지드:3-chloro-4-hydroxybenzenesulfonyl hydrazide:

THF 15mL중 염화 3-클로로-4-히드록시벤젠술포닐 4.82g(21.2mmol)(Popoff, I. C.; Frank, J. R.; Whitaker R. L.; Miller H. J., Demaree K. D. J. Agr. Food Chem. 1969, 17, 810.에 기재된 방법에 따라 제조함)을 50% 히드라진 수화물(54.4mmol, 2.5eq.) 3.4mL에 온도가 10℃ 이하로 유지되도록 교반하면서 적가하였다. 첨가 후 침전의 형성을 완결하였다. 혼합물을 추가의 30분동안 교반하고, 0℃로 냉각시켰다. 고체를 부흐너 깔대기에 수집하고, 증류수로 몇번 세척하고, 공기건조시켰다. 메탄올로부터의 재결정으로 3-클로로-4-히드록시벤젠술포닐 히드라지드 1.20g을 백색 고체로서 얻었다.4.82 g (21.2 mmol) of 3-chloro-4-hydroxybenzenesulfonyl chloride in 15 mL of THF (Popoff, IC; Frank, JR; Whitaker RL; Miller HJ, Demaree KDJ Agr.Food Chem. 1969, 17, 810. Prepared according to the method described) was added dropwise to 3.4 mL of 50% hydrazine hydrate (54.4 mmol, 2.5 eq.) With stirring to keep the temperature below 10 ° C. After addition the formation of precipitate was completed. The mixture was stirred for an additional 30 minutes and cooled to 0 ° C. The solid was collected in a Buchner funnel, washed several times with distilled water and air dried. Recrystallization from methanol gave 1.20 g of 3-chloro-4-hydroxybenzenesulfonyl hydrazide as a white solid.

H NMR (DMSO-d6): δ 4.78 (bs, 4 H), 6.72 (d, J = 8.6 Hz, 1 H), 7.35 (dd, J = 2.3, 8.6 Hz, 1 H), 5.55 ( J = 2.2 Hz, 1 H); MS(CI): m/z 223, 221. H NMR (DMSO-d6): δ 4.78 (bs, 4H), 6.72 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 2.3, 8.6 Hz, 1H), 5.55 (J = 2.2 Hz, 1H); MS (CI): m / z 223, 221.

메탄올 5mL중 상기 3-클로로-4-히드록시벤젠술포닐 히드라지드 105mg(0.48mmol)의 용액에 벤즈알데히드 0.05mL(52mg, 0.49mmol) 및 아세트산 1방울을 가하였다. 30분 후, 혼합물을 농축시켰다. 플래시 크로마토그래피(실리카겔, 헥산/에틸아세테이트 2:1)로 표제의 화합물 67mg(45%)을 고체로서 얻었다.To a solution of 105 mg (0.48 mmol) of 3-chloro-4-hydroxybenzenesulfonyl hydrazide in 5 mL of methanol was added 0.05 mL (52 mg, 0.49 mmol) of benzaldehyde and 1 drop of acetic acid. After 30 minutes, the mixture was concentrated. Flash chromatography (silica gel, hexane / ethyl acetate 2: 1) gave 67 mg (45%) of the title compound as a solid.

1H (DMSO-d6): δ 7.10 (d, J = 8.6 Hz, 1 H), 7.38 (m, 3 H), 7.55 (dd, J = 2.3, 6.0 Hz, 2 H), 7.66 (d, J = 2.2, 8.6 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.90 (s, 1 H), 11.3 (m, 2 H). MS(CI): m/z 311. 1 H (DMSO-d 6 ): δ 7.10 (d, J = 8.6 Hz, 1 H), 7.38 (m, 3 H), 7.55 (dd, J = 2.3, 6.0 Hz, 2 H), 7.66 (d, J = 2.2, 8.6 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.90 (s, 1 H), 11.3 (m, 2 H). MS (CI): m / z 311.

실시예 162Example 162

3-클로로-4-히드록시-벤젠술폰산[4-(4-트리플루오로메톡시벤질옥시)-1-나프틸메틸렌]히드라지드3-Chloro-4-hydroxy-benzenesulfonic acid [4- (4-trifluoromethoxybenzyloxy) -1-naphthylmethylene] hydrazide

메탄올 5ml중 3-클로로-4-히드록시-벤젠술포닐 히드라지드(105mg, 0.48mmol)의 용액에 4-트리플루오로메톡시벤질옥시-1-나트탈알데히드(163mg, 0.49mmol) 및 촉매량의 냉 아세트산(5방울)을 가하였다. 반응혼합물을 하룻밤동안 교반하고, 여과하였다. 여과물을 진공하에서 농축하여 미정제 생성물을 얻었다. 플래시 크로마토그래피(실리카겔, 헥산/에틸아세테이트 1:1)로 표제의 화합물 145mg(56%)을 얻었다.In a solution of 3-chloro-4-hydroxy-benzenesulfonyl hydrazide (105 mg, 0.48 mmol) in 5 ml of methanol, 4-trifluoromethoxybenzyloxy-1-natalaldehyde (163 mg, 0.49 mmol) and a catalytic amount of cold Acetic acid (5 drops) was added. The reaction mixture was stirred overnight and filtered. The filtrate was concentrated in vacuo to afford crude product. Flash chromatography (silica gel, hexane / ethyl acetate 1: 1) gave 145 mg (56%) of the title compound.

1H NMR (DMSO-d6) δ 5.27 (s, 2 H), 6.06 (s, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 2 H), 7.50 - 7.60 (m, 5 H), 7.80 (s, 1 H), 7.85 (dd, J = 3.0, 8.2 Hz, 1 H), 8.08 (d, J = 2.1 Hz, 1 H), 8.26 (s, 1 H), 8.36 (d, J = 7.76 Hz, 1 H), 8.67 (d, J = 8.5 Hz, 1 H). ClMS m/z: 551, 553. 1 H NMR (DMSO-d 6 ) δ 5.27 (s, 2 H), 6.06 (s, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H ), 7.26 (d, J = 7.3 Hz, 2 H), 7.50-7.60 (m, 5 H), 7.80 (s, 1 H), 7.85 (dd, J = 3.0, 8.2 Hz, 1 H), 8.08 ( d, J = 2.1 Hz, 1 H), 8.26 (s, 1 H), 8.36 (d, J = 7.76 Hz, 1 H), 8.67 (d, J = 8.5 Hz, 1 H). ClMS m / z: 551, 553.

상기 방법을 사용하여, 다음 화합물을 제조할 수 있다:Using this method, the following compounds can be prepared:

실시예 163:Example 163:

본 발명에 따라서 알킬히드라지드의 합성:Synthesis of Alkylhydrazides According to the Invention

상기 주어진 알킬리덴 히드라지드를 반응식 V에서 주어진 방법에 의해 디히드로유도체로 환원시킬 수 있다:The alkylidene hydrazide given above can be reduced to the dihydroderivative by the method given in Scheme V:

상기 식에서, A, R4, B, K, D, m 및 n은 화학식 I에서 정의된 바와 같다.Wherein A, R 4 , B, K, D, m and n are as defined in formula (I).

알킬히드라지드 유도체는 상응하는 알킬리덴 히드라지드를 수소화금속, 예컨대 보로히드리드나트륨 또는 시아노보로히드리드나트륨을 사용하여 환원(즉, Lane, C.F.(1975), Synthesis, p135)시킴으로써 제조할 수 있다. 알킬리덴 히드리드 유도체를 메틸알콜, 에틸알콜, 이소프로필알콜, 테트라히드로푸란, 디옥산, 물 또는 상용성인 2 이상의 용매의 혼합물 등의 용매중 시아노보로히드리드나트륨 1-10당량, 바람직하게 1-3당량으로 처리한다. 선택적으로 염산, 트리플루오로아세트산, 아세트산 또는 황산 등의 소량의 산이 촉매로서 사용된다. 반응은 0℃ 내지 60℃, 바람직하게 10℃ 내지 30℃에서 수행한다. 반응을 HPLC 또는 TLC(실리카겔, 용리액으로서 디클로로메탄중 1%메탄올)로 판단하여 완결되었으면, 용매를 제거하고 잔여물을 디클로로메탄 또는 클로로포름중 1% 메탄올을 용리액으로 사용하여 실리카겔상에서 크로마토그래피하였다. 해당하는 분획을 농축시켜 원하는 생성물을 얻었다. 본 발명에 따르는 알킬히드라지드의 제조를 예시하는 구체적인 예는 하기 제공된다.Alkylhydrazide derivatives can be prepared by reducing the corresponding alkylidene hydrazide using metal hydrides such as sodium borohydride or sodium cyanoborohydride (ie Lane, CF (1975), Synthesis, p135). . The alkylidene hydride derivative is 1-10 equivalents of sodium cyanoborohydride in a solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran, dioxane, water or a mixture of two or more solvents which are compatible, preferably 1 Process at -3 equivalents. Optionally a small amount of acid, such as hydrochloric acid, trifluoroacetic acid, acetic acid or sulfuric acid, is used as catalyst. The reaction is carried out at 0 ° C to 60 ° C, preferably 10 ° C to 30 ° C. When the reaction was complete as judged by HPLC or TLC (silica gel, 1% methanol in dichloromethane as eluent), the solvent was removed and the residue was chromatographed on silica gel using 1% methanol in dichloromethane or chloroform as eluent. The corresponding fractions were concentrated to give the desired product. Specific examples illustrating the preparation of alkylhydrazides according to the invention are provided below.

실시예 167:Example 167:

4-히드록시벤조산(1-나프틸메틸)히드라지드4-hydroxybenzoic acid (1-naphthylmethyl) hydrazide

4-히드록시벤조산(1-나프틸메틸렌)히드라지드(100mg, 0.34mmol)을 메탄올 (10ml)에 용해시키고, 시아노보로히드리드(236mg, 4.1mmol)로 처리하고, 이어서 트리플루오로아세트산 2방울로 처리하였다. 반응용액을 실온에서 3시간동안 교반한 후, 용매를 진공에서 증발시켰다. 잔여물을 실리카겔 컬럼에 도입하고, 디클로로메탄/메탄올(99/1)로 용리시켰다. 해당하는 분획을 진공에서 증발시켜 표제의 화합물을 30% 수율로 얻었다. MS(ESI) m/z 293(M+H)*.4-hydroxybenzoic acid (1-naphthylmethylene) hydrazide (100 mg, 0.34 mmol) was dissolved in methanol (10 ml), treated with cyanoborohydride (236 mg, 4.1 mmol), followed by trifluoroacetic acid 2 Treatment with drops After the reaction solution was stirred for 3 hours at room temperature, the solvent was evaporated in vacuo. The residue was introduced into a silica gel column and eluted with dichloromethane / methanol (99/1). The corresponding fractions were evaporated in vacuo to afford the title compound in 30% yield. MS (ESI) m / z 293 (M + H) * .

상기 기재된 바와 같은 동일한 방법을 사용하여 하기 화합물을 제조하였다:The following compounds were prepared using the same method as described above:

실시예 168:Example 168:

3-클로로-4-히드록시벤조산 N-[4-(4-이소프로필벤질옥시)-3,5-디메톡시벤질]히드라지드3-chloro-4-hydroxybenzoic acid N- [4- (4-isopropylbenzyloxy) -3,5-dimethoxybenzyl] hydrazide

1H NMR (DMSO-d6): δ 1.18 (d, 6H), 2.87 (m, 1H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s, 1H), 6.68 (s, 2H), 6.98 (d, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1H), 7.87 (d, 1H), 9.89 (brd s, 1H), 10.80 (s, 1H); MS (APCI): 485.2. 1 H NMR (DMSO-d 6 ): δ 1.18 (d, 6H), 2.87 (m, 1H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s , 1H), 6.68 (s, 2H), 6.98 (d, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1H), 7.87 (d, 1H), 9.89 (brd s , 1H), 10.80 (s, 1H); MS (APCI): 485.2.

더욱이, 하기 화합물을 또한 합성할 수 있다:Moreover, the following compounds can also be synthesized:

화학식 XI의 화합물을 합성하기 위한 일반적인 방법:General Methods for Synthesizing Compounds of Formula (XI):

A 및 B는 화학식 I에서 정의된 바와 같고, -NR5cR5d는(상기 식에서, R5a, R4a, R4b, c, q, d 및 D는 화학식 I에서 정의된 바와 같다)이거나, 친핵기로서 반응할 수 있는 1차 또는 2차 아민을 포함하는 -D의 부분집합으로서 정의된 -D'이다.A and B are as defined in formula I, -NR 5c R 5d is (Wherein R 5a , R 4a , R 4b , c, q, d and D are as defined in formula (I)) or -D comprising a primary or secondary amine capable of reacting as a nucleophilic group -D 'defined as a subset.

단계 A: 반응은 공지되어 있고, 일반적으로 히드록시 벤즈알데히드, 히드록시 나프트알데히드 등을 탄산 리튬, 나트륨, 칼륨 또는 세슘 등의 염기의 존재하에서, 아세톤, 2-메틸-3-펜타논, 테트라히드로푸란, 디옥산, DMSO, DMF, 에틸렌글리콜, 벤젠, 톨루엔 또는 상기 용매의 혼합물 등의 용매중에서 브로모아세트산 에스테르(또는 메틸, 에틸 또는 다른 저급 알킬에스테르)과 함께 교반함으로써 수행될 수 있다. 반응은 0℃ 내지 130℃, 바람직하게는 20℃ 내지 100℃ 사이에서, 가장 바람직하게는 용매의 환류온도에서 또는 그 근처에서 수행한다. 반응은 바람직하게 N2또는 Ar 등의 불활성 분위기하에서 수행한다. TLC 또는 HPLC에 의해 출발 에스테르가 사라진 것으로 반응이 완결되었음이 확인되면, 용매를 대기압 또는 감압하에서 농축시켜 제거할 수 있다. 생성물을 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물, 또는 상기의 2 이상의 혼합물 등의 용매로부터 재결정하여 더 정제할 수 있다. 다른 방법으로, 생성물을 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로서 사용하는 컬럼크로마토그래피에 의해 정제할 수 있다.Step A: The reaction is known and generally hydroxy benzaldehyde, hydroxy naphthaldehyde and the like are prepared in the presence of a base such as lithium carbonate, sodium, potassium or cesium, acetone, 2-methyl-3-pentanone, tetrahydro It may be carried out by stirring with bromoacetic acid esters (or methyl, ethyl or other lower alkyl esters) in a solvent such as furan, dioxane, DMSO, DMF, ethylene glycol, benzene, toluene or a mixture of the above solvents. The reaction is carried out between 0 ° C. and 130 ° C., preferably between 20 ° C. and 100 ° C., most preferably at or near the reflux temperature of the solvent. The reaction is preferably carried out in an inert atmosphere such as N 2 or Ar. If TLC or HPLC confirms that the reaction is complete by disappearance of the starting ester, the solvent can be removed by concentration under atmospheric or reduced pressure. The product may be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water, or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent.

단계 B: 그런 다음, 그 결과의 아세트산에스테르의 유도체를 그 화합물을 저급 알콜(예, 메탄올, 에탄올 또는 이소프로판올), DMF, 디옥산 또는 DMSO 등의 적절한 용매중에 용해시키고, 수산화 리튬, 나트륨 또는 칼륨 등의 수성 염기를 가함는 등의 당업자에게 공지된 방법을 사용하여 비누화한다. 반응은 0℃ 내지 130℃, 바람직하게는 20℃ 내지 100℃의 사이에서 수행한다. TLC 또는 HPLC에 의해 출발 에스테르가 사라진 것으로 반응이 완결되었음이 확인되면, 용매를 대기압 또는 감압하에서 농축시켜 제거할 수 있다. 그런 다음, 생성물은 잔여물을 물 또는 냉수에 붓고, 염산 또는 황산 등의 무기산을 사용하여 혼합물을 산성화시킴으로써 분리시킬 수 있다. 그런 다음, 생성물을 여과하거나 에틸아세테이트, 톨루엔, 디클로로메탄 또는 디에틸에테르 등의 용매를 사용하여 추출하고, 그런 다음 대기압 또는 감압하에서 농축시켜 용매를 제거함으로써 분리시킬 수 있다. 생성물을 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물, 또는 상기의 2 이상의 혼합물 등의 용매로부터 재결정하여 더 정제할 수 있다. 다른 방법으로, 생성물을 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로서 사용하는 컬럼크로마토그래피에 의해 정제할 수 있다.Step B: The resulting derivatives of the acetate esters are then dissolved in a suitable solvent such as lower alcohols (e.g. methanol, ethanol or isopropanol), DMF, dioxane or DMSO, lithium hydroxide, sodium or potassium, etc. The addition of an aqueous base is saponified using methods known to those skilled in the art. The reaction is carried out between 0 ° C and 130 ° C, preferably between 20 ° C and 100 ° C. If TLC or HPLC confirms that the reaction is complete by disappearance of the starting ester, the solvent can be removed by concentration under atmospheric or reduced pressure. The product can then be separated by pouring the residue into water or cold water and acidifying the mixture with an inorganic acid such as hydrochloric acid or sulfuric acid. The product can then be separated by filtration or extracted using a solvent such as ethyl acetate, toluene, dichloromethane or diethyl ether, and then concentrated to remove the solvent by atmospheric or reduced pressure. The product may be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water, or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent.

단계 C: 그 결과의 카르보닐 화합물을 용매중 아실히드라지드로 처리한다. 용매는 다음중 하나일 수 있다: 에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, 아세트산, 물, 또는 상기 용매중 상용성인 2이상의 혼합물. 아세트산 등의 촉매가 가해질 수 있다. 트리에틸오르토포르메이트 등의 탈수화제가 반응혼합물에 가해질 수 있다. 반응은 0℃ 내지 140℃, 바람직하게 10℃ 내지 80℃ 사이의 온도에서, N2또는 Ar의 불활성 분위기하에서 반응혼합물을 교반함으로써 수행된다. 많은 경우, 생성물은 반응이 완결되면 간단히 결정석출되고 흡입여과에 의해 분리된다. 필요하다면 상기 기재된 반응 용매 등의 용매로부터 더 재결정될 수 있다. 생성물은 또한 반응혼합물을 진공에서 농축시키고, 클로로포름/메탄올 또는 디클로로메탄/메탄올 또는 클로로포름/에틸아세테이트 등의 용매계를 사용하는 실리카겔상의 컬럼크로마토그래피에 의해 분리할 수 있다.Step C: The resulting carbonyl compound is treated with acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, Water or a mixture of two or more compatible in the solvent. Catalysts such as acetic acid can be added. Dehydrating agents such as triethylorthoformate can be added to the reaction mixture. The reaction is carried out by stirring the reaction mixture at a temperature between 0 ° C. and 140 ° C., preferably between 10 ° C. and 80 ° C., under an inert atmosphere of N 2 or Ar. In many cases, the product simply crystallizes upon completion of the reaction and is separated by suction filtration. If necessary, it may be further recrystallized from a solvent such as the reaction solvent described above. The product may also be concentrated by vacuum and separated by column chromatography on silica gel using a solvent system such as chloroform / methanol or dichloromethane / methanol or chloroform / ethyl acetate.

단계 D: 그런 다음, 그 결과의 산을 당업자에게 공지된 방법중 하나를 사용하여 1차 또는 2차 아민에 결합시킨다. 이 결합은 활성 에스테르, 수소화물 또는 산 할라이드를 생성시킨 후, 이것을 아민과 반응시켜 화학식 XI의 화합물을 얻는 등의 표준 아미드 또는 펩티드 합성방법중 하나를 사용하여 수행될 수 있다. 단계 D는 또한 선택된 수의 아민과 조합적으로 수행될 수 있다. 그런 다음, 생성물은 여과하거나 에틸아세테이트, 톨루엔, 디클로로메탄 또는 디에틸에테르 등의 용매를 사용하여 추출한 후 용매를 대기압 또는 감압하에서 농축시켜 제거함으로써 분리할 수있다. 생성물은 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물 또는 상기중 2이상의 혼합물 등의 용매로부터 재결정하여 더 정제할 수 있다. 다른 방법으로 생성물을 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로 사용하여 컬럼크로마토그래피함으로써 정제하여 화학식 XI의 화합물을 얻을 수 있다.Step D: The resulting acid is then bound to the primary or secondary amine using one of the methods known to those skilled in the art. This linkage can be carried out using one of the standard amide or peptide synthesis methods, such as generating an active ester, hydride or acid halide and then reacting it with an amine to give a compound of formula (XI). Step D can also be carried out in combination with a selected number of amines. The product can then be separated by filtration or extracted using a solvent such as ethyl acetate, toluene, dichloromethane or diethyl ether and then the solvent is removed by concentration under atmospheric or reduced pressure. The product may be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of them. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent to afford the compound of formula XI.

본 발명에 따라서 화학식 XI의 화합물의 제조를 예시하는 구체적 예를 하기 제공한다.Specific examples illustrating the preparation of compounds of formula (XI) according to the invention are provided below.

실시예 174:Example 174:

2-{4-[(3-클로로-4-히드록시-벤조일)히드라조노메틸]나프틸-1-일옥시}-N-(4-클로로페닐)아세트아미드2- {4-[(3-chloro-4-hydroxy-benzoyl) hydrazonomethyl] naphthyl-1-yloxy} -N- (4-chlorophenyl) acetamide

단계 A: 히드록시나프트알데히드(10g, 58mmol), 탄산칼륨(16g, 110mmol), 및 메틸브로모아세테이트(16g, 100mmol)을 아세톤(120mL)중에서 하룻밤동안 환류시켰다. 반응혼합물을 약 500mL의 얼음조각을 포함하는 엘렌메이어 플라스크에 부었다. 혼합물을 얼음의 전부가 녹을 때까지 교반하였다 (4-포르밀나프트-1-일옥시)아세트산 메틸에스테르(13g, 50mmol)를 여과하고 하룻밤동안 건조시켰다.Step A: Hydroxynaphthaldehyde (10 g, 58 mmol), potassium carbonate (16 g, 110 mmol), and methylbromoacetate (16 g, 100 mmol) were refluxed in acetone (120 mL) overnight. The reaction mixture was poured into an Ellenmeyer flask containing about 500 mL of ice cubes. The mixture was stirred until all of the ice was dissolved (4-formylnaphth-1-yloxy) acetic acid methylester (13 g, 50 mmol) was filtered and dried overnight.

1H NMR (CDCl3): δ 3.86 (s, 3H), 4.93 (s, 2H), 6.80 (d, 1H), 7.61 (t, 1H), 7.72 (t, 1H), 7.90 (d, 1H), 8.42 (d, 1H), 9.29 (d, 1H), 10.22 (s, 1H). 1 H NMR (CDCl 3 ): δ 3.86 (s, 3H), 4.93 (s, 2H), 6.80 (d, 1H), 7.61 (t, 1H), 7.72 (t, 1H), 7.90 (d, 1H) , 8.42 (d, 1 H), 9.29 (d, 1 H), 10.22 (s, 1 H).

단계 B: 상기 에스테르(13g, 50mmol)을 메탄올(100mL)에 용해시키고 2M NaOH(40mL)를 가하였다. 반응용액을 하룻밤동안 교반하고 진공에서 약 100mL로 농축시켰다. 잔여물을 얼음조각 약 500mL에 붓고 혼합물을 3N HCl을 가하여 산성화시켰다(pH 페이퍼로). 혼합물을 얼음의 전부가 녹을 때까지 교반하였다. (4-포르밀나프트-1-일옥시)아세트산을 여과하고 물로 세척하였다.Step B: The ester (13 g, 50 mmol) was dissolved in methanol (100 mL) and 2M NaOH (40 mL) was added. The reaction solution was stirred overnight and concentrated to about 100 mL in vacuo. The residue was poured into about 500 mL of ice cubes and the mixture acidified (with pH paper) by addition of 3N HCl. The mixture was stirred until all of the ice melted. (4-formylnaphth-1-yloxy) acetic acid was filtered off and washed with water.

단계 C: DMSO(20mL)중 3-클로로-4-히드록시벤조산 히드라지드(2g, 10.7mmol)의 용액에 상기 (4-포르밀나프트-1-일옥시)아세트산(3g, 13mmol) 및 촉매량의 아세트산(10방울)을 가하였다. 용액을 하룻밤동안 교반하고 에틸아세테이트로 희석시켰다. 용액을 물(3x), 함수로 세척하고, MgSO4에서 건조시켰다. 부비를 약 100mL로 감소시키고 얼음욕에 놓았다. 그 결과의 고체를 여과하고 냉 에틸아세테이트로 세척하여 {4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}아세트산을 얻었다.Step C: To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2 g, 10.7 mmol) in DMSO (20 mL) of (4-formylnaphth-1-yloxy) acetic acid (3 g, 13 mmol) and catalytic amount Acetic acid (10 drops) was added. The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water (3 ×), brine and dried over MgSO 4 . Bovine was reduced to about 100 mL and placed in an ice bath. The resulting solid was filtered and washed with cold ethyl acetate to obtain {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} acetic acid.

1H NMR (DMSO-d6): δ 4.91 (s, 2H), 6.95 (d, 1H), 7.02 (d, 1H), 7.55 (t, 1H), 7.64 (t, 1H), 7.74 (d, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 8.90 (m, 2H), 10.92 (brd s, 1H), 11.63 (s, 1H), 13.14 (brd s, 1H). 1 H NMR (DMSO-d 6 ): δ 4.91 (s, 2H), 6.95 (d, 1H), 7.02 (d, 1H), 7.55 (t, 1H), 7.64 (t, 1H), 7.74 (d, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 8.90 (m, 2H), 10.92 (brd s, 1H), 11.63 (s, 1H), 13.14 (brd s, 1H).

단계 D: 무수 DMSO중 히드라존카르복실산(50mmol)의 용액에 무수 DMSO중 카르보닐디이미다졸(55mmol)의 용액을 가하였다. 가스분출이 끝난 후(약 3-4분) 후, 아민을 가하고 반응혼합물을 3시간동안 교반하였다. 혼합물을 에틸아세테이트로 희석하고, 물, 함수로 세척하고 황산마그네슘으로 건조시켰다. 용매를 증발시켜 미정제 물질을 얻고 이것을 역상 HPLC 크로마토그래피로 정제하여 표제의 화합물을 얻었다.Step D: To a solution of hydrazonecarboxylic acid (50 mmol) in anhydrous DMSO was added a solution of carbonyldiimidazole (55 mmol) in anhydrous DMSO. After the end of gas evolution (about 3-4 minutes), amine was added and the reaction mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, brine and dried over magnesium sulfate. The solvent was evaporated to afford crude material which was purified by reverse phase HPLC chromatography to give the title compound.

1H NMR (DMSO-d6): δ 4.99 (s, 2H), 7.04 (m, 2H), 7.36 (d, 2H), 7.65 (m, 4H), 7.79 (t, 2H), 7.99 (s, 1H), 8.40 (d, 1H), 8.72 (s, 1H), 8.92 (d, 1H), 10.42 (s, 1H), 10.96 (s, 1H), 11.69 (s, 1H); MS (APCI): 507.9. 1 H NMR (DMSO-d 6 ): δ 4.99 (s, 2H), 7.04 (m, 2H), 7.36 (d, 2H), 7.65 (m, 4H), 7.79 (t, 2H), 7.99 (s, 1H), 8.40 (d, 1H), 8.72 (s, 1H), 8.92 (d, 1H), 10.42 (s, 1H), 10.96 (s, 1H), 11.69 (s, 1H); MS (APCI): 507.9.

동일한 방법을 사용하여, 다음 화합물을 제조하였다:Using the same method, the following compounds were prepared:

실시예 175:Example 175:

N-(1-벤질피롤리딘-3-일)-2-{4-[(3-클로로-4-히드록시-벤조일)히드라조노메틸]나프트-1-일옥시}아세트아미드N- (1-benzylpyrrolidin-3-yl) -2- {4-[(3-chloro-4-hydroxy-benzoyl) hydrazonomethyl] naphth-1-yloxy} acetamide

1H NMR (DMSO-d6): δ 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1H), 6.92 (d, 1H), 7.15 (m, 5H), 7.47 (t, 1H), 7.52 (t, 1H), 7.62 (d, 2H), 7.82 (d, 1H), 8.18 (m, 2H), 8.78 (d, 2H), 10.75 (brd s, 1H), 11.52 (s, 1H); MS (APCI): 556.9. 1 H NMR (DMSO-d 6 ): δ 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1H), 6.92 (d, 1H), 7.15 (m, 5H), 7.47 (t, 1H), 7.52 (t, 1H), 7.62 (d, 2H), 7.82 (d, 1H), 8.18 (m, 2H), 8.78 (d, 2H), 10.75 (brd s, 1H), 11.52 (s, 1 H); MS (APCI): 556.9.

실시예 176:Example 176:

2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}-N-인단-1-일-아세트아미드2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} -N-indan-1-yl-acetamide

1H NMR (DMSO-d6): δ 1.94 (m, 1H), 2.40 (m, 1H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1H), 7.10 (d, 1H), 7.21 (m, 4H), 7.61 (t, 1H), 7.69 (t, 1H), 7.80 (t, 2H), 8.10 (s, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 8.98 (m, 2H), 11.00 (brd s, 1H), 11.68 (s, 1H); MS (APCI): 514, 516. 1 H NMR (DMSO-d 6 ): δ 1.94 (m, 1H), 2.40 (m, 1H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1H), 7.10 ( d, 1H), 7.21 (m, 4H), 7.61 (t, 1H), 7.69 (t, 1H), 7.80 (t, 2H), 8.10 (s, 1H), 8.42 (d, 1H), 8.64 (d , 1H), 8.98 (m, 2H), 11.00 (brd s, 1H), 11.68 (s, 1H); MS (APCI): 514, 516.

실시예 177:Example 177:

2-{4-[(3-클로로-4-히드록시벤질)히드라조노메틸]나프트-1-일옥시}-N-인단-1-일-아세트아미드2- {4-[(3-chloro-4-hydroxybenzyl) hydrazonomethyl] naphth-1-yloxy} -N-indan-1-yl-acetamide

1H NMR (DMSO-d6): δ 1.75(m, 2H), 1.92(m, 2H), 2.74(m, 2H), 4.87(m, 2H), 5.12(m, 1H), 7.12(m, 6H), 7.61(t, 1H), 7.74(t, 1H), 7.84(m, 2H), 8.01(s, 1H), 8.40(d, 1H), 8.62(d, 1H), 8.97(m, 2H), 11.72(s, 1H); MS(APCI): 528,530. 1 H NMR (DMSO-d 6 ): δ 1.75 (m, 2H), 1.92 (m, 2H), 2.74 (m, 2H), 4.87 (m, 2H), 5.12 (m, 1H), 7.12 (m, 6H), 7.61 (t, 1H), 7.74 (t, 1H), 7.84 (m, 2H), 8.01 (s, 1H), 8.40 (d, 1H), 8.62 (d, 1H), 8.97 (m, 2H ), 11.72 (s, 1 H); MS (APCI): 528,530.

실시예 178:Example 178:

2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}-N-[2-(4-클로로페닐)에틸]아세트아미드2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} -N- [2- (4-chlorophenyl) ethyl] acetamide

1H NMR (DMSO-d6): δ 2.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1H), 7.10 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.72 (m, 2H), 7.81 (s, 1H), 8.01 (m, 2H), 8.23 (t, 1H), 8.40 (d, 1H), 8.95 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.70 (s, 1H); MS (APCI) 538.8, 537.8. 1 H NMR (DMSO-d 6 ): δ 2.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1H), 7.10 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.72 (m, 2H), 7.81 (s, 1H), 8.01 (m, 2H), 8.23 (t, 1H), 8.40 (d, 1H), 8.95 (s, 1H ), 9.01 (d, 1 H), 10.98 (brd s, 1 H), 11.70 (s, 1 H); MS (APCI) 538.8, 537.8.

실시예 179:Example 179:

2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}-N-[3-(4-메틸피페라진-1-일)프로필]아세트아미드2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} -N- [3- (4-methylpiperazin-1-yl) propyl] acetamide

1H NMR (DMSO-d6): δ 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1H), 6.89 (d, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 7.5 (t, 2H), 7.76 (d, 1H), 8.01 (t, 1H), 8.22 (d, 1H), 8.68 (d, 1H), 8.74 (s, 1H), 10.74 (brd s, 1H), 11.45 (s, 1H); MS (APCI): 538.0. 1 H NMR (DMSO-d 6 ): δ 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1H), 6.89 (d, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 7.5 (t, 2H), 7.76 (d, 1H), 8.01 (t, 1H), 8.22 (d, 1H ), 8.68 (d, 1 H), 8.74 (s, 1 H), 10.74 (brd s, 1 H), 11.45 (s, 1 H); MS (APCI): 538.0.

실시예 180:Example 180:

3-클로로-4-히드록시벤조산{4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)-2-옥소에톡시]나프트-1-일메틸렌}히드라지드3-Chloro-4-hydroxybenzoic acid {4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) -2-oxoethoxy] naphth-1-ylmethylene} hydrazide

1H NMR (DMSO-d6): δ 2.90 (d, 2H), 2.75 (m, 2H), 4.70 (d, 2H), 5.24 (s, 2H), 6.90 (t, 2H), 7.10 (m, 4H), 7.66 (m, 4H), 8.01 (s, 1H), 8.34 (t, 1H), 8.95 (m, 2H), 10.97 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 514.2. 1 H NMR (DMSO-d 6 ): δ 2.90 (d, 2H), 2.75 (m, 2H), 4.70 (d, 2H), 5.24 (s, 2H), 6.90 (t, 2H), 7.10 (m, 4H), 7.66 (m, 4H), 8.01 (s, 1H), 8.34 (t, 1H), 8.95 (m, 2H), 10.97 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 514.2.

실시예 181:Example 181:

2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}-N-(3-트리플루오로메톡시벤질)아세트아미드2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} -N- (3-trifluoromethoxybenzyl) acetamide

1H NMR (DMSO-d6): δ 4.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1H), 7.68 (dd, 1H), 7.78 (m, 2H), 8.03 (s, 1H), 8.51 (d, 1H), 8.79 (t, 1H), 9.0 (m, 2H), 10.85 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 572.1. 1 H NMR (DMSO-d 6 ): δ 4.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1H), 7.68 (dd, 1H), 7.78 (m, 2H), 8.03 (s, 1H), 8.51 (d, 1H), 8.79 (t, 1H), 9.0 (m, 2H), 10.85 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 572.1.

실시예 182:Example 182:

3-클로로-4-히드록시벤조산(4-{2-[4-(4-브로모페닐)-4-히드록시피페리딘-1-일]-2-옥소에톡시}나프트-1-일메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4- {2- [4- (4-bromophenyl) -4-hydroxypiperidin-1-yl] -2-oxoethoxy} naphth-1- Ilmethylene) hydrazide

MS(APCl): 636,638MS (APCl): 636,638

실시예 183:Example 183:

2-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트-1-일옥시}-N-(4-트리플루오로메틸술파닐벤질)아세트아미드2- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphth-1-yloxy} -N- (4-trifluoromethylsulfanylbenzyl) acetamide

1H NMR (DMSO-d6): δ 4.48 (d, 2H), 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H), 7.82 (m, 2H), 8.01 (d, 1H), 8.52 (d, 1H), 8.87 (t, 1H), 8.96 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 588.2 1 H NMR (DMSO-d 6 ): δ 4.48 (d, 2H), 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H), 7.82 (m, 2H), 8.01 (d, 1H), 8.52 (d, 1H), 8.87 (t, 1H), 8.96 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 588.2

실시예 184:Example 184:

2-{4-[(3-클로로-4-히드록시-벤조일)히드라조노메틸]나프트-1-일옥시}-N-(3,4-디클로로벤질)아세트아미드2- {4-[(3-chloro-4-hydroxy-benzoyl) hydrazonomethyl] naphth-1-yloxy} -N- (3,4-dichlorobenzyl) acetamide

1H NMR (DMSO-d6): δ 4.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1H), 7.11 (d, 1H), 7.22 (d, 1H), 7.48 - 7.76 (m, 4H), 7.82 (d, 2H), 8.04 (d, 1H), 8.51 (dd, 1H), 8.83 (m, 1H), 8.91 (s, 1H), 10.02 (d, 1H), 11.00 (brd s, 1H), 11.73 (s, 1H); MS (APCI): 556.0 1 H NMR (DMSO-d 6 ): δ 4.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1H), 7.11 (d, 1H), 7.22 (d, 1H), 7.48-7.76 ( m, 4H), 7.82 (d, 2H), 8.04 (d, 1H), 8.51 (dd, 1H), 8.83 (m, 1H), 8.91 (s, 1H), 10.02 (d, 1H), 11.00 (brd s, 1 H), 11.73 (s, 1 H); MS (APCI): 556.0

실시예 185:Example 185:

1H NMR (DMSO-D6): δ 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, 1H), 7.08 (d, 1H), 7.60 (t, 1H), 7.68 (t, 1H), 7.80 (d, 2H), 8.01 (d, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.68 (s, 1H); MS (APCI, neg.): 507.1, 509.1. 1 H NMR (DMSO-D 6 ): δ 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, 1H), 7.08 (d, 1H), 7.60 (t, 1H), 7.68 (t, 1H), 7.80 (d, 2H), 8.01 (d, 1H), 8.33 (d, 1H ), 8.94 (s, 1 H), 9.00 (d, 1 H), 11.68 (s, 1 H); MS (APCI, neg.): 507.1, 509.1.

실시예 186:Example 186:

1H NMR (DMSO-D6): δ 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1H), 3.26 (m, 2H), [2.84 (s, 1.5H) + 3.04 (s, 1.5H), 3H], 5.16 (d, 2H), 6.72 (t, 1H), 7.07 (d, 1H), 7.62 (t, 1H), 7.68 (t, 1H), 7.78 (dd, 2H), 8.00 (d, 1H), 8.34 (m, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.65 (brd s, 1H); MS (APCI): 495.2, 497.2. 1 H NMR (DMSO-D 6 ): δ 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1H), 3.26 (m, 2H), [2.84 (s , 1.5H) + 3.04 (s, 1.5H), 3H], 5.16 (d, 2H), 6.72 (t, 1H), 7.07 (d, 1H), 7.62 (t, 1H), 7.68 (t, 1H) , 7.78 (dd, 2H), 8.00 (d, 1H), 8.34 (m, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.65 (brd s, 1H); MS (APCI): 495.2, 497.2.

실시예 187:Example 187:

1H NMR (DMSO-D6): δ 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1H), 2.72 (m, 1H), 3.09 (t, 1H), 3.84 (t, 1H), 4.18 (t, 1H), 5.09 (m, 2H), 7.03 (d, 1H), 7.11 (d, 1H), 7.59 (t, 1H), 7.64 (t, 1H), 7.82 (d, 2H), 8.01 (s, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.0 (brd, 1H), 11.69 (brd s, 1H); MS (APCI): 480.1, 482.1. 1 H NMR (DMSO-D 6 ): δ 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1H), 2.72 (m, 1H), 3.09 (t, 1H), 3.84 (t, 1H), 4.18 (t, 1H), 5.09 (m, 2H), 7.03 (d, 1H), 7.11 (d, 1H), 7.59 (t, 1H), 7.64 (t, 1H), 7.82 (d, 2H ), 8.01 (s, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.0 (brd, 1H), 11.69 (brd s, 1H); MS (APCI): 480.1, 482.1.

실시예 188:Example 188:

1H NMR (DMSO-D6): δ 2.88 (s, 1.5H) + (s, 1.5H), 3H], 2.95 (t, 1H), 3.01 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (t, 1H), 3.69 (t, 1H), 3.81 (t, 1H), 5.05 (d, 2H), [6.66 + 6.95 (d), 1H], 7.10 (d, 1H), [7.20 + 7.38 (d), 1H], 7.29 (d, 1H), 7.67 (m, 5H), 8.01 (s, 1H), 8.30 (t, 1H), 8.53 (dd, 1H), 8.97 (m, 2H), 11.67 (brd s, 1H); MS (APCI): 517.3, 519.2. 1 H NMR (DMSO-D 6 ): δ 2.88 (s, 1.5H) + (s, 1.5H), 3H], 2.95 (t, 1H), 3.01 (s, 1.5H), 3.10 (s, 1.5H ), 3.10 (t, 1H), 3.69 (t, 1H), 3.81 (t, 1H), 5.05 (d, 2H), [6.66 + 6.95 (d), 1H], 7.10 (d, 1H), [7.20 + 7.38 (d), 1H], 7.29 (d, 1H), 7.67 (m, 5H), 8.01 (s, 1H), 8.30 (t, 1H), 8.53 (dd, 1H), 8.97 (m, 2H) , 11.67 (brd s, 1 H); MS (APCI): 517.3, 519.2.

실시예 189:Example 189:

1H NMR (DMSO-D6): δ 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1H), 7.08 (m, 3H), 7.34 (dd, 1H), 7.74 (dd, 1H), 7.79 (d, 1H), 7.95 (s, 1H), 8.37 (s, 1H), 9.74 (s, 1H), 10.03 (m, 1H), 10.96 (brd s, 1H), 11.76 (brd s, 1H); MS (APCI): 534.4, 536.2. 1 H NMR (DMSO-D 6 ): δ 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1H), 7.08 (m, 3H), 7.34 (dd, 1H), 7.74 (dd, 1H), 7.79 (d, 1H), 7.95 (s, 1H), 8.37 (s, 1H), 9.74 (s, 1H), 10.03 (m, 1H), 10.96 (brd s, 1H), 11.76 (brd s , 1H); MS (APCI): 534.4, 536.2.

실시예 190:Example 190:

1H NMR (DMSO-D6): δ 1.18 (d, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1H), 6.78 (d, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.82 (d, 1H), 7.99 (d, 1H), 8.70 (s, 1H), 10.04 (s, 1H), 10.92 (brδ s, 1H), 11.62 (brd s, 1H); MS (APCI): 496.5, 498.2. 1 H NMR (DMSO-D 6 ): δ 1.18 (d, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1H), 6.78 (d, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.82 (d, 1H), 7.99 (d, 1H), 8.70 (s, 1H ), 10.04 (s, 1 H), 10.92 (brδ s, 1 H), 11.62 (brd s, 1 H); MS (APCI): 496.5, 498.2.

실시예 191:Example 191:

1H NMR (DMSO-D6): δ 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47 - 7.70 (m, 6H), 7.86 (d, 1H), 8.30 (d, 1H), 8.80 (s, 1H), 8.87 (d, 1H), 10.34 (s, 1H), 10.82 (brd s, 1H), 11.55 (brd s, 1H); MS (APCI): 558.5, 560.0. 1 H NMR (DMSO-D 6 ): δ 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47-7.70 (m, 6H), 7.86 (d, 1H), 8.30 ( d, 1H), 8.80 (s, 1H), 8.87 (d, 1H), 10.34 (s, 1H), 10.82 (brd s, 1H), 11.55 (brd s, 1H); MS (APCI): 558.5, 560.0.

실시예 192:Example 192:

1H NMR (DMSO-D6): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1H), 6.89 (s, 1H), 7.19 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 523.3, 524.8, 526.6. 1 H NMR (DMSO-D 6 ): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1H), 6.89 (s, 1H), 7.19 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 523.3, 524.8, 526.6.

실시예 193:Example 193:

1H NMR (DMSO-D6): δ 1.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1H), 7.09 (d, 1H), 7.46 (s, 5H), 7.59 (m, 1H), 7.66 (t, 1H), 7.77 (d, 1H), 7.98 (d, 1H), 8.34 (d, 1H), 8.41 (d, 1H), 8.92 (m, 2H), 9.65 (brd s, 1H), 11.02 (brd s, 1H), 11.80 (brd s, 1H); MS (APCI): 571.3, 572.3, 573.3. 1 H NMR (DMSO-D 6 ): δ 1.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1H), 7.09 (d, 1H), 7.46 (s, 5H), 7.59 (m, 1H), 7.66 (t, 1H), 7.77 (d, 1H ), 7.98 (d, 1H), 8.34 (d, 1H), 8.41 (d, 1H), 8.92 (m, 2H), 9.65 (brd s, 1H), 11.02 (brd s, 1H), 11.80 (brd s , 1H); MS (APCI): 571.3, 572.3, 573.3.

실시예 194:Example 194:

1H NMR (DMSO-D6): δ 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1H), 7.26 - 7.30 (m, 3H), 7.61 (t, 1H), 7.67 (t, 1H), 7.76 (m, 2H), 7.99 (d, 1H), 8.24 (t, 1H), 8.38 (d, 1H), 8.91 (s, 1H), 8.98 (d, 1H), 10.94 (s, 1H), 11.67 (s, 1H); MS (APCI): 536.3, 538.2, 539.1. 1 H NMR (DMSO-D 6 ): δ 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1H), 7.26-7.30 (m, 3H), 7.61 (t, 1H), 7.67 (t, 1H), 7.76 (m, 2H), 7.99 (d, 1H), 8.24 (t, 1H), 8.38 (d , 1H), 8.91 (s, 1H), 8.98 (d, 1H), 10.94 (s, 1H), 11.67 (s, 1H); MS (APCI): 536.3, 538.2, 539.1.

실시예 195:Example 195:

1H NMR (DMSO-D6): δ 4.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1H), 7.63 (m, 1H), 7.80 (t, 1H), 7.99 (d, 1H), 8.49 (d, 1H), 8.79 (t, 1HJ), 8.93 (s, 1H), 8.98 (d, 1H), 10.95 (s, 1H), 11.68 (s, 1H); MS (APCI): 558.2, 560.1. 1 H NMR (DMSO-D 6 ): δ 4.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1H), 7.63 (m, 1H), 7.80 (t, 1H), 7.99 (d, 1H), 8.49 (d, 1H), 8.79 (t, 1HJ), 8.93 (s, 1H), 8.98 (d, 1H), 10.95 (s, 1H ), 11.68 (s, 1 H); MS (APCI): 558.2, 560.1.

실시예 196:Example 196:

4-(4-브로모페닐-3,4-디히드로피페라딘일아세트아미드옥시)나프트-1-일 메틸렌-3-클로로-4-히드록시벤조산 히드라존4- (4-Bromophenyl-3,4-dihydropiperazinylacetamideoxy) naphth-1-yl methylene-3-chloro-4-hydroxybenzoic acid hydrazone

(반응식)(Scheme)

4-(4-브로모페닐)-4-피페리디놀 클로로아세트아미드(단계 A):4- (4-Bromophenyl) -4-piperidinol chloroacetamide (step A):

DMF(30mL)중 4-(4-브로모페닐)-4-피페리디놀(5g, 19.5mmol) 및 디이소프로필에틸아민(2.8g, 21.5mmol)의 용액에 염화클로로아세틸(2.2g, 21.5mmol)을 적가하였다. 그 혼합물을 1시간동안 교반한 후, 혼합물을 에틸아세테이트로 희석하고 수성 중탄산나트륨(2x), 1N HCl(3x), 물, 함수로 세척하고 MgSO4로 건조시켰다. 용액을 농축시키고 에틸아세테이트로 실리카겔상에서 크로마토그래피하여 갈색의 고체로서 생성물(4g, 62%)을 얻었다.Chloroacetyl chloride (2.2 g, 21.5) in a solution of 4- (4-bromophenyl) -4-piperidinol (5 g, 19.5 mmol) and diisopropylethylamine (2.8 g, 21.5 mmol) in DMF (30 mL). mmol) was added dropwise. After stirring the mixture for 1 hour, the mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate (2x), 1N HCl (3x), water, brine and dried over MgSO 4 . The solution was concentrated and chromatographed on silica gel with ethyl acetate to give the product (4 g, 62%) as a brown solid.

1H NMR (DMSO-D6): δ 1.21 (d, 2H), 1.71 (t. 1H), 1.96 (t, 1H), 2.71 (t, 1H), 3.37 (t, 1H), 3.70 (d, 1H), 4.27 (d, 1H), 4.54 (s, 2H), 5.26 (s, 1H), 7.42 (d, 2H), 7.51 (d, 2H). 1 H NMR (DMSO-D 6 ): δ 1.21 (d, 2H), 1.71 (t. 1H), 1.96 (t, 1H), 2.71 (t, 1H), 3.37 (t, 1H), 3.70 (d, 1H), 4.27 (d, 1H), 4.54 (s, 2H), 5.26 (s, 1H), 7.42 (d, 2H), 7.51 (d, 2H).

4-(4-브로모페닐)-3,4-디히드로피페리딘 클로로아세트아미드(단계 B):4- (4-Bromophenyl) -3,4-dihydropiperidine chloroacetamide (step B):

얼음욕에 냉각시킨 THF(40mL)중 4-(4-브로모페닐)-4-피페리디놀 클로로아세트아미드(4g, 12mmol)과 디이소프로필에틸아민(4.6mL, 26mmol)의 용액에 염화메탄술포닐(2mL, 26mmol)을 가하고 그 혼합물을 질소분위기에서 16시간동안 환류시켰다. 반응혼합물을 에틸아세테이트로 희석하고 1N HCl(2x), 수성 NaHCO3(2x), 함수(2x)로 세척하고 MgSO4에서 건조시켰다. 용매를 증발시키고 생성물을 에틸아세테이트/헥산(4/6)으로 실리카겔상에서 크로마토그래피하였다. 생성물(1.5g, 32%)을 황색의 고체로서 얻었다.Methane chloride in a solution of 4- (4-bromophenyl) -4-piperidinol chloroacetamide (4 g, 12 mmol) and diisopropylethylamine (4.6 mL, 26 mmol) in THF (40 mL) cooled in an ice bath. Sulfonyl (2 mL, 26 mmol) was added and the mixture was refluxed for 16 h in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with 1N HCl (2x), aqueous NaHCO 3 (2x), brine (2x) and dried over MgSO 4 . The solvent was evaporated and the product was chromatographed on silica gel with ethyl acetate / hexanes (4/6). Product (1.5 g, 32%) was obtained as a yellow solid.

1H NMR (DMSO-D6): δ 2.44 (t, 2H), 3.62 (m, 2H), 4.14 (dd, 2H), 4.42 (d, 2H), 6.21 (s, 1H), 7.36 (m, 2H), 7.51 (d, 2H). 1 H NMR (DMSO-D 6 ): δ 2.44 (t, 2H), 3.62 (m, 2H), 4.14 (dd, 2H), 4.42 (d, 2H), 6.21 (s, 1H), 7.36 (m, 2H), 7.51 (d, 2H).

4-(4-브로모페닐-3,4-디히드로피페라딘일아세트아미드옥시)나프트알데히드(단계 C):4- (4-Bromophenyl-3,4-dihydropiperazinylacetamideoxy) naphthaldehyde (step C):

아세토니트릴(50mL)중 4-(4-브로모페닐)-3,4-디히드로피페리딘 클로로아세트아미드(1.5g, 4.8mmol), 4-히드록시나프트알데히드(1.2g, 7mmol), 및 파우더 탄산칼슘(1g, 7.2mmol)의 혼합물을 16시간동안 환류시켰다. 그 혼합물을 에틸아세테이트로 희석하고 함수(3x)로 세척하고, MgSO4로 건조시키고 농축시켰다. 에틸아세테이트/헥산(1/1)으로 실리카겔 크로마토그래피하여 생성물(1.4g, 6.5%)을 얻었다.4- (4-bromophenyl) -3,4-dihydropiperidine chloroacetamide (1.5 g, 4.8 mmol), 4-hydroxynaphthaldehyde (1.2 g, 7 mmol) in acetonitrile (50 mL), And a mixture of powdered calcium carbonate (1 g, 7.2 mmol) were refluxed for 16 hours. The mixture was diluted with ethyl acetate and washed with brine (3 ×), dried over MgSO 4 and concentrated. Silica gel chromatography with ethyl acetate / hexane (1/1) gave the product (1.4 g, 6.5%).

1H NMR (DMSO-D6): δ 2.27-2.32 (m, 2H), 3.49-3.55 (m, 2H), 3.94 (brd s, 1H), 4.06 (brd s, 1H), 5.08 (s, 1H), 5.13 (s, 1H), 6.05 (s, 1H), 6.97 (t, 1H), 7.20 (t, 1H), 7.34 (d, 2H), 7.42-7.47 (m, 1H), 7.52-7.57 (m, 1H), 7.92 (d, 1H), 8.16 (d, 1H), 9.01 (d, 1H), 9.97 (s, 1H). 1 H NMR (DMSO-D 6 ): δ 2.27-2.32 (m, 2H), 3.49-3.55 (m, 2H), 3.94 (brd s, 1H), 4.06 (brd s, 1H), 5.08 (s, 1H ), 5.13 (s, 1H), 6.05 (s, 1H), 6.97 (t, 1H), 7.20 (t, 1H), 7.34 (d, 2H), 7.42-7.47 (m, 1H), 7.52-7.57 ( m, 1H), 7.92 (d, 1H), 8.16 (d, 1H), 9.01 (d, 1H), 9.97 (s, 1H).

4-(4-브로모페닐-3,4-디히드로피페라딘일아세트아미드옥시)나프트-1-일 메틸렌-3-클로로-4-히드록시벤조산 히드라존(단계 D):4- (4-Bromophenyl-3,4-dihydropiperazinylacetamideoxy) naphth-1-yl methylene-3-chloro-4-hydroxybenzoic acid hydrazone (step D):

표제의 화합물을 3-클로로-4-히드록시벤조산 히드라지드와 4-(4-브로모페닐-3,4-디히드로피페라딘일아세트아미드옥시)나프트알데히드를 축합시켜 알킬리덴 히드라지드를 합성하는 일반적인 방법에 따라서 제조하였다.The title compound was condensed with 3-chloro-4-hydroxybenzoic acid hydrazide and 4- (4-bromophenyl-3,4-dihydropiperazinylacetamideoxy) naphthaldehyde to synthesize alkylidene hydrazide It was prepared according to the general method.

1H NMR (DMSO-D6): δ 2.47-2.58 (m, 2H), 3.72 (br s, 2H), 4.13 (s, 1H), 4.26 (s, 1H), 5.14 (s, 1H), 5.18 (s, 1H), 6.23 (s, 1H), 6.50-6.53 (m, 1H), 7.03-7.06 (m, 1H), 7.35-7.38 (m, 2H), 7.52 (d, 2H), 7.58 (d, 2H), 7.59-7.67 (m, 1H), 7.75 (d, 1H), 7.84 (s, 1H), 8.32 (d, 1H), 8.89 (s, 1H), 8.92 (s, 1H), 11.41 (s, 1H); MS (APCI): 618.1, 620.1, 621.1, 622.1 1 H NMR (DMSO-D 6 ): δ 2.47-2.58 (m, 2H), 3.72 (br s, 2H), 4.13 (s, 1H), 4.26 (s, 1H), 5.14 (s, 1H), 5.18 (s, 1H), 6.23 (s, 1H), 6.50-6.53 (m, 1H), 7.03-7.06 (m, 1H), 7.35-7.38 (m, 2H), 7.52 (d, 2H), 7.58 (d , 2H), 7.59-7.67 (m, 1H), 7.75 (d, 1H), 7.84 (s, 1H), 8.32 (d, 1H), 8.89 (s, 1H), 8.92 (s, 1H), 11.41 ( s, 1 H); MS (APCI): 618.1, 620.1, 621.1, 622.1

화학식 XII의 화합물을 합성하기 위한 일반적인 방법:General Methods for Synthesizing Compounds of Formula XII:

A 및 B는 화학식 I에서 정의된 바와 같고 -NR5cR5d는(상기 식에서, R5a, R4a, R4b, c, q, d 및 D는 화학식 I에서 정의된 바와 같다)이거나, 친핵기로서 반응할 수 있는 1차 또는 2차 아민을 포함하는 -D의 부분집합으로서 정의된 -D'이다.A and B are as defined in formula (I) and -NR 5c R 5d is (Wherein R 5a , R 4a , R 4b , c, q, d and D are as defined in formula (I)) or -D comprising a primary or secondary amine capable of reacting as a nucleophilic group -D 'defined as a subset.

단계 A: 카르보닐 화합물을 용매중에서 아실히드라지드와 반응시킨다. 용매는 다음중 하나가 될 수 있다: 에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, 아세트산, 물 또는 상기 용매중 상용성인 2 이상의 혼합물. 아세트산 등의 촉매가 가해질 수 있다. 트리에틸오르토포르메이트 등의 탈수화제가 또한 반응혼합물에 가해질 수 있다. 반응은 0℃ 내지 140℃, 바람직하게 10℃ 내지 80℃ 사이의 온도에서, 바람직하게 N2또는 Ar의 불활성 분위기하에서 반응혼합물을 교반함으로써 수행된다. 많은 경우, 생성물은 반응이 완결되면 간단히 결정석출되고 흡입여과에 의해 분리된다. 필요하다면 상기 기재된 반응 용매 등의 용매로부터 더 재결정될 수 있다. 생성물은 또한 반응혼합물을 진공에서 농축시키고, 이어서 클로로포름/메탄올 또는 디클로로메탄/메탄올 또는 클로로포름/에틸아세테이트 등의 용매계를 사용하는 실리카겔상의 컬럼크로마토그래피로 분리할 수 있다.Step A: The carbonyl compound is reacted with acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid Two or more mixtures which are compatible in water or in said solvent. Catalysts such as acetic acid can be added. Dehydrating agents such as triethylorthoformate may also be added to the reaction mixture. The reaction is carried out by stirring the reaction mixture at a temperature between 0 ° C. and 140 ° C., preferably between 10 ° C. and 80 ° C., preferably under an inert atmosphere of N 2 or Ar. In many cases, the product simply crystallizes upon completion of the reaction and is separated by suction filtration. If necessary, it may be further recrystallized from a solvent such as the reaction solvent described above. The product can also be concentrated in vacuo and then separated by column chromatography on silica gel using a solvent system such as chloroform / methanol or dichloromethane / methanol or chloroform / ethylacetate.

단계 B: 그런 다음, 그 결과의 산을 당업자에게 공지된 방법중 하나를 사용하여 1차 또는 2차 아민에 결합시킨다. 이 결합은 활성 에스테르, 수소화물 또는 산 할라이드를 생성시킨 후, 이것을 아민과 반응시켜 화학식 XII의 화합물을 얻는 등의 표준 아미드 또는 펩티드 합성방법중 하나를 사용하여 수행될 수 있다. 단계 B는 또한 예비활성화 산 및 아민의 선택으로 조합적으로 수행되었다. 그런 다음, 생성물은 여과하거나 에틸아세테이트, 톨루엔, 디클로로메탄 또는 디에틸에테르 등의 용매를 사용하여 추출한 후 용매를 대기압 또는 감압하에서 농축시켜 제거함으로써 분리할 수 있다. 생성물은 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물 또는 상기중 2 이상의 혼합물 등의 용매로부터 재결정하여 더 정제할 수 있다. 다른 방법으로, 생성물을 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로 사용하여 컬럼크로마토그래피함으로써 정제하여 화학식 XII의 화합물을 얻을 수 있다.Step B: The resulting acid is then bound to the primary or secondary amine using one of the methods known to those skilled in the art. This linkage can be carried out using one of the standard amide or peptide synthesis methods, such as the production of active esters, hydrides or acid halides, followed by reaction with amines to give compounds of formula (XII). Step B was also performed in combination with the selection of preactivated acids and amines. The product can then be separated by filtration or extracted using a solvent such as ethyl acetate, toluene, dichloromethane or diethyl ether and then the solvent is removed by concentration under atmospheric or reduced pressure. The product can be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of them. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent to afford the compound of formula XII.

본 발명에 따라서 화학식 XII의 화합물의 제조를 예시하는 구체적인 실시예를 하기 제공한다.Specific examples illustrating the preparation of compounds of formula (XII) in accordance with the invention are provided below.

4-포르밀-1-나프트아세트산의 제조:Preparation of 4-formyl-1-naphthacetic acid:

이 화합물은 문헌, 즉 1) A.A. Shulezhko and A.I. Kiprianov, J. org. Chem., (USSR) English translation, 4, 1968, p.1052. 2) Zh. Org. Khim., 4, 1968, p. 1089.에 기재된 바와 같이 85% 포름산과 Raney 합금의 존재하에서 4-시아노-1-나프틸아세트산을 환원시켜서 제조하였다.This compound is described in literature, ie 1) A.A. Shulezhko and A.I. Kiprianov, J. org. Chem., (USSR) English translation, 4, 1968, p. 1052. 2) Zh. Org. Khim., 4, 1968, p. Prepared by reducing 4-cyano-1-naphthylacetic acid in the presence of 85% formic acid and Raney alloy as described in 1089.

4-[3-클로로-4-히드록시벤조일)-히드라조노메틸]-1-나프틸아세트산(단계 A)의 제조:Preparation of 4- [3-chloro-4-hydroxybenzoyl) -hydrazonomethyl] -1-naphthylacetic acid (step A):

이 화합물은 상기 4-포르밀-1-나프틸아세트산과 3-클로로-4-히드록시벤조산 히드라지드를 축합시켜 알킬리덴 히드라지드를 합성하는 일반적인 방법에 따라서 제조하였다.This compound was prepared according to the general method of condensing the 4-formyl-1-naphthylacetic acid and 3-chloro-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazide.

1H NMR (DMSO-D6): δ 4.1 (s, 2H), 7.1 (d, 1H), 7.5 (d, 1H), 7.7 (qt, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 8.1 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (brd s, 1H), 11.8 (s, 1H), 12.2 (brd s, 1H); MS (APCI): 383.4, 385.2. 1 H NMR (DMSO-D 6 ): δ 4.1 (s, 2H), 7.1 (d, 1H), 7.5 (d, 1H), 7.7 (qt, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 8.1 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (brd s, 1H), 11.8 (s, 1H), 12.2 (brd s , 1H); MS (APCI): 383.4, 385.2.

(3-포르밀인돌일)아세트산의 제조:Preparation of (3-formylindolyl) acetic acid:

에틸 (3-포르밀인돌일)아세테이트:Ethyl (3-formylindolyl) acetate:

3-포르밀인돌(10.0g, 69mmol)을 DMF(100mL)중에 용해시켰다. N2하에서 미네랄오일(3.0g)중 60% NaH 현탁액을 냉각(온도<15℃)시키면서 조금씩 가하였다. 15℃ 미만에서, DMF(15mL)중 에틸브로모아세테이트의 용액을 30분동안 적가하였다. 그 결과의 혼합물을 실온에서 16시간동안 교반하고 진공에서 증발시켰다. 그 잔여물을 물(300mL)에 가하고 에틸아세테이트(2x150mL)로 추출하고, 합한 유기 추출물을 포화 NH4Cl로 세척하고 MgSO4로 건조시키고 농축시켜 에틸(3-포르밀인돌일)아세테이트 15.9g을 얻었다.3-formylindole (10.0 g, 69 mmol) was dissolved in DMF (100 mL). A 60% NaH suspension in mineral oil (3.0 g) under N 2 was added little by little while cooling (temperature <15 ° C.). Below 15 ° C., a solution of ethylbromoacetate in DMF (15 mL) was added dropwise over 30 minutes. The resulting mixture was stirred at rt for 16 h and evaporated in vacuo. The residue was added to water (300 mL) and extracted with ethyl acetate (2x150 mL), the combined organic extracts were washed with saturated NH 4 Cl, dried over MgSO 4 and concentrated to give 15.9 g of ethyl (3-formylindolyl) acetate. Got it.

1H NMR ( CDCl3) δ 1.26 (t, 3H), 4.22 (q, 2H), 4.90 (s, 2H), 7.21 - 7.35 (m, 3H), 7.72 (s, 1H), 8.30 (d, 1H), 10.0 (s, 1H). 1 H NMR (CDCl 3 ) δ 1.26 (t, 3H), 4.22 (q, 2H), 4.90 (s, 2H), 7.21-7.35 (m, 3H), 7.72 (s, 1H), 8.30 (d, 1H ), 10.0 (s, 1 H).

(3-포르밀인돌일)아세트산:(3-formylindolyl) acetic acid:

에틸 (3-포르밀인돌일)아세테이트(15.9g)를 1,4-디옥산(100mL)에 용해시키고 36% 수성 NaOH(10mL)를 가하였다. 그 결과의 혼합물을 실온에서 4일동안 교반하였다. 물(500mL)을 가하고 혼합물을 디에틸에테르(150mL)로 세척하였다. 수상을 5N HCl로 산성화하고 에틸아세테이트(250+150mL)로 추출하였다. 합한 유기 추출물을 건조(MgSO4)로 건조시키고 진공에서 증발시켜 (3-포르밀인돌일)아세트산 10.3g(두 단계후 73%)을 얻었다.Ethyl (3-formylindolyl) acetate (15.9 g) was dissolved in 1,4-dioxane (100 mL) and 36% aqueous NaOH (10 mL) was added. The resulting mixture was stirred at rt for 4 days. Water (500 mL) was added and the mixture was washed with diethyl ether (150 mL). The aqueous phase was acidified with 5N HCl and extracted with ethyl acetate (250 + 150 mL). The combined organic extracts were dried (MgSO 4 ) and evaporated in vacuo to give 10.3 g (73% after two steps) of (3-formylindolyl) acetic acid.

1H NMR ( DMSO-d6) δ 4.94 (s, 2H), 7.27 - 7.36 (m, 3H), 7.98 (s, 1H), 8.25 (d, 1H), 10.0 (s, 1H), 12.5 (bs, 1H). 1 H NMR (DMSO-d 6 ) δ 4.94 (s, 2H), 7.27-7.36 (m, 3H), 7.98 (s, 1H), 8.25 (d, 1H), 10.0 (s, 1H), 12.5 (bs , 1H).

(4-포르밀인돌일)아세트산의 제조:Preparation of (4-formylindolyl) acetic acid:

4-포르밀인돌:4-formyl indole:

이 화합물을 F. Yamada, M. Somei, Heterocycles 26 (1987) 1173.에 따라서 합성하였다.This compound was synthesized according to F. Yamada, M. Somei, Heterocycles 26 (1987) 1173.

1H NMR ( CDCl3) δ 7.28 - 7.36 (m, 2H), 7.41 (t, J = 3.0 Hz, 1H), 7.60 - 7.70 (m, 2H), 8.62 (brd s, 1H), 10.20 (s, 1H). GC-MS (pos.): 146 1 H NMR (CDCl 3 ) δ 7.28-7.36 (m, 2H), 7.41 (t, J = 3.0 Hz, 1H), 7.60-7.70 (m, 2H), 8.62 (brd s, 1H), 10.20 (s, 1H). GC-MS (pos.): 146

에틸 (4-포르밀인돌일)아세테이트:Ethyl (4-formylindolyl) acetate:

이 화합물을 인돌의 N-알킬화의 일반적인 방법에 따라서 합성하였다.This compound was synthesized according to the general method of N-alkylation of indole.

1H NMR (CDCl3) δ 1.13 (t, J = 6.9 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.22 - 7.35 (m, 3H), 7.49 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 10.20 (s, 1H). 1 H NMR (CDCl 3 ) δ 1.13 (t, J = 6.9 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.22-7.35 (m, 3H), 7.49 ( d, J = 8.6 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 10.20 (s, 1H).

(4-포르밀인돌일)아세트산:(4-formylindolyl) acetic acid:

이 화합물을 에스테르의 비누화의 일반적인 방법에 따라서 합성하였다.This compound was synthesized according to the general method of saponification of esters.

1H NMR ( DMSO-d6) δ 5.15 (s, 2H), 7.12 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 10.20 (s, 1H), 12.94 (brd s, 1H). 1 H NMR (DMSO-d 6 ) δ 5.15 (s, 2H), 7.12 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 10.20 (s, 1H), 12.94 (brd s, 1H).

(5-포르밀인돌일)아세트산의 제조Preparation of (5-formyl indolyl) acetic acid

5-시아노-N-토실인돌:5-cyano-N-tosylindole:

100mL 둥근바닥 플라스크에 미네랄 오일(10mmol)중에 분산시킨 NaH(0.4g, 60%)를 넣고 무수 THF(10mL)를 가하였다. 현탁액에 무수 THF(10mL)중 5-시아노인돌(1.0g, 7mmol)의 용액을 시린지를 통해 0℃에서 가하였다. 혼합물을 10분동안 교반하고 염화토실(1.6g, 8.4mmol)을 가하였다. 실온에서 2시간동안 교반한 후, 물(100mL)을 가하였다. 혼합물을 에틸아세테이트(3x50mL)로 추출하고 건조(MgSO4)시키고 농축시켰다. 그 잔여물을 헥산:에틸아세테이드=2:1을 용리액으로 사용하는 컬럼크로마토그래피로 정제하여 원하는 화합물 1.86g(92%)을 얻었다.Into a 100 mL round bottom flask was added NaH (0.4 g, 60%) dispersed in mineral oil (10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in dry THF (10 mL) at 0 ° C. via syringe. The mixture was stirred for 10 minutes and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 hours, water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 50 mL), dried (MgSO 4 ) and concentrated. The residue was purified by column chromatography using hexane: ethyl acetate = 2: 1 as the eluent to afford 1.86 g (92%) of the desired compound.

1H NMR ( CDCl3) δ 2.32 (s, 3H), 6.65 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H ), 7.41 (d, J = 8.6 Hz, 1H), 7.57 (d, J = 3.6 Hz, 1H), 7.63 (s, 1H), 7.75 ( d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H). 1 H NMR (CDCl 3 ) δ 2.32 (s, 3H), 6.65 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 8.6 Hz, 1H) , 7.57 (d, J = 3.6 Hz, 1H), 7.63 (s, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H).

5-포르밀-N-토실인돌:5-formyl-N-tosylindole:

무수 THF(20mL)중 5-시아노-N-토실인돌(0.66g, 2.2mmol)의 용액에 헥산(1.4mL, 4mmol)중 1M DIBAL을 시린지를 통해 0℃에서 가하였다. 그 혼합물을 실온에서 16시간동안 교반하고, 얼음냉각된 1N 염산(50mL)에 붓고, 에틸아세테이트(3x80mL)로 추출하였다. 합한 유기 추출물을 건조(MgSO4)시키고 농축시켜 오일을 얻었다. 헥산/에틸아세테이트 2:1을 용리액으로 사용한 쇼트 컬럼크로마토그래피후 순수한 5-포르밀-N-토실인돌을 얻었다.To a solution of 5-cyano-N-tosylindole (0.66 g, 2.2 mmol) in dry THF (20 mL) was added 1 M DIBAL in hexane (1.4 mL, 4 mmol) at 0 ° C. via syringe. The mixture was stirred at rt for 16 h, poured into ice-cold 1N hydrochloric acid (50 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated to give an oil. Pure 5-formyl-N-tosylindole was obtained after short column chromatography using hexane / ethyl acetate 2: 1 as eluent.

1H NMR (CDCl3) δ 2.29 (s, 3H), 6.74 (d, J = 3.7 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 3.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.4, 8.6 Hz, 1H), 8.02 (d, J = 1.1 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H ), 9.99 (s, 1H). 1 H NMR (CDCl 3 ) δ 2.29 (s, 3H), 6.74 (d, J = 3.7 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 3.7 Hz, 1H) , 7.77 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.4, 8.6 Hz, 1H), 8.02 (d, J = 1.1 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H) , 9.99 (s, 1 H).

5-포르밀인돌:5-formylindole:

5-포르밀-N-토실인돌(0.5g, 1.7mmol)을 5% 수성 KOH 용액(5mL)을 함유하는 메탄올(10mL)의 혼합물에 용해시켰다. 혼합물을 3시간동안 환류시키고 1N 염산으로 중성화하고, 에틸아세테이트(3x50mL)로 추출하였다. 합한 유기 추출물을 건조(MgSO4)시키고 농축시켰다. 그 잔여물을 쇼트 컬럼크로마토그래피로 정제하여 원하는 생성물 240mg(97%)을 얻었다.5-formyl-N-tosylindole (0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) containing 5% aqueous KOH solution (5 mL). The mixture was refluxed for 3 hours, neutralized with 1N hydrochloric acid and extracted with ethyl acetate (3x50 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated. The residue was purified by short column chromatography to give 240 mg (97%) of the desired product.

1H NMR (CDCl3) δ 6.70 (t, J = 2.1 Hz, 1H), 7.32 (t, J = 2.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.78 ( dd, J = 1.5, 8.6 Hz, 1H), 8.19 (s, 1H), 9.45 (b, 1H), 10.15 (s, 1H). GC-MS (pos.): 146. 1 H NMR (CDCl 3 ) δ 6.70 (t, J = 2.1 Hz, 1H), 7.32 (t, J = 2.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 1.5, 8.6 Hz, 1H), 8.19 (s, 1H), 9.45 (b, 1H), 10.15 (s, 1H). GC-MS (pos.): 146.

에틸 (5-포르밀인돌일)아세테이트:Ethyl (5-formylindolyl) acetate:

이 화합물을 인돌의 N-알킬화의 일반적인 방법에 따라서 합성하였다.This compound was synthesized according to the general method of N-alkylation of indole.

1H NMR (CDCl3) δ 1.27 (t, J = 6.8 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 6.70 (d, J = 3.4 Hz, 1H), 7.18 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.14 (s, 1H), 10.01 (s, 1H). 1 H NMR (CDCl 3 ) δ 1.27 (t, J = 6.8 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 6.70 (d, J = 3.4 Hz, 1H) , 7.18 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.14 (s, 1H), 10.01 (s, 1H) .

(5-포르밀인돌일)아세트산:(5-formylindolyl) acetic acid:

이 화합물을 에스테르의 비누화의 일반적인 방법에 따라 합성하였다.This compound was synthesized according to the general method of saponification of esters.

1H NMR (DMSO-d6) δ 5.10 (s, 2H), 6.66 (d, J = 3.0 Hz, 1H), 7.48 (d, J = 3.0 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 9.97 (s, 1H), 12.9 (brd s, 1H). 1 H NMR (DMSO-d 6 ) δ 5.10 (s, 2H), 6.66 (d, J = 3.0 Hz, 1H), 7.48 (d, J = 3.0 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 9.97 (s, 1H), 12.9 (brd s, 1H).

[(3-클로로-4-히드록시벤조일)히드라조노메틸]인돌일 아세트산 제조의 일반적인 방법:General method for preparing [(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] indolyl acetic acid:

이들 화합물은 여러가지 포르밀인돌일아세트산을 3-클로로-4-히드록시벤조산 히드라지드와 축합하여 알킬리덴 히드라존을 합성하기 위한 일반적인 방법에 따라서 제조하였다.These compounds were prepared according to the general method for condensing various formyl indolyl acetic acid with 3-chloro-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazone.

3-[(3-클로로-4-히드록시벤조일)히드라조노메틸]인돌일 아세트산:3-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] indolyl acetic acid:

1H NMR (DMSO-D6): δ 2.81 (t, J = 6.5, 2H), 4.43 (t, J = 6.5, 2H), 7.06 (d, J = 8.5, 1H), 7.15-7.28 (m, 2H), 7.56 (d, J = 8.1, 1H), 7.75 (d, J = 8.5, 1H), 7.83 (s, 1H), 7.95 (s, 1H), 8.27 (d, J = 7.65, 1H), 8.54 (s, 1H), 10.88 (br s, 1H), 11.41 (s, 1H). C19H16Cl1N3O4(M - H)의 LRMS 계산치 384, 실측치 384.0. 1 H NMR (DMSO-D 6 ): δ 2.81 (t, J = 6.5, 2H), 4.43 (t, J = 6.5, 2H), 7.06 (d, J = 8.5, 1H), 7.15-7.28 (m, 2H), 7.56 (d, J = 8.1, 1H), 7.75 (d, J = 8.5, 1H), 7.83 (s, 1H), 7.95 (s, 1H), 8.27 (d, J = 7.65, 1H), 8.54 (s, 1 H), 10.88 (br s, 1 H), 11.41 (s, 1 H). LRMS calcd for C 19 H 16 Cl 1 N 3 O 4 (M-H) 384, found 384.0.

4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]인돌일 아세트산:4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] indolyl acetic acid:

1H NMR ( DMSO-d6) δ 5.09 (s, 2H), 7.09 (d, J = 8.6 Hz, 1H), 7.16 - 7.25 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.45 - 7.55 (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 8.68 (s, 1H), 10.96 (s, 1H), 11.71 (s, 1H), 12.90 (b, 1H). MS ( APCI, neg.): 370. 1 H NMR (DMSO-d 6 ) δ 5.09 (s, 2H), 7.09 (d, J = 8.6 Hz, 1H), 7.16-7.25 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.45-7.55 (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 8.68 (s, 1H), 10.96 (s, 1H), 11.71 (s , 1H), 12.90 (b, 1H). MS (APCI, neg.): 370.

5-[(3-클로로-4-히드록시벤조일)히드라조노메틸]인돌일 아세트산:5-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] indolyl acetic acid:

1H NMR (DMSO-d6) δ 5.09 (s, 2H), 6.35 (d, J = 2.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.97 (s, 1H), 8.48 (s, 1H), 10.93 (s, 1H), 11.58 (s, 1H), 12.90 (brd s, 1H). MS (APCI, neg. ): 370. 1 H NMR (DMSO-d 6 ) δ 5.09 (s, 2H), 6.35 (d, J = 2.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 3.1 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.97 (s, 1H), 8.48 (s, 1H), 10.93 (s, 1H), 11.58 (s, 1H), 12.90 (brd s, 1H). MS (APCI, neg.): 370.

4-[3-클로로-4-히드록시벤조일)-히드라조노메틸]-1-나프틸아세트아미드 및 여러가지 인돌아세트아미드(단계 B):4- [3-Chloro-4-hydroxybenzoyl) -hydrazonomethyl] -1-naphthylacetamide and various indoleacetamides (step B):

일반적인 라이브러리 제조방법:Common library recipes:

DMSO중 4-[(3-클로로-4-히드록시벤조일)-히드라조노메틸]나프틸아세트산 및 여러가지 인돌일아세트산의 용액에 카르보닐디이미다졸(1.2eq)을 가하였다. 용액을 5분동안 휘젓고 DMSO로 희석시켜 50mM로 농축시켰다. 그런 다음, 용액을 DMSO(50mM)중 아민의 용액을 포함하는 88 딥 웰 플레이트에 분배하였다. 플레이트를 덮고 16시간동안 휘저었다. 생성물을 HPLC로 정제하였다.Carbonyldiimidazole (1.2eq) was added to a solution of 4-[(3-chloro-4-hydroxybenzoyl) -hydrazonomethyl] naphthylacetic acid and various indolyl acetic acids in DMSO. The solution was stirred for 5 minutes, diluted with DMSO and concentrated to 50 mM. The solution was then partitioned into 88 deep well plates containing a solution of amine in DMSO (50 mM). The plate was covered and stirred for 16 hours. The product was purified by HPLC.

화학식 XII의 화합물의 실시예:Examples of Compounds of Formula XII:

실시예 343:Example 343:

1H NMR (DMSO-D6): δ 1.06 (t, 3H), 1.17 (t, 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 (s, 2H), 7.10 (d, 1H), 7.45 (d, 1H), 7.64 (quintet, 2H), 7.83 (d, 1H), 7.88 (d, 1H), 7.98 (m, 2H), 8.87 (d, 1H), 9.09 (s, 1H), 10.99 (brd s, 1H), 11.80 (brd s, 1H); ms (APCI); 438.1, 440.1. 1 H NMR (DMSO-D 6 ): δ 1.06 (t, 3H), 1.17 (t, 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 (s, 2H), 7.10 (d, 1H), 7.45 (d, 1H), 7.64 (quintet, 2H), 7.83 (d, 1H), 7.88 (d, 1H), 7.98 (m, 2H), 8.87 (d, 1H), 9.09 (s, 1H ), 10.99 (brd s, 1 H), 11.80 (brd s, 1 H); ms (APCI); 438.1, 440.1.

실시예 344:Example 344:

1H NMR (DMSO-D6): δ 0.98 (d, 4H), 2.76 (t, 2H), 3.02 (quintet, 1H), 3.59 (t, 2H), 4.40 (s, 2H), 7.10 (d, 1H), 7.48 (d, 1H), 7.48 (d, 1H), 7.59 (qt, 1H), 7.67 (t, 1H), 7.81 (d, 1H), 7.89 (d, 1H), 7.97 (d, 1H), 8.02 (s, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 10.99 (brd s, 1H) 11.80 (brd s, 1H); MS (APCI, neg.): 473.1, 475.1. 1 H NMR (DMSO-D 6 ): δ 0.98 (d, 4H), 2.76 (t, 2H), 3.02 (quintet, 1H), 3.59 (t, 2H), 4.40 (s, 2H), 7.10 (d, 1H), 7.48 (d, 1H), 7.48 (d, 1H), 7.59 (qt, 1H), 7.67 (t, 1H), 7.81 (d, 1H), 7.89 (d, 1H), 7.97 (d, 1H ), 8.02 (s, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 10.99 (brd s, 1H) 11.80 (brd s, 1H); MS (APCI, neg.): 473.1, 475.1.

실시예 345;Example 345;

1H NMR (DMSO-D6): δ 2.50 (2H), 2.68 (t, 2H), 4.00 (s, 2H), 7.10 (d, 1H), 7.53 (d, 1H), 7.65 (tt, 2H), 7.80 (dd, 1H), 7.90 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.62 (t, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.0 (brd s, 1H) 11.80 (s, 1H); MS (APCI): 433.1, 435.1 1 H NMR (DMSO-D 6 ): δ 2.50 (2H), 2.68 (t, 2H), 4.00 (s, 2H), 7.10 (d, 1H), 7.53 (d, 1H), 7.65 (tt, 2H) , 7.80 (dd, 1H), 7.90 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.62 (t, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.0 (brd s, 1 H) 11.80 (s, 1 H); MS (APCI): 433.1, 435.1

실시예 346:Example 346:

1H NMR (DMSO-D6): δ 1.08 (m, 4H), 1.54 (m, 6H), 2.70 (t, 2H), 3.45 (t, 2H), 3.76 (m, 1H), 4.30 (s, 2H), 7.06 (d, 1H), 7.49 (d, 1H), 7.64 (m, 2H), 7.80 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.07 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 10.5 (brd d, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 515.2. 1 H NMR (DMSO-D 6 ): δ 1.08 (m, 4H), 1.54 (m, 6H), 2.70 (t, 2H), 3.45 (t, 2H), 3.76 (m, 1H), 4.30 (s, 2H), 7.06 (d, 1H), 7.49 (d, 1H), 7.64 (m, 2H), 7.80 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.07 (d, 1H ), 8.83 (d, 1 H), 9.09 (s, 1 H), 10.5 (brd d, 1 H), 11.78 (brd s, 1 H); MS (APCI, neg.): 515.2.

실시예 347Example 347

1H NMR (DMSO-D6): δ 1.26 (m, 2H), 1.37 (m, 4H), 1.67 (m, 2H), 2.43 (m, 4H), 2.62 (m, 3H), 3.10 (t, 2H), 3.90 (d, 1H), 4.32 (s, 2H), 4.48 (d, 1H), 7.10 (d, 1H), 7.31 (d, 1H), 7.48 (m, 2H), 7.81 (d, 1H), 7.88 (d, 1H), 8.03 (m, 2H), 8.85 (d, 1H), 9.08 (brd s, 1H), 11.76 (brd s, 1H): MS (APCI): 533.2. 1 H NMR (DMSO-D 6 ): δ 1.26 (m, 2H), 1.37 (m, 4H), 1.67 (m, 2H), 2.43 (m, 4H), 2.62 (m, 3H), 3.10 (t, 2H), 3.90 (d, 1H), 4.32 (s, 2H), 4.48 (d, 1H), 7.10 (d, 1H), 7.31 (d, 1H), 7.48 (m, 2H), 7.81 (d, 1H ), 7.88 (d, 1H), 8.03 (m, 2H), 8.85 (d, 1H), 9.08 (brd s, 1H), 11.76 (brd s, 1H): MS (APCI): 533.2.

실시예 348:Example 348:

1H NMR (DMSO-D6): δ 3.03 (m, 4H), 3.68 (t, 2H), 3.79 (t, 2H), 4.30 (s, 2H), 7.14 (m, 5H), 7.47 (d, 1H), 7.66 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1H), 8.02 (d, 1H), 8.07 (d, 1H), 8.87 (d, 1H), 9.10 (s, 1H), 10.99 (s, 1H), 11.80 (s, 1H); MS (ACPI): 545.6. 1 H NMR (DMSO-D 6 ): δ 3.03 (m, 4H), 3.68 (t, 2H), 3.79 (t, 2H), 4.30 (s, 2H), 7.14 (m, 5H), 7.47 (d, 1H), 7.66 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1H), 8.02 (d, 1H), 8.07 (d, 1H), 8.87 (d, 1H), 9.10 (s, 1H ), 10.99 (s, 1 H), 11.80 (s, 1 H); MS (ACPI): 545.6.

실시예 349:Example 349:

1H NMR (DMSO-D6): d 3.10 (d, 4H), 3.67 (d, 4H), 4.30 (s, 2H), 7.00 (m, 2H), 7.09 (m, 3H), 7.47 (d, 1H), 7.62 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1H), 8.03 (s, 1H), 8.06 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 10.99 (s, 1H), 11.80 (s, 1H); MS (ACPI): 544.5, 545.3. 1 H NMR (DMSO-D 6 ): d 3.10 (d, 4H), 3.67 (d, 4H), 4.30 (s, 2H), 7.00 (m, 2H), 7.09 (m, 3H), 7.47 (d, 1H), 7.62 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1H), 8.03 (s, 1H), 8.06 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H ), 10.99 (s, 1 H), 11.80 (s, 1 H); MS (ACPI): 544.5, 545.3.

실시예 350:Example 350:

1H NMR (DMSO-D6): δ 2.15 (s, 6H), 2.39 (m, 8H), 3.51 (d, 4H), 4.22 (s, 2H), 7.03 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.77 (d, 1H), 7.87 (d, 1H), 7.99 (s, 1H), 8.02 (d, 1H), 8.83 (d, 1H), 9.08 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 522.2. 1 H NMR (DMSO-D 6 ): δ 2.15 (s, 6H), 2.39 (m, 8H), 3.51 (d, 4H), 4.22 (s, 2H), 7.03 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.77 (d, 1H), 7.87 (d, 1H), 7.99 (s, 1H), 8.02 (d, 1H), 8.83 (d, 1H), 9.08 (s, 1H ), 11.80 (brd s, 1 H); MS (APCI): 522.2.

실시예 351:Example 351:

1H NMR (DMSO-D6): δ 3.93 (d, 2H), 4.10 (d, 2H), 4.23 (s, 2H), 5.20 (m, 4H), 5.79 (m, 1H), 5.94 (m, 1H), 7.10 (d, 1H), 7.78 (d, 1H), 7.63 (m, 2H), 7.80 (d, 1H), 7.83 (d, 1H), 7.95 (d, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11 (brd s, 1H), 11.80 (brd s, 1H); MS (ACPI): 462.2 1 H NMR (DMSO-D 6 ): δ 3.93 (d, 2H), 4.10 (d, 2H), 4.23 (s, 2H), 5.20 (m, 4H), 5.79 (m, 1H), 5.94 (m, 1H), 7.10 (d, 1H), 7.78 (d, 1H), 7.63 (m, 2H), 7.80 (d, 1H), 7.83 (d, 1H), 7.95 (d, 1H), 8.02 (d, 1H ), 8.85 (d, 1 H), 9.10 (s, 1 H), 11 (brd s, 1 H), 11.80 (brd s, 1 H); MS (ACPI): 462.2

실시예 352:Example 352:

1H NMR (DMSO-D6): δ 0.9 (t, 3H), 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 (t, 2H), 4.31 (s, 2H), 4.39 (s, 2H), 7.06 (d, 1H) 7.48 (d, 1H), 7.65 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.85 (d, 1H), 9.09 (s, 1H), 11.79 (s, 1H); MS (APCI): 477.01, 479.2. 1 H NMR (DMSO-D 6 ): δ 0.9 (t, 3H), 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 (t, 2H), 4.31 (s, 2H), 4.39 (s, 2H), 7.06 (d, 1H) 7.48 (d, 1H), 7.65 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H) , 8.85 (d, 1 H), 9.09 (s, 1 H), 11.79 (s, 1 H); MS (APCI): 477.01, 479.2.

실시예 353:Example 353:

1H NMR (DMSO-D6): δ 1.17 (m, 4H), 1.54 (m, 4H), 2.68 (m, 1H), 3.77 (d, 1H), 4.18 (s, 2H), 4.33 (m, 1H), 4.76 (brd, 1H), 7.10 (d, 1H), 7.43 (m, 1H), 7.65 (quintet, 2H), 7.81 (d, 1H), 7.88 (d, 1H), 8.02 (s, 1H), 8.04 (d, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.79 (s, 1H); MS (APCI): 464.1, 466.2. 1 H NMR (DMSO-D 6 ): δ 1.17 (m, 4H), 1.54 (m, 4H), 2.68 (m, 1H), 3.77 (d, 1H), 4.18 (s, 2H), 4.33 (m, 1H), 4.76 (brd, 1H), 7.10 (d, 1H), 7.43 (m, 1H), 7.65 (quintet, 2H), 7.81 (d, 1H), 7.88 (d, 1H), 8.02 (s, 1H ), 8.04 (d, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.79 (s, 1H); MS (APCI): 464.1, 466.2.

실시예 354:Example 354:

1H NMR (DMSO-D6): δ 0.85 (qt, 3H), 1.53 (m, 2H), 3.00 (dt, 2H), 3.29 (quintet, 2H), 3.77 (dt, 2H), 4.13 (d, 2H), 7.05 (d, 1H), 7.26 (m, 2H), 7.36 (d, 1H), 7.52 (qt, 1H), 7.69 (m, 2H), 7.87 (m, 2H), 7.95 (d, 1H), 8.00 (s, 1H), 7.87 (dd, 1H), 8.84 (t, 1H), 9.07 (brd, 1H), 11.76 (brd s, 1H); MS (APCI): 529.2, 529.7, 531.2. 1 H NMR (DMSO-D 6 ): δ 0.85 (qt, 3H), 1.53 (m, 2H), 3.00 (dt, 2H), 3.29 (quintet, 2H), 3.77 (dt, 2H), 4.13 (d, 2H), 7.05 (d, 1H), 7.26 (m, 2H), 7.36 (d, 1H), 7.52 (qt, 1H), 7.69 (m, 2H), 7.87 (m, 2H), 7.95 (d, 1H ), 8.00 (s, 1H), 7.87 (dd, 1H), 8.84 (t, 1H), 9.07 (brd, 1H), 11.76 (brd s, 1H); MS (APCI): 529.2, 529.7, 531.2.

실시예 355:Example 355:

1H NMR (DMSO-D6): δ 0.85 (qt, 3H), 1.33 (m, 1H), 1.65 (m, 7H), 2.60 (t, 0.5H), 3.10 (t, 0.5H) 3.80 (m, 1H), 4.21 (s, 2H), 4.24 (m, 1H), 7.11 (d, 1H), 7.45 (t, 1H), 7.65 (m, 2H), 7.75 (d, 1H), 7.89 (d, 1H), 8.01 (d, 1H), 8.05 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (s, 1H); MS (APCI): 478.4, 480.3. 1 H NMR (DMSO-D 6 ): δ 0.85 (qt, 3H), 1.33 (m, 1H), 1.65 (m, 7H), 2.60 (t, 0.5H), 3.10 (t, 0.5H) 3.80 (m , 1H), 4.21 (s, 2H), 4.24 (m, 1H), 7.11 (d, 1H), 7.45 (t, 1H), 7.65 (m, 2H), 7.75 (d, 1H), 7.89 (d, 1H), 8.01 (d, 1H), 8.05 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (s, 1H); MS (APCI): 478.4, 480.3.

실시예 356:Example 356:

1H NMR (DMSO-D6): δ 2.36 (m, 4H), 2.97 (d, 2H), 3.50 (m, 2H), 3.60 (m, 2H), 4.23 (s, 2H), 5.17 (t, 2H), 5.86 (m, 1H), 7.08 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 8.01 (s, 1H), 8.04 (d, 1H), 8.83 (d, 1H), 9.09 (d, 1H), 11.79 (brd s, 1H); MS (APCI): 4.91.2, 493.2. 1 H NMR (DMSO-D 6 ): δ 2.36 (m, 4H), 2.97 (d, 2H), 3.50 (m, 2H), 3.60 (m, 2H), 4.23 (s, 2H), 5.17 (t, 2H), 5.86 (m, 1H), 7.08 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 8.01 (s, 1H ), 8.04 (d, 1H), 8.83 (d, 1H), 9.09 (d, 1H), 11.79 (brd s, 1H); MS (APCI): 4.91.2, 493.2.

실시예 357:Example 357:

1H NMR (DMSO-D6): δ 1.50 (m, 1H), 1.90 (m, 2H), 1.95 (m, 1H), 2.72 (t, 1H), 2.95 (t, 1H), 3.30 (m, 1H), 3.55 (m, 1H), 3.65 (t, 2H), 3.75 (m, 1H), 3.92 (t, 1H), 4.12 (t, 1H) 4.35 (d, 2H), 7.11 (d, 1H), 7.48 (m, 1H), 7.65 (t, 1H), 7.68 (t, 1H), 7.8 (dd, 1H), 7.87 (d, 1H), 8.00 (d, 1H), 8.03 (d, 1H), 8.83 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 519.5, 521.2, 522.2. 1 H NMR (DMSO-D 6 ): δ 1.50 (m, 1H), 1.90 (m, 2H), 1.95 (m, 1H), 2.72 (t, 1H), 2.95 (t, 1H), 3.30 (m, 1H), 3.55 (m, 1H), 3.65 (t, 2H), 3.75 (m, 1H), 3.92 (t, 1H), 4.12 (t, 1H) 4.35 (d, 2H), 7.11 (d, 1H) , 7.48 (m, 1H), 7.65 (t, 1H), 7.68 (t, 1H), 7.8 (dd, 1H), 7.87 (d, 1H), 8.00 (d, 1H), 8.03 (d, 1H), 8.83 (d, 1 H), 9.10 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 519.5, 521.2, 522.2.

실시예 358:Example 358:

1H NMR (DMSO-D6): δ 2.19 (s, 3H), 2.30 (m, 4 H), 3.50 (T, 2H), 3.58 (T, 2H), 4.22 (S, 2H), 7.03 (D, 1H), 7.43 (D, 1H), 7.64 (quint, 2H) 7.77 (dd, 1H), 7.87 (d, 1H), 7.99 (d, 1H), 8.04 (s, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 465.2, 467.3. 1 H NMR (DMSO-D 6 ): δ 2.19 (s, 3H), 2.30 (m, 4H), 3.50 (T, 2H), 3.58 (T, 2H), 4.22 (S, 2H), 7.03 (D , 1H), 7.43 (D, 1H), 7.64 (quint, 2H) 7.77 (dd, 1H), 7.87 (d, 1H), 7.99 (d, 1H), 8.04 (s, 1H), 8.83 (d, 1H ), 9.09 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 465.2, 467.3.

실시예 359:Example 359:

1H NMR (DMSO-D6): δ 2.38 (m, 4H), 3.51 (s, 4H), 3.61 (t, 2H), 4.22 (s, 2H), 7.08 (d, 1H), 7.31 (m, 5H), 7.43 (d, 1H), 7.61 (quintet, 2H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.00 (s, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 541.4, 543.1. 1 H NMR (DMSO-D 6 ): δ 2.38 (m, 4H), 3.51 (s, 4H), 3.61 (t, 2H), 4.22 (s, 2H), 7.08 (d, 1H), 7.31 (m, 5H), 7.43 (d, 1H), 7.61 (quintet, 2H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.00 (s, 1H), 8.02 (d, 1H), 8.85 (d, 1H ), 9.10 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 541.4, 543.1.

실시예 360:Example 360:

1H NMR (DMSO-D6): δ 1.33 (dd, 3H), 2.76 (s, 1.5H), 2.96 (s, 1.5H), 3.61 (d, 1H), 4.14 (quintet, 1H), 4.65 (m, 2H), 7.10 (m, 2H), 7.33 (s, 3H), 7.42 (m, 3H), 7.54 (m, 2H), 8.02 (t, 1H), 8.80 (m, 1H), 9.07 (brd, 1H), 11.80 (brd s, 1H); MS (APCI): 530.2, 532.2. 1 H NMR (DMSO-D 6 ): δ 1.33 (dd, 3H), 2.76 (s, 1.5H), 2.96 (s, 1.5H), 3.61 (d, 1H), 4.14 (quintet, 1H), 4.65 ( m, 2H), 7.10 (m, 2H), 7.33 (s, 3H), 7.42 (m, 3H), 7.54 (m, 2H), 8.02 (t, 1H), 8.80 (m, 1H), 9.07 (brd , 1H), 11.80 (brd s, 1H); MS (APCI): 530.2, 532.2.

실시예 361:Example 361:

1H NMR (DMSO-D6): d[2.94 (s, 1.5H) + 3.10 (s, 1.5H), 3H], 3.54 (m, 2H), 4.00 (d, 1H), 4.28 (d, 1H), 4.81 (t, 1H), 4.96 (t, 1H), 7.09 (d, 1H), 7.35 (m, 3H), 7.43 (m, 3H), 7.61 (m, 2H), 7.83 (m, 3H), 8.04 (s, 1H), 8.85 (t, 1H), 9.11 (d, 1H), 11.80 (brd s, 1H); MS (APCI): 516.3, 518.2. 1 H NMR (DMSO-D 6 ): d [2.94 (s, 1.5H) + 3.10 (s, 1.5H), 3H], 3.54 (m, 2H), 4.00 (d, 1H), 4.28 (d, 1H ), 4.81 (t, 1H), 4.96 (t, 1H), 7.09 (d, 1H), 7.35 (m, 3H), 7.43 (m, 3H), 7.61 (m, 2H), 7.83 (m, 3H) , 8.04 (s, 1 H), 8.85 (t, 1 H), 9.11 (d, 1 H), 11.80 (brd s, 1 H); MS (APCI): 516.3, 518.2.

실시예 362:Example 362:

1H NMR (DMSO-D6): δ 2.75 (t, 1H), 2.95 (t, 1H), 3.59 (t, 1H), 3.80 (t, 1H), 4.38 (brd s, 3H), 4.61 (s, 1H), 4.84 (s, 1H), 6.40 (d, 1H), 6.53 (d, 1H), 7.05 (d, 1H), 7.45 (t, 1H), 7.58 (m, 3H), 7.81 (m, 3H), 8.00 (brd, 2H), 8.83 (d, 1H), 9.10 (s, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 513.3, 514.2. 1 H NMR (DMSO-D 6 ): δ 2.75 (t, 1H), 2.95 (t, 1H), 3.59 (t, 1H), 3.80 (t, 1H), 4.38 (brd s, 3H), 4.61 (s , 1H), 4.84 (s, 1H), 6.40 (d, 1H), 6.53 (d, 1H), 7.05 (d, 1H), 7.45 (t, 1H), 7.58 (m, 3H), 7.81 (m, 3H), 8.00 (brd, 2H), 8.83 (d, 1H), 9.10 (s, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 513.3, 514.2.

실시예 363:Example 363:

1H NMR (DMSO-D6): δ 1.50 (m, 2H), 1.68, (d, 2H), 2.28 (t, 1H), 2.59 (t, 1H), 3.05 (t, 1H), 3.96 (d, 1H), 4.16 (s, 2H), 4.32 (d, 1H), 6.74 (brd s, 1H), 6.95 (d, 1H), 7.22 (brd s, 1H), 7.36 (d, 1H), 7.57 (quintet, 2H), 7.71 (dd, 1H), 7.79 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.76 (d, 1H), 9.01 (s, 1H), 11.80 (brd s, 1H); MS (ACPI): 493.1, 495.2. 1 H NMR (DMSO-D 6 ): δ 1.50 (m, 2H), 1.68, (d, 2H), 2.28 (t, 1H), 2.59 (t, 1H), 3.05 (t, 1H), 3.96 (d , 1H), 4.16 (s, 2H), 4.32 (d, 1H), 6.74 (brd s, 1H), 6.95 (d, 1H), 7.22 (brd s, 1H), 7.36 (d, 1H), 7.57 ( quintet, 2H), 7.71 (dd, 1H), 7.79 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.76 (d, 1H), 9.01 (s, 1H), 11.80 (brd s, 1 H); MS (ACPI): 493.1, 495.2.

실시예 364:Example 364:

1H NMR (DMSO-D6): δ 2.10 (s, 3H), 2.15 (s, 3H), 2.29 (t, 1H), 2.40 (t, 1H), 2.80 (s, 1H), 3.05 (s, 2H), 3.36 (t, 1H), 3.46 (t, 1H), 4.16 (d, 2H), 7.01 (d, 1H), 7.38 (t, 1H), 7.56 (m, 2H), 7.72 (dd, 1H), 7.79 (d, 1H), 7.94 (m, 2H), 8.77 (d, 1H), 9.02 (s, 1H), 11.71 (brd s, 1H); MS (ACPI): 467.3, 469.1. 1 H NMR (DMSO-D 6 ): δ 2.10 (s, 3H), 2.15 (s, 3H), 2.29 (t, 1H), 2.40 (t, 1H), 2.80 (s, 1H), 3.05 (s, 2H), 3.36 (t, 1H), 3.46 (t, 1H), 4.16 (d, 2H), 7.01 (d, 1H), 7.38 (t, 1H), 7.56 (m, 2H), 7.72 (dd, 1H ), 7.79 (d, 1H), 7.94 (m, 2H), 8.77 (d, 1H), 9.02 (s, 1H), 11.71 (brd s, 1H); MS (ACPI): 467.3, 469.1.

실시예 365:Example 365:

1H NMR (DMSO-D6): δ 2.11 (s, 3H), 2.14 (s, 3H), 2.33 (t, 1H), 2.39 (t, 1H), 3.37 (t, 1H), 3.46 (t, 1H), 4.14 (s, 1H), 4.32 (s, 1H), 4.55 (s, 1H), 4.74 (s, 1H), 7.05 (d, 1H), 7.23 (d, 1H), 7.29 (m, 3H), 7.38 (t, 1H), 7.43 (d, 1H), 7.57 (m, 2H), 7.81 (m, 2H), 7.97 (s, 1H), 8.06 (d, 1H), 8.79 (t, 1H), 9.05 (s, 1H), 11.75 (brd s, 1H); MS (APCI): 543.2, 545.2. 1 H NMR (DMSO-D 6 ): δ 2.11 (s, 3H), 2.14 (s, 3H), 2.33 (t, 1H), 2.39 (t, 1H), 3.37 (t, 1H), 3.46 (t, 1H), 4.14 (s, 1H), 4.32 (s, 1H), 4.55 (s, 1H), 4.74 (s, 1H), 7.05 (d, 1H), 7.23 (d, 1H), 7.29 (m, 3H ), 7.38 (t, 1H), 7.43 (d, 1H), 7.57 (m, 2H), 7.81 (m, 2H), 7.97 (s, 1H), 8.06 (d, 1H), 8.79 (t, 1H) , 9.05 (s, 1 H), 11.75 (brd s, 1 H); MS (APCI): 543.2, 545.2.

화학식 XII의 화합물을 합성하기 위한 일반적인 방법:General Methods for Synthesizing Compounds of Formula XII:

A 및 B는 화학식 I에서 정의된 바와 같고 -NR5cR5d는(상기 식에서, R5a, R4a, R4b, c, q, d 및 D는 화학식 I에서 정의된 바와 같다)이거나, 친핵기로서 반응할 수 있는 1차 또는 2차 아민을 포함하는 -D의 부분집합으로서 정의된 -D'이다.A and B are as defined in formula (I) and -NR 5c R 5d is (Wherein R 5a , R 4a , R 4b , c, q, d and D are as defined in formula (I)) or -D comprising a primary or secondary amine capable of reacting as a nucleophilic group -D 'defined as a subset.

단계 A: 카르보닐 화합물을 용매중에서 아실히드라지드로 처리한다. 용매는 다음중 하나가 될 수 있다: 에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, 아세트산, 물 또는 상기 용매중 상용성인 2 이상의 혼합물. 아세트산 등의 촉매가 가해질 수 있다. 트리에틸오르토포르메이트 등의 탈수화제가 또한 반응혼합물에 가해질 수 있다. 반응은 0℃ 내지 140℃, 바람직하게 10℃ 내지 80℃ 사이의 온도에서, 바람직하게 N2또는 Ar의 불활성 분위기하에서 반응혼합물을 교반함으로써 수행된다. 많은 경우, 생성물은 반응이 완결되면 간단히 결정석출되고 흡입여과에 의해 분리된다. 필요하다면 상기 기재된 반응 용매 등의 용매로부터 더 재결정될 수 있다. 생성물은 또한 반응혼합물을 진공에서 농축시키고, 이어서 클로로포름/메탄올 또는 디클로로메탄/메탄올 또는 클로로포름/에틸아세테이트 등의 용매계를 사용하는 실리카겔상의 컬럼크로마토그래피로 분리할 수 있다.Step A: The carbonyl compound is treated with acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid Two or more mixtures which are compatible in water or in said solvent. Catalysts such as acetic acid can be added. Dehydrating agents such as triethylorthoformate may also be added to the reaction mixture. The reaction is carried out by stirring the reaction mixture at a temperature between 0 ° C. and 140 ° C., preferably between 10 ° C. and 80 ° C., preferably under an inert atmosphere of N 2 or Ar. In many cases, the product simply crystallizes upon completion of the reaction and is separated by suction filtration. If necessary, it may be further recrystallized from a solvent such as the reaction solvent described above. The product can also be concentrated in vacuo and then separated by column chromatography on silica gel using a solvent system such as chloroform / methanol or dichloromethane / methanol or chloroform / ethylacetate.

단계 B: 그런 다음, 그 결과의 산을 당업자에게 공지된 방법중 하나를 사용하여 1차 또는 2차 아민에 결합시킨다. 이 결합은 활성 에스테르, 수소화물 또는 산 할라이드를 생성시킨 후, 이것을 아민과 반응시켜 화학식 XIII의 화합물을 얻는 등의 표준 아미드 또는 펩티드 합성방법중 하나를 사용하여 수행될 수 있다. 그런 다음, 생성물은 여과하거나 에틸아세테이트, 톨루엔, 디클로로메탄 또는 디에틸에테르 등의 용매를 사용하여 추출한 후 용매를 대기압 또는 감압하에서 농축시켜 제거함으로써 분리할 수 있다. 생성물은 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물 또는 상기중 2 이상의 혼합물 등의 용매로부터 재결정하여 더 정제할 수 있다. 다른 방법으로, 생성물을 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로 사용하여 컬럼크로마토그래피함으로써 정제하여 화학식 XIII의 화합물을 얻을 수 있다.Step B: The resulting acid is then bound to the primary or secondary amine using one of the methods known to those skilled in the art. This linkage can be carried out using one of the standard amide or peptide synthesis methods, such as the formation of active esters, hydrides or acid halides, followed by reaction with amines to give compounds of formula (XIII). The product can then be separated by filtration or extracted using a solvent such as ethyl acetate, toluene, dichloromethane or diethyl ether and then the solvent is removed by concentration under atmospheric or reduced pressure. The product can be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of them. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent to afford the compound of formula XIII.

본 발명에 따라서 화학식 XIII의 화합물의 제조를 예시하는 구체적인 실시예를 하기 제공한다.Specific examples illustrating the preparation of compounds of formula (XIII) according to the invention are provided below.

4-포르밀나프토산의 제조는 하기에 나타낸다:Preparation of 4-formylnaphthoic acid is shown below:

4-브로모메틸나프토산:4-bromomethylnaphthoic acid:

CCl4(250mL)중 4-메틸나프토산(10g, 54mmol), N-브로모숙신이미드(10g, 56mmol) 및 AIBN(100mg)의 혼합물을 3시간동안 환류시켰다. 반응혼합물을 농축시키고 에틸아세테이트에서 용해시켰다. 유기상을 물, 함수로 세척하고 MgSO4에서 건조시켰다. 용매를 증발시켜 원하는 생성물(16g, 80%)를 얻었다.A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CCl 4 (250 mL) was refluxed for 3 hours. The reaction mixture was concentrated and dissolved in ethyl acetate. The organic phase was washed with water, brine and dried over MgSO 4 . The solvent was evaporated to afford the desired product (16 g, 80%).

1H NMR (DMSO-D6): δ 5.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1H), 8.28 (d, 1H), 8.86 (d, 1H), 13.29 (brd s, 1H). 1 H NMR (DMSO-D 6 ): δ 5.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1H), 8.28 (d, 1H), 8.86 (d, 1H), 13.29 (brd s , 1H).

4-히드록시메틸나프토산:4-hydroxymethylnaphthoic acid:

K2CO3(10%, 100mL)의 수성용액중 4-브로모메틸나프토산(16g, 60mmol)을 70℃에서 30분간 교반하였다. 반응혼합물을 냉각시키고 농 HCl로 산성화하였다. 그 결과의 침전물을 여과시키고 건조시켜 원하는 화합물을 황색고체로서 정량적 수율로 얻었다.4-bromomethylnaphthoic acid (16 g, 60 mmol) in an aqueous solution of K 2 CO 3 (10%, 100 mL) was stirred at 70 ° C. for 30 minutes. The reaction mixture was cooled and acidified with concentrated HCl. The resulting precipitate was filtered and dried to afford the desired compound as a yellow solid in quantitative yield.

1H NMR (DMSO-D6) ; δ 5.01 (s, 2H), 5.96 (s, 1H), 7.70 (m, 3H), 8.10 (m, 2H), 8.90 (d, 1H). 1 H NMR (DMSO-D 6 ); δ 5.01 (s, 2H), 5.96 (s, 1H), 7.70 (m, 3H), 8.10 (m, 2H), 8.90 (d, 1H).

메틸 4-히드록시메틸나프토에이트:Methyl 4-hydroxymethylnaphthoate:

4-히드록시메틸나프토산(10g, 50mmol), 메탄올(300mL) 및 농 H2SO4(2mL)의 혼합물을 하룻밤동안 환류시켰다. 불용성 물질을 여과하여 제거하고 여과물을 농축시켰다. 잔여물을 에틸아세테이트에 흡수시키고 수성 NaHCO3(2x), 함수로 세척하고 MgSO4로 건조시키고 농축시켜 황색의 오일을 얻었다. 에틸아세테이트/헥산(1/3)을사용하는 실리카겔 컬럼크로마토그래피로 황색의 오일로서 원하는 생성물(3.3g, 35%)을 얻었다.A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL) and concentrated H 2 SO 4 (2 mL) was refluxed overnight. Insoluble matter was removed by filtration and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO 3 (2 ×), brine, dried over MgSO 4 and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate / hexanes (1/3) gave the desired product as a yellow oil (3.3 g, 35%).

1H NMR (CDCl3): δ 2.05 (t, 1H), 4.01 (s, 3H), 5.22 (s, 2H), 7.66 (m, 3H), 8.09 (d, 1H), 8.16 (d, 1H), 8.96 (d, 1H). 1 H NMR (CDCl 3 ): δ 2.05 (t, 1H), 4.01 (s, 3H), 5.22 (s, 2H), 7.66 (m, 3H), 8.09 (d, 1H), 8.16 (d, 1H) , 8.96 (d, 1 H).

메틸 4-포르밀나프토에이트:Methyl 4-formylnaphthoate:

디클로로메탄(20mL)중 상기 메틸 4-히드록시메틸나프토에이트(3.3g, 15.3mmol)의 용액에 MnO2(6.6g, 76mmol)를 가하였다. 암색의 혼합물을 16시간동안 교반한 후, 불용성 물질을 셀라이트 베드를 통과시켜 여과시켰다. 용매를 증발시켜 원하는 생성물을 백색 고체로서 정량적 수율로 얻었다.MnO 2 (6.6 g, 76 mmol) was added to a solution of methyl 4-hydroxymethylnaphthoate (3.3 g, 15.3 mmol) in dichloromethane (20 mL). The dark mixture was stirred for 16 hours, after which the insoluble material was filtered through a bed of celite. The solvent was evaporated to give the desired product in quantitative yield as a white solid.

1H NMR (CDCl3): δ 4.06 (S, 3H), 7.75 (m, 2H), 8.03 (d, 1H), 8.20 (d, 1H), 8.80 (d, 1H), 9.27 (d, 1H), 10.50 (s, 1H). 1 H NMR (CDCl 3 ): δ 4.06 (S, 3H), 7.75 (m, 2H), 8.03 (d, 1H), 8.20 (d, 1H), 8.80 (d, 1H), 9.27 (d, 1H) , 10.50 (s, 1 H).

4-포르밀나프토산:4-formylnaphthoic acid:

물(30mL)중 상기 메틸 4-포르밀나프토에이트(2.3g, 1mmol) 및 Na2CO3(1.25g, 12mmol)의 혼합물을 맑은 용액이 얻어질 때까지 약 2시간동안 수욕에서 가열하였다. 용액을 냉각시키고 여과시켰다. 여과물을 농 HCl로 산성화하여 황색의 침전물을 얻었다. 고체를 수집하고 밤동안 건조시키고 원하는 생성물(1.86g, 87%)을 얻었다.The mixture of methyl 4-formylnaphthoate (2.3 g, 1 mmol) and Na 2 CO 3 (1.25 g, 12 mmol) in water (30 mL) was heated in a water bath for about 2 hours until a clear solution was obtained. The solution was cooled and filtered. The filtrate was acidified with concentrated HCl to give a yellow precipitate. The solid was collected and dried overnight to afford the desired product (1.86 g, 87%).

1H NMR (DMSO-D6): δ 7.76 (m, 2H), 8.22 (m, 2H), 8.71 (d, 1H), 9.20 (d, 1H), 10.49 (s, 1H). 1 H NMR (DMSO-D 6 ): δ 7.76 (m, 2H), 8.22 (m, 2H), 8.71 (d, 1H), 9.20 (d, 1H), 10.49 (s, 1H).

4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프토산(단계 A):4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthoic acid (step A):

DMSO(20mL)중 3-클로로-4-히드록시벤조산 히드라지드(1.53g, 8.23mmol)의 용액에 DMSO(2mL)중 4-포르밀나프토산(1.65g, 8.23mmol)의 용액을 가하였다. 용액을 16시간동안 교반한 후, 반응물을 에틸아세테이트(30mL) 및 물(30mL)로 희석시켰다. 침전물이 형성되었다. 침전물을 수집하고 헥산으로 세척하고 건조시켜 생성물을 백색 고체로서 정량적 수율로 얻었다.To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO (20 mL) was added a solution of 4-formylnaphthoic acid (1.65 g, 8.23 mmol) in DMSO (2 mL). After stirring the solution for 16 hours, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). A precipitate formed. The precipitate was collected, washed with hexanes and dried to give the product in quantitative yield as a white solid.

1H NMR (DMSO-D6): δ 4.70 (d, 1H), 7.70 (m, 2H), 7.83 (d, 1H), 8.03 (m, 2H), 8.18 (d, 1H), 8.72 (s, 1H), 8.90 (d, 1H), 9.17 (s, 1H), 11.0 (brd s, 1H), 11.94 (s, 1H), 13.4 (brd s, 1H); MS (APCI, neg): 368.5, 370.2). 1 H NMR (DMSO-D 6 ): δ 4.70 (d, 1H), 7.70 (m, 2H), 7.83 (d, 1H), 8.03 (m, 2H), 8.18 (d, 1H), 8.72 (s, 1H), 8.90 (d, 1H), 9.17 (s, 1H), 11.0 (brd s, 1H), 11.94 (s, 1H), 13.4 (brd s, 1H); MS (APCI, neg): 368.5, 370.2).

일반적인 방법Common way

4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프트아미드의 유도체(단계 B):Derivatives of 4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthamide (step B):

DMSO중 4-[(4-히드록시벤조일)히드라조노메틸]나프토산의 용액 유도체에 카르보닐디이미다졸(1.2eq)을 가하였다. 용액을 5분동안 휘젓고 DMSO로 50mM의 농도까지 희석시켰다. 그런 다음, 용액을 DMSO(50mM)중 아민 용액을 포함하는 88 딥 웰 플레이트에 분배하였다. 플레이트를 덮고 16시간동안 휘저었다. 생성물을 HPLC로 정제하였다.Carbonyldiimidazole (1.2eq) was added to a solution derivative of 4-[(4-hydroxybenzoyl) hydrazonomethyl] naphthoic acid in DMSO. The solution was stirred for 5 minutes and diluted with DMSO to a concentration of 50 mM. The solution was then partitioned into 88 deep well plates containing an amine solution in DMSO (50 mM). The plate was covered and stirred for 16 hours. The product was purified by HPLC.

화학식 XIII의 다음 화합물을 제조하였다:The following compounds of formula XIII were prepared:

실시예 455:Example 455:

1H NMR (DMSO-D6): δ 2.91 (t, 2H), 3.67 (t, 2H), 7.12 (d, 1H), 7.38 (qt, 4H), 7.58 (t, 2H), 7.70 (t, 1H), 7.50 (d, 1H), 7.95 (d, 2H), 8.03 (s, 1H), 8.69 (brd t. 1H), 8.81 (d. 1H), 9.12 (s, 1H), 11.02 (s, 1H), 11.89 (s, 1H); MS (APCI): 507.3, 508.5. 1 H NMR (DMSO-D 6 ): δ 2.91 (t, 2H), 3.67 (t, 2H), 7.12 (d, 1H), 7.38 (qt, 4H), 7.58 (t, 2H), 7.70 (t, 1H), 7.50 (d, 1H), 7.95 (d, 2H), 8.03 (s, 1H), 8.69 (brd t. 1H), 8.81 (d. 1H), 9.12 (s, 1H), 11.02 (s, 1H), 11.89 (s, 1 H); MS (APCI): 507.3, 508.5.

실시예 456:Example 456:

1H NMR (DMSO-D6): δ 2.20 (brd m, 1H), 2.30 (brd m, 1H), 2.55 (m, 2H), 3.10 (brd m, 2H), 3.50 (s, 2H), 3.72 (brd m, 1H), 3.85 (brd m, 1H), 7.10 (d, 1H), 7.36 (qt, 4H), 7.53 (d, 1H), 7.70 (m, 2H), 7.82 (m, 2H), 7.95 (d, 1H), 8.03 (s, 1H), 8.88 (d, 1H), 9.11 (s, 1H), 11.00 (brd s, 1H), 11.89 (s, 1H); MS (APCI, neg.): 559.2, 561.2. 1 H NMR (DMSO-D 6 ): δ 2.20 (brd m, 1H), 2.30 (brd m, 1H), 2.55 (m, 2H), 3.10 (brd m, 2H), 3.50 (s, 2H), 3.72 (brd m, 1H), 3.85 (brd m, 1H), 7.10 (d, 1H), 7.36 (qt, 4H), 7.53 (d, 1H), 7.70 (m, 2H), 7.82 (m, 2H), 7.95 (d, 1 H), 8.03 (s, 1 H), 8.88 (d, 1 H), 9.11 (s, 1 H), 11.00 (brd s, 1 H), 11.89 (s, 1 H); MS (APCI, neg.): 559.2, 561.2.

실시예 507:Example 507:

화학식 XIV의 화합물을 합성하기 위한 일반적인 방법:General Methods for Synthesizing Compounds of Formula XIV:

A 및 B는 화학식 I에서 정의된 바와 같고 -NR5cR5d는(상기 식에서, R5a, R4a, R4b, c, q, d 및 D는 화학식 I에서 정의된 바와 같다)이거나, 친핵기로서 반응할 수 있는 1차 또는 2차 아민을 포함하는 -D의 부분집합으로서 정의된 -D'이다.A and B are as defined in formula (I) and -NR 5c R 5d is (Wherein R 5a , R 4a , R 4b , c, q, d and D are as defined in formula (I)) or -D comprising a primary or secondary amine capable of reacting as a nucleophilic group -D 'defined as a subset.

단계 A: 산을 당업자에게 공지된 방법중 하나를 사용하여 1차 또는 2차 아민에 결합시킨다. 이 결합은 활성 에스테르, 무수물 또는 산 할라이드를 생성시킨 후, 이것을 아민과 반응시켜 화학식 XIV의 화합물을 얻는 등의 표준 아미드 또는 펩티드 합성방법중 하나를 사용하여 수행될 수 있다. 생성물은 여과하거나 에틸아세테이트, 톨루엔, 디클로로메탄 또는 디에틸에테르 등의 용매를 사용하여 추출한 후 용매를 대기압 또는 감압하에서 농축시켜 제거함으로써 분리할 수 있다. 생성물은 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물 또는 상기중 2 이상의 혼합물 등의 용매로부터 재결정하여 더 정제할 수 있다. 다른 방법으로, 생성물을 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로 사용하여 컬럼크로마토그래피함으로써 정제하여 화학식 XIV의 화합물을 얻을 수 있다.Step A: The acid is bound to the primary or secondary amine using one of the methods known to those skilled in the art. This linkage can be carried out using one of the standard amide or peptide synthesis methods, such as the production of active esters, anhydrides or acid halides, followed by reaction with amines to give compounds of formula XIV. The product can be separated by filtration or extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethyl ether and then removing the solvent by concentration under atmospheric or reduced pressure. The product can be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of them. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent to afford the compound of formula XIV.

단계 B: 그런 다음, 카르보닐 화합물을 용매중에서 아실히드라지드로 처리한다. 용매는 다음중 하나가 될 수 있다: 에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, 아세트산, 물 또는 상기 용매중 상용성인 2 이상의 혼합물. 아세트산 등의 촉매가 가해질 수 있다. 트리에틸오르토포르메이트 등의 탈수화제가 또한 반응혼합물에 가해질 수 있다. 반응은 0℃ 내지 140℃, 바람직하게 10℃ 내지 80℃ 사이의 온도에서, 바람직하게 N2또는 Ar의 불활성 분위기하에서 반응혼합물을 교반함으로써 수행된다. 많은 경우, 생성물은 반응이 완결되면 간단히 결정석출되고 흡입여과에 의해 분리된다. 필요하다면 상기 기재된 반응 용매 등의 용매로부터 더 재결정될 수 있다. 생성물은 또한 반응혼합물을 진공에서 농축시키고, 이어서 클로로포름/메탄올 또는 디클로로메탄/메탄올 또는 클로로포름/에틸아세테이트 등의 용매계를 사용하는 실리카겔상의 컬럼크로마토그래피로 분리할 수 있다.Step B: The carbonyl compound is then treated with acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid Two or more mixtures which are compatible in water or in said solvent. Catalysts such as acetic acid can be added. Dehydrating agents such as triethylorthoformate may also be added to the reaction mixture. The reaction is carried out by stirring the reaction mixture at a temperature between 0 ° C. and 140 ° C., preferably between 10 ° C. and 80 ° C., preferably under an inert atmosphere of N 2 or Ar. In many cases, the product simply crystallizes upon completion of the reaction and is separated by suction filtration. If necessary, it may be further recrystallized from a solvent such as the reaction solvent described above. The product can also be concentrated in vacuo and then separated by column chromatography on silica gel using a solvent system such as chloroform / methanol or dichloromethane / methanol or chloroform / ethylacetate.

본 발명에 따라서 화학식 XIV의 화합물의 제조를 예시하는 구체적인 예를 하기 제공한다.Specific examples illustrating the preparation of compounds of formula XIV according to the invention are provided below.

3-(4-포르밀나프탈렌)프로판산의 제조를 하기 나타낸다:Preparation of 3- (4-formylnaphthalene) propanoic acid is shown below:

4-트리플루오로메틸술포닐옥시 나프트알데히드:4-trifluoromethylsulfonyloxy naphthaldehyde:

디클로로메탄(200mL)과 피리딘(19mL, 18.58g, 0.23mol)중 4-히드록시 나프트알데히드(34.4g, 0.20mol)의 용액에 트리플루오로메탄 술폰산 무수물(46.75g, 0.16mol)을 0℃에서 적가하였다. 그 혼합물을 0℃에서 2시간동안 교반하고 실온에서 16시간동안 교반하였다. 물(200mL)에 붓고, 에테르(3x100mL)로 추출하였다. 합한 유기 추출물을 물(100mL), 0.1N 염산(2x100mL), 물(100mL), 함수(100mL)로 세척하고 건조(MgSO4)하고 농축시켰다.To a solution of 4-hydroxy naphthaldehyde (34.4 g, 0.20 mol) in dichloromethane (200 mL) and pyridine (19 mL, 18.58 g, 0.23 mol) add trifluoromethane sulfonic anhydride (46.75 g, 0.16 mol) to 0 ° C. Dropped at The mixture was stirred at 0 ° C. for 2 hours and at room temperature for 16 hours. Pour into water (200 mL) and extract with ether (3x100 mL). The combined organic extracts were washed with water (100 mL), 0.1N hydrochloric acid (2x100 mL), water (100 mL), brine (100 mL), dried (MgSO 4 ) and concentrated.

1H NMR (CDCl3) δ 7.89 - 7.97 (m, 3H), 8.09 (dd, J = 2.8, 6.5 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 9.24 (dd, J = 2.8, 6.5 Hz, 1H), 10.45 (s, 1H).1 H NMR (CDCl 3 ) δ 7.89-7.97 (m, 3H), 8.09 (dd, J = 2.8, 6.5 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 9.24 (dd, J = 2.8, 6.5 Hz, 1H), 10.45 (s, 1H).

2-(4-트리플루오로메틸술포닐옥시 나프틸)디옥솔란:2- (4-trifluoromethylsulfonyloxy naphthyl) dioxolane:

톨루엔(250mL)중 4-트리플루오로메틸술포닐옥소 나프트알데히드(4.09g, 13.4mmol), 에틸렌글리콜(1.5mL, 1.67g, 26.9mmol), 및 p-톨루엔 술폰산(250mg)의 용액을 딘-스탁 트랩을 사용하여 16시간동안 환류시켰다. 용액을 실온까지 식히고 포화 NaHCO3-용액(2x80mL), 함수(80mL)로 세척하고, 건조(MgSO4)하고 농축시켜 황색오일(4.79g, 정량)을 얻었다.A solution of 4-trifluoromethylsulfonyloxo naphthaldehyde (4.09 g, 13.4 mmol), ethylene glycol (1.5 mL, 1.67 g, 26.9 mmol), and p-toluene sulfonic acid (250 mg) in toluene (250 mL) Reflux for 16 hours using a stock trap. The solution was cooled to room temperature, washed with saturated NaHCO 3 -solution (2x80 mL), brine (80 mL), dried (MgSO 4 ) and concentrated to give a yellow oil (4.79 g, quantitative).

1H NMR (CDCl3) δ 4.19 (m, 4H), 6.47 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.66- 7.70 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 3.3, 6.3 Hz, 1H), 8.30 (dd, J = 3.3, 6.3 Hz, 1H).1 H NMR (CDCl 3 ) δ 4.19 (m, 4H), 6.47 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.66-7.70 (m, 2H), 7.81 (d, J = 8.0 Hz , 1H), 8.13 (dd, J = 3.3, 6.3 Hz, 1H), 8.30 (dd, J = 3.3, 6.3 Hz, 1H).

GCMS: 348.GCMS: 348.

2-[4-(2-에톡시카르보닐비닐)나프틸]디옥솔란:2- [4- (2-ethoxycarbonylvinyl) naphthyl] dioxolane:

질소를 DMF(6mL)중 2-(4-트리플루오로메틸술포닐옥시나프틸)디옥솔란(2.46g, 7.06mmol), 에틸아크릴레이트(2.3mL, 2.1g, 21.2mmol), 트리에틸아민(4.3g, 42.3mmol)의 용액을 15분동안 통과시키고 2염화비스(트리페틸포스핀)팔라디움을 가하였다. 잘 교반된 용액을 90℃에서 8시간동안 가열하고 농축시켰다. 잔여물을 에틸아세테이트(50mL)에 용해시키고 함수(2x50mL)로 세척하고, 건조(Na2SO4)하고 농축시켰다. 헥산/에틸아세테이트 9:1을 용리액으로서 사용하는 플래시 크로마토그래피로 정제하여 황색의 고체(1.13g, 53%)를 얻었다.Nitrogen was added to 2- (4-trifluoromethylsulfonyloxynaphthyl) dioxolane (2.46 g, 7.06 mmol) in DMF (6 mL), ethyl acrylate (2.3 mL, 2.1 g, 21.2 mmol), triethylamine ( 4.3 g, 42.3 mmol) was passed for 15 minutes and bis (tripetylphosphine) palladium was added. The well stirred solution was heated at 90 ° C. for 8 h and concentrated. The residue was dissolved in ethyl acetate (50 mL) and washed with brine ( 2 × 50 mL), dried (Na 2 SO 4 ) and concentrated. Hexane / ethyl acetate 9: 1 was purified by flash chromatography using eluent to give a yellow solid (1.13 g, 53%).

1H NMR (CDCl3) δ 1.38 (t, J = 7.0 Hz, 3H), 3.74 - 4.22 (m, 4H), 8.65 (q, J = 7.0 Hz, 2H), 6.50 (s, 1H), 6.53 (d, J = 15.7 Hz, 1H), 7.58-7.62 (m, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.52 (d, J = 15.2 Hz, 1H). 1 H NMR (CDCl 3 ) δ 1.38 (t, J = 7.0 Hz, 3H), 3.74-4.22 (m, 4H), 8.65 (q, J = 7.0 Hz, 2H), 6.50 (s, 1H), 6.53 ( d, J = 15.7 Hz, 1H), 7.58-7.62 (m, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 8.21-8.28 (m, 2H ), 8.52 (d, J = 15.2 Hz, 1H).

2-[4-(2-에톡시카르보닐에틸)나프틸]디옥솔란:2- [4- (2-ethoxycarbonylethyl) naphthyl] dioxolane:

에틸아세테이트(15mL)중 2-[4-(2-에톡시카르보닐비닐)나프틸]디옥솔란(701mg, 2.35mmol)의 용액에 팔라디움(BaCO3상의 5%, 51mg)을 가하였다. 혼합물을 질소분위기하에서 16시간동안 교반하고, 셀라이트를 통과시켜 흡입여과하고 농축시켜 무색의 오일 689mg(98%)을 얻었다.To a solution of 2- [4- (2-ethoxycarbonylvinyl) naphthyl] dioxolane (701 mg, 2.35 mmol) in ethyl acetate (15 mL) was added palladium (5% on BaCO 3 , 51 mg). The mixture was stirred for 16 h under nitrogen atmosphere, filtered through celite, suction filtered and concentrated to give 689 mg (98%) of a colorless oil.

1H NMR (CDCl3) δ 1.25 (t, J = 7.0 Hz, 3H), 2.75 (t, J = 8.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 4.12- 4.22 (m, 6H), 6.46 (s, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.54 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.07 (dd, J = 3.3, 6.5 Hz, 1H), 8.26 (dd, J = 3.3, 6.5 Hz, 1H). 1 H NMR (CDCl 3 ) δ 1.25 (t, J = 7.0 Hz, 3H), 2.75 (t, J = 8.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 4.12- 4.22 (m, 6H), 6.46 (s, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.54-7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.07 (dd, J = 3.3 , 6.5 Hz, 1H), 8.26 (dd, J = 3.3, 6.5 Hz, 1H).

에틸 3-(4-포르밀나프탈렌)프로판산;Ethyl 3- (4-formylnaphthalene) propanoic acid;

THF(15mL)중 2-[4-(2-에톡시카르보닐에틸)나프틸]디옥솔란(689mg, 2.29mmol)의 용액에 6N 염산(2mL)을 가하였다. 그 혼합물을 16시간동안 실온에서 교반하고 에틸아세테이트(20mL)로 희석하고 포화 NaHCO3용액(20mL)으로 세척하고 건조(MgSO4)하고 농축시켜 무색의 오일(407mg, 68%)로서 생성물을 얻어 방치하면서 결정화시켰다.To a solution of 2- [4- (2-ethoxycarbonylethyl) naphthyl] dioxolane (689 mg, 2.29 mmol) in THF (15 mL) was added 6N hydrochloric acid (2 mL). The mixture was stirred for 16 h at room temperature, diluted with ethyl acetate (20 mL), washed with saturated NaHCO 3 solution (20 mL), dried (MgSO 4 ) and concentrated to afford the product as a colorless oil (407 mg, 68%). Crystallized.

3-(4-포르밀나프탈렌)프로판산:3- (4-formylnaphthalene) propanoic acid:

에틸 3-(4-포르밀나프탈렌)프로판산(310mg, 1.2mmol)을 물(10mL)에 현탁시키고 Na2CO3(130mg, 1.2mmol)를 가하였다. 혼합물을 5시간동안 환류시키고 실온까지 냉각시켰다. 농 염산으로 산성화한 후, 침전물을 생성하였다. 침전물을 흡입하여 수집하고 진공으로 80℃에서 16시간동안 건조시켜 백색의 고체(300mg, 73%)를 얻었다.Ethyl 3- (4-formylnaphthalene) propanoic acid (310 mg, 1.2 mmol) was suspended in water (10 mL) and Na 2 CO 3 (130 mg, 1.2 mmol) was added. The mixture was refluxed for 5 hours and cooled to room temperature. After acidification with concentrated hydrochloric acid, a precipitate formed. The precipitate was collected by suction and dried in vacuo at 80 ° C. for 16 hours to give a white solid (300 mg, 73%).

1H NMR (DMSO-D6) δ 2.69 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 7.66-7.77 (m, 2H), 8.10 (d, J = 7.3 Hz, 1H), 8.23 (dd, J = 1.1, 8.0 Hz, 1H), 9.22 (dd, J = 1.1 , 9.0 Hz, 1H), 10.33 (s, 1H), 12.30 (br s, 1H). 1 H NMR (DMSO-D 6 ) δ 2.69 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 7.66-7.77 (m, 2H), 8.10 (d, J = 7.3 Hz, 1H), 8.23 (dd, J = 1.1, 8.0 Hz, 1H), 9.22 (dd, J = 1.1, 9.0 Hz, 1H), 10.33 (s, 1H), 12.30 (br s, 1H).

일반적인 방법(단계 A):General Method (Step A):

3-(4-포르밀나프탈렌)프로판아미드의 제조:Preparation of 3- (4-formylnaphthalene) propanamide:

DMF(3mL)중 3-(4-포르밀나프탈렌)프로판산(100mg, 0.437mmol)의 용액에 카르보닐디이미다졸(140mg, 0.863mmol)을 가하였다. 이 혼합물을 실온에서 1시간동안 교반하고, 아민(1.3당량)을 가하였다. 실온에서 16시간동안 교반한 후, 혼합물을 에틸아세테이트(5mL)로 희석시키고, 물(5mL), 1N 염산(5mL) 및 물(3x5mL)로 추출하고 건조(MgSO4)시키고 농축시켰다. 헥산/에틸아세테이트 1:1을 사용하여 플래시 크로마토그래피한 후, 순수한 아미드를 분리하였다.Carbonyldiimidazole (140 mg, 0.863 mmol) was added to a solution of 3- (4-formylnaphthalene) propanoic acid (100 mg, 0.437 mmol) in DMF (3 mL). The mixture was stirred at rt for 1 h and amine (1.3 equiv) was added. After stirring for 16 hours at room temperature, the mixture was diluted with ethyl acetate (5 mL), extracted with water (5 mL), 1N hydrochloric acid (5 mL) and water (3x5 mL), dried (MgSO 4 ) and concentrated. After flash chromatography using hexane / ethyl acetate 1: 1, pure amide was isolated.

아미드의 실시예:Examples of amides:

1H NMR (CDCl3) δ 1.06 (t, J = 7.0 Hz, 3H),1.12 (t, J = 7.0 Hz, 3H), 2.79 (t, J = 8.0 Hz, 2H), 3.50 (t, J = 8.0 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1 H), 7.64 - 7.71 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 8.18 (dd, J = 1.3, 8.0 Hz, 1H), 9.34 (dd, J = 1.3, 8.0 Hz, 1H), 10.34 (s, 1H). MS (APCI, pos.) 284.1 1 H NMR (CDCl 3 ) δ 1.06 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H), 2.79 (t, J = 8.0 Hz, 2H), 3.50 (t, J = 8.0 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.64-7.71 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H ), 8.18 (dd, J = 1.3, 8.0 Hz, 1H), 9.34 (dd, J = 1.3, 8.0 Hz, 1H), 10.34 (s, 1H). MS (APCI, pos.) 284.1

1H NMR (CDCl3) δ 0.77 (t, J = 7.0 Hz, 3 H), 0.86 (t, J = 7.0 Hz, 3 H), 1.15 -1.82 (m, 8 H), 2.58 (dt, 0.5 H), 2.65 - 2.88 (m, 2H), 2.92 (dt, 0.5H), 3.39 - 3.60 (m, 2.5H), 3.62- 3.73 (m, 0.5H), 4.58 (dd, 0.5H), 4.73 (m, 0.5H), 7.56 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.61 - 7.72 (m, 2H), 8.16 (d, J = 8.3 Hz, 1H), 9.33 (d, J = 8.0 Hz, 1H), 10.34 (s, 1H). MS (APCI, pos.) 325.2 1 H NMR (CDCl 3 ) δ 0.77 (t, J = 7.0 Hz, 3 H), 0.86 (t, J = 7.0 Hz, 3 H), 1.15 -1.82 (m, 8 H), 2.58 (dt, 0.5 H ), 2.65-2.88 (m, 2H), 2.92 (dt, 0.5H), 3.39-3.60 (m, 2.5H), 3.62- 3.73 (m, 0.5H), 4.58 (dd, 0.5H), 4.73 (m , 0.5H), 7.56 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.61-7.72 (m, 2H), 8.16 (d, J = 8.3 Hz, 1H), 9.33 (d, J = 8.0 Hz, 1 H), 10.34 (s, 1 H). MS (APCI, pos.) 325.2

4-[(4-히드록시벤조일)히드라조노메틸]나프틸프로판아미드의 유도체(단계 B):Derivatives of 4-[(4-hydroxybenzoyl) hydrazonomethyl] naphthylpropanamide (step B):

이들 화합물을 4-포르밀-1-나프틸 프로판아미드(단계 A로부터)와 4-히드록시벤조산 히드라지드 유도체를 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.These compounds were prepared according to the general method of condensing 4-formyl-1-naphthyl propanamide (from Step A) with 4-hydroxybenzoic acid hydrazide derivatives to synthesize alkylidene hydrazones.

실시예 508:Example 508:

1H NMR (DMSO-D6) δ 0.95 - 1.02 (m, 6H), 2.69 (t, J = 7.3 Hz, 2H), 3.19 (q, J = 7.0 Hz, 2H), 3.25 (q, J = 7.0 Hz, 2H), 3.33 (t, J = 7.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.65 (m, 2H), 7.81 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 9.17 (dd, J = 2.4, 6.5 Hz, 1H), 8.87 (d, J = 7.6 Hz, 1H), 9.05 (s, 1H), 11.00 (s, 1H), 11.77 (s, 1H). MS (APCI, pos. ): 452.2, 454.2 1 H NMR (DMSO-D 6 ) δ 0.95-1.02 (m, 6H), 2.69 (t, J = 7.3 Hz, 2H), 3.19 (q, J = 7.0 Hz, 2H), 3.25 (q, J = 7.0 Hz, 2H), 3.33 (t, J = 7.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.65 (m, 2H), 7.81 ( m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 9.17 (dd, J = 2.4, 6.5 Hz, 1H), 8.87 (d, J = 7.6 Hz, 1H), 9.05 (s, 1H), 11.00 (s, 1 H), 11.77 (s, 1 H). MS (APCI, pos.): 452.2, 454.2

실시예 509:Example 509:

1H NMR (DMSO-D6) δ 0.68 (t, J = 7.5 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H), 0.76 (dd, 0.5 H), 0.90 (dd, 0.5 H), 1.02 - 1.68 (m, 8H), 2.49 (m. 0.5H), 2.75 (m, 2H), 2.90 (t, J = 14.0 Hz, 0.5H), 3.33 (m, 2H), 3.61 (d, J = 12.0, Hz, 0.5H), 3.75 (m, 0.5H), 4.36 (d, J = 12.0 Hz, 0.5H), 4.53 (m, 0.5H), 7.08 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.64 - 7.66 (m, 2H), 7.80 (dd, J = 1.9, 8.5 Hz, 1 ), 7.83 (d, J =7.5 Hz, 1H), 8.00 (d, J = 1.9, Hz, 1H), 8.17 (m, 1H), 8.88 (d, J = 7.5 Hz, H), 7.25 (s, 1H), 11.0 (s, 1H), 11.76 (s, 1H). MS (APCI, pos.): 492.1, 494.1 1 H NMR (DMSO-D 6 ) δ 0.68 (t, J = 7.5 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H), 0.76 (dd, 0.5 H), 0.90 (dd, 0.5 H), 1.02-1.68 (m, 8H), 2.49 (m. 0.5H), 2.75 (m, 2H), 2.90 (t, J = 14.0 Hz, 0.5H), 3.33 (m, 2H), 3.61 (d, J = 12.0, Hz, 0.5H), 3.75 (m, 0.5H), 4.36 (d, J = 12.0 Hz, 0.5H), 4.53 (m, 0.5H), 7.08 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.64-7.66 (m, 2H), 7.80 (dd, J = 1.9, 8.5 Hz, 1), 7.83 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 1.9, Hz, 1H), 8.17 (m, 1H), 8.88 (d, J = 7.5 Hz, H), 7.25 (s, 1H), 11.0 (s, 1H), 11.76 (s, 1H). MS (APCI, pos.): 492.1, 494.1

실시예 510:Example 510:

에틸 4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프틸 프로파네이트Ethyl 4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl propanoate

이 화합물은 에틸 4-포르밀-1-나프틸프로파네이트(단계 E로부터)와 3-클로로-4-히드록시 벤조산 히드라지드를 축합시켜 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.This compound was prepared according to the general method of synthesizing alkylidene hydrazone by condensing ethyl 4-formyl-1-naphthylpropanoate (from step E) with 3-chloro-4-hydroxy benzoic acid hydrazide.

1H NMR (DMSO-D6) δ 1.14 (t, J = 7.0 Hz, 3H), 2.73 (t, J = 7.5 Hz, 2H), 3.35 (t, J = 7.5 Hz, 2H), 4.02 (q, J = 7.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 1H), 7.66 (m, 2H), 7.79 (dd, J = 1.8, 8.6 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 11.0 (brd s, 1H), 11.78 (s, 1H). MS (APCI, pos.): 425.5, 427.3 1 H NMR (DMSO-D 6 ) δ 1.14 (t, J = 7.0 Hz, 3H), 2.73 (t, J = 7.5 Hz, 2H), 3.35 (t, J = 7.5 Hz, 2H), 4.02 (q, J = 7.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 1H), 7.66 (m, 2H), 7.79 (dd, J = 1.8, 8.6 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 11.0 (brd s, 1H), 11.78 (s, 1H). MS (APCI, pos.): 425.5, 427.3

실시예 511:Example 511:

3-클로로-4-히드록시벤조산(4-트리플루오로메틸술포닐옥시 나프틸리덴)히드라지드3-Chloro-4-hydroxybenzoic acid (4-trifluoromethylsulfonyloxy naphthylidene) hydrazide

이 화합물은 4-트리플루오로메틸술포닐옥시 나프트알데히드 3-클로로-4-히드록시벤조산 히드라지드를 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.This compound was prepared according to the general method of condensing 4-trifluoromethylsulfonyloxy naphthaldehyde 3-chloro-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazone.

1H NMR (DMSO-D6) δ 7.09 (d, J = 8.7 Hz, 1H), 7.68 - 7.95 (m, 4H), 8.00 - 8.10 (m, 3H), 8.90 (s, 1H), 9.10 (s, 1H), 11.02 (s, 1H), 11.96 (s, 1H). MS (APCI, pos.): 473.2, 475.1 1 H NMR (DMSO-D 6 ) δ 7.09 (d, J = 8.7 Hz, 1H), 7.68-7.95 (m, 4H), 8.00-8.10 (m, 3H), 8.90 (s, 1H), 9.10 (s , 1H), 11.02 (s, 1H), 11.96 (s, 1H). MS (APCI, pos.): 473.2, 475.1

화학식 XV의 화합물을 합성하기 위한 일반적인 방법:General Methods for Synthesizing Compounds of Formula XV:

A 및 B는 화학식 I에서 정의된 바와 같고 -NR5cR5d는(상기 식에서, R5a, R4a, R4b, c, q, d 및 D는 화학식 I에서 정의된 바와 같다)이거나, 친핵기로서 반응할 수 있는 1차 또는 2차 아민을 포함하는 -D의 부분집합으로서 정의된 -D'이다.A and B are as defined in formula (I) and -NR 5c R 5d is (Wherein R 5a , R 4a , R 4b , c, q, d and D are as defined in formula (I)) or -D comprising a primary or secondary amine capable of reacting as a nucleophilic group -D 'defined as a subset.

단계 A: 카르보닐 화합물을 용매중에서 아실히드라지드로 처리한다. 용매는 다음중 하나가 될 수 있다: 에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, 아세트산, 물 또는 상기 용매중 상용성인 2 이상의 혼합물. 아세트산 등의 촉매가 가해질 수 있다. 트리에틸오르토포르메이트 등의 탈수화제가 또한 반응혼합물에 가해질 수 있다. 반응은 0℃ 내지 140℃, 바람직하게 10℃ 내지 80℃ 사이의 온도에서, 바람직하게 N2또는 Ar의 불활성 분위기하에서 반응혼합물을 교반함으로써 수행된다. 많은 경우, 생성물은 반응이 완결되면 간단히 결정석출되고 흡입여과에 의해 분리된다. 필요하다면 상기 기재된 반응 용매 등의 용매로부터 더 재결정될 수 있다. 생성물은 또한 반응혼합물을 진공에서 농축시키고, 이어서 클로로포름/메탄올 또는 디클로로메탄/메탄올 또는 클로로포름/에틸아세테이트 등의 용매계를 사용하는 실리카겔상의 컬럼크로마토그래피로 분리할 수 있다.Step A: The carbonyl compound is treated with acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid Two or more mixtures which are compatible in water or in said solvent. Catalysts such as acetic acid can be added. Dehydrating agents such as triethylorthoformate may also be added to the reaction mixture. The reaction is carried out by stirring the reaction mixture at a temperature between 0 ° C. and 140 ° C., preferably between 10 ° C. and 80 ° C., preferably under an inert atmosphere of N 2 or Ar. In many cases, the product simply crystallizes upon completion of the reaction and is separated by suction filtration. If necessary, it may be further recrystallized from a solvent such as the reaction solvent described above. The product can also be concentrated in vacuo and then separated by column chromatography on silica gel using a solvent system such as chloroform / methanol or dichloromethane / methanol or chloroform / ethylacetate.

단계 B: 그런 다음, 에폭사이드를 당업자에게 공지된 방법중 하나를 사용하여 1차 또는 2차 아민에 의해 고리개열하여 화학식 XV의 화합물을 얻는다. 용매는 다음중 하나가 될 수 있다: 에틸알콜, 메틸알콜, 이소프로필알콜, tert-부틸알콜, 디옥산, 테트라히드로푸란, 톨루엔, 클로로벤젠, 아니솔, 벤젠, 클로로포름, 디클로로메탄, DMSO, DMF, NMP, 물 또는 상기 용매중 상용성인 2 이상의 혼합물. 그런 다음, 생성물은 여과하거나 에틸아세테이트, 톨루엔, 디클로로메탄 또는 디에틸에테르 등의 용매를 사용하여 추출한 후 용매를 대기압 또는 감압하에서 농축시켜 제거함으로써 분리할 수 있다. 생성물은 에틸알콜, 메틸알콜, 이소프로필알콜, 톨루엔, 크실렌, 헥산, 테트라히드로푸란, 디에틸에테르, 디부틸에테르, 물 또는 상기중 2 이상의 혼합물 등의 용매로부터 재결정하여 더 정제할 수 있다. 다른 방법으로, 생성물을 디클로로메탄/메탄올 또는 클로로포름/메탄올 또는 이소프로필알콜을 용리액으로 사용하여 컬럼크로마토그래피함으로써 정제하여 화학식 XV의 화합물을 얻을 수 있다.Step B: The epoxide is then ring cleaved by the primary or secondary amine using one of the methods known to those skilled in the art to obtain a compound of formula XV. The solvent can be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, DMF , NMP, water or a mixture of two or more compatible in said solvent. The product can then be separated by filtration or extracted using a solvent such as ethyl acetate, toluene, dichloromethane or diethyl ether and then the solvent is removed by concentration under atmospheric or reduced pressure. The product can be further purified by recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of them. Alternatively, the product can be purified by column chromatography using dichloromethane / methanol or chloroform / methanol or isopropyl alcohol as eluent to afford the compound of formula XV.

본 발명에 따라서 화학식 XV의 화합물의 제조를 예시하는 구체적인 예를 하기 제공한다.Specific examples illustrating the preparation of compounds of formula XV according to the invention are provided below.

4-(2,3-에폭시프로판옥시)-1-나프트알데히드의 제조를 하기 나타낸다:Preparation of 4- (2,3-epoxypropaneoxy) -1-naphthaldehyde is shown below:

4-(2,3-에폭시프로판옥시)-1-나프트알데히드:4- (2,3-epoxypropaneoxy) -1-naphthaldehyde:

DMSO(20mL)중 4-히드록시-1-나프트알데히드(1g, 5.8mmol)의 용액에 K2CO3(1g, 7.2mmol)를 가하였다. 혼합물을 실온에서 30분간 교반한 다음, 브롬화 2,3-에폭시프로필(0.96g, 7mmol)을 가하였다. 24시간동안 교반한 후, 물(100mL)을 가하였다. 혼합물을 에틸아세테이트(3x80mL)로 추출하고, 건조(MgSO4)하고, 농축시켜 갈색 고체(1.23g, 93%)를 얻었다.To a solution of 4-hydroxy-1-naphthaldehyde (1 g, 5.8 mmol) in DMSO (20 mL) was added K 2 CO 3 (1 g, 7.2 mmol). The mixture was stirred at rt for 30 min and then brominated 2,3-epoxypropyl (0.96 g, 7 mmol) was added. After stirring for 24 hours, water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 80 mL), dried (MgSO 4 ) and concentrated to give a brown solid (1.23 g, 93%).

1H NMR (CDCl3) δ 2.88 (dd, J = 2.6, 4.8 Hz, 1H), 3.02 (dd, J = 4.0, 4.6 Hz, 1H), 3.51 - 3.57 (m, 1H), 4.22 (dd, J = 5.8, 11.1 Hz, 1H), 4.55 (dd, J = 2.8, 11.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 9.31 (d, J = 8.6 Hz, 1H), 10.22 (s, 1H). 1 H NMR (CDCl 3 ) δ 2.88 (dd, J = 2.6, 4.8 Hz, 1H), 3.02 (dd, J = 4.0, 4.6 Hz, 1H), 3.51-3.57 (m, 1H), 4.22 (dd, J = 5.8, 11.1 Hz, 1H), 4.55 (dd, J = 2.8, 11.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.71 (t , J = 7.7 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 9.31 (d, J = 8.6 Hz, 1H), 10.22 (s, 1H) ).

일반적인 방법;General method;

4-히드록시벤조산 4-(2,3-에폭시프로판옥시)-1-나프틸리덴 히드라지드 유도체(단계 A):4-hydroxybenzoic acid 4- (2,3-epoxypropaneoxy) -1-naphthylidene hydrazide derivative (step A):

이 화합물은 상기 에폭시-알데히드를 4-히드록시벤조산 히드라지드 유도체와 축합하여 알킬리덴 히드라존을 합성하기 위한 일반적인 방법에 따라서 제조하였다.This compound was prepared according to the general method for the condensation of the above epoxy-aldehydes with 4-hydroxybenzoic acid hydrazide derivatives to synthesize alkylidene hydrazones.

1H NMR (DMSO-d6) δ 2.84 (dd, J = 2.2, 4.9 Hz, 1H), 2.92 (dd, J = 4.5, 4.5 Hz, 1H), 3.45 - 3.57 (m, 1H), 4.11 (dd, J = 6.4, 11.3 Hz, 1H), 4.60 (d, J = 11.3 Hz, 1H), 7.02 - 7.18 (m, 2H), 7.55 - 7.90 (m, 4H), 7.99 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.90 - 9.05 (d, 2H), 10.94 (s, 1H), 11.66 (s, 1H). MS ( APCI, negative ): 395. 1 H NMR (DMSO-d 6 ) δ 2.84 (dd, J = 2.2, 4.9 Hz, 1H), 2.92 (dd, J = 4.5, 4.5 Hz, 1H), 3.45-3.57 (m, 1H), 4.11 (dd , J = 6.4, 11.3 Hz, 1H), 4.60 (d, J = 11.3 Hz, 1H), 7.02-7.18 (m, 2H), 7.55-7.90 (m, 4H), 7.99 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.90-9.05 (d, 2H), 10.94 (s, 1H), 11.66 (s, 1H). MS (APCI, negative): 395.

에폭사이드 고리개열을 위한 일반적인 방법(단계 B):General method for epoxide cleavage (step B):

에탄올 10mL중 에폭사이드(0.2mmol)와 아민(0.3mmol)의 혼합물을 4시간동안 환류시켰다. 농축후 적색 오일을 얻었다. 생성물을 조제용 HPLC로 정제하였다.A mixture of epoxide (0.2 mmol) and amine (0.3 mmol) in 10 mL of ethanol was refluxed for 4 hours. After concentration a red oil was obtained. The product was purified by preparative HPLC.

화학식 XV의 화합물의 실시예 :Examples of compounds of formula XV:

실시예 512:Example 512:

1H NMR (DMSO-d6) δ 0.95 (t, J = 6.9 Hz, 6H), 1.90 (s, 3H), 2.50, 2.62 (2q, J = 6.6 Hz, 4H), 2.70 (dd, J = 6.6, 13.0 Hz, 1H), 2.88 (dd, J = 7.0, 14.2 Hz, 1H), 3.95 - 4.35 (m, 3H), 7.02 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 7.55 - 7.85 (m, 4H), 7.96 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.60 (s, 1H); MS (APCI, pos.): 470. 1 H NMR (DMSO-d 6 ) δ 0.95 (t, J = 6.9 Hz, 6H), 1.90 (s, 3H), 2.50, 2.62 (2q, J = 6.6 Hz, 4H), 2.70 (dd, J = 6.6 , 13.0 Hz, 1H), 2.88 (dd, J = 7.0, 14.2 Hz, 1H), 3.95-4.35 (m, 3H), 7.02 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 8.3 Hz , 1H), 7.55-7.85 (m, 4H), 7.96 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.85-9.05 (d, 2H), 11.60 (s, 1H); MS (APCI, pos.): 470.

실시예 513:Example 513:

1H NMR (DMSO-d6) δ 1.67 (brd s, 4H), 1.88 (s, 3H), 2.50 - 2.85 (m, 6H), 4.0 - 4.3 (m, 3H), 7.00 - 7.12 (t, 2H), 7.55 - 7.85 (m, 4H), 7.97 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.63 (s, 1H); MS ( APCI, pos.): 468. 1 H NMR (DMSO-d 6 ) δ 1.67 (brd s, 4H), 1.88 (s, 3H), 2.50-2.85 (m, 6H), 4.0-4.3 (m, 3H), 7.00-7.12 (t, 2H ), 7.55-7.85 (m, 4H), 7.97 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.85-9.05 (d, 2H), 11.63 (s, 1H); MS (APCI, pos.): 468.

실시예 514:Example 514:

1H NMR (DMSO-d6) δ 1.30 -1.55 (m, 6H), 1.88 (s, 3H), 2.35 -2.60 (m, 6H), 4.05 - 4.30 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.55 - 7.85 (m, 4H), 7.97 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.62 (s, 1H); MS (APCI, pos.): 470. 1 H NMR (DMSO-d 6 ) δ 1.30 -1.55 (m, 6H), 1.88 (s, 3H), 2.35 -2.60 (m, 6H), 4.05-4.30 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.55-7.85 (m, 4H), 7.97 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H) , 8.85-9.05 (d, 2H), 11.62 (s, 1H); MS (APCI, pos.): 470.

실시예 515:Example 515:

1H NMR (DMSO-d6) δ 1.25 -1.82 (m, 8H), 1.88 (s, 3H), 2.68 -2.90 (m, 2H), 3.08 ( m, 1H), 4.0 - 4.25 (m, 3H), 7.03 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.52 - 7.85 (m, 4H), 7.97 (d, J = 1.4 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.85 - 9.0 (d, 2H), 11.61 (s, 1H); MS (APCI, pos.): 482. 1 H NMR (DMSO-d 6 ) δ 1.25 -1.82 (m, 8H), 1.88 (s, 3H), 2.68 -2.90 (m, 2H), 3.08 (m, 1H), 4.0-4.25 (m, 3H) , 7.03 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.52-7.85 (m, 4H), 7.97 (d, J = 1.4 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.85-9.0 (d, 2H), 11.61 (s, 1H); MS (APCI, pos.): 482.

실시예 516:Example 516:

1H NMR (DMSO-d6) δ 0.95 -1.80 ( m, 10H ), 1.88 (s, 3H ), 2.45 (m, 1H ), 2.70 -2.90 (m, 2H ), 3.98-4.30 (m, 3H), 7.02 (d, J = 8.52 Hz, 1H), 7.07 (d, J = 8.2 Hz, H ), 7.52 -- 7.75 (m, 4H), 7.97 (d, J = 2.05 Hz, 1H), 8.34 (d, J = 8.33 Hz, 1H), 8.87 - 9.00 (m, 2H), 11.61 (s, 1H); MS ( APCI, pos.): 496. 1 H NMR (DMSO-d 6 ) δ 0.95 -1.80 (m, 10H), 1.88 (s, 3H), 2.45 (m, 1H), 2.70 -2.90 (m, 2H), 3.98-4.30 (m, 3H) , 7.02 (d, J = 8.52 Hz, 1H), 7.07 (d, J = 8.2 Hz, H), 7.52-7.75 (m, 4H), 7.97 (d, J = 2.05 Hz, 1H), 8.34 (d , J = 8.33 Hz, 1H), 8.87-9.00 (m, 2H), 11.61 (s, 1H); MS (APCI, pos.): 496.

실시예 517:Example 517:

3-클로로-4-히드록시벤조산 4-(3-히드록시프로필)나프틸메틸렌 히드라지드3-Chloro-4-hydroxybenzoic acid 4- (3-hydroxypropyl) naphthylmethylene hydrazide

2-[4-(3-히드록시프로필)나프틸]디옥솔란(단계 A):2- [4- (3-hydroxypropyl) naphthyl] dioxolane (step A):

무수 THF(5mL)중 2-[4-(2-에톡시카르보닐에틸)나프틸]디옥솔란(210mg, 0.70mmol)의 용액에 THF중 1M 수소화리튬알루미늄(0.5mL)을 0℃에서 가하였다. THF(5mL)를 가하고 혼합물을 실온에서 16시간동안 교반하고, 물(10mL)로 희석하고 농 염산으로 산성화하고 에테르(3x10mL)로 추출하였다. 합한 유기 추출물을 건조(MgSO4)하고 농축시켰다. 잔여물을 헥산/에틸아세테이트 2:1을 용리액으로 하는플래시 크로마토그래피하여 정제함으로써 무색의 오일 67mg(37%)을 얻었다.To a solution of 2- [4- (2-ethoxycarbonylethyl) naphthyl] dioxolane (210 mg, 0.70 mmol) in dry THF (5 mL) was added 1 M lithium aluminum hydride (0.5 mL) in THF at 0 ° C. . THF (5 mL) was added and the mixture was stirred for 16 h at rt, diluted with water (10 mL), acidified with concentrated hydrochloric acid and extracted with ether (3 × 10 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated. The residue was purified by flash chromatography with hexane / ethyl acetate 2: 1 as eluent to give 67 mg (37%) of a colorless oil.

1H NMR (CDCl3) δ 1.51 (brd s, 1H), 1.99 - 2.04 (m, 2H), 3.19 (t, J = 7.4 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 4.16 - 4.22 (m, 4H), 6.47 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.52 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.11 (d, J = 9.8 Hz, 1H), 8.25 (d, J = 9.8 Hz, 1H). GCMS: 258 1 H NMR (CDCl 3 ) δ 1.51 (brd s, 1H), 1.99-2.04 (m, 2H), 3.19 (t, J = 7.4 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 4.16 -4.22 (m, 4H), 6.47 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.52-7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.11 ( d, J = 9.8 Hz, 1H), 8.25 (d, J = 9.8 Hz, 1H). GCMS: 258

1-포르밀-4-(3-히드록시프로필)나프탈렌(단계 B):1-formyl-4- (3-hydroxypropyl) naphthalene (step B):

무수 THF(5mL)중 2-[4-(3-히드록시프로필)나프틸]디옥솔란(67mg, 0.26mmol)의 용액에 1N 염산(1mL)을 가하였다. 혼합물을 실온에서 48시간동안 교반하고 에틸아세테이트(20mL)로 희석하고, 포화 NaHCO3용액(2x10mL)으로 세척하고, 건조(MgSO4)하고 농축시켜 CHCl3(3x10mL)로 공증발(coevaporation)시켜 무색의 오일 40mg(72%)을 얻었다.1N hydrochloric acid (1 mL) was added to a solution of 2- [4- (3-hydroxypropyl) naphthyl] dioxolane (67 mg, 0.26 mmol) in anhydrous THF (5 mL). The mixture was stirred for 48 h at rt, diluted with ethyl acetate (20 mL), washed with saturated NaHCO 3 solution (2 × 10 mL), dried (MgSO 4 ) and concentrated to coevaporated with CHCl 3 ( 3 × 10 mL) to give colorlessness. 40 mg (72%) of oil was obtained.

1H NMR (CDCl3) δ 1.56 (brd s, 1 H), 2.02 - 2.08 (m, 2H), 3.27 (t, J = 7.5 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 7.53 (d, J = 7.3 Hz, H), 7.62 -7.70 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 9.17 (d, J = 8.3 Hz, 1H), 9.34 (d, J = 8.6 Hz, 1H), 10.34 (s, 1H). 1 H NMR (CDCl 3 ) δ 1.56 (brd s, 1 H), 2.02-2.08 (m, 2H), 3.27 (t, J = 7.5 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 7.53 (d, J = 7.3 Hz, H), 7.62 -7.70 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 9.17 (d, J = 8.3 Hz, 1H), 9.34 (d, J = 8.6 Hz, 1H), 10.34 (s, 1H).

3-클로로-4-히드록시벤조산 4-(3-히드록시프로필)나프틸메틸렌 히드라지드(단계 C):3-Chloro-4-hydroxybenzoic acid 4- (3-hydroxypropyl) naphthylmethylene hydrazide (step C):

이 화합물을 단계 B로부터의 1-포르밀-4-(3-히드록시프로필)나프탈렌과 3-클로로-4-히드록시벤조산 히드라지드를 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.This compound was prepared according to the general method of condensing 1-formyl-4- (3-hydroxypropyl) naphthalene and 3-chloro-4-hydroxybenzoic acid hydrazide from Step B to synthesize alkylidene hydrazone. .

1H NMR DMSO-D6) δ 1.83 (m, 2H), 3.12 (t, J = 7.5 Hz, 2H), 3.51 (dt, J = 4.9, 7.0 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.65 (m, 2H), 7.80 (dd, J = 2.0, 8.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H),8.19 (dd, J = 2.5, 7.0 Hz, 1H), 8.84 (d, J = 8.4 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H). 1 H NMR DMSO-D 6 ) δ 1.83 (m, 2H), 3.12 (t, J = 7.5 Hz, 2H), 3.51 (dt, J = 4.9, 7.0 Hz, 2H), 7.09 (d, J = 8.5 Hz , 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.65 (m, 2H), 7.80 (dd, J = 2.0, 8.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 8.19 (dd, J = 2.5, 7.0 Hz, 1H), 8.84 (d, J = 8.4 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H) , 11.76 (s, 1 H).

MS (APCI, pos.): 383.1, 385.1.MS (APCI, pos.): 383.1, 385.1.

실시예 518:Example 518:

4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프틸 디에틸아크릴아미드4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl diethylacrylamide

에틸 (4-히드록시메틸)나프탈렌 아크릴레이트(단계 A):Ethyl (4-hydroxymethyl) naphthalene acrylate (step A):

THF(10mL)중 수소화나트륨(160mg, 미네랄오일중 60% 분산물, 4.00mmol)의 용액에 트리에틸포스포노아세테이트(0.77mL, 670mg, 3.88mmol)를 0℃에서 가하였다. 혼합물을 0℃에서 1시간동안 교반하고, THF(5mL)중 4-히드록시메틸 나프트알데히드(600mg, 3.2mmol)를 동일한 온도에서 가하였다. 혼합물을 실온에서 16시간동안 교반하고 포화 NH4Cl-용액(10mL)로 희석시키고 에틸아세테이트(3x10mL)로 추출하였따. 합한 유기 추출물을 건조(MgSO4)하고 농축시켜 무색의 오일 900mg을 얻고 다음 단계에서 추가의 정제없이 사용하였다.To a solution of sodium hydride (160 mg, 60% dispersion in mineral oil, 4.00 mmol) in THF (10 mL) was added triethylphosphonoacetate (0.77 mL, 670 mg, 3.88 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 1 h, and 4-hydroxymethyl naphthaldehyde (600 mg, 3.2 mmol) in THF (5 mL) was added at the same temperature. The mixture was stirred at rt for 16 h, diluted with saturated NH 4 Cl-solution (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried (MgSO 4 ) and concentrated to afford 900 mg of a colorless oil which was used without further purification in the next step.

1H NMR (CDCl3) δ 1.37 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 5.17 (s, 2H), 6.50 (d, J = 15.7 Hz, 1H), 7.54 - 7.62 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 8.13 (dd, J = 2.8, 9.8 Hz, 1H), 8.21 (dd, J = 2.8, 9.8 Hz, 1H), 8.49 (d, J = 15.7 Hz, 1H). 1 H NMR (CDCl 3 ) δ 1.37 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 5.17 (s, 2H), 6.50 (d , J = 15.7 Hz, 1H), 7.54-7.62 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 8.13 (dd, J = 2.8, 9.8 Hz, 1H), 8.21 (dd, J = 2.8, 9.8 Hz, 1H), 8.49 (d, J = 15.7 Hz, 1H).

에틸 4-포르밀나프탈렌 아클릴레이트(단계 B):Ethyl 4-formylnaphthalene acrylate (step B):

단계 A로부터의 미정제 물질(900mg)을 클로로포름(10mL)에 용해시키고 2산화망간(1.5g, 17mmol)을 가하였다. 실온에서 16시간동안 교반한 후, 현탁액을 셀라이트를 통과시켜 흡입여과하고 여과물을 농축하였다. 헥산/에틸아세테이트 5:1을 사용하여 플래시 크로마토그래피하여 무색의 오일 491mg(2단계에 걸쳐 60%)을 얻었다.The crude material (900 mg) from Step A was dissolved in chloroform (10 mL) and manganese dioxide (1.5 g, 17 mmol) was added. After stirring for 16 hours at room temperature, the suspension was suction filtered through celite and the filtrate was concentrated. Flash chromatography using hexane / ethyl acetate 5: 1 gave 491 mg (60% over 2 steps) of a colorless oil.

1H NMR (CDCl3) δ 1.39 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 6.60 (d, J = 15.7 Hz, 1H), 7.68 - 7.75 (m, 2H), 7.85 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 15.7 Hz, 1H), 9.31 (dd, J = 1.3, 8.1 Hz, 1H), 10.43 (s, 1H). MS (APCI, neg.): 254.1 1 H NMR (CDCl 3 ) δ 1.39 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 6.60 (d, J = 15.7 Hz, 1H ), 7.68-7.75 (m, 2H), 7.85 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.50 (d , J = 15.7 Hz, 1H), 9.31 (dd, J = 1.3, 8.1 Hz, 1H), 10.43 (s, 1H). MS (APCI, neg.): 254.1

4-포르밀나프탈렌 아크릴산(단계 C):4-formylnaphthalene acrylic acid (step C):

물(10mL)중 에틸 4-포르밀나프탈렌 아크릴레이트(391mg, 1.53mmol), 탄산나트륨(195mg, 1.84mmol)의 현탁액을 16시간동안 환류시켰다. 냉용액을 여과하고 여과물을 농 염산으로 산성화하였다. 침전물을 흡입하여 수집하고 48시간동안 진공에서 건조하여 황색의 고체로서 생성물(325mg, 94%)을 얻었다.A suspension of ethyl 4-formylnaphthalene acrylate (391 mg, 1.53 mmol) and sodium carbonate (195 mg, 1.84 mmol) in water (10 mL) was refluxed for 16 h. The cold solution was filtered and the filtrate was acidified with concentrated hydrochloric acid. The precipitate was collected by suction and dried in vacuo for 48 hours to give the product (325 mg, 94%) as a yellow solid.

1H NMR (DMSO-D6) δ 6.72 (d, J = 15.7 Hz, 1H), 7.71 - 7.75 (m, 2H), 8.12 (d, J = 7.45Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 15.7 Hz, 1H), 9.21 (d, J = 8.0 Hz, 1H), 10.43 (s,1 H). 1 H NMR (DMSO-D 6 ) δ 6.72 (d, J = 15.7 Hz, 1H), 7.71-7.75 (m, 2H), 8.12 (d, J = 7.45 Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 15.7 Hz, 1H), 9.21 (d, J = 8.0 Hz, 1H), 10.43 (s, 1H).

4-포르밀나프탈렌 디에틸아크릴아미드(단계 D):4-formylnaphthalene diethylacrylamide (step D):

DMF(4mL)중 4-포르밀나프탈렌 아크릴산(210mg, 0.92mmol)의 용액에 카르보닐디이미다졸(180mg, 1.10mmol)을 가하였다. 혼합물을 실온에서 1시간동안 교반하고 디에닐아민(0.1mL, 71mg, 0.97mmol)을 가하였다. 실온에서 16시간동안 교반한 후, 혼합물을 에틸아세테이트(5mL)로 희석하고, 물(5mL), 1N 염산(5mL) 및 물(3x5mL)로 추출하고 건조(MgSO4)하고 농축시켰다. 헥산/에틸아세테이트 1:1을 용리액으로 하는플래시 크로마토그래피하여 정제함으로써 황색의 오일 115mg(43%)을 얻었다.Carbonyldiimidazole (180 mg, 1.10 mmol) was added to a solution of 4-formylnaphthalene acrylic acid (210 mg, 0.92 mmol) in DMF (4 mL). The mixture was stirred at rt for 1 h and dienylamine (0.1 mL, 71 mg, 0.97 mmol) was added. After stirring for 16 hours at room temperature, the mixture was diluted with ethyl acetate (5 mL), extracted with water (5 mL), 1N hydrochloric acid (5 mL) and water (3x5 mL), dried (MgSO 4 ) and concentrated. 115 mg (43%) of a yellow oil was obtained by flash chromatography using hexane / ethyl acetate 1: 1 as an eluent.

1H NMR (CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.55 (m, 4H), 6.97 (d, J = 15.7 Hz, 1H), 7.63 - 7.76 (m, 2 H), 7.80 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 7.4 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 15.7 Hz, 1H), 9.30 (d, J = 8.3 Hz, 1H), 10.43 (s, 1H). 1 H NMR (CDCl 3 ) δ 1.25 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.55 (m, 4H), 6.97 (d, J = 15.7 Hz, 1H) , 7.63-7.76 (m, 2H), 7.80 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 7.4 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.51 (d , J = 15.7 Hz, 1H), 9.30 (d, J = 8.3 Hz, 1H), 10.43 (s, 1H).

4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프틸 디에틸아크릴아미드(단계 E):4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl diethylacrylamide (step E):

이 화합물을 4-포르밀-1-나프틸 디에틸아크릴아미드(단계 D로부터)과 3-클로로-4-히드록시벤조산 히드라지드를 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라 제조하였다.This compound was prepared according to the general method of condensing 4-formyl-1-naphthyl diethylacrylamide (from step D) with 3-chloro-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazone.

1H NMR (DMSO-D6) δ 1.11 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H), 3.42 (q, J = 7.0 Hz, 1H), 3.56 (q, J = 7.0 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 15.1 Hz, 1H), 7.67 - 7.72 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.96-8.03 (m, 2H), 8.06 (d, J = 7.7 Hz, 1H), 8.26 (dd, J = 2.1, 7.2 Hz, 1H), 8.32 (d, J = 15.1 Hz, 1H), 8.83 (d, J = 7.0 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1H), 11.86 (s, 1H). MS (APCI, pos.): 450.3 1 H NMR (DMSO-D 6 ) δ 1.11 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H), 3.42 (q, J = 7.0 Hz, 1H), 3.56 (q, J = 7.0 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 15.1 Hz, 1H), 7.67-7.72 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.96-8.03 (m, 2H), 8.06 (d, J = 7.7 Hz, 1H), 8.26 (dd, J = 2.1, 7.2 Hz, 1H), 8.32 (d, J = 15.1 Hz, 1H), 8.83 (d, J = 7.0 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1H), 11.86 (s, 1H). MS (APCI, pos.): 450.3

실시예 519:Example 519:

에틸 4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프틸 아크릴레이트Ethyl 4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl acrylate

이 화합물을 에틸 4-포르밀-1-나프틸 아크릴레이트(단계 B로부터)와 3-클로로-4-히드록시벤조산 히드라지드를 축합하여 알킬리덴 히드라존을 합성하는 일반적인 방법에 따라서 제조하였다.This compound was prepared according to the general method of condensing ethyl 4-formyl-1-naphthyl acrylate (from step B) with 3-chloro-4-hydroxybenzoic acid hydrazide to synthesize alkylidene hydrazone.

1H NMR (DMSO-D6) δ 1.29 (t, J = 7.1 Hz, 3H), 4.25 (q, J = 7.1 Hz, 2H), 6.75 (d, J 15.7 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.71 (m, 2H), 7.92 (d, J = 8.5 Hz, 1H), 8.01 (m, 2H), 8.07 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 15.7 Hz, 1H), 8.81 (d, J = 7.1 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1H), 11.89 (s, 1H). MS (APCI, pos.): 421.1, 423.0 1 H NMR (DMSO-D 6 ) δ 1.29 (t, J = 7.1 Hz, 3H), 4.25 (q, J = 7.1 Hz, 2H), 6.75 (d, J 15.7 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.71 (m, 2H), 7.92 (d, J = 8.5 Hz, 1H), 8.01 (m, 2H), 8.07 (d, J = 8.0 Hz, 1H), 8.46 (d, J = 15.7 Hz, 1H), 8.81 (d, J = 7.1 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1H), 11.89 (s, 1H). MS (APCI, pos.): 421.1, 423.0

실시예 520:Example 520:

4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프틸 아크릴레이트4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl acrylate

이 화합물은 4-포르밀-1-나프틸 아크릴레이트(단계 C로부터)와 3-클로로-4-히드록시벤조산 히드라지드를 축합하여 알킬리덴히드라존을 합성하는 일반적인 방법에 따라 제조하였다.This compound was prepared according to the general method of condensing 4-formyl-1-naphthyl acrylate (from Step C) with 3-chloro-4-hydroxybenzoic acid hydrazide to synthesize alkylidenehydrazone.

1H NMR (DMSO-D6) δ 6.65 (d, J = 15.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.66 - 7.74 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.97 - 8.05 (m, 3H), 8.29 (dd, J = 2.2, 7.1 Hz, 1H), 8.41 (d, J = 15.6 Hz, 1H), 8.82 (d, J = 7.6 Hz, 1 H), 9.12 (s, 1 H), 10.92 (s, 1 H), 11.89 (s, 1H), 12.62 (s, 1H). MS (APCI, pos.): 394.1, 395.3 1 H NMR (DMSO-D6) δ 6.65 (d, J = 15.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.66-7.74 (m, 2H), 7.81 (d, J = 8.5 Hz , 1H), 7.97-8.05 (m, 3H), 8.29 (dd, J = 2.2, 7.1 Hz, 1H), 8.41 (d, J = 15.6 Hz, 1H), 8.82 (d, J = 7.6 Hz, 1 H ), 9.12 (s, 1H), 10.92 (s, 1H), 11.89 (s, 1H), 12.62 (s, 1H). MS (APCI, pos.): 394.1, 395.3

치환 피페라진-아릴-알데히드의 합성과 이후의 히드라존 생성을 위한 일반적인 방법:General methods for the synthesis of substituted piperazine-aryl-aldehydes and subsequent generation of hydrazones:

치환 피페라진-아릴-알데히드를 상기 정의된 바와 같이 -(K)m-D 부분을 도입하는 다양한 친핵성 알킬화제를 사용하여 상응하는 미치환 피페라진-아릴-알데히드의 N-알킬화에 의해 제조할 수 있다.Substituted piperazine-aryl-aldehydes can be prepared by N-alkylation of the corresponding unsubstituted piperazine-aryl-aldehydes using various nucleophilic alkylating agents which introduce a-(K) m -D moiety as defined above. have.

상기 식에서, Lx는 -Cl, -Br, -I, -OSO2CH3, -OSO2p-톨릴 또는 -OSO2CF3등의 이탈기이고; A, R3a, R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R14및 R15는 화학식 I에서 정의된 바와 같다.In the above formula, Lx is a leaving group such as -Cl, -Br, -I, -OSO 2 CH 3 , -OSO 2 p-tolyl or -OSO 2 CF 3 or the like; A, R 3a , R 3b , R 4a , R 4b , a, b, c, d, f, p, q, D, M, R 14 and R 15 are as defined in formula (I).

상기 반응식에 따라서 치환 피페라진-아릴-알데히드는 아세톤, 메틸에틸케톤, 디메틸포름아미드, DMSO, 디옥산, 테트라히드로푸란, 톨루엔, 에틸렌글리콜 디메틸에테르, 술폴란, 디에틸에테르, 물 또는 상기 용매중 상용성인 2 이상의 혼합물 등의 유기 용매에서 수소화나트륨, 수소화칼륨, 메톡시화, 에톡시화 또는 tert-부톡시화 나트륨 또는 칼륨, 탄산 나트륨, 칼륨 또는 세슘, 또는 플루오로화 칼륨 또는 세슘, 수산화 나트륨 또는 칼륨 등의 염기, 또는 디이소프로필에틸아민, 2,4,6-콜리딘, 또는 메톡시화 또는 수산화 벤질디메틸암모늄 등의 유기염기 1 내지 15당량(바람직하게 1 내지 5당량)에서 피페라진일벤즈알데히드 또는 피페라진일나프트알데히드를 알킬 할라이드 또는 아릴-저급알킬 할라이드의 등몰량과 교반함으로써 제조될 수 있다. 반응을 0℃ 내지 150℃, 바람직하게 20℃ 내지 100℃에서 바람직하게 N2또는 Ar의 불활성 분위기에서 수행할 수 있다. 반응이 완결되면 혼합물을 여과하고 진공에서 농축하고, 그 결과의 생성물을 선택적으로 에틸아세테이트/헥산을 용리액으로 사용하여 실리카겔상의 컬럼크로마토그래피로 정제한다. 화합물을 또한 에틸알콜, 에틸아세테이트, 이소프로필알콜, 물, 헥산, 톨루엔 또는 이들의 상용성인 혼합물 등의 적당한 용매로부터 재결정하여 (적절한 때)정제할 수 있다. 미치환 피페라진아릴-알데히드의 제조를 예시하는 구체적인 실시예가 하기 제공된다.According to the above scheme, the substituted piperazine-aryl-aldehydes are acetone, methylethylketone, dimethylformamide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethyl ether, water or in the solvent Sodium hydride, potassium hydride, methoxylated, ethoxylated or tert-butoxylated sodium or potassium, sodium carbonate, potassium or cesium, or potassium fluoride or cesium, sodium hydroxide or potassium in organic solvents such as two or more mixtures that are compatible Piperazinylbenzaldehyde or pipepe at 1 to 15 equivalents (preferably 1 to 5 equivalents) of an organic base such as base, or diisopropylethylamine, 2,4,6-collidine, or methoxylated or benzyldimethylammonium hydroxide Razinylnaphthaldehyde can be prepared by stirring with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide. The reaction can be carried out at 0 ° C. to 150 ° C., preferably at 20 ° C. to 100 ° C., preferably in an inert atmosphere of N 2 or Ar. Upon completion of the reaction the mixture is filtered and concentrated in vacuo and the resulting product is purified by column chromatography on silica gel, optionally using ethyl acetate / hexane as eluent. The compound may also be purified (if appropriate) by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or a compatible mixture thereof. Specific examples illustrating the preparation of unsubstituted piperazinearyl-aldehydes are provided below.

다음 단계, 히드라존 생성은 일반적으로 상기 나타나 있고 상세히 하기 나타낸다.The next step, hydrazone generation, is generally shown above and in detail below.

4-피페라진일-2,5-디메틸벤즈알데히드의 제조:Preparation of 4-piperazinyl-2,5-dimethylbenzaldehyde:

4-(2,5-트리메틸페틸)-1-벤질피페라진:4- (2,5-trimethylfetyl) -1-benzylpiperazine:

2,5-디메틸페닐피페라진(20g, 105mmol)의 용액을 아세토니트릴(300mL)에서 제조하고 0℃까지 냉각시켰다. 브롬화벤질(19g, 111mmol)을 가하고 탄산칼륨(16g, 116mmol)을 가하기 전에 반응혼합물을 15분동안 교반하였다. 2시간동안 혼합물을 교반한 후, 아세토니트릴을 증발시키고 잔여물을 물과 에틸아세테이트에 흡수시켰다. 유기층을 분리하고 함수로 세척하고 황산마그네슘에서 건조시켰다. 벤질화 생성물을 구배 헥산/에틸아세테이트(10/0에서 8/2)를 사용하는 실리카겔 컬럼크로마토그래피로 정제하였다. 생성물(21g, 71%)을 오일의 형태로 얻었다.A solution of 2,5-dimethylphenylpiperazine (20 g, 105 mmol) was prepared in acetonitrile (300 mL) and cooled to 0 ° C. Benzyl bromide (19 g, 111 mmol) was added and the reaction mixture was stirred for 15 minutes before potassium carbonate (16 g, 116 mmol) was added. After stirring the mixture for 2 hours, acetonitrile was evaporated and the residue was taken up in water and ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate. Benzylation products were purified by silica gel column chromatography using gradient hexanes / ethyl acetate (10/0 to 8/2). The product (21 g, 71%) was obtained in the form of an oil.

1H NMR (CDCl-3) δ 2.24 (s, 3H), 2.29 (s, 3H), 2.60 (brd s, 4H), 2.92 (brd s, 4H), 3.55 (s, 2H), 6.78 (m, 1H), 6.84 (s, 1H), 7.04 (m, 1H), 7.30 (m, 5H). 1 H NMR (CDCl- 3 ) δ 2.24 (s, 3H), 2.29 (s, 3H), 2.60 (brd s, 4H), 2.92 (brd s, 4H), 3.55 (s, 2H), 6.78 (m, 1H), 6.84 (s, 1H), 7.04 (m, 1H), 7.30 (m, 5H).

4-(2,5-디메틸-4-포르밀페닐)-1-벤질피페라진:4- (2,5-dimethyl-4-formylphenyl) -1-benzylpiperazine:

4-(2,5)-디메틸페닐)-1-벤질피페라진(10g, 35mmol)을 무수 DMF(30mL, 390mmol)에 용해시키고 0℃까지 냉각시켰다. 새롭게 POCl3(70mL, 750mmol)을 교반하면서 적가하였다. 첨가가 완결되면, 암색의 혼합물을 75℃까지 5시간동안 또는 TLC분석이 출발물질이 사라졌음을 나타낼 때까지 가열하였다. 과량의 옥시염화인을 증류제거하고 전체 혼합물을 에틸아세테이트로 희석하고 얼음조각 500mL로 천천히 가하였다. 용액을 중화하고 농 NaOH로 염기성화하였다. 중화 및 염기성화는 부생성불이 생기는 것을 피하기 위햐 저온에서 실시하여야 한다. 포르밀화 생성물을 에틸아세테이트(5x)로 추출하였다. 유기층을 물(2x), 함수로 세척하고 황산마그네슘으로 건조시키고, 구배 헥산/에틸아세테이트(10/0에서 8/2)를 사용하는 실리카겔 컬럼크로마토그래피로 정제하였다. 생성물(9g, 81%)을 오일의 형태로 얻었다.4- (2,5) -dimethylphenyl) -1-benzylpiperazine (10 g, 35 mmol) was dissolved in anhydrous DMF (30 mL, 390 mmol) and cooled to 0 ° C. Fresh POCl 3 (70 mL, 750 mmol) was added dropwise with stirring. Once the addition was complete, the dark mixture was heated to 75 ° C. for 5 hours or until TLC analysis indicated the disappearance of the starting material. Excess phosphorus oxychloride was distilled off and the whole mixture was diluted with ethyl acetate and slowly added to 500 mL ice cubes. The solution was neutralized and basified with concentrated NaOH. Neutralization and basicization should be carried out at low temperatures to avoid formation of byproducts. The formylation product was extracted with ethyl acetate (5 ×). The organic layer was washed with water (2 ×), brine, dried over magnesium sulfate and purified by silica gel column chromatography using gradient hexane / ethyl acetate (10/0 to 8/2). The product (9 g, 81%) was obtained in the form of an oil.

1H NMR (CDCl3) δ 2.29 (s, 3H), 2.28 (s + t, 7H), 3.03 (t, 4H), 3.59 (s, 2H), 6.75 (s, 1H), 7.31 (m, 5H), 7.58 (s, 1H), 10.12 (s, 1H). 1 H NMR (CDCl 3 ) δ 2.29 (s, 3H), 2.28 (s + t, 7H), 3.03 (t, 4H), 3.59 (s, 2H), 6.75 (s, 1H), 7.31 (m, 5H ), 7.58 (s, 1 H), 10.12 (s, 1 H).

4-(2,5-디메틸-4-포르밀페닐)-1-(1-클로로에톡시카르보닐)피페라진:4- (2,5-dimethyl-4-formylphenyl) -1- (1-chloroethoxycarbonyl) piperazine:

4-(2,5-디메틸-4-포르밀페닐)-1-벤질피페라진(9g, 19mmol)을 무수 1,2-디클로로에탄(100mL)에 용해시키고 1-클로로에틸 클로로포르메이트(4.5g, 31.5mmol)를 가하였다. 용액을 30분동안 또는 TLC분석이 출발물질이 사라졌음을 나타낼 때까지 환류시켰다. 생성물은 헥산/EtOAc(3/1)를 사용하여 TLC에 의해 출발물질보다 단지 약간 덜 극성이었다. 디클로로에탄을 증발시키고 잔여물을 구배 헥산/EtOAc(10/0에서 8/2)를 사용하는 컬럼크로마토그래피로 정제하여 생성물(6g, 64%)을 오일의 형태로 얻었다.4- (2,5-dimethyl-4-formylphenyl) -1-benzylpiperazine (9 g, 19 mmol) was dissolved in anhydrous 1,2-dichloroethane (100 mL) and 1-chloroethyl chloroformate (4.5 g) , 31.5 mmol) was added. The solution was refluxed for 30 minutes or until TLC analysis indicated that the starting material had disappeared. The product was only slightly less polar than the starting material by TLC using hexanes / EtOAc (3/1). Dichloroethane was evaporated and the residue was purified by column chromatography using gradient hexanes / EtOAc (10/0 to 8/2) to give the product (6 g, 64%) in the form of an oil.

1H NMR (CDCl3) δ 1.84 (d, 3H), 2.32 (s, 3H), 2.61 (s, 3H), 2.99 (brd m, 4H), 3.70 (brd m, 4H), 6.62 (qt, 1H), 6.76 (s, 1H), 7.62 (s, 1H), 10.14 (s, 1H). 1 H NMR (CDCl 3 ) δ 1.84 (d, 3H), 2.32 (s, 3H), 2.61 (s, 3H), 2.99 (brd m, 4H), 3.70 (brd m, 4H), 6.62 (qt, 1H ), 6.76 (s, 1 H), 7.62 (s, 1 H), 10.14 (s, 1 H).

4-피페라진일-2,5-디메틸벤즈알데히드:4-piperazinyl-2,5-dimethylbenzaldehyde:

THF(50mL)중 상기 디메틸페닐피레라진일카르바메이트(6g, 18.5mmol)의 용액에 1N HCl(50mL, 50mmol)을 가하였다. 혼합물을 CO2의 분출이 멈출 때까지 약 80℃로 가열하였다. 대부분의 THF를 회전식 증발로 제거하고 그 잔여물을 동결건조하여 2수소염화물염으로서 생성물(5.5g, 99%)을 얻었다.To a solution of the dimethylphenylpyrazinylcarbamate (6 g, 18.5 mmol) in THF (50 mL) was added 1N HCl (50 mL, 50 mmol). The mixture was heated to about 80 ° C. until the ejection of CO 2 stopped. Most of the THF was removed by rotary evaporation and the residue was lyophilized to give the product (5.5 g, 99%) as a dihydrochloride salt.

1H NMR (DMSO-D6) δ 2.2 (s, 3H), 2.50 (s, 3H), 3.13 (brd s, 8H), 6.85 (s, 1H), 7.54 (s, 1H), 9.49 (brd s, 2H), 10.02 (s, 1H). 1 H NMR (DMSO-D 6 ) δ 2.2 (s, 3H), 2.50 (s, 3H), 3.13 (brd s, 8H), 6.85 (s, 1H), 7.54 (s, 1H), 9.49 (brd s , 2H), 10.02 (s, 1H).

4-피페라진일-2,3-디메틸벤즈알데히드:4-piperazinyl-2,3-dimethylbenzaldehyde:

4-피페라진일-2,3-디메틸벤즈알데히드를 상기와 동일한 방식으로 제조하였다. N-벤질-피페라진일-2,3-디메틸벤젠의 생성은 더 느리고 70℃에서 하룻밤동안의 가열이 필요하였다. 그 외 모든 다른 단계는 매우 유사하였고 수율은 거의 동등하였다.4-piperazinyl-2,3-dimethylbenzaldehyde was prepared in the same manner as above. The production of N-benzyl-piperazinyl-2,3-dimethylbenzene was slower and required heating at 70 ° C. overnight. All other steps were very similar and yields were nearly equal.

1H NMR (DMSO-D6) δ 2.15 (s, 3H), 2.47 (s, 3H), 3.07 (brd m, 4H), 3.17 (brd m, 4H), 5.90 (brd s, 1H, NH), 7.02 (d, 1H), 7.50 (d, 1H), 9.54 (brd s, 2H, NH2), 10.10 (s, 1H). 1 H NMR (DMSO-D 6 ) δ 2.15 (s, 3H), 2.47 (s, 3H), 3.07 (brd m, 4H), 3.17 (brd m, 4H), 5.90 (brd s, 1H, NH), 7.02 (d, 1 H), 7.50 (d, 1 H), 9.54 (brd s, 2H, NH 2 ), 10.10 (s, 1H).

4-피페라진일-3,5-디메틸벤즈알데히드:4-piperazinyl-3,5-dimethylbenzaldehyde:

4-피페라진일-3,5-디메틸벤즈알데히드를 상기와 동일한 방식으로 제조하였다.4-piperazinyl-3,5-dimethylbenzaldehyde was prepared in the same manner as above.

N-알킬화와 히드라존 생성을 위한 일반적인 라이브러리 방법:General library methods for N-alkylation and hydrazone generation:

88 딥 웰 플레이트에 분산시킨 DMSO중 미치환 피페라진일-아릴-알데히드의 용액에 DMSO중 원하는 알킬화제(1eq)를 가하고 이어서 디이소프로필에틸아민(5eq)을 가하였다. 고체 탄산칼륨(5eq)은 또한 치환될 수 있다. 16시간동안 용액을 교반한 후, DMSO중 4-히드록시벤조산 히드라지드 유도체(1eq)의 용액과 DMSO중 아세트산(촉매) 용액을 각 웰에 가하였다. 반응혼합물을 16시간동안 교반하고 미정제 생성물을 얻어 HPLC로 정제하였다.To a solution of unsubstituted piperazinyl-aryl-aldehyde in DMSO dispersed in a 88 deep well plate, the desired alkylating agent (1eq) in DMSO was added followed by diisopropylethylamine (5eq). Solid potassium carbonate (5eq) may also be substituted. After stirring the solution for 16 hours, a solution of 4-hydroxybenzoic acid hydrazide derivative (1eq) in DMSO and acetic acid (catalyst) solution in DMSO was added to each well. The reaction mixture was stirred for 16 h and the crude product was obtained and purified by HPLC.

생성물의 실시예:Examples of products:

실시예 521:Example 521:

1H NMR (DMSO-D6): δ 2.26 (s, 3H), 2.38 (s, 3H), 2.65 (brd s, 4H), 2.73 (t, 2H), 2.89 (brd s, 4H), 4.07 (t, 2H), 6.03 (d, 2H), 6.84 (t, 2H), 7.02 (d, 1H), 7.13 (d, 1H), 7.72 (d, 1H), 7.82 (dd, 1H), 8.01 (s, 1H), 8.86 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 480.7, 482.3. 1 H NMR (DMSO-D 6 ): δ 2.26 (s, 3H), 2.38 (s, 3H), 2.65 (brd s, 4H), 2.73 (t, 2H), 2.89 (brd s, 4H), 4.07 ( t, 2H), 6.03 (d, 2H), 6.84 (t, 2H), 7.02 (d, 1H), 7.13 (d, 1H), 7.72 (d, 1H), 7.82 (dd, 1H), 8.01 (s , 1H), 8.86 (brd s, 1 H), 11.68 (brd s, 1 H); MS (APCI): 480.7, 482.3.

실시예 522:Example 522:

1H NMR (DMSO-D6): δ 2.49 (s, 6H), 2.68 (brd s 4H), 3.22 (brd s, 4H), 3.72 (s, 2H), 7.22 (d, 1H), 7.44 (m, 1H), 7.52 (m, 6H), 7.92 (dd, 1H), 8.13 (s, 1H), 8.46 (s, 1H), 11.12 (brd s, 1H), 11.80 (s, 1H); MS (APCI): 477.5, 479.2. 1 H NMR (DMSO-D 6 ): δ 2.49 (s, 6H), 2.68 (brd s 4H), 3.22 (brd s, 4H), 3.72 (s, 2H), 7.22 (d, 1H), 7.44 (m , 1H), 7.52 (m, 6H), 7.92 (dd, 1H), 8.13 (s, 1H), 8.46 (s, 1H), 11.12 (brd s, 1H), 11.80 (s, 1H); MS (APCI): 477.5, 479.2.

실시예 523:Example 523:

1H NMR (DMSO-D6): δ 1.25 (s, 3H), 1.27 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 2.57 (brd s, 4H), 2.95 (brd s, 4H), 3.56 (s, 2H), 7.02 (d, 1H), 7.12 (d, 1H), 7.30 (qt, 4H), 7.72 (d, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.83 (s, 1H), 11.0 (brd s, 1H), 11.1 (s, 1H); MS (APCI): 519.7, 521.5. 1 H NMR (DMSO-D 6 ): δ 1.25 (s, 3H), 1.27 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 2.57 (brd s, 4H), 2.95 (brd s, 4H), 3.56 (s, 2H), 7.02 (d, 1H), 7.12 (d, 1H), 7.30 (qt, 4H), 7.72 (d, 1H), 7.82 (d, 1H), 8.01 (s , 1H), 8.83 (s, 1H), 11.0 (brd s, 1H), 11.1 (s, 1H); MS (APCI): 519.7, 521.5.

실시예 524:Example 524:

1H NMR (DMSO-D6): δ 2.22 (s, 3H), 2.33 (s, 3H), 3.17 (brd s, 4H), 3.23 (m, 2H), 3.36 (m, 2H), 4.41 (s, 2H), 6.98 (d, 1H), 7.10 (d, 1H), 7.48 (m, 3H), 7.68 (m, 3H), 7.71 (d, 1H), 7.97 (s, 1H), 8.83 (s, 1H), 11.00 (s, 1H), 11.02 (brd s, 1H), 11.69 (s, 1H); MS (APCI): 477.4, 479.2. 1 H NMR (DMSO-D 6 ): δ 2.22 (s, 3H), 2.33 (s, 3H), 3.17 (brd s, 4H), 3.23 (m, 2H), 3.36 (m, 2H), 4.41 (s , 2H), 6.98 (d, 1H), 7.10 (d, 1H), 7.48 (m, 3H), 7.68 (m, 3H), 7.71 (d, 1H), 7.97 (s, 1H), 8.83 (s, 1H), 11.00 (s, 1H), 11.02 (brd s, 1H), 11.69 (s, 1H); MS (APCI): 477.4, 479.2.

실시예 525:Example 525:

1H NMR (DMSO-D6): δ 2.20 (s, 3H), 2.31 (s, 3H), 2.59 (s, 4H), 2.87 (s, 4H), 3.69 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.64 (m, 2H), 7.75 (dd, 1H), 7.82 (d, 1H), 7.94 (d, 1H), 8.12 (dd, 1H), 8.19 (s, 1H), 8.74 (s, 1H), 10.94 (brd s, 1H), 11.54 (s, 1H); MS (APCI): 522.2, 524.3. 1 H NMR (DMSO-D 6 ): δ 2.20 (s, 3H), 2.31 (s, 3H), 2.59 (s, 4H), 2.87 (s, 4H), 3.69 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.64 (m, 2H), 7.75 (dd, 1H), 7.82 (d, 1H), 7.94 (d, 1H), 8.12 (dd, 1H), 8.19 (s, 1H ), 8.74 (s, 1 H), 10.94 (brd s, 1 H), 11.54 (s, 1 H); MS (APCI): 522.2, 524.3.

실시예 526;Example 526;

1H NMR (DMSO-D6): δ 2.20 (s, 3H), 2.31 (s, 3H), 2.62 (brd s, 4H), 2.87 (brd s, 4H), 3.68 (s, 2H), 6.98 (d, 1H), 7.04 (d, 1H), 7.55 (d, 1H), 7.61 (d, 1H), 7.74 (dd, 1H), 7.91 (s, 1H), 7.92 (d, 1H), 8.01 (d, 1H), 8.74 (s, 1H), 10.93 (brd s, 1H), 11.54 (s, 1H); MS (APCI): 519.2, 521.3. 1 H NMR (DMSO-D 6 ): δ 2.20 (s, 3H), 2.31 (s, 3H), 2.62 (brd s, 4H), 2.87 (brd s, 4H), 3.68 (s, 2H), 6.98 ( d, 1H), 7.04 (d, 1H), 7.55 (d, 1H), 7.61 (d, 1H), 7.74 (dd, 1H), 7.91 (s, 1H), 7.92 (d, 1H), 8.01 (d , 1H), 8.74 (s, 1H), 10.93 (brd s, 1H), 11.54 (s, 1H); MS (APCI): 519.2, 521.3.

실시예 527:Example 527:

1H NMR (DMSO-D6): δ 2.21 (s, 3H), 2.37 (s, 3H), 2.66 (brd s, 4H), 2.91 (brd s, 4H), 3.76 (s, 2H), 6.83 (s, 1H), 7.05 (d, 1H), 7.62 (s, 1H), 7.69 (s, 1H), 7.75 (dd, 1H), 7.86 (d, 2H), 7.94 (s, 1H), 8.15 (d, 2H), 8.60 (s, 1H), 10.92 (brd s, 1H), 11.55 (s, 1H); MS (APCI): 628.3, 630.2, 631.2. 1 H NMR (DMSO-D 6 ): δ 2.21 (s, 3H), 2.37 (s, 3H), 2.66 (brd s, 4H), 2.91 (brd s, 4H), 3.76 (s, 2H), 6.83 ( s, 1H), 7.05 (d, 1H), 7.62 (s, 1H), 7.69 (s, 1H), 7.75 (dd, 1H), 7.86 (d, 2H), 7.94 (s, 1H), 8.15 (d , 2H), 8.60 (s, 1 H), 10.92 (brd s, 1 H), 11.55 (s, 1 H); MS (APCI): 628.3, 630.2, 631.2.

N-치환 인돌알데히드의 합성과 이후의 히드라존의 생성을 위한 일반적인 방법:General methods for the synthesis of N-substituted indolealdehyde and subsequent generation of hydrazones:

N-치환 인돌 알데히드를 상기 정의된 바와 같은 -(K)m-D부분을 도입하는 다양한 친전자성 알킬화제를 사용하여 상응하는 미치환 인돌알데히드를 N-알킬화시킴으로써 제조할 수 있다.N-substituted indole aldehydes can be prepared by N-alkylating the corresponding unsubstituted indole aldehydes using various electrophilic alkylating agents which introduce a-(K) m -D moiety as defined above.

상기 식에서, Lx는 -Cl, -Br, -I, -OSO2CH3, -OSO2p-톨릴 또는 -OSO2CF3등의 이탈기이고; A, R3a, R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R14및 R15는 화학식 I에서 정의된 바와 같다.In the above formula, Lx is a leaving group such as -Cl, -Br, -I, -OSO 2 CH 3 , -OSO 2 p-tolyl or -OSO 2 CF 3 or the like; A, R 3a , R 3b , R 4a , R 4b , a, b, c, d, f, p, q, D, M, R 14 and R 15 are as defined in formula (I).

상기 반응식에 따라서 N-치환 인돌알데히드는 아세톤, 메틸에틸케톤, 디메틸포름아미드, DMSO, 디옥산, 테트라히드로푸란, 톨루엔, 에틸렌글리콜 디메틸에테르, 술폴란, 디에틸에테르, 물 또는 상기 용매중 상용성인 2 이상의 혼합물 등의 유기 용매에서, 수소화나트륨, 수소화칼륨, 메톡시화, 에톡시화 또는 tert-부톡시화 나트륨 또는 칼륨, 탄산 나트륨, 칼륨 또는 세슘, 또는 플루오로화 칼륨 또는 세슘, 수산화 나트륨 또는 칼륨 등의 염기, 또는 디이소프로필에틸아민, 2,4,6-콜리딘, 또는 메톡시화 또는 수산화 벤질디메틸암모늄 등의 염기 1 내지 15당량(바람직하게 1 내지 5당량)의 존재하에서 포르밀인돌을 알킬 할라이드 또는 아릴-저급알킬 할라이드의 등몰량과 교반함으로써 제조될 수 있다. 반응을 0℃ 내지 150℃, 바람직하게 20℃ 내지 100℃에서, 바람직하게 N2또는 Ar의 불활성 분위기에서 수행할 수 있다. 반응이 완결되면 혼합물을 여과하고 진공에서 농축하고, 그 결과의 생성물을 선택적으로 에틸아세테이트/헥산을 용리액으로 사용하여 실리카겔상의 컬럼크로마토그래피로 정제한다. 화합물을 또한 에틸알콜, 에틸아세테이트, 이소프로필알콜, 물, 헥산, 톨루엔 또는 이들의 상용성인 혼합물 등의 적당한 용매로부터 재결정하여 (적절한 때)정제할 수 있다.According to the above reaction formula, N-substituted indolealdehyde is compatible with acetone, methyl ethyl ketone, dimethylformamide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethyl ether, water or the solvent. In organic solvents such as mixtures of two or more, such as sodium hydride, potassium hydride, methoxylated, ethoxylated or tert-butoxylated sodium or potassium, sodium carbonate, potassium or cesium, or potassium fluoride or cesium, sodium hydroxide or potassium Alkyl halides of formyl indole in the presence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base or a base such as diisopropylethylamine, 2,4,6-collidine, or methoxylated or benzyldimethylammonium hydroxide Or by stirring with an equimolar amount of aryl-lower alkyl halide. The reaction can be carried out at 0 ° C. to 150 ° C., preferably at 20 ° C. to 100 ° C., preferably in an inert atmosphere of N 2 or Ar. Upon completion of the reaction the mixture is filtered and concentrated in vacuo and the resulting product is purified by column chromatography on silica gel, optionally using ethyl acetate / hexane as eluent. The compound may also be purified (if appropriate) by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or a compatible mixture thereof.

다음 단계, 히드라존 생성은 일반적으로 상기 나타나 있고 하기 상세히 나타낸다.The next step, hydrazone generation, is generally shown above and detailed below.

인돌 알킬화의 라이브러리 방법(단계 A):Library Method of Indole Alkylation (Step A):

인돌의 나트륨염의 제조:Preparation of Sodium Salt of Indole:

인돌-3-카르복스알데히드(1.45g)을 건조냉동 100mL 3-구 둥근바닥 플라스크내 건조 DMF 8.6mL에 용해시켰다.Indole-3-carboxaldehyde (1.45 g) was dissolved in 8.6 mL of dry DMF in a dry frozen 100 mL three-neck round bottom flask.

이 단계중 대량의 수소가스가 분출한다. 불활성 가스를 안정되게 유출시키는 것에 주의해야하고 수소가스를 분출시키기위해 적절한 환기를 유지한다.During this stage, a large amount of hydrogen gas is ejected. Care should be taken to ensure stable outflow of inert gas and maintain adequate ventilation to release hydrogen gas.

3-구 둥근바닥 플라스크를 통해 질소 또는 아르곤의 안정된 유출을 유지하는 동안, 수소화나트륨 1.1당량(건조 95% 시약중 0.27g)을 인돌용액에 옮겼다. 불활성 가스의 유출을 유지하면서 혼합물을 15분동안 교반하였다. 다음 단계를 즉시 진행시킨다.While maintaining a stable outflow of nitrogen or argon through a three-neck round bottom flask, 1.1 equivalents of sodium hydride (0.27 g in dry 95% reagent) were transferred to the indole solution. The mixture was stirred for 15 minutes while maintaining the outflow of inert gas. Proceed immediately to the next step.

알킬 할라이드 용액의 제조:Preparation of Alkyl Halide Solutions:

암버(Amber) 유리 바이알(원액의 제조)를 적어도 4시간동안 110℃에서 건조시킨 다음, 데시케이터에서 아르곤분위기하에서 냉각시켰다. 알킬 할라이드 용액(1.0M)을 건조 바이알내 무수 DMF중에서 제조하였다. 각 알킬 할라이드 용액(100㎕)를 딥-웰 플레이트(매트용 1x88x1)의 각 해당하는 웰에 가하였다.Amber glass vials (preparation of stock) were dried at 110 ° C. for at least 4 hours and then cooled in an argon atmosphere in a desiccator. Alkyl halide solution (1.0 M) was prepared in dry DMF in dry vial. Each alkyl halide solution (100 μl) was added to each corresponding well of a deep-well plate (1 × 88 × 1 for the mat).

인돌나트륨염의 알킬화:Alkylation of Indole Sodium Salt:

1.0M 인돌나트륨 100㎕를 신속히 딥-웰 플레이트중의 각 알킬 할라이드에 가하였다. 플레이트를 간단히 와동시켜 혼합한 다음 2시간동안 반응시켰다.100 μl of 1.0 M sodium indole was quickly added to each alkyl halide in a deep-well plate. The plates were simply vortexed to mix and allowed to react for 2 hours.

히드라존 생성을 위한 라이브러리 방법(단계 B):Library Method for Hydrazone Creation (Step B):

아실 히드라존 생성:Acyl Hydrazone Generation:

3-클로로-4-히드록시벤조산 히드라지느(1.86g)을 건조 DMSO 5mL에 용해시키고 이어서 트리플루오로아세트산(0.77mL)에 용해시켰다. 그 결과의 용액을 희석시켜 최종부피 10.0mL로 만들었다. 1.0M 산 히드라지드 TFA 염용액 100㎕를 딥 웰 플레이트 각 웰에 가하였다. 플레이트를 혼합을 위해 1분간 와동시킨 다음 30분간 반응시켰다.3-Chloro-4-hydroxybenzoic acid hydrazine (1.86 g) was dissolved in 5 mL of dry DMSO and then in trifluoroacetic acid (0.77 mL). The resulting solution was diluted to a final volume of 10.0 mL. 100 μl of 1.0 M acid hydrazide TFA salt solution was added to each well of a deep well plate. The plate was vortexed for 1 minute for mixing and then allowed to react for 30 minutes.

생성물을 에틸아세테이트/헥산 용리액을 사용하여 실리카겔상의 크로마토그래피로 정제하였다.The product was purified by chromatography on silica gel using ethyl acetate / hexane eluent.

다음의 화합물을 제조하였다:The following compounds were prepared:

실시예 528:Example 528:

1H NMR (DMSO-D6): δ 5.46 (s, 2H), 7.10 (d, J = 8.7, 2H), 7.20 (m, 2H), 7.28 (m, 5H), 7.51 (d, J = 7.53, 1H), 7.79 (d, J = 7.9, 1H), 7.99 (s, 1H), 8.01 (s, 1H) 8.33 (d, J = 6.96, 1H), 8.62 (s, 1H), 10.9 (s, 1H), 11.5 (s, 1H); C26H24Cl1N3O2(M - H)의 LRMS 계산치 402, 실측치 402.1. 1 H NMR (DMSO-D 6 ): δ 5.46 (s, 2H), 7.10 (d, J = 8.7, 2H), 7.20 (m, 2H), 7.28 (m, 5H), 7.51 (d, J = 7.53 , 1H), 7.79 (d, J = 7.9, 1H), 7.99 (s, 1H), 8.01 (s, 1H) 8.33 (d, J = 6.96, 1H), 8.62 (s, 1H), 10.9 (s, 1H), 11.5 (s, 1H); LRMS calcd for C 26 H 24 Cl 1 N 3 O 2 (M-H) 402, found 402.1.

실시예 529:Example 529:

1H NMR (DMSO-D6): δ 1.14 (d, J = 6.8, 6H), 2.81 (sept, J = 6.9, 1H), 5.41 (s, 2H), 7.07 (d, J = 8.3, 1H), 7.20 (m, 6H), 7.54 (d, J = 7.6, 1H), 7.77 (d, J = 7.9, 1H), 7.97 (s, 1H), 8.01 (s, 1H), 8.29 (d, J = 7.2, 1H), 8.59 (s, 1H), 10.88 (s, 1H), 11.44 (s, 1H). C26H24Cl1N3O2(M - H)의 LRMS 계산치 445, 실측치 445.9 1 H NMR (DMSO-D 6 ): δ 1.14 (d, J = 6.8, 6H), 2.81 (sept, J = 6.9, 1H), 5.41 (s, 2H), 7.07 (d, J = 8.3, 1H) , 7.20 (m, 6H), 7.54 (d, J = 7.6, 1H), 7.77 (d, J = 7.9, 1H), 7.97 (s, 1H), 8.01 (s, 1H), 8.29 (d, J = 7.2, 1H), 8.59 (s, 1H), 10.88 (s, 1H), 11.44 (s, 1H). LRMS calcd for C 26 H 24 Cl 1 N 3 O 2 (M-H) 445, found 445.9.

실시예 530:Example 530:

1H NMR (DMSO-D6): δ 5.47 (s, 2H), 7.08, (d, J = 8.7, 1H), 7.13-7.25 (m, 5H), 7.18 (t, J = 74.2, 1H), 7.35 (d, J = 8.7, 1H), 7.54 (d, J = 7.9, 1H), 7.77 (dd, J = 8.7, 1.7, 1H), 7.97 (d, J = 1.7, 1H), 8.02 (s, 1H), 8.30 (d, J = 7.2, 1H), 8.59 (s, 1H), 10.89 (s, 1H), 11.45 (s, 1H). C24H18Cl1F2N3O3(M - H)의 LRMS 계산치 468, 실측치 468.1. 1 H NMR (DMSO-D 6 ): δ 5.47 (s, 2H), 7.08, (d, J = 8.7, 1H), 7.13-7.25 (m, 5H), 7.18 (t, J = 74.2, 1H), 7.35 (d, J = 8.7, 1H), 7.54 (d, J = 7.9, 1H), 7.77 (dd, J = 8.7, 1.7, 1H), 7.97 (d, J = 1.7, 1H), 8.02 (s, 1H), 8.30 (d, J = 7.2, 1H), 8.59 (s, 1H), 10.89 (s, 1H), 11.45 (s, 1H). LRMS calcd for C 24 H 18 Cl 1 F 2 N 3 O 3 (M-H) 468, found 468.1.

실시예 531:Example 531:

1H NMR (DMSO-D6): δ 0.94 (d, J = 6.2, 6H), 1.54 (sept, J = 6.2, 1H), 1.66-1.73 (m, 2H), 4.23 (t, J = 7.0, 2H), 7.08 (d, J = 8.7, 1H), 7.16-7.29 (m, 2H), 7.54 (d, J = 7.95, 1H), 7.77 (d, J = 8.7, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 8.29 (d, J = 7.5, 1H), 8.57 (s, 1H), 10.88 (s, 1H). 11.42 (s, 1H). C21H22Cl1N3O2(M + H)의 LRMS 계산치 384, 실측치 384.2. 1 H NMR (DMSO-D 6 ): δ 0.94 (d, J = 6.2, 6H), 1.54 (sept, J = 6.2, 1H), 1.66-1.73 (m, 2H), 4.23 (t, J = 7.0, 2H), 7.08 (d, J = 8.7, 1H), 7.16-7.29 (m, 2H), 7.54 (d, J = 7.95, 1H), 7.77 (d, J = 8.7, 1H), 7.88 (s, 1H ), 7.97 (s, 1 H), 8.29 (d, J = 7.5, 1 H), 8.57 (s, 1 H), 10.88 (s, 1 H). 11.42 (s, 1 H). LRMS calcd for C 21 H 22 Cl 1 N 3 O 2 (M + H) 384, found 384.2.

실시예 532:Example 532:

1H NMR (DMSO-D6): δ 7.06 (d, J = 8.5, 1H), 7.12-7.26 (m,3H), 7.46-7.49 (M,2H), 7.78 (d, J = 8.1, 1H), 7.99 (s, 1H), 11.33 (s, 1H), 11.65 (s, 1H). C16H12Cl1N3O2(M - H) LRMS 계산치 312, 실측치 312.0. 1 H NMR (DMSO-D 6 ): δ 7.06 (d, J = 8.5, 1H), 7.12-7.26 (m, 3H), 7.46-7.49 (M, 2H), 7.78 (d, J = 8.1, 1H) , 7.99 (s, 1 H), 11.33 (s, 1 H), 11.65 (s, 1 H). C 16 H 12 Cl 1 N 3 O 2 (M-H) LRMS calcd 312, found 312.0.

알킬/아릴-술포닐옥시 아릴-알데히드의 합성과 이후의 히드라존 생성을 위한 일반적인 방법:General methods for the synthesis of alkyl / aryl-sulfonyloxy aryl-aldehydes and subsequent generation of hydrazones:

알킬/아릴-술포닐옥시 아릴-알데히드를 상기 정의된 바와 같은 -(K)m-D부분을 도입하는 다양한 친전자성 술포닐화제를 사용하여 상응하는 페놀성 화합물을 O-술포닐화시킴으로써 제조할 수 있다.Alkyl / aryl-sulfonyloxy aryl-aldehydes can be prepared by O-sulfonylating the corresponding phenolic compounds using various electrophilic sulfonylating agents which introduce the-(K) m -D moiety as defined above. Can be.

상기 식에서, Lx는 -Cl, -Br, -I, -OSO2CH3, -OSO2p-톨릴 또는 -OSO2CF3등의 이탈기이고; A, R3a, R3b, R4a, R4b, a, b, c, d, f, p, q, D, M, R14및 R15는 화학식 I에서 정의된 바와 같다.In the above formula, Lx is a leaving group such as -Cl, -Br, -I, -OSO 2 CH 3 , -OSO 2 p-tolyl or -OSO 2 CF 3 or the like; A, R 3a , R 3b , R 4a , R 4b , a, b, c, d, f, p, q, D, M, R 14 and R 15 are as defined in formula (I).

상기 반응식에 따라서 알킬/아릴-술포닐옥시아릴알데히드는 히드록시벤즈알데히드 또는 히드록시나프트알데히드를 아세톤, 메틸에틸케톤, 디메틸포름아미드, 디옥산, 테트라히드로푸란, 톨루엔, 에틸렌글리콜디메틸에테르, 술폴란, 디에틸에테르, 물 또는 상기 용매중 상용성인 2 이상의 혼합물 등의 유기 용매에서, 수소화나트륨, 수소화칼륨, 메톡시화, 에톡시화 또는 tert-부톡시화 나트륨 또는 칼륨, 탄산 나트륨, 칼륨 또는 세슘, 또는 플루오로화 칼륨 또는 세슘, 수산화 나트륨 또는 칼륨 등의 염기, 또는 디이소프로필에틸아민, 2,4,6-콜리딘, 또는 메톡시화 또는 수산화 벤질디메틸암모늄 등의 염기 1 내지 15당량(바람직하게 1 내지 5당량)의 존재하에서 등몰량의 알킬술포닐할라이드, 아릴술포닐할라이드 또는 아릴-저급알킬 술포닐할라이드와 교반함으로써 제조될 수 있다. 반응을 0℃ 내지 150℃, 바람직하게 20℃ 내지 100℃에서, 바람직하게 N2또는 Ar의 불활성 분위기에서 수행할 수 있다. 반응이 완결되면 혼합물을 여과하고 진공에서 농축하고, 그 결과의 생성물을 선택적으로 에틸아세테이트/헥산을 용리액으로 사용하여 실리카겔상의 컬럼크로마토그래피로 정제한다. 화합물을 또한 에틸알콜, 에틸아세테이트, 이소프로필알콜, 물, 헥산, 톨루엔 또는 이들의 상용성인 혼합물 등의 적당한 용매로부터 재결정하여 (적절한 때)정제할 수 있다.According to the above scheme, the alkyl / aryl-sulfonyloxyaryl aldehyde is hydroxybenzaldehyde or hydroxy naphthaldehyde to acetone, methyl ethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane , In an organic solvent such as diethyl ether, water or a mixture of two or more compatible in the above solvents, sodium hydride, potassium hydride, methoxylated, ethoxylated or tert-butoxylated sodium or potassium, sodium carbonate, potassium or cesium, or fluorine 1 to 15 equivalents (preferably 1 to 1 base, such as potassium fluoride or cesium, sodium hydroxide or potassium, or diisopropylethylamine, 2,4,6-collidine, or methoxylated or benzyldimethylammonium hydroxide) Stirring with an equimolar amount of alkylsulfonyl halide, arylsulfonyl halide or aryl-lower alkyl sulfonyl halide in the presence of 5 equivalents) It can be manufactured by. The reaction can be carried out at 0 ° C. to 150 ° C., preferably at 20 ° C. to 100 ° C., preferably in an inert atmosphere of N 2 or Ar. Upon completion of the reaction the mixture is filtered and concentrated in vacuo and the resulting product is purified by column chromatography on silica gel, optionally using ethyl acetate / hexane as eluent. The compound may also be purified (if appropriate) by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or a compatible mixture thereof.

다음 단계, 히드라존 생성은 일반적으로 상기 나타나 있다.The next step, hydrazone generation, is generally shown above.

기재된 방법을 사용하여 합성된 화합물의 예는 하기 주어진다:Examples of compounds synthesized using the described method are given below:

실시예 533:Example 533:

1H NMR (DMSO-D6): δ 7.03 (d, 1H), 7.28 (d, 1H), 7.39 (d, 1H), 7.61 (t, 1H), 7.67 (t, 1H), 7.75 (m, 2H), 7.87 (d, 2H), 7.95 (s, 1H), 8.75 (d, 1H), 9.02 (s, 1H), 11.00 (s, 1H), 11.88 (s, 1H); MS (APCI): 521.0, 523.0. 1 H NMR (DMSO-D 6 ): δ 7.03 (d, 1H), 7.28 (d, 1H), 7.39 (d, 1H), 7.61 (t, 1H), 7.67 (t, 1H), 7.75 (m, 2H), 7.87 (d, 2H), 7.95 (s, 1H), 8.75 (d, 1H), 9.02 (s, 1H), 11.00 (s, 1H), 11.88 (s, 1H); MS (APCI): 521.0, 523.0.

실시예 534:Example 534:

1H NMR (DMSO-D6): δ 1.38 (d, 6H), 3.91 (septet, 1H), 6.97 (d, 1H), 7.46 (d, 1H), 7.61 (m, 2H), 7.71 (d, 1H), 7.81 (d, 1H), 7.89 (s, 1H), 8.01 (d, 1H), 8.69 (d, 1H), 9.11 (s, 1H), 11.00 (brd s, 1H), 11.98 (s, 1H); MS (APCI, neg.): 445.0, 487.0, 339 - iprso2. 1 H NMR (DMSO-D 6 ): δ 1.38 (d, 6H), 3.91 (septet, 1H), 6.97 (d, 1H), 7.46 (d, 1H), 7.61 (m, 2H), 7.71 (d, 1H), 7.81 (d, 1H), 7.89 (s, 1H), 8.01 (d, 1H), 8.69 (d, 1H), 9.11 (s, 1H), 11.00 (brd s, 1H), 11.98 (s, 1H); MS (APCI, neg.): 445.0, 487.0, 339-iprso 2 .

고체 지지체상에서 병렬적 합성을 수반하는 본 발명에 따르는 알킬리덴 히드라지드의 제조를 위한 일반적인 방법:General method for the preparation of alkylidene hydrazide according to the invention with parallel synthesis on a solid support:

실시예 535 내지 614의 화합물은 다음의 식The compounds of Examples 535 to 614 are

수지-[빌딩블록 1] →Resin- [Building Block 1] →

수지-[빌딩블록 1]-[빌딩블록 2] →Resin- [Building Block 1]-[Building Block 2] →

수지-[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3]Resin- [Building Block 1]-[Building Block 2]-[Building Block 3]

에 따라서 제조하였고 동시에 탈보호화하고 디클로로메탄중 50% 트리플루오로아세트산으로 수지로부터 절단하여 다음 식Prepared in accordance with the following procedure and simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane

[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3][Building Block 1]-[Building Block 2]-[Building Block 3]

에 따르는 개개의 개체로서 원하는 화합물을 얻었다.The desired compound was obtained as an individual object according to the present invention.

다음의 80개의 화합물은 고체 지지체 상에서 병렬적 합성에 의해 단일체로서 얻었다. 수지-[빌딩블록 1]-[빌딩블록 2]의 제조는 수동으로 하였고, 반면 [빌딩블록 3]의 부착과 수지로부터의 절단은 Advanced ChemTech Model 384 HTS상에서 수행하였다.The following 80 compounds were obtained as a single body by parallel synthesis on a solid support. Preparation of Resin- [Building Block 1]-[Building Block 2] was done manually, whereas attachment of [Building Block 3] and cleavage from the resin were performed on Advanced ChemTech Model 384 HTS.

출발 수지, 수지-[빌딩블록 1]-[빌딩블록 2]는 모두 하기 기재된 바와 같이 제조되었다.Starting resin, Resin- [Building Block 1]-[Building Block 2] were all prepared as described below.

사용된 수지는 Wang 링커를 가지는 폴리스티렌 수지이고 치환용량은 0.9mmol/g이었다.The resin used was a polystyrene resin with Wang linker and a substitution capacity of 0.9 mmol / g.

80개의 모든 화합물은 완전히 조합적 방식으로 다음 반응식에 따르는 Heck 반응을 사용하여 [빌딩블록 3]의 수지-[빌딩블록 1]-[빌딩블록 2]에의 부착을 기본으로 한다.All 80 compounds are based on the attachment of [Building Block 3] to Resin- [Building Block 1]-[Building Block 2] using the Heck reaction according to the following scheme in a completely combinatorial manner.

(반응식)(Scheme)

상기 식에서, Lea는 이탈기이고 바람직하게 브롬, 요오드 및 트리플루오로메탄술포닐옥시로부터 선택되고, R14및 R15는 화학식 I에서 정의된 바와 같다.Wherein Lea is a leaving group and is preferably selected from bromine, iodine and trifluoromethanesulfonyloxy, and R 14 and R 15 are as defined in formula (I).

여기서 수지-[빌딩블록 1]으로서 나타낸 다음의 수지를 사용하였다.The following resin shown here as Resin- [Building Block 1] was used.

상기 식에서 PS는 폴리스티렌이고, 아래에서 수지는 Wang 링커를 가진 폴리스티렌 수지이다.Wherein PS is polystyrene and below the resin is a polystyrene resin with Wang linker.

즉 In other words

다음의 빌딩블록을 사용하였다:The following building blocks were used:

[빌딩블록 2]:[Building Block 2]:

[빌딩블록 3]:[Building Block 3]:

완전히 조합적인 방식으로 이들 빌딩블록을 조합하여 1x4x20=80개의 화합물을 제조하였다.These building blocks were combined in a completely combinatorial manner to prepare 1 × 4 × 20 = 80 compounds.

[빌딩블록 2]의 제조:Preparation of [Building Block 2]:

3,4-디메톡시-5-요오도벤즈알데히드의 제조:Preparation of 3,4-dimethoxy-5-iodobenzaldehyde:

요오도메탄(2.5mL, 40mmol)을 DMF(100mL)중 5-요오도바닐린(10g, 36mmol), 탄산칼륨(25g, 180mmol)의 혼합물에 가하였고 그 결과의 혼합물을 실온에서 16시간동안 교반하였다. 혼합물을 물(0.5L)에 붓고 에틸아세테이트(2x200mL)로 추출하였다. 합한 유기상을 물(200mL)로 세척하고, MgSO4로 건조시키고 진공에서 증발시켜 3,4-디메톡시-5-요오도벤즈알데히드 9.78g(93%)을 얻었다. 융점 58-63℃.Iodomethane (2.5 mL, 40 mmol) was added to a mixture of 5-iodovanillin (10 g, 36 mmol) and potassium carbonate (25 g, 180 mmol) in DMF (100 mL) and the resulting mixture was stirred at rt for 16 h. . The mixture was poured into water (0.5 L) and extracted with ethyl acetate (2x200 mL). The combined organic phases were washed with water (200 mL), dried over MgSO 4 and evaporated in vacuo to give 9.78 g (93%) of 3,4-dimethoxy-5-iodobenzaldehyde. Melting point 58-63 ° C.

트리플루오로메탄술폰산 4-포르밀-1-나프틸 에스테르의 제조:Preparation of trifluoromethanesulfonic acid 4-formyl-1-naphthyl ester:

4-히드록시-1-나프트알데히드(10g, 58mmol)을 피리딘(50mL)에 용해시키고 혼합물을 0℃까지 냉각시켰다. 트리플루오로메탄술폰산 무수물(11.7mL, 70mmol)을 5℃ 이하의 온도를 유지하면서 적가하였다. 첨가가 완결되면, 혼합물은 30분동안 실온에서 교반하였다. 디에틸에테르(200mL)를 가하고 혼합물을 물(2x250mL), 3N 염산(200mL) 및 포화 NaCl(200mL)로 연속적으로 세척하였다. 유기상을 MgSO4에서 건조시켰고 진공에서 증발시켰다. 잔여물을 에틸아세테이트와 헵탄(1:4)의 혼합물을 전개용매로하여 실리카겔(800mL)상의 컬럼크로마토그래피로 정제하였다. Rf=0.46로 유출된 순수한 분획을 모으고 진공에서 증발시켜 트리플로오로메탄술폰산 4-포르밀-1-나프틸 에스테르 8.35g(47%)을 얻었다. 융점 44-47℃. 다른 [빌딩블록 2]의 (3-브로모벤즈알데히드와 4-브로모벤즈알데히드)는 시중에서 입수가능하다.4-hydroxy-1-naphthaldehyde (10 g, 58 mmol) was dissolved in pyridine (50 mL) and the mixture was cooled to 0 ° C. Trifluoromethanesulfonic anhydride (11.7 mL, 70 mmol) was added dropwise while maintaining the temperature below 5 ° C. Once the addition was complete, the mixture was stirred for 30 minutes at room temperature. Diethyl ether (200 mL) was added and the mixture was washed successively with water (2 × 250 mL), 3N hydrochloric acid (200 mL) and saturated NaCl (200 mL). The organic phase was dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) using a mixture of ethyl acetate and heptane (1: 4) as a developing solvent. The pure fractions withdrawn to R f = 0.46 were collected and evaporated in vacuo to give 8.35 g (47%) of trifluoromethanesulfonic acid 4-formyl-1-naphthyl ester. Melting point 44-47 ° C. Other (3-bromobenzaldehyde and 4-bromobenzaldehyde) of [Building Block 2] are commercially available.

수지-[빌딩블록 1]의 제조:Preparation of Resin- [Building Block 1]:

(수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드)(3-Chloro-4-hydroxybenzoic acid hydrazide bonded with resin)

Wang 링커(0.92mmol/g)에 부가된 폴리스티렌 수지(15g)를 DMF(3x40mL) 및 CH2CHl2(3x40mL)로 연속적으로 세척하였다. 수지를 CH2CHl2(80mL)에 현탁시키고 디이소프로필에틸아민(60mL)을 가하였다. 혼합물을 0℃까지 냉각시키고 CH2CHl2(80mL)에 용해시킨 염화메탄술포닐(5.8mL)을 5℃ 이하의 온도를 유지하면서 적가하였다. 첨가가 완결되면 혼합물을 0℃에서 30분간 교반한 다음 실온에서 30분동안 교반하였다. 수지를 CH2CHl2(3x80mL) 및 N-메틸피롤리돈(NMP)(3x80mL)로 연속적으로 세척하였다. 이 수지 및 탄산세슘(12.3g)을 NMP(200mL)중에 용해시킨 에틸 3-클로로-4-히드록시벤조에이트(15g)에 가하고 혼합물을 4시간동안 80℃에서 교반하였다. 냉각후 수지를 NMP(3x80mL)와 메탄올(3x80mL)로 연속적으로 세척하였다.Polystyrene resin (15 g) added to Wang linker (0.92 mmol / g) was washed successively with DMF (3 × 40 mL) and CH 2 CHl 2 ( 3 × 40 mL). The resin was suspended in CH 2 CHl 2 (80 mL) and diisopropylethylamine (60 mL) was added. The mixture was cooled to 0 ° C. and methanesulfonyl chloride (5.8 mL) dissolved in CH 2 CHl 2 (80 mL) was added dropwise while maintaining the temperature below 5 ° C. When the addition was complete the mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 30 minutes. The resin was washed successively with CH 2 CHl 2 ( 3 × 80 mL) and N-methylpyrrolidone (NMP) (3 × 80 mL). This resin and cesium carbonate (12.3 g) were added to ethyl 3-chloro-4-hydroxybenzoate (15 g) dissolved in NMP (200 mL) and the mixture was stirred at 80 ° C for 4 h. After cooling the resin was washed successively with NMP (3x80 mL) and methanol (3x80 mL).

상기 수지를 1,4-디옥사(150mL) 및 물(36mL)에 현탁시켰다. 수소화리튬(2.6g)을 가하고 혼합물을 60℃, N2하에서 16시간동안 교반하였다. 냉각후 수지를 DMF(3x80mL), CH2Cl2(3x20mL) 및 메탄올(80mL)로 연속적으로 세척하고 50℃의 진공에서 3일동안 건조시켰다.The resin was suspended in 1,4-dioxa (150 mL) and water (36 mL). Lithium hydride (2.6 g) was added and the mixture was stirred at 60 ° C. under N 2 for 16 h. After cooling the resin was washed successively with DMF (3 × 80 mL), CH 2 Cl 2 (3 × 20 mL) and methanol (80 mL) and dried for 3 days in a vacuum at 50 ° C.

상기 수지(3.0g)을 CH2Cl2(20mL)에 현탁시키고, 1-히드록시벤즈트리아졸(0.6g), N-(3-디메틸아미노프로필)-N'-에틸카르보디이미드, 염화수소(0.9g) 및 DMF(10mL)를 가하였다. 혼합물을 실온에서 45분간 흔들어 섞고 히드라진 수화물(300㎕)를 가하고 혼합물을 실온에서 하룻밤동안 흔들어 섞었다. 수지를 DMF(3x20mL) 및 CH2Cl2(3x20mL)로 연속적으로 세척하여 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])를 얻었다.The resin (3.0 g) was suspended in CH 2 Cl 2 (20 mL), 1-hydroxybenztriazole (0.6 g), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide, hydrogen chloride ( 0.9 g) and DMF (10 mL) were added. The mixture was shaken at room temperature for 45 minutes, hydrazine hydrate (300 μl) was added and the mixture was shaken at room temperature overnight. The resin was washed successively with DMF (3 × 20 mL) and CH 2 Cl 2 (3 × 20 mL) to give 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) to which the resin was bound.

수지-[빌딩블록 1]-[빌딩블록 2]의 제조:Preparation of Resin- [Building Block 1]-[Building Block 2]:

수지가 결합된 3-클로로-4-히드록시벤조산(3,4-디메톡시-5-요오도벤질리덴)히드라지드의 제조:Preparation of 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5-iodobenzylidene) hydrazide bound with resin:

상기 수지(수지-[빌딩블록 1])(4g)을 DMF(50mL)중에 현탁시키고 3,4-디메톡시-5-요오도벤즈알데히드(5.8g) 및 트리에틸오르토포르메이트(25mL)을 가하고 그 혼합물을 실온에서 16시간동안 흔들어 섞었다. 수지를 DMF(4x40mL) 및 CH2Cl2(6x40mL)로 연속적으로 세척하고 50℃의 진공에서 16시간동안 건조시켜 수지가 결합된 3-클로로-4-히드록시벤조산(3,4-디메톡시-5-요오도벤질리덴)히드라지드를 얻었다.The resin (resin- [building block 1]) (4 g) was suspended in DMF (50 mL) and 3,4-dimethoxy-5-iodobenzaldehyde (5.8 g) and triethylorthoformate (25 mL) were added thereto. The mixture was shaken for 16 hours at room temperature. The resin was washed successively with DMF (4 × 40 mL) and CH 2 Cl 2 (6 × 40 mL) and dried for 16 hours in a vacuum at 50 ° C. to bind the resin to 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy- 5-iodobenzylidene) hydrazide was obtained.

수지가 결합된 트리플루오로메탄술폰산 4-[(3-클로로-4-히드록시벤조일)-히드라조노메틸]나프탈렌-1-일 에스테르의 제조:Preparation of resin bound trifluoromethanesulfonic acid 4-[(3-chloro-4-hydroxybenzoyl) -hydrazonomethyl] naphthalen-1-yl ester:

3,4-디메톡시-5-요오도벤즈알데히드 대신 트리플루오로메탄술폰산 4-포르밀-1-나프틸 에스테르를 사용한 것을 제외하고 상기 기재된 방법과 유사하게 수지가 결합된 트리플루오로메탄술폰산 4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]나프탈렌-1-일 에스테르를 얻었다.Trifluoromethanesulfonic acid 4-bonded with resin similar to the method described above, except that trifluoromethanesulfonic acid 4-formyl-1-naphthyl ester was used instead of 3,4-dimethoxy-5-iodobenzaldehyde. [(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthalen-1-yl ester was obtained.

수지가 결합된 3-클로로-4-히드록시벤조산 (3-브로모벤질리덴)히드라지드의 제조:Preparation of 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene) hydrazide bound with resin:

3,4-디메톡시-5-요오도벤즈알데히드 대신 3-브로모벤즈알데히드를 사용한 것을 제외하고 상기 기재된 방법과 유사하게 수지가 결합된 3-클로로-4-히드록시벤조산 (3-브로모벤질리덴)히드라지드를 얻었다.3-Chloro-4-hydroxybenzoic acid (3-bromobenzylidene) with resins bound similarly to the process described above except that 3-bromobenzaldehyde was used instead of 3,4-dimethoxy-5-iodobenzaldehyde Obtained hydrazide.

수지가 결합된 3-클로로-4-히드록시벤조산 (4-브로모벤질리덴)히드라지드의 제조:Preparation of 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene) hydrazide bound with resin:

3,4-디메톡시-5-요오도벤즈알데히드 대신 4-브로모벤즈알데히드를 사용한 것을 제외하고 상기 기재된 방법과 유사하게 수지가 결합된 3-클로로-4-히드록시벤조산 (4-브로모벤질리덴)히드라지드를 얻었다.3-Chloro-4-hydroxybenzoic acid (4-bromobenzylidene) with resins bound similarly to the method described above except that 4-bromobenzaldehyde was used instead of 3,4-dimethoxy-5-iodobenzaldehyde Obtained hydrazide.

실시예 535:Example 535:

3-클로로-4-히드록시벤조산[3-(1-아미노시클로헥실에틴일)-4,5-디메톡시벤질리덴]히드라지드3-chloro-4-hydroxybenzoic acid [3- (1-aminocyclohexylethynyl) -4,5-dimethoxybenzylidene] hydrazide

수지가 결합된 3-클로로-4-히드록시벤조산(3-브로모벤질리덴)히드라지드 (0.05mmol)에 요오드화제1구리(10mg)을 가하였다. 디이소프로필에틸아민(0.2mL), NMP(0.4M, 0.5mL)중 트리페닐포스핀용액, 물중 염화테트라부틸암모늄(0.66M, 0.3mL)의 용액, NMP중 아세트산제2팔라늄(0.16M, 0.25mL)의 용액 및 NMP중 1-에틴일시클로헥실아민([빌딩블록 3])의 용액(0.1M, 0.5mL)를 연속적으로 가하고, 혼합물을 15시간동안 90℃에서 흔들어 섞었다. 수지를 NMP(1.5mL, 3회), DMF중 50% 물(1.5mL, 3회), NMP(1.5mL, 2회), 1% 디에틸아미노디티오카바메이트 3수화물(1.5mL, 9회), NMP(1.5mL, 2회) 및 CH2Cl2(1.5mL, 6회)로 2분동안 반복적으로 세척하고 여과하였다.Copper iodide (10 mg) was added to 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene) hydrazide (0.05 mmol) to which the resin was bound. Diisopropylethylamine (0.2 mL), triphenylphosphine solution in NMP (0.4 M, 0.5 mL), a solution of tetrabutylammonium chloride (0.66 M, 0.3 mL) in water, di-pallanium acetate (0.16 M in NMP) , 0.25 mL) and a solution of 1-ethynylcyclohexylamine ([Building Block 3]) in NMP (0.1 M, 0.5 mL) were added sequentially and the mixture was shaken at 90 ° C. for 15 h. Resin was NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 mL, 2 times), 1% diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times) ), NMP (1.5 mL, twice) and CH 2 Cl 2 (1.5 mL, 6 times) were washed repeatedly for 2 minutes and filtered.

화합물을 CH2Cl2중 50% 트리플루오로아세트산 용액(1.5mL)로 실온에서 45분간 흔들어 섞어 완전히 절단하였다. 혼합물을 여과시키고 수지를 CH2Cl2(0.5mL)로 추출하였다. 합한 CH2Cl2추출물을 진공에서 농축시켰다. 잔여물을 메탄올과 CH2Cl21:1 혼합물(1mL)에 용해시켜 진공에서 농축시켜 표제의 화합물을 얻었다.The compound was cleaved thoroughly by shaking for 45 minutes at room temperature with a 50% trifluoroacetic acid solution (1.5 mL) in CH 2 Cl 2 . The mixture was filtered and the resin extracted with CH 2 Cl 2 (0.5 mL). The combined CH 2 Cl 2 extracts were concentrated in vacuo. The residue was dissolved in methanol and CH 2 Cl 2 1: 1 mixture (1 mL) and concentrated in vacuo to afford the title compound.

얻어진 최종 생성물을 분석용 RP-HPLC(체류시간)과 LC-MS(분자량)으로 특성규명하였다.The final product obtained was characterized by analytical RP-HPLC (ret. Time) and LC-MS (molecular weight).

RP-HPLC 분석을 Waters600S 콘트롤러, Waters996 Photodiode Array 디텍터, Waters717 오토샘플러, Waters616 펌프, Waters3mm x 150mm 3.5μ C-18 Symmetry 컬럼 및 Millenium QuickSet Control Ver. 2.15로 구성되는 Waters HPLC 시스템상에서 214nm에서 UV 검출을 사용하여 수행하였다. 1mL/분에서 15분동안의 5%에서 90% 아세토니트릴/0.1% 트리플루오로아세트산/물의 구배.Waters RP-HPLC Analysis 600S controllers, waters 996 Photodiode Array Detector, Waters 717 autosampler, Waters 616 pumps, Waters 3mm x 150mm 3.5μ C-18 Symmetry Column and Millenium QuickSet Control Ver. UV detection was performed at 214 nm on a Waters HPLC system consisting of 2.15. Gradient from 5% to 90% acetonitrile / 0.1% trifluoroacetic acid / water for 15 minutes at 1 mL / min.

LC-MS 분석은 Waters3 mm x 150 mm 3.5μ C-18 Symmetry 컬럼 및 20㎕/분의 유출속도를 가지는 양성 이온분사를 사용하여 PE Sciex API 100 LC/MS 시스템상에서 수행하였다.LC-MS analysis of Waters This was performed on a PE Sciex API 100 LC / MS system using a 3 mm x 150 mm 3.5 μ C-18 Symmetry column and positive ion injection with a flow rate of 20 μl / min.

실시예 536 내지 614:Examples 536-614:

다음의 79개의 화합물의 라이브러리는 다음의 합성장치의 작동을 조절하기 위한 다음의 ChemFile을 사용하여 Advanced ChemTech Model 384 HTS상에서 실시예 535와 유사하게 개개의 개체로서 병렬적으로 합성될 수 있다. 유형 수지-[빌딩블록 1]-[빌딩블록 2]의 4개의 수지를 장치를 초기화하기 전에 합성장치에서 80개의 웰에 동등하게 분배하였다.The following library of 79 compounds can be synthesized in parallel as individual entities on Advanced ChemTech Model 384 HTS, similar to Example 535, using the following ChemFile to control the operation of the following synthesizer. Four resins of type resin- [buildingblock 1]-[buildingblock 2] were equally distributed to 80 wells in the synthesis apparatus before the apparatus was initialized.

ChemFile C:\ACT\90250004.CHM 1면ChemFile C: \ ACT \ 90250004.CHM Page 1

1 Empty RB_Heating_All_1to36 for 2.000 minute(s)1 Empty RB_Heating_All_1to36 for 2.000 minute (s)

2 REM Addition of DIPEA2 REM Addition of DIPEA

3 Transfer 200㎕ from Monomers_1to36 [25] () to RB_Heating_All_1to96 [1-80] using DCE3 Transfer 200μl from Monomers_1to36 [25] () to RB_Heating_All_1to96 [1-80] using DCE

4 Mix for 1.00 minutes at 600 rpm(s)4 Mix for 1.00 minutes at 600 rpm (s)

5 REM Addition of Ph3P in NMP5 REM Addition of Ph3P in NMP

6 Transfer 500㎕ from Monomers_1to36 [21] () to RB Heating_All_1to96 [1-80] using DCE6 Transfer 500 μl from Monomers_1to36 [21] () to RB Heating_All_1to96 [1-80] using DCE

7 REM Addition of Bu4NCl in water7 REM Addition of Bu4NCl in water

8 Transfer 300㎕ from Monomers_1to36 [22] () to RB Heating_All_1to96 [1-80] using DCE8 Transfer 300μl from Monomers_1to36 [22] () to RB Heating_All_1to96 [1-80] using DCE

9 Mix for 1.00 minutes at 600 rpm(s)9 Mix for 1.00 minutes at 600 rpm (s)

10 REM Addition of Pd(OAc)2 in NMP10 REM Addition of Pd (OAc) 2 in NMP

11 Transfer 250㎕ from Monomers_1to36 [22] () to RB_Heating_All_1to96 [1-80] using DCE11 Transfer 250 μl from Monomers_1to36 [22] () to RB_Heating_All_1to96 [1-80] using DCE

12 Mix for 2.00 minutes at 600 rpm(s)12 Mix for 2.00 minutes at 600 rpm (s)

13 Dispense Sequence C:\ACT\ALKYNES.DSP with 500㎕ to RB_Heating_All_1to96 rack13 Dispense Sequence C: \ ACT \ ALKYNES.DSP with 500µl to RB_Heating_All_1to96 rack

14 Set Temperature to 90.0 degrees Celsius14 Set Temperature to 90.0 degrees Celsius

15 Mix for 15.00 minutes at 600 rpm(s)15 Mix for 15.00 minutes at 600 rpm (s)

16 Wait for 15.000 minute(s)16 Wait for 15.000 minute (s)

17 Repeat from step 15, 47 times17 Repeat from step 15, 47 times

18 Turn Temperature Controller Off18 Turn Temperature Controller Off

19 Mix for 15.00 minutes at 600 rpm(s)19 Mix for 15.00 minutes at 600 rpm (s)

20 Wait for 15.000 minute(s)20 Wait for 15.000 minute (s)

21 Repeat from step 19, 7 times21 Repeat from step 19, 7 times

22 Empty RB_Heating_All_1to96 for 2.000 minute(s)22 Empty RB_Heating_All_1to96 for 2.000 minute (s)

23 Dispense System Fluid NMP1 1500㎕ to RB_Cleavage_All_1to96 [1-80]23 Dispense System Fluid NMP1 1500µl to RB_Cleavage_All_1to96 [1-80]

24 Mix for 3.00 minutes at 600 rpm(s)24 Mix for 3.00 minutes at 600 rpm (s)

25 Empty RB_Heating_All_1to96 for 2.000 minute(s)25 Empty RB_Heating_All_1to96 for 2.000 minute (s)

26 Repeat from step 23, 2 times26 Repeat from step 23, 2 times

27 REM Wash with 50% H2O/NMP27 REM Wash with 50% H2O / NMP

28 Transfer 1500㎕ from Reagent_3 [1] () to RB_Heating_All_1to96 [1-80] using NMP128 Transfer 1500 μl from Reagent_3 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

29 Mix for 3.00 minutes at 600 rpm(s)29 Mix for 3.00 minutes at 600 rpm (s)

30 Empty RB_Heating_All_1to96 for 2.000 minute(s)30 Empty RB_Heating_All_1to96 for 2.000 minute (s)

31 Repeat from step 28, 2 times31 Repeat from step 28, 2 times

32 Dispense System Fluid NMP1 1500㎕ to RB_Cleavage_All_1to96 [1-80]32 Dispense System Fluid NMP1 1500µl to RB_Cleavage_All_1to96 [1-80]

33 Mix for 3.00 minutes at 600 rpm(s)33 Mix for 3.00 minutes at 600 rpm (s)

34 Empty RB_Heating_All_1to96 for 2.000 minute(s)34 Empty RB_Heating_All_1to96 for 2.000 minute (s)

35 Repeat from step 32, 1 times35 Repeat from step 32, 1 times

36 REM Wash with Sodium diethylaminodithiocarbamate36 REM Wash with Sodium diethylaminodithiocarbamate

37 Transfer 1500㎕ from Reagent_3 [1] () to RB_Heating_All_1to96 [1-80] using NMP137 Transfer 1500μl from Reagent_3 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

38 Mix for 3.00 minutes at 600 rpm(s)38 Mix for 3.00 minutes at 600 rpm (s)

39 Empty RB_Heating_All_1to96 for 2.000 minute(s)39 Empty RB_Heating_All_1to96 for 2.000 minute (s)

40 Repeat from step 37, 2 times40 Repeat from step 37, 2 times

41 Transfer 1500㎕ from REAGENT_4 [1] () to RB_Heating_All_1to96 [1-80] using NMP141 Transfer 1500 μl from REAGENT_4 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

42 Mix for 3.00 minutes at 600 rpm(s)42 Mix for 3.00 minutes at 600 rpm (s)

43 Empty RB_Heating_All_1to96 for 2.000 minute(s)43 Empty RB_Heating_All_1to96 for 2.000 minute (s)

44 Repeat from step 41, 2 times44 Repeat from step 41, 2 times

45 Transfer 1500㎕ from REAGENT_5 [1] () to RB_Heating_All_1to96 [1-80] using NMP145 Transfer 1500μl from REAGENT_5 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

46 Mix for 2.00 minutes at 600 rpm(s)46 Mix for 2.00 minutes at 600 rpm (s)

47 Empty RB_Heating_All_1to96 for 2.000 minute(s)47 Empty RB_Heating_All_1to96 for 2.000 minute (s)

48 Repeat from step 45, 2 times48 Repeat from step 45, 2 times

49 Dispense System Fluid NMP1 1500㎕ to RB_Cleavage_All_1to96 [1-80]49 Dispense System Fluid NMP1 1500µl to RB_Cleavage_All_1to96 [1-80]

50 Mix for 3.00 minutes at 600 rpm(s)50 Mix for 3.00 minutes at 600 rpm (s)

51 Empty RB_Heating_All_1to96 for 2.000 minute(s)51 Empty RB_Heating_All_1to96 for 2.000 minute (s)

52 Repeat from step 49, 4 times52 Repeat from step 49, 4 times

53 Dispense System Fluid DCE1 1500㎕ to RB_Cleavage_All_1to96 [1-80]53 Dispense System Fluid DCE1 1500µl to RB_Cleavage_All_1to96 [1-80]

54 Mix for 3.00 minutes at 600 rpm(s)54 Mix for 3.00 minutes at 600 rpm (s)

55 Empty RB_Heating_All_1to96 for 2.000 minute(s)55 Empty RB_Heating_All_1to96 for 2.000 minute (s)

56 Repeat from step 53, 5 times56 Repeat from step 53, 5 times

57 REM Cleavage from Resin57 REM Cleavage from Resin

58 REM with 50% TFA/DCM58 REM with 50% TFA / DCM

59 Transfer 1500㎕ from Reagent _3 [1] () to RB_Cleavage_All_1to96 [1-80] using DCM159 Transfer 1500μl from Reagent _3 [1] () to RB_Cleavage_All_1to96 [1-80] using DCM1

60 Mix for 45.00 minutes at 600 rpm(s)60 Mix for 45.00 minutes at 600 rpm (s)

61 Empty RB_Cleavage_All_1to96 for 1.000 minute(s)61 Empty RB_Cleavage_All_1to96 for 1.000 minute (s)

62 Dispense System Fluid DCM1 500㎕ to RB_Cleavage_All_1to96 [1-80]62 Dispense System Fluid DCM1 500µl to RB_Cleavage_All_1to96 [1-80]

63 Mix for 1.00 minutes at 300 rpm(s)63 Mix for 1.00 minutes at 300 rpm (s)

64 Empty RB_Cleavage_All_1to96 for 1.000 minute(s)64 Empty RB_Cleavage_All_1to96 for 1.000 minute (s)

6565

6666

Dispense Sequence C:\ACT\ALKYNES.DSP는 유형 [빌딩블록 3]의 20개의 알킨의 합성장치중 80개의 웰에의 조합적 첨가를 조절하기 위한 서브루틴이다.Dispense Sequence C: \ ACT \ ALKYNES.DSP is a subroutine for controlling combinatorial addition to 80 wells of 20 alkyne synthesizing apparatus of type [Building Block 3].

하기 목록된 화합물을 포함하는 라이브러리를 합성하였다. 얻어진 라이브러리의 서브세트는 분석용 RP-HPLC(체류시간)과 LC-MS(분자량)에 의해 특성규명되었다.A library comprising the compounds listed below was synthesized. The subset of libraries obtained was characterized by analytical RP-HPLC (ret. Time) and LC-MS (molecular weight).

실시예 614 내지 694의 제조를 위한 일반적인 방법General Methods for the Preparation of Examples 614-694

하기 80개의 화합물은 고체 지지체에서 병렬적 합성에 의해 단일 개체로서 제조되었다. [빌딩블록 3]의 부착과 수지로부터의 절단은 Advanced ChemTech Model 384 HTS상에서 수행되었다.The following 80 compounds were prepared as single individuals by parallel synthesis on a solid support. Attachment of [Blocking Block 3] and cleavage from resin were performed on Advanced ChemTech Model 384 HTS.

화합물은 다음 식:The compound is of the following formula:

수지-[빌딩블록 1] →Resin- [Building Block 1] →

수지-[빌딩블록 1]-[빌딩블록 2] →Resin- [Building Block 1]-[Building Block 2] →

수지-[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3]Resin- [Building Block 1]-[Building Block 2]-[Building Block 3]

에 따라서 제조하였고 동시에 디클로로메탄중 50% 트리플루오로아세트산으로 수지로부터 절단(보호되었다면 탈보호화)하여 다음 식:Prepared according to the following formula, and at the same time cleaved from the resin (deprotected if protected) with 50% trifluoroacetic acid in dichloromethane,

[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3][Building Block 1]-[Building Block 2]-[Building Block 3]

에 따르는 개개의 개체로서 원하는 화합물을 얻었다.The desired compound was obtained as an individual object according to the present invention.

출발 수지, 수지-[빌딩블록 1]-[빌딩블록 2]는 모두 하기 기재된 바와 같이 제조되었다.Starting resin, Resin- [Building Block 1]-[Building Block 2] were all prepared as described below.

사용된 수지는 Wang 링커를 가지는 폴리스티렌 수지이고 치환용량은 0.9mmol/g이었다.The resin used was a polystyrene resin with Wang linker and a substitution capacity of 0.9 mmol / g.

80개의 모든 화합물은 완전히 조합적 방식으로 다음 반응식에 따르는 Suzuki 반응을 사용하여 [빌딩블록 3]의 수지-[빌딩블록 1]-[빌딩블록 2]에의 부착을 기본으로 한다.All 80 compounds are based on the attachment of [Building Block 3] to Resin- [Building Block 1]-[Building Block 2] using the Suzuki reaction according to the following scheme in a completely combinatorial manner.

(반응식)(Scheme)

즉 B-Lea는 B-Lea is

상기 식에서, Lea는 이탈기이고 R14및 R15는 화학식 I에서 정의된 바와 같다.Wherein Lea is a leaving group and R 14 and R 15 are as defined in formula (I).

사용된 출발물질은 실시예 535 내지 614에서 사용된 것, 즉 수지-[빌딩블록 1]과 동일하였고, [빌딩블록 2]와 [빌딩블록 3]은 실시예 535 내지 614에서 사용된 것과 동일하였다. 실시예 615 내지 694에서의 생성물이 가지는 유일한 차이점은 실시예 535 내지 614의 생성물이 삼중결합을 가지는 데 반하여 이중결합을 가지는 것이다.The starting materials used were the same as those used in Examples 535 to 614, namely Resin- [Building Block 1], and [Building Block 2] and [Building Block 3] were the same as those used in Examples 535 to 614. . The only difference that the product in Examples 615-694 has is that the product of Examples 535-614 has a double bond as opposed to having a triple bond.

실시예 615:Example 615:

3-클로로-4-히드록시벤조산{3-[2-(1-아미노시클로헥실)비닐]-4,5-디메톡시벤질리덴}히드라지드3-chloro-4-hydroxybenzoic acid {3- [2- (1-aminocyclohexyl) vinyl] -4,5-dimethoxybenzylidene} hydrazide

1,4-디옥산/THF중 1-(2-벤조[1,3,2]디옥사보롤-2-일비닐)시클로헥실아민 용액의 제조:Preparation of 1- (2-benzo [1,3,2] dioxaborole-2-ylvinyl) cyclohexylamine solution in 1,4-dioxane / THF:

1,4-디옥산(1M, 0.5mL)중 1-에틴일시클로헥실아민([빌딩블록 3])의 용액에 THF(1M, 0.5mL)중 카테콜보란의 용액을 가하고 이 혼합물을 60℃에서 4시간동안 가열하였다. 용액을 실온까지 냉각시키고 Suzuki 결합반응에 직접 사용하였다.To a solution of 1-ethynylcyclohexylamine ([Building Block 3]) in 1,4-dioxane (1M, 0.5 mL) was added a solution of catecholborane in THF (1 M, 0.5 mL) and the mixture was 60 ° C. Heated at for 4 h. The solution was cooled to room temperature and used directly for the Suzuki binding reaction.

수지가 결합된 3-클로로-4-히드록시벤조산(3-브로모벤질리덴)히드라지드(0.05mmol)에 물중 탄산세슘 용액(1.25M, 0.2mL), NMP중 트리페닐포스핀용액 및 염화테트라부틸암모늄(둘다 0.4M, 0.5mL), NMP중 아세트산제2팔라늄의 용액(0.16M, 0.25mL)를 가하고 혼합하고 1,4-디옥산/THF중 1-(2-벤조[1,3,2]디옥사보롤-2-일비닐)시클로헥실아민 용액을 가하고, 혼합물을 15시간동안 70℃에서 흔들어 섞었다. 수지를 NMP(1.5mL, 3회), DMF중 50% 물(1.5mL, 3회), NMP(1.5mL, 2회), 1% 나트륨 디에틸아미노디티오카르바메이트 3수화물(1.5mL, 9회), NMP(1.5mL, 5회) 및 CH2Cl2(0.5mL, 6회)로 2분동안 반복적으로 세척하고 여과하였다.Resin-bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene) hydrazide (0.05 mmol) in cesium carbonate solution (1.25 M, 0.2 mL) in water, triphenylphosphine solution in NMP and tetrachloride Butyl ammonium (both 0.4 M, 0.5 mL), a solution of dipalladium acetate (0.16 M, 0.25 mL) in NMP was added and mixed and 1- (2-benzo [1,3 in 1,4-dioxane / THF) , 2] dioxaborole-2-ylvinyl) cyclohexylamine solution was added and the mixture was shaken for 15 hours at 70 ° C. The resin was divided into NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 mL, 2 times), 1% sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP (1.5 mL, 5 times) and CH 2 Cl 2 (0.5 mL, 6 times) repeatedly washed for 2 minutes and filtered.

화합물을 CH2Cl2중 50% 트리플루오로아세트산 용액(1.5mL)로 실온에서 45분간 흔들어 섞어 완전히 절단하였다. 혼합물을 여과시키고 수지를 CH2Cl2(0.5mL)로 추출하였다. 합한 CH2Cl2추출물을 진공에서 농축시켰다. 잔여물을 메탄올과 CH2Cl2(1mL)의 1:1 혼합물에 용해시키고 농축시켜 표제의 화합물을 얻었다.The compound was cleaved thoroughly by shaking for 45 minutes at room temperature with a 50% trifluoroacetic acid solution (1.5 mL) in CH 2 Cl 2 . The mixture was filtered and the resin extracted with CH 2 Cl 2 (0.5 mL). The combined CH 2 Cl 2 extracts were concentrated in vacuo. The residue was dissolved in a 1: 1 mixture of methanol and CH 2 Cl 2 (1 mL) and concentrated to afford the title compound.

얻어진 최종 생성물을 분석용 RP-HPLC(체류시간)과 LC-MS(분자량)으로 특성규명하였다.The final product obtained was characterized by analytical RP-HPLC (ret. Time) and LC-MS (molecular weight).

RP-HPLC 분석을 Waters600S 콘트롤러, Waters996 Photodiode Array 디텍터, Waters717 오토샘플러, Waters616 펌프, Waters3mm x 150mm 3.5μ C-18 Symmetry 컬럼 및 Millenium QuickSet Control Ver. 2.15로 구성되는 Waters HPLC 시스템상에서 214nm에서 UV 검출을 사용하여 수행하였다. 1mL/분에서 15분동안의 5%에서 90% 아세토니트릴/0.1% 트리플루오로아세트산/물의 구배.Waters RP-HPLC Analysis 600S controllers, waters 996 Photodiode Array Detector, Waters 717 autosampler, Waters 616 pumps, Waters 3mm x 150mm 3.5μ C-18 Symmetry Column and Millenium QuickSet Control Ver. UV detection was performed at 214 nm on a Waters HPLC system consisting of 2.15. Gradient from 5% to 90% acetonitrile / 0.1% trifluoroacetic acid / water for 15 minutes at 1 mL / min.

LC-MS 분석은 Waters3 mm x 150 mm 3.5μ C-18 Symmetry 컬럼 및 20㎕/분의 유출속도를 가지는 양성 이온분사를 사용하여 PE Sciex API 100 LC/MS 시스템상에서 수행하였다.LC-MS analysis of Waters This was performed on a PE Sciex API 100 LC / MS system using a 3 mm x 150 mm 3.5 μ C-18 Symmetry column and positive ion injection with a flow rate of 20 μl / min.

실시예 616 내지 694:Examples 616-694:

다음의 79개의 화합물의 라이브러리는 합성장치의 작동을 조절하기 위한 다음의 ChemFile을 사용하여 Advanced ChemTech Model 496 HTS상에서 실시예 615와 유사하게 개개의 개체로서 병렬적으로 제조될 수 있다. 유형 수지-[빌딩블록 1]-[빌딩블록 2]의 4개의 수지를 장치를 초기화하기 전에 합성장치에서 80개의 웰에 동등하게 분배하였다.The following 79 library of compounds can be prepared in parallel as individual individuals on Advanced ChemTech Model 496 HTS, similar to Example 615, using the following ChemFile to control the operation of the synthesizer. Four resins of type resin- [buildingblock 1]-[buildingblock 2] were equally distributed to 80 wells in the synthesis apparatus before the apparatus was initialized.

ChemFile C:\ACT\90250003.CHM 1면ChemFile C: \ ACT \ 90250003.CHM Page 1

1 Empty RB_Heating_All_1to96 for 2.000 minute(s)1 Empty RB_Heating_All_1to96 for 2.000 minute (s)

22

3 REM Addition of Cs2C03 in water3 REM Addition of Cs2C03 in water

44

5 Transfer 200㎕ from Monomers_1to36 [25] () to RB_Heating_All_lto96 [1-80] using DCE5 Transfer 200μl from Monomers_1to36 [25] () to RB_Heating_All_lto96 [1-80] using DCE

6 Mix for 1.00 minutes at 600 rpm(s)6 Mix for 1.00 minutes at 600 rpm (s)

77

8 REM Addition of Ph3P + Bu4NCl in NMP8 REM Addition of Ph3P + Bu4NCl in NMP

99

10 Transfer 500㎕ from Monomers_1to36 [21] () to RB_Heating_All_1to96 [1-80] using DCE10 Transfer 500 μl from Monomers_1to36 [21] () to RB_Heating_All_1to96 [1-80] using DCE

11 Mix for 1.00 minutes at 600 rpm(s)11 Mix for 1.00 minutes at 600 rpm (s)

1212

13 REM Addition of Pd(OAc)2 in NMP13 REM Addition of Pd (OAc) 2 in NMP

1414

15 Transfer 500㎕ from Monomers_1to36 [22] () to RB_Heating_All_1to96 [1-80] using DCE15 Transfer 500 μl from Monomers_1to36 [22] () to RB_Heating_All_1to96 [1-80] using DCE

16 Mix for 2.00 minutes at 600 rpm(s)16 Mix for 2.00 minutes at 600 rpm (s)

17 Dispense Sequence C:\ACT\ALKYNES.DSP with 500㎕ to RB_Heating_All_1to96 rack17 Dispense Sequence C: \ ACT \ ALKYNES.DSP with 500µl to RB_Heating_All_1to96 rack

18 Set Temperature to 70.0 degrees Celsius18 Set Temperature to 70.0 degrees Celsius

19 Mix for 15.00 minutes at 600 rpm(s)19 Mix for 15.00 minutes at 600 rpm (s)

20 Wait for 15.000 minute(s)20 Wait for 15.000 minute (s)

21 Repeat from step 19, 29 times21 Repeat from step 19, 29 times

22 Turn Temperature Controller Off22 Turn Temperature Controller Off

23 Mix for 15.00 minutes at 600 rpm(s)23 Mix for 15.00 minutes at 600 rpm (s)

24 Wait for 15.000 minute(s)24 Wait for 15.000 minute (s)

25 Repeat from step 23, 7 times25 Repeat from step 23, 7 times

26 Empty RB_Heating_All 1to96 for 2.000 minute(s)26 Empty RB_Heating_All 1to96 for 2.000 minute (s)

27 Dispense System Fluid NMP1 1500㎕ to RB_Cleavage_All_1to96 [1-80]27 Dispense System Fluid NMP1 1500µl to RB_Cleavage_All_1to96 [1-80]

28 Mix for 3.00 minutes at 600 rpm(s)28 Mix for 3.00 minutes at 600 rpm (s)

29 Empty RB_Heating_All_1to96 for 2.000 minute(s)29 Empty RB_Heating_All_1to96 for 2.000 minute (s)

30 Repeat from step 27, 2 times30 Repeat from step 27, 2 times

3131

32 REM Wash with 50% H2O/NMP32 REM Wash with 50% H2O / NMP

3333

34 Transfer 1500㎕ from Reagent _3 [1] () to RB_Heating_All_1to96 [1-80] using NMP134 Transfer 1500μl from Reagent _3 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

35 Mix for 3.00 minutes at 600 rpm(s)35 Mix for 3.00 minutes at 600 rpm (s)

36 Empty RB_Heating_All_1to96 for 2.000 minute(s)36 Empty RB_Heating_All_1to96 for 2.000 minute (s)

37 Repeat from step 34, 2 times37 Repeat from step 34, 2 times

38 Dispense System Fluid NMP1 1500㎕ to RB_Cleavage_All_1to96 [1-80]38 Dispense System Fluid NMP1 1500µl to RB_Cleavage_All_1to96 [1-80]

39 Mix for 3.00 minutes at 600 rpm(s)39 Mix for 3.00 minutes at 600 rpm (s)

40 Empty RB_Heating_All_1to96 for 2.000 minute(s)40 Empty RB_Heating_All_1to96 for 2.000 minute (s)

41 Repeat from step 38, l times41 Repeat from step 38, l times

4242

43 REM Wash with Sodium diethylaminodithiocarbamate43 REM Wash with Sodium diethylaminodithiocarbamate

4444

45 Transfer 1500㎕ from Reagent_3 [1] () to RB_Heating_All_1to96 [1-80] using NMP145 Transfer 1500μl from Reagent_3 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

46 Mix for 3.00 minutes at 600 rpm(s)46 Mix for 3.00 minutes at 600 rpm (s)

47 Empty RB_Heating_All_1to96 for 2.000 minute(s)47 Empty RB_Heating_All_1to96 for 2.000 minute (s)

48 Repeat from step 45, 2 times48 Repeat from step 45, 2 times

49 Transfer 1500㎕ from REAGENT_4 [1] () to RB_Heating_All_1to96 [1-80] using NMP149 Transfer 1500 μl from REAGENT_4 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

50 Mix for 3.00 minutes at 600 rpm(s)50 Mix for 3.00 minutes at 600 rpm (s)

51 Empty RB_Heating_All_1to96 for 2.000 minute(s)51 Empty RB_Heating_All_1to96 for 2.000 minute (s)

52 Repeat from step 49, 2 times52 Repeat from step 49, 2 times

53 Transfer 1500㎕ from REAGENT_5 [1] () to RB_Heating_All_1to96[ 1-80] using NMP153 Transfer 1500μl from REAGENT_5 [1] () to RB_Heating_All_1to96 [1-80] using NMP1

54 Mix for 2.00 minutes at 600 rpm(s)54 Mix for 2.00 minutes at 600 rpm (s)

55 Empty RB_Heating_All_1to96 for 2.000 minute(s)55 Empty RB_Heating_All_1to96 for 2.000 minute (s)

56 Repeat from step 53, 2 times56 Repeat from step 53, 2 times

57 Dispense System Fluid NMP1 1500㎕ to RB_Cleavage_All_1to96 [1-80]57 Dispense System Fluid NMP1 1500µl to RB_Cleavage_All_1to96 [1-80]

58 Mix for 3.00 minutes at 600 rpm(s)58 Mix for 3.00 minutes at 600 rpm (s)

59 Empty RB_Heating_All_1to96 for 2.000 minute(s)59 Empty RB_Heating_All_1to96 for 2.000 minute (s)

60 Repeat from step 57, 4 times60 Repeat from step 57, 4 times

61 Dispense System Fluid DCE1 1500㎕ to RB_Cleavage_All_1to96 [1-80]61 Dispense System Fluid DCE1 1500µl to RB_Cleavage_All_1to96 [1-80]

62 Mix for 3.00 minutes at 600 rpm(s)62 Mix for 3.00 minutes at 600 rpm (s)

63 Empty RB_Heating_All_1to96 for 2.000 minute(s)63 Empty RB_Heating_All_1to96 for 2.000 minute (s)

64 Repeat from step 61, 5 times64 Repeat from step 61, 5 times

6565

66 REM Cleavage from Resin66 REM Cleavage from Resin

67 REM with 50% TFA/DCM67 REM with 50% TFA / DCM

6868

69 Transfer 1500㎕ from Reagent_3 [1] () to RB_Cleavage_All_1to96 [1-80] using DCM169 Transfer 1500μl from Reagent_3 [1] () to RB_Cleavage_All_1to96 [1-80] using DCM1

70 Mix for 45.00 minutes at 600 rpm(s)70 Mix for 45.00 minutes at 600 rpm (s)

71 Empty RB_Cleavage_All_1to96 for 1.000 minute(s)71 Empty RB_Cleavage_All_1to96 for 1.000 minute (s)

72 Dispense System Fluid DCM1 500㎕ to RB_Cleavage_All_1to96 [1-80]72 Dispense System Fluid DCM1 500µl to RB_Cleavage_All_1to96 [1-80]

73 Mix for 1.00 minutes at 300 rpm(s)73 Mix for 1.00 minutes at 300 rpm (s)

74 Empty RB_Cleavage_All_1to96 for 1.000 minute(s)74 Empty RB_Cleavage_All_1to96 for 1.000 minute (s)

7575

Dispense Sequence C:\ACT\ALKYNES.DSP는 유형 [빌딩블록 3]의 20개의 2-비닐-벤조[1,3,2]디옥사보롤의 용액의 합성장치중 80개의 웰에의 조합적 첨가를 조절하기 위한 서브루틴이다.Dispense Sequence C: \ ACT \ ALKYNES.DSP allows for the combined addition of 20 [2] -vinyl-benzo [1,3,2] dioxaborole solutions of type [Building Block 3] to 80 wells in the synthesis unit. Subroutine to control.

하기 목록된 화합물을 포함하는 라이브러리를 합성하였다. 얻어진 라이브러리의 서브세트는 분석용 RP-HPLC(체류시간)과 LC-MS(분자량)에 의해 특성규명되었다.A library comprising the compounds listed below was synthesized. The subset of libraries obtained was characterized by analytical RP-HPLC (ret. Time) and LC-MS (molecular weight).

실시예 695 내지 701을 위한 일반적인 방법General Method for Examples 695-701

화합물은 다음 식:The compound is of the following formula:

수지-[빌딩블록 1] →Resin- [Building Block 1] →

수지-[빌딩블록 1]-[빌딩블록 2] →Resin- [Building Block 1]-[Building Block 2] →

수지-[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3]Resin- [Building Block 1]-[Building Block 2]-[Building Block 3]

에 따라서 제조하였고 동시에 탈보호화하고 디클로로메탄중 50% 트리플루오로아세트산으로 수지로부터 절단하여 다음 식:Prepared in accordance with the following formula and simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane:

[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3][Building Block 1]-[Building Block 2]-[Building Block 3]

에 따르는 개개의 개체로서 원하는 화합물을 얻었다.The desired compound was obtained as an individual object according to the present invention.

다음의 화합물은 고체 지지체상에서 병렬적 합성에 의해 단일체로서 얻었다. 수지-[빌딩블록 1]의 제조는 수동으로 하였고, 반면 [빌딩블록 2] 및 [빌딩블록 3]의 부착과 수지로부터의 절단은 Advanced ChemTech Model 384 HTS상에서 수행하였다.The following compounds were obtained as a single body by parallel synthesis on a solid support. Preparation of Resin- [Building Block 1] was done manually, while attachment of [Building Block 2] and [Building Block 3] and cleavage from the resin were performed on Advanced ChemTech Model 384 HTS.

출발 수지, 수지-[빌딩블록 1]은 하기 기재된 바와 같이 제조되었다.Starting resin, Resin- [Building Block 1], was prepared as described below.

사용된 수지는 Wang 링커를 가지는 폴리스티렌 수지이고 치환용량은 0.9mmol/g이었다.The resin used was a polystyrene resin with Wang linker and a substitution capacity of 0.9 mmol / g.

모든 화합물은 조합적 방식으로 다음 반응식에 따르는 친핵치환반응을 사용하여 [빌딩블록 2] 및 [빌딩블록 3]의 수지-[빌딩블록 1]에의 연속적인 부착을 기본으로 한다. 반응식은 화학식 II에 관련된다.All compounds are based on the continuous attachment of [Building Block 2] and [Building Block 3] to Resin- [Building Block 1] using a nucleophilic substitution reaction according to the following scheme in a combinatorial fashion. The scheme is related to formula II.

(반응식)(Scheme)

및And

상기 식에서, R14및 R15는 화학식 I에서 정의된 바와 같고 -NR5cR5d는(상기 식에서, R5a, R4a, R4b, c, q, d 및 D는 화학식 I에서 정의된 바와 같다)이거나, 친핵기로서 반응할 수 있는 1차 또는 2차 아민을 포함하는 -D의 부분집합으로서 정의된 -D'이다.Wherein R 14 and R 15 are as defined in Formula I and -NR 5c R 5d is (Wherein R 5a , R 4a , R 4b , c, q, d and D are as defined in formula (I)) or -D comprising a primary or secondary amine capable of reacting as a nucleophilic group -D 'defined as a subset.

여기서 수지-[빌딩블록 1]로서 나타낸 다음의 수지를 사용하였다.The following resin shown here as Resin- [Building Block 1] was used.

상기 식에서 PS는 폴리스티렌이고, 아래에서 "수지"는 Wang 링커를 가진 폴리스티렌 수지이다.Wherein PS is polystyrene and below "resin" is a polystyrene resin with Wang linker.

다음의 빌딩블록을 사용하였다:The following building blocks were used:

[빌딩블록 2]:[Building Block 2]:

[빌딩블록 3]:[Building Block 3]:

수지-[빌딩블록 1]의 제조:Preparation of Resin- [Building Block 1]:

이 수지는 상기 기재된 바와 같이 제조하였다.This resin was prepared as described above.

[빌딩블록 2]의 제조:Preparation of [Building Block 2]:

4-(2-브로모에톡시)-2-메톡시벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -2-methoxybenzaldehyde:

1,2-디브로모에탄(57mL, 0.66mol)을 DMF(130mL)중 4-히드록시-2-메톡시벤즈알데히드(10g, 66mmol) 및 탄산칼륨(45g, 0.33mol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(0.8L)에 붓고 에틸아세테이트(3x300mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(400mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-(2-브로모에톡시)-2-메톡시벤즈알데히드 17.4g(99%)을 얻었다. 융점 78-79℃.1,2-dibromoethane (57 mL, 0.66 mol) was added to a mixture of 4-hydroxy-2-methoxybenzaldehyde (10 g, 66 mmol) and potassium carbonate (45 g, 0.33 mol) in DMF (130 mL) and as a result The mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3x300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO 4 and evaporated in vacuo to give 17.4 g (99%) of 4- (2-bromoethoxy) -2-methoxybenzaldehyde. Melting point 78-79 ° C.

4-(2-브로모에톡시)-3-메톡시벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -3-methoxybenzaldehyde:

1,2-디브로모에탄(57mL, 0.66mol)을 DMF(130mL)중 4-히드록시-3-메톡시벤즈알데히드(10g, 66mmol) 및 탄산칼륨(45g, 0.33mol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(1.2L)에 붓고 에틸아세테이트(500+4x300mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(500mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-(2-브로모에톡시)-3-메톡시벤즈알데히드 16.3g(95%)을 얻었다. 융점 61-64℃.1,2-dibromoethane (57 mL, 0.66 mol) was added to a mixture of 4-hydroxy-3-methoxybenzaldehyde (10 g, 66 mmol) and potassium carbonate (45 g, 0.33 mol) in DMF (130 mL) and as a result The mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1.2 L) and extracted with ethyl acetate (500 + 4 × 300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO 4 and evaporated in vacuo to give 16.3 g (95%) of 4- (2-bromoethoxy) -3-methoxybenzaldehyde. Melting point 61-64 ° C.

4-(2-브로모에톡시)-3-클로로-5-메톡시벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -3-chloro-5-methoxybenzaldehyde:

1,2-디브로모에탄(46mL, 0.54mol)을 DMF(180mL)중 3-클로로-4-히드록시-5-메톡시벤즈알데히드(10g, 54mmol) 및 탄산칼륨(37g, 0.27mol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(100mL)에 붓고 에틸아세테이트(2x100mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(150mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-(2-브로모에톡시)-3-클로로-5-메톡시벤즈알데히드 9.33g(59%)을 얻었다. 융점 52-54℃.1,2-dibromoethane (46 mL, 0.54 mol) was mixed with 3-chloro-4-hydroxy-5-methoxybenzaldehyde (10 g, 54 mmol) and potassium carbonate (37 g, 0.27 mol) in DMF (180 mL). And the resulting mixture was stirred vigorously for 16 hours at room temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO 4 and evaporated in vacuo to give 9.33 g (59%) of 4- (2-bromoethoxy) -3-chloro-5-methoxybenzaldehyde. Melting point 52-54 ° C.

4-(2-브로모에톡시)-3,5-디메틸벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -3,5-dimethylbenzaldehyde:

1,2-디브로모에탄(26mL, 0.3mol)을 DMF(90mL)중 3,5-디메틸-4-히드록시벤즈알데히드(4.57g, 30mmol) 및 탄산칼륨(21g, 150mmol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(0.3L)에 붓고 포화 염화나트륨(200mL)을 가하고 에틸아세테이트(2x200mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(300mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-(2-브로모에톡시)-3,5-디메틸벤즈알데히드 8.2g(95%)을 오일로서 얻었다.1,2-dibromoethane (26 mL, 0.3 mol) was added to a mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (4.57 g, 30 mmol) and potassium carbonate (21 g, 150 mmol) in DMF (90 mL). The resulting mixture was stirred vigorously for 16 hours at room temperature. The mixture was poured into water (0.3 L), saturated sodium chloride (200 mL) was added, and extracted with ethyl acetate (2x200 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO 4 and evaporated in vacuo to give 8.2 g (95%) of 4- (2-bromoethoxy) -3,5-dimethylbenzaldehyde as an oil.

1H-NMR (300 MHz, CDCl3): δ = 2.33 (6H, s), 3.83 (2H, t), 4.18 (2H, t), 7.60 (2H, s), 9.88 (1H, s). 1 H-NMR (300 MHz, CDCl 3 ): δ = 2.33 (6H, s), 3.83 (2H, t), 4.18 (2H, t), 7.60 (2H, s), 9.88 (1H, s).

4-(2-브로모에톡시)-3,5-디브로모벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -3,5-dibromobenzaldehyde:

1,2-디브로모에탄(62mL, 0.72mol)을 DMF(100mL)중 3,5-디브로모-4-히드록시벤즈알데히드(10g, 36mmol) 및 탄산칼륨(25g, 180mmol)의 혼합물에 가하고 그 결과의 혼합물을 70℃에서 16시간동안 격렬하게 교반하였다. 냉각후, 혼합물을 물(300mL)에 붓고 에틸아세테이트(400mL)로 추출하였다. 물(200mL)을 수상에 가하고 이것을 에틸아세테이트(150mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(3x150mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켰다. 잔여물을 환류 96%에탄올(60mL)에 용해시켰다. 물(15mL)을 가하고 냉각, 여과, 60%메탄올로 세척하고 건조시킨 후, 4-(2-브로모에톡시)-3,5-디브로모벤즈알데히드 10.7g(77%)을 두 생성물에서 분리시켰다. 융점 84-84℃1,2-dibromoethane (62 mL, 0.72 mol) was added to a mixture of 3,5-dibromo-4-hydroxybenzaldehyde (10 g, 36 mmol) and potassium carbonate (25 g, 180 mmol) in DMF (100 mL) The resulting mixture was stirred vigorously at 70 ° C. for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chloride (3 × 150 mL), dried over MgSO 4 and evaporated in vacuo. The residue was dissolved in reflux 96% ethanol (60 mL). Water (15 mL) was added, cooled, filtered, washed with 60% methanol and dried, then 10.7 g (77%) of 4- (2-bromoethoxy) -3,5-dibromobenzaldehyde was separated from both products. . Melting point 84-84 ℃

4-(2-브로모에톡시)-3-에톡시-5-페닐벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -3-ethoxy-5-phenylbenzaldehyde:

디클로로메탄(300mL)중 4-히드록시-3-요오도-5-메톡시벤즈알데히드(20g, 72mmol), 에틸렌글리콜(8.0mL, 144mmol), 및 클로로트리메틸실란(36.5mL, 0.29mol)의 혼합물을 16시간동안 환류가열하였다. 혼합물을 실온까지 냉각시키고 포화 탄산수소나트륨(3x200mL)로 세척하였다. 합한 수상을 디클로로메탄(3x150mL)로 추출하였다. 합한 유기 추출물을 포화 염화나트륨(200mL)으로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-[1,3]디옥솔란-2-일-2-요오도-6-메톡시페놀 22.1g(95%)을 얻었다. 융점 120-121℃.A mixture of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (20 g, 72 mmol), ethylene glycol (8.0 mL, 144 mmol), and chlorotrimethylsilane (36.5 mL, 0.29 mol) in dichloromethane (300 mL) was prepared. Heated to reflux for 16 hours. The mixture was cooled to room temperature and washed with saturated sodium hydrogen carbonate (3x200 mL). The combined aqueous phases were extracted with dichloromethane (3x150 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO 4 and evaporated in vacuo to give 22.1 g (95%) of 4- [1,3] dioxolan-2-yl-2-iodo-6-methoxyphenol. ) Melting point 120-121 ° C.

N2하, 테트라키스-트리페닐포스핀팔라디움(0)을 상기 디옥솔란(10g, 31mmol), 벤젠보론산(4.5g, 37mmol), 톨루엔(67mL), 2M 수성 탄산나트륨(33mL) 및 메탄올(20mL)의 혼합물에 가하였다. 그 결과의 혼합물을 N2하에서 16시간동안 환류가열하였다. 냉각후, 혼합물을 물(150mL)로 희석하고 헵탄(400mL)으로 세척하였다. 수상을 3N 염산으로 산성화하고 에틸아세테이트(3x300mL)로 추출하였다. 합한 유기상을 MgSO4에서 건조시키고 진공에서 증발시켰다. 잔여물을 에틸아세테이트 및 헵탄(1:2)의 혼합물을 용리액으로 하는 실리카겔(800mL)상의 컬럼크로마토그래피로 정제하여 4-히드록시-3-메톡시-5-페닐벤즈알데히드 5.49g(77%)을 얻었다. 융점 107-108℃.Under N 2 , tetrakis-triphenylphosphinepalladium (0) was added to the dioxolane (10 g, 31 mmol), benzeneboronic acid (4.5 g, 37 mmol), toluene (67 mL), 2M aqueous sodium carbonate (33 mL) and methanol (20 mL). ) Was added to the mixture. The resulting mixture was heated to reflux under N 2 for 16 h. After cooling, the mixture was diluted with water (150 mL) and washed with heptane (400 mL). The aqueous phase was acidified with 3N hydrochloric acid and extracted with ethyl acetate (3x300 mL). The combined organic phases were dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) using a mixture of ethyl acetate and heptane (1: 2) as eluent to give 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. Got it. Melting point 107-108 ° C.

1,2-디브로모에탄(41mL, 0.48mol)을 DMF(80mL)중 상기 4-히드록시-3-메톡시-5-페닐벤즈알데히드(5.49g, 24mmol) 및 탄산칼륨(17g, 123mmol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(1L)에 붓고 에틸아세테이트(3x300mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(200mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-(2-브로모에톡시)-3-메톡시-5-페닐벤즈알데히드 8.1g(100%)을 오일로서 얻었다.1,2-dibromoethane (41 mL, 0.48 mol) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmol) and potassium carbonate (17 g, 123 mmol) in DMF (80 mL) It was added to the mixture and the resulting mixture was stirred vigorously for 16 hours at room temperature. The mixture was poured into water (1 L) and extracted with ethyl acetate (3x300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO 4 and evaporated in vacuo to give 8.1 g (100%) of 4- (2-bromoethoxy) -3-methoxy-5-phenylbenzaldehyde as an oil.

1H-NMR (300 MHz, DMSO-d6): δ = 3.50 (2H, t), 3.96 (3H, s), 4.19 (2H, t), 7.4-7.6 (11H, m). 1 H-NMR (300 MHz, DMSO-d 6 ): δ = 3.50 (2H, t), 3.96 (3H, s), 4.19 (2H, t), 7.4-7.6 (11H, m).

4-(2-브로모에톡시)-1-나프트알데히드의 제조:Preparation of 4- (2-bromoethoxy) -1-naphthaldehyde:

1,2-디브로모에탄(30mL, 0.35mol)을 DMF(110mL)중 4-히드록시-4-나프트알데히드(6g, 35mmol) 및 탄산칼륨(24g, 175mmol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(0.5L)에 붓고 에틸아세테이트(3x300mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(300mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켰다. 잔여물을 에틸아세테이트와 헵탄(1:1)의 혼합물을 용리시키는 실리카겔(800mL)상의 컬럼크로마토그래피로 정제하여 4-(2-브로모에톡시)-1-나프트알데히드 8.5g(88%)을 고체로서 얻었다. 융점: 83-84℃.1,2-dibromoethane (30 mL, 0.35 mol) was added to a mixture of 4-hydroxy-4-naphthaldehyde (6 g, 35 mmol) and potassium carbonate (24 g, 175 mmol) in DMF (110 mL) and the resulting The mixture was stirred vigorously for 16 h at room temperature. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3x300 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting a mixture of ethyl acetate and heptane (1: 1) to give 8.5 g (88%) of 4- (2-bromoethoxy) -1-naphthaldehyde. Obtained as a solid. Melting point: 83-84 ° C.

C13H11BrO2의 계산치: C, 55.94%; H, 3.97%.Calcd for C 13 H 11 BrO 2 : C, 55.94%; H, 3.97%.

실측치: C, 56.10%; H, 3.98%; C, 56.30%; H, 3.97%.Found: C, 56.10%; H, 3.98%; C, 56.30%; H, 3.97%.

4-(2-브로모에톡시)-3,5-디메톡시벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -3,5-dimethoxybenzaldehyde:

1,2-디브로모에탄(47mL, 0.55mol)을 DMF(150mL)중 시린지알데히드(10g, 55mmol) 및 탄산칼륨(38g, 275mmol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(0.5L)에 붓고 에틸아세테이트(3x300mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(500mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-(2-브로모에톡시)-3,5-디메톡시벤즈알데히드 3.44g(22%)을 얻었다.1,2-dibromoethane (47 mL, 0.55 mol) was added to a mixture of syringealdehyde (10 g, 55 mmol) and potassium carbonate (38 g, 275 mmol) in DMF (150 mL) and the resulting mixture was heated at room temperature for 16 hours. Was stirred. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3x300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO 4 and evaporated in vacuo to give 3.44 g (22%) of 4- (2-bromoethoxy) -3,5-dimethoxybenzaldehyde.

1H-NMR (300 MHz, DMSO-d6): δ = 3.70 (2H, t), 3.88 (3H, s), 4.27 (2H, t), 7.27 (2H, s). 1 H-NMR (300 MHz, DMSO-d 6 ): δ = 3.70 (2H, t), 3.88 (3H, s), 4.27 (2H, t), 7.27 (2H, s).

3-(2-브로모에톡시)-4-메톡시벤즈알데히드의 제조:Preparation of 3- (2-bromoethoxy) -4-methoxybenzaldehyde:

1,2-디브로모에탄(56mL, 0.66mol)을 DMF(170mL)중 3-히드록시-4-메톡시벤즈알데히드(10g, 66mmol) 및 탄산칼륨(45g, 328mmol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반하였다. 혼합물을 물(0.5L)에 붓고 에틸아세테이트(3x200mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(500mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켰다. 잔여물을 에틸아세테이트와 헵탄(1:1)의 혼합물을 전개용매로 하는 실리카겔(800mL)상의 컬럼크로마토그래피로 정제하여 3-(2-브로모에톡시)-4-메톡시벤즈알데히드 9.8g(58%)을 얻었다.1,2-dibromoethane (56 mL, 0.66 mol) was added to a mixture of 3-hydroxy-4-methoxybenzaldehyde (10 g, 66 mmol) and potassium carbonate (45 g, 328 mmol) in DMF (170 mL) and the resulting The mixture was stirred vigorously for 16 h at room temperature. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3x200 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) using a mixture of ethyl acetate and heptane (1: 1) as a developing solvent, to give 9.8 g (58%) of 3- (2-bromoethoxy) -4-methoxybenzaldehyde. )

1H-NMR (300 MHz, DMSO-d6): δ = 3.82 (2H, t), 3.90 (3H, s), 4.40 (2H, t), 7.22 (1H, d), 7.44 (1H, d), 7.59 (1H, dd). 1 H-NMR (300 MHz, DMSO-d 6 ): δ = 3.82 (2H, t), 3.90 (3H, s), 4.40 (2H, t), 7.22 (1H, d), 7.44 (1H, d) , 7.59 (1H, doublet of doublets).

4-(2-브로모에톡시)-3-브로모-5-메톡시벤즈알데히드의 제조:Preparation of 4- (2-bromoethoxy) -3-bromo-5-methoxybenzaldehyde:

1,2-디브로모에탄(37mL, 0.43mol)을 DMF(150mL)중 5-브로모발린(10g, 43mmol) 및 탄산칼륨(30g, 216mmol)의 혼합물에 가하고 그 결과의 혼합물을 실온에서 16시간동안 격렬하게 교반한 후 60℃에서 16시간동안 격렬하게 교반하였다. 냉각시킨 혼합물을 물(1L)에 붓고 에틸아세테이트(3x250mL)로 추출하였다. 합한 유기상을 포화 염화나트륨(300mL)로 세척하고 MgSO4에서 건조시키고 진공에서 증발시켜 4-(2-브로모에톡시)-3-브로모-5-메톡시벤즈알데히드 13.7g(94%)을 얻었다.1,2-dibromoethane (37 mL, 0.43 mol) was added to a mixture of 5-bromovaline (10 g, 43 mmol) and potassium carbonate (30 g, 216 mmol) in DMF (150 mL) and the resulting mixture was 16 at room temperature. The mixture was stirred vigorously for an hour and then vigorously stirred for 16 hours at 60 ° C. The cooled mixture was poured into water (1 L) and extracted with ethyl acetate (3 × 250 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO 4 and evaporated in vacuo to give 13.7 g (94%) of 4- (2-bromoethoxy) -3-bromo-5-methoxybenzaldehyde.

1H-NMR (300 MHz, DMSO-d6): δ = 3.79 (2H, t), 3.93 (3H, s), 4.40 (2H, t), 7.55 (1H, d), 7.79 (1H, d). 1 H-NMR (300 MHz, DMSO-d 6 ): δ = 3.79 (2H, t), 3.93 (3H, s), 4.40 (2H, t), 7.55 (1H, d), 7.79 (1H, d) .

실시예 695:Example 695:

3-클로로-4-히드록시벤조산{4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]-2-메톡시벤질리덴}히드라지드3-chloro-4-hydroxybenzoic acid {4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -2-methoxybenzylidene} hydrazide

수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])(3g, ~3mmol)을 30분동안 DMF(35mL)중에 팽창시켰다. 그런 다음, 4-(2-브로모에톡시)-2-메톡시벤즈알데히드(2.33g, 9mmol) 및 트리에틸 오르토포르메이트(18mL)를 가하고 혼합물을 16시간동안 실온에서 흔들어 섞었다. 수지를 DMF(35mL, 4회), CH2Cl2(35mL, 6회) 및 N-메틸-2-피롤리디논(NMP)(35mL, 2회)에서 반복적으로 팽창시키고 여과시켰다. 수지를 NMP(40mL)에서 팽창시키고 1,2,3,4-테트라히드로이소퀴놀린(3.75mL, 30mmol) 및 요오드화칼륨(1.0g, 6mmol)을 가하였다. 수지를 실온에서 16시간동안 흔들어 섞고 여과시켰다. 수지를 DMF(40mL, 5회), CH2Cl2(40mL, 10회)에서 반복적으로 팽창시키고 여과시켰다. 화합물은 CH2Cl2(40mL)중 50% 트리플루오로아세트산 용액으로 실온에서 1시간동안 흔들어 섞어 수지로부터 완전히 절단시켰다. 혼합물을 여과하고 수지를 CH2Cl2(40mL, 2회)로 추출하였다. 합한 CH2Cl2추출물을 진공에서 농축시켰다. 잔여물을 CH2Cl2(40mL)에서 용해시키고 진공에서 농축시켰다. 잔여물을 메탄올(40mL)에서 용해시키고 진공에서 농축시켰다. 잔여물을 에틸아세테이트(50mL)와 포화 탄산수소나트륨(50mL)에서 분배하였다. 수상을 에틸아세테이트(50mL)로 추출하였고 합한 유기 추출물을 MgSO4에서 건조시키고 진공에서 농축시켰다. 잔여물을 CH2Cl2와 메탄올(9:1)의 혼합물을 용리시키는 실리카겔(200mL)상에서 컬럼크로마토그래피하여 정제하였다. 이렇게 하여 표제의 화합물 280mg을 얻었다.Resin-bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (3 g, ˜3 mmol) was expanded in DMF (35 mL) for 30 minutes. Then 4- (2-bromoethoxy) -2-methoxybenzaldehyde (2.33 g, 9 mmol) and triethyl orthoformate (18 mL) were added and the mixture was shaken for 16 hours at room temperature and mixed. The resin was repeatedly expanded and filtered in DMF (35 mL, 4 times), CH 2 Cl 2 (35 mL, 6 times) and N-methyl-2-pyrrolidinone (NMP) (35 mL, 2 times). The resin was expanded in NMP (40 mL) and 1,2,3,4-tetrahydroisoquinoline (3.75 mL, 30 mmol) and potassium iodide (1.0 g, 6 mmol) were added. The resin was shaken for 16 hours at room temperature and filtered. The resin was repeatedly expanded and filtered in DMF (40 mL, 5 times), CH 2 Cl 2 (40 mL, 10 times). The compound was cleaved completely from the resin by shaking for 1 hour at room temperature with a 50% trifluoroacetic acid solution in CH 2 Cl 2 (40 mL). The mixture was filtered and the resin extracted with CH 2 Cl 2 (40 mL, twice). The combined CH 2 Cl 2 extracts were concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 (40 mL) and concentrated in vacuo. The residue was dissolved in methanol (40 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL) and the combined organic extracts were dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (200 mL) eluting a mixture of CH 2 Cl 2 and methanol (9: 1). This gave 280 mg of the title compound.

HPLC-MS (방법 A): Rt= 8.44 min; m/z = 480 (M+1).HPLC-MS (Method A): R t = 8.44 min ; m / z = 480 (M + 1).

1H-NMR (300 MHz, DMSO-d6) δ = 2.80 (4H, m), 2.90 (2H, t), 3.69 (2H, s), 3.86 (3H, s), 4.25 (2H, t), 6.68 (2H, m), 7.04 (1H, d), 7.07-7.14 (5H, m), 7.75 (1H, dd), 7.80 (1H, bs), 7.96 (1H, d), 8.58 (1H, s), 11.6 (1H, s). 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 2.80 (4H, m), 2.90 (2H, t), 3.69 (2H, s), 3.86 (3H, s), 4.25 (2H, t), 6.68 (2H, m), 7.04 (1H, d), 7.07-7.14 (5H, m), 7.75 (1H, dd), 7.80 (1H, bs), 7.96 (1H, d), 8.58 (1H, s) , 11.6 (1H, s).

HR-MS: C26H26ClN3O4의 계산치: 479.1611; 실측치: 479.1604.HR-MS: Calcd for C 26 H 26 ClN 3 O 4 : 479.1611. Found: 479.1604.

실시예 696:Example 696:

3-클로로-4-히드록시벤조산{2-메톡시-4-[2-(4-트리플루오로메틸벤질아미노)에톡시]벤질리덴}히드라지드3-chloro-4-hydroxybenzoic acid {2-methoxy-4- [2- (4-trifluoromethylbenzylamino) ethoxy] benzylidene} hydrazide

이 화합물을 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])(2g, ~2mmol), 4-(2-브로모에톡시)-2-메톡시벤즈알데히드([빌딩블록 2])(0.73g, 1.5당량), 및 4-트리플루오로메틸벤즈아민([빌딩블록 3])(3.3g, 10당량)으로부터 출발하여 상기 실시예에 기재된 화합물과 유사하게 합성하였다. 50% 트리플루오로아세트산으로 절단한 후, 잔여물(1g)을 25% 암모니아수, 에탄올 및 디클로로메탄(1:9:115)의 혼합물을 용리액으로 하는 실리카겔(20g)상의 컬럼크로마토그래피로 정제하였다. 표제의 화합물 130g을 얻었다.This compound was converted to 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (2 g, ˜2 mmol), 4- (2-bromoethoxy) -2-methoxybenzaldehyde ( Synthesis similar to the compounds described in the above examples starting from [Building Block 2]) (0.73 g, 1.5 equivalents), and 4-trifluoromethylbenzamine ([Building Block 3]) (3.3 g, 10 equivalents) It was. After cleavage with 50% trifluoroacetic acid, the residue (1 g) was purified by column chromatography on silica gel (20 g) using a mixture of 25% ammonia water, ethanol and dichloromethane (1: 9: 115) as eluent. 130 g of the title compound were obtained.

HPLC-MS (방법 A): Rt= 9.4 분; m/z = 522 (M+1).HPLC-MS (Method A): R t = 9.4 min; m / z = 522 (M + 1).

실시예 697:Example 697:

3-클로로-4-히드록시벤조산{4-[2-(4-벤질피페라진-1-일)에톡시]-2-메톡시벤질리덴}히드라지드3-chloro-4-hydroxybenzoic acid {4- [2- (4-benzylpiperazin-1-yl) ethoxy] -2-methoxybenzylidene} hydrazide

이 화합물을 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])(2g, ~2mmol), 4-(2-브로모에톡시)-2-메톡시벤즈알데히드([빌딩블록 2])(0.73g, 1.5당량), 및 1-벤질피페라진([빌딩블록 3])(3.3g, 10당량)으로부터 출발하여 상기 실시예에 기재된 화합물과 유사하게 합성하였다. 50% 트리플루오로아세트산으로 절단한 후, 잔여물(1.4g)을 2-프로판올(50mL)에 용해시키고 20mL까지 농축시켰다. 혼합물을 5℃에서 1시간동안 두고 여과시켰다. 모액을 진공에서 농축시키고 그 잔여물을 메탄올과 디클로로메탄(1:9)을 용리액으로 하는 실리카겔(20g)상의 컬럼크로마토그래피로 정제하였다. 표제의 화합물 0.98g을 얻었다.This compound was converted to 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (2 g, ˜2 mmol), 4- (2-bromoethoxy) -2-methoxybenzaldehyde ( It was synthesized similarly to the compounds described in the above examples starting from [Building Block 2]) (0.73 g, 1.5 equiv), and 1-benzylpiperazine ([Building Block 3]) (3.3 g, 10 equiv). After cleavage with 50% trifluoroacetic acid, the residue (1.4 g) was dissolved in 2-propanol (50 mL) and concentrated to 20 mL. The mixture was kept at 5 ° C. for 1 hour and filtered. The mother liquor was concentrated in vacuo and the residue was purified by column chromatography on silica gel (20 g) using methanol and dichloromethane (1: 9) as eluent. 0.98 g of the title compound were obtained.

1H-NMR (400 MHz, DMSO-d6): δH= 2.4 (2H, bs), 2.55 (2H, bs), 2.62 (2H, bs), 3.50 (2H, bs), 3.85 (3H, s), 4.15 (2H, t), 6.62 (2H, m), 7.05 (1H, d), 7.30 (5H, m), 7.75 (2H, t), 7.97 (1H, s), 8.67 (1H, s), 11 (1H, bs), 11.5 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): δ H = 2.4 (2H, bs), 2.55 (2H, bs), 2.62 (2H, bs), 3.50 (2H, bs), 3.85 (3H, s ), 4.15 (2H, t), 6.62 (2H, m), 7.05 (1H, d), 7.30 (5H, m), 7.75 (2H, t), 7.97 (1H, s), 8.67 (1H, s) , 11 (1H, bs), 11.5 (1H, s).

HPLC-MS(방법 A): Rf=7.7분; m/z=523(M+1).HPLC-MS (Method A): R f = 7.7 min; m / z = 523 (M + l).

실시예 698:Example 698:

3-클로로-4-히드록시벤조산{2-메톡시-4-[2-(2-페닐피페리딘-1-일)에톡시]벤질리덴}히드라지드3-chloro-4-hydroxybenzoic acid {2-methoxy-4- [2- (2-phenylpiperidin-1-yl) ethoxy] benzylidene} hydrazide

이 화합물을 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])(2g, ~2mmol), 4-(2-브로모에톡시)-2-메톡시벤즈알데히드([빌딩블록 2])(0.73g, 1.5당량), 및 2-페닐피페리딘([빌딩블록 3])(3.0g, 10당량)으로부터 출발하여 상기 실시예에 기재된 화합물과 유사하게 합성하였다. 50% 트리플루오로아세트산으로 절단한 후, 잔여물(1.0g)을 메탄올과 디클로로메탄(1:13)을 용리액으로 하는 실리카겔(28g)상의 컬럼크로마토그래피로 정제하였다. 표제의 화합물 0.24g을 얻었다.This compound was converted to 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (2 g, ˜2 mmol), 4- (2-bromoethoxy) -2-methoxybenzaldehyde ( It was synthesized similarly to the compounds described in the above examples starting from [Building Block 2]) (0.73 g, 1.5 equiv), and 2-phenylpiperidine ([Building Block 3]) (3.0 g, 10 equiv). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was purified by column chromatography on silica gel (28 g) using methanol and dichloromethane (1:13) as eluent. 0.24 g of the title compound were obtained.

1H-NMR (400 MHz, DMSO-d6): δH= 1.4 (2H, m), 1.65 (4H, m), 2.25 (2H, m), 2.75 (1H, m), 3.16 (1H, d), 3.25 (2H, d), 3.83 (3H, s), 4.0 (2H, m), 6.50 (1H, d), 6.54 (1H, s), 7.07 (1H, d), 7.23 (1H, t), 7.35 (4H, m), 7.73 (1H, d), 7.77 (1H, dd), 7.96 (1H, d), 8.65 (1H, s), 10.9 (1H, s), 11.6 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): δ H = 1.4 (2H, m), 1.65 (4H, m), 2.25 (2H, m), 2.75 (1H, m), 3.16 (1H, d ), 3.25 (2H, d), 3.83 (3H, s), 4.0 (2H, m), 6.50 (1H, d), 6.54 (1H, s), 7.07 (1H, d), 7.23 (1H, t) , 7.35 (4H, m), 7.73 (1H, d), 7.77 (1H, dd), 7.96 (1H, d), 8.65 (1H, s), 10.9 (1H, s), 11.6 (1H, s).

HPLC-MS(방법 A): Rf=9.1분; m/z=508(M+1).HPLC-MS (Method A): R f = 9.1 min; m / z = 508 (M + l).

실시예 699:Example 699:

3-클로로-4-히드록시벤조산{3-클로로-4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]-5-메톡시벤질리덴}히드라지드3-Chloro-4-hydroxybenzoic acid {3-chloro-4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -5-methoxybenzylidene} hydrazide

이 화합물을 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])(2g, ~2mmol), 4-(2-브로모에톡시)-3-클로로-5-메톡시벤즈알데히드([빌딩블록 2])(0.81g, 1.5당량), 및 1,2,3,4-테트라히드로이소퀴놀린([빌딩블록 3])(2.5g, 10당량)으로부터 출발하여 상기 실시예에 기재된 화합물과 유사하게 합성하였다. 50% 트리플루오로아세트산으로 절단한 후, 잔여물(1.0g)을 25% 암모니아수, 메탄올 및 디클로로메탄(1:9:90)의 혼합물 15mL에 용해시키고 메탄올과 디클로로메탄(1:12)의 혼합물을 용리액으로 하는 실리카겔(25g)상의 컬럼크로마토그래피로 정제하였다. 표제의 화합물 0.11g을 얻었다.This compound was converted to 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (2 g, ˜2 mmol), 4- (2-bromoethoxy) -3-chloro-5-, to which a resin was bound. The above procedure starts from methoxybenzaldehyde ([building block 2]) (0.81 g, 1.5 equiv) and 1,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equiv) Synthesis similar to the compounds described in the examples. After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was dissolved in 15 mL of a mixture of 25% ammonia water, methanol and dichloromethane (1: 9: 90) and a mixture of methanol and dichloromethane (1:12) Was purified by column chromatography on silica gel (25 g) as an eluent. 0.11 g of the title compound were obtained.

1H-NMR (400 MHz, DMSO-d6): δH= 1.9 (1H, p), 2.18 (1H, t), 2.90 (2H, t), 3.70 (2H, s), 3.90 (3H, s), 4.19 (2H, t), 7.05 (5H, m), 7.37 (2H, s), 7.78 (1H, d), 7.95 (1H, s), 8.33 (1H, s), 11 (1H, bs), 11.8 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): δ H = 1.9 (1H, p), 2.18 (1H, t), 2.90 (2H, t), 3.70 (2H, s), 3.90 (3H, s ), 4.19 (2H, t), 7.05 (5H, m), 7.37 (2H, s), 7.78 (1H, d), 7.95 (1H, s), 8.33 (1H, s), 11 (1H, bs) , 11.8 (1H, s).

HPLC-MS (방법 A): Rt= 9.0 분; m/z = 514 (M+1).HPLC-MS (Method A): R t = 9.0 min; m / z = 514 (M + 1).

실시예 700:Example 700:

3-클로로-4-히드록시벤조산{6-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]-5-메톡시비페닐-3-일메틸렌}히드라지드3-Chloro-4-hydroxybenzoic acid {6- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -5-methoxybiphenyl-3-ylmethylene} hydrazide

이 화합물을 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])(2g, ~2mmol), 4-(2-브로모에톡시)-3-메톡시-5-페닐벤즈알데히드([빌딩블록 2])(0.93g, 1.5당량), 및 1,2,3,4-테트라히드로이소퀴놀린([빌딩블록 3])(2.5g, 10당량)으로부터 출발하여 상기 실시예에 기재된 화합물과 유사하게 합성하였다. 50% 트리플루오로아세트산으로 절단한 후, 잔여물을 25% 암모니아수, 메탄올 및 디클로로메탄(1:9:90)의 혼합물 15mL에 용해시키고 메탄올과 디클로로메탄(1:12)의 혼합물을 용리액으로 하는 실리카겔(25g)상의 컬럼크로마토그래피로 정제하였다. 표제의 화합물 0.31g을 얻었다.This compound was converted to 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (2 g, ˜2 mmol) and 4- (2-bromoethoxy) -3-methoxy-5 to which a resin was bound. Starting from -phenylbenzaldehyde ([building block 2]) (0.93 g, 1.5 equivalents), and 1,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivalents) Synthesis similar to the compounds described in the examples. After cleavage with 50% trifluoroacetic acid, the residue was dissolved in 15 mL of a mixture of 25% aqueous ammonia, methanol and dichloromethane (1: 9: 90), and the mixture of methanol and dichloromethane (1:12) was taken as eluent. Purified by column chromatography on silica gel (25 g). 0.31 g of the title compound were obtained.

1H-NMR (400 MHz, DMSO-d6): δH= 2.60 (4H, m), 2.70 (2H, m), 3.48 (2H, s), 3.92 (3H, s), 3.96 (2H, t), 6.98 (1H, m), 7.10 (4H, m), 7.22 (1H, s), 7.40 (4H, m), 7.55 (2H, d), 7.78 (1H, d), 8.00 (1H, s), 8.40 (1H, s), 11 (1H, bs), 11.7 (1H, s). 1 H-NMR (400 MHz, DMSO-d 6 ): δ H = 2.60 (4H, m), 2.70 (2H, m), 3.48 (2H, s), 3.92 (3H, s), 3.96 (2H, t ), 6.98 (1H, m), 7.10 (4H, m), 7.22 (1H, s), 7.40 (4H, m), 7.55 (2H, d), 7.78 (1H, d), 8.00 (1H, s) , 8.40 (1 H, s), 11 (1 H, bs), 11.7 (1 H, s).

HPLC-MS (방법 A): Rt= 9.6 분; m/z = 557 (M+1).HPLC-MS (Method A): R t = 9.6 min; m / z = 557 (M + l).

실시예 701:Example 701:

3-클로로-4-히드록시벤조산{3,5-디브로모-4-{2-[4-(4-클로로페닐)피페라진-1-일]에톡시}벤질리덴)히드라지드3-chloro-4-hydroxybenzoic acid {3,5-dibromo-4- {2- [4- (4-chlorophenyl) piperazin-1-yl] ethoxy} benzylidene) hydrazide

DMF(0.6M, 1mL)중 4-(2-브로모에톡시)-3,5-디브로모벤즈알데히드([빌딩블록 2])의 용액을 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])(0.05mmol)에 가하고 이어서 트리에틸오르토포르메이트(0.5mL)를 가하고 이 혼합물을 15시간동안 실온에서 흔들어 섞었다. 수지를 DMF(1.5mL, 3회), CH2Cl2(1.5mL, 2회) 및 NMP(1.5mL, 2회)에서 5분동안 반복적으로 팽창시키고 여과시켰다. 그 결과의 수지(수지-[빌딩블록 1]-[빌딩블록 2])를 1-(4-클로로페닐)피페라진(0.4M, 1mL)의 용액에 가하고, NMP중 요오드화칼륨(0.08M, 0.5mL)의 용액을 가하고 이 혼합물을 실온에서 16시간동안 흔들어 섞었다. 수지를 DMF(1.5mL, 5회) 및 CH2Cl2(1.5mL, 6회)에서 반복적으로 2분동안 팽창시키고 여과시켰다.A solution of 4- (2-bromoethoxy) -3,5-dibromobenzaldehyde ([Building Block 2]) in DMF (0.6M, 1 mL) was bound to a resin with 3-chloro-4-hydroxybenzoic acid hydra. Zide (resin- [building block 1]) (0.05 mmol) was added followed by triethylorthoformate (0.5 mL) and the mixture was shaken for 15 h at room temperature and mixed. The resin was repeatedly expanded and filtered for 5 minutes in DMF (1.5 mL, 3 times), CH 2 Cl 2 (1.5 mL, 2 times) and NMP (1.5 mL, 2 times). The resulting resin (resin- [building block 1]-[building block 2]) was added to a solution of 1- (4-chlorophenyl) piperazine (0.4M, 1 mL) and potassium iodide (0.08M, 0.5 in NMP). mL) was added and the mixture was shaken at room temperature for 16 hours to mix. The resin was expanded repeatedly in DMF (1.5 mL, 5 times) and CH 2 Cl 2 (1.5 mL, 6 times) for 2 minutes and filtered.

화합물은 CH2Cl2(1.5mL)중 50% 트리플루오로아세트산 용액으로 실온에서 1시간동안 흔들어 섞어 수지로부터 완전히 절단시켰다. 혼합물을 여과하고 수지를 CH2Cl2(0.5mL)로 추출하였다. 합한 CH2Cl2추출물을 진공에서 농축시켰다. 잔여물을 메탄올(1mL)에 용해시키고 진공에서 농축시켰다. 잔여물을 메탄올과 CH2Cl2(1mL) 1:1 혼합물에서 용해시키고 진공에서 농축시켜 표제이 화합물을 얻었다.The compound was cleaved completely from the resin by shaking for 1 hour at room temperature with a 50% trifluoroacetic acid solution in CH 2 Cl 2 (1.5 mL). The mixture was filtered and the resin extracted with CH 2 Cl 2 (0.5 mL). The combined CH 2 Cl 2 extracts were concentrated in vacuo. The residue was dissolved in methanol (1 mL) and concentrated in vacuo. The residue was dissolved in methanol and CH 2 Cl 2 (1 mL) 1: 1 mixture and concentrated in vacuo to afford the title compound.

HPLC-MS (방법 B): Rt= 15.02 분; m/z = 671.HPLC-MS (method B): R t = 15.02 min; m / z = 671.

실시예 702 내지 791:Examples 702-791:

다음의 80개의 화합물은 합성장치의 작동을 조절하기 위한 다음의 ChemFile을 사용하여 Advanced ChemTech Model 384 HTS상에서 상기 실시예와 유사하게 개개의 개체로서 병렬적으로 합성하였다.The following 80 compounds were synthesized in parallel as individual individuals on the Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer.

게다가 상기 목록된 빌딩블럭들([빌딩블록 1], [빌딩블록 2] 및 [빌딩블록 3])의 모든 가능한 화합물의 조합의 라이브러리를 합성장치의 작동을 조절하기 위한 다음의 ChemFile을 사용하여 Advanced ChemTech Model 384 HTS상에서 상기 실시예와 유사하게 개개의 개체로서 병렬적으로 합성하였다. 화합물은 모두 각 웰에 존재하는 것으로 예상된다.In addition, a library of combinations of all possible compounds of the building blocks listed above ([Building Block 1], [Building Block 2] and [Building Block 3]) was developed using the following ChemFile to control the operation of the synthesizer. Synthesis was performed in parallel on individual ChemTech Model 384 HTS as individual individuals similar to the above examples. All compounds are expected to be present in each well.

수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])은 장치를 초기화하기 전에 합성장치내의 웰에 동등하게 분배된다.Resin-bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) is equally distributed to the wells in the synthesis apparatus prior to initiating the apparatus.

ChemFile C:\ACT_1328\90250012.CHM:ChemFile C: \ ACT_1328 \ 90250012.CHM:

1 REM Filtration of resin1 REM Filtration of resin

2 Empty RB1_1to96 for 5.000 minute(s)2 Empty RB1_1to96 for 5.000 minute (s)

3 Empty RB2_1to96 for 5.000 minute(s)3 Empty RB2_1to96 for 5.000 minute (s)

4 Empty RB3_1to96 for 5.000 minute(s)4 Empty RB3_1to96 for 5.000 minute (s)

5 Empty RB4_1to96 for 5.000 minute(s)5 Empty RB4_1to96 for 5.000 minute (s)

6 Pause6 Pause

77

8 REM Washing of resin8 REM Washing of resin

99

10 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]10 Dispense System Fluid Disdu1_4 * 1500ul to RB1_1to96 [1-96]

11 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96]11 Dispense System Fluid Disdu1_4 * 1500ul to RB2_1to96 [1-96]

12 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96]12 Dispense System Fluid Disdu1_4 * 1500ul to RB3_1to96 [1-96]

13 Dispense System Fluid Disdu1_4* 1500ul to RB4_1to96[1-96]13 Dispense System Fluid Disdu1_4 * 1500ul to RB4_1to96 [1-96]

14 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.14 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

15 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.15 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

16 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.16 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

17 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.17 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

18 Wait for 25.000 minute(s)18 Wait for 25.000 minute (s)

19 Repeat from step 14, 1000 times19 Repeat from step 14, 1000 times

20 Empty RB1_1to96 for 5.000 minute(s)20 Empty RB1_1to96 for 5.000 minute (s)

21 Empty RB2_1to96 for 5.000 minute(s)21 Empty RB2_1to96 for 5.000 minute (s)

22 Empty RB3_1to96 for 5.000 minute(s)22 Empty RB3_1to96 for 5.000 minute (s)

23 Empty RB4_1to96 for 5.000 minute(s)23 Empty RB4_1to96 for 5.000 minute (s)

24 Pause24 Pause

2525

26 REM Coupling with aldehydes26 REM Coupling with aldehydes

2727

28 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96]28 Dispense System Fluid Disdu2_3 * 1500ul to RB1_1to96 [1-96]

29 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96]29 Dispense System Fluid Disdu2_3 * 1500ul to RB2_1to96 [1-96]

30 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96]30 Dispense System Fluid Disdu2_3 * 1500ul to RB3_1to96 [1-96]

31 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96]31 Dispense System Fluid Disdu2_3 * 1500ul to RB4_1to96 [1-96]

32 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.32 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

33 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.33 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

34 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.34 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

35 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.35 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

36 Empty RB1_1to96 for 5.000 minute(s)36 Empty RB1_1to96 for 5.000 minute (s)

37 Empty RB2_1to96 for 5.000 minute(s)37 Empty RB2_1to96 for 5.000 minute (s)

38 Empty RB3_1to96 for 5.000 minute(s)38 Empty RB3_1to96 for 5.000 minute (s)

39 Empty RB4_1to96 for 5.000 minute(s)39 Empty RB4_1to96 for 5.000 minute (s)

40 Pause40 Pause

4141

42 Dispense Sequence c:\ACT13_28\R2-A.DSP with 1000ul to RB1_1to96 rack using DMF42 Dispense Sequence c: \ ACT13_28 \ R2-A.DSP with 1000ul to RB1_1to96 rack using DMF

43 Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait.43 Mix "RB1_1to96" for 2.00 minutes at 600 rpm (s) and wait.

44 Dispense Sequence c:\ACT13_28\R2-B.DSP with 1000ul to RB2_1to96 rack using DMF44 Dispense Sequence c: \ ACT13_28 \ R2-B.DSP with 1000ul to RB2_1to96 rack using DMF

45 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.45 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

46 Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait.46 Mix "RB2_1to96" for 2.00 minutes at 600 rpm (s) and wait.

47 Dispense Sequence c:\ACT13_28\R2-C.DSP with 1000ul to RB3_1to96 rack using DMF47 Dispense Sequence c: \ ACT13_28 \ R2-C.DSP with 1000ul to RB3_1to96 rack using DMF

48 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.48 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

49 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue.49 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm (s) and continue.

50 Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait.50 Mix "RB3_1to96" for 2.00 minutes at 600 rpm (s) and wait.

51 Dispense Sequence c:\ACT13_28\R2-D.DSP with 1000ul to RB4_1to96 rack using DMF51 Dispense Sequence c: \ ACT13_28 \ R2-D.DSP with 1000ul to RB4_1to96 rack using DMF

52 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.52 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

53 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue.53 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm (s) and continue.

54 Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm(s) and continue.54 Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm (s) and continue.

55 Mix "RB4_1to96" for 2.00 minutes at 600 rpm(s) and wait.55 Mix "RB4_1to96" for 2.00 minutes at 600 rpm (s) and wait.

5656

57 Pause57 Pause

58 REM Manual addition of CH(OC2H5)358 REM Manual addition of CH (OC2H5) 3

59 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.59 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

60 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.60 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

61 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.61 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

62 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.62 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

63 Wait for 25.000 minute(s)63 Wait for 25.000 minute (s)

64 Repeat from step 59, 200 times64 Repeat from step 59, 200 times

65 Empty RB1_1to96 for 5.000 minute(s)65 Empty RB1_1to96 for 5.000 minute (s)

66 Empty RB2_1to96 for 5.000 minute(s)66 Empty RB2_1to96 for 5.000 minute (s)

67 Empty RB3_1to96 for 5.000 minute(s)67 Empty RB3_1to96 for 5.000 minute (s)

68 Empty RB4_1to96 for 5.000 minute(s)68 Empty RB4_1to96 for 5.000 minute (s)

69 Pause69 Pause

7070

71 REM Wash after coupling with aldehydes71 REM Wash after coupling with aldehydes

7272

73 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter73 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter

74 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96]74 Dispense System Fluid Disdu2_3 * 1500ul to RB1_1to96 [1-96]

75 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96]75 Dispense System Fluid Disdu2_3 * 1500ul to RB2_1to96 [1-96]

76 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96]76 Dispense System Fluid Disdu2_3 * 1500ul to RB3_1to96 [1-96]

77 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96]77 Dispense System Fluid Disdu2_3 * 1500ul to RB4_1to96 [1-96]

78 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.78 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

79 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.79 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

80 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.80 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

81 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.81 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

82 Empty RB1_1to96 for 5.000 minute(s)82 Empty RB1_1to96 for 5.000 minute (s)

83 Empty RB2_1to96 for 5.000 minute(s)83 Empty RB2_1to96 for 5.000 minute (s)

84 Empty RB3_1to96 for 5.000 minute(s)84 Empty RB3_1to96 for 5.000 minute (s)

85 Empty RB4_1to96 for 5.000 minute(s)85 Empty RB4_1to96 for 5.000 minute (s)

86 Repeat from step 74, 2 times86 Repeat from step 74, 2 times

87 Pause87 Pause

88 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]88 Dispense System Fluid Disdu1_4 * 1500ul to RB1_1to96 [1-96]

89 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96]89 Dispense System Fluid Disdu1_4 * 1500ul to RB2_1to96 [1-96]

90 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96]90 Dispense System Fluid Disdu1_4 * 1500ul to RB3_1to96 [1-96]

91 Dispense System Fluid Disdu1_4* 1500ul to RB4_1to96[1-96]91 Dispense System Fluid Disdu1_4 * 1500ul to RB4_1to96 [1-96]

92 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.92 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

93 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.93 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

94 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.94 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

95 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.95 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

96 Empty RB1_1to96 for 5.000 minute(s)96 Empty RB1_1to96 for 5.000 minute (s)

97 Empty RB2_1to96 for 5.000 minute(s)97 Empty RB2_1to96 for 5.000 minute (s)

98 Empty RB3_1to96 for 5.000 minute(s)98 Empty RB3_1to96 for 5.000 minute (s)

99 Empty RB4_1to96 for 5.000 minute(s)99 Empty RB4_1to96 for 5.000 minute (s)

100 Repeat from step 88, 1 times100 Repeat from step 88, 1 times

101 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96]101 Dispense System Fluid Disdu2_3 * 1500ul to RB1_1to96 [1-96]

102 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96]102 Dispense System Fluid Disdu2_3 * 1500ul to RB2_1to96 [1-96]

103 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96]103 Dispense System Fluid Disdu2_3 * 1500ul to RB3_1to96 [1-96]

104 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96]104 Dispense System Fluid Disdu2_3 * 1500ul to RB4_1to96 [1-96]

105 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.105 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

106 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.106 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

107 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.107 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

108 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.108 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

109 Wait for 25.000 minute(s)109 Wait for 25.000 minute (s)

110 Repeat from step 105, 1000 times110 Repeat from step 105, 1000 times

111 Pause111 Pause

112 Empty RB1_1to96 for 5.000 minute(s)112 Empty RB1_1to96 for 5.000 minute (s)

113 Empty RB2_1to96 for 5.000 minute(s)113 Empty RB2_1to96 for 5.000 minute (s)

114 Empty RB3_1to96 for 5.000 minute(s)114 Empty RB3_1to96 for 5.000 minute (s)

115 Empty RB4_1to96 for 5.000 minute(s)115 Empty RB4_1to96 for 5.000 minute (s)

116 Repeat from step 101, 1 times116 Repeat from step 101, 1 times

117117

118 REM Coupling with amines118 REM Coupling with amines

119 Flush Arm1 with Disdu2_3*, Arm2 with Disdu2_3*119 Flush Arm1 with Disdu2_3 *, Arm2 with Disdu2_3 *

120 Dispense Sequence c:\ACT13_28\R3-A.DSP with 1000ul to RB1_1to96 rack using NMP120 Dispense Sequence c: \ ACT13_28 \ R3-A.DSP with 1000ul to RB1_1to96 rack using NMP

121 Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait.121 Mix "RB1_1to96" for 2.00 minutes at 600 rpm (s) and wait.

122 Dispense Sequence c:\ACT13_28\R3-B.DSP with 1000ul to RB2_1to96 rack using NMP122 Dispense Sequence c: \ ACT13_28 \ R3-B.DSP with 1000ul to RB2_1to96 rack using NMP

123 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.123 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

124 Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait.124 Mix "RB2_1to96" for 2.00 minutes at 600 rpm (s) and wait.

125 Dispense Sequence c:\ACT13_28\R3-C.DSP with 1000ul to RB3_1to96 rack using NMP125 Dispense Sequence c: \ ACT13_28 \ R3-C.DSP with 1000ul to RB3_1to96 rack using NMP

126 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.126 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

127 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue.127 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm (s) and continue.

128 Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait.128 Mix "RB3_1to96" for 2.00 minutes at 600 rpm (s) and wait.

129 Dispense Sequence c:\ACT13_28\R3-D.DSP with 1000ul to RB4_1to96 rack using NMP129 Dispense Sequence c: \ ACT13_28 \ R3-D.DSP with 1000ul to RB4_1to96 rack using NMP

130 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.130 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

131 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue.131 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm (s) and continue.

132 Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm(s) and continue.132 Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm (s) and continue.

133 Mix "RB4_1to96" for 2.00 minutes at 600 rpm(s) and wait.133 Mix "RB4_1to96" for 2.00 minutes at 600 rpm (s) and wait.

134 Pause134 Pause

135 Transfer 500ul from REAGENT_3[1]() to RB1_1to96[1-96] using NMP135 Transfer 500ul from REAGENT_3 [1] () to RB1_1to96 [1-96] using NMP

136 Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait.136 Mix "RB1_1to96" for 2.00 minutes at 600 rpm (s) and wait.

137 Pause137 Pause

138 Transfer 500ul from REAGENT_3[1]() to RB2_1to96[1-96] using NMP138 Transfer 500ul from REAGENT_3 [1] () to RB2_1to96 [1-96] using NMP

139 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.139 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

140 Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait.140 Mix "RB2_1to96" for 2.00 minutes at 600 rpm (s) and wait.

141 Pause141 Pause

142 Transfer 500ul from REAGENT_3[1]() to RB3_1to96[1-96] using NMP142 Transfer 500ul from REAGENT_3 [1] () to RB3_1to96 [1-96] using NMP

143 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.143 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm (s) and continue.

144 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue.144 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm (s) and continue.

145 Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait.145 Mix "RB3_1to96" for 2.00 minutes at 600 rpm (s) and wait.

146 Pause146 Pause

147 Transfer 500ul from REAGENT_3[1]() to RB4_1to96[1-96] using NMP147 Transfer 500ul from REAGENT_3 [1] () to RB4_1to96 [1-96] using NMP

148 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.148 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

149 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.149 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

150 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.150 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

151 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.151 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

152 Wait for 25.000 minute(s)152 Wait for 25.000 minute (s)

153 Repeat from step 148, 200 times153 Repeat from step 148, 200 times

154 Pause154 Pause

155155

156 Empty RB1_1to96 for 5.000 minute(s)156 Empty RB1_1to96 for 5.000 minute (s)

157 Empty RB2_1to96 for 5.000 minute(s)157 Empty RB2_1to96 for 5.000 minute (s)

158 Empty RB3_1to96 for 5.000 minute(s)158 Empty RB3_1to96 for 5.000 minute (s)

159 Empty RB4_1to96 for 5.000 minute(s)159 Empty RB4_1to96 for 5.000 minute (s)

160160

161161

162 REM Wash after coupling with amines162 REM Wash after coupling with amines

163163

164 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter164 Flush Arm1 with Flush Diluter 1 and Flush Diluter 2, Arm2 with Flush Diluter

165165

166 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96]166 Dispense System Fluid Disdu2_3 * 1500ul to RB1_1to96 [1-96]

167 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96]167 Dispense System Fluid Disdu2_3 * 1500ul to RB2_1to96 [1-96]

168 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96]168 Dispense System Fluid Disdu2_3 * 1500ul to RB3_1to96 [1-96]

169 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96]169 Dispense System Fluid Disdu2_3 * 1500ul to RB4_1to96 [1-96]

170 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.170 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

171 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.171 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

172 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.172 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

173 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.173 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

174 Empty RB1_1to96 for 5.000 minute(s)174 Empty RB1_1to96 for 5.000 minute (s)

175 Empty RB2_1to96 for 5.000 minute(s)175 Empty RB2_1to96 for 5.000 minute (s)

176 Empty RB3_1to96 for 5.000 minute(s)176 Empty RB3_1to96 for 5.000 minute (s)

177 Empty RB4_1to96 for 5.000 minute(s)177 Empty RB4_1to96 for 5.000 minute (s)

178 Repeat from step 166, 2 times178 Repeat from step 166, 2 times

179 Pause179 Pause

180 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]180 Dispense System Fluid Disdu1_4 * 1500ul to RB1_1to96 [1-96]

181 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96]181 Dispense System Fluid Disdu1_4 * 1500ul to RB2_1to96 [1-96]

182 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96]182 Dispense System Fluid Disdu1_4 * 1500ul to RB3_1to96 [1-96]

183 Dispense System Fluid Disdu1_4* 1500ul to RB4_1to96[1-96]183 Dispense System Fluid Disdu1_4 * 1500ul to RB4_1to96 [1-96]

184 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.184 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

185 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.185 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

186 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.186 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

187 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.187 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

188 Empty RB1_1to96 for 5.000 minute(s)188 Empty RB1_1to96 for 5.000 minute (s)

189 Empty RB2_1to96 for 5.000 minute(s)189 Empty RB2_1to96 for 5.000 minute (s)

190 Empty RB3_1to96 for 5.000 minute(s)190 Empty RB3_1to96 for 5.000 minute (s)

191 Empty RB4_1to96 for 5.000 minute(s)191 Empty RB4_1to96 for 5.000 minute (s)

192192

193 Repeat from step 180, 5 times193 Repeat from step 180, 5 times

194194

195 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]195 Dispense System Fluid Disdu1_4 * 1500ul to RB1_1to96 [1-96]

196 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96]196 Dispense System Fluid Disdu1_4 * 1500ul to RB2_1to96 [1-96]

197 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96]197 Dispense System Fluid Disdu1_4 * 1500ul to RB3_1to96 [1-96]

198 Dispense System Fluid Disdu1_4* 1500ul to RB4_1to96[1-96]198 Dispense System Fluid Disdu1_4 * 1500ul to RB4_1to96 [1-96]

199 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.199 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm (s) and continue.

200 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.200 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm (s) and continue.

201 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.201 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm (s) and continue.

202 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.202 Mix "RB4_1to96" for 5.00 minutes at 600 rpm (s) and wait.

203 Wait for 25.000 minute(s)203 Wait for 25.000 minute (s)

204 Repeat from step 199, 1000 times204 Repeat from step 199, 1000 times

205205

206 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3206 Flush Arm1 with Flush Diluter 1 and Flush Diluter 2, Arm2 with Flush Diluter 3

207 Empty RB4_1to96 for 5.000 minute(s)207 Empty RB4_1to96 for 5.000 minute (s)

208 Pause208 Pause

209209

210 REM Clevage (50%TFA/DCM manually added, one rack at a time)210 REM Clevage (50% TFA / DCM manually added, one rack at a time)

211 Flush Arm1 with Flush Diluter1, Arm2 with Flush Diluter 4211 Flush Arm1 with Flush Diluter 1, Arm2 with Flush Diluter 4

212 Mix "RB1_1to96" for 5.00 minutes at 600 rpm(s) and wait.212 Mix "RB1_1to96" for 5.00 minutes at 600 rpm (s) and wait.

213 Wait for 5.000 minute(s)213 Wait for 5.000 minute (s)

214 Repeat from step 7, 5 times214 Repeat from step 7, 5 times

215 Empty RB1_1to96 for 1 second(s)215 Empty RB1_1to96 for 1 second (s)

216 Wait for 4 second(s)216 Wait for 4 second (s)

217 Repeat from step 10, 25 times217 Repeat from step 10, 25 times

218 Empty RB1_1to96 for 5.000 minute(s)218 Empty RB1_1to96 for 5.000 minute (s)

219219

220 Dispense System Fluid Disdu1_4* 500ul to RB1_1to96[1-96]220 Dispense System Fluid Disdu1_4 * 500ul to RB1_1to96 [1-96]

221 Wait for 1.000 minute(s)221 Wait for 1.000 minute (s)

222 Empty RB1_1to96 for 1 second(s)222 Empty RB1_1to96 for 1 second (s)

223 Wait for 4 second(s)223 Wait for 4 second (s)

224 Repeat from step 17, 25 times224 Repeat from step 17, 25 times

225 Empty RB1_1to96 for 5.000 minute(s)225 Empty RB1_1to96 for 5.000 minute (s)

226226

Dispense sequence 화일 C:\ACT13_28\R3-A.DSP, C:\ACT13_28\R3-B.DSP, C:\ACT 13_28\R3-C.DSP 및 C:\ACT13_28\R3-D.DSP는 합성장치네 96웰를 포함하는 각 4개의 반응블록에 아민의 조합적 첨가를 조절하기 위한 서브루틴이다.Dispense sequence files C: \ ACT13_28 \ R3-A.DSP, C: \ ACT13_28 \ R3-B.DSP, C: \ ACT 13_28 \ R3-C.DSP and C: \ ACT13_28 \ R3-D.DSP Subroutine to control the combinatorial addition of amines to each of the four reaction blocks comprising four 96 wells.

다음의 화합물을 함유하는 라이브러리를 합성하고 생성물을 HPLC-MS(분자량 & 체류시간)에 의해 특성규명하였다.Libraries containing the following compounds were synthesized and the product was characterized by HPLC-MS (molecular weight & residence time).

실시예 792:Example 792:

3-아미노-4-히드록시벤조산{4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]-2-메톡시벤질리덴}히드라지드3-amino-4-hydroxybenzoic acid {4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -2-methoxybenzylidene} hydrazide

상기 4-(2-브로모에톡시)-2-메톡시벤즈알데히드(16.8g, 65mmol)([빌딩블록 2])을 아세톤(300mL)에 용해시키고 탄산칼륨(44.9g, 0.33mol), 요오드화칼륨(2g)을 가한 후, 1,2,3,4-테트라히드로이소퀴놀린(9.07g, 72mmol)을 가하였다. 그 결과의 혼합물을 16시간동안 환류온도에서 격렬하게 교반하였다. 냉각 후, 혼합물을 여과하고 무기 침전물을 아세톤(100mL)로 세척하였다. 합한 아세톤 여과물을 진공에서 농축시켰따. 잔여물을 에틸아세테이트(50mL)에 용해시키고 물(2x20mL), 포화 염화나트륨(20mL)로 세척하고, MgSO4에서 건조시키고 진공에서 농축시켰다. 잔여물(23g을 에틸아세테이트와 헵탄(1:1, 2L)의 혼합물로 먼저 용리시킨 후 에틸아세테이트와 헵탄(2:1, 5L)의 혼합물로 용리시키는 실리카겔(400g)상의 컬럼크로마토그래피로 정제하여 4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]-2-메톡시벤즈알데히드 12g(60%)을 고체로서 얻었다. 융점 69-71℃.The 4- (2-bromoethoxy) -2-methoxybenzaldehyde (16.8 g, 65 mmol) ([building block 2]) was dissolved in acetone (300 mL), and potassium carbonate (44.9 g, 0.33 mol) and potassium iodide ( 2 g) was added followed by 1,2,3,4-tetrahydroisoquinoline (9.07 g, 72 mmol). The resulting mixture was stirred vigorously at reflux for 16 h. After cooling, the mixture was filtered and the inorganic precipitate was washed with acetone (100 mL). The combined acetone filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with water (2 × 20 mL), saturated sodium chloride (20 mL), dried over MgSO 4 and concentrated in vacuo. The residue (23 g was first eluted with a mixture of ethyl acetate and heptane (1: 1, 2 L) and then purified by column chromatography on silica gel (400 g) eluting with a mixture of ethyl acetate and heptane (2: 1, 5 L). 12 g (60%) of 4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -2-methoxybenzaldehyde was obtained as a solid, melting point 69-71 ° C.

C19H21NO3.0.25H2O의 계산치: C, 72.24%; H, 6.86%; N, 4.43%.Calcd. For C 19 H 21 NO 3 .0.25H 2 O: C, 72.24%; H, 6.86%; N, 4.43%.

실측치: C, 72.79%; H, 6.86%; N, 4.46%; C, 72.65%; H, 6.88%; N, 4.47%.Found: C, 72.79%; H, 6.86%; N, 4.46%; C, 72.65%; H, 6.88%; N, 4.47%.

메틸 3-아미노-4-히드록시벤조에이트(5.0g, 30mmol)을 에탄올(50mL)에 용해시키고 히드라진 수화물(4.4mL, 90mmol)을 가하고 그 결과의 혼합물을 환류온도에서 16시간동안 가열하였다. 냉각후, 혼합물을 여과하고 고체를 에탄올로 세척하고 건조후 3-아미노-4-히드록시벤조산 히드라지드 1.4g(28%)을 고체로서 얻었다. 융점:242-243℃.Methyl 3-amino-4-hydroxybenzoate (5.0 g, 30 mmol) was dissolved in ethanol (50 mL) and hydrazine hydrate (4.4 mL, 90 mmol) was added and the resulting mixture was heated at reflux for 16 h. After cooling, the mixture was filtered and the solid was washed with ethanol and dried to give 1.4 g (28%) of 3-amino-4-hydroxybenzoic acid hydrazide as a solid. Melting point: 242-243 ° C.

C7H9N3O2의 계산치: C, 50.30%; H, 5.43%; N, 25.14%.Calcd for C 7 H 9 N 3 0 2 : C, 50.30%; H, 5.43%; N, 25.14%.

실측치: C, 50.27%; H, 5.46%; N, 24.35%; C, 50.41%; H, 5.47%; N, 24.38%.Found: C, 50.27%; H, 5.46%; N, 24.35%; C, 50.41%; H, 5.47%; N, 24.38%.

상기 3-아미노-4-히드록시벤조산 히드라지드(50mg, 0.3mmol) 및 상기 4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]-2-메톡시벤즈알데히드(93mg, 0.3mmol)를 2-프로판올(4mL)에 용해시키고 혼합물을 16시간동안 환류온도에서 가열하였다. 냉각시킨 혼합물을 여과하고 침전물을 2-프로판올(2x4mL)로 세척하고 흡입하여 건조시켜 표제의 화합물 66mg(48%)을 고체로서 얻었다. 융점:162-164℃.The 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the 4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -2-meth Toxybenzaldehyde (93 mg, 0.3 mmol) was dissolved in 2-propanol (4 mL) and the mixture was heated at reflux for 16 h. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 × 4 mL) and sucked to dryness to give 66 mg (48%) of the title compound as a solid. Melting point: 162-164 ° C.

HPLC -MS (방법 B): Rt= 6.50 분. m/z = 461.-MS HPLC (method B): R t = 6.50 min. m / z = 461.

실시예 793:Example 793:

3-아미노-4-히드록시벤조산[4-(4-이소프로필벤질옥시)-3,5-디메톡시벤질리덴]히드라지드3-amino-4-hydroxybenzoic acid [4- (4-isopropylbenzyloxy) -3,5-dimethoxybenzylidene] hydrazide

시린지알데히드(4-히드록시-3,5-디메톡시벤즈알데히드)(10.2g, 55mmol)을 DMF(45mL)에 용해시키고 염화 4-이소프로필벤질(9.7g, 55mmol)과 탄산칼륨(11.5g)을 연속적으로 가하였다. 그 결과의 혼합물을 16시간동안 60℃에서 가열하였다. 냉각 후, 혼합물을 물(150mL)와 에틸아세테이트(3x100mL)에서 분배하였다. 합한 유기 추출물을 물(100mL), 포화 염화나트륨(100mL)로 세척하고, 건조(MgSO4)시키고 활성탄으로 처리하고 여과하고 진공에서 농축시켜 4-(4-이소프로필벤질옥시)-3,5-디메톡시벤즈알데히드 15g(100%)을 오일로서 얻었다.Syringealdehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) (10.2 g, 55 mmol) was dissolved in DMF (45 mL) and 4-isopropylbenzyl chloride (9.7 g, 55 mmol) and potassium carbonate (11.5 g) were dissolved. It was added continuously. The resulting mixture was heated at 60 ° C. for 16 hours. After cooling, the mixture was partitioned between water (150 mL) and ethyl acetate (3x100 mL). The combined organic extracts were washed with water (100 mL), saturated sodium chloride (100 mL), dried (MgSO 4 ), treated with activated charcoal, filtered and concentrated in vacuo to 4- (4-isopropylbenzyloxy) -3,5-dime 15 g (100%) of oxybenzaldehyde was obtained as an oil.

1H-NMR (400 MHz, DMSO-d6): δH= 1.20 (9H, d), 2.89 (1H, h), 3.86 (6H, s), 4.98 (2H, s), 7.23 (2H, d), 7.27 (2H, s), 7.36 (2H, d). 1 H-NMR (400 MHz, DMSO-d 6 ): δ H = 1.20 (9H, d), 2.89 (1H, h), 3.86 (6H, s), 4.98 (2H, s), 7.23 (2H, d ), 7.27 (2H, s), 7.36 (2H, d).

상기 3-아미노-4-히드록시벤조산 히드라지드(50mg, 0.3mmol) 및 상기 4-(4-이소프로필벤질옥시)-3,5-디메톡시벤즈알데히드(93mg, 0.3mmol)를 2-프로판올(4mL)에 용해시키고 혼합물을 16시간동안 환류온도에서 가열하였다. 냉각시킨 혼합물을 여과하고 침전물을 2-프로판올(2x4mL)로 세척하고 흡입하여 건조시켜 표제의 화합물 144mg(100%)을 고체로서 얻었다. 융점:174-175℃.The 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the 4- (4-isopropylbenzyloxy) -3,5-dimethoxybenzaldehyde (93 mg, 0.3 mmol) were 2-propanol (4 mL). ) And the mixture was heated at reflux for 16 h. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 × 4 mL) and sucked to dryness to give 144 mg (100%) of the title compound as a solid. Melting point: 174-175 ° C.

HPLC-MS (방법 B): Rt= 10.40 분. m/z = 464.HPLC-MS (Method B): R t = 10.40 min. m / z = 464.

실시예 794:Example 794:

(R)-2-{4-[(3-아미노-4-히드록시벤조일)히드라조노메틸]-3-메톡시페녹시}-N-(1-벤질피롤리딘-3-일)아세트아미드(R) -2- {4-[(3-amino-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenoxy} -N- (1-benzylpyrrolidin-3-yl) acetamide

(R)-(-)-1-벤질-3-아미노피롤리딘(5g, 28mmol)을 디클로로메탄(10mL)에 용해시켰다. 이 용액에 디클로로메탄(5mL)중 염화브로모아세틸(4.55g, 28mmol)의 용액을 실온에서 가하였다. 이 혼합물을 실온에서 16시간동안 교반하였다. 혼합물을 여과하고 디클로로메탄으로 세척하고 진공에서 건조시켜 (3R)-N-(1-벤질피롤리딘-3-일)-2-브로모아세트아미드 염산염 6.8g(72%)을 고체로서 얻고 다음 단계에서 바로 사용하였다.(R)-(-)-1-benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane (10 mL). To this solution was added a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane (5 mL) at room temperature. The mixture was stirred at rt for 16 h. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 6.8 g (72%) of (3R) -N- (1-benzylpyrrolidin-3-yl) -2-bromoacetamide hydrochloride as a solid and then It was used directly in the step.

4-히드록시-2-메톡시벤즈알데히드(2.05g, 13mmol)을 DMF(7mL)에 용해시키고 탄산칼륨(6.2g, 45mmol)을 가하고 이어서 DMF(16mL)중 상기 (3R)-N-(1-벤질피롤리딘-3-일)-2-브로모아세트아미드 염산염(3.0g, 9mmol)의 현탁액을 가하였다. 그 결과의 혼합물을 실온에서 16시간동안 교반하였다. 이 혼합물을 물(100mL)와 에틸아세테이트(30mL)에서 분배하였다. 수상을 에틸아세테이트(2x20mL)로 추출하고 합한 유기 추출물을 포화 염화나트륨(3x15mL)로 세척하고, 건조(MgSO4)시키고 진공에서 농축시켰다. 그 잔여물을 디에틸에테르로부터 결정화하여 (R)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀-4-메톡시페녹시)아세트아미드 2.11g(64%)을 고체로서 얻었다. 융점:98-101℃.4-hydroxy-2-methoxybenzaldehyde (2.05 g, 13 mmol) was dissolved in DMF (7 mL) and potassium carbonate (6.2 g, 45 mmol) was added followed by the above (3R) -N- (1-D) in DMF (16 mL). A suspension of benzylpyrrolidin-3-yl) -2-bromoacetamide hydrochloride (3.0 g, 9 mmol) was added. The resulting mixture was stirred at rt for 16 h. The mixture was partitioned between water (100 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL) and the combined organic extracts were washed with saturated sodium chloride (3 × 15 mL), dried (MgSO 4 ) and concentrated in vacuo. The residue was crystallized from diethyl ether to give 2.11 g (64) of (R) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formyl-4-methoxyphenoxy) acetamide. %) Was obtained as a solid. Melting point: 98-101 ° C.

C21H24N2O4.0.5H2O의 계산치: C, 66.83%; H, 6.68%; N, 7.42%.Calcd for C 21 H 24 N 2 O 4 .0.5H 2 O: C, 66.83%; H, 6.68%; N, 7.42%.

실측치: C, 67.15%; H, 6.57%; N, 7.75%; C, 66.96%; H, 6.57%; N, 7.77%.Found: C, 67.15%; H, 6.57%; N, 7.75%; C, 66.96%; H, 6.57%; N, 7.77%.

상기 3-아미노-4-히드록시벤조산 히드라지드(50mg, 0.3mmol) 및 상기 (R)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀-3-메톡시페녹시)아세트아미드(110mg, 0.3mmol)를 2-프로판올(4mL)에 용해시키고 혼합물을 16시간동안 환류온도에서 가열하였다. 냉각시킨 혼합물을 여과하고 침전물을 2-프로판올(2x3mL)로 세척하고 흡입하여 건조시켜 표제의 화합물 109mg(70%)을 고체로서 얻었다. 융점:157-160℃.3-Amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and (R) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formyl-3-meth Toxiphenoxy) acetamide (110 mg, 0.3 mmol) was dissolved in 2-propanol (4 mL) and the mixture was heated at reflux for 16 h. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 × 3 mL) and sucked to dryness to give 109 mg (70%) of the title compound as a solid. Melting Point: 157-160 ° C.

HPLC-MS (방법 B): Rt= 3.10 분. m/z = 518.HPLC-MS (method B): R t = 3.10 min. m / z = 518.

실시예 795:Example 795:

(R)-2-{4-[(3-아미노-4-히드록시벤조일)히드라조노메틸]나프틸-1-일옥시}-N-(1-벤질피롤리딘-3-일)아세트아미드(R) -2- {4-[(3-amino-4-hydroxybenzoyl) hydrazonomethyl] naphthyl-1-yloxy} -N- (1-benzylpyrrolidin-3-yl) acetamide

4-히드록시-1-나프트알데히드(2.32g, 13mmol)을 DMF(7mL)에 용해시키고 탄산칼륨(6.2g, 45mmol)을 가하고 이어서 DMF(16mL)중 상기 (3R)-N-(1-벤질피롤리딘-3-일)-2-브로모아세트아미드 염산염(3.0g, 9mmol)의 현탁액을 가하였다. 그 결과의 혼합물을 실온에서 16시간동안 교반하였다. 그런 다음, 이 혼합물을 물(100mL)과 에틸아세테이트(30mL)에서 분배하였다. 수상을 에틸아세테이트(2x20mL)로 추출하고 합한 유기 추출물을 포화 염화나트륨(3x15mL)으로 세척하고, 건조(MgSO4)시키고 진공에서 농축시켰다. 그 잔여물을 에틸아세테이트를 용리액으로 하는 실리카겔(110g)상의 컬럼크로마토그래피로 정제하여 (R)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀나프틸-1-일옥시)아세트아미드 1.7g(49%)을 고체로서 얻었다. 융점:105-107℃.4-hydroxy-1-naphthaldehyde (2.32 g, 13 mmol) was dissolved in DMF (7 mL) and potassium carbonate (6.2 g, 45 mmol) was added followed by the above (3R) -N- (1-D) in DMF (16 mL). A suspension of benzylpyrrolidin-3-yl) -2-bromoacetamide hydrochloride (3.0 g, 9 mmol) was added. The resulting mixture was stirred at rt for 16 h. This mixture was then partitioned between water (100 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL) and the combined organic extracts were washed with saturated sodium chloride (3 × 15 mL), dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (110 g) using ethyl acetate as eluent to give (R) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formylnaphthyl- 1.7 g (49%) of 1-yloxy) acetamide was obtained as a solid. Melting point: 105-107 ° C.

C24H24N2O3.0.25H2O의 계산치: C, 73.36%; H, 6.28%; N, 7.13%.Calcd for C 24 H 24 N 2 0 3 .0.25H 2 0: C, 73.36%; H, 6.28%; N, 7.13%.

실측치: C, 73.81%; H, 6.22%; N, 7.11%; C, 73.92%; H, 6.23%; N, 7.11%.Found: C, 73.81%; H, 6. 22%; N, 7.11%; C, 73.92%; H, 6. 23%; N, 7.11%.

상기 3-아미노-4-히드록시벤조산 히드라지드(50mg, 0.3mmol) 및 상기 (R)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀나프틸-1-일옥시)아세트아미드(116mg, 0.3mmol)를 2-프로판올(4mL)에 용해시키고 혼합물을 16시간동안 환류온도에서 가열하였다. 냉각시킨 혼합물을 여과하고 그 침전물을 2-프로판올(6x2mL)로 세척하고 흡입하여 건조시켜 표제의 화합물 140mg(87%)을 고체로서 얻었다. 융점:187-192℃.3-Amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and (R) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formylnaphthyl-1 -Yloxy) acetamide (116 mg, 0.3 mmol) was dissolved in 2-propanol (4 mL) and the mixture was heated at reflux for 16 h. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 × 2 mL) and sucked to dryness to afford 140 mg (87%) of the title compound as a solid. Melting point: 187-192 ° C.

HPLC-MS (방법 B): Rt= 5.72 분. m/z = 538.HPLC-MS (method B): R t = 5.72 min. m / z = 538.

실시예 796:Example 796:

(S)-2-{4-[(3-아미노-4-히드록시벤조일)-히드라조노메틸]-3-메톡시페녹시}-N-(1-벤질피롤리딘-3-일)아세트아미드(S) -2- {4-[(3-amino-4-hydroxybenzoyl) -hydrazonomethyl] -3-methoxyphenoxy} -N- (1-benzylpyrrolidin-3-yl) acet amides

(S)-(+)-1-벤질-3-아미노피롤리딘(6g, 34mmol)을 디클로로메탄(12mL)에 용해시켰다. 이 용액에 디클로로메탄(5mL)중 염화브로모아세틸(5.46g, 34mmol)의 용액을 실온에서 가하였다. 이 혼합물을 실온에서 16시간동안 교반하였다. 혼합물을 여과하고 디클로로메탄으로 세척하고 진공에서 건조시켜 (3S)-N-(1-벤질피롤리딘-3-일)-2-브로모아세트아미드 염산염 7.3g(64%)을 고체로서 얻고 다음 단계에서 바로 사용하였다.(S)-(+)-1-benzyl-3-aminopyrrolidine (6 g, 34 mmol) was dissolved in dichloromethane (12 mL). To this solution was added a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane (5 mL) at room temperature. The mixture was stirred at rt for 16 h. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 7.3 g (64%) of (3S) -N- (1-benzylpyrrolidin-3-yl) -2-bromoacetamide hydrochloride as a solid and then It was used directly in the step.

4-히드록시-2-메톡시벤즈알데히드(2.39g, 16mmol)을 DMF(10mL)에 용해시키고 탄산칼륨(7.3g, 52mmol)을 가하고 이어서 DMF(20mL)중 상기 (3S)-N-(1-벤질피롤리딘-3-일)-2-브로모아세트아미드 염산염(3.5g, 10mmol)의 현탁액을 가하였다. 그 결과의 혼합물을 실온에서 16시간동안 교반하였다. 그런 다음, 이 혼합물을 물(100mL)와 에틸아세테이트(30mL)에서 분배하였다. 수상을 에틸아세테이트(2x20mL)로 추출하고 합한 유기 추출물을 포화 염화나트륨(3x15mL)로 세척하고, 건조(MgSO4)시키고 진공에서 농축시켰다. 그 잔여물(4g)을 디에틸에테르와 헵탄으로부터 결정화하고 여과하고 진공에서 건조시켜 (S)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀-3-메톡시페녹시)아세트아미드 2.7g(71%)을 고체로서 얻었다. 융점:96-100℃.4-hydroxy-2-methoxybenzaldehyde (2.39 g, 16 mmol) was dissolved in DMF (10 mL) and potassium carbonate (7.3 g, 52 mmol) was added followed by (3S) -N- (1- in DMF (20 mL). A suspension of benzylpyrrolidin-3-yl) -2-bromoacetamide hydrochloride (3.5 g, 10 mmol) was added. The resulting mixture was stirred at rt for 16 h. This mixture was then partitioned between water (100 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL) and the combined organic extracts were washed with saturated sodium chloride (3 × 15 mL), dried (MgSO 4 ) and concentrated in vacuo. The residue (4 g) was crystallized from diethyl ether and heptane, filtered and dried in vacuo to give (S) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formyl-3- 2.7 g (71%) of methoxyphenoxy) acetamide were obtained as a solid. Melting Point: 96-100 ° C.

C21H24N2O4.0.25H2O의 계산치: C, 67.63%; H, 6.62%; N, 7.51%.Calcd for C 21 H 24 N 2 O 4 .0.25H 2 O: C, 67.63%; H, 6.62%; N, 7.51%.

실측치: C, 67.35%; H, 6.61%; N, 7.85%; C, 67.24%; H, 6.59%; N, 7.82%.Found: C, 67.35%; H, 6.61%; N, 7.85%; C, 67.24%; H, 6.59%; N, 7.82%.

상기 3-아미노-4-히드록시벤조산 히드라지드(50mg, 0.3mmol) 및 상기 (S)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀-3-메톡시페녹시)아세트아미드(110mg, 0.3mmol)를 2-프로판올(4mL)에 용해시키고 혼합물을 16시간동안 환류온도에서 가열하였다. 냉각시킨 혼합물을 여과하고 침전물을 2-프로판올(6x2mL)로 세척하고 흡입하여 건조시켜 표제의 화합물 109mg(70%)을 고체로서 얻었다. 융점:139-141℃.3-Amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and (S) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formyl-3-meth Toxiphenoxy) acetamide (110 mg, 0.3 mmol) was dissolved in 2-propanol (4 mL) and the mixture was heated at reflux for 16 h. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 × 2 mL) and sucked to dryness to give 109 mg (70%) of the title compound as a solid. Melting point: 139-141 ° C.

HPLC-MS (방법 B): Rt= 3.15 분. m/z = 518.HPLC-MS (method B): R t = 3.15 min. m / z = 518.

실시예 797:Example 797:

(S)-2-{4-[(3-아미노-4-히드록시벤조일)히드라조노메틸]나프틸-1-일옥시}-N-(1-벤질피롤리딘-3-일)아세트아미드(S) -2- {4-[(3-amino-4-hydroxybenzoyl) hydrazonomethyl] naphthyl-1-yloxy} -N- (1-benzylpyrrolidin-3-yl) acetamide

4-히드록시-1-나프트알데히드(2.71g, 6mmol)을 DMF(10mL)에 용해시키고 탄산칼륨(7.25g, 52mmol)을 가하고 이어서 DMF(20mL)중 상기 (3S)-N-(1-벤질피롤리딘-3-일)-2-브로모아세트아미드 염산염(3.0g, 10mmol)의 현탁액을 가하였다. 그 결과의 혼합물을 실온에서 16시간동안 교반하였다. 그런 다음, 이 혼합물을 물(100mL)과 에틸아세테이트(30mL)에서 분배하였다. 수상을 에틸아세테이트(2x20mL)로 추출하고 합한 유기 추출물을 포화 염화나트륨(3x15mL)으로 세척하고, 건조(MgSO4)시키고 진공에서 농축시켰다. 그 잔여물(4g)을 에틸아세테이트를 용리액으로 하는 실리카겔(110g)상의 컬럼크로마토그래피로 정제하여 (S)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀나프틸-1-일옥시)아세트아미드 1.8g(45%)을 고체로서 얻었다. 융점:96-97℃.4-hydroxy-1-naphthaldehyde (2.71 g, 6 mmol) was dissolved in DMF (10 mL) and potassium carbonate (7.25 g, 52 mmol) was added followed by (3S) -N- (1- in DMF (20 mL). A suspension of benzylpyrrolidin-3-yl) -2-bromoacetamide hydrochloride (3.0 g, 10 mmol) was added. The resulting mixture was stirred at rt for 16 h. This mixture was then partitioned between water (100 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2 × 20 mL) and the combined organic extracts were washed with saturated sodium chloride (3 × 15 mL), dried (MgSO 4 ) and concentrated in vacuo. The residue (4 g) was purified by column chromatography on silica gel (110 g) using ethyl acetate as eluent, to give (S) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formyl. 1.8 g (45%) of naphthyl-1-yloxy) acetamide was obtained as a solid. Melting point: 96-97 ° C.

C24H24N2O3.0.25H2O의 계산치: C, 73.36%; H, 6.28%; N, 7.13%.Calcd for C 24 H 24 N 2 0 3 .0.25H 2 0: C, 73.36%; H, 6. 28%; N, 7.13%.

실측치: C, 73.58%; H, 6.28%; N, 7.05%; C, 73.55%; H, 6.27%; N, 7.03%.Found: C, 73.58%; H, 6. 28%; N, 7.05%; C, 73.55%; H, 6. 27%; N, 7.03%.

상기 3-아미노-4-히드록시벤조산 히드라지드(50mg, 0.3mmol) 및 상기 (S)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀나프틸-1-일옥시)아세트아미드(116mg, 0.3mmol)를 2-프로판올(4mL)에 용해시키고 혼합물을 16시간동안 환류온도에서 가열하였다. 냉각시킨 혼합물을 여과하고 침전물을 2-프로판올(3x3mL)로 세척하고 흡입하여 건조시켜 표제의 화합물 143mg(89%)을 고체로서 얻었다. 융점:192-193℃.3-Amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and (S) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formylnaphthyl-1 -Yloxy) acetamide (116 mg, 0.3 mmol) was dissolved in 2-propanol (4 mL) and the mixture was heated at reflux for 16 h. The cooled mixture was filtered and the precipitate was washed with 2-propanol (3 × 3 mL) and sucked to dryness to give 143 mg (89%) of the title compound as a solid. Melting point: 192-193 ° C.

HPLC-MS (방법 B): Rt= 5.18 분. m/z = 538.HPLC-MS (method B): R t = 5.18 min. m / z = 538.

실시예 798:Example 798:

(S)-2-{4-[(3-플루오로-4-히드록시벤조일)히드라조노메틸]나프틸-1-일옥시}-N-(1-벤질피롤리딘-3-일)아세트아미드(S) -2- {4-[(3-fluoro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl-1-yloxy} -N- (1-benzylpyrrolidin-3-yl) acet amides

이 화합물은 수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드를 사용하여, 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드을 위해 상기 기재된 바와 유사하게 고체상에서 제조하였다. 따라서, 메틸 3-플루오로-4-히드록시벤조에이트를 수지에 부착시켰다. 메틸에스테르(수성 LiOH, 디옥산, 60℃)로 가수분해한 후, 히드라진(PyBOP, 히드라진, DMF)과 반응시켜 수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드를 얻었다.This compound was prepared in solid phase similar to that described above for 3-chloro-4-hydroxybenzoic acid hydrazide with resin bound using 3-fluoro-4-hydroxybenzoic acid hydrazide with resin bound. Thus, methyl 3-fluoro-4-hydroxybenzoate was attached to the resin. After hydrolysis with methyl ester (aqueous LiOH, dioxane, 60 DEG C), it was reacted with hydrazine (PyBOP, hydrazine, DMF) to obtain 3-fluoro-4-hydroxybenzoic acid hydrazide to which the resin was bound.

수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드를 DMF(1mL)에서 30분간 팽창시키고 여과시켰다. 이것을 한번 더 반복하였다. DMF(4mL)와 상기 (S)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀나프틸-1-일옥시)아세트아미트(0.4g, 0.94mmol)을 가하고 티에틸 오르토포르메이트(1.5mL)를 가한 후, 그 결과의 혼합물을 실온에서 16시간동안 흔들어 섞었다. 이 혼합물을 여과하고 수지를 DMF(5x4mL)와 디클로로메탄(5x4mL)로 연속적으로 세척하였다. 화합물을 디클로로메탄(6mL)중 50% TFA를 가해 수지를 완전히 절단하고 실온에서 1시간동안 흔들어 섞었다. 여과 후, 메탄올과 디클로로메탄(4:6)(2x4mL)의 혼합물로 추출하고 디클로로메탄(4mL)으로 추출하였다. 합한 여과물을 진공에서 농축시키고 물기있는 메탄올, 디클로로메탄, 메탄올 및 디클로로메탄으로 연속적으로 스트리핑하였다. 잔여물(0.39g)을 디클로로메탄, 에탄올 및 25% 암모니아수(90:9:1)의 혼합물로 먼저 용리시키고 그런 다음, (85:13.5:1.5)의 혼합물로, 최종적으로 (80:18.2)의 혼합물로 용리시키는 실리카겔상(40g)의 컬럼크로마토그래피로 정제하였다. 순수한 분획을 모으고 진공에서 농축시켜 표제의 화합물 0.15g을 얻었다.The resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide was expanded in DMF (1 mL) for 30 minutes and filtered. This was repeated once more. DMF (4 mL) and (S) -N- (1-benzylpyrrolidin-3-yl) -2- (4-formylnaphthyl-1-yloxy) acetamide (0.4 g, 0.94 mmol) To this was added thiethyl orthoformate (1.5 mL), and the resulting mixture was shaken for 16 hours at room temperature. The mixture was filtered and the resin was washed successively with DMF (5x4 mL) and dichloromethane (5x4 mL). The compound was added to 50% TFA in dichloromethane (6 mL) to cut the resin completely and shake for 1 hour at room temperature. After filtration, the mixture was extracted with a mixture of methanol and dichloromethane (4: 6) (2 × 4 mL) and extracted with dichloromethane (4 mL). The combined filtrates were concentrated in vacuo and successively stripped with wet methanol, dichloromethane, methanol and dichloromethane. The residue (0.39 g) was eluted first with a mixture of dichloromethane, ethanol and 25% aqueous ammonia (90: 9: 1) and then with a mixture of (85: 13.5: 1.5), finally of (80: 18.2) Purification was by column chromatography on silica gel eluting with the mixture. Pure fractions were combined and concentrated in vacuo to yield 0.15 g of the title compound.

HPLC-MS (방법 B): Rt= 8.82 분; m/z = 541.HPLC-MS (method B): R t = 8.82 min; m / z = 541.

C31H29N4O4F.0.25CH2Cl2의 계산치: C, 66.81%; H, 5.29%; N, 9.97%. C 31 H 29 N 4 O 4 F.0.25CH 2 Calcd for Cl 2: C, 66.81%; H, 5.29%; N, 9.97%.

실측치: C, 67.30%; H, 5.48%; N, 10.03%; C, 67.33%; H, 5.49%; N, 10.02%.Found: C, 67.30%; H, 5.48%; N, 10.03%; C, 67.33%; H, 5.49%; N, 10.02%.

실시예 799:Example 799:

(R)-2-{4-[(3-플루오로-4-히드록시벤조일)히드라조노메틸]나프틸-1-일옥시}-N-(1-벤질피롤리딘-3-일)아세트아미드(R) -2- {4-[(3-fluoro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl-1-yloxy} -N- (1-benzylpyrrolidin-3-yl) acet amides

이 화합물은 수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드(1g, 0.94mmol)와 상기 (R)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀나프틸-1-일옥시)아세트아미드(0.4g, 0.94mmol)을 출발물질로 하여 상기 실시예에 기재된 바와 유사하게 제조하였다. 절단 후, 이 화합물을 컬럼크로마토그래피로 정제하여 표제의 화합물 0.14g을 얻었다.This compound is composed of 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) to which a resin is bound and (R) -N- (1-benzylpyrrolidin-3-yl) -2- (4 -Formylnaphthyl-1-yloxy) acetamide (0.4 g, 0.94 mmol) was prepared similarly to that described in the above examples using starting material. After cleavage, this compound was purified by column chromatography to give 0.14 g of the title compound.

HPLC-MS (방법 B): Rt= 9.02 분. m/z = 541.HPLC-MS (method B): R t = 9.02 min. m / z = 541.

C31H29N4O4F.0.25CH2Cl2의 계산치: C, 66.81%; H, 5.29%; N, 9.97%. C 31 H 29 N 4 O 4 F.0.25CH 2 Calcd for Cl 2: C, 66.81%; H, 5. 29%; N, 9.97%.

실측치: C, 66.77%; H, 5.46%; N, 10.02%; C, 67.14%; H, 5.42%; N, 9.97%.Found: C, 66.77%; H, 5.46%; N, 10.02%; C, 67.14%; H, 5. 42%; N, 9.97%.

실시예 800:Example 800:

(S)-2-{4-[(3-플루오로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페녹시}-N-(1-벤질피롤리딘-3-일)아세트아미드(S) -2- {4-[(3-fluoro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenoxy} -N- (1-benzylpyrrolidin-3-yl) acet amides

이 화합물은 수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드(1g, 0.94mmol)와 상기 (S)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀-3-메톡시페녹시)아세트아미드(0.4g, 0.94mmol)을 출발물질로 하여 상기 실시예에 기재된 바와 유사하게 제조하였다. 절단 후, 이 화합물을 컬럼크로마토그래피로 정제하여 표제의 화합물 0.13g을 얻었다.This compound is composed of 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) to which resin is bound and (S) -N- (1-benzylpyrrolidin-3-yl) -2- (4 -Formyl-3-methoxyphenoxy) acetamide (0.4 g, 0.94 mmol) was prepared similarly to that described in the examples above as starting material. After cleavage, this compound was purified by column chromatography to give 0.13 g of the title compound.

HPLC-MS (방법 B): Rt= 3.68 분. m/z = 521.HPLC-MS (method B): R t = 3.68 min. m / z = 521.

C28H29N4O5F.0.25CH2Cl2의 계산치: C, 62.63%; H, 5.49%; N, 10.34%.Calcd for C 28 H 29 N 4 0 5 F.0.25CH 2 Cl 2 : C, 62.63%; H, 5.49%; N, 10.34%.

실측치: C, 62.92%; H, 5.83%; N, 10.15%; C, 62.71%; H, 5.81%; N, 10.16%.Found: C, 62.92%; H, 5.83%; N, 10.15%; C, 62.71%; H, 5.81%; N, 10.16%.

실시예 801:Example 801:

(R)-2-{4-[(3-플루오로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페녹시}-N-(1-벤질피롤리딘-3-일)아세트아미드(R) -2- {4-[(3-fluoro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenoxy} -N- (1-benzylpyrrolidin-3-yl) acet amides

이 화합물은 수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드(1g, 0.94mmol)와 상기 (R)-N-(1-벤질피롤리딘-3-일)-2-(4-포르밀-3-메톡시페녹시)아세트아미드(0.4g, 0.94mmol)을 출발물질로 하여 상기 실시예에 기재된 바와 유사하게 제조하였다. 절단 후, 이 화합물을 컬럼크로마토그래피로 정제하여 표제의 화합물 0.16g을 얻었다.This compound is composed of 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) to which a resin is bound and (R) -N- (1-benzylpyrrolidin-3-yl) -2- (4 -Formyl-3-methoxyphenoxy) acetamide (0.4 g, 0.94 mmol) was prepared similarly to that described in the examples above as starting material. After cleavage, this compound was purified by column chromatography to give 0.16 g of the title compound.

HPLC-MS (방법 B): Rt= 4.18 분. m/z = 521.HPLC-MS (method B): R t = 4.18 min. m / z = 521.

C28H29N4O5F.0.25CH2Cl2의 계산치: C, 62.63%; H, 5.49%; N, 10.34%.Calcd for C 28 H 29 N 4 0 5 F.0.25CH 2 Cl 2 : C, 62.63%; H, 5.49%; N, 10.34%.

실측치: C, 62.65%; H, 5.73%; N, 10.31%; C, 62.84%; H, 5.81%; N, 10.30%.Found: C, 62.65%; H, 5.73%; N, 10.31%; C, 62.84%; H, 5.81%; N, 10.30%.

실시예 802:Example 802:

3-플루오로-4-히드록시벤조산{4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]메톡시벤질리덴}히드라지드3-fluoro-4-hydroxybenzoic acid {4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] methoxybenzylidene} hydrazide

이 화합물은 수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드(1g, 0.94mmol)와 상기 4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시-2-메톡시벤즈알데히드(0.4g, 0.94mmol)을 출발물질로 하여 상기 실시예에 기재된 바와 유사하게 제조하였다. 절단 후, 이 화합물을 컬럼크로마토그래피로 정제하여 표제의 화합물 0.13g을 얻었다.This compound is composed of 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) to which a resin is bound and 4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl). Ethoxy-2-methoxybenzaldehyde (0.4 g, 0.94 mmol) was prepared similarly to that described in the above examples using starting material. After cleavage, this compound was purified by column chromatography to give 0.13 g of the title compound.

HPLC-MS (방법 B): Rt= 7.60 분. m/z = 464.HPLC-MS (method B): R t = 7.60 min. m / z = 464.

C26H26N3O4F.0.5CH2Cl2의 계산치: C, 62.91%; H, 5.38%; N, 8.30%.Calcd for C 26 H 26 N 3 0 4 F.0.5CH 2 Cl 2 : C, 62.91%; H, 5.38%; N, 8.30%.

실측치: C, 62.68%; H, 5.47%; N, 8.02%; C, 62.48%; H, 5.43%; N, 8.01%.Found: C, 62.68%; H, 5.47%; N, 8.02%; C, 62.48%; H, 5.43%; N, 8.01%.

HPLC-MS (방법 A) 분석은 Waters3 mm x 150 mm 3.5 μC-18 Symmetry 컬럼과 20㎕/분의 유출속도를 가지는 양성 이온분사를 사용하여 PE Sciex API 100 LC/MS System상에서 수행하였다. 컬럼을 1mL/분(용매 A=아세토니트릴, 용매 B=물 및 용매 C=물중 0.1% 트리플루오로아세트산)의 유출속도에서 15분에 5-90% A, 85-0% B 및 10% C의 선상 구배로 용리시켰다.HPLC-MS (Method A) analysis was performed by Waters It was performed on a PE Sciex API 100 LC / MS System using a 3 mm x 150 mm 3.5 μC-18 Symmetry column and positive ion injection with a flow rate of 20 μl / min. Run the column at 5-90% A, 85-0% B and 10% C at 15 min at 1 mL / min (solvent A = acetonitrile, solvent B = water and solvent C = 0.1% trifluoroacetic acid in water). Eluted with a linear gradient of.

HPLC-MS (방법 B)분석은 용리액을 제외하고 상기 기재된 것과 동일한 시스템상에서 수행하였다. 컬럼을 1mL/분(용매 A=아세토니트릴, 용매 B=물 및 용매 C=물중 20mM 아세트산암모늄, pH 7)의 유출속도에서 15분에 30-80% A, 60-10% B 및 10% D의 선상 구배로 용리시켰다.HPLC-MS (Method B) analysis was performed on the same system as described above except for the eluent. The column was run at 30-80% A, 60-10% B and 10% D at 15 min at 1 mL / min (solvent A = acetonitrile, solvent B = water and solvent C = 20 mM ammonium acetate in water, pH 7). Eluted with a linear gradient of.

실시예 803:Example 803:

3-클로로-4-히드록시벤조산{4-[2-(1,2,3,4-테트라히드로이소퀴놀린-2-일)에톡시]-8-메톡시나프탈렌-1-일메틸렌}히드라지드3-Chloro-4-hydroxybenzoic acid {4- [2- (1,2,3,4-tetrahydroisoquinolin-2-yl) ethoxy] -8-methoxynaphthalen-1-ylmethylene} hydrazide

4-히드록시-8-메톡시나프탈렌-1-카르브알데히드(1g, 5mmol)을 DMF(15mL)에 용해시켰다. 이 용액에 탄산칼륨(3.4g, 25mmol) 및 1,2-디브로모에탄(4mL, 50mmol)을 가하고 그 결과의 혼합물을 실온에서 16시간동안 교반하였다. 물(150mL)을 가하고 그 결과의 혼합물을 에틸아세테이트(3x90mL)에서 추출하였다. 합한 유기 추출물을 포화 염화나트륨(100mL)으로 세척하고, 건조(MgSO4)시키고 진공에서 농축시켜 4-(2-브로모에톡시)-8-메톡시나프탈렌-1-카르브알데히드 1.13g(74%)을 얻었다.4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). Potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 50 mmol) were added to this solution, and the resulting mixture was stirred at room temperature for 16 hours. Water (150 mL) was added and the resulting mixture was extracted in ethyl acetate (3 × 90 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO 4 ) and concentrated in vacuo to give 1.13 g (74%) of 4- (2-bromoethoxy) -8-methoxynaphthalene-1-carbaldehyde. Got.

HPLC-MS (방법 A): Rt= 14.1 분. m/z = 309.HPLC-MS (Method A): R t = 14.1 minutes. m / z = 309.

1H-NMR (300 MHz, DMSO-d6): δH= 3.99 (3H, s), 7.00 (1H, d), 7.20 (1H, d), 7.47 (1H, t), 7.88 (2H, m), 10.9 (1H, s). 1 H-NMR (300 MHz, DMSO-d 6 ): δ H = 3.99 (3H, s), 7.00 (1H, d), 7.20 (1H, d), 7.47 (1H, t), 7.88 (2H, m ), 10.9 (1H, s).

수지가 결합된 3-플루오로-4-히드록시벤조산 히드라지드(2g, 1.8mmol)를 DMF(25mL)에서 30분간 팽창시키고 상기 4-(2-브로모에톡시)-8-메톡시나프탈렌-1-카르브알데히드(1.7g, 5.4mmol)을 가하고 티에틸 오르토포르메이트(1.2mL)를 가한 후, 그 결과의 혼합물을 실온에서 16시간동안 흔들어 섞었다. 이 혼합물을 여과하고 수지를 DMF(3x25mL)와 디클로로메탄(4x25mL) 및 N-메틸 피롤리딘-2-온(NMP)(2x25mL)로 연속적으로 세척하였다. NMP(25mL)를 가하고 요오드화칼륨(0.6g) 및 1,2,3,4-테트라히드로이소퀴놀린(2.25mL, 18mmol)를 가하고 그 결과의 혼합물을 실온에서 16시간동안 흔들어 섞었다. 혼합물을 여과하고 수지를 NMP(2x25mL)와 디클로로메탄(6x25mL)로 연속적으로 세척하였다. 이 화합물을 디클로로메탄중 50% TFA(30mL)를 가해 수지를 완전히 절단하고 실온에서 1시간동안 흔들어 섞었다. 여과 후, 디클로로메탄(2x30mL)으로 수지를 추출하고 합한 여과물을 진공에서 농축시켰다. 잔여물을 에틸아세테이트(80mL)와 포화 탄산수소나트륨(100mL)에 분배시켰다. 수상을 에틸아세테이트(2x80mL)로 추출하고 합한 유기 추출물을 건조(MgSO4)시키고 진공에서 농축시켰다. 잔여물을 디클로로메탄과 메탄올(9:1)의 혼합물을 용리액으로 하는 실리카겔상(200mL)의 컬럼크로마토그래피로 정제하였다. 표제의 화합물 217g을 얻었다.Resin-bonded 3-fluoro-4-hydroxybenzoic acid hydrazide (2 g, 1.8 mmol) was expanded in DMF (25 mL) for 30 minutes and the 4- (2-bromoethoxy) -8-methoxynaphthalene-1 Carbaldehyde (1.7 g, 5.4 mmol) was added and thiethyl orthoformate (1.2 mL) was added and the resulting mixture was shaken for 16 hours at room temperature. The mixture was filtered and the resin was washed successively with DMF (3 × 25 mL), dichloromethane (4 × 25 mL) and N-methyl pyrrolidin-2-one (NMP) (2 × 25 mL). NMP (25 mL) was added and potassium iodide (0.6 g) and 1,2,3,4-tetrahydroisoquinoline (2.25 mL, 18 mmol) were added and the resulting mixture was shaken for 16 hours at room temperature. The mixture was filtered and the resin was washed successively with NMP (2 × 25 mL) and dichloromethane (6 × 25 mL). 50% TFA (30 mL) in dichloromethane was added to the compound to completely dissolve the resin and shake for 1 hour at room temperature. After filtration, the resin was extracted with dichloromethane (2x30 mL) and the combined filtrates were concentrated in vacuo. The residue was partitioned between ethyl acetate (80 mL) and saturated sodium bicarbonate (100 mL). The aqueous phase was extracted with ethyl acetate (2 × 80 mL) and the combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (200 mL) using a mixture of dichloromethane and methanol (9: 1) as eluent. 217 g of the title compound were obtained.

HPLC-MS (방법 A): Rt= 9.14 분. m/z = 530.HPLC-MS (Method A): R t = 9.14 min. m / z = 530.

실시예 804 내지 824를 위한 일반적인 방법General Method for Examples 804-824

화합물은 다음 식:The compound is of the following formula:

수지-[빌딩블록 1] →Resin- [Building Block 1] →

수지-[빌딩블록 1]-[빌딩블록 2] →Resin- [Building Block 1]-[Building Block 2] →

수지-[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3]Resin- [Building Block 1]-[Building Block 2]-[Building Block 3]

에 따라서 제조하였고 동시에 탈보호화(필요하다면)하고 디클로로메탄중 50% 트리플루오로아세트산으로 수지로부터 절단하여 다음 식:Deprotected (if necessary) at the same time and cut from the resin with 50% trifluoroacetic acid in dichloromethane according to the following formula:

[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3][Building Block 1]-[Building Block 2]-[Building Block 3]

에 따르는 개개의 개체로서 원하는 화합물을 얻었다.The desired compound was obtained as an individual object according to the present invention.

다음의 화합물은 고체 지지체상에서 병렬적 합성에 의해 단일체로서 제조하였다. 수지-[빌딩블록 1]의 제조 및 [빌딩블록 2]의 부착은 수동으로 하였고, 반면 [빌딩블록 3]의 부착과 수지로부터의 절단은 Advanced ChemTech Model 496 HTS상에서 여러번 작동시켜 수행하였다.The following compounds were prepared as monoliths by parallel synthesis on a solid support. The preparation of Resin- [Building Block 1] and the attachment of [Building Block 2] were done manually, whereas the attachment of [Building Block 3] and cleavage from the resin were performed several times on Advanced ChemTech Model 496 HTS.

출발 수지, 수지-[빌딩블록 1]은 하기 기재된 바와 같이 제조되었다.Starting resin, Resin- [Building Block 1], was prepared as described below.

사용된 수지는 Wang 링커를 가지는 폴리스티렌 수지이고 치환용량은 0.9mmol/g이었다.The resin used was a polystyrene resin with Wang linker and a substitution capacity of 0.9 mmol / g.

모든 화합물은 조합적 방식으로 다음 반응식에 따라서 [빌딩블록 2] 및 [빌딩블록 3]의 수지-[빌딩블록 1]에의 연속적인 부착을 기본으로 한다. 반응식은 화학식 II에 관련된다.All compounds are based on the continuous attachment of [Building Block 2] and [Building Block 3] to Resin- [Building Block 1] in a combinatorial manner according to the following scheme. The scheme is related to formula II.

(반응식)(Scheme)

상기 식에서, R8, R9,R14, R15및Wherein R 8 , R 9 , R 14 , R 15 and

는 화학식 I에서 정의된 바와 같다.Is as defined in formula (I).

여기서 수지-[빌딩블록 1]로서 나타낸 다음의 수지를 사용하였다.The following resin shown here as Resin- [Building Block 1] was used.

상기 식에서 PS는 폴리스티렌이고, 아래에서 "수지"는 Wang 링커를 가진 폴리스티렌 수지이다.Wherein PS is polystyrene and below "resin" is a polystyrene resin with Wang linker.

다음의 빌딩블록을 사용하였다:The following building blocks were used:

[빌딩블록 2]:[Building Block 2]:

[빌딩블록 3]:[Building Block 3]:

수지-[빌딩블록 1]의 제조:Preparation of Resin- [Building Block 1]:

이 수지는 상기 기재된 바와 같이 제조하였다.This resin was prepared as described above.

[빌딩블록 2]의 제조:Preparation of [Building Block 2]:

(4-포르밀-3-메톡시페닐)카르밤산 9H-플루오렌-9-일메틸에스테르(4-formyl-3-methoxyphenyl) carbamic acid 9H-fluorene-9-ylmethyl ester

메틸 4-아미노-2-메톡시벤조에이트(14.7g, 7.3mmol) 및 Fmoc-Osu(26.1g, 77.3mmol)을 아세토니트릴과 물(1:1, 320mL)의 혼합물에서 16시간동안 환류교반하였다. 반응혼합물을 부피의 반까지 농축시키고 침전물을 여과하여 분리하였다. 분리된 고체를 에틸아세테이트(300mL)에 용해시키고 0.4N 염산(200mL), 0.2N 염산(200mL), 물(200mL) 및 염화나트륨의 20% 포화용액(200mL)으로 세척하였다. 건조(황산마그네슘)후, 유기상을 진공에서 농축시키고 고체 잔여물을 메탄올로 세척하고 건조시켰다.Methyl 4-amino-2-methoxybenzoate (14.7 g, 7.3 mmol) and Fmoc-Osu (26.1 g, 77.3 mmol) were refluxed for 16 hours in a mixture of acetonitrile and water (1: 1, 320 mL). . The reaction mixture was concentrated to half the volume and the precipitate was separated by filtration. The separated solid was dissolved in ethyl acetate (300 mL) and washed with 0.4 N hydrochloric acid (200 mL), 0.2 N hydrochloric acid (200 mL), water (200 mL) and 20% saturated solution of sodium chloride (200 mL). After drying (magnesium sulfate), the organic phase was concentrated in vacuo and the solid residue was washed with methanol and dried.

미정제 생성물(12g)을 디클로로메탄(1L)에 질소하에서 용해시키고 수소화디이소부틸알루미늄(90mL, 톨루엔중 1.2M)을 0-5℃에서 적가하였다. 반응혼합물을 20℃에서 16시간동안 교반하고 물(58mL)를 0-5℃에서 적가하여 급냉하였다. 반응혼합물을 20℃에서 3시간동안 교반하고 여과시켰다. 여과물을 진공에서 농축시켰다. 미정제 생성물(6.8g)을 디클로로메탄(400mL)에 현탁시키고 2산화망간(15.6g, 180mmol)을 가하였다. 혼합물을 20℃에서 16시간동안 교반하고 여과시켰다. 여과물을 진공에서 농축시켜 표제의 화합물 5.1g을 얻었다.The crude product (12 g) was dissolved in dichloromethane (1 L) under nitrogen and diisobutylaluminum hydride (90 mL, 1.2 M in toluene) was added dropwise at 0-5 ° C. The reaction mixture was stirred at 20 ° C. for 16 hours and quenched by dropwise addition of water (58 mL) at 0-5 ° C. The reaction mixture was stirred at 20 ° C. for 3 hours and filtered. The filtrate was concentrated in vacuo. The crude product (6.8 g) was suspended in dichloromethane (400 mL) and manganese dioxide (15.6 g, 180 mmol) was added. The mixture was stirred at 20 ° C. for 16 h and filtered. The filtrate was concentrated in vacuo to give 5.1 g of the title compound.

융점. 187-188℃Melting point. 187-188 ℃

HPLC-MS (방법 A): Rt= 15.1 분, m/z= 374.HPLC-MS (Method A): R t = 15.1 bun, m / z = 374.

미량분석: 계산치: C, 73.98; H, 5.13; N, 3.75%Microanalysis: calcd: C, 73.98; H, 5.13; N, 3.75%

실측치: C, 73.44; H, 5.20; N, 3.56%Found: C, 73.44; H, 5.20; N, 3.56%

(4-포르밀-2-메톡시페닐)카르밤산 9H-플루오렌-9-일메틸에스테르(4-formyl-2-methoxyphenyl) carbamic acid 9H-fluorene-9-ylmethyl ester

염화티오닐(12.8g, 108mmol)을 메탄올(250mL)중 4-아미노-3-메톡시벤조산(12.3g, 72mmol)의 얼음 냉 현탁물에 적가하였다. 반응혼합물을 16시간동안 20℃에서 교반하였고 진공에서 농축시켰다. 에틸아세테이트(250mL)와 탄산수소나트륨의 포화용액(150mL)을 가하고 유기상을 탄산수소나트륨의 포화용액(2x50mL)으로 세척하고, 건조(황산마그네슘)하고 진공에서 농축시켰다. 미정제 생성물(12.5g) 및 FmocOsu(28g, 83mmol)를 아세토니트릴과 물(1:1, 240mL)의 혼합물에서 90℃에서 16시간동안 교반하였다. 반응혼합물을 부피의 반까지 농축시켰다. 에틸아세테이트(200mL)를 0.4N 염산(150mL)와 함께 가하였다. 유기상을 0.2N 염산(100mL), 물(100mL) 및 염화나트륨의 포화용액(2x100mL)로 세척하였다. 건조(황산마그네슘)후, 유기상을 진공에서 농축시키고 잔여물을 메탄올로부터 결정화하여 건조시켰다.Thionyl chloride (12.8 g, 108 mmol) was added dropwise to an ice cold suspension of 4-amino-3-methoxybenzoic acid (12.3 g, 72 mmol) in methanol (250 mL). The reaction mixture was stirred for 16 h at 20 ° C. and concentrated in vacuo. Ethyl acetate (250 mL) and a saturated solution of sodium hydrogen carbonate (150 mL) were added, and the organic phase was washed with a saturated solution of sodium hydrogen carbonate (2x50 mL), dried (magnesium sulfate) and concentrated in vacuo. The crude product (12.5 g) and FmocOsu (28 g, 83 mmol) were stirred for 16 h at 90 ° C. in a mixture of acetonitrile and water (1: 1, 240 mL). The reaction mixture was concentrated to half the volume. Ethyl acetate (200 mL) was added together with 0.4N hydrochloric acid (150 mL). The organic phase was washed with 0.2N hydrochloric acid (100 mL), water (100 mL) and saturated solution of sodium chloride (2x100 mL). After drying (magnesium sulfate), the organic phase was concentrated in vacuo and the residue was crystallized from methanol and dried.

융점. 96-98℃Melting point. 96-98 ℃

HPLC (방법 1) Rt= 32.4 분HPLC (method 1) R t = 32.4 min

미량분석: 계산치: C, 71.45; H, 5.25; N, 3.47%Microanalysis: calcd: C, 71.45; H, 5. 25; N, 3.47%

실측치: C, 71.32; H, 5.24; N, 3.41%Found: C, 71.32; H, 5. 24; N, 3.41%

생성물(12g, 29.7mmol)을 디클로로메탄(800mL)에 질소하에서 용해시키고 수소화디이소부틸알루미늄의 용액(90mL, 톨루엔중 1.2M)을 0-5℃에서 적가하였다. 반응 혼합물을 20℃에서 16시간동안 교반하고 물(58mL)를 0-5℃에서 적가하여 급냉하였다. 반응혼합물을 20℃에서 3시간동안 교반하고 여과시켰다. 여과물을 진공에서 농축시켜 생성물 5.5g(융점. 169-171℃)을 얻었다. 생성물(5.5g)을 디클로로메탄(325mL)에 현탁시키고 2산화망간(12.8g, 148mmol)을 가하였다. 혼합물을 20℃에서 16시간동안 교반하고 여과시켰다. 여과물을 진공에서 농축시켜 표제의 화합물 3.5g을 얻었다. 에틸아세테이트로부터 재결정.The product (12 g, 29.7 mmol) was dissolved in dichloromethane (800 mL) under nitrogen and a solution of diisobutylaluminum hydride (90 mL, 1.2 M in toluene) was added dropwise at 0-5 ° C. The reaction mixture was stirred at 20 ° C for 16 h and quenched by dropwise addition of water (58 mL) at 0-5 ° C. The reaction mixture was stirred at 20 ° C. for 3 hours and filtered. The filtrate was concentrated in vacuo to give 5.5 g of product (melting point 169-171 ° C.). The product (5.5 g) was suspended in dichloromethane (325 mL) and manganese dioxide (12.8 g, 148 mmol) was added. The mixture was stirred at 20 ° C. for 16 h and filtered. The filtrate was concentrated in vacuo to give 3.5 g of the title compound. Recrystallization from ethyl acetate.

융점. 150-152℃Melting point. 150-152 ℃

HPLC (방법 1) Rt= 30.6 분HPLC (method 1) R t = 30.6 min

미량분석: 계산치: C, 73.98; H, 5.13; N, 3.75%Microanalysis: calcd: C, 73.98; H, 5.13; N, 3.75%

실측치: C, 73.54; H, 5.18; N, 3.65%Found: C, 73.54; H, 5. 18; N, 3.65%

3-(tert-부틸디메틸실란일옥시)-4-포르밀페닐)카르밤산 9H-플루오렌-9-일메틸에스테르3- (tert-butyldimethylsilanyloxy) -4-formylphenyl) carbamic acid 9H-fluorene-9-ylmethylester

4-(9H-플루오렌-9-일메톡시카르보닐아미노)-2-히드록시벤조산 메틸에스테르:4- (9H-Fluoren-9-ylmethoxycarbonylamino) -2-hydroxybenzoic acid methyl ester:

염화티오닐(19.4g, 163mmol)을 메탄올(200mL)중 4-아미노살리실산(10.3g, 65.3mmol)의 얼음 냉 용액에 적가하였다. 이 후, 반응혼합물을 6시간동안 65℃에서 가열하였다. 반응혼합물을 진공에서 농축시키고 미정제 생성물을 아세토니트릴과 물(1:1, 220mL)의 혼합물에 용해시켰다. FmocOsu(22.0g, 65.3mmol)를 가하고 반응혼합물을 90℃에서 16시간동안 교반하였다. 반응혼합물을 진공에서 100mL까지 농축시키고, 물(50mL) 및 에틸아세테이트(250mL)를 가하였다. 유기상을 분리하고 물(2x50mL) 및 염화나트륨의 포화용액(2x50mL)로 세척하고 건조(황산마그네슘)시킨 후, 진공에서 농축시켰다.Thionyl chloride (19.4 g, 163 mmol) was added dropwise to an ice cold solution of 4-aminosalicylic acid (10.3 g, 65.3 mmol) in methanol (200 mL). Thereafter, the reaction mixture was heated at 65 ° C. for 6 hours. The reaction mixture was concentrated in vacuo and the crude product was dissolved in a mixture of acetonitrile and water (1: 1, 220 mL). FmocOsu (22.0 g, 65.3 mmol) was added and the reaction mixture was stirred at 90 ° C. for 16 h. The reaction mixture was concentrated to 100 mL in vacuo and water (50 mL) and ethyl acetate (250 mL) were added. The organic phase was separated, washed with water (2x50 mL) and saturated solution of sodium chloride (2x50 mL), dried (magnesium sulfate) and concentrated in vacuo.

잔여물을 용리액으로서 에틸아세테이트와 n-헵탄(1:2)을 사용하여 실리카켈(300g)상에서 정제하였다. 이 혼합물을 메탄올로부터 재결정하여 4-(9H-플루오렌-9-일메톡시카르보닐아미노)-2-히드록시벤조산 메틸에스테르를 얻었다.The residue was purified on silica gel (300 g) using ethyl acetate and n-heptane (1: 2) as eluent. This mixture was recrystallized from methanol to obtain 4- (9H-fluorene-9-ylmethoxycarbonylamino) -2-hydroxybenzoic acid methyl ester.

융점.156-9Melting Point.

HPLC (방법 1) Rt= 31.7 분HPLC (method 1) R t = 31.7 min

미량분석: 계산치: C, 70.94; H, 4.92; N, 3.60%Microanalysis: calcd: C, 70.94; H, 4.92; N, 3.60%

실측치: C, 70.73; H, 4.98; N, 3.37%Found: C, 70.73; H, 4.98; N, 3.37%

4-(9H-플루오렌-9-일메톡시카르보닐아미노)-2-히드록시벤조산 메틸에스테르(4.36g, 11.2mmol)을 디메틸포름아미드(20mL)에 용해시키고 이미다졸을 가하였다. 디메틸포름아미드(10mL)에 용해시킨 염화 tert-부틸디메틸실릴(2.09g, 13.4mmol)을 적가하고 반응혼합물을 20℃에서 16시간동안 교반하였다. 반응혼합물을 물(160mL)에 붓고 에틸아세테이트(4x50mL)로 추출하였다. 수집한 유기상을 염화나트륨의 포화용액(4x50mL)로 세척하고 건조(황산마그네슘)시키고 진공에서 농축시켰다. 잔여물을 용리액으로서 에틸아세테이트와 n-헵탄(15:85)을 사용하여 실리카켈(150g)상에서 정제하였다. 이 분리된 생성물(3.10g, 6.15mmol)을 디클로로메탄(200mL)에 질소하에서 용해시켰다. 수소화디이소부틸알루미늄의 용액(18.5mL, 톨루엔중 1.2M)을 0-5℃에서 적가하였다. 혼합물을 20℃에서 3.5시간동안 교반하고 물을 0-5℃에서 적가하여 급냉하였다. 20℃에서 2.5시간후, 반응물을 여과하고 여과물을 진공에서 농축하였다. 잔여물을 에틸아세테이트와 n-헵탄(1:3)을 사용하는 실리카겔상에서 정제하였다. 분리된 생성물(2.40g)을 디클로로메탄(120mL)에 용해시키고 2산화망간(4.39g, 5.05mmol)을 가하였다. 반응혼합물을 0℃에서 16시간동안 교반하고 여과시켰다. 여과물을 진공에서 농축시키고 잔여물을 에틸아세테이트와 n-헵탄(15:85)을 사용하는 실리카겔상에서 정제하여 표제의 화합물 1.0g을 얻었다.4- (9H-Fluoren-9-ylmethoxycarbonylamino) -2-hydroxybenzoic acid methyl ester (4.36 g, 11.2 mmol) was dissolved in dimethylformamide (20 mL) and imidazole was added. Tert-butyldimethylsilyl chloride (2.09 g, 13.4 mmol) dissolved in dimethylformamide (10 mL) was added dropwise and the reaction mixture was stirred at 20 ° C. for 16 hours. The reaction mixture was poured into water (160 mL) and extracted with ethyl acetate (4x50 mL). The collected organic phases were washed with saturated solution of sodium chloride (4x50 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified on silica gel (150 g) using ethyl acetate and n-heptane (15:85) as eluent. This isolated product (3.10 g, 6.15 mmol) was dissolved in dichloromethane (200 mL) under nitrogen. A solution of diisobutylaluminum hydride (18.5 mL, 1.2 M in toluene) was added dropwise at 0-5 ° C. The mixture was stirred at 20 ° C. for 3.5 h and quenched by dropwise addition of water at 0-5 ° C. After 2.5 hours at 20 ° C., the reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel using ethyl acetate and n-heptane (1: 3). The separated product (2.40 g) was dissolved in dichloromethane (120 mL) and manganese dioxide (4.39 g, 5.05 mmol) was added. The reaction mixture was stirred at 0 ° C. for 16 h and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel using ethyl acetate and n-heptane (15:85) to afford 1.0 g of the title compound.

HPLC (방법 1) Rt= 30.7 분 및 36.8 분HPLC (method 1) R t = 30.7 min and 36.8 min

(5-포르밀-2-메톡시페닐)카르밤산 9H-플루오렌-9-일메틸에스테르:(5-formyl-2-methoxyphenyl) carbamic acid 9H-fluorene-9-ylmethylester:

염화티오닐(10.3g, 85mmol)을 메탄올(180mL)중 3-아미노-4-메톡시벤조산(9.48g, 56.7mmol)의 얼음 냉 용액에 적가하였다. 이 후, 반응혼합물을 16시간동안 20℃에서 교반하고 진공에서 농축시켰다. 에틸아세테이트(100mL) 및 탄산수소나트륨의 포화용액(100mL)을 가하고 유기상을 탄산수소나트륨의 포화용액(2x40mL)으로 세척하고, 건조(황산마그네슘)하고 진공에서 농축시켰다. 미정제 생성물(7.7g) 및 Fmoc-Osu(12.9g, 38.2mmol)을 아세토니트릴과 물(1:1, 75mL)의 혼합물에서 20℃에서 16시간동안 교반하고 환류온도에서 3.5시간동안 교반하였다. 반응혼합물을 부피의 반까지 농축시키고 침전물을 혼합물을 여과함으로써 분리하여 중간체 미정제 생성물 15g을 얻었다.Thionyl chloride (10.3 g, 85 mmol) was added dropwise to an ice cold solution of 3-amino-4-methoxybenzoic acid (9.48 g, 56.7 mmol) in methanol (180 mL). After this time, the reaction mixture was stirred for 16 h at 20 ° C. and concentrated in vacuo. Ethyl acetate (100 mL) and saturated solution of sodium hydrogen carbonate (100 mL) were added and the organic phase was washed with saturated solution of sodium hydrogen carbonate (2 × 40 mL), dried (magnesium sulfate) and concentrated in vacuo. The crude product (7.7 g) and Fmoc-Osu (12.9 g, 38.2 mmol) were stirred for 16 h at 20 ° C. and 3.5 h at reflux in a mixture of acetonitrile and water (1: 1, 75 mL). The reaction mixture was concentrated to half the volume and the precipitate was separated by filtration to give 15 g of intermediate crude product.

생성물(5g, 12mmol)을 디클로로메탄(400mL)에 질소하에서 용해시키고 수소화디이소부틸알루미늄의 용액(38mL, 톨루엔중 1.2M)을 0-5℃에서 적가하였다. 반응혼합물을 20℃에서 16시간동안 교반하고 물(23mL)을 0-5℃에서 적가하여 급냉하였다. 반응혼합물을 20℃에서 1.5시간 교반하고 여과시켰다. 여과물을 진공에서 농축하여 중간체 생성물 4.9g을 얻었다. 생성물(4.9g)을 디클로로메탄(180mL)에 현탁시키고 2산화망간(11.2g, 129mmol)을 가하였다. 혼합물을 20℃에서 16시간동안 교반하고 여과시켰다. 여과물을 진공에서 농축시켜 미정제 생성물 4.3g을 얻고 에틸아세테이트와 n-헵탄(3:7)을 사용하는 실리카겔(150g)상에서 정제하여 표제의 화합물 1.9g을 얻었다.The product (5 g, 12 mmol) was dissolved in dichloromethane (400 mL) under nitrogen and a solution of diisobutylaluminum hydride (38 mL, 1.2 M in toluene) was added dropwise at 0-5 ° C. The reaction mixture was stirred at 20 ° C. for 16 hours and quenched by dropwise addition of water (23 mL) at 0-5 ° C. The reaction mixture was stirred at 20 ° C. for 1.5 hours and filtered. The filtrate was concentrated in vacuo to give 4.9 g of intermediate product. The product (4.9 g) was suspended in dichloromethane (180 mL) and manganese dioxide (11.2 g, 129 mmol) was added. The mixture was stirred at 20 ° C. for 16 h and filtered. The filtrate was concentrated in vacuo to give 4.3 g of crude product, which was purified on silica gel (150 g) using ethyl acetate and n-heptane (3: 7) to give 1.9 g of the title compound.

융점. 139-142℃Melting point. 139-142 ℃

HPLC (방법 1) Rt= 29.8 분HPLC (method 1) R t = 29.8 min

미량분석: 계산치: C, 73.98; H, 5.13; N, 3.75%Microanalysis: calcd: C, 73.98; H, 5.13; N, 3.75%

실측치: C, 73.45; H, 5.17; N, 3.72%Found: C, 73.45; H, 5. 17; N, 3.72%

실시예 804:Example 804:

N-(4-[3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐)-2-(4-트리플루오로메톡시페녹시)아세트아미드N- (4- [3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl) -2- (4-trifluoromethoxyphenoxy) acetamide

단계 1: 알데히드 [빌딩블록 2]의 수지[빌딩블록 1]에의 결합Step 1: Binding of Aldehyde [Building Block 2] to Resin [Building Block 1]

수지(3-클로로-4-히드록시벤조산 히드라지드가 부가된 Wang수지) 0.75g을 디메틸포름아미드(6mL)에 30분간 팽창시키고 배출시켰다. 디메틸포름아미드(3mL)에 용해시킨 알데히드 (4-포르밀-3-메톡시페닐)카르밤산 9H-플루오렌-9-일메틸 에스테르(0.5g, 1.36mmol)를 가하고 이어서 트리에틸오르토포르메이트(1.5mL)을 가하였다. 혼합물을 20℃에서 16시간동안 흔들어 섞고 배출시켰다. 수지를 디메틸포름아미드(5x4mL), 디클로로메탄(5x4mL) 및 디메틸포름아미드(5x4mL)로 세척하였다. 알데히드의 결합을 2회 반복하였다.0.75 g of the resin (Wan resin to which 3-chloro-4-hydroxybenzoic acid hydrazide was added) was expanded in dimethylformamide (6 mL) for 30 minutes and discharged. Aldehyde (4-formyl-3-methoxyphenyl) carbamic acid 9H-fluorene-9-ylmethyl ester (0.5 g, 1.36 mmol) dissolved in dimethylformamide (3 mL) was added followed by triethylorthoformate ( 1.5 mL) was added. The mixture was shaken for 16 hours at 20 ° C. and discharged. The resin was washed with dimethylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL). The binding of the aldehyde was repeated twice.

단계 2: 아닐린의 탈보호화Step 2: Deprotection of Aniline

수지를 디메틸포름아미드(5mL)에 팽창시키고 피페리딘(1.25mL)을 가하였다. 30분동안 흔들어 섞은 후, 수지를 배출하고 디메틸포름아미드(5x4mL), N-메틸피롤리디논(5x4mL) 및 디메틸포름아미드(5x4mL)로 세척하였다.The resin was expanded to dimethylformamide (5 mL) and piperidine (1.25 mL) was added. After shaking for 30 minutes, the resin was drained and washed with dimethylformamide (5x4 mL), N-methylpyrrolidinone (5x4 mL) and dimethylformamide (5x4 mL).

단계 3: 산[빌딩블록 3]의 수지[빌딩블록 1][빌딩블록 2]에의 결합Step 3: Binding of Acid [Building Block 3] to Resin [Building Block 1] [Building Block 2]

수지[빌딩블록 1][빌딩블록 2]를 디메틸포름아미드(2.5mL)에 팽창시키고 산(4-트리플루오로메톡시)페녹시 아세트산(0.64g, 2.7mmol)을 디이소프로필카르보디이미드(0.21mL)와 함께 가하였다. 5분간 흔들어 섞은 후, 디메틸아미노피리딘(0.34mL)을 가하고 혼합물을 3시간동안 흔들어 섞고 배출시켰다. 수지를 디메틸포름아미드(5x4mL), 디클로로메탄(5x4mL) 및 디메틸포름아미드(5x4mL)로 세척하였다. 산의 결합을 반복을 위한 16시간의 반응시간을 가지고 2회 반복하였다.The resin [Building Block 1] [Building Block 2] was expanded in dimethylformamide (2.5 mL) and the acid (4-trifluoromethoxy) phenoxy acetic acid (0.64 g, 2.7 mmol) was diisopropylcarbodiimide (0.21 mL). After shaking for 5 minutes, dimethylaminopyridine (0.34 mL) was added, and the mixture was shaken for 3 hours and discharged. The resin was washed with dimethylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL). Acid binding was repeated twice with a 16 hour reaction time for the repetition.

단계 4: 수지로부터의 절단Step 4: Cutting from Resin

수지를 디클로로메탄(2.5mL)에 팽창시키고 트리플루오로아세트산(2.5mL)을 가하였다. 1시간동안 흔들어 섞은 후, 수지를 배출하였다. 용리액을 수집하고 진공에서 농축시켰다. 잔여물을 메탄올로부터 결정화하여 표제의 화합물 0.2g을 얻었다.The resin was expanded to dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was added. After shaking for 1 hour, the resin was discharged. Eluent was collected and concentrated in vacuo. The residue was crystallized from methanol to give 0.2 g of the title compound.

융점. 235-236.5℃Melting point. 235-236.5 ℃

HPLC-MS (방법 A) Rt= 13.5 분 m/z = 538HPLC-MS (Method A) R t = 13.5 min m / z = 538

미량분석: 계산치: C, 53.59; H, 3.56; N, 7.81%Microanalysis: calcd: C, 53.59; H, 3.56; N, 7.81%

실측치: C, 53.57; H, 3.58; N, 7.51%Found: C, 53.57; H, 3.58; N, 7.51%

게다가, 상기 목록된 빌딩블록([빌딩블록 1], [빌딩블록 2] 및 [빌딩블록 3]의 모든 가능한 화합물의 조합의 라이브러리를 합성장치의 작동을 조절하기 ㅜ이한 다음의 ChemFile을 사용하여 Advanced ChemTech Model 384 HTS상에서 상기 실시예와 동일하게 개개의 개체로서 병렬적으로 제조하였다. 화합물은 각 웰에 존재하는 것으로 ㅂ모두 기대된다.In addition, a library of combinations of all possible compounds of the building blocks listed above ([Building Block 1], [Building Block 2] and [Building Block 3]) can be used using the following ChemFile to control the operation of the synthesizer. Prepared in parallel as individual individuals on the Advanced ChemTech Model 384 HTS in the same manner as in the above example Compounds are expected to be present in each well.

4개의 [빌딩블록 2]알데히드, (4-포르밀-3-메톡시페닐)카르밤산 9H-플루오렌 9-일메틸에스테르, (4-포르밀-2-메톡시페닐)카르밤산 9H-플루오렌-9-일메틸에스테르, 3-(tert-부틸디메틸실란일옥시)-4-포르밀페닐)카르밤산 9H-플루오렌-9-일메틸에스테르 및 (5-포르밀-2-메톡시페닐)카르밤산 9H-플루오렌-9-일메틸에스테르를 상기 실시예 단계 1에 기재된 바와 동일한 방법을 사용하여 수지가 결합된 3-클로로-4-히드록시벤조산 히드라지드(수지-[빌딩블록 1])의 4개의 개개의 배치에 결합시킨다. 이어서 아닐리노기의 Fmoc 탈보호화를 상기 실시예 단계 2에 기재된 바와 같이 수행하였다.4 [building block 2] aldehyde, (4-formyl-3-methoxyphenyl) carbamic acid 9H-fluorene 9-ylmethylester, (4-formyl-2-methoxyphenyl) carbamic acid 9H-flu Oren-9-ylmethyl ester, 3- (tert-butyldimethylsilanyloxy) -4-formylphenyl) carbamic acid 9H-fluorene-9-ylmethyl ester and (5-formyl-2-methoxyphenyl Carbamic Acid 9H-Fluoren-9-ylmethylester was prepared in the same manner as described in Example 1, above, in which the resin was bound to 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1] ) Into four separate batches. Fmoc deprotection of the alino group was then performed as described in Example Step 2 above.

이렇게 제조된 4개의 서로 다른 수지[빌딩블록 1][빌딩블록 2]를 장치를 초기화하기전에 합성장치내 웰에 동등하게 분배하였다. 상기 언급된 [빌딩블록 3]의 열의 부착은 상기 실시예 단계 3에 기재된 바와 같은 일반적인 방법을 사용하여 4개의 유형의 수지[빌딩블록 1][빌딩블록 2]와 완전히 조합적인 방식으로 수행하였따. 최종 절단은 상기 실시예 단계 4에 기재된 바와 같은 동일한 일반적인 방법을 사용하여 수행하였다. 이 절단단계동안에, 산에 민감한 보호기의 탈보호화가 또한 일어났다. 이들 2단계 3 및 4는 장치를 조절하기 위한 하기 ChemFile을 사용하여 ACT 496 자동화 합성장치에서 수행하였다(여러번 작동).The four different resins [Building Block 1] [Building Block 2] thus prepared were equally distributed to the wells in the synthesis apparatus prior to initializing the apparatus. The attachment of the columns of [building block 3] mentioned above was carried out in a completely combined manner with the four types of resins [building block 1] [building block 2] using the general method as described in Example step 3 above. . Final cleavage was performed using the same general method as described in Example Step 4 above. During this cleavage step, deprotection of acid sensitive protecting groups also occurred. These two steps 3 and 4 were performed on the ACT 496 automated synthesizer using the following ChemFile to control the device (multiple operations).

ChemFile: C:\DATA\90250017.CHMChemFile: C: \ DATA \ 90250017.CHM

1 Empty RB1to96 for 2.000 minute(s)1 Empty RB1to96 for 2.000 minute (s)

2 Flush Arm1 with NMParm1 and DCMarm12 Flush Arm1 with NMParm1 and DCMarm1

33

4 REM Adding acids 1 to 364 REM Adding acids 1 to 36

55

6 Dispense Sequence C:\act\ACID1-36.DSP with 1000ul to RB1to96 rack using NMParm16 Dispense Sequence C: \ act \ ACID1-36.DSP with 1000ul to RB1to96 rack using NMParm1

7 Mix for 2.00 minutes at 600 rpm(s)7 Mix for 2.00 minutes at 600 rpm (s)

8 Pause8 Pause

9 Mix for 2.00 minutes at 600 rpm(s)9 Mix for 2.00 minutes at 600 rpm (s)

1010

11 REM Adding acids 37 to 4811 REM Adding acids 37 to 48

1212

13 Dispense Sequence ACI37-48.DSP with 1000ul to RB1to96 rack using NMParm113 Dispense Sequence ACI37-48.DSP with 1000ul to RB1to96 rack using NMParm1

14 Mix for 2.00 minutes at 600 rpm(s)14 Mix for 2.00 minutes at 600 rpm (s)

1515

16 Pause16 Pause

1717

18 REM Adding DIC18 REM Adding DIC

1919

20 Transfer 300ul from Monomer1to36[12]() to RB1to96[2-48] using NMParm120 Transfer 300ul from Monomer1to36 [12] () to RB1to96 [2-48] using NMParm1

21 Mix for 2.00 minutes at 600 rpm(s)21 Mix for 2.00 minutes at 600 rpm (s)

22 Transfer 300ul from Monomer1to36[13]() to RB1to96[50-96] using NMParm122 Transfer 300ul from Monomer1to36 [13] () to RB1to96 [50-96] using NMParm1

23 Mix for 10.00 minutes at 600 rpm(s)23 Mix for 10.00 minutes at 600 rpm (s)

2424

25 REM Adding DMAP25 REM Adding DMAP

2626

27 Transfer 200ul from Monomer1to36[14]() to RB1to96[2-48] using NMParm127 Transfer 200ul from Monomer1to36 [14] () to RB1to96 [2-48] using NMParm1

28 Transfer 200ul from Monomer1to36[14]() to RB1to96[50-96] using NMParm128 Transfer 200ul from Monomer1to36 [14] () to RB1to96 [50-96] using NMParm1

2929

30 REM Mixing overnight30 REM Mixing overnight

3131

32 Mix for 10.00 minutes at 600 rpm(s)32 Mix for 10.00 minutes at 600 rpm (s)

33 Wait for 20.000 minute(s)33 Wait for 20.000 minute (s)

34 Repeat from step 32, 150 times34 Repeat from step 32, 150 times

3535

36 REM wash36 REM wash

3737

38 Empty RB1to96 for 2.000 minute(s)38 Empty RB1to96 for 2.000 minute (s)

39 Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96]39 Dispense System Fluid NMPdualarms * 1000ul to RB1to96 [1-96]

40 Mix for 3.00 minutes at 600 rpm(s)40 Mix for 3.00 minutes at 600 rpm (s)

41 Empty RB1to96 for 2.000 minute(s)41 Empty RB1to96 for 2.000 minute (s)

42 Repeat from step 39, 5 times42 Repeat from step 39, 5 times

4343

44 REM de fmoc44 REM de fmoc

45 Mix for 3.00 minutes at 600 rpm(s)45 Mix for 3.00 minutes at 600 rpm (s)

46 Dispense Sequence C:\act\DEFMOC.DSP with 1500ul to RB1to96 rack using NMParm146 Dispense Sequence C: \ act \ DEFMOC.DSP with 1500ul to RB1to96 rack using NMParm1

47 Mix for 15.00 minutes at 600 rpm(s)47 Mix for 15.00 minutes at 600 rpm (s)

48 Empty RB1to96 for 3.000 minute(s)48 Empty RB1to96 for 3.000 minute (s)

49 Empty RB1to24 for 3.000 minute(s)49 Empty RB1to24 for 3.000 minute (s)

50 Empty RB49to72 for 2.000 minute(s)50 Empty RB49to72 for 2.000 minute (s)

51 Pause51 Pause

5252

53 REM wash53 REM wash

54 Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96]54 Dispense System Fluid NMPdualarms * 1000ul to RB1to96 [1-96]

55 Mix for 3.00 minutes at 600 rpm(s)56 Empty RB1to96 for 3.000 minute(s)55 Mix for 3.00 minutes at 600 rpm (s) 56 Empty RB1to96 for 3.000 minute (s)

57 Repeat from step 54, 2 times57 Repeat from step 54, 2 times

58 Flush Arm1 with NMParm1 and DCMarm1, Arm2 with DCMarm258 Flush Arm1 with NMParm1 and DCMarm1, Arm2 with DCMarm2

59 Dispense System Fluid DCMdualarm* 1000ul to RB1to96[1-96]59 Dispense System Fluid DCMdualarm * 1000ul to RB1to96 [1-96]

60 Mix for 3.00 minutes at 600 rpm(s)60 Mix for 3.00 minutes at 600 rpm (s)

61 Empty RB1to96 for 3.000 minute(s)61 Empty RB1to96 for 3.000 minute (s)

62 Repeat from step 59, 5 times62 Repeat from step 59, 5 times

6363

64 REM TFA CLEAVAGE64 REM TFA CLEAVAGE

6565

66 Mix for 1.00 minutes at 300 rpm(s)66 Mix for 1.00 minutes at 300 rpm (s)

67 Transfer 1000ul from Reagent2[1]() to RBcleavage1to96[1-96] using DCMarm167 Transfer 1000ul from Reagent2 [1] () to RBcleavage1to96 [1-96] using DCMarm1

68 Mix for 1.00 hours at 600 rpm(s)68 Mix for 1.00 hours at 600 rpm (s)

69 Empty RBcleavage1to96 for 30 second(s)69 Empty RBcleavage1to96 for 30 second (s)

70 Dispense System Fluid DCMdualarm* 500ul to RBcleavage1to96[1-96]70 Dispense System Fluid DCMdualarm * 500ul to RBcleavage1to96 [1-96]

71 Mix for 5.00 minutes at 300 rpm(s)71 Mix for 5.00 minutes at 300 rpm (s)

72 Empty RBcleavage1to96 for 30 second(s)72 Empty RBcleavage1to96 for 30 second (s)

7373

Dispense sequence 화일 C:\act\ACID1-36.DSP은 합성장치내 96웰을 각각 포함하는 4개의 반응블록에의 아민의 조합적 첨가를 조절하는 서브루틴이다.Dispense sequence file C: \ act \ ACID1-36.DSP is a subroutine that controls the combinatorial addition of amines to four reaction blocks each containing 96 wells in a synthesiser.

이 라이브러리로부터의 화합물의 실시예는 HPLC-MS(분자량 & 체류시간)으로 특성규명되고 다음을 포함한다:Examples of compounds from this library are characterized by HPLC-MS (molecular weight & residence time) and include:

실시예 805:Example 805:

퀴놀린-2-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}아미드Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} amide

융점 236-238℃Melting point 236-238 ℃

HPLC-MS (방법 1) Rt=26.2 분HPLC-MS (method 1) R t = 26.2 bun

실시예 806:Example 806:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-2-메톡시페닐}-2-(4-트리플루오로메톡시페노일)아세트아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -2-methoxyphenyl} -2- (4-trifluoromethoxyphenoyl) acetamide

융점 216-218℃Melting point 216-218 ℃

HPLC(방법 1) Rt=26.6분HPLC (method 1) R t = 26.6 min

실시예 807:Example 807:

퀴놀린-2-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-2-메톡시페닐}아미드Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -2-methoxyphenyl} amide

융점 159-162℃Melting point 159-162 ℃

HPLC(방법 1) Rt=27.7분HPLC (method 1) R t = 27.7 min

실시예 808:Example 808:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-2-(4-클로로페녹시)아세트아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -2- (4-chlorophenoxy) acetamide

융점 216-218℃Melting point 216-218 ℃

HPLC-MS(방법 A) Rt=27.7분, m/Z=488HPLC-MS (Method A) R t = 27.7 min, m / Z = 488

실시예 809:Example 809:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-6-메틸니코틴아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -6-methylnicotinamide

HPLC-MS (방법 A) Rt=8.2 분, m/z=439HPLC-MS (Method A) R t = 8.2 min, m / z = 439

실시예 810:Example 810:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-2-(3-트리플루오로메틸페닐)아세트아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -2- (3-trifluoromethylphenyl) acetamide

HPLC-MS (방법 A) Rt=13.4 분, m/z=506HPLC-MS (Method A) R t = 13.4 min, m / z = 506

실시예 811:Example 811:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-2-(2,4-디클로로페녹시)아세트아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -2- (2,4-dichlorophenoxy) acetamide

HPLC-MS (방법 A) Rt=14.3 분, m/z=524HPLC-MS (Method A) R t = 14.3 min, m / z = 524

실시예 812:Example 812:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-3-(4-트리플루오로메틸페닐)프로피온아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -3- (4-trifluoromethylphenyl) propionamide

HPLC-MS (방법 A) Rt=14.0 분, m/z=520HPLC-MS (Method A) R t = 14.0 min, m / z = 520

실시예 813:Example 813:

이소퀴놀린-1-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}아미드Isoquinoline-1-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} amide

HPLC-MS (방법 A) Rt=13.0 분, m/z=475HPLC-MS (Method A) R t = 13.0 min, m / z = 475

실시예 814:Example 814:

7-에톡시벤조푸란-2-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}아미드7-ethoxybenzofuran-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} amide

HPLC-MS (방법 A) Rt=13.3 분, m/z=508HPLC-MS (Method A) R t = 13.3 min, m / z = 508

실시예 815:Example 815:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-2-(톨루엔-4-술로닐)아세트아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -2- (toluene-4-sulonyl) acetamide

HPLC-MS (방법 A) Rt=10.8 분, m/z=517HPLC-MS (Method A) R t = 10.8 min, m / z = 517

실시예 816:Example 816:

벤조푸란-2-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-아미드Benzofuran-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -amide

HPLC-MS (방법 A) Rt=12.3 분, m/z=465HPLC-MS (Method A) R t = 12.3 min, m / z = 465

실시예 817:Example 817:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}-3-시아노벤즈아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} -3-cyanobenzamide

HPLC-MS (방법 A) Rt=10.8 분, m/z=450HPLC-MS (Method A) R t = 10.8 min, m / z = 450

실시예 818:Example 818:

5-클로로-4-메톡시티오펜-3-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}아미드5-Chloro-4-methoxythiophene-3-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} amide

HPLC-MS (방법 A) Rt=9.8 분, m/z=495HPLC-MS (Method A) R t = 9.8 min, m / z = 495

실시예 819:Example 819:

5-브로모푸란-2-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-3-메톡시페닐}아미드5-Bromofuran-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -3-methoxyphenyl} amide

HPLC-MS (방법 A) Rt=11.4 분, m/z=494HPLC-MS (Method A) R t = 11.4 min, m / z = 494

실시예 820:Example 820:

2-벤조[b]티엔-3-일-N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-2-메톡시페닐}아세트아미드2-benzo [b] thien-3-yl-N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -2-methoxyphenyl} acetamide

HPLC-MS (방법 A) Rt=13.4 분, m/z=494HPLC-MS (Method A) R t = 13.4 min, m / z = 494

실시예 821:Example 821:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-2-메톡시페닐}-2-(4-클로로페녹시)-2-메틸프로피온아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -2-methoxyphenyl} -2- (4-chlorophenoxy) -2-methylpropionamide

HPLC-MS (방법 A) Rt=14.7 분, m/z=516HPLC-MS (Method A) R t = 14.7 min, m / z = 516

실시예 822:Example 822:

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-2-메톡시페닐}-3-(3-트리플루오로메틸페닐)아크릴아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -2-methoxyphenyl} -3- (3-trifluoromethylphenyl) acrylamide

HPLC-MS (방법 A) Rt=14.3 분, m/z=518HPLC-MS (Method A) R t = 14.3 min, m / z = 518

실시예 823Example 823

N-{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-2-메톡시페닐}-2-플루오로-3-페닐아크릴아미드N- {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -2-methoxyphenyl} -2-fluoro-3-phenylacrylamide

HPLC-MS (방법 A) Rt=14.3 분, m/z=468HPLC-MS (Method A) R t = 14.3 min, m / z = 468

실시예 824:Example 824:

2-벤조[b]티에오펜-2-카르복실산{4-[(3-클로로-4-히드록시벤조일)히드라조노메틸]-2-메톡시페닐}아미드2-benzo [b] thiophene-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl] -2-methoxyphenyl} amide

HPLC-MS (방법 A) Rt=13.8 분, m/z=480HPLC-MS (Method A) R t = 13.8 min, m / z = 480

HPLC 방법 1.HPLC Method 1.

RP-HPLC 분석은 254nm에서 UV 검출기와 Merck Hibar LiChrosorb RP-18(5㎛) 미리 팩킹된 컬럼(Cat. No. 50333)을 사용하여 수행하였다. 컬럼은 1mL/분에서 유출시켰다. 2개의 용매계를 사용하였다:RP-HPLC analysis was performed using a UV detector and Merck Hibar LiChrosorb RP-18 (5 μm) prepacked column (Cat. No. 50333) at 254 nm. The column flowed out at 1 mL / min. Two solvent systems were used:

용매계 I: 아세토니트릴중 0.1% 트리플루오로아세트산. 용매계 II: 물중 0.1% 트리플루오로아세트산.Solvent system I: 0.1% trifluoroacetic acid in acetonitrile. Solvent System II: 0.1% trifluoroacetic acid in water.

컬럼을 용매계 I 20%와 용매계 II 80%로 구성되는 혼합물로 평형화하였다. 샘플을 주입한 후, 용매계 II중 20%의 용매계 I 에서 80%까지의 구배를 30분에 걸처서 유출시켰다. 그런 다음 구배를 5분에 걸쳐서 용매계 I 100%로 연장시키고 이어서 이 계 100%로 6분동안 동등하게 유출시켰다.The column was equilibrated with a mixture consisting of 20% solvent system I and 80% solvent system II. After injecting the sample, a gradient of 20% Solvent System I to 80% in Solvent System II was allowed to flow over 30 minutes. The gradient was then extended to 100% of solvent system I over 5 minutes and then flowed equally to 100% of this system for 6 minutes.

실시예 825 내지 875를 위한 일반적인 방법:General Method for Examples 825-875:

이 화합물은 다음의 식This compound is of the formula

수지-[빌딩블록 1] →Resin- [Building Block 1] →

수지-[빌딩블록 1]-[빌딩블록 2] →Resin- [Building Block 1]-[Building Block 2] →

수지-[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3]Resin- [Building Block 1]-[Building Block 2]-[Building Block 3]

에 따라서 단일체로서 제조하였고 동시에 탈보호화하고 디클로로메탄중 50% 트리플루오로아세트산으로 수지로부터 절단하여 다음 식Prepared as a monolith and simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane

[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3][Building Block 1]-[Building Block 2]-[Building Block 3]

에 따르는 개개의 개체로서 원하는 화합물을 얻었다.The desired compound was obtained as an individual object according to the present invention.

다음의 화합물은 고체 지지체 상에서 병렬적 합성에 의해 단일체로서 제조되었다. 수지-[빌딩블록 1]-[빌딩블록 2]의 제조는 수동으로 하였고, 반면 [빌딩블록 3]의 부착과 수지로부터의 절단은 Advanced ChemTech Model 384 HTS상에서 수행하였다.The following compounds were prepared as monoliths by parallel synthesis on a solid support. Preparation of Resin- [Building Block 1]-[Building Block 2] was done manually, whereas attachment of [Building Block 3] and cleavage from the resin were performed on Advanced ChemTech Model 384 HTS.

출발 수지, 수지-[빌딩블록 1]는 하기 기재된 바와 같이 제조되었다.Starting resin, Resin- [Building Block 1], was prepared as described below.

사용된 수지는 Wang 링커를 가지는 폴리스티렌 수지이고 치환용량은 0.9mmol/g이었다.The resin used was a polystyrene resin with Wang linker and a substitution capacity of 0.9 mmol / g.

모든 화합물은 완전히 조합적 방식으로 다음 반응식에 따르는 친핵성 치환 반응을 사용하여 [빌딩블록 2] 및 [빌딩블록 3]의 수지-[빌딩블록 1]에의 연속적인 부착을 기본으로 한다. 방응식은 화학식 II와 관련된다:All compounds are based on the continuous attachment of [Building Block 2] and [Building Block 3] to Resin- [Building Block 1] using a nucleophilic substitution reaction according to the following scheme in a completely combinatorial manner. The equation relates to formula II:

(반응식)(Scheme)

및And

상기 식에서, R14및 R15는 화학식 I에서 정의된 바와 같고 -NR5cR5d는(상기 식에서 R5a, R4a, R4b, c, q, d, 및 D는 화학식 I에서 정의된 바와 같다)이거나 친핵기로서 반응할 수 있는 1차 또는 2차 아민을 포함하는 -D의 부분집합으로서 정의된 -D'이고; -SR5c는Wherein R 14 and R 15 are as defined in Formula I and -NR 5c R 5d is A moiety of -D wherein R 5a , R 4a , R 4b , c, q, d, and D are as defined in Formula I or comprising a primary or secondary amine capable of reacting as a nucleophilic group -D 'defined as a set; -SR 5c is

(상기 식에서, R4a, R4b, c, q, d, 및 D는 화학식 I에서 정의된 바와 같다)이거나, 친핵기로서 반응할 수 있는 티올을 포함하는 -D의 부분집합으로서 정의된 -D'이다.(Wherein R 4a , R 4b , c, q, d, and D are as defined in formula (I)) or defined as a subset of -D containing a thiol capable of reacting as a nucleophilic group 'to be.

여기서 수지-[빌딩블록 1]으로서 나타낸 다음의 수지를 사용하였다.The following resin shown here as Resin- [Building Block 1] was used.

상기 식에서 PS는 폴리스티렌이고, 아래에서 "수지"는 Wang 링커를 가진 폴리스티렌 수지이다.Wherein PS is polystyrene and below "resin" is a polystyrene resin with Wang linker.

즉 In other words

다음의 빌딩블록을 사용하였다:The following building blocks were used:

[빌딩블록 2]:[Building Block 2]:

[빌딩블록 3]:[Building Block 3]:

[빌딩블록 1]의 제조:Preparation of [Building Block 1]:

이 수지는 상기 기재된 바와 같이 제조되었다.This resin was prepared as described above.

4-히드록시메틸나프트알데히드([빌딩블록 2])의 제조:Preparation of 4-hydroxymethylnaphthaldehyde ([Building Block 2]):

이 화합물의 제조는 상기 기재되어 있다.The preparation of this compound is described above.

수지-[빌딩블록 1]-[빌딩블록 2]의 제조:Preparation of Resin- [Building Block 1]-[Building Block 2]:

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드의 제조:Preparation of 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide bound with resin:

수지-[빌딩브록 1](4g)을 DMF(40mL)에 현탁시키고 15분간 팽창시킨 다음, DMF(2x40mL), DCM(3x40mL) 및 DMSO(2x40mL)로 세척한다. 용매를 여과하여 제거하였다. 4-히드록시메틸나프트알데히드(1.488g, 8mmol)를 DMSO 40mL에 용해시키고 수지에 가하고 냉 아세트산 4mL를 가하였다. 현탁물을 25℃에서 16시간동안 흔들어 섞었다. 수지를 DMSO(2x40mL), THF(3x40mL), CH3OH(40mL), CH2Cl2(40mL), CH3OH(40mL), CH2Cl2(40mL)로 연속적으로 세척하고 40℃의 진공에서 16시간동안 건조시켜 수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드를 얻었다.Resin- [Building Block 1] (4 g) is suspended in DMF (40 mL) and inflated for 15 min, then washed with DMF (2 × 40 mL), DCM (3 × 40 mL) and DMSO (2 × 40 mL). The solvent was removed by filtration. 4-hydroxymethylnaphthaldehyde (1.488 g, 8 mmol) was dissolved in 40 mL of DMSO, added to the resin and 4 mL of cold acetic acid. The suspension was shaken at 25 ° C. for 16 hours. The resin was washed successively with DMSO (2x40 mL), THF (3x40 mL), CH 3 OH (40 mL), CH 2 Cl 2 (40 mL), CH 3 OH (40 mL), CH 2 Cl 2 (40 mL) and vacuum at 40 ° C. It was dried for 16 hours to give 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide to which the resin was bound.

실시예 825:Example 825:

3-클로로-4-히드록시벤조산(4-(1H-1,2,4-트리아졸-3-일술파닐메틸)나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4- (1H-1,2,4-triazol-3-ylsulfanylmethyl) naphthylmethylene) hydrazide

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드((수지-[빌딩블록 1]-[빌딩블록 2])(2g, ~2mmol)를 CH2Cl2(20mL)에서 15분간 팽창시킨 후, CH2Cl2(20mL)로 세척하였다. CH2Cl2(8mL)와 디이소프로필에틸아민(8mL)를 연속적으로 가하고 현탁물을 0℃에서 냉각시켰다. 염화메탈술포닐(2mL)을 CH2Cl2(6mL)에 용해시키고 현탁물에 가하였다. 혼합물을 0℃에서 30분간 반응시킨 다음 25℃에서 1시간 반응시켰다. 수지를 여과하여 분리하고 CH2Cl2(2x20mL) 및 N-메틸-2-피롤리돈(2x20mL)로 세척하였다. 1H-1,2,4-트리아졸-3-티올(0.8g) 및 KI(0.4g)을 N-메틸-2-피롤리돈 10mL와 디메틸술폭시드 10mL에 용해시키고 수지에 가하였다. 혼합물을 2일동안 25℃에서 흔들어 섞었다. 용매를 흡입하여 제거하고 수지를 N-메틸-2-피롤리돈(3x20mL), THF(3x20mL), CH3OH(20mL), CH2Cl2(20mL), CH3OH(20mL), CH2Cl2(4x20mL)로 세척하였다. 화합물을 CH2Cl2(20mL)중 50% 트리플루오로아세트산의 용액으로 25℃에서 1시간동안 흔들어 섞어 수지로부터 절단하였다. 혼합물을 여과하고 수지를 아세토니트릴(20mL)로 추출하였다. 합한 추출물을 진공에서 농축시켰다. 잔여물을 CH3OH(10mL)와 아세토니트릴(10mL)의 혼합물에 재용해시키고 진공에서 농축시켰다. 잔여물을 CH3OH(4mL)로 25℃에서 처리하여 회백색 침전물을 얻고 여과하여 분리시켰다. 고체를 CH3OH(3x2mL)로 세척하고 40℃의 진공에서 건조시켰다. 표제의 화합물 275mg을 얻었다.3-chloro-4-hydroxybenzoic acid the resin is combined (4-hydroxymethyl-naphthyl-methylene) hydrazide ((Resin - [Building block 1] - [Building block 2]) (2g, ~ 2mmol ) a CH 2 after 15 minutes swelling in Cl 2 (20mL), CH 2 Cl and washed with 2 (20mL). CH 2 Cl 2 (8mL) and di-isopropyl cooling the suspension were added successively ethyl amine (8mL) at 0 ℃ Metal sulfonyl chloride (2 mL) was dissolved in CH 2 Cl 2 (6 mL) and added to the suspension The mixture was reacted at 0 ° C. for 30 minutes and then at 25 ° C. for 1 hour. Washed with CH 2 Cl 2 ( 2 × 20 mL) and N-methyl-2-pyrrolidone (2 × 20 mL) 1H-1,2,4-triazole-3-thiol (0.8 g) and KI (0.4 g) 10 mL of methyl-2-pyrrolidone and 10 mL of dimethylsulfoxide were added to the resin and the mixture was shaken for 2 days at 25 ° C. The solvent was aspirated off and the resin was removed with N-methyl-2-pyrroli. Don (3x20 mL), THF (3x20 mL), CH 3 OH (20 mL), CH 2 Cl 2 (20 mL), CH 3 OH (20 mL), CH 2 Cl 2 (4 × 20 mL) The compound was shaken for 1 h at 25 ° C. with a solution of 50% trifluoroacetic acid in CH 2 Cl 2 (20 mL). The mixture was filtered and the resin extracted with acetonitrile (20 mL) The combined extracts were concentrated in vacuo The residue was redissolved in a mixture of CH 3 OH (10 mL) and acetonitrile (10 mL) and vacuumed The residue was treated with CH 3 OH (4 mL) at 25 ° C. to yield an off white precipitate which was separated by filtration The solid was washed with CH 3 OH ( 3 × 2 mL) and dried in vacuo at 40 ° C. The title compound 275 mg were obtained.

HPLC-MS (방법 B): Rt = 2.48 분; m/z = 438 (M+1).HPLC-MS (Method B): Rt = 2.48 min; m / z = 438 (M + l).

1H-NMR (300 MHz, DMSO-d6) δ = 4.9 (2H, s), 7.1 (1H, d),7.5-7.9 (5H, m), 8.0 (1H, s), 8.25 (1H, d), 8.9 (1H, d), 9.1 (1H, s), 11.0 (1H, s), 11.8 (1H, s) 1 H-NMR (300 MHz, DMSO-d 6 ) δ = 4.9 (2H, s), 7.1 (1H, d), 7.5-7.9 (5H, m), 8.0 (1H, s), 8.25 (1H, d ), 8.9 (1H, d), 9.1 (1H, s), 11.0 (1H, s), 11.8 (1H, s)

실시예 826:Example 826:

3-클로로-4-히드록시벤조산(4-(이소부틸아미노메틸)나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid (4- (isobutylaminomethyl) naphthylmethylene) hydrazide

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드((수지-[빌딩블록 1]-[빌딩블록 2])(50mg, ~0.05mmol)를 CH2Cl2(1mL)에서 15분간 팽창시킨 후, CH2Cl2(2x0.5mL)로 세척하였다. CH2Cl2(0.4mL)와 디이소프로필에틸아민(0.4mL)를 연속적으로 가하고 현탁물을 0℃에서 냉각시켰다. 염화메탈술포닐(0.1mL)을 CH2Cl2(0.3mL)에 용해시키고 현탁물에 가하였다. 혼합물을 0℃에서 30분간 반응시킨 다음 25℃에서 1시간 반응시켰다. 수지를 여과하여 분리하고 CH2Cl2(2x0.5mL) 및 DMSO(0.5mL)로 세척하였다. DMSO(0.5mL)를 가하고 이소부틸아민 50㎕, 디이소프로필에틸아민 100㎕를 가하였다. 혼합물을 16시간동안 25℃에서 흔들어 섞고 여과하고 DMSO(2x0.5mL), THF(3x0.5mL), CH3OH(0.5mL), CH2Cl2(0.5mL), CH3OH(0.5mL), CH2Cl2(4x0.5mL)로 세척하였다. 화합물을 CH2Cl2(1mL)중 50% 트리플루오로아세트산의 용액으로 25℃에서 1시간동안 흔들어 섞어 수지로부터 절단하였다. 혼합물을 여과하고 수지를 아세토니트릴(1mL)로 추출하였다. 합한 추출물을 진공에서 농축시켰다. 잔여물을 CH3OH(0.5mL)와 아세토니트릴(0.5mL)의 혼합물에 재용해시키고 진공에서 농축시켜 표제의 화합물을 얻었다.Resin-coupled 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide ((resin- [building block 1]-[building block 2]) (50 mg, ˜0.05 mmol) 2 after 15 minutes from the expansion Cl 2 (1mL), CH 2 Cl and washed with 2 (2x0.5mL). CH 2 Cl 2 (0.4mL) and diisopropylethylamine were added successively with the amine (0.4mL) suspension of The metal sulfonyl chloride (0.1 mL) was dissolved in CH 2 Cl 2 (0.3 mL) and added to the suspension The mixture was reacted at 0 ° C. for 30 minutes and then at 25 ° C. for 1 hour. The resin was separated by filtration and washed with CH 2 Cl 2 ( 2 × 0.5 mL) and DMSO (0.5 mL) DMSO (0.5 mL) was added and 50 μl of isobutylamine and 100 μl of diisopropylethylamine were added. The mixture was shaken for 16 h at 25 ° C., filtered and filtered, DMSO (2 × 0.5 mL), THF ( 3 × 0.5 mL), CH 3 OH (0.5 mL), CH 2 Cl 2 (0.5 mL), CH 3 OH (0.5 mL) Washed with CH 2 Cl 2 (4 × 0.5 mL) The compound was washed in CH 2 Cl 2 (1 mL). % Trifluoroacetic with a solution of ethyl shaking for 1 hour at 25 ℃ was cleaved from the resin. The mixture was filtered and extracted the resin in acetonitrile (1mL). The combined extracts were concentrated in vacuo. The residue CH 3 OH (0.5 mL) and acetonitrile (0.5 mL) were redissolved and concentrated in vacuo to afford the title compound.

HPLC-MS (방법 B): Rt = 4.20 분; m/z = 410 (M+1)HPLC-MS (Method B): Rt = 4.20 min; m / z = 410 (M + 1)

실시예 827:Example 827:

3-클로로-4-히드록시벤조산((4-(4-트리플루오로메톡시벤질아미노)메틸)나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid ((4- (4-trifluoromethoxybenzylamino) methyl) naphthylmethylene) hydrazide

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드:(수지-[빌딩블록 1]-[빌딩블록 2])(50mg)을 CH2Cl2와 N-메틸-2-피롤리돈(0.5mL)의 1:1 혼합물에서 15분동안 팽창시키고 CH2Cl2(3x0.5mL)로 세척하였다. CH2Cl2와 디이소프로필에틸아민의 1:1 혼합물 800㎕를 수지에 가하고 이어서 -3℃에서 냉각시켰다. 300㎕에 용해시킨 염화메탄술포닐 100㎕의용액을 가하고 -30℃에서 30분동안 반응시킨 다음 25℃에서 1시간동안 반응시켰다. 수지를여과하고 CH2Cl2(2x1mL)와 N-메틸-2피롤리돈(2x0.5mL)으로 세척하였다. N-메틸-2피롤리돈(0.5mL) 및 디이소프로필에틸아민(0.1mL)중 4-트리플루오로메톡시벤질아민 (45.8mg, 0.24mmol, 0.4M) 및 KI(10mg, 0.06mmol, 0.1M)의 용액 600㎕를 가하고 25℃에서 16시간동안 반응시켰다. 수지를 여과하여 분리하고 N-메틸-2-피롤리돈(5x0.5mL), THF(3x0.8mL), CH3OH(0.8mL), CH2Cl2(0.8mL), CH3OH(0.8mL) 및 CH2Cl2(3x0.8mL)로 세척하였다. 화합물을 CH2Cl2(1mL)중 50% 트리플루오로아세트산의 용액으로 25℃에서 1시간동안 흔들어 섞어 수지로부터 절단하였다. 혼합물을 여과하고 수지를 아세토니트릴(1mL)로 추출하였다. 합한 추출물을 진공에서 농축시켰다. 잔여물을 CH3OH(0.5mL)와 아세토니트릴(0.5mL)의 혼합물에 재용해시키고 진공에서 농축시켜 표제의 화합물을 얻었다.3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide bound with resin: (resin- [building block 1]-[building block 2]) (50 mg) was mixed with CH 2 Cl 2 Swell for 15 minutes in a 1: 1 mixture of N-methyl-2-pyrrolidone (0.5 mL) and wash with CH 2 Cl 2 (3 × 0.5 mL). 800 μl of a 1: 1 mixture of CH 2 Cl 2 and diisopropylethylamine was added to the resin and then cooled at −3 ° C. A solution of 100 µl of methanesulfonyl chloride dissolved in 300 µl was added and reacted at -30 ° C for 30 minutes, and then at 25 ° C for 1 hour. The resin was filtered and washed with CH 2 Cl 2 ( 2 × 1 mL) and N-methyl-2pyrrolidone ( 2 × 0.5 mL). 4-trifluoromethoxybenzylamine (45.8 mg, 0.24 mmol, 0.4 M) and KI (10 mg, 0.06 mmol, 0.1 in N-methyl-2pyrrolidone (0.5 mL) and diisopropylethylamine (0.1 mL) 600 μl of M) solution was added and reacted at 25 ° C. for 16 hours. The resin was isolated by filtration, N-methyl-2-pyrrolidone (5x0.5 mL), THF (3x0.8 mL), CH 3 OH (0.8 mL), CH 2 Cl 2 (0.8 mL), CH 3 OH (0.8 mL) and CH 2 Cl 2 (3 × 0.8 mL). The compound was cleaved from the resin by shaking for 1 h at 25 ° C. with a solution of 50% trifluoroacetic acid in CH 2 Cl 2 (1 mL). The mixture was filtered and the resin extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH 3 OH (0.5 mL) and acetonitrile (0.5 mL) and concentrated in vacuo to afford the title compound.

HPLC-MS (방법 A): Rt = 10.07 분; m/z = 528 (M+1)HPLC-MS (Method A): Rt = 10.07 min; m / z = 528 (M + 1)

실시예 828 내지 875:Examples 828-875:

상기 목록된 빌딩블록([빌딩블록 1], [빌딩블록 2] 및 [빌딩블록 3]의 모든 가능한 조합의 화합물의 라이브러리를 합성장치의 작동을 조절하기 위한 다음의 ChemFile을 사용하여 Advanced ChemTech Model 384 HTS상에서 상기 실시예와 동일하게 개개의 개체로서 병렬적으로 제조하였다. 화합물은 각 웰에 존재하는 것으로 모두 기대된다.A library of all possible combinations of the building blocks listed above ([Building Block 1], [Building Block 2] and [Building Block 3]) was developed using Advanced ChemTech Model 384 using the following ChemFile to control the operation of the synthesizer. Prepared in parallel as individual individuals on HTS as in the above examples Compounds are expected to be present in each well.

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드: CH2Cl2와 N-메틸-2-피롤리돈(0.5mL)의 1:1 혼합물중 (수지-[빌딩블록 1]-[빌딩블록 2])(50mg)를 장치를 초기화하기 전에 합성장치내 각 웰에 동등하게 분배한다.3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide bound with resin: in a 1: 1 mixture of CH 2 Cl 2 and N-methyl-2-pyrrolidone (0.5 mL) (Resin- [Building Block 1]-[Building Block 2]) (50 mg) is equally distributed to each well in the synthesis apparatus before initialization of the apparatus.

ChemFile C:\ACT_1328\MAIN.CHMChemFile C: \ ACT_1328 \ MAIN.CHM

1 REM Nucleophilic displacement of benzylic alcohol1 REM Nucleophilic displacement of benzylic alcohol

2 REM via mesylation2 REM via mesylation

33

44

5 REM Dipense resin bound benzylic alchohol to wells5 REM Dipense resin bound benzylic alchohol to wells

66

77

8 REM Setup Diluter1=DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM8 REM Setup Diluter1 = DCM, D2 = NMP (N-methyl-2-pyrrolidone), D3 = NMP, D4 = DCM

9 REM Adjust pressure9 REM Adjust pressure

10 REM Add 100 mL DIEA/DCM 1:1 mixture to Reagent110 REM Add 100 mL DIEA / DCM 1: 1 mixture to Reagent1

11 REM Add 70 mL MsCl/DCM 1:3 mixture to Reagent211 REM Add 70 mL MsCl / DCM 1: 3 mixture to Reagent2

12 REM Add 100 mL TFA/DCM 1:1 mixture to Reagent312 REM Add 100 mL TFA / DCM 1: 1 mixture to Reagent3

13 REM Add 100 mL CH3CN to Reagent413 REM Add 100 mL CH3CN to Reagent4

14 REM Nitrogen for cooling14 REM Nitrogen for cooling

1515

16 Pause16 Pause

17 REM Initialising...17 REM Initialising ...

1818

19 REM Subroutine Empty1_72_3min is called twice to remove DCM/NMP from dispensed resin19 REM Subroutine Empty1_72_3min is called twice to remove DCM / NMP from dispensed resin

20 Go to ChemFile MTY72_3M.CHM, line 120 Go to ChemFile MTY72_3M.CHM, line 1

21 Go to ChemFile MTY72_3M.CHM, line 121 Go to ChemFile MTY72_3M.CHM, line 1

2222

23 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and with Flush Diluter 423 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter 3 and with Flush Diluter 4

2424

25 REM Washing with DCM, 3 times25 REM Washing with DCM, 3 times

26 Dispense System Fluid Disdu1_4* 500ul to RB1_1to96[1-72]26 Dispense System Fluid Disdu1_4 * 500ul to RB1_1to96 [1-72]

27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm (s) and wait.

28 REM Subroutine Empty1_72_3min28 REM Subroutine Empty1_72_3min

29 Go to ChemFile MTY72_3M.CHM, line 129 Go to ChemFile MTY72_3M.CHM, line 1

30 Repeat from step 26, 2 times30 Repeat from step 26, 2 times

3131

32 REM Adding DCM/DIEA mixture from Reagent132 REM Adding DCM / DIEA mixture from Reagent1

33 Transfer 800ul from REAGENT_1[1](DCM/DIEA) to RB1_1to96[1-72] using Flush Diluter133 Transfer 800ul from REAGENT_1 [1] (DCM / DIEA) to RB1_1to96 [1-72] using Flush Diluter1

34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Tempererature to reach setpoint35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Tempererature to reach setpoint

36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

37 REM Ensure complete cooling37 REM Ensure complete cooling

38 Wait for 15.000 minute(s)38 Wait for 15.000 minute (s)

3939

40 REM Adding mesylchloride40 REM Adding mesylchloride

41 Transfer 400ul from REAGENT_2[1](MsCl/DCM) to RB1_1to96[1-72] using Flush Diluter141 Transfer 400ul from REAGENT_2 [1] (MsCl / DCM) to RB1_1to96 [1-72] using Flush Diluter1

42 REM Reacts 30 min @ -3℃42 REM Reacts 30 min @ -3 ℃

43 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.43 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

44 Wait for 4.000 minute(s)44 Wait for 4.000 minute (s)

45 Repeat from step 43, 5 times45 Repeat from step 43, 5 times

4646

47 REM Reacts 60 min @ 25 C47 REM Reacts 60 min @ 25 C

48 Set Temperature of rack "RB1_1to96" to 25.0 degrees Celsius and wait for Tempererature to reach setpoint48 Set Temperature of rack "RB1_1to96" to 25.0 degrees Celsius and wait for Tempererature to reach setpoint

49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

50 Wait for 4.000 minute(s)50 Wait for 4.000 minute (s)

51 Repeat from step 46, 11 times51 Repeat from step 46, 11 times

5252

53 REM Subroutine Empty1_72_3min53 REM Subroutine Empty1_72_3min

54 Go to ChemFile MTY72_3M.CHM, line 154 Go to ChemFile MTY72_3M.CHM, line 1

5555

56 REM Initiate washing procedure, 2XDCM56 REM Initiate washing procedure, 2XDCM

57 Dispense System Fluid Disdu1_4* 1000ul to RB1_1to96[1-72]57 Dispense System Fluid Disdu1_4 * 1000ul to RB1_1to96 [1-72]

58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm (s) and wait.

59 Go to ChemFile MTY72_3M.CHM, line 159 Go to ChemFile MTY72_3M.CHM, line 1

60 Repeat from step 57, 1 times60 Repeat from step 57, 1 times

6161

62 REM NMP wash62 REM NMP wash

6363

64 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72]64 Dispense System Fluid Disdu2_3 * 500ul to RB1_1to96 [1-72]

65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm(s) and wait.65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm (s) and wait.

66 Go to ChemFile MTY72_3M.CHM, line 166 Go to ChemFile MTY72_3M.CHM, line 1

6767

68 Go to ChemFile MTY72_3M.CHM, line 168 Go to ChemFile MTY72_3M.CHM, line 1

69 Repeat from step 64, 1 times69 Repeat from step 64, 1 times

7070

71 REM Make sure that nucleophiles are dissolved and ready for addition71 REM Make sure that nucleophiles are dissolved and ready for addition

72 Pause72 Pause

7373

74 Dispense Sequence C:\ACT_1328\R2-A.DSP with 600ul to RB1_1to96 rack using Flush Diluter 274 Dispense Sequence C: \ ACT_1328 \ R2-A.DSP with 600ul to RB1_1to96 rack using Flush Diluter 2

75 REM Nucleophiles react @ 25 C for 16 hr75 REM Nucleophiles react @ 25 C for 16 hr

76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

77 Wait for 4.000 minute(s)77 Wait for 4.000 minute (s)

78 Repeat from step 76, 11 times78 Repeat from step 76, 11 times

79 Repeat from step 76, 15 times79 Repeat from step 76, 15 times

8080

81 REM End of reaction81 REM End of reaction

82 Go to ChemFile MTY72_3M.CHM, line 182 Go to ChemFile MTY72_3M.CHM, line 1

83 Go to ChemFile MTY72_3M.CHM, line 183 Go to ChemFile MTY72_3M.CHM, line 1

8484

85 REM Commence final washing procedure85 REM Commence final washing procedure

86 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72]86 Dispense System Fluid Disdu2_3 * 500ul to RB1_1to96 [1-72]

87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

88 Go to ChemFile MTY72_3M.CHM, line 188 Go to ChemFile MTY72_3M.CHM, line 1

89 Go to ChemFile MTY72_3M.CHM, line 189 Go to ChemFile MTY72_3M.CHM, line 1

90 Repeat from step 86, 4 times90 Repeat from step 86, 4 times

9191

92 REM Change systemfluids:92 REM Change systemfluids:

93 REM * Diluter2: THF93 REM * Diluter 2: THF

94 REM * Diluter3: MeOH94 REM * Diluter 3: MeOH

95 Pause95 Pause

9696

97 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 497 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter 3 and Flush Diluter 4

98 REM THF wash 3 times98 REM THF wash 3 times

99 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96[1-72]99 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96 [1-72]

100 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.100 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

101 Go to ChemFile MTY72_3M.CHM, line 1101 Go to ChemFile MTY72_3M.CHM, line 1

102 Go to ChemFile MTY72_3M.CHM, line 1102 Go to ChemFile MTY72_3M.CHM, line 1

103 Repeat from step 99, 2 times103 Repeat from step 99, 2 times

104104

105 REM Alternating MeOH/DCM wash, 2 cycles105 REM Alternating MeOH / DCM wash, 2 cycles

106 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96[1-72]106 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96 [1-72]

107 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.107 Mix "RB1_1to96" for 3.00 minutes at 300 rpm (s) and wait.

108 Go to ChemFile MTY72_3M.CHM, line 1108 Go to ChemFile MTY72_3M.CHM, line 1

109109

110 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72]110 Dispense System Fluid Disdu1_4 * 800ul to RB1_1to96 [1-72]

111 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.111 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

112 Go to ChemFile MTY72_3M.CHM, line 1112 Go to ChemFile MTY72_3M.CHM, line 1

113 Go to ChemFile MTY72_3M.CHM, line 1113 Go to ChemFile MTY72_3M.CHM, line 1

114114

115 Repeat from step 106, 1 times115 Repeat from step 106, 1 times

116116

117 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72]117 Dispense System Fluid Disdu1_4 * 800ul to RB1_1to96 [1-72]

118 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.118 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

119 Go to ChemFile MTY72_3M.CHM, line 1119 Go to ChemFile MTY72_3M.CHM, line 1

120 Repeat from step 117, 1 times120 Repeat from step 117, 1 times

121121

122 REM Washing procedure has ended122 REM Washing procedure has ended

123123

124 REM Setup for cleavage:124 REM Setup for cleavage:

125 REM * Cleavage vials125 REM * Cleavage vials

126 REM * Lower pressure126 REM * Lower pressure

127 REM * Add 100 mL TFA/DCM 1:1 mixture to Reagent3127 REM * Add 100 mL TFA / DCM 1: 1 mixture to Reagent3

128 REM * Add 100 mL CH3CN to Reagent4128 REM * Add 100 mL CH3CN to Reagent4

129 Pause129 Pause

130130

131 REM Adding cleavage solution, 1hr131 REM Adding cleavage solution, 1hr

132 Transfer 1000ul from REAGENT_3[1](TFA/DCM) to RB1_1to96[1-72] using Flush Diluter1132 Transfer 1000ul from REAGENT_3 [1] (TFA / DCM) to RB1_1to96 [1-72] using Flush Diluter1

133 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.133 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

134 Wait for 4.000 minute(s)134 Wait for 4.000 minute (s)

135 Repeat from step 133, 11 times135 Repeat from step 133, 11 times

136 REM PULSE EMPTY!136 REM PULSE EMPTY!

137 Go to ChemFile PULSEMP1.CHM, line 1137 Go to ChemFile PULSEMP1.CHM, line 1

138138

139 REM Washing with CH3CN139 REM Washing with CH3CN

140 Transfer 500ul from REAGENT_4[1](CH3CN) to RB1_1to96[1-72] using Flush Diluter1140 Transfer 500ul from REAGENT_4 [1] (CH3CN) to RB1_1to96 [1-72] using Flush Diluter1

141 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.141 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

142 REM PULSE EMPTY!142 REM PULSE EMPTY!

143 Go to ChemFile PULSEMP1.CHM, line 1143 Go to ChemFile PULSEMP1.CHM, line 1

144144

145 REM The End145 REM The End

146146

다음의 chemfile은 반응 블록의 웰을 비우기위해 불려들여진다.The following chemfile is loaded to empty the wells of the reaction block.

ChemFile C:\ACT_1328\MTY72_3M.CHMChemFile C: \ ACT_1328 \ MTY72_3M.CHM

1 REM Subroutine Empty1_72_3min1 REM Subroutine Empty1_72_3min

2 Empty RB1_1to96 for 5.000 minute(s)2 Empty RB1_1to96 for 5.000 minute (s)

3 Return3 Return

다음의 chemfile은 반응블록의 웰을 비우고 최종 생성물을 포함하는 바이알을 제어식으로 절단하기 위해 불려들여진다.The following chemfile is loaded to empty the wells of the reaction block and to controlally cut the vial containing the final product.

ChemFile C:\ACT_1328\PULSEMP1.CHMChemFile C: \ ACT_1328 \ PULSEMP1.CHM

1 Empty RB1_1to96 for 1 second(s)1 Empty RB1_1to96 for 1 second (s)

2 Wait for 4 second(s)2 Wait for 4 second (s)

3 Repeat from step 1, 11 times3 Repeat from step 1, 11 times

4 Empty RB1_1to96 for 5.000 minute(s)4 Empty RB1_1to96 for 5.000 minute (s)

5 Return5 Return

Dispense sequence C:\ACT_1328\R2-A.DSP는 아민의 합성장치내 반응블록으로의 조합적 첨가를 조절하는 서브루틴이다.Dispense sequence C: \ ACT_1328 \ R2-A.DSP is a subroutine that controls the combinatorial addition of amines to the reaction block in the synthesis apparatus.

이 라이브러리로부터의 화합물의 예는 HPLC-MS(분자량 & 체류시간)으로 특성규명되고 다음의 실시예 828 내지 875를 포함한다.Examples of compounds from this library are characterized by HPLC-MS (molecular weight & residence time) and include the following Examples 828-875.

실시예 874:Example 874:

1H NMR (DMSO-D6) δ 2.37 (m, 8H), 3.44 (s, 2H), 3.90 (s, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.67 (m, 2H), 7.81 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 8.36 (dd, J = 1.7, 7.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 9.08 (s, 1H), 10.99 (s, 1H), 11.78 (s, 1H). MS (APCI, pos.): 547.1, 550.1 1 H NMR (DMSO-D6) δ 2.37 (m, 8H), 3.44 (s, 2H), 3.90 (s, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz , 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.67 (m, 2H), 7.81 (d, J = 8.7 Hz, 1H), 7.86 (d , J = 7.3 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 8.36 (dd, J = 1.7, 7.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 9.08 (s , 1H), 10.99 (s, 1H), 11.78 (s, 1H). MS (APCI, pos.): 547.1, 550.1

실시예 875:Example 875:

1H NMR (DMSO-D6) δ 2.66 - 2.75 (m, 4H), 3.69 (s, 2H), 4.06 (s, 2H), 6.36 (m, 1H), 6.40 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.51 - 7.66 (m, 4H), 7.77 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.98 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.80 (d, J = 8.5 Hz, 1H), 9.04 (s, 1H), 10.94 (s, 1H), 11.77 (s, 1H). MS (APCI, pos.): 485.1, 487.1 1 H NMR (DMSO-D 6 ) δ 2.66-2.75 (m, 4H), 3.69 (s, 2H), 4.06 (s, 2H), 6.36 (m, 1H), 6.40 (m, 1H), 7.06 (d , J = 8.5 Hz, 1H), 7.51-7.66 (m, 4H), 7.77 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.98 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.80 (d, J = 8.5 Hz, 1H), 9.04 (s, 1H), 10.94 (s, 1H), 11.77 (s, 1H). MS (APCI, pos.): 485.1, 487.1

실시예 876 내지 877의 일반적인 방법:General Methods of Examples 876-877:

화합물은 다음의 식The compound is of the formula

수지-[빌딩블록 1] →Resin- [Building Block 1] →

수지-[빌딩블록 1]-[빌딩블록 2] →Resin- [Building Block 1]-[Building Block 2] →

수지-[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3] →Resin- [Building Block 1]-[Building Block 2]-[Building Block 3] →

수지-[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3]-[빌딩블록 4]Resin- [Building Block 1]-[Building Block 2]-[Building Block 3]-[Building Block 4]

에 따라서 단일체로서 제조하였고 동시에 탈보호화하고 디클로로메탄중 50% 트리플루오로아세트산으로 수지로부터 절단하여 다음 식Prepared as a monolith and simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane

[빌딩블록 1]-[빌딩블록 2]-[빌딩블록 3]-[빌딩블록 4][Building Block 1]-[Building Block 2]-[Building Block 3]-[Building Block 4]

에 따르는 개개의 개체로서 원하는 화합물을 얻었다.The desired compound was obtained as an individual object according to the present invention.

다음의 화합물은 고체 지지체 상에서 병렬적 합성에 의해 단일체로서 제조하였다. 수지-[빌딩블록 1]-[빌딩블록 2]의 제조는 수동으로 하였고, 반면 [빌딩블록 3]의 부착, [빌딩블록 4]의 부착 및 수지로부터의 절단은 Advanced ChemTech Model 384 HTS상에서 수행하였다.The following compounds were prepared as monoliths by parallel synthesis on a solid support. Preparation of Resin- [Building Block 1]-[Building Block 2] was done manually, whereas the attachment of [Building Block 3], the attachment of [Building Block 4] and cleavage from the resin were performed on Advanced ChemTech Model 384 HTS. .

출발 수지, 수지-[빌딩블록 1]은 모두 상기 기재된 바와 같이 제조되었다.Starting resin, Resin- [Building Block 1] were all prepared as described above.

사용된 수지는 Wang 링커를 가지는 폴리스티렌 수지이고 치환용량은 0.9mmol/g이었다.The resin used was a polystyrene resin with Wang linker and a substitution capacity of 0.9 mmol / g.

모든 화합물은 완전히 조합적 방식으로 다음 반응식에 따라서 친핵 치환반응후, [빌딩블록 4]를 부착시키는 아실화 반응을 사용하여 [빌딩블록 2]와 [빌딩블록 3]의 수지-[빌딩블록 1]에의 연속적인 부착을 기본으로 한다. 다음 반응식은 화학식 II와 관련된다:All compounds were prepared in a totally combinatorial manner, after the nucleophilic substitution reaction, using an acylation reaction to which [building block 4] was attached, the resins of [building block 2] and [building block 3]-[building block 1] Based on successive attachments to The following scheme relates to formula II:

(반응식)(Scheme)

상기 식에서, R5a, R14및 R15는 화학식 I에서 정의된 바와 같고, R5c는Wherein R 5a , R 14 and R 15 are as defined in Formula I and R 5c is

(상기 식에서, R4a, R4b, c, q, d 및 D는 화학식 I에서 정의된 바와 같다)이거나 친핵기로서 반응할 수 있는 활성화 카르복시산을 포함하는 -D의 부분집합으로서 정의된 -D'인 -D'이다. Lea는 염소, 브롬, 요오드, 카르복실레이트,(Wherein R 4a , R 4b , c, q, d and D are as defined in formula I) or -D ′ defined as a subset of -D comprising an activated carboxylic acid capable of reacting as a nucleophilic group Is -D '. Lea is chlorine, bromine, iodine, carboxylate,

등의 이탈기이다.This is a leaving group.

여기서 수지-[빌딩블록 1]으로서 나타낸 다음의 수지를 사용하였다.The following resin shown here as Resin- [Building Block 1] was used.

상기 식에서 PS는 폴리스티렌이고, 아래에서 "수지"는 Wang 링커를 가진 폴리스티렌 수지이다.Wherein PS is polystyrene and below "resin" is a polystyrene resin with Wang linker.

즉 In other words

다음의 빌딩블록을 사용하였다:The following building blocks were used:

[빌딩블록 2]:[Building Block 2]:

[빌딩블록 3]:[Building Block 3]:

[빌딩블록 4]:[Building Block 4]:

수지-[빌딩블록 1]의 제조:Preparation of Resin- [Building Block 1]:

이 수지는 상기 기재된 바와 같이 제조하였다.This resin was prepared as described above.

수지-[빌딩블록 1]-[빌딩블록 2]의 제조:Preparation of Resin- [Building Block 1]-[Building Block 2]:

이 수지는 상기 기재된 바와 같이 제조하였다.This resin was prepared as described above.

실시예 876:Example 876:

N-{4-[(3-클로로-4-히드록시벤조일)-히드라조노메틸]나프틸메틸}-N-이소부틸프롤린아미드N- {4-[(3-chloro-4-hydroxybenzoyl) -hydrazonomethyl] naphthylmethyl} -N-isobutylprolineamide

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드(수지-[빌딩블록 1]-[빌딩블록 2])(50mg, ~50μmol)를 CH2Cl2(0.5mL)에서 15분간 팽창시킨 후, CH2Cl2(0.5mL)로 2회 세척하였다. CH2Cl2(0.4mL)와 디이소프로필에틸아민(0.4mL)를 연속적으로 가하고 현탁물을 0℃까지 냉각시켰다. 염화메탈술포닐(0.1mL)을 CH2Cl2(0.3mL)에 용해시키고 현탁물에 가하였다. 혼합물을 0℃에서 30분간 반응시킨 다음 25℃에서 1시간 반응시켰다. 수지를 여과하여 분리하고 CH2Cl2(2x0.5mL) 및 DMSO(0.5mL)로 세척하였다. DMSO(0.5mL)를 수지에 가하고 이소부틸아민 50㎕, 디이소프로필에틸아민 100㎕를 가하였다. 혼합물을 16시간동안 25℃에서 흔들어 섞었다. 용매를 흡입하여 제거하고 DMSO(2x0.5mL) 및 THF(3x0.5mL)로 세척하였다. THF(0.5mL)중 N-tert-부톡시카르보닐프롤린(46mg, 0.21mmol)의 용액에 디이소프로필카르보디이미드(16㎕, 0.2mmol)을 가하였다. 이 용액을 25℃에서 10분간 반응시키고 수지에 가하였다. 이 현탁액을 25℃에서 16시간동안 흔들어 섞은 후, THF(3x0.5mL), DMF(3x0.5mL), THF(3x0.5mL), CH3OH(0.5mL), CH2Cl2(0.5mL), CH3OH(0.5mL), CH2Cl2(4x0.5mL)로 세척하였다. 화합물을 CH2Cl2(1mL)중 50% 트리플루오로아세트산의 용액으로 25℃에서 1시간동안 흔들어 섞어 수지로부터 절단하였다. 혼합물을 여과하고 수지를 아세토니트릴(1mL)로 추출하였다. 합한 추출물을 진공에서 농축시켰다. 잔여물을 CH3OH(0.5mL)와 아세토니트릴(0.5mL)의 혼합물에 재용해시키고 진공에서 농축시켜 표제의 화합물을 얻었다.Resin-bonded 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide (resin- [building block 1]-[building block 2]) (50 mg, ˜50 μmol) was replaced with CH 2 Cl then in 2 (0.5mL) swelling for 15 minutes, washed twice with CH 2 Cl 2 (0.5mL). CH 2 Cl 2 (0.4 mL) and diisopropylethylamine (0.4 mL) were added sequentially and the suspension was cooled to 0 ° C. Metal sulfonyl chloride (0.1 mL) was dissolved in CH 2 Cl 2 (0.3 mL) and added to the suspension. The mixture was reacted at 0 ° C. for 30 minutes and then at 25 ° C. for 1 hour. The resin was separated by filtration and washed with CH 2 Cl 2 ( 2 × 0.5 mL) and DMSO (0.5 mL). DMSO (0.5 mL) was added to the resin, and 50 µl of isobutylamine and 100 µl of diisopropylethylamine were added. The mixture was shaken at 25 ° C. for 16 h. The solvent was removed by suction and washed with DMSO (2 × 0.5 mL) and THF (3 × 0.5 mL). To a solution of N-tert-butoxycarbonylproline (46 mg, 0.21 mmol) in THF (0.5 mL) was added diisopropylcarbodiimide (16 μl, 0.2 mmol). The solution was reacted at 25 ° C. for 10 minutes and added to the resin. After shaking this suspension for 16 hours at 25 ° C., THF ( 3 × 0.5 mL), DMF ( 3 × 0.5 mL), THF ( 3 × 0.5 mL), CH 3 OH (0.5 mL), CH 2 Cl 2 (0.5 mL) Washed with CH 3 OH (0.5 mL), CH 2 Cl 2 (4 × 0.5 mL). The compound was cleaved from the resin by shaking for 1 h at 25 ° C. with a solution of 50% trifluoroacetic acid in CH 2 Cl 2 (1 mL). The mixture was filtered and the resin extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH 3 OH (0.5 mL) and acetonitrile (0.5 mL) and concentrated in vacuo to afford the title compound.

HPLC-MS (방법 B): Rt= 3.90 분; m/z = 507 (M+1).HPLC-MS (method B): R t = 3.90 min; m / z = 507 (M + l).

실시예 877:Example 877:

3-클로로-4-히드록시벤조산((4-(4-트리플루오로메톡시벤질아미노)메틸)나프틸메틸렌)히드라지드3-Chloro-4-hydroxybenzoic acid ((4- (4-trifluoromethoxybenzylamino) methyl) naphthylmethylene) hydrazide

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드(수지-[빌딩블록 1]-[빌딩블록 2])(50mg)을 CH2Cl2와 N-메틸-2-피롤리돈 (0.5mL)의 1:1 혼합물에서 15분동안 팽창시킨 후, CH2Cl2(3x0.5mL)로 세척하였다. CH2Cl2와 디이소프로필에틸아민의 1:1 혼합물 800㎕를 수지에 가하고 이어서 -3℃까지 냉각시켰다. 300㎕에 용해시킨 염화메탄술포닐 100㎕의 용액을 가하고 -3℃에서 30분동안 반응시킨 다음 25℃에서 1시간동안 반응시켰다. 수지를 여과하고 CH2Cl2(2x1mL)와 N-메틸-2피롤리돈(2x0.5mL)으로 세척하였다. N-메틸-2-피롤리돈(0.5mL)과 디이소프로필에틸아민(0.1mL)중 4-트리플루오로메톡시벤질아민(45.8mg, 0.24mmol, 0.4M) 및 KI(10mg, 0.06mmol, 0.1M)의 용액 600㎕를 가하고 25℃에서 16시간동안 반응시켰다. 수지를 여과하여 분리하고 N-메틸-2-피롤리돈(5x0.5mL)과 THF(3x0.5mL)로 연속적으로 세척하였다. THF(480㎕)중 아세트산 무수물(120㎕, 130mg, 1.27mmol)의 용액 600㎕를 수지에 가하였다. 혼합물을 25℃에서 16시간동안 반응시켰다. 수지를 여과하고, THF(2x0.8mL), CH3OH(0.8mL), CH2Cl2(0.8mL), CH3OH(0.8mL) 및 CH2Cl2(3x0.8mL)로 연속적으로 세척하였다. 이 화합물을 CH2Cl2(1mL)중 50% 트리플루오로아세트산의 용액으로 25℃에서 1시간동안 흔들어 섞어 수지로부터 절단하였다. 혼합물을 여과하고 수지를 아세토니트릴(1mL)로 추출하였다. 합한 추출물을 진공에서 농축시켰다. 잔여물을 CH3OH(0.5mL)와 아세토니트릴(0.5mL)의 혼합물에 재용해시키고 진공에서 농축시켜 표제의 화합물을 얻었다.Resin-bonded 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide (resin- [building block 1]-[building block 2]) (50 mg) was replaced with CH 2 Cl 2 and N Expanded in a 1: 1 mixture of methyl-2-pyrrolidone (0.5 mL) for 15 minutes, then washed with CH 2 Cl 2 (3 × 0.5 mL). 800 μl of a 1: 1 mixture of CH 2 Cl 2 and diisopropylethylamine was added to the resin and then cooled to −3 ° C. A solution of 100 µl of methanesulfonyl chloride dissolved in 300 µl was added and reacted at -3 ° C for 30 minutes, and then at 25 ° C for 1 hour. The resin was filtered off and washed with CH 2 Cl 2 ( 2 × 1 mL) and N-methyl-2pyrrolidone ( 2 × 0.5 mL). 4-trifluoromethoxybenzylamine (45.8 mg, 0.24 mmol, 0.4 M) and KI (10 mg, 0.06 mmol, in N-methyl-2-pyrrolidone (0.5 mL) and diisopropylethylamine (0.1 mL) 0.1 μl) of a solution was added and reacted at 25 ° C. for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 × 0.5 mL) and THF (3 × 0.5 mL). 600 μl of a solution of acetic anhydride (120 μl, 130 mg, 1.27 mmol) in THF (480 μl) was added to the resin. The mixture was reacted at 25 ° C. for 16 hours. Filtering the resin, THF (2x0.8mL), CH 3 OH (0.8mL), CH 2 Cl 2 (0.8mL), CH 3 OH (0.8mL) and CH 2 Cl 2 was washed successively with (3x0.8mL) It was. This compound was cleaved from the resin by shaking for 1 hour at 25 ° C. with a solution of 50% trifluoroacetic acid in CH 2 Cl 2 (1 mL). The mixture was filtered and the resin extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH 3 OH (0.5 mL) and acetonitrile (0.5 mL) and concentrated in vacuo to afford the title compound.

HPLC-MS (방법 B): Rt= 6.42 분; m/z = 492 (M+1)HPLC-MS (method B): R t = 6.42 min; m / z = 492 (M + 1)

실시예 878 내지 881:Examples 878 to 881:

상기 목록된 빌딩블록([빌딩블록 1], [빌딩블록 2], [빌딩블록 3] 및 [빌딩블록 4]로서 아세트산 무수물)의 모든 가능한 조합의 화합물의 라이브러리를 합성장치의 작동을 조절하기 위한 다음의 ChemFile을 사용하여 Advanced ChemTech Model 384 HTS상에서 상기 실시예와 동일하게 개개의 개체로서 병렬적으로 제조하였다. 화합물은 각 웰에 존재하는 것으로 모두 기대된다.A library of compounds of all possible combinations of the building blocks listed above ([Building Block 1], [Building Block 2], [Building Block 3] and [Building Block 4] as acetic anhydride) is used to control the operation of the synthesis apparatus. The following ChemFiles were prepared in parallel as individual individuals on the Advanced ChemTech Model 384 HTS in the same manner as in the above examples. The compound is expected to be present in each well.

수지가 결합된 3-클로로-4-히드록시벤조산(4-히드록시메틸나프틸메틸렌)히드라지드: CH2Cl2와 N-메틸-피롤리돈(0.5mL)의 1:1 혼합물중 (수지-[빌딩블록 1]-[빌딩블록 2])(50mg)를 장치를 초기화하기 전에 합성장치내 각 웰에 동등하게 분배한다.3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide bound with resin: in a 1: 1 mixture of CH 2 Cl 2 and N-methyl-pyrrolidone (0.5 mL) (resin -[Building Block 1]-[Building Block 2]) (50 mg) are equally distributed to each well in the synthesis apparatus prior to initializing the apparatus.

ChemFile C:\ACT_1328\MAIN.CHMChemFile C: \ ACT_1328 \ MAIN.CHM

1 REM Nucleophilic displacement of benzylic alcohol1 REM Nucleophilic displacement of benzylic alcohol

2 REM via mesylation2 REM via mesylation

33

44

5 REM Dipense resin bound benzylic alchohol to wells5 REM Dipense resin bound benzylic alchohol to wells

66

77

8 REM Setup Diluter1=DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM8 REM Setup Diluter1 = DCM, D2 = NMP (N-methyl-2-pyrrolidone), D3 = NMP, D4 = DCM

9 REM Adjust pressure9 REM Adjust pressure

10 REM Add 100 mL DIEA/DCM 1:1 mixture to Reagent110 REM Add 100 mL DIEA / DCM 1: 1 mixture to Reagent1

11 REM Add 70 mL MsCl/DCM 1:3 mixture to Reagent211 REM Add 70 mL MsCl / DCM 1: 3 mixture to Reagent2

12 REM Add 100 mL TFA/DCM 1:1 mixture to Reagent312 REM Add 100 mL TFA / DCM 1: 1 mixture to Reagent3

13 REM Add 100 mL CH3CN to Reagent413 REM Add 100 mL CH3CN to Reagent4

14 REM Nitrogen for cooling14 REM Nitrogen for cooling

1515

16 Pause16 Pause

17 REM Initialising...17 REM Initialising ...

1818

19 REM Subroutine Empty1_72_3min is called twice to remove DCM/NMP from dispensed resin19 REM Subroutine Empty1_72_3min is called twice to remove DCM / NMP from dispensed resin

20 Go to ChemFile MTY72_3M.CHM, line 120 Go to ChemFile MTY72_3M.CHM, line 1

21 Go to ChemFile MTY72_3M.CHM, line 121 Go to ChemFile MTY72_3M.CHM, line 1

2222

23 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and with Flush Diluter 423 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter 3 and with Flush Diluter 4

2424

25 REM Washing with DCM, 3 times25 REM Washing with DCM, 3 times

26 Dispense System Fluid Disdu1_4* 500ul to RB1_1to96[1-72]26 Dispense System Fluid Disdu1_4 * 500ul to RB1_1to96 [1-72]

27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm (s) and wait.

28 REM Subroutine Empty1_72_3min28 REM Subroutine Empty1_72_3min

29 Go to ChemFile MTY72_3M.CHM, line 129 Go to ChemFile MTY72_3M.CHM, line 1

30 Repeat from step 26, 2 times30 Repeat from step 26, 2 times

3131

32 REM Adding DCM/DIEA mixture from Reagent132 REM Adding DCM / DIEA mixture from Reagent1

33 Transfer 800ul from REAGENT_1[1](DCM/DIEA) to RB1_1to96[1-72] using Flush Diluter133 Transfer 800ul from REAGENT_1 [1] (DCM / DIEA) to RB1_1to96 [1-72] using Flush Diluter1

34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Temperature to reach setpoint35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Temperature to reach setpoint

36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

37 REM Ensure complete cooling37 REM Ensure complete cooling

38 Wait for 15.000 minute(s)38 Wait for 15.000 minute (s)

3939

40 REM Adding mesylchloride40 REM Adding mesylchloride

41 Transfer 400ul from REAGENT_2[1](MsCl/DCM) to RB1_1to96[1-72] using Flush Diluter141 Transfer 400ul from REAGENT_2 [1] (MsCl / DCM) to RB1_1to96 [1-72] using Flush Diluter1

42 REM Reacts 30 min @ -3 ℃42 REM Reacts 30 min @ -3 ° C

43 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.43 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

44 Wait for 4.000 minute(s)44 Wait for 4.000 minute (s)

45 Repeat from step 43, 5 times45 Repeat from step 43, 5 times

4646

47 REM Reacts 60 min @ 25 C47 REM Reacts 60 min @ 25 C

48 Set Temperature of rack "RB1_1to96" to 25.0 degrees Celsius and wait for Temperature to reach setpoint48 Set Temperature of rack "RB1_1to96" to 25.0 degrees Celsius and wait for Temperature to reach setpoint

49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

50 Wait for 4.000 minute(s)50 Wait for 4.000 minute (s)

51 Repeat from step 46, 11 times51 Repeat from step 46, 11 times

5252

53 REM Subroutine Empty1_72_3min53 REM Subroutine Empty1_72_3min

54 Go to ChemFile MTY72_3M.CHM, line 154 Go to ChemFile MTY72_3M.CHM, line 1

5555

56 REM Initiate washing procedure, 2XDCM56 REM Initiate washing procedure, 2XDCM

57 Dispense System Fluid Disdu1_4* 1000ul to RB1_1to96[1-72]57 Dispense System Fluid Disdu1_4 * 1000ul to RB1_1to96 [1-72]

58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm (s) and wait.

59 Go to ChemFile MTY72_3M.CHM, line 159 Go to ChemFile MTY72_3M.CHM, line 1

60 Repeat from step 57, 1 times60 Repeat from step 57, 1 times

6161

62 REM NMP wash62 REM NMP wash

6363

64 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72]64 Dispense System Fluid Disdu2_3 * 500ul to RB1_1to96 [1-72]

65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm(s) and wait.65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm (s) and wait.

66 Go to ChemFile MTY72_3M.CHM, line 166 Go to ChemFile MTY72_3M.CHM, line 1

6767

68 Go to ChemFile MTY72_3M.CHM, line 168 Go to ChemFile MTY72_3M.CHM, line 1

69 Repeat from step 64, 1 times69 Repeat from step 64, 1 times

7070

71 REM Make sure that nucleophiles are dissolved and ready for addition71 REM Make sure that nucleophiles are dissolved and ready for addition

72 Pause72 Pause

7373

74 Dispense Sequence C:\ACT_1328\R2-A.DSP with 600ul to RB1_1to96 rack using Flush Diluter 274 Dispense Sequence C: \ ACT_1328 \ R2-A.DSP with 600ul to RB1_1to96 rack using Flush Diluter 2

75 REM Nucleophiles react @ 25 C for 16 hr75 REM Nucleophiles react @ 25 C for 16 hr

76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

77 Wait for 4.000 minute(s)77 Wait for 4.000 minute (s)

78 Repeat from step 76, 11 times78 Repeat from step 76, 11 times

79 Repeat from step 76, 15 times79 Repeat from step 76, 15 times

8080

81 REM End of nucleophilic substitution reaction81 REM End of nucleophilic substitution reaction

82 Go to ChemFile MTY72_3M.CHM, line 182 Go to ChemFile MTY72_3M.CHM, line 1

83 Go to ChemFile MTY72_3M.CHM, line 183 Go to ChemFile MTY72_3M.CHM, line 1

8484

85 REM Commence washing procedure85 REM Commence washing procedure

86 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72]86 Dispense System Fluid Disdu2_3 * 500ul to RB1_1to96 [1-72]

87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

88 Go to ChemFile MTY72_3M.CHM, line 188 Go to ChemFile MTY72_3M.CHM, line 1

89 Go to ChemFile MTY72_3M.CHM, line 189 Go to ChemFile MTY72_3M.CHM, line 1

90 Repeat from step 86, 4 times90 Repeat from step 86, 4 times

9191

92 REM Change systemfluids:92 REM Change systemfluids:

93 REM * Diluter2: THF93 REM * Diluter 2: THF

94 REM * Diluter3: MeOH94 REM * Diluter 3: MeOH

95 Pause95 Pause

9696

97 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 497 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter 3 and Flush Diluter 4

98 REM THF wash 3 times98 REM THF wash 3 times

99 Dispense System Fluid Flush Diluter 2 500ul to RB1_1to96[1-72]99 Dispense System Fluid Flush Diluter 2 500ul to RB1_1to96 [1-72]

100 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.100 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

101 Go to ChemFile MTY72_3M.CHM, line 1101 Go to ChemFile MTY72_3M.CHM, line 1

102 Go to ChemFile MTY72_3M.CHM, line 1102 Go to ChemFile MTY72_3M.CHM, line 1

103 Repeat from step 99, 2 times103 Repeat from step 99, 2 times

104 Go to ChemFile Acylation.CHM, line 1104 Go to ChemFile Acylation.CHM, line 1

105 Go to ChemFile WASH.CHM, line 1105 Go to ChemFile WASH.CHM, line 1

106 Go to ChemFile Cleavage.CHM, line 1106 Go to ChemFile Cleavage.CHM, line 1

107 REM The End107 REM The End

다음의 chemfile은 아민의 아실화를 위해 불려들여진다.The following chemfile is called for the acylation of amines.

ChemFile C:\ACT_1328\Acetyl.CHMChemFile C: \ ACT_1328 \ Acetyl.CHM

1 REM Acetylation procedure1 REM Acetylation procedure

2 REM Charge REAGENT_5 with 100 mL Acetic anhydride/THF 1:4 v/v2 REM Charge REAGENT_5 with 100 mL Acetic anhydride / THF 1: 4 v / v

3 REM * Diluter2: THF3 REM * Diluter 2: THF

4 REM Addition of acylation reagent4 REM Addition of acylation reagent

5 Dispense Sequence C:\R3-A.DSP with 600 ㎕ to RB1to96 rack using Flush Diluter 25 Dispense Sequence C: \ R3-A.DSP with 600 μl to RB1to96 rack using Flush Diluter 2

6 Mix for 1.00 minutes at 300 rpm(s)6 Mix for 1.00 minutes at 300 rpm (s)

7 Wait for 5.000 minute(s)7 Wait for 5.000 minute (s)

8 Repeat from step 6, 60 times8 Repeat from step 6, 60 times

9 Go to ChemFile MTY72_3M.CHM, line 19 Go to ChemFile MTY72_3M.CHM, line 1

10 Go to ChemFile MTY72_3M.CHM, line 110 Go to ChemFile MTY72_3M.CHM, line 1

11 Return11 Return

다음의 chemfile은 수지가 결합된 생성물을 세척하기 위해 불려들여진다.The following chemfile is loaded to wash the resin bound product.

ChemFile C:\ACT_1328\WASH.CHMChemFile C: \ ACT_1328 \ WASH.CHM

1 REM Washing procedure1 REM Washing procedure

2 REM Systemfluids:2 REM Systemfluids:

33

4 REM * Diluter2: THF4 REM * Diluter 2: THF

5 REM * Diluter3: MeOH5 REM * Diluter 3: MeOH

66

7 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 47 Flush Arm1 with Flush Diluter 1 and Flush Diluter 2, Arm2 with Flush Diluter 3 and Flush Diluter 4

8 REM THF wash 3 times8 REM THF wash 3 times

9 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96[1-72]9 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96 [1-72]

10 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.10 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

11 Go to ChemFile MTY72_3M.CHM, line 111 Go to ChemFile MTY72_3M.CHM, line 1

12 Go to ChemFile MTY72_3M.CHM, line 112 Go to ChemFile MTY72_3M.CHM, line 1

13 Repeat from step 9, 2 times13 Repeat from step 9, 2 times

1414

15 REM Alternating MeOH/DCM wash, 2 cycles15 REM Alternating MeOH / DCM wash, 2 cycles

16 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96[1-72]16 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96 [1-72]

17 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.17 Mix "RB1_1to96" for 3.00 minutes at 300 rpm (s) and wait.

18 Go to ChemFile MTY72_3M.CHM, line 118 Go to ChemFile MTY72_3M.CHM, line 1

1919

20 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72]20 Dispense System Fluid Disdu1_4 * 800ul to RB1_1to96 [1-72]

21 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.21 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

22 Go to ChemFile MTY72_3M.CHM, line 122 Go to ChemFile MTY72_3M.CHM, line 1

23 Go to ChemFile MTY72_3M.CHM, line 123 Go to ChemFile MTY72_3M.CHM, line 1

2424

25 Repeat from step 16, 1 times25 Repeat from step 16, 1 times

2626

27 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72]27 Dispense System Fluid Disdu1_4 * 800ul to RB1_1to96 [1-72]

28 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.28 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

29 Go to ChemFile MTY72_3M.CHM, line 129 Go to ChemFile MTY72_3M.CHM, line 1

30 Repeat from step 117, 1 times30 Repeat from step 117, 1 times

3131

32 REM Washing procedure has ended32 REM Washing procedure has ended

33 Return33 Return

다음의 chemfile은 수지로부터 생성물을 절단하기 위해 불려들여진다. ChemFile C:\ACT_1328\Cleavage.CHMThe following chemfile is loaded to cleave the product from the resin. ChemFile C: \ ACT_1328 \ Cleavage.CHM

1 REM Setup for cleavage:1 REM Setup for cleavage:

2 REM * Cleavage vials2 REM * Cleavage vials

3 REM * Lower pressure3 REM * Lower pressure

4 REM * Add 100 mL TFA/DCM 1:1 mixture to Reagent34 REM * Add 100 mL TFA / DCM 1: 1 mixture to Reagent3

5 REM * Add 100 mL CH3CN to Reagent45 REM * Add 100 mL CH3CN to Reagent4

6 Pause6 Pause

77

8 REM Adding cleavage solution, 1hr8 REM Adding cleavage solution, 1hr

9 Transfer 1000ul from REAGENT_3[1](TFA/DCM) to RB1_1to96[1-72] using Flush Diluter19 Transfer 1000ul from REAGENT_3 [1] (TFA / DCM) to RB1_1to96 [1-72] using Flush Diluter1

10 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.10 Mix "RB1_1to96" for 1.00 minutes at 300 rpm (s) and wait.

11 Wait for 4.000 minute(s)11 Wait for 4.000 minute (s)

12 Repeat from step 133, 11 times12 Repeat from step 133, 11 times

13 REM PULSE EMPTY!13 REM PULSE EMPTY!

14 Go to ChemFile PULSEMP1.CHM, line 114 Go to ChemFile PULSEMP1.CHM, line 1

1515

16 REM Washing with CH3CN16 REM Washing with CH3CN

17 Transfer 500ul from REAGENT_4[1](CH3CN) to RB1_1to96[1-72] using Flush Diluter117 Transfer 500ul from REAGENT_4 [1] (CH3CN) to RB1_1to96 [1-72] using Flush Diluter1

18 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.18 Mix "RB1_1to96" for 10.00 minutes at 300 rpm (s) and wait.

19 REM PULSE EMPTY!19 REM PULSE EMPTY!

20 Go to ChemFile PULSEMP1.CHM, line 120 Go to ChemFile PULSEMP1.CHM, line 1

21 Return21 Return

다음의 chemfile은 반응블록의 웰을 비우기 위해 불려들여진다.The following chemfile is loaded to empty the wells of the reaction block.

ChemFile C:\ACT_1328\MTY72_3M.CHM Page 1ChemFile C: \ ACT_1328 \ MTY72_3M.CHM Page 1

1 REM Subroutine Empty1_72_3min1 REM Subroutine Empty1_72_3min

2 Empty RB1_1to96 for 5.000 minute(s)2 Empty RB1_1to96 for 5.000 minute (s)

3 Return3 Return

다음의 chemfile은 반응블록의 웰을 비우고 최종 생성물을 포함하는 바이알을 제어식으로 절단하기 위해 불려들여진다.The following chemfile is loaded to empty the wells of the reaction block and to controlally cut the vial containing the final product.

ChemFile C:\ACT_1328\PULSEMP1.CHM Page 1ChemFile C: \ ACT_1328 \ PULSEMP1.CHM Page 1

1 Empty RB1_1to96 for 1 second(s)1 Empty RB1_1to96 for 1 second (s)

2 Wait for 4 second(s)2 Wait for 4 second (s)

3 Repeat from step 1, 11 times3 Repeat from step 1, 11 times

4 Empty RB1_1to96 for 5.000 minute(s)4 Empty RB1_1to96 for 5.000 minute (s)

5 Return5 Return

Dispense sequence C:\ACT_1328\R2-A.DSP는 아민의 합성장치내 반응블록에의 조합적 첨가를 조절하는 서브루틴이다.Dispense sequence C: \ ACT_1328 \ R2-A.DSP is a subroutine that controls the combinatorial addition of amines to the reaction block in the synthesis apparatus.

Dispense sequence C:\ACT_1328\R3-A.DSP는 아실화제의 합성장치내 반응블록에의 조합적 첨가를 조절하는 서브루틴이다.Dispense sequence C: \ ACT_1328 \ R3-A.DSP is a subroutine that controls the combinatorial addition of acylating agents to the reaction block in the synthesis apparatus.

이 라이브러리로부터의 화합물의 실시예는 다음의 실시예 878 내지 881을 포함하여 HPLC-MS(분자량 & 체류시간)로 특성규명하였다.Examples of compounds from this library were characterized by HPLC-MS (molecular weight & residence time), including the following Examples 878 to 881.

실시예 882:Example 882:

N-{4-[3-클로로-4-히드록시벤조일)-히드라조노메틸]-나프틸}메틸 이소프로필아미드N- {4- [3-chloro-4-hydroxybenzoyl) -hydrazonomethyl] -naphthyl} methyl isopropylamide

N-포르밀나프틸메틸 이소프로필아미드의 제조:Preparation of N-formylnaphthylmethyl isopropylamide:

DMF 10mL중 4-브로모메틸-1-나프트알데히드 에틸렌아세탈(447mg, 1.52mmol) 및 NaN3(221mg, 3.4mmol)의 혼합물을 100℃까지 가열하고 30분간 교반하였다. 용액이 오렌지색으로 변하였다. 반응을 여과하고 맑은 용액을 농축하여 황색 오일 391mg을 얻었다. 이 오일(249mg)을 트리페닐포스핀(260mg, 0.99mmol)과 함께 THF 10mL에 용해시켰다. 반응 혼합물을 하룻밤동안 방치하고 물을 첨가하였다. 닌히드린 시험으로 아민의 생성을 확인하였다. 이 아민을 에틸아세테이트 층으로 추출시키고 건조시켜 오일을 얻었다. 이 오일을 CH2Cl2, EDC, DMAP에서 용해시키고 2-메틸프로피온산에 가하였다. 반응 혼합물을 2일동안 방치하였다. 에틸아세테이트로 용리시킨 컬럼크로마토그래피로 아민을 얻었다. 디에틸렌아세탈을 탈보호화를 THF중 10% HCl에서 달성한 후, 표제의 화합물(50mg)을 얻었다.A mixture of 4-bromomethyl-1-naphthaldehyde ethyleneacetal (447 mg, 1.52 mmol) and NaN 3 (221 mg, 3.4 mmol) in 10 mL DMF was heated to 100 ° C. and stirred for 30 minutes. The solution turned orange. The reaction was filtered and the clear solution was concentrated to give 391 mg of yellow oil. This oil (249 mg) was dissolved in 10 mL THF with triphenylphosphine (260 mg, 0.99 mmol). The reaction mixture was left overnight and water was added. The ninhydrin test confirmed the production of amines. This amine was extracted with an ethyl acetate layer and dried to give an oil. This oil was dissolved in CH 2 Cl 2 , EDC, DMAP and added to 2-methylpropionic acid. The reaction mixture was left for 2 days. An amine was obtained by column chromatography eluted with ethyl acetate. After deprotection of diethyleneacetal was achieved in 10% HCl in THF, the title compound (50 mg) was obtained.

1H NMR (CDCl3): d 1.2 (d, 6H), 2.4 (m, 1H), 4.9 (d, 2H), 6.1 (b, 1H), 7.5 (d, 1H), 7.6 (m, 2H), 7.8 (d, 1H), 8.0 (d, 1H), 9.2 (d, 1H), 10.3 (s, 1H). 1 H NMR (CDCl 3 ): d 1.2 (d, 6H), 2.4 (m, 1H), 4.9 (d, 2H), 6.1 (b, 1H), 7.5 (d, 1H), 7.6 (m, 2H) , 7.8 (d, 1H), 8.0 (d, 1H), 9.2 (d, 1H), 10.3 (s, 1H).

표제의 화합물을 상기 기재된 바와 유사하게 제조하였다.The title compound was prepared similar to that described above.

1H NMR (DMSO-D6): d 1.0 (d, 6H), 2.4 (m, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.4 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 7.9 (s, 1H), 8.1 (d, 1H), 8.3 (s, 1H), 8.8 (d, 1H), 9.0 (s, 1H), 10.9 (s, 1H), 11.7 (s, 1H); ms (APCI negative); 422. 1 H NMR (DMSO-D 6 ): d 1.0 (d, 6H), 2.4 (m, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.4 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 7.9 (s, 1H), 8.1 (d, 1H), 8.3 (s, 1H), 8.8 (d, 1H), 9.0 (s, 1H ), 10.9 (s, 1 H), 11.7 (s, 1 H); ms (APCI negative); 422.

실시예 883;Example 883;

4-[(3-클로로-4-히드록시벤조일)-히드라조노메틸]-1-나프틸메틸 이소프로필술폭시드4-[(3-chloro-4-hydroxybenzoyl) -hydrazonomethyl] -1-naphthylmethyl isopropylsulfoxide

4-에틸렌아세탈-4-포르밀-나프틸메틸 이소프로필티오에테르:4-ethyleneacetal-4-formyl-naphthylmethyl isopropylthioether:

4-브로모메틸 나프트알데히드 에틸렌아세탈(232mg, 0.79mmol)과 이소프로필티오알콜(0.08mL, 0.81mmol) 및 트리에틸아민 0.21mL의 혼합물을 실온에서 12시간동안 방치하였다. 반응 혼합물을 농축시키고 잔여물을 에틸아세테이트/헥산(1/5)를 용리시키는 컬럼크로마토그래피로 정제하여 원하는 생성물 93g을 담적색 오일로서 얻었다.A mixture of 4-bromomethyl naphthaldehyde ethylene acetal (232 mg, 0.79 mmol), isopropylthioalcohol (0.08 mL, 0.81 mmol) and 0.21 mL of triethylamine was left at room temperature for 12 hours. The reaction mixture was concentrated and the residue was purified by column chromatography eluting ethyl acetate / hexanes (1/5) to give 93 g of the desired product as a pale red oil.

1H NMR (CDCl3): d 1.3 (d, 6H), 2.9 (m, 1H), 4.2 (m, 6H), 6.5 (s, 1H), 7.4 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 8.2 (m, 1H). 1 H NMR (CDCl 3 ): d 1.3 (d, 6H), 2.9 (m, 1H), 4.2 (m, 6H), 6.5 (s, 1H), 7.4 (d, 1H), 7.6 (m, 2H) 7.7 (d, 1 H), 8.2 (m, 1 H).

4-에틸렌아세탈-나프틸메틸 이소프로필술폭시드:4-ethyleneacetal-naphthylmethyl isopropylsulfoxide:

디클로로메탄 5mL중 상기 4-에틸렌아세탈-나프틸메틸 이소프로필티오에테르 (79mg, 0.27mmol)의 혼합물에 m-클로로 퍼벤조산(82mg, 순도 55%, 0.28mmol)를 가하였다. 반응 혼합물을 1시간 40분동안 방치하였다. 그런 다음, NaHSO3용액과 NaHCO3를 차례로 가하였다. 혼합물을 물과 디클로로메탄으로 추출하였다. 유기층을 합하고 MgSO4상에서 건조시켰다. 용매를 제거하고 잔여물을 에틸아세테이트를 용리시킨 컬럼크로마토그래피로 정제하여 원하는 생성물 56g을 오일로서 얻었다.To the mixture of 4-ethyleneacetal-naphthylmethyl isopropylthioether (79 mg, 0.27 mmol) in 5 mL of dichloromethane was added m-chloro perbenzoic acid (82 mg, purity 55%, 0.28 mmol). The reaction mixture was left for 1 hour 40 minutes. Then, NaHSO 3 solution was added, followed by NaHCO 3 . The mixture was extracted with water and dichloromethane. The organic layers were combined and dried over MgSO 4 . The solvent was removed and the residue was purified by column chromatography eluting with ethyl acetate to give 56 g of the desired product as an oil.

1H NMR (CDCl3): d 1.3 (d, 3H), 1.4 (d, 3H), 2.7 (m, 1H), 4.2 (m, 4H), 4.4 (dd, 2H), 6.5 (s, 1H), 7.5 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 8.1 (m, 1H), 8.2 (m, 1H). 1 H NMR (CDCl 3 ): d 1.3 (d, 3H), 1.4 (d, 3H), 2.7 (m, 1H), 4.2 (m, 4H), 4.4 (dd, 2H), 6.5 (s, 1H) , 7.5 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 8.1 (m, 1H), 8.2 (m, 1H).

4-[3-클로로-4-히드록시벤조일)-히드라조노메틸]-1-나프틸메틸 이소프로필술폭시드:4- [3-Chloro-4-hydroxybenzoyl) -hydrazonomethyl] -1-naphthylmethyl isopropylsulfoxide:

표제의 화합물을 상기 기재된 바와 유사하게 제조하였다.The title compound was prepared similar to that described above.

1H NMR (DMSO-D6): d 1.3 (dd, 6H), 3.0 (m, 1H), 4.3 (d, 1H), 4.7 (d, 1H), 7.1 (d, 1H), 7.6 (m, 3H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 8.2 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (s, 1H), 11.8 (s, 1H); ms (APCI negative); 427, 337. 1 H NMR (DMSO-D 6 ): d 1.3 (dd, 6H), 3.0 (m, 1H), 4.3 (d, 1H), 4.7 (d, 1H), 7.1 (d, 1H), 7.6 (m, 3H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 8.2 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (s, 1H ), 11.8 (s, 1 H); ms (APCI negative); 427, 337.

실시예 884:Example 884:

4-[3-클로로-4-히드록시벤조일)-히드라조노메틸]-1-나프틸메틸 이소프로필술폰4- [3-Chloro-4-hydroxybenzoyl) -hydrazonomethyl] -1-naphthylmethyl isopropylsulfone

유사하게, 표제의 화합물을 제조하였다.Similarly, the title compound was prepared.

1H NMR (DMSO-D6): d 1.3 (d, 6H), 3.4 (m, 1H), 5.0 (s, 2H), 7.0 (d, 1H), 7.6 (m, 3H), 7.7 (d, 1H), 7.9 (d, 2H), 8.2 (d, 1H), 8.7 (d, 1H), 9.0 (s, 1H), 10.9 (s, 1H), 11.8 (s, 1H); ms (APCI negative); 443, 336. 1 H NMR (DMSO-D 6 ): d 1.3 (d, 6H), 3.4 (m, 1H), 5.0 (s, 2H), 7.0 (d, 1H), 7.6 (m, 3H), 7.7 (d, 1H), 7.9 (d, 2H), 8.2 (d, 1H), 8.7 (d, 1H), 9.0 (s, 1H), 10.9 (s, 1H), 11.8 (s, 1H); ms (APCI negative); 443, 336.

실시예 885:Example 885:

4-[3-클로로-4-히드록시벤조일)-히드라조노메틸]-1-나프틸메틸 이소프로필술피드4- [3-chloro-4-hydroxybenzoyl) -hydrazonomethyl] -1-naphthylmethyl isopropyl sulfide

유사하게, 표제의 화합물을 제조하였다.Similarly, the title compound was prepared.

본 발명의 추가의 실시예는 다음 화합물이다:A further embodiment of the invention is the following compound:

본 발명의 모든 화합물을 제조하기 위한 상기 방법이 다른 출발물질과 다른 중간체 화합물로 대체될 수 있음이 상기로부터 명백할 것이다. 여기에 개시된 방법은 확립된 화학적 방법에 근거한 것이고, 당업자에게 명백할 것이다. 그러므로 본 발명의 모든 화합물은 앞서의 개시에 의해 광범위하게 가능할 것이다.It will be apparent from the above that the process for preparing all compounds of the present invention can be replaced with other starting materials and other intermediate compounds. The methods disclosed herein are based on established chemical methods and will be apparent to those skilled in the art. Therefore, all compounds of the present invention will be widely possible by the foregoing disclosure.

따라서, 본 발명은 그것의 사상 또는 본질적인 특성에서 벗어나지 않는 다른 구체적인 형태로 구체화될 수 있다. 기재된 구체예는 제한이 아니라 예시로서만으로 모든 측면에서 고려되어지고, 따라서 본 발명의 범위는 앞서의 발명의 상세한 설명에 의하기보다 첨부된 청구범위에 의해 나타내어진다. 청구항의 법적 균등성의 의미와 범위내에 있는 모든 변형은 본 발명의 사상내에 포함되어진다.Accordingly, the present invention can be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive, and therefore the scope of the invention is indicated by the appended claims rather than by the foregoing description of the invention. All modifications that come within the meaning and range of legal equivalency of the claims are to be embraced within their spirit.

Claims (43)

다음 화학식 I의 화합물 및 그것의 모든 광학이성체 또는 기하이성체 또는 이들의 혼합물을 포함하는 호변체 또는 그것의 약학적으로 허용되는 염인 것을 특징으로 하는 화합물.And a tautomer comprising a compound of formula (I) and all of its optical isomers or geometric isomers or mixtures thereof, or a pharmaceutically acceptable salt thereof. (화학식 I)Formula I 상기 식에서, R1및 R2는 독립적으로 수소 또는 저급 알킬이거나 또는 함께 원자가 결합을 형성하고;Wherein R 1 and R 2 are independently hydrogen or lower alkyl or together form a valent bond; R3및 R4는 독립적으로 수소 또는 저급 알킬이고;R 3 and R 4 are independently hydrogen or lower alkyl; n은 0, 1, 2 또는 3이고;n is 0, 1, 2 or 3; m은 0 또는 1이고;m is 0 or 1; X는 >C=O, >C=S, >C=NR5또는 >SO2이고;X is> C = O,> C = S,> C = NR 5 or> SO 2 ; 상기 식에서, R5는 수소, 저급 알킬, 아릴-저급 알킬 또는 -OR6이고;In which R 5 is hydrogen, lower alkyl, aryl-lower alkyl or —OR 6 ; 상기 식에서 R6은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A는A is 이고;ego; 상기 식에서, R7은 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SO2NR11R12, -SR11,-CHF2, -OCHF2, -OSO2R11, -CONR11R12, -OCH2CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13또는 -OSO2CF3이며;Wherein, R 7 is hydrogen, halogen, -CN, -CF 3, -OCF 3 , -OCH 2 CF 3, -NO 2, -OR 11, -NR 11 R 12, lower alkyl, aryl, aryl-lower alkyl , -SCF 3 , -SO 2 NR 11 R 12 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -OCH 2 CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 ; R8및 R9는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, 저급 알킬, 아릴, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13또는 -OSO2CF3이거나, 또는 R8및 R9는 함께 다리 -OCH2O- 또는 -OCH2CH2O-를 형성하고;R 8 and R 9 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 , or R 8 and R 9 together form a bridge —OCH 2 O— or —OCH 2 CH 2 O—; 상기 식에서, R11및 R12는 독립적으로 수소, -COR13, -SO2R13, 저급 알킬 또는 아릴이고;Wherein R 11 and R 12 are independently hydrogen, —COR 13 , —SO 2 R 13 , lower alkyl or aryl; 상기 식에서, R13은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;In which R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; R10은 수소, 저급 알킬, 아릴-저급 알킬 또는 아릴이고;R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; B는B is 이거나 또는 원자가 결합이며;Or a valence bond; 상기 식에서, R14및 R15는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -O(CH2)lCF3, -NO2, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)lCONR16R17, -O(CH2)lCONR16R17, -(CH2)lCOR16, -(CH2)lCOR16, -(CH2)lOR16, -O(CH2)lOR16, -(CH2)lNR16R17, -O(CH2)lNR16R17, -OCOR16, -CO2R18, -O(CH2)lCO2R18, -O(CH2)lCN, -O(CH2)lCl이거나, 또는 R14및 R15는 함께 다리 -O(CH2)lO- 또는 -(CH2)l-을 형성하고;Wherein R 14 and R 15 are independently hydrogen, halogen, —CN, —CF 3 , —OCF 3 , —O (CH 2 ) 1 CF 3 , —NO 2 , —OR 16 , —NR 16 R 17 , Lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 ,-(CH 2 ) l CONR 16 R 17 , -O (CH 2 ) l CONR 16 R 17 ,-(CH 2 ) l COR 16 ,-(CH 2 ) l COR 16 ,-(CH 2 ) l OR 16 , -O (CH 2 ) l OR 16 ,-(CH 2 ) l NR 16 R 17 , -O (CH 2 ) l NR 16 R 17 , -OCOR 16 , -CO 2 R 18 , -O (CH 2 ) l CO 2 R 18 ,- O (CH 2 ) 1 CN, —O (CH 2 ) 1 Cl, or R 14 and R 15 together form a bridge —O (CH 2 ) 1 O— or — (CH 2 ) 1 −; 상기 식에서, l은 1, 2, 3 또는 4이고;Wherein l is 1, 2, 3 or 4; R16및 R17은 독립적으로 수소, -COR18, -SO2R18, 저급 알킬, 아릴이거나, 또는 R16및 R17은 함께 2 내지 7개의 탄소원자를 포함하는 고리형 알킬 다리를 형성하고;R 16 and R 17 are independently hydrogen, —COR 18 , —SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing 2 to 7 carbon atoms; 상기 식에서 R18은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W는 -N= 또는 -CR19=이고;W is -N = or -CR 19 =; Y는 -N= 또는 -CR20=이고;Y is -N = or -CR 20 =; Z는 -N= 또는 -CR21=이고;Z is -N = or -CR 21 =; V는 -N= 또는 -CR22=이고;V is -N = or -CR 22 =; Q는 -NR23-, -O- 또는 -S-이고;Q is -NR 23- , -O- or -S-; 상기 식에서, R19, R20, R21및 R22는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24또는 -CO2R24이거나, 또는 R19및 R20, R20및 R21, 또는 R21및 R22는 함께 다리 -OCH2O-를 형성하고;Wherein R 19 , R 20 , R 21 and R 22 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 24 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 , Or R 21 and R 22 together form a bridge -OCH 2 O-; 상기 식에서, R24및 R25는 독립적으로 수소, -COR26, -SO2R26, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;Wherein R 24 and R 25 are independently hydrogen, —COR 26 , —SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl; 상기 식에서, R26은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R23은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K는K is 이고;ego; 상기 식에서, R3a, R3b, R4a및 R4b는 독립적으로 수소, 할로겐, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a또는 -CO2R24a이고;Wherein R 3a , R 3b , R 4a and R 4b are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24a , -NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 25a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ; 상기 식에서, R24a및 R25b는 독립적으로 수소, -COR26a, -SO2R26a, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;Wherein R 24a and R 25b are independently hydrogen, —COR 26a , —SO 2 R 26a , lower alkyl, aryl or aryl-lower alkyl; 상기 식에서, R26a는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl; 또는 R3a및 R3b, R4a및 R4b, 또는 R3a및 R4b는 함께 다리 -(CH2)i-를 형성하고;Or R 3a and R 3b , R 4a and R 4b , or R 3a and R 4b together form a bridge — (CH 2 ) i —; 상기 식에서, i는 1, 2, 3 또는 4이고;Wherein i is 1, 2, 3 or 4; a, b, c 및 d는 독립적으로 0, 1, 2, 3 또는 4이고;a, b, c and d are independently 0, 1, 2, 3 or 4; e, f 및 p는 독립적으로 0 또는 1이고;e, f and p are independently 0 or 1; q는 0, 1 또는 2이고;q is 0, 1 or 2; L 및 M은 독립적으로 -O-, -S-, -CH=CH-, -C≡C-, -NR5a, -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5aSO2-, -NR5aCONR5b-, -CONR5aNR5b-, -NR5aCSNR5b-, -OCONR5b-, -CH2CONR5b, -OCH2CONR5b-, -P(O)(OR5a)O-, -NR5aC(O)O- 또는L and M are independently selected from -O-, -S-, -CH = CH-, -C≡C-, -NR 5a, -CH 2 NR 5a -, -CO-, -OCO-, -COO-, - CONR 5a -, -CONR 5b -, -NR 5a CO-, -SO-, -SO 2 -, -OSO 2 -, -SO 2 NR 5a -, -NR 5a SO 2 -, -NR 5a CONR 5b -, -CONR 5a NR 5b -, -NR 5a CSNR 5b -, -OCONR 5b -, -CH 2 CONR 5b, -OCH 2 CONR 5b -, -P (O) (OR 5a) O-, -NR 5a C (O O- or 이고;ego; 상기 식에서, R5a및 R5b는 독립적으로 수소, 저급 알킬, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6aR6b, 아릴, 아릴-저급 알킬, -(CH2)g-COOR43또는 -(CH2)g-CF3이고;Wherein R 5a and R 5b are independently hydrogen, lower alkyl, -OH,-(CH 2 ) k -OR 6a , -COR 6a ,-(CH 2 ) k -CH (OR 6a ) 2 ,-(CH 2 ) k -CN,-(CH 2 ) k -NR 6a R 6b , aryl, aryl-lower alkyl,-(CH 2 ) g -COOR 43 or-(CH 2 ) g -CF 3 ; 상기 식에서, k는 1, 2, 3 또는 4이고;Wherein k is 1, 2, 3 or 4; R6a및 R6b는 독립적으로 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 6a and R 6b are independently hydrogen, lower alkyl, aryl or aryl-lower alkyl; g는 0, 1, 2, 3 또는 4이고;g is 0, 1, 2, 3 or 4; R43은 수소 또는 저급 알킬이고;R 43 is hydrogen or lower alkyl; G"는 -OCH2CO-, -CH2CO-, -CO- 또는 원자가 결합이고;G ″ is —OCH 2 CO—, —CH 2 CO—, —CO— or a valence bond; E"는 -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- 또는 -CH2CH2NH-이고;E ″ is —CH 2 —, —CH 2 CH 2 —, —CH═CH—, —CH 2 NH— or —CH 2 CH 2 NH—; D는 수소,D is hydrogen, 이고;ego; 상기 식에서, r은 O 또는 1이고;Wherein r is 0 or 1; s는 0, 1, 2 또는 3이고;s is 0, 1, 2 or 3; E, E', F, G 및 G'는 독립적으로 -CHR38-, >C=O, >NR39, -O- 또는 -S-이고;E, E ', F, G and G' are independently -CHR 38 -,> C = O,> NR 39 , -O- or -S-; F'는 >CR38- 또는 >N-이고;F 'is> CR 38 -or>N-; Y'는 -N= 또는 -CR32=이고;Y 'is -N = or -CR 32 =; Z'는 -N= 또는 -CR33=이고;Z 'is -N = or -CR 33 =; V'는 -N= 또는 -CR34=이고;V 'is -N = or -CR 34 =; W'는 -N= 또는 -CR35=이고;W 'is -N = or -CR 35 =; Q'는 -NR36-, -O- 또는 -S-이고;Q 'is -NR 36- , -O- or -S-; 상기 식에서, R27, R28, R32, R33, R34및 R35는 독립적으로 수소, 할로겐, -CN, -CF3, -O(CH2)yCF3, -(CH2)yNHCOCF3, -NO2, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -COR29또는 -CO2R29이거나;Wherein R 27 , R 28 , R 32 , R 33 , R 34 and R 35 are independently hydrogen, halogen, -CN, -CF 3 , -O (CH 2 ) y CF 3 ,-(CH 2 ) y NHCOCF 3 , -NO 2 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 ,-(CH 2 ) y CONR 29 R 30 , -O (CH 2 ) y CONR 29 R 30 ,-(CH 2 ) y OR 29 ,-(CH 2 ) y NR 29 R 30 , -OCOR 29 , -COR 29 or —CO 2 R 29 ; 또는 R27및 R28, R32및 R33, R33및 R34, 또는 R34및 R35는 함께 다리 -0(CH2)yO-를 형성하고;Or R 27 and R 28 , R 32 and R 33 , R 33 and R 34 , or R 34 and R 35 together form a bridge —0 (CH 2 ) y O—; 상기 식에서, y는 0, 1, 2, 3 또는 4이고;Wherein y is 0, 1, 2, 3 or 4; R29및 R30은 독립적으로 수소, -COR31, -CO2R31, -SO2R31, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 29 and R 30 are independently hydrogen, —COR 31 , —CO 2 R 31 , —SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl; 상기 식에서, R31은 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;In which R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R36및 R39는 독립적으로 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 36 and R 39 are independently hydrogen, lower alkyl, aryl or aryl-lower alkyl; R38은 수소, -OR40, -NR40R41, 저급 알킬, 아릴, 아릴-저급 알킬, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)xCONR40R41, -(CH2)xOR40, -(CH2)xNR40R41, -OCOR40또는 -CO2R40이고;R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 ,-(CH 2 ) x CONR 40 R 41 , -O (CH 2 ) x CONR 40 R 41 ,-(CH 2 ) x OR 40 ,-(CH 2 ) x NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ; 상기 식에서, x는 1, 2, 3 또는 4이고;Wherein x is 1, 2, 3 or 4; R40및 R41은 독립적으로 수소, -COR42, -SO2R42, 저급 알킬, 아릴 또는 아릴-저급 알킬이고;R 40 and R 41 are independently hydrogen, —COR 42 , —SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl; 상기 식에서, R42는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬이다.Wherein R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl. 제 1 항에 있어서, 다음 화학식 II를 가지는 것을 특징으로 하는 화합물.A compound according to claim 1 having the formula II. (화학식 II)Formula II 상기 식에서, A, B, K, D, R3, R4, n 및 m은 제 1 항에서 정의된 바와 같다.Wherein A, B, K, D, R 3 , R 4 , n and m are as defined in claim 1. 제 1 항에 있어서, 다음 화학식 III을 가지는 것을 특징으로 하는 화합물.A compound according to claim 1 having the formula III. (화학식 III)Formula III 상기 식에서, A, B, K, D, R3, R4, n 및 m은 제 1 항에서 정의된 바와 같다.Wherein A, B, K, D, R 3 , R 4 , n and m are as defined in claim 1. 제 1 항에 있어서, 다음 화학식 IV를 가지는 것을 특징으로 하는 화합물.A compound according to claim 1 having the formula IV. (화학식 IV)Formula IV 상기 식에서, A, B, K, D, R3, R4, n 및 m은 제 1 항에서 정의된 바와 같다.Wherein A, B, K, D, R 3 , R 4 , n and m are as defined in claim 1. 제 1 항 내지 제 4 항중 어느 한 항에 있어서, R3이 수소인 것을 특징으로 하는 화합물.The compound of any of claims 1-4, wherein R 3 is hydrogen. 제 1 항 내지 제 5 항중 어느 한 항에 있어서, R4가 수소인 것을 특징으로 하는 화합물.A compound according to any one of claims 1 to 5, wherein R 4 is hydrogen. 제 1 항 내지 제 6 항중 어느 한 항에 있어서, A가The compound according to any one of claims 1 to 6, wherein A is (상기 식에서, R7, R8, R9및 R10은 제 1 항에서 정의된 바와 같다)로 구성되는 군에서 선택되는 것을 특징으로 하는 화합물.Wherein R 7 , R 8 , R 9 and R 10 are as defined in claim 1. 제 7 항에 있어서, A가8. A compound according to claim 7, wherein A is (상기 식에서, R7, R8및 R9는 제 1 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.Wherein R 7 , R 8 and R 9 are as defined in claim 1. 제 7 항 또는 제 8 항에 있어서, R7이 할로겐, 저급 알킬, -OH, -NO2, -CN, -CO2H, -O-저급 알킬, 아릴, 아릴-저급 알킬, -CO2CH3, -CONH2, -OCH2CONH2, -NH2, -N(CH3)2, -SO2NH2, -OCHF2, -CF3또는 -OCF3인 것을 특징으로 하는 화합물.9. The compound of claim 7 , wherein R 7 is halogen, lower alkyl, —OH, —NO 2 , —CN, —CO 2 H, —O-lower alkyl, aryl, aryl-lower alkyl, —CO 2 CH 3 , -CONH 2 , -OCH 2 CONH 2 , -NH 2 , -N (CH 3 ) 2 , -SO 2 NH 2 , -OCHF 2 , -CF 3 or -OCF 3 . 제 7 항 내지 제 9 항중 어느 한 항에 있어서, R8및 R9는 독립적으로 수소, 할로겐, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-저급 알킬, 저급 알킬, 또는 페닐이고, R10은 수소, 저급 알킬 또는 페닐인 것을 특징으로 하는 화합물.10. The compound of claim 7, wherein R 8 and R 9 are independently hydrogen, halogen, —OH, —NO 2 , —NH 2 , —CN, —OCF 3 , —SCF 3 , —CF 3. , -OCH 2 CF 3 , -O-lower alkyl, lower alkyl, or phenyl, R 10 is hydrogen, lower alkyl or phenyl. 제 10 항에 있어서, R8및 R9는 독립적으로 수소, 할로겐, -O-저급 알킬, -NH2, -CN 또는 -NO2이고, R10은 수소인 것을 특징으로 하는 화합물.The compound of claim 10, wherein R 8 and R 9 are independently hydrogen, halogen, —O-lower alkyl, —NH 2 , —CN or —NO 2 , and R 10 is hydrogen. 제 8 항에 있어서, A가9. A compound according to claim 8 wherein A is (상기 식에서, R8및 R9는 독립적으로 제 10 항 또는 제 11 항중 어느 한 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.Wherein R 8 and R 9 are independently as defined in any of claims 10 or 11. 제 12 항에 있어서, A가13. The compound of claim 12 wherein A is (상기 식에서, R8은 수소, 할로겐, -O-저급 알킬, -NH2, -CN 또는 -NO2이고, R9는 수소 또는 할로겐이다)인 것을 특징으로 하는 화합물.Wherein R 8 is hydrogen, halogen, —O-lower alkyl, —NH 2 , —CN or —NO 2 , and R 9 is hydrogen or halogen. 제 7 항 내지 제 13 항중 어느 한 항에 있어서, 다음 화학식 V를 가지는 것을 특징으로 하는 화합물.14. A compound according to any one of claims 7 to 13 having the formula (V). (화학식 V)Formula V 상기 식에서, R8및 R9는 제 1 항, 제 10 항, 제 11 항 또는 제 13 항중 어느 한 항에서 정의된 바와 같고, R4, B, K, D 및 m은 제 1 항에서 정의된 바와 같다.Wherein R 8 and R 9 are as defined in any one of claims 1, 10, 11 or 13 and R 4 , B, K, D and m are defined in claim 1 As shown. 제 1 항 내지 제 14 항중 어느 한 항에 있어서, B는15. The method of any of claims 1-14, wherein B is (상기 식에서, V, W, Z, Y 및 Q는 제 1 항에서 정의된 바와 같고; R14및 R15는 독립적으로 수소, 할로겐, -CF3, -OCF3, -OR16, -NR16R17, 저급 알킬, 아릴, 아릴-저급 알킬, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16또는 -CO2R18이거나; 또는 R14및 R15는 함께 다리 -OCH2O- 또는 -(CH2)l-을 형성하고; 상기 식에서 l, R16, R17및 R18은 제 1 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.Wherein V, W, Z, Y and Q are as defined in claim 1; R 14 and R 15 are independently hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; Or R 14 and R 15 together form a bridge -OCH 2 O- or-(CH 2 ) l -wherein l, R 16 , R 17 and R 18 are as defined in claim 1); Characterized by a compound. 제 15 항에 있어서, Q가 -O- 또는 -NH-인 것을 특징으로 하는 화합물.The compound of claim 15, wherein Q is -O- or -NH-. 제 15 항에 있어서, B는The method of claim 15, wherein B is (상기 식에서, R14및 R15는 제 15 항에서 정의된 바와 같고, V, W, Z 및 Y는 제 1 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.Wherein R 14 and R 15 are as defined in claim 15 and V, W, Z and Y are as defined in claim 1. 제 17 항에 있어서, 다음 화학식 VI을 가지는 것을 특징으로 하는 화합물.18. A compound of claim 17 having the formula VI: (화학식 VI)Formula VI 상기 식에서, R14및 R15는 제 15 항에서 정의된 바와 같고, R8및 R9는 제 1 항, 제 10 항, 제 11 항 또는 제 13 항중 어느 한 항에서 정의된 바와 같고, K, D 및 m은 제 1 항에서 정의된 바와 같다.Wherein R 14 and R 15 are as defined in claim 15, R 8 and R 9 are as defined in any one of claims 1, 10, 11 or 13, K, D and m are as defined in claim 1. 제 17 항에 있어서, 다음 화학식 VII을 가지는 것을 특징으로 하는 화합물.18. Compounds according to claim 17, having the general formula (VII). (화학식 VII)Formula VII 상기 식에서, R14및 R15는 제 15 항에서 정의된 바와 같고, R8및 R9는 제 1 항, 제 10 항, 제 11 항 또는 제 13 항중 어느 한 항에서 정의된 바와 같고, K, D 및 m은 제 1 항에서 정의된 바와 같다.Wherein R 14 and R 15 are as defined in claim 15, R 8 and R 9 are as defined in any one of claims 1, 10, 11 or 13, K, D and m are as defined in claim 1. 제 17 항에 있어서, 다음 화학식 VIIIa 또는 VIIIb를 가지는 것을 특징으로 하는 화합물.18. The compound of claim 17, having the formula VIIIa or VIIIb. (화학식 VIIIa)Formula VIIIa 또는or (화학식 VIIIb)Formula VIIIb 상기 식에서, R14및 R15는 제 15 항에서 정의된 바와 같고, R8및 R9는 제 1 항, 제 10 항, 제 11 항 또는 제 13 항중 어느 한 항에서 정의된 바와 같고, K, D 및 m은 제 1 항에서 정의된 바와 같다.Wherein R 14 and R 15 are as defined in claim 15, R 8 and R 9 are as defined in any one of claims 1, 10, 11 or 13, K, D and m are as defined in claim 1. 제 15 항 내지 제 20 항중 어느 한 항에 있어서, R14및 R15는 독립적으로 수소, 할로겐, 저급 알킬, -O-저급 알킬 또는 아릴인 것을 특징으로 하는 화합물.21. The compound of any of claims 15-20, wherein R 14 and R 15 are independently hydrogen, halogen, lower alkyl, -O-lower alkyl or aryl. 제 1 항 내지 제 21 항중 어느 한 항에 있어서, K가22. The method of any one of claims 1 to 21 wherein K is (상기 식에서, R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p 및 q는 제 1 항에서 정의된 바와 같다)로 구성되는 군에서 선택되는 것을 특징으로 하는 화합물.Wherein R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined in claim 1 Compound characterized by the above-mentioned. 제 22 항에 있어서, K가23. The compound of claim 22 wherein K is (상기 식에서, R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p 및 q는 제 1 항에서 정의된 바와 같다)로 구성되는 군에서 선택되는 것을 특징으로 하는 화합물.Wherein R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined in claim 1 Compound characterized by the above-mentioned. 제 23 항에 있어서, K가The method of claim 23, wherein K is (상기 식에서, R3a, R3b, R4a, R4b, R5a, R5b, b, c, d, p 및 q는 제 1 항에서 정의된 바와 같다)로 구성되는 군에서 선택되는 것을 특징으로 하는 화합물.Wherein R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , b, c, d, p and q are as defined in claim 1 Compound made into. 제 22 항 내지 24 항중 어느 한 항에 있어서, R5a및 R5b는 독립적으로 수소, 저급 알킬, -OH, -(CH2)kOR6a, 아릴, 아릴-저급 알킬, -CH2CF3, -(CH2)g-COOR43, -COOR43, -(CH2)k-CN 또는 -(CH2)k-NR6aR6b(상기 식에서, g, k, R43, R6a및 R6b는 제 1 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.The compound of claim 22, wherein R 5a and R 5b are independently hydrogen, lower alkyl, —OH, — (CH 2 ) k OR 6a , aryl, aryl-lower alkyl, —CH 2 CF 3 , -(CH 2 ) g -COOR 43 , -COOR 43 ,-(CH 2 ) k -CN or-(CH 2 ) k -NR 6a R 6b (wherein g, k, R 43 , R 6a and R 6b Is as defined in claim 1). 제 25 항에 있어서, g 및 k는 독립적으로 1, 2 또는 3이고, R6a및 R6b는 독립적으로 수소, 메틸 또는 에틸과 같은 저급 알킬, 또는 페닐과 같은 아릴인 것을 특징으로 하는 화합물.The compound of claim 25, wherein g and k are independently 1, 2 or 3 and R 6a and R 6b are independently hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl. 제 22 항 내지 제 26 항중 어느 한 항에 있어서, R3a및 R3b는 독립적으로 수소, 할로겐, -OH, -O-저급 알킬, -COO-저급 알킬, 저급 알킬 또는 아릴-저급 알킬인 것을 특징으로 하는 화합물.27. The compound of any of claims 22 to 26, wherein R 3a and R 3b are independently hydrogen, halogen, -OH, -O-lower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl. Compound made into. 제 22 항 내지 제 27 항중 어느 한 항에 있어서, R4a및 R4b는 독립적으로 수소, -CN, -CONH2, -(CH2)-N(CH3)2, -O-저급 알킬, -CH2OH, -CH2O-아릴, -N(CH3)2, -OH, -CO2-저급 알킬 또는 저급 알킬인 것을 특징으로 하는 화합물.28. The compound of any one of claims 22-27, wherein R 4a and R 4b are independently hydrogen, -CN, -CONH 2 ,-(CH 2 ) -N (CH 3 ) 2 , -O-lower alkyl,- CH 2 OH, —CH 2 O-aryl, —N (CH 3 ) 2 , —OH, —CO 2 —lower alkyl or lower alkyl. 제 1 항 내지 제 28 항중 어느 한 항에 있어서, D가 수소,29. The method of any one of claims 1 to 28, wherein D is hydrogen, (상기 식에서, s, r, R27, R28, V', Y', Q', Z', W', E, E', F, F', G 및 G'는 제 1 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.Wherein s, r, R 27 , R 28 , V ', Y', Q ', Z', W ', E, E', F, F ', G and G' are defined in claim 1 Compound). 제 29 항에 있어서, D가 수소,The method of claim 29, wherein D is hydrogen, (상기 식에서, s, r, R27, R28, V', Y', Z', Q', Z', W', E, E', F, F', G 및 G'는 제 1 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.Wherein s, r, R 27 , R 28 , V ', Y', Z ', Q', Z ', W', E, E ', F, F', G and G 'are As defined in the above). 제 29 항에 있어서, D가 수소,The method of claim 29, wherein D is hydrogen, (상기 식에서, E 및 E'는 독립적으로 >CHR38, >NR39또는 -O-이고; F, G 및 G'는 독립적으로 >CHR38, >C=O, 또는 >NR39이고; F'는 >CR38- 또는 >N-이고; s, r, R27, R28, R38, R39, V', Y', Z', Q' 및 W'는 제 1 항에서 정의된 바와 같다)인 것을 특징으로 하는 화합물.Wherein E and E 'are independently> CHR 38 ,> NR 39 or -O-; F, G and G' are independently> CHR 38 ,> C = O, or> NR 39 ; F 'Is> CR 38 -or>N-; s, r, R 27 , R 28 , R 38 , R 39 , V ', Y', Z ', Q' and W 'are as defined in claim 1 ) Compound. 제 29 항 내지 제 31 항중 어느 한 항에 있어서, R27및 R28은 독립적으로 수소; -Cl, -Br 또는 -F와 같은 할로겐; -CF3; -OCF3; -OCHF2; -OCH2CF3; -(CH2)yNHCOCF3; -NHCOCF3; -CN; -NO2; -COR29, -COOR29, -(CH2)yOR29또는 OR29(상기 식에서, R29는 수소, 아릴 또는 저급 알킬이고, y는 1, 2, 3 또는 4이다); 메틸, 에틸, 2-프로펜일, 이소프로필, tert-부틸 또는 시클로헥실과 같은 저급 알킬; 저급 알킬티오; -SCF3; 페닐과 같은 아릴; -(CH2)yNR29R30또는 -NR29R30(상기 식에서, R29및 R30은 독립적으로 수소, -COO-저급 알킬 또는 저급 알킬이고, y는 1, 2, 3 또는 4이다); 또는 -CONH2이거나; 또는 R27및 R28은 함께 다리 -OCH2O-를 형성하고; R38은 수소; -OCHF2; -OR40(상기 식에서, R40은 수소 또는 저급 알킬이다); 메틸, 이소프로필 또는 tert-부틸과 같은 저급 알킬; 저급 알킬티오; -SCF3; -CH2OH; -COO-저급 알킬 또는 -CONH2이고; R39는 수소, 저급 알킬, 아릴 또는 아릴-저급 알킬인 것을 특징으로 하는 화합물.32. The compound of any of claims 29 to 31, wherein R 27 and R 28 are independently hydrogen; Halogen, such as -Cl, -Br or -F; -CF 3 ; -OCF 3 ; -OCHF 2 ; -OCH 2 CF 3 ; -(CH 2 ) y NHCOCF 3 ; -NHCOCF 3 ; -CN; -NO 2 ; -COR 29 , -COOR 29 ,-(CH 2 ) y OR 29 or OR 29 (wherein R 29 is hydrogen, aryl or lower alkyl and y is 1, 2, 3 or 4); Lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; Lower alkylthio; -SCF 3 ; Aryl such as phenyl; — (CH 2 ) y NR 29 R 30 or —NR 29 R 30 , wherein R 29 and R 30 are independently hydrogen, —COO-lower alkyl or lower alkyl, and y is 1, 2, 3 or 4 ); Or -CONH 2 ; Or R 27 and R 28 together form a bridge —OCH 2 O—; R 38 is hydrogen; -OCHF 2 ; -OR 40 , wherein R 40 is hydrogen or lower alkyl; Lower alkyl such as methyl, isopropyl or tert-butyl; Lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl or -CONH 2 ; R 39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl. 제 1 항 내지 제 32 항중 어느 한 항에 있어서, 약제로서 사용되는 것을 특징으로 하는 화합물.33. A compound according to any one of claims 1 to 32, which is used as a medicament. 1개 이상의 약학적으로 허용되는 담체 또는 부형제와 함께 활성 성분으로서 적어도 하나의 제 1 항 내지 제 32 항중 어느 한 항에 따르는 화합물로 이루어지는 것을 특징으로 하는 약학적 조성물.A pharmaceutical composition, comprising at least one compound according to any one of claims 1 to 32 as an active ingredient together with one or more pharmaceutically acceptable carriers or excipients. 제 34 항에 있어서, 제 1 항 내지 제 32항중 어느 한 항에 따르는 화합물 약 0.05mg 내지 약 1000mg, 바람직하게 약 0.5mg 내지 약 250mg과 같은 약 0.1mg 내지 약 500mg을 포함하는 단위 제형인 것을 특징으로 하는 약학적 조성물.35. A unit dosage form according to claim 34 comprising from about 0.1 mg to about 500 mg, such as from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compound according to any one of claims 1 to 32. Pharmaceutical compositions. 타입 I 또는 타입 II 당뇨병을 치료하는 방법에 있어서, 제 1 항 내지 제 32 항중 어느 한 항에 따르는 화합물의 유효량을 상기 치료가 필요한 환자에게 투여하는 것으로 이루어지는 것을 특징으로 방법.33. A method of treating type I or type II diabetes comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 32. 고혈당을 치료하는 방법에 있어서, 제 1 항 내지 제 32 항중 어느 한 항에 따르는 화합물의 유효량을 상기 치료가 필요한 환자에게 투여하는 것으로 이루어지는 것을 특징으로 하는 방법.33. A method of treating hyperglycemia, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 32. 포유동물에서 혈당을 낮추는 방법에 있어서, 제 1 항 내지 제 32 항중 어느 한 항에 따르는 화합물의 유효량을 상기 포유동물에 투여하는 것으로 이루어지는 것을 특징으로 하는 방법.33. A method of lowering blood sugar in a mammal, comprising administering to said mammal an effective amount of a compound according to any one of claims 1 to 32. 제 36 항 내지 제 38 항중 어느 한 항에 있어서, 약 0.05mg 내지 약 1000mg, 바람직하게 약 0.5mg 내지 약 250mg 등과 같은 약 0.1mg 내지 약 500mg의 범위의 양의 제 1 항 내지 제 33 항중 어느 한 항에서 정의된 바와 같은 화합물을 1일당 1 내지 3회와 같이, 1일당 1회 이상 상기 치료가 필요한 환자에게 투여하는 것으로 이루어지는 것을 특징으로 하는 방법.The method of any one of claims 36-38, wherein the amount is in the range of about 0.1 mg to about 500 mg, such as about 0.05 mg to about 1000 mg, preferably about 0.5 mg to about 250 mg, and the like. And administering to the patient in need of said treatment at least once a day, such as 1-3 times per day, as defined in claim. 타입 I 또는 타입 II 당뇨병을 치료하기 위한 약제를 제조하기 위한 제 1 항 내지 제 32 항중 어느 한 항에 따르는 화합물의 사용.Use of a compound according to any one of claims 1 to 32 for the manufacture of a medicament for treating type I or type II diabetes. 저혈당을 치료하기 위한 약제를 제조하기 위한 제 1 항 내지 제 32 항중 어느 한 항에 따르는 화합물의 사용.Use of a compound according to any one of claims 1 to 32 for the manufacture of a medicament for the treatment of hypoglycemia. 포유동물에서 혈당을 낮추기 위한 약제를 제조하기 위한 제 1 항 내지 제 32 항중 어느 한 항에 따르는 화합물의 사용.Use of a compound according to any one of claims 1 to 32 for the manufacture of a medicament for lowering blood sugar in a mammal. 제 1 항 내지 제 32 항중 어느 한 항에 있어서, 명세서에 개시된 글루카곤 결합시험 I 또는 글루카곤 결합시험 II에 의해 측정될 때 1μM 미만의 IC50값, 바람직하게 500nM 미만, 보다 더 바람직하게 100nM 미만의 IC50값에 해당하는 글루카곤 길항활성을 가지는 것을 특징으로 하는 화합물.33. The IC of any one of the preceding claims, wherein an IC 50 value of less than 1 μM, preferably less than 500 nM, even more preferably less than 100 nM, as measured by the glucagon binding test I or glucagon binding test II disclosed herein. Compound having a glucagon antagonist activity corresponding to a value of 50 .
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Families Citing this family (132)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6613942B1 (en) * 1997-07-01 2003-09-02 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6927214B1 (en) 1999-01-15 2005-08-09 Novo Nordisk A/S Non-peptide GLP-1 agonists
EP1147094A1 (en) * 1999-01-15 2001-10-24 Novo Nordisk A/S Non-peptide glp-1 agonists
JP2002544254A (en) * 1999-05-17 2002-12-24 ノボ ノルディスク アクティーゼルスカブ Glucagon antagonist / inverse agonist
US6503949B1 (en) 1999-05-17 2003-01-07 Noro Nordisk A/S Glucagon antagonists/inverse agonists
AUPQ262499A0 (en) 1999-09-02 1999-09-23 University Of Queensland, The Novel iron chelators
ES2436610T3 (en) 2000-01-21 2014-01-03 Novartis Ag Combinations containing dipeptidylpeptidase-IV inhibitors and antidiabetic agents
WO2001055107A2 (en) * 2000-01-28 2001-08-02 Melacure Therapeutics Ab Aromatic amines and amides acting on the melanocortin receptors
HUP0301501A2 (en) * 2000-06-23 2003-08-28 Novo Nordisk A/S Glucagon antagonists/inverse agonists, pharmaceutical compositions containing them and their use for preparation of pharmaceutical compositions
US6562807B2 (en) 2000-06-23 2003-05-13 Novo Nordisk A/S Glucagon antagonists/inverse agonists
US6706744B2 (en) 2000-11-17 2004-03-16 Novo Nordisk A/S Glucagon antagonists/inverse agonists
AU2002223501A1 (en) * 2000-11-17 2002-05-27 Agouron Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
AU2002223502A1 (en) * 2000-11-17 2002-05-27 Novo-Nordisk A/S Glucagon antagonist/inverse agonist
US6821960B2 (en) 2000-11-17 2004-11-23 Noyo Nordisk Pharmaceuticals, Inc. Glucagon antagonists/inverse agonists
JP2004513935A (en) * 2000-11-17 2004-05-13 ノボ　ノルディスク　アクティーゼルスカブ Glucagon antagonist / inverse agonist
UA74912C2 (en) 2001-07-06 2006-02-15 Merck & Co Inc Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes
EP2243776A1 (en) 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Substituted piperidines and their use for the treatment of diseases related to the histamine H3 receptor
US6881746B2 (en) 2001-12-03 2005-04-19 Novo Nordick A/S Glucagon antagonists/inverse agonists
US6762318B2 (en) 2001-12-03 2004-07-13 Novo Nordisk A/S Glucagon antagonists
CZ2004747A3 (en) 2001-12-21 2004-11-10 Novo Nordisk A/S Amide derivatives functioning as GK activators
CN100543022C (en) * 2002-02-01 2009-09-23 大日本住友制药株式会社 2-furancarboxylic acid hydrazide compound and contain the pharmaceutical composition of this compound
AUPS120902A0 (en) * 2002-03-19 2002-04-18 Unisearch Limited Iron chelators as anti-proliferative agents against tumour cells
WO2003097031A1 (en) * 2002-05-22 2003-11-27 Sanwa Kagaku Kenkyusho Co., Ltd. Obesity preventive or ameliorator containing methylidene hydrazide compound as active ingredient
JP4881559B2 (en) 2002-06-27 2012-02-22 ノボ・ノルデイスク・エー／エス Arylcarbonyl derivatives as therapeutic agents
US7196106B2 (en) 2002-11-05 2007-03-27 Merck & Co., Inc Cyanothiophene derivatives, compositions containing such compounds and methods of use
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
EP1615698B1 (en) 2003-04-11 2010-09-29 High Point Pharmaceuticals, LLC New amide derivatives and pharmaceutical use thereof
JP2005060385A (en) * 2003-07-31 2005-03-10 Dainippon Pharmaceut Co Ltd Medicine comprising 2-furancarboxylic acid hydrazide compound
CA2539596A1 (en) 2003-09-30 2005-04-07 Kilian Waldemar Conde-Frieboes Melanocortin receptor agonists
ATE498404T1 (en) 2003-12-09 2011-03-15 Novo Nordisk As REGULATION OF FOOD PREFERENCE WITH GLP-1 AGONISTS
DK1723128T3 (en) 2004-01-06 2013-02-18 Novo Nordisk As Heteroarlurines and their use as glucokinase activators
US8410047B2 (en) 2004-06-11 2013-04-02 Novo Nordisk A/S Counteracting drug-induced obesity using GLP-1 agonists
DE102004030987A1 (en) * 2004-06-26 2006-01-12 Merck Patent Gmbh Ortho-substituted (3-hydroxyphenyl) -acetic acid benzylidene hydrazides
EP1841749A1 (en) 2004-09-02 2007-10-10 Metabasis Therapeutics, Inc. Derivatives of thiazole and thiadiazole inhibitors of tyrosine phosphatases
US8263551B2 (en) 2004-11-22 2012-09-11 Novo Nordisk A/S Soluble, stable insulin-containing formulations with a protamine salt
JP2008521864A (en) 2004-12-03 2008-06-26 トランステック・ファーマ、インコーポレイテッド Heteroaromatic glucokinase activator
PT1853266E (en) 2005-01-10 2012-01-20 Cortendo Ab Publ 2s,4r ketoconazole for treating diabetes, metabolic syndrome and other conditions
US20080171695A1 (en) 2005-02-02 2008-07-17 Novo Nordisk A/S Insulin Derivatives
US8067362B2 (en) 2005-02-02 2011-11-29 Novo Nordisk As Insulin derivatives
US8318760B2 (en) 2005-03-21 2012-11-27 Merck Sharp & Dohme Corp. Substituted aryl and heteroaryl derivatives, compositions containing such compounds and methods of use
US7803951B2 (en) 2005-03-30 2010-09-28 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
BRPI0612730A2 (en) 2005-06-30 2010-11-30 Novo Nordisk As compounds, their preparations and their use
CN103110635A (en) 2005-07-04 2013-05-22 海波因特制药有限责任公司 Histamine H3 receptor antagonist
CA2615938C (en) 2005-07-14 2014-04-29 Novo-Nordisk A/S Urea glucokinase activators
WO2007015805A1 (en) 2005-07-20 2007-02-08 Eli Lilly And Company 1-amino linked compounds
PL1931350T5 (en) 2005-09-14 2021-11-15 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
TW200745031A (en) 2005-10-13 2007-12-16 Merck & Co Inc Acyl indoles, compositions containing such compounds and methods of use
EP1801098A1 (en) 2005-12-16 2007-06-27 Merck Sante 2-Adamantylurea derivatives as selective 11B-HSD1 inhibitors
CA2631390C (en) 2005-12-22 2014-03-11 Per Sauerberg Phenoxy acetic acids as ppar delta activators
AU2007229850A1 (en) 2006-03-23 2007-10-04 Merck & Co., Inc. Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
JP2009531376A (en) 2006-03-28 2009-09-03 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー Benzothiazole having histamine H3 receptor activity
JP2009537525A (en) 2006-05-16 2009-10-29 メルク エンド カムパニー インコーポレーテッド Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
NZ571972A (en) 2006-05-29 2011-09-30 High Point Pharmaceuticals Llc 3- (1, 3-benz0di0x0l-5-yl) -6- (4-cyclopropylpiperazin-1-yl) -pyridazine, its salts and solvates and its use as histamine h3 receptor antagonist
EP2076265A4 (en) 2006-10-02 2010-09-22 Cortendo Invest Ab Ketoconazole enantiomer in humans
TW200821284A (en) 2006-10-03 2008-05-16 Merck & Co Inc Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use
ES2377322T3 (en) 2006-11-15 2012-03-26 High Point Pharmaceuticals, Llc New 2- (2-hydroxyphenyl) benzothiadiazines useful for the treatment of obesity and diabetes
US7786139B2 (en) 2006-11-21 2010-08-31 Omeros Corporation PDE10 inhibitors and related compositions and methods
EP1935420A1 (en) 2006-12-21 2008-06-25 Merck Sante 2-Adamantyl-butyramide derivatives as selective 11beta-HSD1 inhibitors
EP2099777B1 (en) 2007-01-11 2015-08-12 Novo Nordisk A/S Urea glucokinase activators
BRPI0808157A2 (en) * 2007-02-02 2014-07-01 Redpoint Bio Corp USE OF TRPM5 INHIBITOR FOR REGULATING INSULIN AND GLP-1 RELEASE
EP2110374A1 (en) 2008-04-18 2009-10-21 Merck Sante Benzofurane, benzothiophene, benzothiazol derivatives as FXR modulators
FR2932481B1 (en) * 2008-06-13 2010-10-08 Sanofi Aventis 4- {2-4-PHENYL-3,6-DIHYDRO-2H-PYRIDIN-1-YL] -2-OXO-ALKYL} -1-PIPERAZIN-2-ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE.
FR2932482B1 (en) * 2008-06-13 2010-10-08 Sanofi Aventis NOVEL (PHENYL-3,6-DIHYDRO-2H-PYRIDINYL) - (PIPERAZINYL PONTE) -1-ALKANONE DERIVATIVES AND THEIR USE AS P75 INHIBITORS
US20100035932A1 (en) * 2008-08-07 2010-02-11 Schepetkin Igor A Novel formyl peptide receptor like 1 agonists that induce macrophage tumor necrosis factor alpha and computational structure-activity relationship analysis of thereof
JO2870B1 (en) 2008-11-13 2015-03-15 ميرك شارب اند دوهم كورب Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2010056717A1 (en) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Substituted bicyclic amines for the treatment of diabetes
KR20110088575A (en) 2008-11-21 2011-08-03 하이 포인트 파마슈티칼스, 엘엘씨 Adamantyl benzamide compounds
CA2768577A1 (en) 2009-07-23 2011-01-27 Schering Corporation Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
WO2011011506A1 (en) 2009-07-23 2011-01-27 Schering Corporation Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
EP2464228B1 (en) 2009-08-13 2017-12-06 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
WO2011028455A1 (en) 2009-09-02 2011-03-10 Merck Sharp & Dohme Corp. Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2011041293A1 (en) 2009-09-30 2011-04-07 Takeda Pharmaceutical Company Limited Pyrazolo [1, 5-a] pyrimidine derivatives as apoptosis signal-regulating kinase 1 inhibitors
EP2501685A1 (en) 2009-11-16 2012-09-26 Mellitech [1,5]-diazocin derivatives
FR2953839A1 (en) 2009-12-14 2011-06-17 Sanofi Aventis NOVEL (HETEROCYCLE-PIPERIDINE CONDENSEE) - (PIPERAZINYL) -1ALCANONE OR (HETEROCYCLE-PYRROLIDINE CONDENSED) - (PIPERAZINYL) -1ALCANONE DERIVATIVES AND THEIR USE AS INHIBITORS OF P75
FR2953836B1 (en) 2009-12-14 2012-03-16 Sanofi Aventis NOVEL DERIVATIVES (HETEROCYCLE-TETRAHYDRO-PYRIDINE) - (PIPERAZINYL) -1-ALKANONE AND (HETEROCYCLE-DIHYDRO-PYRROLIDINE) - (PIPERAZINYL) -1-ALKANONE AND THEIR USE AS INHIBITORS OF P75
US8648073B2 (en) 2009-12-30 2014-02-11 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
CA2787360C (en) 2010-02-03 2019-03-05 Takeda Pharmaceutical Company Limited Pyrrol0[3,2-c]pyridinyl-4-benzamide compounds and their use as apoptosis signal-regulating kinase 1 inhibitors
WO2011103256A1 (en) 2010-02-22 2011-08-25 Merck Sharp & Dohme Corp. Substituted aminotetrahydrothiopyrans and derivatives thereof as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes
BR112012021231A2 (en) 2010-02-26 2015-09-08 Basf Plant Science Co Gmbh method for enhancing plant yield, plant, construct, use of a construct, method for producing a transgenic plant, collectable parts of a plant, products derived from a plant, use of a nucleic acid and method for producing a product
WO2011104378A1 (en) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides for treatment of obesity
RU2559320C2 (en) 2010-03-26 2015-08-10 Ново Нордиск А/С Novel glucagon analogues
EP2571876B1 (en) 2010-05-21 2016-09-07 Merck Sharp & Dohme Corp. Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes
US8742110B2 (en) 2010-08-18 2014-06-03 Merck Sharp & Dohme Corp. Spiroxazolidinone compounds
US8609672B2 (en) 2010-08-27 2013-12-17 University Of The Pacific Piperazinylpyrimidine analogues as protein kinase inhibitors
AU2011346670B2 (en) 2010-12-23 2015-05-07 Pfizer Inc. Glucagon receptor modulators
WO2012107850A1 (en) 2011-02-08 2012-08-16 Pfizer Inc. Glucagon receptor modulator
CA2830974A1 (en) 2011-03-28 2012-10-04 Jesper F. Lau Novel glucagon analogues
EP2693882B1 (en) 2011-04-08 2017-06-28 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
JP2014518890A (en) 2011-06-02 2014-08-07 インターベット インターナショナル ベー． フェー． Imidazole derivatives
CA2838079A1 (en) 2011-06-16 2012-12-20 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds, and methods of treatment
US8927577B2 (en) 2011-07-22 2015-01-06 Pfizer Inc. Quinolinyl glucagon receptor modulators
KR20140070612A (en) 2011-09-23 2014-06-10 노보 노르디스크 에이/에스 Novel glucagon analogues
WO2013048916A1 (en) 2011-09-30 2013-04-04 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds, compositions containing such compounds and methods of treatment
EP2771000B1 (en) 2011-10-24 2016-05-04 Merck Sharp & Dohme Corp. Substituted piperidinyl compounds useful as gpr119 agonists
WO2013068328A1 (en) 2011-11-07 2013-05-16 Intervet International B.V. Bicyclo [2.2.2] octan-1-ylcarboxylic acid compounds as dgat-1 inhibitors
WO2013068439A1 (en) 2011-11-09 2013-05-16 Intervet International B.V. 4-amino-5-oxo-7,8-dihydropyrimido[5, 4 -f] [1, 4] oxazepine compounds as dgat1 inhibitors
JP2015501792A (en) 2011-11-10 2015-01-19 メモリアル スローン−ケタリング キャンサー センター Treatment of ovarian cancer with benzylidene benzohydrazide
WO2013074388A1 (en) 2011-11-15 2013-05-23 Merck Sharp & Dohme Corp. Substituted cyclopropyl compounds useful as gpr119 agonists
EP2606894A1 (en) 2011-12-20 2013-06-26 Sanofi Novel therapeutic use of p75 receptor antagonists
WO2013122920A1 (en) 2012-02-17 2013-08-22 Merck Sharp & Dohme Corp. Dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes
WO2013155600A1 (en) 2012-04-16 2013-10-24 Kaneq Pharma Fused aromatic phosphonate derivatives as precursors to ptp-1b inhibitors
WO2014018350A1 (en) 2012-07-23 2014-01-30 Merck Sharp & Dohme Corp. Treating diabetes with dipeptidyl peptidase-iv inhibitors
WO2014093696A2 (en) 2012-12-12 2014-06-19 Massachusetts Institute Of Technology Insulin derivatives for diabetes treatment
WO2014170496A1 (en) 2013-04-18 2014-10-23 Novo Nordisk A/S Stable, protracted glp-1/glucagon receptor co-agonists for medical use
WO2015066252A1 (en) 2013-11-04 2015-05-07 Merck Sharp & Dohme Corp. Glucagon receptor antagonist compounds, compositions thereof, and methods of use
WO2015112465A1 (en) 2014-01-24 2015-07-30 Merck Sharp & Dohme Corp. Isoquinoline derivatives as mgat2 inhibitors
CN106456998B (en) 2014-04-17 2020-07-28 默沙东公司 Sitagliptin tannate complex
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
BR112017008160A8 (en) 2014-10-24 2023-04-11 Merck Sharp & Dohme PEPTIDE, COMPOSITION, METHODS FOR TREATMENT OF A PATIENT OR INDIVIDUAL AND FOR TREATMENT OF A METABOLIC DISEASE, AND, USES OF A PEPTIDE AND A COMPOSITION
EP3233799B1 (en) 2014-12-19 2021-05-19 The Broad Institute, Inc. Dopamine d2 receptor ligands
WO2016100940A1 (en) 2014-12-19 2016-06-23 The Broad Institute, Inc. Dopamine d2 receptor ligands
CN104592120A (en) * 2015-02-13 2015-05-06 佛山市赛维斯医药科技有限公司 Cyclopropyl hydrazide and methoxybenzene-containing GPR119 agonist as well as preparation method and application thereof
CN104592121A (en) * 2015-02-13 2015-05-06 佛山市赛维斯医药科技有限公司 Compound containing hydrazide and nitrobenzene structure, as well as preparation method and application thereof
CN104610151A (en) * 2015-02-13 2015-05-13 佛山市赛维斯医药科技有限公司 Compound containing hydrazide and alkoxy benzene structures as well as preparation method and application thereof
CN104610156A (en) * 2015-02-13 2015-05-13 佛山市赛维斯医药科技有限公司 GPR119 agonist containing cyclopropyl hydrazide and cyanobenzene as well as preparation method and application thereof
CN104557717A (en) * 2015-02-13 2015-04-29 佛山市赛维斯医药科技有限公司 GPR119 hydrazide agonist, preparation method and use thereof
CN104610150A (en) * 2015-02-13 2015-05-13 佛山市赛维斯医药科技有限公司 Compound containing hydrazide and cyanobenzene structures as well as preparation method and application thereof
CN104610157A (en) * 2015-02-13 2015-05-13 佛山市赛维斯医药科技有限公司 GPR119 agonist containing cyclopropyl hydrazide and halogenated benzene structures and application thereof
CN104672144A (en) * 2015-02-13 2015-06-03 佛山市赛维斯医药科技有限公司 GPR119 agonist containing cyclopropyl hydrazide and nitrobenzene structures as well as preparation method and application thereof
WO2017062334A1 (en) 2015-10-05 2017-04-13 Merck Sharp & Dohme Corp. Antibody peptide conjugates that have agonist activity at both the glucagon and glucagon-like peptide 1 receptors
CN107151220B (en) * 2015-10-19 2021-07-20 中国医学科学院药物研究所 Phenol compound containing benzyloxy phenyl, preparation method and application thereof
EP3496715B1 (en) 2016-08-15 2021-11-03 Merck Sharp & Dohme Corp. Compounds useful for altering the levels of bile acids for the treatment of diabetes and cardiometabolic disease
WO2018034918A1 (en) 2016-08-15 2018-02-22 Merck Sharp & Dohme Corp. Compounds useful for altering the levels of bile acids for the treatment of diabetes and cardiometabolic disease
MA49883A (en) 2017-03-15 2021-04-21 Novo Nordisk As BICYCLIC COMPOUNDS SUITABLE TO BIND TO MELANOCORTIN 4 RECEPTOR
US20210221867A1 (en) 2018-05-15 2021-07-22 Novo Nordisk A/S Compounds Capable of Binding to Melanocortin 4 Receptor
WO2020053414A1 (en) 2018-09-14 2020-03-19 Novo Nordisk A/S Bicyclic compounds capable of acting as melanocortin 4 receptor agonists
WO2020074958A1 (en) 2018-10-12 2020-04-16 Strongbridge Dublin Limited Levoketoconazole for treatment of congenital adrenal hyperplasia and primary aldosteronism
WO2020205688A1 (en) 2019-04-04 2020-10-08 Merck Sharp & Dohme Corp. Inhibitors of histone deacetylase-3 useful for the treatment of cancer, inflammation, neurodegeneration diseases and diabetes
CN110229056B (en) * 2019-06-21 2022-11-08 天津科技大学 Novel curcumin analogue and preparation method and application thereof
EP3842061A1 (en) 2019-12-23 2021-06-30 Merck Sharp & Dohme Corp. Stapled triazole co-agonists of the glucagon and glp-1 receptors
EP3842449A1 (en) 2019-12-23 2021-06-30 Merck Sharp & Dohme Corp. Stapled olefin co-agonists of the glucagon and glp-1 receptors
EP3842060A1 (en) 2019-12-23 2021-06-30 Merck Sharp & Dohme Corp. Stapled lactam co-agonists of the glucagon and glp-1 receptors

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3746703A (en) * 1971-07-01 1973-07-17 American Home Prod 2,6-dichlorobenzylidenehydrazides
US3836580A (en) * 1971-07-01 1974-09-17 American Home Prod 2,6-dichlorobenzylidenehydrazides
US3859281A (en) * 1971-07-01 1975-01-07 American Home Prod 2,6-dichlorobenzylidenehydrazides
US4334015A (en) * 1979-05-23 1982-06-08 Minnesota Mining And Manufacturing Company Imaging compositions
DE4033808A1 (en) * 1990-04-11 1991-10-17 Bayer Ag NAPHTHALINE DERIVATIVES
JPH04121717A (en) * 1990-09-12 1992-04-22 Fuji Photo Film Co Ltd Novel organic nonlinear optical material and method for converting light wavelength by using this material
JP3529491B2 (en) * 1995-05-16 2004-05-24 旭電化工業株式会社 Thermal recording material
AU702887B2 (en) * 1995-10-31 1999-03-11 Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use

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