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KR20050026033A - New effector conjugates, process for their production and their pharmaceutical use - Google Patents

New effector conjugates, process for their production and their pharmaceutical use Download PDF

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KR20050026033A
KR20050026033A KR1020057001569A KR20057001569A KR20050026033A KR 20050026033 A KR20050026033 A KR 20050026033A KR 1020057001569 A KR1020057001569 A KR 1020057001569A KR 20057001569 A KR20057001569 A KR 20057001569A KR 20050026033 A KR20050026033 A KR 20050026033A
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dione
dihydroxy
tetramethyl
methyl
oxacyclohexades
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KR1020057001569A
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Korean (ko)
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마르쿠스 베르거
게르하르트 지마이스터
울리히 클라르
예르크 빌루다
안드레아스 멘라트
클라우스 보슬레트
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쉐링 악티엔게젤샤프트
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Priority claimed from DE10305098A external-priority patent/DE10305098A1/en
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Abstract

적합한 생분자 (인식 단위로서)를 갖는 에포틸론 및 에포틸론 유도체 (효과기로서)의 접합체를 기재한다. 이의 제조는 효과기를 적합한 연결기와 반응시킴으로써 수행하며, 제조된 화합물은 인식 단위에 접합된다. 증식 과정 또는 혈관신생과 관련된 과정을 치료하기 위한 접합체의 제약적 용도를 기재한다.Conjugates of epothilones and epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) are described. Its preparation is carried out by reacting an effector with a suitable linker, and the compound produced is conjugated to a recognition unit. The pharmaceutical use of the conjugate for treating proliferative processes or processes associated with angiogenesis is described.

Description

신규 효과기 접합체, 그의 제조 방법 및 그의 약학적 용도 {New Effector Conjugates, Process for Their Production and Their Pharmaceutical Use} New Effector Conjugates, Methods of Making the Same and Their Pharmaceutical Uses {New Effector Conjugates, Process for Their Production and Their Pharmaceutical Use}

연결기 (L)의 합성의 실시예Example of the synthesis of the linking group (L)

실시예 L1 Example L1

(S) 2-[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-프로판산 (S) 2-[(3-methyltrisulfanyl-propionyl) -methyl-amino] -propanoic acid

실시예 L1a Example L1a

(S) 2-[(3-아세틸술파닐-프로피오닐)-메틸-아미노]-프로판산 에틸 에스테르 (S) 2-[(3-acetylsulfanyl-propionyl) -methyl-amino] -propanoic acid ethyl ester

무수 테트라히드로푸란 850 ml 중 N-메틸알라닌 에틸 에스테르-히드로클로라이드 15 g (89.5 mmol)의 용액을 23℃에서 대략 60％의 수소화나트륨 분산물 4.1 g과 혼합하고, 3시간 후 3-아세틸술파닐-프로판산 클로라이드 23.5 g과 혼합하였다. 이를 2일 동안 반응시키고, 포화 중탄산나트륨 용액과 혼합하고, 에틸 아세테이트로 수회 추출하였다. 합한 유기 추출물을 포화 염화나트륨 용액으로 세척하고, 황산나트륨상에서 건조시키고, 여과 및 용매 제거 후 수득된 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 17.6 g (67.3 mmol, 75％)을 무색의 오일로서 단리하였다. A solution of 15 g (89.5 mmol) of N-methylalanine ethyl ester-hydrochloride in 850 ml of anhydrous tetrahydrofuran was mixed with 4.1 g of approximately 60% sodium hydride dispersion at 23 ° C., and after 3 hours 3-acetylsulfanyl Mixed with 23.5 g of propanoic chloride. It was reacted for 2 days, mixed with saturated sodium bicarbonate solution, and extracted several times with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue obtained after filtration and solvent removal was purified by chromatography on fine silica gel. 17.6 g (67.3 mmol, 75%) of the title compound were isolated as a colorless oil.

실시예 L1b Example L1b

(S) 2-[(3-메르캅토-프로피오닐)-메틸-아미노]-프로판산 (S) 2-[(3-mercapto-propionyl) -methyl-amino] -propanoic acid

메탄올 150 ml 중 실시예 L1a에 따라 제조된 화합물 17.6 g (67.3 mmol)의 용액을 23℃에서 5M 수산화나트륨 용액 44 ml와 혼합하고, 이를 5시간 동안 교반하였다. 4N 염산을 첨가하여 pH를 2로 설정하고, 이를 디클로로메탄으로 추출하였다. 합한 유기 추출물을 포화 염화나트륨 용액으로 세척하고, 황산나트륨상에서 건조시켰다. 여과 및 용매 제거 후 수득된 잔류물 (13.0 g, 최대 67.3 mmol)을 정제하지 않고 추가로 반응시켰다. A solution of 17.6 g (67.3 mmol) of the compound prepared according to Example L1a in 150 ml of methanol was mixed with 44 ml of 5M sodium hydroxide solution at 23 ° C. and stirred for 5 hours. 4N hydrochloric acid was added to set the pH to 2, which was extracted with dichloromethane. The combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The residue (13.0 g, up to 67.3 mmol) obtained after filtration and solvent removal was further reacted without purification.

실시예 L1c Example L1c

(S) 2-[(3-메르캅토-프로피오닐)-메틸-아미노]-프로판산 메틸 에스테르 (S) 2-[(3-mercapto-propionyl) -methyl-amino] -propanoic acid methyl ester

디에틸 에테르 135 ml 중 실시예 L1b에 따라 제조된 조 생성물 4.53 g (최대 23.7 mol)의 용액을 0℃에서 디아조메탄의 에테르성 용액으로 에스테르화하였다. 용매 제거 후, 표제 화합물 4.59 g (22.4 mmol, 94％)을 연황색 오일로서 단리하고, 이를 정제하지 않고 추가로 반응시켰다. A solution of 4.53 g (up to 23.7 mol) of crude product prepared according to Example L1b in 135 ml of diethyl ether was esterified with an ethereal solution of diazomethane at 0 ° C. After solvent removal, 4.59 g (22.4 mmol, 94%) of the title compound were isolated as pale yellow oil, which was reacted further without purification.

실시예 L1d Example L1d

(S) 2-[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-프로판산 메틸 에스테르 (S) 2-[(3-methyltrisulfanyl-propionyl) -methyl-amino] -propanoic acid methyl ester

트리클로로메탄 180 ml 중 실시예 L1c에 따라 제조된 화합물 14 g (68.2 mmol)의 용액을 트리클로로메탄 420 ml 중 2-메틸디술파닐-이소인돌-1,3-디온 21 g의 용액에 첨가하고, 이를 23℃에서 16시간 동안 교반하였다. 이를 증발로 농축시키고, 디클로로메탄에 용해시키고, 0.5시간 동안 교반하였다. 고체를 여과해 내고, 여액을 증발로 농축시키고, 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 16.2 g (57.2 mmol, 84％)을 무색의 오일로서 단리하였다. A solution of 14 g (68.2 mmol) of the compound prepared according to Example L1c in 180 ml of trichloromethane was added to a solution of 21 g of 2-methyldisulfanyl-isoindole-1,3-dione in 420 ml of trichloromethane and It was stirred at 23 ° C. for 16 hours. It was concentrated by evaporation, dissolved in dichloromethane and stirred for 0.5 h. The solid was filtered off, the filtrate was concentrated by evaporation and the residue was purified by chromatography on fine silica gel. 16.2 g (57.2 mmol, 84%) of the title compound were isolated as a colorless oil.

실시예 L1 Example L1

(S) 2-[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-프로판산 (S) 2-[(3-methyltrisulfanyl-propionyl) -methyl-amino] -propanoic acid

에탄올 20 ml 중 실시예 L1d에 따라 제조된 화합물 10 g (35.3 mmol)의 용액을 pH 7의 돼지 간 에스테라제의 인산염 완충액 1 L와 혼합하고, 이를 27℃에서 46시간 동안 인큐베이션하였다. 4N 염산을 첨가하여 pH를 1로 조정하고, 이를 디클로로메탄으로 추출하고, 황산나트륨상에서 건조시키고, 여과 및 용매 제거 후 표제 화합물 8.3 g (30.8 mmol, 87％)을 무색의 오일로서 단리하고, 이를 추가의 정제 없이 반응시켰다. A solution of 10 g (35.3 mmol) of the compound prepared according to Example L1d in 20 ml of ethanol was mixed with 1 L of phosphate buffer of swine liver esterase at pH 7 and incubated at 27 ° C. for 46 hours. Adjust the pH to 1 by adding 4N hydrochloric acid, extract it with dichloromethane, dry over sodium sulfate, filter and remove the solvent, 8.3 g (30.8 mmol, 87%) of the title compound is isolated as a colorless oil, which is added The reaction was carried out without purification.

실시예 L2Example L2

[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-아세트산 [(3-Methyltrisulfanyl-propionyl) -methyl-amino] -acetic acid

실시예 L2aExample L2a

2-[(3-아세틸술파닐-프로피오닐)-메틸-아미노]-아세트산 에틸 에스테르 2-[(3-acetylsulfanyl-propionyl) -methyl-amino] -acetic acid ethyl ester

N-메틸글리신 에틸 에스테르-히드로클로라이드 7.13 g (46.4 mmol)을 실시예 L1a와 유사하게 반응시키고, 표제 화합물 6.9 g (27.9 mmol, 60％)을 무색의 오일로서 단리하였다. 7.13 g (46.4 mmol) of N-methylglycine ethyl ester-hydrochloride were reacted similarly to Example Lla and 6.9 g (27.9 mmol, 60%) of the title compound were isolated as a colorless oil.

실시예 L2bExample L2b

[(3-메르캅토-프로피오닐)-메틸-아미노]-아세트산 [(3-mercapto-propionyl) -methyl-amino] -acetic acid

실시예 L2a에 따라 제조된 화합물 7.6 g (30.7 mmol)을 실시예 L1b와 유사하게 반응시키고, 표제 화합물 4.92 g (27.8 mmol, 90％)을 무색의 오일로서 단리하였다. 7.6 g (30.7 mmol) of compound prepared according to Example L2a were reacted similarly to Example L1b, and 4.92 g (27.8 mmol, 90%) of the title compound were isolated as a colorless oil.

실시예 L2cExample L2c

[(3-메르캅토-프로피오닐)-메틸-아미노]-아세트산 메틸 에스테르 [(3-mercapto-propionyl) -methyl-amino] -acetic acid methyl ester

실시예 L2b에 따라 제조된 화합물 4.92 g (27.8 mmol)을 실시예 L1c와 유사하게 반응시키고, 표제 화합물 5.01 g (26.2 mmol, 94％)을 무색의 오일로서 단리하였다. 4.92 g (27.8 mmol) of the compound prepared according to Example L2b were reacted similarly to Example L1c, and 5.01 g (26.2 mmol, 94%) of the title compound were isolated as a colorless oil.

실시예 L2dExample L2d

[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-아세트산 메틸 에스테르 [(3-Methyltrisulfanyl-propionyl) -methyl-amino] -acetic acid methyl ester

실시예 L2c에 따라 제조된 화합물 2.00 g (10.5 mmol)을 실시예 L1d와 유사하게 반응시키고, 표제 화합물 2.33 g (8.65 mmol, 82％)을 무색의 오일로서 단리하였다. 2.00 g (10.5 mmol) of the compound prepared according to Example L2c were reacted similarly to Example L1d, and 2.33 g (8.65 mmol, 82%) of the title compound were isolated as a colorless oil.

실시예 L2 Example L2

[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-아세트산 [(3-Methyltrisulfanyl-propionyl) -methyl-amino] -acetic acid

실시예 L2d에 따라 제조된 화합물 2.00 g (7.83 mmol)을 실시예 L1과 유사하게 반응시키고, 표제 화합물 0.64 g (2.51 mmol, 32％)을 무색의 오일로서 단리하였다. 2.00 g (7.83 mmol) of the compound prepared according to Example L2d were reacted similarly to Example L1, and 0.64 g (2.51 mmol, 32%) of the title compound were isolated as a colorless oil.

실시예 L3 Example L3

(S) 2-[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-3-페닐-프로피온산 (S) 2-[(3-methyltrisulfanyl-propionyl) -methyl-amino] -3-phenyl-propionic acid

실시예 L3a Example L3a

(S) 2-[(3-아세틸술파닐-프로피오닐)-메틸-아미노]-3-페닐-프로판산 에틸 에스테르 (S) 2-[(3-acetylsulfanyl-propionyl) -methyl-amino] -3-phenyl-propanoic acid ethyl ester

N-메틸페닐알라닌 에틸 에스테르-히드로클로라이드 7.73 g (31.7 mmol)을 실시예 L1a와 유사하게 반응시키고, 표제 화합물 2.3 g (6.82 mmol, 22％)을 무색의 오일로서 단리하였다. 7.73 g (31.7 mmol) of N-methylphenylalanine ethyl ester-hydrochloride were reacted similarly to Example Lla and 2.3 g (6.82 mmol, 22%) of the title compound were isolated as a colorless oil.

실시예 L3b Example L3b

(S) 2-[(3-메르캅토-프로피오닐)-메틸-아미노]-3-페닐-프로판산 (S) 2-[(3-mercapto-propionyl) -methyl-amino] -3-phenyl-propanoic acid

실시예 L3a에 따라 제조된 화합물 1.09 g (3.23 mmol)을 실시예 L1b와 유사하게 반응시키고, 표제 화합물 0.744 g (2.78 mmol, 86％)을 무색의 오일로서 단리하였다. 1.09 g (3.23 mmol) of the compound prepared according to Example L3a were reacted similarly to Example L1b and 0.744 g (2.78 mmol, 86%) of the title compound were isolated as a colorless oil.

실시예 L3c Example L3c

(S) 2-[(3-메르캅토-프로피오닐)-메틸-아미노]-3-페닐-프로판산 메틸 에스테르 (S) 2-[(3-mercapto-propionyl) -methyl-amino] -3-phenyl-propanoic acid methyl ester

실시예 L3b에 따라 제조된 화합물 0.74 g (2.77 mmol)을 실시예 L1c와 유사하게 반응시키고, 표제 화합물 0.77 g (2.74 mmol, 99％)을 무색의 오일로서 단리하였다. 0.74 g (2.77 mmol) of the compound prepared according to Example L3b were reacted similarly to Example L1c and 0.77 g (2.74 mmol, 99%) of the title compound was isolated as a colorless oil.

실시예 L3d Example L3d

(S) 2-[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-3-페닐-프로판산 메틸 에스테르 (S) 2-[(3-methyltrisulfanyl-propionyl) -methyl-amino] -3-phenyl-propanoic acid methyl ester

실시예 L3c에 따라 제조된 화합물 0.77 g (2.74 mmol)을 실시예 L1d와 유사하게 반응시키고, 표제 화합물 0.72 g (2.00 mmol, 73％)을 무색의 오일로서 단리하였다. 0.77 g (2.74 mmol) of the compound prepared according to Example L3c were reacted similarly to Example L1d and 0.72 g (2.00 mmol, 73%) of the title compound was isolated as a colorless oil.

실시예 L3 Example L3

(S) 2-[(3-메틸트리술파닐-프로피오닐)-메틸-아미노]-3-페닐-프로판산 (S) 2-[(3-methyltrisulfanyl-propionyl) -methyl-amino] -3-phenyl-propanoic acid

실시예 L3d에 따라 제조된 화합물 0.72 g (2.00 mmol)을 실시예 L1과 유사하게 반응시키고, 표제 화합물 0.49 g (1.42 mmol, 71％)을 무색의 오일로서 단리하였다. 0.72 g (2.00 mmol) of the compound prepared according to Example L3d were reacted similarly to Example L1 and 0.49 g (1.42 mmol, 71%) of the title compound was isolated as a colorless oil.

실시예 L4 Example L4

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산4- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -butanoic acid

4-아미노부티르산 20.0 g (193.9 mmol)을 말레산 무수물 19 g, 아세트산 290 ml와 혼합하고, 이를 오일조에서 130℃에서 4시간 동안 가열하였다. 이를 톨루엔의 반복 첨가와 함께 증발에 의해 공비 농축하고, 잔류물을 디클로로메탄에 용해시키고, 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 17.1 g (93.4 mmol, 48％)을 결정질 고체로서 단리하였다. 20.0 g (193.9 mmol) of 4-aminobutyric acid were mixed with 19 g of maleic anhydride and 290 ml of acetic acid, which was heated in an oil bath at 130 ° C. for 4 hours. It was azeotropically concentrated by evaporation with repeated addition of toluene, the residue was dissolved in dichloromethane and purified by chromatography on finely divided silica gel. 17.1 g (93.4 mmol, 48%) of the title compound were isolated as crystalline solid.

실시예 L4aExample L4a

1-(3-이소시아나토-프로필)-피롤-2,5-디온1- (3-Isocyanato-propyl) -pyrrole-2,5-dione

실시예 L4에 따라 제조된 화합물 5.0 g (27.3 mmol)을 테트라히드로푸란 90 ml에 용해시키고, 트리에틸아민 8 ml 및 인산 디페닐에스테르 아지드 6.17 ml와 혼합하고, 이를 23℃에서 1.5시간 동안 교반하였다. 이어서, 이를 톨루엔 110 ml와 혼합하고, 테트라히드로푸란을 증류해 내고, 2시간 동안 70℃로 가열하였다. 조 생성물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 1.77 g (9.82 mmol, 36％)을 단리하였다. 5.0 g (27.3 mmol) of the compound prepared according to Example L4 are dissolved in 90 ml of tetrahydrofuran and mixed with 8 ml of triethylamine and 6.17 ml of diphenyl phosphate azide, which is stirred at 23 ° C. for 1.5 hours. It was. It was then mixed with 110 ml of toluene, tetrahydrofuran was distilled off and heated to 70 ° C. for 2 hours. The crude product was purified by chromatography on fine silica gel. 1.77 g (9.82 mmol, 36%) of the title compound were isolated.

실시예 L5 Example L5

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid

6-아미노카프로산 100 g (762 mmol)을 실시예 L5와 유사하게 반응시키고, 표제 화합물 93.8 g (444 mmol, 58％)을 결정질 고체로서 단리하였다. 100 g (762 mmol) of 6-aminocaproic acid were reacted similarly to Example L5 and 93.8 g (444 mmol, 58%) of the title compound were isolated as crystalline solid.

실시예 L5aExample L5a

1-(5-이소시아나토-펜틸)-피롤-2,5-디온1- (5-Isocyanato-pentyl) -pyrrole-2,5-dione

실시예 L5에 따라 제조된 화합물 10.0 g (47.3 mmol)을 실시예 L4a와 유사하게 반응시키고, 표제 화합물 3.19 g (15.3 mmol, 32％)을 무색의 오일로서 단리하였다. 10.0 g (47.3 mmol) of the compound prepared according to Example L5 were reacted similarly to Example L4a, and 3.19 g (15.3 mmol, 32%) of the title compound were isolated as a colorless oil.

실시예 L6Example L6

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 11- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoic acid

11-아미노운데칸산 10 g (49.7 mmol)을 실시예 L5와 유사하게 반응시키고, 표제 화합물 6.29 g (22.4 mmol, 45％)을 결정질 고체로서 단리하였다. 10 g (49.7 mmol) of 11-aminoundecanoic acid were reacted similarly to Example L5 and 6.29 g (22.4 mmol, 45%) of the title compound were isolated as crystalline solid.

실시예 L6aExample L6a

1-(10-이소시아나토-데실)-피롤-2,5-디온 1- (10-isocyanato-decyl) -pyrrole-2,5-dione

실시예 L6에 따라 제조된 화합물 5.28 g (18.8 mmol)을 실시예 L4a와 유사하게 반응시키고, 표제 화합물 3.37 g (12.1 mmol, 64％)을 무색의 오일로서 단리하였다. 5.28 g (18.8 mmol) of the compound prepared according to Example L6 were reacted similarly to Example L4a and 3.37 g (12.1 mmol, 64%) of the title compound were isolated as a colorless oil.

실시예 L7Example L7

1-(4-아미노-페닐)-피롤-2,5-디온 1- (4-amino-phenyl) -pyrrole-2,5-dione

테트라히드로푸란 200 ml 중 1,4-페닐렌디아민 21.6 g (200 mmol)의 용액을 1.5시간에 걸쳐 말레산 무수물 19.6 g의 용액과 혼합하고, 23℃에서 22시간 동안 교반하였다. 이를 여과하고, 테트라히드로푸란으로 재세척하고, 여액을 건조시켰다. 표제 화합물 37.1 g (197 mmol, 98％)을 결정질 고체로서 단리하였다. A solution of 21.6 g (200 mmol) of 1,4-phenylenediamine in 200 ml of tetrahydrofuran was mixed with a solution of 19.6 g of maleic anhydride over 1.5 hours and stirred at 23 ° C. for 22 hours. It was filtered, rewashed with tetrahydrofuran and the filtrate was dried. 37.1 g (197 mmol, 98%) of the title compound were isolated as crystalline solid.

실시예 L8Example L8

1-(4-히드록시-페닐)-피롤-2,5-디온 1- (4-hydroxy-phenyl) -pyrrole-2,5-dione

4-아미노페놀 5.0 g (45.8 mmol), 말레산 무수물 4.49 g 및 아세트산 40 ml로 이루어진 현탁액을 3시간 동안 환류하였다. 이를 증발로 농축시키고, 잔류 아세트산을 아세트산과의 반복 증류로 공비 제거하고, 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 2.83 g (15.0 mmol, 33％)을 단리하였다. A suspension consisting of 5.0 g (45.8 mmol) of 4-aminophenol, 4.49 g of maleic anhydride and 40 ml of acetic acid was refluxed for 3 hours. It was concentrated by evaporation, the residual acetic acid was azeotropically removed by repeated distillation with acetic acid and the residue was purified by chromatography on fine silica gel. 2.83 g (15.0 mmol, 33%) of the title compound were isolated.

실시예 L9 Example L9

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-히드록시메틸-2-니트로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -butanoic acid 4-hydroxymethyl-2-nitro-phenyl ester

디클로로메탄 250 ml 중 4-히드록시메틸-2-니트로-페놀 5.0 g (29.6 mmol)의 용액을 N,N'-디시클로헥실카르보디이미드 6.1 g 및 피리딘 2.4 ml와 혼합하고, 디클로로메탄 250 ml 중 실시예 L4에 따라 제조된 화합물 5.5 g의 용액을 15분 이내에 적가하였다. 이를 23℃에서 1시간 동안 더 교반하고, 여과하고, 여액을 증발로 농축시키고, 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 1.73 g (5.2 mmol, 18％)을 단리하였다. A solution of 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro-phenol in 250 ml of dichloromethane is mixed with 6.1 g of N, N'-dicyclohexylcarbodiimide and 2.4 ml of pyridine and 250 ml of dichloromethane A solution of 5.5 g of the compound prepared according to Example L4 in was added dropwise within 15 minutes. It was further stirred at 23 ° C. for 1 h, filtered, the filtrate was concentrated by evaporation and purified by chromatography on fine silica gel. 1.73 g (5.2 mmol, 18%) of the title compound were isolated.

실시예 L10 Example L10

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-히드록시메틸-2-니트로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4-hydroxymethyl-2-nitro-phenyl ester

실시예 L9와 유사하게, 4-히드록시메틸-2-니트로-페놀 5.0 g (29.6 mmol)을 실시예 L5에 따라 제조된 화합물 6.34 g과 반응시키고, 후처리 및 정제 후 표제 화합물 3.78 g (10.4 mmol,35％)을 단리하였다. Similar to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro-phenol were reacted with 6.34 g of the compound prepared according to Example L5, and 3.78 g (10.4 g of the title compound after workup and purification). mmol, 35%).

실시예 L11Example L11

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-히드록시메틸-2-니트로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4-hydroxymethyl-2-nitro-phenyl ester

실시예 L9와 유사하게, 4-히드록시메틸-2-니트로-페놀 5.0 g (29.6 mmol)을 실시예 L6에 따라 제조된 화합물 8.44 g과 반응시키고, 후처리 및 정제 후 표제 화합물 3.78 g (10.4 mmol, 35％)을 단리하였다. Similar to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro-phenol were reacted with 8.44 g of a compound prepared according to Example L6, and after treatment and purification, 3.78 g (10.4) of the title compound. mmol, 35%).

실시예 L12 Example L12

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-히드록시메틸-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -butanoic acid 4-hydroxymethyl-phenyl ester

4-tert-부틸디메틸실라닐옥시메틸-페놀 5.5 g (23.1 mmol), N,N-디메틸-4-아미노피리딘 20 mg 및 실시예 L4에 따라 제조된 화합물 4.23 g (23.1 mmol)을 디클로로메탄 92 ml에 용해시키고, 0℃로 냉각시켰다. 디클로로메탄 24 ml 중의 N,N'-디시클로헥실카르보디이미드 4.77 g (23.1 mmol)을 15분의 기간에 걸쳐 상기 냉각 용액에 적가하였다. 혼합물을 23℃에서 16시간 동안 교반하고, 여과하고, 여액을 농축하고, 미분 실리카 겔상의 크로마토그래피로 정제하였다. 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산-4-tert-부틸디메틸실라닐옥시메틸-페닐 에스테르 7.18 g (17.8 mmol, 77％)을 단리하였다. 상기 물질 1.42 g을 THF 63 ml 및 물 7 ml에 용해시키고, p-톨루엔술폰산 0.67 g (3.52 mmol)을 실온에서 첨가하였다. 16시간 후, 포화 중탄산나트륨 용액을 첨가하고, 혼합물을 에틸 아세테이트로 수회 추출하였다. 합한 유기층을 염화나트륨 포화 용액으로 세척하고, 황산나트륨상에서 건조시키고, 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 0.43 g (1.5 mmol, 42％)을 단리하였다. 5.5 g (23.1 mmol) of 4-tert-butyldimethylsilanyloxymethyl-phenol, 20 mg of N, N-dimethyl-4-aminopyridine and 4.23 g (23.1 mmol) of the compound prepared according to Example L4 were diluted with dichloromethane 92 dissolved in ml and cooled to 0 ° C. 4.77 g (23.1 mmol) of N, N'-dicyclohexylcarbodiimide in 24 ml of dichloromethane were added dropwise to the cooling solution over a period of 15 minutes. The mixture was stirred at 23 ° C. for 16 h, filtered, the filtrate was concentrated and purified by chromatography on fine silica gel. 7.18 g (17.8 mmol, 77%) of 4- (2,5-dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid-4-tert-butyldimethylsilanyloxymethyl-phenyl ester Isolated. 1.42 g of this material was dissolved in 63 ml of THF and 7 ml of water, and 0.67 g (3.52 mmol) of p-toluenesulfonic acid were added at room temperature. After 16 h, saturated sodium bicarbonate solution was added and the mixture was extracted several times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate and purified by chromatography on fine silica gel. 0.43 g (1.5 mmol, 42%) of the title compound were isolated.

실시예 L13 Example L13

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-히드록시메틸-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4-hydroxymethyl-phenyl ester

실시예 L12와 유사하게, 4-tert-부틸디메틸실라닐옥시메틸-페놀 4.02 g (13.8 mmol)을 실시예 L5에 따라 제조된 화합물 3.56 g (13.8 mmol)과 반응시켰다. 후처리하고, 정제하고, p-톨루엔술폰산으로 유사하게 처리한 후, 표제 화합물 3,19 g (10.1 mmol, 60％)을 단리하였다. Similar to Example L12, 4.02 g (13.8 mmol) of 4-tert-butyldimethylsilanyloxymethyl-phenol were reacted with 3.56 g (13.8 mmol) of the compound prepared according to Example L5. After work-up, purification and similar treatment with p-toluenesulfonic acid, 3,19 g (10.1 mmol, 60%) of the title compound were isolated.

실시예 L14Example L14

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-히드록시메틸-페닐 에스테르11- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoic acid 4-hydroxymethyl-phenyl ester

실시예 L12와 유사하게, 4-tert-부틸디메틸실라닐옥시메틸-페놀 5.41 g (22.7 mmol)을 실시예 L6에 따라 제조된 화합물 6.39 g (22.7 mmol)과 반응시켰다. 후처리하고, 정제하고, p-톨루엔술폰산으로 유사하게 처리한 후, 표제 화합물 5.91 g (15.3 mmol, 67％)을 단리하였다. Similar to Example L12, 5.41 g (22.7 mmol) of 4-tert-butyldimethylsilanyloxymethyl-phenol were reacted with 6.39 g (22.7 mmol) of the compound prepared according to Example L6. After workup, purification and similar treatment with p-toluenesulfonic acid, 5.91 g (15.3 mmol, 67%) of the title compound were isolated.

실시예 L15 Example L15

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-히드록시메틸-2-클로로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4-hydroxymethyl-2-chloro-phenyl ester

실시예 L9와 유사하게, 4-히드록시메틸-2-클로로-페놀 5.0 g (29.6 mmol)을 실시예 L4에 따라 제조된 화합물 5.42 g과 반응시켰다. 후처리 및 정제 후 표제 화합물 8.49 g (26.2 mmol, 89％)을 단리하였다. Similar to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-chloro-phenol were reacted with 5.42 g of the compound prepared according to Example L4. 8.49 g (26.2 mmol, 89%) of the title compound were isolated after workup and purification.

실시예 L16 Example L16

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-히드록시메틸-2-클로로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -hexanoic acid 4-hydroxymethyl-2-chloro-phenyl ester

실시예 L9와 유사하게, 4-히드록시메틸-2-클로로-페놀 5.0 g (29.6 mmol)을 실시예 L5에 따라 제조된 화합물 6.24 g과 반응시켰다. 후처리 및 정제 후 표제 화합물 5.11 g (14.5 mmol, 49％)을 단리하였다. Similar to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-chloro-phenol were reacted with 6.24 g of the compound prepared according to Example L5. After workup and purification 5.11 g (14.5 mmol, 49%) of the title compound were isolated.

실시예 L17Example L17

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-히드록시메틸-2-클로로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoic acid 4-hydroxymethyl-2-chloro-phenyl ester

실시예 L9와 유사하게, 4-히드록시메틸-2-클로로-페놀 4.61 g (29 mmol)을 실시예 L6에 따라 제조된 화합물 8.17 g과 반응시켰다. 후처리 및 정제 후 표제 화합물 4.61 g (10.9 mmol, 38％)을 단리하였다. Similar to Example L9, 4.61 g (29 mmol) of 4-hydroxymethyl-2-chloro-phenol were reacted with 8.17 g of the compound prepared according to Example L6. After workup and purification 4.61 g (10.9 mmol, 38%) of the title compound were isolated.

실시예 L18Example L18

1-(6-히드록시-헥실)-피롤-2,5-디온 1- (6-hydroxy-hexyl) -pyrrole-2,5-dione

테트라히드로푸란 중 보란-테트라히드로푸란-복합체의 1.0 M 용액 26 ml를 무수 테트라히드로푸란 50 ml 중 실시예 L5에 따라 제조된 산 5.0 g (23.7 mmol)의 용액에 첨가하고, 혼합물을 23℃에서 3시간 동안 교반하였다. 혼합물을 중탄산나트륨 포화 용액에 붓고, 에틸 아세테이트로 수회 추출하고, 합한 유기 추출물을 황산나트륨상에서 건조시켰다. 여과 및 용매 제거 후, 잔류물을 크로마토그래피로 정제하였다. 표제 화합물 2.53 g (12.8 mmol, 54％)을 단리하였다. 26 ml of a 1.0 M solution of borane-tetrahydrofuran-complex in tetrahydrofuran are added to a solution of 5.0 g (23.7 mmol) of the acid prepared according to Example L5 in 50 ml of anhydrous tetrahydrofuran and the mixture at 23 ° C. Stir for 3 hours. The mixture was poured into saturated sodium bicarbonate solution, extracted several times with ethyl acetate, and the combined organic extracts were dried over sodium sulfate. After filtration and solvent removal, the residue was purified by chromatography. 2.53 g (12.8 mmol, 54%) of the title compound were isolated.

효과기-연결기 접합체 (EL)의 합성의 실시예Examples of the synthesis of effector-linker conjugates (EL)

실시예 EL1 Example EL1

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-7-allyl-8 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester

실시예 EL1a Example EL1a

(4S,7R,8S,9S,13Z,16S)-7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -4-hydroxy-5,5,9,13-tetramethyl-16- (2-Methyl-benzothiazol-5-yl) -oxacyclohexades-13-ene-2,6-dione

무수 디클로로메탄 186 ml 중, WO 00/66589에 기재된 방법과 유사하게 제조된 (4S,7R,8S,9S,13Z,16S)-7-알릴-4,8-비스(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온 6.0 g (7.93 mmol)의 용액을 0℃에서 디클로로메탄 중 트리플루오로아세트산의 20％ 용액 26.4 ml와 혼합하고, 이를 0℃에서 6시간 동안 교반하였다. 이를 포화 중탄산나트륨 용액에 붓고, 디클로로메탄으로 추출하고, 합한 유기 추출물을 물로 세척하고, 황산마그네슘상에서 건조시켰다. 여과 및 용매 제거 후 수득된 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 3.32 g (5.17 mmol, 65％)을 무색의 고체로서 단리하였다. (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4,8-bis (tert-butyl-dimethyl-sila prepared in 186 ml of anhydrous dichloromethane similar to the method described in WO 00/66589 Nyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexades-13-ene-2,6-dione 6.0 g (7.93 mmol) ) Was mixed with 26.4 ml of a 20% solution of trifluoroacetic acid in dichloromethane at 0 ° C. and stirred at 0 ° C. for 6 hours. It was poured into saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic extracts were washed with water and dried over magnesium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography on fine silica gel. 3.32 g (5.17 mmol, 65%) of the title compound were isolated as a colorless solid.

실시예 EL1b Example EL1b

(4S,7R,8S,9S,13Z,16S)-3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-7-알릴-8-tert-부틸-디메틸실릴옥시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-7-allyl-8- tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene -4-yl ester

실시예 EL1a에 따라 제조된 화합물 50 mg (78 μmol)을 트리클로로메탄 1.5 ml 및 디메틸포름아미드 1.5 ml의 혼합물에 용해시키고, 실시예 L4a에 따라 제조된 연결기 144 mg, 염화구리(I) 79 mg과 혼합하고, 이를 18시간 동안 70℃로 가열하였다. 조 혼합물을 박층 플레이트상의 크로마토그래피로 정제하고, 표제 화합물 51 mg (62 μmol, 80％)을 무색의 오일로서 단리하였다. 50 mg (78 μmol) of the compound prepared according to Example EL1a are dissolved in a mixture of 1.5 ml of trichloromethane and 1.5 ml of dimethylformamide, 144 mg of the linking group prepared according to Example L4a, 79 mg of copper (I) Mixed with and heated to 70 ° C. for 18 h. The crude mixture was purified by chromatography on thin plate and 51 mg (62 μmol, 80%) of the title compound was isolated as a colorless oil.

실시예 EL1 Example EL1

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소옥사시클로헥사데스-13-엔-4-일 에스테르(4S, 7R, 8S, 9S, 13Z, 16S)-[3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-7-allyl-8 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxooxacyclohexades-13-en-4-yl ester

테트라히드로푸란 0.8 ml 및 아세토니트릴 0.8 ml의 혼합물 중 실시예 1b에 따라 제조된 화합물 41 mg (50 μmol)의 용액을 헥사플루오로규산 310 ㎕, 불화수소-피리딘 복합체 310 ㎕와 혼합하고, 23℃에서 23시간 동안 교반하였다. 이를 5％ 수산화나트륨 용액에 붓고, 에틸 아세테이트로 추출하고, 합한 유기 추출물을 포화 염화나트륨 용액으로 세척하고, 황산나트륨상에서 건조시켰다. 여과 및 용매 제거 후 수득된 잔류물을 박층 플레이트상의 크로마토그래피로 정제하고, 표제 화합물 26 mg (36.7 μmol, 73％)을 무색의 발포체로서 단리하였다. A solution of 41 mg (50 μmol) of the compound prepared according to Example 1b in a mixture of 0.8 ml tetrahydrofuran and 0.8 ml acetonitrile was mixed with 310 μl of hexafluorosilicic acid and 310 μl hydrogen fluoride-pyridine complex, and 23 ° C. Stir at 23 h. It was poured into 5% sodium hydroxide solution, extracted with ethyl acetate, and the combined organic extracts washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography on a thin plate and 26 mg (36.7 μmol, 73%) of the title compound was isolated as a colorless foam.

실시예 EL2Example EL2

(1S,3S,7S,10R,11S,12S,16R)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (B)(1S, 3S, 7S, 10R, 11S, 12S, 16R)-[3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-10-allyl -11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1 .0] heptades-7-yl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[3- (2,5-dioxo-2,5-dihydro-pyrrole- 1-yl) -propyl] -carbamic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9 -Dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester (B)

디클로로메탄 2.0 ml 중 실시예 1에 따라 제조된 화합물 44 mg (62.2 μmol)의 용액을 -50℃로 냉각시키고, 아세톤 중 디메틸 디옥시란의 대략 0.1 M 용액 총 1.7 ml와 1.5시간의 기간에 걸쳐 조금씩 혼합하였다. 이를 포화 티오황산나트륨 용액에 붓고, 디클로로메탄으로 추출하고, 합한 유기 추출물을 황산나트륨상에서 건조시켰다. 여과 및 용매 제거 후 수득된 잔류물을 박층 플레이트상의 크로마토그래피로 정제하고, 표제 화합물 A 22.7 mg (31.4 μmol, 50％) 뿐만 아니라 표제 화합물 B 7.6 mg (10.5 μmol, 17％)을 각 경우에 무색의 발포체로 단리하였다. A solution of 44 mg (62.2 μmol) of the compound prepared according to Example 1 in 2.0 ml of dichloromethane was cooled to −50 ° C. and over a period of 1.5 hours with a total of 1.7 ml of approximately 0.1 M solution of dimethyl dioxirane in acetone Mix little by little. It was poured into saturated sodium thiosulfate solution, extracted with dichloromethane and the combined organic extracts were dried over sodium sulfate. The residue obtained after filtration and solvent removal is purified by chromatography on a thin plate, and 22.7 mg (31.4 μmol, 50%) of the title compound A as well as 7.6 mg (10.5 μmol, 17%) of the title compound B are in each case colorless It was isolated by the foam of.

실시예 EL3 Example EL3

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[5- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-7-allyl-8 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester

실시예 EL3a Example EL3a

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-7-알릴-8-tert-부틸-디메틸실릴옥시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[5- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-7-allyl-8 -tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13- En-4-yl ester

실시예 EL1a에 따라 제조된 화합물 50 mg (78 μmol)을 실시예 EL1b와 유사하게 실시예 L5a에 따라 제조된 연결기와 반응시키고, 정제 후 표제 화합물 39 mg (45.9 μmol, 59％)을 무색의 오일로서 단리하였다. 50 mg (78 μmol) of a compound prepared according to Example EL1a are reacted with a linker prepared according to Example L5a similarly to Example EL1b, and after purification 39 mg (45.9 μmol, 59%) of the title compound are colorless oils. It was isolated as.

실시예 EL3 Example EL3

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[5- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-7-allyl-8 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester

실시예 EL3a에 따라 제조된 화합물 84 mg (98.8 μmol)을 실시예 EL1과 유사하게 반응시키고, 정제 후 표제 화합물 43 mg (58.4 μmol, 59％)을 무색의 발포체로서 단리하였다. 84 mg (98.8 μmol) of the compound prepared according to Example EL3a were reacted similarly to Example EL1 and 43 mg (58.4 μmol, 59%) of the title compound after purification were isolated as a colorless foam.

실시예 EL4Example EL4

(1S,3S,7S,10R,11S,12S,16R)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[5- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-10-allyl -11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1 .0] heptades-7-yl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[5- (2,5-dioxo-2,5-dihydro-pyrrole- 1-yl) -pentyl] -carbamic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9 -Dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester (B)

실시예 EL3에 따라 제조된 화합물 26 mg (35.3 μmol)을 실시예 EL2와 유사하게 반응시키고, 정제 후 표제 화합물 A 9.1 mg (12.1 μmol, 34％) 뿐만 아니라 표제 화합물 B 3.0 mg (4.0 μmol, 11％)을 각 경우에 무색의 발포체로서 단리하였다. 26 mg (35.3 μmol) of the compound prepared according to Example EL3 were reacted similarly to Example EL2 and after purification, 9.1 mg (12.1 μmol, 34%) of the title compound A as well as 3.0 mg (4.0 μmol, 11) of the title compound B. %) Was isolated in each case as a colorless foam.

실시예 EL5 Example EL5

(4S,7R,8S,9S,13Z,16S)-[10-(2,5-디옥소-2,5-디히드로-피롤-1-일)-데실]-카르밤산-7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[10- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -decyl] -carbamic acid-7-allyl-8 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester

실시예 EL5a Example EL5a

(4S,7R,8S,9S,13Z,16S)-[10-(2,5-디옥소-2,5-디히드로-피롤-1-일)-데실]-카르밤산-7-알릴-8-tert-부틸-디메틸실릴옥시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[10- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -decyl] -carbamic acid-7-allyl-8 -tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13- En-4-yl ester

실시예 EL1a에 따라 제조된 화합물 50 mg (78 μmol)을 실시예 EL1b와 유사하게 실시예 L6a에 따라 제조된 연결기와 반응시키고, 정제 후 표제 화합물 56 mg (60.8 μmol, 78％)을 무색의 오일로서 단리하였다. 50 mg (78 μmol) of a compound prepared according to Example EL1a are reacted with a linker prepared according to Example L6a similarly to Example EL1b, and after purification, 56 mg (60.8 μmol, 78%) of the title compound are colorless oils. It was isolated as.

실시예 EL5 Example EL5

(4S,7R,8S,9S,13Z,16S)-[10-(2,5-디옥소-2,5-디히드로-피롤-1-일)-데실]-카르밤산-7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[10- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -decyl] -carbamic acid-7-allyl-8 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester

실시예 EL5a에 따라 제조된 화합물 20 mg (21.7 μmol)을 실시예 EL1과 유사하게 반응시키고, 정제 후 표제 화합물 10 mg (12.4 μmol, 57％)을 무색의 발포체로서 단리하였다. 20 mg (21.7 μmol) of the compound prepared according to Example EL5a were reacted similarly to Example EL1, and after purification 10 mg (12.4 μmol, 57%) of the title compound were isolated as a colorless foam.

실시예 EL6Example EL6

(1S,3S,7S,10R,11S,12S,16R)-[10-(2,5-디옥소-2,5-디히드로-피롤-1-일)-데실]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-[10-(2,5-디옥소-2,5-디히드로-피롤-1-일)-데실]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -decyl] -carbamic acid-10-allyl -11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1 .0] heptades-7-yl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10- (2,5-dioxo-2,5-dihydro-pyrrole- 1-yl) -decyl] -carbamic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9 -Dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester (B)

실시예 EL5에 따라 제조된 화합물 18 mg (22 μmol)을 실시예 EL2와 유사하게 반응시키고, 정제 후 표제 화합물 A 9.2 mg (11.2 μmol, 51％) 뿐만 아니라 표제 화합물 B 3.2 mg (3.9 μmol, 18％)을 각 경우에 무색의 발포체로서 단리하였다. 18 mg (22 μmol) of compound prepared according to Example EL5 were reacted similarly to Example EL2 and after purification, 3.2 mg (3.9 μmol, 18) of title compound B as well as 9.2 mg (11.2 μmol, 51%) of title compound A. %) Was isolated in each case as a colorless foam.

실시예 EL7 Example EL7

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-[3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-7-allyl-4 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-8-yl ester

실시예 EL7a Example EL7a

(4S,7R,8S,9S,13Z,16S)-7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4- (tert-butyl-dimethyl-silanyloxy) -8-hydroxy-5,5,9,13-tetramethyl-16- (2-Methyl-benzothiazol-5-yl) -oxacyclohexades-13-ene-2,6-dione

테트라히드로푸란 85 ml 및 아세토니트릴 85 ml의 혼합물 중, WO 00/66589에 기재된 방법과 유사하게 제조된 (4S,7R,8S,9S,13Z,16S)-7-알릴-4,8-비스(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온 5.3 g (7.01 mmol)의 용액을 헥사플루오로규산 31.7 ml와 혼합하고, 0℃로 냉각시키고, 트리플루오로아세트산 8.1 ml를 적가하고, 0℃에서 20시간 동안 교반하였다. 이를 물에 붓고, 포화 중탄산나트륨 용액을 첨가하여 중화시키고, 에틸 아세테이트로 수회 추출하였다. 합한 유기 추출물을 포화 염화나트륨 용액으로 세척하고, 황산나트륨상에서 건조시키고, 여과 및 용매 제거 후 수득된 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 2.82 g (4.39 mmol, 63％)을 무색의 고체로서 단리하였다. In a mixture of 85 ml of tetrahydrofuran and 85 ml of acetonitrile, (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4,8-bis (), prepared analogously to the process described in WO 00/66589 tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexades-13-ene-2,6 A solution of 5.3 g (7.01 mmol) of dione was mixed with 31.7 ml of hexafluorosilicic acid, cooled to 0 ° C., 8.1 ml of trifluoroacetic acid was added dropwise and stirred at 0 ° C. for 20 hours. It was poured into water, neutralized by addition of saturated sodium bicarbonate solution and extracted several times with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue obtained after filtration and solvent removal was purified by chromatography on fine silica gel. 2.82 g (4.39 mmol, 63%) of the title compound were isolated as a colorless solid.

실시예 EL7b Example EL7b

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-7-알릴-4-tert-부틸-디메틸실릴옥시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르(4S, 7R, 8S, 9S, 13Z, 16S)-[3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-7-allyl-4 -tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13- N-8-yl ester

실시예 EL7a에 따라 제조된 화합물 100 mg (156 μmol)을 실시예 EL1b와 유사하게 실시예 L4a에 따라 제조된 연결기와 반응시키고, 정제 후 표제 화합물 121 mg (147 μmol, 94％)을 무색의 오일로서 단리하였다. 100 mg (156 μmol) of a compound prepared according to Example EL7a are reacted with a linker prepared according to Example L4a similarly to Example EL1b, and after purification, 121 mg (147 μmol, 94%) of the title compound are colorless oils. It was isolated as.

실시예 EL7 Example EL7

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소옥사시클로헥사데스-13-엔-8-일 에스테르(4S, 7R, 8S, 9S, 13Z, 16S)-[3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-7-allyl-4 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxooxacyclohexades-13-ene-8-yl ester

실시예 EL7b에 따라 제조된 화합물 46 mg (56 μmol)을 실시예 EL1과 유사하게 반응시키고, 정제 후 표제 화합물 17 mg (24 μmol, 43％)을 무색의 발포체로서 단리하였다. 46 mg (56 μmol) of compound prepared according to Example EL7b were reacted similarly to Example EL1, and after purification 17 mg (24 μmol, 43%) of the title compound were isolated as a colorless foam.

실시예 EL8 Example EL8

(1S,3S,7S,10R,11S,12S,16R)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르 (A) 및 (1S,3S,7S,10R,11S,12S,16R)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]-헵타데스-11-일 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-10-allyl -7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1 .0] heptades-11-yl ester (A) and (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[3- (2,5-dioxo-2,5-dihydro-pyrrole- 1-yl) -propyl] -carbamic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9 -Dioxo-4,17-dioxabicyclo [14.1.0] -heptades-11-yl ester (B)

실시예 EL7에 따라 제조된 화합물 29 mg (41 μmol)을 실시예 EL2와 유사하게 반응시키고, 정제 후 표제 화합물 A 18 mg (24.9 μmol, 61％) 뿐만 아니라 표제 화합물 B 3.0 mg (4.1 μmol, 10％)을 각 경우에 무색의 발포체로서 단리하였다. 29 mg (41 μmol) of the compound prepared according to Example EL7 were reacted similarly to Example EL2 and after purification, 3.0 mg (4.1 μmol, 10) of the title compound B as well as 18 mg (24.9 μmol, 61%) of the title compound A were purified. %) Was isolated in each case as a colorless foam.

실시예 EL9Example EL9

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소옥사시클로헥사데스-13-엔-8-일 에스테르(4S, 7R, 8S, 9S, 13Z, 16S)-[5- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-7-allyl-4 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxooxacyclohexades-13-ene-8-yl ester

실시예 EL9aExample EL9a

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-7-알릴-4-tert-부틸-디메틸실릴옥시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소옥사시클로헥사데스-13-엔-8-일 에스테르(4S, 7R, 8S, 9S, 13Z, 16S)-[5- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-7-allyl-4 -tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxooxacyclohexades-13-ene -8-yl ester

실시예 EL7a에 따라 제조된 화합물 100 mg (156 μmol)을 실시예 EL1b와 유사하게 실시예 L5a에 따라 제조된 연결기와 반응시키고, 정제 후 표제 화합물 (65.9 μmol, 42％)을 무색의 오일로서 단리하였다. 100 mg (156 μmol) of a compound prepared according to Example EL7a were reacted with a linker prepared according to Example L5a similarly to Example EL1b, and after purification, the title compound (65.9 μmol, 42%) was isolated as a colorless oil. It was.

실시예 EL9Example EL9

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소옥사시클로헥사데스-13-엔-8-일 에스테르(4S, 7R, 8S, 9S, 13Z, 16S)-[5- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-7-allyl-4 -Hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxooxacyclohexades-13-ene-8-yl ester

실시예 EL7b에 따라 제조된 화합물 56 mg (65.9 μmol)을 실시예 EL1과 유사하게 반응시키고, 정제 후 표제 화합물 24.7 mg (33.6 μmol, 51％)을 무색의 발포체로서 단리하였다. 56 mg (65.9 μmol) of the compound prepared according to Example EL7b were reacted similarly to Example EL1, and after purification 24.7 mg (33.6 μmol, 51%) of the title compound were isolated as a colorless foam.

실시예 EL10 Example EL10

(1S,3S,7S,10R,11S,12S,16R)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르 (A) 및 (1S,3S,7S,10R,11S,12S,16R)-[5-(2,5-디옥소-2,5-디히드로-피롤-1-일)-펜틸]-카르밤산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타-데스-11-일 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[5- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -pentyl] -carbamic acid-10-allyl -7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1 .0] heptades-11-yl ester (A) and (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[5- (2,5-dioxo-2,5-dihydro-pyrrole- 1-yl) -pentyl] -carbamic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9 -Dioxo-4,17-dioxabicyclo [14.1.0] hepta-des-11-yl ester (B)

실시예 EL9에 따라 제조된 화합물 24.7 mg (33.6 μmol)을 실시예 EL2와 유사하게 반응시키고, 정제 후 표제 화합물 A 16.7 mg (22.2 μmol, 66％) 뿐만 아니라 표제 화합물 B 2.0 mg (2.7 μmol, 8％)을 각 경우에 무색의 발포체로서 단리하였다. 24.7 mg (33.6 μmol) of the compound prepared according to Example EL9 were reacted similarly to Example EL2 and after purification, 16.7 mg (22.2 μmol, 66%) of the title compound A as well as 2.0 mg (2.7 μmol, 8) of the title compound B were purified. %) Was isolated in each case as a colorless foam.

실시예 EL11 Example EL11

(1S,3S(E),7S,10R,11S,12S,16R)-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필]-카르밤산 7-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필카르바모일옥시]-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르(1S, 3S (E), 7S, 10R, 11S, 12S, 16R)-[3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid 7 -[3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -propylcarbamoyloxy] -8,8,10,12,16-pentamethyl-3- [1 -Methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-11-yl ester

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데칸 10 mg (19.7 μmol)을 실시예 EL1b와 유사하게 실시예 L4a에 따라 제조된 연결기와 반응시키고, 정제 후 표제 화합물 7 mg (8.06 μmol, 41％)을 무색의 오일로서 단리하였다. (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- ( 10 mg (19.7 μmol) of 2-methyl-thiazol-4-yl) -vinyl] -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptadecane are similar to Example EL1b And reacted with a linker prepared according to Example L4a, and after purification 7 mg (8.06 μmol, 41%) of the title compound was isolated as a colorless oil.

실시예 EL12 Example EL12

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -phenyl ester

실시예 EL 12a Example EL 12a

(4S,7R,8S,9S,13Z,16S)-클로로포름산-7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -Chloroformatic Acid-7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2 -Methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester

디클로로메탄 20 ml 중 실시예 EL1a에 따라 제조된 화합물 1.0 g (1.56 mmol)의 용액을 0℃에서 디클로로메탄 6 ml, 피리딘 160 ㎕ 중 트리포스겐 285 mg의 용액과 혼합하고, 23℃에서 2.5시간 동안 교반하였다. 이를 증발로 농축시키고, 잔류물을 에틸 아세테이트에 용해시키고, 물 및 포화 염화나트륨 용액으로 세척하고, 황산마그네슘상에서 건조시켰다. 여과 및 용매 제거 후 수득된 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 1.08 g (1.53 mmol, 98％)을 단리하였다. A solution of 1.0 g (1.56 mmol) of the compound prepared according to Example EL1a in 20 ml of dichloromethane is mixed with a solution of 6 ml of dichloromethane, 285 mg of triphosgene in 160 μl of pyridine at 0 ° C., and 2.5 hours at 23 ° C. Stirred. It was concentrated by evaporation and the residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography on fine silica gel. 1.08 g (1.53 mmol, 98%) of the title compound were isolated.

실시예 EL12b Example EL12b

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrole-1 -Yl) -phenyl ester

에틸 아세테이트 16 ml 중 실시예 EL12a에 따라 제조된 화합물 267 mg (370 μmol)의 용액을 트리에틸아민 51 ㎕, 실시예 L8에 따라 제조된 화합물 700 mg과 혼합하고, 23℃에서 16시간 동안 교반하였다. 이를 물에 붓고, 에틸 아세테이트로 수회 추출하고, 합한 유기 추출물을 포화 염화나트륨 용액으로 세척하고, 황산마그네슘상에서 건조시켰다. 여과 및 용매 제거 후 수득된 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 188 mg (219 μmol, 59％)을 단리하였다. A solution of 267 mg (370 μmol) of the compound prepared according to Example EL12a in 16 ml of ethyl acetate was mixed with 51 μl of triethylamine, 700 mg of the compound prepared according to Example L8, and stirred at 23 ° C. for 16 hours. . It was poured into water, extracted several times with ethyl acetate and the combined organic extracts were washed with saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography on fine silica gel. 188 mg (219 μmol, 59%) of the title compound were isolated.

실시예 EL12 Example EL12

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -phenyl ester

실시예 EL1과 유사하게, 실시예 EL12a에 따라 제조된 화합물 248 mg (289 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 149 mg (201 μmol, 69％)을 단리하였다. Similar to Example EL1, 248 mg (289 μmol) of compound prepared according to Example EL12a were reacted and 149 mg (201 μmol, 69%) of the title compound was isolated after workup and purification.

실시예 EL13Example EL13

(1S,3S,7S,10R,11S,12S,16R)-탄산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르 (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5 -Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrole -1-yl) -phenyl ester

실시예 EL2와 유사하게, 실시예 EL12에 따라 제조된 화합물 144 mg (194 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 89 mg (117 μmol, 60％)을 단리하였다. Similar to Example EL2, 144 mg (194 μmol) of compound prepared according to Example EL12 were reacted and 89 mg (117 μmol, 60%) of the title compound were isolated after workup and purification.

실시예 EL14 Example EL14

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -phenyl ester

실시예 EL14a Example EL14a

(4S,7R,8S,9S,13Z,16S)-클로로포름산-7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -Chloroformatic Acid-7-allyl-4- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2 -Methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-8-yl ester

실시예 EL12a와 유사하게, 실시예 EL7a에 따라 제조된 화합물 1.0 g (1.56 mmol)을 반응시키고, 표제 화합물 1.05 g (1.49 mmol, 96％)을 단리하였다. Similar to Example EL12a, 1.0 g (1.56 mmol) of compound prepared according to Example EL7a was reacted and 1.05 g (1.49 mmol, 96%) of the title compound was isolated.

실시예 EL14b Example EL14b

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrole-1 -Yl) -phenyl ester

에틸 아세테이트 19 ml 중 실시예 EL14a에 따라 제조된 화합물 313 mg (0.44 mmol)의 용액을 실시예 L8에 따라 제조된 화합물 840 mg, 트리에틸아민 61.5 ㎕와 혼합하고, 이를 23℃에서 16시간 동안 교반하였다. 이를 물과 혼합하고, 에틸 아세테이트로 수회 추출하고, 합한 유기 추출물을 포화 염화나트륨 용액으로 세척하고, 황산나트륨상에서 건조시켰다. 여과 및 용매 제거 후 수득된 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 298 mg (348 μmol, 79％)을 단리하였다. A solution of 313 mg (0.44 mmol) of the compound prepared according to Example EL14a in 19 ml of ethyl acetate was mixed with 840 mg of the compound prepared according to Example L8, 61.5 μl of triethylamine, and stirred at 23 ° C. for 16 hours. It was. It was mixed with water, extracted several times with ethyl acetate and the combined organic extracts washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and solvent removal was purified by chromatography on fine silica gel. 298 mg (348 μmol, 79%) of the title compound were isolated.

실시예 EL14 Example EL14

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -phenyl ester

실시예 EL1과 유사하게, 실시예 EL14a에 따라 제조된 화합물 304 mg (355 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 67 mg (90 μmol, 25％)을 단리하였다. Similar to Example EL1, 304 mg (355 μmol) of the compound prepared according to Example EL14a were reacted and 67 mg (90 μmol, 25%) of the title compound was isolated after workup and purification.

실시예 EL15 Example EL15

(1S,3S,7S,10R,11S,12S,16R)-탄산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일 에스테르 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-페닐 에스테르(1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5 -Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrole -1-yl) -phenyl ester

실시예 EL2와 유사하게, 실시예 EL14에 따라 제조된 화합물 67 mg (90 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 32 mg (42 μmol, 47％)을 단리하였다. Similar to Example EL2, 67 mg (90 μmol) of compound prepared according to Example EL14 were reacted and 32 mg (42 μmol, 47%) of the title compound were isolated after workup and purification.

실시예 EL16Example EL16

(1S,3S(E),7S,10R,11S,12S,16R)-N-[1-({4-[2-(7,11-디히드록시-8,8,10,12,16-펜타메틸-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-3-일)-프로페닐]-티아졸-2-일메틸}-카르바모일)-에틸]-3-메틸트리술파닐-N-메틸-프로피온아미드(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -N- [1-({4- [2- (7,11-dihydroxy-8,8,10,12,16- Pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-3-yl) -propenyl] -thiazol-2-ylmethyl} -carbamoyl)- Ethyl] -3-methyltrisulfanyl-N-methyl-propionamide

디클로로메탄 0.5 ml 중, WO 99/01124에 기재된 방법과 유사하게 제조된 (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-메틸-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온 7 mg (13 μmol)의 용액을 실시예 L1에 따라 제조된 화합물 7 mg과 혼합하고, 4-디메틸아미노피리딘 0.4 mg 및 N,N'-디시클로헥실카르보디이미드 4 mg을 첨가하고, 23℃에서 20분 동안 교반하였다. 침전된 우레아를 여과해 내고, 정제용(preparative) 박층 플레이트상의 크로마토그래피로 정제하였다. 표제 화합물 5 mg (6.5 μmol, 50％)을 단리하였다.(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazole, prepared in 0.5 ml of dichloromethane, analogous to the method described in WO 99/01124 -4-yl) -1-methyl-vinyl] -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane A solution of 7 mg (13 μmol) of -5,9-dione was mixed with 7 mg of the compound prepared according to Example L1, 0.4 mg of 4-dimethylaminopyridine and 4 mg of N, N'-dicyclohexylcarbodiimide Was added and stirred at 23 ° C. for 20 minutes. The precipitated urea was filtered off and purified by chromatography on a preparative thin layer plate. 5 mg (6.5 μmol, 50%) of the title compound were isolated.

실시예 EL17Example EL17

(1S,3S(E),7S,10R,11S,12S,16R)-2-[메틸-(3-메틸트리술파닐-프로피오닐)-아미노]-프로피온산-4-[2-(7,11-디히드록시-8,8,10,12,16-펜타메틸-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-3-일)-프로페닐]-티아졸-2-일메틸 에스테르(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -2- [Methyl- (3-methyltrisulfanyl-propionyl) -amino] -propionic acid-4- [2- (7,11 -Dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-3-yl) -propenyl] -Thiazol-2-ylmethyl ester

실시예 EL16과 유사하게, WO 99/01124에 기재된 방법과 유사하게 제조된 (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온 10 mg (19 μmol)을 반응시키고, 표제 화합물 2.2 mg (2.8 μmol, 15％)을 단리하였다. Similar to Example EL16, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2 prepared similarly to the method described in WO 99/01124 -(2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] 10 mg (19 μmol) of heptadecan-5,9-dione were reacted and 2.2 mg (2.8 μmol, 15%) of the title compound was isolated.

실시예 EL18 Example EL18

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxooxacyclohexades-13-en-4-yloxycarbonyl Oxymethyl] -2-nitro-phenyl ester

실시예 EL18a Example EL18a

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2- 니트로-페닐 에스테르4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-en-4-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 200 mg (284 μmol)을 실시예 L9에 따라 제조된 화합물 770 mg과 반응시키고, 후처리 및 정제 후 표제 화합물 129 mg (129 μmol, 45％)을 단리하였다. Similar to Example EL12b, 200 mg (284 μmol) of a compound prepared according to Example EL12a were reacted with 770 mg of a compound prepared according to Example L9 and 129 mg (129 μmol, 45) of the title compound after workup and purification. %) Was isolated.

실시예 EL18 Example EL18

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxooxacyclohexades-13-en-4-yloxycarbonyl Oxymethyl] -2-nitro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL18a에 따라 제조된 화합물 129 mg (129 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 71 mg (80 μmol, 62％)을 단리하였다. Similar to Example EL1, 129 mg (129 μmol) of compound prepared according to Example EL18a were reacted and 71 mg (80 μmol, 62%) of the title compound was isolated after workup and purification.

실시예 EL19 Example EL19

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (A) 및 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (B) 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -part 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL18에 따라 제조된 화합물 71 mg (80 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 A 41 mg (45 μmol, 57％) 뿐만 아니라 표제 화합물 B 12 mg (13 μmol, 17％)을 단리하였다. Similar to Example EL2, 71 mg (80 μmol) of the compound prepared according to Example EL18 were reacted and after treatment and purification 41 mg (45 μmol, 57%) of the title compound A as well as 12 mg of the title compound B ( 13 μmol, 17%) was isolated.

실시예 EL20 Example EL20

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL20a Example EL20a

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2- 니트로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-en-4-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 243 mg (345 μmol)을 실시예 L10에 따라 제조된 화합물 1 g과 반응시키고, 후처리 및 정제 후 표제 화합물 25 mg (24 μmol, 7％)을 단리하였다.Similar to Example EL12b, 243 mg (345 μmol) of a compound prepared according to Example EL12a were reacted with 1 g of a compound prepared according to Example L10 and 25 mg (24 μmol, 7) of the title compound after workup and purification. %) Was isolated.

실시예 EL20 Example EL20

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL20a에 따라 제조된 화합물 212 mg (206 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 117 mg (128 μmol, 62％)을 단리하였다.Similar to Example EL1, 212 mg (206 μmol) of compound prepared according to Example EL20a were reacted and 117 mg (128 μmol, 62%) of the title compound were isolated after workup and purification.

실시예 EL21Example EL21

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (A) 및 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (B)6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexane Acid 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL20에 따라 제조된 화합물 117 mg (128 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 A 63 mg (68 μmol, 53％) 뿐만 아니라 표제 화합물 B 19 mg (20 μmol, 16％)을 단리하였다. Similar to Example EL2, 117 mg (128 μmol) of the compound prepared according to Example EL20 were reacted and 63 mg (68 μmol, 53%) of the title compound A as well as 19 mg of the title compound B after workup and purification ( 20 μmol, 16%) was isolated.

실시예 EL22Example EL22

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL22a Example EL22a

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methylbenzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13 -En-4-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 243 mg (345 μmol)을 실시예 11에 따라 제조된 화합물 1.19 g과 반응시키고, 후처리 및 정제 후 표제 화합물 171 mg (155 μmol, 45％)을 단리하였다. Similar to Example EL12b, 243 mg (345 μmol) of a compound prepared according to Example EL12a were reacted with 1.19 g of a compound prepared according to Example 11, and after treatment and purification 171 mg (155 μmol, 45 of the title compound) %) Was isolated.

실시예 EL22Example EL22

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL22a에 따라 제조된 화합물 171 mg (155 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 108 mg (110 μmol, 71％)을 단리하였다. Similar to Example EL1, 171 mg (155 μmol) of compound prepared according to Example EL22a was reacted and 108 mg (110 μmol, 71%) of the title compound were isolated after workup and purification.

실시예 EL23Example EL23

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,7-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (A) 및 11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,7-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (B)11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,7-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -unde Carboxylic Acid 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,7-dioxa-bicyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL22에 따라 제조된 화합물 108 mg (110 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 A 65.9 mg (65.8 μmol, 60％) 뿐만 아니라 표제 화합물 B 19.8 mg (20 μmol, 18％)을 단리하였다. Similar to Example EL2, 108 mg (110 μmol) of the compound prepared according to Example EL22 were reacted and after treatment and purification, 65.9 mg (65.8 μmol, 60%) of the title compound A as well as 19.8 mg of the title compound B ( 20 μmol, 18%) was isolated.

실시예 EL24Example EL24

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydrate Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL24aExample EL24a

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 271 mg (385 μmol)을 실시예 L9에 따라 제조된 화합물 1.04 g과 반응시키고, 후처리 및 정제 후 표제 화합물 193 mg (193 μmol, 50％)을 단리하였다. Similar to Example EL12b, 271 mg (385 μmol) of the compound prepared according to Example EL14a were reacted with 1.04 g of the compound prepared according to Example L9, and after treatment and purification, 193 mg (193 μmol, 50) of the title compound. %) Was isolated.

실시예 EL24Example EL24

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydrate Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL24a에 따라 제조된 화합물 193 mg (193 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 107 mg (120 μmol, 62％)을 단리하였다. Similar to Example EL1, 193 mg (193 μmol) of compound prepared according to Example EL24a were reacted and 107 mg (120 μmol, 62%) of the title compound was isolated after workup and purification.

실시예 EL25Example EL25

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (A) 및 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (B) 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -part 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL19에 따라 제조된 화합물 102 mg (115 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 A 65 mg (72 μmol, 63％) 뿐만 아니라 표제 화합물 B 3 mg (3.3 μmol, 3％)을 단리하였다. Similar to Example EL2, 102 mg (115 μmol) of the compound prepared according to Example EL19 were reacted and after treatment and purification 65 mg (72 μmol, 63%) of the title compound A as well as 3 mg of the title compound B ( 3.3 μmol, 3%) was isolated.

실시예 EL26 Example EL26

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL26a Example EL26a

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2- 니트로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 273 mg (387 μmol)을 실시예 L10에 따라 제조된 화합물 1.12 g과 반응시키고, 후처리 및 정제 후 표제 화합물 69 mg (67 μmol, 17％)을 단리하였다. Similar to Example EL12b, 273 mg (387 μmol) of the compound prepared according to Example EL14a were reacted with 1.12 g of the compound prepared according to Example L10, and 69 mg (67 μmol, 17) of the title compound after workup and purification. %) Was isolated.

실시예 EL26 Example EL26

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL26a에 따라 제조된 화합물 69 mg (67 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 26 mg (28 μmol, 42％)을 단리하였다. Similar to Example EL1, 69 mg (67 μmol) of compound prepared according to Example EL26a were reacted and 26 mg (28 μmol, 42%) of the title compound was isolated after workup and purification.

실시예 EL27Example EL27

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (A) 및 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (B) 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexane 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL19에 따라 제조된 화합물 38 mg (41 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 A 14 mg (15 μmol, 37％) 뿐만 아니라 표제 화합물 B 2 mg (2 μmol, 5％)을 단리하였다. Similar to Example EL2, 38 mg (41 μmol) of the compound prepared according to Example EL19 were reacted and after treatment and purification 14 mg (15 μmol, 37%) of the title compound A as well as 2 mg of the title compound B ( 2 μmol, 5%) was isolated.

실시예 EL28 Example EL28

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL28a Example EL28a

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

EL12b와 유사하게 실시예, 실시예 EL14a에 따라 제조된 화합물 273 mg (387 μmol)을 실시예 L11에 따라 제조된 화합물 1.34 g과 반응시키고, 후처리 및 정제 후 표제 화합물 196 mg (178 μmol, 46％)을 단리하였다. Similar to EL12b, 273 mg (387 μmol) of a compound prepared according to Example, Example EL14a were reacted with 1.34 g of a compound prepared according to Example L11, and after treatment and purification, 196 mg (178 μmol, 46) of the title compound. %) Was isolated.

실시예 EL28 Example EL28

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-nitro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL28a에 따라 제조된 화합물 196 mg (178 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 100 mg (101 μmol, 57％)을 단리하였다. Similar to Example EL1, 196 mg (178 μmol) of compound prepared according to Example EL28a was reacted and 100 mg (101 μmol, 57%) of the title compound was isolated after workup and purification.

실시예 EL29Example EL29

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (A) 및 11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (B)11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -unde Carboxylic Acid 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL19에 따라 제조된 화합물 100 mg (101 μmol)을 반응시키고, 후처리 및 정제 후 표제 화합물 A 21 mg (21 μmol, 21％) 뿐만 아니라 표제 화합물 B 2 mg (2 μmol, 2％)을 단리하였다. Similar to Example EL2, 100 mg (101 μmol) of the compound prepared according to Example EL19 were reacted and after treatment and purification 21 mg (21 μmol, 21%) of the title compound A as well as 2 mg of the title compound B ( 2 μmol, 2%) was isolated.

실시예 EL30Example EL30

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7allyl-8-hydroxy -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbonyl Oxymethyl] -phenyl ester

실시예 EL30a Example EL30a

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]페닐 에스테르4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methylbenzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13 -En-4-yloxycarbonyloxymethyl] phenyl ester

EL12b와 유사하게 실시예, 실시예 EL12a에 따라 제조된 화합물 218 mg (309 μmol)을 실시예 L12에 따라 제조된 화합물 314 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 103 mg (118 μmol, 35％)을 단리하였다. Similar to EL12b, 218 mg (309 μmol) of the compound prepared according to Example, Example EL12a were reacted with 314 mg of the compound prepared according to Example L12. 103 mg (118 μmol, 35%) of the title compound were isolated after workup and purification.

실시예 EL30 Example EL30

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL1과 유사하게, 실시예 EL30a에 따라 제조된 화합물 103 mg (118 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 13 mg (15 μmol, 13％)을 단리하였다. Similar to Example EL1, 103 mg (118 μmol) of the compound prepared according to Example EL30a were reacted. 13 mg (15 μmol, 13%) of the title compound were isolated after workup and purification.

실시예 EL31 Example EL31

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL2와 유사하게, 실시예 EL30에 따라 제조된 화합물 13 mg (15 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 5.7 mg (6.6 μmol, 44％)을 단리하였다. Similar to Example EL2, 13 mg (15 μmol) of the compound prepared according to Example EL30 were reacted. After workup and purification 5.7 mg (6.6 μmol, 44%) of the title compound were isolated.

실시예 EL32 Example EL32

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL32a Example EL32a

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-en-4-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 218 mg (309 μmol)을 실시예 L13에 따라 제조된 화합물 396 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 157 mg (159 μmol, 51％)을 단리하였다.Similar to Example EL12b, 218 mg (309 μmol) of compound prepared according to Example EL12a were reacted with 396 mg of compound prepared according to Example L13. After workup and purification 157 mg (159 μmol, 51%) of the title compound were isolated.

실시예 EL32 Example EL32

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL1과 유사하게, 실시예 EL32a에 따라 제조된 화합물 157 mg (159 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 32 mg (37 μmol, 23％)을 단리하였다.Similar to Example EL1, 157 mg (159 μmol) of the compound prepared according to Example EL32a were reacted. 32 mg (37 μmol, 23%) of the title compound was isolated after workup and purification.

실시예 EL33Example EL33

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL2와 유사하게, 실시예 EL32에 따라 제조된 화합물 30 mg (34 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 13 mg (15 μmol, 44％)을 단리하였다. Similar to Example EL2, 30 mg (34 μmol) of the compound prepared according to Example EL32 were reacted. 13 mg (15 μmol, 44%) of the title compound was isolated after workup and purification.

실시예 EL34Example EL34

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL34aExample EL34a

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-en-4-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 218 mg (309 μmol)을 실시예 L14에 따라 제조된 화합물 422 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 77 mg (73 μmol, 24％)을 단리하였다.Similar to Example EL12b, 218 mg (309 μmol) of compound prepared according to Example EL12a were reacted with 422 mg of compound prepared according to Example L14. After workup and purification 77 mg (73 μmol, 24%) of the title compound was isolated.

실시예 EL34Example EL34

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL1과 유사하게, 실시예 EL34a에 따라 제조된 화합물 77 mg (73 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 14 mg (15 μmol, 20％)을 단리하였다.Similar to Example EL1, 77 mg (73 μmol) of the compound prepared according to Example EL34a was reacted. After workup and purification 14 mg (15 μmol, 20%) of the title compound was isolated.

실시예 EL35Example EL35

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL2와 유사하게, 실시예 EL34에 따라 제조된 화합물 14 mg (15 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 6 mg (6 μmol, 42％)을 단리하였다. Similar to Example EL2, 14 mg (15 μmol) of the compound prepared according to Example EL34 were reacted. 6 mg (6 μmol, 42%) of the title compound was isolated after workup and purification.

실시예 EL36Example EL36

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydrate Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL36a Example EL36a

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 330 mg (470 μmol)을 실시예 L12에 따라 제조된 화합물 544 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 170 mg (178 μmol, 38％)을 단리하였다. Similar to Example EL12b, 330 mg (470 μmol) of compound prepared according to Example EL14a were reacted with 544 mg of compound prepared according to Example L12. 170 mg (178 μmol, 38%) of the title compound was isolated after workup and purification.

실시예 EL36Example EL36

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydrate Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL1과 유사하게, 실시예 EL36a에 따라 제조된 화합물 170 mg (178 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 21 mg (24 μmol, 14％)을 단리하였다. Similar to Example EL1, 170 mg (178 μmol) of the compound prepared according to Example EL36a were reacted. After workup and purification 21 mg (24 μmol, 14%) of the title compound was isolated.

실시예 EL37 Example EL37

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 (A) 및 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-페닐 에스테르 (B) 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -part 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -phenyl ester (B)

실시예 EL36에 따라 제조된 화합물 32 mg (38 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 10.1 mg (12 μmol, 31％) 뿐만 아니라 표제 화합물 B 1.2 mg (1.4 μmol, 3.7％)을 단리하였다. 32 mg (38 μmol) of the compound prepared according to Example EL36 was reacted. After workup and purification 11.2 mg (12 μmol, 31%) of the title compound A as well as 1.2 mg (1.4 μmol, 3.7%) of the title compound B were isolated.

실시예 EL38Example EL38

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL38a Example EL38a

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 450 mg (640 μmol)을 실시예 L13에 따라 제조된 화합물 811 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 108 mg (110 μmol, 17％)을 단리하였다.Similar to Example EL12b, 450 mg (640 μmol) of compound prepared according to Example EL14a were reacted with 811 mg of compound prepared according to Example L13. 108 mg (110 μmol, 17%) of the title compound were isolated after workup and purification.

실시예 EL38Example EL38

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -phenyl ester

디클로로메탄 22 ml 중 실시예 EL38a에 따라 제조된 화합물 108 mg (110 μmol)을 디클로로메탄 중 트리플루오로아세트산의 20％ 용액 1.06 ml (2.74 mmol)와 혼합하였다. 16시간 후, 혼합물을 디클로로메탄으로 희석하고, 중탄산나트륨 포화 용액에 부었다. 혼합물을 디클로로메탄으로 수회 추출하고, 합한 유기 추출물을 황산나트륨상에서 건조시켰다. 여과 및 용매 제거로 수득된 잔류물을 미분 실리카 겔상의 크로마토그래피로 정제하였다. 표제 화합물 64 mg (73 μmmol, 67％)을 단리하였다. 108 mg (110 μmol) of the compound prepared according to Example EL38a in 22 ml of dichloromethane were mixed with 1.06 ml (2.74 mmol) of a 20% solution of trifluoroacetic acid in dichloromethane. After 16 hours, the mixture was diluted with dichloromethane and poured into saturated sodium bicarbonate solution. The mixture was extracted several times with dichloromethane and the combined organic extracts were dried over sodium sulfate. The residue obtained by filtration and solvent removal was purified by chromatography on fine silica gel. 64 mg (73 μmmol, 67%) of the title compound were isolated.

실시예 EL39 Example EL39

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-페닐 에스테르 (A) 및 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-페닐 에스테르 (B) 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -phenyl ester (A) and 6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- ( 1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl ) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL38에 따라 제조된 화합물 64 mg (73 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 25 mg (28 μmol, 39％) 뿐만 아니라 표제 화합물 B 5.4 mg (6.1 μmol, 8.3％)을 단리하였다. Similar to Example EL2, 64 mg (73 μmol) of compound prepared according to Example EL38 were reacted. After workup and purification 25 mg (28 μmol, 39%) of the title compound A as well as 5.4 mg (6.1 μmol, 8.3%) of the title compound B were isolated.

실시예 EL40Example EL40

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL40aExample EL40a

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 450 mg (640 μmol)을 실시예 L14에 따라 제조된 화합물 992 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 67 mg (63 μmol, 10％)을 단리하였다.Similar to Example EL12b, 450 mg (640 μmol) of compound prepared according to Example EL14a were reacted with 992 mg of compound prepared according to Example L14. 67 mg (63 μmol, 10%) of the title compound was isolated after workup and purification.

실시예 EL40Example EL40

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -phenyl ester

실시예 EL38과 유사하게, 실시예 EL40a에 따라 제조된 화합물 67 mg (63 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 23 mg (24 μmol, 38％)을 단리하였다.Similar to Example EL38, 67 mg (63 μmol) of the compound prepared according to Example EL40a were reacted. After workup and purification 23 mg (24 μmol, 38%) of the title compound was isolated.

실시예 EL41Example EL41

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-페닐 에스테르 (A) 및 11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-페닐 에스테르 (B) 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -phenyl ester (A) and 11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoic acid 4- ( 1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl ) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL40에 따라 제조된 화합물 33 mg (73 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 13 mg (14 μmol, 38％) 뿐만 아니라 표제 화합물 B 4 mg (4 μmol, 12％)을 단리하였다.Similar to Example EL2, 33 mg (73 μmol) of compound prepared according to Example EL40 were reacted. After workup and purification 13 mg (14 μmol, 38%) of the title compound A as well as 4 mg (4 μmol, 12%) of the title compound B were isolated.

실시예 EL42 Example EL42

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-클로르-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-chlor-phenyl ester

실시예 EL42a Example EL42a

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2- 클로르-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-en-4-yloxycarbonyloxymethyl] -2-chlor-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 329 mg (467 μmol)을 실시예 L15에 따라 제조된 화합물 885 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 126 mg (127 μmol, 27％)을 단리하였다. Similar to Example EL12b, 329 mg (467 μmol) of compound prepared according to Example EL12a were reacted with 885 mg of compound prepared according to Example L15. After workup and purification 126 mg (127 μmol, 27%) of the title compound were isolated.

실시예 EL42 Example EL42

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-클로르-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-chlor-phenyl ester

실시예 EL1과 유사하게, 실시예 EL42a에 따라 제조된 화합물 126 mg (127 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 79 mg (90 μmol, 71％)을 단리하였다.Similar to Example EL1, 126 mg (127 μmol) of the compound prepared according to Example EL42a were reacted. After workup and purification 79 mg (90 μmol, 71%) of the title compound were isolated.

실시예 EL43 Example EL43

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1S,3S,7S, 10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로르-페닐 에스테르 (A) 및 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로르-페닐 에스테르 (B) 4- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -2-chlor-phenyl ester (A) and 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -part 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-chlor-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL42에 따라 제조된 화합물 66 mg (75 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 29.4 mg (32.9 μmol, 44％) 뿐만 아니라 표제 화합물 B 9.7 mg (10.9 μmol, 14％)을 단리하였다. Similar to Example EL2, 66 mg (75 μmol) of compound prepared according to Example EL42 were reacted. After workup and purification 29.4 mg (32.9 μmol, 44%) of the title compound A as well as 9.7 mg (10.9 μmol, 14%) of the title compound B were isolated.

실시예 EL44 Example EL44

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL44aExample EL44a

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2- 클로로-페닐 에스테르6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-en-4-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 329 mg (467 μmol)을 실시예 L16에 따라 제조된 화합물 821 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 120 mg (118 μmol, 25％)을 단리하였다.Similar to Example EL12b, 329 mg (467 μmol) of compound prepared according to Example EL12a were reacted with 821 mg of compound prepared according to Example L16. 120 mg (118 μmol, 25%) of the title compound was isolated after workup and purification.

실시예 EL44Example EL44

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL44a에 따라 제조된 화합물 120 mg (118 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 60 mg (66 μmol, 56％)을 단리하였다. Similar to Example EL1, 120 mg (118 μmol) of the compound prepared according to Example EL44a were reacted. After workup and purification 60 mg (66 μmol, 56%) of the title compound were isolated.

실시예 EL45Example EL45

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (A) 및 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (B) 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (A) and 6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexane Acid 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL44에 따라 제조된 화합물 60 mg (66 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 32 mg (34.7 μmol, 53％) 뿐만 아니라 표제 화합물 B 11 mg (11.9 μmol, 18％)을 단리하였다. Similar to Example EL2, 60 mg (66 μmol) of the compound prepared according to Example EL44 were reacted. After workup and purification 32 mg (34.7 μmol, 53%) of the title compound A as well as 11 mg (11.9 μmol, 18%) of the title compound B were isolated.

실시예 EL46Example EL46

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL46a Example EL46a

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methylbenzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13 -En-4-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 323 mg (459 μmol)을 실시예 L17에 따라 제조된 화합물 790 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 96 mg (88 μmol, 19％)을 단리하였다. Similar to Example EL12b, 323 mg (459 μmol) of compound prepared according to Example EL12a were reacted with 790 mg of compound prepared according to Example L17. After workup and purification 96 mg (88 μmol, 19%) of the title compound was isolated.

실시예 EL46Example EL46

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-8-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL46a에 따라 제조된 화합물 59 mg (54 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 27 mg (27.7 μmol, 51％)을 단리하였다. Similar to Example EL1, 59 mg (54 μmol) of the compound prepared according to Example EL46a were reacted. After workup and purification 27 mg (27.7 μmol, 51%) of the title compound were isolated.

실시예 EL47Example EL47

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (A) 및 11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (B) 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-11 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-7-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (A) and 11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -unde Carboxylic Acid 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL46에 따라 제조된 화합물 27 mg (27 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 14 mg (14.1 μmol, 52％) 뿐만 아니라 표제 화합물 B 5 mg (5.0 μmol, 19％)을 단리하였다. Similar to Example EL2, 27 mg (27 μmol) of the compound prepared according to Example EL46 were reacted. After workup and purification 14 mg (14.1 μmol, 52%) of the title compound A as well as 5 mg (5.0 μmol, 19%) of the title compound B were isolated.

실시예 EL48 Example EL48

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydrate Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL48aExample EL48a

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2- 클로로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 340 mg (482 μmol)을 실시예 L15에 따라 제조된 화합물 885 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 151 mg (152 μmol, 32％)을 단리하였다. Similar to Example EL12b, 340 mg (482 μmol) compound prepared according to Example EL14a was reacted with 885 mg compound prepared according to Example L15. After workup and purification 151 mg (152 μmol, 32%) of the title compound were isolated.

실시예 EL48 Example EL48

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydrate Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL48a에 따라 제조된 화합물 151 mg (152 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 46 mg (52 μmol, 34％)을 단리하였다. Similar to Example EL1, 151 mg (152 μmol) of the compound prepared according to Example EL48a were reacted. After workup and purification 46 mg (52 μmol, 34%) of the title compound were isolated.

실시예 EL49 Example EL49

4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (A) 및 4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부탄산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (B) 4- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (A) and 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -part 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL48에 따라 제조된 화합물 46 mg (52 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 6 mg (6.7 μmol, 13％) 뿐만 아니라 표제 화합물 B 1 mg (1.1 μmol, 2％)을 단리하였다.Similar to Example EL2, 46 mg (52 μmol) of the compound prepared according to Example EL48 were reacted. After workup and purification 6 mg (6.7 μmol, 13%) of the title compound A as well as 1 mg (1.1 μmol, 2%) of the title compound B were isolated.

실시예 EL50 Example EL50

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL50aExample EL50a

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2- 클로로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 340 mg (482 μmol)을 실시예 L16에 따라 제조된 화합물 848 mg과 반응시켰다. 후처리 및 정제 후, 표제 화합물 158 mg (155 μmol, 32％)을 단리하였다. Similar to Example EL12b, 340 mg (482 μmol) compound prepared according to Example EL14a was reacted with 848 mg compound prepared according to Example L16. After workup and purification, 158 mg (155 μmol, 32%) of the title compound were isolated.

실시예 EL50 Example EL50

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL50a에 따라 제조된 화합물 158 mg (155 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 58 mg (64 μmol, 41％)을 단리하였다. Similar to Example EL1, 158 mg (155 μmol) of the compound prepared according to Example EL50a were reacted. After workup and purification 58 mg (64 μmol, 41%) of the title compound were isolated.

실시예 EL51 Example EL51

6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (A) 및 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥산산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (B) 6- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (A) and 6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexane Acid 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL50에 따라 제조된 화합물 58 mg (64 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 25 mg (27 μmol, 42％) 뿐만 아니라 표제 화합물 B 7 mg (7.6 mol, 12％)을 단리하였다. Similar to Example EL2, 58 mg (64 μmol) of the compound prepared according to Example EL50 were reacted. After workup and purification 25 mg (27 μmol, 42%) of the title compound A as well as 7 mg (7.6 mol, 12%) of the title compound B were isolated.

실시예 EL52Example EL52

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL52a Example EL52a

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4- ( tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades- 13-ene-8-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 355 mg (476μmol)을 실시예 L17에 따라 제조된 화합물 790 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 122 mg (112 μmol, 24％)을 단리하였다.Similar to Example EL12b, 355 mg (476 μmol) of compound prepared according to Example EL14a were reacted with 790 mg of compound prepared according to Example L17. After workup and purification 122 mg (112 μmol, 24%) of the title compound was isolated.

실시예 EL52Example EL52

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(4S,7R,8S,9S,13Z,16S)-[7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (4S, 7R, 8S, 9S, 13Z, 16S)-[7-allyl-4-hydride Roxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-ene-8-yloxycarbo Nyloxymethyl] -2-chloro-phenyl ester

실시예 EL1과 유사하게, 실시예 EL52a에 따라 제조된 화합물 122 mg (112 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 28 mg (29 μmol, 26％)을 단리하였다. Similar to Example EL1, 122 mg (112 μmol) of the compound prepared according to Example EL52a were reacted. After workup and purification 28 mg (29 μmol, 26%) of the title compound was isolated.

실시예 EL53Example EL53

11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (A) 및 11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데칸산 4-(1R,3S,7S,10R,11S,12S,16S)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 (B) 11- (2,5-Dioxo-2,5-dihydro-pyrrole-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10-allyl-7 -Hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1. 0] heptades-11-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (A) and 11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -unde Carboxylic Acid 4- (1R, 3S, 7S, 10R, 11S, 12S, 16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole -5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-chloro-phenyl ester (B)

실시예 EL2와 유사하게, 실시예 EL52에 따라 제조된 화합물 28 mg (29 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 6.2 mg (6.3 μmol, 22％) 뿐만 아니라 표제 화합물 B 0.3 mg (0.3 μmol, 1％)을 단리하였다. Similar to Example EL2, 28 mg (29 μmol) of the compound prepared according to Example EL52 were reacted. After workup and purification 6.2 mg (6.3 μmol, 22%) of the title compound A as well as 0.3 mg (0.3 μmol, 1%) of the title compound B were isolated.

실시예 EL54 Example EL54

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-3-니트로-부티릴아미노]-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -3- Nitro-butyrylamino] -benzyl ester

실시예 EL54a Example EL54a

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-아미노-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4-amino-benzyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 160 mg (227 μmol)을 (4-아미노-3-니트로-페닐)-메탄올 191 mg과 반응시켰다. 후처리 및 정제 후 표제 화합물 51 mg (61 μmol, 27％)을 단리하였다.Similar to Example EL12b, 160 mg (227 μmol) of compound prepared according to Example EL12a were reacted with 191 mg of (4-amino-3-nitro-phenyl) -methanol. After workup and purification 51 mg (61 μmol, 27%) of the title compound was isolated.

실시예 EL54b Example EL54b

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부티릴아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [4- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -butyrylamino] -3-nitro-benzyl ester

실시예 L4에 따라 제조된 화합물 153 mg (837 μmol)을 티오닐 클로라이드 1.82 ml와 혼합하고, 3.5시간 동안 환류시켰다. 혼합물을 톨루엔으로 희석하고 증발시켰다. 디클로로메탄 6 ml 중 실시예 54a에 따라 제조된 화합물 130 mg (156 μmol)의 용액을 첨가하고, 피리딘 75 ㎕를 혼합하고, 혼합물을 23℃에서 16시간 동안 교반하였다. 이를 물에 붓고, 디클로로메탄으로 수회 추출하고, 합한 유기 추출물을 물로 세척하고, 황산나트륨상에서 건조시켰다. 여과 및 용매 제거 후, 잔류물을 크로마토그래피로 정제하였다. 표제 화합물 101 mg (101 μmol, 65％)을 단리하였다. 153 mg (837 μmol) of compound prepared according to Example L4 were mixed with 1.82 ml of thionyl chloride and refluxed for 3.5 hours. The mixture was diluted with toluene and evaporated. A solution of 130 mg (156 μmol) of the compound prepared according to Example 54a in 6 ml of dichloromethane was added, 75 μl of pyridine was mixed and the mixture was stirred at 23 ° C. for 16 h. It was poured into water, extracted several times with dichloromethane and the combined organic extracts were washed with water and dried over sodium sulfate. After filtration and solvent removal, the residue was purified by chromatography. 101 mg (101 μmol, 65%) of the title compound were isolated.

실시예 EL54 Example EL54

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부티릴아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S)-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2methyl-benzothiazol-5-yl)- 2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -butyrylamino ] -3-nitro-benzyl ester

실시예 EL1과 유사하게, 실시예 EL54a에 따라 제조된 화합물 101 mg (101 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 62 mg (70 μmol, 69％)을 단리하였다. Similar to Example EL1, 101 mg (101 μmol) of the compound prepared according to Example EL54a were reacted. After workup and purification 62 mg (70 μmol, 69%) of the title compound were isolated.

실시예 EL55Example EL55

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부티릴아미노]-3-니트로-벤질 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로피롤-1-일)-부티릴아미노]-3-니트로-벤질 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester 4- [4- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -butyrylamino] -3-nitro-benzyl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S) -carbonate 10-allyl-11-hydroxy-8, 8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7 -Yl ester 4- [4- (2,5-dioxo-2,5-dihydropyrrole-1-yl) -butyrylamino] -3-nitro-benzyl ester (B)

실시예 EL2와 유사하게, 실시예 EL54에 따라 제조된 화합물 62 mg (70 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 38 mg (42 μmol, 60％) 뿐만 아니라 표제 화합물 B 11 mg (12 μmol, 17％)을 단리하였다. Similar to Example EL2, 62 mg (70 μmol) of the compound prepared according to Example EL54 were reacted. After workup and purification 38 mg (42 μmol, 60%) of the title compound A as well as 11 mg (12 μmol, 17%) of the title compound B were isolated.

실시예 EL56 Example EL56

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoyl Amino] -3-nitro-benzyl ester

실시예 EL56a Example EL56a

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [6- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -hexanoylamino] -3-nitro-benzyl ester

실시예 EL54b와 유사하게, 실시예 EL54a에 따라 제조된 화합물 50 mg (60 μmol)을 실시예 L5에 따라 제조된 화합물과 반응시켰다. 후처리 및 정제 후 표제 화합물 58 mg (56 μmol, 94％)을 단리하였다. Similar to Example EL54b, 50 mg (60 μmol) of the compound prepared according to Example EL54a were reacted with the compound prepared according to Example L5. 58 mg (56 μmol, 94%) of the title compound were isolated after workup and purification.

실시예 EL56 Example EL56

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르(4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoyl Amino] -3-nitro-benzyl ester

실시예 EL1과 유사하게, 실시예 EL56a에 따라 제조된 화합물 82 mg (80 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 34 mg (37 μmol, 46％)을 단리하였다. Similar to Example EL1, 82 mg (80 μmol) of the compound prepared according to Example EL56a were reacted. After workup and purification 34 mg (37 μmol, 46%) of the title compound were isolated.

실시예 EL57Example EL57

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 4-[6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-[6-(2,5-디옥소-2,5-디히드로피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester 4- [6- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -hexanoylamino] -3-nitro-benzyl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S) -carbonate 10-allyl-11-hydroxy-8, 8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7 -Yl ester 4- [6- (2,5-dioxo-2,5-dihydropyrrole-1-yl) -hexanoylamino] -3-nitro-benzyl ester (B)

실시예 EL2와 유사하게, 실시예 EL56에 따라 제조된 화합물 34 mg (37 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 19 mg (20.4 μmol, 55％) 뿐만 아니라 표제 화합물 B 6 mg (6.4 μmol, 17％)을 단리하였다. Similar to Example EL2, 34 mg (37 μmol) of the compound prepared according to Example EL56 were reacted. After workup and purification 19 mg (20.4 μmol, 55%) of the title compound A as well as 6 mg (6.4 μmol, 17%) of the title compound B were isolated.

실시예 EL58 Example EL58

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -undecano Ylamino] -3-nitro-benzyl ester

실시예 EL58a Example EL58a

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [11- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -undecanoylamino] -3-nitro-benzyl ester

실시예 EL54b와 유사하게, 실시예 EL54a에 따라 제조된 화합물 130 mg (156 μmol)을 실시예 L6에 따라 제조된 화합물과 반응시켰다. 후처리 및 정제 후 표제 화합물 120 mg (109 μmol, 70％)을 단리하였다. Similar to Example EL54b, 130 mg (156 μmol) of the compound prepared according to Example EL54a were reacted with the compound prepared according to Example L6. After workup and purification 120 mg (109 μmol, 70%) of the title compound were isolated.

실시예 EL58 Example EL58

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 4-[11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 4- [11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -undecano Ylamino] -3-nitro-benzyl ester

실시예 EL1과 유사하게, 실시예 EL58a에 따라 제조된 화합물 120 mg (109 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 89 mg (90 μmol, 83％)을 단리하였다. Similar to Example EL1, 120 mg (109 μmol) of the compound prepared according to Example EL58a were reacted. After workup and purification 89 mg (90 μmol, 83%) of the title compound was isolated.

실시예 EL59Example EL59

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 4-[11-(2,5-디옥소-2,5-디히드로-피롤-1-일)- 운데카노일아미노]-3-니트로-벤질 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-[11-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester 4- [11- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -undecanoylamino] -3-nitro-benzyl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S) -carbonate 10-allyl-11-hydroxy-8 , 8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades- 7-yl ester 4- [11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoylamino] -3-nitro-benzyl ester (B)

실시예 EL2와 유사하게, 실시예 EL58에 따라 제조된 화합물 89 mg (90 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 45 mg (μmol, ％) 뿐만 아니라 표제 화합물 B 15 mg (μmol, ％)을 단리하였다. Similar to Example EL2, 89 mg (90 μmol) of compound prepared according to Example EL58 were reacted. After workup and purification 45 mg (μmol,%) of the title compound A as well as 15 mg (μmol,%) of the title compound B were isolated.

실시예 EL60 Example EL60

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥실 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexyl ester

실시예 EL60a Example EL60a

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥실 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 6- (2,5-dioxo-2,5-dihydro-pyrrole-1 -Yl) -hexyl ester

실시예 EL12b와 유사하게, 실시예 EL12a에 따라 제조된 화합물 1.25 g (1.77 mmol)을 L18에 따라 제조된 화합물 1.75 g과 반응시켰다. 후처리 및 정제 후 표제 화합물 119 mg (138 μmol, 8％)을 단리하였다. Similar to Example EL12b, 1.25 g (1.77 mmol) of the compound prepared according to Example EL12a were reacted with 1.75 g of the compound prepared according to L18. After workup and purification 119 mg (138 μmol, 8%) of the title compound were isolated.

실시예 EL60 Example EL60

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-8-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-4-일 에스테르 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥실 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-4-yl ester 6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexyl ester

실시예 EL1과 유사하게, 실시예 EL60a에 따라 제조된 화합물 101 mg (117 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 68 mg (91 μmol, 77％)을 단리하였다. Similar to Example EL1, 101 mg (117 μmol) of the compound prepared according to Example EL60a were reacted. 68 mg (91 μmol, 77%) of the title compound were isolated after workup and purification.

실시예 EL61Example EL61

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥실 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 6-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥실 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester 6- (2,5-dioxo-2,5-dihydro-pyrrole-1 -Yl) -hexyl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- ( 2-Methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-7-yl ester 6- (2,5-dioxo- 2,5-dihydro-pyrrole-1-yl) -hexyl ester (B)

실시예 EL2와 유사하게, 실시예 EL60에 따라 제조된 화합물 68 mg (91 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 26 mg (34 μmol, 37％) 뿐만 아니라 표제 화합물 B 10 mg (13 μmol, 14％)을 단리하였다. Similar to Example EL2, 68 mg (91 μmol) of the compound prepared according to Example EL60 were reacted. After workup and purification 26 mg (34 μmol, 37%) of the title compound A as well as 10 mg (13 μmol, 14%) of the title compound B were isolated.

실시예 EL62 Example EL62

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-3-니트로-부티릴아미노]-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -3- Nitro-butyrylamino] -benzyl ester

실시예 EL62a Example EL62a

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-아미노-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4-amino-benzyl ester

실시예 EL12b와 유사하게, 실시예 EL14a에 따라 제조된 화합물 1.73 g (2.46 mmol)을 (4-아미노-3-니트로-페닐)-메탄올 2.06 g과 반응시켰다. 후처리 및 정제 후 표제 화합물 420 mg (502 μmol, 20％)을 단리하였다. Similar to Example EL12b, 1.73 g (2.46 mmol) of the compound prepared according to Example EL14a were reacted with 2.06 g of (4-amino-3-nitro-phenyl) -methanol. After workup and purification 420 mg (502 μmol, 20%) of the title compound were isolated.

실시예 EL62b Example EL62b

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부티릴아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -butyrylamino] -3-nitro-benzyl ester

실시예 EL54b와 유사하게, 실시예 EL62a에 따라 제조된 화합물 140 mg (167 μmol)을 실시예 L4에 따라 제조된 화합물과 반응시켰다. 후처리 및 정제 후 표제 화합물 150 mg (150 μmol, 90％)을 단리하였다. Similar to Example EL54b, 140 mg (167 μmol) of the compound prepared according to Example EL62a were reacted with the compound prepared according to Example L4. After workup and purification 150 mg (150 μmol, 90%) of the title compound was isolated.

실시예 EL62 Example EL62

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-3-니트로-부티릴아미노]-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -3- Nitro-butyrylamino] -benzyl ester

실시예 EL1과 유사하게, 실시예 EL62a에 따라 제조된 화합물 145 mg (145 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 67 mg (76 μmol, 52％)을 단리하였다. Similar to Example EL1, 145 mg (145 μmol) of the compound prepared according to Example EL62a were reacted. 67 mg (76 μmol, 52%) of the title compound were isolated after workup and purification.

실시예 EL63 Example EL63

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-부티릴아미노]-3-니트로-벤질 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-탄산 10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)- 부티릴아미노]-3-니트로-벤질 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yl ester 4- [4- (2,5-dioxo-2,5-dihydro -Pyrrol-1-yl) -butyrylamino] -3-nitro-benzyl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S) -carbonate 10-allyl-7-hydroxy-8 , 8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-11 -Yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -butyrylamino] -3-nitro-benzyl ester (B)

실시예 EL2와 유사하게, 실시예 EL62에 따라 제조된 화합물 67 mg (76 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 37 mg (41 μmol, 54％) 뿐만 아니라 표제 화합물 B 12 mg (13 μmol, 18％)을 단리하였다. Similar to Example EL2, 67 mg (76 μmol) of compound prepared according to Example EL62 were reacted. After workup and purification 37 mg (41 μmol, 54%) of the title compound A as well as 12 mg (13 μmol, 18%) of the title compound B were isolated.

실시예 EL64 Example EL64

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-3-니트로-헥사노일아미노]-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -3- Nitro-hexanoylamino] -benzyl ester

실시예 EL64a Example EL64a

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -hexanoylamino] -3-nitro-benzyl ester

실시예 EL54b와 유사하게, 실시예 EL62a에 따라 제조된 화합물 140 mg (167 μmol)을 실시예 L5에 따라 제조된 화합물과 반응시켰다. 후처리 및 정제 후 표제 화합물 155 mg (150 μmol, 90％)을 단리하였다. Similar to Example EL54b, 140 mg (167 μmol) of the compound prepared according to Example EL62a were reacted with the compound prepared according to Example L5. After workup and purification 155 mg (150 μmol, 90%) of the title compound were isolated.

실시예 EL64 Example EL64

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-3-니트로-헥사노일아미노]-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -3- Nitro-hexanoylamino] -benzyl ester

실시예 EL1과 유사하게, 실시예 EL64a에 따라 제조된 화합물 150 mg (151 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 68 mg (74 μmol, 49％)을 단리하였다. Similar to Example EL1, 150 mg (151 μmol) of the compound prepared according to Example EL64a was reacted. 68 mg (74 μmol, 49%) of the title compound were isolated after workup and purification.

실시예 EL65 Example EL65

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-탄산 10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yl ester 4- [4- (2,5-dioxo-2,5-dihydro -Pyrrole-1-yl) -hexanoylamino] -3-nitro-benzyl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S) -carbonate 10-allyl-7-hydroxy-8 , 8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades-11 -Yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoylamino] -3-nitro-benzyl ester (B)

실시예 EL2와 유사하게, 실시예 EL64에 따라 제조된 화합물 68 mg (74 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 44 mg (47 μmol, 64％) 뿐만 아니라 표제 화합물 B 3 mg (3 μmol, 4％)을 단리하였다. Similar to Example EL2, 68 mg (74 μmol) of compound prepared according to Example EL64 were reacted. After workup and purification 44 mg (47 μmol, 64%) of the title compound A as well as 3 mg (3 μmol, 4%) of the title compound B were isolated.

실시예 EL66 Example EL66

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-3-니트로-운데카노일아미노]-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -3- Nitro-Undecanoylamino] -Benzyl Ester

실시예 EL66a Example EL66a

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-(tert-부틸-디메틸-실라닐옥시)-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4- (tert-butyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl -Benzothiazol-5-yl) -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro- Pyrrole-1-yl) -undecanoylamino] -3-nitro-benzyl ester

실시예 EL54b와 유사하게, 실시예 EL62a에 따라 제조된 화합물 140 mg (167 μmol)을 실시예 L6에 따라 제조된 화합물과 반응시켰다. 후처리 및 정제 후 표제 화합물 165 mg (150 μmol, 90％)을 단리하였다.Similar to Example EL54b, 140 mg (167 μmol) of the compound prepared according to Example EL62a were reacted with the compound prepared according to Example L6. After workup and purification 165 mg (150 μmol, 90%) of the title compound were isolated.

실시예 EL66 Example EL66

(4S,7R,8S,9S,13Z,16S)-탄산 7-알릴-4-히드록시-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-2,6-디옥소-옥사시클로헥사데스-13-엔-8-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-3-니트로-운데카노일아미노]-벤질 에스테르 (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -carbonate -2,6-dioxo-oxacyclohexades-13-en-8-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -3- Nitro-Undecanoylamino] -Benzyl Ester

실시예 EL1과 유사하게, 실시예 EL66a에 따라 제조된 화합물 145 mg (132 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 106 mg (108 μmol, 82％)을 단리하였다. Similar to Example EL1, 145 mg (132 μmol) of the compound prepared according to Example EL66a were reacted. After workup and purification, 106 mg (108 μmol, 82%) of the title compound were isolated.

실시예 EL67Example EL67

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (A) 및 (1R,3S,7S,10R,11S,12S,16S)-탄산 10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르 4-[4-(2,5-디옥소-2,5-디히드로-피롤-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (B) (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yl ester 4- [4- (2,5-dioxo-2,5-dihydro -Pyrrol-1-yl) -undecanoylamino] -3-nitro-benzyl ester (A) and (1R, 3S, 7S, 10R, 11S, 12S, 16S) -carbonate 10-allyl-7-hydroxy- 8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptades- 11-yl ester 4- [4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -undecanoylamino] -3-nitro-benzyl ester (B)

실시예 EL2와 유사하게, 실시예 EL66에 따라 제조된 화합물 106 mg (108 μmol)을 반응시켰다. 후처리 및 정제 후 표제 화합물 A 58 mg (58 μmol, 54％) 뿐만 아니라 표제 화합물 B 6 mg (6 μmol, 6％)을 단리하였다. Similar to Example EL2, 106 mg (108 μmol) of the compound prepared according to Example EL66 was reacted. After workup and purification 58 mg (58 μmol, 54%) of the title compound A as well as 6 mg (6 μmol, 6%) of the title compound B were isolated.

효과기-연결기 인식 단위 (ELE)의 합성의 실시예Embodiment of Synthesis of Effector-Connector Recognition Unit (ELE)

실시예 ELE1 Example ELE1

[3-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-프로필]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 [3- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -propyl] -carbamic acid-10-allyl-11-hydroxy-8,8,12, 16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yl ester

실시예 ELE1a Example ELE1a

말단 시스테인을 이용한 항체 단편의 환원Reduction of Antibody Fragments Using Terminal Cysteines

피브로넥틴 도메인 B (ED-B)를 특이적으로 인식하고 AP39로서 명명되는, 아미노산 서열Amino acid sequence that specifically recognizes fibronectin domain B (ED-B) and is named AP39

의 항체 중쇄 및 경쇄 (단일쇄 Fv, scFv)의 가변 도메인으로 이루어진 단일-가닥 단백질을 c-말단 시스테인의 환원 후 커플링을 위해 사용하였다. A single-stranded protein consisting of the variable domains of the antibody heavy and light chains (single chain Fv, scFv) of was used for coupling after reduction of the c-terminal cysteine.

환원을 위해, PBS 236 ㎕ 중 트리(2-카르복시에틸)포스핀-히드로클로라이드 661 ㎍의 용액을 PBS 1.12 ml 중 AP39 1.54 mg의 용액과 혼합하고, 25℃에서 1.5시간 동안 인큐베이션하였다. 미리-평형화된 NAP-5 컬럼을 이용하여 AP39r 450 ㎕ 및 PBS 50 ㎕의 농도로 담수화를 수행하였다. PBS 1 ml로 용출한 후, 환원된 항체 단편 AP39r을 0.7 mg/ml의 농도로 단리하였다. For reduction, a solution of 661 μg of tri (2-carboxyethyl) phosphine-hydrochloride in 236 μl of PBS was mixed with a solution of 1.54 mg of AP39 in 1.12 ml of PBS and incubated at 25 ° C. for 1.5 hours. Desalination was performed using a pre-equilibrated NAP-5 column at a concentration of 450 μl of AP39r and 50 μl of PBS. After eluting with 1 ml of PBS, the reduced antibody fragment AP39r was isolated at a concentration of 0.7 mg / ml.

실시예 ELE1 Example ELE1

(1S,3S,7S(3RS),10R,11S,12S,16R)-[3-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-프로필]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 (1S, 3S, 7S (3RS), 10R, 11S, 12S, 16R)-[3- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -propyl] -Carbamic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17 -Dioxa-bicyclo [14.1.0] heptades-7-yl ester

실시예 EL2에 따라 제조된, DMSO 중 효과기-연결기 접합체의 1.38 mmol 용액 22.5 ㎕를 실시예 ELE1a에 따라 제조된 환원된 항체 단편의 용액 400 ㎕에 첨가하고, PBS 77.5 ㎕와 혼합하고, 25℃에서 1시간 동안 인큐베이션하였다. 미리-평형화된 NAP5 컬럼을 이용하여 반응 용액 500 ㎕의 농도로 담수화를 수행하였다. PBS로 용출한 후, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. 22.5 μl of a 1.38 mmol solution of the effector-linker conjugate in DMSO, prepared according to Example EL2, is added to 400 μl of a solution of the reduced antibody fragment prepared according to Example ELE1a, mixed with 77.5 μl of PBS and mixed at 25 ° C. Incubate for 1 hour. Desalination was performed at a concentration of 500 μl of reaction solution using a pre-equilibrated NAP5 column. After eluting with PBS, a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26203.1 m/z (실험치) : 26218 ±20 m / z (calculated): 26203.1 m / z (experimental): 26218 ± 20

실시예 ELE2Example ELE2

(1S,3S,7S(3RS),10R,11S,12S,16R)-[5-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-펜틸]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (1S, 3S, 7S (3RS), 10R, 11S, 12S, 16R)-[5- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -pentyl] -Carbamic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17 -Dioxabicyclo [14.1.0] heptades-7-yl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL4에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL4, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26231.2 m/z (실험치) : 26236 ±20 m / z (calculated): 26231.2 m / z (experimental): 26236 ± 20

실시예 ELE3Example ELE3

(1S,3S,7S(3RS),10R,11S,12S,16R)-[10-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-데실]-카르밤산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-7-일 에스테르 (1S, 3S, 7S (3RS), 10R, 11S, 12S, 16R)-[10- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -decyl] -Carbamic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17 -Dioxabicyclo [14.1.0] heptades-7-yl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL6에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL6, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26301.4 m/z (실험치) : 26303 ±20 m / z (calculated): 26301.4 m / z (experimental): 26303 ± 20

실시예 ELE4Example ELE4

(1S,3S,7S,10R,11S(3RS),12S,16R)-[3-(3-AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-프로필]-카르밤산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르 (1S, 3S, 7S, 10R, 11S (3RS), 12S, 16R)-[3- (3-AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -propyl]- Carbamic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17- Dioxabicyclo [14.1.0] heptades-11-yl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL8에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL8, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26203.2 m/z (실험치): 26206 ±20 m / z (calculated): 26203.2 m / z (experimental): 26206 ± 20

실시예 ELE5Example ELE5

(1S,3S,7S,10R,11S(3RS),12S,16R)-[5-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-펜틸]-카르밤산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데스-11-일 에스테르 (1S, 3S, 7S, 10R, 11S (3RS), 12S, 16R)-[5- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -pentyl] -Carbamic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17 -Dioxabicyclo [14.1.0] heptades-11-yl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL10에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL10 and the solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26231.2 m/z (실험치) : 26225 ±20 m / z (calculated): 26231.2 m / z (experimental): 26225 ± 20

실시예 ELE6Example ELE6

(1S,3S(E),7S,10R,11S,12S,16R)-[3-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-프로필]-카르밤산-7-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필카르바모일옥시]-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐-3-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일 에스테르 (A) 및 (1S,3S(E),7S,10R,11S,12S,16R)-[3-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-프로필]-카르밤산-11-[3-(2,5-디옥소-2,5-디히드로-피롤-1-일)-프로필카르바모일옥시]-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 (B) (1S, 3S (E), 7S, 10R, 11S, 12S, 16R)-[3- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -propyl] -Carbamic acid-7- [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propylcarbamoyloxy] -8,8,10,12,16-pentamethyl -3- [1-Methyl-2- (2-methyl-thiazol-4-yl) -vinyl-3-5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades -11-yl ester (A) and (1S, 3S (E), 7S, 10R, 11S, 12S, 16R)-[3- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrroli Din-1-yl) -propyl] -carbamic acid-11- [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propylcarbamoyloxy] -8,8 , 10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-7-yl ester (B)

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL11에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다.Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL11, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z(계산치) : 26347.3 m/z (실험치): 26358 ±20 m / z (calculated): 26347.3 m / z (experimental): 26358 ± 20

실시예 ELE7Example ELE7

(1S,3S(E),7S,10R,11S,12S,16R)-N-[1-({4-[2-(7,11-디히드록시-8,8,10,12,16-펜타메틸-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-3-일)-프로페닐]-티아졸-2-일메틸}-카르바모일)-에틸]-3-(AP39r)-디술파닐-N-메틸-프로피온아미드 (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -N- [1-({4- [2- (7,11-dihydroxy-8,8,10,12,16- Pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-3-yl) -propenyl] -thiazol-2-ylmethyl} -carbamoyl)- Ethyl] -3- (AP39r) -disulfanyl-N-methyl-propionamide

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL16에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL16 and the solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26173 m/z (실험치) : 26174 ±20 m / z (calculated): 26173 m / z (experimental): 26174 ± 20

실시예 ELE8Example ELE8

(1S,3S(E),7S,10R,11S,12S,16R)-2-[메틸-(3-(AP39r)-디술파닐-프로피오닐)-아미노]-프로피온산-4-[2-(7,11-디히드록시-8,8,10,12,16-펜타메틸-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-3-일)-프로페닐]-티아졸-2-일메틸 에스테르 (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -2- [Methyl- (3- (AP39r) -disulfanyl-propionyl) -amino] -propionic acid-4- [2- (7 , 11-Dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-3-yl) -pro Phenyl] -thiazol-2-ylmethyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL17에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL17, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26174 m/z (실험치) : 26163 ±20 m / z (calculated): 26174 m / z (experimental): 26163 ± 20

실시예 ELE9 Example ELE9

(1S,3S,7S,10R,11S,12S,16R)-탄산-10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-페닐 에스테르 (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5 -Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yl ester 4- (3- (AP39r) -sulfanyl-2,5-dioxo -Pyrrolidin-1-yl) -phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL13에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL13, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26238 m/z (실험치) : 26224 ±20 m / z (calculated): 26238 m / z (experimental): 26224 ± 20

실시예 ELE10Example ELE10

(1S,3S,7S,10R,11S,12S,16R)-탄산-10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일 에스테르 4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-페닐 에스테르 (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5 -Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-11-yl ester 4- (3- (AP39r) -sulfanyl-2,5-dioxo -Pyrrolidin-1-yl) -phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL15에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL15, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26238 m/z (실험치) : 26243 ±20 m / z (calculated): 26238 m / z (experimental): 26243 ± 20

실시예 ELE11Example ELE11

4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL19에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL19, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26383 m/z (실험치) : 26377 ±20m / z (calculated): 26383 m / z (experimental): 26377 ± 20

실시예 ELE12Example ELE12

4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL25에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL25, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26383 m/z (실험치) : 26381 ±20m / z (calculated): 26383 m / z (experimental): 26381 ± 20

실시예 ELE13Example ELE13

6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 6- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL21에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL21 and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26411 m/z (실험치) : 26384 ±30 m / z (calculated): 26411 m / z (experimental): 26384 ± 30

m/z (계산치) : 25673 m/z (실험치): 25657 ±20 (6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 단편) m / z (calculated): 25673 m / z (experimental): 25657 ± 20 (6- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid fragment )

실시예 ELE14Example ELE14

11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL23에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다.Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL23, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26482 m/z (실험치) : 26477 ±20 m / z (calculated): 26482 m / z (experimental): 26477 ± 20

m/z (계산치) : 25744 m/z (실험치): 26752 ±20 (11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 단편) m / z (calculated): 25744 m / z (experimental): 26752 ± 20 (11- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid fragment )

실시예 ELE15Example ELE15

6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 6- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL27에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다.Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL27, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26411 m/z (실험치) : 26398 ±20 m / z (calculated): 26411 m / z (experimental): 26398 ± 20

m/z (계산치) : 25673 m/z (실험치): 25665 ±20 (6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 단편) m / z (calculated): 25673 m / z (experimental): 25665 ± 20 (6- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid fragment )

실시예 ELE16Example ELE16

11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 11- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL29에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다.Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL29, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26482 m/z (실험치) : 26491 ±20 m / z (calculated): 26482 m / z (experimental): 26491 ± 20

m/z (계산치) : 25744 m/z (실험치): 25757 ±20 (11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 단편) m / z (calculated): 25744 m / z (experimental): 25757 ± 20 (11- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid fragment )

실시예 ELE17Example ELE17

4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-페닐 에스테르 4- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL31에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다.Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL31 and the solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26338 m/z (실험치) : 26304 ±30 m / z (calculated): 26338 m / z (experimental): 26304 ± 30

실시예 ELE18Example ELE18

6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL33에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다.Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL33, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26366 m/z (실험치) : 26347 ±30 m / z (calculated): 26366 m / z (experimental): 26347 ± 30

실시예 ELE19Example ELE19

11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL35에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL35, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26437 m/z (실험치) : 26412 ±30 m / z (calculated): 26437 m / z (experimental): 26412 ± 30

실시예 ELE20Example ELE20

4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL37에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL37, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) :26338 m/z (실험치) : 26338 ±20 m / z (calculated): 26338 m / z (experimental): 26338 ± 20

실시예 ELE21Example ELE21

6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-페닐 에스테르 6- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL39에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL39 and the solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26366 m/z (실험치) : 26384 ±30 m / z (calculated): 26366 m / z (experimental): 26384 ± 30

실시예 ELE22Example ELE22

11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-페닐 에스테르 11- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL41에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL41, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26437 m/z (실험치) : 26421 ±30 m / z (calculated): 26437 m / z (experimental): 26421 ± 30

실시예 ELE23Example ELE23

4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 4- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL43에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL43, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26373 m/z (실험치) : 26358 ±20 m / z (calculated): 26373 m / z (experimental): 26358 ± 20

m/z (계산치) : 25645 m/z (실험치) : 25627 ±20 (4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 단편) m / z (calculated): 25645 m / z (experimental): 25627 ± 20 (4- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid fragment )

실시예 ELE24Example ELE24

6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 6- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL45에 따라 제조된 반응시 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A in the reaction prepared according to Example EL45, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26401 m/z (실험치) : 26395 ±20 m / z (calculated): 26401 m / z (experimental): 26395 ± 20

실시예 ELE25Example ELE25

11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일옥시카르보닐옥시메틸]-2-클로르-페닐 에스테르 11- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-r Cyclo [14.1.0] heptades-7-yloxycarbonyloxymethyl] -2-chlor-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL47에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL47, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26471 m/z (실험치) : 26463 ±20 m / z (calculated): 26471 m / z (experimental): 26463 ± 20

실시예 ELE26Example ELE26

4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로로-페닐 에스테르 4- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-chloro-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL49에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL49 and the solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26373 m/z (실험치) : 26341 ±30 m / z (calculated): 26373 m / z (experimental): 26341 ± 30

실시예 ELE27Example ELE27

6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥산산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로르-페닐 에스테르 6- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -hexanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-chlor-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL51에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL51, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26401 m/z (실험치) : 26391 ±20 m / z (calculated): 26401 m / z (experimental): 26391 ± 20

실시예 ELE28Example ELE28

11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데칸산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-클로르-페닐 에스테르 11- (3- (AP39r) -Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -undecanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R)-[10 -Allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-ratio Cyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-chlor-phenyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL53에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL53, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26471 m/z (실험치) : 26466 ±20 m / z (calculated): 26471 m / z (experimental): 26466 ± 20

실시예 ELE29Example ELE29

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-[4-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-부티릴아미노]-3-니트로-벤질 에스테르 (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yl ester 4- [4- (3- (AP39r) -sulfanyl-2,5- Dioxo-pyrrolidin-1-yl) -butyrylamino] -3-nitro-benzyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL55에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL55, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26337 m/z (실험치) : ±20 m / z (calculated): 26337 m / z (experimental): ± 20

실시예 ELE30Example ELE30

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-[6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥사노일아미노]-3-니트로-벤질 에스테르 (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yl ester 4- [6- (3- (AP39r) -sulfanyl-2,5- Dioxo-pyrrolidin-1-yl) -hexanoylamino] -3-nitro-benzyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL57에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다.Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL57 and the solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26365 m/z (실험치) : ±20 m / z (calculated): 26365 m / z (experimental): ± 20

실시예 ELE31Example ELE31

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르 4-[11-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-운데카노일아미노]-3-니트로-벤질 에스테르 (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yl ester 4- [11- (3- (AP39r) -sulfanyl-2,5- Dioxo-pyrrolidin-1-yl) -undecanoylamino] -3-nitro-benzyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL59에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL59 and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26436 m/z (실험치) : ±20 m / z (calculated): 26436 m / z (experimental): ± 20

실시예 ELE32Example ELE32

(1S,3S,7S,10R,11S,12S,16R)-탄산 10-알릴-11-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-7-일 에스테르6-(3-(AP39r)-술파닐-2,5-디옥소-피롤리딘-1-일)-헥실 에스테르 (1S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonate 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole-5- Yl) -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptades-7-yl ester 6- (3- (AP39r) -sulfanyl-2,5-dioxo- Pyrrolidin-1-yl) -hexyl ester

실시예 ELE1과 유사하게, 실시예 ELE1a에 따라 환원된 항체 단편을 실시예 EL61에 따라 제조된 효과기-연결기 접합체 A와 반응시키고, 표제 화합물의 용액을 단리하였다. 항체 단편에 대한 희석 인자는 대략 2.5였다. Similar to Example ELE1, the antibody fragment reduced according to Example ELE1a was reacted with effector-linker conjugate A prepared according to Example EL61, and a solution of the title compound was isolated. Dilution factor for antibody fragments was approximately 2.5.

m/z (계산치) : 26246 m/z (실험치) : ±20 m / z (calculated): 26246 m / z (experimental): ± 20

실시예 ELE33Example ELE33

4-(3-(2H8-Ab)x-술파닐-2,5-디옥소-피롤리딘-1-일)-부탄산 4-(1S,3S,7S,10R,11S,12S,16R)-[10-알릴-7-히드록시-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-5,9-디옥소-4,17-디옥사-비시클로[14.1.0]헵타데스-11-일옥시카르보닐옥시메틸]-2-니트로-페닐 에스테르 4- (3- (2H8-Ab) x-Sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -butanoic acid 4- (1S, 3S, 7S, 10R, 11S, 12S, 16R) -[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-di Oxa-bicyclo [14.1.0] heptades-11-yloxycarbonyloxymethyl] -2-nitro-phenyl ester

실시예 ELE33a에 따라 제조된 티오닐화된 항체의 용액 100 ㎕ (약 3 nmol, 약 6개의 티올기)를 실시예 EL25에 따라 제조된 효과기-연결기 접합체의 PBS 중의 1.1 mM 용액 42.3 ㎕와 혼합하고, 혼합물을 23℃에서 1시간 동안 인큐베이션하였다. 미리-평형화된 NAP5 컬럼을 사용하여 반응 용액 150 ㎕를 로딩하여 담수화를 수행하였다. PBS로 용출한 후, 표제 화합물의 용액을 단리하였다. 효과기-연결기에 대한 항체 2H8-A의 로딩 인자 x는 약 1:4 내지 1:5였다. 100 μl of a solution of thionylated antibody prepared according to Example ELE33a (about 3 nmol, about 6 thiol groups) was mixed with 42.3 μl of a 1.1 mM solution in PBS of the effector-linker conjugate prepared according to Example EL25, and The mixture was incubated at 23 ° C. for 1 hour. Desalination was performed by loading 150 μl of reaction solution using a pre-equilibrated NAP5 column. After eluting with PBS, a solution of the title compound was isolated. The loading factor x of antibody 2H8-A for the effector-linker was about 1: 4 to 1: 5.

실시예 ELE33a Example ELE33a

완전한 면역글로불린 (IgG), 예를 들어 2H8 항체의 티오닐화Thionylation of complete immunoglobulin (IgG), for example 2H8 antibody

티오닐기의 도입을 위해, 약 1 내지 10 mg/ml 범위의 농도를 갖는 인산염 완충액 중 2H8 항체의 아민-비함유 용액을 10배 내지 100배 과량의 2-이미노티올란과 pH 7.2에서 혼합하고, 23℃에서 1시간 동안 반응시켰다. 도입된 티올기의 수는 시약의 과량 정도에 따라 1 내지 약 15였다. For introduction of thionyl groups, an amine-free solution of 2H8 antibody in phosphate buffer having a concentration ranging from about 1 to 10 mg / ml was mixed with 10 to 100 times excess 2-iminothiolane at pH 7.2 and The reaction was carried out at 23 ° C. for 1 hour. The number of thiol groups introduced was 1 to about 15 depending on the excess of reagent.

결합 구역의 인식에 관한 이해, 특히 특정 종양 항원에 대한 모노클로날 항체 또는 그의 단편의 분야에서의 이해가 발전함으로써 표적 부위에서 항-종양 활성제의 특이적인 방출에 의한 선택적인 종양 치료법을 고려할 수 있게 되었다. Understanding of the recognition of binding zones, in particular in the field of monoclonal antibodies or fragments thereof against specific tumor antigens, has led to the possibility of considering selective tumor therapies by the specific release of anti-tumor actives at the target site. It became.

고활성 (독성) 활성제 (효과기)가 고분자량 종양-특이적 인식 단위, 예컨대 항체와 커플링되는 이러한 접근법에서의 전제조건은, 최소 성분들이 인식 단위 및 효과기에 의해 표시되는 접합체가 표적 부위 (종양)에 도달할 때까지 실질적으로 비활성이라는 것이다. 표적 부위에 도달하면, 접합체는 세포 표면과 결합하고, 활성 성분은 임의로 전체 복합체의 선행 내재화 후에 방출될 수 있다. A prerequisite in this approach in which a highly active (toxic) active agent (effector) is coupled with a high molecular weight tumor-specific recognition unit, such as an antibody, is that the conjugates with minimal components represented by the recognition unit and effector are targeted to the target site (tumor). Until it reaches). Upon reaching the target site, the conjugate binds to the cell surface and the active ingredient can be released, optionally after prior internalization of the entire complex.

그러나, 고형 종양, 특히 모노클로날 항체를 가진 고형 종양의 성공적인 치료법은 종양으로의 항체의 부적당한 침투 뿐만 아니라 종양 조직에서의 상응하는 종양-관련 항원의 불균질 분산에 의해 제한될 수 있다. However, successful treatment of solid tumors, especially solid tumors with monoclonal antibodies, may be limited by the inadequate penetration of the antibody into the tumor as well as the heterogeneous dispersion of the corresponding tumor-associated antigen in the tumor tissue.

이러한 제한점은 종양-혈관계가 특정 방법으로 공격당한다는 점에서 회피될 수 있다. 부피 약 2 mm3 미만인 종양의 성장은 신생혈관형성에 의존한다. 그 후의 종양 성장은 영양소의 공급 또는 폐기물의 제거를 담당하는 무손상 혈관계를 바탕으로 한다. 그러므로, 상기 혈관계의 선택적 파괴는 종양의 괴저를 유발할 것이다. 종양의 혈관계에 대한 공격은 종양 자체에 대한 직접적인 공격에 비해 수많은 장점을 보증한다. 종양 조직은 침투될 필요가 없으므로, 종양 세포와 비교할 때 내피 세포는 접근이 더욱 쉽다. 개별적인 종양 맥관의 손상은 수천개의 종양 세포의 괴저를 유발할 것이다. 종양 맥관을 손상시키기 위해, 모든 내피 세포를 죽일 필요는 없다. 종양내 또는 종양 근처의 내피 세포에 대한 특이적인 공격으로 전신적인 부작용이 최소화된다. 내피 세포는 발생학적으로 매우 안정하므로, 종양 치료제에 대한 내성이 발전할 가능성은 적다.This limitation can be avoided in that the tumor-blood system is attacked in a certain way. The growth of tumors less than about 2 mm 3 in volume depends on angiogenesis. Subsequent tumor growth is based on an intact vascular system responsible for the supply of nutrients or removal of waste. Therefore, selective destruction of the vascular system will cause tumor necrosis. Attacks of the tumor's vascular system warrant numerous advantages over direct attacks on the tumor itself. Because tumor tissue does not need to penetrate, endothelial cells are easier to access as compared to tumor cells. Damage to individual tumor vasculature will cause necrosis of thousands of tumor cells. To damage the tumor vasculature, not all endothelial cells need to be killed. Specific attacks on endothelial cells in or near the tumor minimize systemic side effects. Endothelial cells are developmentally very stable and therefore less likely to develop resistance to tumor therapeutics.

매우 놀랍게도, 이제 본 발명의 범위 내에서 화학적으로 매우 민감하고 고도로-관능화된 종류의 에포틸론 활성제 및 그의 유사체를 활성제의 여러 위치에서 여러가지 연결기를 통해 고분자량 인식 단위에 연결할 수 있는 가능성을 발견하였다. Very surprisingly, within the scope of the present invention, it has now been found the possibility to link chemically very sensitive and highly-functionalized kinds of epothilone activators and their analogues to high molecular weight recognition units through various linking groups at various positions of the activator. .

따라서, 본 발명의 목적은 그 중에서도Therefore, the object of the present invention is

1. 에포틸론 및 에포틸론 유도체의 구조적 종류로부터의 고활성 활성제를 적합한 연결기에 연결하는 방법을 발견하는 것, 1. to find a method of linking a highly active agent from a structural class of epothilones and epothilone derivatives to a suitable linking group,

2. 적합한 연결기를 합성하는 것, 2. synthesizing a suitable coupler,

3. 상기 에포틸론-연결기 접합체를 인식 단위, 예를 들어 모노클로날 항체 또는 그의 단편에 연결하여, 의약의 개발을 위해 화학적 및 대사적으로 모두 충분히 안정하며 그의 치료 범위, 그의 작용 선택성 및(또는) 바람직하지 못한 독성 부작용 및(또는) 그의 활성 정도에 관한 것을 근거로 하여 에포틸론 또는 에포틸론 유도체보다 우수한 면역 접합체를 형성하는 방법을 개발하는 것이다. 3. Linking said epothilone-linker conjugate to a recognition unit, eg, a monoclonal antibody or fragment thereof, sufficiently stable both chemically and metabolically for the development of a medicament, its therapeutic range, its action selectivity and / or To develop an immunoconjugate that is superior to an epothilone or epothilone derivative based on the undesirable toxic side effects and / or the degree of activity thereof.

따라서, 본 발명은 단일 이성질체 또는 여러가지 이성질체들의 혼합물로서 및(또는) 그의 제약상 허용되는 염으로서의 하기 화학식 (I)의 효과기 접합체를 포함한다:Accordingly, the present invention includes effector conjugates of formula (I) as single isomers or mixtures of various isomers and / or as pharmaceutically acceptable salts thereof:

상기 식에서,Where

R1a, R1b는 서로 독립적으로 수소, C1-C10 알킬, 아릴, 아르알킬이거나, 함께 -(CH2)m 기 (여기서, m은 2 내지 5임)이고,R 1a , R 1b are independently of each other hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a — (CH 2 ) m group where m is 2 to 5,

R2a, R2b는 서로 독립적으로 수소, C1-C10 알킬, 아릴, 아르알킬이거나, 함께 -(CH2)n 기 (여기서, n은 2 내지 5임) 또는 C2-C10 알케닐 또는 C2-C10 알키닐이고,R 2a , R 2b are independently of each other hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a — (CH 2 ) n group where n is 2 to 5 or C 2 -C 10 alkenyl Or C 2 -C 10 alkynyl,

R3은 수소, C1-C10 알킬, 아릴 또는 아르알킬이고,R 3 is hydrogen, C 1 -C 10 alkyl, aryl or aralkyl,

R4a, R4b는 서로 독립적으로 수소, C1-C10 알킬, 아릴, 아르알킬이거나, 함께 -(CH2)p 기 (여기서, p는 2 내지 5임)이고,R 4a , R 4b are independently of each other hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a — (CH 2 ) p group, where p is 2 to 5,

R5는 수소, C1-C10 알킬, 아릴, 아르알킬, CO2H, CO2알킬, CH2OH, CH2O알킬 ,CH2O아실, CN, CH2NH2, CH2N(알킬, 아실)1,2, 또는 CH2Hal이고,R 5 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, CO 2 H, CO 2 alkyl, CH 2 OH, CH 2 Oalkyl, CH 2 O acyl, CN, CH 2 NH 2 , CH 2 N ( Alkyl, acyl) 1,2 , or CH 2 Hal,

Hal은 할로겐 원자이고, Hal is a halogen atom,

각 경우에서 R6, R7은 수소이거나, 함께 부가적인 결합, 또는 함께 산소 원자, 또는 함께 NH기, 또는 함께 N-알킬기, 또는 함께 CH2기이고,In each case R 6 , R 7 are hydrogen, or are additional bonds together, or oxygen atoms together, or NH groups together, or N-alkyl groups together, or CH 2 groups together,

G는 산소 원자 또는 CH2이고,G is an oxygen atom or CH 2 ,

D-E는 기 H2C-CH2, HC=CH, C≡C, CH(OH)-CH(OH), CH(OH)-CH2, CH2 -CH(OH), , O-CH2이거나, G가 CH2기를 나타내는 경우, D-E는 CH2-O이고,DE is a group H 2 C-CH 2 , HC = CH, C≡C, CH (OH) -CH (OH), CH (OH) -CH 2 , CH 2 -CH (OH), Or O-CH 2 or when G represents a CH 2 group, DE is CH 2 -O,

W는 기 C(=X)R8, 또는 비- 또는 트리시클릭 방향족 또는 헤테로방향족 라디칼이고,W is a group C (═X) R 8 , or a non- or tricyclic aromatic or heteroaromatic radical,

L3은 수소이거나, W에서의 라디칼이 히드록실기를 함유하는 경우 히드록실기와 기 O-L4를 형성하거나, W에서의 라디칼이 아미노기를 함유하는 경우 아미노기와 기 NR25-L4를 형성하고,L 3 is hydrogen, or if the radical at W contains a hydroxyl group, forms a hydroxyl group and the group OL 4 , or if the radical at W contains an amino group, forms an amino group and the group NR 25 -L 4 ; ,

R25는 수소 또는 C1-C10 알킬이고,R 25 is hydrogen or C 1 -C 10 alkyl,

X는 산소 원자, 또는 2개의 OR20기, 또는 직쇄 또는 분지쇄일 수 있는 C2-C10 알킬렌디옥시기, 또는 H/OR9, 또는 CR10R11기이고,X is an oxygen atom, or two OR 20 groups, or a C 2 -C 10 alkylenedioxy group, which may be straight or branched, or H / OR 9 , or CR 10 R 11 ,

R8은 수소, C1-C10 알킬, 아릴, 아르알킬, 할로겐 또는 CN이고,R 8 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, halogen or CN,

R9는 수소 또는 보호기 PGX이고,R 9 is hydrogen or a protecting group PG X ,

각 경우에서 R10, R11은 서로 독립적으로 수소, C1-C20 알킬, 아릴, 아르알킬이거나, 메틸렌 탄소 원자와 함께 5- 내지 7-원 카르보시클릭 고리를 형성하고,In each case R 10 , R 11 are independently of each other hydrogen, C 1 -C 20 alkyl, aryl, aralkyl or together with the methylene carbon atom form a 5- to 7-membered carbocyclic ring,

Z는 산소 또는 H/OR12를 나타낼 수 있고,Z can represent oxygen or H / OR 12 ,

R12는 수소 또는 보호기 PGZ를 나타낼 수 있고,R 12 may represent hydrogen or a protecting group PG Z ,

A-Y는 기 O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O) 또는 NR21-SO 2를 나타낼 수 있고,AY may represent the group OC (═O), O—CH 2 , CH 2 —C (═O), NR 21 -C (═O) or NR 21 -SO 2 ,

R20은 C1-C20 알킬을 나타낼 수 있고,R 20 may represent C 1 -C 20 alkyl,

R21은 수소 원자 또는 C1-C10 알킬을 나타낼 수 있고,R 21 may represent a hydrogen atom or C 1 -C 10 alkyl,

PGX, PGY 및 PGZ는 보호기 PG를 나타낼 수 있고,PG X , PG Y and PG Z may represent the protecting group PG,

L1, L2 및 L4는 서로 독립적으로 수소, 기 C(=O)Cl, 기 C(=S)Cl, 기 PG Y 또는 하기 화학식 (III) 또는 (IV)의 연결기를 나타낼 수 있으되, 단, 치환기 L1, L2 및 L4 중 적어도 하나는 화학식 (III) 또는 (IV)의 연결기를 나타내고,L 1 , L 2 and L 4 may independently represent hydrogen, a group C (═O) Cl, a group C (= S) Cl, a group PG Y or a linking group of formula (III) or (IV), Provided that at least one of substituents L 1 , L 2 and L 4 represents a linking group of formula (III) or (IV),

화학식 (III)의 연결기는 하기 구조를 갖고:The linking group of formula (III) has the structure

상기 식에서,Where

T는 산소 또는 황을 나타낼 수 있고, T can represent oxygen or sulfur,

U는 산소, CHR22, CHR22-NR23-C(=O)-, CHR22-NR23-C(=S)-, O-C(=O)-CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23-C(=S)- 또는 NR24a를 나타낼 수 있고,U is oxygen, CHR 22 , CHR 22 -NR 23 -C (= O)-, CHR 22 -NR 23 -C (= S)-, OC (= O) -CHR 22 -NR 23 -C (= O) —, OC (═O) —CHR 22 —NR 23 —C (═S) — or NR 24a , and

o는 0 내지 15를 나타낼 수 있고,o can represent 0 to 15,

V는 결합, 아릴, 기 또는 기 를 나타낼 수 있고,V is a bond, aryl, group Or flag Can represent

s는 0 내지 4를 나타낼 수 있고,s can represent 0 to 4,

Q는 결합, O-C(=O)-NR24c, O-C(=S)-NR24c, 또는 를 나타낼 수 있고,Q is a bond, OC (= O) -NR 24c , OC (= S) -NR 24c , or Can represent

R22는 수소, C1-C10 알킬, 아릴 또는 아르알킬을 나타낼 수 있고,R 22 may represent hydrogen, C 1 -C 10 alkyl, aryl or aralkyl,

R23은 수소 또는 C1-C10 알킬을 나타낼 수 있고,R 23 may represent hydrogen or C 1 -C 10 alkyl,

R24a, R24b 및 R24c는 서로 독립적으로 수소 또는 C1-C10 알킬을 나타낼 수 있고,R 24a , R 24b and R 24c may independently represent hydrogen or C 1 -C 10 alkyl,

q는 0 내지 15를 나타낼 수 있고,q can represent 0 to 15,

FG1은 C1-C10 알킬-S3, 또는 CO2H를 나타낼 수 있고,FG 1 is C 1 -C 10 alkyl-S 3 , Or CO 2 H,

화학식 (IV)의 연결기는 하기 구조를 갖고: The linking group of formula (IV) has the structure

상기 식에서,Where

T는 산소 또는 황을 나타낼 수 있고,T can represent oxygen or sulfur,

W1, W2는 동일하거나 상이하고, 산소 또는 NR24a를 나타낼 수 있고,W 1 , W 2 are the same or different and can represent oxygen or NR 24a ,

o는 0 내지 5를 나타낼 수 있고,o can represent 0 to 5,

R22는 수소, C1-C10 알킬, 아릴 또는 아르알킬을 나타낼 수 있고,R 22 may represent hydrogen, C 1 -C 10 alkyl, aryl or aralkyl,

R23은 수소, 또는 C1-C10 알킬을 나타낼 수 있고,R 23 may represent hydrogen or C 1 -C 10 alkyl,

R24a는 수소 또는 C1-C10 알킬을 나타낼 수 있고,R 24a can represent hydrogen or C 1 -C 10 alkyl,

R27은 할로겐, CN, N02, CO2R28, 또는 OR28을 나타낼 수 있고,R 27 may represent halogen, CN, NO 2 , CO 2 R 28 , or OR 28 ,

R28은 수소, C1-C10 알킬, 아릴 또는 아르알킬을 나타낼 수 있고,R 28 may represent hydrogen, C 1 -C 10 alkyl, aryl or aralkyl,

q는 0 내지 5를 나타낼 수 있고,q can represent 0 to 5,

U는 산소, CHR22, CHR22-NR23-C(=O)-, CHR22-NR23-C(=S)- 또는 C1-C20 알킬을 나타낼 수 있고,U can represent oxygen, CHR 22 , CHR 22 -NR 23 -C (= 0)-, CHR 22 -NR 23 -C (= S)-or C 1 -C 20 alkyl,

r은 0 내지 20을 나타낼 수 있고, r can represent 0 to 20,

FG1은 C1-C10 알킬-S3, 또는 CO2H를 나타낼 수 있다.FG 1 is C 1 -C 10 alkyl-S 3 , Or CO 2 H.

또한, 본 발명은 화학식 (I)의 효과기 인식 단위 접합체의 제조 방법을 기재하는데, 여기서 화학식 (I)에서의 치환기는 상기 언급한 의미를 가지나, 적어도 하나의 기 FG1은 기 FG2a 또는 FG2b로 대체되며, 이 때, FG2a 또는 FG2b는 하기 의미를 가질 수 있고:The present invention also describes a method for preparing an effector recognition unit conjugate of formula (I), wherein the substituents in formula (I) have the meanings mentioned above, but at least one group FG 1 is a group FG 2a or FG 2b Where FG 2a or FG 2b may have the following meanings:

FG2a: -S-S-, FG 2a : -SS-,

FG2b: -CONH-,FG 2b : -CONH-,

여기서, 인식 단위는 황 원자 (여기서, 지적된 황 원자는 인식 단위의 성분임)를 통해 기 FG2a와 접합되거나, 아미드 관능기 (여기서, 지적된 질소 원자는 인식 단위의 성분임)를 통해 기 FG2b와 접합되고; 이 때, 인식 단위는 예를 들어, 펩티드, 가용성 수용체, 사이토킨, 림포킨, 압타머, 스피에겔머, 재조합 단백질, 골격 구조, 모노클로날 항체 또는 모노클로날 항체의 단편일 수 있다.Wherein the recognition unit is conjugated to the group FG 2a via a sulfur atom (wherein the indicated sulfur atom is a component of the recognition unit) or the group FG via an amide functional group (wherein the indicated nitrogen atom is a component of the recognition unit) Conjugated with 2b ; In this case, the recognition unit may be, for example, a peptide, soluble receptor, cytokine, lymphokine, aptamer, spiegelmer, recombinant protein, skeletal structure, monoclonal antibody or fragment of monoclonal antibody.

본 발명에 따라, 상기 언급된 효과기 인식 단위 접합체는 하나 이상의 인식 단위를 포함할 수 있고, 이 경우 접합체에 속하는 인식 단위들은 동일하거나 상이할 수 있다. 접합체의 인식 단위들은 동일한 것이 바람직하다. According to the invention, the above mentioned effector recognition unit conjugate may comprise one or more recognition units, in which case the recognition units belonging to the conjugate may be the same or different. The recognition units of the conjugate are preferably the same.

본 발명에 따른 효과기 인식 단위 접합체는 그의 α-, β- 또는 γ-시클로덱스트린-클라트레이트의 형태 또는 리포솜 조성물 또는 페길화된 조성물의 형태로 사용할 수 있다. The effector recognition unit conjugates according to the invention can be used in the form of their α-, β- or γ-cyclodextrin-clates or in the form of liposome compositions or pegylated compositions.

본 발명에 따른 접합체는 증식 과정과 관련된 질환의 치료를 위해 사용하는 것이 바람직하다. 예를 들면, 여러가지 종양의 치료법, 염증성 및(또는) 신경퇴행성 질환, 예를 들어 다발 경화증 또는 알쯔하이머병의 치료법, 혈관신생-관련 질환, 예를 들어 고형 종양의 성장, 류마티스성 관절염 또는 안저(眼底) 질환의 치료법을 언급할 수 있다. The conjugates according to the invention are preferably used for the treatment of diseases associated with the proliferative process. For example, treatment of various tumors, treatment of inflammatory and / or neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease, angiogenesis-related diseases such as solid tumor growth, rheumatoid arthritis or fundus ) The treatment of the disease.

화학식 (I)의 에포틸론, 에포틸론 전구체 및 유도체의 제조는 예를 들어, DE 19907588, WO 98/25929, WO 99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01/81342, WO 01/73103, WO 01/64650, WO 01/70716, US 6204388, US 6387927, US 6380394, US 02/52028, US02/58286, US 02/62030, WO 02/32844, WO 02/30356, WO 02/32844, WO 02/14323, 및 WO 02/8440에 기재된 바와 같은 당업자에게 공지된 방법에 따라 수행한다. The preparation of epothilones, epothilone precursors and derivatives of formula (I) is described, for example, in DE 19907588, WO 98/25929, WO 99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99 / 7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00 / 57874, WO 01/92255, WO 01/81342, WO 01/73103, WO 01/64650, WO 01/70716, US 6204388, US 6387927, US 6380394, US 02/52028, US02 / 58286, US 02/62030 , According to methods known to those skilled in the art as described in WO 02/32844, WO 02/30356, WO 02/32844, WO 02/14323, and WO 02/8440.

알킬기 R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R8, R10, R11, R20, R21 , R22, R23, R24a, R24b, R24C, R25 및 R26으로서는, 탄소 원자수 1 내지 20의 직쇄 또는 분지쇄 알킬기, 예를 들어 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, tert-부틸, 펜틸, 이소펜틸, 네오펜틸, 헵틸, 헥실, 및 데실을 고려할 수 있다.Alkyl group R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 20 , R 21 , R 22 , R 23 , R 24a , R As 24b , R 24C , R 25 and R 26 , a straight or branched chain alkyl group having 1 to 20 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl , Neopentyl, heptyl, hexyl, and decyl may be considered.

알킬기 R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R8, R10, R11, R20, R21 , R22, R23, R24a, R24b, R24c, R25 및 R26은 또한 퍼플루오르화되거나, 1 내지 5개의 할로겐 원자, 히드록시기, C1-C4-알콕시기 또는 C6-C12-아릴기 (이는 1 내지 3개의 할로겐 원자로 치환될 수 있음)로 치환될 수 있다.Alkyl group R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 20 , R 21 , R 22 , R 23 , R 24a , R 24b , R 24c , R 25 and R 26 are also perfluorinated, or 1 to 5 halogen atoms, hydroxy groups, C 1 -C 4 -alkoxy groups or C 6 -C 12 -aryl groups (which are 1 to 3 halogens) May be substituted with an atom).

아릴 라디칼 R1a, R1b, R2a, R2b, R3, R4a , R4b, R5, R8, R10, R11, R22, R26 및 V로서는, 하나 이상의 위치에서 할로겐, OH, 0-알킬, C02H, C02-알킬, -NH2, -NO2, -N3, -CN, C1-C20-알킬, C1-C20-아실 또는 C1-C20 -아실옥시기로 치환될 수 있는, 하나 이상의 헤테로원자를 가진 치환 및 비치환 카르보시클릭 또는 헤테로시클릭 라디칼, 예를 들어 페닐, 나프틸, 푸릴, 티에닐, 피리딜, 피라졸릴, 피리미디닐, 옥사졸릴, 피리다지닐, 피라지닐, 퀴놀릴, 티아졸릴, 벤조티아졸릴 또는 벤족사졸릴이 적합하다. 헤테로원자는 산화로 인해 방향족 특성을 잃어버리지 않는 한 산화될 수 있고, 피리딜의 피리딜-N-옥시드로의 산화가 그 예이다.As the aryl radicals R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 22 , R 26 and V, halogen, at one or more positions OH, 0-alkyl, C0 2 H, C0 2 -alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C 1 -C 20 -alkyl, C 1 -C 20 -acyl or C 1 -C Substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, which may be substituted with a 20 -acyloxy group, for example phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidy Neyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl or benzoxazolyl are suitable. Heteroatoms can be oxidized as long as they do not lose their aromatic properties due to oxidation, for example the oxidation of pyridyl to pyridyl-N-oxide.

비시클릭 및 트리시클릭 아릴 라디칼 W로서는, 하나 이상의 위치에서 할로겐, OH, 0-알킬, C02H, C02-알킬, -NH2, -NO2, -N3, -CN, C1-C20-알킬, C1-C20-아실 또는 C1-C20-아실옥시기로 치환될 수 있는, 하나 이상의 헤테로원자를 가진 치환 및 비치환 카르보시클릭 또는 헤테로시클릭 라디칼, 예를 들어 나프틸, 안트릴, 벤조티아졸릴, 벤족사졸릴, 벤즈이미다졸릴, 퀴놀릴, 이소퀴놀릴, 벤족사지닐, 벤조푸라닐, 인돌릴, 인다졸릴, 퀴녹살리닐, 테트라히드로이소퀴놀리닐, 테트라히드로퀴놀리닐, 티에노피리디닐, 피리도피리디닐, 벤조피라졸릴, 벤조트리아졸릴, 또는 디히드로인돌릴이 적합하다. 헤테로원자는 산화로 인해 방향족 특성을 잃어버리지 않는 한 산화될 수 있고, 퀴놀릴의 퀴놀릴-N-옥시드로의 산화가 그 예이다.As the bicyclic and tricyclic aryl radicals W, halogen, OH, 0-alkyl, C0 2 H, C0 2 -alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C 1 -C at one or more positions Substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as naphthyl, which may be substituted with a 20 -alkyl, C 1 -C 20 -acyl or C 1 -C 20 -acyloxy group , Anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuranyl, indolyl, indazolyl, quinoxalinyl, tetrahydroisoquinolinyl, tetra Hydroquinolinyl, thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl are suitable. Heteroatoms can be oxidized as long as they do not lose their aromatic properties due to oxidation, for example the oxidation of quinolyl to quinolyl-N-oxide.

R1a, R1b, R2a, R2b, R3, R4a, R4b , R5, R8, R10, R11, R22 및 R26에서의 아르알킬기는 고리 내에 14개 이하의 탄소 원자, 바람직하게는 6 내지 10개의 탄소 원자를 함유하고, 알킬쇄 내에 1 내지 8개의 원자, 바람직하게는 1 내지 4개의 원자를 함유할 수 있다. 아르알킬 라디칼로서, 예를 들면 벤질, 페닐에틸, 나프틸메틸, 나프틸에틸, 푸릴메틸, 티에닐에틸 또는 피리딜프로필이 적합하다. 고리는 하나 이상의 위치에서 할로겐, OH, 0-알킬, C02H, C02-알킬, -NO2, -N3, -CN, C1-C20-알킬, C1-C20-아실 또는 C1-C20-아실옥시기로 치환될 수 있다.Aralkyl groups at R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 22 and R 26 have up to 14 carbons in the ring It may contain atoms, preferably 6 to 10 carbon atoms, and may contain 1 to 8 atoms, preferably 1 to 4 atoms in the alkyl chain. As aralkyl radicals, for example benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl are suitable. The ring is halogen, OH, 0-alkyl, C0 2 H, C0 2 -alkyl, -NO 2 , -N 3 , -CN, C 1 -C 20 -alkyl, C 1 -C 20 -acyl or It may be substituted with a C 1 -C 20 -acyloxy group.

보호기 PG의 대표예로서, 트리스(C1-C20 알킬)실릴, 비스(C1-C20 알킬)-아릴실릴, (C1-C20 알킬)-디아릴실릴, 트리스(아르알킬)-실릴, C1-C20-알킬, C2-C20-알케닐, 추가로 고리 내에 산소 원자를 함유할 수 있는 C4-C7-시클로알킬, 아릴, C7-C 20-아르알킬, C1-C20-아실, 아로일, C1-C20-알콕시카르보닐, C1 -C20-알킬술포닐 뿐만 아니라 아릴술포닐을 언급할 수 있다.Representative examples of the protecting group PG include tris (C 1 -C 20 alkyl) silyl, bis (C 1 -C 20 alkyl) -arylsilyl, (C 1 -C 20 alkyl) -diarylsilyl, tris (aralkyl)- Silyl, C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl, C 4 -C 7 -cycloalkyl, which may further contain an oxygen atom in the ring, aryl, C 7 -C 20 -aralkyl, C 1 -C 20 -acyl, aroyl, C 1 -C 20 -alkoxycarbonyl, C 1 -C 20 -alkylsulfonyl as well as arylsulfonyl may be mentioned.

보호기 PG에 대한 알킬-, 실릴- 및 아실 라디칼로서는 특히 당업자에게 공지된 라디칼이 고려된다. 상응하는 알킬 및 실릴 에테르로부터 쉽게 절단될 수 있는 알킬 또는 실릴 라디칼, 예를 들어 메톡시메틸, 메톡시에틸, 에톡시에틸, 테트라히드로피라닐, 테트라히드로푸라닐, 트리메틸실릴, 트리에틸실릴, tert-부틸디메틸실릴, tert-부틸디페닐실릴, 트리벤질실릴, 트리이소프로필실릴, 벤질, 파라-니트로벤질, 및 파라-메톡시벤질 라디칼 뿐만 아니라 알킬술포닐 및 아릴술포닐 라디칼이 바람직하다. 알콕시카르보닐 라디칼로서, 예를 들어 트리클로로에틸옥시카르보닐 (Troc)이 적합하다. 아실 라디칼로서, 예를 들어 라디칼이 아미노 및(또는) 히드록시기로 치환될 수 있는 포르밀, 아세틸, 프로피오닐, 이소프로피오닐, 트리클로로메틸카르보닐, 피발릴, 부티릴 또는 벤조일이 적합하다. As the alkyl-, silyl- and acyl radicals for the protecting group PG, radicals known in particular to those skilled in the art are contemplated. Alkyl or silyl radicals that can be easily cleaved from the corresponding alkyl and silyl ethers, for example methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert Preference is given to butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, and para-methoxybenzyl radicals as well as alkylsulfonyl and arylsulfonyl radicals. As the alkoxycarbonyl radical, for example trichloroethyloxycarbonyl (Troc) is suitable. As acyl radicals, for example, formyl, acetyl, propionyl, isopropionyl, trichloromethylcarbonyl, pivalyl, butyryl or benzoyl, in which the radicals can be substituted with amino and / or hydroxy groups, are suitable.

아미노 보호기 PG로서는 당업자에게 공지된 라디칼이 적합하다. 예를 들면, Alloc, Boc, Z, 벤질, f-Moc, Troc, 스타베이스(starbase) 또는 벤조스타베이스기를 언급할 수 있다. As the amino protecting group PG, radicals known to those skilled in the art are suitable. For example, mention may be made of the Alloc, Boc, Z, benzyl, f-Moc, Troc, starbase or benzostarbase groups.

할로겐 원자로서는 불소, 염소, 브롬 또는 요오드를 고려할 수 있다.As the halogen atom, fluorine, chlorine, bromine or iodine can be considered.

아실기는 1 내지 20개의 탄소 원자를 함유할 수 있으며, 포르밀, 아세틸, 프로피오닐, 이소프로피오닐 및 피발릴기가 바람직하다. Acyl groups may contain 1 to 20 carbon atoms, with formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.

X에 대해 가능한 C2-C10-알킬렌-α,ω-디옥시기는 바람직하게는 에틸렌 케탈 또는 네오펜틸 케탈기이다.Possible C 2 -C 10 -alkylene-α, ω-dioxy groups for X are preferably ethylene ketal or neopentyl ketal groups.

화학식 (I)의 바람직한 화합물은 A-Y가 O-C(=O) 또는 NR21-C(=O)를 나타내고; D-E가 H2C-CH2기를 나타내고; G가 CH2기를 나타내고; Z가 산소 원자를 나타내고; 각 경우에서 R1a, R1b가 C1-C10 알킬을 나타내거나, 함께 p가 2 또는 3 또는 4인 -(CH2)p 기를 나타내고; R2a, R2b가 서로 독립적으로 수소, C1-C10 알킬, C2-C10 알케닐, 또는 C2-C10 알키닐을 나타내고; R3이 수소를 나타내고; R4a, R4b가 서로 독립적으로 수소 또는 C1-C10 알킬을 나타내고; R5가 수소, C1-C4 알킬 또는 CH2OH 또는 CH2NH2 또는 CH2N(알킬, 아실)1,2 또는 CH2Hal을 나타내고; R6 및 R7이 함께 부가적인 결합, 또는 함께 NH기, 또는 함께 N-알킬기, 또는 함께 CH2기, 또는 함께 산소 원자를 나타내고; W가 기 C(=X)R8 또는 2-메틸벤조티아졸-5-일 라디칼 또는 2-메틸벤족사졸-5-일 라디칼 또는 퀴놀린-7-일 라디칼 또는 2-아미노메틸벤조티아졸-5-일 라디칼 또는 2-히드록시메틸벤조티아졸-5-일 라디칼 또는 2-아미노메틸벤족사졸-5-일 라디칼 또는 2-히드록시메틸벤족사졸-5-일 라디칼을 나타내고; X가 CR10R11기를 나타내고; R8이 수소 또는 C1-C4 알킬 또는 불소 원자 또는 염소 원자 또는 브롬 원자를 나타내고; R10/R11이 수소/2-메틸티아졸-4-일 또는 수소/2-피리딜 또는 수소/2-메틸옥사졸-4-일 또는 수소/2-아미노메틸티아졸-4-일 또는 수소/2-아미노메틸옥사졸-4-일 또는 수소/2-히드록시메틸티아졸-4-일 또는 수소/2-히드록시메틸옥사졸-4-일을 나타내는 화합물이다.Preferred compounds of formula (I) are those in which AY represents OC (= 0) or NR 21 -C (= 0); DE represents a H 2 C-CH 2 group; G represents a CH 2 group; Z represents an oxygen atom; In each case R 1a , R 1b represent C 1 -C 10 alkyl, or together represent a — (CH 2 ) p group wherein p is 2 or 3 or 4; R 2a , R 2b independently of one another represent hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl; R 3 represents hydrogen; R 4a , R 4b independently of one another represent hydrogen or C 1 -C 10 alkyl; R 5 represents hydrogen, C 1 -C 4 alkyl or CH 2 OH or CH 2 NH 2 or CH 2 N (alkyl, acyl) 1,2 or CH 2 Hal; R 6 and R 7 together represent an additional bond, or together NH group, or together N-alkyl group, or together CH 2 group, or together an oxygen atom; W is a group C (= X) R 8 or 2-methylbenzothiazol-5-yl radical or 2-methylbenzoxazol-5-yl radical or quinolin-7-yl radical or 2-aminomethylbenzothiazole-5 -Yl radical or 2-hydroxymethylbenzothiazol-5-yl radical or 2-aminomethylbenzoxazol-5-yl radical or 2-hydroxymethylbenzoxazol-5-yl radical; X represents a CR 10 R 11 group; R 8 represents hydrogen or C 1 -C 4 alkyl or fluorine atom or chlorine atom or bromine atom; R 10 / R 11 is hydrogen / 2-methylthiazol-4-yl or hydrogen / 2-pyridyl or hydrogen / 2-methyloxazol-4-yl or hydrogen / 2-aminomethylthiazol-4-yl or Hydrogen / 2-aminomethyloxazol-4-yl or hydrogen / 2-hydroxymethylthiazol-4-yl or hydrogen / 2-hydroxymethyloxazol-4-yl.

화학식 (III)의 연결기로서는, V가 결합 또는 아릴 라디칼을 나타내고, o가 0이고, T가 산소 원자를 나타내는 화합물이 바람직하다.As the linking group of the formula (III), a compound in which V represents a bond or an aryl radical, o is 0 and T represents an oxygen atom is preferable.

화학식 (III)의 연결기로서는, V가 결합 또는 아릴 라디칼 또는 기 를 나타내고; Q가 결합 또는 기 를 나타내고; o가 0 내지 4인 화합물도 또한 바람직하다. V가 결합 또는 기 를 나타내고; Q가 결합 또는 기 를 나타내고; o가 0, 2, 또는 3이고, s가 1이고, T가 산소 원자인 화학식 (III)의 화합물이 특히 바람직하다.As the linking group of formula (III), V is a bond or an aryl radical or group Represents; Q is combined or Represents; Also preferred are compounds wherein o is from 0 to 4. V is a bond or group Represents; Q is combined or Q Represents; Particular preference is given to compounds of the formula (III) in which o is 0, 2 or 3, s is 1 and T is an oxygen atom.

화학식 (IV)의 연결기로서는, o가 0 내지 4이고, q가 0 내지 3인 화합물이 바람직하다. o가 0, 2 또는 3이고; W1이 산소 원자이고; q가 0이고; R22가 수소, C1-C3 알킬 또는 아르알킬이고; R23이 수소 또는 C1-C3 알킬이고; R24a가 수소 또는 C1-C3 알킬이고; R27이 불소, 염소, CN, NO2, CO2R 28 또는 OR28이고; R28이 수소 또는 C1-C5 알킬이고; U가 산소, CHR22 또는 CHR22-NR23-C(=O)-인 화학식 (IV)의 화합물이 특히 바람직하다.As the linking group of the formula (IV), a compound wherein o is 0 to 4 and q is 0 to 3 is preferable. o is 0, 2 or 3; W 1 is an oxygen atom; q is 0; R 22 is hydrogen, C 1 -C 3 alkyl or aralkyl; R 23 is hydrogen or C 1 -C 3 alkyl; R 24a is hydrogen or C 1 -C 3 alkyl; R 27 is fluorine, chlorine, CN, NO 2 , CO 2 R 28 or OR 28 ; R 28 is hydrogen or C 1 -C 5 alkyl; Particular preference is given to compounds of the formula (IV) wherein U is oxygen, CHR 22 or CHR 22 -NR 23 -C (= 0)-.

인식 단위로서 사용하기 위한 재조합 단백질로는 예를 들어 항체로부터 유도된 결합 구역, 소위 CDR이 적합하다. Suitable recombinant proteins for use as recognition units are, for example, binding regions derived from antibodies, so-called CDRs.

인식 단위로서 사용하기 위한 골격 구조로는 예를 들어 항체로부터 유도되지 않은 고분자량 구조가 적합하다. 예를 들면, 피브로넥틴 3형 및 결정체의 구조를 언급할 수 있다. Suitable framework structures for use as recognition units are, for example, high molecular weight structures not derived from antibodies. For example, mention may be made of the structure of fibronectin type 3 and crystals.

인식 단위로서 사용하기 위한 모노클로날 항체의 단편으로는 예를 들어 단일쇄 Fv, Fab, F(ab)2 뿐만 아니라 재조합 다량체를 언급할 수 있다.Fragments of monoclonal antibodies for use as recognition units may, for example, mention single chain Fv, Fab, F (ab) 2 as well as recombinant multimers.

바람직한 인식 단위로는 예를 들어 조혈계의 고형 종양 및 악성 질환의 인식 및(또는) 진단 및(또는) 치료에 적합한 것들이 고려된다. Preferred units of recognition are for example those suitable for the recognition and / or diagnosis and / or treatment of solid tumors and malignant diseases of the hematopoietic system.

추가적으로 바람직한 인식 단위로는 질환-특이적 혈관계, 바람직하게는 혈관신생을 선택적으로 인식하는 것들이 고려된다. Additionally preferred recognition units are contemplated as those which selectively recognize disease-specific vasculature, preferably angiogenesis.

표 1에서는 고형 종양의 치료를 위한 특히 바람직한 인식 단위의 예를 언급한다. Table 1 refers to examples of particularly preferred recognition units for the treatment of solid tumors.

혈액 종양을 치료하기 위한 특히 바람직한 인식 단위로서는, 항체 또는 항체 단편, 예를 들어 CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD5, CD37 및 CD30을 또한 언급할 수 있다. Particularly preferred recognition units for treating blood tumors include antibodies or antibody fragments, for example CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD5, CD37 and CD30 may also be mentioned.

항-혈관신생 치료법을 위한 특히 바람직한 인식 단위로서는, 항체 또는 그의 단편, 예를 들어 VCAM, CD31, ELAM, 엔도글린, VEGFRI/II, αvβ3, Tie1/2, TES23 (CD44ex6), 포스파티딜세린, PSMA, VEGFR/VEGF 복합체 또는 ED-B-피브로넥틴을 언급할 수 있다.Particularly preferred recognition units for anti-angiogenic therapy include antibodies or fragments thereof, such as VCAM, CD31, ELAM, endoglin, VEGFRI / II, α v β 3 , Tie1 / 2, TES23 (CD44ex6), phosphatidylserine , PSMA, VEGFR / VEGF complex or ED-B-fibronectin.

하기 언급하는 화합물들은 본 발명에 따라 효과기 요소로서 특히 바람직하다: The compounds mentioned below are particularly preferred as effector elements according to the invention:

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2- Methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-1-메틸-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- ( 2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-메닐-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-menyl-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- ( 2-methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-1-메틸-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2 -(2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-메틸-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2 -Methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro- Vinyl] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로- 비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Roxy-5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro Rho-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2- Methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- ( 2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.O]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.O] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro- Vinyl] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로- 비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Hydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro- 2- (2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro Rho-vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- ( 2-methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2 -(2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-메틸-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2- Pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- ( 2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-메틸-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- ( 2-pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-메틸-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2 -(2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-플루오로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2 -Pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-플루오로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-클로로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2- Pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-클로로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- ( 2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-플루오로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-플루오로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro- 2- (2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-클로로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- ( 2-pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-클로로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2 -(2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2- Methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- ( 2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- ( 2-methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2 -(2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2 -Methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro- Vinyl] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Roxy-5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluor Rho-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2- Methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- ( 2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro- Vinyl] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Hydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro- 2- (2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluor Rho-vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- ( 2-methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2 -(2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [2- (2-methyl-thiazole -4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -5, 5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -4,8-dihydroxy-5,5 , 7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [2- (2-methyl- Thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl]- 8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -7,11-dihydroxy-8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [2- (2-methyl- Thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -7- Ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -4,8-dihydroxy-7-ethyl -5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [2- (2- Methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl]- 10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -7,11-dihydroxy-10 -Ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [2- (2-pyridyl)- Vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [2- (2-pyridyl ) -Vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [2- (2-pyridyl ) -Vinyl] -oxacyclohexades-13-ene-2,6-dione,

(1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [2- (2- Pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- (2-methyl-benzothiazol-5-yl) -Oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -5,5,7,9,13- Pentamethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-5,5,7,9,13-penta Methyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzothiazole-5- Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -8,8,10,12, 16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-8,8,10,12,16 -Pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-ethyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-ethyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-ethyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-propyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-propyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-propyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-propyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-butyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-butyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-butyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-butyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-allyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-allyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸벤조티아졸-5-일)-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-allyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzo Thiazol-5-yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-prop-2-ynyl-5 , 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5, 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl -Benzothiazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-prop-2-ynyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothia Zol-5-yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-but-3-enyl-5, 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-enyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzothiazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-but-3-enyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothia Zol-5-yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S-4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-but-3-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,125,16R)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 125,16R) -7,11-dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzothiazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-but-3-ynyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- (2-methyl-benzoxazol-5-yl)- Oxcyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -5,5,7,9,13-penta Methyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-5,5,7,9,13-pentamethyl -Oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzoxazol-5-yl ) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -8,8,10,12,16 -Pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-8,8,10,12,16- Pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-ethyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-ethyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-ethyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-propyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-propyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-propyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-propyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-butyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-butyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-butyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-butyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-allyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-allyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-allyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzone Sazol-5-yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-prop-2-ynyl-5, 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl -Benzoxazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-prop-2-ynyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazole -5-yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-enyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but-3-enyl-5,5, 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzoxazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-enyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8, 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazole -5-yl) -oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5, 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzoxazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-ynyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione,

(1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온.(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-8, 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione.

상기 언급한 요소 중 하나를 함유하는 본 발명에 따른 화학식 (I)의 화합물에서, 상기 언급한 요소 중의 수소 원자는 화학식 (I)에 지시된 위치에서 라디칼 L1 내지 L3 (여기서, 라디칼 L1 내지 L3은 상기 지시된 의미를 가짐)으로 대체된다.In the compounds of formula (I) according to the present invention containing any of the above-mentioned elements, the hydrogen atoms in the above-mentioned element is the radical in the position indicated in formula (I), L 1 to L 3 (where the radical L 1 To L 3 has the meaning indicated above.

또한, 본 발명은 하기 화학식 III1의 연결기, 하기 화학식 III2의 연결기 뿐만 아니라 하기 화학식 (III3)의 연결기에 관한 것이나, 단, 화합물 1-(4-아미노-페닐)-피롤-2,5-디온은 포함되지 않는다:In addition, the present invention relates to a to a linking group, of the general formula III 1 would relates to a linkage group of general formula (III 3), as well as to a linking group of the formula III 2, however, the compound l- (4-amino-phenyl) -pyrrole-2,5 Dion not included:

상기 식에서,Where

RG1은 O=C=N기 또는 S=C=N기일 수 있고,RG 1 may be an O = C = N group or an S = C = N group,

RG2는 Hal-C(=T)-CHR22기 또는 Hal-C(=T)-CHR22-NR23-C(=T)기 또는 R26-C(=O)-O-C(=T)-CHR22기 또는 R26-C(=O)-O-C(=T)-CHR22-NR23-C(=T)기일 수 있고, R26은 C1-C10 알킬, 아릴, 또는 아르알킬일 수 있고,RG 2 is a Hal-C (= T) -CHR 22 group or a Hal-C (= T) -CHR 22 -NR 23 -C (= T) group or a R 26 -C (= O) -OC (= T) May be a -CHR 22 group or a R 26 -C (= O) -OC (= T) -CHR 22 -NR 23 -C (= T) group, R 26 is C 1 -C 10 alkyl, aryl, or aralkyl Can be,

RG3은 OH기 또는 NHR24a기 또는 COOH기일 수 있고,RG 3 may be an OH group or an NHR 24a group or a COOH group,

o, V, q, T 및 FG1은 상기 언급된 의미를 가진다.o, V, q, T and FG 1 have the meanings mentioned above.

또한, 본 발명은 하기 화학식 (IV1)의 연결기, 하기 화학식 (IV2)의 연결기또는 하기 화학식 (IV3)의 연결기에 관한 것이다:The invention also relates to a linking group of formula (IV 1 ), a linking group of formula (IV 2 ) or a linking group of formula (IV 3 ):

상기 식에서,Where

RG1은 O=C=N기 또는 S=C=N기이고,RG 1 is O = C = N group or S = C = N group,

RG2는 Hal-C(=T)-CHR22기 또는 Hal-C(=T)-CHR22-NR23-C(=T)기 또는 R26-C(=O)-O-C(=T)-CHR22기 또는 R26-C(=0)-O-C(=T)-CHR22-NR23-C(=T)기이고, 여기서 R26은 C1-C10 알킬, 아릴, 또는 아르알킬이고,RG 2 is a Hal-C (= T) -CHR 22 group or a Hal-C (= T) -CHR 22 -NR 23 -C (= T) group or a R 26 -C (= O) -OC (= T) Is a -CHR 22 group or a R 26 -C (= 0) -OC (= T) -CHR 22 -NR 23 -C (= T) group, wherein R 26 is C 1 -C 10 alkyl, aryl, or aralkyl ego,

RG3은 OH기 또는 NHR24a기 또는 COOH기이고,RG 3 is an OH group or an NHR 24a group or a COOH group,

o, q, r, W2, R27, U, R22, R23, T, R24a 및 FG 1은 청구항 1에 언급된 의미를 가진다.o, q, r, W 2 , R 27 , U, R 22 , R 23 , T, R 24a and FG 1 have the meanings mentioned in claim 1.

본 발명에 따라, 화학식 (III1), (III2) 또는 (III3)의 연결기는 V가 결합 또는 아릴 라디칼을 나타내고, o가 0이고, T가 산소 원자인 것이 바람직하다.According to the invention, it is preferred that the linking group of the formula (III 1 ), (III 2 ) or (III 3 ) represents a V bond or an aryl radical, o is 0 and T is an oxygen atom.

또한, 본 발명에 따른 화학식 (III1), (III2) 또는 (III3)의 연결기는 V가 결합 또는 아릴 라디칼 또는 를 나타내고, Q가 결합 또는 기 를 나타내고, o가 0 내지 4인 것이 바람직하다. 이 중에서 V가 결합 또는 를 나타내고, Q가 결합 또는 기 를 나타내고, o가 0, 2 또는 3이고, s가 1이고, T가 산소 원자인 상기 연결기가 특히 바람직하다.In addition, the linking group of formula (III 1 ), (III 2 ) or (III 3 ) according to the present invention is a V-valent bond or an aryl radical or Q is a bond or a group It is preferable that o is 0-4. Where V is a bond or Q is a bond or a group Is particularly preferred, wherein o is 0, 2 or 3, s is 1 and T is an oxygen atom.

또한, o가 0 내지 4이고, q가 0 내지 3인 화학식 (IV1), (IV2) 또는 (IV3)의 연결기가 본 발명에 따라 바람직하다. 이 중에서, o가 0, 2 또는 3이고; W1이 산소 원자이고; q가 0이고; R22가 수소, C1-C3 알킬 또는 아르알킬이고; R23 이 수소 또는 C1-C3 알킬이고; R24a가 수소 또는 C1-C3 알킬이고; R27이 불소, 염소, CN, NO2, CO2R28 또는 OR28이고; R28이 수소 또는 C1-C5 알킬이고; U가 산소, CHR22 또는 CHR22-NR23-C(=O)-인 상기 연결기가 특히 바람직하다.Also preferred in accordance with the invention are linking groups of formula (IV 1 ), (IV 2 ) or (IV 3 ) wherein o is 0-4 and q is 0-3. Wherein o is 0, 2 or 3; W 1 is an oxygen atom; q is 0; R 22 is hydrogen, C 1 -C 3 alkyl or aralkyl; R 23 is hydrogen or C 1 -C 3 alkyl; R 24a is hydrogen or C 1 -C 3 alkyl; R 27 is fluorine, chlorine, CN, NO 2 , CO 2 R 28 or OR 28 ; R 28 is hydrogen or C 1 -C 5 alkyl; Particular preference is given to such linking groups wherein U is oxygen, CHR 22 or CHR 22 -NR 23 -C (= 0)-.

추가로, 본 발명은 In addition, the present invention

화학식 (III1) 또는 (IV1)의 연결기를, 기 L1, L2 또는 L4 중 적어도 하나가 연결기를 나타낸다는 조건이 충족될 필요가 없고, L1 및(또는) L2 및(또는) L4 가 수소 원자의 의미를 가지며, 반응에서 요구되지 않는 유리 히드록실기 및(또는) 아미노기가 임의로 보호된 화학식 (I)의 화합물과 반응시키는 방법,The linking group of formula (III 1 ) or (IV 1 ) need not be satisfied that at least one of the groups L 1 , L 2 or L 4 represents a linking group, and L 1 and / or L 2 and / or ) A method in which L 4 has the meaning of a hydrogen atom and is reacted with a compound of formula (I) in which free hydroxyl and / or amino groups, which are not required in the reaction, are optionally protected,

화학식 (III2) 또는 (IV2)의 연결기를, 기 L1, L2 또는 L4 중 적어도 하나가 연결기를 나타낸다는 조건이 충족될 필요가 없고, L1 및(또는) L2 및(또는) L4 가 수소 원자의 의미를 가지며, 반응에서 요구되지 않는 유리 히드록실기 및(또는) 아미노기가 임의로 보호된 화학식 (I)의 화합물과 반응시키는 방법, 또는The linking group of formula (III 2 ) or (IV 2 ) need not be satisfied that at least one of the groups L 1 , L 2 or L 4 represents a linking group, and L 1 and / or L 2 and / or ) A method in which L 4 has the meaning of a hydrogen atom and is reacted with a compound of formula (I) in which free hydroxyl and / or amino groups, which are not required in the reaction, are optionally protected, or

화학식 (III3) 또는 (IV3)의 연결기를, 기 L1, L2 또는 L4 중 적어도 하나가 연결기를 나타낸다는 조건이 충족될 필요가 없고, L1 및(또는) L2 및(또는) L4 가 C(=O)Hal기 또는 C(=S)Hal기의 의미를 가지며, 반응에서 요구되지 않는 유리 히드록실기 및(또는) 아미노기가 임의로 보호된 화학식 (I)의 화합물과 반응시키는 방법에 관한 것이다.The linking group of formula (III 3 ) or (IV 3 ) need not be satisfied that at least one of the groups L 1 , L 2 or L 4 represents a linking group, and L 1 and / or L 2 and / or ) L 4 reacts with a compound of formula (I) having the meaning of a C (= O) Hal group or a C (= S) Hal group, wherein the free hydroxyl and / or amino groups not required for the reaction are optionally protected It is about how to let.

또한, 본 발명은 상기 기재된 바와 같은 방법에서, 치환기가 상기 언급된 의미를 가지나, 치환기 L1, L2 또는 L4 중 적어도 하나가 화학식 (III) 또는 (IV)의 연결기를 나타낸다는 조건이 충족될 필요가 없고, 치환기 L1, L2 또는 L4 중 적어도 하나가 수소, 기 C(=O)Cl, 또는 기 C(S)Cl을 나타내는 화학식 (I)의 화합물의 용도에 관한 것이다.The present invention also provides a method as described above wherein the substituents have the meanings mentioned above, but the condition that at least one of the substituents L 1 , L 2 or L 4 represents a linking group of formula (III) or (IV) is met. Need not be, and at least one of the substituents L 1 , L 2 or L 4 relates to the use of a compound of formula (I) in which the group represents hydrogen, group C (═O) Cl, or group C (S) Cl.

또한, 본 발명은 상기 기재된 바와 같은 효과기 인식 단위 접합체의 제조를 위한, 치환기가 상기 언급한 의미를 가지나, 치환기 L1, L2 또는 L4 중 적어도 하나가 화학식 (III) 또는 (IV)의 연결기를 나타낸다는 조건이 충족될 필요가 없고, 치환기 L1, L2 또는 L4 중 적어도 하나가 수소, 기 C(=O)Cl, 또는 기 C(S)Cl을 나타내는 화학식 (I)의 화합물의 용도에 관한 것이다.In addition, the present invention, in the preparation of the effector recognition unit conjugate as described above, the substituent has the above-mentioned meaning, but at least one of the substituents L 1 , L 2 or L 4 is a linking group of the formula (III) or (IV) Of the compound of formula (I) in which at least one of the substituents L 1 , L 2 or L 4 represents hydrogen, the group C (═O) Cl, or the group C (S) Cl It is about a use.

또한, 본 발명은 상기 기재된 바와 같은 효과기 접합체의 제조를 위한 화학식 (III1), (III2), (III3), (IV1), (IV2) 또는 (IV3)의 연결기의 용도에 관한 것이다.The invention also relates to the use of linking groups of formula (III 1 ), (III 2 ), (III 3 ), (IV 1 ), (IV 2 ) or (IV 3 ) for the preparation of effector conjugates as described above. It is about.

또한, 본 발명은 상기 기재된 바와 같은 효과기 인식 단위 접합체의 제조를 위한 화학식 (III1), (III2), (III3), (IV1), (IV2) 또는 (IV3)의 연결기의 용도에 관한 것이다.The invention also relates to the linking groups of formula (III 1 ), (III 2 ), (III 3 ), (IV 1 ), (IV 2 ) or (IV 3 ) for the preparation of effector recognition unit conjugates as described above. It is about a use.

또한, 본 발명은 본 발명에 따른 방법에서, 상기 기재된 바와 같은 효과기 인식 단위 접합체의 제조를 위한 상기 기재된 바와 같은 인식 단위의 용도에 관한 것이다. The present invention furthermore relates to the use of a recognition unit as described above for the production of an effector recognition unit conjugate as described above in the method according to the invention.

또한, 본 발명은 의약으로서 사용하기 위한 또는 의약 또는 제약 조성물의 제조를 위한 본 발명에 따른 효과기 인식 단위 접합체에 관한 것이다. The invention also relates to an effector recognition unit conjugate according to the invention for use as a medicament or for the manufacture of a medicament or pharmaceutical composition.

본 발명은 최종적으로 증식 과정과 관련된 질환, 예를 들어 종양, 염증성 및(또는) 신경퇴행성 질환, 다발 경화증, 알쯔하이머병의 치료, 또는 혈관신생-관련 질환, 예를 들어 종양 성장, 류마티스성 관절염 또는 안저 질환의 치료를 위한 의약의 제조를 위한 본 발명에 따른 효과기 인식 단위 접합체의 용도에 관한 것이다. The present invention finally provides for treatment of diseases associated with the proliferative process, such as tumors, inflammatory and / or neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, or angiogenesis-related diseases such as tumor growth, rheumatoid arthritis or The use of an effector recognition unit conjugate according to the invention for the manufacture of a medicament for the treatment of ocular fundus disease.

Claims (28)

단일 이성질체 또는 여러가지 이성질체들의 혼합물로서 및(또는) 그의 제약상 허용되는 염으로서의 하기 화학식 (I)의 효과기 접합체:Effector conjugates of formula (I) as single isomers or as mixtures of various isomers and / or as pharmaceutically acceptable salts thereof: <화학식 I><Formula I> 상기 식에서,Where R1a, R1b는 서로 독립적으로 수소, C1-C10 알킬, 아릴, 아르알킬이거나, 함께 -(CH2)m 기 (여기서, m은 2 내지 5임)이고,R 1a , R 1b are independently of each other hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a — (CH 2 ) m group where m is 2 to 5, R2a, R2b는 서로 독립적으로 수소, C1-C10 알킬, 아릴, 아르알킬이거나, 함께 -(CH2)n 기 (여기서, n은 2 내지 5임) 또는 C2-C10 알케닐 또는 C2-C10 알키닐이고,R 2a , R 2b are independently of each other hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a — (CH 2 ) n group where n is 2 to 5 or C 2 -C 10 alkenyl Or C 2 -C 10 alkynyl, R3은 수소, C1-C10 알킬, 아릴 또는 아르알킬이고,R 3 is hydrogen, C 1 -C 10 alkyl, aryl or aralkyl, R4a, R4b는 서로 독립적으로 수소, C1-C10 알킬, 아릴, 아르알킬이거나, 함께 -(CH2)p 기 (여기서, p는 2 내지 5임)이고,R 4a , R 4b are independently of each other hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a — (CH 2 ) p group, where p is 2 to 5, R5는 수소, C1-C10 알킬, 아릴, 아르알킬, CO2H, CO2알킬, CH2OH, CH2O알킬, CH2O아실, CN, CH2NH2, CH2N(알킬, 아실)1,2, 또는 CH2Hal이고,R 5 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, CO 2 H, CO 2 alkyl, CH 2 OH, CH 2 Oalkyl, CH 2 O acyl, CN, CH 2 NH 2 , CH 2 N ( Alkyl, acyl) 1,2 , or CH 2 Hal, Hal은 할로겐 원자이고, Hal is a halogen atom, 각 경우에서 R6, R7은 수소이거나, 함께 부가적인 결합, 또는 함께 산소 원자, 또는 함께 NH기, 또는 함께 N-알킬기, 또는 함께 CH2기이고,In each case R 6 , R 7 are hydrogen, or are additional bonds together, or oxygen atoms together, or NH groups together, or N-alkyl groups together, or CH 2 groups together, G는 산소 원자 또는 CH2이고,G is an oxygen atom or CH 2 , D-E는 기 H2C-CH2, HC=CH, C≡C, CH(OH)-CH(OH), CH(OH)-CH2, CH2 -CH(OH), , O-CH2이거나, G가 CH2기를 나타내는 경우, D-E는 CH2-O이고,DE is a group H 2 C-CH 2 , HC = CH, C≡C, CH (OH) -CH (OH), CH (OH) -CH 2 , CH 2 -CH (OH), Or O-CH 2 or when G represents a CH 2 group, DE is CH 2 -O, W는 기 C(=X)R8, 또는 비시클릭 또는 트리시클릭 방향족 또는 헤테로방향족 라디칼이고,W is a group C (═X) R 8 , or a bicyclic or tricyclic aromatic or heteroaromatic radical, L3은 수소이거나, W에서의 라디칼이 히드록실기를 함유하는 경우 히드록실기와 기 O-L4를 형성하거나, W에서의 라디칼이 아미노기를 함유하는 경우 아미노기와 기 NR25-L4를 형성하고,L 3 is hydrogen, or if the radical at W contains a hydroxyl group, forms a hydroxyl group and the group OL 4 , or if the radical at W contains an amino group, forms an amino group and the group NR 25 -L 4 ; , R25는 수소 또는 C1-C10 알킬이고,R 25 is hydrogen or C 1 -C 10 alkyl, X는 산소 원자, 또는 2개의 OR20기, 또는 직쇄 또는 분지쇄일 수 있는 C2-C10 알킬렌디옥시기, 또는 H/OR9, 또는 CR10R11기이고,X is an oxygen atom, or two OR 20 groups, or a C 2 -C 10 alkylenedioxy group, which may be straight or branched, or H / OR 9 , or CR 10 R 11 , R8은 수소, C1-C10 알킬, 아릴, 아르알킬, 할로겐 또는 CN이고,R 8 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, halogen or CN, R9는 수소 또는 보호기 PGX이고,R 9 is hydrogen or a protecting group PG X , 각 경우에서 R10, R11은 서로 독립적으로 수소, C1-C20 알킬, 아릴, 아르알킬이거나, 메틸렌 탄소 원자와 함께 5- 내지 7-원 카르보시클릭 고리를 형성하고,In each case R 10 , R 11 are independently of each other hydrogen, C 1 -C 20 alkyl, aryl, aralkyl or together with the methylene carbon atom form a 5- to 7-membered carbocyclic ring, Z는 산소 또는 H/OR12를 나타낼 수 있고,Z can represent oxygen or H / OR 12 , R12는 수소 또는 보호기 PGZ를 나타낼 수 있고,R 12 may represent hydrogen or a protecting group PG Z , A-Y는 기 O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O) 또는 NR21-SO 2를 나타낼 수 있고,AY may represent the group OC (═O), O—CH 2 , CH 2 —C (═O), NR 21 -C (═O) or NR 21 -SO 2 , R20은 C1-C20 알킬을 나타낼 수 있고,R 20 may represent C 1 -C 20 alkyl, R21은 수소 원자 또는 C1-C10 알킬을 나타낼 수 있고,R 21 may represent a hydrogen atom or C 1 -C 10 alkyl, PGX, PGY 및 PGZ는 보호기 PG를 나타낼 수 있고,PG X , PG Y and PG Z may represent the protecting group PG, L1, L2 및 L4는 서로 독립적으로 수소, 기 C(=O)Cl, 기 C(=S)Cl, 기 PG Y 또는 하기 화학식 (III) 또는 (IV)의 연결기를 나타낼 수 있으되, 단, 치환기 L1, L2 및 L4 중 적어도 하나는 화학식 (III) 또는 (IV)의 연결기를 나타내고,L 1 , L 2 and L 4 may independently represent hydrogen, a group C (═O) Cl, a group C (= S) Cl, a group PG Y or a linking group of formula (III) or (IV), Provided that at least one of substituents L 1 , L 2 and L 4 represents a linking group of formula (III) or (IV), 화학식 (III)의 연결기는 하기 구조를 갖고:The linking group of formula (III) has the structure <화학식 III><Formula III> 상기 식에서,Where T는 산소 또는 황을 나타낼 수 있고, T can represent oxygen or sulfur, U는 산소, CHR22, CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23 -C(=O)-, O-C(=O)-CHR22-NR23-C(=S)-, CHR22-NR23-C(=S)- 또는 NR24a를 나타낼 수 있고,U is oxygen, CHR 22 , CHR 22 -NR 23 -C (= O)-, OC (= O) -CHR 22 -NR 23 -C (= O)-, OC (= O) -CHR 22 -NR 23 -C (= S)-, CHR 22 -NR 23 -C (= S)-or NR 24a , and o는 0 내지 15를 나타낼 수 있고,o can represent 0 to 15, V는 결합, 아릴, 기 또는 기 를 나타낼 수 있고,V is a bond, aryl, group Or flag Can represent s는 0 내지 4를 나타낼 수 있고,s can represent 0 to 4, Q는 결합, O-C(=O)-NR24c, O-C(=S)-NR24c, 또는 를 나타낼 수 있고,Q is a bond, OC (= O) -NR 24c , OC (= S) -NR 24c , or Can represent R22는 수소, C1-C10 알킬, 아릴 또는 아르알킬을 나타낼 수 있고,R 22 may represent hydrogen, C 1 -C 10 alkyl, aryl or aralkyl, R23은 수소 또는 C1-C10 알킬을 나타낼 수 있고,R 23 may represent hydrogen or C 1 -C 10 alkyl, R24a, R24b 및 R24c는 서로 독립적으로 수소 또는 C1-C10 알킬을 나타낼 수 있고,R 24a , R 24b and R 24c may independently represent hydrogen or C 1 -C 10 alkyl, q는 0 내지 15를 나타낼 수 있고,q can represent 0 to 15, FG1은 C1-C10 알킬-S3, 또는 CO2H를 나타낼 수 있고,FG 1 is C 1 -C 10 alkyl-S 3 , Or CO 2 H, 화학식 (IV)의 연결기는 하기 구조를 갖고: The linking group of formula (IV) has the structure <화학식 IV><Formula IV> 상기 식에서,Where T는 산소 또는 황을 나타낼 수 있고,T can represent oxygen or sulfur, W1, W2는 동일하거나 상이하고, 산소 또는 NR24a를 나타낼 수 있고,W 1 , W 2 are the same or different and can represent oxygen or NR 24a , o는 0 내지 5를 나타낼 수 있고,o can represent 0 to 5, R24a는 수소 또는 C1-C10 알킬을 나타낼 수 있고,R 24a can represent hydrogen or C 1 -C 10 alkyl, R27은 할로겐, CN, N02, CO2R28, 또는 OR28을 나타낼 수 있고,R 27 may represent halogen, CN, NO 2 , CO 2 R 28 , or OR 28 , R28은 수소, C1-C10 알킬, 아릴 또는 아르알킬을 나타낼 수 있고,R 28 may represent hydrogen, C 1 -C 10 alkyl, aryl or aralkyl, q는 0 내지 5를 나타낼 수 있고,q can represent 0 to 5, U는 산소, CHR22, CHR22-NR23-C(=O)-, CHR22-NR23-C(=S)- 또는 C1-C20 알킬을 나타낼 수 있고,U can represent oxygen, CHR 22 , CHR 22 -NR 23 -C (= 0)-, CHR 22 -NR 23 -C (= S)-or C 1 -C 20 alkyl, R22는 수소, C1-C10 알킬, 아릴 또는 아르알킬을 나타낼 수 있고,R 22 may represent hydrogen, C 1 -C 10 alkyl, aryl or aralkyl, R23은 수소 또는 C1-C10 알킬을 나타낼 수 있고,R 23 may represent hydrogen or C 1 -C 10 alkyl, r은 0 내지 20을 나타낼 수 있고, r can represent 0 to 20, FG1은 C1-C10 알킬-S3, 또는 CO2H를 나타낼 수 있다.FG 1 is C 1 -C 10 alkyl-S 3 , Or CO 2 H. 제1항에 있어서, The method of claim 1, A-Y가 O-C(=O) 또는 NR21-C(=O)를 나타내고;AY represents OC (= 0) or NR 21 -C (= 0); D-E가 H2C-CH2기를 나타내고;DE represents a H 2 C-CH 2 group; G가 CH2기를 나타내고;G represents a CH 2 group; Z가 산소 원자를 나타내고; Z represents an oxygen atom; 각 경우에서 R1a, R1b가 C1-C10 알킬을 나타내거나, 함께 p가 2 또는 3 또는 4인 -(CH2)p기를 나타내고;In each case R 1a , R 1b represent C 1 -C 10 alkyl, or together represent a — (CH 2 ) p group wherein p is 2 or 3 or 4; R2a, R2b가 서로 독립적으로 수소, C1-C10 알킬, C2-C 10 알케닐, 또는 C2-C10 알키닐을 나타내고;R 2a , R 2b independently of one another represent hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl; R3이 수소를 나타내고;R 3 represents hydrogen; R4a, R4b가 서로 독립적으로 수소 또는 C1-C10 알킬을 나타내고;R 4a , R 4b independently of one another represent hydrogen or C 1 -C 10 alkyl; R5가 수소 또는 C1-C4 알킬 또는 CH2OH 또는 CH2NH 2 또는 CH2N(알킬, 아실)1,2 또는 CH2Hal을 나타내고;R 5 represents hydrogen or C 1 -C 4 alkyl or CH 2 OH or CH 2 NH 2 or CH 2 N (alkyl, acyl) 1,2 or CH 2 Hal; R6 및 R7이 함께 부가적인 결합, 또는 함께 NH기, 또는 함께 N-알킬기, 또는 함께 CH2기, 또는 함께 산소 원자를 나타내고;R 6 and R 7 together represent an additional bond, or together NH group, or together N-alkyl group, or together CH 2 group, or together an oxygen atom; W가 기 C(=X)R8 또는 2-메틸벤조티아졸-5-일 라디칼 또는 2-메틸벤족사졸-5-일 라디칼 또는 퀴놀린-7-일 라디칼 또는 2-아미노메틸벤조티아졸-5-일 라디칼 또는 2-히드록시메틸벤조티아졸-5-일 라디칼 또는 2-아미노메틸벤족사졸-5-일 라디칼 또는 2-히드록시메틸벤족사졸-5-일 라디칼을 나타내고;W is a group C (= X) R 8 or 2-methylbenzothiazol-5-yl radical or 2-methylbenzoxazol-5-yl radical or quinolin-7-yl radical or 2-aminomethylbenzothiazole-5 -Yl radical or 2-hydroxymethylbenzothiazol-5-yl radical or 2-aminomethylbenzoxazol-5-yl radical or 2-hydroxymethylbenzoxazol-5-yl radical; X가 CR10R11기를 나타내고;X represents a CR 10 R 11 group; R8이 수소 또는 C1-C4 알킬 또는 불소 원자 또는 염소 원자 또는 브롬 원자를 나타내고;R 8 represents hydrogen or C 1 -C 4 alkyl or fluorine atom or chlorine atom or bromine atom; R10/R11이 수소/2-메틸티아졸-4-일 또는 수소/2-피리딜 또는 수소/2-메틸옥사졸-4-일 또는 수소/2-아미노메틸티아졸-4-일 또는 수소/2-아미노메틸옥사졸-4-일 또는 수소/2-히드록시메틸티아졸-4-일 또는 수소/2-히드록시메틸옥사졸-4-일을 나타내는 효과기 접합체.R 10 / R 11 is hydrogen / 2-methylthiazol-4-yl or hydrogen / 2-pyridyl or hydrogen / 2-methyloxazol-4-yl or hydrogen / 2-aminomethylthiazol-4-yl or Effector conjugates representing hydrogen / 2-aminomethyloxazol-4-yl or hydrogen / 2-hydroxymethylthiazol-4-yl or hydrogen / 2-hydroxymethyloxazol-4-yl. 제1항 또는 제2항에 있어서, 효과기 요소가The effector element according to claim 1 or 2, wherein the effector element is (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2- Methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-1-메틸-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- ( 2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-메닐-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-menyl-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- ( 2-methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-1-메틸-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-메틸-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2 -(2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-메틸-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-메틸-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2 -Methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro- Vinyl] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로- 비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Roxy-5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro Rho-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2- Methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- ( 2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.O]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.O] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro- Vinyl] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로- 비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Hydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-플루오로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro- 2- (2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-플루오로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro Rho-vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- ( 2-methyl-thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-클로로-2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2 -(2-methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-1-클로로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-1-클로로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-메틸-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2- Pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- ( 2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-메틸-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- ( 2-pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-메틸-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2 -(2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-플루오로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2 -Pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-플루오로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-클로로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2- Pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-클로로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- ( 2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-플루오로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-플루오로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro- 2- (2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-클로로-2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- ( 2-pyridyl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-클로로-2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2 -(2-pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2- Methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- ( 2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- ( 2-methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-메틸-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2 -(2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-메틸-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-메틸-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온, (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2 -Methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro- Vinyl] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Roxy-5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluor Rho-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2- Methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl ] -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -5,5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- ( 2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro -Vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro- Vinyl] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -4,8-dihydrate Hydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-플루오로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro- 2- (2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-플루오로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluor Rho-vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-플루오로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -7,11- Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- ( 2-methyl-oxazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-디히드록시-16-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl ] -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (Z))-16- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -4,8-dihydroxy -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[1-클로로-2-(2-메틸-옥사졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2 -(2-methyl-oxazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-옥사졸-4-일)-1-클로로-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro -Vinyl] -10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-옥사졸-4-일)-1-클로로-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타-데칸-5,9-디온,(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7,11-di Hydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [2- (2-methyl-thiazole -4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -5, 5,7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-비닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -4,8-dihydroxy-5,5 , 7,9,13-pentamethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [2- (2-methyl- Thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl]- 8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-비닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -7,11-dihydroxy-8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[2-(2-메틸-티아졸-4-일)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [2- (2-methyl- Thiazol-4-yl) -vinyl] -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-16-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -7- Ethyl-5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-아미노메틸-티아졸-4-일)-비닐]-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-16- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -4,8-dihydroxy-7-ethyl -5,5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[2-(2-메틸-티아졸-4-일)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [2- (2- Methyl-thiazol-4-yl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-3-[2-(2-히드록시메틸-티아졸-4-일)-비닐]-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl]- 10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-아미노메틸-티아졸-4-일)-비닐]-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -vinyl] -7,11-dihydroxy-10 -Ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-[2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [2- (2-pyridyl)- Vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [2- (2-pyridyl ) -Vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-[2-(2-피리딜)-비닐]-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S (E))-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [2- (2-pyridyl ) -Vinyl] -oxacyclohexades-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-[2-(2-피리딜)-비닐]-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [2- (2- Pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- (2-methyl-benzothiazol-5-yl) -Oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -5,5,7,9,13- Pentamethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-5,5,7,9,13-penta Methyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzothiazole-5- Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -8,8,10,12, 16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-8,8,10,12,16 -Pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-ethyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-ethyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-ethyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-propyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-propyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-propyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-propyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-butyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-butyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-butyl-8,8, 12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-butyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazole-5- Yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-allyl-5,5,9, 13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-allyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazole- 5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸벤조티아졸-5-일)-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-allyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzo Thiazol-5-yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-prop-2-ynyl-5 , 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5, 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl -Benzothiazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-prop-2-ynyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothia Zol-5-yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-but-3-enyl-5, 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-enyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzothiazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-but-3-enyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤조티아졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothia Zol-5-yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S-4,8-디히드록시-16-(2-히드록시메틸-벤조티아졸-5-일)-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S-4,8-dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-but-3-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤조티아졸-5-일)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,125,16R)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤조티아졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 125,16R) -7,11-dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzothiazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤조티아졸-5-일)-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-but-3-ynyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤조티아졸-5-일)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-5,5,7,9,13-펜타메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- (2-methyl-benzoxazol-5-yl)- Oxcyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -5,5,7,9,13-penta Methyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-5,5,7,9,13-펜타메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-5,5,7,9,13-pentamethyl -Oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzoxazol-5-yl ) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -8,8,10,12,16 -Pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-8,8,10,12,16- Pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-ethyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-에틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-ethyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-ethyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-에틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-propyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-프로필-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-propyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-propyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-프로필-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-propyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-butyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-부틸-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-butyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-butyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-부틸-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-butyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -Oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-allyl-5,5,9,13 Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-알릴-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-allyl-5,5,9,13- Tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazole-5 -Yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-allyl-8,8,12 , 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-알릴-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzone Sazol-5-yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-prop-2-ynyl-5, 5,9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-프로프-2-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl -Benzoxazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-prop-2-ynyl- 8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-프로프-2-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazole -5-yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-enyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-부트-3-에닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but-3-enyl-5,5, 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzoxazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-enyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-부트-3-에닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8, 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-16-(2-메틸-벤족사졸-5-일)-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but-3-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazole -5-yl) -oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-디히드록시-16-(2-히드록시메틸-벤족사졸-5-일)-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온, (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-ynyl-5,5 , 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-아미노메틸-벤족사졸-5-일)-4,8-디히드록시-7-부트-3-이닐-5,5,9,13-테트라메틸-옥사시클로헥사데스-13-엔-2,6-디온,(4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5, 9,13-tetramethyl-oxacyclohexades-13-ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-3-(2-메틸-벤족사졸-5-일)-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온,(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-3- (2-methyl- Benzoxazol-5-yl) -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11-디히드록시-3-(2-히드록시메틸-벤족사졸-5-일)-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온, (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-ynyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-3-(2-아미노메틸-벤족사졸-5-일)-7,11-디히드록시-10-부트-3-이닐-8,8,12,16-테트라메틸-4,17-디옥사-비시클로[14.1.0]헵타데칸-5,9-디온(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-8, 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione 으로 이루어진 군으로부터 선택되며, 여기서 상기 언급된 효과기 요소 중의 수소 원자가 화학식 (I)에 지시된 위치에서 라디칼 L1 내지 L3으로 대체된 것인 효과기 접합체.An effector conjugate, wherein the hydrogen atoms in the above-mentioned effector elements are replaced with radicals L 1 to L 3 at the positions indicated in formula (I). 제1항 내지 제3항 중 어느 한 항에 있어서, 연결기가 The method of claim 1, wherein the linker is V가 결합 또는 아릴 라디칼을 나타내고,V represents a bond or an aryl radical, o가 0이고, o is 0, T가 산소 원자인 화학식 (III)의 화합물들로 이루어진 군으로부터 선택된 것인 효과기 접합체. An effector conjugate selected from the group consisting of compounds of formula (III) wherein T is an oxygen atom. 제1항 내지 제3항 중 어느 한 항에 있어서, 연결기가 The method of claim 1, wherein the linker is V가 결합 또는 아릴 라디칼 또는 기 이고,V is a bond or an aryl radical or group ego, o가 0 내지 4이고, o is 0 to 4, Q가 결합 또는 기 인 화학식 (III)의 화합물들로 이루어진 군으로부터 선택된 것인 효과기 접합체.Q is combined or An effector conjugate selected from the group consisting of compounds of formula (III). 제5항에 있어서, The method of claim 5, V가 결합 또는 기 이고,V is a bond or group ego, Q가 결합 또는 기 이고,Q is combined or ego, o가 0, 2 또는 3이고, o is 0, 2 or 3, s가 1이고,s is 1, T가 산소 원자인 효과기 접합체. An effector conjugate wherein T is an oxygen atom. 제1항 내지 제3항 중 어느 한 항에 있어서, 연결기가 The method of claim 1, wherein the linker is o가 0 내지 4이고, o is 0 to 4, q가 0 내지 3인 화학식 (IV)의 화합물들로 이루어진 군으로부터 선택된 것인 효과기 접합체. An effector conjugate selected from the group consisting of compounds of formula (IV) wherein q is 0-3. 제7항에 있어서, The method of claim 7, wherein o가 0, 2 또는 3이고; o is 0, 2 or 3; W1이 산소이고;W 1 is oxygen; q가 0이고; q is 0; R22가 수소, C1-C3 알킬 또는 아르알킬이고;R 22 is hydrogen, C 1 -C 3 alkyl or aralkyl; R23이 수소 또는 C1-C3 알킬이고;R 23 is hydrogen or C 1 -C 3 alkyl; R24a가 수소 또는 C1-C3 알킬이고;R 24a is hydrogen or C 1 -C 3 alkyl; R27이 불소, 염소, CN, NO2, CO2R28 또는 OR28이고;R 27 is fluorine, chlorine, CN, NO 2 , CO 2 R 28 or OR 28 ; R28이 수소 또는 C1-C5 알킬이고;R 28 is hydrogen or C 1 -C 5 alkyl; U가 산소, CHR22 또는 CHR22-NR23-C(=O)-인 효과기 접합체.An effector conjugate wherein U is oxygen, CHR 22 or CHR 22 -NR 23 -C (= 0)-. 단일 이성질체 또는 여러가지 이성질체들의 혼합물로서 및(또는) 그의 제약상 허용되는 염으로서의 하기 화학식 (I)의 효과기 인식 단위 접합체:Effector recognition unit conjugates of formula (I) as single isomers or mixtures of various isomers and / or as pharmaceutically acceptable salts thereof: <화학식 I><Formula I> 상기 식에서, 치환기는 청구항 1에서 언급된 의미를 가지나, 적어도 하나의 기 FG1은 기 FG2a 또는 FG2b로 대체되며, 여기서 FG2a 또는 FG2b는 하기 의미를 가질 수 있고:Wherein the substituents have the meanings mentioned in claim 1, but at least one group FG 1 is replaced with a group FG 2a or FG 2b , wherein FG 2a or FG 2b may have the following meanings: FG2a: -S-S-, ;FG 2a : -SS-, ; FG2b: -CONH-;FG 2b : -CONH-; 여기서, 인식 단위는 황 원자를 통해 기 FG2a와 접합되거나, 아미드 관능기를 통해 기 FG2b와 접합되고; 이 때, 인식 단위는 펩티드, 가용성 수용체, 사이토킨, 림포킨, 압타머, 스피에겔머, 재조합 단백질, 신규 골격 구조, 모노클로날 항체 또는 모노클로날 항체의 단편으로 이루어진 군으로부터 선택된다.Wherein the recognition unit is conjugated with the group FG 2a via a sulfur atom or with the group FG 2b via an amide functional group; At this time, the recognition unit is selected from the group consisting of peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegelmers, recombinant proteins, novel skeletal structures, monoclonal antibodies or fragments of monoclonal antibodies. 제9항에 있어서, 접합체가 하나 이상의 인식 단위를 함유하고, 여기서 인식 단위들이 동일한 것인 효과기 인식 단위 접합체. 10. The effector recognition unit conjugate of claim 9, wherein the conjugate contains one or more recognition units, wherein the recognition units are identical. 제9항 또는 제10항에 있어서, 인식 단위가 표 1에 언급된 항원 뿐만 아니라 CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, VCAM, CD31, ELAM, 엔도글린, VEGFRI/II, αvβ3, Tie1/2, TES23 (CD44ex6), 포스파티딜세린, PSMA, VEGFR/VEGF 복합체 및 ED-B-피브로넥틴으로 이루어진 군으로부터 선택된 항원에 특이적인 항체 또는 그의 항원-결합 단편인 효과기 인식 단위 접합체.The method according to claim 9 or 10, wherein the recognition unit is CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4 as well as the antigens mentioned in Table 1. , CD21, CD37, CD30, VCAM, CD31, ELAM, endoglin, VEGFRI / II, α v β 3 , Tie1 / 2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR / VEGF complex and ED-B-fibronectin An effector recognition unit conjugate that is an antibody specific for an antigen selected from the group consisting of or antigen-binding fragments thereof. 하기 화학식 (III1)의 연결기, 하기 화학식 (III2)의 연결기 또는 하기 화학식 (III3)의 연결기 (단, 화합물 1-(4-아미노-페닐)-피롤-2,5-디온은 포함되지 않음):The linking group of formula (III 1 ), the linking group of formula (III 2 ) or the linking group of formula (III 3 ), provided that compound 1- (4-amino-phenyl) -pyrrole-2,5-dione is not included. Not): <화학식 III1><Formula III 1 > <화학식 III2><Formula III 2 > <화학식 III3><Formula III 3 > 상기 식에서,Where RG1은 O=C=N기 또는 S=C=N기이고,RG 1 is O = C = N group or S = C = N group, RG2는 Hal-C(=T)-CHR22기 또는 Hal-C(=T)-CHR22-NR23-C(=T)기 또는 R26-C(=O)-O-C(=T)-CHR22기 또는 R26-C(=O)-O-C(=T)-CHR22-NR23-C(=T)기이고, 여기서 R26은 C1-C10 알킬, 아릴, 또는 아르알킬이고,RG 2 is a Hal-C (= T) -CHR 22 group or a Hal-C (= T) -CHR 22 -NR 23 -C (= T) group or a R 26 -C (= O) -OC (= T) Is a -CHR 22 group or a R 26 -C (= O) -OC (= T) -CHR 22 -NR 23 -C (= T) group, wherein R 26 is C 1 -C 10 alkyl, aryl, or aralkyl ego, RG3은 OH기 또는 NHR24a기 또는 COOH기이고,RG 3 is an OH group or an NHR 24a group or a COOH group, o, V, q 및 FG1은 제1항에 언급된 의미를 가진다.o, V, q and FG 1 have the meanings referred to in claim 1 . 하기 화학식(IV1)의 연결기, 하기 화학식 (IV2)의 연결기 또는 하기 화학식 (IV3)의 연결기:A linking group of formula (IV 1 ), a linking group of formula (IV 2 ) or a linking group of formula (IV 3 ): <화학식 IV1><Formula IV 1 > <화학식 IV2><Formula IV 2 > <화학식 IV3><Formula IV 3 > 상기 식에서,Where RG1은 O=C=N기 또는 S=C=N기이고,RG 1 is O = C = N group or S = C = N group, RG2는 Hal-C(=T)-CHR22기 또는 Hal-C(=T)-CHR22-NR23-C(=T)기 또는 R26-C(=O)-O-C(=T)-CHR22기 또는 R26-C(=0)-O-C(=T)-CHR22-NR23-C(=T)기이고, 여기서 R26은 C1-C10 알킬, 아릴, 또는 아르알킬이고,RG 2 is a Hal-C (= T) -CHR 22 group or a Hal-C (= T) -CHR 22 -NR 23 -C (= T) group or a R 26 -C (= O) -OC (= T) Is a -CHR 22 group or a R 26 -C (= 0) -OC (= T) -CHR 22 -NR 23 -C (= T) group, wherein R 26 is C 1 -C 10 alkyl, aryl, or aralkyl ego, RG3은 OH기 또는 NHR24a기 또는 COOH기이고,RG 3 is an OH group or an NHR 24a group or a COOH group, o, q, r, W2, R27, U, R22, R23, T, R24a 및 FG 1은 제1항에 언급된 의미를 가진다.o, q, r, W 2 , R 27 , U, R 22 , R 23 , T, R 24a and FG 1 have the meanings mentioned in claim 1 . 제12항에 있어서, V가 결합 또는 아릴 라디칼을 나타내고, o가 0이고, T가 산소 원자인 연결기.13. The linking group of claim 12, wherein V represents a bond or an aryl radical, o is 0 and T is an oxygen atom. 제12항에 있어서, The method of claim 12, V가 결합 또는 아릴 라디칼 또는 기 를 나타내고,V is a bond or an aryl radical or group Indicates, o가 0 내지 4이고, o is 0 to 4, Q가 결합 또는 기 인 연결기.Q is combined or Q Coupler. 제15항에 있어서, The method of claim 15, V가 결합 또는 기 이고,V is a bond or group ego, Q가 결합 또는 기 이고,Q is combined or Q ego, o가 0, 2 또는 3이고, o is 0, 2 or 3, s가 1이고,s is 1, T가 산소 원자인 연결기.A linking group wherein T is an oxygen atom. 제13항에 있어서, o가 0 내지 4이고, The method of claim 13, wherein o is 0 to 4, q가 0 내지 3인 연결기. a linker wherein q is 0-3. 제17항에 있어서, The method of claim 17, o가 0, 2 또는 3이고; o is 0, 2 or 3; W1이 산소이고;W 1 is oxygen; q가 0이고; q is 0; R22가 수소, C1-C3 알킬 또는 아르알킬이고;R 22 is hydrogen, C 1 -C 3 alkyl or aralkyl; R23이 수소 또는 C1-C3 알킬이고;R 23 is hydrogen or C 1 -C 3 alkyl; R24a가 수소 또는 C1-C3 알킬이고;R 24a is hydrogen or C 1 -C 3 alkyl; R27이 불소, 염소, CN, NO2, CO2R28 또는 OR28이고;R 27 is fluorine, chlorine, CN, NO 2 , CO 2 R 28 or OR 28 ; R28이 수소 또는 C1-C5 알킬이고;R 28 is hydrogen or C 1 -C 5 alkyl; U가 산소, CHR22 또는 CHR22-NR23-C(=O)-인 연결기.A linker where U is oxygen, CHR 22 or CHR 22 -NR 23 -C (= 0)-. 치환기가 제1항에 언급된 의미를 가지나, 치환기 L1, L2 또는 L4 중 적어도 하나가 화학식 (III) 또는 (IV)의 연결기를 나타낸다는 조건이 충족될 필요가 없고, 치환기 L1, L2 또는 L4 중 적어도 하나가 수소, 기 C(=O)Cl, 또는 기 C(=S)Cl을 나타내는 화학식 (I)의 화합물을 제12항 내지 제18항 중 어느 한 항에 기재된 바와 같은 화학식(III1), (III2), (III3), (IV1), (IV2) 또는 (IV3)의 연결기로 이루어진 군으로부터 선택된 연결기와 반응시키는, 제1항 내지 제8항 중 어느 한 항의 효과기 접합체의 제조 방법.Although the substituents have the meanings mentioned in claim 1 , the condition that at least one of the substituents L 1 , L 2 or L 4 represents a linking group of the formula (III) or (IV) need not be satisfied, and the substituents L 1 , A compound of formula (I) wherein at least one of L 2 or L 4 represents hydrogen, a group C (═O) Cl, or a group C (═S) Cl, as described in any one of claims 12-18. A compound reacted with a linking group selected from the group consisting of linking groups of the same formula (III 1 ), (III 2 ), (III 3 ), (IV 1 ), (IV 2 ) or (IV 3 ). Method for producing the effector conjugate of any one of the preceding. 제1항 내지 제8항 중 어느 한 항의 효과기 접합체를 제9항 및 제11항 중 어느 한 항에 기재된 바와 같은 하나 이상의 인식 단위와 반응시키는, 제9항 내지 제11항 중 어느 한 항의 효과기 인식 단위 접합체의 제조 방법. The effector recognition of any one of claims 9 to 11, wherein the effector conjugate of any one of claims 1 to 8 is reacted with one or more recognition units as described in any one of claims 9 and 11. Method for producing unit conjugates. 치환기가 제1항에 언급된 의미를 가지나, 치환기 L1, L2 또는 L4 중 적어도 하나가 화학식 (III) 또는 (IV)의 연결기를 나타낸다는 조건이 충족될 필요가 없고, 치환기 L1, L2 또는 L4 중 적어도 하나가 수소, 기 C(=O)Cl, 또는 기 C(=S)Cl을 나타내는 화학식 (I)의 화합물의 제19항의 제조 방법에서의 용도.Although the substituents have the meanings mentioned in claim 1 , the condition that at least one of the substituents L 1 , L 2 or L 4 represents a linking group of the formula (III) or (IV) need not be satisfied, and the substituents L 1 , Use of the compound of formula (I) in the process of claim 19 wherein at least one of L 2 or L 4 represents hydrogen, group C (═O) Cl, or group C (═S) Cl. 제9항 내지 제11항 중 어느 한 항의 효과기 인식 단위 접합체의 제조를 위한 화학식 (I)의 화합물의 용도. Use of a compound of formula (I) for the preparation of the effector recognition unit conjugate of any one of claims 9-11. 화학식 (III1), (III2), (III3), (IV1), (IV2) 또는 (IV3)의 연결기의 제19항의 제조 방법에서의 용도.Use of the linking group of formula (III 1 ), (III 2 ), (III 3 ), (IV 1 ), (IV 2 ) or (IV 3 ) in the process of claim 19. 제9항 내지 제11항 중 어느 한 항의 효과기 인식 단위 접합체의 제조를 위한 화학식 (III1), (III2), (III3), (IV1), (IV2) 또는 (IV3)의 연결기의 용도.Of the formula (III 1 ), (III 2 ), (III 3 ), (IV 1 ), (IV 2 ) or (IV 3 ) for the preparation of the effector recognition unit conjugate of any one of claims 9-11. Use of the connector. 제9항 또는 제11항에 정의된 바와 같은 인식 단위의 제20항의 제조 방법에서의 용도. Use of the recognition unit as defined in claim 9 or 11 in the method of claim 20. 제9항 내지 제11항 중 어느 한 항에 있어서, 의약으로서 사용하기 위한 효과기 인식 단위 접합체. The effector recognition unit conjugate according to any one of claims 9 to 11, for use as a medicament. 제9항 내지 제11항 중 어느 한 항에 있어서, 증식 과정과 관련된 질환의 치료용 의약으로서 사용하기 위한 효과기 인식 단위 접합체. The effector recognition unit conjugate according to any one of claims 9 to 11, for use as a medicament for the treatment of a disease associated with a proliferative process. 제9항 내지 제11항 중 어느 한 항에 있어서, 종양, 염증성 질환, 신경퇴행성 질환, 혈관신생-관련 질환, 다발 경화증, 알쯔하이머병 및 류마티스성 관절염으로 이루어진 군으로부터 선택된 질환의 치료용 의약으로서 사용하기 위한 효과기 인식 단위 접합체. Use according to any one of claims 9 to 11 as a medicament for the treatment of a disease selected from the group consisting of tumors, inflammatory diseases, neurodegenerative diseases, angiogenesis-related diseases, multiple sclerosis, Alzheimer's disease and rheumatoid arthritis. Effector recognition unit conjugate for
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