CN108570032B - 新型罗丹明染料及其在抗致病菌中的应用 - Google Patents
新型罗丹明染料及其在抗致病菌中的应用 Download PDFInfo
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- CN108570032B CN108570032B CN201710137629.4A CN201710137629A CN108570032B CN 108570032 B CN108570032 B CN 108570032B CN 201710137629 A CN201710137629 A CN 201710137629A CN 108570032 B CN108570032 B CN 108570032B
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- alkyl
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- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
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- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
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- 206010040872 skin infection Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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Abstract
本发明涉及新型罗丹明染料及其在抗致病菌中的应用。具体而言,本发明涉及下式A所示的化合物,式中,X‑和R1‑R9如文中所述。本发明的新型罗丹明染料对革兰氏阳性菌和革兰氏阴性菌有抑菌、杀菌作用和抗菌增效作用。
Description
技术领域
本发明涉及生物医药领域,特别是涉及新型罗丹明染料及其在抗致病菌中的应用。
背景技术
抗生素是上世纪人类开发出来对抗细菌感染的武器。从上世纪30年代到70年代短短几十年里,共发现超过20大类结构和作用机制都相同的抗生素。它们的广泛使用挽救了大量病患的生命。因此,抗生素被誉为医学史上最伟大的发明之一。
进入上世纪80年代,由于抗生素发现难度逐渐增加,回报也相对较低,主要大制药公司均已退出或极大缩减其抗生素部门,因此新抗生素开发已经大大放缓。同时,由于抗生素在临床及养殖业的滥用及无序排放,细菌已经对临床上主要使用的各类抗生素产生抗药性。在世界不同国家,受耐药菌感染致病而无药可治的病例层出不穷。据统计,2013年,在美国有超过两百万耐药菌感染病例,其中超过23、000人最终死于细菌感染。据总部在伦敦的Wellcome Trust估计,到2050年,中国每年因耐药菌导致的死亡人数可能会超过百万。针对细菌抗药性这一重大公共卫生安全问题,世界卫生组织于2015年推出全球行动计划对抗细菌耐药,并于2016年10月5日在联合国大会通过。世界主要国家也都制定了对抗细菌抗药的行动计划。主要措施包括严格规范抗生素使用,减少向环境排放并同时鼓励高校及制药企业加快新型抗生素的开发。
新型抗生素的两条主要开发方法包括对已知抗生素进行结构衍生开发me too类药物和对新型化学空间进行筛选发现全新抗生素种类。一般而言,对于已有药物的me too类药物也较易引发细菌抗性,因此最终的出路仍然是寻找有望发现新型抗生素的化学空间,进一步筛选发现活性先导,并进行药物开发。
发明内容
本文第一方面提供通式A所示的化合物,包括通式BI、BII、BIII、BIV、BV、BVI、BVII、BVIII、BIX以及CI-CXIII的化合物。
本文第二方面提供含有通式A所示化合物的一种或多种和药学上可接受的载体的药物组合物;和任选的已知抗菌药。
本文第三方面提供通式A所示化合物在抗菌或增强已知抗菌药抗菌活性中的应用,包括用于制备抗菌药,或用于制备用来增强已知抗菌药的抗菌活性的药物。
本文第四方面提供一种抗菌方法,包括给予需要的对象本发明通式A所示的任意一种或多种化合物。
本文第五方面提供一种提高抗菌药抗菌活性的方法,包括在给予抗菌药之前、同时或之后给予一种或多种通式A所示的化合物或其药物组合物。
本发明第六方面提供了一种制备通式A化合物的方法。
附图说明
图1:化合物CXIIIo、万古霉素、利萘唑胺、替加环素对处于对数生长早期的耐甲氧西林金黄色葡萄球菌(ATCC43300)的杀菌曲线。
图2:化合物CXIIIo、替加环素对处于对数生长早期的鲍氏不动杆菌(ATCC19606)的杀菌曲线。
图3:化合物CXIIIo、万古霉素、利萘唑胺对处于对数生长早期的抗万古霉素粪肠球菌(ATCC51299)的杀菌曲线。
图4:耐甲氧西林金黄色葡萄球菌(ATCC43300)对CXIIIo的诱导耐药实验。
图5:甲氧西林敏感株金黄色葡萄球菌(ATCC25923)对CXIIIo的诱导耐药实验。
具体实施方式
应理解,在本发明范围内中,本发明上下文所述的各技术特征(包括实施例中具体描述的技术特征)之间都可以互相组合,从而构成新的技术方案。这些技术方案也包括在本发明的范围之内。
基于本发明人开发的一条新型罗丹明染料合成路线,本发明合成了一个具有结构多样性的罗丹明染料库。利用不同细菌模型筛选后发现,该化合物库中的化合物对革兰氏阳性菌(含耐药菌)和革兰氏阴性菌有杀菌效果,同时也发现该化合物库中的部分分子能够增强耐药菌对β-内酰胺类抗生素的敏感性。曾有文献报到,罗丹明修饰的抗菌肽或者罗丹明修饰的具有抗菌活性的精胺有一定抗菌活性。在这些文献中,作为对照化合物的罗丹明染料本身没有被发现有抗菌活性。所以,本发明是首次明确证实合理取代的罗丹明染料可以具有强杀菌、抑菌及抗菌增效活性。
一、术语和定义
本文中,烷基通常指碳原子数在10以内的烷基,即C1-C10烷基,例如C1-6烷基或C1-4烷基。本文所用的烷基可以是直链或直链烷基。典型的烷基包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基。本文中,烷基可被取代。当指明烷基可被取代时,取代基的数量可以是1、2、3或4个,取代基可包括但不限于桥环烷烃基(如金刚烷基)、羟基、烷氧基、任选取代的芳基、羧基、任选取代的芳烷基、卤素和硝基等。
本文中,烯基指直链或支链的C2-C10烯基,通常链中至少含有一个双键。烯基的碳链长度可以为2-6个碳原子。典型的烯基包括乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基等。本文中,烯基可被取代。当指明烯基可被取代时,取代基的数量可以是1、2、3或4个,取代基可包括但不限于羧基、卤素、羟基、烷氧基、硝基、任选取代的芳基和任选取代的以下基团:
本文中,烷氧基指被本文所述烷基取代的氧基,例如C1-C10烷氧基、C1-C6烷氧基或C1-C4烷氧基。烷氧基中的烷基可如前文所述被任意取代。
本文中,烷巯基指被本文所述烷基取代的巯基,即烷基-S-,如C1-C6烷基-S-。烷巯基中的烷基可如前文所述被任意取代。
本文中,卤素包括氟、氯、溴和碘。
本文中,芳基指单环、双环或多环芳族基团,例如,芳基可包括C6-C14芳基,或C6-C10芳基。典型芳基包括苯基、萘基、菲基、蒽基、茚基、薁基、茀基和二萘嵌苯基(苝基)。本文中,芳基可被取代。当指明芳基可被取代时,取代基的数量可以是1、2、3、4或5个,取代基可包括但不限于卤素、羟基、硝基、羧基、C1-C6烷氧基、C1-C6烷氧基羰基、任选取代的芳基重氮基、烷巯基、烷氧基、(CO)3Cr-、-SO3、-SO2Cl、任选取代的C1-C6烷基、C1-C6醛基、巯基、NRaRb、任选取代的芳基、PPh2、氰基、叔丁基二甲基硅基-O-(-OTBS)、桥环烷烃基或以下基团:
本文中,所用杂芳基指含有5-14个环原子,并且有6个,10个或14个π电子在环体系上共用的基团,通常,杂芳基所含环原子是碳原子和从氧、氮、硫中任选的1-3个杂原子。杂芳基的例子包括但不限于噻吩基、苯并[d]异噻唑-3-基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、色烯基、夹氧蒽基、、吡咯基、咪唑基、吡唑基、吡啶基(包括但不限于2-吡啶基、3-吡啶基和4-吡啶基)、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基、萘啶基、喹唑啉基、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌间二氮(杂)苯基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异恶唑基、呋咱基、吩恶嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、四氢化五员[c]吡唑-3-基、吡唑[1,5-a]嘧啶基、吡咯并吡啶基如吡咯[2,3-b]吡啶基、苯并异恶唑基如1,2-苯并异恶唑-3-基、苯并咪唑基、2-羟吲哚基、噻重氮基、1,3-苯并二氧戊环基和2-氧代苯并咪唑基。本文中,杂芳基可任选地被取代。当被取代时,杂芳基上的取代基数量可以是1、2、3或4个,可选自C1-C6烷基、NRaRb、卤素、羧基、C1-C6烷氧基、硝基、芳基取代的C1-C6烷基(如三苯甲基)、任选取代的联苯基-C1-C6烷基和羟基等。
本文中,除非另有说明,Ra和Rb各自独立选自:H、C1-C6烷基和C1-C6酰基。
本文中,碳环基包括饱和的或部分饱和的碳环基团。饱和的碳环基团包括环烷基和桥环烷烃基,如C3-8环烷基、二环烃基、三环烃基、四环烃基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。典型的桥环烷烃基如金刚烷基。部分饱和的碳环基团是可以是环烯基,如C3-8环烯基,例如环戊烯基、环庚烯基和环辛烯基。
本文中,杂环或杂环基指饱和或部分饱和的3-7元单环,或7-10元双环体系,或多环体系,它由碳原子和从O、N、S中任选1-4个杂原子组成,包括双环体系中上述定义的任意杂环与苯环的融合。饱和或部分饱和杂环基团的例子包括但不限于四氢呋喃基、四氢吡喃基、吡喃基,哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异色满基、色满基、吡唑烷基、吡唑啉基、tetronoyl、tetramoyl以及以下基团:
杂环基可任选地被1、2、3或4个选自以下的取代基取代:任选取代的C1-C6烷基、C1-C6环烷基、卤素、NRaRb、任选被1-3个C1-C6烷基取代的哌嗪基、羟基和羧基等。
除上述特别指出的取代基外,通常本文中,当被取代时,芳基、杂芳基、碳环基和杂环基可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代:卤素、羟基、羧基、氨基、硝基、氰基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、芳氧基、烷硫基、C1-6烷基、C6-10芳基、C3-8环烷基、C2-6链烯基、C2-6炔基、C6-10芳基(C2-6)链烯基、C6-10芳基(C2-6)炔基、饱和和不饱和的杂环基或杂芳基、亚甲基二氧基、C1-6卤代烷基、C6-10芳基(C1-6)烷基、C1-6羟烷基、脲基、巯基、叠氮基、羰基、二(C1-10烷基)氨基、烷磺酰基、氨磺酰基、二烷基氨磺酰基和烷基亚磺酰基等。其中取代基本身也可被任意取代。
本文中,当被取代时,烷基、烷氧基、烷硫基、链烯基、炔基、环烷基、可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代:卤素、羟基、羧基、氨基、硝基、氰基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、芳氧基、烷硫基、C1-6烷基、C6-10芳基、C3-8环烷基、C2-6链烯基、C2-6炔基、C6-10芳基(C2-6)链烯基、C6-10芳基(C2-6)炔基、饱和和不饱和的杂环基或杂芳基、亚甲基二氧基、C1-6卤代烷基、C6-10芳基(C1-6)烷基、C1-6羟烷基、脲基、巯基、叠氮基、羰基、二(C1-10烷基)氨基、烷磺酰基、氨磺酰基、二烷基氨磺酰基和烷基亚磺酰基等。其中取代基本身也可被任意取代。
在优选的实施方案中,当被取代时,烷基、烷氧基、烷硫基、链烯基、炔基、环烷基、羰基、碳环和杂环可被一个或多个(例如1、2、3或4个)选自以下基团的取代基取代:卤素、羟基、羧基、氨基、硝基、氰基、C1-6酰氨基、C1-6酰氧基、C1-6烷氧基、芳氧基、烷硫基、C1-6烷基、C6-10芳基、C3-8环烷基、C2-6链烯基、C2-6炔基、C6-10芳基(C2-6)链烯基、C6-10芳基(C2-6)炔基、饱和和不饱和的杂环基或杂芳基。
本文中,C1-C6酰基指C1-C5烷基-C(O)-,例如乙酰基。
除非另有说明,文中涉及的其它术语的含义为本领域惯常理解的含义。
二、化合物
本发明提供下式A的化合物:
式中,
X-为可构成盐的阴离子,包括但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -;
R1、R2、R3、R4各自独立选自H、卤素和C1-C6烷基;
R5、R6、R7、R8各自独立选自H和C1-C6烷基;
其中,R5和R7可与它们所连接的N形成任选取代的5或6元含氮杂环,和/或R6和R8可与它们所连接的N形成任选取代的5或6元含氮杂环;其中,所述5或6元含氮杂环任选地含有环氧原子;或R3与R7与它们各自所连接的原子一起形成6元含氮杂环,和/或R4与R8与它们各自所连接的原子一起形成6元含氮杂环;
其中,R1和R5可与它们所连接的原子形成任选取代的6元含氮杂环,同时R3和R7可与它们所连接的原子形成任选取代的6元含氮杂环,和/或R2和R6可与它们所连接的原子形成任选取代的6元含氮杂环,同时R4和R8可与它们所连接的原子形成任选取代的6元含氮杂环;
R9选自H,任选取代的C1-C6烷基,任选取代的芳基,任选取代的杂芳基,任选取代的杂环基,和任选取代的C2-C6烯基。
在某些实施方案中,上述被任选取代的基团的取代基如前文第一部分所定义,或为下文针对任一具体结构式中对应位置上的取代基。
在某些实施方案中,R1和R2各自独立为H。
在某些实施方案中,R3和R4各自独立为H或C1-C6烷基。
在某些实施方案中,R5、R6、R7、R8各自独立选自H和C1-C6烷基。
在某些实施方案中,R5和R7与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基),和/或R6和R8可与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基);其中,所述5或6元含氮杂环任选地含有环氧原子(如吗啉基)。
在某些实施方案中,R1和R2各自独立为H,R5和R6各自独立为H或C1-C6烷基;R3与R7与它们各自所连接的原子一起形成6元含氮杂环且R4与R8与它们各自所连接的原子一起形成6元含氮杂环。
在某些实施方案中,R9选自:C1-C6烷基,任选被金刚烷基或苯基取代,所述金刚烷基任选被1~3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代,所述苯基任选被1~3个选自羟基和C1-C6烷氧基的取代基取代;苯基,任选被1~3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代,其中,所述苯基重氮基或萘基重氮基任选被1~3个选自卤素和NRaRb的取代基取代;任选被硝基取代的1,3-苯并二氧戊环基。
在某些实施方案中,R1和R2各自独立为H或C1-C6烷基;R3和R4各自独立为H或C1-C6烷基;R9选自:C1-C6烷基,任选被金刚烷基或苯基取代,所述金刚烷基任选被1~3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代,所述苯基任选被1~3个选自羟基和C1-C6烷氧基的取代基取代;苯基,任选被1~3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代,其中,所述苯基重氮基或萘基重氮基任选被1~3个选自卤素和NRaRb的取代基取代;任选被硝基取代的1,3-苯并二氧戊环基。
在某些实施方案中,通式A中,R1和R2各自独立为H;R3和R4各自独立为H或C1-C6烷基;R5、R6、R7、R8各自独立选自H和C1-C6烷基,或R5和R7与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基),和/或R6和R8可与它们所连接的N形成任选取代的5或6元含氮杂环(如吡咯烷基或哌啶基);其中,所述5或6元含氮杂环任选地含有环氧原子(如吗啉基),或R3与R7与它们各自所连接的原子一起形成6元含氮杂环且R4与R8与它们各自所连接的原子一起形成6元含氮杂环;和R9选自:C1-C6烷基,任选被金刚烷基或苯基取代,所述金刚烷基任选被1~3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代,所述苯基任选被1~3个选自羟基和C1-C6烷氧基的取代基取代;苯基,任选被1~3个选自硝基、卤素、C1-C6烷基、苯基重氮基或萘基重氮基的取代基取代,其中,所述苯基重氮基或萘基重氮基任选被1~3个选自卤素和NRaRb的取代基取代;任选被硝基取代的1,3-苯并二氧戊环基。
在某些实施方案中,通式A的化合物不包括以下化合物:化合物BIb、BIf、BIg、BIIb、BIIe、BIIf、BIIIa、BIIIc、BIIIf、BIIIg、BIIIk、BVIa、BVIIIb、BIXa-BIXe、CIa-CIe、CIg、CIk、CIu和CXIIIb。
在某些实施方案中,通式A化合物的结构如下式BI所示:
式中,
R9选自任选取代的C1-C6烷基,任选取代的芳基和任选取代的杂芳基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的C1-C6烷基为任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,所述任选取代的杂芳基为任选地被1~3个选自C1-C6烷基、羟基、三苯基甲基、苯基取代的C1-C6烷基、卤素和羧基取代的杂芳基。优选地,所述杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基或吡咯基。在某些实施方案中,式BI中的R9选自任选地被金刚烷基取代的C1-C6烷基和任选地被1~3个选自卤素、硝基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,R9为金刚烷基取代的C1-C6烷基。
式BI的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,通式BI的化合物不包括化合物BIb、BIf和BIg。
在某些实施方案中,通式A化合物的结构如下式BII所示:
式中,
R9选自任选取代的C1-C6烷基,任选取代的芳基和任选取代的杂芳基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的C1-C6烷基为任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,所述任选取代的杂芳基为任选地被1~3个选自C1-C6烷基、羟基、三苯基甲基、苯基取代的C1-C6烷基、卤素和羧基取代的杂芳基。优选地,所述杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基或吡咯基。在某些实施方案中,式BII中的R9选自任选地被金刚烷基取代的C1-C6烷基和任选地被1~3个选自硝基和苯基重氮基的取代基取代的苯基。在某些实施方案中,R9为金刚烷基取代的C1-C6烷基。
式BII的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,通式BII的化合物不包括化合物BIIb、BIIe和BIIf。
在某些实施方案中,通式A化合物的结构如下式BIII所示:
式中,
R9选自任选取代的C1-C6烷基,任选取代的芳基和任选取代的杂芳基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的C1-C6烷基任选地被金刚烷基或羟基取代的C1-C6烷基。在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷基、C1-C6烷氧基羰基、苯基重氮基、-Cr(CO)3和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,所述任选取代的杂芳基为任选地被1~3个选自C1-C6烷基、羟基、三苯基甲基、苯基取代的C1-C6烷基、卤素和羧基取代的杂芳基。优选地,所述杂芳基为吡啶基、嘧啶基、吡嗪基、哒嗪基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基或吡咯基。在某些实施方案中,式BIII中的R9选自任选地被金刚烷基取代的C1-C6烷基和任选地被1~3个选自硝基和C1-C6烷氧基的取代基取代的苯基。在某些实施方案中,R9为金刚烷基取代的C1-C6烷基。式BIII的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,式BIII中的R9为任选地被1~3个C1-C6烷基取代的吡啶基。优选的,在某些实施方案中,R9为被1个C1-C6烷基取代的吡啶基,其取代基在N原子上。在这些实施方案中,式BIII化合物具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中,通式BIII的化合物不包括化合物BIIIa、BIIIc、BIIIf、BIIIg和BIIIk。
在某些实施方案中,通式A化合物的结构如下式BIV所示:
式中,
R9选自任选取代的芳基,任选取代的杂芳基,任选取代的杂环基,和任选取代的C2-C6烯基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的芳基,任选取代的杂芳基,任选取代的杂环基,和任选取代的C2-C6烯基的取代基如前文第一部分所述,或如下文式CI-CXIII对应的基团所述。
在某些实施方案中,通式BIV的化合物不包括化合物CIa-CIe、CIg、CIk、CIu和CXIIIb。
在某些实施方案中,通式A化合物的结构如下式BV所示:
式中,
R9选自任选取代的芳基和任选取代的C1-C6烷基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,式BV中,R9选自苯基和金刚烷基取代的C1-C6烷基。
式BV的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,通式A化合物的结构如下式BVI所示:
式中,
R9选自任选取代的芳基和任选取代的C1-C6烷基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,式BVI中R9选自金刚烷基取代的C1-C6烷基。
式BVI的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,通式BVI的化合物不包括化合物BVIa。
在某些实施方案中,通式A化合物的结构如下式BVII所示:
式中,
R9选自任选取代的芳基和任选取代的C1-C6烷基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,式BVII中R9选自苯基和金刚烷基取代的C1-C6烷基。
式BVII的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,通式A化合物的结构如下式BVIII所示:
式中,
R5和R6各自独立选自H和C1-C6烷基;
R9选自任选取代的芳基和任选取代的C1-C6烷基;和
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的C1-C6烷基任选地被金刚烷基取代的C1-C6烷基。在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、苯基重氮基和C1-C6烷巯基的取代基取代的苯基。在某些实施方案中,式BVIII中R9选自金刚烷基取代的C1-C6烷基。
式BVIII的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,通式BVIII化合物不包括化合物BVIIIb。
在某些实施方案中,通式A化合物的结构如下式BIX所示:
式中,
R9选自任选取代的芳基;和
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根和NO3 -。
在某些实施方案中,所述任选取代的芳基为任选地被1~3个选自C1-C6烷基、卤素、羟基、硝基、羧基、C1-C6烷氧基羰基、-SO3或-SO2Cl取代的苯基。
在某些实施方案中,式BIX中,R9为苯基。在这些实施方案中,式BIX的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,式BIX中,R9为羧基、C1-C6烷氧基羰基、-SO3或-SO2Cl取代的苯基。在这些实施方案中,式IX的化合物具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中,通式BIX化合物不包括化合物BIXa-BIXe。
在某些实施方案中,通式A化合物的结构如下式CI到CXIII中任一所示:
式中,
R10、R11、R12、R13和R14各自独立选自H,硝基,任选取代的C1-C6烷基,C1-C6烷氧基,羧基,卤素,羟基,巯基,C1-C6烷巯基,NRaRb,任选取代的芳基,二苯磷基,和任选取代的芳基重氮基和C1-C6酰基,其中,Ra和Rb独立选自H、C1-C6烷基和C1-C6酰基;或者R10、R11、R12、R13和R14中的两个或两个以上可与它们所连接的苯基一起形成任选取代的萘基、蒽基、喹啉基、二萘嵌苯基(苝基)、苯并咪唑基或1,3-苯并二氧戊环基;
Y选自O、S、或NR19;
R16、R17、R18、R20、R21、R22、R24和R25各自独立选自H和C1-C6烷基;或者,Y与R25及所述含Y的环一同形成任选取代的下式结构:
R19选自H和任选取代的C1-C6烷基,如苯基取代的C1-C6烷基,如三苯甲基或苄基;
R27、R28各自独立选自H和C1-C6烷基;
R30、R31、R32和R33各自独立选自H,卤素和C1-C6烷基;
R34、R35、R36和R37各自独立选自H,卤素和C1-C6烷基;
R38、R39和R40各自独立选自H,卤素和C1-C6烷基;
R41、R42和R43各自独立选自H,卤素和C1-C6烷基;
R44、R45和R46各自独立选自H,卤素,羧基和C1-C6烷基;
R47、R48和R49各自独立选自H,卤素和C1-C6烷基;
R50、R51和R52各自独立选自H,羧基,任选取代的芳基,或任选取代的以下基团:
或者,R50、R51和R52与它们所连接的C原子一起形成任选取代的以下基团:
其中,取代基选自C1-C6烷基、NRaRb、卤素、羟基、C1-C6烷氧基、和C1-C6烷基取代的哌嗪基;其中,Ra和Rb各自独立选自H和C1-C6烷基;
R53、R54和R55各自独立选自H,任选取代的C1-C6烷基,羧基;或者R53、R54和R55中的任意两个与它们所连接的C一起形成任选取代的C3-C8环烷基或任选取代的以下基团:
其中,取代基选自羟基,羧基,任选取代的C1-C6烷基,NRaRb,C1-C6烷氧基,C2-C6烯基,任选被羟基、C1-C6烷氧基或C1-C6烷基取代的金刚烷基,任选取代的芳烷基(如任选被羟基、C1-C6烷氧基、NRaRb、硝基或氰基取代的苯基-C1-C6烷基);其中,Ra和Rb各自独立选自H和C1-C6烷基;
X-可选自但不限于F-、Cl-、Br-、I-、OAc-、HSO4 -、H2PO4 -、ClO4 -、F3CCOO-、CH3SO3 -、CF3SO3 -、BF4 -、PF6 -、柠檬酸根或NO3 -。
在某些实施方案中,式CI中,R10和R14各自独立选自:H、C1-C6酰基、卤素、羟基、巯基、C1-C6烷巯基、氨基、任选取代的芳基、二苯磷基、C1-C6烷氧基和任选取代的芳基重氮基;R11和R13各自独立选自:H、C1-C6烷氧基和卤素;R12选自H、任选取代的芳基、和任选取代的芳基重氮基。在某些实施方案中,式CI中,R10、R11、R12、R13和R14中的两个或两个以上可与它们所连接的苯基一起形成任选取代的蒽基、喹啉基、二萘嵌苯基(苝基)和苯并咪唑基。在这些实施方案中,式CI的化合物可用于抑制耐药菌,例如耐甲氧西林金黄色葡萄球菌和鲍曼不动杆菌敏感株。
在某些实施方案中,式CI中,R10和R14各自独立选自:H、任选被羟基取代的C1-C6烷基、NRaRb和任选取代的苯基(如任选被羟基或OTBS取代的苯基);R11-R13各自为H;其中,Ra和Rb独立选自H和C1-C6酰基,优选NRaRb为-NH(C1-C6酰基)。在这些实施方案中,式CI的化合物具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中,式CII中,Y选自O、S或N;R16选自H或C1-C6烷基;R17选自H或C1-C6烷基;R18选自H或C1-C6烷基。在某些实施方案中,R16选自H或C1-C6烷基;R17选自H;R18选自H或C1-C6烷基。
在某些实施方案中,式CIII中,Y选自O、S或NR19;R19选自C1-C6烷基;R20、R21和R22各自为H。
在某些实施方案中,式CIII中,Y选自NR19;R19选自C1-C6烷基;R20、R21和R22各自为H。这类化合物可具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中,式CIV中,Y选自S或NR19;R19选自三苯基甲基;R24选自H或C1-C6烷基;R25选自H。
在某些实施方式中,式CV中,Y选自NR19;R19选自苯基取代的C1-C6烷基;R27和R28各自独立为H。
在某些实施方案中,式CVI中,R30-R33各自独立为H。
在某些实施方案中,式CVII中,R34和R37各自独立为C1-C6烷基或卤素;R35和R36各自独立为H。
在某些实施方案中,式CVIII中,R38选自卤素,R39为H,R40为C1-C6烷基。
在某些实施方案中,式CIX中,R41和R42各自独立为H,R43选自卤素。
在某些实施方案中,式CX中,R44选自H或羧基;R45选自H或卤素;R46选自H。
在某些实施方案中,式CXI中,R47选自H、卤素和C1-C6烷基;R48和R49各自独立为H。在某些实施方案中,R47选自H、F和C1-C6烷基;R48和R49各自独立为H。
在某些实施方案中,式CXI中,R47选自卤素和C1-C6烷基;R48和R49各自独立为H。这类化合物可具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中,式CXII中,R50为H,R51和R52中,一个为H,另一个选自任选被1~3个选自C1-C6烷基、卤素、羟基、C1-C6烷氧基的取代基取代的苯基或以下基团:
或者,R50、R51和R52与它们所连接的C原子一起形成任选被1~3个选自C1-C6烷基、NRaRb、卤素、羟基、C1-C6烷氧基、和C1-C6烷基取代的哌嗪基的取代基取代的以下基团:
在某些实施方案中,式CXII中,R50为H,R51和R52中,一个为H,另一个选自羧基或苯基:或R50、R51和R52与它们所连接的C原子一起形成任选被1~3个选自C1-C6烷基、卤素和C1-C6烷基取代的哌嗪基的取代基取代的以下基团:
这些化合物可具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
在某些实施方案中,式CXIII中,R53、R54和R55都为H,或其中任意两个为H,另一个选自:羧基或C1-C6烷基,其中该C1-C6烷基任选被羟基,羧基,任选被1~3个选自羟基、C1-C6烷氧基和C1-C6烷基的取代基取代的金刚烷基,任选被1~3个选自羟基、氰基、NRaRb和C1-C6烷氧基的取代基取代的苯基取代;或者R53、R54和R55中的一个为H,余下两个与它们所连接的C一起形成任选被1~4个选自羧基、C1-C6烷基和C2-C6烯基的取代基取代的C3-C8环烷基或任选被1~3个选自羧基和C1-C6烷基的取代基取代的以下基团:
在某些实施方案中,式CXIII中,R53、R54和R55都为H,或其中任意两个为H,另一个选自:羧基或C1-C6烷基,其中该C1-C6烷基任选被选自羧基和任选被1~3个选自羟基、氰基和C1-C6烷氧基的取代基取代的苯基取代;或者R53、R54和R55中一个为H,余下两个与它们所连接的C一起形成任选被1~4个选自羧基和C1-C6烷基的取代基取代的C3-C8环烷基或任选被羧基取代的以下基团:
这些化合物可具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
尤其是,在本发明的化合物中,那些R9为被1~3个选自羟基、C1-C6烷氧基和氰基的取代基取代的苯基取代的C1-C6烷基的化合物特别具有抗菌增效作用,可与增强其它抗菌化合物的抗菌效果,例如,可增强针对耐甲氧西林金黄色葡萄球菌的抗菌药的抗菌活性。
优选地,本文通式A化合物(包括本文所述的各通式的化合物)为具有抗菌活性和/或抗菌增效活性的化合物,尤其优选表1中MIC值小于等于16μg/ml和/或FICI值小于等于1、优选小于等于0.5的那些化合物。
本文的化合物可以作为立体异构体,包括旋光异构体存在。本文包括所有立体异构体和这样的立体异构体的外消旋混合物,以及可以根据本领域技术人员众所周知的方法分离出来的单独的对映体。
在某些实施方案中,本发明各通式的具体化合物可选自以下化合物:
通式BI:
通式BII:
通式BIII:
通式BV:
通式BVI:
通式BVII:
通式BVIII:
通式BVIX:
通式CI:
通式CII:
通式CIII:
通式CIV:
通式CV:
通式CVI:
通式CVII:
通式CVIII:
通式CIX:
通式CX:
通式CXI:
通式CXII:
通式CXIII:
本文还包括上述化合物的前药。本文前药的实施例包括含有羧酸的化合物的简单酯(例如依据本领域已知方法通过与C1-4醇缩合而获得的酯);含有羟基的化合物的酯(例如依据本领域已知方法通过与C1-4羧酸、C3-6二酸或其酸酐例如琥珀酸酐和富马酸酐缩合而获得的酯);含有氨基的化合物的亚胺(例如依据本领域已知方法通过与C1-4醛或酮缩合而获得的亚胺);含有氨基的化合物的氨基甲酸酯,例如Leu等人(J.Med.Chem.1999,42:3623-3628)和Greenwald等人(J.Med.Chem.1999,42:3657-3667)描述的那些酯;含有醇的化合物的醛缩醇或酮缩醇(例如依据本领域已知方法通过与氯甲基甲基醚或氯甲基乙基醚缩合而获得的那些缩醇)。
三、化合物的制备
可采用以下通用制备流程一和二来制备本发明通式A化合物。
通用制备流程一:
将取代的3-氨基苯酚(2eq)与取代醛基化合物(1eq)加入装有30毫升甲磺酸的圆底烧瓶中,加热至回流反应8小时,TLC点板监测反应完全后将反应液倒入冰水中,有固体析出。布氏漏斗过滤,收集固体,用50毫升二氯甲烷溶解在圆底烧瓶中,加入DDQ(1eq)的二氯甲烷溶液,常温搅拌反应半个小时。反应液用水和二氯甲烷体系萃取三次,取有机相并用无水硫酸镁干燥,过滤后收集滤液后旋干,通过柱层析(洗脱剂:二氯甲烷:甲醇=25:1,v/v)分离得到为紫红色固体产物,产率10%-40%。
通用制备流程二:
将制备好的二溴苯甲醚化合物(1eq)和50毫升无水四氢呋喃置于100毫升的圆底烧瓶中,氩气保护。圆底烧瓶置于杜瓦瓶中,倒入乙酸乙酯没至瓶颈,用液氮降温至零下78摄氏度,用针管加入正丁基锂试剂(2eq),15分钟后加入羰基化合物的无水四氢呋喃溶液,反应一个小时。往反应液中加入1毫升碳酸氢钠溶液,用水和二氯甲烷体系萃取三次,取有机相并用无水硫酸镁干燥,过滤后收集滤液后旋干,通过柱层析(洗脱剂:二氯甲烷:甲醇=25:1,v/v)分离得到为紫红色固体产物,产率30%-95%。
上述两个通用制备流程中,R1-R9及X-如前文任一实施方案所定义。
在某些实施方案中,本文提供一种制备本文通式A化合物的方法,所述方法包括使下式所示的二溴苯甲醚和羰基化合物在有机溶剂和烷基锂试剂的存在下进行反应,从而制备得到式A化合物:
式中,R1-R9如前文任一实施方案所定义;LG为离去基团,可选自卤素如Cl或Br,氰基,C1-C6烷氧基和C1-C6烷基-COO-等。
适用于本文所述方法的有机溶剂可以是醚类溶剂,如四氢呋喃、乙醚、甲基叔丁基醚和1,4-二氧六环。有机溶剂还可以是正己烷等。适用于本文所述方法的烷基锂试剂通常为C1-C6烷基锂试剂,包括但不限于正丁基锂、叔丁基锂和仲丁基锂等。上述反应可在零下78℃到0℃之间进行。通常,二溴苯甲醚化合物与烷基锂试剂的摩尔比在1:2-3之间。
反应时间可根据实际反应条件确定。反应结束后,可采用常规的方法进行分离纯化。例如,可向反应液中加入氢氧化钠溶液,之后用水和二氯甲烷体系萃取,有机相用无水硫酸镁干燥。柱层析的洗脱剂可以是二氯甲烷:甲醇。
在某些实施方案中,将制备好的二溴苯甲醚化合物和适量有机溶剂置于圆底烧瓶中,惰性气体(如氩气)保护。降温至零下78摄氏度后加入烷基锂试剂,约10到20分钟后加入羰基化合物的有机溶剂溶液,反应一段时间,即可制备得到通式A化合物。
四、组合物
本文所公开的化合物可被制成组合物的形式,尤其是药物组合物的形式。药物组合物可含有本文所公开的一种或多种化合物和药学上可接受的载体。通常,药物组合物中,本文化合物的含量为治疗或预防有效量。有效量指某成分的用量足以产生所期望的反应。具体的有效量取决于多种因素,如待治疗的具体病症、患者的身体条件(如患者体重、年龄或性别)、治疗持续时间、同时进行的其它疗法以及所用的具体配方等。有效量也指在该用量下,化合物的毒性或负面效果不及于其所带来的正面疗效。
本文中,药学上可接受的载体通常是安全、无毒的,且广义上可包括制药产业中用于制备药物组合物的任何已知物质,如填充剂、稀释剂、凝结剂、黏合剂、润滑剂、助流剂、稳定剂、着色剂、润湿剂、崩解剂等。在选择适用于投递本文化合物的载体时,主要需考虑该药物组合物的给药方式,本领域技术人员熟知此项技术。因此,可将本发明的药物组合物制备成不同的剂型,例如适合口服给药的片剂、胶囊等,适合肠外给药的注射剂,以及外用制剂如油剂、霜剂、乳液剂和药膏等。
可根据已知的药学程序来制备上述药物组合物,譬如《雷明顿制药科学》(Remington’s Pharmaceutical Sciences)(第17版,Alfonoso R.Gennaro编,麦克出版公司(Mack Publishing Company),伊斯顿,宾夕法尼亚(1985))一书中有详细的记载。
例如,当将化合物制备成口服片剂时,要求浓度为40%-80%(w/w),每片可含0.5-2g的本发明化合物,可以淀粉、碳酸镁、二氧化硅等为辅料。当将化合物制备成注射剂时,成人的日剂量可为1~2g/日,儿童可为20~40mg/kg/日,以例如10%葡萄糖溶液为溶剂,稀释后缓慢注射。当将化合物制备成外用制剂比如药膏时,可采用1%-5%的浓度,可以聚乙二醇400和聚乙二醇3350等为辅料。
本文化合物具有抗菌增效的作用。因此,在某些实施方案中,本文的药物组合物中除含有一种或多种本发明化合物以外,还可含有一种或多种已知的抗菌药物,如下文所述的一种或多种已知的抗菌药物。
在某些实施方案中,本发明的组合物含有化合物CXIIIt和CXIIIt2。在某些实施方案中,该组合物是溶液。
五、方法和应用
本文的化合物可用于抗菌,尤其是与人类健康相关的各类革兰氏阳性菌和革兰氏阴性菌,包括但不限于杀菌、抑菌。本文的化合物还可用于抗菌增效。本文中,“抗菌增效”指本文的化合物能增强已知抗菌药的抗菌活性。尤其是,如前文所述,本发明的某些化合物特别可用于抗菌增效。在某些实施方案中,本文提供罗丹明染料在抑制或杀灭革兰氏阳性菌和革兰氏阴性菌中的应用,或在增强已知抗菌药的抗菌活性中的应用。
目前,世界范围内广泛传播和扩散的“超级细菌”主要:ESKAPE,即万古霉素耐药粪肠球菌(Enterococcus faecium)、甲氧西林耐药金黄色葡萄球菌(Staphylococcusaureus)、碳青霉烯耐药肺炎克雷伯菌(Klebsiella pneumoniae)、泛耐药鲍曼不动杆菌(Acinetobacter baumanii)、多药耐药铜绿假单胞菌(Pseudomonas aeruginosa)、以及多药耐药肠杆菌(Enterobacter species),严重威胁着人类的生命健康。
金黄色葡萄球菌可引起广泛的人类感染。最常见的是皮肤和软组织感染;在这些部位的感染表现为毛囊炎、疖、痈、疮、乳腺炎、伤口感染、金黄色葡萄球菌烫伤样皮肤综合症。更严重的感染,包括菌血症、肺炎、心内膜炎、骨关节感染和中毒性休克综合征。金黄色葡萄球菌也可导致食物中毒的爆发。金黄色葡萄球菌的多样性也延伸到其宿主范围,包括家畜、马、山羊、绵羊、牛、兔、猪和家禽。各种感染已在这些物种中报道,但与人类经济最相关的是奶牛和其他反刍动物的乳腺炎感染,养殖兔子的致死性全身感染,以及家禽的禽掌感染(溃疡性掌皮炎)。耐甲氧西林金黄色葡萄球菌(MRSA)是目前最常见的社区和医院获得性感染病原菌之一。MRSA感染导致日益增加的发病率、死亡率,恶性侵染、多重耐药性和医院感染的爆发,成为主要的公共健康问题之一。当前临床上用于MRSA治疗的抗生素主要是万古霉素、替考拉宁、利奈唑胺等。然而,MRSA可以获得抗多种替代抗生素耐药性,其中包括万古霉素,万古霉素被认为是一个严重的MRSA感染的最后一道防线的,同样对于相对较新的药物如利奈唑胺和达托霉素也出现了抗药性。为了保证有效的治疗,开发新型的抗MRSA的抗生素已经成为了一个迫切问题。
肠球菌作为感染性心内膜炎的致病菌为人们所知,目前已成为引起院内感染的主要致病菌之一,近来因其多重耐药特性而引起更多的关注。肠球菌引起的常见感染有:泌尿系统感染、菌血症、感染性心内膜炎、腹腔感染、胆道感染以及伤口感染。肠球菌还可以引起新生儿脑膜炎,成人中枢神经系统的感染(特别是有中枢神经手术史及鞘内化疗的患者);肠球菌还可引起肝脏移植术后肝脏及胆道的感染。较少见的感染有骨髓炎和下呼吸道感染。肠球菌属共有17个种,临床上多数的感染是由于粪肠球菌和屎肠球菌引起,其中80%的感染是由粪肠球菌引起,但屎肠球菌更易出现多重耐药特别是对万古霉素的耐药,其引起的感染比例在不断上升。肠球菌对于传统的抗生素的耐药性正在上升,并且随着耐万古霉素肠球菌的快速播散使得肠球菌感染治疗极为困难。为了保证有效的治疗,开发新型的抗VRE的抗生素已经成为了一个迫切问题。
肺炎链球菌是社区获得性感染的主要病原菌之一。同时也是化脓性脑膜炎、胸膜炎、腹膜炎以及中耳炎、鼻窦炎等等的常见致病菌。临床治疗中的主要难题集中在耐药菌株的增加。因此开发新型的抗肺炎链球菌的抗生素已经成为了一个迫切问题。表皮葡萄球菌(表葡菌)是人体皮肤和黏膜上定居的正常菌群之一,通常情况下致病力很低。近几年来,随着留置静脉导管等侵袭性操作的增多,表葡菌已成为医院感染的重要致病菌。同时,目前,临床分离的表葡菌耐药现象非常严重。因此发展新的抗菌药物已经成为了一个迫切问题。
鲍曼不动杆菌是一种广泛存在于医院的机会致病菌,占医院革兰氏阴性菌感染的2-10%,死亡率高达35-100%。在世界范围内的重症监护病房中,感染高达20%。由于鲍曼不动杆菌对目前临床应用的绝大多数抗生素具有耐药性,因而也被称之为“甲氧西林耐药金黄色葡萄球菌(MRSA)金的革兰阴性菌。2012年,我国将鲍曼不动杆菌列为目前最重要的“超级细菌”。2013年,美国将其列为最为严重的超级细菌之一。因此开发新型的抗鲍曼不动杆菌的抗生素已经成为了一个迫切问题。
肺炎克雷伯菌是革兰阴性杆菌属,是条件致病菌之一,常寄生于人体呼吸道和肠道,当机体免疫力降低时,易引起下呼吸道及尿路感染,是下呼吸道及尿路感染的重要病原。近年来,随着广谱抗生索的广泛使用,肺炎克雷伯菌的耐药性也逐年升高,给临床的治疗带来了困难。因此开发新型的抗肺炎克雷伯菌的抗生素已经成为了一个迫切问题。
本文化合物对以上各类菌有良好的抗菌、杀菌及增效活性,因此可以用于以上临床易感染菌及临床耐药菌感染的有效治疗。具体而言,这类菌包括但不限于:金黄色葡萄球菌,如甲氧西林耐药金黄色葡萄球菌;万古霉素耐药粪肠球菌;碳青霉烯耐药肺炎克雷伯菌;泛耐药鲍曼不动杆菌;多药耐药铜绿假单胞菌;多药耐药肠杆菌;抗万古霉素屎肠球菌;肺炎链球菌;甲氧西林敏感表皮葡萄球菌;化脓性链球菌;肺炎克雷伯菌(ESBL+);肺炎克雷伯菌(ESBL-);抗碳青霉烯肺炎克雷伯菌;大肠埃细菌(ESBL+);大肠埃细菌(ESBL-);和痢疾桿菌。本文化合物或药物组合物可用于治疗由这些菌导致的各种疾病和/或症状。本文的化合物可用于已知各种抗菌化合物的协同增效作用,这些已知抗菌化合物包括但不限于β内酰胺类抗生素,如头孢克洛、头孢吡肟、青霉素钠、氨苄西林、舒巴坦和苯唑西林;喹诺酮类,如左氧氟沙星;氨基糖苷类,如阿米卡星和庆大霉素;和糖肽类,如万古霉素等。尤其优选的是,本文化合物对β内酰胺类抗生素具有协同增效作用。
因此,本文也提供本文前文各实施方案所述的通式A化合物在制备抗菌药或制备用于增加已知抗菌化合物的抗菌效果的药物中的用途。本文还提供一种抗菌方法,所述方法包括给予需要的对象抗菌有效量的本文所述的一种或多种化合物,或其药物组合物,或含有本文所述的一种或多种化合物以及一种或多种已知抗菌化合物的药物组合物。给予的方法可以是本领域常规的方法,包括但不限于口服、注射或其它合适的给药方式。
下列实施例是举例说明,而不是限制本发明的方法和制剂。实施例中所采用的方法和材料,除非另有说明,否则均为本领域常规的方法和材料。其他对于本领域技术人员来说是显而易见的,和在临床治疗中通常会遇到的对各种条件和参数的适当修改和改进,都在本发明的精神和范围内。
制备例
实施例1:BIa的制备
利用通用制备流程一制备,化合物为紫红色固体,产率33%。
1H NMR(400MHz,CDCl3):δ8.08(d,J=8.3Hz,2H),7.07(dd,J=8.3Hz,1.2Hz,2H),6.65(d,J=1.2Hz,2H),2.99(s,3H).13C NMR(101MHz,CDCl3):δ157.3,155.4,130.1,114.0,113.87,95.0,15.0.ESI-HRMS calculated for C14H13N2O[M]+225.1023,found 225.1025。
实施例2:BIc的制备
利用通用制备流程一制备,化合物为紫红色固体,产率24%。
1H NMR(400MHz,CDCl3):δ7.77(d,J=7.8Hz,1H),7.54(t,J=7.0Hz,1H),7.45(t,J=7.2Hz,1H),7.21(d,J=7.8Hz,1H),7.01(d,J=9.1Hz,2H),6.92(d,J=8.9Hz,2H),6.80(s,2H);13C NMR(101MHz,CDCl3)δ160.1,157.8,157.5,134.6,134.2,133.8,131.6,130.3,128.5,123.0,114.9,113.0,96.1;ESI-MS(m/z):[M]+calcd.for C19H14BrN2O,365.0285;found 365.0283。
实施例3:BId的制备
利用通用制备流程一制备,化合物为紫红色固体,产率27%。
1H NMR(400MHz,CD3OD):δ7.45(t,J=7.2Hz,1H),7.33(d,J=9.5Hz,2H),7.21(dd,J=7.2Hz,1.4Hz,1H),7.17-7.15(m,2H),7.02(dd,J=9.6Hz,1.9Hz,2H),6.91(d,J=2.1Hz,2H).13C NMR(101MHz,CDCl3)δ158.0,155.4,155.1,133.5,132.6,131.2,131.1,130.8,130.6,128.4,114.1,113.3,96.1.ESI-MS(m/z):[M]+calcd.for C19H15N2O2,303.1129;found 303.1130。
实施例4:BIe的制备
利用通用制备流程一制备,化合物为紫红色固体,产率25%。
1H NMR(400MHz,CDCl3):δ8.40(d,J=8.2Hz,1H),8.02(t,J=7.5Hz,1H),7.81(t,J=7.5Hz,1H),7.46(d,J=7.5Hz,1H),7.03(d,J=9.4Hz,2H),6.96(dd,J=9.4Hz,1.7Hz,2H),6.71(d,J=1.8Hz,2H);13C NMR(101MHz,CDCl3)δ158.0,156.7,155.2,148.8,135.7,131.2,131.0,130.7,129.3,128.4,127.8,125.2,114.9,112.2,96.1.ESI-HRMS(m/z):[M]+calcd.for C19H14N3O3,332.1030;found 332.1031。
实施例5:BIh的制备
利用通用制备流程一制备,化合物为紫红色固体,产率23%。
1H NMR(400MHz,CDCl3):δ8.17(d,J=8.2Hz,2H),8.02(dd,J=8.1Hz,1.8Hz,2H),7.61-7.53(m,5H),7.43(d,J=9.4Hz,2H),6.93(dd,J=9.5Hz,2.2Hz,2H),6.88(d,J=2.1Hz,2H);13C NMR(101MHz,CDCl3)δ158.1,156.3,155.7,153.6,152.6,134.2,132.0,131.9,130.6,129.4,123.4,123.3,114.5,113.3,96.9.ESI-HRMS(m/z):[M]+calcd.forC25H19N4O,391.1554;found 391.1555。
实施例6:BIi的制备
利用通用制备流程一制备,化合物为紫红色固体,产率27%。
1H NMR(400MHz,CDCl3):δ8.81(d,J=8.0Hz,1H),8.67(s,1H),7.89(d,J=7.7Hz,1H),7.61(m,1H),7.22(d,J=9.1Hz,2H),6.99(dd,J=9.5Hz,1.9Hz,2H),6.77(d,J=2.0Hz,2H);13C NMR(101MHz,CDCl3):δ158.2,156.8,154.1,152.6,149.9,137.5,132.5,128.1,125.1,114.0,112.5,97.3.ESI-MS(m/z):[M]+calcd.for C18H14N3O,288.1132;found288.1134。
实施例7:BIj的制备
利用通用制备流程一制备,化合物为紫红色固体,产率24%。
1H NMR(400MHz,CDCl3):δ7.81(d,J=3.9Hz,1H),7.70(d,J=9.1Hz,2H),7.33(s,2H),7.02(d,J=9.1Hz,2H),6.82(s,2H);13C NMR(101MHz,CDCl3)δ158.0,156.5,150.7,132.8,132.5,131.8,130.1,129.4,114.6,114.0,96.9.ESI-MS(m/z):[M]+calcd.forC17H13N2OS,293.0744;found 293.0745。
实施例8:BIk的制备
利用通用制备流程一制备,化合物为紫红色固体,产率35%。
1H NMR(400MHz,CDCl3):δ7.84(d,J=9.4Hz,2H),6.91(dd,J=9.5Hz,2H),6.59(d,J=1.8Hz,2H),3.05(s,2H),1.81(s,3H),1.51-1.41(m,12H).13C NMR(101MHz,CDCl3):δ158.1,157.3,155.6,131.3,114.6,113.8,96.1,44.2,40.8,38.2,36.3,28.9.EI-HRMS(m/z):[M]+calcd.for C24H27N2O,359.2118;found 359.2119。
实施例9:BIl的制备
利用通用制备流程一制备,化合物为紫红色固体,产率26%。
1H NMR(400MHz,CDCl3):δ7.60-7.53(m,2H),7.34(t,J=7.0Hz,1H),7.14-7.12(m,3H),6.86(d,J=9.4Hz,2H),6.80(s,2H),2.84(t,J=7.6Hz,2H),1.49-1.43(m,2H),1.26-1.20(m,2H),0.80(t,J=7.3Hz,3H);13C NMR(101MHz,CDCl3):δ158.6,156.1,155.2,136.9,131.7,131.5,130.4,129.5,128.5,125.7,115.1,114.6,96.2,33.6,30.0,21.9,13.9;ESI-MS(m/z):[M]+calcd.for C23H23N2OS,375.1526;found 375.1525。
实施例10:BIIa的制备
利用通用制备流程一制备,化合物为紫红色固体,产率22%。
1H NMR(400MHz,CDCl3):δ6.99(s,2H),6.89(s,2H),3.52(q,J=7.1Hz,4H),2.98(s,3H),2.10(s,6H),1.33(t,J=7.0Hz,6H).13C NMR(101MHz,CDCl3):δ158.5,156.1,134.2,116.4,113.7,95.6,46.1,15.1,14.6,13.2;ESI-MS(m/z):[M]+calcd.for C20H25N2O,309.1962;found 309.1963。
实施例11:BIIc的制备
利用通用制备流程一制备,化合物为紫红色固体,产率19%。
1H NMR(400MHz,CDCl3):δ7.93(d,J=8.0Hz,1H),7.62(t,J=7.0Hz,1H),7.53(t,J=7.2Hz,1H),7.23(d,J=8.0Hz,1H),δ6.97(s,2H),6.83(s,2H),3.48(q,J=7.2Hz,4H),2.09(s,6H),1.32(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ159.0,156.8,156.5,134.7,134.2,132.8,131.6,130.8,128.1,123.2,114.7,113.3,96.8,46.5,14.2,12.9;ESI-MS(m/z):[M]+calcd.for C25H26FN2O,389.2024;found 389.2023。
实施例12:BIId的制备
利用通用制备流程一制备,化合物为紫红色固体,产率23%。
1H NMR(400MHz,CDCl3):δ8.32(d,J=7.4Hz,1H),8.11(t,J=7.5Hz,1H),7.88(t,J=7.5Hz,1H),7.41(d,J=7.5Hz,1H),δ6.92(s,2H),6.85(s,2H),3.63(q,J=7.0Hz,4H),2.02(s,6H),1.25(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ157.7,155.3,154.6,147.3,136.1,133.9,131.6,130.4,129.8,128.2,127.3,125.1,114.9,112.1,96.8,46.2,13.5,12.9.ESI-HRMS(m/z):[M]+calcd.for C25H26N3O3,416.1969;found 416.1969。
实施例13:BIIg的制备
利用通用制备流程一制备,化合物为紫红色固体,产率33%。
1H NMR(400MHz,CDCl3):δ8.21(d,J=8.3Hz,2H),8.02(dd,J=8.1Hz,1.8Hz,2H),7.62-7.56(m,5H),δ6.88(s,2H),6.73(s,2H),3.65(q,J=7.1Hz,4H),2.07(s,6H),1.33(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ158.7,156.7,155.8,153.4,152.2,135.2,133.0,131.9,130.6,129.8,124.4,123.1,115.5,113.3,96.9,46.2,13.1,12.8.ESI-HRMS(m/z):[M]+calcd.for C31H31N4O,475.2493;found 475.2495。
实施例14:BIIh的制备
利用通用制备流程一制备,化合物为紫红色固体,产率27%。
1H NMR(400MHz,CDCl3):δ8.62(d,J=7.0Hz,2H),7.85(d,J=7.0Hz,2H),6.97(s,2H),6.87(s,2H),3.64(q,J=7.0Hz,4H),2.03(s,6H),1.31(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3):δ158.2,156.8,154.1,152.6,149.9,138.5,132.5,128.9,124.9,115.8,114.5,97.1,46.4,13.6,12.8.ESI-MS(m/z):[M]+calcd.for C24H26N3O,372.2071;found372.2072。
实施例15:BIIi的制备
利用通用制备流程一制备,化合物为紫红色固体,产率25%。
1H NMR(400MHz,CDCl3):δ7.77(d,J=3.9Hz,1H),7.53(m,1H),7.33(d,J=3.9Hz,1H),6.98(s,2H),6.80(s,2H),3.64(q,J=6.8Hz,4H),2.04(s,6H),1.35(t,J=6.8Hz,6H);13C NMR(101MHz,CDCl3)δ157.8,155.3,152.1,134.2,132.1,131.4,130.2,128.8,114.3,113.9,95.6,46.3,13.4,12.8.ESI-MS(m/z):[M]+calcd.for C23H25N2OS,377.1683;found377.1684。
实施例16:BIIj的制备
利用通用制备流程一制备,化合物为紫红色固体,产率31%。
1H NMR(400MHz,CDCl3):δ6.86(s,2H),6.67(s,2H),3.52(q,J=7.0Hz,4H),3.06(s,2H),2.05(s,6H),1.81(s,3H),1.51-1.41(m,12H),1.26(t,J=7.1Hz,6H).13CNMR(101MHz,CDCl3):δ157.8,157.0,155.3,131.9,114.6,113.0,97.6,45.5,43.4,42.8,37.1,36.1,28.6,13.6,12.6.EI-HRMS(m/z):[M]+calcd.for C30H39N2O,443.3062;found443.3061。
实施例17:BIIk的制备
利用通用制备流程一制备,化合物为紫红色固体,产率29%。
1H NMR(400MHz,CDCl3):δ7.58-7.50(m,2H),7.36(t,J=7.1Hz,1H),7.01-6.99(m,3H),6.83(d,J=9.6Hz,2H),3.60(q,J=7.3Hz,4H),2.82(t,J=7.4Hz,2H),2.02(s,6H),1.49-1.43(m,2H),1.27(t,J=7.2Hz,6H),1.28-1.21(m,2H),0.81(t,J=7.1Hz,3H);13CNMR(101MHz,CDCl3):δ158.4,156.1,155.6,137.7,133.8,131.6,130.1,129.9,128.3,125.8,116.1,114.3,96.2,46.1,33.1,30.8,21.9,13.6,13.0,12.6;ESI-MS(m/z):[M]+calcd.for C29H35N2OS,459.2470;found 459.2469。
实施例18:BIIIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率78%。
1H NMR(400MHz,CDCl3):δ8.16(d,J=8.8Hz,2H),7.13(dd,J=9.0Hz,1.7Hz,2H),6.80(d,J=1.7Hz,2H),3.80(t,J=5Hz,2H),3.61-3.58(m,2H),3.31(s,12H),1.95-1.92(m,2H);13C NMR(101MHz,CDCl3)δ161.7,158.6,156.4,132.6,114.8,114.2,96.8,79.5,78.0,75.8,62.3,38.9,34.9,25.4;ESI-MS(m/z):[M]+calcd.for C20H25N2O2,325.1916;found 325.1915。
实施例19:BIIId的制备
利用通用制备流程二制备,化合物为紫红色固体,产率75%。
1H NMR(400MHz,CDCl3):δ7.78(d,J=7.9Hz,1H),7.59(t,J=7.0Hz,1H),7.59(t,J=7.1Hz,1H),7.24(d,J=7.9Hz,1H),7.17(d,J=8.8Hz,2H),6.91(d,J=8.9Hz,2H),6.82(s,2H),3.28(s,12H);13C NMR(101MHz,CDCl3)δ157.8,155.3,155.2,135.6,134.2,132.8,131.9,131.8,129.0,122.1,116.7,115.3,97.8,38.2;ESI-MS(m/z):[M]+calcd.forC23H22ClN2O,377.1421;found 377.1422。
实施例20:BIIIe的制备
利用通用制备流程二制备,化合物为紫红色固体,产率71%。
1H NMR(400MHz,CDCl3):δ8.38(d,J=8.1Hz,1H),8.11(t,J=7.6Hz,1H),7.88(t,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),7.11(d,J=9.5Hz,2H),6.98(dd,J=9.5Hz,1.8Hz,2H),6.82(d,J=1.8Hz,2H),3.31(s,12H);13C NMR(101MHz,CDCl3)δ157.7,155.8,153.9,147.3,136.0,132.9,132.7,131.6,129.9,128.9,128.5,125.2,115.9,113.8,96.5,39.1.ESI-HRMS(m/z):[M]+calcd.for C23H22N3O3,388.1661;found 388.1662。
实施例21:BIIIh的制备
利用通用制备流程二制备,化合物为紫红色固体,产率65%。
1H NMR(400MHz,CDCl3):δ8.19(d,J=8.2Hz,2H),8.01(dd,J=8.1Hz,1.8Hz,2H),7.62-7.58(m,5H),7.42(d,J=9.5Hz,2H),6.97(dd,J=9.5Hz,2.2Hz,2H),6.90(d,J=2.2Hz,2H),3.30(s,12H);13C NMR(101MHz,CDCl3)δ158.2,157.3,156.7,154.6,152.9,133.2,132.4,131.3,130.4,129.0,124.4,123.2,115.5,113.7,96.9,40.1.ESI-HRMS(m/z):[M]+calcd.for C29H27N4O,447.2185;found 447.2185。
实施例22:BIIIi的制备
利用通用制备流程二制备,化合物为紫红色固体,产率63%。
1H NMR(400MHz,CDCl3):δ8.76(d,J=3.9Hz,1H),8.58(s,1H),7.83(d,J=3.9Hz,1H),7.67(m,1H),7.24(d,J=9.0Hz,2H),6.93(dd,J=9.3Hz,1.9Hz,2H),6.85(d,J=2.0Hz,2H),4.28(s,3H),3.29(s,12H);13C NMR(101MHz,CDCl3):δ157.6,156.8,153.7,152.6,149.8,137.7,130.5,127.2,125.1,115.6,114.5,97.1,39.8,38.3.ESI-MS(m/z):1/2[M]2+calcd.for C27H33N3O,207.6310;found 207.6309。
实施例23:BIIIj的制备
利用通用制备流程二制备,化合物为紫红色固体,产率80%。
1H NMR(400MHz,CDCl3)δ8.10(d,J=8.1Hz,1H),7.99(d,J=8.2Hz,1H),7.62(t,J=7.1Hz,1H),7.59(d,J=7.7Hz,1H),7.48(t,J=8.0Hz,1H),7.37(d,J=8.9Hz,1H),7.05(d,J=8.8Hz,2H),6.95(d,J=1.9Hz,2H),6.84(dd,J=8.8,2.0Hz,2H),3.26(s,12H);13CNMR(101MHz,CDCl3):δ158.3,153.1,151.8,138.2,135.3,132.9,129.8,129.3,128.5,128.1,126.8,126.4,126.2,121.7,112.6,108.5,96.4,40.0;EI-HRMS(m/z):[M]+calcd.for C27H25N2O,393.1967;found 393.1966。
实施例24:BIIIl的制备
利用通用制备流程二制备,化合物为紫红色固体,产率82%。
1H NMR(400MHz,CDCl3):δ7.91(d,J=8.9Hz,2H),6.91(dd,J=9.2Hz,2H),6.66(d,J=1.9Hz,2H),3.27(s,12H),3.02(s,2H),1.88(s,3H),1.52-1.43(m,12H).13C NMR(101MHz,CDCl3):δ158.0,157.2,155.8,131.9,115.3,114.2,96.1,43.5,40.8,39.5,37.2,36.1,28.6.EI-HRMS(m/z):[M]+calcd.for C28H35N2O,415.2749;found 415.2750。
实施例25:BIIIm的制备
利用通用制备流程二制备,化合物为紫红色固体,产率78%。
1H NMR(400MHz,CDCl3):δ7.58(d,J=7.1Hz,1H),7.48(t,J=7.1Hz,1H),7.33(t,J=7.1Hz,1H),7.18-7.16(m,3H),6.85(d,J=9.6Hz,2H),6.80(s,2H),3.27(s,12H),2.83(t,J=7.4Hz,2H),1.48-1.43(m,2H),1.29-1.24(m,2H),0.77(t,J=7.3Hz,3H);13C NMR(101MHz,CDCl3):δ158.1,157.1,155.2,137.2,132.9,132.6,130.3,129.1,128.7,125.2,114.4,113.5,97.0,40.2,33.1,30.8,22.0,13.9,;ESI-MS(m/z):[M]+calcd.forC27H31N2OS,431.2157;found 431.2155。
实施例26:BIIIn的制备
利用通用制备流程二制备,化合物为紫红色固体,产率73%。
1H NMR(400MHz,CD3Cl):δ7.52(t,J=7.2Hz,1H),7.39(d,J=9.3Hz,2H),7.21(dd,J=7.2Hz,1.4Hz,1H),7.09(d,J=9.6Hz,2H),7.05(dd,J=9.6Hz,2.1Hz,2H),6.93(d,J=2.1Hz,2H),4.05(q,J=7.1Hz,2H),3.30(s,12H),1.34(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3)δ157.8,155.4,155.2,134.1,133.2,131.7,131.5,130.3,130.2,128.7,114.5,113.6,96.5,65.1,46.3,39.8,14.7.ESI-MS(m/z):[M]+calcd.for C25H27N2O2,387.2073;found 387.2074。
实施例27:BIIIo的制备
利用通用制备流程二制备,化合物为紫红色固体,产率50%。
1H NMR(400MHz,CDCl3):δ7.45(d,J=8.8Hz,2H),6.60(d,J=8.7Hz,2H),6.38(s,2H),5.55(d,J=6.5Hz,2H),5.33-5.31(m,1H),5.03(t,J=6.4Hz,2H),3.33(s,12H);13CNMR(101MHz,CDCl3)δ153.3,153.2,148.9,148.7,128.7,108.3,108.0,97.4,94.4,88.9,40.2;ESI-MS(m/z):[M]+calcd.for C26H23CrN2O4,479.1063;found 479.1062。
实施例28:BVa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率75%。
1H NMR(400MHz,CDCl3):δ7.50-7.45(m,3H),7.27(d,J=7.5Hz,2H),7.16(d,J=9.5Hz,2H),6.95(dd,J=9.5,2.2Hz,2H),6.84(d,J=2.2Hz,2H),3.34(t,J=6.6Hz,8H),2.01(t,J=6.6Hz,8H);13C NMR(101MHz,CDCl3)δ159.3,159.1,156.4,137.2,133.4,132.4,131.9,131.2,130.1,127.3,116.6,114.7,97.9,50.1,19.6;ESI-MS(m/z):[M]+calcd.forC27H27N2O,395.2123;found 395.2124。
实施例29:BVb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率71%。
1H NMR(400MHz,CDCl3):δ7.85(d,J=9.2Hz,2H),6.95(dd,J=9.1Hz,2H),6.63(d,J=2.0Hz,2H),3.41(t,J=7.0Hz,8H),3.06(s,2H),2.06(t,J=7.0Hz,8H),1.85(s,3H),1.51-1.43(m,12H).13C NMR(101MHz,CDCl3):δ157.6,156.9,155.0,130.9,114.4,113.3,95.6,50.2,43.7,41.3,37.8,36.3,29.0,19.5.EI-HRMS(m/z):[M]+calcd.for C32H39N2O,467.3062;found 467.3063。
实施例30:BVIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率65%。
1H NMR(400MHz,CDCl3):δ7.88-7.76(m,3H),7.36-7.26(m,3H),7.15(d,J=9.5Hz,2H),6.99(d,J=9.5Hz,2H),3.67-3.65(m,8H),1.71-1.66(m,12H).13C NMR(101MHz,CDCl3):δ158.0,156.2,155.0,138.0,131.5,131.0,130.9,114.9,113.1,97.3,96.7,49.1,25.8,24.0.EI-HRMS(m/z):[M]+calcd.for C29H30FN2O,441.2342;found 441.2345。
实施例31:BVIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率70%。
1H NMR(400MHz,CDCl3)δ8.01(d,J=9.6Hz,2H),7.22(dd,J=9.6,2.2Hz,2H),6.77(d,J=2.2Hz,2H),3.66-3.63(m,8H),3.06(s,2H),1.82(s,3H),1.72-1.67(m,12H),1.52-1.40(m,12H);13C NMR(125MHz,CDCl3)δ157.7,156.4,156.3,130.1,114.8,114.0,96.8,48.8,43.5,40.6,37.1,36.0,28.6,25.8,12.8;EI-HRMS(m/z):[M]+calcd.for C34H43N2O,495.3375;found 495.3376。
实施例32:BVIIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率65%。
1H NMR(400MHz,CDCl3):δ7.63-7.62(m,3H),7.30-7.23(m,4H),6.92(dd,J=8.0Hz,1.6Hz,2H),6.89(d,J=1.6Hz,2H),3.87-3.85(m,8H),3.79-3.77(m,8H).13C NMR(101MHz,CDCl3)δ160.2,157.5,155.9,155.5,137.2,134.5,132.8,132.6,131.1,131.0,130.4,114.5,96.3,67.4,48.2.EI-HRMS(m/z):[M]+calcd.for C27H27N2O3,427.2022;found427.2021。
实施例33:BVIIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率60%。
1H NMR(400MHz,CD3OD):δ7.42-7.36(m,3H),7.31(d,J=9.5Hz,2H),7.18-7.15(m,2H),7.10(dd,J=9.6Hz,2.1Hz,2H),6.95(d,J=2.0Hz,2H),3.89-3.84(m,8H),3.72-3.68(m,8H).13C NMR(101MHz,CDCl3)δ160.0,158.5,158.2,155.0,137.2,133.8,133.0,131.9,131.2,128.9,115.7,114.5,97.3,68.0,48.5.EI-HRMS(m/z):[M]+calcd.for C27H27N2O4,443.1971;found 443.1970。
实施例34:BVIIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率68%。
1H NMR(400MHz,CDCl3)δ8.04(d,J=9.5Hz,2H),7.29(dd,J=9.5,2.1Hz,2H),6.74(d,J=2.2Hz,2H),3.86-3.81(m,8H),3.66-3.63(m,8H),3.03(s,2H),1.87(s,3H),1.52-1.44(m,12H);13C NMR(125MHz,CDCl3)δ157.6,156.1,156.0,131.1,115.8,115.0,97.8,49.0,44.2,40,9,37.0,36.1,28.3,19.8;EI-HRMS(m/z):[M]+calcd.for C32H39N2O3,499.2961;found 499.2963。
实施例35:BVIIIa的制备
利用通用制备流程一制备,化合物为紫红色固体,产率37%。
1H NMR(400MHz,CDCl3)δ7.60-7.56(m,3H),7.33-7.29(m,2H),6.71(s,2H),6.65(s,2H),3.44(t,J=7.0Hz,4H),1.98-1.95(m,4H),2.69(t,J=7.0Hz,4H);13C NMR(125MHz,CDCl3)δ160.2,157.5,155.9,155.5,137.6,134.2,132.3,132.1,131.7,131.4,130.9,115.5,96.3,43.2,27.2,18.7;EI-HRMS(m/z):[M]+calcd.for C25H22N2O,366.1732;found366.1733。
实施例36:BVIIIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率69%。
1H NMR(400MHz,CDCl3)δ6.69(s,2H),6.58(s,2H),3.42(t,J=7.0Hz,4H),1.97-1.93(m,4H),3.03(s,2H),3.01(s,6H),2.67(t,J=7.0Hz,4H),1.53-1.43(m,12H),1.80(s,3H);13C NMR(125MHz,CDCl3)δ157.7,157.0,155.0,130.9,114.9,114.3,96.6,45.7,43.5,40.8,37.2,36.1,28.6,27.0,18.2;EI-HRMS(m/z):[M]+calcd.for C32H39N2O,467.3062;found 467.3065。
实施例37:CIf的制备。
利用通用制备流程二制备,化合物为紫红色固体,产率73%。
1H NMR(400MHz,CDCl3):δ7.79(d,J=7.9Hz,1H),7.57(t,J=7.0Hz,1H),7.49(t,J=7.2Hz,1H),7.27(d,J=7.9Hz,1H),7.11(d,J=9.1Hz,2H),6.94(d,J=8.9Hz,2H),6.84(s,2H),3.65(q,J=7.2Hz,8H),1.32(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.1,155.8,155.5,133.6,133.2,131.8,131.6,130.8,128.1,122.2,114.7,113.3,96.8,46.5,12.8;ESI-MS(m/z):[M]+calcd.for C27H30BrN2O,477.1542;found 477.1548。
实施例38:CIh的制备
利用通用制备流程二制备,化合物为紫红色固体,产率78%。
1H NMR(400MHz,CD3OD):δ7.80(t,J=8.0Hz,1H),7.62(t,J=7.7Hz,1H),7.49(t,J=7.7Hz,1H),7.20(d,J=7.4Hz,1H),7.08(d,J=9.5Hz,2H),6.87(dd,J=9.5Hz,1.8Hz,2H),6.76(d,J=1.8Hz,2H),4.79(s,1H),3.60(q,J=7.4Hz,8H),1.27(t,J=7.0Hz,12H).13C NMR(101MHz,CDCl3)δ157.9,155.7,155.0,133.3,132.8,131.7,131.2,130.5,130.0,128.1,114.5,113.6,96.5,46.3,12.7.ESI-MS(m/z):[M]+calcd.For C27H31N2OS,431.2157;found 431.2157。
实施例39:CIi的制备
利用通用制备流程二制备,化合物为紫红色固体,产率89%
1H NMR(400MHz,CDCl3):δ7.57-7.49(m,2H),7.36(t,J=7.1Hz,1H),7.14-7.12(m,3H),6.83(d,J=9.6Hz,2H),6.78(s,2H),3.59(q,J=7.4Hz,8H),2.81(t,J=7.4Hz,2H),1.49-1.41(m,2H),1.30(t,J=7.2Hz,12H),1.28-1.21(m,2H),0.79(t,J=7.3Hz,3H);13CNMR(101MHz,CDCl3):δ158.0,156.6,155.7,136.7,131.8,131.6,130.7,12965,128.1,125.8,114.1,113.6,96.5,46.2,33.1,30.8,21.9,13.6,12.6;ESI-MS(m/z):[M]+calcd.forC31H39N2OS,487.2783;found 487.2782。
实施例40:CIj的制备
利用通用制备流程二制备,化合物为紫红色固体,产率84%。
1H NMR(400MHz,CDCl3):δ10.85(s,1H),7.86(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.52(d,J=9.4Hz,2H),7.30(t,J=7.5Hz,1H),7.14(d,J=7.5Hz,1H),6.88(d,J=8.2Hz,2H),6.70(s,2H),3.59-3.52(m,8H),1.93(s,3H),1.28(t,J=7.0Hz,12H);13CNMR(101MHz,CDCl3):δ170.8,158.4,158.1,155.4,137.0,133.3,131.1,130.2,127.5,127.0,125.1,113.9,113.5,96.0,45.9,29.8,23.4,12.7;ESI-MS(m/z):[M]+calcd.forC29H34N3O2,456.2651;found 456.2653。
实施例41:CIl的制备
利用通用制备流程二制备,化合物为紫红色固体,产率73%。
1H NMR(400MHz,CDCl3):δ7.69(t,J=7.6Hz,1H),7.61(d,J=7.4Hz,1H),7.57(t,J=7.6Hz,1H),7.29(d,J=7.5Hz,1H),7.26(d,J=9.5Hz,2H),7.14-7.13(m,3H),7.07-7.06(m,2H),6.85(dd,J=9.5Hz,2.2Hz,2H),6.76(d,J=2.2Hz,2H),3.62(q,J=7.1Hz,8H),1.31(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ157.8,157.8,155.6,141.9,139.6,132.1,131.0,130.8,130.6,130.4,128.6,128.5,127.9,127.8,114.2,113.8,96.6,46.3,12.8.;ESI-MS(m/z):[M]+calcd.for C33H35N2O,475.2749;found 475.2750。
实施例42:CIm的制备
利用通用制备流程二制备,化合物为紫红色固体,产率69%。
1H NMR(400MHz,CDCl3):δ7.59(t,J=5.0Hz,2H),7.39(d,J=6.6Hz,1H),7.30-7.26(m,7H),7.11(t,J=7.3Hz,4H),6.88(d,J=9.4Hz,2H),6.79(s,2H),6.61(d,J=9.1Hz,2H),3.64(q,J=6.4Hz,8H),1.33(t,J=6.5Hz,12H);13C NMR(101MHz,CDCl3)δ157.7,157.6,157.5,155.5,138.2,137.9,137.8,137.7,135.3,135.2,134.5,134.0,133.8,131.9,130.3,129.7,129.3,129.3,129.2,128.8,128.7,114.2,114.2,113.7,96.4,46.3,12.8.ESI-HRMS(m/z):[M]+calcd.for C39H40N2OP,583.2878;found583.2878。
实施例43:CIn的制备
利用通用制备流程二制备,化合物为紫红色固体,产率84%。
1H NMR(400MHz,CDCl3):δ7.49(d,J=7.4Hz,1H),7.37(t,J=7.3Hz,1H),7.33(t,J=7.3Hz,1H),7.01(d,J=6.4Hz,1H),6.93(d,J=7.5Hz,1H),6.68(d,J=8.8Hz,1H),6.42-6.35(m,4H),6.27(s,1H),3.53(s,3H),3.38-3.32(m,8H),1.19-1.14(m,12H).13C NMR(101MHz,CDCl3)δ157.2,155.9,154.5,137.3,134.5,132.8,132.5,131.1,131.0,130.4,114.5,113.7,96.3,70.1,58.9,46.5,12.7.ESI-HRMS(m/z):[M+H]+calcd.for C28H31N2O2,427.2386;found427.2383。
实施例44:CIo的制备
利用通用制备流程二制备,化合物为紫红色固体,产率68%
1H NMR(400MHz,CDCl3):δ7.27-7.20(m,4H),6.93(d,J=8.8Hz,2H),6.87-6.82(m,7H),6.74-6.73(m,3H),6.94-6.68(m,2H),6.63(t,J=7.6Hz,2H),6.44(dd,J=8.8Hz,1.8Hz,2H),6.05(d,J=7.3Hz,2H),6.03(d,J=1.8Hz,2H),3.36-3.29(m,8H),1.15(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ169.1,152.6,152.4,149.0,148.2,143.0,139.4,138.8,138.7,137.6,136.0,135.7,131.4,130.6,130.6,129.5,128.8,127.3,127.1,126.9,126.6,126.3,125.9,125.9,122.0,108.2,106.3,98.0,44.7,12.6.ESI-HRMS(m/z):[M+H]+calcd.for C52H47N2O3,747.3587;found 747.3588。
实施例45:CIp的制备
利用通用制备流程二制备,化合物为紫红色固体,产率70%。
1H NMR(400MHz,CDCl3):δ8.68(s,1H),7.83(d,J=7.7Hz,1H),7.74(d,J=7.5Hz,1H),7.53(s,1H),7.46(t,J=7.5Hz,1H),7.33(t,J=7.4Hz,1H),7.13(d,J=7.5Hz,1H),6.96(t,J=7.3Hz,1H),6.87(d,J=9.5Hz,2H),6.71(t,J=7.4Hz,1H),6.55(s,1H),6.54(d,J=7.5Hz,2H),3.62-3.46(m,8H),1.38-1.06(m,12H);13C NMR(101MHz,CDCl3)δ173.3,159.9,157.7,154.9,143.4,142.3,137.2,132.8,130.3,130.1,129.9,129.7,128.8,127.1,126.4,126.2,114.4,95.5,45.8,12.7.ESI-HRMS(m/z):[M]+calcd.for C34H35N2O3,519.2648;found519.2651。
实施例46:CIr的制备
利用通用制备流程二制备,化合物为紫红色固体,产率61%。
1H NMR(400MHz,CDCl3):δ7.97(d,J=8.0Hz,4H),7.55(d,J=8.0Hz,4H),7.49(d,J=9.6Hz,4H),6.96(dd,J=9.5Hz,1.6Hz,4H),6.79(d,J=1.5Hz,4H),3.63(q,J=7.0Hz,16H),1.32(t,J=7.0Hz,24H);13C NMR(101MHz,CDCl3):δ158.1,157.2,155.7,142.1,132.5,131.5,130.5,128.1,114.7,113.4,96.5,46.4,12.9.ESI-MS(m/z):1/2[M]2+calcd.for C27H30N2O,398.2358;found 398.2358。
实施例47:CIs的制备
利用通用制备流程二制备,化合物为紫红色固体,产率53%。
1H NMR(400MHz,CDCl3):δ8.06(s,3H),8.02(d,J=7.9Hz,6H),7.54(d,J=7.9Hz,6H),7.50(d,J=9.6Hz,6H),6.99(dd,J=9.5Hz,1.3Hz,6H),6.77(d,J=1.2Hz,6H),3.60(q,J=7.0Hz,24H),1.29(t,J=6.9Hz,36H);13C NMR(101MHz,CDCl3)δ158.0,157.1,155.6,142.9,141.7,132.3,131.1,130.4,128.1,126.2,114.5,113.3,96.3,46.1,12.6.ESI-HRMS(m/z):1/3[M]3+calcd.for C87H93N6O3,423.2436;found 423.2438。
实施例48:CIt的制备
利用通用制备流程二制备,化合物为紫红色固体,产率68%。
1H NMR(400MHz,CDCl3):δ7.77(d,J=7.9Hz,1H),7.67(d,J=8.5Hz,1H),7.29(t,J=7.5Hz,1H),7.08(t,J=7.5Hz,1H),7.02(d,J=8.8Hz,2H),6.87(d,J=7.7Hz,1H),6.51(dd,J=8.5Hz,2.2Hz,1H),6.41(d,J=2.4Hz,2H),6.30-6.27(m,3H),3.33(q,J=7.0Hz,8H),1.15(t,J=7.0Hz,12H),0.93(s,9H),0.14(s,6H);13C NMR(101MHz,CDCl3)δ157.2,153.9,151.8,148.9,137.4,130.7,130.2,129.3,127.6,126.9,123.3,120.4,115.6,113.6,111.8,110.0,107.7,97.5,44.5,25.8,18.3,12.8,-4.3.ESI-MS(m/z):[M+H]+calcd.for C39H49N2O3Si,621.3512;found 621.3515。
实施例49:CIv的制备
利用通用制备流程二制备,化合物为紫红色固体,产率85%。
1H NMR(400MHz,CDCl3):δ8.55(d,J=7.0Hz,1H),8.20(d,J=8.2Hz,1H),7.89(d,J=8.2Hz,1H),7.72(t,J=7.8Hz,1H),7.49(t,J=8.2Hz,1H),7.22(d,J=7.2Hz,1H),6.71(d,J=8.9Hz,2H),6.43(d,J=2.5Hz,2H),6.27(dd,J=8.9Hz,2.5Hz,2H),3.33(q,J=7.0Hz,8H),1.15(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3):δ163.5,151.9,149.1,136.6,133.5,131.8,129.9,129.4,128.6,128.2,126.9,126.8,126.2,121.1,111.4,108.1,97.4,44.5,12.6;EI-HRMS(m/z):[M+H]+calcd.for C32H33N2O3,493.2491;found 493.2491。
实施例50:CIw的制备
利用通用制备流程二制备,化合物为紫红色固体,产率81%。
1H NMR(400MHz,CDCl3):δ8.72(s,1H),8.15(d,J=8.5Hz,2H),7.52(d,J=7.0Hz,2H),7.41-7.34(m,4H),7.02(d,J=2.0Hz,2H),6.76(dd,J=9.5Hz,1.6Hz,2H),6.67(dd,J=9.5Hz,2.1Hz,2H),3.63(q,J=7.0Hz,8H),1.30(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.0,156.3,155.9,131.9,131.0,130.0,129.9,129.1,127.7,126.0,125.0,115.2,114.5,96.9,46.4,12.8.ESI-MS(m/z):[M]+calcd.for C35H35N2O,499.2749;found499.2751。
实施例51:CIx的制备
利用通用制备流程二制备,化合物为紫红色固体,产率72%。
1H NMR(400MHz,CDCl3):δ9.04(s,1H),8.60(s,1H),8.39(s,1H),8.04(s,1H),7.98(s,1H),7.77(s,1H),7.52(s,2H),7.17(d,J=8.4Hz,2H),6.66(s,4H),3.50(q,J=7.8Hz,8H),1.23(t,J=7.8Hz,12H);13C NMR(101MHz,CDCl3)δ157.6,154.8,133.6,133.4,132.7,132.0,130.9,130.5,129.4,128.8,128.7,128.3,127.0,126.8,126.60,114.0,113.3,96.1,45.9,12.7.ESI-HRMS(m/z):[M+H]+calcd.for C36H35N2O3,543.2648;found.543.2651。
实施例52:CIy的制备
利用通用制备流程二制备,化合物为紫红色固体,产率85%。
1H NMR(400MHz,CDCl3):δ9.06(d,J=3.1Hz,1H),8.38(d,J=8.1Hz,1H),8.32(d,J=8.1Hz,1H),7.97(s,1H),7.66(d,J=8.0Hz,1H),7.58(m,1H),7.33(d,J=9.4Hz,2H),6.92(d,J=9.6Hz,2H),6.87(s,2H),3.65(q,J=6.9Hz,8H),1.32(t,J=6.9Hz,12H);13CNMR(101MHz,CDCl3):δ13C NMR(101MHz,CDCl3)δ158.1,156.3,155.7,152.4,148.4,137.0,132.1,130.4,130.1,129.9,129.7,128.1,122.8,114.5,113.5,96.7,46.4,12.8.ESI-MS(m/z):[M]+calcd.for C30H32N3O,450.2545;found 450.2548。
实施例53:CIz的制备
利用通用制备流程二制备,化合物为紫红色固体,产率57%。
1H NMR(400MHz,CDCl3):δ8.59(d,J=7.7Hz,1H),8.49(d,J=7.7Hz,1H),8.44(d,J=7.7Hz,1H),8.36(d,J=7.6Hz,1H),7.59-7.48(m,4H),7.32-7.25(m,6H),6.90-6.88(m,8H),3.66(q,J=6.4Hz,16H),1.35(t,J=6.4Hz,24H);13C NMR(101MHz,CDCl3)δ158.0,156.3,155.8,133.1,132.8,132.7,132.0,131.3,130.9,129.8,129.3,128.7,128.5,128.3,126.0,125.5,122.3,122.0,120.8,120.5,114.4,114.1,96.5,46.2,12.6,ESI-HRMS(m/z):1/2[M]2+calcd.for C62H62N4O2,894.4873;found 447.2434。
实施例54:CIaa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率57%。
1H NMR(400MHz,CDCl3):δ7.77(d,J=6.9Hz,1H),7.65(t,J=7.6Hz,1H),7.56-7.50(m,3H),7.41-7.40(m,2H),7.29-7.19(m,5H),7.01(d,J=7.9Hz,2H),6.88(d,J=7.9Hz,2H),6.83(d,J=9.4Hz,2H),6.70(s,2H),5.34(s,2H),3.85(s,3H),3.58(q,J=8.0Hz,8H),2.72-2.68(m,5H),1.68-1.62(m,2H),1.27(t,J=7.8Hz,12H),0.87(t,J=7.2Hz,3H);13C NMR(101MHz,CDCl3)δ157.5,157.4,156.5,155.4,154.5,140.9,139.1,136.6,135.8,135.2,131.8,130.9,130.6,130.3,130.1,129.3,128.8,127.8,126.6,123.8,123.6,122.6,122.4,119.2,114.2,113.6,109.8,108.6,96.3,46.7,46.1,32.1,29.6,21.4,16.8,13.9,12.6.ESI-HRMS(m/z):[M]+calcd.for C53H55N6O+,791.4437;found791.4438。
实施例55:CIab的制备
利用通用制备流程二制备,化合物为紫红色固体,产率71%。
1H NMR(400MHz,CDCl3):δ8.11(s,1H),8.09(d,J=8.6Hz,1H),7.96(d,J=8.5Hz,1H),7.87(s,2H),7.61(s,1H),7.57(d,J=8.3Hz,1H),7.45(d,J=8.3Hz,1H),7.41(d,J=9.5Hz,2H),7.00(d,J=8.4Hz,1H),6.85(d,J=9.7Hz,2H),6.82(s,2H),3.88(s,3H),3.60(q,J=6.7Hz,8H),2.17(s,6H),2.08(s,3H),1.77(s,6H),1.30(t,J=6.8Hz,12H);13C NMR(101MHz,CDCl3)δ159.1,158.1,157.6,155.6,141.2,139.2,134.3,132.4,132.4,131.5,129.4,129.0,128.9,128.8,127.5,126.8,126.0,125.9,124.9,114.3,113.5,112.3,96.7,55.3,46.3,40.7,37.3,37.2,29.2,12.8.ESI-HRMS(m/z):[M]+calcd.for C48H53N2O2 +,689.4107;found 689.4106。
实施例56:CIac的制备
利用通用制备流程二制备,化合物为紫红色固体,产率45%。
1H NMR(400MHz,CDCl3):δ6.82(d,J=7.8Hz,1H),6.67(d,J=8.7Hz,1H),6.33(s,2H),6.29(s,1H),6.28(d,J=8.5Hz,1H),6.17(d,J=5.2Hz,1H),5.90(d,J=9.9Hz,2H),3.75(s,3H),3.70(s,3H),3.64(s,1H),3.35-3.27(m,8H),3.06(s,3H),2.67-2.60(m,3H),2.54(s,3H),1.34-1.25(m,2H),1.17-1.10(m,14H);13C NMR(101MHz,CDCl3)δ152.9,152.1,151.5,148.5,148.3,143.4,141.1,134.4,130.8,128.7,118.0,113.1,108.1,107.3,102.8,100.74,98.1,97.6,70.7,62.4,59.7,59.0,56.2,44.5,12.8.ESI-HRMS(m/z):[M]+calcd.for C42H49N3O7,707.3571;found 707.3571。
实施例57:CIad的制备
利用通用制备流程二制备,化合物为紫红色固体,产率55%。
1H NMR(400MHz,CDCl3):δ7.78(d,J=7.9Hz,1H),7.68-7.63(m,2H),7.42(t,J=7.6Hz,1H),7.32-7.26(m,2H),7.15(t,J=8.0Hz,2H),6.92(d,J=9.5Hz,2H),6.83(d,J=7.5Hz,1H),6.76(s,2H),6.68(d,J=9.4Hz,2H),6.46(d,J=8.0Hz,2H),4.72-4.66(m,4H),3.56-3.51(m,8H),1.46(t,J=7.1Hz,3H),1.16(t,J=7.2Hz,12H);13C NMR(101MHz,CDCl3)δ158.3,157.0,155.1,153.3,143.4,141.2,136.8,136.4,133.7,133.3,131.5,130.5,129.6,128.5,127.8,125.2,122.9,121.7,119.5,118.6,114.2,114.0,113.9,109.9,96.0,66.9,46.0,45.8,14.4,12.3.ESI-HRMS(m/z):[M]+calcd.for C44H44N5O2 +,674.3495;found674.3494。
实施例58:CIae的制备
利用通用制备流程二制备,化合物为紫红色固体,产率74%。
1H NMR(400MHz,CDCl3):δ8.36(d,J=8.2Hz,1H),8.01(t,J=7.4Hz,1H),7.86(t,J=7.4Hz,1H),7.46(d,J=7.4Hz,1H),7.01(d,J=9.5Hz,2H),6.92(dd,J=9.5Hz,1.7Hz,2H),6.77(d,J=1.7Hz,2H),3.61(q,J=7.0Hz,8H),1.28(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ157.8,155.7,154.2,147.8,135.1,131.9,131.7,130.6,129.0,128.2,127.5,125.5,114.9,112.8,96.5,46.3,12.7.ESI-HRMS(m/z):[M]+calcd.for C27H30N3O3,444.2287;found 444.2285。
实施例59:CIaf的制备
利用通用制备流程二制备,化合物为紫红色固体,产率65%。
1H NMR(400MHz,CDCl3):δ8.05(s,1H),7.31(s,1H),6.92(dd,J=9.5Hz,1.7Hz,2H),6.77(d,J=1.7Hz,2H),3.63(q,J=7.0Hz,8H),1.30(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ157.3,155.9,146.8,135.6,132.9,130.6,129.0,128.4,127.7,125.3,114.9,111.8,101.2,96.8,46.3,12.8.ESI-HRMS(m/z):[M]+calcd.for C28H30N3O5,488.2185;found 488.2186。
实施例60:CIag的制备
利用通用制备流程二制备,化合物为紫红色固体,产率57%。
1H NMR(400MHz,CDCl3):δ8.06(d,J=8.2Hz,1H),7.65(d,J=8.2Hz,1H),7.55(s,1H),7.08(d,J=9.4Hz,2H),6.88(dd,J=9.4Hz,1.9Hz,2H),6.72(d,J=1.9Hz,2H),3.59(q,J=7.0Hz,8H),1.25(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.0,155.9,155.2,147.6,134.9,131.8,130.3,129.5,127.1,125.1,114.9,113.8,96.5,46.1,12.6.ESI-HRMS(m/z):[M]+calcd.for C27H29ClN3O3,478.1897;found 478.1898。
实施例61:CIah的制备
利用通用制备流程二制备,化合物为紫红色固体,产率68%。
1H NMR(400MHz,CDCl3):δ8.00(d,J=8.2Hz,1H),7.45(s,1H),7.34(d,J=8.2Hz,1H),7.10(d,J=9.3Hz,2H),6.78(dd,J=9.2Hz,1.9Hz,2H),6.71(d,J=2.1Hz,2H),3.59(q,J=7.0Hz,8H),1.25(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.2,155.9,154.5,147.6,134.9,131.8,131.3,129.5,127.5,123.1,114.7,113.1,96.2,46.2,21.7,12.8.ESI-HRMS(m/z):[M]+calcd.for C28H32N3O3,458.2444;found 458.2446。
实施例62:CIai的制备
利用通用制备流程二制备,化合物为紫红色固体,产率81%。
1H NMR(400MHz,CDCl3):δ7.98(d,J=8.1Hz,1H),7.68(t,J=7.6Hz,1H),7.55(t,J=7.3Hz,1H),7.35(d,J=9.1Hz,2H),7.31(d,J=7.4Hz,1H),7.23(d,J=9.5Hz,2H),6.88(d,J=2.2Hz,2H),6.77(dd,J=9.5Hz,2.2Hz,2H),6.53(d,J=9.2Hz,2H),3.61(q,J=7.0Hz,8H),3.36(q,J=7.1Hz,4H),1.30(t,J=7.0Hz,12H),1.14(t,J=7.1Hz,6H);13CNMR(101MHz,CDCl3)δ158.4,157.8,155.5,151.2,150.8,142.8,132.4,131.2,130.1,129.7,129.0,125.9,117.9,114.3,113.9,110.9,96.5,46.2,44.8,12.8,12.7.ESI-HRMS(m/z):[M]+calcd.for C37H44N5O,574.3546;found 574.3549。
实施例63:CIaj的制备
利用通用制备流程二制备,化合物为紫红色固体,产率75%。
1H NMR(400MHz,CDCl3):δ7.97(d,J=8.1Hz,1H),7.70(t,J=7.6Hz,1H),7.58(t,J=7.3Hz,1H),7.32(s,1H),7.30(d,J=7.4Hz,1H),7.23(d,J=9.4Hz,1H),7.15(d,J=9.4Hz,1H),6.88(d,J=2.1Hz,2H),6.77(dd,J=9.2Hz,2.1Hz,2H),6.53(d,J=9.2Hz,2H),3.60(q,J=7.0Hz,8H),3.34(q,J=7.1Hz,4H),1.31(t,J=7.0Hz,12H),1.13(t,J=7.1Hz,6H);13C NMR(101MHz,CDCl3)δ158.6,157.7,156.5,152.2,151.8,142.0,134.4,132.2,130.4,129.8,129.3,126.9,117.0,114.3,113.3,110.1,96.5,46.5,45.4,12.8,12.6.ESI-HRMS(m/z):[M]+calcd.for C37H43ClN5O,608.3156;found 608.3157。
实施例64:CIak的制备
利用通用制备流程二制备,化合物为紫红色固体,产率74%。
1H NMR(400MHz,CDCl3):δ7.98(d,J=8.1Hz,1H),7.68(d,J=8.1Hz,1H),7.335(d,J=9.1Hz,2H),7.30(s,1H),7.21(d,J=9.1Hz,2H),6.85(d,J=2.2Hz,2H),6.67(dd,J=9.0Hz,2.2Hz,2H),6.57(d,J=9.0Hz,2H),3.60(q,J=7.0Hz,8H),3.35(q,J=7.1Hz,4H),2.30(s,3H),1.31(t,J=7.0Hz,12H),1.15(t,J=7.1Hz,6H);13C NMR(101MHz,CDCl3)δ158.2,157.9,155.1,152.2,151.8,143.7,132.5,131.7,130.8,129.3,129.0,126.9,118.9,114.0,113.9,111.0,96.5,46.4,44.7,21.3,12.8,12.6.ESI-HRMS(m/z):[M]+calcd.for C38H46N5O,588.3702;found 588.3704。
实施例65:CIal的制备
利用通用制备流程二制备,化合物为紫红色固体,产率84%。
1H NMR(400MHz,CDCl3):δ8.14(d,J=8.3Hz,2H),7.99(dd,J=8.1Hz,1.8Hz,2H),7.59-7.52(m,5H),7.39(d,J=9.5Hz,2H),6.95(dd,J=9.6Hz,2.2Hz,2H),6.90(d,J=2.2Hz,2H),3.67(q,J=7.1Hz,8H),1.34(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.1,156.3,155.7,153.6,152.6,134.2,132.0,131.9,130.6,129.4,123.4,123.3,114.5,113.3,96.9,46.4,12.8.ESI-HRMS(m/z):[M]+calcd.for C33H35N4O,503.2811;found503.2808。
实施例66:CIam的制备
利用通用制备流程二制备,化合物为紫红色固体,产率83%。
1H NMR(400MHz,CDCl3):δ8.15(d,J=8.3Hz,2H),7.97(dd,J=8.1Hz,1.8Hz,2H),7.57-7.50(m,4H),7.39(d,J=9.5Hz,2H),6.91(dd,J=9.6Hz,1.9Hz,2H),6.87(d,J=1.9Hz,2H),3.62(q,J=7.0Hz,8H),3.33(q,J=7.1Hz,4H),1.31(t,J=7.0Hz,12H),1.16(t,J=7.1Hz,6H);13C NMR(101MHz,CDCl3)δ158.0,157.5,155.7,151.5,150.7,142.3,132.6,131.7,130.7,129.3,129.2,126.3,118.9,114.9,113.0,110.9,96.5,46.1,44.5,12.9,12.5.ESI-HRMS(m/z):[M]+calcd.for C37H44N5O,574.3546;found 574.3549。
实施例67:CIan的制备
利用通用制备流程二制备,化合物为紫红色固体,产率72%。
1H NMR(400MHz,CDCl3):δ7.95-7.91(m,3H),7.39(d,J=9.4Hz,2H),7.26-7.19(m,2H),6.93-6.90(m,4H),6.73(d,J=9.2Hz,2H),3.67(q,J=7.1Hz,8H),3.48(q,J=7.0Hz,4H),1.33(t,J=7.1Hz,12H),1.23(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ158.1,155.7,155.0,151.3,143.8,142.7,131.7,126.6,125.9,125.9,118.9,118.3,118.1,114.5,113.0,111.2,97.0,46.4,45.0,12.8,12.8.ESI-HRMS(m/z):[M]+calcd.forC37H43FN5O,592.3452;found 592.3450。
实施例68:CIao的制备
利用通用制备流程二制备,化合物为紫红色固体,产率75%。
1H NMR(400MHz,CDCl3):δ7.90(d,J=9.2Hz,2H),7.84-7.82(m,2H),7.25-7.19(m,3H),6.94(d,J=2.1Hz,2H),6.86(dd,J=9.6Hz,2.1Hz,2H),6.75(d,J=9.5Hz,2H),3.67(q,J=7.1Hz,8H),3.48(q,J=7.1Hz,4H),2.13(s,3H),1.34(t,J=7.0Hz,12H),1.24(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ158.1,157.4,155.8,154.6,143.2,137.1,132.0,131.7,129.9,126.0,124.1,120.2,114.3,113.6,111.2,97.0,46.4,44.9,20.0,12.8.ESI-HRMS(m/z):[M]+calcd.for C38H46N5O,588.3702;found 588.3701。
实施例69:CIap的制备
利用通用制备流程二制备,化合物为紫红色固体,产率68%。
1H NMR(400MHz,CDCl3):δ8.20-8.13(m,3H),7.84-7.82(m,3H),7.45-7.39(m,3H),6.90(d,J=2.0Hz,2H),6.82(dd,J=9.6Hz,2.0Hz,2H),6.71(d,J=9.5Hz,2H),3.67(q,J=7.1Hz,8H),2.86(s,6H),2.13(s,3H),1.34(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.1,157.4,156.8,156.2,155.8,154.6,143.2,137.1,132.0,131.7,130.1,129.9,126.0,124.1,120.2,114.3,113.6,111.2,110.3,97.0,46.6,44.7,20.0,12.6.ESI-HRMS(m/z):[M]+calcd.for C38H46N5O,610.3546;found 610.3545。
实施例70:CIIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率84%。
1H NMR(400MHz,CDCl3):δ8.00(d,J=9.7Hz,2H),7.93(s,1H),7.16(d,J=2.9Hz,1H),7.04(d,J=9.5Hz,2H),6.84(s,1H),6.77(s,2H),3.65(q,J=7.0Hz,8H),1.33(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.1,155.3,147.4,145.8,143.0,132.1,120.5,114.5,113.4,111.6,96.7,46.3,12.8.ESI-MS(m/z):[M]+calcd.for C25H29N2O2,389.2229;found 389.2230。
实施例71:CIIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率83%。
1H NMR(400MHz,CDCl3):δ7.76(d,J=3.8Hz,1H),7.67(d,J=9.5Hz,2H),7.34(s,2H),6.98(d,J=9.3Hz,2H),6.80(s,2H),3.65(q,J=6.8Hz,8H),1.32(t,J=6.8Hz,12H);13C NMR(101MHz,CDCl3)δ157.8,155.5,150.1,132.2,132.1,131.0,130.6,128.4,114.4,113.8,96.6,46.3,12.8.ESI-MS(m/z):[M]+calcd.for C25H29N2OS,405.2001;found405.2000。
实施例72:CIIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率67%。
1H NMR(400MHz,CDCl3):δ8.00(d,J=9.7Hz,2H),7.04(d,J=9.5Hz,2H),6.84(s,1H),6.79(s,2H),3.89(s,3H),3.64(q,J=7.0Hz,8H),2.19(s,3H),2.12(s,3H),1.33(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.0,155.3,147.5,145.2,143.8,132.1,120.5,114.5,96.7,46.3,33.4,14.1,13.2,12.8.ESI-MS(m/z):[M]+calcd.for C28H36N3O,430.2858;found 430.2859。
实施例73:CIIIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率82%。
1H NMR(400MHz,CDCl3):δ8.15(s,1H),7.25(d,J=3.0Hz,1H),7.18(d,J=9.4Hz,2H),7.04(d,J=9.5Hz,2H),6.80(d,J=3.0Hz,1H),6.77(s,2H),3.63(q,J=7.0Hz,8H),1.32(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.3,156.3,147.8,145.2,143.1,132.3,120.9,114.2,114.4,112.6,96.1,46.6,12.8.ESI-MS(m/z):[M]+calcd.forC25H29N2O2,389.2229;found 389.2227。
实施例74:CIIIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率77%。
1H NMR(400MHz,CDCl3):δ7.73(d,J=9.5Hz,1H),7.67(s,1H),7.65(d,J=9.5Hz,2H),7.22(d,J=9.5Hz,1H),6.99(d,J=9.3Hz,2H),6.84(s,2H),3.64(q,J=6.8Hz,8H),1.34(t,J=6.8Hz,12H);13C NMR(101MHz,CDCl3)δ157.2,156.5,151.1,132.5,132.0,131.6,130.7,128.5,114.9,113.2,96.4,46.1,12.8.ESI-MS(m/z):[M]+calcd.forC25H29N2OS,405.2001;found 405.2003。
实施例75:CIIIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率69%。
1H NMR(400MHz,CDCl3):δ7.33-7.24(m,7H),7.65(d,J=9.5Hz,2H),7.12(S,1H),6.99(d,J=9.4Hz,2H),6.84(s,2H),3.64(q,J=6.8Hz,8H),1.34(t,J=6.8Hz,12H);13CNMR(101MHz,CDCl3)δ157.1,156.5,155.2,154.6,151.9,151.1,132.5,132.0,131.6,130.7,128.5,127.4,126.6,114.9,113.2,96.4,56.4,46.1,12.8.ESI-MS(m/z):[M]+calcd.for C32H36N3O,478.2858;found 478.2858。
实施例76:CIVa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率48%。
1H NMR(400MHz,CDCl3):δ8.74(s,1H),8.26(s,1H),8.02(d,J=9.2Hz,2H),7.07(d,J=8.7Hz,2H),6.78(s,2H),3.64(q,J=7.0Hz,8H),1.34(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.1,155.6,152.4,143.3,132.1,129.4,114.7,112.8,96.6,46.3,12.9.ESI-HRMS(m/z):[M]+calcd.for C24H28N3O2,390.2182;found 390.2181。
实施例77:CIVb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率39%。
1H NMR(400MHz,CDCl3):δ7.78(s,1H),7.72(d,J=9.3Hz,2H),6.98(d,J=9.1Hz,2H),6.73(s,2H),3.62(q,J=6.8Hz,8H),2.82(s,3H),1.29(t,J=6.8Hz,12H);13C NMR(101MHz,CDCl3)δ168.0,158.1,155.5,149.3,145.2,132.3,125.1,114.5,113.1,96.4,46.2,29.7,19.4,12.8.ESI-HRMS(m/z):[M]+calcd.for C25H30N3OS+,420.2110;found420.2106。
实施例78:CIVc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率50%。
1H NMR(400MHz,CDCl3):δ7.99(d,J=9.6Hz,2H),7.80(s,1H),7.42-7.41(m,9H),7.30(s,1H),7.22-7.20(m,6H),6.88(dd,J=9.6Hz,1.8Hz,2H),6.73(d,J=1.9Hz,2H),3.88(s,3H),3.63(q,J=7.0Hz,8H),1.31(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.2,155.3,148.7,141.7,141.1,141.0,132.5,129.7,128.9,128.7,127.5,114.0,112.6,96.6,46.2,12.9.ESI-HRMS(m/z):[M]+calcd.for C43H43N4O,631.3437;found631.3438。
实施例79:CIVd的制备
利用通用制备流程二制备,化合物为紫红色固体,产率21%。
1H NMR(400MHz,CDCl3):δ8.19(s,1H),7.91(d,J=7.8Hz,1H),7.78(d,J=7.8Hz,1H),7.74(dd,J=8.4Hz,2.2Hz,1H),7.65-7.62(m,1H),7.43-7.35(m,2H),6.90(d,J=9.9Hz,1H),6.79(s,2H),3.72-3.55(m,10H),2.93(s,3H),1.34(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ165.7,163.0,161.0,147.8,137.2,132.9,132.6,131.2,131.1,129.2,128.6,128.6,124.8,124.8,120.5,120.3,119.5,119.3,116.4,113.7,96.5,70.7,46.4,46.1,43.6,36.4,12.8.ESI-HRMS(m/z):[M]+calcd.for C33H35FN5O2 +,552.2775;found552.2777。
实施例80:CVa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率41%。
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.30(d,J=9.6Hz,2H),7.09-7.02(m,4H),6.98(d,J=9.5Hz,1H),6.89(s,1H),6.77-6.74(m,3H),6.56(dd,J=9.3Hz,1.5Hz,1H),5.01(q,J=6.8Hz,1H),3.69(q,J=7.0Hz,4H),3.60(q,J=7.0Hz,4H),1.86(d,J=6.9Hz,3H),1.36(t,J=7.0Hz,6H),1.30(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ157.7,157.6,155.8,155.6,144.7,140.5,131.4,130.8,129.0,128.4,125.8,115.0,114.2,113.9,113.8,97.0,96.8,57.0,46.4,22.4,12.8.ESI-HRMS(m/z):[M]+calcd.for C32H37N4O+,493.2967;found 493.2968。
实施例81:CVIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率83%。
1H NMR(400MHz,CDCl3):δ8.86(d,J=4.0Hz,1H),8.61(s,1H),7.85(d,J=7.6Hz,1H),7.66(m,1H),7.27(d,J=9.0Hz,2H),6.97(dd,J=9.5Hz,1.9Hz,2H),6.87(d,J=2.0Hz,2H),3.66(q,J=7.0Hz,8H),1.33(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3):δ157.9,155.8,153.1,151.6,149.2,137.5,131.5,128.3,124.1,114.8,113.5,96.9,46.4,12.8.ESI-MS(m/z):[M]+calcd.for C26H30N3O,400.2389;found 400.2389。
实施例82:CVIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率54%。
1H NMR(400MHz,CDCl3):δ8.80(s,1H),7.94(d,J=7.6Hz,1H),7.35(m,1H),7.29(d,J=9.0Hz,2H),6.87(dd,J=9.0Hz,1.9Hz,2H),6.82(d,J=2.0Hz,2H),3.65(q,J=7.1Hz,8H),1.33(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3):δ157.8,155.7,153.4,151.5,149.6,137.2,131.3,128.5,124.2,114.9,113.2,97.0,46.6,12.8.ESI-MS(m/z):[M]+calcd.for C26H29N3O,434.1999;found 434.1998。
实施例83:CVIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率51%。
1H NMR(400MHz,CDCl3):δ8.65(s,1H),7.88(d,J=7.6Hz,1H),7.30(m,1H),7.19(d,J=9.0Hz,2H),6.83(dd,J=9.0Hz,1.9Hz,2H),6.77(d,J=2.0Hz,2H),3.63(q,J=7.1Hz,8H),1.32(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3):δ157.1,155.3,153.8,151.2,149.9,137.5,131.7,128.6,124.7,114.0,113.1,96.5,46.3,23.9,12.8.ESI-MS(m/z):[M]+calcd.for C27H32N3O,414.2545;found 414.2546。
实施例84:CVIIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率42%。
1H NMR(400MHz,CDCl3):δ8.39(d,J=4.0Hz,1H),7.41(s,1H),7.31(d,J=4.0Hz,1H),7.20(d,J=9.0Hz,2H),6.82(dd,J=9.0Hz,1.9Hz,2H),6.71(d,J=2.0Hz,2H),3.64(q,J=7.1Hz,8H),1.31(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3):δ156.9,155.5,153.9,151.3,149.7,138.5,135.7,128.7,124.9,115.0,113.7,96.8,46.2,12.8.ESI-MS(m/z):[M]+calcd.for C26H29FN3O,418.2295;found 418.2296。
实施例85:CVIIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率46%。
1H NMR(400MHz,CDCl3):δ8.60(m,1H),7.63(m,1H),7.41(s,1H),7.15(d,J=9.0Hz,2H),6.84(dd,J=9.0Hz,1.9Hz,2H),6.65(d,J=2.0Hz,2H),3.62(q,J=7.1Hz,8H),2.51(s,3H),1.31(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3):δ159.7,156.5,154.9,152.3,149.5,137.5,136.7,127.7,125.9,116.0,114.7,96.8,46.4,24.3,12.8.ESI-MS(m/z):[M]+calcd.for C26H29FN3O,418.2295;found 418.2296。
实施例86:CVIIIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率36%。
1H NMR(400MHz,CDCl3):δ9.24(s,1H),7.25(d,J=9.1Hz,2H),7.01(d,J=9.1Hz,2H),6.87(s,2H),3.67(q,J=7.0Hz,8H),2.42(s,3H),1.33(t,J=6.7Hz,12H);13C NMR(101MHz,CDCl3)δ160.9,157.9,156.8,156.5,148.7,130.2,129.3,115.7,114.5,97.6,46.8,19.5,12.9.ESI-HRMS(m/z):[M]+calcd.for C26H30FN4O,433.2404;found 433.2406。
实施例87:CIXa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率43%。
1H NMR(400MHz,CDCl3):δ8.58(d,J=8.7Hz,1H),7.28(d,J=8.4Hz,1H),7.33(d,J=9.5Hz,2H),6.95(dd,J=9.6Hz,1.8Hz,2H),6.78(d,J=1.8Hz,2H),3.63(q,J=7.0Hz,8H),1.34(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.4,158.2,155.8,154.2,150.0,133.3,131.8,130.6,115.0,113.2,100.1,96.6,77.5,12.8.ESI-HRMS(m/z):[M]+calcd.for C25H28ClN4O,435.1952;found 435.1953。
实施例88:CXa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率44%。
1H NMR(400MHz,CDCl3):δ8.94(s,1H),8.70(s,1H),7.16(s,2H),6.76(s,2H),6.68(s,2H),3.53(q,J=8.0Hz,8H),1.25(t,J=6.6Hz,12H);13C NMR(101MHz,CDCl3)δ157.9,157.9,154.9,131.9,131.8,113.9,113.8,112.6,112.5,96.3,46.0,12.8.ESI-HRMS(m/z):[M+H]+calcd.for C26H29N4O3,445.2240;found445.2242。
实施例89:CXb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率31%。
1H NMR(400MHz,CDCl3):δ8.98(s,1H),8.79(s,1H),7.19(s,2H),6.76(s,2H),6.66(s,2H),3.51(q,J=8.0Hz,8H),1.33(t,J=6.6Hz,12H);13C NMR(101MHz,CDCl3)δ159.4,159.1,154.5,131.4,131.0,113.5,112.8,112.3,112.0,96.6,46.0,12.8.ESI-HRMS(m/z):[M]+calcd.for C25H28FN4O3,419.2247;found 419.2245。
实施例90:CXIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率41%。
1H NMR(400MHz,CDCl3):δ9.48(s,1H),8.85(s,2H),7.21(d,J=9.2Hz,2H),7.01(d,J=9.4Hz,2H),6.97(s,2H),3.67(q,J=7.0Hz,8H),1.34(t,J=6.7Hz,12H);13C NMR(101MHz,CDCl3)δ160.1,157.8,156.9,156.0,148.5,130.7,115.2,113.5,97.5,46.6,12.9.ESI-HRMS(m/z):[M]+calcd.for C25H29N4O,401.2341;found 401.2342。
实施例91:CXIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率39%。
1H NMR(400MHz,CDCl3):δ8.86(s,2H),7.27(d,J=9.3Hz,2H),7.04(d,J=9.3Hz,2H),6.99(s,2H),3.65(q,J=7.0Hz,8H),1.33(t,J=6.7Hz,12H);13C NMR(101MHz,CDCl3)δ160.5,158.8,156.4,156.1,148.8,130.9,116.2,114.5,97.1,46.5,12.8.ESI-HRMS(m/z):[M]+calcd.for C25H28ClN4O,435.1952;found 435.1953。
实施例92:CXIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率37%。
1H NMR(400MHz,CDCl3):δ8.89(s,2H),7.17(d,J=9.2Hz,2H),7.01(d,J=9.2Hz,2H),6.98(s,2H),3.65(q,J=7.0Hz,8H),1.32(t,J=6.9Hz,12H);13C NMR(101MHz,CDCl3)δ160.0,157.5,156.1,155.8,147.5,132.7,116.2,114.5,97.8,46.7,12.8.ESI-HRMS(m/z):[M]+calcd.for C25H28FN4O,419.2247;found 419.2246。
实施例93:CXId的制备
利用通用制备流程二制备,化合物为紫红色固体,产率41%。
1H NMR(400MHz,CDCl3):δ8.80(s,2H),7.15(d,J=9.3Hz,2H),6.97(d,J=9.3Hz,2H),6.88(s,2H),3.63(q,J=7.0Hz,8H),2.18(s,3H),1.33(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ159.5,157.8,156.6,155.0,148.5,132.3,116.1,115.5,97.3,46.7,21.5,12.8.ESI-HRMS(m/z):[M]+calcd.for C26H31N4O,415.2498;found 415.2499。
实施例94:CXIIa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率63%。
1H NMR(400MHz,CDCl3):δ7.28(d,J=5.4Hz,1H),7.99(d,J=8.8Hz,2H),6.44(dd,J=8.8Hz,1.9Hz,2H),6.39(d,J=1.9Hz,2H),6.29(d,J=5.4Hz,1H),3.36(t,J=7.0Hz,8H),1.17(q,J=7.0Hz,12H);13C NMR(101MHz,CDCl3):δ173.2,157.8,152.8,149.7,128.2,120.4,108.0,102.5,98.2,44.6,12.6.ESI-HRMS(m/z):[M+H]+calcd.for C24H29N2O3,393.2178;found 393.2176。
实施例95:CXIIb的制备
利用通用制备流程二制备,化合物为紫红色固体,产率68%。
1H NMR(400MHz,CDCl3):δ7.80(d,J=9.4Hz,1H),7.46(d,J=7.8Hz,1H),7.27(d,J=7.5Hz,1H),7.08-7.02(m,3H),6.91(s,1H),6.85(t,J=7.6Hz,1H),6.75(d,J=8.9Hz,1H),6.33(d,J=8.4Hz,1H),4.69(s,1H),3.73(q,J=7.0Hz,4H),3.59(q,J=7.2Hz,4H),3.15-3.11(m,1H),2.99-2.87(m,3H),2.77(d,J=16.6Hz,2H),2.18-2.12(m,2H),2.01-1.94(m,2H),1.87(d,J=13.6Hz,1H),1.64(d,J=12.7Hz,1H),1.50(t,J=13.6Hz,12H),1.37(t,J=7.0Hz,6H),1.28(t,J=7.1Hz,6H),1.01(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3):δ158.3,157.6,156.2,155.7,148.2,133.6,131.4,130.0,128.7,126.6,123.6,123.5,121.2,119.2,115.3,114.9,113.7,112.7,110.9,109.5,97.6,97.0,56.0,51.8,46.6,46.3,45.3,38.9,30.0,27.4,19.9,16.4,12.8,9.0.ESI-MS(m/z):[M]+calcd.forC40H47N4O,599.3750;found 599.3751。
实施例96:CXIIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率35%。
1H NMR(400MHz,CDCl3):δ8.03(d,J=9.4Hz,2H),7.91(s,1H),7.34(d,J=9.0Hz,1H),7.04(s,1H),6.81(dd,J=9.6Hz,1.6Hz,2H),6.54(d,J=1.9Hz,2H),6.24(d,J=9.0Hz,1H),3.53(q,J=7.0Hz,8H),3.46(q,J=7.1Hz,4H),1.30(t,J=7.0Hz,12H),1.24(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ161.5,156.68,153.7,130.6,112.2,112.0,111.3,105.5,96.4,45.5,45.1,13.1,12.8.;ESI-MS(m/z):[M]+calcd.for C34H40N3O3,538.3070;found 538.3072。
实施例97:CXIId的制备
利用通用制备流程二制备,化合物为紫红色固体,产率46%。
1H NMR(400MHz,CDCl3):δ8.60(s,1H),7.84(d,J=9.3Hz,1H),7.61(d,J=12.4Hz,1H),7.84(d,J=9.5Hz,1H),6.92(d,J=8.8Hz,1H),6.79(dd,J=9.5Hz,2.2Hz,1H),6.10(dd,J=5.3Hz,2.3Hz,2H),5.61(s,1H),4.47(s,2H),3.58-3.48(m,8H),3.46-3.38(m,4H),2.69(s,4H),2.44(s,3H),1.53(d,J=6.0Hz,3H),1.27-1.22(m,12H);13C NMR(101MHz,CDCl3)δ173.4,173.4,158.2,157.9,156.9,155.6,155.1,154.4,154.1,142.8,140.2,140.1,133.3,132.4,131.2,131.1,125.1,122.0,121.9,114.6,114.3,114.1,113.4,111.7,104.7,104.5,95.8,95.7,68.9,55.4,54.0,49.9,49.9,45.9,45.8,45.8,18.9,12.6.ESI-HRMS(m/z):[M]+calcd.for C38H45FN5O3 +,638.3506;found638.3502。
实施例98:CXIIe的制备
利用通用制备流程二制备,化合物为紫红色固体,产率35%。
1H NMR(400MHz,CDCl3):δ8.00(d,J=9.6Hz,2H),7.60(d,J=16.2Hz,1H),7.55-7.45(m,5H),7.25(d,J=8.0Hz,2H),7.20(d,J=16.2Hz,1H),7.02(dd,J=9.6Hz,2.2Hz,2H),6.71(d,J=2.2Hz,2H),3.63(q,J=7.1Hz,8H),1.32(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ157.6,155.2,154.4,144.8,141.5,132.7,130.3,130.1,127.1,117.4,114.2,112.5,96.2,46.1,12.6;ESI-MS(m/z):[M]+calcd.for C29H33N2O,425.2593;found425.2594。
实施例99:CXIIf的制备
利用通用制备流程二制备,化合物为紫红色固体,产率34%。
1H NMR(400MHz,CDCl3):δ8.00(d,J=9.6Hz,2H),7.63(d,J=16.2Hz,1H),7.59(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),7.15(d,J=16.2Hz,1H),7.02(dd,J=9.6Hz,2.2Hz,2H),6.71(d,J=2.2Hz,2H),3.62(q,J=7.1Hz,8H),2.38(s,3H),1.31(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ157.7,155.3,154.1,145.0,141.2,132.4,130.9,130.0,128.1,117.7,114.0,112.2,96.5,46.1,21.6,12.8;ESI-MS(m/z):[M]+calcd.for C30H35N2O,439.2749;found 439.2749。
实施例100:CXIIg的制备
利用通用制备流程二制备,化合物为紫红色固体,产率30%。
1H NMR(400MHz,CDCl3):δ8.12(d,J=9.6Hz,2H),7.86-7.79(m,3H),7.18-7.14(m,3H),7.07(dd,J=9.6Hz,2.5Hz,2H),6.74(d,J=2.5Hz,2H),3.64(q,J=7.1Hz,8H),1.33(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ157.8,155.5,154.4,143.6,131.4,130.5,130.4,116.6,116.3,114.2,112.5,96.6,46.2,12.8;ESI-MS(m/z):[M]+calcd.forC29H32FN2O,443.2499;found 443.2495。
实施例101:CXIIh的制备
利用通用制备流程二制备,化合物为紫红色固体,产率47%。
1H NMR(400MHz,CDCl3):δ7.82(d,J=9.6Hz,2H),7.77(d,J=16.2Hz,1H),7.63(d,J=8.2Hz,1H),7.37(d,J=16.2Hz,1H),7.36(d,J=8.2Hz,1H),7.12(t,J=7.6Hz,1H),6.75(dd,J=9.6Hz,1.8Hz,2H),6.73(t,J=7.6Hz,1H),6.55(d,J=1.8Hz,2H),3.50(q,J=7.0Hz,8H),1.23(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ158.6,157.3,155.1,154.8,143.6,131.9,130.8,129.2,122.1,119.1,118.3,118.1,113.4,111.7,96.3,45.9,12.7.ESI-HRMS(m/z):[M]+calcd.forC29H33N2O2,441.2542;found 441.2542。
实施例102:CXIIi的制备
利用通用制备流程二制备,化合物为紫红色固体,产率44%。
1H NMR(400MHz,CDCl3):δ8.02(d,J=9.5Hz,2H),7.92(d,J=15.8Hz,1H),7.57(d,J=15.8Hz,1H),7.35(d,J=2.0Hz,1H),7.30(d,J=8.7Hz,1H),6.86(dd,J=9.6Hz,1.9Hz,2H),6.61(d,J=1.9Hz,2H),6.39(dd,J=8.7Hz,2.0Hz,1H),3.86(s,3H),3.57(q,J=7.1Hz,8H),1.31(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ164.0,161.8,157.5,154.7,146.0,131.2,130.9,115.9,115.5,113.1,111.8,108.4,101.8,96.3,55.9,45.8,12.8;ESI-MS(m/z):[M]+calcd.for C30H35N2O3,471.2648;found 471.2646。
实施例103:CXIIj的制备
利用通用制备流程二制备,化合物为紫红色固体,产率42%。
1H NMR(400MHz,CDCl3):δ7.97(d,J=9.5Hz,2H),7.78(t,J=16.2Hz,1H),7.52-7.45(m,3H),6.90(d,J=9.5Hz,2H),6.66(d,J=11.4Hz,1H),6.65(s,2H),4.13(s,3H),3.54(q,J=7.0Hz,8H),3.36(q,J=7.1Hz,4H),1.30(t,J=7.0Hz,12H),1.25(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ157.5,155.0,154.8,147.6,146.0,144.8,142.6,133.3,131.1,122.4,120.6,118.4,114.4,113.7,112.0,107.1,96.3,61.1,45.9,12.8.ESI-HRMS(m/z):[M]+calcd.for C32H35N2O4 +,511.2597;found 511.2594。
实施例104:CXIIIc的制备
利用通用制备流程二制备,化合物为紫红色固体,产率83%。
1H NMR(400MHz,CDCl3):δ8.19(d,J=9.5Hz,2H),7.03(dd,J=9.5Hz,1.7Hz,2H),6.71(d,J=1.7Hz,2H),3.80(t,J=5Hz,2H),3.59-3.52(m,10H),1.99-1.92(m,10H),1.27(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ162.7,157.6,155.4,130.6,114.2,113.2,95.8,77.5,77.2,76.8,60.8,45.9,34.9,25.4,12.7;ESI-MS(m/z):[M]+calcd.forC24H33N2O2,381.2542;found381.2542。
实施例105:CXIIId的制备
利用通用制备流程二制备,化合物为紫红色固体,产率81%。
1H NMR(400MHz,CDCl3):δ8.22(d,J=9.4Hz,2H),7.03(d,J=9.4Hz,2H),6.64(s,2H),3.72(t,J=7.4Hz,2H),3.60(q,J=7.0Hz,8H),3.01(t,J=7.4Hz,2H),1.32(q,J=7.0Hz,12H);13C NMR(101MHz,CDCl3):δ159.8,157.7,155.5,130.5,114.4,113.2,96.0,46.0,36.6,24.2,12.7;EI-HRMS(m/z):[M]+calcd.for C24H31N2O3,395.2335;found395.2333。
实施例106:CXIIIe的制备
利用通用制备流程二制备,化合物为紫红色固体,产率84%。
1H NMR(400MHz,CDCl3):δ7.54(d,J=8.8Hz,1H),7.25(d,J=7.4Hz,1H),6.50(dd,J=8.8Hz,2.5Hz,1H),6.45(dd,J=8.7Hz,2.5Hz,1H),6.40(d,J=2.5Hz,1H),6.37(d,J=2.5Hz,1H),6.31(dd,J=5.8Hz,1.4Hz,1H),6.19(dd,J=5.8Hz,1.4Hz,1H),4.86(s,1H),4.69(t,J=8.8Hz,1H),4.31(d,J=1.0Hz,1H),4.19(dd,J=8.8Hz,4.9Hz,1H),3.39-3.31(m,8H),2.91-2.86(m,1H),2.33(d,J=7.7Hz,1H),1.17(t,J=6.9Hz,6H),1.16(t,J=6.9Hz,6H);13C NMR(101MHz,CDCl3)δ152.3,151.0,148.3,147.9,137.7,136.8,129.1,125.8,119.2,112.1,107.9,107.5,98.6,98.2,82.7,80.7,79.9,73.8,62.0,47.9,44.5,12.7,12.6.ESI-HRMS(m/z):[M+H]+calcd.for C28H34N2O3,447.2648;found447.2648。
实施例107:CXIIIf和CXIIIg的制备
利用通用制备流程二制备,化合物为紫红色固体,产率80%。
1H NMR(400MHz,CDCl3):δ7.56(d,J=8.9Hz,1H),7.23(d,J=7.4Hz,1H),6.56(dd,J=8.8Hz,2.3Hz,1H),6.45(dd,J=8.7Hz,2.3Hz,1H),6.40(d,J=2.3Hz,1H),6.37(d,J=2.3Hz,1H),6.33(dd,J=5.8Hz,1.4Hz,1H),6.21(dd,J=5.8Hz,1.4Hz,1H),4.91(s,1H),4.71(t,J=8.8Hz,1H),4.41(d,J=1.0Hz,1H),4.27(dd,J=8.8Hz,4.9Hz,1H),3.37-3.32(m,8H),1.17(t,J=7.0Hz,6H),1.16(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ156.3,153.0,149.3,148.9,138.7,137.8,129.9,125.2,119.7,112.6,108.0,107.6,98.2,98.1,83.7,80.4,79.9,74.5,62.3,47.9,12.8,12.7.ESI-HRMS(m/z):[M+H]+calcd.forC28H32N2O4,461.2440;found 461.2441。
实施例108:CXIIIh的制备
利用通用制备流程二制备,化合物为紫红色固体,产率59%。
1H NMR(400MHz,CDCl3):δ7.02(d,J=9.2Hz,2H),6.93(d,J=8.1Hz,1H),6.39-6.37(m,4H),6.33(d,J=1.5Hz,1H),6.24(dd,J=8.1Hz,1.5Hz,1H),513.84(s,3H),3.34(q,J=7.0Hz,8H),2.68(s,3H),2.65(t,J=6.1Hz,2H),2.03(t,J=6.1Hz,2H),1.18(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ159.6,152.5,148.1,128.6,127.8,116.3,115.0,107.2,99.7,98.5,97.6,77.5,77.2,76.8,58.6,55.4,44.5,41.5,35.4,23.9,12.8;ESI-MS(m/z):[M]+calcd.forC31H40N3O2,486.3121;found 486.3121。
实施例109:CXIIIi和CXIIIj的制备
利用通用制备流程二制备,化合物为紫红色固体,产率71%。
1H NMR(400MHz,CDCl3):δ8.38(s,.1H),7.82(s,1H),6.95(d,J=9.0Hz,2H),6.62(s,2H),3.57(q,J=7.0Hz,8H),2.80(d,J=6.2Hz,1H),2.23(d,J=6.2Hz,1H),1.60(s,3H),1.29(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ174.4,159.5,157.8,155.3,131.8,115.3,113.9,95.8,46.0,38.6,30.9,26.8,24.2,20.3,12.7.ESI-HRMS(m/z):[M+H]+calcd.forC27H35N2O3,435.2648;found435.2648。
实施例110:CXIIIk和CXIIIl的制备
利用通用制备流程二制备,化合物为紫红色固体,产率68%。
1H NMR(400MHz,CDCl3):δ7.38(d,J=7.2Hz,1H),7.25(d,J=8.8Hz,1H),7.16(t,J=7.4Hz,1H),7.12-7.06(m,2H),7.01-6.93(m,3H),6.89(d,J=7.3Hz,1H),6.55(d,J=2.1Hz,1H),6.44(d,J=8.8Hz,1H),6.43(s,1H),6.39(dd,J=8.8Hz,2.2Hz,1H),6.34(dd,J=8.7Hz,2.3Hz,1H),4.78(d,J=4.2Hz,1H),3.86(d,J=1.8Hz,1H),3.62(dd,J=9.7Hz,4.2Hz,1H),3.44(q,J=7.0Hz,4H),3.31(q,J=7.0Hz,4H),2.69(dd,J=9.7Hz,1.9Hz,1H),1.25(t,J=7.0Hz,6H),1.12(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3):δ176.7,153.1,151.6,149.0,148.5,145.1,142.0,141.9,138.5,128.7,128.5,126.6,126.3,126.0,125.6,125.1,124.3,123.3,123.2,116.8,108.6,107.3,106.4,99.2,98.7,82.2,57.0,47.8,46.1,45.5,44.7,44.6,12.8,12.6.EI-HRMS(m/z):[M+H]+calcd.forC38H39N2O3,571.2961;found 571.2966。
实施例111:CXIIIm的制备
利用通用制备流程二制备,化合物为紫红色固体,产率83%。
1H NMR(400MHz,CDCl3):δ7.93(s,2H),6.97(s,2H),6.69(s,2H),5.13(d,J=8.4Hz,1H),3.63(q,J=8.0Hz,8H),1.96(d,J=6.2Hz,1H),1.85-1.77(m,7H),1.39(s,3H),1.31(t,J=7.8Hz,12H),0.80(s,3H);13C NMR(101MHz,CDCl3)δ158.8,155.4,136.8,131.0,121.2,115.3,113.8,96.2,46.1,33.2,32.2,29.7,26.4,26.0,24.2,21.5,18.6,12.8.ESI-HRMS(m/z):[M]+calcd.for C26H29N4O3 +,445.3219;found445.3220。
实施例112:CXIIIn的制备
利用通用制备流程二制备,化合物为紫红色固体,产率70%。
1H NMR(400MHz,CDCl3):δ8.11(d,J=9.9Hz,1H),8.02(d,J=9.7Hz,1H),7.11(d,J=9.0Hz,1H),6.95(d,J=8.7Hz,1H),6.67(dd,J=6.2Hz,1.4Hz,2H),4.39(t,J=8.3Hz,1H),3.61(q,J=7.8Hz,8H),2.98-2.90(m,1H),2.33(s,2H),1.88-1.85(m,1H),1.45(s,3H),1.31(t,J=7.0Hz,12H),1.20(s,3H),0.81(s,3H);13C NMR(101MHz,CDCl3)δ162.4,157.8,157.3,155.3,154.6,132.2,130.8,115.4,114.6,113.8,113.0,96.2,57.1,51.2,48.1,46.1,46.0,35.0,30.1,25.6,25.2,20.8,12.9.ESI-HRMS(m/z):[M]+calcd.forC30H41N2O3 +,477.3117;found477.3120。
实施例113:CXIIIo的制备
利用通用制备流程二制备,化合物为紫红色固体,产率82%。
1H NMR(400MHz,CDCl3):δ7.87(d,J=9.6Hz,2H),6.96(d,J=9.5Hz,2H),6.57(d,J=1.0Hz,2H),3.53(q,J=7.0Hz,8H),3.05(s,2H),1.81(s,3H),1.51-1.41(m,12H),1.21(t,J=7.1Hz,12H).13C NMR(101MHz,CDCl3):δ157.6,156.9,155.0,130.9,114.4,113.3,95.6,45.7,43.5,40.8,37.2,36.1,28.6,12.5.EI-HRMS(m/z):[M]+calcd.For C32H43N2O,471.3375;found 471.3376。
实施例114:CXIIIp的制备
利用通用制备流程二制备,化合物为紫红色固体,产率61%。
1H NMR(400MHz,CDCl3):δ8.02(d,J=9.6Hz,2H),7.05(d,J=9.5Hz,2H),6.64(s,2H),3.59(q,J=7.0Hz,8H),3.24(s,2H),2.10(s,3H),1.60(s,6H),1.45-1.42(m,6H),1.30(t,J=7.1Hz,12H).13C NMR(101MHz,CDCl3):δ157.8,157.3,155.4,131.4,114.9,113.8,95.9,68.3,50.7,45.9,43.9,42.7,40.3,40.1,35.2,30.9,29.7,23.2,12.7.EI-HRMS(m/z):[M]+calcd.for C32H43N2O2,487.3325;found 487.3327。
实施例115:CXIIIq的制备
利用通用制备流程二制备,化合物为紫红色固体,产率79%。
1H NMR(400MHz,CDCl3):δ7.97(d,J=9.4Hz,2H),7.00(d,J=9.4Hz,2H),6.66(s,2H),3.96(s,3H),3.58(q,J=7.1Hz,8H),3.26(s,2H),2.12(s,3H),1.61(s,6H),1.43-1.40(m,6H),1.30(t,J=7.1Hz,12H).13C NMR(101MHz,CDCl3):δ157.7,157.2,156.4,134.4,112.9,111.8,95.6,64.3,52.7,46.9,43.3,42.4,40.3,40.0,36.2,30.7,29.4,23.2,19.8,12.7.EI-HRMS(m/z):[M]+calcd.for C33H45N2O2,501.3481;found 501.3482。
实施例116:CXIIIr的制备
利用通用制备流程二制备,化合物为紫红色固体,产率77%。
1H NMR(400MHz,CDCl3):δ7.95(d,J=9.4Hz,2H),7.04(d,J=9.4Hz,2.2Hz,2H),6.70(d,J=2.2Hz,2H),3.96(s,3H),3.64(q,J=7.1Hz,8H),3.18(s,2H),2.00(m,1H),1.34-1.31(m,14H),1.22-1.19(m,8H),1.09-1.00(m,2H),0.73(s,6H).13C NMR(101MHz,CDCl3):δ157.9,157.4,155.4,131.2,114.8,113.6,96.1,50.7,50.2,46.1,42.6,42.3,40.6,39.1,31.9,30.5,29.9,12.8.EI-HRMS(m/z):[M]+calcd.for C33H45N2O2,499.3688;found 499.3687。
实施例117:CXIIIs的制备
利用通用制备流程二制备,化合物为紫红色固体,产率67%。
1H NMR(400MHz,CDCl3):δ7.32(dd,J=8.8Hz,1.9Hz,1H),7.20-7.16(m,3H),7.04(dd,J=8.8Hz,1.9Hz,1H),6.97(t,J=8.9Hz,1H),6.43(d,J=2.1Hz,2H),6.36(dd,J=8.8Hz,2.1Hz,2H),3.37-3.28(m,8H),2.11(s,2H),1.17(s,6H),1.14(t,J=7.0Hz,12H);13CNMR(101MHz,CDCl3)δ155.1,152.7,148.2,131.5,127.5,127.0,126.6,120.7,117.4,116.4,107.5,99.0,72.9,52.2,44.6,32.1,31.3,12.7;ESI-MS(m/z):[M]+calcd.forC31H39N2O2,471.3012;found 471.3010。
实施例118:CXIIIt的制备
利用通用制备流程二制备,化合物为紫红色固体,产率57%。
1H NMR(400MHz,CDCl3):δ7.18(d,J=8.7Hz,2H),6.95(d,J=8.8Hz,1H),6.85(d,J=2.9Hz,1H),6.76(dd,J=8.8Hz,2.9Hz,1H),6.42(d,J=2.1Hz,2H),6.36(dd,J=8.7Hz,2.1Hz,2H),3.82(s,3H),3.32(q,J=7.0Hz,8H),2.13(s,2H),1.18(s,6H),1.14(t,J=7.0Hz,12H);13C NMR(101MHz,CDCl3)δ153.7,152.7,149.2,148.2,132.7,126.7,118.0,116.3,112.8,112.0,107.4,98.9,72.7,55.9,52.1,44.6,31.9,31.8,12.7;ESI-MS(m/z):[M]+calcd.for C32H41N2O3,501.3117;found 501.3115。
实施例119:CXIIIu的制备
利用通用制备流程二制备,化合物为紫红色固体,产率55%。
1H NMR(400MHz,CDCl3):δ7.24(d,J=8.9Hz,2H),6.93(d,J=8.7Hz,1H),6.70(s,1H),6.67(d,J=8.8Hz,1H),6.41(s,2H),6.37(d,J=8.9Hz,2H),3.31-3.27(m,12H),2.10(s,2H),1.17-1.12(m,24H);13C NMR(101MHz,CDCl3)δ152.7,148.1,147.1,142.8,131.8,126.8,117.7,116.8,114.4,112.6,107.5,99.0,72.2,52.4,45.5,44.6,32.0,31.6,12.8,12.7.;ESI-MS(m/z):[M]+calcd.forC35H48N3O2,542.3747;found 542.3743。
实施例120:CXIIIv的制备
利用通用制备流程二制备,化合物为紫红色固体,产率53%。
1H NMR(400MHz,CDCl3):δ8.28(d,J=2.7Hz,1H),8.09(d,J=9.0Hz,2.7Hz,1H),7.12-7.10(m,3H),6.46(d,J=2.5Hz,2H),6.39(dd,J=9.0Hz,2.5Hz,2H),3.34(q,J=7.1Hz,12H),2.21(s,2H),1.28(s,6H),1.17(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ161.0,152.7,148.5,141.6,132.4,126.2,123.7,123.7,118.0,114.6,107.4,98.8,51.2,44.5,31.9,31.8,12.6;ESI-MS(m/z):[M]+calcd.forC31H38N3O4,516.2862;found516.2864。
实施例121:CXIIIw的制备
利用通用制备流程二制备,化合物为紫红色固体,产率56%。
1H NMR(400MHz,CDCl3):δ7.22(d,J=8.9Hz,2H),6.96(d,J=8.7Hz,1H),6.57(d,J=8.8Hz,1H),6.50(s,1H),6.46(s,2H),6.39(d,J=8.9Hz,2H),3.30-3.26(m,12H),2.10(s,2H),1.18-1.13(m,24H);13C NMR(101MHz,CDCl3)δ153.7,148.7,147.3,142.9,131.5,126.3,117.9,115.8,115.4,112.6,108.5,99.2,72.1,52.4,45.7,44.0,32.4,31.2,12.8,12.7.;ESI-MS(m/z):[M]+calcd.forC35H48N3O2,542.3747;found 542.3746。
实施例122:CXIIIx的制备
利用通用制备流程二制备,化合物为紫红色固体,产率51%。
1H NMR(400MHz,CDCl3):δ8.16(d,J=2.5Hz,1H),8.00(d,J=9.0Hz,2.5Hz,1H),7.05-7.01(m,3H),6.48(d,J=2.5Hz,2H),6.29(dd,J=9.0Hz,2.5Hz,2H),3.34(q,J=7.1Hz,12H),2.19(s,2H),1.27(s,6H),1.17(t,J=7.1Hz,12H);13C NMR(101MHz,CDCl3)δ160.5,152.2,148.3,142.6,132.9,126.0,124.7,122.7,118.0,115.6,106.4,97.8,51.4,44.6,32.2,31.5,12.8;ESI-MS(m/z):[M]+calcd.forC32H38N3O2,496.2964;found496.2965。
实施例123:CXIIIy的制备
利用通用制备流程二制备,化合物为紫红色固体,产率59%。
1H NMR(400MHz,CDCl3):δ8.13(d,J=9.4Hz,2H),6.86(dd,J=9.2Hz,1.8Hz,2H),6.58(d,J=1.8Hz,2H),3.55(q,J=7.1Hz,8H),1.30(t,J=7.1Hz,12H).13C NMR(101MHz,CDCl3):δ159.1,155.4,134.2,113.2,110.5,100.1,95.6,45.8,12.7.EI-HRMS(m/z):[M]+calcd.forC22H27N2O3,367.2022;found 367.2021。
实施例124:CXIIIz的制备
利用通用制备流程二制备,化合物为紫红色固体,产率75%。
1H NMR(400MHz,CDCl3):δ7.19(d,J=8.6Hz,1H),7.01(d,J=8.6Hz,1H),6.48-6.42(m,4H),6.33-6.31(m,1H),6.17-6.15(m,1H),3.57(dd,J=8.9Hz,5.1Hz,1H),3.40-3.32(m,8H),3.28(s,1H),2.92(dd,J=8.9Hz,3.7Hz,1H),2.61(s,1H),1.46(d,J=8.0Hz,1H),1.25(d,J=5.7Hz,1H),1.19(t,J=7.0Hz,6H),1.16(t,J=7.0Hz,6H);13C NMR(101MHz,CDCl3)δ178.4,153.1,151.8,148.8,148.4,136.0,134.9,127.4,123.3,117.9,110.8,107.4,106.3,99.4,98.8,81.6,58.2,53.1,48.5,46.0,45.5,44.6,44.6,12.7,12.7.ESI-HRMS(m/z):[M+H]+calcd.for C29H34N2O3,459.2648;found459.2646。
实施例125:CXIIIaa的制备
利用通用制备流程二制备,化合物为紫红色固体,产率69%。
1H NMR(400MHz,CDCl3):δ7.26(d,J=8.6Hz,1H),7.07(d,J=8.6Hz,1H),6.50-6.40(m,4H),3.40-3.29(m,8H),3.25(t,J=7.6Hz,1H),2.32-2.17(m,2H),1.54-1.42(m,2H),1.20(s,3H),1.17(t,J=7.0Hz,12H),1.09-0.97(m,4H);13C NMR(101MHz,CDCl3)δ178.9,153.0,152.8,148.4,148.4,126.3,124.1,113.4,110.2,106.9,106.7,106.6,99.4,98.8,81.3,77.4,77.0,76.7,48.0,47.3,44.5,44.4,39.1,38.0,35.1,32.4,31.4,31.3,30.3,29.2,26.9,22.9,22.6,22.2,12.6,12.5.ESI-HRMS(m/z):[M+H]+calcd.forC29H39N2O3,463.2961;found 463.2968。
生物实验
1、罗丹明系列化合物对耐甲氧西林金黄色葡萄球菌(ATCC43300)和鲍曼不动杆菌敏感株(ATCC19606)的最低抑菌浓度和抗菌增效活性。采用微量稀释法,参照CLSI M07-A9标准制备倍比稀释的抗菌药物,测定CXIIIo最低抑菌活性(MICs)。
采用生长方法制备相当于0.5麦氏单位的标准化接种物,再用MHB培养基按1:150稀释,得到用于实验的初始菌液,并在15min内接种,用于测定药物MIC实验。以不含药物的CAMHB接种管为阳性对照,不接种细菌的培养物作为阴性对照,使每管最终菌液浓度约为0.25-0.5×106CFU/ml。将培养物置于37℃,培养16h-20h后,观察细菌的生长情况,并判读药物单独的最低抑菌浓度(MICs)。化合物抗菌活性的评判标准:MIC>64μg/ml,化合物无抗菌活性;16μg/ml<MIC≤64μg/ml,化合物具有弱抗菌活性;MIC≤16μg/ml,化合物具有较强的抗菌活性。
对MIC>32μg/ml的化合物,进一步与64μg/ml苯唑西林联合,筛选其对耐甲氧西林金黄色葡萄球菌(ATCC43300)的抗菌增效活性。采用微量稀释法,固定不同罗丹明染料化合物的终浓度,再按照M07-A9操作步骤依次将苯唑西林倍比稀释。以含单一苯唑西林或单一罗丹明染料化合物的培养液为阳性对照,不接种细菌的培养物为阴性对照,使培养液最终菌浓度约为0.25-0.5×106CFU/ml。将培养物置于37℃,培养16h-20h后,观察细菌的生长情况,判读各组合药物中苯唑西林的MICs。
FIC指数(FICI)=A药联合时MIC/A药单测时MIC+B药联合时MIC/B药单测MIC,其中判断标准:FICI≤0.5,增效;0.5<FICI≤1,叠加,1.0<FICI≤2.0,无关;FICI>2.0,拮抗。
结果如下表1所示。结果证明,罗丹明染料是可以高效发现具有抑菌杀菌活性化合物的化学结构空间,同时也是可以高效发现具有抗菌增效活性化合物的化学结构空间。
表1
2、化合物CXIIIo对不同细菌的最低抑菌浓度。
采用微量稀释法,参照CLSI M07-A9标准制备倍比稀释的抗菌药物,测定CXIIIo最低抑菌活性(MICs)。采用生长方法制备相当于0.5麦氏单位的标准化接种物,再用MHB培养基按1∶150稀释,得到用于实验的初始菌液,并在15min内接种,用于测定药物MIC实验。以不含药物的CAMHB接种管为阳性对照,不接种细菌的培养物作为阴性对照,使每管最终菌液浓度约为0.25-0.5×106CFU/ml。将培养物置于37℃,培养16h-20h后,观察细菌的生长情况,并判读药物单独的最低抑菌浓度(MICs)。
结果如下表2所示。结果证明化合物CXIIIo对多种革兰氏阳性菌和革兰氏阴性菌均有较好杀菌活性。
表2
3、化合物CXIIIo、万古霉素、利萘唑胺、替加环素对处于对数生长早期的耐甲氧西林金黄色葡萄球菌的杀菌曲线。
将过夜培养的ATCC43300(37℃,12h)1:10000接种于20ml MHB液体培养基中。将37℃、225rpm培养2h后的菌液作为初始菌液。向制备好的初始菌液中加入2.5倍,5倍,10倍MIC的CXIIIo化合物及10倍MIC的万古霉素,利奈唑胺,替加环素,同时以不加任何药物做空白对照组,分别于0h,2h,4h,8h,16h,24h定量取样。将取出的菌液依次10倍稀释,分别取适宜稀释倍数的稀释液100μl涂布于计数培养基平板上,且每个稀释倍数涂布2-3个平行板,在36℃±1℃恒温培养箱中倒置培养16~20h,进行菌落计数,以菌落形成单位(CFU)表示。将各培养管菌落计数的对数与培养时间在直角坐标作图,得到时间-杀菌曲线,评价CXIIIo的杀菌效力。
结果如图1所示。图1显示,CXIIIo在同等浓度下或更低的浓度下对耐甲氧西林金黄色葡萄球菌的杀菌效果较临床药物万古霉素、利萘唑胺、替加环素等更好。
4、化合物CXIIIo、替加环素对处于对数生长早期的鲍氏不动杆菌的杀菌曲线。
将过夜培养(37℃,220rpm,16h)的ATCC19606(鲍曼不动杆菌)1:1000接种于LB液体培养基的菌液作为初始菌液。向制备好的初始菌液中加入2.5倍,5倍,10倍MIC的CXIIIo化合物及10倍MIC的替加环素,同时以不加任何药物的做空白对照组,分别于0h,1h,2h,4h,8h,24h定量取样。将取出的菌液依次10倍稀释,分别取适宜稀释倍数的稀释液100μl涂布于计数培养基平板上,且每个稀释倍数涂布2-3个平行板,在36℃±1℃恒温培养箱中倒置培养16~20h,进行菌落计数,以菌落形成单位(CFU)表示。将各培养管菌落计数的对数与培养时间在直角坐标作图,得到时间-杀菌曲线,评价CXIIIo的杀菌效力。
结果如图2所示。图2显示,CXIIIo在等倍数MIC浓度(10*MIC)下鲍氏不动杆菌的杀菌效果较替加环素效果更好。
5、化合物CXIIIo、万古霉素、利萘唑胺对处于对数生长早期的抗万古霉素粪肠球菌(ATCC51299)的杀菌曲线。
将过夜培养的ATCC51299(37℃,12h)1:10000接种于20mlBHI(4μg/ml万古霉素)液体培养基中,37℃,225rpm培养2h后的菌液作为初始菌液。向制备好的初始菌液中加入2.5倍,5倍,10倍MIC的CXIIIo化合物及10倍MIC的利奈唑胺,同时以等浓度(20μg/ml)的万古霉素做阴性对照组,分别于0h,2h,4h,8h,16h,24h定量取样。将取出的菌液依次10倍稀释,分别取适宜稀释倍数的稀释液100μl涂布于计数培养基平板上,且每个稀释倍数涂布2-3个平行板,在36℃±1℃恒温培养箱中倒置培养16~20h,进行菌落计数,以菌落形成单位(Colony-Forming Units,CFU)表示。将各培养管菌落计数的对数与培养时间在直角坐标作图,得到时间-杀菌曲线,评价CXIIIo的杀菌效力。
结果如图3所示。图3显示,CXIIIo在等倍数MIC浓度(10*MIC)或者更低倍数MIC浓度下(2.5MIC或5MIC)对抗万古霉素粪肠球菌的杀菌效果较万古霉素和利萘唑胺效果更好。
6、耐甲氧西林金黄色葡萄球菌(ATCC43300)对CXIIIo的诱导耐药实验。
对左氧氟沙星(Levofloxacin)、万古霉素(Vancomycin)、68#化合物的诱导浓度从0.25MIC开始诱导,第一天诱导浓度为0.25MIC 220rmp 37℃培养24h,第二天浓度梯度为0.25MIC,0.5MIC,1MIC,2MIC,4MIC。37℃培养24h培养以OD600>1.8且cfu/ml>109的最高浓度为第三天浓度梯度的中间浓度进行诱导,接种量为1:100,重复25天。
结果如图4所示,耐甲氧西林金黄色葡萄球菌(ATCC43300)在25天内没有对CXIIIo产生耐药性。
7、甲氧西林敏感株金黄色葡萄球菌(ATCC25923)对CXIIIo的诱导耐药实验。
选用的抗生素有左氧氟沙星(Levofloxacin)、万古霉素(Vancomycin)、四环素(Tetracycline)、庆大霉素(Gentamycin)、红霉素(Erythromycin)等抗生素为对照。CXIIIo及对照抗生素的诱导浓度从0.25MIC开始诱导,第一天诱导浓度为0.25MIC,220rmp,37℃培养24h,第二天浓度梯度为0.25MIC,0.5MIC,1MIC,2MIC,4MIC。37℃培养24h培养以OD600>1.8且cfu/ml>109的最高浓度为第三天浓度梯度的中间浓度进行诱导,接种量为1:100,重复25天。
结果如图5所示,甲氧西林敏感株金黄色葡萄球菌(ATCC25923)在25天内没有对CXIIIo产生耐药性。
8、不同罗丹明染料化合物的浓度与苯唑西林共同作用于甲氧西林金黄色葡萄球菌(ATCC43300)时的部分抑菌浓度。
进一步测定有较好增效活性的罗丹明染料化合物的浓度与增效活性间的关系。采用微量稀释法,固定不同罗丹明染料化合物的终浓度分别为4μg/ml,2μg/ml,1μg/ml,0.5μg/ml,再按照M07-A9操作步骤依次将组合药物中的待测抗生素倍比稀释.以含苯唑西林或单一罗丹明染料化合物的培养液为阳性对照,不接种细菌的培养物为阴性对照,使培养液最终菌浓度约为0.25-0.5×106CFU/ml。将培养物置于37℃,培养16h-20h后,观察细菌的生长情况,判读各组合药物中抗生素的MICs。FIC指数(FICI)=A药联合时MIC/A药单测时MIC+B药联合时MIC/B药单测MIC,其中判断标准:FICI≤0.5,增效;0.5<FICI≤1,叠加,1.0<FICI≤2.0,无关;FICI>2.0,拮抗。
结果如下表3所示,罗丹明染料还是可以发现具有抗菌增效活性化合物的化学结构空间。
表3:浓度-增效活性依赖关系
由实验结果可知,增效活性和化合物浓度依赖关系良好。其中化合物CXIIIt增效活性最佳。
9、CXIIIt的广谱抗菌增效实验。
采用微量稀释法,固定CXIIIt的终浓度分别为4μg/ml,2μg/ml,1μg/ml,0.5μg/ml,再按照M07-A9操作步骤依次将组合药物中的待测抗生素倍比稀释。以含单一抗生素(包括β内酰胺类抗生素:头孢克洛、头孢吡肟、青霉素钠、氨苄西林舒巴坦苯唑西林;喹诺酮类:左氧氟沙星;氨基糖苷类:阿米卡星、庆大霉素;糖肽类:万古霉素等)或CXIIIt的培养液为阳性对照,不接种细菌的培养物为阴性对照,使培养液最终菌浓度约为0.25-0.5×106CFU/ml。将培养物置于37℃,培养16h-20h后,观察细菌的生长情况,判读各组合药物中抗生素的MICs。FIC指数(FICI)=A药联合时MIC/A药单测时MIC+B药联合时MIC/B药单测MIC,其中判断标准:FICI≤0.5,增效;0.5<FICI≤1,叠加,1.0<FICI≤2.0,无关;FICI>2.0,拮抗。
结果如下表4所示,表明CXIIIt对各种β内酰胺类抗生素均有抗菌增效效果。
表4
研究发现,化合物CXIIIt的溶液中还含有下式化合物CXIIIt2:
推测可能是化合物CXIIIt关环形成该化合物CXIIIt2。且溶液中两种化合物形成一个化学平衡,这个平衡受酸碱影响。酸性情况下,CXIIIt会多一些,碱性或中性条件下,CXIIIt2会多一些。
Claims (15)
3.一种药物组合物,含有权利要求1或2所述的化合物和药学上可接受的载体,和任选的抗菌药。
4.权利要求1或2所述的化合物在制备抗菌药中的应用。
5.如权利要求4所述的应用,其特征在于,所述抗菌药用于抑制或杀死选自以下的细菌:甲氧西林耐药金黄色葡萄球菌和泛耐药鲍曼不动杆菌。
6.一种抑菌或杀菌方法,所述方法包括给予需要的对象有效量的权利要求1或2所述的化合物或权利要求3所述的药物组合物。
7.如权利要求6所述的方法,其特征在于,所述细菌选自:甲氧西林耐药金黄色葡萄球菌和泛耐药鲍曼不动杆菌。
9.如权利要求8所述的方法,其特征在于,所述离去基团选自卤素,氰基,C1-C6烷氧基和C1-C6烷基-COO-。
10.如权利要求8所述的方法,其特征在于,所述有机溶剂是正己烷,或是醚类溶剂。
11.如权利要求8所述的方法,其特征在于,所述有机溶剂选自四氢呋喃、乙醚、甲基叔丁基醚和1,4-二氧六环。
12.如权利要求8所述的方法,其特征在于,所述烷基锂试剂为C1-C6烷基锂试剂。
13.如权利要求12所述的方法,其特征在于,所述C1-C6烷基锂试剂选自正丁基锂、叔丁基锂和仲丁基锂。
14.如权利要求8所述的方法,其特征在于,所述反应在零下78℃到0℃之间进行。
15.如权利要求8所述的方法,其特征在于,所述二溴苯甲醚化合物与烷基锂试剂的摩尔比在1:2-3之间。
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