CN109265396A - 多环酰胺化合物的合成新方法与抗癌活性 - Google Patents
多环酰胺化合物的合成新方法与抗癌活性 Download PDFInfo
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- CN109265396A CN109265396A CN201811059785.4A CN201811059785A CN109265396A CN 109265396 A CN109265396 A CN 109265396A CN 201811059785 A CN201811059785 A CN 201811059785A CN 109265396 A CN109265396 A CN 109265396A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明涉及一种新型多环酰胺化合物及其制备方法和用途，该化合物具有细胞毒的生物活性，特别是治疗和/或预防细胞增殖性疾病如癌症。该化合物为式I所示化合物或其药物可接受的盐、溶剂化物、多晶型体、对映体或外消旋混合物，前药及N‑氧化物，其中，R,R1‑R3独立地选自氢、C1‑5烷基，或者带有羟基或卤素的C1‑5、相互之间也可以连接成环，Z为任意取代基团，X1和X2可以分别为碳或氮，Q为氧或硫。与已知的多环酰胺化合物相比，具有更强效的细胞毒性，可用于治疗如肿瘤、癌症、阿尔茨海默病、自身免疫性疾病、白内障、心里障碍、抑郁症和/或焦虑症。其制备方法具有操作简便、反应条件温和等优点，便于工业化生产。
Description
技术领域
本发明涉及一类具有细胞毒性的新型多环酰胺化合物及其制备方法，含有它们的药物组合物及其在治疗中的用途，特别是用于治疗和预防细胞增殖性疾病如癌症。
背景技术
DNA拓扑异构酶是近年来分子生物学研究的热点之一,实验证明它直接与细胞增殖、 DNA复制、基因表达以及抗癌药的研究密切相关。而许多药物如阿霉素、Vp16、喜树碱等都是通过影响DNA拓扑异构酶活性而发挥细胞毒,拓扑异构酶常常作为筛选抗癌药物的新靶点(Journal of Medicinal Chemistry，2011,5796-5810)。带有阳离子侧链的多环芳香族生色团已经成功地成为DNA嵌入型拓扑异构酶抑制剂，已知的显示出细胞毒性作用并具有作为抗癌药物的用途的三环化合物两个代表如DACA(1)，也称为XR5000，为吖啶衍生物(US4,590,277)，化合物(2)(J.Med.Chem.2003,46, 1049-1054)以及吩嗪-1-甲酰胺(3)(EP0172744A2)对DNA调节酶拓扑异构酶I和 II都有活性，并且已经进入I期临床实验(J.Med.Chem.1999,42,2383-2393，和 Research&Reviews:Journal of Medicinal&Organic Chemistry，2015，67-76)。苯并[b] [1,6]萘啶-1(2H)-酮的衍生物(4)(AU2003221640B2)也属于这类化合物，并表现出更优越的生物活性。这几种类型的化合物的共同特征是带有阳离子侧链的酰胺。除此之外，也可将两个这样的三环化合物的主体结构通过柔性链连接。
虽然这三个类型的化合物的三环结构及酰胺侧链具有不同的结构，但其最初的发明者认为化学结构和抗癌药物的潜在效用之间的关系还不是完全明确(AU2003221640B2)。在DACA(1)的研究过程中，连接到吖啶环上的酰胺基通式为-CONH(CH2)nNR1R2，R1和 R2可以为分别为带有羟基或氨基的低碳烷烃。通过检测，在一系列化合物中，R1和R2同时为甲基的化合物时活性最高(US4,590,277)，鉴于这个结论，在苯并[b][1,6]萘啶- 1(2H)-酮的衍生物的研究中，发明者主要研究的酰胺侧链为-CONH(CH2)2NMe2，并将其连接到众多不同三环结构上的。许多类似三环化合物的结构与活性研究也基本上限于标准侧链-CONH(CH2)2NMe2(Biooganic&Medicinal Chemistry,2006,1160-1168)，这是因为N,N-二甲基乙二胺容易得到而且价格便宜。虽然在上述几个专利的权利要求中，发明者都定义酰胺侧链末端氮上的取代基可以分别为不同的烷基或取代烷基，但据我们所知，这种类型的化合物还从未出现过。对苯并[b][1,6]萘啶-1(2H)酮类化合物，虽然发明者对其他酰胺侧链也进行了研究，但也仅限于-CONHCHMeCH2NMe2和- CONHCHMeCONMe2(AU2003221640B2)，从结构上看，它们与前者只有很微小的差别，而就是这种微小的差别使得化合物的活性大大降低，最多降低了达四个数量级(17000 对2)，而发明者对其他酰胺侧链也就没有进行更深入地研究。
从上面的结果换一个角度看，对生物活性的影响不仅仅限于化合物的三环结构，酰胺侧链也扮演着极其重要的角色，因此居于这些化合物的潜在用途，扩展这些酰胺侧链的结构类型对药物开发将具有重大的意义。
而当我们将5-甲基吖啶-4-羧酸与8-氨基喹啉反应生成酰胺，经过生物活性检测，惊奇地发现其活性比专利已经报道的大近4倍。这进一步证实了我们的猜测，即通过酰胺侧链的改变可以大大改进上述三类化合物的生物活性。
为了能合成酰胺侧链末端氮上不同基团的化合物，我们设计的合成路线为：
式中的文字定义见后面的发明内容部分。
我们所列举的三环羧酸都可以参照文献合成，所得三环羧酸先与羟胺反应，生成氮上带有末端羟基的烷基酰胺，然后将末端的羟基磺酰化，最后与各种不同的伯胺和仲胺反应得到目标化合物。从上式可以看出，这个合成方法使末端氮上很容易地连接上不同的取代基。
这里需要特别指出，尽管本文列举了许多现有技术和专利，但本发明所展示的合成方法，以及合成并检验的一系列三环酰胺化合物更新和更广泛，他们与以前所报道的化合物不同。而这些化合物的代表性实例可用作为细胞毒性剂和抗癌药物。
发明内容
本发明目的在于提供一种三环酰胺类化合物及制备方法。
本发明提出的三环酰胺类化合物，其结构通式如下：
根据第一方面，本发明提供化学结构I化合物
其中位置编号如上化学结构所示，Z为H，卤素，OH，CO2H,CO2R4,SO2R4,NR4R5，硝基，氰基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C1-6卤代烷氧基，C1-6氨基烷基， C1-6氨基烷氧基，或氮杂官能团取代环CH官能团，或桥接6-7,7-8或8-9位的碳或碳/ 氮骨架，以形成另外的稠合的5至6元碳环或杂环；
R和R1-R3各自独立地为H或任意取代的C1-4烷基，或R和R1-R3与它们所连接的氮原子一起形成任意取代的饱和或不饱和杂环基。n是从0到6的整数。
Y为H，C1-6烷基，带有与Z的定义一样活性基团的C1-C6烷基，或(CH2)m—X2— (CH2)pU，其中
X2为CH2,C═O,CH═CH,O,S,NR；和
m和p是从0到6的整数，和
U是H，CF3，卤素，NR4R5,+NRR4R5，氰基，C(═O)NR4R5OR4,CO2R4；
R4和R5的任选取代基与R和R1-R3的定义一样。
优选情况下，通式(I)中Z为6-H，X1为-CH＝，X2-C＝，Y为H，Q为H，R1a和R1b不同时为H，如式Ia所示：
可以用下列表1中列出的化合物来说明本发明的代表性化合物，但本发明不限定于这些化合物。
表1：
优选情况下，通式(I)中Z为6-Me，X1为-N＝，X2-C＝，Y为H，Q为H，R1a和R1b不同时为H，如式Ib所示：
可以用下列表2中列出的化合物来说明本发明的代表性化合物，但本发明不限定于这些化合物。
表2：
优选情况下，通式(I)中Z为6-Me，X1为-CH＝，X2-N-，Q为氧
但不包括已经公开的下面三个酰胺侧链：
-CONHCH2CH2N(CH3)2，-CONHCHMeCH2N(CH3)2，-CONHCHMeCON(CH3)2。
如式Ic所示：
可以用下列表3中列出的化合物来说明本发明的代表性化合物，但本发明不限定于这些化合物。
表3：
本发明还提供式II的化合物：
其中式II中x是2至4的整数；和
Y是化合价x的连接基团；或其药学上可接受的盐，N-氧化物，水合物，溶剂化物，药学上可接受的衍生物，前药，互变异构体和/或异构体。
为避免任何疑问，应理解化合物的每个单体亚单元可以是不同的，条件是在每个亚单元中，取代基各自在所提供的定义内。换句话说，具有两个或更多个不同的式I单元连接在一起的化合物被认为是在上面的式II的定义内。
x优选为2。
Y1最优选自以下：
—(CH2)2NH(CH2)2—
—(CH2)3-NMe-(CH2)3—
—(CH2)2NH(CH2)2NH(CH2)2—
—(CH2)2NH(CH2)3NH(CH2)2—
—(CH2)2NMe(CH2)2NMe(CH2)2—
—(CH2)2NMe(CH2)3NMe(CH2)2—
—N,N′-双(乙烯)哌嗪-
—N,N′-双(丙烯基)哌嗪-,
—(CH2)sNH(CH2)t—
—(CH2)sNAlkyl(CH2)t—
—(CH2)sNH(CH2)tNH(CH2)u—,and
—(CH2)sNAlkyl(CH2)tNAlkyl(CH2)u—,
其中s，t和u是2到6的整数。
但不包括已经公开的如下三个酰胺侧链：
-CONHCH2CH2N(CH3)2，-CONHCHMeCH2N(CH3)2，-CONHCHMeCON(CH3)2，
可以用下列表4中列出的化合物来说明本发明的代表性化合物，但本发明不限定于这些化合物。
表4：
通式(I)化合物及其药学上可接受的盐及其N-氧化物有下述两种方法来制备。第一种方法的具体步骤如下：
第一步：向干燥的圆底烧瓶中加入通式(III)的三环酸(1克)和DMF(10毫升)， 3摩尔当量的通式(IV)的胺及1.2摩尔量的O-苯并三氮唑-四甲基脲六氟磷酸酯 (HBTU)。
第二步：在室温下磁力搅拌进行10-20分钟后慢慢加入N，N-二异丙基乙胺(2.0摩尔量)，然后将反应液加热至50℃反应12小时，TLC跟踪反应进度。
第三步：待反应完成后，冷却，将反应液倒入冰水中，乙酸乙酯提取，合并提取液，干燥后减压蒸去溶剂，残留物以乙酸乙酯：石油醚＝1∶1-1∶9为淋洗液进行柱层析分离提纯，浓缩淋洗液后在乙酸乙酯和石油醚混合溶剂中重结晶即得。
第二种方法的具体步骤如下：
第一步：向干燥的圆底烧瓶中加入通式(III)的三环酸(1克)和DMF(10毫升)， 3摩尔当量的通式(V)的醇胺及1.2摩尔量的O-苯并三氮唑-四甲基脲六氟磷酸酯 (HBTU)。
第二步：在室温下磁力搅拌进行10-20分钟后慢慢加入N，N-二异丙基乙胺(2.0摩尔量)，然后将反应液加热至50℃反应12小时，TLC跟踪反应进度。
第三步：待反应完成后，冷却，将反应液倒入冰水中，乙酸乙酯提取，合并提取液，干燥后减压蒸去溶剂，残留物以乙酸乙酯：石油醚＝1∶1-1∶9为淋洗液进行柱层析分离提纯，浓缩淋洗液后在乙酸乙酯和石油醚混合溶剂中重结晶即得通式(VI)的醇。
第四步：向干燥的圆底烧瓶中加入通式(VI)的醇(1克)和二氯甲烷(10毫升)和1.5当量的三乙胺。
第五步：在冰水冷却下磁力搅拌，10-20分钟后慢慢加入1.3摩尔当量的甲基磺酰氯，反应1小时，TLC跟踪反应进度。
第六步：待反应完成后，加入碳酸氢钠水溶液20毫升，搅拌10分钟后，分层，水层用二氯甲烷提取，合并提取液，分别用稀盐酸，碳酸氢钠水溶液，饱和氯化钠水溶液洗涤。干燥后减压蒸去溶剂得通式(VII)的化合物。
第七步：向干燥的圆底烧瓶中加入通式(VII)的化合物(0.1克)和DMSO(2毫升)， 3摩尔当量的通式(VIII)。室温搅拌过夜，然后加入水20毫升，搅拌10分钟后，用二氯甲烷提取，合并提取液，分别用稀盐酸，碳酸氢钠水溶液，饱和氯化钠水溶液洗涤。干燥后减压蒸去溶剂得通式(I)和(II)的化合物。
本发明中，提供药物或兽医用组合物，其包含如上定义的式I，II的化合物，以及药学上或兽医学上可接受的载体。
本发明提供治疗和预防细胞增殖性疾病的方法，包括给予有需要的受试者治疗有效量的式I，II的化合物。
本发明还提供式I，II化合物在制备用于治疗和预防细胞增殖性疾病的药物中的用途。
本发明进一步提供式I，II的化合物，其用于治疗和预防细胞增殖性疾病。
本发明还进一步提供式I，II化合物作为细胞毒性，抗肿瘤，抗肿瘤和/或抗癌剂的用途。
本发明的优点在于：本发明以简单易得的三环甲酸、各种胺为原料，使用HBTU做缩水剂。该合成路线具有原料易得、操作简便、反应条件温和、反应时间短、节省溶剂和减少污染等优点，便于工业化生产。
具体实施方式
本说明书的词语“包括”意味着“包括但不限于”。在本说明书中使用单数形式“一”，“一个”和“该”包括多个方面，除非上下文另有明确规定。因此如果提及“式I或II的化合物”则包括单一化合物，也可以指两种或更多种化合物；等等。
术语“C1-4烷基”或“C1-6烷基”可单独使用或以复合词使用，例如“任选取代的C1-4或C1-6烷基”，“C1-6卤代烷基”或“C1-6氨基烷基”“烷基”是指具有1至6个碳原子的直链，支链或环状烃基。这种烷基的例子有甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，戊基，新戊基，己基，环丙基，环丁基，环戊基或环己基。
单独或在复合词中使用的术语“C1-6烷氧基”如“C1-6卤代烷氧基”或“C1-6氨基烷氧基”是指直链或支链的含氧基团，其各自具有1至约6个碳的烷基部分。原子。烷氧基的实例包括甲氧基，乙氧基，丙氧基，丁氧基和叔丁氧基。
术语“连接基团”在本文中以其最广泛的含义使用，是指将化合物的相邻单元连接在一起的任何有机基团，并且可以是对称的或非对称的。虽然连接基团优选是含氮连接基团，但应理解它可以是O；S；任选取代的C1-20亚烷基，亚烯基或亚炔基链，其可任选地散布有一个或多个任意取代的芳基或任选取代的杂环基或一个或多个O，S或N原子；或任选取代的饱和或不饱和芳基或杂环基。
制备式I，II化合物的方法包括直接在脱水剂存在下与胺反应，也可以包含中间步骤，如将式III化合物转化为咪唑化物，然后与适当的胺反应而得到式I或II。或者将式 III的羧酸转化为酰卤，然后与胺反应，得到式I，II的目标酰胺。该第二路线中的试剂优选为亚硫酰氯。在以上描述中将清楚地理解，在双化合物的情况下，两个单元的羧酸将与适当的二胺反应以形成目标二酰胺。
式I或II化合物的盐优选是药学上可接受的，但应理解非药学上可接受的盐也属于本发明的范围，因为它们可用作制备药学上可接受的中间体。药学上可接受的盐的实例包括药学上可接受的阳离子的盐，例如钠，钾，锂，钙，镁，铵和烷基铵；药学上可接受的无机酸的酸加成盐，例如盐酸，正磷酸，硫酸，磷酸，硝酸，碳酸，硼酸，氨基磺酸和氢溴酸；或药学上可接受的有机酸的盐，如乙酸，氯乙酸，二氯乙酸，丙酸，丁酸，酒石酸，马来酸，羟基马来酸，富马酸，柠檬酸，乳酸，粘液，葡萄糖酸，苯甲酸，琥珀酸，草酸，苯乙酸，甲磺酸，三卤甲磺酸，甲苯磺酸，苯磺酸，水杨酸，磺胺酸，天冬氨酸，谷氨酸，乙二胺四乙酸，硬脂酸，棕榈酸，油酸，月桂酸，泛酸，单宁酸，抗坏血酸和戊酸。
此外，本发明的一些化合物可与水或普通有机溶剂形成溶剂化物。这些溶剂化物也包括在本发明的范围内。
“药学上可接受的衍生物”是指任何药学上可接受的盐，水合物，酯，酰胺，活性代谢物，类似物，残基或任何其它不具有生物学或其他方面不合需要的化合物并诱导所需的药理学或生理学作用。
术语“前药”在本文中以其最广泛的含义使用，包括在体内转化为式I或II化合物的那些化合物。
术语“互变异构体”在本文中以其最广泛的含义使用，包括能够以两种异构形式之间的平衡状态存在的式I或II的化合物。这些化合物在连接两个原子或基团的键和化合物中这些原子或基团的位置上可以不同。
术语“异构体”在本文中以其最广泛的含义使用，包括结构，几何和立体异构体。由于式I或II的化合物可具有一个或多个手性中心，因此它能够以对映体形式存在。
本发明的组合物包含至少一种式I，II的化合物以及一种或多种药学上可接受的载体和任选的其它治疗剂。在与组合物的其他成分相容并且对受试者无害的意义上，每种载体，稀释剂，佐剂或赋形剂必须是药学上“可接受的”。组合物包括适合口服，直肠，鼻，局部(包括口腔和舌下)，阴道或肠胃外(包括皮下，肌肉内，静脉内和皮内) 给药的那些。组合物可以方便地以单剂型存在，并且可以通过药学领域熟知的方法制备。这些方法包括使活性成分与构成一种或多种辅助成分的载体结合的步骤。通常，通过将活性成分与液体载体，稀释剂，佐剂或赋形剂或细碎的固体载体或两者均匀且紧密地结合，然后如果需要使产品成形，制备组合物。
“细胞增殖性疾病”是指一种或多种细胞表现出异常生长，通常是异常生长，导致肿瘤，肿瘤或癌症。
细胞增殖性疾病包括，例如，乳腺癌，肺癌，前列腺癌，肾癌，皮肤癌，神经癌，卵巢癌，子宫癌，肝癌，胰腺癌，上皮癌，胃癌，肠癌，外分泌癌，内分泌癌，淋巴管，造血系统或头颈部组织。。
通常，肿瘤疾病是细胞异常增殖导致大量组织称为肿瘤或肿瘤的病症。肿瘤在结构和行为方面有不同程度的异常。一些肿瘤是良性的，而另一些是恶性的。肿瘤疾病的有效治疗被认为是对寻求癌症预防或治疗程序的有价值的贡献。本发明化合物优选用于治疗白血病，淋巴瘤，多发性骨髓瘤，肉瘤和脑肿瘤，以及肺癌，乳腺癌，卵巢癌，睾丸癌和结肠癌。
其他药物可包括一种或多种其他抗肿瘤剂，包括但不限于抗有丝分裂剂如紫杉醇，抗代谢物如5-氟尿嘧啶，激素调节剂如他莫昔芬，DNA反应剂如：顺铂，或生物制剂，如白细胞介素-2(IL-2)或抗体。
第二种结合DNA的抗癌治疗剂可与式I或II化合物的给药联合使用，以减少对式I化合物之一或两者的接受者的毒副作用或副作用。或II或其他抗癌剂。
预期本发明化合物还可以以肿瘤活化前药的形式给药，其中活性剂与“触发”结构域连接；例如，这些化合物可以设计成通过肿瘤块内的局部缺氧来激活。
本发明化合物还可以与减轻药物治疗引起的副作用的药剂如粒细胞-巨噬细胞集落刺激因子(GM-CSF)或止吐药联合使用。
如本文所用，“药物载体”是药学上可接受的溶剂，悬浮剂或载体，用于将式I，II的化合物递送至受试者。载体可以是液体或固体，并且考虑到计划的给药方式来选择。在与组合物的其他成分相容并且对受试者无害的意义上，每种载体必须是药学上“可接受的”。
式I，II的化合物可以以含有常规无毒药学上可接受的载体，佐剂和赋形剂的剂量单位制剂口服，局部或肠胃外给药。本文所用的术语肠胃外包括皮下注射，用于给予肺或鼻腔的气雾剂，静脉内，肌肉内，鞘内，颅内，注射或输注技术。
本发明还提供了适用于本发明的局部，口服和肠胃外药物制剂的治疗新方法。本发明化合物可以以片剂，水性或油性悬浮液，锭剂，锭剂，粉剂，颗粒剂，乳剂，胶囊剂，糖浆剂或酏剂口服给药。口服使用的组合物可含有一种或多种选自甜味剂，调味剂，着色剂和防腐剂的试剂，以制备药学上可口的制剂。合适的甜味剂包括蔗糖，乳糖，葡萄糖，阿斯巴甜或糖精。合适的崩解剂包括玉米淀粉，甲基纤维素，聚乙烯吡咯烷酮，黄原胶，膨润土，海藻酸或琼脂。合适的调味剂包括薄荷油，冬青油，樱桃，橙或覆盆子调味剂。合适的防腐剂包括苯甲酸钠，维生素E，α-生育酚，抗坏血酸，对羟基苯甲酸甲酯，对羟基苯甲酸丙酯或亚硫酸氢钠。合适的润滑剂包括硬脂酸镁，硬脂酸，油酸钠，氯化钠或滑石。合适的延时剂包括单硬脂酸甘油酯或二硬脂酸甘油酯。片剂含有活性成分与适合制备片剂的无毒的药学上可接受的赋形剂的混合物。
这些赋形剂可以是，例如，(1)惰性稀释剂，如碳酸钙，乳糖，磷酸钙或磷酸钠；(2)造粒和崩解剂，如玉米淀粉或海藻酸；(3)粘合剂，如淀粉，明胶或阿拉伯胶；(4) 润滑剂，如硬脂酸镁，硬脂酸或滑石粉。这些片剂可以通过已知技术未包衣或包衣，以延迟在胃肠道中的崩解和吸收，从而在较长时间内提供持续作用。例如，可以使用延时材料，例如单硬脂酸甘油酯或二硬脂酸甘油酯。涂覆也可以使用美国专利 No.4,522,587中描述的技术进行。US4,256,108；US4,160,452；和US4,265,874，以形成用于控制释放的渗透性治疗片剂。
式I，II的化合物以及可用于本发明方法的药物活性剂可以单独或一起给药，用于体内应用，胃肠外注射或逐渐灌注。给药可以是静脉内，动脉内，腹膜内，肌肉内，皮下，腔内，透皮或通过例如渗透泵输注。对于体外研究，可以将试剂加入或溶解在合适的生物学上可接受的缓冲液中，并加入细胞或组织中。
肠胃外给药的制剂包括无菌水溶液或非水溶液，悬浮液和乳液。非水溶剂的实例是丙二醇，聚乙二醇，植物油如橄榄油，和可注射的有机酯如油酸乙酯。含水载体包括水，醇/水溶液，乳液或悬浮液，包括盐水和缓冲介质。肠胃外载体包括氯化钠溶液，林格氏葡萄糖，右旋糖和氯化钠，乳酸林格氏静脉载体包括液体和营养补充剂，电解质补充剂(例如基于林格氏葡萄糖)等。还可以存在防腐剂和其他添加剂，例如抗微生物剂，抗氧化剂，螯合剂，生长因子和惰性气体等。
本发明包括可用于改善疾病的各种药物组合物。根据本发明一个实施方案的药物组合物通过式I或II的化合物，其类似物，衍生物或盐，或式I或II的化合物与一种或多种药物活性剂的组合来制备。使用载体，赋形剂和添加剂或助剂将其制成适于给予受试者的形式。经常使用的载体或助剂包括碳酸镁，二氧化钛，乳糖，甘露醇和其他糖，滑石，乳蛋白，明胶，淀粉，维生素，纤维素及其衍生物，动植物油，聚乙二醇和溶剂，如无菌水，醇，甘油和多元醇。静脉内载体包括液体和营养补充剂。防腐剂包括抗微生物剂，抗氧化剂，螯合剂和惰性气体。其它药学上可接受的载体包括水溶液，无毒赋形剂，包括盐，防腐剂，缓冲剂等。
式I或II的化合物也可以以脂质体递送系统的形式给药，例如小单层囊泡，大单层囊泡和多层囊泡。脂质体可以由多种磷脂形成，例如胆固醇，硬脂酰胺或磷脂酰胆碱。
式I或II的化合物也可以以兽医用组合物的形式使用，其可以例如通过本领域常规的方法制备。这种兽医用组合物的实例包括适用于：
(a)口服给药，外用，例如浸液(例如水溶液或非水溶液或悬浮液)；片剂或大丸剂；用于与饲料混合的粉末，颗粒或颗粒；适用于舌头的糊状物；
(b)肠胃外给药，例如通过皮下，肌肉内或静脉内注射，例如，作为无菌溶液或悬浮液；或者(适当时)通过乳房内注射，其中通过乳头将乳悬浮液或溶液引入乳房；
(c)局部应用，例如作为涂抹在皮肤上的乳膏，软膏或喷雾剂；或者
(d)阴道内，例如作为子宫托，乳膏或泡沫。
术语“治疗有效量”是指有效产生所需治疗反应的本发明的式I或II化合物的量。“预防有效量”具有相似的定义。
下述通过实施例进一步说明本发明，但不能限制本发明的内容。
表1-4总结了本发明代表性化合物的结构。
实施例1：带羟基的三环甲酰胺的制备。
按如下方式进行：向干燥的圆底烧瓶中加入三环羧酸(III，A＝OH)(1.1克，5.6毫摩尔)和DMF(10毫升)，3摩尔当量的醇胺及O-苯并三氮唑-四甲基脲六氟磷酸酯 (HBTU，2.55克，6.7毫摩尔)。在室温下磁力搅拌进行10-20分钟后慢慢加入N，N- 二异丙基乙胺(1.44克，11.2毫摩尔)，然后将反应液加热至50℃反应12小时， TLC跟踪反应进度。待反应完成后，冷却，将反应液倒入冰水中，乙酸乙酯提取，合并提取液，干燥后减压蒸去溶剂，残留物以乙酸乙酯：石油醚＝1∶1-1∶9为淋洗液进行柱层析分离提纯，浓缩淋洗液后在乙酸乙酯和石油醚混合溶剂中重结晶即得通式 (VI)的醇。
实施例2：通式(VII)的化合物的制备。
向干燥的圆底烧瓶中加入通式(VI)的醇(1克)和二氯甲烷(10毫升)和1.5当量的三乙胺。在冰水冷却下磁力搅拌，10-20分钟后慢慢加入1.3摩尔当量的甲基磺酰氯，反应1小时，TLC跟踪反应进度。待反应完成后，加入碳酸氢钠水溶液20毫升，搅拌10分钟后，分层，水层用二氯甲烷提取，合并提取液，分别用稀盐酸，碳酸氢钠水溶液，饱和氯化钠水溶液洗涤。干燥后减压蒸去溶剂得通式(VII)的化合物粗品，在乙酸乙酯和石油醚混合溶剂中重结晶提纯。
实施例3：通式(VII)的化合物的胺化。
向干燥的圆底烧瓶中加入通式(VII)的化合物(0.1克)和DMSO(2毫升)，3摩尔当量的通式(VIII)的胺。室温搅拌过夜，然后加入水20毫升，搅拌10分钟后，用二氯甲烷提取，合并提取液，分别用稀盐酸，碳酸氢钠水溶液，饱和氯化钠水溶液洗涤。干燥后减压蒸去溶剂得通式(I)和(II)的化合物。
实施例4：吖啶-4-羧酸的制备
吖啶-4-羧酸参考文献(J.Med.Chem.2003,46,183-189及Bioorg.Med.Chem.Lett.2014，24，5710–5715)制备。
实施例5：N-(2-甲基-2-羟基乙基)吖啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.16(d,J＝6.9Hz,3H),2.82(br s,1H), 3.52(dd,J＝11.0,6.0Hz,1H),5.10(t,J＝5.4Hz,1H),7.63-8.42(m,6H,acridineprotons),8.75(d,J＝6.2Hz,1H,ArH-3),9.35(s,1H,ArH-9),11.85(t,J＝5.4Hz, 1H,CONH).
实施例6：N-(2-甲基-2-甲磺酰氧基乙基)吖啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.31(d,J＝6.9Hz,3H),2.82(br s,1H), 3.52(dd,J＝11.0,6.0Hz,1H),4.50(br s,3H),5.10(t,J＝5.4Hz,1H),7.63-8.42(m,6H,acridine protons),8.75(d,J＝6.2Hz,1H,ArH-3),9.35(s,1H,ArH-9),11.85(t, J＝5.4Hz,1H,CONH).
实施例7：化合物N-[2-甲基-2-(N-异丙基甲基胺基)乙基]吖啶-4-甲酰胺(10)。
按实施例3所述的方式:1H NMR(D2O)δ1.05(d,J＝7.2Hz,6H),3.10(m,1H),3.12(s,3H,NCH3),3.61(m,1H),4.02(dd,J＝6.2Hz,2H,NHCH2),7.02(m,1H),7.88 (m,1H),7.95(m,1H),8.30(m,1H),8.44-8.61(m,2H),9.47(s,1H),10.82(t, J＝5.4Hz,1H,CONH).
实施例8：N-(1-甲基-2-羟基乙基)吖啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.17(d,J＝6.9Hz,3H),2.81(br s,1H), 3.53(dd,J＝11.0,6.0Hz,1H),5.10(t,J＝5.4Hz,1H),7.63-8.42(m,6H,acridineprotons),8.75(d,J＝6.2Hz,1H,ArH-3),9.35(s,1H,ArH-9),11.23(t,J＝5.4Hz, 1H,CONH).
实施例9：N-(1-甲基-2-甲磺酰氧基乙基)吖啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.32(d,J＝6.9Hz,3H),2.84(br s,1H), 3.51(dd,J＝11.0,6.0Hz,1H),4.51(br s,3H),5.12(t,J＝5.4Hz,1H),7.63-8.42(m,6H,acridine protons),8.75(d,J＝6.2Hz,1H,ArH-3),9.35(s,1H,ArH-9),11.85(t, J＝5.4Hz,1H,CONH).
实施例10：化合物N-[1-甲基-2-(N-异丙基甲基胺基)乙基]吖啶-4-甲酰胺(26)。
按实施例3所述的方式:1H NMR(D2O)δ1.05(d,J＝7.2Hz,6H),3.10(m,1H),3.12(s,3H,NCH3),3.61(m,1H),4.02(dd,J＝6.2Hz,2H,NHCH2),7.02(m,1H),7.88 (m,1H),7.95(m,1H),8.30(m,1H),8.44-8.61(m,2H),9.47(s,1H),11.33(t, J＝5.4Hz,1H,CONH).
实施例11：1-甲基-9-羧基吩嗪的制备：
参考文献(J.Med.Chem.2000,43,1350-1358)制备1-甲基-9-羧基吩嗪:mp 110-112℃；NMR 1H NMR(500MHz,CDCl3)δ2.10(s,3H,CH3),7.72(d,J＝8.2Hz, 1H,H-3),8.03-8.11(m,2H,H-7,8),8.32(dd,J＝8.4,1.8Hz,1H,H-6 or H-4), 8.49(dd,J＝7.6,1.6Hz,1H,H-6 or H-4),8.91(d,J＝7.7Hz,1H,H-2),15.35(s,1 H,CO2H).
实施例12：N-(2-甲基-2-羟基乙基)1-甲基吩嗪-9-甲酰胺的制备。
按实施例1所述的方式:1H NMR(500MHz,CDCl3)δ1.15(d,J＝6.9Hz,3H),2.11(s,3H,CH3),2.82(br s,1H),3.51(dd,J＝11.0,6.0Hz,1H),3.67(dd,J＝11.0,3.8Hz,1H),4.05(m,1H),5.88(br s,1H),7.72(d,J＝8.2Hz,1H,H-3),8.03-8.11(m,2H,H-7,8), 8.32(dd,J＝8.4,1.8Hz,1H,H-6 or H-4),8.49(dd,J＝7.6,1.6Hz,1H,H-6 or H- 4),8.91(d,J＝7.7Hz,1H,H-2),11.84(t,J＝5.4Hz,1H,CONH).
实施例13：N-(2-甲基-2-甲磺酰氧基乙基)1-甲基吩嗪-9-甲酰胺的制备。
按实施例2所述的方式:1H NMR(500MHz,CDCl3)δ1.13(d,J＝6.9Hz,3H),2.12(s,3H,CH3),2.81(br s,1H),3.52(dd,J＝11.0,6.0Hz,1H),3.64(dd,J＝11.0,3.8Hz,1H),4.05(m,1H),4.51(br s,3H),5.88(br s,1H),7.72(d,J＝8.2Hz,1H,H-3),8.03-8.11 (m,2H,H-7,8),8.32(dd,J＝8.4,1.8Hz,1H,H-6 or H-4),8.49(dd,J＝7.6,1.6Hz, 1H,H-6 orH-4),8.91(d,J＝7.7Hz,1H,H-2),11.84(t,J＝5.4Hz,1H,CONH).
实施例14：N-[2-甲基-2-(N-异丙基甲基胺基)乙基]-1-甲基吩嗪-9-甲酰胺的制备 (50)。
按实施例3所述的方式:1H NMR(500MHz,CDCl3)δ1.05(d,J＝7.2Hz,6H),3.10(m,1H),3.12(s,3H,NCH3),3.61(m,1H),4.02(dd,J＝6.2Hz,2H,NHCH2),4.05(m, 1H),5.88(brs,1H),7.72(d,J＝8.2Hz,1H,H-3),8.03-8.11(m,2H,H-7,8),8.32 (dd,J＝8.4,1.8Hz,1H,H-6 or H-4),8.49(dd,J＝7.6,1.6Hz,1H,H-6 or H-4), 8.91(d,J＝7.7Hz,1H,H-2),11.84(t,J＝5.4Hz,1H,CONH).
实施例15：N-(1-甲基-2-羟基乙基)1-甲基吩嗪-9-甲酰胺的制备。
按实施例1所述的方式:1H NMR(500MHz,CDCl3)δ1.16(d,J＝6.9Hz,3H),2.10(s,3H,CH3),2.82(br s,1H),3.52(dd,J＝11.0,6.0Hz,1H),3.66(dd,J＝11.0,3.8Hz,1H),4.05(m,1H),5.88(br s,1H),7.72(d,J＝8.2Hz,1H,H-3),8.03-8.11(m,2H,H-7,8), 8.32(dd,J＝8.4,1.8Hz,1H,H-6 or H-4),8.49(dd,J＝7.6,1.6Hz,1H,H-6 or H- 4),8.91(d,J＝7.7Hz,1H,H-2),11.86(t,J＝5.4Hz,1H,CONH).
实施例16：N-(1-甲基-2-甲磺酰氧基乙基)1-甲基吩嗪-9-甲酰胺的制备。
按实施例2所述的方式:1H NMR(500MHz,CDCl3)δ1.15(d,J＝6.9Hz,3H),2.12(s,3H,CH3),2.83(br s,1H),3.55(dd,J＝11.0,6.0Hz,1H),3.68(dd,J＝11.0,3.8Hz,1H),4.05(m,1H),4.51(br s,3H),5.88(br s,1H),7.72(d,J＝8.2Hz,1H,H-3),8.03-8.11 (m,2H,H-7,8),8.32(dd,J＝8.4,1.8Hz,1H,H-6 or H-4),8.49(dd,J＝7.6,1.6Hz, 1H,H-6 orH-4),8.91(d,J＝7.7Hz,1H,H-2),11.86(t,J＝5.4Hz,1H,CONH).
实施例17：N-[1-甲基-2-(N-异丙基甲基胺基)乙基]-1-甲基吩嗪-9-甲酰胺的制备 (66)。
按实施例3所述的方式:1H NMR(500MHz,CDCl3)δ1.06(d,J＝7.2Hz,6H),3.11(m,1H),3.12(s,3H,NCH3),3.61(m,1H),4.02(dd,J＝6.2Hz,2H,NHCH2),5.88(br s, 1H),7.72(d,J＝8.2Hz,1H,H-3),8.03-8.11(m,2H,H-7,8),8.32(dd,J＝8.4,1.8 Hz,1H,H-6 or H-4),8.49(dd,J＝7.6,1.6Hz,1H,H-6 or H-4),8.91(d,J＝7.7Hz, 1H,H-2),11.86(t,J＝5.4Hz,1H,CONH).
实施例18：2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-羧酸的制备
按专利(AU2003221640B2)方法：1H NMR(d6-DMSO):δ2.73(s,3H,CH3),3.76(s,3H,N-CH3),7.65(t,1H,J＝7.6Hz,H-8),7.93(d,1H,J＝6.6Hz),8.24(d,1H,J＝8.1Hz),8.84(s, 1H,H-3),9.48(s,1H,H-10),16.3(s,1H,COOH).
实施例19：N-(2-羟基乙基)-2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ2.73(s,3H,CH3),3.63(q,J＝5.8Hz,2H,CH2CH2-OH),3.73(q,J＝5.8Hz,2H,CH2CH2OH),3.76(s,3H,N-CH3),5.10 (t,J＝5.4Hz,1H,CH2CH2OH),7.65(t,1H,J＝7.6Hz,H-8),7.93(d,1H,J＝6.6Hz),8.24 (d,1H,J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.44(t,J＝5.4Hz,1H,CONH).
实施例20：N-(2-甲磺酰氧基乙基)-2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ2.75(s,3H,CH3),3.64(q,J＝5.8Hz,2H,CH2CH2-OH),3.72(q,J＝5.8Hz,2H,CH2CH2OMs),3.74(s,3H,N-CH3), 4.51(br s,3H),5.11(t,J＝5.4Hz,1H,CH2CH2OH),7.65(t,1H,J＝7.6Hz,H-8),7.93 (d,1H,J＝6.6Hz),8.24(d,1H,J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.23(t, J＝5.4Hz,1H,CONH).
实施例21：N-[2-(N-异丙基甲基胺基)乙基]--2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备(93)。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.06(d,J＝7.2Hz,6H),2.75(s,3H,CH3), 3.10(m,1H),3.12(s,3H,NCH3),3.61(m,2H),4.02(dd,J＝6.2Hz,2H,NHCH2), 3.74(s,3H,N-CH3),7.65(t,1H,J＝7.6Hz,H-8),7.93(d,1H,J＝6.6Hz),8.24(d,1H,J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.23(t,J＝5.4Hz,1H,CONH).
实施例22：N-[(1-甲基吡咯-2-基)甲基]-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(108)的制备。
按实施例1所述的方式，用1-甲基-2-氨基甲基吡咯烷代替醇胺:1H NMR(d6-DMSO):δ1.60(m,4H),2.00(s.3H),2.30(m,5H),2.75(s,3H,CH3),3.10(m,4H),3.54,m,1H0, 3.61(m,2H),4.02(m,2H),3.63(m,2H),3.73(m,2H),6.15(m,1H),7.38-7.43(m, 2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s,1H),11.85 (t,J＝5.4Hz,1H,CONH).
实施例23：N-(2-甲基-2-羟基乙基)-2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.14(d,J＝6.9Hz,3H),2.74(s,3H,CH3), 2.81(br s,1H),3.53(dd,J＝11.0,6.0Hz,1H),3.65(dd,J＝11.0,3.8Hz,1H),3.76(s,3H, N-CH3),4.05(m,1H),5.88(br s,1H),7.65(t,1H,J＝7.6Hz,H-8),7.93(d,1H,J＝6.6Hz), 8.24(d,1H,J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.85(t,J＝5.4Hz,1H, CONH).
实施例24：N-(2-甲基-2-甲磺酰氧基乙基)-2，6-二甲基-1-氧代-1,2-二氢苯并[b] [1,6]萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.15(d,J＝6.9Hz,3H),2.75(s,3H,CH3), 2.81(br s,1H),3.51(dd,J＝11.0,6.0Hz,1H),3.61(dd,J＝11.0,3.8Hz,1H),3.72(s,3H, N-CH3),4.05(m,1H),4.51(br s,3H),5.88(br s,1H),7.65(t,1H,J＝7.6Hz,H-8),7.93(d, 1H,J＝6.6Hz),8.24(d,1H,J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.85(t, J＝5.4Hz,1H,CONH).
实施例25：N-[2-甲基-2-(N-异丙基甲基胺基)乙基]-2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(114)的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.06(d,J＝7.2Hz,6H),3.11(m,1H),3.12 (s,3H,NCH3),3.61(m,1H),3.72(s,3H,N-CH3),4.02(dd,J＝6.2Hz,2H,NHCH2), 4.05(m,1H),5.88(br s,1H),7.65(t,1H,J＝7.6Hz,H-8),7.93(d,1H,J＝6.6Hz),8.24(d,1H, J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.00(t,J＝5.4Hz,1H,CONH).
实施例26：N-(1-甲基-2-羟基乙基)-2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.16(d,J＝6.9Hz,3H),2.73(s,3H,CH3), 2.82(br s,1H),3.52(dd,J＝11.0,6.0Hz,1H),3.66(dd,J＝11.0,3.8Hz,1H),3.76(s,3H, N-CH3),4.05(m,1H),5.88(br s,1H),7.65(t,1H,J＝7.6Hz,H-8),7.93(d,1H,J＝6.6Hz), 8.24(d,1H,J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.85(t,J＝5.4Hz,1H, CONH).
实施例27：N-(1-甲基-2-甲磺酰氧基乙基)-2，6-二甲基-1-氧代-1,2-二氢苯并[b] [1,6]萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.13(d,J＝6.9Hz,3H),2.71(s,3H,CH3), 2.85(br s,1H),3.22(dd,J＝11.0,6.0Hz,1H),3.36(dd,J＝11.0,3.8Hz,1H),3.76(s,3H, N-CH3),4.05(m,1H),4.51(br s,3H),5.88(br s,1H),7.65(t,1H,J＝7.6Hz,H-8),7.93(d, 1H,J＝6.6Hz),8.24(d,1H,J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.85(t, J＝5.4Hz,1H,CONH).
实施例28：N-[1-甲基-2-(N-异丙基甲基胺基)乙基]-2，6-二甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(130)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.06(d,J＝7.2Hz,6H),3.11(m,1H),3.12 (s,3H,NCH3),3.61(m,1H),3.76(s,3H,N-CH3),4.02(dd,J＝6.2Hz,2H,NHCH2), 4.05(m,1H),5.88(br s,1H),7.65(t,1H,J＝7.6Hz,H-8),7.93(d,1H,J＝6.6Hz),8.24(d,1H, J＝8.1Hz),8.84(s,1H,H-3),9.48(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例29：2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-羧酸的制备。
按专利(AU2003221640B2)方法制备：1H NMR(d6-DMSO):δ1.30(t,J＝7.1Hz,3H,CH2CH3),2.65(s,3H,ArCH3),4.12(q,J＝7.1Hz,2H,CH2CH3),7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9),8.74(s,1H,H-3),9.36(s,1H,H-10),15.89(s,1H,COOH).
实施例30：N-(2-羟基乙基)-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶- 4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.30(t,J＝7.1Hz,3H,CH2CH3),2.65(s, 3H,ArCH3),3.63(q,J＝5.8Hz,2H,CH2CH2-OH),3.73(q,J＝5.8Hz,2H, CH2CH2OH),4.12(q,J＝7.1Hz,2H,CH2CH3),5.10(t,J＝5.4Hz,1H,CH2CH2OH), 7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9),8.74(s, 1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例31：N-(2-甲磺酰氧基乙基)-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b][1,6] 萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.31(t,J＝7.1Hz,3H,CH2CH3),2.65(s, 3H,ArCH3),3.41(m,2H),3.53(m,2H),4.12(q,J＝7.1Hz,2H,CH2CH3),4.51(br s, 3H),7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9), 8.74(s,1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例32：N-[2-(N-乙基甲胺基)乙基]-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b] [1,6]萘啶-4-甲酰胺的制备(90)。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.06(d,J＝7.2Hz,3H),2.75(s,3H,CH3), 3.10(m,2H),3.12(s,3H,NCH3),3.61(m,2H),4.02(dd,J＝6.2Hz,2H,NHCH2), 4.12(q,J＝7.1Hz,2H,CH2CH3),7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7), 8.12(d,J＝8.3Hz,1H,H-9),8.74(s,1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例33：N-(2-甲基-2-羟基乙基)-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b][1,6] 萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.14(d,J＝6.9Hz,3H),1.30(t,J＝7.1Hz, 3H,CH2CH3),2.65(s,3H,ArCH3),2.81(br s,1H),3.53(dd,J＝11.0,6.0Hz,1H),3.65(dd, J＝11.0,3.8Hz,1H),3.76(s,3H,N-CH3),4.05(m,1H),4.12(q,J＝7.1Hz,2H,CH2CH3), 7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9),8.74(s, 1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例34：N-(2-甲基-2-甲磺酰氧基乙基)-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b] [1,6]萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.12(d,J＝6.9Hz,3H),1.31(t,J＝7.1Hz, 3H,CH2CH3),2.65(s,3H,ArCH3),2.81(br s,1H),3.23(dd,J＝11.0,6.0Hz,1H),3.65(dd, J＝11.0,3.8Hz,1H),3.76(s,3H,N-CH3),4.51(br s,3H),4.12(q,J＝7.1Hz,2H,CH2CH3),7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9),8.74(s,1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例35：N-[2-甲基-2-(N-异丙基乙基胺基)乙基]-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(115)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.05(d,J＝7.2Hz,6H),3.10(m,2H),1.12 (d,J＝6.9Hz,3H),1.31(t,J＝7.1Hz,3H,CH2CH3),1.35(t,J＝7.1Hz,3H,CH2CH3),2.65(s, 3H,ArCH3),2.81(br s,1H),3.12 3.61(m,1H),3.23(dd,J＝11.0,6.0Hz,1H),3.65(dd,J ＝11.0,3.8Hz,1H),3.76(s,3H,N-CH3),4.02(dd,J＝6.2Hz,2H,NHCH2),4.12(q,J＝7.1Hz,2H,CH2CH3),7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d, J＝8.3Hz,1H,H-9),8.74(s,1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例36：N-(1-甲基-2-羟基乙基)-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b][1,6] 萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.13(d,J＝6.9Hz,3H),1.31(t,J＝7.1Hz, 3H,CH2CH3),2.66(s,3H,ArCH3),2.82(br s,1H),3.53(dd,J＝11.0,6.0Hz,1H),3.65(dd, J＝11.0,3.8Hz,1H),3.76(s,3H,N-CH3),4.05(m,1H),4.12(q,J＝7.1Hz,2H,CH2CH3), 7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9),8.74(s, 1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例37：N-(1-甲基-2-甲磺酰氧基乙基)-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b] [1,6]萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.12(d,J＝6.9Hz,3H),1.33(t,J＝7.1Hz, 3H,CH2CH3),2.65(s,3H,ArCH3),2.81(br s,1H),3.23(dd,J＝11.0,6.0Hz,1H),3.65(dd, J＝11.0,3.8Hz,1H),3.76(s,3H,N-CH3),4.51(br s,3H),4.12(q,J＝7.1Hz,2H,CH2CH3),7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9),8.74(s,1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例38：N-[1-甲基-2-(N-异丙基乙基胺基)乙基]-2-乙基-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(131)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.05(d,J＝7.2Hz,6H),3.10(m,2H),1.12 (d,J＝6.9Hz,3H),1.31(t,J＝7.1Hz,3H,CH2CH3),1.35(t,J＝7.1Hz,3H,CH2CH3),2.65(s, 3H,ArCH3),2.81(br s,1H),3.12(m,1H),3.23(dd,J＝11.0,6.0Hz,1H),3.65(dd,J＝11.0,3.8Hz,1H),3.76(s,3H,N-CH3),4.02(dd,J＝6.2Hz,2H,NHCH2),4.12(q,J＝7.1Hz,2H,CH2CH3),7.59(t,J＝7.6Hz,1H,H-8),7.86(d,J＝6.8Hz,1H,H-7),8.12(d,J＝8.3Hz,1H,H-9),8.74(s,1H,H-3),9.36(s,1H,H-10),11.85(t,J＝5.4Hz,1H,CONH).
实施例39：2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-羧酸的制备。
按专利(AU2003221640B2)方法制备：1H NMR(d6-DMSO):δ2.75(s,3H,CH3),7.38-7.43(m,2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s,1H), 9.53(s,1H).
实施例40：N-(2-羟基乙基)-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ2.75(s,3H,CH3),3.63(q,J＝5.8Hz,2H,CH2CH2-OH),3.73(q,J＝5.8Hz,2H,CH2CH2OH),5.10(t,J＝5.4Hz,1H, CH2CH2OH),7.38-7.43(m,2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d, J＝8.4Hz,1H),8.48(s,1H),11.85(t,J＝5.4Hz,1H,CONH).
实施例41：N-(2-甲磺酰氧基乙基)-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ2.75(s,3H,CH3),3.63(q,J＝5.8Hz,2H,CH2CH2-OH),3.73(q,J＝5.8Hz,2H,CH2CH2OH),4.51(br s,3H),7.38-7.43 (m,2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s,1H), 11.85(t,J＝5.4Hz,1H,CONH).
实施例42：N-[2-(N,N-二乙胺基)乙基]-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(91)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.06(m,6H),2.75(s,3H,CH3),3.10(m,4H),3.61(m,2H),4.02(m,2H),3.63(m,2H),3.73(m,2H),7.38-7.43(m,2-H),7.60- 7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s,1H),11.85(t,J＝5.4 Hz,1H,CONH).
实施例43：N-(2-甲基-2-羟基乙基)-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并 [b][1,6]萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.16(d,J＝6.9Hz,3H),2.75(s,3H,CH3), 2.82(br s,1H),3.52(dd,J＝11.0,6.0Hz,1H),3.66(dd,J＝11.0,3.8Hz,1H),4.05(m,1H), 7.38-7.43(m,2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s, 1H),11.85(t,J＝5.4Hz,1H,CONH).
实施例44：N-(2-甲基-2-甲磺酰氧基乙基)-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.15(d,J＝6.9Hz,3H),2.77(s,3H,CH3), 2.81(br s,1H),3.52(m,1H),3.66(m,1H),4.05(m,1H),4.51(br s,3H),7.38-7.43(m,2- H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s,1H),11.85(t, J＝5.4Hz,1H,CONH).
实施例45：N-[2-甲基-2-(N-异丁基甲胺基)乙基]-2-(4-氟苯基)-6-甲基-1-氧代- 1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(121)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.05(d,J＝7.2Hz,6H),1.08(m,1H),3.10 (m,2H),1.15(d,J＝6.9Hz,3H),2.77(s,3H,CH3),2.81(br s,1H),3.12(s,3H,NCH3),3.61(m,1H),4.02(dd,J＝6.2Hz,2H,NHCH2),3.52(m,1H),3.66(m,1H),4.05(m, 1H),7.38-7.43(m,2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H), 8.48(s,1H),11.85(t,J＝5.4Hz,1H,CONH).
实施例46：N-(1-甲基-2-羟基乙基)-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并 [b][1,6]萘啶-4-甲酰胺的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.15(d,J＝6.9Hz,3H),2.76(s,3H,CH3), 2.81(br s,1H),3.52(dd,J＝11.0,6.0Hz,1H),3.65(dd,J＝11.0,3.8Hz,1H),4.05(m,1H), 7.38-7.43(m,2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s, 1H),11.85(t,J＝5.4Hz,1H,CONH).
实施例47：N-(1-甲基-2-甲磺酰氧基乙基)-2-(4-氟苯基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.23(d,J＝6.9Hz,3H),2.74(s,3H,CH3), 2.81(br s,1H),3.51(m,1H),3.65(m,1H),4.05(m,1H),4.51(br s,3H),7.38-7.43(m,2- H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s,1H),11.85(t, J＝5.4Hz,1H,CONH).
实施例48：N-[2-甲基-2-(N-环丙基甲胺基)乙基]-2-(4-氟苯基)-6-甲基-1-氧代- 1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺(133)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.13(m,4H),1.23(d,J＝6.9Hz,3H),2.74 (s,3H,CH3),2.81(br s,1H),3.10(m,1H),3.51(m,1H),3.65(m,1H),4.05(m,1H),7.38- 7.43(m,2-H),7.60-7.77(m,3H),7.95(d,J＝6.0Hz,1H),8.25(d,J＝8.4Hz,1H),8.48(s,1H), 11.85(t,J＝5.4Hz,1H,CONH).
实施例49：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-羧酸}的制备
按专利(AU2003221640B2)方法制备：1H NMR(d6-DMSO):δ1.45-1.49(m,2H),2.13(s, 6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),4.01-4.05(m,4H),7.36(t,J＝7.4 Hz,2H),7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),9.13(s,2H).
实施例50：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-(2-羟基乙基)-6- 甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.45-1.49(m,2H),2.13(s,6H,2xN-CH3), 2.28-2.34(m,4H),2.48-2.55(m,10H),3.63(q,J＝5.8Hz,4H,CH2CH2-OH),3.73(q, J＝5.8Hz,4H,CH2CH2OH),4.01-4.05(m,4H),5.10(t,J＝5.4Hz,2H, CH2CH2OH),7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49 (s,2H),11.85(t,J＝5.4Hz,2H,CONH).
实施例51：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-(2-甲磺酰氧基乙基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.45-1.49(m,2H),2.13(s,6H,2xN-CH3), 2.28-2.34(m,4H),2.48-2.55(m,10H),3.63(q,J＝5.8Hz,4H,CH2CH2-OH),3.73(q, J＝5.8Hz,4H,CH2CH2OH),4.01-4.05(m,4H),4.51(br s,6H),7.36(t,J＝7.4Hz,2H), 7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t,J＝5.4Hz,2H, CONH).
实施例52：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-[2-(N,N-二乙胺基)乙基]-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}(134)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.06(m,12H),1.45-1.49(m,2H),2.13(s, 6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),2.75(s,6H,CH3),3.10(m,4H),3.61(m,2H),4.02(m,2H),4.01-4.05(m,4H),7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t,J＝5.4Hz,2H,CONH).
实施例53：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-(1-甲基-2-羟基乙基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.16(d,J＝6.9Hz,6H),1.45-1.49(m,2H),2.13(s,6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),2.82(br s,2H),3.52(dd, J＝11.0,6.0Hz,2H),3.66(dd,J＝11.0,3.8Hz,2H),4.01-4.05(m,6H),5.88(br s,2H), 7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t, J＝5.4Hz,2H,CONH).
实施例54：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-(1-甲基-2-甲磺酰氧基乙基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.15(d,J＝6.9Hz,6H),1.45-1.49(m,2H),2.13(s,6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),2.82(br s,2H),3.52(dd, J＝11.0,6.0Hz,2H),3.66(dd,J＝11.0,3.8Hz,2H),4.01-4.05(m,6H),4.51(br s,6H), 7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t, J＝5.4Hz,2H,CONH).
实施例55：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-[1-(N,N-二乙胺基)乙基])-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}(139)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.06(m,12H),1.15(d,J＝6.9Hz,6H),1.45-1.49(m,2H),2.13(s,6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),2.75(s,6H,CH3),2.82(br s,2H),3.10(m,8H),3.52(dd,J＝11.0,6.0Hz,2H),3.61(m,4H),3.66(dd,J＝11.0,3.8Hz,2H),4.01-4.05(m,10H),7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz,2H), 7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t,J＝5.4Hz,2H,CONH).
实施例56：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-(2-甲基-2-羟基乙基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}的制备。
按实施例1所述的方式:1H NMR(d6-DMSO):δ1.17(d,J＝6.9Hz,6H),1.45-1.49(m,2H),2.13(s,6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),2.82(br s,2H),3.52(dd, J＝11.0,6.0Hz,2H),3.66(dd,J＝11.0,3.8Hz,2H),4.01-4.05(m,6H),5.88(br s,2H), 7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t, J＝5.4Hz,2H,CONH).
实施例57：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-(2-甲基-2-甲磺酰氧基乙基)-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}的制备。
按实施例2所述的方式:1H NMR(d6-DMSO):δ1.14(d,J＝6.9Hz,6H),1.45-1.49(m,2H),2.13(s,6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),2.82(br s,2H),3.52(dd, J＝11.0,6.0Hz,2H),3.66(dd,J＝11.0,3.8Hz,2H),4.01-4.05(m,6H),4.51(br s,6H), 7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz,2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t, J＝5.4Hz,2H,CONH).
实施例58：2,2'–{1,3-丙二基双[(甲基亚氨基)-2,1乙二基]}双{N-[2-(N,N-二乙胺基)乙基])-6-甲基-1-氧代-1,2-二氢苯并[b][1,6]萘啶-4-甲酰胺}(144)的制备。
按实施例3所述的方式:1H NMR(d6-DMSO):δ1.04-1.08(m,12H),1.15(d,J＝6.9Hz,6H),1.45-1.49(m,2H),2.13(s,6H,2xN-CH3),2.28-2.34(m,4H),2.48-2.55(m,10H),2.75(s,6H,CH3),2.82(br s,2H),3.10(m,8H),3.52(dd,J＝11.0,6.0Hz,2H),3.61(m,4H),3.66(dd,J＝11.0,3.8Hz,2H),4.01-4.05(m,10H),7.36(t,J＝7.4Hz,2H),7.62(d,J＝6.5Hz, 2H),7.93(d,J＝7.7Hz,2H),8.49(s,2H),11.85(t,J＝5.4Hz,2H,CONH).
其他化合物参照上述方法合成。
实施例59：本发明化合物的生物学试验。
本发明化合物的体外细胞毒性，通过化合物对人口腔上皮癌细胞(KB)、人肺癌细胞 (A-549)、乳腺癌细胞(MDA)三种肿瘤细胞的体外生长抑制率来测试，测试药物浓度为 4μg/mL，37℃下培养3天，结果总结在表5中：
表5：
结果表明，本发明化合物对动物和人肿瘤细胞系具有细胞毒活性。因此，它们具有作为抗癌药物的潜在用途。
本领域技术人员将理解，在不脱离广泛描述的本发明的精神或范围的情况下，可以对具体实施方案中所示的本发明进行多种变化和/或修改。因此，本发明的实施例在所有方面都被认为是说明性的而非限制性的。
Claims (10)
1.一种式(I)的三环衍生化合物，所述式(I)如下：
式中位置编号按上述系统，其中：X1和X2可以分别或同时为-CH＝或-N＝；及
Q是O或S；
R和R1-R3独立地为H或任选取代的C1-4烷基或R和R1-R3与它们所连接的氮原子一起形成任选取代的饱和或不饱和杂环基，及n是0至6的整数；
但当X2为碳时，n个R1不同时为H；而当X2为氮及n＝2时，R2和R3不同时为Me。
Z为H，卤素，OH，CO2H，CO2R4，SO2R4，NR4R5，硝基，氰基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C1-6卤代烷氧基，C1-6氨基烷基，C1-6氨基烷氧基，或氮杂官能团取代环CH官能团，或桥接6-7,7-8或8-9位的碳或碳/氮骨架，以形成另外的稠合的5至6元碳环或杂环；以及
Y为H，C1-6烷基，带有与Z的定义一样活性基团的C1-C6烷基，或(CH2)m—X2—(CH2)pU，其中
X2为CH2,C═O,CH═CH,O,S,NR；和
m和p是从0到6的整数，和
U是H，CF3，卤素，NR4R5,+NRR4R5，氰基，C(═O)NR4R5OR4,CO2R4；
R4和R5的任选取代基与R和R1-R3的定义一样。
或其药学上可接受的盐，N-氧化物，水合物，溶剂化物，药学上可接受的衍生物，前药，互变异构体和/或异构体。
2.根据权利要求1，该化合物为式(Ia)的吖啶衍生物，或其药学上可以接受的盐或其N氧化物：
R1-R3独立地为H，或任选取代的C1-4烷基，或R1-R3相互间形成饱和或者不饱和环基，或者与它们所连接的氮或者氧原子一起形成任选取代的饱和或不饱和杂环基，和其药学上可接受的盐，N-氧化物，水合物，溶剂化物，药学上可接受的衍生物，前药，互变异构体和/或异构体。但R1a和R1b不同时为H。
3.根据权利要求1，该化合物为式(Ib)的吩嗪-1-甲酰胺衍生物，或其药学上可以接受的盐或其N氧化物：
R1-R3独立地为H，或任选取代的C1-4烷基，或R1-R3相互间形成饱和或者不饱和环基，或者与它们所连接的氮或者氧原子一起形成任选取代的饱和或不饱和杂环基，和其药学上可接受的盐，N-氧化物，水合物，溶剂化物，药学上可接受的衍生物，前药，互变异构体和/或异构体。但R1a和R1b不同时为H。
4.根据权利要求1，该化合物为式(Ic)的苯并[b][1,6]萘啶-1(2H)-酮的衍生物，或其药学上可以接受的盐或其N氧化物：
R1-R3独立地为H，或任选取代的C1-C4烷基，或R1-R3相互间形成饱和或者不饱和环基，或者与它们所连接的氮或者氧原子一起形成任选取代的饱和或不饱和杂环基。但不包括已经公开的酰胺侧链：即当R2,R3同时为甲基时，R1a和R1b为H，以及当R2,R3,R1a同时为甲基时，R1b为H或羰基。用化学式表示即：-CONHCH2CH2N(CH3)2，-CONHCHMeCH2N(CH3)2，-CONHCHMeCON(CH3)2。
Z为H，卤素，OH，CO2H，CO2R4，SO2R4，NR4R5，硝基，氰基，C1-6烷基，C1-6卤代烷基，C1-6烷氧基，C1-6卤代烷氧基，C1-6氨基烷基，C1-6氨基烷氧基，或氮杂官能团取代环CH官能团，或桥接6-7,7-8或8-9位的碳或碳/氮骨架，以形成另外的稠合的5至6元碳环或杂环；以及：
Y为H，C1-C6烷基，带有与Z的定义一样的活性基团的C1-C6烷基，或芳香基团；
或其药学上可接受的盐，N-氧化物，水合物，溶剂化物，药学上可接受的衍生物，前药，互变异构体和/或异构体。
5.根据权利要求1，该化合物为式(IIc)的苯并[b][1,6]萘啶-1(2H)-酮的衍生物，或其药学上可以接受的盐或其N氧化物：
R1-R3独立地为H，或任选取代的C1-4烷基，或R1-R3相互间形成饱和或者不饱和环基，或者与它们所连接的氮或者氧原子一起形成任选取代的饱和或不饱和杂环基，但不包括已经公开的酰胺侧链：即当R2,R3同时为甲基时，R1a和R1b为H，以及当R2,R3,R1a同时为甲基时，R1b为H或羰基。用化学式表示为：-CONHCH2CH2N(CH3)2，-CONHCHMeCH2N(CH3)2，-CONHCHMeCON(CH3)2。
Y1是化合价x的连接基团-(CH2)m—X2—(CH2)pU，其中
X2为CH2,C═O,CH═CH,O,S,NR；和
m和p是从0到6的整数，和
U是H，CF3，卤素，NR4R5,+NRR4R5，氰基，C(═O)NR4R5OR4,CO2R4；
R4和R5的任选取代基与R和R1-R3的定义一样。
或其药学上可接受的盐，N-氧化物，水合物，溶剂化物，药学上可接受的衍生物，前药，互变异构体和/或异构体。
6.制备如权利要求1所定义的化合物的方法，该方法包括将通式(VII)的化合物与通式(VIII)的伯胺或仲胺反应，所述通式(VII)和(VIII)如下：
式中Q，X，Y，Z，R和R1如权利要求1的定义。
式中R2和R3如权利要求1的定义。以及如果需要，可将所得到的化合物转化为其药学上可以接受的盐或其N-氧化物。
7.根据权利要求6，制备通式(VII)的化合物的方法，该方法包括将通式(VI)的化合物在碱性条件下与甲基磺酰氯反应，所述通式(VI)如下：
式中Q，X，Y，Z，R和R1如权利要求1的定义。
8.据权利要求7，制备通式(VI)的化合物的方法，该方法包括将通式(III)的化合物与通式(V)的醇胺反应，所述通式(III)和(V)如下：
式中Q，X，Y，Z如权利要求1的定义，及A是OH，Cl或N-咪唑基。
式中R1和n如权利要求1的定义。
9.制备如权利要求1所定义的化合物的方法，该方法包括将通式(III)的化合物和式(IV)的胺反应，所述式(III)和(IV)如下：
式中Q，X，Y，Z如权利要求1的定义，及A是OH，Cl或N-咪唑基。
式中n，R,R1-R3的定义如权利要求1所述；以及如果需要，可将所得到的化合物转化为其药学上可以接受的盐或其N-氧化物。
10.权利要求1的化合物在用作抗肿瘤药物生产中的用途。
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| CN119350330B (zh) * | 2024-12-23 | 2025-03-21 | 世华合创生物技术开发(山东)有限公司 | 一种二氮杂三环胺化合物、制备方法及其应用 |
| CN119350329B (zh) * | 2024-12-23 | 2025-03-21 | 世华合创生物技术开发(山东)有限公司 | 一种二氮杂三环胺化合物、制备方法及应用 |
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