CN112759550A - 一种平滑受体拮抗剂 - Google Patents
一种平滑受体拮抗剂 Download PDFInfo
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- CN112759550A CN112759550A CN201911066517.XA CN201911066517A CN112759550A CN 112759550 A CN112759550 A CN 112759550A CN 201911066517 A CN201911066517 A CN 201911066517A CN 112759550 A CN112759550 A CN 112759550A
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- nmr
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- dione
- chloroform
- chlorophenyl
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及有机化学领域，特别是涉及一种平滑受体拮抗剂。本发明提供一种配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，所述配体分子的化学结构式如下所示：
Description
技术领域
本发明涉及有机化学领域，特别是涉及一种平滑受体拮抗剂。
背景技术
平滑受体(Smoothened receptor,SMO)是G蛋白偶联受体(G protein-coupledreceptors，GPCRs)中F家族中的一员，在刺猬(Hedgehog,Hh)信号通路中发挥着关键作用。Hh信号通路的异常激活可导致肿瘤的发生与发展，因此平滑受体是重要抗癌药物靶标。目前，FDA已批准三个靶向平滑受体的上市药物用于基底细胞癌和急性髓性白血病的治疗。然而一些药物上市不久后由于平滑受体结合口袋附近突变导致严重抗药性，失去治疗作用。
发明内容
鉴于以上所述现有技术的缺点，本发明的目的在于提供一种平滑受体拮抗剂，用于解决现有技术中的问题。
为实现上述目的及其他相关目的，本发明一方面提供一种配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，所述配体分子的化学结构式如下所示：
其中，A1、A2、A3、A4、A5、A6、A7、A8各自独立地选自C、N或C-R5；
X选自O或S；
m选自1或2；
n选自1或2；
p选自0、1或2；
R1、R2、R5各自独立地选自H、卤素、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、硝基、氰基、叠氮基、氨基、COOR11、CONR12R13、异氰酸酯基、异硫氰酸酯基、-OR6、-SR7、-(CH2)y-NR8R9、-SO2R10、CN2R14、芳基、杂芳基；
y选自0、1或2；
R3、R4各自独立地选自氢原子、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、芳基；
R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地选自H、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、芳基。
本发明另一方面提供所述的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物在制备药物中的用途。
本发明另一方面提供一种药物组合物，包括所述的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，以及至少一种药学上可接受的载体、添加剂、助剂或赋形剂。
附图说明
图1显示为本发明中平滑受体拮抗剂Allo-1结合位点的示意图。其中，1A为Allo-1分子在平滑受体上的结合口袋；1B为Allo-1分子与平滑受体的结合远离蛋白耐药性突变位点Asp 473；1C为基于Allo-1分子设计化合物TC929；1D为TC929在荧光素酶报告基因实验中对平滑受体抑制活性大大优于Allo-1分子。
具体实施方式：
本发明发明人经过大量研究，提供了一类新型的配体分子，所述配体分子通过在分子中引入靶向受体特定结合位点的基团，进一步增强配体和受体之间的相互作用，提高小分子对受体的活性，在此基础上完成了本发明。
本发明第一方面提供一种配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，所述配体分子的化学结构式如下所示：
其中，A1、A2、A3、A4、A5、A6、A7、A8各自独立地选自C、N或C-R5；
X选自O或S；
m选自1或2；
n选自1或2；
p选自0、1或2；
R1、R2、R5各自独立地选自H、卤素、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、C1-C6烯基、C1-C6炔基、硝基、氰基、叠氮基、氨基、COOR11、CONR12R13、异氰酸酯基、异硫氰酸酯基、-OR6、-SR7、-(CH2)y-NR8R9、-SO2R10、CN2R14、芳基、杂芳基；
y选自0、1或2；
R3、R4各自独立地选自氢原子、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、芳基；
R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地选自H、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、芳基。
除非另外指明，本发明的配体分子的同位素标记的形式也包括在本发明的保护范围以内。例如，具有上述所给出的具有本发明结构的化合物中，至少一个氢原子被氘或氚替代，或至少一个碳被13C-或14C-富集的碳替代，或至少一个氮被15N-富集的氮替代。
本发明中，术语“盐”应当被理解为由本发明使用的任何形式的活性化合物，其中所述化合物可以为离子形式或带电荷或被偶联到反离子(阳离子或阴离子)或在溶液中。这个定义还可以包括活性分子与其它分子和离子的季铵盐和络合物，特别是通过离子相互作用的络合物。该定义尤其包括生理上可接受的盐，该术语可以被理解为与“药理学上可接受的盐”等同。
本发明中，术语“药学上可接受的盐”通常指当以适当的方式用于治疗时(特别是在人类和/或哺乳动物中应用或使用时)在生理学上可耐受的任何盐(通常来说，这意味着它是无毒的，特别是作为抗衡离子的结果是无毒的)。这些生理上可接受的盐可以是与阳离子或碱形成的，并且在本发明的上下文中，尤其是在人类和/或哺乳动物中施用时，它们应该被理解为由按照本发明所提供的至少一种化合物，通常为酸(去质子化的)，如阴离子和至少一种生理学上耐受的阳离子(优选无机阳离子)形成的盐。在本发明的上下文中，具体地可以包括与碱金属和碱土金属形成的盐、以及与铵阳离子(NH4 +)形成的盐，具体可以是包括但不限于与(单)或(二)钠、(单)或(二)钾、镁或钙形成的盐。这些生理上可接受的盐也可以是与阴离子或酸形成的，并且在本发明的上下文中，特别是在人类和/或哺乳动物中施用时，它们应该被理解为由按照本发明所提供的至少一种化合物，通常质子化的(例如在氮上)，如阳离子和至少一种生理上可耐受的阴离子形成的盐。在本发明的上下文中，具体地可以包括由生理上可耐受的酸形成的盐，即特定的活性化合物与生理上可耐受的有机或无机酸形成的盐，具体可以是包括但不限于与盐酸、氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、苹果酸、酒石酸、扁桃酸、富马酸、乳酸或柠檬酸形成的盐。
由上述本发明所提供的配体分子可以包括取决于存在的手性中心的对映体或取决于存在的双键的异构体(例如Z,E)。单一异构体、对映异构体、非对映异构体或顺反异构体和它们的混合物均落入本发明的范围之内。
本发明中术语“前药”以其最广泛的意义使用，并且包括在体内可以转化为本发明的化合物的那些衍生物。制备指定的起作用化合物的前药的方法对于本领域技术人员来说应该是已知的，例如，可以参阅如Krogsgaard-Larsen等人，“药物设计和发现教科书”(Textbook of Drug design and Discovery)泰勒弗朗西斯出版社Taylor&Francis(2002年4月)中所公开的相关内容。
本发明中，术语“溶剂化物”通常指任何形式的根据本发明的活性化合物通过非共价键与另一分子(通常为极性溶剂)相结合，所获得的物质，具体可以是包括但不限于水化物和醇化物，例如甲醇化物。
本发明中，所述“卤素”或“卤代”通常指氟、氯、溴或碘。
本发明中，所述“烷基”通常指饱和脂肪族基团，它们可以是直链或支链。例如，C1-C6烷基通常指包括1个、2个、3个、4个、5个、6个碳原子的烷基基团，所述烷基基团具体可以是包括但不限于甲基、乙基、丙基、丁基、戊基、己基等。
本发明中，“环烷基”通常指具有三个以上碳原子的饱和或不饱和(但不是芳族)环烃。例如，C3-C9环烷基通常指包括3个、4个、5个、6个、7个、8个、9个碳原子的饱和或不饱和环烃,。所述环烷基具体可以是包括但不限于环丙基、2-甲基环丙基、环丙基甲基、环丁基、环戊基、环戊基甲基、环己基、环庚基、环辛基、金刚烷基、降金刚烷基等。
本发明中，“卤代烷基”通常指卤代的饱和脂肪族基团，它们可以是直链或支链的、并且任选被被独立地选自氟、氯、溴或碘单取代或多取代。例如，C1-C6卤代烷基通常指包括1个、2个、3个、4个、5个、6个碳原子的卤代烷基基团，所述卤代烷基基团具体可以是包括但不限于卤代甲基、卤代乙基、卤代丙基、卤代丁基、卤代戊基、卤代己基等。
本发明中，“烯基”通常指包括至少一个C＝C双键的不饱和脂肪族基团。例如，C2-C6烯基通常指包括2个、3个、4个、5个、6个碳原子的烯基基团，所述烯基基团具体可以是包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基等。
本发明中，“炔基”通常指包括至少一个碳碳三键的不饱和脂肪族基团。例如，C2-C6炔基通常指包括2个、3个、4个、5个、6个碳原子的炔基基团，所述炔基基团具体可以是包括但不限于乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。
本发明中，“杂环烷基”通常指饱和或不饱和(但不是芳族)环烃，并且在其结构中具有至少一个选自N、O或S的杂原子。所述杂环烷基具体可以是包括但不限于吡咯啉、吡咯烷、吡唑啉、氮丙啶、氮杂环丁烷、四氢吡咯、环氧乙烷、氧杂环丁烷、二氧杂环丁烷、四氢吡喃、四氢呋喃、二恶烷、二氧戊环、恶唑烷、哌啶、哌嗪、吗啉、氮杂环庚烷或二氮杂环庚烷等。优选的，本发明中的杂环烷基通常是5或6元环体系。
本发明中，“芳基”通常指具有至少一个芳环但没有杂原子的基团。所述芳基基团具体可以是包括但不限于苯基、萘基、荧蒽基、芴基、四氢萘基、茚满基或蒽基等。优选的，本发明中的芳基是任选地至少单取代的5或6元环体系。
本发明中，“杂芳基”通常指具有至少一个芳族环并且可以任选地含有一个或多个选自N、O的杂原子的杂环体系。所述杂芳基具体可以是包括但不限于呋喃、苯并呋喃、吡咯、吡啶、嘧啶、哒嗪、吡嗪、喹啉、异喹啉、酞嗪、三唑、吡唑、异恶唑、吲哚、苯基吡唑基、苯并三唑、苯并二氧戊环、苯并二恶烷、苯并咪唑、咔唑和喹唑啉等。优选的，本发明中的杂芳基是任选至少单取代的5或6元环体系。
在本发明一些优选实施例中，n选自1，p选自0，所述配体分子的化学结构式如下所示：
在本发明一些优选实施例中，R1选自H、F、Cl、Br、I、C1-C3烷基、C1-C3卤代烷基、氨基、硝基、氰基、叠氮基、COOR11、-OR6、-SO2R10；其中，R6选自C1-C3卤代烷基，R10选自C1-C3烷基，R11选自C1-C4烷基。
在本发明一些优选实施例中，A1、A2、A3、A4各自独立地选自选自C、N、或C-R5；其中，R5各自独立地选自C1-C3烷基、C1-C3卤代烷基、F、Cl、Br、I、氨基、硝基、或叠氮基，其中，卤代烷基的卤代基团选自F、Cl、Br、I。
在本发明更加优选的实施例中，A1选自C、N、或C-R5；A2选自C、N；A3选自C、或C-R5；A4选自C、或C-R5；R5各自独立地选自C1-C3烷基、C1-C3卤代烷基、F、Cl、Br、I、氨基、硝基、或叠氮基，其中，卤代烷基的卤代基团选自F、Cl、Br、I。
在本发明一些优选实施例中，R2选自H、F、Cl、Br、I、C1-C3烷基、C1-C3卤代烷基、叠氮基、COOR11、CONR12R13、-OR6、-(CH2)y-NR8R9、苯基、或结构式如下所示的基团：
R6选自C1-C3卤代烷基；
y＝1，R8、R9各自独立地选自H、苯基；
R11选自C1-C4烷基；
R12、R13各自独立地选自H、C1-C3烷基、苯基。
在本发明一些优选实施例中，A5、A6、A7、A8各自独立地选自C、或C-R5；其中，R5各自独立地选自F、Cl、Br、I、氨基、或叠氮基。
在本发明更加优选的实施例中，A5选自C；A6选自C、或C-R5；A7选自C、或C-R5；A8选自C；其中，R5各自独立地选自F、Cl、Br、I、氨基、或叠氮基。
在本发明一些优选实施例中，R3、R4各自独立地选自H、C1-C3烷基。
在本发明进一步优选的具体实施例中，所述配体分子选自化学结构式如下所示的化合物：
(S)-3-(4-chlorophenyl)-5-methyl-1-(4-nitrobenzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(4-硝基苄基)咪唑烷-2,4-二酮
(I)
(S)-1-(4-aminobenzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-氨基苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(II)
(S)-3-(4-aminophenyl)-1-benzyl-5-methylimidazolidine-2,4-dione
(S)-3-(4-氨基苯基)-1-苄基-5-甲基咪唑烷-2,4-二酮
(III)
(S)-5-methyl-1-(4-nitrobenzyl)-3-(p-tolyl)imidazolidine-2,4-dione
(S)-5-甲基-1-(4-硝基苄基)-3-(对甲苯基)咪唑烷-2,4-二酮
(IV)
(S)-1-benzyl-3-(4-chlorophenyl)-5-isopropylimidazolidine-2,4-dione
(S)-1-苄基-3-(4-氯苯基)-5-异丙基咪唑烷-2,4-二酮
(V)
(S)-3-(4-chlorophenyl)-5-isopropyl-1-(4-nitrobenzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-异丙基-1-(4-硝基苄基)咪唑烷-2,4-二酮
(VI)
(S)-1-(4-azidobenzyl)-5-methyl-3-(p-tolyl)imidazolidine-2,4-dione
(S)-1-(4-叠氮基苄基)-5-甲基-3-(对甲苯基)咪唑烷-2,4-二酮
(VII)
(S)-3-(4-chlorophenyl)-5-methyl-1-(3-nitrobenzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(3-硝基苄基)咪唑烷-2,4-二酮
(VIII)
(S)-1-benzyl-3-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(4-氟苯基)-5-甲基咪唑烷-2,4-二酮
(IX)
(S)-1-benzyl-3-(4-bromophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(4-溴苯基)-5-甲基咪唑烷-2,4-二酮
(X)
(S)-1-benzyl-5-methyl-3-(p-tolyl)imidazolidine-2,4-dione
(S)-1-苄基-5-甲基-3-(对甲苯基)咪唑烷-2,4-二酮
(XI)
(S)-1-benzyl-5-methyl-3-(4-(trifluoromethyl)phenyl)imidazolidine-2,4-dione
(S)-1-苄基-5-甲基-3-(4-(三氟甲基)苯基)咪唑烷-2,4-二酮
(XII)
(S)-1-benzyl-5-methyl-3-(4-(trifluoromethoxy)phenyl)imidazolidine-2,4-dione
(S)-1-苄基-5-甲基-3-(4-(三氟甲氧基)苯基)咪唑烷-2,4-二酮
(XIII)
(S)-1-benzyl-3-(3-chloro-4-methylphenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(3-氯-4-甲基苯基)-5-甲基咪唑烷-2,4-二酮
(XIV)
(S)-1-(4-aminobenzyl)-3-(4-chlorophenyl)-5-isopropylimidazolidine-2,4-dione
(S)-1-(4-氨基苄基)-3-(4-氯苯基)-5-异丙基咪唑烷-2,4-二酮
(XV)
(S)-1-(4-azidobenzyl)-3-(4-chlorophenyl)-5-isopropylimidazolidine-2,4-dione(S)-1-(4-叠氮基苄基)-3-(4-氯苯基)-5-isopropylimidazolidine-2,4-二酮
(XVI)
(S)-1-(3-aminobenzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(3-氨基苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XVII)
(S)-1-(3-azidobenzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(3-叠氮基苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XVIII)
(S)-1-benzyl-5-methyl-3-(3-nitrophenyl)imidazolidine-2,4-dione
(S)-1-苄基-5-甲基-3-(3-硝基苯基)咪唑烷-2,4-二酮
(XIX)
(R)-1-benzyl-3-(4-chlorophenyl)-5-isopropylimidazolidine-2,4-dione
(R)-1-苄基-3-(4-氯苯基)-5-isopropylimidazolidine-2,4-二酮
(XX)
(R)-1-benzyl-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(R)-1-苄基-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XXI)
(S)-3-(3-aminophenyl)-1-benzyl-5-methylimidazolidine-2,4-dione
(S)-3-(3-氨基苯基)-1-苄基-5-甲基咪唑烷-2,4-二酮
(XXII)
1-benzyl-3-(4-chlorophenyl)-5,5-dimethylimidazolidine-2,4-dione
1-苄基-3-(4-氯苯基)-5,5-二甲基咪唑烷-2,4-二酮
(XXIII)
1-benzyl-3-(4-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione
1-苄基-3-(4-氯苯基)二氢嘧啶-2,4(1H，3H)-二酮
(XXIV)
(S)-3-(3-azidophenyl)-1-benzyl-5-methylimidazolidine-2,4-dione
(S)-3-(3-叠氮基苯基)-1-苄基-5-甲基咪唑烷-2,4-二酮
(XXV)
(S)-3-(4-chlorophenyl)-5-methyl-1-(4-nitrophenethyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(4-硝基苯乙基)咪唑烷-2,4-二酮
(XXVI)
(S)-1-(4-aminophenethyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-氨基苯乙基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XXVII)
(S)-1-(4-azidophenethyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-叠氮基苯乙基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XXVIII)
(S)-1,3-dibenzyl-5-methylimidazolidine-2,4-dione
(S)-1,3-二苄基-5-甲基咪唑烷-2,4-二酮
(XXIX)
(S)-1-(4-(tert-butyl)benzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-(叔丁基)苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XXX)
1-benzyl-3-(4-chlorophenyl)imidazolidine-2,4-dione
1-苄基-3-(4-氯苯基)咪唑烷-2,4-二酮
(XXXI)
(S)-1-benzyl-3-(4-chlorophenyl)-5-ethylimidazolidine-2,4-dione
(S)-1-苄基-3-(4-氯苯基)-5-乙基咪唑烷-2,4-二酮
(XXXII)
(S)-3-(4-chlorophenyl)-1-(4-fluorobenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(4-氯苯基)-1-(4-氟苄基)-5-甲基咪唑烷-2,4-二酮
(XXXIII)
(S)-3-(4-chlorophenyl)-5-methyl-1-(4-(trifluoromethyl)benzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(4-(三氟甲基)苄基)咪唑烷-2,4-二酮)
(XXXIV)
(S)-1-(4-bromobenzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-溴苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XXXV)
(S)-3-(4-chlorophenyl)-5-methyl-1-(4-(methylsulfonyl)benzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(4-(甲基磺酰基)苄基)咪唑烷-2,4-二酮
(XXXVI)
(S)-3-(4-chlorophenyl)-1-(3,5-dimethylbenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(4-氯苯基)-1-(3,5-二甲基苄基)-5-甲基咪唑烷-2,4-二酮
(XXXVII)
(S)-4-((3-(4-chlorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl)methyl)benzonitrile
(S)-4-((3-(4-氯苯基)-5-甲基-2,4-二氧代咪唑烷-1-基)甲基)苯甲腈
(XXXVIII)
(S)-2-(4-chlorophenyl)-10,10a-dihydroimidazo[1,5-b]isoquinoline-1,3(2H,5H)-dione
(S)-2-(4-氯苯基)-10,10a二氢咪唑并[1,5-b]异喹啉-1,3(2H，5H)-二酮
(XXXIX)
(S)-3-(4-chlorophenyl)-5-methyl-1-(4-methylbenzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(4-甲基苄基)咪唑烷-2,4-二酮
(XL)
(S)-3-(4-chlorophenyl)-1-(2,4-difluorobenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(4-氯苯基)-1-(2,4-二氟苄基)-5-甲基咪唑烷-2,4-二酮
(XLI)
(S)-1-(3,5-bis(trifluoromethyl)benzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(3,5-双(三氟甲基)苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(XLII)
methyl(S)-4-((3-(4-chlorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl)methyl)benzoate
(S)-4-((3-(4-氯苯基)-5-甲基-2,4-二氧代咪唑烷-1-基)甲基)苯甲酸甲酯
(XLIII)
(S)-3-(4-chlorophenyl)-5-methyl-1-(pyridin-2-ylmethyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(吡啶-2-基甲基)咪唑烷-2,4-二酮
(XLIV)
(S)-3-(4-chlorophenyl)-5-methyl-1-(pyridin-3-ylmethyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(吡啶-3-基甲基)咪唑烷-2,4-二酮
(XLV)
(S)-3-(4-chlorophenyl)-5-methyl-1-((6-methylpyridin-3-yl)methyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-((6-甲基吡啶-3-基)甲基)咪唑烷-2,4-二酮
(XLVI)
(S)-3-(4-chlorophenyl)-5-methyl-1-((6-methylpyridin-2-yl)methyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-((6-甲基吡啶-2-基)甲基)咪唑烷-2,4-二酮
(XLV)
(S)-3-(3-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-1-(4-(trifluoromethyl)benzyl)imidazolidine-2,4-dione
(S)-3-(3-氯-4-(三氟甲氧基)苯基)-5-甲基-1-(4-(三氟甲基)苄基)咪唑烷-2,4-二酮
(XLVI)
(S)-3-(3-chloro-4-(trifluoromethoxy)phenyl)-5-methyl-1-(4-(trifluoromethoxy)benzyl)imidazolidine-2,4-dione
(S)-3-(3-氯-4-(三氟甲氧基)苯基)-5-甲基-1-(4-(三氟甲氧基)苄基)咪唑烷-2,4-二酮
(XLVII)
(S)-1-benzyl-3-(3-chloro-4-(trifluoromethoxy)phenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(3-氯-4-(三氟甲氧基)苯基)-5-甲基咪唑烷-2,4-二酮
(XLVIII)
(S)-3-(3-chloro-4-(trifluoromethyl)phenyl)-5-methyl-1-(4-(trifluoromethyl)benzyl)imidazolidine-2,4-dione
(S)-3-(3-氯-4-(三氟甲基)苯基)-5-甲基-1-(4-(三氟甲基)苄基)咪唑烷-2,4-二酮
(XLIX)
(S)-3-(3-chloro-4-(trifluoromethyl)phenyl)-5-methyl-1-(4-(trifluoromethoxy)benzyl)imidazolidine-2,4-dione
(S)-3-(3-氯-4-(三氟甲基)苯基)-5-甲基-1-(4-(三氟甲氧基)苄基)咪唑烷-2,4-二酮
(L)
(S)-1-benzyl-3-(3-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(3-氯苯基)-5-甲基咪唑烷-2,4-二酮
(LI)
(S)-1-benzyl-3-(3-fluorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(3-氟苯基)-5-甲基咪唑烷-2,4-二酮
(LII)
(S)-1-benzyl-3-(3-bromophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(3-溴苯基)-5-甲基咪唑烷-2,4-二酮
(LIII)
(S)-1-benzyl-3-(3-iodophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(3-碘苯基)-5-甲基咪唑烷-2,4-二酮
(LIV)
(S)-3-([1,1'-biphenyl]-4-yl)-1-benzyl-5-methylimidazolidine-2,4-dione
(S)-3-([1,1'-联苯]-4-基)-1-苄基-5-甲基咪唑烷-2,4-二酮
(LV)
(S)-3-(4-chlorophenyl)-1-(4-iodobenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(4-氯苯基)-1-(4-碘苄基)-5-甲基咪唑烷-2,4-二酮
(LVI)
methyl(S)-4-(3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)benzoate
(S)-4-(3-苄基-4-甲基-2,5-二氧代咪唑烷-1-基)苯甲酸甲酯
(LVII)
(S)-1-benzyl-3-(4-iodophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(4-碘苯基)-5-甲基咪唑烷-2,4-二酮
(LVIII)
benzyl(S)-4-(3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)benzoate
(S)-4-(3-苄基-4-甲基-2,5-二氧代咪唑烷-1-基)苯甲酸苄酯
(LIX)
(S)-4-(3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-N-phenylbenzamide
(S)-4-(3-苄基-4-甲基-2,5-二氧代咪唑烷-1-基)-N-苯基苯甲酰胺
(LX)
(S)-4-(3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)-N-methyl-N-phenylbenzamide
(S)-4-(3-苄基-4-甲基-2,5-二氧代咪唑烷-1-基)-N-甲基-N-苯基苯甲酰胺
(LXI)
(S)-3-(4-chlorophenyl)-1-(4-isothiocyanatobenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(4-氯苯基)-1-(4-异硫氰酸苯基)-5-甲基咪唑烷-2,4-二酮
(LXII)
(S)-1-benzyl-5-methyl-3-(4-((phenylamino)methyl)phenyl)imidazolidine-2,4-dione
(S)-1-苄基-5-甲基-3-(4-((苯基氨基)甲基)苯基)咪唑烷-2,4-二酮
(LXIII)
(S)-1-(4-chlorobenzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-氯苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(LXIV)
(S)-1-benzyl-3-(3,4-dichlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(3,4-二氯苯基)-5-甲基咪唑烷-2,4-二酮
(LXV)
(S)-3-(4-chlorophenyl)-5-methyl-1-(4-(trifluoromethoxy)benzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(4-(三氟甲氧基)苄基)咪唑烷-2,4-二酮
(LXVI)
(S)-1-(4-aminobenzyl)-5-methyl-3-(p-tolyl)imidazolidine-2,4-dione
(S)-1-(4-氨基苄基)-5-甲基-3-(对甲苯基)咪唑烷-2,4-二酮
(LXVII)
(S)-1-(4-azidobenzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-叠氮基苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
(LXVIII)
(S)-3-(4-azidophenyl)-1-benzyl-5-methylimidazolidine-2,4-dione
(S)-3-(4-叠氮基苯基)-1-苄基-5-甲基咪唑烷-2,4-二酮
(LXIX)
(S)-1-benzyl-3-(4-chlorophenyl)-5-methyl-2-thioxoimidazolidin-4-one
(S)-1-苄基-3-(4-氯苯基)-5-甲基-2-硫代咪唑烷-4-酮
(LXX)
(S)-3-(4-chlorophenyl)-5-methyl-1-(4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzyl)imidazolidine-2,4-dione
(S)-3-(4-氯苯基)-5-甲基-1-(4-(3-(三氟甲基)-3H-二氮杂-3-基)苄基)咪唑烷-2,4-二酮
(LXXI)
(S)-1-benzyl-3-(4-hydroxyphenyl)-5-methylimidazolidine-2,4-dione
(S)-1-苄基-3-(4-羟基苯基)-5-甲基咪唑烷-2,4-二酮
(LXXII)
methyl(S)-4-((3-(4-chlorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl)methyl)benzoate
(S)-4-(((3-(4-氯苯基)-5-甲基-2,4-二氧杂咪唑啉-1-基)甲基)苯甲酸甲酯
LXXIII
(S)-3-(4-chlorophenyl)-1-(4-(hydroxymethyl)benzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(4-氯苯基)-1-(4-(羟甲基)苄基)-5-甲基咪唑烷-2,4-二酮
LXXIV
(S)-3-(4-chlorophenyl)-1-(4-hydroxybenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(4-氯苯基)-1-(4-羟基苄基)-5-甲基咪唑烷-2,4-二酮
LXXV
(S)-1-(4-bromobenzyl)-3-(4-bromophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(4-溴苄基)-3-(4-溴苯基)-5-甲基咪唑烷-2,4-二酮
LXXVI
(S)-1-(3-bromobenzyl)-3-(4-chlorophenyl)-5-methylimidazolidine-2,4-dione
(S)-1-(3-溴苄基)-3-(4-氯苯基)-5-甲基咪唑烷-2,4-二酮
LXXVII
(S)-3-(3-bromo-4-methylphenyl)-1-(4-bromobenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(3-溴-4-甲基苯基)-1-(4-溴苄基)-5-甲基咪唑烷-2,4-二酮
LXXVIII
(S)-3-(3-bromo-4-(trifluoromethyl)phenyl)-1-(4-bromobenzyl)-5-methylimidazolidine-2,4-dione
(S)-3-(3-溴-4-(三氟甲基)苯基)-1-(4-溴苄基)-5-甲基咪唑烷-2,4-二酮
LXXIX。
本发明发明人发现平滑受体与Allo-1分子的结合位点位于跨膜区深处，主要作用力包括了卤键、氢键、疏水相互作用、π-cage堆积等(图1A)。相关结合模型很好地解释Allo-1分子克服耐药性的机理，即Allo-1分子的结合口袋远离了产生平滑受体耐药性的突变位点Asp473，因而大大规避了突变造成的小分子结合力减弱，保留了拮抗活性(图1B)。发明人在原有基础上通过改造Allo-1分子，构建新的卤键、氢键等相互作用，提高了配体分子对平滑受体的活性。
本发明第二方面提供所述的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物在制备药物中的用途。如上所述，本发明所提供的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物对平滑受体具有明显的抑制活性，甚至相比于现有技术中的Allo-1更优，所述配体分子可以靶向于平滑受体新结合位点，并可以与平滑受体结合，从而表现出优良的对平滑受体的拮抗活性，可以用于制备用于调控平滑受体的药物，例如，可以是平滑受体拮抗剂等。在本发明一具体实施例中，当细胞处于所述配体分子存在的条件下时，平滑受体的活性被明显抑制。此外，本领域技术人员已经发现，平滑受体在刺猬信号通路中发挥着关键作用，Hh信号通路的异常激活可导致肿瘤的发生与发展，因此平滑受体是重要抗癌药物靶标，通过对平滑受体的抑制，可以有效抑制肿瘤细胞的增殖。所以说，所述药物可以用于治疗平滑受体相关的疾病，例如，可以是平滑受体过表达或高活性相关的疾病，更具体可以是Hh信号通路异常的相关疾病，例如，可以是Hh信号通路异常激活的相关疾病。所述疾病具体可以选自肿瘤、髓瘤或实体瘤，癌症，白血病，淋巴瘤，结肠直肠癌，脑癌，骨癌，上皮细胞-来源的肿瘤(上皮癌)，基底细胞癌，腺癌，胃肠癌，唇癌，口腔癌，食道癌，小肠癌，胃癌，结肠癌，肝癌，膀胱癌，胰腺癌，卵巢癌，宫颈癌，肺癌，乳腺癌，皮肤癌，鳞状细胞和/或基底细胞癌，前列腺癌，神经胶质瘤，胶质母细胞瘤，肾细胞癌和其他已知影响全身上皮细胞的癌症，慢性粒细胞白血病(CML)，急性髓性白血病(AML)和急性早幼粒细胞白血病(APL)等。
本发明第三方面提供一种药物组合物，包括所述的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，以及至少一种药学上可接受的载体、添加剂、助剂或赋形剂。
本发明中，所述组合物可以包括一种或多种药学上可接受的载体，其通常指用于治疗剂给药的载体，它们本身不诱导产生对接受该组合物的个体有害的抗体，且给药后没有过分的毒性。这些载体是本领域技术人员所熟知的，例如，在Remington’sPharmaceutical Sciences(Mack Pub.Co.,N.J.1991)中公开了关于药学上可接受的载体的相关内容。具体来说，所述载体可以是包括但不限于盐水、缓冲液、葡萄糖、水、甘油、乙醇、佐剂等中的一种或多种的组合。
本发明所提供的药物组合物中，所述配体分子可以是单一有效成分，也可以与其他活性组分进行组合，构成联合制剂。所述其他活性组分可以是其他各种可以用于治疗肿瘤、髓瘤或实体瘤、癌症的药物。组合物中活性组分的含量通常为安全有效量，所述安全有效量对于本领域技术人员来说应该是可以调整的，例如，所述配体分子和药物组合物的活性成分的施用量通常依赖于患者的体重、应用的类型、疾病的病情和严重程度等因素。
本发明所提供的配体分子可以适应于任何形式的给药方式，可以是口服或胃肠外给药，例如，可以是经肺、经鼻、经直肠和/或静脉注射，更具体可以是真皮内、皮下、肌内、关节内、腹膜内、肺部、口腔、舌下含服、经鼻、经皮、阴道、口服或胃肠外给药。本领域技术人员可根据给药方式，选择合适的制剂形式，例如，适合于口服给药的制剂形式可以是包括但不限于丸剂、片剂、咀嚼剂、胶囊剂、颗粒剂、滴剂或糖浆等，再例如，适合于胃肠外给药的制剂形式可以是包括但不限于溶液、悬浮液、可复水的干制剂或喷雾剂等，再例如，适合于直肠给药的通常可以是栓剂。
本发明第四方面提供一种治疗方法包括：向个体施用治疗有效量的本发明第一方面所提供的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物、或本发明第三方面所提供的药物组合物。
本发明中，“个体”通常包括人类、非人类的灵长类，如哺乳动物、狗、猫、马、羊、猪、牛等，其可因利用所述制剂、试剂盒或联合制剂进行治疗而获益。
本发明中，“治疗有效量”通常指一用量在经过适当的给药期间后，能够达到治疗如上所列出的疾病的效果。
本发明发明人通过靶向平滑受体新结合位点，精确地在小分子的相应位置引入新的取代基团，进一步增强配体和受体之间的相互作用，所提供的配体分子可以有效提高了配体分子对平滑受体的活性，相关配体分子对平滑受体的抑制活性比Allo-1更优，可以作为工具分子应用于平滑受体的功能和结构研究，也可以用于制备平滑受体相关疾病的药物，具有良好的产业化前景。
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精神下进行各种修饰或改变。
须知，下列实施例中未具体注明的工艺设备或装置均采用本领域内的常规设备或装置。
此外应理解，本发明中提到的一个或多个方法步骤并不排斥在所述组合步骤前后还可以存在其他方法步骤或在这些明确提到的步骤之间还可以插入其他方法步骤，除非另有说明；还应理解，本发明中提到的一个或多个设备/装置之间的组合连接关系并不排斥在所述组合设备/装置前后还可以存在其他设备/装置或在这些明确提到的两个设备/装置之间还可以插入其他设备/装置，除非另有说明。而且，除非另有说明，各方法步骤的编号仅为鉴别各方法步骤的便利工具，而非为限制各方法步骤的排列次序或限定本发明可实施的范围，其相对关系的改变或调整，在无实质变更技术内容的情况下，当亦视为本发明可实施的范畴。
实施例1
平滑受体配体小分子的合成：
化合物TC936,TC 938，TC 939，TC 942，TC 943，TC 944，TC 945，TC 946，TC 947，TC 952，TC 953，TC 954，TC 956，TC 957，TC962，TC966，TC967，TC968，TC987，TC988，TC989，TC990，TC991，TC993，TC994，TC995，TC996，TC997，TC999，TC1202，TC1203，TC 1207，TC1209,TC437,TC 439，TC 440采用如下方法合成：
将1当量氨基酸叔丁酯盐酸盐溶于乙腈中，加入2当量的二异丙基乙基胺，0.9当量的对应的溴代苯基化合物，反应在室温下搅拌过夜。反应液适量浓缩，加入水和乙酸乙酯。水层用乙酸乙酯萃取两次，合并乙酸乙酯层，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后，浓缩，柱层析，得到中间体1。
将1当量的中间体1，溶于乙腈中，加入1.1当量相应的苯基异氰酸酯，反应室温搅拌过夜，然后加入适量浓盐酸(0.3mL/mmol)，室温继续反应4小时。将反应液置于冰浴中，小心滴加饱和碳酸氢钠溶液至中性，然后用乙酸乙酯萃取，乙酸乙酯层用饱和氯化钠溶液洗涤，无水硫酸钠干燥，然后柱层析，得到相应终产物。
具体反应方程式如下：
试剂与反应条件：a：DIPEA、BnBr、CH3CN，室温条件，反应过夜；b：(1)isocyanatobenzene、CH3CN，室温条件，反应过夜，(2)HCl，室温条件，反应四小时。
反应中所用的溴代苯基化合物和苯基异氰酸酯及其对应的化合物编号如下：
表1
化合物TC933，TC 941，TC959，TC963，TC964，TC 965，TC969，TC970，TC971，TC972，TC973，TC974，TC975，TC978，TC979，TC980，TC981，TC982，TC983，TC984，TC986，TC998，TC1206，TC1208，TC438,TC480，TC483均采用如下方法合成：
L-丙氨酸叔丁酯盐酸盐(1当量)溶于乙腈中，加入1.5当量的三乙胺、1.1当量的4-氯苯基异氰酸酯，然后将反应液加热到70℃搅拌1小时，之后待反应液冷却到室温，加入适量浓盐酸(0.3mL/mmol)，反应液重新加热到70℃保持1小时，然后室温搅拌过夜。将反应液置于冰浴中，小心滴加饱和碳酸氢钠溶液至中性，然后用乙酸乙酯萃取，乙酸乙酯层用饱和氯化钠溶液洗涤，无水硫酸钠干燥，然后柱层析，得到中间体2(白色固体)。
将1当量的中间体2溶于乙腈中，加入1当量的碳酸铯，1.5当量的相应的溴代苯基化合物，反应加热到40℃过夜。将反应液适量浓缩，加入乙酸乙酯，乙酸乙酯层用饱和氯化钠溶液洗涤，无水硫酸钠干燥，之后浓缩，柱层析，得到产物。
试剂与反应条件:a：(1)Et3N，1-chloro-4-isocyanatobenzene，CH3CN，70℃，1小时，(2)HCl，70℃-室温，反应过夜；b：Cs2CO3，BnBr，CH3CN，40℃，反应过夜。
反应中所用的溴代苯基化合物及其对应的化合物编号如下：
表2
化合物TC1204，TC1205采用以下合成方法：
中间体3的合成方法参考化合物TC942的合成方法。
将1当量的中间体3溶于甲醇和乙酸乙酯混合溶剂中，加入20wt％的钯碳，将反应液在常温下于氢气环境下搅拌2小时，抽滤浓缩后得到中间体4，用于下步反应。
将1当量的中间体4溶于干燥二氯甲烷中，分别加入1.5当量的HATU以及2.5当量的DIPEA，然后加入1当量对应的苯胺。反应溶液常温下搅拌两小时后，将反应液加入适量的饱和氯化铵溶液。加入二氯甲烷，二氯甲烷层用饱和氯化钠溶液洗涤，无水硫酸钠干燥，之后浓缩，柱层析，得到产物。
具体反应方程式如下：
试剂与反应条件:a：氢气，Pd/C，2小时；b：HATU，DIPEA，二氯甲烷，室温，两小时。
化合物TC977采用以下合成方法：
将1.1当量1,2,3,4-四氢异喹啉-3-羧酸甲酯盐酸盐与1当量三乙胺加入到乙醚中，搅拌10分钟后，将1当量对氯苯基异氰酸酯加入到溶液中，搅拌过夜。将反应液适量浓缩，加入乙酸乙酯，乙酸乙酯层用饱和氯化钠溶液洗涤，无水硫酸钠干燥，之后浓缩，柱层析，得到产物中间体5。
将中间体5加入到三氟乙酸中，常温搅拌过夜。将反应液适量浓缩，加入乙酸乙酯，乙酸乙酯层用饱和碳酸氢钠溶液和氯化钠溶液洗涤，无水硫酸钠干燥，之后浓缩，柱层析，得到产物。
化合物TC929,TC931,TC934，TC935，TC937，TC940，TC948，TC949，TC950，TC951，TC955，TC958，TC960，TC961，采用以下合成方法：
将1当量对应的硝基底物溶解于甲醇与水(3:1)的混合溶剂中，加入10当量的氯化铵和5当量的铁粉，将反应体系在70度条件下搅拌过夜。将反应液适量浓缩，加入饱和碳酸氢钠溶液调至碱性，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，之后浓缩，柱层析，得到对应的氨基底物。
将1当量对应的氨基底物置于6N盐酸溶液中，在零度条件下缓慢加入1.5当量的亚硝酸钠水溶液，反应在零度搅拌半小时。将叠氮化钠水溶液缓慢加入到反应液中，将反应体系移至室温，搅拌四十分钟后结束。加入饱和碳酸氢钠溶液调至弱碱性，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥，之后浓缩，柱层析，得到对应的叠氮化合物。
试剂与反应条件:a：铁粉，氯化铵，甲醇:水＝3：1，70度，过夜；b：(1)亚硝酸钠，稀盐酸，冰浴，半小时，(2)叠氮化钠，水，冰浴到常温，40分钟。
化合物TC479，TC484采用以下合成方法：中间体6和中间体7的合成参考TC938和TC933的合成步骤。
将1当量的中间体6和中间体7溶于甲醇溶剂中，加入20wt％的钯碳，将反应液在常温下于氢气环境下搅拌2小时，抽滤浓缩柱层析纯化之后得到终产物TC479和TC484。
具体反应方程式如下：
试剂与反应条件：a：(1)isocyanatobenzene、CH3CN，室温条件，反应过夜，(2)HCl，室温条件，反应四小时；b：氢气，Pd/C，2小时；c：Cs2CO3，1-(benzyloxy)-4-(bromomethyl)benzene，CH3CN，40度，反应过夜。
将以上合成的配体进行结构表征，具体如下：
TC929,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.49-7.37(m,4H),7.31(d,J＝8.7Hz,2H),7.03(d,J＝8.7Hz,2H),4.99(d,J＝15.3Hz,1H),4.24(d,J＝15.3Hz,1H),3.94(q,J＝7.0Hz,1H),1.47(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.0,154.8,140.2,133.7,132.15,130.25,129.8,129.2,127.0,119.6,77.2,54.7,44.3,15.4；高分辨质谱C17H15ClN5O2[M+H]+:356.0909；实际值：356.0906.
TC931,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.46(d,J＝8.8Hz,2H),7.41-7.28(m,4H),7.11(d,J＝8.8Hz,2H),5.07(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.95(q,J＝6.9Hz,1H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.3,154.9,139.6,135.4,129.0,128.4,128.24,128.20,127.3,119.5,54.5,44.8,15.3；高分辨质谱C17H16N5O2[M+H]+:322.1299；实际值：322.1345.
TC933,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)8.25(d,J＝8.7Hz,2H),7.52(d,J＝8.7Hz,2H),7.48-7.37(m,4H),5.00(d,J＝15.8Hz,1H),4.49(d,J＝15.8Hz,1H),4.01(q,J＝7.0Hz,1H),1.49(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)171.6,155.0,147.9,143.0,134.0,130.0,129.3,128.9,127.0,124.3,55.3,44.5,15.6.
TC934,黄色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.42(s,4H),7.10(d,J＝8.2Hz,2H),6.66(d,J＝8.2Hz,2H),4.98(d,J＝15.0Hz,1H),4.06(d,J＝15.0Hz,1H),3.93(q,J＝7.0Hz,1H),3.73(s,2H),1.47(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.4,154.6,146.5,133.6,130.4,129.6,129.1,127.1,124.9,115.3,54.3,44.3,15.3；高分辨质谱C17H17ClN3O2[M+H]+:330.1004；实际值：330.1012.
TC935,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.41-7.29(m,5H),7.20-7.12(m,2H),6.75-6.70(m,2H),5.06(d,J＝15.2Hz,1H),4.21(d,J＝15.2Hz,1H),3.91(q,J＝7.0Hz,1H),3.78(s,2H),1.46(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.9,155.7,146.4,135.7,129.0,128.2,128.2,127.4,122.3,115.2,54.6,44.8,15.39；高分辨质谱C17H18N3O2[M+H]+:296.1394；实际值：296.1462.
TC936，白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)8.25(d,J＝8.3Hz,2H),7.52(d,J＝8.3Hz,2H),7.33-7.26(m,4H),4.99(d,J＝15.8Hz,1H),4.49(d,J＝15.8Hz,1H),4.00(q,J＝6.9Hz,1H),2.39(s,3H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ172.0,155.6,147.8,143.3,138.4,129.8,128.9,125.8,124.3,77.2,55.3,44.5,21.2,15.6；高分辨质谱C18H18N3O4[M+H]+:340.1292；实际值：340.1291.
TC937，白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.38-7.23(m,4H),7.13(d,J＝8.2Hz,2H),6.68(d,J＝8.2Hz,2H),5.01(d,J＝15.0Hz,1H),4.09(d,J＝15.0Hz,1H),3.94(q,J＝6.9Hz,1H),2.40(s,3H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.8,155.2,146.4,138.0,129.6,129.6,129.2,125.9,125.2,115.3,54.3,44.3,21.2,15.4；高分辨质谱C18H20N3O2[M+H]+:310.1550；实际值:310.1552.
TC938,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.45-7.41(m,2H),7.41-7.32(m,5H),7.32-7.27(m,2H),5.16(d,J＝15.2Hz,1H),4.15(d,J＝15.2Hz,1H),3.80(d,J＝3.1Hz,1H),2.31(dtt,J＝10.1,6.9,3.1Hz,1H),1.16(d,J＝6.9Hz,3H),0.97(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)170.7,155.6,135.4,133.7,130.3,129.2,129.1,128.3,127.2,63.0,45.0,28.7,17.6,16.1；高分辨质谱C19H20ClN2O2[M+H]+:343.1208；实际值：343.1258.
TC939，白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)8.26(d,J＝8.7Hz,2H),7.51(d,J＝8.7Hz,2H),7.48-7.33(m,4H),5.07(d,J＝15.7Hz,1H),4.42(d,J＝15.7Hz,1H),3.85(d,J＝3.1Hz,1H),2.34-2.18(m,1H),1.18(d,J＝7.0Hz,3H),0.95(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)170.1,155.8,147.8,143.0,134.0,123.0,129.3,129.0,127.2,124.3,63.9,44.7,29.0,17.6,16.1；高分辨质谱C19H19ClN3O2[M+H]+:388.1059；实际值:388.2495.
TC940，白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.40-7.20(m,6H),7.07-6.98(m,2H),4.99(d,J＝15.3Hz,1H),4.24(d,J＝15.3Hz,1H),3.93(q,J＝6.9Hz,1H),2.38(s,3H),1.47(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.40,155.36,140.07,138.20,132.42,129.77,129.70,129.01,125.88,119.59,54.72,44.29,21.21,15.47；高分辨质谱C18H18N5O2[M+H]+:336.1455；实际值:336.1505.
TC941，黄色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)8.27-8.15(m,2H),7.75-7.67(m,1H),7.59(t,J＝7.9Hz,1H),7.48-7.40(m,4H),5.02(d,J＝15.6Hz,1H),4.47(d,J＝15.6Hz,1H),4.02(q,J＝6.9Hz,1H),1.50(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)171.6,155.0,148.6,137.9,134.2,133.9,130.2,130.1,129.3,127.0,123.4,122.9,55.2,44.4,15.6.
TC942,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.47-7.41(m,2H),7.41-7.29(m,5H),7.19-7.11(m,2H),5.07(d,J＝15.2Hz,1H),4.23(d,J＝15.1Hz,1H),3.95(q,J＝6.9Hz,1H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.4,162.8,160.8,155.0,135.5,129.1,128.3,128.2,127.8,127.8,116.1,115.9,54.6,44.8,15.4；高分辨质谱C17H16FN2O2[M+H]+:299.1190；实际值：299.1191.
TC943,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.64-7.55(m,2H),7.43-7.28(m,7H),5.07(d,J＝15.2Hz,1H),4.22(d,J＝15.2Hz,1H),3.95(q,J＝6.9Hz,1H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.10,154.70,135.39,132.15,130.88,129.09,128.31,128.25,127.33,121.68,54.60,44.82,15.35；高分辨质谱C17H16BrN2O2[M+H]+:359.0390；实际值：359.0389.
TC944,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.41-7.36(m,2H),7.36-7.29(m,4H),7.29-7.24(m,3H),5.07(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.94(q,J＝6.9Hz,1H),2.38(s,3H),1.47(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.6,155.3,138.1,135.6,129.7,129.1,129.0,128.2,128.2,125.9,54.6,44.8,21.2,15.4；高分辨质谱C18H19N2O2[M+H]+:295.1441；实际值：295.1519.
TC945,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.73(d,J＝8.5Hz,2H),7.67(d,J＝8.5Hz,2H),7.41-7.37(m,2H),7.37-7.31(m,3H),5.08(d,J＝15.2Hz,1H),4.24(d,J＝15.2Hz,1H),3.98(q,J＝7.0Hz,1H),1.50(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.0,154.5,135.3,135.1,129.8,129.1,128.4,128.3,126.08,126.06,125.8,54.6,44.9,15.34；高分辨质谱C18H16F3N2O2[M+H]+:349.1158；实际值：349.1159.
TC946,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.55-7.52(m,2H),7.40-7.37(m,2H),7.36-7.28(m,5H),5.07(d,J＝15.2Hz,1H),4.24(d,J＝15.2Hz,1H),3.96(q,J＝7.0Hz,1H),1.49(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.2,154.8,148.2,135.4,130.3,129.1,128.3,128.2,127.2,121.5,54.6,44.8,15.3；高分辨质谱C18H16F3N2O3[M+H]+:365.1108；实际值：365.1111.
TC947,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.49(d,J＝2.1Hz,1H),7.40-7.36(m,2H),7.36-7.30(m,4H),7.27(dd,J＝8.2,2.1Hz,1H),5.06(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.94(q,J＝7.0Hz,1H),2.39(s,3H),1.47(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.2,154.8,136.2,135.5,134.5,131.0,130.4,129.1,128.27,128.23,126.5,124.1,54.6,44.8,19.8,15.4；高分辨质谱C18H18ClN2O2[M+H]+:329.1051；实际值：329.1063.
TC948，淡黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.44-7.40(m,2H),7.40-7.35(m,2H),7.10-7.04(m,2H),6.68-6.64(m,2H),5.06(d,J＝15.0Hz,1H),4.01(d,J＝15.0Hz,1H),3.79(d,J＝3.1Hz,1H),2.31(pd,J＝7.0,3.1Hz,1H),1.16(d,J＝7.0Hz,3H),0.96(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)170.9,155.5,146.4,133.6,130.39,129.6,129.1,127.2,125.0,115.3,62.7,44.5,28.6,17.6,16.1；高分辨质谱C19H21ClN3O2[M+H]+:358.1317；实际值:358.1492.
TC949，无色油状物。1H NMR(500MHz,Chloroform-d)δ(ppm)7.43(d,J＝8.5Hz,2H),7.37(d,J＝8.5Hz,2H),7.31(d,J＝8.0Hz,1H),7.03(d,J＝8.0Hz,2H),5.07(d,J＝15.2Hz,1H),4.18(d,J＝15.2Hz,1H),3.79(d,J＝3.0Hz,1H),2.29(pd,J＝7.0,3.0Hz,1H),1.16(d,J＝7.0Hz,3H),0.96(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)170.5,155.6,140.1,133.8,132.1,130.2,129.8,129.2,127.2,119.6,63.2,44.5,28.8,17.6,16.1；高分辨质谱C19H19ClN5O2[M+H]+:384.1222；实际值:358.1221.
TC950,黄色油状。1H NMR(800MHz,Chloroform-d)δ(ppm)7.45-7.41(m,4H),7.14(t,J＝7.7Hz,1H),6.66(d,J＝7.5Hz,1H),6.65-6.61(m,2H),4.99(d,J＝15.1Hz,1H),4.08(d,J＝15.1Hz,1H),3.96(q,J＝7.1Hz,1H),3.73(s,2H),1.48(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.2,154.8,147.2,136.6,133.6,130.4,129.9,129.1,127.1,118.3,114.9,114.5,54.5,44.7,15.3；高分辨质谱C17H17ClN3O2[M+H]+:330.1004；实际值：330.1233.
TC951,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.47-7.40(m,4H),7.37(t,J＝7.8Hz,1H),7.09(d,J＝7.6Hz,1H),7.03(d,J＝8.1Hz,1H),6.95(s,1H),5.00(d,J＝15.3Hz,1H),4.25(d,J＝15.3Hz,1H),3.96(q,J＝7.0Hz,1H),1.48(d,J＝7.0Hz,3H)；13CNMR(126MHz,Chloroform-d)δ(ppm)171.9,154.8,141.0,137.6,133.8,130.5,130.2,129.2,127.0,124.6,118.8,54.8,44.5,15.4；高分辨质谱C17H15ClN5O2[M+H]+:356.0909；实际值：356.0906.
TC952,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)8.46(t,J＝2.1Hz,1H),8.22(ddd,J＝8.3,2.2,1.0Hz,1H),7.90(ddd,J＝8.0,2.0,1.0Hz,1H),7.65(t,J＝8.2Hz,1H),7.41-7.38(m,2H),7.37-7.31(m,3H),5.09(d,J＝15.2Hz,1H),4.25(d,J＝15.2Hz,1H),4.00(q,J＝7.0Hz,1H),1.51(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.8,154.2,148.4,135.1,133.1,131.4,129.7,129.2,128.4,128.3,122.5,120.8,54.7,44.9,15.3；高分辨质谱C17H16N3O4[M+H]+:326.1135；实际值：326.1137.
TC953,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.46-7.41(m,2H),7.41-7.32(m,5H),7.32-7.28(m,2H),5.16(d,J＝15.2Hz,1H),4.16(d,J＝15.2Hz,1H),3.80(d,J＝3.1Hz,1H),2.41-2.22(m,1H),1.16(d,J＝7.0Hz,3H),0.97(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)170.7,155.6,135.4,133.7,130.3,129.2,129.1,128.3,127.2,77.3,63.0,45.0,28.7,17.6,16.1；高分辨质谱C19H20ClN2O2[M+H]+:343.1208；实际值：343.1230.
TC954,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.45-7.42(m,4H),7.41-7.36(m,2H),7.36-7.28(m,3H),5.07(d,J＝15.2Hz,1H),4.22(d,J＝15.2Hz,1H),3.95(q,J＝7.0Hz,1H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.2,154.8,135.4,133.7,130.3,129.2,129.1,128.3,128.2,127.1,54.6,44.8,15.4；高分辨质谱C17H16ClN2O2[M+H]+:315.0895；实际值：315.0893.
TC955,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.40-7.36(m,2H),7.35-7.30(m,3H),7.22(t,J＝8.0Hz,1H),6.81(ddd,J＝7.9,1.9,0.9Hz,1H),6.74(t,J＝2.1Hz,1H),6.66(ddd,J＝8.1,2.3,0.9Hz,1H),5.06(d,J＝15.2Hz,1H),4.22(d,J＝15.2Hz,1H),3.92(q,J＝6.9Hz,1H),3.76(s,2H),1.46(d,J＝6.9Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.5,155.2,147.2,135.7,129.8,129.0,128.2,128.2,116.0,114.9,112.6,54.6,44.8,15.4；高分辨质谱C17H18N3O2[M+H]+:296.1394；实际值：296.1505.
TC956,黄色油状物。1H NMR(500MHz,Chloroform-d)δ(ppm)7.48-7.41(m,4H),7.40-7.27(m,5H),4.62(s,2H),1.38(s,6H)；13C NMR(126MHz,Chloroform-d)δ(ppm)175.3,154.45,137.5,133.6,130.4,129.1,128.8,128.0,127.9,127.1,62.1,43.6,23.6；高分辨质谱C18H18ClN2O2[M+H]+:329.1051；实际值：329.1096.
TC957,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.46-7.40(m,2H),7.40-7.29(m,5H),7.18-7.11(m,2H),4.66(s,2H),3.44(t,J＝6.8Hz,2H),2.83(t,J＝6.8Hz,2H)；13C NMR(126MHz,Chloroform-d)δ(ppm)169.2,153.5,136.1,134.3,134.1,130.2,129.3,129.0,128.3,128.1,77.2,51.8,40.4,32.0；高分辨质谱C17H16ClN2O2[M+H]+:315.0895；实际值：315.0895.
TC958,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.44(t,J＝8.0Hz,1H),7.41-7.37(m,2H),7.36-7.30(m,3H),7.29-7.26(m,1H),7.18(t,J＝2.1Hz,1H),7.03(ddd,J＝8.1,2.3,0.9Hz,1H),5.07(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.95(q,J＝7.0Hz,1H),1.48(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.1,154.7,140.9,135.4,133.2,130.2,129.1,128.3,128.3,122.3,118.6,116.7,54.6,44.8,15.4；高分辨质谱C17H16N5O2[M+H]+:322.1299；实际值：322.1300.
TC959,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)8.25-8.15(m,2H),7.47-7.40(m,4H),7.38-7.32(m,2H),4.00(q,J＝6.9Hz,1H),3.93(ddd,J＝14.3,8.5,6.9Hz,1H),3.52(ddd,J＝14.3,8.3,6.0Hz,1H),3.18-2.91(m,2H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)171.7,154.6,147.1,145.5,133.8,130.1,129.6,129.2,127.0,124.1,77.2,55.6,42.0,34.3,28.8,15.6；高分辨质谱C18H16ClN3NaO4[M+Na]+:396.0722；实际值：396.0720.
TC960,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.46-7.31(m,5H),7.01(d,J＝8.6Hz,2H),6.64(d,J＝8.6Hz,2H),3.92(ddd,J＝14.4,8.0,6.4Hz,1H),3.87(q,J＝6.9Hz,1H),3.74-3.48(m,2H),3.33(ddd,J＝14.4,8.0,6.4Hz,1H),2.94-2.73(m,2H),1.41(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)172.4,154.4,145.2,133.6,130.4,129.5,129.3,129.1,127.7,127.2,127.1,115.5,55.6,42.6,33.5,15.4；高分辨质谱C18H19ClN3O2[M+H]+:344.1160；实际值：344.1205.
TC961,无色油状。1H NMR(800MHz,Chloroform-d)δ(ppm)7.43-7.40(m,2H),7.38-7.35(m,2H),7.23-7.22(m,2H),7.01-6.97(m,2H),3.95-3.89(m,2H),3.41(ddd,J＝14.4,8.1,6.3Hz,1H),2.97(ddd,J＝14.4,8.1,6.3Hz,1H),2.94-2.88(m,1H),1.44(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.0,154.5,138.8,134.6,133.7,130.3,130.1,129.2,127.1,119.5,55.7,42.5,33.8,15.5；高分辨质谱C18H17ClN5O2[M+H]+:370.1065；实际值：370.1068.
TC962,黄色油状。1H NMR(800MHz,Chloroform-d)δ(ppm)7.42-7.38(m,2H),7.36-7.32(m,4H),7.32-7.27(m,2H),7.25-7.22(m,2H),4.97(d,J＝15.2Hz,1H),4.74-4.63(m,2H),4.15(d,J＝15.2Hz,1H),3.79(q,J＝7.0Hz,1H),1.34(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)173.3,156.1,136.2,135.8,129.0,129.7,128.5,128.1,128.1,127.9,54.8,44.6,42.6,15.2；高分辨质谱C18H19N2O2[M+H]+:295.1441；实际值：295.1459.
TC963,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.43(s,4H),7.41-7.37(m,2H),7.25-7.22(m,2H),5.07(d,J＝15.1Hz,1H),4.15(d,J＝15.1Hz,1H),3.95(q,J＝6.9Hz,1H),1.49(d,J＝6.9Hz,3H),1.32(s,9H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.3,154.7,151.4,133.6,132.3,130.4,129.1,128.0,127.0,126.0,54.4,44.4,34.6,31.3,15.3；高分辨质谱C21H24ClN2O2[M+H]+:371.1521；实际值：371.1518.
TC964,黄色油状。1H NMR(800MHz,Chloroform-d)δ(ppm)7.45-7.40(m,4H),7.38-7.34(m,2H),7.25-7.21(m,2H),5.00(d,J＝15.4Hz,1H),4.28(d,J＝15.4Hz,1H),3.96(q,J＝7.0Hz,1H),1.49(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.9,154.8,149.1,134.3,133.8,130.2,129.7,129.2,127.0,121.6,54.8,44.2,15.4；高分辨质谱C18H15ClF3N2O3[M+H]+:399.0718；实际值：399.0718.
TC965,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.47-7.42(m,2H),7.41-7.33(m,2H),6.38(s,1H),4.25(d,J＝7.1Hz,1H),1.55(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)173.2,156.0,134.0,129.9,129.3,127.2,52.8,28.6,17.8；高分辨质谱C10H10ClN2O2[M+H]+:225.0425；实际值：225.0422.
TC966,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.47(d,J＝8.2Hz,2H),7.41-7.34(m,5H),7.31(d,J＝8.2Hz,2H),5.78(d,J＝15.1Hz,1H),4.50(d,J＝15.1Hz,1H),4.07(q,J＝7.0Hz,1H),1.54(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)182.0,173.2,135.1,134.8,131.8,129.8,129.3,129.2,128.5,128.3,57.2,48.6,15.3；高分辨质谱C17H16ClN2OS[M+H]+:331.0666；实际值：331.0666.
TC967,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.47-7.38(m,6H),7.37-7.34(m,1H),7.31(d,J＝7.5Hz,2H),4.63(s,2H),3.89(s,2H)；13C NMR(201MHz,Chloroform-d)δ(ppm)168.4,155.2,135.0,133.8,130.3,129.23,129.15,128.43,128.35,127.1,49.0,47.0；高分辨质谱C16H14ClN2O2[M+H]+:301.0738；实际值：301.0756.
TC968,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.45-7.40(m,4H),7.40-7.36(m,2H),7.36-7.30(m,3H),5.12(d,J＝15.1Hz,1H),4.13(d,J＝15.1Hz,1H),3.97(dd,J＝5.3,3.1Hz,1H),2.04(dqd,J＝14.7,7.3,3.1Hz,1H),1.89(dtd,J＝14.7,7.3,5.3Hz,1H),0.89(t,J＝7.3Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.5,155.4,135.4,133.7,130.4,129.2,129.1,128.33,128.31,127.1,59.1,44.8,21.5,7.15；高分辨质谱C18H18ClN2O2[M+H]+:329.1051；实际值：329.1060.
TC969,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.45-7.40(m,4H),7.30(dd,J＝8.3,5.3Hz,2H),7.06(t,J＝8.4Hz,2H),4.98(d,J＝15.3Hz,1H),4.24(d,J＝15.3Hz,1H),3.94(q,J＝7.0Hz,1H),1.47(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.0,163.2,162.0,154.8,133.7,131.3,130.3,130.03,129.99,129.2,127.0,116.1,116.0,54.7,44.2,15.4；高分辨质谱C17H15ClFN2O2[M+H]+:333.0801；实际值：333.0800.
TC970,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.65(d,J＝7.9Hz,2H),7.45(d,J＝8.3Hz,2H),7.44-7.40(m,4H),5.02(d,J＝15.5Hz,1H),4.37(d,J＝15.5Hz,1H),3.97(q,J＝7.0Hz,1H),1.48(dd,J＝7.0,1.4Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.8,154.9,139.7,133.8,130.2,129.2,128.5,127.0,126.1,126.1,55.0,44.5,15.5；高分辨质谱C18H15ClF3N2O2[M+H]+:383.0769；实际值：383.0709.
TC971,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.52-7.48(m,2H),7.44-7.40(m,4H),7.22-7.18(m,2H),4.94(d,J＝15.4Hz,1H),4.23(d,J＝15.4Hz,1H),3.94(q,J＝7.0Hz,1H),1.46(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.9,154.8,134.6,133.8,132.2,130.3,129.9,129.2,127.0,122.3,54.8,44.3,15.4；高分辨质谱C17H15BrClN2O2[M+H]+:393.0000；实际值：392.9999.
TC972,黄色油状。1H NMR(500MHz,Chloroform-d)δ(ppm)7.46-7.39(m,4H),7.36(d,J＝8.2Hz,2H),7.21(d,J＝8.0Hz,2H),5.00(d,J＝15.4Hz,1H),4.30(d,J＝15.4Hz,1H),3.94(q,J＝7.0Hz,1H),1.47(d,J＝6.9Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)171.8,154.8,137.4,133.8,130.2,129.3,129.2,128.6,127.2,127.0,77.2,54.9,44.4,15.4；高分辨质谱C19H15ClF3N4O2[M+H]+:423.0830；实际值：423.0758.
TC973,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.95(d,J＝8.3Hz,2H),7.53(d,J＝8.4Hz,2H),7.46-7.40(m,4H),4.99(d,J＝15.7Hz,1H),4.44(d,J＝15.7Hz,1H),4.00(q,J＝6.9Hz,1H),3.05(s,3H),1.48(d,J＝6.9Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.6,155.0,142.0,140.6,133.9,130.1,129.2,129.0,128.2,127.0,55.2,44.6,44.5,15.6；高分辨质谱C18H18ClN2O4S[M+H]+:393.0670；实际值：393.0605.
TC974,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.47-7.40(m,4H),6.97(s,1H),6.91(s,2H),5.02(d,J＝15.0Hz,1H),4.10(d,J＝15.0Hz,1H),3.99-3.91(m,1H),2.32(s,6H),1.48(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.3,154.7,138.7,135.2,133.6,130.4,129.9,129.1,127.0,126.0,54.5,44.6,21.3,15.3；高分辨质谱C19H20ClN2O2[M+H]+:343.1208；实际值：343.1162.
TC975,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.70-7.66(m,2H),7.47-7.38(m,6H),4.95(d,J＝15.8Hz,1H),4.41(d,J＝15.8Hz,1H),3.98(q,J＝6.9Hz,1H),1.47(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.6,155.0,141.1,133.89,132.87,130.1,129.2,128.7,127.0,118.3,112.3,55.2,44.7,15.6；高分辨质谱C18H15ClN3O2[M+H]+:340.0847；实际值：340.0847.
TC977,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.52-7.38(m,4H),7.34-7.14(m,4H),5.11(d,J＝16.8Hz,1H),4.51(d,J＝16.8Hz,1H),4.27(dd,J＝11.7,4.6Hz,1H),3.37(dd,J＝15.6,4.6Hz,1H),3.08-2.89(m,1H)；13C NMR(126MHz,Chloroform-d)δ(ppm)171.4,154.0,133.8,130.8,130.7,130.1,129.5,129.3,127.6,127.4,127.1,126.7,77.2,54.7,41.9,31.0；高分辨质谱C17H14ClN2O2[M+H]+:313.0738；实际值：313.0771.
TC978,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.43(s,4H),7.23-7.15(m,4H),5.03(d,J＝15.1Hz,1H),4.17(d,J＝15.1Hz,1H),3.93(q,J＝7.0Hz,1H),2.36(s,3H),1.47(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.2,154.7,138.1,133.6,132.3,130.4,129.7,129.1,128.2,127.1,54.5,44.5,21.2,15.3；高分辨质谱C18H18ClN2O2[M+H]+:329.1051；实际值：329.1048.
TC979,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.47-7.37(m,5H),6.94-6.88(m,1H),6.88-6.82(m,1H),4.91(d,J＝15.4Hz,1H),4.39(d,J＝15.4Hz,1H),4.03-3.93(m,1H),1.53(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.9,154.8,133.7,132.22,130.2,129.2,127.0,118.7,112.2,112.1,104.3,104.2,104.0,55.1,37.77,37.76,15.3；高分辨质谱C17H14ClF2N2O2[M+H]+:351.0706；实际值：351.0700.
TC980,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.87(s,1H),7.79(s,2H),7.47-7.40(m,4H),4.98(d,J＝15.8Hz,1H),4.53(d,J＝15.8Hz,1H),4.02(q,J＝7.0Hz,1H),1.50(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.44,155.09,138.6,134.0,132.6,132.5,130.0,129.3,128.2,127.0,123.7,122.4,55.4,44.5,15.7；高分辨质谱C19H14ClF6N2O2[M+H]+:451.0643；实际值：451.0636.
TC981,无色油状。1H NMR(800MHz,Chloroform-d)δ(ppm)8.05(d,J＝8.0Hz,2H),7.47-7.41(m,4H),7.39(d,J＝8.3Hz,2H),5.01(d,J＝15.4Hz,1H),4.36(d,J＝15.6Hz,1H),3.96(q,J＝6.9Hz,1H),3.92(d,J＝0.8Hz,3H),1.46(dd,J＝6.9,1.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ171.9,166.5,154.9,140.6,133.8,130.4,130.2,130.2,129.2,128.1,127.0,55.0,52.3,44.7,15.5；高分辨质谱C19H18ClN2O4[M+H]+:373.0950；实际值：373.0935.
TC982,无色油状。1H NMR(800MHz,Chloroform-d)δ(ppm)8.59-8.53(m,1H),7.70(td,J＝7.7,1.8Hz,1H),7.46-7.40(m,4H),7.34(d,J＝7.8,1.0Hz,1H),7.24(ddd,J＝7.5,4.8,1.1Hz,1H),5.05(d,J＝15.7Hz,1H),4.44(d,J＝15.7Hz,1H),4.27(q,J＝7.0Hz,1H),1.52(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)172.45,155.53,155.07,149.64,137.11,133.62,130.42,129.13,127.08,122.96,122.57,55.66,46.25,15.26；高分辨质谱C16H15ClN3O2[M+H]+:316.0847；实际值：316.0927.
TC983,黄色油状。1H NMR(500MHz,Chloroform-d)δ(ppm)8.64-8.52(m,2H),7.70(dt,J＝8.0,2.1Hz,1H),7.48-7.38(m,4H),7.33(dd,J＝7.8,4.8Hz,1H),4.98(d,J＝15.5Hz,1H),4.34(d,J＝15.5Hz,1H),3.97(q,J＝7.0Hz,1H),1.50(d,J＝6.9Hz,3H)；13CNMR(126MHz,Chloroform-d)δ(ppm)171.7,154.9,149.9,149.4,136.1,133.8,131.4,130.1,129.2,127.0,124.0,55.0,42.5,15.6；高分辨质谱C16H15ClN3O2[M+H]+:316.0847；实际值：316.0890.
TC984,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)8.44(s,1H),7.57(dd,J＝8.0,2.4Hz,1H),7.44-7.37(m,4H),7.17(d,J＝8.0Hz,1H),4.93(d,J＝15.4Hz,1H),4.27(d,J＝15.4Hz,1H),3.93(q,J＝6.9Hz,1H),2.55(s,3H),1.47(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.8,158.8,154.8,148.7,136.5,133.8,130.2,129.2,128.2,127.0,123.6,54.8,42.2,24.2,15.5；高分辨质谱C17H17ClN3O2[M+H]+:330.1004；实际值：330.1134.
TC986,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.57(t,J＝7.7Hz,1H),7.47-7.40(m,4H),7.12(d,J＝7.7Hz,1H),7.08(d,J＝7.7Hz,1H),5.00(d,J＝15.7Hz,1H),4.40(d,J＝15.7Hz,1H),4.29(q,J＝7.0Hz,1H),2.53(s,3H),1.52(d,J＝7.0Hz,3H)；13CNMR(201MHz,Chloroform-d)δ(ppm)172.6,158.5,155.1,154.8,137.3,133.6,130.45,129.1,127.1,122.4,119.3,55.7,46.4,24.5,15.3；高分辨质谱C17H17ClN3O2[M+H]+:330.1004；实际值：330.1277.
TC987，无色油状物。1H NMR(800MHz,Chloroform-d)δ(ppm)7.71(s,1H),7.65(d,J＝7.9Hz,2H),7.51-7.48(m,1H),7.45(d,J＝7.9Hz,2H),7.41(d,J＝8.9Hz,1H),5.03(d,J＝15.6Hz,1H),4.37(d,J＝15.6Hz,1H),3.99(q,J＝7.0Hz,1H),1.49(d,J＝7.0Hz,3H)；13CNMR(201MHz,Chloroform-d)δ(ppm)171.4,154.4,144.4,139.4,130.9,128.5,127.98,127.9,126.1,125.0,122.7,55.0,44.6,15.4；高分辨质谱C19H14ClF6N2O3[M+H]+:467.0592；实际值:467.0651.
TC988，白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.70(d,J＝2.5Hz,1H),7.49(dd,J＝8.8,2.5Hz,1H),7.43-7.40(m,1H),7.38-7.34(m,2H),7.25-7.22(m,2H),5.01(d,J＝15.4Hz,1H),4.28(d,J＝15.3Hz,1H),3.98(q,J＝7.0Hz,1H),1.50(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ(ppm)171.6,154.3,149.2,144.3,134.0,131.0,129.7,128.0,127.9,125.0,122.7,121.6,54.8,44.2,15.4；高分辨质谱C19H14ClF6N2O4[M+H]+:483.0541；实际值:483.0552.
TC989,黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.71(d,J＝2.5Hz,1H),7.50(dd,J＝8.8,2.5Hz,1H),7.42-7.37(m,3H),7.36-7.33(m,1H),7.33-7.30(m,2H),5.07(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.96(q,J＝7.0Hz,1H),1.49(d,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ(ppm)172.0,154.4,144.4,135.3,131.2,129.3,128.5,128.4,128.1,128.0,125.1,122.8,54.7,45.0,15.5.高分辨质谱C18H14ClF3N2O3[M+H]+:399.0723；实际值：399.0719.
TC990，白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.81-7.76(m,2H),7.66(d,J＝8.0Hz,2H),7.61(dd,J＝8.4,2.0Hz,1H),7.46(d,J＝8.0Hz,2H),5.04(d,J＝15.5Hz,1H),4.38(d,J＝15.5Hz,1H),4.00(q,J＝7.0Hz,1H),1.50(d,J＝7.0Hz,3H)；13CNMR(201MHz,Chloroform-d)δ(ppm)171.3,154.1,139.3,135.7,132.9,128.5,128.0,127.8,126.2,123.2,54.9,44.6,15.4；高分辨质谱C19H14ClF6N2O2[M+H]+:451.0643；实际值:451.0621.
TC991，白色固体。1H NMR(800MHz,Chloroform-d)δ7.80-7.76(m,2H),7.61(dd,J＝8.6,2.0Hz,1H),7.38-7.35(m,2H),7.25-7.22(m,2H),5.02(d,J＝15.3Hz,1H),4.29(d,J＝15.3Hz,1H),3.99(q,J＝7.0Hz,1H),1.51(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ171.4,154.0,149.2,135.8,133.9,132.9,129.7,128.0,127.8,123.2,121.6,54.8,44.2,15.4；高分辨质谱C19H14ClF6N2O3[M+H]+:467.0592；实际值:467.0618.
TC993,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.56-7.54(m,1H),7.43-7.39(m,4H),7.38-7.35(m,2H),7.35-7.32(m,2H),5.09(d,J＝15.2Hz,1H),4.26(d,J＝15.2Hz,1H),3.97(q,J＝7.0Hz,1H),1.50(d,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ172.2,154.7,135.5,134.6,133.1,130.0,129.2,128.42,128.36,128.3,126.2,124.1,54.7,45.0,15.5.高分辨质谱C17H15ClN2O2[M+H]+:315.0900；实际值：315.0903.
TC994,淡黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.44-7.40(m,1H),7.40-7.36(m,2H),7.36-7.29(m,4H),7.29-7.26(m,1H),7.09-7.05(m,1H),5.07(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.95(q,J＝7.0Hz,1H),1.48(d,J＝7.0Hz,3H).13CNMR(201MHz,CDCl3)δ172.2,163.3,162.0,154.8,135.5,133.3,130.2,130.2,129.2,128.4,128.4,121.5,115.1,115.0,113.5,113.4,54.7,44.9,15.5.高分辨质谱C17H15FN2O2[M+H]+:299.1196；实际值：299.1189.
TC995,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.67(t,J＝2.0Hz,1H),7.49(ddd,J＝8.0,1.9,1.0Hz,1H),7.44(ddd,J＝8.1,2.0,1.0Hz,1H),7.40–7.36(m,2H),7.36–7.29(m,4H),5.06(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.95(q,J＝6.9Hz,1H),1.48(d,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ(ppm)172.1,154.7,135.5,133.2,131.2,130.3,129.2,129.0,128.4,128.3,124.6,122.4,54.7,44.9,15.5.高分辨质谱C17H15BrN2O2[M+H]+:359.0395；实际值：359.0390.
TC996,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.84(t,J＝1.9Hz,1H),7.70(dt,J＝7.9,1.3Hz,1H),7.46(ddd,J＝8.0,2.1,1.0Hz,1H),7.40-7.37(m,2H),7.36-7.29(m,3H),7.19(t,J＝8.0Hz,1H),5.06(d,J＝15.2Hz,1H),4.23(d,J＝15.2Hz,1H),3.94(q,J＝6.9Hz,1H),1.47(d,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ(ppm)172.1,154.7,137.1,135.5,134.7,133.0,130.5,129.2,128.42,128.35,125.3,93.6,54.7,45.0,15.5.高分辨质谱C17H15IN2O2[M+H]+:407.0256；实际值：407.0247.
TC997,淡黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.72-7.66(m,2H),7.63–7.59(m,2H),7.57-7.52(m,2H),7.46(t,J＝7.6Hz,2H),7.42-7.32(m,6H),5.10(d,J＝15.2Hz,1H),4.26(d,J＝15.2Hz,1H),3.98(q,J＝6.9Hz,1H),1.50(d,J＝6.9Hz,3H).13CNMR(201MHz,CDCl3)δ(ppm)172.6,155.3,141.1,140.4,135.7,131.1,129.2,129.0,128.37,128.35,127.9,127.7,127.3,126.3,54.8,45.0,15.5.高分辨质谱C23H20N2O2[M+H]+:357.1603；实际值：357.1597.
TC998，淡黄色油状物。1H NMR(800MHz,Chloroform-d)δ(ppm)7.73-7.70(m,2H),7.45-7.40(m,4H),7.09-7.05(m,2H),4.94(d,J＝15.4Hz,1H),4.21(d,J＝15.4Hz,1H),3.94(q,J＝7.0Hz,1H),1.46(d,J＝7.0Hz,3H)；13C NMR(201MHz,Chloroform-d)δ171.89,154.82,138.20,135.20,133.76,130.25,130.11,129.20,127.02,93.90,54.79,44.44,15.43；高分辨质谱C17H15ClIN2O2[M+H]+:440.9861；实际值：440.9850.
TC999，白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)8.13(d,J＝8.7Hz,2H),7.61(d,J＝8.7Hz,2H),7.38(t,J＝7.3Hz,2H),7.33(dd,J＝19.6,7.1Hz,3H),5.07(d,J＝15.2Hz,1H),4.24(d,J＝15.2Hz,1H),3.97(q,J＝6.9Hz,1H),3.93(s,3H),1.49(d,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ(ppm)172.0,166.3,154.5,135.9,135.3,130.3,129.2,129.1,128.3,128.2,125.3,54.6,52.3,44.8,15.3.高分辨质谱C19H18N2O4[M+H]+:339.1345；实际值：339.1338.
TC1202,棕色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.81-7.76(m,2H),7.38(tt,J＝7.9,1.5Hz,2H),7.35-7.32(m,1H),7.32-7.29(m,2H),7.25-7.22(m,2H),5.05(d,J＝15.2Hz,1H),4.22(d,J＝15.2Hz,1H),3.94(q,J＝6.9Hz,1H),1.47(d,J＝7.0Hz,3H).13CNMR(201MHz,CDCl3)δ(ppm)172.1,154.8,138.2,135.5,131.8,129.2,128.4,128.4,127.6,93.2,54.7,44.9,15.5.高分辨质谱C17H15IN2O2[M+H]+:407.0256；实际值：407.0261.
TC1203,无色油状物。1H NMR(500MHz,Chloroform-d)δ(ppm)8.17(d,J＝8.7Hz,2H),7.61(d,J＝8.7Hz,2H),7.47-7.42(m,2H),7.42-7.27(m,7H),5.07(d,J＝15.1Hz,1H),4.23(d,J＝15.2Hz,1H),3.96(q,J＝6.9Hz,1H),1.48(d,J＝6.9Hz,3H)；13C NMR(126MHz,CDCl3)δ(ppm)172.1,165.7,154.6,136.2,136.0,135.4,130.5,129.3,129.2,128.7,128.4,128.34,128.26,125.4,67.0,54.7,44.9,15.5.高分辨质谱C25H22N2O4[M+H]+:415.1658,实际值:415.1639.
TC1204,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)8.19(s,1H),7.96-7.85(m,2H),7.71-7.62(m,2H),7.59-7.53(m,2H),7.43-7.30(m,7H),7.17-7.09(m,1H),5.06(d,J＝15.2Hz,1H),4.25(d,J＝15.2Hz,1H),3.98(q,J＝7.0Hz,1H),1.49(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)172.2,165.1,154.7,138.1,135.4,134.9,134.3,129.2,129.2,128.4,128.3,127.9,125.8,124.7,120.4,54.8,44.9,15.5.高分辨质谱C24H21N3O3[M+H]+:400.1661；实际值:400.1594.
TC1205,黄色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.44-7.31(m,7H),7.30-7.22(m,4H),7.20-7.12(m,1H),7.08-7.02(m,2H),5.03(d,J＝15.2Hz,1H),4.19(d,J＝15.2Hz,1H),3.89(q,J＝7.0Hz,1H),1.44(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)172.1,169.7,154.7,135.5,135.0,133.1,129.6,129.5,129.2,128.4,128.3,127.0,126.9,124.7,54.6,44.9,38.7,15.4.高分辨质谱C25H23N3O3[M+H]+:414.1818；实际值:414.1802.
TC1206，白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.47-7.37(m,4H),7.31(d,J＝8.4Hz,2H),7.25-7.21(m,2H),4.96(d,J＝15.4Hz,1H),4.29(d,J＝15.4Hz,1H),3.95(q,J＝7.0Hz,1H),1.47(d,J＝7.0Hz,3H)；13C NMR(126MHz,Chloroform-d)δ(ppm)171.8,154.8,136.2,134.8,133.8,131.4,130.2,129.4,129.2,127.0,126.4,54.9,44.4,15.5；高分辨质谱C18H15ClN3O2S[M+H]+:372.0568；实际值:372.0564.
TC1207,黄色固体。1H NMR(500MHz,Chloroform-d)δ7.46(d,J＝8.5Hz,2H),7.43-7.29(m,7H),7.16(dd,J＝8.6,7.3Hz,2H),6.73-6.70(m,1H),6.63-6.59(m,2H),5.06(d,J＝15.2Hz,1H),4.35(s,2H),4.22(d,J＝15.2Hz,1H),3.94(q,J＝7.0Hz,1H),1.47(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ172.6,155.2,148.0,139.6,135.7,130.8,129.4,129.1,128.3,128.1,126.3,117.8,113.0,54.7,47.9,44.9,15.5.高分辨质谱C24H23N3O2[M+H]+:386.1869；实际值：386.1866.
TC1208,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.42(d,J＝2.3Hz,3H),7.35(d,J＝8.5Hz,2H),7.26(d,J＝8.4Hz,2H),4.97(d,J＝15.3Hz,1H),4.25(d,J＝15.3Hz,1H),3.95(q,J＝7.0Hz,1H),1.47(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)172.0,154.9,134.3,134.1,133.8,130.3,129.7,129.4,129.3,127.1,54.9,44.4,15.5.高分辨质谱C17H14Cl2N2O2[M+H]+:349.0511；实际值：349.0498.
TC1209,淡黄色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.67(d,J＝2.5Hz,1H),7.52(d,J＝8.7Hz,1H),7.42-7.28(m,6H),5.06(d,J＝15.2Hz,1H),4.22(d,J＝15.2Hz,1H),3.95(q,J＝7.0Hz,1H),1.48(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)172.0,154.4,135.3,133.0,132.0,131.3,130.6,129.2,128.5,128.3,127.6,125.0,54.7,44.9,15.4.高分辨质谱C17H14Cl2N2O2[M+H]+:349.0511；实际值：349.0502.
TC432,淡黄色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.71-7.69(m,2H),7.44-7.41(m,2H),7.17-7.08(m,4H),4.86(d,J＝15.3Hz,1H),4.15(d,J＝15.3Hz,1H),3.86(q,J＝7.0Hz,1H),1.38(d,J＝7.0Hz,1H).13C NMR(126MHz,CDCl3)δ(ppm)171.9,154.8,138.2,134.6,132.3,131.6,130.0,127.6,122.4,93.3,54.9,44.4,15.5.高分辨质谱C17H14BrIN2O2[M+H]+:494.9362；实际值：494.9357.
TC437,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.53-7.49(m,2H),7.46-7.41(m,2H),7.32-7.25(m,2H),7.15-7.10(m,2H),4.87(d,J＝15.3Hz,1H),4.16(d,J＝15.3Hz,1H),3.87(q,J＝7.0Hz,1H),1.39(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)171.9,154.8,134.7,132.35,132.27,130.9,130.0,127.4,122.4,121.9,116.8,54.9,44.5,15.5.高分辨质谱C17H14Br2N2O2[M+H]+:436.9500；实际值：436.9502.
TC438,白色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.50-7.45(m,2H),7.43(s,4H),7.28-7.22(m,2H),4.97(d,J＝15.3Hz,1H),4.23(d,J＝15.3Hz,1H),3.97(q,J＝7.0Hz,1H),1.47(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)172.0,154.9,137.9,133.8,131.6,131.2,130.7,130.3,129.3,127.1,126.9,123.2,54.9,44.4,15.5.高分辨质谱C17H14BrClN2O2[M+H]+:393.0005；实际值：393.0001.
TC440,淡黄色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.97(d,J＝2.0Hz,1H),7.77(d,J＝8.6Hz,1H),7.65-7.63(m,1H),7.52(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),4.96(d,J＝15.3Hz,1H),4.24(d,J＝15.3Hz,1H),3.98(q,J＝6.9Hz,1H),1.49(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)171.5,154.1,135.7,134.3,132.4,131.3,130.0,128.2(d,J＝5.4Hz),123.9,122.6,120.3,120.0,54.9,44.5,15.5.高分辨质谱C18H13Br2F3N2O2[M+H]+:504.9374；实际值：504.9329.
TC439,黄色固体。1H NMR(500MHz,Chloroform-d)δ(ppm)7.65(s,1H),7.48(d,J＝8.4Hz,2H),7.30(d,J＝1.5Hz,2H),7.18(d,J＝8.4Hz,2H),4.90(d,J＝15.3Hz,1H),4.22(d,J＝15.3Hz,1H),3.92(q,J＝7.0Hz,1H),2.40(s,3H),1.44(d,J＝7.0Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)171.9,154.9,138.1,134.6,132.2,130.8,130.3,129.9,129.6,124.8,124.6,122.3,54.8,44.3,22.7,15.4.高分辨质谱C18H16Br2N2O2[M+H]+:450.9657；实际值：450.9621.
TC479,白色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.40-7.38(m,2H),7.36-7.30(m,3H),6.72-6.69(m,2H),5.06(d,J＝15.2Hz,1H),4.24(d,J＝15.2Hz,1H),3.96(q,J＝6.9Hz,1H),1.48(d,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ(ppm)173.1,156.3,156.0,135.4,129.0,128.24,128.17,127.8,123.3,116.3,54.8,44.8,15.3.高分辨质谱C17H16N2O3[M+H]+:297.1239；实际值：297.1229.
TC480,淡黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)8.04(d,J＝8.3Hz,2H),7.42(s,4H),7.38(d,J＝8.4Hz,2H),5.00(d,J＝15.5Hz,1H),4.36(d,J＝15.6Hz,1H),3.95(q,J＝6.9Hz,1H),3.91(s,3H),1.45(d,J＝7.0Hz,3H).13C NMR(201MHz,CDCl3)δ(ppm)171.8,166.4,154.8,140.6,133.7,130.2,130.2,130.1,129.1,128.0,127.0,54.9,52.2,44.6,15.4.高分辨质谱C19H17ClN2O4[M+H]+:373.0955；实际值：373.0912.
TC484,淡黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.47-7.38(m,4H),7.14(d,J＝8.5Hz,1H),6.78(d,J＝8.4Hz,2H),4.97(d,J＝15.1Hz,1H),4.13(d,J＝15.1Hz,1H),3.93(q,J＝6.9Hz,1H),1.47(d,J＝7.0Hz,2H).13C NMR(201MHz,CDCl3)δ(ppm)172.4,156.0,154.8,133.8,130.2,129.8,129.2,129.1,127.2,126.1,115.9,54.5,44.3,15.3.高分辨质谱C17H15ClN2O3[M+H]+:331.0849；实际值：331.0831.
TC483,淡黄色固体。1H NMR(800MHz,Chloroform-d)δ(ppm)7.42(s,4H),7.36(d,J＝7.7Hz,2H),7.29(d,J＝7.7Hz,2H),5.02(d,J＝15.2Hz,1H),4.22(d,J＝15.2Hz,1H),3.93(q,J＝6.9Hz,1H),1.46(d,J＝6.9Hz,3H).13C NMR(126MHz,CDCl3)δ(ppm)172.1,154.7,141.1,134.6,133.6,130.3,129.1,128.4,127.5,127.0,64.7,54.6,44.5,15.3.高分辨质谱C18H17ClN2O3[M+H]+:345.1006；实际值：345.0984.
实施例2
对实施例1中合成的小分子配体进行生物学活性评价：
1、细胞活性实验：使用NIH3T3细胞进行荧光素酶报告实验测定配体化合物作为平滑受体拮抗剂的活性。信号使用100nM SAG(Sellect，货号S7779)激活。具体步骤如下：转基因有荧光素酶报告基因NIH3T3的细胞(Clontech，货号631197)在96孔板中培养至(6*105)个细胞/孔，然后加入浓度为10000nM、2000nM、400nM、80nM、16nM、3.2nM、0.64nM、0.128nM、0.0256nM、0.00512nM的梯度浓度的配体化合物在37℃共孵育1小时，加入终浓度为100nM的激活剂SAG，继续在37℃共孵育24小时。加入
荧光素报告系统(Promega，货号，货号E2920)并使用Envision酶标仪(PerkinElmer)对Gli荧光素酶报告水平进行测定。平行测定三组数据，根据下述公式拟合曲线并得到化合物的IC50值。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X代表化合物浓度，Y代表酶标仪测定的荧光读数，Top表示曲线的上平台值，Bottom代表曲线的下平台值，HillSlope代表曲线最大斜率的绝对值。
实验结果如下表所示：
表3
上表中的多数化合物表现出对平滑受体的拮抗活性，并有部分化合物活性明显优于原母体分子Allo-1(81.85±19.37nM)，说明此类小分子配体与平滑受体的相互作用增强，并具有开发为新一代平滑受体相关疾病药物候选的潜力。
综上所述，本发明有效克服了现有技术中的种种缺点而具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
Claims (11)
1.一种配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，所述配体分子的化学结构式如下所示：
其中，A1、A2、A3、A4、A5、A6、A7、A8各自独立地选自C、N或C-R5；
X选自O或S；
m选自1或2；
n选自1或2；
p选自0、1或2；
R1、R2、R5各自独立地选自H、卤素、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、硝基、氰基、叠氮基、氨基、COOR11、CONR12R13、异氰酸酯基、异硫氰酸酯基、-OR6、-SR7、-(CH2)y-NR8R9、-SO2R10、CN2R14、芳基、杂芳基；
y选自0、1或2；
R3、R4各自独立地选自氢原子、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、芳基；
R6、R7、R8、R9、R10、R11、R12、R13、R14各自独立地选自H、C1-C6烷基、C3-C9环烷基、杂环烷基、C1-C6卤代烷基、芳基。
2.如权利要求1所述的配体分子，其特征在于，n选自1，p选自0，所述配体分子的化学结构式如下所示：
3.如权利要求1所述的配体分子，其特征在于，R1选自H、F、Cl、Br、I、C1-C3烷基、C1-C3卤代烷基、氨基、硝基、氰基、叠氮基、COOR11、-OR6、-SO2R10；
R6选自C1-C3卤代烷基，R10选自C1-C3烷基，R11选自C1-C4烷基。
4.如权利要求1所述的配体分子，其特征在于，A1选自C、N、或C-R5；
A2选自C、N；
A3选自C、或C-R5；
A4选自C、或C-R5；
R5各自独立地选自C1-C3烷基、C1-C3卤代烷基、F、Cl、Br、I、氨基、硝基、或叠氮基，其中，卤代烷基的卤代基团选自F、Cl、Br、I。
5.如权利要求1所述的配体分子，其特征在于，R2选自H、F、Cl、Br、I、C1-C3烷基、C1-C3卤代烷基、叠氮基、COOR11、CONR12R13、-OR6、-(CH2)y-NR8R9、苯基、或结构式如下所示的基团：
R6选自C1-C3卤代烷基；
y＝1，R8、R9各自独立地选自H、苯基；
R11选自C1-C4烷基；
R12、R13各自独立地选自H、C1-C3烷基、苯基。
6.如权利要求1所述的配体分子，其特征在于，A5选自C；
A6选自C、或C-R5；
A7选自C、或C-R5；
A8选自C；
R5各自独立地选自F、Cl、Br、I、氨基、或叠氮基。
7.如权利要求1所述的配体分子，其特征在于，R3、R4各自独立地选自H、C1-C3烷基。
8.如权利要求1所述的配体分子，其特征在于，所述配体分子的化学结构式如下所示：
9.如权利要求1～8任一权利要求所述的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物在制备药物中的用途。
10.如权利要求9所述的用途，其特征在于，所述药物用于调控平滑受体，优选为平滑受体拮抗剂；
和/或，所述药物用于治疗平滑受体相关的疾病；
和/或，所述药物用于治疗肿瘤。
11.一种药物组合物，包括如权利要求1～8任一权利要求所述的配体分子或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，以及至少一种药学上可接受的载体、添加剂、助剂或赋形剂。
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