CN103476752B - 取代的芳香族硫化合物及其使用方法 - Google Patents
取代的芳香族硫化合物及其使用方法 Download PDFInfo
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- CN103476752B CN103476752B CN201280010475.8A CN201280010475A CN103476752B CN 103476752 B CN103476752 B CN 103476752B CN 201280010475 A CN201280010475 A CN 201280010475A CN 103476752 B CN103476752 B CN 103476752B
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- Prior art keywords
- phenyl
- ethenesulfonyl
- cyano group
- isobutyramide
- ethyl
- Prior art date
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- 239000000203 mixture Substances 0.000 claims description 159
- 229940047889 isobutyramide Drugs 0.000 claims description 76
- 150000003839 salts Chemical group 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 24
- 201000011510 cancer Diseases 0.000 claims description 23
- 125000004175 fluorobenzyl group Chemical group 0.000 claims description 16
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- 210000000496 pancreas Anatomy 0.000 claims description 6
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- MTFFZUXZVMPRTP-MKMNVTDBSA-N (e)-3-[4-(2-methyl-1-oxo-1-piperidin-1-ylpropan-2-yl)phenyl]sulfonylprop-2-enenitrile Chemical compound C=1C=C(S(=O)(=O)\C=C\C#N)C=CC=1C(C)(C)C(=O)N1CCCCC1 MTFFZUXZVMPRTP-MKMNVTDBSA-N 0.000 claims description 2
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract description 3
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 31
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- 235000011152 sodium sulphate Nutrition 0.000 description 24
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- 238000000746 purification Methods 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 125000002947 alkylene group Chemical group 0.000 description 18
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- 125000003118 aryl group Chemical group 0.000 description 17
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07C317/00—Sulfones; Sulfoxides
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/62—Oxygen or sulfur atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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Abstract
本发明描述了式II的化合物,以及药物组合物和使用式II的化合物在患者中治疗腹膜癌转移或降低腹膜癌转移风险的方法,其中D、n、Ra、Rb和Rc如本文中所定义:
Description
技术领域
本发明涉及取代的芳香族硫化合物以及使用它们治疗和预防癌症、特别是腹膜癌转移的方法。
背景技术
腹膜癌转移是致命的转移瘤形式,其在腹内癌侵袭到腹膜腔中并附着于腹膜(一种衬于腹腔及其内部器官的弹性组织)时发生。腹膜癌转移也可能在腹内癌的手术切除后发生,所述手术切除将癌细胞、血液和淋巴释放到腹膜腔中。在患有胃癌的患者中,腹膜和肝脏是扩大淋巴结切除术后复发的主要位点(Maruyama等,World J Surg1987,11:418-25;Kaibara等,Am J Surg1990,159:218-21;Korenaga等,Surg Gynecol Obstet1992,174:387-93)。在卵巢癌切除后,最常见的复发位点是腹膜腔(Armstrong等,NEJM2006,354:34-43)。
在大约50%的患者中,腹腔内的局部复发是胃癌切除后复发的第一位点(Sugarbaker等,Seminars in Surgical Oncology2003,21:233-248)。腹内局部复发影响患者存活的证据来自于多项研究,所述多项研究表明,在许多病例中,即使在死亡时,复发的胃癌仍局限于腹腔(Gunderson等,Int J Radiat Oncol Biol Phys1992,8:1-11;Wisbeck等,Radiother Oncol1986,7:13-18;Landry等,Int J Radiat Oncol BiolPhys1990:1357-1362)。
其他腹内恶性肿瘤,尤其是腹膜假粘液瘤、阑尾癌和间皮瘤,通常也引起腹膜癌转移。
癌的标志是侵袭和转移。最常见地,当癌细胞得以进入淋巴管或血管,通过所述淋巴管或血管移动并随后离开而进入次级组织的毛细血管床时,发生转移。转移中的限速步骤是循环的癌细胞重新粘附于次级位点中的组织时。众所周知,患有晚期癌症的患者通常具有高水平的循环癌细胞。在晚期恶性肿瘤的手术切除期间,通常也存在循环癌细胞的瞬时增加。由于循环细胞的转移潜力,高水平的循环细胞预示着更加不良的存活。
经历卵巢癌切除的大多数女性都会经历腹膜腔内复发,而全身性扩散则少见得多。最近在患有III期卵巢癌的女性中比较静脉内和腹膜内紫杉醇(总共每3周6个周期)的大型随机试验显示,接受腹膜内化疗的女性的长期存活增加了15.9个月(Armstrong等,NewEngland Journal of Medicine2006,354:34-43)。尽管事实上仅有42%的患者完成所有6个化疗周期,但这种存活的改进仍然发生。这些结果使NCI宣布腹膜内疗法是用于最佳摧毁卵巢癌的推荐管理策略。
因此,需要用于治疗和预防腹膜癌转移的改进和更有效的化合物和方法。
国际公布号WO2009/124272A2公开了抑制癌细胞增殖、癌细胞重新粘附的方法,利用NF-κB抑制剂和JNK激活剂的其他方法,以及可用于这些方法的化合物。
发明内容
本发明涉及式II的化合物或其药学可接受的盐形式:
其中D、n、Ra、Rb和Rc如本文中所定义。
本发明还描述了包含式II的化合物或其药学可接受的盐形式的药物组合物。本发明还包含使用式II的化合物或其药学可接受的盐形式的方法。
具体实施方式
本发明涉及式II的化合物或其药学可接受的盐形式:
其中:
D是
n是0、1或2;
Ra是氢、烷基或苯基;
Rb是氢、氰基、烷基、苯基、氨甲酰基或烷氧基羰基;
Rc是氢、氰基、烷基、苯基、氨甲酰基或烷氧基羰基;
A1和A2独立地是氢、
其中
Q是O或S;
R1和R2各自独立地是取代或未取代的烷基,或者R1和R2与它们所连接的碳原子一起形成3至7元取代或未取代的环烷基环,或者R1和R2与它们所连接的碳原子一起形成取代或未取代的杂环烷基;
R3是–OH、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的杂环烷基、取代或未取代的杂环烷基烷基或-NR4R5;
R4和R5各自独立地是H、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的亚烷基氧化物、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的芳烷基、取代或未取代的杂芳基、取代或未取代的杂芳烷基、-COO烷基、-CO烷基、-CO环烷基、-NHCO烷基、-NHCO芳基或-NHCO环烷基;或者R4和R5与它们所连接的原子一起形成取代或未取代的杂环烷基环;
R6是取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的芳烷基或者取代或未取代的杂芳烷基;
Rd是取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的芳烷基或者取代或未取代的杂芳烷基;
Re和Rf独立地是取代或未取代的烷基,或者Re和Rf与它们所连接的碳原子一起形成3至7元取代或未取代的环烷基环,或者Re和Rf与它们所连接的碳原子一起形成取代或未取代的杂环烷基;
Rg是–OH、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的杂环烷基、取代或未取代的杂环烷基烷基;或-NR4R5;并且
Rh是H、取代或未取代的烷基或者取代或未取代的苯基;
前提是A1或A2之一不是氢;并且另一个前提是
当D是n是2,Ra、Rc和A1是氢,并且Rb是氰基时,则A2不是叔丁基。
本发明的实施方式涉及式II的化合物或其药学可接受的盐形式,其中D是
本发明的另一种实施方式涉及式II的化合物或其药学可接受的盐形式,其中D是
本发明的另一种实施方式涉及式II的化合物或其药学可接受的盐形式,其中D是
本发明的另一种实施方式涉及式II的化合物或其药学可接受的盐形式,其中D是
本发明的另一种实施方式涉及式II的化合物或其药学可接受的盐形式,其中Q是O。
本发明的优选实施方式涉及式
如本文中所定义。
的化合物,其中D
D是时,D值的符号表示取代基A1和A2分别在噻吩环的3位和2位处,并且含硫侧链可以在噻吩环的4位或5位处,
D是时,D值的符号表示含硫侧链在萘环的2-位处,而取代基A1和A2可以在萘环的5位、6位、7位或8位处,
本发明的另一种实施方式涉及式I的化合物或其药学可接受的盐形式:
其中A在苯环的3-位或4-位处;并且
A是
R1和R2各自独立地是取代或未取代的烷基,或者R1和R2与它们所连接的碳原子一起形成3至7元取代或未取代的环烷基环;
R3是–OH、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的环烷基烷基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的杂环烷基、取代或未取代的杂环烷基烷基或-NR4R5;
R4和R5各自独立地是H、取代或未取代的烷基、取代或未取代的亚烷基氧化物、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的芳烷基、取代或未取代的杂芳基、取代或未取代的杂芳烷基、-COO烷基、-CO烷基、-CO环烷基、-NHCO烷基、-NHCO芳基或-NHCO环烷基;或者R4和R5与它们所连接的原子一起形成取代或未取代的杂环烷基环;并且
R6是取代或未取代的杂芳基。
包含式I或式II的化合物或其药学可接受的盐形式的药物组合物,也在本发明的范围之内。
本发明的化合物以及包含本发明的化合物的药物组合物可用于在患者中治疗腹膜癌转移或降低腹膜癌转移的风险。具体来说,所述化合物可用于在患者中治疗腹膜癌转移或降低腹膜癌转移的风险,其中从所述患者通过手术移除腹内癌,并向患者施用包含式I或式II的化合物或其药学可接受的盐形式的药物组合物。
因此,本发明提供了在已进行腹内癌移除的患者中治疗腹膜癌转移或降低腹膜癌转移的风险的方法,所述方法包括向所述患者施用治疗有效量的本发明化合物。在本发明的实施方式中,腹内癌位于患者的结肠处或附近、卵巢处或附近、直肠处或附近、胃处或附近或者胰腺处或附近。
此外,本发明提供了本发明的化合物用于在已进行腹内癌移除的患者中治疗腹膜癌转移或降低腹膜癌转移的风险的应用。在本发明的实施方式中,腹内癌位于患者的结肠处或附近、卵巢处或附近、直肠处或附近、胃处或附近或者胰腺处或附近。
此外,本发明提供了本发明的化合物在制造用于在已进行腹内癌移除的患者中治疗腹膜癌转移或降低腹膜癌转移的风险的药物中的应用。在本发明的实施方式中,腹内癌位于患者的结肠处或附近、卵巢处或附近、直肠处或附近、胃处或附近或者胰腺处或附近。
在本发明的优选实施方式中,式I的A在苯环的4-位处。在其他实施方式中,A在苯环的3-位处。
本发明的优选化合物包括其中A为的化合物。
在这些实施方式中,A的R1和R2优选各自独立地是取代或未取代的烷基例如-CH3。在其他实施方式中,R1和R2与它们所连接的碳原子一起形成3至7元取代或未取代的环烷基环例如环丙基或环丁基。
在其中A为的实施方式中,R3优选为–OH。在其他实施方式中,R3是取代或未取代的烷基。在其他实施方式中,R3是取代或未取代的环烷基。在其他实施方式中,R3是取代或未取代的环烷基烷基。在其他实施方式中,R3是取代或未取代的烷氧基。在其他实施方式中,R3是取代或未取代的芳基。在其他实施方式中,R3是取代或未取代的杂芳基。在其他实施方式中,R3是取代或未取代的杂环烷基。在其他实施方式中,R3是取代或未取代的杂环烷基烷基。
在其中A为的其他优选实施方式中,R3优选为-NR4R5。优选实施方式包括其中R4是氢的实施方式。在其他实施方式中,R4是未取代的烷基例如-CH3。
在其中A为并且R3为-NR4R5的优选实施方式中,R5是氢。在其他实施方式中,R5优选为取代或未取代的烷基。在其他实施方式中,R5是取代或未取代的芳基。在其他实施方式中,R5是取代或未取代的芳烷基。在其他实施方式中,R5是取代或未取代的杂芳基。在某些实施方式中,R5是取代或未取代的杂芳烷基。在其他实施方式中,R5是取代或未取代的环烷基。在其他实施方式中,R5是取代或未取代的杂环烷基。在其他实施方式中,R5是取代或未取代的亚烷基氧化物。在其他实施方式中,R5是–NHCO环烷基。在其他实施方式中,R5是–COO烷基。在其他实施方式中,R5是–CO烷基。在其他实施方式中,R5是–NHCO烷基。在其他实施方式中,R5是–NHCO芳基。
在其中A是并且R3是-NR4R5的其他实施方式中,其中R4和R5与它们所连接的原子一起形成取代或未取代的杂环烷基环,例如取代或未取代的吗啉基、取代或未取代的哌嗪基、取代或未取代的四氢异喹啉基或者取代或未取代的哌啶基。
在其他实施方式中,A为在这些实施方式中,R1和R2各自独立地是取代或未取代的烷基例如-CH3。或者,R1和R2与它们所连接的碳原子一起形成3至7元取代或未取代的环烷基环,例如环丙基或环丁基。
在其中A是的实施方式中,R6是取代或未取代的杂芳基,例如取代或未取代的二唑基、取代或未取代的苯并咪唑基、取代或未取代的苯并唑基或者取代或未取代的唑基。
当在本文中使用时,术语“烷基”是指支链或非支链饱和烃链。其实例包括但不限于甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基、异丙基、叔丁基、异丁基等。烷基通常含有1-10个碳原子,优选1-6或1-3个碳原子,并且可以是取代或未取代的。
当在本文中使用时,术语“烯基”是指含有如本文中对“烷基”所描述的必需数量的碳原子并含有至少一个双键的“烷基”。烯基的代表性实例包括但不限于乙烯基、烯丙基、异丙烯基和2-甲基-1-丙烯基。
当在本文中使用时,术语“亚烷基”是指二价烷基基团。其实例包括但不限于亚甲基、亚乙基、亚丙基等。
当在本文中使用时,术语“烷氧基”是指–O-烷基,其中烷基如本文中所定义。
当在本文中使用时,术语“烷氧基羰基”是指烷基-O(C=O)-基团。
当在本文中使用时,术语“炔基”是指含有如本文中对“烷基”所描述的必需数量的碳原子并含有至少一个叁键的“烷基”。炔基的代表性实例包括但不限于乙炔基、丙炔基以及1-和2-丁炔基。
当在本文中使用时,术语“芳基”是指苯基或萘基。
当在本文中使用时,术语“芳烷基”是指通过亚烷基部分直接键合的如本文中所定义的芳基。所述亚烷基部分可以具有1-10个碳原子,优选1-6个碳原子,更优选1或2个碳原子。此外,芳烷基的亚烷基部分可以是未取代或取代的。在取代的亚烷基的实施方式中,取代基可以是本文中定义的任何取代基,并优选为–OH、-NH2、亚烷基-OH或烷基。
当在本文中使用时,术语“亚烷基氧化物”是指其中亚烷基的一个或多个亚甲基单元已被氧原子代替的亚烷基。
当在本文中使用时,“氨甲酰基”是指NH2C(=O)-基团。
当在本文中使用时,术语“环烷基”是指单环或二环的碳环。其实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、二环[2.2.1]庚基等。环烷基通常含有3-12个碳原子,优选3-6个碳原子。
当在本文中使用时,术语“环烷基烷基”是指通过亚烷基部分直接键合的如本文中所定义的环烷基。所述亚烷基部分可以具有1-10个碳原子,优选1-6个碳原子,更优选1或2个碳原子。此外,环烷基烷基的亚烷基部分可以是未取代或取代的。在取代的亚烷基的实施方式中,取代基可以是本文中定义的任何取代基,并优选为–OH、-NH2或烷基。
当在本文中使用时,术语“杂环烷基”是指含有1至5个N、O或S原子的单环或二环碳环。其实例包括但不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢吡喃基、吡喃基、噻喃基、吖丙啶基、环氧乙烷基、异唑烷基、1,3-唑烷-3-基、异噻唑烷基、1,2-吡唑烷-2-基、1,3-吡唑烷-1-基、哌啶基、硫代吗啉基、吗啉基、1,2-四氢噻嗪-2-基、哌嗪基等。本领域的普通技术人员将会理解,在可能时,杂环烷基环的连接可以是通过碳原子或通过氮杂原子。术语“杂环烷基”还包括含有–NH-CO-基团的单环或二环碳环,例如吡咯烷基-2-酮、哌啶基-2-酮和氮杂环庚烷基-2-酮。
在“杂环烷基”的定义中包括稠合环系统,其包括例如其中芳基或杂芳基环稠合于杂环烷基环的环系统。其实例包括吲哚啉、异吲哚啉、色满和异色满。
当在本文中使用时,术语“杂环烷基烷基”是指通过亚烷基部分直接键合的如本文中所定义的杂环烷基。所述亚烷基部分可以具有1-10个碳原子,优选1-6个碳原子,更优选1或2个碳原子。此外,杂环烷基烷基的亚烷基部分可以是未取代或取代的。在取代的亚烷基的实施方式中,取代基可以是本文中定义的任何取代基,并优选为–OH、-NH2或烷基。
当在本文中使用时,术语“杂芳基”是指含有5至10个环碳原子,其中一个或多个环碳原子被至少一个杂原子例如-O-、-N-或-S-代替的芳香族基团。杂芳基的实例包括吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噻唑基、异噻唑基、异唑基、唑基、氧硫杂环戊二烯基、二唑基、三唑基、三唑基、呋咱基、四唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、甲代吡啶基、吲哚基、异吲哚基、吲唑基、苯并呋喃基、异苯并呋喃基、嘌呤基、喹唑啉基、喹啉基、异喹啉基、苯并咪唑基、苯并噻唑基、苯并噻吩基、硫茚基、苯并唑基、苯并异唑基、噌啉基、酞嗪基、萘啶基和喹喔啉基。
当在本文中使用时,术语“杂芳烷基”是指通过亚烷基部分直接键合的如本文中所定义的杂芳基。所述亚烷基部分可以具有1-10个碳原子,优选1-6个碳原子,更优选1或2个碳原子。此外,芳烷基的亚烷基部分可以是未取代或取代的。在取代的亚烷基的实施方式中,取代基可以是本文中定义的任何取代基,并优选为–OH、-NH2或烷基。
当在本文中使用时,术语“卤素”是指氟、氯、溴和碘。
当在本文中使用时,术语“取代的”或“取代基”是指任意1、2或3个氢被1、2或3个官能团代替。这些官能团包括但不限于-OH、-CN、-C≡CH、-C=CH2、-COOH、-NH2、-NH烷基、-NH芳基、-NHC(O)O烷基、-NHC(O)烷基、-NHC(O)环烷基、卤素、烷基、环烷基、杂芳基、烷氧基、亚烷基-OH、亚烷基氧化物、环烷基、杂环烷基、芳基、杂芳基、-SO2烷基、-SO2-NH2、-SO2-NH烷基和-SO2-NH芳基。
本发明的化合物以“治疗有效量”施用于患者。当在本文中使用时,“治疗有效量”是指本发明的化合物有效预防、治疗或降低所宣称的疾病或障碍的发生的量。治疗有效量的确定取决于数种因素,包括患者的年龄和体重以及待治疗的疾病或障碍。这样的确定在本领域技术人员的技术范围之内。
当在本文中使用时,“药学可接受的载体或稀释剂”是指生理相容的溶剂、分散介质、涂层、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。药学可接受的载体的实例包括水、盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇、糖、多元醇例如甘露糖醇、山梨糖醇和氯化钠中的一种或多种。药学可接受的载体还可以包括辅助性物质例如润湿剂或乳化剂、防腐剂和缓冲剂。
当在本文中使用时,“药物组合物”是指适合于在医学或兽医学应用中施用的组合物。这样的组合物优选包括本发明的化合物与一种或多种载体和/或稀释剂的组合。
当在本文中使用时,“施用”是指本领域内可以将本发明的化合物递送至患者的任何手段。优选的施用方法包括局部施用,即将本发明的化合物直接施用到需要化合物的效果的位置,以及全身性施用。施用方法的实例包括但不限于经口、经肠、舌下、唇下(sublavial)、皮下、经鼻、静脉内、动脉内、肌内和腹膜内施用。优选的方法包括通过喷雾或洗涤将本发明的化合物局部施用到治疗位点例如腹膜腔。
本发明包括式I的化合物的药学可接受的盐。式I的化合物的药学可接受的酸加成盐包括但不限于源自于无机酸例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸和磷酸的盐,以及源自于有机酸例如脂族单羧酸和二羧酸、苯基取代的烷酸、羟基烷酸、烷链二酸、芳香族酸以及脂族磺酸和芳香族磺酸的盐。因此,这样的盐包括但不限于硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、延胡索酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯代苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、邻苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐和甲磺酸盐。还考虑到了氨基酸的盐例如精氨酸盐、葡萄糖酸盐、半乳糖醛酸盐等;参见例如Berge等,“制药用盐”(Pharmaceutical Salts),J.ofPharmaceutical Science,1977;66:1-19。
碱性化合物的酸加成盐可以通过以常规方式将游离碱形式与足够量的所需酸进行接触以生产所述盐来制备。可以通过以常规方式将盐形式与碱进行接触并分离游离碱,来再生所述游离碱形式。游离碱形式与其相应的盐形式在某些物理性质例如在极性溶剂中的溶解性方面多少有些差异,但是在其他方面,对于本发明的目的来说,盐与其相应的游离碱总体上等同。
使用金属或胺,例如碱金属氢氧化物和碱土金属氢氧化物或有机胺来形成式I的化合物的药学可接受的碱加成盐。用作阳离子的金属的实例包括但不限于钠、钾、镁和钙。适合的胺的实例包括但不限于N,N′-二苯甲基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺(乙烷-1,2-二胺)、N-甲基葡萄糖胺和普鲁卡因;参见例如Berge等,同上,1977。
酸性化合物的碱加成盐可以通过以常规方式将游离酸形式与足够量的所需碱进行接触以生产所述盐来制备。可以通过以常规方式将盐形式与酸进行接触并分离游离酸,来再生所述游离酸形式。游离酸形式与其相应的盐形式在某些物理性质例如在极性溶剂中的溶解性方面多少有些差异,但是在其他方面,对于本发明的目的来说,盐与其相应的游离酸总体上等同。
本发明的某些化合物可以作为立体异构体存在,所述立体异构体包括对映异构体、非对映异构体和几何异构体。几何异构体包括具有烯基的本发明化合物,其可以作为异侧(E)或同侧(Z)构型存在,在这种情形中,其所有几何形式,即异侧和同侧、顺式和反式两者及其混合物,都在本发明的范围之内。本发明的某些化合物具有环烷基,所述环烷基可以在大于一个的碳原子处被取代,在这样的情形中,其所有几何形式,即顺式和反式两者及其混合物,都在本发明的范围之内。在本发明的化合物中设想了所有这些形式,包括(R)、(S)、差向异构体、非对映异构体、顺式、反式、正、反、(E)、(Z)、互变异构体及其混合物。
在本发明中使用的化合物可以以非溶剂化形式以及包括水合形式在内的溶剂化形式存在。一般来说,包括水合形式在内的溶剂化形式与非溶剂化形式是等同的,并打算被涵盖在本发明的范围之内。
本发明的化合物可以以有机合成领域的技术人员公知的多种方式来制备。可以使用下面描述的方法以及使用有机化学领域的技术人员已知的方法或其被本领域技术人员所认识到的变体来合成本发明的化合物。优选的方法包括但不限于下面描述的方法。除非另有陈述,否则起始化合物和中间化合物是商业来源的,或者可以通过有机合成领域的技术人员公知的标准方法容易地合成。
可以使用本部分中描述的反应和技术来制备本发明的化合物。在适合于反应试剂的溶剂中进行反应,并且所使用的材料适合于所执行的转化。此外,在下面的合成方法描述中,应该理解所有提出的反应条件被选择为所述反应的标准条件,所述反应条件包括溶剂、反应气氛、反应温度、实验持续时间和后处理(workup)程序的选择,所述反应的标准条件应当是有机合成领域的技术人员很容易认识到的。
应该理解,本文描述的实施例和实施方式仅仅出于说明的目的,本领域技术人员将会根据所述实施例和实施方式提出各种修改或变化,并且所述修改或变化被包含在本申请的精神和范围以及权利要求书的范围之内。具体的化学转化列于随后的反应路线中,并且本领域技术人员将会认识到,可以使用各种不同的反应试剂来代替列出的反应试剂。这样的反应试剂的常见替代可以在例如但不限于下列文献的文本中找到:《有机合成反应试剂百科全书》(Encyclopedia of Reagents for Organic Synthesis),Leo A.Paquette,John Wiley&Son Ltd (1995),或《综合有机转化:官能团制备指南》(ComprehensiveOrganic Transformations:A Guide to Functional Group Preparations),RichardC.Larock.Wiley-VCH,和《有机合成中指定反应的策略应用》(Strategic Applications ofNamed Reactions in Organic Synthesis),Kurti和Czako,Elsevier,2005,以及其中的参考文献。
反应路线1
式Ia的化合物,例如其中Y、R1和R2为例如烷基的式Ia的化合物,可以如反应路线1中所示来制备。在第一个步骤中,将芳基卤化物例如3-叔丁基溴苯用烷基或芳基锂反应试剂例如正丁基锂或苯基锂,在非质子溶剂例如四氢呋喃或醚中进行处理。将新形成的有机金属物质用二氧化硫淬灭以提供亚磺酸,其作为锂盐通过过滤而被分离。或者,将苯磺酰氯例如3-叔丁基苯磺酰氯用亚硫酸钠在水中进行处理,以制备3-叔丁基苯基亚磺酸钠盐。将所述亚磺酸锂盐或钠盐用取代的1,2-二卤代乙烷反应试剂(即其中X是卤素)进行处理,以提供式Ia的芳基磺酰基乙烯化合物。
反应路线2
类似地,其中R1和R2是例如烷基的式Ib的化合物,可以如反应路线2中所示来制备。例如,将2-(4-溴苯基)异丁酸或2-(3-溴苯基)异丁酸用苯基锂、随后用正丁基锂进行处理,然后用二氧化硫淬灭以提供二锂盐。将所述二锂盐与2-氯丙烯腈在水:甲醇:乙酸的混合物中进行反应。在完成亚磺酸向2-氯丙烯腈的加成之后,进行水性后处理,随后用胺类碱例如三乙胺处理,以实现氯化物的消除并形成式Ib的磺酰基丙烯腈。
反应路线3
为了制备如反应路线3中所示并且例如其中R1和R2是甲基的通式Ic的酰胺,可以将如反应路线2中所示制备的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸或2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸,与其中R4和R5如本文中所定义的伯胺或仲胺或其合成前体,在非质子溶剂例如二氯甲烷、四氢呋喃、二甲基甲酰胺等中,在酰胺偶联反应试剂存在下进行反应。适合的酰胺偶联反应试剂的实例包括碳二亚胺(例如二环己基碳二亚胺或N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐)、盐(例如(苯并三唑-1-基氧基)三(二甲基氨基)六氟磷酸盐或溴三吡咯烷六氟磷酸盐)、丙基膦酸酐等。在酰胺键形成后,通过在硅胶上纯化或通过反相HPLC容易地分离化合物。
反应路线4
通式Id的杂环衍生物的形成被示出在反应路线4中。R1和R2如本文中所定义。R是如本文中所定义的取代基。与本领域中已知的程序(Piatnitski Checkler,E.L.;Elokdah,H.M.;Butera,J.Tetrahedron Lett.2008,49,6709.)类似,对于例如其中R1和R2为甲基的化合物来说,2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸或2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸与硫代氨基脲在偶联剂例如N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐存在下的反应,提供了通式Id的2-取代的氨基-1,3,4-二唑。
反应路线5
其中J为O或NR4、其中R4如本文中所定义、R1和R2如本文中所定义并且R是如本文中所定义的一个或多个取代基的通式Ie的苯并咪唑或苯并唑化合物的形成,如反应路线5中所示。所述形成开始于如反应路线3中所述的酰胺偶联,然后将2-羟基-或2-氨基-苯基酰胺在乙酸存在下加热,以提供通式Ie的苯并唑或苯并咪唑化合物。
反应路线6
反应路线6描述了通式If的唑衍生物的制备,其中R1和R2如本文中所定义,并且R是如本文中所定义的取代基。利用如反应路线3中所描述的酰胺偶联,将炔丙基胺与羧酸偶联以提供通式If的炔丙基酰胺。通过本领域中已知的方法(Hashmi,A.S.K.;Weyrauch,J.P.;Frey,W.;Bats,J.W.Org.Lett.2004,6,4391.)将炔丙基酰胺用催化性氯化金(III)在乙腈中处理,提供通式Ig的环异构化产物。
反应路线7
其中R1和R2如本文中所定义并且R是如本文中所定义的取代基的通式Ij的化合物,可以如下制备:例如将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸或2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸,在N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐或其他适合的酰胺偶联反应试剂存在下,在极性非质子溶剂例如乙腈中与酰肼进行偶联,以得到通式Ii的酰肼。通过脱水可以从所述酰肼制备通式Ij的2-取代的-1,3,4-二唑,所述脱水可以使用反应试剂例如三氯氧磷、亚硫酰氯或Burgess反应试剂,在存在或不存在极性或非极性非质子溶剂例如乙腈或二烷的条件下来实现。
为了防止转移和进一步的疾病发展,防止无赖性癌细胞植入到腹膜内是关键的。
在腺癌细胞粘附期间,NF-kB(核因子κB)被短暂但强烈激活(Scaife等,CancerResearch2002,62:6870-78)。用本发明的化合物处理悬浮的腺癌细胞,引起在粘附期间诱导凋亡。在小鼠腹膜癌转移模型中,用本发明的化合物对人类结肠和胰腺腺癌细胞进行4小时的预处理,然后进行IP注射并随后在9天内进行另外3次处理(例如1mg/kg),显著抑制了腹膜肿瘤植入。本发明的化合物也在无胸腺小鼠中抑制结肠癌细胞增殖(例如10μM)和结肠癌异种移植物。
本发明的化合物靶向癌细胞中的多种激酶。本发明的化合物抑制NF-kB的内源抑制剂IkB的IKK介导的磷酸化,但是也激活JNK和p38/SAPK(Pierce等,J Biol Chem1999)。现在已显示,JNK激活对于本发明的化合物在人类结肠和胰腺癌细胞中的凋亡活性是重要的。此外,JNK激活靶向FLIP(FLICE抑制蛋白),以在癌细胞中降解。FLICE(caspase8)通常在癌中过表达,并且是死亡受体诱导的凋亡的关键介导物。FLIP的表达受到NF-kB的调控,并且用本发明的化合物处理癌细胞以JNK依赖性方式快速降低FLIP表达。结肠和胰腺癌细胞中FLIP表达的抑制,增强了本发明的化合物在粘附期间诱导细胞凋亡的能力,而结肠和胰腺癌细胞中FLIP的过表达使得它们对本发明化合物的凋亡效果具有抗性。因此,已确定,本发明的化合物在癌细胞中的凋亡活性需要对NF-kB和JNK的双重活性。
下面的表I中示出了本发明的某些化合物针对各种细胞系的测试结果。SU86是胰腺癌细胞系。HT29是结肠癌细胞系。BxPC3是胰腺细胞系。A2780是卵巢癌细胞系。
表I
*=荧光素酶活性相对降低<10%
**=荧光素酶活性相对降低10-50%
***=荧光素酶活性相对降低50-85%
****=荧光素酶活性相对降低>85%
实验部分
所有反应试剂和溶剂从商业来源获得并以接收时的状态使用。在Bruker Avance上,在指定溶剂中以400MHz获得1H-NMR谱,其中四甲基硅烷作为内标。分析型HPLC使用Zorbax Eclipse XDB-C83.5μm4.6x75mm柱来运行,其中用乙腈与含0.1%三氟乙酸的水的混合物,使用5分钟的10-100%梯度进行洗脱。在两种仪器中的任一种上获得LCMS结果。带有Waters Aquity UPLC BEH C181.7μm2.1x50mm柱的Waters Aquity超高效LC(WatersAquity Ultra Performance LC)与带有电喷雾电离的Micromass-ZQ2000四级杆质谱仪配对。或者,带有Zorbax Eclipse XDB-C83.5μm2.1x30mm柱的Agilent1100系列HPLC与带有电喷雾电离的Bruker Esquire3000质谱仪配对。制备型HPLC在Gilson HPLC上使用Phenomenex Gemini NX5μm C18,21.2x100mm柱和UV检测来进行,或在Waters HPLC上使用Waters XBridge PrepC85μm OBD30x75mm柱并在带有电喷雾电离的Micromass-ZQ2000四级杆质谱仪上进行MS检测来进行。自动化柱层析在CombiFlash Companion(Teledyne IscoInc.)上进行。在Mel-Temp装置上获取熔点并且是未校正的。
实施例1
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸
在氮气和-80℃(醚/干冰)下,向2-(4-溴苯基)-2-甲基丙酸(2.43g,10mmol)在无水THF(150ml)中的溶液缓慢加入在甲苯中的苯基锂(1.8M,11mmol)。在5min后,向该混合物加入n-BuLi(2.5M,在己烷中,11mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将SO2流鼓泡通过混合物15min。然后允许反应混合物升温至室温,并在真空中去除溶剂。将亚磺酸盐残留物溶解在水(15ml)、乙酸(8ml)和MeOH(20ml)中,然后添加2-氯丙烯腈(18mmol)。将得到的混合物在室温搅拌过夜。在真空中去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x100ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(20mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,然后在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/EtOAc,梯度),得到作为白色固体的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(1.2g,43%)。1H-NMR(DMSO-d6,400MHz)δ12.65(s,1H),8.23(d,1H,J=15.6Hz),7.88(m,2H),7.68(m,2H),6.91(d,1H,J=15.6Hz),1.51(s,6H);13C-NMR:(DMSO-d6,100MHz)δ176.7,152.4,149.1,135.6,128.2,127.5,114.6,112.0,46.4,26.1。
实施例2
2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸
在N2和-80℃(醚/干冰)下,向2-(3-溴苯基)-2-甲基丙酸(7.3g,30mmol)在无水THF(300ml)中的溶液缓慢加入在甲苯中的苯基锂(1.8M,33mmol)。在5min后,向该混合物加入n-BuLi(2.5M,在己烷中,33mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将SO2流鼓泡通过混合物15min。然后允许反应混合物升温至室温,并在真空中去除溶剂。将亚磺酸盐残留物溶解在水(50ml)、乙酸(25ml)和MeOH(50ml)中,然后添加2-氯丙烯腈(60mmol)。将得到的混合物在室温搅拌过夜。在真空中去除有机溶剂,并将残留物用50ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH~5-6,然后用二氯甲烷萃取(2x100ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(20mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/EtOAc,梯度),得到作为白色固体的2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(4.1g,49%)。1H-NMR(DMSO-d6,400MHz)δ12.65(s,1H),8.30(d,1H,J=15.6Hz),7.82(m,2H),7.80(m,1H),7.69(m,1H),6.94(d,1H,J=15.6Hz),1.53(s,6H);13C-NMR:(DMSO-d6,100MHz)δ176.8,149.0,147.2,137.6,132.7,130.1,126.4,124.8,114.6,112.3,46.1,26.1。
实施例3
(E)-3-[4-(1,1-二甲基-2-吗啉-4-基-2-氧代-乙基)-苯磺酰基]-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(50.0mg,0.179mmol)、吗啉(0.0156mL,0.179mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(34.3mg,0.179mmol)和1-羟基苯并三唑(12.1mg,0.0895mmol)溶解在四氢呋喃(5.0ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到(E)-3-[4-(1,1-二甲基-2-吗啉-4-基-2-氧代-乙基)-苯磺酰基]-丙烯腈(11mg,17%)。MS:349(M+H);1H-NMR(DMSO-d6400MHz)δ8.24(d,1H,J=15.7Hz),7.91(d,2H,J=7.7Hz),7.55(d,2H,J=7.7Hz),6.90(d,1H,J=15.7Hz),3.57(br s,8H),1.47(s,6H)。
实施例4
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-乙基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、乙醇胺(0.0162mL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在四氢呋喃(7.5ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-乙基)-异丁酰胺(10mg,12%)。MS:323(M+H);1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.7Hz),7.85(d,2H,J=7.4Hz),7.62(d,2H,J=7.4Hz),7.45(m,1H),6.90(d,1H,J=15.7Hz),4.39(t,1H,J=5.3Hz),3.40(m,2H),3.11(m,2H),1.47(s,6H)。
实施例5
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-苯基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(300.0mg,1.074mmol)、苯胺(0.0979mL,1.07mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(206mg,1.07mmol)和1-羟基苯并三唑(72.6mg,0.537mmol)溶解在四氢呋喃(30ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过快速柱进行纯化(己烷/乙酸乙酯),得到作为泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-苯基-异丁酰胺(171mg,45%)。MS:355(M+H);1H-NMR(DMSO-d6,400MHz)δ9.22(s,1H),8.23(d,1H,J=15.7Hz),7.90(d,2H,J=7.8Hz),7.68(d,2H,J=7.8Hz),7.57(d,2H,J=7.7Hz),7.27(m,2H),7.05(m,1H),6.90(d,1H,J=15.7Hz),1.60(s,6H);13C-NMR:(DMSO-d6,100MHz)δ173.7,153.2,149.2,139.0,135.5,128.4,128.2,127.6,123.5,120.4,114.6,112.0,47.9,26.5。
实施例6
N-苯甲基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(300.0mg,1.074mmol)、苯甲胺(0.115g,1.07mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(206mg,1.07mmol)和1-羟基苯并三唑(72.6mg,0.537mmol)溶解在四氢呋喃(30ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Isco快速柱进行纯化(己烷/乙酸乙酯),得到作为白色粉末的N-苯甲基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺(173mg,44%)。MS:369(M+H);1H-NMR(DMSO-d6,400MHz)δ8.24(d,1H,J=15.6Hz),8.06(t,1H,J=5.6Hz),7.86(d,2H,J=7.6Hz),7.63(d,2H,J=7.6Hz),7.27(m,2H),7.21(m,1H),7.11(d,2H,J=7.3Hz),6.90(d,1H,J=15.6Hz),4.24(d,2H,J=5.6Hz),1.52(s,6H);13C-NMR:(DMSO-d6,100MHz)δ174.6,153.4,149.2,139.6,135.3,128.0,127.9,127.6,126.7,126.5,114.5,111.9,46.6,42.3,26.3。
实施例7
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-吡啶-2-基甲基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、吡啶-2-基-甲基胺(0.0290g,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在四氢呋喃(7.5mL,92mmol)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为TFA盐的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-吡啶-2-基甲基-异丁酰胺(24mg,24%)。MS:370(M+H);1H-NMR(DMSO-d6,400MHz)δ8.63(d,1H,J=4.8Hz),8.26(m,2H),8.06(t,1H,J=5.4Hz),7.89(d,2H,J=8.1Hz),7.67(d,2H,J=8.1Hz),7.54(m,1H),7.35(d,1H,J=7.8Hz),6.92(d,1H,J=15.6Hz),4.43(d,2H,J=5.4Hz),1.57(s,6H)。
实施例8
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-异丁基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、异丁胺(0.0255mL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在四氢呋喃(7.5ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-异丁基-异丁酰胺(18mg,20%)。MS:335(M+H);1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.9Hz),7.86(d,2H,J=7.6Hz),7.61(d,2H,J=7.6Hz),7.45(m,1H),6.90(d,1H,J=15.9Hz),2.84(m,2H),1.67(m,1H),1.48(s,6H),0.74(d,6H,J=6.6Hz)。
实施例9
(E)-3-{4-[1,1-二甲基-2-(4-甲基-哌嗪-1-基)-2-氧代-乙基]-苯磺酰基}-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、1-甲基哌嗪(0.0298mL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在四氢呋喃(7.5ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为TFA盐的(E)-3-{4-[1,1-二甲基-2-(4-甲基-哌嗪-1-基)-2-氧代-乙基]-苯磺酰基}-丙烯腈(17mg,17%)。MS:362(M+H);1H-NMR(DMSO-d6,400MHz)δ9.67(br s,1H),8.25(d,1H,J=15.8Hz),7.92(d,2H,J=7.9Hz),7.56(d,2H,J=7.9Hz),6.91(d,1H,J=15.8Hz),3.53(br s,4H),3.27(br s,2H),2.84(br s,2H),2.73(s,3H),1.50(s,6H)。
实施例10
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环丙基甲基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(100.0mg,0.3580mmol)、环丙基甲基胺(0.0307mL,0.358mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(68.6mg,0.358mmol)和1-羟基苯并三唑(24.2mg,0.179mmol)溶解在四氢呋喃(10ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环丙基甲基-异丁酰胺(45mg,38%)。MS:333(M+H);1H-NMR(CDCl3,400MHz)δ7.87(d,2H,J=7.8Hz),7.63(d,2H,J=7.8Hz),7.21(d,1H,J=15.8Hz),6.55(d,1H,J=15.8Hz),5.36(br s,1H),3.10(m,2H),1.61(s,6H),0.87(m,1H),0.47(m,2H),0.15(m,2H)。
实施例11
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2,2-二氟-乙基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(100.0mg,0.3580mmol)、2,2-二氟-乙基胺(0.0290g,0.358mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(68.6mg,0.358mmol)和1-羟基苯并三唑(24.2mg,0.179mmol)溶解在四氢呋喃(10ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2,2-二氟-乙基)-异丁酰胺(40mg,32%)。1H-NMR(CDCl3,400MHz)δ7.89(d,2H,J=7.6Hz),7.60(d,2H,J=7.6Hz),7.23(d,1H,J=15.7Hz),6.57(d,1H,J=15.7Hz),5.84(tt,1H,J=4.0,56Hz),5.46(m,1H),3.61(m,2H),1.62(s,6H)。
实施例12
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环己基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(100mg,0.358mmol)、环己胺(35.5mg,0.358mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(68.6mg,0.358mmol)和1-羟基苯并三唑(24.2mg,0.179mmol)溶解在四氢呋喃(10.0ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.2mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环己基-异丁酰胺(79mg,61%),mp=191-193℃。MS:361(M+H);1H-NMR(CDCl3,400MHz)δ7.86(d,2H,J=8.1Hz),7.60(d,2H,J=8.1Hz),7.21(d,1H,J=15.6Hz),6.55(d,1H,J=15.6Hz),5.05(m,1H),3.76(m,1H),1.83(m,2H),1.64(m,3H),1.62(s,6H),1.34(m,2H),1.13(m,1H),1.00(m,2H)。
实施例13
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(四氢-吡喃-4-基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(100.0mg,0.3580mmol)、四氢吡喃-4-基胺(0.0362g,0.358mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(68.6mg,0.358mmol)和1-羟基苯并三唑(24.2mg,0.179mmol)溶解在四氢呋喃(10ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为白色粉末的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(四氢-吡喃-4-基)-异丁酰胺(45mg,35%)。MS:363(M+H);1H-NMR(CDCl3,400MHz)δ7.87(d,2H,J=7.6Hz),7.60(d,2H,J=7.6Hz),7.21(d,1H,J=15.6Hz),6.56(d,1H,J=15.6Hz),5.08(m,1H),3.98(m,1H),3.90(m,2H),3.44(m,2H),1.83(m,2H),1.59(s,6H),1.34(m,2H)。
实施例14
N-(4-氯-苯甲基)-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(100.0mg,0.3580mmol)、对氯苯甲胺(0.0507g,0.358mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(68.6mg,0.358mmol)和1-羟基苯并三唑(24.2mg,0.179mmol)溶解在四氢呋喃(10ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为白色粉末的N-(4-氯-苯甲基)-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺(69mg,48%)。1H-NMR(CDCl3,400MHz)δ7.86(d,2H,J=7.4Hz),7.60(d,2H,J=7.4Hz),7.27(d,2H,J=7.4Hz),7.20(d,1H,J=15.6Hz),7.11(d,2H,J=7.4Hz),6.55(d,1H,J=15.6Hz),5.53(br s,1H),4.37(d,2H,J=5.6Hz),1.62(s,6H)。
实施例15
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-噻吩-2-基甲基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(100.0mg,0.3580mmol)、噻吩-2-甲胺(0.0405g,0.358mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(68.6mg,0.358mmol)和1-羟基苯并三唑(24.2mg,0.179mmol)溶解在四氢呋喃(10ml)中,并允许反应混合物在室温下搅拌过夜。将反应混合物倒在饱和碳酸氢钠上,并使用二氯甲烷/乙酸乙酯萃取有机相。然后将合并的萃取物在硫酸钠上干燥,过滤并浓缩。粗反应混合物通过Gilson反相层析进行纯化。将合并的级分冷冻干燥,得到作为白色粉末的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-噻吩-2-基甲基-异丁酰胺(67mg,50%)。MS:375(M+H);1H-NMR(CDCl3,400MHz)δ7.85(d,2H,J=7.4Hz),7.60(d,2H,J=7.4Hz),7.20(m,2H),6.90(m,2H),6.54(d,1H,J=15.4Hz),5.55(br s,1H),4.59(d,2H,J=5.4Hz),1.62(s,6H)。
实施例16
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-1-苯基-乙基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、(S)-1-苯基-乙胺(34.3uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.3mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为无定形白色固体的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-1-苯基-乙基)-异丁酰胺(66mg,64%)。MS:383(M+H);1H-NMR(CDCl3,400MHz)δ7.84(d,2H,J=7.6Hz),7.55(d,2H,J=7.6Hz),7.37-7.25(m,3H),7.24-7.14(m,3H),6.53(d,1H,J=15.7Hz),5.59(d,1H,J=7.1Hz),5.16-5.06(m,1H),1.61(s,3H),1.60(s,3H),1.43(d,3H,J=6.8Hz)。
实施例17
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((R)-1-苯基-乙基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、(R)-1-苯基-乙胺(34.2uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.3mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为无定形白色固体的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((R)-1-苯基-乙基)-异丁酰胺(69mg,67%)。MS:383(M+H);1H-NMR(CDCl3,400MHz)δ7.84(d,2H,J=7.3Hz),7.54(d,2H,J=7.3Hz),7.37-7.26(m,3H),7.23-7.15(m,3H),6.54(d,1H,J=15.6Hz),5.68(d,1H,J=6.8Hz),5.16-5.06(m,1H),1.62(s,3H),1.60(s,3H),1.44(d,3H,J=6.8Hz)。
实施例18
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、4-氟-苯甲胺(30.5uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.2mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-异丁酰胺(34mg,34%)。MS:387(M+H);1H-NMR(CDCl3,400MHz)δ7.85(d,2H,J=7.4Hz),7.59(d,2H,J=7.4Hz),7.30-7.24(m,1H),7.20-7.10(m,2H),7.04-6.95(m,2H),6.55(d,1H,J=15.6Hz),5.63-5.50(m,1H),4.37(d,2H,J=5.6Hz),1.63(s,6H)。
实施例19
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-丙-2-炔基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(145mg,0.519mmol)、丙-2-炔基胺(50.0uL,0.729mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(139mg,0.727mmol)和1-羟基苯并三唑(37mg,0.28mmol)合并在二氯甲烷(3.00ml)中。在1h后,将混合物浓缩至干燥。将残留物转移至DMSO中并纯化(质谱指导的HPLC,15-55%MeCN:H2O,TFA改性剂),得到作为灰白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-丙-2-炔基-异丁酰胺(66mg,40%)。MS:317(M+H);1H-NMR(CDCl3,400MHz)δ7.88(d,2H,J=8.1Hz),7.61(d,2H,J=8.1Hz),7.23(d,1H,J=15.7Hz),6.56(d,1H,J=15.7Hz),5.40(s,1H),4.03(m,2H),2.21(s,1H),1.62(s,6H)。
实施例20
(E)-3-{4-[2-(3,4-二氢-1H-异喹啉-2-基)-1,1-二甲基-2-氧代-乙基]-苯磺酰基}-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、1,2,3,4-四氢异喹啉(35.8mg,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.2mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色固体的(E)-3-{4-[2-(3,4-二氢-1H-异喹啉-2-基)-1,1-二甲基-2-氧代-乙基]-苯磺酰基}-丙烯腈(23mg,22%),mp=54-60℃。MS:395(M+H);1H-NMR(CDCl3,400MHz)δ8.00-7.60(m,2H),7.60-7.33(m,2H),7.25-6.87(m,5H),6.65-6.41(m,1H),4.93-4.62(m,1H),4.22-3.72(m,2H),3.31-3.03(m,1H),3.00-2.78(m,1H),2.52-2.23(m,1H),1.62(s,6H)。
实施例21
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-吡唑-1-基-苯甲基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、4-吡唑-1-基-苯甲胺(46.5mg,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.2mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为浅黄色固体的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-吡唑-1-基-苯甲基)-异丁酰胺三氟乙酸盐(33mg,28%),mp=47-53℃。MS:435(M+H);1H-NMR(CDCl3,400MHz)δ7.92-7.83(m,3H),7.80-7.76(m,1H),7.64-7.57(m,4H),7.30-7.25(m,2H),7.21(d,1H,J=15.6Hz),6.55(d,1H,J=15.6Hz),6.52-6.47(m,1H),5.73-5.63(m,1H),4.44(d,2H,J=5.7Hz),1.64(s,6H)。
实施例22
N-苯甲基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-甲基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、N-甲基-苯甲胺(34.6uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.2mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的N-苯甲基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-甲基-异丁酰胺(33mg,32%)。MS:383(M+H);1H-NMR(CDCl3,400MHz,旋转异构体的混合物)δ7.92-7.76(m,2H),7.49(d,2H,J=8.0Hz),7.40-7.01(m,6H),6.55(d,1H,J=14.7Hz),4.72-3.94(m,2H),3.02-2.31(m,3H),1.63(s,6H)。
实施例23
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-甲氧基-苯基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、4-甲氧基苯胺(33.1mg,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.2mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色固体的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-甲氧基-苯基)-异丁酰胺(53mg,52%),mp=123-126℃。MS:385(M+H);1H-NMR(CDCl3,400MHz)δ7.90(d,2H,J=8.2Hz),7.69(d,2H,J=8.2Hz),7.28(d,2H,J=8.6Hz),7.21(d,1H,J=15.7Hz),6.83(d,2H,J=8.6Hz),6.77(bs,1H),6.57(d,1H,J=15.7Hz),3.78(s,3H),1.71(s,6H)。
实施例24
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-苯乙基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、苯基乙基胺(33.7uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.2mL乙腈中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-苯乙基-异丁酰胺(39mg,38%)。MS:383(M+H);1H-NMR(CDCl3,400MHz)δ7.79(d,2H,J=8.6Hz),7.49(d,2H,J=8.6Hz),7.29-7.21(m,3H),7.19(d,1H,J=15.7Hz),7.07-7.02(m,2H),6.55(d,1H,J=15.7Hz),5.20-5.08(m,1H),3.53-3.46(m,2H),2.76(t,2H,J=6.7Hz),1.54(s,6H)。
实施例25
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(150.0mg,0.5370mmol)、3-甲氧基苯胺(80.3uL,0.715mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(143mg,0.745mmol)和1-羟基苯并三唑(36.1mg,0.267mmol)溶解在乙腈(2.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应用0.4mL DMSO稀释,过滤并纯化。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯基)-异丁酰胺(108mg,52.3%)。MS:385(M+H);1H-NMR(CDCl3,400MHz)δ7.91(d,2H,J=8.5Hz),7.68(d,2H,J=8.5Hz),7.25-7.16(m,3H),6.86-6.78(m,2H),6.67(dd,1H,J=1.9,8.3Hz),6.57(d,1H,J=15.7Hz),3.79(s,3H),1.71(s,6H)。
实施例26
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氨磺酰基-苯甲基)-异丁酰胺
将4-氨基甲基-苯磺酰胺盐酸盐(59.8mg,0.268mmol)置于二氯甲烷(10.00ml)中并加入大孔碳酸酯树脂(3.16mmol/g载量;255mg,0.806mmol)。将反应在室温下搅拌30分钟,然后过滤以去除树脂。将该溶液加入到含有2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、1-羟基苯并三唑(18.1mg,0.134mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)的小瓶中。将反应在40℃下搅拌过夜,然后在减压下进行浓缩。将残留物转移至1.6mL DMSO中,通过制备型HPLC,使用均含有0.1%TFA的10-45%MeCN/水的梯度作为洗脱溶剂进行纯化,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氨磺酰基-苯甲基)-异丁酰胺(17mg,14%)。MS:448(M+H);1H-NMR(DMSO-d6,400MHz)δ8.24(d,1H,J=15.6Hz),8.16(t,1H,J=5.8Hz),7.88(d,2H,J=8.4Hz),7.73(d,2H,J=8.1Hz),7.64(d,2H,J=8.4Hz),7.35-7.26(m,4H),6.91(d,1H,J=15.6Hz),4.28(d,2H,J=5.8Hz),1.52(s,6H)。
实施例27
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-甲磺酰基-苯甲基)-异丁酰胺
将4-甲磺酰基-苯甲胺盐酸盐(59.5mg,0.268mmol)置于二氯甲烷(10.00ml)中并加入大孔碳酸酯树脂(3.16mmol/g载量,255mg,0.806mmol)。将反应在室温下搅拌30分钟,然后过滤以去除大孔碳酸酯树脂。将该溶液加入到含有2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、1-羟基苯并三唑(18.1mg,0.134mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)的小瓶中。将反应在40℃下搅拌过夜,然后在减压下进行浓缩。将残留物转移至1.6mL DMSO中,通过制备型HPLC,使用均含有0.1%TFA的10-45%MeCN/水的梯度作为洗脱溶剂进行纯化,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-甲磺酰基-苯甲基)-异丁酰胺(33mg,28%)。MS:447(M+H);1H-NMR(CDCl3,400MHz)δ7.87(d,2H,J=8.4Hz),7.80(d,2H,J=8.2Hz),7.62(d,2H,J=8.4Hz),7.32(d,2H,J=8.2Hz),7.22(d,1H,J=15.6Hz),6.57(d,1H,J=15.6Hz),5.99(t,1H,J=5.6Hz),4.49(d,2H,J=6.0Hz),3.03(s,3H),1.66(s,6H)。
实施例28
(E)-3-[4-(1,1-二甲基-2-氧代-2-哌啶-1-基-乙基)-苯磺酰基]-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、哌啶(26.6uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.6mLDMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为黄色油状物的(E)-3-[4-(1,1-二甲基-2-氧代-2-哌啶-1-基-乙基)-苯磺酰基]-丙烯腈(25mg,27%)。MS:347(M+H);1H-NMR(CDCl3,400MHz)δ7.88(d,2H,J=8.4Hz),7.49(d,2H,J=8.4Hz),7.22(d,1H,J=15.6Hz),6.56(d,1H,J=15.6Hz),3.26-2.64(m,3H),1.93-1.68(m,1H),1.57(s,6H),1.56-1.44(m,4H),1.25-0.95(m,2H);13C-NMR:(DMSO-d6,100MHz,95℃)δ172.3,153.9,149.6,135.7,128.6,126.4,114.3,111.5,47.1,45.1,28.1,24.9,23.7。
实施例29
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-2-羟基-1-苯基-乙基)-异丁酰胺
向在二氯甲烷(6.0ml)中的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(153mg,0.548mmol)、(S)-2-氨基-2-苯基-乙醇(86.0mg,0.627mmol)和1-羟基苯并三唑(6.8mg,0.050mmol)加入N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(116mg,0.602mmol)并搅拌1h。将混合物在真空中浓缩,溶解在DMSO中并纯化(质谱指导的HPLC,15-55%MeCN/水,TFA改性剂)。对产物级分进行浓缩,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-2-羟基-1-苯基-乙基)-异丁酰胺(143mg,65.5%)。MS:399(M+H);1H-NMR(DMSO-d6,400MHz)δ8.25(d,1H,J=15.6Hz),7.83(d,2H,J=8.4Hz),7.69(d,1H,J=8.0Hz),7.61(d,2H,J=8.4Hz),7.25(m,2H),7.17(m,3H),6.91(d,1H,J=15.6Hz),4.87(m,1H),3.53(d,2H,J=6.7Hz),1.51(s,6H)。
实施例30
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-2-氧代-氮杂环庚烷-3-基)-异丁酰胺
将(S)-3-氨基-氮杂环庚烷-2-酮盐酸盐(44.2mg,0.268mmol)置于二氯甲烷(10.00ml)中并加入大孔碳酸酯树脂(3.16mmol/g载量,255mg,0.806mmol)。将反应在室温下搅拌30分钟,然后过滤以去除树脂。将该溶液加入到含有2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、1-羟基苯并三唑(18.1mg,0.134mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)的小瓶中。将反应在40℃下搅拌过夜,然后在减压下进行浓缩。将残留物转移至1.6mL DMSO中,并通过制备型HPLC,使用均含有0.1%TFA的10-45%MeCN/水的梯度作为洗脱溶剂进行纯化,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-2-氧代-氮杂环庚烷-3-基)-异丁酰胺(60mg,57%)。MS:390(M+H);HNMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.6Hz),7.90-7.84(m,1H),7.86(d,2H,J=8.5Hz),7.69(d,2H,J=6.5Hz),7.23(d,1H,J=6.2Hz),6.90(d,1H,J=15.6Hz),4.41-4.30(m,1H),3.23-3.10(m,1H),3.10-2.97(m,1H),1.93-1.82(m,1H),1.82-1.69(m,2H),1.69-1.55(m,1H),1.51(s,6H),1.41-1.26(m,1H),1.25-1.10(m,1H)。
实施例31
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-[4-(2-甲氧基-乙氧基甲基)-苯基]-异丁酰胺
a)向对硝基苯甲基溴化物(2.048g,9.480mmol)在2-甲氧基乙醇(20.0mL,254mmol)中的悬液加入氢氧化钾(0.682g,10.3mmol),并将混合物在小瓶中在105℃下加热。在90min后,将混合物冷却至室温。将混合物倒入EtOAc(100ml)中,并用水(3X10ml)、盐水(20ml)洗涤,在硫酸钠上干燥。在过滤后真空浓缩得到油状物,将其在ISCO上进行纯化(25g预装载w/DCM,80g柱子,5-40%EtOAc:Hex)。将纯级分合并并浓缩,得到作为橙色油状物的1-(2-甲氧基-乙氧基甲基)-4-硝基-苯(1.245g,62.18%)。
b)将1-(2-甲氧基-乙氧基甲基)-4-硝基-苯(200mg,0.947mmol)溶解在甲醇(9.5ml)中,并加入5%的硫化(0.5%)碳载铂(36.9mg,0.00947mmol)。将反应在50psi下加氢60分钟,然后通过硅藻土进行过滤以去除催化剂。然后将滤液在减压下浓缩,得到作为黄色油状物的4-(2-甲氧基-乙氧基甲基)-苯胺。
c)将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、4-(2-甲氧基-乙氧基甲基)-苯胺(48.7mg,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在二氯甲烷(7.50ml)中,并允许反应混合物在室温下搅拌过夜。将反应在减压下浓缩,并将残留物转移到1.6mL DMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为橙色油状物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-[4-(2-甲氧基-乙氧基甲基)-苯基]-异丁酰胺(57mg,48%)。MS:465(M+Na);HNMR(DMSO-d6,400MHz)δ9.23(s,1H),8.23(d,1H,J=15.7Hz),7.89(d,2H,J=8.6Hz),7.67(d,2H,J=8.6Hz),7.54(d,2H,J=8.6Hz),7.22(d,2H,J=8.6Hz),6.0(d,1H,J=15.7Hz),4.40(s,2H),3.53-3.43(m,4H),3.24(s,3H),1.60(s,6H)。
实施例32
(2-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-乙基)-氨基甲酸叔丁基酯
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(1.00E2mg,0.358mmol)、N-(2-氨基乙基)(叔丁氧基)甲酰胺(62.3uL,0.394mmol)和N,N-二异丙基乙基胺(168uL,0.967mmol)置于二氯甲烷(3.00ml)中,并加入溴三(吡咯烷)六氟磷酸盐(184mg,0.394mmol)。将反应在室温下搅拌45分钟,然后在减压下浓缩。将残留物转移到DMSO中,并使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过制备型HPLC进行纯化,得到作为白色泡沫的(2-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-乙基)-氨基甲酸叔丁基酯(101mg,67%)。MS:444(M+Na);HNMR(CDCl3,400MHz)δ7.85(d,2H,J=8.6Hz),7.61(d,2H,J=8.6Hz),7.20(d,1H,J=15.6Hz),6.77-6.66(m,1H),6.53(d,1H,J=15.6Hz),4.93-4.80(m,1H),3.38-3.21(m,4H),1.61(s,6H),1.41(s,9H)。
实施例33
(6-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-己基)-氨基甲酸叔丁基酯
将N-叔丁基氧基羰基-1,6-二氨基己烷盐酸盐(90.5mg,0.358mmol)置于含有450mg大孔碳酸酯树脂(3mmol/g)的5.0mL DCM中并搅拌30分钟,然后过滤以去除树脂。将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(100mg,0.358mmol)、1-羟基苯并三唑(24.2mg,0.179mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(68.6mg,0.358mmol)和N,N-二异丙基乙基胺(187uL,1.07mmol)置于5.0mL DCM中,并加入N-叔丁基氧基羰基-1,6-二氨基己烷溶液。将反应在室温下搅拌2小时,然后在减压下浓缩。将残留物转移到1.5mLDMSO中,并使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过制备型HPLC进行纯化,得到作为白色泡沫的(6-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-己基)-氨基甲酸叔丁基酯(119mg,70%)。MS:500(M+H);HNMR(CDCl3,400MHz)δ7.86(d,2H,J=8.5Hz),7.61(d,2H,J=8.5Hz),7.23(d,1H,J=15.7Hz),6.56(d,1H,J=15.7Hz),5.61-5.42(m,1H),4.64-4.42(m,1H),3.25-3.15(m,2H),3.11-3.00(m,2H),1.60(s,6H),1.53-1.34(m,13H),1.34-1.16(m,4H)。
实施例34
{2-[2-(2-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-乙氧基)-乙氧基]-乙基}-氨基甲酸叔丁基酯
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(150mg,0.537mmol)、{2-[2-(2-氨基-乙氧基)-乙氧基]-乙基}-氨基甲酸叔丁基酯(147mg,0.591mmol)、N,N-二异丙基乙基胺(252uL,1.45mmol)置于二氯甲烷(4.50ml)中,并加入溴三(吡咯烷)六氟磷酸盐(275mg,0.591mmol)。将反应在室温下搅拌45分钟,然后在减压下浓缩。将残留物转移到DMSO中,并使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过制备型HPLC进行纯化,得到作为油状物的{2-[2-(2-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-乙氧基)-乙氧基]-乙基}-氨基甲酸叔丁基酯(214mg,78%)。MS:532(M+Na);HNMR(CDCl3,400MHz)δ7.86(d,2H,J=8.4Hz),7.61(d,2H,J=8.4Hz),7.23(d,1H,J=15.7Hz),6.55(d,1H,J=15.7Hz),5.83-5.30(m,2H),3.60-3.48(m,8H),3.48-3.38(m,2H),3.34-3.20(m,2H),1.61(s,6H),1.45(s,9H)。
实施例35
2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环己基-异丁酰胺
将2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(83.0mg,0.297mmol)、环己胺(45.2uL,0.396mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(79.0mg,0.412mmol)和1-羟基苯并三唑(20.0mg,0.148mmol)溶解在乙腈(1.50ml)中,并允许反应混合物在室温下搅拌1h。将反应用0.4mL DMSO稀释,过滤并纯化。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环己基-异丁酰胺(78mg,73%)。MS:361(M+H);1H-NMR(DMSO-d6,400MHz)δ8.25(d,1H,J=15.6Hz),7.78(m,1H),7.74(m,2H),7.67(m,1H),7.20(d,1H,J=8.0Hz),6.90(d,1H,J=15.6Hz),3.55(m,1H),1.64(m,4H),1.55(m,1H),1.47(s,6H),1.0-1.3(m,5H)。
实施例36
2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯基)-异丁酰胺
将2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(83.0mg,0.297mmol)、3-甲氧基苯胺(44.4uL,0.396mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(79.0mg,0.412mmol)和1-羟基苯并三唑(20.0mg,0.148mmol)溶解在乙腈(1.50ml)中,并允许反应混合物在室温下搅拌1h。将反应用0.4mL DMSO稀释,过滤并纯化。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为浅粉色冻干物的2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯基)-异丁酰胺(29mg,25%)。MS:385(M+H);1H-NMR(DMSO-d6,400MHz)δ9.19(s,1H),8.28(d,1H,J=15.6Hz),7.85(m,1H),7.82(m,1H),7.77(m,1H),7.70(m,1H),7.25(m,1H),7.16(m,2H),6.91(d,1H,J=15.6Hz),6.62(m,1H),3.70(s,3H),1.61(s,6H)。
实施例37
2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-异丁酰胺
将2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(83.0mg,0.297mmol)、4-氟-苯甲胺(45.0uL,0.396mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(79.0mg,0.412mmol)和1-羟基苯并三唑(20.0mg,0.148mmol)溶解在乙腈(1.50ml)中,并允许反应混合物在室温下搅拌1h。将反应用0.4mL DMSO稀释,过滤并纯化。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为米色冻干物的2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-异丁酰胺(61mg,53%)。MS:387(M+H);1H-NMR(DMSO-d6,400MHz)δ8.25(d,1H,J=15.6Hz),8.08(m,1H),7.90(m,2H),7.73(m,1H),7.70(m,1H),7.15(m,2H),7.08(m,2H),6.91(d,1H,J=15.6Hz),4.22(d,2H,J=6.0Hz),1.53(s,6H)。
实施例38
N-(4-氨基-苯甲基)-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(83.0mg,0.297mmol)、4-氨基苯甲胺(44.8uL,0.396mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(79.0mg,0.412mmol)和1-羟基苯并三唑(20.0mg,0.148mmol)溶解在乙腈(1.50ml)中,并允许反应混合物在室温下搅拌1h。将反应用0.4mL DMSO稀释,过滤并纯化。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色冻干物的N-(4-氨基-苯甲基)-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺三氟乙酸盐(69mg,47%)。MS:384(M+H);1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.7Hz),8.05(t,1H,J=5.9Hz),7.86(d,2H,J=8.6Hz),7.62(d,2H,J=8.6Hz),7.12(d,2H,J=8.4Hz),7.02(d,2H,J=8.4Hz),6.90(d,1H,J=15.7Hz),4.35(br s,3H),4.19(d,2H,J=5.9Hz),1.51(s,6H)。
实施例39
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-氟-苯甲基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、3-氟苯甲胺(30.6uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在乙腈(1.00ml)中,并允许反应混合物在室温下搅拌2小时。将反应在减压下浓缩,并将残留物转移至1.6mL DMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色冻干物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-氟-苯甲基)-异丁酰胺(17mg,16%)。MS:387(M+H);1H-NMR(CDCl3,400MHz)δ7.87(d,2H,J=8.7Hz),7.61(d,2H,J=8.7Hz),7.32-7.23(m,1H),7.20(d,1H,J=15.6Hz),7.00-6.91(m,2H),6.84-6.78(m,1H),6.55(d,1H,J=15.6Hz),5.62-5.49(m,1H),4.40(d,2H,J=5.9Hz),1.64(s,6H)。
实施例40
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-氟-苯甲基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、2-氟苯甲胺(30.6uL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在乙腈(1.00ml)中,并允许反应混合物在室温下搅拌2小时。将反应在减压下浓缩,并将残留物转移至1.6mL DMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色冻干物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-氟-苯甲基)-异丁酰胺(40mg,38%)。MS:387(M+H);1H-NMR(CDCl3,400MHz)δ7.83(d,2H,J=8.7Hz),7.56(d,2H,J=8.7Hz),7.31-7.22(m,2H),7.19(d,1H,J=15.6Hz),7.12-7.06(m,1H),7.05-6.98(m,1H),6.54(d,1H,J=15.7Hz),5.69-5.54(m,1H),4.44(d,2H,J=5.9Hz),1.60(s,6H)。
实施例41
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-N-甲基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、(4-氟-苯甲基)-甲基胺(37.4mg,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在乙腈(1.00ml)中,并允许反应混合物在室温下搅拌2小时。将反应在减压下浓缩,并将残留物转移至1.6mLDMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色冻干物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-N-甲基-异丁酰胺(24mg,22%)。MS:401(M+H);1H-NMR(CDCl3,400MHz,旋转异构体的混合物)δ7.84(d,2H,J=8.6Hz),7.46(d,2H,J=8.6Hz),7.32-7.13(m,3H),7.06-6.96(m,2H),6.55(d,1H,J=15.7Hz),4.68-3.79(m,2H),3.00-2.24(m,3H),1.61(s,6H)。
实施例42
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-[3-(2-甲氧基-乙氧基)-苯基]-异丁酰胺
a)向间硝基酚(1.00g,7.19mmol)和碳酸钾(1.49g,10.8mmol)在N-甲基吡咯烷酮(6.0ml)中的混合物加入2-溴乙基甲基醚(0.800mL,8.51mmol),并将混合物在小瓶中在50℃加热过夜,然后冷却至室温。将混合物用水(6ml)稀释,并用2:1EtOAc:Hex(3X18ml)萃取。将合并的有机相用饱和NaHCO3水溶液(30ml)和盐水(30ml)洗涤,在硫酸钠上干燥,过滤,并真空浓缩,得到作为橙色油状物的1-(2-甲氧基-乙氧基)-3-硝基-苯(1.328g,93%)。
b)将1-(2-甲氧基-乙氧基)-3-硝基-苯(1.32g,6.69mmol)与10%的碳载钯(50%水分)(0.210g,0.0987mmol)在甲醇(15.0ml)中,在氢气气氛(30psi)下摇动2h,通过硅藻土过滤并真空浓缩,得到作为橙色油状物的3-(2-甲氧基-乙氧基)-苯胺(1.064g,95%)。
c)将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(85.0mg,0.304mmol)、3-(2-甲氧基-乙氧基)-苯胺(65mg,0.39mmol)、N-(3-二甲基氨基-丙基)-N′-乙基碳二亚胺盐酸盐(88mg,0.46mmol)和1-羟基苯并三唑(41.0mg,0.303mmol)溶解在乙腈(1.5mL,29mmol)中,并允许反应混合物在室温下搅拌过夜。将反应用0.4mL DMSO稀释,过滤并纯化。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-[3-(2-甲氧基-乙氧基)-苯基]-异丁酰胺(72mg,55%)。MS:429(M+H);1H-NMR(CDCl3,400MHz)δ7.91(d,2H,J=8.6Hz),7.68(d,2H,J=8.6Hz),7.23(d,1H,J=15.6Hz),7.22(m,1H),7.18(m,1H),6.84(ddd,1H,J=0.6,1.9,8.0Hz),6.79(br s,1H),6.68(ddd,1H,J=0.6,2.4,8.3Hz),6.58(d,1H,J=15.6Hz),4.11(m,2H),3.73(m,2H),3.44(s,3H),1.70(s,6H)。
实施例43
(3-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-苯氧基)-乙酸
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(85.0mg,0.304mmol)、(3-氨基-苯氧基)-乙酸叔丁基酯(91mg,0.41mmol,如Takeda,Y.等,Chem.Pharm.Bull.1993,46,434中制备的)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(88mg,0.46mmol)和1-羟基苯并三唑(42mg,0.31mmol)溶解在乙腈(2.0ml)中,并允许反应混合物在室温下搅拌过夜。然后将混合物用三氟乙酸(1.00mL,13.0mmol)进行处理。在搅拌过夜后,将混合物过滤并通过质谱指导的HPLC进行纯化,得到作为白色冻干物的(3-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-苯氧基)-乙酸(69mg,53%)。MS:429(M+H);1H-NMR(DMSO-d6,400MHz)δ12.98(br s,1H),9.20(s,1H),8.23(d,1H,J=15.6Hz),7.90(d,2H,J=8.6Hz),7.67(d,2H,J=8.6Hz),7.28(m,1H),7.21(m,1H),7.16(m,1H),6.91(d,1H,J=15.6Hz),6.59(ddd,1H,J=1.1,2.5,8.0Hz),4.61(s,2H),1.59(s,6H)。
实施例44
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯甲基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、3-甲氧基-苯甲胺(34.7μL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在乙腈(1.00ml)中,并允许反应混合物在室温下搅拌2小时。将反应在减压下浓缩,并将残留物转移至1.6mL DMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色冻干物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯甲基)-异丁酰胺(40mg,37%)。MS:399(M+H);1H-NMR(CDCl3,400MHz)δ7.85(d,2H,J=8.6Hz),7.61(d,2H,J=8.6Hz),7.25-7.16(m,2H),6.84-6.78(m,1H),6.77-6.72(m,1H),6.69-6.65(m,1H),6.54(d,1H,J=15.7Hz),5.57-5.48(m,1H),4.38(d,2H,J=5.7Hz),3.77(s,3H),1.64(s,6H)。
实施例45
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-甲氧基-苯甲基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、2-甲氧基-苯甲胺(34.7μL,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在乙腈(1.00ml)中,并允许反应混合物在室温下搅拌2小时。将反应在减压下浓缩,并将残留物转移至1.6mL DMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色冻干物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-甲氧基-苯甲基)-异丁酰胺(48mg,45%)。MS:399(M+H);HNMR(CDCl3,400MHz)δ7.81(d,2H,J=8.7Hz),7.53(d,2H,J=8.7Hz),7.30-7.23(m,1H),7.23-7.16(m,2H),6.94-6.87(m,1H),6.85-6.80(m,1H),6.54(d,1H,J=15.7Hz),5.89-5.80(m,1H),4.38(d,2H,J=5.8Hz),3.69(s,3H),1.58(s,6H)。
实施例46
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-甲氧基-苯甲基)-N-甲基-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(75.0mg,0.268mmol)、(2-甲氧基-苯甲基)-甲基胺(40.6mg,0.268mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51.5mg,0.268mmol)和1-羟基苯并三唑(18.1mg,0.134mmol)溶解在乙腈(1.00ml)中,并允许反应混合物在室温下搅拌2小时。将反应在减压下浓缩,并将残留物转移至1.6mL DMSO中。使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色冻干物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-甲氧基-苯甲基)-N-甲基-异丁酰胺(28mg,25%)。MS:413(M+H);1H-NMR(DMSO-d6,400MHz,100℃)δ8.03(d,1H,J=15.7Hz),7.87-7.81(m,2H),7.55-7.49(m,2H),7.24-7.17(m,1H),7.02-6.96(m,1H),6.96-6.85(m,2H),6.75(d,1H,J=15.7Hz),4.35(s,2H),3.74(s,3H),2.48(s,3H),1.52(s,6H)。
实施例47
(E)-3-{4-[1-甲基-1-(5-苯基氨基-[1,3,4]二唑-2-基)-乙基]-苯磺酰基}-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(101mg,0.362mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(211mg,1.10mmol)和4-苯基-3-硫代氨基脲(65mg,0.39mmol)合并在二氯甲烷(3.00ml)中并搅拌过夜。将混合物真空浓缩,转移至DMSO中并通过质谱指导的HPLC进行纯化(25-75%MeCN/水,TFA改性剂)。在冷冻干燥后,分离作为灰白色冻干物的(E)-3-{4-[1-甲基-1-(5-苯基氨基-[1,3,4]二唑-2-基)-乙基]-苯磺酰基}-丙烯腈三氟乙酸盐(35mg,19%)。MS:395(M+H);1H-NMR(DMSO-d6,400MHz)δ10.38(s,1H),8.23(d,1H,J=15.6Hz),7.91(d,2H,J=8.0Hz),7.66(d,2H,J=8.0Hz),7.52(d,2H,J=7.8Hz),7.32(m,2H),6.98(m,1H),6.92(d,1H,J=15.6Hz),1.77(s,6H)。
实施例48
(E)-3-{4-[1-(5-乙基氨基-[1,3,4]二唑-2-基)-1-甲基-乙基]-苯磺酰基}-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(105mg,0.376mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(241mg,1.26mmol)和4-乙基-3-硫代氨基脲(60.0mg,0.503mmol)合并在二氯甲烷(3.00ml)中并搅拌过夜。将混合物真空浓缩,转移至DMSO中并通过质谱指导的HPLC进行纯化(25-75%MeCN/水,TFA改性剂)。在冷冻干燥后,分离作为米色冻干物的(E)-3-{4-[1-(5-乙基氨基-[1,3,4]二唑-2-基)-1-甲基-乙基]-苯磺酰基}-丙烯腈三氟乙酸盐(19mg,11%)。MS:347(M+H);1H-NMR(acetone-d6,400MHz)δ7.94(d,2H,J=8.1Hz),7.89(d,1H,J=15.7Hz),7.66(d,2H,J=8.1Hz),6.83(d,1H,J=15.7Hz),6.53(br s,1H),3.30(q,2H,J=7.2Hz),1.76(s,6H),1.20(t,3H,J=7.2Hz)。
实施例49
(E)-3-{4-[1-(1H-苯并咪唑-2-基)-1-甲基-乙基]-苯磺酰基}-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(112mg,0.401mmol)、1,2-苯二胺(51.0mg,0.472mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(98mg,0.51mmol)和1-羟基苯并三唑(27mg,0.20mmol)合并在四氢呋喃(6.0ml)中并在室温下搅拌。在1h后,加入二氯甲烷(1.0ml)以帮助溶解。在搅拌过夜后,加入乙酸(0.65mL,11mmol)并将混合物加热到70℃直至苯胺-酰胺完全环化。将混合物真空浓缩,转移至DMSO中并通过质谱指导的HPLC进行纯化,得到作为灰白色冻干物的(E)-3-{4-[1-(1H-苯并咪唑-2-基)-1-甲基-乙基]-苯磺酰基}-丙烯腈三氟乙酸盐(45mg,24%)。MS:352(M+H);1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.7Hz),7.90(d,2H,J=8.2Hz),7.65(m,4H),7.39(br s,2H),6.91(d,1H,J=15.7Hz),1.89(s,6H)。
实施例50
(E)-3-{4-[1-甲基-1-(5-甲基-苯并唑-2-基)-乙基]-苯磺酰基}-丙烯腈
a)将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(124mg,0.444mmol)、2-氨基-4-甲基酚(61.0mg,0.495mmol)和1-羟基苯并三唑(6.0mg,0.044mmol)合并在1,2-二氯乙烷(4.0mL,51mmol)中,并加入N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(105mg,0.548mmol)。在小瓶中在室温下搅拌2h,然后将混合物真空浓缩,转移到DMSO中并通过质谱指导的HPLC进行纯化,得到作为油状物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-5-甲基-苯基)-异丁酰胺。
b)将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-5-甲基-苯基)-异丁酰胺(42mg,0.11mmol)溶解在乙酸(2.0mL,35mmol)中,并在105℃下加热3d。将混合物真空浓缩,转移到DMSO中并通过质谱指导的HPLC进行纯化(25-85%MeCN:水,TFA改性剂),得到作为灰白色冻干物的(E)-3-{4-[1-甲基-1-(5-甲基-苯并唑-2-基)-乙基]-苯磺酰基}-丙烯腈三氟乙酸盐(15mg,28%)。MS:367(M+H);1H-NMR(DMSO-d6,400MHz)δ8.21(d,1H,J=15.6Hz),7.88(d,2H,J=8.4Hz),7.63(d,2H,J=8.4Hz),7.56(s,1H),7.52(d,1H,J=8.3Hz),7.18(d,1H,J=8.3Hz),6.90(d,1H,J=15.6Hz),2.42(s,3H),1.84(s,6H)。
实施例51
(E)-3-{4-[1-甲基-1-(5-甲基-唑-2-基)-乙基]-苯磺酰基}-丙烯腈
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-丙-2-炔基-异丁酰胺(53mg,0.17mmol)和氯化金(III)(5.0mg,0.016mmol)合并在乙腈-d3(1.0ml)中,并通过1H-NMR监测异构化速率。一旦完成(4天)后,将混合物过滤,通过质谱指导的HPLC进行纯化并冷冻干燥,得到油状物。从MeCN重新浓缩留下油状物,其缓慢变成紫色。将混合物重新溶解在MeCN中,用大孔碳酸酯树脂(3mmol/g,0.1g)处理30min并过滤,得到透明溶液和被捕获在滤纸上的紫色固体。作为游离碱重新冷冻干燥,得到作为灰白色蜡状物的(E)-3-{4-[1-甲基-1-(5-甲基-唑-2-基)-乙基]-苯磺酰基}-丙烯腈(16mg,30%)。MS:317(M+H);1H-NMR(DMSO-d6,400MHz)δ8.22(d,1H,J=15.6Hz),7.86(d,2H,J=8.6Hz),7.54(d,2H,J=8.6Hz),6.91(d,1H,J=15.6Hz),6.79(s,1H),2.22(s,3H),1.71(s,6H)。
实施例52
环己烷甲酸N′-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰基}-肼
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(131mg,0.469mmol)、环己烷甲酸肼(72.0mg,0.506mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(119mg,0.621mmol)和1-羟基苯并三唑(7.0mg,0.052mmol)合并在乙腈(3.0ml)中并在室温下搅拌。在4h后,将混合物用DMSO(0.4ml)稀释,过滤,并通过质谱指导的HPLC进行纯化(25-85%MeCN:水,TFA改性剂),得到作为白色冻干物的环己烷甲酸N′-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰基}-肼(108mg,57%)。MS:404(M+H);1H-NMR(DMSO-d6,400MHz)δ9.52(s,1H),9.39(s,1H),8.24(d,1H,J=15.6Hz),7.86(d,2H,J=8.7Hz),7.73(d,2H,J=8.7Hz),6.90(d,1H,J=15.6Hz),2.15(m,1H),1.6-1.7(m,5H),1.50(s,6H),1.1-1.4(m,5H)。
实施例53
(E)-3-{4-[1-(5-环己基-[1,3,4]二唑-2-基)-1-甲基-乙基]-苯磺酰基}-丙烯腈
将环己烷甲酸N′-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰基}-肼(52mg,0.13mmol)溶解在1,4-二烷(2.00ml)中,加入磷酰氯(0.200mL,2.14mmol)并将混合物在80℃加热2h,然后在冰上冷却,随后加入5g冰。将混合物用饱和碳酸氢钠(10ml)稀释并用DCM(3X10ml)萃取。将有机萃取物用1:1的盐水:饱和碳酸氢钠(10ml)洗涤,在硫酸钠上干燥,过滤并真空浓缩,得到作为白色泡沫的(E)-3-{4-[1-(5-环己基-[1,3,4]二唑-2-基)-1-甲基-乙基]-苯磺酰基}-丙烯腈(38mg,76%)。MS:386(M+H);HNMR(CDCl3,400MHz)δ7.85(d,2H,J=8.7Hz),7.51(d,2H,J=8.7Hz),7.20(d,1H,J=15.7Hz),6.55(d,1H,J=15.7Hz),2.84(tt,1H,J=3.7,11.3Hz),2.03(m,2H),1.84(s,6H),1.79(m,2H),1.71(m,2H),1.24-1.40(m,4H)。
实施例54
(E)-3-(3-叔丁基-苯磺酰基)-丙烯腈
在氮气和-80℃(醚/干冰)下,向3-叔丁基-溴苯(2.13g,10mmol)在无水THF(50ml)中的溶液缓慢加入n-BuLi(2.5M,在己烷中,11mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将二氧化硫流鼓泡通过混合物15min。然后允许反应混合物升温至室温,并在减压下去除溶剂。将亚磺酸盐残留物溶解在水(15ml)、乙酸(8ml)和MeOH(20ml)中,然后添加2-氯丙烯腈(18mmol)。将得到的混合物在室温搅拌过夜。在真空中去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x50ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(20mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,然后在MgSO4上干燥。粗产物通过快速柱层析进行纯化(硅胶,二氯甲烷/EtOAc,梯度),得到作为白色固体的(E)-3-(3-叔丁基-苯磺酰基)-丙烯腈(0.76g,31%)。MS:250(M+H);1H-NMR(CDCl3,400MHz)δ7.89(s,1H),7.76(d,1H,J=7.7Hz),7.70(d,1H,J=7.9Hz),7.55(m,1H),7.23(d,1H,J=15.9Hz),6.55(d,1H,J=15.9Hz),1.37(s,9H)。
实施例55
(E)-3-(4-叔丁基-苯磺酰基)-丙烯酰胺
a)将4-叔丁基-溴苯(500mg,2.34mmol)在无水THF(10ml)中的溶液冷却至-80℃,用苯基锂(1.5M,2.58mmol)和n-BuLi(1.5M,2.58mmol)在-80℃下逐滴处理。在30min后,将二氧化硫气体鼓泡通入混合物中1小时,然后允许混合物回到室温。将反应混合物浓缩并用二乙醚洗涤,得到作为白色固体的4-叔丁基苯亚磺酸锂盐(450mg,94%)。
b)将4-叔丁基苯亚磺酸锂盐(500mg,2.4mmol)和2,3-二溴-丙酰胺(678mg,2.93mmol)在DMF(5ml)中的溶液加热至80℃15小时。然后将反应混合物用水稀释,用乙酸乙酯萃取,在硫酸钠上干燥,过滤并浓缩。粗产物通过硅胶柱层析进行纯化(20%乙酸乙酯:己烷),得到作为灰白色固体的(E)-3-(4-叔丁基-苯磺酰基)-丙烯酰胺(50mg,8%),mp=151℃。LCMS(ESI):268(M+H);1H-NMR(400MHz,DMSO-d6)δ1.31(s,9H),6.95-6.98(d,J=14.8Hz,1H),7.40-7.44(d,J=14.8Hz,1H),7.69-7.71(d,J=8.0Hz,2H),7.83-7.85(d,J=8.0Hz,2H),8.03(brs,2H)。
实施例56
1-叔丁基-4-[((E)-丙-1-烯)-1-磺酰基]-苯
a)将碳酸氢钠(1.44g,17.2mmol)和亚硫酸钠(2.16g,17.2mmol)在水(9ml)中的溶液加热至80℃3h,然后分两部分加入4-叔丁基苯基磺酰氯(2g,8.59mmol),并再次加热至80℃1h。将混合物冷却至室温,将其静置2h,通过过滤收集固体,然后在高真空下干燥,得到作为白色固体的4-叔丁基苯亚磺酸钠盐(1.61g。85%)。
b)类似于实施例57b,使用1,2-二溴丙烷和4-叔丁基苯亚磺酸钠盐(0.7g)得到作为灰白色固体的1-叔丁基-4-[((E)-丙-1-烯)-1-磺酰基]-苯(130mg,17%),mp=80℃。LCMS(ESI):239(M+H);1H-NMR(400MHz,CDCl3)δ1.34(s,9H),1.91-1.93(dd,J=6.8,1.6Hz,3H),6.32-6.37(m,1H),6.93-6.99(m,1H),7.53-7.55(d,J=8.8Hz,2H),7.78-7.80(d,J=8.8Hz,2H)。
实施例57
1-叔丁基-4-((E)-2-苯基-乙烯磺酰基)-苯
将4-叔丁基苯亚磺酸钠盐(3.0g,13.6mmol)和1,2-二溴乙基苯(4.31g,16.3mmol)在DMF(30ml)中的溶液加热至80℃15h。将反应混合物通过硅胶柱层析进行纯化(5%乙酸乙酯:己烷),得到作为灰白色固体的1-叔丁基-4-((E)-2-苯基-乙烯磺酰基)-苯(104mg,3%),mp=95℃。LCMS(ESI):301(M+H);1H-NMR(400MHz,CDCl3)δ1.34(s,9H),6.84-6.88(d,J=15.6Hz,1H),7.38-7.49(m,5H),7.54-7.57(d,J=8.4Hz,2H),7.65-7.69(d,J=15.6Hz,1H),7.85-7.88(d,J=8.4Hz,2H)。
实施例58
1-叔丁基-4-(1-苯基-乙烯磺酰基)-苯
从实施例59中描述的反应混合物,也分离到作为灰白色固体的1-叔丁基-4-(1-苯基-乙烯磺酰基)-苯(147mg,4%),mp=99℃。LCMS(ESI):301(M+H);1H-NMR(400MHz,CDCl3)δ1.29(s,9H),5.93(s,1H),6.59(s,1H),7.28-7.62(m,9H)。
实施例59
(E)-3-(4-叔丁基-苯磺酰基)-丙烯酸乙基酯
将4-叔丁基苯亚磺酸锂盐(500mg,2.44mmol)和2,3-二溴丙酸乙酯(700mg,2.69mmol)在DMF(5ml)中的溶液加热至80℃20h。将反应混合物用水稀释,用乙酸乙酯萃取,在Na2SO4上干燥,过滤并浓缩。将粗产物通过硅胶柱层析进行纯化(5%乙酸乙酯:己烷),得到作为灰白色固体的(E)-3-(4-叔丁基-苯磺酰基)-丙烯酸乙基酯(100mg,15%),mp=88-91℃。LCMS(ESI):297(M+H);1H-NMR(400MHz,CDCl3)δ1.29-1.32(t,J=7.2Hz,3H),1.35(s,9H),4.22-4.27(q,J=7.2Hz,2H),6.79-6.83(d,J=15.2Hz,1H),7.31-7.35(d,J=15.2Hz,1H),7.58-7.60(d,J=8.0Hz,2H),7.83-7.85(d,J=8.0Hz,2H)。
实施例60
(E)-3-(4-叔丁基-苯硫基)-丙烯腈
将(E)-3-(4-叔丁基-苯磺酰基)-丙烯腈(100.0mg,0.4011mmol)溶解在氯仿(2.00ml)中并加入4-叔丁基-苯硫醇(69uL,0.40mmol),然后加入三乙胺(57uL,0.41mmol)并将混合物在室温下搅拌3h,然后施加到ISCO装载的柱(5g,DCM用于转移)。层析(ISCO12g,0-20%EtOAc:Hex)得到作为透明无色油状物的(E)-3-(4-叔丁基-苯硫基)-丙烯腈(84mg,97%)。LCMS(ESI):m/z=218(M+H)+;1H-NMR(CDCl3,400MHz)δ7.3-7.5(m,5H),4.96(d,1H,J=15.6Hz),1.34(s,9H);13C-NMR(CDCl3,100MHz)δ153.7,152.7,133.5,127.2,124.8,117.3,92.6,34.9,31.2。
实施例61
[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-乙酸
在氮气和-80℃(醚/干冰)下,向2-(4-溴-2-叔丁基苯氧基)乙酸(2.86g,10mmol)在无水THF(100ml)中的溶液缓慢加入在甲苯中的1.8M苯基锂(7mL,12.5mmol)。在5min后向该混合物加入n-BuLi(2.5M,在己烷中)(5.2mL,13mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将二氧化硫流鼓泡通过混合物15min。然后允许反应混合物升温至室温,并在真空中去除溶剂。将亚磺酸盐残留物溶解在水(15ml)、乙酸(8ml)和MeOH(20ml)中,然后添加2-氯丙烯腈(1.3g,15mmol)。将得到的混合物在室温搅拌过夜。去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x50ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(2.8mL,20mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,然后在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/乙酸乙酯,梯度),得到作为白色固体的[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-乙酸(1.03g,32%)。LCMS(ESI):m/z=322(M-H)-;1H-NMR(DMSO-d6,400MHz)13.19(s,1H),8.22(d,1H,J=16.6Hz),7.74(dd,1H,J=2.3,8.7Hz),7.68(d,1H,J=2.3Hz),7.18(d,1H,J=8.7Hz),6.84(d,1H,J=16.6Hz),4.90(s,2H),1.40(s,9H);13C-NMR(DMSO-d6,100MHz)δ169.3,161.4,149.8,139.0,128.6,128.5,126.4,114.7,113.3,110.7,64.9,34.9,29.0。
实施例62
1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸
在氮气和-80℃(醚/干冰)下,向1-(4-溴苯基)环丙烷甲酸(1.0g,4.15mmol)在无水THF(50ml)中的溶液缓慢加入在甲苯中的1.8M苯基锂(2.77mL,4.98mmol)。在5min后向该混合物加入n-BuLi(2.5M,在己烷中)(2.2mL,5.4mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将二氧化硫流鼓泡通过混合物10min。然后允许反应混合物升温至室温,并在真空中去除溶剂。将亚磺酸盐残留物溶解在水(10ml)、乙酸(5ml)和MeOH(15ml)中,然后添加2-氯丙烯腈(0.54g,6.23mmol)。将得到的混合物在室温搅拌过夜。去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x30ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(1.16mL,8.3mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,然后在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/乙酸乙酯,梯度),得到作为白色固体的1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸(112mg,10%)。LCMS(ESI):m/z=232(M-CO2H)-;1H-NMR(DMSO-d6,400MHz)δ12.59(s,1H),8.24(d,1H,J=16.6Hz),7.83(d,2H,J=8.5Hz),7.66(d,2H,J=8.5Hz),6.91(d,1H,J=16.6Hz),1.51(m,2H),1.22(m,2H)。
实施例63
2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-环己基-乙酰胺
将[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-乙酸(57mg,0.18mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(41.0mg,0.214mmol)、1-羟基苯并三唑(5.1mg,0.038mmol)和环己胺(25uL,0.22mmol)在乙腈(0.70ml)中在室温下搅拌5h,然后过滤,用DMSO(0.3ml)漂洗小瓶,并将滤液通过质谱指导的HPLC进行纯化(25-95%MeCN:水,两者均含有0.1%TFA),得到作为灰白色冻干物的2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-环己基-乙酰胺(27mg,38%)。LCMS(ESI):m/z=405(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.22(d,1H,J=15.6Hz),7.94(d,1H,J=7.8Hz),7.74(dd,1H,J=2.4,7.8Hz),7.67(d,1H,J=2.4Hz),4.67(s,2H),3.60(m,1H),1.6-1.8(m,4H),1.55(m,1H),1.38(s,9H),1.1-1.3(m,5H)。
实施例64
2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-(4-氟-苯甲基)-乙酰胺
将[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-乙酸(104mg,0.322mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(77mg,0.40mmol)、1-羟基苯并三唑(51mg,0.38mmol)和4-氟-苯甲胺(45uL,0.40mmol)在乙腈(2.0ml)中在室温下搅拌1h,然后添加到ISCO预装柱(5g)上并进行层析(ISCO12g,0-20%乙酸乙酯:己烷)。一些洗脱的乙腈带有产物以及一些HOBt。将含有产物的级分浓缩,用MeCN和DCM(各3mL)稀释,并用大孔碳酸酯树脂处理1h。在过滤并浓缩后,将残留物溶解在MeCN中,用水稀释,然后冷冻干燥,得到作为灰白色冻干物的2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-(4-氟-苯甲基)-乙酰胺(64mg,46%)。LCMS(ESI):431(M+H);1H-NMR(DMSO-d6):δ8.63(t,1H,J=5.9Hz),8.23(d,1H,J=15.6Hz),7.74(dd,1H,J=2.4,8.7Hz),7.68(d,1H,J=2.4Hz),7.32(m,2H),7.1-7.2(m,3H),6.84(d,1H,J=15.6Hz),4.79(s,2H),4.33(d,2H,J=5.9Hz),1.38(s,9H)。
实施例65
2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-(3-甲氧基-苯基)-乙酰胺
将[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-乙酸(81mg,0.25mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(58.3mg,0.304mmol)、1-羟基苯并三唑(22mg,0.16mmol)和3-甲氧基苯胺(35uL,0.31mmol)在乙腈(1.0ml)中在室温下搅拌5h,然后过滤,用DMSO(0.3ml)漂洗小瓶,并将滤液通过制备型HPLC进行纯化(25-95%MeCN:水,两者均含有0.1%TFA),得到作为白色冻干物的2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-(3-甲氧基-苯基)-乙酰胺(41mg,38%)。LCMS(ESI):429(M+H);1H-NMR(DMSO-d6):δ10.26(s,1H),8.22(d,1H,J=15.6Hz),7.77(dd,1H,J=2.4,8.6Hz),7.69(d,1H,J=2.4Hz),7.30(m,1H),7.23(m,1H),7.17(d,1H,J=8.8Hz),7.12(m,1H),6.84(d,1H,J=15.6Hz),6.67(dd,1H,J=2.5,8.2Hz),4.95(s,2H),3.73(s,3H),1.42(s,9H)。
实施例66
(E)-3-{3-[1-甲基-1-(5-甲基-苯并唑-2-基)-乙基]-苯磺酰基}-丙烯腈;具有三氟乙酸的化合物
将1-羟基苯并三唑(40.5mg,0.300mmol)、2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(78.5mg,0.281mmol)、2-氨基-4-甲基酚(38.5mg,0.313mmol)合并在乙腈(2.0ml)中并在小瓶中搅拌6h,然后加入乙酸(3.0mL,53mmol),并将混合物在密封小瓶中在90℃下加热4天。将混合物真空浓缩,溶解在DMSO中,并通过质谱指导的制备型HPLC进行纯化(25-75%MeCN:水,二者均含有0.1%TFA),得到作为浅紫色-白色冻干物的(E)-3-{3-[1-甲基-1-(5-甲基-苯并唑-2-基)-乙基]-苯磺酰基}-丙烯腈,具有三氟乙酸的化合物(15mg,11%)。LCMS(ESI):m/z=367(M+H)+;1H-NMR(CD3CN,400MHz)δ7.84(m,1H),7.79(m,1H),7.73(m,1H),7.61(m,1H),7.52(m,1H),7.51(d,1H,J=15.7Hz),7.38(d,1H,J=8.3Hz),7.17(m,1H),6.60(d,1H,J=15.7Hz),2.44(s,3H),1.88(s,6H);13C-NMR(DMSO-d6,100MHz)δ170.3,148.9,148.6,147.2,140.6,137.9,133.9,132.8,130.4,126.8,126.1,124.7,119.6,114.6,112.4,110.2,41.6,27.3,20.9。
实施例67
1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸4-氟-苯甲基酰胺
将1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸(51mg,0.18mmol)、4-氟-苯甲胺(24.2uL,0.213mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(42.3mg,0.221mmol)和1-羟基苯并三唑(29mg,0.21mmol)合并在乙腈(1.0ml)中,并允许反应混合物在室温下搅拌60min。将反应用0.5mL DMSO稀释,过滤,并使用均含有0.1%TFA的25-75%AcN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸4-氟-苯甲基酰胺(49mg;69%)。LCMS(ESI):m/z=385(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.6Hz),7.87(m,2H),7.66(m,3H),7.20(m,2H),7.11(m,2H),6.90(d,1H,J=15.6Hz),4.18(d,2H,J=6.0Hz),1.42(dd,2H,J=4.2,7.0Hz),1.08(dd,2H,J=4.2,7.0Hz).LCMS=385(M+H)。
实施例68
1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸环己基酰胺
将1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸(37mg,0.13mmol)、环己胺(18uL,0.16mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(32mg,0.17mmol)和1-羟基苯并三唑(23mg,0.17mmol)合并在乙腈(1.0ml)中,并允许反应混合物在室温下搅拌60min。将反应用0.3mL DMSO稀释,过滤,并使用均含有0.1%TFA的25-75%MeCN/水的梯度作为洗脱溶剂,通过质谱指导的HPLC进行纯化,得到作为白色泡沫的1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丙烷甲酸环己基酰胺(26mg;54%)。LCMS(ESI):m/z=359(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.6Hz),7.84(m,2H),7.59(m,2H),7.20(d,1H,J=8.1Hz),6.90(d,1H,J=15.6Hz),3.54(m,1H),1.63(m,4H),1.53(m,1H),1.37(dd,2H,J=4.4,7.0Hz),1.05(dd,2H,J=4.4,7.0Hz),1.02(m,1H).LCMS=359(M+H)。
实施例69
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-5-甲基-苯基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(256mg,0.916mmol)、2-氨基-4-甲基酚(0.133g,1.08mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(221mg,1.15mmol)和1-羟基苯并三唑(124mg,0.916mmol)溶解在乙腈(7.0ml)中,并允许反应混合物在室温下搅拌48h。将反应浓缩至约1mL,然后用DMSO稀释,并通过质谱指导的HPLC进行纯化(25-75%MeCN:水,二者均含有0.1%TFA)。分离到作为米色冻干物的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-5-甲基-苯基)-异丁酰胺(78mg;22%)。LCMS(ESI):m/z=385(M+H)+;1H-NMR(DMSO-d6,400MHz)δ9.42(s,1H),8.30(s,1H),8.24(d,1H,J=15.7Hz),7.91(d,2H,J=8.7Hz),7.76(d,2H,J=8.7Hz),7.53(s,1H),6.91(d,1H,J=15.7Hz),6.74(dd,1H,J=2.5,8.1Hz),6.70(d,1H,J=8.1Hz),2.17(s,3H),1.62(s,6H)。
实施例70
(E)-3-(2-叔丁基-喹啉-6-磺酰基)-丙烯腈
a)在室温下,向2-氨基-5-溴-苯甲醛(0.933g,4.66mmol)和3,3-二甲基-2-丁酮(0.700mL,5.60mmol)的混合物加入氢氧化钾(0.322g,5.74mmol)和水(1.3ml)。在5min后,将混合物加热回流3h。将混合物用水(40ml)稀释,然后用DCM萃取(40mL,2X20ml)。将有机萃取物用盐水(20ml)洗涤,在硫酸钠上干燥,过滤并真空浓缩。将残留物纯化(DCM装载在24g装载柱上,然后ISCO40g,0-20%乙酸乙酯:己烷),得到作为黄色油状物的6-溴-2-叔丁基-喹啉(0.97g,64%),其中有少量晶体形成。
b)在氮气和-80℃(醚/干冰)下,向6-溴-2-叔丁基喹啉(1g,3.8mmol)在无水THF(50ml)中的溶液缓慢加入n-BuLi(2.5M,在己烷中)(2mL,4.94mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将二氧化硫流鼓泡通过混合物15min。然后允许反应混合物升温至室温,并在减压下去除溶剂。将亚磺酸盐残留物溶解在水(10ml)、乙酸(5ml)和MeOH(15ml)中,然后添加2-氯丙烯腈(0.54g,6.23mmol)。将得到的混合物在室温搅拌过夜。去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x50ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(1.16mL,8.3mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,然后在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/乙酸乙酯,梯度),得到作为白色固体的(E)-3-(2-叔丁基-喹啉-6-磺酰基)-丙烯腈(0.68g,59%)。LCMS(ESI):m/z=301(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.68(d,1H,J=2.1Hz),8.61(d,1H,J=8.8Hz),8.30(d,1H,J=15.7Hz),8.21(d,1H,J=8.9H),8.07(dd,1H,J=2.2,8.9Hz),7.92(d,1H,J=8.8Hz),6.96(d,1H,J=15.7Hz),1.43(s,9H)。
实施例71
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-苯基-丙-2-炔基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(0.254g,0.909mmol)、3-苯基-丙-2-炔基胺盐酸盐(0.272g,1.62mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(0.225g,1.18mmol)和1-羟基苯并三唑(0.019g,0.14mmol)合并在乙腈(6.0ml)中。在1h后,由于仅有痕量转化成酰胺,因此加入4-甲基吗啉(0.100mL,0.909mmol)。在4h后,将混合物真空浓缩至~1mL,加入DMSO(1ml),并将混合物过滤。通过质谱指导的制备型HPLC纯化滤液(25-75%MeCN:水,二者均含有0.1%TFA),在部分真空蒸发并冷冻干燥后得到2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-苯基-丙-2-炔基)-异丁酰胺(165mg;46%)。LCMS(ESI):m/z=393(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.22(d,1H,J=15.6Hz),8.08(t,1H,J=5.5Hz),7.86(d,2H,J=8.7Hz),7.64(d,2H,J=8.7Hz),7.37(m,5H),6.90(d,1H,J=15.6Hz),4.08(d,2H,J=5.5Hz),1.51(s,6H)。
实施例72
(E)-3-{4-[1-甲基-1-(5-苯基-[1,3,4]二唑-2-基)-乙基]-苯磺酰基}-丙烯腈
a)将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(0.262g,0.938mmol)、苯肼(0.160g,1.17mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(0.232g,1.21mmol)和1-羟基苯并三唑(0.019g,0.14mmol)溶解在乙腈(6.0ml)中,并允许反应混合物在室温下搅拌4h。将混合物倒入乙酸乙酯(60ml)中,用1N HCl(20ml)和盐水(20ml)洗涤,在硫酸钠上干燥,过滤并真空浓缩。将苯甲酸N′-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰基}-肼不经纯化用于下一步骤中。
b)将苯甲酸N′-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰基}-肼(324mg,0.815mmol)溶解在1,4-二烷(12.0ml)中,加入磷酰氯(0.500mL,5.36mmol),并将混合物在90℃加热2h,然后冷却至室温并用乙酸乙酯(50ml)稀释。将混合物用饱和NaHCO3(25ml)和盐水(10ml)洗涤,在硫酸钠上干燥,过滤并真空浓缩。将残留物溶解在DCM中,施加到ISCO柱(5g)上并进行纯化(ISCO24g,0-50%乙酸乙酯:己烷),在将含有产物的级分浓缩后得到泡沫。将该泡沫溶解在MeCN和水中,然后冷冻干燥,得到作为白色固体的(E)-3-{4-[1-甲基-1-(5-苯基-[1,3,4]二唑-2-基)-乙基]-苯磺酰基}-丙烯腈(223mg,72%)。LCMS(ESI):m/z=380(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.22(d,1H,J=15.7Hz),7.97(m,2H),7.90(d,2H,J=8.7Hz),7.70(d,2H,J=8.7Hz),7.55-7.65(m,3H),6.91(d,1H,J=15.7Hz),1.86(s,6H);13C-NMR(DMSO-d6,100MHz)δ170.5,164.5,151.6,149.0,136.2,132.0,129.4,128.6,127.5,126.6,123.3,114.5,112.3,40.2,27.1。
实施例73
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-苯基)-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(0.336g,1.20mmol)、2-氨基酚(0.234g,2.14mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(0.298g,1.56mmol)和1-羟基苯并三唑(0.162g,1.20mmol)溶解在乙腈(11.1ml)中,并允许反应混合物在室温下搅拌20h。将混合物倒入乙酸乙酯(200ml)中,用1N HCl(25ml)和盐水(50ml)洗涤,在硫酸钠上干燥,过滤并真空浓缩。将残留物作为DCM溶液施加到ISCO装载柱(24g)上,并在硅胶上进行纯化(ISCO40g,5-50%乙酸乙酯:己烷),得到作为灰白色固体的2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-苯基)-异丁酰胺(213mg,48%)。LCMS(ESI):m/z=371(M+H)+;1H-NMR(DMSO-d6,400MHz)δ9.70(s,1H),8.32(s,1H),8.24(d,1H,J=15.7Hz),7.91(d,2H,J=8.6Hz),7.77(d,2H,J=8.6Hz),7.70(dd,1H,J=1.5,8.0Hz),6.88-6.96(m,2H),6.82(dd,1H,J=1.5,8.0Hz),6.75(dd,1H,J=1.2Hz,7.5Hz),1.62(s,6H)。
实施例74
1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸
在氮气和-80℃(醚/干冰)下,向1-(4-溴苯基)环丁烷甲酸(5.1g,20mmol)在无水THF(150ml)中的溶液缓慢加入在甲苯中的1.8M苯基锂(13.9mL,25mmol)。在5min后,向该混合物加入n-BuLi(2.5M,在己烷中)(10.4mL,26mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将二氧化硫流鼓泡通过混合物15min。然后允许反应混合物升温至室温,并在真空中去除溶剂。将亚磺酸盐残留物溶解在水(30ml)、乙酸(16ml)和MeOH(40ml)中,然后添加2-氯丙烯腈(2.6g,30mmol)。将得到的混合物在室温搅拌过夜。去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x100ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(5.6mL,40mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,然后在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/乙酸乙酯,梯度),得到作为白色固体的1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸(1.52g,26%)。LCMS(ESI):m/z=246(M-CO2H)+;1H-NMR(DMSO-d6,400MHz)δ12.66(s,1H),8.23(d,1H,J=15.7Hz),7.88(d,2H,J=8.5Hz),7.58(d,2H,J=8.5Hz),6.91(d,1H,J=15.7Hz),2.75(m,2H),2.45(m,2H),2.01(m,1H),1.81(m,1H);13C-NMR(DMSO-d6,100MHz)δ175.5,151.4,149.1,135.5,128.2,127.8,114.6,112.0,52.0,31.8,16.1。
实施例75
1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸苯基酰胺
将1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸(58mg,0.20mmol)、1-羟基苯并三唑(6mg,0.04mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51mg,0.27mmol)和苯胺(21uL,0.23mmol)在乙腈(0.5ml)中,在小瓶中在室温下搅拌1h。将混合物用DMSO(0.2ml)稀释,过滤并通过质谱指导的HPLC进行纯化,得到1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸苯基酰胺(34mg;47%)。LCMS(ESI):m/z=367(M+H)+;1H-NMR(DMSO-d6,400MHz)δ9.55(s,1H),8.20(d,1H,J=15.6Hz),7.91(d,2H,J=8.6Hz),7.77(d,2H,J=8.7Hz),7.58(m,2H),7.27(m,2H),7.02(m,1H),6.90(d,1H,J=15.6Hz),2.90(M,2H),2.53(m,2H),1.86(m,2H);13C-NMR(DMSO-d6,100MHz)δ172.6,151.6,149.1,139.0,135.5,128.5,128.3,127.6,123.5,119.9,114.6,112.0,54.1,32.2,15.7。
实施例76
1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸4-氯-苯甲酰胺
将1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸(62mg,0.21mmol)、1-羟基苯并三唑(6mg,0.04mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(52mg,0.27mmol)和对氯苯甲胺(31uL,0.25mmol)在乙腈(1.0ml)中,在小瓶中在室温下搅拌4h。将混合物真空浓缩,用DMSO(0.6ml)稀释,过滤并通过质谱指导的HPLC进行纯化,得到1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸4-氯-苯甲酰胺(44mg;50%)。LCMS(ESI):m/z=367(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.37(t,1H,J=6.0Hz),8.25(d,1H,J=15.8Hz),7.89(d,2H,J=8.5Hz),7.64(d,2H,J=8.5Hz),7.28(d,2H,J=8.5Hz),7.06(d,2H,J=8.5Hz),6.92(d,1H,J=15.8Hz),4.19(d,2H,J=6.0Hz),2.78(M,2H),2.43(m,2H),1.84(m,2H);13C-NMR(DMSO-d6,100MHz)δ173.8,152.2,149.2,138.7,135.4,131.1,128.5,128.13,128.08,127.5,114.6,112.0,53.3,41.7,32.1,16.0。
实施例77
1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸环己基酰胺
将1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸(58mg,0.20mmol)、1-羟基苯并三唑(6mg,0.04mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(51mg,0.27mmol)和环己胺(26uL,0.23mmol)在乙腈(1.0ml)中,在小瓶中在室温下搅拌。在5h后,将混合物倒入乙酸乙酯中,用1N HCl、盐水洗涤,在硫酸钠上干燥,过滤并浓缩。将残留物纯化,得到1-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-环丁烷甲酸环己基酰胺(32mg;43%)。LCMS(ESI):m/z=373(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.6Hz),7.86(d,2H,J=8.5Hz),7.64(d,2H,J=8.5Hz),7.51(d,1H,J=8.0Hz),6.90(d,1H,J=15.6Hz),3.46(m,1H),2.74(M,2H),2.35(m,2H),1.78(m,2H),1.57(m,5H),1.0-1.2(m,5H)。
实施例78
(E)-3-[4-(1-苯并唑-2-基-1-甲基-乙基)-苯磺酰基]-丙烯腈
在小瓶中,将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-羟基-苯基)-异丁酰胺(99mg,0.27mmol)和甲磺酸(0.50mL,7.7mmol)在1,4-二烷(3.0ml)中在90℃下加热24h。将混合物冷却至室温,在乙酸乙酯(60ml)与饱和碳酸氢钠(60ml)之间分配。在分离后,将水相用乙酸乙酯(30ml)萃取,然后将合并的有机相用盐水(50ml)洗涤,在硫酸钠上干燥,过滤并真空浓缩。将残留物溶解在DCM中并施加到ISCO柱(5g)上,随后通过层析进行纯化(ISCO40g,0-40%乙酸乙酯:己烷),得到作为白色固体的(E)-3-[4-(1-苯并唑-2-基-1-甲基-乙基)-苯磺酰基]-丙烯腈(55%得率)。LCMS(ESI):m/z=353(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.22(d,1H,J=15.6Hz),7.89(d,2H,J=8.7Hz),7.78(m,1H),7.66(m,3H),7.38(m,2H),6.90(d,1H,J=15.6Hz),1.86(s,6H);13C-NMR(DMSO-d6,100MHz)δ170.2,152.3,150.4,149.0,140.4,136.0,128.5,127.6,125.2,124.5,119.8,114.6,112.2,110.9,41.9,27.3。
实施例79
2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-(2-羟基-5-甲基-苯基)-乙酰胺
将[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-乙酸(186mg,0.575mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(138mg,0.719mmol)、1-羟基苯并三唑(85.5mg,0.633mmol)和2-氨基-4-甲基酚(0.142g,1.15mmol)合并在乙腈(6.0ml)中,并在小瓶中搅拌3h。然后将混合物加入到乙酸乙酯(100ml)中,并用1N HCl(15ml)和盐水(20ml)洗涤。将有机相在硫酸钠上干燥,用己烷(20ml)稀释并通过4mL硅胶(己烷床)过滤,用60mL1:1的乙酸乙酯:己烷漂洗。将滤液真空浓缩,溶解在DCM中,施加到ISCO柱(5g)上并进行纯化(ISCO24g,0-50%的乙酸乙酯:己烷),得到2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-(2-羟基-5-甲基-苯基)-乙酰胺(0.195g;79%)。LCMS(ESI):m/z=429(M+H)+;1H-NMR(DMSO-d6,400MHz)δ9.80(s,1H),9.18(s,1H),8.23(d,1H,J=15.6Hz),7.89(s,1H),7.77(dd,1H,J=2.4,8.7Hz),7.71(d,1H,J=2.4Hz),7.25(d,1H,J=8.7Hz),6.84(d,1H,J=15.6Hz),6.75(m,2H),5.00(s,2H),2.19(s,3H),1.44(s,9H);13C-NMR(DMSO-d6,100MHz)δ165.2,161.3,149.7,144.5,139.0,128.8,128.7,127.6,126.5,125.5,124.7,121.1,114.7,114.7,113.7,110.8,67.5,34.9,29.2,20.5。
实施例80
N-丁-3-炔基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺
将2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酸(0.254g,0.909mmol)、丁-3-炔-1-胺盐酸盐(0.171g,1.62mmol)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(0.225g,1.18mmol)、4-甲基吗啉(0.100mL,0.909mmol)和1-羟基苯并三唑(0.019g,0.14mmol)合并在乙腈(6.0ml)中。在45m后,将混合物真空浓缩至~1mL,加入DMSO(1ml)并将混合物过滤。通过质谱指导的HPLC对滤液进行纯化(25-75%MeCN:水,0.1%TFA),得到N-丁-3-炔基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺(48mg,16%)。LCMS(ESI):m/z=331(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.7Hz),7.85(d,2H,J=8.7Hz),7.66(t,1H,J=5.7Hz),7.62(d,2H,J=8.7Hz),6.90(d,1H,J=15.7Hz),3.16(m,2H),2.79(t,1H,J=2.7Hz),2.28(dt,2H,J=2.7,7.1Hz),1.47(s,6H)。
实施例81
(E)-3-[3-叔丁基-4-(5-甲基-苯并唑-2-基甲氧基)-苯磺酰基]-丙烯腈
将2-[2-叔丁基-4-((E)-2-氰基-乙烯磺酰基)-苯氧基]-N-(2-羟基-5-甲基-苯基)-乙酰胺(0.178g,0.415mmol)在1,4-二烷(6.0ml)中与甲磺酸(1.0mL,15mmol)在90℃下加热8h。将混合物冷却至室温,搅拌48h,然后用附加的甲磺酸(1ml)处理,并在90℃下加热3h。将混合物冷却并加入到乙酸乙酯(80ml)和饱和NaHCO3(40ml)中。进行层分离,并将有机相用盐水(20ml)洗涤,在硫酸钠上干燥,过滤并真空浓缩。将残留物溶解在DCM中,施加到ISCO柱(5g)上并进行纯化(ISCO40g,0-40%的乙酸乙酯:己烷),得到(E)-3-[3-叔丁基-4-(5-甲基-苯并唑-2-基甲氧基)-苯磺酰基]-丙烯腈(86mg;50%)。LCMS(ESI):m/z=411(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.7Hz),7.80(dd,1H,J=2.4,8.7Hz),7.72(d,1H,J=2.4Hz),7.64(d,1H,J=8.4Hz),7.61(m,1H),7.46(d,1H,J=8.7Hz),7.26(dd,1H,J=1.2,8.4Hz),6.85(d,1H,J=15.7Hz),5.67(s,2H),2.43(s,3H),1.39(s,9H)。
实施例82
4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸
在氮气和-80℃(醚/干冰)下,向1-(4-溴苯基)四氢-2H-吡喃-4-甲酸(2.85g,10mmol)在无水THF(100ml)中的溶液缓慢加入在甲苯中的1.8M苯基锂(7mL,12.5mmol)。在5min后,向该混合物加入n-BuLi(2.5M,在己烷中)(5.2mL,13mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将二氧化硫流鼓泡通过混合物15min。然后允许反应混合物升温至室温,并在真空中去除溶剂。将亚磺酸盐残留物溶解在水(15ml)、乙酸(8ml)和MeOH(20ml)中,然后添加2-氯丙烯腈(1.3g,15mmol)。将得到的混合物在室温搅拌过夜。去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x50ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(2.8mL,20mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/乙酸乙酯,梯度),得到作为白色固体的4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸(0.87g,27%)。LCMS(ESI):m/z=276(M-CO2H)+;1H-NMR(DMSO-d6,400MHz)δ13.00(s,1H),8.23(d,1H,J=15.7Hz),7.91(d,2H,J=8.7Hz),7.74(d,2H,J=8.7Hz),6.92(d,1H,J=15.7Hz),3.82(m,2H),3.48(m,2H),2.40(m,2H),1.88(m,2H);13C-NMR(DMSO-d6,100MHz)δ174.3,150.2,149.0,136.1,128.4,127.6,114.6,112.2,64.6,48.5,33.7。
实施例83
4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸环己基酰胺
将4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸(61mg,0.19mmol)、环己胺(33uL,0.29mmol)、1-羟基苯并三唑(25.6mg,0.190mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(46mg,0.24mmol)合并在乙腈(6.0ml)中并在室温下搅拌。在4h后,将混合物真空浓缩,溶解在DMSO中并通过质谱指导的HPLC进行纯化(25-75%MeCN:水,0.1%TFA),得到4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸环己基酰胺(39mg,51%)。LCMS(ESI):m/z=403(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.23(d,1H,J=15.6Hz),7.87(d,2H,J=8.6Hz),7.66(d,2H,J=8.6Hz),7.45(d,1H,8.0Hz),6.91(d,1H,J=15.7Hz),3.77(m,2H),3.56(m,1H),3.44(m,2H),1.83(m,2H),1.62(m,6H),1.12(m,6H)。
实施例84
4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸苯基酰胺
将4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸(67mg,0.21mmol)、苯胺(29uL,0.32mmol)、1-羟基苯并三唑(7.0mg,0.052mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(50.0mg,0.261mmol)合并在乙腈(3.00ml)中并在室温下搅拌。在24h后,将混合物真空浓缩,溶解在DMSO中并通过质谱指导的HPLC进行纯化(25-75%MeCN:水,0.1%TFA),得到4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸苯基酰胺(23mg,28%)。LCMS(ESI):m/z=397(M+H)+;1H-NMR(DMSO-d6,400MHz)δ9.38(s,1H),8.22(d,1H,J=15.7Hz),7.93(d,2H,J=8.7Hz),7.76(d,2H,J=8.7Hz),7.54(m,2H),7.28(m,2H),7.06(m,1H),6.91(d,1H,J=15.7Hz),3.81(m,2H),3.55(m,2H),2.60(m,2H),2.00(m,2H)。
实施例85
4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸4-氯-苯甲基酰胺
将4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸(72mg,0.22mmol)、对氯苯甲胺(45uL,0.37mmol)、1-羟基苯并三唑(9.0mg,0.067mmol)和N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(57mg,0.30mmol)合并在乙腈(6.0mL,110mmol)中并在室温下搅拌。在2h后,将混合物真空浓缩,溶解在DMSO中并通过质谱指导的HPLC进行纯化(25-75%MeCN:水,0.1%TFA),得到4-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-四氢吡喃-4-甲酸4-氯-苯甲基酰胺(32mg,32%)。LCMS(ESI):m/z=445(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.36(t,1H,J=5.9Hz),8.26(d,1H,J=15.6Hz),7.90(d,2H,J=8.6Hz),7.69(d,2H,J=8.6Hz),7.27(d,2H,J=8.4Hz),7.03(d,2H,J=8.4Hz),6.93(d,1H,J=15.6Hz),4.21(d,2H,J=5.9Hz),3.76(m,2H),3.46(m,2H),2.52(m,2H),1.90(m,2H)。
实施例86
2-[5-((E)-2-氰基-乙烯磺酰基)-吡啶-2-基]-N-环己基-异丁酰胺
a)在室温和氮气下,向2-(5-溴吡啶-2-基)-2-甲基丙酸(1.22g,5mmol)在25mLDMF中的悬液加入TEA(2.1mL,15mmol)和环己胺(0.86mL,7.5mmol),然后加入丙基膦酸酐(在DMF中的50%溶液)(8.9mL,15mmol)。将得到的混合物在室温下搅拌2h。将混合物真空浓缩,溶解在DCM(100mL)和盐水(50ml)中,分离,并将有机相真空浓缩。将粗产物通过快速柱层析进行纯化(硅胶,二氯甲烷/丙酮,梯度),得到作为白色固体的2-(5-溴-吡啶-2-基)-N-环己基-异丁酰胺(0.83g,51%)。
b)在氮气和-80℃(醚/干冰)下,向2-(5-溴-吡啶-2-基)-N-环己基-异丁酰胺(0.8g,3.3mmol)在无水THF(100ml)中的溶液缓慢加入在甲苯中的1.8M苯基锂(2.3mL,4.1mmol)。在5min后,向该混合物加入n-BuLi(2.5M,在己烷中)(1.7mL,4.3mmol)。缓慢形成云雾状悬液。在添加BuLi后20分钟,将二氧化硫流鼓泡通过混合物10min。然后允许反应混合物升温至室温,并在真空中去除溶剂。将亚磺酸盐残留物溶解在水(10ml)、乙酸(5ml)和MeOH(15ml)中,然后添加2-氯丙烯腈(0.43g,5.0mmol)。将得到的混合物在室温搅拌过夜。去除有机溶剂,并将残留物用20ml水稀释。使用饱和K2HPO4水溶液将溶液调整到pH5-6,然后用二氯甲烷萃取(2x30ml)并在MgSO4上干燥。在过滤后,将滤液与三乙胺(0.92mL,6.6mmol)搅拌1h。将溶液用10%柠檬酸水溶液和盐水洗涤,然后在MgSO4上干燥。终产物通过快速柱层析进行纯化(硅胶,二氯甲烷/乙酸乙酯,梯度),得到作为白色固体的2-[5-((E)-2-氰基-乙烯磺酰基)-吡啶-2-基]-N-环己基-异丁酰胺(182mg,15%)。LCMS(ESI):m/z=362(M+H)+;1H-NMR(DMSO-d6,400MHz)δ8.97(dd,1H,J=0.6,2.4Hz),8.28(d,1H,J=15.7Hz),8.24(dd,1H,J=2.4,8.5Hz),7.62(dd,1H,J=0.6,8.5Hz),7.22(d,1H,J=8.0Hz),6.97(d,1H,J=15.7Hz),3.55(m,1H),1.66(m,4H),1.53(m,1H),1.49(s,6H),1.0-1.2(m,5H)。
细胞培养物和转染。BxPc-3和Su.86.86胰腺癌和HT-29结肠癌和A2780卵巢癌细胞系购自ATCC,并被培养在增补有10%胎牛血清、谷氨酰胺、青霉素和链霉素的DMEM中。所有细胞在加湿培养箱中在37℃下和5%CO2气氛中进行培养。将癌细胞系用含有组成型荧光素酶报告基因pLuc-puro的反转录病毒转导,并在含有G418的培养基中进行选择。pcDNA3载体中全长人类c-FLIP构建物的瞬时转染按照以前的描述进行。Scaife等,CancerResearch2002,62:6870-78。
细胞存活和粘附测定法。将用萤火虫荧光素酶构建物稳定转染的胰腺癌细胞培养物(BxPc-3和Su.86.86)和结肠癌(HT-29)和卵巢癌(A2780)细胞,用胰蛋白酶-PBS短暂悬浮。将105个细胞铺在96孔板中人类间皮细胞的合生单层上,同时加入各种浓度的本发明化合物或DMSO5小时。用100μl/孔的阻断缓冲液(1%BSA,在PBS中)洗涤两次并用冰冷的PBS再次洗涤两次,仔细地将未粘附的细胞从孔中洗掉。粘附和存活的细胞如下所述在光度计中通过荧光素酶活性进行检测。将细胞在0.1%TritonX-100、25mM Gly-Gly(7.8)、MgSO4、4mMEGTA和1mM DTT中裂解。使用裂解缓冲液将总蛋白浓度归一化。向96孔微量滴定板的每个孔添加50μl细胞裂解物。每个孔加入50μl荧光素底物(Promega),然后在光度计中测定光输出。表I中示出了浓度为10μM的本发明化合物的结果。
无胸腺小鼠癌症研究。动物研究得到犹他大学(University of Utah)和夏威夷大学动物护理和使用学术委员会(University of Hawaii Institutional Animal Care andUse Committee)批准并按照其要求执行。将5周龄雌性无胸腺nu/nu小鼠随机分配成用本发明化合物(5mg/kg)或等体积介质(DMSO)进行腹膜内(IP)处理,并在4小时后IP注射106个悬浮的Su.86.86、BxPc-3或HT-29细胞或FLIP–high(CD133+)。每3天小鼠继续IP接受DMSO或本发明的化合物(5mg/kg),共8-9天。就在生物发光成像之前,IP注射10μl/gm的萤火虫D-荧光素(15mg/ml储液)(Xenogen)、200μl(储液=100mg/ml)盐酸开他敏和20μl甲苯噻嗪(储液=100mg/ml)在pH7.4PBS中的混合物,以便麻醉小鼠并为表达荧光素酶的癌细胞提供底物。将小鼠安乐死并手术暴露出腹腔。使用Xenogen生物发光成像系统对腹膜肿瘤植入物进行成像。使用解剖变焦显微镜和组织病理学来验证每只小鼠的肿瘤植入物。
参考文献
Burns,T.F.和El-Deiry,W.S.(2001).在TRAIL敏感性结肠癌细胞系SW480中使用遗传方法鉴定TRAIL诱导的死亡(ITID)的抑制剂(Identification of inhibitors ofTRAIL-induced death(ITIDs)in the TRAIL-sensitive colon carcinoma cell lineSW480using a genetic approach),J Biol Chem276,37879-37886。
De Vita,V.T.,Hellman,S.和Rosenberg,S.A.(2001).《癌症:肿瘤学原理与实践》(Cancer:Principles and Practice of Oncology),第5版,(Philadelphia:LippincottWilliams and Wilkins)。
Elnemr,A.,Ohta,T.,Yachie,A.,Kayahara,M.,Kitagawa,H.,Fujimura,T.,Ninomiya,I.,Fushida,S.,Nishimura,G.I.,Shimizu,K.和Miwa,K.(2001).人类胰腺癌细胞在Fas信号转导途径中的数种水平上使Fas受体功能失效(Human pancreatic cancercells disable function of Fas receptors at several levels in Fas signaltransduction pathway),Int J Oncol18,311-316。
Fujiwara,K.(2000).卵巢癌管控中的腹膜内化疗和腹膜内清洗液细胞学(Intraperitoneal chemotherapy and intraperitoneal washing cytology inmanagement of ovarian cancer),Gan To Kagaku Ryoho27Suppl2,354-358。
Johnstone,P.A和Sindelar,W.F.(1993).使用手术和辅助性放疗的胰腺腺癌权威疗法后疾病复发的模式:临床试验的关联性(Patterns of disease recurrencefollowing definitive therapy of adenocarcinoma of the pancreas using surgeryand adjuvant radiotherapy:correlations of a clinical trial),Int J RadiatOncol Biol Phys27,831-834。
Kanellos,I.,Demetriades,H.,Zintzaras,E.,Mandrali,A.,Mantzoros,I.和Betsis,D.(2003).阳性腹膜细胞学在结肠直肠癌中的发生率和预后价值(Incidence andprognostic value of positive peritoneal cytology in colorectal cancer),DisColon Rectum46,535-539。
Nakatsuka,A.,Yamaguchi,K.,Shimizu,S.,Yokohata,K.,Morisaki,T.,Chijiiwa,K.和Tanaka,M.(1999).胰腺癌患者中的阳性清洗液细胞学指示了胰腺切除术的禁忌症(Positive washing cytology in patients with pancreatic cancer indicatesa contraindication of pancreatectomy),Int J Surg Investig1,311-317。
Santala,M.,Talvensaari-Mattila,A.和Kauppila,A.(2003).腹膜细胞学和手术前血清CA125水平是晚期子宫内膜癌中总体生存率的重要预后指示物(Peritonealcytology and preoperative serum CA125level are important prognosticindicators of overall survival in advanced endometrial cancer),AnticancerRes23,3097-3103。
Terauchi,F.,Moritake,T.,Yamamoto,Y.和Ogura,H.(2002).使用紫杉醇和腹膜内顺铂的组合化学疗法用于在腹膜和横膈膜中具有散播病变的卵巢癌(Combinationchemotherapy with paclitaxel and intraperitoneal cisplatin for ovarian cancerwith disseminated lesions in the peritoneum and the diaphragm),Int J ClinOncol7,356-360。
Yachida,S.,Fukushima,N.,Sakamoto,M.,Matsuno,Y.,Kosuge,T.和Hirohashi,S.(2002).腹膜清洗液细胞学在具有潜在可切除胰腺癌的患者中的隐含涵义(Implications of peritoneal washing cytology in patients with potentiallyresectable pancreatic cancer),Br J Surg89,573-578。
Yu,W.,Whang,I.,Suh,I.,Averbach,A.,Chang,D.和Sugarbaker,P.H.(1998).作为可切除胃癌的辅助手段的早期手术后腹膜内化疗的前瞻性随机试验(Prospectiverandomized trial of early postoperative intraperitoneal chemotherapy as anadjuvant to resectable gastric cancer),Ann Surg228,347-354。
Zhang,L.和Fang,B.(2005).对癌症中TRAIL诱导的凋亡的耐受性机制(Mechanisms of resistance to TRAIL-induced apoptosis in cancer),Cancer GeneTher12,228-237。
Claims (6)
1.式I的化合物
或其药学可接受的盐形式,
其中A在苯环的3-位或4-位处;以及
A是
R1和R2各自独立地是C1-10烷基;
R3是-NR4R5;以及
R4和R5各自独立地是H,C1-10烷基,被苯基或C3-6环烷基取代的C1-10烷基,C3-6环烷基,或苯基。
2.化合物,其是:
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-苯基-异丁酰胺;
N-苯甲基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-异丁基-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环丙基甲基-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环己基-异丁酰胺;
N-(4-氯-苯甲基)-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-噻吩-2-基甲基-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-1-苯基-乙基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((R)-1-苯基-乙基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-异丁酰胺;
(E)-3-{4-[2-(3,4-二氢-1H-异喹啉-2-基)-1,1-二甲基-2-氧代-乙基]-苯磺酰基}-丙烯腈;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-吡唑-1-基-苯甲基)-异丁酰胺;
N-苯甲基-2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-甲基-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-甲氧基-苯基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-苯乙基-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯基)-异丁酰胺;
(E)-3-[4-(1,1-二甲基-2-氧代-2-哌啶-1-基-乙基)-苯磺酰基]-丙烯腈;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-2-羟基-1-苯基-乙基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-((S)-2-氧代-氮杂环庚烷-3-基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-[4-(2-甲氧基-乙氧基甲基)-苯基]-异丁酰胺;
(2-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-乙基)-氨基甲酸叔丁基酯;
(6-{2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-2-甲基-丙酰氨基}-己基)-氨基甲酸叔丁基酯;
2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-环己基-异丁酰胺;
2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯基)-异丁酰胺;
2-[3-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-氟-苯甲基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(4-氟-苯甲基)-N-甲基-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-[3-(2-甲氧基-乙氧基)-苯基]-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(3-甲氧基-苯甲基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-甲氧基-苯甲基)-异丁酰胺;
2-[4-((E)-2-氰基-乙烯磺酰基)-苯基]-N-(2-甲氧基-苯甲基)-N-甲基-异丁酰胺;
(E)-3-{4-[1-甲基-1-(5-苯基氨基-[1,3,4]恶二唑-2-基)-乙基]-苯磺酰基}-丙烯腈;
(E)-3-{4-[1-甲基-1-(5-甲基-苯并恶唑-2-基)-乙基]-苯磺酰基}-丙烯腈;
(E)-3-{4-[1-甲基-1-(5-甲基-恶唑-2-基)-乙基]-苯磺酰基}-丙烯腈;
(E)-3-{4-[1-(5-环己基-[1,3,4]恶二唑-2-基)-1-甲基-乙基]-苯磺酰基}-丙烯腈;或
其药学可接受的盐形式。
3.药物组合物,其包含权利要求1或2的化合物或其药学可接受的盐,以及药学可接受的载体或稀释剂。
4.权利要求1或2的化合物或其药学可接受的盐在制备用于在已进行腹内癌移除的患者中治疗腹膜癌转移或降低腹膜癌转移的风险的药物中的应用。
5.权利要求3的药物组合物在制备用于在已进行腹内癌移除的患者中治疗腹膜癌转移或降低腹膜癌转移的风险的药物中的应用。
6.权利要求4或5的应用,其中所述腹内癌位于所述患者的结肠处或附近、卵巢处或附近、直肠处或附近、胃处或附近或者胰腺处或附近。
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AU2012220601B2 (en) | 2017-03-09 |
IL227703A (en) | 2017-04-30 |
JP2014513677A (ja) | 2014-06-05 |
TW201309634A (zh) | 2013-03-01 |
CN103476752A (zh) | 2013-12-25 |
CA2826651A1 (en) | 2012-08-30 |
US9475766B2 (en) | 2016-10-25 |
WO2012116151A3 (en) | 2013-01-03 |
US20170029367A1 (en) | 2017-02-02 |
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