CN101472914B - C-fms激酶抑制剂 - Google Patents
C-fms激酶抑制剂 Download PDFInfo
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- CN101472914B CN101472914B CN200780023190.7A CN200780023190A CN101472914B CN 101472914 B CN101472914 B CN 101472914B CN 200780023190 A CN200780023190 A CN 200780023190A CN 101472914 B CN101472914 B CN 101472914B
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- compound
- alkyl
- phenyl
- thiazolinyl
- imidazoles
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明涉及式I化合物及其溶剂合物、水合物、互变异构体和药学上可接受的盐:其中Z、X、J、R2和W在说明书中阐明,该化合物抑制蛋白酪氨酸激酶,尤其c-fms激酶。还提供了用式I化合物治疗以下疾病的方法:自身免疫性疾病;和含炎性成分的疾病;卵巢癌、子宫癌、乳腺癌、***癌、肺癌、结肠癌、胃癌、毛细胞白血病的转移;和疼痛,这些疼痛包括由肿瘤转移或骨关节炎造成的骨骼疼痛,或内脏、炎性和神经原疼痛;和骨质疏松症、佩吉特病和其中由骨吸收介导发病的其它疾病,这些疾病包括类风湿性关节炎和其它形式的炎性关节炎、骨关节炎、修复术失败、溶骨肉瘤、骨髓瘤和转移至骨的肿瘤。
Description
相关申请交叉参考
本申请要求2006年4月20日提交的美国专利临时申请序号60/793,667的优先权,其内容通过引用整体结合到本文中。
发明背景
本发明涉及新的具有蛋白酪氨酸激酶抑制剂功能的化合物。更尤其是,本发明涉及新的具有c-fms激酶抑制剂功能的化合物。
蛋白激酶是用作信号转导途径的关键成分的酶,它们是使5’-三磷酸腺苷(ATP)的末端磷酸酯转运至蛋白的酪氨酸、丝氨酸和苏氨酸残基中羟基的催化剂。因此,蛋白激酶抑制剂和底物是评价蛋白激酶激活的生理结果的有价值的工具。已证实正常或突变蛋白激酶在哺乳动物中过度表达或不适当表达对多种疾病的发生有重要作用,这些疾病包括癌症和糖尿病。
蛋白激酶可分为两类:可优先将酪氨酸残基磷酸化的那些激酶(蛋白酪氨酸激酶)和可优先将丝氨酸和/或苏氨酸残基磷酸化的那些激酶(蛋白丝氨酸/苏氨酸激酶)。蛋白酪氨酸激酶具有从激活细胞生长和分化到抑制细胞增殖的多种功能。它们可分为受体蛋白酪氨酸激酶或细胞内蛋白酪氨酸激酶。受体蛋白酪氨酸激酶分布在20个亚族中,它们具有固有酪氨酸激酶活性的细胞外配体结合域和细胞内催化域。
表皮生长因子(“EGF”)家族中的受体酪氨酸激酶包括HER-1、HER-2/neu和HER-3受体,它们含有细胞外结合域、跨膜域和细胞内胞质催化域。受体结合导致多个依赖细胞内酪氨酸激酶的磷酸化过程起动,最终导致致癌基因转录。乳腺癌、结肠直肠癌和***癌与该受体家族有关。
胰岛素受体(“IR”)和***I受体(“IGF-1R”)在结构和功能上相关,但具有不同生物作用。IGF-1R过度表达与乳腺癌有关。
血小板衍生生长因子(“PDGF”)受体介导细胞反应,这些反应包括增殖、迁移和存活,血小板衍生生长因子包括PDGFR、干细胞因子受体(c-kit)和c-fms。这些受体与疾病例如动脉粥样硬化、纤维变性和增殖性玻璃体视网膜病有关。
成纤维细胞生长因子(“FGR”)受体由4种受体组成,它们负责血管产生、四肢生长和无数类型细胞的生长和分化。
血管内皮生长因子(“VEGF”)是内皮细胞的活性***原,包括卵巢癌在内的多种肿瘤可增加该因子的量。VEGF的已知受体被命名为VEGFR-1(Flt-1)、VEGFR-2(KDR)、VEGFR-3(Flt-4)。已在血管内皮和造血细胞中,鉴定出tie-1和tie-2激酶的相关组受体。VEGF受体与血管发生和血管生成有关。
细胞内蛋白酪氨酸激酶又称为非受体蛋白酪氨酸激酶。已鉴定的此类激酶超过24种,它们分为11亚族。丝氨酸/苏氨酸蛋白激酶和细胞蛋白酪氨酸激酶一样,它们主要是细胞内激酶。
糖尿病、血管发生、银屑病、再狭窄、眼病、精神***症、类风湿性关节炎、心血管病和癌症是病症的示例,它们与异常蛋白酪氨酸激酶活性有关。因此,存在对选择性和活性小分子蛋白酪氨酸激酶抑制剂的需求。美国专利6,383,790;6,346,625;6,235,746;6,100,254号和PCT国际申请WO 01/47897、WO 00/27820和WO 02/068406是合成此类抑制剂最新尝试的代表文献。
发明概述
通过提供活性c-fms激酶抑制剂,本发明解决了对选择性和活性蛋白酪氨酸激酶抑制剂的当前需求。本发明涉及新的式I化合物或其溶剂合物、水合物、互变异构体或药学上可接受的盐:
其中:
W为
其中各R4独立为H、F、Cl、Br、I、OH、OCH3、OCH2CH3、SC(1-4)烷基、SOC(1-4)烷基、SO2C(1-4)烷基、-C(1-3)烷基、CO2Rd、CONReRf、C≡CRg或CN;
其中Rd为H或-C(1-3)烷基;
Re为H或-C(1-3)烷基;
Rf为H或-C(1-3)烷基;且
Rg为H、-CH2OH或-CH2CH2OH;
R2为环烷基、螺环取代的环烯基、杂环基、螺环取代的哌啶基、噻吩基、二氢磺酰基吡喃基(dihydrosulfonopyranyl)、苯基、呋喃基、四氢吡啶基或二氢吡喃基,其中任何基团可独立被一个或两个各以下基团取代:氯、氟、羟基、C(1-3)烷基和C(1-4)烷基;
Z为H、F或CH3;
J为CH或N;
X为
其中R1为-C(1-4)烷基、-ORa、-CN、-NA1A2、-SO2CH3、-COORa、-CO2CH3、-CH2-NA1A2、-CONA1A2、-CH2ORa、-OC(1-4)烷基ORa、-NHCH2CH2CO2Ra、-NHCH2CH2ORa、-NRaCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2Ra、-CH2CO2Ra、-CH2CH2SO2C(1-4)烷基、-SO2CH2CH2NA1A2、-SOCH2CH2NA1A2、-SCH2CH2NA1A2、-NHSO2CH2CH2NA1A2、苯基、咪唑基、噻唑基、4H-[1,2,4]噁二唑-5-酮基、4H-吡咯并[2,3-b]吡嗪基、吡啶基、[1,3,4]噁二唑基、4H-[1,2,4]***基、四唑基、吡唑基、[1,3,5]三嗪基和[1,3,4]噻二唑基;
Rz和Ry独立为H或-C(1-4)烷基,其中两个Rz可具有顺式或反式立体化学;或者两个顺式关系的Rz可连接在一起形成-(CH2)n-,其中n为2或3;
R3为H、C(1-4)烷基、C(1-3)烷基-CF3、CH2CH2NH2、CH2CH2ORa、-COCH3、CONH2或CO2Ra;
A1为H、-C(1-4)烷基或CH2CH2ORa;
A2为H、-C(1-4)烷基、CORa、CH2CON(CH3)2、-CH2CH2ORa、-CH2CH2SC(1-4)烷基、-CH2CH2SOC(1-4)烷基或-CH2CH2SO2C(1-4)烷基;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
其中Ra为H或C(1-4)烷基;
Raa为H或C(1-4)烷基;
Rbb为H、-C(1-4)烷基、-CH2CH2OCH2CH2OCH3、-CH2CO2H、-C(O)C(1-4)烷基或-CH2C(O)C(1-4)烷基;
在此和本申请全文中,当变量例如Ra在式I实施方案中出现次数大于一次时,每一个这种取代独立定义。在此和本申请全文中,术语“Me”、“Et”、“Pr”和“Bu”分别指甲基、乙基、丙基和丁基。
发明详述
本发明涉及新的式I化合物或其溶剂合物、水合物、互变异构体或药学上可接受的盐:
其中:
W为
其中各R4独立为H、F、Cl、Br、I、OH、OCH3、OCH2CH3、SC(1-4)烷基、SOC(1-4)烷基、SO2C(1-4)烷基、-C(1-3)烷基、CO2Rd、CONReRf、C≡CRg或CN;
其中Rd为H或-C(1-3)烷基;
Re为H或-C(1-3)烷基;
Rf为H或-C(1-3)烷基;且
Rg为H、-CH2OH或-CH2CH2OH;
R2为环烷基(包括环己烯基和环庚烯基)、螺环取代的环烯基(包括螺[2.5]辛-5-烯基、螺[3.5]壬-6-烯基、螺[4.5]癸-7-烯基和螺[5.5]十一碳-2-烯基)杂环基(包括哌啶基)、螺环取代的哌啶基(包括3-氮杂-螺[5.5]十一烷基和8-氮杂-螺[4.5]癸烷基)、噻吩基、二氢磺酰基吡喃基、苯基、呋喃基、四氢吡啶基或二氢吡喃基,其中任何基团可独立被一个或两个各以下基团取代:氯、氟、羟基、C(1-3)烷基和C(1-4)烷基(所述取代的环烷基包括4,4-二甲基环己烯基、4,4-二乙基环己烯基、4-甲基环己烯基、4-乙基环己烯基、4-正丙基环己烯基、4-异丙基环己烯基和4-叔丁基环己烯基;所述取代的哌啶基包括4-甲基哌啶基、4-乙基哌啶基、4-(1’羟基乙-2’基)哌啶基和4,4二甲基哌啶基);
Z为H、F或CH3;
J为CH或N;
X为
其中R1为-C(1-4)烷基、-ORa、-CN、-NA1A2、-SO2CH3、-COORa、-CO2CH3、-CH2-NA1A2、-CONA1A2、-CH2ORa、-OC(1-4)烷基ORa、-NHCH2CH2CO2Ra、-NHCH2CH2ORa、-NRaCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2Ra、-CH2CO2Ra、-CH2CH2SO2C(1-4)烷基、-SO2CH2CH2NA1A2、-SOCH2CH2NA1A2、-SCH2CH2NA1A2、-NHSO2CH2CH2NA1A2、苯基、咪唑基、噻唑基、4H-[1,2,4]噁二唑-5-酮基、4H-吡咯并[2,3-b]吡嗪基、吡啶基、[1,3,4]噁二唑基、4H-[1,2,4]***基、四唑基、吡唑基、[1,3,5]三嗪基和[1,3,4]噻二唑基;
Rz和Ry独立为H或-C(1-4)烷基,其中两个Rz可具有顺式或反式立体化学,或者具有顺式关系的两个Rz可连接在一起形成-(CH2)n-,其中n为2或3;
R3为H、C(1-4)烷基、C(1-3)烷基-CF3(包括-CH2CF3)、CH2CH2NH2、CH2CH2ORa、-COCH3、CONH2或CO2Ra;
A1为H、-C(1-4)烷基或CH2CH2ORa;
A2为H、-C(1-4)烷基、CORa、CH2CON(CH3)2、-CH2CH2ORa(包括-CH2CH2OCH3)、-CH2CH2SC(1-4)烷基(包括-CH2CH2SCH3)、-CH2CH2SOC(1-4)烷基(包括-CH2CH2SOCH3)或-CH2CH2SO2C(1-4)烷基(包括-CH2CH2SO2CH3);
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
其中Ra为H或C(1-4)烷基;
Raa为H或C(1-4)烷基;
Rbb为H、-C(1-4)烷基、-CH2CH2OCH2CH2OCH3、-CH2CO2H、-C(O)C(1-4)烷基或-CH2C(O)C(1-4)烷基。
在优选的本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COORa、-CO2CH3、-CH2-NA1A2、-CONA1A2、-CH2ORa、-NHCH2CH2CO2Ra、-NHCH2CH2ORa、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2Ra或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
Ra为H或-C(1-4)烷基;
Raa为H或-C(1-4)烷基;
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-COCH3、-CH2CF3、-CH3、-CO2CH3、-CONH2或-CO2H。
在另一个本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COOH、-CO2CH3、-CH2-NA1A2、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2CO2CH3、-NHCH2CH2OCH3、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2H或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-COCH3、-CH2CF3、-CH3、-CO2CH3、-CONH2或-CO2H。
在另一个本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COOH、-CO2CH3、-CH2-NA1A2、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2CO2CH3、-NHCH2CH2OCH3、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2H或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮连接一起形成杂环,所述杂环选自以下杂环:
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-COCH3、-CH2CF3、-CH3、-CO2CH3、-CONH2或-CO2H。
在另一个本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2 is
Z为H;
J为CH或N;
X为
其中R1为-OH、-NH2、-N(CH3)2、-SO2CH3、-COOH、-CO2CH3、-CH2-吗啉基、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2OCH3、-OCH2CO2H、吗啉基、哌嗪基、N-甲基哌嗪基、哌嗪基-CH2CO2H或四唑基;
Rz为H或-CH3;
R3为-COCH3、-CH2CF3或-CO2H。
在另一个本发明实施方案中:
W为
其中各R4独立为H、F、Cl、Br、I、OH、OCH3、OCH2CH3、SC(1-4)烷基、SOC(1-4)烷基、SO2C(1-4)烷基、-C(1-3)烷基、CO2Rd、CONReRf、C≡CRg或CN;
其中Rd为H或-C(1-3)烷基;
Re为H或-C(1-3)烷基;
Rf为H或-C(1-3)烷基;且
Rg为H、-CH2OH或-CH2CH2OH;
R2为环烷基(包括环己烯基和环庚烯基)、螺环取代的环烯基(包括螺[2.5]辛-5-烯基、螺[3.5]壬-6-烯基、螺[4.5]癸-7-烯基和螺[5.5]十一碳-2-烯基)杂环基(包括哌啶基)、螺环取代的哌啶基(包括3-氮杂-螺[5.5]十一烷基和8-氮杂-螺[4.5]癸烷基)、噻吩基、二氢磺酰基吡喃基、苯基、呋喃基、四氢吡啶基或二氢吡喃基,其中任何基团可独立被一个或两个各以下基团取代:氯、氟、羟基、C(1-3)烷基和C(1-4)烷基(所述取代的环烷基包括4,4-二甲基环己烯基、4,4-二乙基环己烯基、4-甲基环己烯基、4-乙基环己烯基、4-正丙基环己烯基、4-异丙基环己烯基和4-叔丁基环己烯基;所述取代的哌啶基包括4-甲基哌啶基、4-乙基哌啶基、4-(1’羟基乙-2’基)哌啶基和4,4二甲基哌啶基);
Z为H、F或CH3;
J为CH或N;
X为
其中R1为-C(1-4)烷基、-ORa、-CN、-NA1A2、-SO2CH3、-COORa、-CO2CH3、-CH2-NA1A2、-CONA1A2、-CH2ORa、-OC(1-4)烷基ORa、-NHCH2CH2CO2Ra、-NHCH2CH2ORa、-NRaCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2Ra、-CH2CO2Ra、-CH2CH2SO2C(1-4)烷基、-SO2CH2CH2NA1A2、-SOCH2CH2NA1A2、-SCH2CH2NA1A2、-NHSO2CH2CH2NA1A2、苯基、咪唑基、噻唑基、4H-[1,2,4]噁二唑-5-酮基、4H-吡咯并[2,3-b]吡嗪基、吡啶基、[1,3,4]噁二唑基、4H-[1,2,4]***基、四唑基、吡唑基、[1,3,5]三嗪基和[1,3,4]噻二唑基;
Rz和Ry独立为H或-C(1-4)烷基,其中两个Rz可具有顺式或反式立体化学;或者两个顺式关系的Rz可连接在一起形成-(CH2)n-,其中n为2或3;
R3为H、C(1-4)烷基、CH2CH2NH2、CH2CH2ORa、-COCH3、CONH2或CO2Ra;
A1为H、-C(1-4)烷基或CH2CH2ORa;
A2为H、-C(1-4)烷基、CORa、CH2CON(CH3)2、-CH2CH2ORa(包括-CH2CH2OCH3)、-CH2CH2SC(1-4)烷基(包括-CH2CH2SCH3)、-CH2CH2SOC(1-4)烷基(包括-CH2CH2SOCH3)或-CH2CH2SO2C(1-4)烷基(包括-CH2CH2SO2CH3);
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
其中Ra为H或C(1-4)烷基;
Raa为H或C(1-4)烷基;
Rbb为H、-C(1-4)烷基、-CH2CH2OCH2CH2OCH3、-CH2CO2H、-C(O)C(1-4)烷基或-CH2C(O)C(1-4)烷基。
在优选的本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COORa、-CO2CH3、-CH2-NA1A2、-CONA1A2、-CH2ORa、-NHCH2CH2CO2Ra、-NHCH2CH2ORa、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2Ra或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
Ra为H或-C(1-4)烷基;
Raa为H或-C(1-4)烷基;
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-COCH3、-CH3、-CO2CH3、-CONH2或-CO2H。
在另一个本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COOH、-CO2CH3、-CH2-NA1A2、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2CO2CH3、-NHCH2CH2OCH3、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2H或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-COCH3、-CH3、-CO2CH3、-CONH2或-CO2H。
在另一个本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COOH、-CO2CH3、-CH2-NA1A2、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2CO2CH3、-NHCH2CH2OCH3、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2H或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-COCH3、-CH3、-CO2CH3、-CONH2或-CO2H。
在另一个本发明实施方案及其溶剂合物、水合物、互变异构体和药学上可接受的盐中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-OH、-NH2、-N(CH3)2、-SO2CH3、-COOH、-CO2CH3、-CH2-吗啉基、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2OCH3、-OCH2CO2H、吗啉基、哌嗪基、N-甲基哌嗪基、哌嗪基-CH2CO2H或四唑基;
Rz为H或-CH3;
R3为-COCH3或-CO2H。
另一个本发明实施方案为选自以下的化合物:
及其溶剂合物、水合物、互变异构体和药学上可接受的盐。
另一个本发明实施方案是选自以下的化合物:
及其溶剂合物、水合物、互变异构体和药学上可接受的盐。
另一个本发明实施方案是选自以下的化合物:
及其溶剂合物、水合物、互变异构体和药学上可接受的盐。
本发明还涉及在哺乳动物中抑制蛋白酪氨酸激酶活性的方法,该方法包括给予治疗有效量的至少一种式I化合物。优选的酪氨酸激酶是c-fms。
可认为本发明包括所有式I化合物的对映、非对映和互变异构形式和它们的外消旋混合物。另外,式I代表的某些化合物可以是前药,即作用药物的衍生物,该衍生物的递药性能和治疗价值比所述作用药物更优。通过体内酶或化学过程,前药转化为活性药物。
I.定义
术语“烷基”是指含最高达12个碳原子,优选最高达6个碳原子的直链或支链基团,除另有说明外,它们包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、异己基、庚基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基和十二烷基。
术语“环烷基”是指由3-8个碳原子组成的饱和或部分不饱和的环。在环上可任选存在最高达4个烷基取代基。实例包括环丙基、1,1-二甲基环丁基、1,2,3-三甲基环戊基、环己基、环戊烯基、环己烯基和4,4-二甲基环己烯基。
术语“烷基氨基”是指含一个烷基取代基的氨基,其中氨基是该基团与分子的其余部分的连接点。
术语“杂芳基”是指5元-7元单环或8元-10元双环芳族环***,其中任何环可包括选自N、O或S的1-4个杂原子,其中氮和硫原子可存在任何允许的氧化状态。实例包括苯并咪唑基、苯并噻唑基、苯并噻吩基、苯并噁唑基、呋喃基、咪唑基、异噻唑基、异噁唑基、噁唑基、吡嗪基、吡唑基、吡啶基、嘧啶基、吡咯基、喹啉基、噻唑基和噻吩基。
术语“杂原子”是指氮原子、氧原子或硫原子,其中氮和硫原子可存在任何容许的氧化状态。
除另有说明外,术语“烷氧基”是指含最高达12个碳原子的直链或支链基团,所述基团与氧原子结合。实例包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基。
术语“螺环取代的环烯基”是指共享一个碳原子的环烷基环对,其中至少一个环部分不饱和,例如:
II.治疗用途
式I化合物代表新的蛋白酪氨酸激酶例如c-fms的活性抑制剂,可用于预防和治疗由这些激酶作用产生的病症。
本发明还提供抑制蛋白酪氨酸激酶的方法,该方法包括使蛋白酪氨酸激酶与有效抑制量的至少一种式I化合物接触。优选的酪氨酸激酶是c-fms。本发明化合物还是FLT3酪氨酸激酶活性抑制剂。在一个抑制蛋白酪氨酸激酶的实施方案中,使至少一种式I化合物与已知酪氨酸激酶抑制剂联合。
在各种本发明实施方案中,被式I化合物抑制的蛋白酪氨酸激酶位于细胞、哺乳动物中或体外。在包括人的哺乳动物的情况,给予治疗有效量的药学上可接受形式的至少一种式I化合物。
本发明还提供在包括人的哺乳动物中治疗癌症的方法,该方法包括给予治疗有效量的至少一种式I化合物的药学上可接受的组合物。示例性癌症包括但不限于急性骨髓白血病、急性淋巴细胞白血病、卵巢癌、子宫癌、***癌、肺癌、乳腺癌、结肠癌、胃癌和毛细胞白血病。本发明还提供治疗包括骨髓纤维变性在内的某些前期癌损害的方法。在一个本发明实施方案中,将有效量的至少一种式I化合物与有效量的化疗药物联合给予。
本发明还提供治疗和预防癌转移的方法,这些癌包括但不限于卵巢癌、子宫癌、***癌、肺癌、乳腺癌、结肠癌、胃癌和毛细胞白血病。
本发明还提供治疗以下疾病的方法:骨质疏松症、佩吉特病和其中骨吸收介导发病的其它疾病,包括类风湿性关节炎和其它形式的炎性关节炎、骨关节炎、修复术失败、溶骨肉瘤、骨髓瘤和在癌症中经常发生的转移到骨的肿瘤,这些癌包括但不限于乳腺癌、***癌和结肠癌。
本发明还提供治疗疼痛,尤其由肿瘤转移或骨关节炎造成的骨骼疼痛和内脏、炎性和神经原性疼痛的方法。
本发明还提供在包括人的哺乳动物中治疗心血管、炎性和自身免疫性疾病的方法,该方法包括给予治疗有效量的药学上可接受形式的至少一种式I化合物。具有炎性成分的疾病的实例包括肾小球肾炎、炎性肠病、修复术失败、结节病、充血性阻塞性肺病、自发性肺纤维变性、哮喘、胰腺炎、HIV感染、银屑病、糖尿病、与肿瘤有关的血管发生、与年龄有关的黄斑变性、糖尿病性视网膜病、再狭窄、精神***症或早老性痴呆。可用本发明化合物有效治疗这些疾病。可有效治疗的其它疾病包括但不限于动脉粥样硬化和心脏肥大。
也可用本发明化合物治疗自身免疫性疾病例如全身性红斑狼疮、类风湿性关节炎和其它形式的炎性关节炎、银屑病、斯耶格伦综合征、多发性硬化或葡萄膜炎。
本文中使用的术语“治疗有效量”表示研究人员、兽医、医师或其它临床技师正在寻找的在组织***、动物或人中引起生物或医学反应的活性化合物或药物的量,该反应包括缓解、预防、治疗或延迟所治疗疾病或病症的症状发作或发展。
当作为蛋白酪氨酸激酶抑制剂使用时,可按约0.5mg-约10g,优选约0.5mg-约5g剂量范围内的有效量,每日以单剂量或分剂量给予本发明化合物。给药剂量可受因素例如给药途径、接受者的健康、体重和年龄、治疗的频次和同时和无关的治疗存在的影响。
本发明化合物或其药用组合物的治疗有效剂量因需要的作用而变化对本领域技术人员而言也是显而易见的。因此,本领域技术人员可容易地确定最佳给药剂量,该剂量将随使用的具体化合物、给药模式、制剂强度和疾病状态进展而变化。另外,与所治疗的具体患者有关的因素会引起将剂量调至适当治疗水平的需要,这些因素包括患者的年龄、体重、饮食和给药时间。因此,以上剂量是一般情况的示例。自然存在个别情况,其中应该具有更高或更低剂量范围,且它们在本发明范围内。
可将式I化合物配制成含任何已知药学上可接受的载体的药用组合物。示例性载体包括但不限于任何合适的溶剂、分散介质、包衣剂、抗菌剂和抗真菌剂以及等渗剂。也可为制剂成分的赋形剂的示例包括填充剂、粘合剂、崩解剂和润滑剂。
式I化合物的药学上可接受的盐包括由无机或有机酸或碱形成的常规无毒盐或季铵盐。此类酸加成盐的实例包括乙酸盐、己二酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、樟脑酸盐、十二烷基硫酸盐、盐酸盐、氢溴酸盐、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、草酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐和酒石酸盐。碱式盐包括铵盐;碱金属盐例如钠和钾盐;碱土金属盐例如钙和镁盐;有机碱的盐例如二环己基氨基盐和例如精氨酸的氨基酸的盐。也可用例如烷基卤化物将碱性含氮的基团季铵化。
可按达到预定目的的任何方式给予本发明药用组合物。实例包括通过肠胃外、皮下、静脉内、肌内、腹膜内、透皮、含服或眼途径给药。也可通过口服途径交替或同时给药。合适的肠胃外给药制剂包括活性化合物的水溶性形式例如水溶性盐的水溶液、酸性溶液、碱性溶液、葡萄糖水溶液、等渗碳水化合物溶液和环糊精包合复合物。
本发明还包括制备药用组合物的方法,该方法包括将药学上可接受的载体与任何本发明化合物混合。另外,本发明还包括通过将药学上可接受的载体与任何本发明化合物混合制备的药用组合物。本文中使用的术语“组合物”将包括含特定量的特定成分的产品,和由特定量的特定成分的组合直接或间接产生的任何产品。
多晶型和溶剂合物
另外,本发明化合物还可具有一种或多种多晶型或无定形晶型,且因此也包括在本发明范围内。另外,这些化合物可与例如普通有机溶剂或水(即水合物)形成溶剂合物。本文中使用的术语“溶剂合物”表示本发明化合物与一个或多个溶剂分子的物理缔合物。该物理缔合物涉及各种程度的离子键和包括氢键的共价键。在某些情况下,例如当一个或多个溶剂分子掺入结晶固体的晶格时,可将溶剂合物分离。术语“溶剂合物”将包括溶液相和可分离溶剂合物。合适溶剂合物的非限制性实例包括乙醇化物、甲醇化物等。
本发明在其范围内将包括本发明化合物的溶剂合物。因此,在本发明治疗方法中,术语“给予”应包括用本发明化合物或其溶剂合物治疗、缓解或预防本文中所述综合征、病症或疾病的手段,很明显,尽管未明确公开,但它应包括在本发明范围内。
制备方法
流程1
流程1是制备其中Rb为X的式I化合物(当原料或按后续流程中所示制备的化合物具有X时)或其中Rb为离去基团(优选溴、氯或氟)的式1-6化合物通用方法的举例说明,式1-6化合物是可用于后续流程的有用中间体。为举例说明该流程方法,对制备其中J为CH的化合物的试剂和条件进行定义。本领域技术人员会认识到,当J为N,可能需要对反应条件和优选的试剂进行略微改变。
式1-1胺可有市售,或可用标准合成方法,通过还原式1-0硝基化合物得到(参见Reductions in Organic Chemistry,M.Hudlicky,Wiley,New York,1984)。优选的条件是在合适的溶剂例如甲醇或乙醇中用钯催化剂催化氢化。在Rb为卤素的情况,且式1-1胺中不存在Rb时,可在合适的溶剂例如乙酸中用铁或锌,或在乙醇和水中用铁和氯化铵将硝基还原。
可通过将式1-1氨基化合物的邻位卤化,优选溴化,然后使中间体卤代化合物与硼酸或硼酸酯进行金属催化偶合反应(Suzuki反应,其中R2M为R2B(OH)2或硼酸酯,参见N.Miyaura and A.Suzuki,Chem.Rev.,95:2457(1995);A.Suzuki in Metal-Catalyzed Coupling Reactions(Suzuki金属催化偶合反应),F.Deiderich,P.Stang,Eds.,Wiley-VCH,Weinheim(1988)),或与锡试剂进行金属催化偶合反应(Stille反应,其中R2M为R2Sn(烷基)3,参见J.K.Stille,Angew.Chem,Int.Ed.Engl.,25:508-524(1986)),得到式1-2化合物,其中R2为环烷基。当Rb为Br时,可引入碘以使它在金属催化偶合反应中先于溴反应(当J为CH时,该化合物有市售)。优选的1-1的溴化条件是在合适的溶剂例如N,N-二甲基甲酰胺(DMF)、二氯甲烷(DCM)或乙腈中使用N-溴代琥珀酰亚胺(NBS)。可按照标准方法,优选在钯催化剂例如四(三苯基膦)合钯(0)(Pd(PPh3)4);碱水溶液例如Na2CO3水溶液和合适的溶剂例如甲苯、乙醇、1,4-二噁烷、二甲氧基乙烷(DME)或DMF的存在下进行金属催化偶合反应,优选Suzuki反应。
可在合适的碱例如K2CO3、N,N-二异丙基乙胺(DIEA)或NEt3的存在下,用环烷基胺(R2H;例如哌啶)将被硝基活化的式1-3化合物的离去基团L1(优选氟或氯)亲核芳族取代,得到化合物1-4,然后按上述将硝基还原,得到式1-2化合物,其中R2为环烷基氨基(例如哌啶子基)。
然后可使式1-2化合物的氨基与杂环酸P1-WCOOH(或其相应的盐P1-WCOOM2,其中M2为Li、Na或K)偶合,其中P1为任选的保护基(例如2-(三甲基甲硅烷基)乙氧基甲基(SEM),例如当W为咪唑、***、吡咯或苯并咪唑时),或其中P1不存在,例如当W为呋喃时。(有关W的保护基的目录,参见Theodora W.Greene and Peter G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley and Sons,Inc.,NY (1991))。可按照酰胺键形成的标准方法(有关综述参见:M.Bodansky and A.Bodansky,The Practice of Peptide Synthesis,Springer-Verlag,NY(1984))进行偶合,或通过与酰氯P1-WCOCl或活化酯P1-WCO2Rq(其中Rq为离去基团例如五氟苯基或N-琥珀酰亚胺)反应,形成式1-5化合物。优选的与P1-WCOOH或P1-WCOOM2偶合的反应条件是:当W为呋喃(任选的保护基P1不存在),以草酰氯的二氯甲烷(DCM)和DMF溶液为催化剂,形成酰氯WCOCl,然后在三烷基胺例如N,N-二异丙基乙胺(DIEA)的存在下偶合;当W为吡咯(任选的保护基P1不存在)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和1-羟基苯并***(HOBt);和当W为咪唑、吡咯或苯并咪唑(存在任选的P1)时,优选的条件为六氟磷酸三吡咯烷-1-基溴化磷鎓(PyBroP)和DIEA溶液,溶剂为例如DCM或DMF。
当式1-5化合物中的W含有任选的前述保护基P1时,可在该点将其除去,得到式1-6化合物。例如,当W为氮被SEM基团保护的咪唑时,可用酸性试剂例如三氟乙酸(TFA)或氟化物源例如氟化四丁铵(TBAF)将SEM基团除去(参见以上Greene and Wuts)。
可以理解,最后可将式I化合物(即式1-6,其中Rb为X)进一步衍生化。进一步衍生化的实例包括但不限于:当式I化合物含氰基时,可在酸性或碱性条件下,将该基团水解为酰胺或酸;当式I化合物含酯时,可将该酯水解为酸,且可通过上述酰胺键形成方法将酸转化为酰胺。可通过Curtius或Schmidt反应将酰胺转化为胺(有关综述参加Angew.Chemie Int.Ed.,44(33),5188-5240,(2005)),或通过还原氰基得到胺(Synthesis,12,995-6,(1988)and Chem.Pharm.Bull,38(8),2097-101,(1990))。可将酸还原为醇,且可将醇氧化为醛和酮。在氰基的存在下,优选的羧酸的还原条件包括硼氢化钠和氯甲酸乙酯的四氢呋喃(THF)溶液;和可用戴斯-马丁氧化剂(Dess-Martin periodinane)将醇氧化(Adv.Syn.Catalysis,346,111-124(2004))。可在还原剂例如三乙酰氧基硼氢化钠的存在下,使醛和酮与伯或仲胺反应(参见J.Org.Chem.,61,3849-3862,(1996)),通过还原性胺化得到胺。可通过催化氢化将烯烃还原。当式I化合物含非环或环状硫化物时,可将该硫化物进一步氧化为相应的亚砜或砜。可通过用适当氧化剂例如1当量间氯过苯甲酸(MCPBA)氧化或通过用NaIO4处理,得到亚砜(参见例如J.Med.Chem.,46:4676-86(2003)),可用2当量MCPBA或通过用4-甲基吗啉N-氧化物和催化量的四氧化锇处理,得到砜(参见例如PCT申请WO 01/47919)。也可在异丙醇钛(IV)的存在下,通过分别使用1当量和2当量H2O2制备亚砜和砜(参见例如J.Chem.Soc.,Perkin Trans.2,1039-1051(2002))。
流程2
流程2是制备式I化合物通用方法的举例说明,其中X为其中Ry和Rz为H、C(1-4)烷基或ORa;E为O、NR3、S或SO2;R1为CO2Ra、CH2OH、C(O)NA1A2和CH2NA1A2。
为举例说明该流程的合成策略,根据用于该流程的其中Ry为Rz为H的底物限定试剂和条件。本领域技术人员会认识到,该化学适用于所有所述X、Ry和Rz,对所述试剂和条件几乎不作修改或略微修改。另外,尽管按流程1中所述,根据其中J为CH的底物限定试剂和条件,但也可以理解,当J为N时,也可使用经过略微修改的类似合成方法。
当式I中的R2为环烷基(包括环烯基)时,以2-2化合物为原料开始合成,可通过先用合适的碱例如六甲基二硅烷基氨基化锂(didilylamide lithium)(LHMDS)或优选二异丙基氨基化锂(LDA)处理酯2-1(Ra为C(1-4)烷基),然后用得到的阴离子中间体亲核芳族取代4-卤硝基苯化合物1-0(按流程1制备)中的离去基团Rb(优选氟或氯),得到化合物2-2。
可用标准合成方法(参见Reductions in Organic Chemistry,M.Hudlicky,Wiley,New York,1984),将硝基化合物2-2还原,得到2-3。优选的条件是在合适的溶剂例如甲醇或乙醇中用钯催化剂催化氢化。
可通过将氨基化合物2-4的邻位卤化,优选溴化,然后按流程1中所述,使中间体卤代化合物与硼酸或硼酸酯进行金属催化偶合反应(Suzuki反应,其中R2M为R2B(OH)2或硼酸酯)或与锡试剂进行金属催化偶合反应(Stille反应,其中R2M为R2Sn(烷基)3),得到化合物2-4。
当式I中的R2为环烷基氨基(例如哌啶子基)时,制备2-4化合物的备选方法是按流程1中所述以其中Rb优选为氯或氟的1-4为原料开始合成。可通过同样的将化合物1-0转化为化合物2-2的所述方法,由1-4和2-1得到化合物2-5。然后可用流程1中所述将化合物1-0转化为化合物1-1的标准合成方法,将硝基还原,由化合物2-5得到化合物2-4。
可通过先使2-4与羧酸P1-WCOOH偶合,然后按流程1中所述将1-2转化为1-6的方法将任选的保护基P1除去,得到式I化合物,其中R1为酯(Ra为C(1-4)烷基)。
可通过合适的金属氢氧化物试剂例如氢氧化钠将其中R1为酯(Ra为C(1-4)烷基)的这些式I化合物进一步水解,得到式I化合物,其中R1为酸(Ra为H)。
可通过先用氯甲酸烷基酯例如氯甲酸乙酯处理其中R1为酸(Ra为H)的式I化合物,然后用合适的伯或仲胺(HNA1A2)捕获中间体活化的酰基碳酸酯(acylcarbonate),得到式I化合物,其中R1为酰胺(R1为C(O)NA1A2)。类似的,可通过使同样中间体活化的酰基碳酸酯与合适的还原试剂例如NaBH4反应,得到式I化合物,其中R1为羟基甲基(参见例如Tetrahedron,62(4),647-651;(2006))。
可通过氧化反应例如Swern氧化(J.Am.Chem.Soc.102,1390(1980))或优选戴斯-马丁氧化剂氧化(参见例如Tetrahedron Lett.,29,995(1988);J.Org.Chem.,55,1636(1990)),将其中R1为羟基甲基(R1为CH2OH)的式I化合物进一步转化为醛2-6。
可在合适的还原剂例如NaBH4或NaBH3CN,或优选NaBH(OAc)3的存在下,按流程1中所述还原性胺化的标准方法,使醛2-6与合适的伯和仲胺(HNA1A2)反应,形成式I化合物,其中R1为氨基甲基(R1为R1为CH2NA1A2)。
可以理解,可按流程1中所述方法,将该流程中化合物的官能团进一步衍生化。
流程3
流程3是制备式I化合物通用方法的举例说明,其中X为其中Ry和Rz为H、C(1-4)烷基或ORa;E为O、NR3、S或SO2;R1为-CN或杂芳基。
为说明该流程的合成策略,根据用于该流程的其中Ry为Rz为H的底物限定试剂和条件。本领域技术人员会认识到,该化学适用于所有所述X、Ry和Rz,对试剂和条件几乎未做或略微修改。另外,尽管按流程1所述,根据其中J为CH的底物限定试剂和条件,但还应理解当J为N时,可使用略微修改的类似合成方法。
可通过合适的金属氢氧化物试剂例如氢氧化钠将酯2-2(Ra为C(1-4)烷基)水解,得到酸2-2(Ra为H)。可通过标准方法将酸2-2转化为腈3-1,一般而言,方法是先将酸活化,将其转化为酰胺或异羟肟酸酯(hydroxamate),然后脱水(参见例如J.Med.Chem.,33(10),2828-41;(1990)),或优选按一步法在合适的溶剂例如环丁砜中用磺酰胺和亚硫酰氯处理(参见Tetrahedron Lett.,23(14),1505-08;(1982))。可通过标准还原方法,优选流程1中所述催化氢化,由3-1得到化合物3-2。
通过将胺3-2邻位卤化,优选溴化,得到化合物3-3(L2为卤素)。优选的3-2溴化的条件是在合适的溶剂中使用N-溴代琥珀酰亚胺(NBS),该溶剂为例如N,N-二甲基甲酰胺(DMF)、二氯甲烷(DCM)或乙腈。
在该点,可按流程3a中所述,通过1,3偶极进行[2+3]环加成或用二烯或杂二烯进行[2+4]环加成,将3-3中的氰基转化为3-4中的不饱和杂环。可用表中提供的参考文献中的条件制备的各种杂环参见表1所示。
当存在的不饱和杂环对卤化惰性时,得到3-4的备选路线涉及按刚阐述的先形成不饱和杂环,然后通过卤化引入3-4中的L2方法处理腈3-2。
可通过使3-4与硼酸或硼酸酯进行金属催化偶合反应(Suzuki反应,其中R2M为R2B(OH)2或硼酸酯)或与锡试剂进行金属催化偶合反应(Stille反应,其中R2M为R2Sn(烷基)3),得到化合物3-5。可按流程1中所述标准方法进行金属催化偶合反应,优选Suzuki反应。
当式I中的R2为环烷基氨基(例如哌啶子基)时,制备化合物3-5的备选方法是从按流程2制备的原料2-4开始。可通过合适的金属氢氧化物试剂例如氢氧化钠将酯2-4(Ra为C(1-4)烷基)水解,得到酸2-4(Ra为H)。可按照将2-2转化为3-1的所述方法将酸2-4转化为腈3-6。可按照将3-3转化为3-4的所述方法,将化合物3-6转化为化合物3-5。
可通过先使3-6与羧酸P1-WCOOH偶合,然后按流程1中所述将1-2转化为1-6的方法将任选的保护基P1除去,得到式I化合物,其中R1为腈(R1为CN)。
类似的,可按流程1中所述将1-2转化为1-6的2步法,即使3-5与羧酸P1-WCOOH偶合,然后将任选的保护基除去,得到式I化合物,其中R1为不饱和杂环。
可以理解,可按流程1中所述方法,将该流程中化合物的官能团进一步衍生化。
流程3a
流程4
流程4是对式I化合物的合成的阐述,其中X为为说明该方法目的,根据其中Ry和Rz为H;E为O、NR3、S或SO2;J为CH的底物限定在该流程中的试剂和条件。本领域技术人员会认识到,该化学适用于所有X、Ry、Rz,使用上述J时,对试剂和条件进行略微修改。
可按流程1中所述得到化合物1-6原料,其中Rb为卤素,优选Br。可通过先用合适的碱例如异丙基氯化镁(i-PrMgCl)脱质子,然后用合适的锂试剂例如正丁基锂或优选叔丁基锂进行锂-卤素交换,然后用合适的酮捕获有机锂中间体,将卤代化合物1-6转化为醇4-1。化合物4-1既是式I化合物,又可用作合成含不同R1基团的其它化合物的有用中间体。
也可通过用试剂例如亚硫酰氯(SOCl2)将4-1活化,再用伯或仲胺(A2A1NH)将得到的中间体捕获,将化合物4-1中的叔羟基转化为化合物I (R1为NA1A2)中的氨基。
可通过用酸性试剂例如硫酸或优选三氟乙酸(TFA)处理羟基化合物4-1,然后用醇R7OH(其中R7为CH2CH2NA1A2或CH2CH2ORa,其中A1、A2或Ra不为H)捕获得到的三级(tertiary)阳离子,得到式I化合物,其中R1为烷氧基(OR7)。
也可在合适的溶剂例如THF中,在Lewis酸(L.A.)例如***合三氟化硼(BF3·OEt2)的存在下,使羟基化合物4-1与磺酰胺R8SO2NRaH反应,得到化合物I(R1为NHSO2R8,其中R8为CH2CH2NA1A2或Ra,其中A1、A2或Ra不为H)。
可通过用酸性试剂例如TFA或Lewis酸例如BF3·OEt2处理化合物4-1,然后用硫醇R8SH(其中R8为CH2CH2NA1A2或Ra)捕获得到的三级阳离子,得到式I化合物,其中R1为硫化物(R1为SR8)。
可按照流程1中所述硫化物氧化方法,将其中R1为硫化物(R1为SR8)的式I化合物进一步氧化为相应的亚砜(式I,其中R1为SOR8)或砜(式I,其中R1为SO2R8)。
也可通过使化合物4-1与金属亚磺酸盐R8SO2M(其中M为Na或K)反应,直接得到式I化合物,其中R1为砜(参见例如B.Koutek,etal,Synth.Commun.,6(4),305-8(1976))。
可按照文献方法(参见例如:Dolan,S.,et al,J.Chem.,Soc.,Chem.Commun.,1588-9(1985)、WO专利98/06700和Wustrow,D.,et al,Tetrahedron Lett.,35,61-4(1994)),由相应的其中R1为OH的化合物,通过脱氧化反应得到式I化合物,其中X为R1为H。
可以理解,可按流程1中所述方法将该流程中的官能团进一步衍生化。例如,可使化合物4-2中的氨基与各种亲电试剂反应。可按酰胺键形成标准方法,使氨基与羧酸反应,或按流程1中所述,与酰氯或活化酯反应,形成酰胺化合物。也可在碱例如吡啶或DIEA的存在下,使其与合适的羰基化试剂例如光气、羰基二咪唑或优选三光气反应。可用伯或仲胺捕获由此形成的中间体,得到相应的脲化合物。类似的,可在碱例如吡啶或DIEA的存在下,使化合物4-2中的氨基与合适的草酰化试剂例如草酰氯反应,然后可用伯或仲胺捕获由此形成的中间体,得到草酰胺化合物。另外,还可按流程1中所述还原性胺化标准方法,在合适的还原剂例如NaBH4或NaBH3CN,或优选NaBH(OAc)3的存在下,使氨基与合适的醛或酮反应,形成式I化合物,其中R1为NA1A2。
流程5
流程5描述了有用的式1-0中间体的合成,其中X为为说明该方法目的,Ry和Rz为H;E为O、S、SO2或NR3。本领域技术人员会认识到,该化学适用于所有所述X、Ry和Rz,对试剂和条件仅做略微修改。另外,尽管按照前述流程1,根据其中J为CH的底物限定试剂和条件,但也可理解,当J为N时,可使用经略微修改的类似合成方法。
流程6
流程6举例说明制备其中Ra为H或C(1-4)烷基,Rd为H、烷基、-CN或-CONH2的式6-52-咪唑甲酸酯的路线,该化合物可用作合成其中W为咪唑的式I化合物的中间体。
其中Ra为H或C(1-4)烷基,Rc为H、C(1-4)烷基或-CN的式6-1咪唑有市售,或在其中Rc为-CN的情况,可通过使市售醛(6-1,其中Rc为CHO)与羟胺反应,然后用合适的试剂例如磷酰氯或乙酸酐脱水(Synthesis,677,2003),容易地得到。可用合适的基团(P1)例如甲氧基甲胺(MOM)或优选SEM基团将式6-1咪唑保护,得到式6-2化合物(参见Theodora W.Greene and Peter G.M.Wuts,Protective Groups inOrganic Synthesis,John Wiley and Sons,Inc.,NY(1991))。
在亲电性条件下,在溶剂例如DCM或CH3CN中,或在自由基条件下,在引发剂例如偶氮二(异丁腈)(AIBN)的存在下,在溶剂例如CCl4中,将其中Rc为-CN的式6-2咪唑用合适的试剂例如N-溴代琥珀酰亚胺或N-碘代琥珀酰亚胺卤化,得到式6-3化合物,其中L8为离去基团(优选溴或碘)。通过使式6-3化合物进行卤素-镁交换,得到有机镁化合物,然后与合适的亲电试剂反应,得到式6-4化合物。优选的卤素-镁交换条件是在合适的溶剂例如THF中,在-78℃至0℃温度下,使用烷基镁试剂,优选异丙基氯化镁。优选的亲电试剂是氯甲酸乙酯或氰基甲酸乙酯。有关在氰基咪唑中进行卤素-镁交换的实例参见J.Org.Chem.65,4618,(2000)。
可通过用合适的碱例如烷基锂脱质子化,然后与如上述有机镁化合物的亲电试剂反应,将其中Rc不为-CN的式6-2咪唑直接转化为式6-4咪唑。优选的条件是在-78℃下在THF中用正丁基锂处理咪唑,和用氯甲酸乙酯淬灭得到的有机锂类化合物(例如参见TetrahedronLett.,29,3411-3414,(1988))。
然后可用1当量金属氢氧化物(MOH)水溶液,优选溶于合适溶剂例如乙醇或甲醇的氢氧化钾溶液,将式6-4酯水解为式6-5羧酸(M为H)或羧酸盐(M为Li、Na或K)。可通过先将其中Rc为-CN的式6-4化合物用适当醇盐例如乙醇钾处理,将氰基转化成亚氨酸酯基(Pinner反应),然后用2当量的金属氢氧化物水溶液将酯和亚氨酸酯基水解,完成其中Rd为-CONH2的式6-5化合物的合成。
流程7
流程7阐述了制备式7-3或7-52-咪唑甲酸盐的路线,其中Re为氯或溴,M为H、Li、K或Na,它们用作合成其中W为咪唑的式I化合物的中间体。
先按流程6中所述方法,优选用SEM基团将市售咪唑甲酸乙酯保护,制备式7-1化合物。
可通过在25℃下,在合适的溶剂例如CH3CN、DCM或DMF中,使式7-1化合物与1当量合适的卤化剂例如NBS或NCS反应,制备式7-2化合物。可在30℃-80℃温度下,在合适的溶剂例如CH3CN或DMF中,通过使式7-1化合物与2当量合适的卤化剂例如NBS或NCS反应,制备式7-4化合物。然后由相应的酯,通过流程6中所述水解,得到式7-3和7-5咪唑。
流程8
流程8阐述了制备其中Rf为-SCH3、-SOCH3或-SO2CH3,M为H、Li、K或Na的式8-3咪唑的方法,它们是用作合成其中W为咪唑的式I化合物的中间体。
按流程6中所述方法,优选用SEM保护基将咪唑8-1(WO1996011932)保护,得到式8-2化合物。按流程6中所述方法进行酯水解,得到式8-3化合物,其中Rf为-SCH3。将式8-22-甲硫基咪唑用1当量合适的氧化剂氧化,然后按流程6方法将酯水解,得到式8-3化合物,其中Rf为-SOCH3。用2当量合适的氧化剂氧化,然后按流程6中所述方法进行酯水解,得到式8-3化合物,其中Rf为-SO2CH3。优选的氧化剂是MCPBA的DCM溶液。流程1中给出使硫化物转化为亚砜和砜的参考方法。
实施例1
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-四氢-吡喃-4-基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺
a)1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-4-甲腈
将咪唑-4-甲腈(0.50g,5.2mmol)(Synthesis,677,2003)、2-(三甲基甲硅烷基)乙氧基甲基氯(SEMCl)(0.95mL,5.3mmol)、K2CO3(1.40g,10.4mmol)和丙酮(5mL)加入烧瓶,在室温下搅拌10h。将混合物用EtOAc(20mL)稀释,用水(20mL)、盐水(20mL)洗涤,有机层经MgSO4干燥。用30%EtOAc/己烷将20-g SPE短柱(硅胶)上的粗产物洗脱,得到0.80g(70%)标题化合物,为无色油状物。质谱(CI(CH4),m/z):C10H17N3OSi的理论值,224.1(M+H),实测值224.1。
b)2-溴-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-4-甲腈
向1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-4-甲腈(0.70g,3.1mmol)(按前一步骤制备)的CCl4(10mL)溶液加入N-溴代琥珀酰亚胺(NBS)(0.61g,3.4mmol)和偶氮二(异丁腈)(AIBN)(催化量),将混合物在60℃下加热4h。将反应物用EtOAc(30mL)稀释,用NaHCO3(2×30mL)、盐水(30mL)洗涤,有机层经Na2SO4干燥,然后浓缩。用30%EtOAc/己烷将20-g SPE短柱(硅胶)上的标题化合物洗脱,得到0.73g(77%)黄色固体。质谱(CI(CH4),m/z):C10H16BrN3OSi的理论值302.0/304.0(M+H),实测值302.1/304.1。
c)4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸乙酯
在-40℃下,向2-溴-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-4-甲腈(0.55g,1.8mmol)(按前一步骤制备)的四氢呋喃(THF)(6mL)溶液中滴加2M i-PrMgCl的THF溶液(1mL)。将反应物在-40℃下搅拌10分钟,然后冷却至-78℃,加入氰基甲酸乙酯(0.30g,3.0mmol)。让反应物升至室温,然后搅拌1h。用饱和NH4Cl水溶液将反应淬灭,用EtOAc(20mL)稀释,用盐水(2×20mL)洗涤。有机层经Na2SO4干燥,然后浓缩。用30%EtOAc/己烷将20-g SPE短柱(硅胶)上的标题化合物洗脱,得到0.40g(74%)无色油状物。质谱(ESI,m/z):C13H21N3O3Si的理论值296.1(M+H),实测值296.1。
d)4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾盐
向4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸乙酯(0.40g,1.3mmol)(按前一步骤制备)的乙醇(3mL)溶液加入6M KOH(0.2mL,1.2mmol)溶液,将反应物搅拌10分钟,然后浓缩,得到0.40g(100%)标题化合物,为黄色固体。1H-NMR(CD3OD;400MHz)δ7.98(s,1H),5.92(s,2H),3.62(m,2H),0.94(m,2H),0.00(s,9H).质谱(ESI-neg,m/z):C11H16KN3O3Si的理论值266.1(M-K),实测值266.0。
e)4-溴-2-(4,4-二甲基-环己-1-烯基)-苯胺
将4-溴-2-碘-苯胺(1.10g,3.70mmol)、4,4-二甲基环己烯-1-基硼酸(0.630g,4.07mmol)、Pd(PPh3)4(0.24g,5mol%)、2M Na2CO3(16mL)、EtOH(16mL)和甲苯(32mL)加入烧瓶,在80℃下加热6h。将反应物用EtOAc(100mL)稀释,然后用饱和NaHCO3水溶液(2×100mL)和盐水(100mL)洗涤,有机层经Na2SO4干燥,蒸发。粗产物经闪硅胶层析纯化,用10%EtOAc/己烷洗脱,得到0.680g(66%)标题化合物,为浅黄色油状物。质谱(ESI,m/z):C14H18BrN的理论值280.1(M+H),实测值280.1。
f)N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺
向4-溴-2-(4,4-二甲基-环己-1-烯基)-苯胺(0.640g,2.29mmol)(按前一步骤制备)和4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾盐(0.700g,2.30mmol)(在本实施例步骤(d)中制备的)的DCM(12mL)悬浮液中加入DIPEA(0.800mL,4.60mmol)和PyBroP(1.29g,2.76mmol),将混合物在室温下搅拌10h。将混合物用DCM(50mL)稀释,然后用NaHCO3(2×50mL)洗涤,有机层经Na2SO4干燥,浓缩。用1∶1的DCM/己烷将20-g SPE上的标题化合物洗脱,得到1.04g(86%)标题化合物,为白色固体。质谱(ESI,m/z):C25H33BrN4O2Si的理论值529.1(M+H),实测值529.1。
g)N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
向N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺(0.95g,1.80mmol)(按前一步骤制备)的10mL DCM溶液中加入0.4mL EtOH和10mL TFA,将混合物在室温下搅拌1h。将混合物浓缩,用Et2O研磨,得到0.68g(95%)白色固体:1H-NMR(400MHz,CDCl3):δ11.23(br s,1H),9.52(br s,1H),8.27(d,J=8.7Hz,1H),7.72(s,1H),7.41(dd,J=2.3,8.7Hz,1H),7.33(d,J=2.3Hz,1H),5.82(m,1H),2.28(m,2H),2.10(m,2H),1.58(m,2H),1.08(s,6H).质谱(ESI,m/z):C19H19BrN4O的理论值399.1(M+H),实测值399.0。
h)N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-四氢-吡喃-4-基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺
在-40℃下,向N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(0.550g,1.38mmol)(按前一步骤制备)的20mLTHF悬浮液中加入i-PrMgCl(1.40mL,2.80mmol,2M的THF溶液),然后让溶液升温至0℃,搅拌10分钟。然后将溶液冷却至-78℃,在5分钟内,滴加t-BuLi(2.15mL,3.65mmol,1.7M的戊烷溶液),然后立即加入四氢吡喃-4-酮(0.650mL,7.05mmol)。在-78℃下保持5分钟后,将反应用饱和NH4Cl(20mL)淬灭,然后用EtOAc(3×20mL)萃取,经Na2SO4干燥。标题化合物经闪层析(Si胶)纯化,用50%EtOAc/DCM洗脱,得到0.460g(79%)白色固体。1H-NMR(400MHz,DMSO-d6).δ14.28(s,1H),9.77(s,1H),8.21(s,1H),7.98(d,J=8.5Hz,1H),7.38(dd,J=8.5,2.2Hz,1H),7.34(d,J=2.2Hz,1H),5.67(m,1H),5.03(s,1H),3.83-3.66(m,4H),2.31-2.22(m,2H),2.04-1.92(m,4H),1.58-1.46(m,4H),1.01(s,6H).质谱(ESI,m/z):C24H28N4O3的理论值421.2(M+H),实测值421.1。
实施例2
N-[4-[4-(2-二甲基氨基-乙氧基)-四氢-吡喃-4-基]-2-(4,4-二甲基-环己-1-烯基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺三氟乙酸盐
向N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-四氢-吡喃-4-基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺(48.0mg,0.114mmol)(实施例1步骤(h)产物)的1mL DCM悬浮液加入2-二甲基氨基乙醇(0.114mL,1.14mmol)、TFA(0.130mL,1.17mmol)。将混合物加热至50℃,保持8h。将混合物浓缩,标题化合物经C18柱RP-HPLC纯化,用线性梯度30-50%CH3CN/0.1%TFA/H2O洗脱12分钟,得到14mg(20%)白色固体。1H-NMR(400MHz,δ8.21(d,J=8.6Hz,1H),7.91(s,1H),7.35(dd,J=8.6,2.2Hz,1H),7.21(d,J=2.2Hz,1H),5.67(m,1H),3.83-3.66(m,4H),3.30-3.15(m,4H),2.76(s,6H),2.26-2.20(m,2H),2.12-1.94(m,6H),1.51(t,J=6.3Hz,2H),1.00(s,6H).质谱(ESI,m/z):C28H37N5O3的理论值492.3(M+H),实测值492.0。
实施例3
{4-[4-[(5-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-基氧基}-乙酸
向N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-四氢-吡喃-4-基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺(48.0mg,0.114mmol)(实施例1步骤(h)产物)的1mL DCM悬浮液加入羟乙酸甲酯(0.215mL,2.78mmol)、TFA (0.036mL,0.464mmol)。将混合物在室温下搅拌8h。将混合物浓缩,用50%EtOAc/己烷将10-g SPE柱上的标题化合物的甲酯洗脱。将得到的酯溶于1mL MeOH,加入2N KOH(0.30mL,0.60mmol),将混合物在室温下搅拌8h,标题化合物经C18柱RP-HPLC纯化,用线性梯度30-60%CH3CN/0.1%TFA/H2O洗脱12分钟,得到13mg(30%)白色固体。1H-NMR(400MHz,δ8.34(d,J=8.6Hz,1H),7.85(s,1H),7.60(s,1H),7.37(dd,J=8.6,2.2Hz,1H),7.28(d,J=2.2Hz,1H),5.79(m,1H),4.03-3.94(m,2H),3.88-3.80(m,2H),3.72(s,2H),2.35-2.27(m,2H),2.13-2.06(m,4H),1.60(t,J=6.3Hz,2H),1.11(s,6H).质谱(ESI,m/z):C26H30N4O5的理论值477.2(M-H),实测值477.2。
实施例4
N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-(2-甲氧基-乙基氨基)-四氢-吡喃-4-基]-苯基}-4-氰基-1H-咪唑-2-甲酰胺
在0℃下,在Ar下,向N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(实施例1步骤(h)产物,50.0mg,0.120mmol)的1.5mL DCM悬浮液中加入SOCl2(26.0μL,0.360mmol)。在室温下搅拌2h后,将混合物冷却至0℃。然后向反应物中加入2-甲氧基乙胺(104μL,1.20mmol),将得到的混合物在0℃下搅拌2h。将混合物用EtOAc(30mL)稀释,然后用H2O(2×10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,真空浓缩,残渣经硅胶层析(1-4%MeOH/DCM)纯化,得到标题化合物(36.8mg,65%),为白色固体。1H-NMR(1∶5CD3OD/CDCl3;400MHz):δ8.31(d,1H,J=8.6Hz),7.70(s,1H),7.30(dd,1H,J=8.6,2.3Hz),7.20(d,1H,J=2.3Hz),5.77(m,1H),3.94(m,2H),3.69(m,2H),3.41(t,2H,J=6.1Hz),3.28(s,3H),2.38(t,2H,J=6.1Hz),2.28(m,2H),2.07-2.20(m,4H),1.88(m,2H),1.59(t,2H,J=6.3Hz),1.10(s,6H).质谱(ESI,m/z):C27H35N5O3的理论值476.3(M-H),实测值476.3。
按实施例4的方法制备实施例5-9
实施例10
(4-{4-[4-[(5-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-基}-哌嗪-1-基)-乙酸三氟乙酸盐
向N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-哌嗪-1-基-四氢-吡喃-4-基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺三氟乙酸盐(22mg,0.036mmol)(实施例1步骤(h)产物)的DCM(0.3mL)悬浮液中加入NEt3(0.015mL,0.11mmol)和溴乙酸乙酯(0.0044mL,0.040mmol),将混合物在室温下搅拌10h。将混合物浓缩,将残渣溶于1mL EtOH,加入7N KOH (0.031mL,0.22mmol),然后在室温下将化合物搅拌3h。将混合物用5mL H2O稀释,将pH调至2,标题化合物经C18柱RP-HPLC纯化,用线性梯度20-50%CH3CN/0.1%TFA/H2O洗脱10分钟,得到22mg(91%)白色固体。1H-NMR(400MHz,δ8.41(d,J=8.6Hz,1H),8.01(s,1H),7.44(dd,J=8.6,2.2Hz,1H),7.31(d,J=2.2Hz,1H),5.81(m,1H),4.00-3.92(m,2H),3.70(s,2H),3.42-3.34(m,2H),3.26-2.86(m,8H),2.70-2.58(m,2H),2.38-2.29(m,2H),2.23-2.05(m,4H),1.60(t,J=6.3Hz,2H),1.10(s,6H).质谱(APCI,m/z):C30H38N6O4的理论值545.3(M-H),实测值545.3。
实施例11
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-四氢-噻喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在-78℃下,在Ar下,向N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备,120mg,0.300mmol)的4mL THF溶液中加入异丙基氯化镁(165μL,0.331mmol,2.0M的THF溶液)。使得到的的混合物升温至室温,搅拌5分钟,再冷却至-78℃。向混合物中加入叔丁基锂(530μL,0.902mmol,1.7M的戊烷溶液),将得到的混合物在-78℃下搅拌10min。然后加入四氢噻喃-4-酮(175mg,1.50mmol)的1mL THF溶液,使反应物升温至室温,在Ar下搅拌0.5h。将混合物依次用2mL饱和NH4Cl、20mL EtOAc处理,用盐水(10mL)洗涤,干燥(Na2SO4)。将溶剂减压除去,然后残渣经硅胶闪层析(1-2%MeOH/DCM)纯化,得到85.0mg(65%)标题化合物,为白色固体。1H-NMR(CDCl3;400MHz):δ12.62(s,1H),9.72(s,1H),8.32(d,1H,J=8.6Hz),7.74(d,1H,J=2.3Hz),7.42(dd,1H,J=8.6,2.3Hz),7.33(d,1H,J=2.3Hz),5.78(m,1H),3.12-3.33(br s,2H),2.46-2.54(m,2H),2.26-2.33(m,2H),2.16-2.22(m,2H),2.00-2.13(m,4H),1.79(s,1H),1.59(t,2H,J=6.3Hz),1.10(s,6H).质谱(ESI,m/z):C24H28N4O2S的理论值437.2(M+H),实测值437.2。
实施例12
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-1,1-二氧代-六氢-1λ6-噻喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在-78℃下,向N-[2-环己-1-烯基-4-(2-羟基-1-羟基甲基-乙基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例11制备,45.0mg,0.103mmol)的2mL 3∶1的DCM/1,4-二噁烷溶液中加入MCPBA(57.0mg,0.165mmol)的2mL 3∶1的DCM/1,4-二噁烷溶液。在Ar下,将得到的混合物在-78℃下搅拌3h。升温至0℃后,将反应物依次用2mL 15%Na2S2O3水溶液、2mL饱和NaHCO3水溶液处理,用EtOAc(2×30mL)萃取。将合并的有机层干燥(Na2SO4),真空浓缩。残渣经硅胶闪层析纯化,用1-2%MeOH/DCM洗脱,得到28mg(58%)标题化合物,为白色固体:1H-NMR(CD3OD;400MHz):δ8.26(d,1H,J=8.6Hz),7.83(s,1H),7.40(dd,1H,J=8.6,2.3Hz),7.31(d,1H,J=2.3Hz),5.74(m,1H),3.57(td,2H,J=13.4,3.0Hz),2.95(m,2H),2.60(td,2H,J=14.4,3.0Hz),2.29(m,2H),2.13(m,2H),2.07(m,2H),1.58(t,2H,J=6.3Hz),1.08(s,6H).质谱(ESI,m/z):C24H28N4O4S的理论值469.2(M+H),实测值469.1。
实施例13
N-[4-(1-乙酰基-4-氨基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺乙酸盐
a)N-[4-(1-乙酰基-4-叠氮基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在0℃下,在Ar下,向N-[4-(1-乙酰基-4-羟基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(实施例35产物,40.0mg,0.0867mmol)和NaN3(56.3mg,0.0867mmol)在2mL DCM中的混合物中加入TFA(100μL,1.30mmol)。在0℃下,在Ar下,将得到的混合物搅拌0.5h,在室温下搅拌2天。用20mL EtOAc处理,将混合物用饱和NaHCO3水溶液(10mL)、盐水(5mL)洗涤,干燥(Na2SO4)。将溶剂减压除去,然后残渣经硅胶闪层析(1-3%MeOH/DCM)纯化,得到40.0mg(95%)标题化合物,为白色固体。质谱(ESI,m/z):C26H30N8O2的理论值487.3(M+H),实测值487.0。
b)N-[4-(1-乙酰基-4-氨基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺乙酸盐
向N-[4-(1-乙酰基-4-叠氮基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备,40.0mg,0.0822mmol)和锌(54.0mg,0.822mmol)在1.6mL THF中的混合物中加入乙酸(0.40mL)。在Ar下,将得到的混合物在室温下搅拌16h。通过硅藻土过滤将固体除去,将滤液真空浓缩。残渣经硅胶闪层析(10%MeOH/DCM)纯化,得到13mg(30%)标题化合物,为白色固体。1H-NMR(CD3OD;400MHz):δ8.33(d,1H,J=8.6Hz),7.91(s,1H),7.52(dd,1H,J=8.6,2.3Hz),7.40(s,1H),5.77(m,1H),3.76-3.98(m,2H),3.42(m,2H),2.46(m,2H),2.32(m,2H),2.13(s,3H),2.07(m,2H),1.86-2.03(m,2H),1.93(s,6H),1.59(t,2H,J=6.1Hz).质谱(ESI-neg,m/z):C26H32N6O2的理论值459.3(M-H),实测值459.5。
实施例14
N-[2-环己-1-烯基-4-(4-羟基-四氢-噻喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)4-溴-2-环己-1-烯基-苯胺
向4-溴-2-碘-苯胺(2.00g,6.71mmol)、2-环己-1-烯基-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(1.40g,6.71mmol)和Pd(PPh3)4(388mg,0.336mmol)在40mL 1,4-二噁烷中的混合物中加入2.0M Na2CO3水溶液(26.8mL,53.7mmol)。在Ar下,在80℃下搅拌5h后,将反应物冷却至室温。将混合物用EtOAc(100mL)处理,用H2O(3×30mL)和盐水(20mL)洗涤。将有机层干燥(Na2SO4),真空浓缩。残渣经硅胶闪层析(10-20%EtOAc/己烷)纯化,得到1.47g(87%)标题化合物,为浅棕色油状物。质谱(ESI,m/z):C12H14BrN的理论值252.0(M+H),实测值252.0。
b)N-(4-溴-2-环己-1-烯基-苯基)-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺
向4-溴-2-环己-1-烯基-苯胺(按前一步骤制备,1.23g,4.88mmol)、4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H咪唑-2-甲酸钾(实施例1步骤(d)产物,1.49g,4.88mmol)和六氟磷酸溴代三吡咯烷-1-基磷鎓(PyBroP)(2.27g,4.88mmol)在25mL DMF中的混合物中加入N,N-二异丙基乙胺(DIEA)(,14.6mmol)。在室温下搅拌16h后,将混合物用100mL EtOAc处理,然后用H2O()、盐水(30mL)洗涤,干燥(Na2SO4)。将有机溶剂蒸发,残渣经硅胶闪层析(5-10%EtOAc/己烷)纯化,得到2.21g(90%)标题化合物,为白色固体。1H-NMR(CDCl3;400MHz):9.70(s,1H),8.26(d,1H,J=8.6Hz),7.78(s,1H),7.36(dd,1H,J=8.6,2.3Hz),7.31(d,1H,J=2.3Hz),5.94(s,2H),5.86(m,1H),3.66(t,2H,J=8.3Hz),2.19-2.33(m,4H),1.75-1.88(m,4H),0.97(t,2H,J=8.3Hz),0.00(s,9H).
c)N-(4-溴-2-环己-1-烯基-苯基)-4-氰基-1H-咪唑-2-甲酰胺
向N-(4-溴-2-环己-1-烯基-苯基)-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺(按前一步骤制备,1.20g,2.39mmol)的10mL DCM(CH2Cl2)溶液中依次加入0.30mL EtOH、5.0mL TFA。在室温下搅拌3h后,将混合物用20mL正丙醇处理,真空浓缩。将残渣用DCM研磨,得到853mg(96%)标题化合物,为白色固体。1H-NMR(DMSO-d6;400MHz):9.80(s,1H),8.30(s,1H),7.94(d,1H,J=8.6Hz),7.50(dd,1H,J=8.6,2.3Hz),7.39(d,1H,J=2.3Hz),5.80(m,1H),2.12-2.25(m,4H),1.61-1.77(m,4H).质谱(ESI,m/z):C17H15BrN4O的理论值371.0(M+H),实测值371.0。
d)N-[2-环己-1-烯基-4-(4-羟基-四氢-噻喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
通过实施例11的方法,用N-(4-溴-2-环己-1-烯基-苯基)-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备,120mg,0.323mmol)和四氢-噻喃-4-酮(188mg,1.62mmol)制备标题化合物。经硅胶层析(1-3%MeOH/DCM)纯化,得到标题化合物(82.3mg,62%),为白色固体。1H-NMR(CDCl3;400MHz):δ(s,1H),9.66(s,1H),8.29(d,1H,J=8.6Hz),7.74(d,1H,J=2.5Hz),7.42(dd,1H,J=8.6,2.3Hz),7.33(d,1H,J=2.3Hz),5.86(m,1H),3.22(m,2H),2.46-2.54(m,2H),2.22-2.33(m,4H),2.16-2.22(m,2H),2.01-2.09(m,2H),1.73-1.89(m,5H).质谱(ESI,m/z):C22H24N4O2S的理论值409.2(M+H),实测值409.1。
实施例15
N-[2-环己-1-烯基-4-(4-羟基-1,1-二氧代-六氢-1λ6-噻喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
通过实施例12的方法,用N-[2-环己-1-烯基-4-(4-羟基-四氢-噻喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例14,步骤(d)制备,60.0mg,0.147mmol)制备标题化合物。经硅胶层析(10-40%EtOAc/DCM)纯化,得到标题化合物(25.7mg,40%),为白色固体。1H-NMR(CD3OD;400MHz):δ8.26(d,1H,J=8.6Hz),7.83(s,1H),7.40(dd,1H,J=8.6,2.3Hz),7.31(d,1H,J=2.3Hz),5.74(m,1H),3.57(td,2H,J=13.4,3.0Hz),2.95(m,2H),2.60(td,2H,J=14.4,3.0Hz),2.29(m,2H),2.13(m,2H),2.07(m,2H),1.58(t,2H,J=6.3Hz),1.08(s,6H).质谱(ESI,m/z):C24H28N4O4S理论值469.2(M+H),实测值469.1。
实施例16
4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯
a)4-(4-硝基-苯基)-四氢-吡喃-4-甲酸甲酯
在-78℃下,向二异丙基氨基化锂(12.2mL,22.0mmol,1.8M)的40mL THF溶液中滴加四氢吡喃-4-甲酸甲酯(2.88g,20.0mmol)。将得到的混合物在-78℃下搅拌15分钟,升温至室温。加入1,3-二甲基-四氢嘧啶-2-酮(2.69g,22.0mmol)。将反应物再冷却至-78℃,缓慢加入1-氟-4-硝基-苯(3.10g,22.0mmol)。将得到的混合物升温至室温,然后在Ar下搅拌1天。将反应物用30mL饱和NH4Cl处理,用80mL
EtOAc萃取。将有机萃取液用H2O(50mL)、盐水(20mL)洗涤,干燥(Na2SO4),浓缩。残渣经硅胶闪层析(5-20%EtOAc/己烷)纯化,得到1.61g(30%)标题化合物,为黄色固体。1H-NMR(CDCl3;400MHz):δ.8.21(d,1H,J=9.0Hz),7.56(d,1H,J=9.0Hz),3.97(m,2H),3.70(s,3H),3.57(m,2H),2.56(m,2H),2.00(m,2H).
b)4-(4-氨基-苯基)-四氢-吡喃-4-甲酸甲酯
在室温下,在H2(气瓶压力)下,将4-(4-硝基-苯基)-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,2.12g,8.00mmol)和10%Pd/C(1.06g,50%(重量))在20mL MeOH中的混合物搅拌2h。使Pd催化剂通过硅藻土过滤除去,将滤液浓缩,得到1.69g(90%)标题化合物,为白色固体。质谱(ESI,m/z):C13H17NO3的理论值236.1(M+H),实测值236.2。
c)4-(4-氨基-3-溴-苯基)-四氢-吡喃-4-甲酸甲酯
在0℃下,在Ar下,向4-(4-氨基-苯基)-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,1.65g,7.01mmol)的100mL 1∶1DCM/CH3CN溶液中缓慢加入N-溴代琥珀酰亚胺(NBS)(1.25g,7.01mmol)的25mL 1∶1DCM/CH3CN溶液。在0℃下搅拌0.5h后,将混合物用50mL EtOAc处理,然后用H2O(2×30mL)和盐水H2O(20mL)洗涤。将有机层干燥(Na2SO4),真空浓缩。残渣经硅胶闪层析(1-4%EtOAc/DCM)纯化,得到1.85g(84%)标题化合物,为白色固体。质谱(ESI,m/z):C13H16BrNO3的理论值314.0(M+H),实测值314.2。
d)4-[4-氨基-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯
向4-(4-氨基-3-溴-苯基)-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,1.45g,4.61mmol)、4,4-二甲基环己烯-1-基硼酸(782mg,5.08mmol)和二氯(1,1-二(二苯膦基-二茂铁)合钯(II)(Pd(dppf)Cl2)二氯甲烷加合物(337mg,0.461mmol)在40mL DMF中的混合物中加入K3PO4(3.91g,18.4mmol)。在70℃下,在Ar下,将得到的混合物搅拌18h。冷却至室温后,将混合物用150mL EtOAc处理,用H2O(3×30mL)和盐水(30mL)洗涤。将有机层干燥(Na2SO4),真空浓缩。残渣经硅胶闪层析(0-2%EtOAc/DCM)纯化,得到1.14g(72%)标题化合物,为白色固体。质谱(ESI,m/z):C21H29NO3的理论值344.2(M+H),实测值344.4。
e)4-[4-{[4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-羰基]-氨基}-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯
通过实施例1步骤(f)偶合方法,用4-[4-氨基-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,650mg,1.89mmol)和4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾(实施例1步骤(d)产物,636mg,2.08mmol)制备标题化合物。经硅胶层析(DCM)纯化,得到标题化合物(1.01g,90%),为无色油状物。质谱(ESI,m/z):C32H44N4O5Si的理论值593.3(M+H),实测值593.0。
f)4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯
通过实施例1步骤(g)方法,用4-[4-{[4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-羰基]-氨基}-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,550mg,0.927mmol)制备标题化合物。标题化合物(411mg,96%)为白色固体。1H-NMR(CDCl3;400MHz):δ(s,1H),9.66(s,1H),8.34(d,1H,J=8.6Hz),7.74(d,1H,J=2.5Hz),7.34(dd,1H,J=8.6,2.3Hz),7.18(d,1H,J=2.3Hz),5.78(m,1H),3.96(m,2H),3.71(s,3H),3.57(m,2H),2.54(m,2H),2.28(m,2H),2.11(m,2H),2.0(m,2H),1.59(t,2H,J=6.2Hz),1.11(s,6H).质谱(ESI,m/z):C26H30N4O4的理论值463.2(M+H),实测值463.2。
实施例17
4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸
向4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯(按实施例16步骤(f)制备,129mg,0.279mmol)的2mL 1∶1THF/MeOH溶液中加入6N NaOH(400μL,2.40mmol)。在室温下搅拌2天后,将混合物用10mL H2O处理,然后用EtOAc(3×10mL)洗涤。用15%柠檬酸将水层酸化至pH=5,然后用10∶1的EtOAc-MeOH(3×10mL)萃取。将合并的有机层干燥(Na2SO4),真空浓缩,得到119mg(95%)标题化合物,为白色固体。1H-NMR(CD3OD;400MHz):8.20(d,1H,J=8.8Hz),8.00(s,1H),7.37(dd,1H,J=8.8,2.3Hz),7.24(d,1H,J=2.3Hz),5.75(m,1H),3.91(m,2H),3.61(t,2H,J=11.5Hz),2.49(m,2H),2.30(m,2H),2.08(m,2H),1.95(m,2H),1.60(t,2H,J=6.1Hz),1.09(s,6H).质谱(ESI,m/z):C25H28N4O4的理论值449.2(M+H),实测值449.2。
实施例18
4-{4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-环己-1-烯基-苯基}-四氢-吡喃-4-甲酸
a)4-(4-氨基-3-环己-1-烯基-苯基)-四氢-吡喃-4-甲酸甲酯
通过实施例16步骤(d)Suzuki偶合方法,用4-(4-氨基-3-溴-苯基)-四氢-吡喃-4-甲酸甲酯(按实施例16步骤(c)制备,380mg,1.21mmol)和2-环己-1-烯基-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(277mg,1.33mmol)制备标题化合物。经硅胶层析(0-2%EtOAc/DCM)纯化,得到标题化合物(268mg,70%),为白色固体。质谱(ESI,m/z):C19H25NO3的理论值316.2(M+H),实测值316.2。
b)4-(4-{[4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-羰基]-氨基}-3-环己-1-烯基-苯基)-四氢-吡喃-4-甲酸甲酯
通过实施例1步骤(f)偶合方法,用4-(4-氨基-3-环己-1-烯基-苯基)-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,250mg,0.793mmol)和4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾(按实施例1步骤(d)制备,266mg,0.872mmol)制备标题化合物。经硅胶层析(20%EtOAc-己烷)纯化,得到标题化合物(348mg,78%),为无色油状物。质谱(ESI,m/z):C30H40N4O5Si的理论值565.3(M+H),实测值565.0。
c)4-{4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-环己-1-烯基-苯基}-四氢-吡喃-4-甲酸甲酯
通过实施例1步骤(g)方法,用4-(4-{[4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-羰基]-氨基}-3-环己-1-烯基-苯基)-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,339mg,0.600mmol)制备标题化合物。标题化合物(249mg,95%)为微黄色固体。质谱(ESI,m/z):C24H26N4O4的理论值435.2(M+H),实测值435.2。
d)4-{4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-环己-1-烯基-苯基}-四氢-吡喃-4-甲酸
通过实施例17方法,用4-{4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-环己-1-烯基-苯基}-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,239mg,0.550mmol)制备标题化合物。标题化合物(227mg,98%)为白色固体。1H-NMR(CD3OD;400MHz):δ8.25(d,1H,J=8.6Hz),7.84(s,1H),7.35(dd,1H,J=8.6,2.3Hz),7.23(d,1H,J=2.3Hz),5.84(m,1H),3.94(m,2H),3.66(m,2H),2.54(m,2H),2.20-2.34(m,4H),1.97(m,2H),1.74-1.89(m,4H).质谱(ESI,m/z):C23H24N4O4的理论值421.2(M+H),实测值421.1。
实施例19
N-[4-(4-氨基甲酰基-四氢-吡喃-4-基)-2-环己-1-烯基-苯基]-4-氰基-1H-咪唑-2-甲酰胺
向4-{4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-环己-1-烯基-苯基}-四氢-吡喃-4-甲酸(按实施例18步骤(d)制备,14.5mg,0.0345mmol)的1mL THF溶液中加入ClCO2Me(3.6mg,0.038mmol)。将混合物冷却至0℃,加入DIEA(18μL,0.10mmol)。升温至室温后,搅拌1h,将混合物再冷却至0℃。加入浓氢氧化铵(25μL,0.37mmol),使得到的混合物升温至室温,搅拌16h。将反应物用30mL EtOAc处理,用盐水(10mL)洗涤。有机层经Na2SO4干燥,真空浓缩。残渣经硅胶层析(1-5MeOH/DCM)纯化,得到标题化合物(4.7mg,32%),为白色固体。1H-NMR(CDCl3;400MHz):δ(s,1H),9.53(s,1H),8.33(d,1H,J=8.6Hz),7.74(d,1H,J=2.3Hz),7.33(dd,1H,J=8.6,2.3Hz),7.20(d,1H,J=2.3Hz),5.85(m,1H),5.81(br s,1H),5.32(br s,1H),3.82(m,4H),2.38(m,2H),2.19-2.34(m,4H),2.11(m,2H),1.82(m,2H).质谱(ESI,m/z):C23H25N5O3的理论值420.2(M+H),实测值420.1。
实施例20
N-[2-环己-1-烯基-4-(4-羟基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在0℃下,向4-{4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-环己-1-烯基-苯基}-四氢-吡喃-4-甲酸(按实施例18步骤(d)制备,20.0mg,0.0476mmol)和三乙胺(Et3N)(7.3μL,0.052mmol)在1mL THF中的混合物加入ClCO2Et(3.6mg,0.038mmol)。将混合物在室温下搅拌0.5h,加入NaBH4(5.4mg,0.14mmol)。在室温下搅拌16h后,将混合物用30mLEtOAc和10ml10%柠檬酸处理。将水层分离,用EtOAc(10mL)萃取。将合并的有机层用饱和NaHCO3水溶液(10mL)、H2O(10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,真空浓缩,残渣经硅胶层析(1-2%MeOH/DCM)纯化,得到标题化合物(14mg,70%),为白色固体。1H-NMR(1∶5CD3OD/CDCl3;400MHz):δ8.24(d,1H,J=8.6Hz),7.72(s,1H),7.26(dd,1H,J=8.6,2.3Hz),7.14(d,1H,J=2.3Hz),5.84(m,1H),3.82(m,2H),3.57(s,2H),3.54-3.60(m,2H),2.27(m,4H),2.14(m,2H),1.95(m,2H),1.82(m,4H).质谱(ESI,m/z):C23H26N4O3的理论值407.2(M+H),实测值407.1。
实施例21
N-[2-环己-1-烯基-4-(4-吗啉-4-基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)N-[2-环己-1-烯基-4-(4-甲酰基-四氢吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在0℃下,将N-[2-环己-1-烯基-4-(4-羟基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例20制备,75.4mg,0.185mmol)、戴斯-马丁periodinane(157mg,0.369mmol)和NaHCO3(155mg,1.85mmol)在3mL DCM中的混合物搅拌0.5h,在室温下搅拌1h。向反应物中加入2mL 10%Na2S2O3,将得到的混合物剧烈搅拌5分钟。将混合物用20mL H2O处理,然后用EtOAc(2×40mL)萃取。将合并的有机层用饱和NaHCO3水溶液(10mL)、H2O(10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,真空浓缩,残渣经硅胶层析(10-20%EtOAc/DCM)纯化,得到标题化合物(45mg,60%),为白色固体。质谱(ESI,m/z):C23H24N4O3的理论值405.2(M+H),实测值405.1。
b)N-[2-环己-1-烯基-4-(4-吗啉-4-基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在室温下,将N-[2-环己-1-烯基-4-(4-甲酰基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备,30.5mg,0.0754mmol)、吗啉(14μL,0.15mmol)和硼氢化钠(6.0mg,0.16mmol)在2mL1∶1DCM/THF中的混合物搅拌3h。然后将混合物用饱和NaHCO3水溶液(10mL)处理,然后用EtOAc(3×10mL)萃取。将合并的有机层用H2O(10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,真空浓缩,残渣经硅胶层析(10-30%EtOAc/DCM)纯化,得到标题化合物(28mg,77%),为白色固体。1H-NMR(CDCl3;400MHz):δ12.61(s,1H),9.66(s,1H),8.31(d,1H,J=8.6Hz),7.76(s,1H),7.28(dd,1H,J=8.6,2.3Hz),7.17(d,1H,J=2.3Hz),5.86(m,1H),3.79(m,2H),3.59(m,2H),3.53(m,4H),2.45(s,2H),2.29(m,4H),2.13-2.21(m,6H),1.77-1.98(m,6H).质谱(ESI,m/z):C27H33N5O3的理论值476.3(M+H),实测值476.2。
实施例22
N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯基}-4-氰基-1H-咪唑-2-甲酰胺
a)4-(4-硝基-苯基)-四氢吡喃-4-甲酸
通过实施例17方法,用4-(4-硝基-苯基)-四氢-吡喃-4-甲酸甲酯(按实施例16步骤(a)制备,531mg,2.00mmol)制备标题化合物,得到465mg(92%)白色固体。1H-NMR(CD3OD;400MHz):8.24(d,1H,J=9.1Hz),7.70(d,1H,J=9.1Hz),3.93(ddd,2H,J=11.9,3.8,3.5Hz),3.64(ddd,2H,J=11.9,11.1,2.3Hz),2.55(m,2H),1.98(m,2H)。
b)4-(4-硝基-苯基)-四氢-吡喃-4-甲腈
向4-(4-硝基-苯基)-四氢-吡喃-4-甲酸(按前一步骤制备,251mg,1.00mmol)和磺酰胺(115mg,1.20mmol)在1mL环丁砜中的混合物加入亚硫酰氯(80μL,1.10mmol)。将得到的混合物在120℃下搅拌16h。冷却至0℃后,用1N NaOH溶液将混合物中和至pH 7,然后用30mLEtOAc处理。将有机层分离,用H2O(2×10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,真空浓缩,残渣经硅胶层析(3∶7己烷/DCM)纯化,得到标题化合物(223mg,96%),为微黄色固体。1H-NMR(CDCl3;400MHz):8.30(d,1H,J=9.1Hz),7.56(d,1H,J=9.1Hz),4.13(m,2H),3.93(m,2H),2.17(m,2H),2.07(m,2H).
c)4-(4-氨基-苯基)-四氢-吡喃-4-甲腈
在室温下,在H2(气瓶压力)下,将4-(4-硝基-苯基)-四氢-吡喃-4-甲腈(按前一步骤制备,223mg,0.960mmol)和10%Pd/C(112mg,50%(重量))在10mL MeOH中的混合物搅拌1h。将Pd催化剂通过硅藻土过滤除去,将滤液浓缩,得到195mg(100%)标题化合物,为微黄色固体。质谱(ESI,m/z):C12H14N2O的理论值203.1(M+H),实测值203.2。
d)4-(4-氨基-3-溴-苯基)-四氢-吡喃-4-甲腈
通过实施例16步骤(c)方法,用4-(4-氨基-苯基)-四氢-吡喃-4-甲腈(按前一步骤制备,195mg,0.964mmol)制备标题化合物。经硅胶层析(20%EtOAc/己烷)纯化,得到标题化合物(166mg,61%),为白色固体。质谱(ESI,m/z):C12H13BrN2O的理论值281.0(M+H),实测值281.2。
e)2-溴-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯胺
在Ar下,将4-(4-氨基-3-溴-苯基)-四氢-吡喃-4-甲腈(按前一步骤制备,141mg,0.500mmol)、三甲基甲硅烷基叠氮化物(133μL,1.00mmol)和氟化四丁铵(65mg,0.25mmo1)的混合物在120℃下搅拌18h。冷却至室温后,将混合物用30mL EtOAc处理,然后用H2O(2×10mL)、15%柠檬酸水溶液(3×10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,将有机层真空浓缩,得到标题化合物(147mg,91%),为微黄色固体。质谱(ESI,m/z):C12H14BrN5O的理论值324.0(M+H),实测值324.1。
f)N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯基}-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺
向2-溴-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯胺(70.0mg,0.216mmol)、4,4-二甲基环己烯-1-基硼酸(36.6mg,0.238mmol)和Pd(PPh3)4(25.0mg,0.0216mmol)在2mL 1,4-二噁烷中的混合物中加入2.0MNa2CO3水溶液(0.85mL,1.7mmol)。在Ar下,在80℃下,将得到的化合物搅拌2天。冷却至室温后,将反应物用H2O(20mL)处理,然后用EtOAc(2×10mL)洗涤。将水层混合物用15%柠檬酸水溶液中和至PH 6,用EtOAc(3×10mL)萃取。合并的有机层经Na2SO4干燥,真空浓缩,得到76mg 2-(4,4-二甲基-环己-1-烯基)-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯胺粗产物,为棕色油状物。该产物立即用于下一步实验,无需进一步纯化。
向2-(4,4-二甲基-环己-1-烯基)-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯胺粗产物(76mg,约0.22mmol)的2.5mL DMF溶液中加入4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾(按实施例1步骤(d)制备,72mg,0.24mmol)、PyBroP(110mg,0.236mmol)和DIEA(112μL,0.645mmol)。在室温下搅拌2天后,将混合物用20mL H2O处理,然后用EtOAc(2×20mL)萃取。将合并的有机层用H2O(2×10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,真空浓缩,残渣经硅胶层析(1-3MeOH/DCM)纯化,得到标题化合物(55mg,42%2步合计),为微棕色固体。质谱(ESI,m/z):C31H42N8O3Si的理论值603.3(M+H),实测值602.9。
g)N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯基}-4-氰基-1H-咪唑-2-甲酰胺
通过实施例11步骤(g)方法,用N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-(2H-四唑-5-基)-四氢-吡喃-4-基]-苯基}-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺(按前一步骤制备,51.2mg,0.0850mmol)制备标题化合物。经硅胶层析(1-4%MeOH/DCM)纯化,得到标题化合物(17mg,43%),为白色固体。1H-NMR(CD3OD;400MHz):δ8.26(d,1H,J=8.6Hz),7.90(s,1H),7.22(dd,1H,J=8.6,2.3Hz),7.12(d,1H,J=2.3Hz),5.73(m,1H),3.95(m,2H),3.54(m,2H),2.70(m,2H),2.42(m,2H),2.26(m,2H),2.08(m,2H),1.58(t,2H,J=6.3Hz),1.09(s,6H).质谱(ESI,m/z):C25H28N8O2的理论值473.2(M+H),实测值473.2。
实施例23
4-[4-[(4-氰基-1H-吡咯-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸
a)4-[4-[(4-氰基-1H-吡咯-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯
在室温下,在Ar下,将4-[4-氨基-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯(按实施例16步骤(d)制备,68.7mg,0.200mmol)、4-氰基-1H-吡咯-2-甲酸(Canadian J.Chem.59,2673(1981),40.8mg,0.300mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(57.5mg,0.300mmol)、羟基苯并***(HOBt)(40.5mg,0.300mmol)和DIEA(105μL,0.600mmol)的2.5mL DMF溶液搅拌2天。将得到的混合物用H2O(20mL)处理,然后用EtOAc(2×25mL)萃取。将合并的有机层用H2O(10mL)和盐水(10mL)洗涤。经Na2SO4干燥后,真空浓缩,残渣经硅胶层析(10-20%EtOAc/DCM)纯化,得到标题化合物(46mg,50%),为白色固体。质谱(ESI,m/z):C27H31N3O4的理论值462.2(M+H),实测值462.2。
b)4-[4-[(4-氰基-1H-吡咯-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸
通过实施例17方法,用4-[4-[(4-氰基-1H-吡咯-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯(按前一步骤制备,28.0mg,0.0607mmol)制备标题化合物。标题化合物(11.1mg,41%)为白色固体。1H-NMR(1∶1CDCl3/CD3OD;400MHz):δ7.65(d,1H,J=8.6Hz),7.51(d,1H,J=1.5Hz),7.36(dd,1H,J=8.6,2.3Hz),7.26(d,1H,J=2.3Hz),7.04(s,1H),5.69(m,1H),3.94(m,2H),3.65(m,2H),2.53(m,2H),2.29(m,2H),1.91-2.01(m,4H),1.50(t,2H,J=6.3Hz),0.98(s,6H).质谱(ESI,m/z):C26H29N3O4的理论值448.2(M+H),实测值448.2。
实施例24
N-[4-(4-氨基甲酰基-四氢-吡喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
通过实施例19方法,用4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸(按实施例17制备,13.0mg,0.0290mmol)制备标题化合物。经硅胶层析(5%MeOH/DCM)纯化,得到标题化合物(4.0mg,31%),为白色固体。1H-NMR(CD3OD;400MHz):8.27(d,1H,J=8.6Hz),7.91(s,1H),7.35(dd,1H,J=8.6,2.3Hz),7.24(d,1H,J=2.3Hz),5.76(m,1H),3.81-3.89(m,2H),3.68-3.76(m,2H),2.42-2.50(m,2H),2.26-2.36(m,2H),1.98-2.12(m,4H),1.60(t,2H,J=6.3Hz),1.10(s,6H).质谱(ESI,m/z):C25H29N5O3的理论值448.2(M+H),实测值448.2。
实施例25
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在80℃下,在20分钟内,向4-[4-[(4-氰基-1H-吡咯-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-四氢-吡喃-4-甲酸甲酯(按实施例16步骤(f)制备,300mg,0.649mmol)和NaBH4(123mg,3.24mmol)在10mL t-BuOH中的混合物加入MeOH(1.30mL)。在Ar下,在80℃下,将得到的混合物搅拌32h。冷却至室温后,将混合物用15%柠檬酸水溶液处理至pH 5。然后将混合物用30mL H2O处理,然后用EtOAc(3×20mL)萃取。合并的有机层用H2O(20mL)、盐水(10mL)洗涤,干燥(Na2SO4),真空浓缩。残渣经硅胶闪层析纯化,用2-3%Me0H/DCM洗脱,得到107mg(38%)标题化合物,为白色固体:δ8.19(d,1H,J=8.6Hz),7.95(s,1H),7.31(dd,1H,J=8.6,2.3Hz),7.19(d,1H,J=2.3Hz),5.75(m,1H),3.80(m,2H),3.47-3.57(m,2H),3.52(s,2H),2.32(m,2H),2.05-2.17(m,4H),1.90-1.99(m,2H),1.59(t,2H,J=6.3Hz),1.08(s,6H).质谱(ESI,m/z):C25H30N4O3的理论值435.2(M+H),实测值435.1。
实施例26
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-吗啉-4-基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-甲酰基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
通过实施例21步骤(a)方法,用N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例25制备,40.0mg,0.0921mmol)和戴斯-马丁氧化剂(80.5mg,0.184mmol)制备标题化合物。得到标题化合物(40mg,100%),为白色固体,其在下一步中使用,无需进一步纯化。质谱(ESI,m/z):C25H28N4O3的理论值433.2(M+H),实测值433.4。
b)N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-吗啉-4-基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
通过实施例21步骤(b)的方法,用N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-甲酰基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备,40.0mg,0.0921mmol)、吗啉(13μL,0.14mmol)和三乙酰氧基硼氢化钠(5.2mg,0.14mmol)制备标题化合物。经硅胶层析(依次为10-20%EtOAc/DCM、1-2%MeOH/DCM)纯化,得到标题化合物(20mg,43%),为白色固体。1H-NMR(CDCl3;400MHz):δ12.61(s,1H),9.70(s,1H),8.33(d,1H,J=8.6Hz),7.75(s,1H),7.28(dd,1H,J=8.6,2.3Hz),7.16(d,1H,J=2.3Hz),5.78(m,1H),3.79(m,2H),3.59(m,2H),3.50-3.62(m,4H),2.45(s,2H),2.25-2.31(m,2H),2.11-2.22(m,8H),1.93(m,2H),1.61(t,2H,J=6.3Hz),1.13(s,6H).质谱(ESI,m/z):C29H37N5O3的理论值504.3(M+H),实测值504.3。
按指定实施例制备以下化合物:
实施例30和31
N-[2-(4,4-二甲基-环己-1-烯基)-4-(顺-4-羟基-顺-2,6-二甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺和N-[2-(4,4-二甲基-环己-1-烯基)-4-(反-4-羟基-顺-2,6-二甲基-四氢吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)中所述,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1(步骤g)制备)和顺-2,6-二甲基四氢吡喃-4-酮(Monatshefte fuer Chemie,136(7),1197-1203,(2005))制备标题化合物。
31:质谱(ESI,m/z):C26H32N4O3的理论值449.2(M+H),实测值449.2。
32:质谱(ESI,m/z):C26H32N4O3的理论值449.2(M+H),实测值449.2。
实施例32
N-[2-(4,4-二甲基-环己-1-烯基)-6-(4-羟基-顺-2,6-二甲基-四氢-吡喃-4-基)-吡啶-3-基]-4-氰基-1H-咪唑-2-甲酰胺
a)6-溴-2-碘-吡啶-3-基胺
搅拌下,向6-溴-吡啶-3-基胺(10.2g,0.0580mol)和Ag2SO4(18.1g,0.0580mol)的EtOH(150mL)溶液中加入I2(7.59g,0.0580mol),将反应物搅拌过夜。在此时加入己烷(200mL),使得到的混合物通过硅藻土过滤。将溶剂真空除去,将残渣溶于CHCl3(200mL),用饱和Na2S2O3水溶液(100mL)、水(1×100mL)洗涤,干燥(Na2SO4)。将溶剂真空浓缩,将残渣溶于热EtOAc(100mL),过滤,用己烷(100mL)处理。过滤,得到11.2g(65%)6-溴-2-碘-吡啶-3-基胺,为白色结晶物。1H-NMR(CDCl3;400MHz):δ7.10(d,1H,J=8.2Hz),6.74(d,1H,J=8.2Hz),4.06(br s,2H).
b)6-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基胺
将6-溴-2-碘-吡啶-3-基胺(按前一步骤制备,1.00g,3.35mmol)的甲苯(27mL)和EtOH(13.5mL)溶液用2.0M Na2CO3水溶液(13.4mL,26.8mmol)和4,4-二甲基-环己-1-烯基硼酸(567mg,3.68mmol)处理。通过超声将混合物脱气,置于Ar下,用Pd(PPh3)4(271mg,0.234mmol)处理,加热至80℃保持5h。将冷却的混合物用EtOAc(100mL)稀释,然后用水(2×50mL)洗涤。将合并的水层用EtOAc(1×100mL)萃取。合并的有机层经MgSO4干燥,真空浓缩。残渣经Varian MegaBond Elut50-g硅胶柱层析纯化,用10%EtOAc-己烷洗脱,得到668mg(71%)6-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基胺,为棕褐色固体。1H-NMR(CDCl3;400MHz):δ7.06(d,1H,J=8.3Hz),6.85(d,1H,J=8.3Hz),5.95(m,1H),3.86(br s,2H),2.43-2.39(m,2H),1.99-1.97(m,2H),1.51(t,2H,J=6.4Hz),0.99(s,6H).
c)N-[6-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基]-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺
按实施例1步骤(f)方法,由6-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基胺(按前一步骤制备,60mg,0.21mmol)、4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾(按实施例1步骤(d)制备,91.0mg,0.290mmol)、PyBroP(157mg,0.330mmol)和DIEA(,0.520mmol)制备标题化合物(84mg,78%)。1H-NMR(CDCl3;400MHz):δ9.91(s,1H),8.64(d,1H,J=8.6Hz),7.79(s,1H),7.38(d,1H,J=8.6Hz),6.00(m,1H),5.92(s,2H),3.67(m,2H),2.46(m,2H),2.14(m,2H),1.62(t,2H,J=6.3Hz),1.12(s,6H),0.98(m,2H)。
d)N-[6-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基]-5-氰基-1H-咪唑-2-甲酰胺
按照实施例1步骤(g)方法,由N-[6-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基]-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺(按前一步骤制备)制备标题化合物。1H-NMR(CD3OD;400MHz):δ8.53(d,1H,J=8.8Hz),8.03(s,1H),7.48(d,1H,J=8.8Hz),6.04-5.99(m,1H),2.48-2.40(m,2H),2.13-2.08(m,2H),1.61(t,2H,J=6.0Hz),1.09(s,6H).质谱(ESI,m/z):C18H18BrN5O理论值400.1(M+H),实测值400.0。
e)N-[2-(4,4-二甲基-环己-1-烯基)-6-(4-羟基-顺-2,6-二甲基-四氢-吡喃-4-基)-吡啶-3-基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)所述,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基]-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备)和顺-2,6-二甲基四氢吡喃-4-酮(Monatshefte fuer Chemie,136(7),1197-1203,(2005))制备标题化合物。
质谱(ESI,m/z):C25H31N5O3的理论值450.2(M+H),实测值450.2。
实施例33
N-[2-(4,4-二甲基-环己-1-烯基)-6-(4-羟基-四氢-吡喃-4-基)-吡啶-3-基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)所述,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例32步骤(d)制备)和四氢吡喃-4-酮制备标题化合物。质谱(ESI,m/z):C25H27N5O3的理论值422.2(M+H),实测值422.2。
实施例34
N-[2-环己-1-烯基-4-(4-甲磺酰基-四氢吡喃-4-基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺
向N-[2-环己-1-烯基-4-(4-羟基-四氢-吡喃-4-基)-苯基]-5-氰基-1H-咪唑-2-甲酰胺(按实施例27制备,75mg,0.19mmol)和甲基亚磺酸钠(195mg,1.90mmol)在4mL甲醇中的混合物中加入0.28mL(3.80mmol)TFA。将混合物在70℃下搅拌过夜,然后真空浓缩。使粗残渣在EtOAc(20mL)和饱和NaHCO3水溶液(20mL)中分配,将有机层干燥(Na2SO4),然后真空浓缩。残渣经制备硅胶TLC(20%乙酸乙酯-己烷)纯化,得到标题化合物,为浅棕色油状物(18mg,21%)。1H-NMR(CDCl3;400MHz):δ9.64(s,1H),8.32(d,1H,J=8.0),7.71(s,1H),7.33(m,1H),7.23(d,1H,J=1.8Hz),5.87(s,1H),3.90-3.81(m,4H),3.01(s,3H),2.30-2.25(m,4H),2.07-1.79(m,8H).
实施例35
N-[4-(1-乙酰基-4-羟基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
通过实施例11方法,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备,80.0mg,0.200mmol)和1-乙酰基-哌啶-4-酮(123μL,1.00mmol)制备标题化合物。经硅胶层析(2-5%MeOH/DCM)纯化,得到标题化合物(59.1mg,64%),为无色油状物。1H-NMR(CD3OD;400MHz):8.18(d,1H,J=8.6Hz),8.00(s,1H),7.39(dd,1H,J=8.6,2.3Hz),7.35(d,1H,J=2.3Hz),5.74(m,1H),4.45(m,1H),3.84(m,1H),3.60(m,1H),3.11(m,1H),2.28-2.35(m,2H),2.15(s,3H),1.91-2.10(m,4H),1.76(m,2H),1.59(t,2H,J=6.3Hz),1.09(s,6H).质谱(ESI,m/z):C26H31N5O3的理论值462.2(M+H),实测值462.0。
按前述实施例方法,用下表中所示相应试剂制备以下实施例:
实施例73
N-[4-(4-氨基甲基-四氢-吡喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)4-(4-硝基-苯基)-四氢-吡喃-4-甲腈
通过分批加入4-(硝基-苯基)-乙腈(1当量)处理NaH(95%,无水,2.4当量)的DMSO浆状物,然后在室温下搅拌至H2发生停止。将混合物用1-溴-2-(2-溴-乙氧基)-乙烷(1.2当量)处理,然后在70℃下搅拌3h。将溶液用EtOAc稀释,然后用水洗涤。将有机层干燥(MgSO4),真空浓缩。残渣经硅胶层析纯化,用适当溶剂洗脱,得到标题化合物。
b)C-[4-(4-硝基-苯基)-四氢-吡喃-4-基]-甲胺
将4-(4-硝基-苯基)-四氢-吡喃-4-甲腈(按前一步骤制备)的THF溶液在室温下用ZrCl4和NaBH4(Synthesis,(12),995-6(1988))处理。将混合物用EtOAc稀释,然后用水洗涤。将有机层干燥(MgSO4),真空浓缩。残渣经硅胶层析纯化,用适当溶剂洗脱,得到标题化合物。
c)[4-(4-硝基-苯基)-四氢-吡喃-4-基甲基]-氨基甲酸叔丁酯
在室温下,将C-[4-(4-硝基-苯基)-四氢-吡喃-4-基]-甲胺(按前一步骤制备)的THF溶液用BOC2O处理。将混合物用EtOAc稀释,然后用水洗涤。将有机层干燥(MgSO4),真空浓缩。残渣经硅胶层析纯化,用适当溶剂洗脱,得到标题化合物。
d)N-[4-(4-氨基甲基-四氢-吡喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例22步骤(c)和实施例1步骤(e)-(g)方法,由[4-(4-硝基-苯基)-四氢-吡喃-4-基甲基]-氨基甲酸叔丁酯(按前一步骤制备)制备标题化合物。
实施例74
N-[4-(4-氨基甲酰基-1,1-二氧代-六氢-1λ6噻喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)4-(4-硝基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈
按实施例73步骤(a)的方法,由4-(硝基-苯基)-乙腈和1-溴-2-(2-溴-乙磺酰基)-乙烷制备标题化合物。
b)4-(4-硝基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲酰胺
将4-(4-硝基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈(按前一步骤制备)的乙醇和水溶液用NaBO3(Synthetic Communications,20(4),563-71,(1990))处理。将混合物用EtOAc稀释,然后用水洗涤。将有机层干燥(MgSO4),真空浓缩。残渣经硅胶层析纯化,用适当溶剂洗脱,得到标题化合物。
c)N-[4-(4-氨基甲酰基-1,1-二氧代-六氢-1λ6噻喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例22步骤(c)和实施例1步骤(e)-(g)方法,由4-(4-硝基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲酰胺(按前一步骤制备)制备标题化合物。
实施例75
N-(2-(4,4-二甲基-环己-1-烯基)-4-{4-[(2-甲氧基-乙基氨基)-甲基]-四氢-吡喃-4-基}-苯基)-4-氰基-1H-咪唑-2-甲酰胺
a)(2-甲氧基-乙基)-[4-(4-硝基-苯基)-四氢-吡喃-4-基甲基]-胺
将C-[4-(4-硝基-苯基)-四氢-吡喃-4-基]-甲胺(按实施例73步骤(b)制备)的THF溶液用1-溴-2-甲氧基-乙烷和TEA处理。将混合物用EtOAc稀释,然后用水洗涤。将有机层干燥(MgSO4),真空浓缩。残渣经硅胶层析纯化,用适当溶剂洗脱,得到标题化合物。
b)N-(2-(4,4-二甲基-环己-1-烯基)-4-{4-[(2-甲氧基-乙基氨基)-甲基]-四氢-吡喃-4-基}-苯基)-4-氰基-1H-咪唑-2-甲酰胺
按实施例22步骤(c)和实施例1步骤(e)-(g)方法,由(2-甲氧基-乙基)-[4-(4-硝基-苯基)-四氢-吡喃-4-基甲基]-胺(按前一步骤制备)制备标题化合物。
实施例76
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-甲基氨基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)甲基-[4-(4-硝基-苯基)-四氢-吡喃-4-基-甲基]-胺
按在J.Org.Chem.,61,3849-3862,(1996)中找到的文献方法,将C-[4-(4-硝基-苯基)-四氢-吡喃-4-基]-甲胺(按实施例73步骤(b)制备)的DCM溶液用甲醛处理。将混合物用EtOAc稀释,然后用水洗涤。将有机层干燥(MgSO4),真空浓缩。残渣经硅胶层析纯化,用适当溶剂洗脱,得到标题化合物。
b)N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-甲基氨基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例22步骤(c)和实施例1步骤(e)-(g)方法,由甲基-[4-(4-硝基-苯基)-四氢-吡喃-4-基-甲基]-胺(按前一步骤制备)制备标题化合物。
实施例77
N-[4-(1-乙酰基-4-甲基氨基甲基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)4-(4-硝基-苯基)-哌啶-4-甲腈
按实施例73步骤(a)方法,由4-(硝基-苯基)-乙腈和盐酸氮芥制备标题化合物。
b)1-乙酰基-4-(4-硝基-苯基)-哌啶-4-甲腈
将4-(4-硝基-苯基)-哌啶-4-甲腈(按前一步骤制备)的CH2Cl2溶液用CH3COCl和DIEA处理。将混合物用水洗涤,然后将有机层干燥(MgSO4),真空浓缩。残渣经硅胶层析纯化,用适当溶剂洗脱,得到标题化合物。
c)1-乙酰基-4-(4-硝基-苯基)-哌啶-4-甲酸
将1-乙酰基-4-(4-硝基-苯基)-哌啶-4-甲腈(按前一步骤制备)的EtOH溶液和NaOH水溶液加热至回流。将混合物用HCl水溶液处理,然后用EtOAc萃取。有机层经MgSO4干燥,真空浓缩。残渣经反相层析纯化,得到标题化合物。
d)N-[4-(1-乙酰基-4-甲基氨基甲基-哌啶-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例20、实施例21步骤(a)-(b)、实施例22步骤(c)-(d)和实施例1步骤(e)-(g)方法,由1-乙酰基-4-(4-硝基-苯基)-哌啶-4-甲酸(按前一步骤制备)制备标题化合物。
实施例78
4-氰基-4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-哌啶-1-甲酰胺
a)4-氰基-4-(4-硝基-苯基)-哌啶-1-甲酰胺
按QSAR & Combinatorial Science,23(10),854-858(2004)中方法,由4-(4-硝基-苯基)-哌啶-4-甲腈(按实施例77步骤(a)制备),用氯甲酸4-硝基-苯酯和氨的1,4-二噁烷溶液制备标题化合物。
b)4-氰基-4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4,4-二甲基-环己-1-烯基)-苯基]-哌啶-1-甲酰胺
按实施例22步骤(c)和实施例1步骤(e)-(g)方法,由4-氰基-4-(4-硝基-苯基)-哌啶-1-甲酰胺(按前一步骤制备)制备标题化合物。
按前述实施例方法,用下表中所示相应试剂制备以下实施例:
实施例82
N-{2-(4,4-二甲基-环己-1-烯基)-6-[4-(4-甲基-哌嗪-1-基)-四氢-吡喃-4-基]-吡啶-3-基}-4-氰基-1H-咪唑-2-甲酰胺
a)N-[2-(4,4-二甲基-环己-1-烯基)-6-(4-羟基-四氢-吡喃-4-基)-吡啶-3-基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)方法,由N-[6-溴-2-(4,4-二甲基-环己-1-烯基)-吡啶-3-基]-5-氰基-1H-咪唑-2-甲酰胺(按实施例32步骤(d)制备)和四氢-吡喃-4-酮制备标题化合物。
b)N-{2-(4,4-二甲基-环己-1-烯基)-6-[4-(4-甲基-哌嗪-1-基)-四氢-吡喃-4-基]-吡啶-3-基}-4-氰基-1H-咪唑-2-甲酰胺
按实施例4方法,由N-[2-(4,4-二甲基-环己-1-烯基)-6-(4-羟基-四氢-吡喃-4-基)-吡啶-3-基]-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备)和N-甲基哌嗪制备标题化合物。
按前述实施例方法,用下表中所示相应试剂制备以下实施例:
实施例86
N-[2-(4-甲基-哌啶-1-基)-4-(4-吡咯烷-1-基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)4-[3-(4-甲基-哌啶-1-基)-4-硝基-苯基]-四氢-吡喃-4-甲酸甲酯
按实施例16步骤(a)方法,用四氢-吡喃-4-甲酸甲酯和1-(5-溴-2-硝基-苯基)-4-甲基-哌啶(US 2005131022 A1)制备标题化合物。
b)4-[4-氨基-3-(4-甲基-哌啶-1-基)-苯基]-四氢-吡喃-4-甲酸甲酯
按实施例16步骤(b)反应方法,用4-[3-(4-甲基-哌啶-1-基)-4-硝基-苯基]-四氢-吡喃-4-甲酸甲酯(按前一步骤制备)制备标题化合物。
c)4-[4-{[4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-羰基]-氨基}-3-(4-甲基-哌啶-1-基)-苯基]-四氢-吡喃-4-甲酸甲酯
按实施例16步骤(e)方法,用4-[4-氨基-3-(4-甲基-哌啶-1-基)-苯基]-四氢-吡喃-4-甲酸甲酯(按前一步骤制备)和4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾(按实施例1步骤(d)制备)制备标题化合物。
d)4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4-甲基-哌啶-1-基)-苯基]-四氢-吡喃-4-甲酸甲酯
按实施例16步骤(f)方法,用4-[4-{[4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-羰基]-氨基}-3-(4-甲基-哌啶-1-基)-苯基]-四氢-吡喃-4-甲酸甲酯(按前一步骤制备)制备标题化合物。
e)N-[4-(4-羟基甲基-四氢-吡喃-4-基)-2-(4-甲基-哌啶-1-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例25方法,用4-[4-[(4-氰基-1H-咪唑-2-羰基)-氨基]-3-(4-甲基-哌啶-1-基)-苯基]-四氢-吡喃-4-甲酸甲酯(按前一步骤制备)制备标题化合物。
f)N-[4-(4-甲酰基-四氢-吡喃-4-基)-2-(4-甲基-哌啶-1-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例26步骤(a)方法,用N-[4-(4-羟基甲基-四氢-吡喃-4-基)-2-(4-甲基-哌啶-1-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备)制备标题化合物。
g)N-[2-(4-甲基-哌啶-1-基)-4-(4-吡咯烷-1-基甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例26步骤(b)方法,用N-[4-(4-甲酰基-四氢-吡喃-4-基)-2-(4-甲基-哌啶-1-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按前一步骤制备)和吡咯烷制备标题化合物。
实施例87
N-[4-(4-氰基-1,1-二氧代-六氢-1λ6-噻喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
a)4-(4-硝基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈
将NaH(71.4mg,1.79mmol,60%分散体)的DMSO(3mL)和THF(1mL)浆状物用固体(4-硝基-苯基)-乙腈(121mg,0.744mmol)处理,在室温下搅拌3分钟。加入1-溴-2-(2-溴乙磺酰基)-乙烷(250mg,0.893mmol)的THF(3mL)溶液,将混合物加热至70℃保持1.5h。使混合物在EtOAc(100mL)和水(75mL)之间分配,然后加入盐水(25mL)。将水层用EtOAc(1×50mL)萃取。合并的有机层经MgSO4干燥,真空浓缩。残渣经20-g Isolute SPE柱硅胶层析纯化,用10-50%EtOAc-己烷洗脱,得到标题化合物(205mg,98%),为白色固体。1H-NMR(CDCl3;400MHz):δ8.33(d,2H,J=8.8Hz),7.75(d,2H,J=8.8Hz),3.64-3.52(m,2H),3.29-3.19(m,2H),2.88-2.76(m,2H),2.54-2.44(m,2H).
b)4-(4-氨基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈
将4-(4-硝基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈(205mg,0.731mmol,按前一步骤制备)的EtOH(5mL)和水(5mL)悬浮液用固体NH4Cl(204mg,3.66mmol)和Fe粉(392mg,7.31mmol)处理,加热至50℃保持1.5h。通过硅藻土将冷却的混合物过滤,将滤饼用MeOH洗涤。将溶剂真空蒸发。将残渣用水(30mL)稀释,然后用EtOAc(2×30mL)萃取。合并的有机层经MgSO4干燥,真空浓缩。残渣经50-g VarianMegaBond Elut SPE柱硅胶层析纯化,用50%EtOAc-己烷洗脱,得到标题化合物(114mg,62%),为浅黄色固体。质谱(ESI,m/z):C12H14N2O2S的理论值251.1(M+H),实测值251.2。
c)4-(4-氨基-3-溴-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈
将4-(4-氨基-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈(114mg,0.455mmol,按前一步骤制备)的CH2Cl2(15mL)溶液冷却至0℃,用固体NBS(77.0mg,0.433mmol)处理,在该温度下搅拌30分钟。将混合物用CH2Cl2(20mL)稀释,然后用饱和NaHCO3水溶液(1×20mL)洗涤。将水层用CH2Cl2(1×20mL)萃取。合并的有机层经MgSO4干燥,真空浓缩。残渣经50-g Varian MegaBond Elut SPE柱硅胶层析纯化,用50%EtOAc-己烷洗脱,得到标题化合物(136mg,90%),为白色固体。1H-NMR(CDCl3;400MHz):δ7.53(d,1H,J=2.0Hz),7.23(dd,1H,J=8.4,2.0Hz),6.79(d,1H,J=8.0Hz),4.40-4.15(br s,2H),3.60-3.45(m,2H),3.26-3.11(m,2H),2.78-2.63(m,2H),2.51-2.38(m,2H).
d)4-[4-氨基-3-(4,4-二甲基-环己-1-烯基)-苯基]-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈
将4-(4-氨基-3-溴-苯基)-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈(109mg,0.332mmol,按前一步骤制备)的DMF(4mL)溶液用2-(4,4-二甲基-环己-1-烯基)-4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷(94.1mg,0.398mmol)和Na2CO3水溶液(1.32mL,2.66mmol,2.0M)处理。通过超声使混合物脱气,将该混合物置于Ar下,用Pd(dppf)Cl2(24.3mg,0.034mmol)处理,加热至60℃保持24h。将冷却的混合物用EtOAc和水稀释。将水层用EtOAc(4×)萃取。合并的有机层经MgSO4干燥,真空浓缩。残渣经10-g Isolute SPE柱硅胶层析(FlashMaster***)纯化,用25%EtOAc-己烷洗脱,得到标题化合物(119mg,100%),为白色固体。质谱(ESI,m/z):C20H26N2O2S的理论值359.2(M+H),实测值359.3。
e)N-[4-(4-氰基-1,1-二氧代-六氢-1λ6-噻喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺
在室温下,将4-[4-氨基-3-(4,4-二甲基-环己-1-烯基)-苯基]-1,1-二氧代-六氢-1λ6-噻喃-4-甲腈(119mg,0.332mmol,按前一步骤制备)和4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酸钾盐(123mg,0.398mmol,按实施例1,步骤(d)制备)的CH2Cl2(10mL)溶液用PyBroP(217mg,0.465mmol)和DIEA(231μL,1.33mmol)处理45min。将混合物用CH2Cl2(30mL)稀释,然后用饱和NaHCO3水溶液(1×30mL)洗涤。将水层用CH2Cl2(1×30mL)萃取,合并的有机层经MgSO4干燥,真空浓缩。残渣经20-g Isolute SPE柱硅胶层析(FlashMaster***)纯化,用10-25%EtOAc-己烷洗脱,得到标题化合物(193mg,95%),为灰白色固体。质谱(ESI,m/z):C31H41N5O4SSi的理论值608.3(M+H),实测值608.3。
f)N-[4-(4-氰基-1,1-二氧代-六氢-1λ6-噻喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在室温下,将N-[4-(4-氰基-1,1-二氧代-六氢-1λ6-噻喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1-(2-三甲基硅烷基-乙氧基甲基)-1H-咪唑-2-甲酰胺(193mg,0.318mmol,按前一步骤制备)的CH2Cl2(10mL)溶液用TFA(2mL)处理,搅拌3h。加入EtOH(5mL),将混合物浓缩至干。将残渣溶于CH2Cl2,然后用饱和NaHCO3水溶液(1×)小心洗涤。将水层用CH2Cl2(1×)萃取,合并的水层经MgSO4干燥,真空浓缩。残渣经20-g Isolute SPE柱硅胶层析(FlashMaster***)纯化,用25-50%EtOAc-己烷洗脱,得到标题化合物(50.4mg,33%),为白色固体。1H-NMR(CD3OD;400MHz):δ8.39(d,1H,J=8.8Hz),8.01(s,1H),7.53(dd,1H,J=8.8,2.0Hz),7.42(d,1H,J=2.0Hz),5.85-5.80(m,1H),3.59-3.46(m,2H),2.81-2.69(m,2H),2.62-2.52(m,2H),2.39-2.32(m,2H),2.17-2.10(m,2H),1.68-1.58(m,4H),1.13(s,6H).质谱(ESI,m/z):C25H27N5O3S的理论值478.2(M+H),实测值478.2。
实施例88
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-2,2,6,6-四甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)所述方法,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备)和2,2,6,6-四甲基四氢吡喃-4-酮(WO 2005012220)制备标题化合物。1H-NMR(CD3OD;400MHz):δ8.16(d,1H,J=8.4Hz),7.98(s,1H),7.38(dd,1H,J=8.4,2.0Hz),7.34(d,1H,J=2.0Hz),5.74(br s,1H),2.32(m,2H),2.08(m,2H),1.87(m,4H),1.56-1.58(m,8H),1.56(s,6H),1.21(s,6H).
实施例89
N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-1-甲氧基-2,2,6,6-四甲基-哌啶-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)所述方法,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备)和1-甲氧基-2,2,6,6-四甲基-哌啶-4-酮(WO 9854174)制备标题化合物。1H-NMR(CD3OD;400MHz):δ8.21(d,1H,J=8.4Hz),8.01(s,1H),7.45(dd,1H,J=8.4,2.0Hz),7.37(d,1H,J=2.0Hz),5.75(br s,1H),4.08(s,3H),2.35(m,4H),2.09(m,4H),1.72(s,6H),1.61(m,2H),1.50(s,6H),1.10(s,6H).质谱(ESI,m/z):C29H39N5O3的理论值506.3(M+H),实测值506.3。
实施例90
N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-羟基-1-(2,2,2-三氟-乙基)-哌啶-4-基]-苯基}-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)中所述方法,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备)和1-(2,2,2-三氟-乙基)-哌啶-4-酮(WO 9621452)制备标题化合物。1H-NMR(CD3OD;400MHz):δ12.9(br s,1H),9.62(s,1H),8.21(d,1H,J=8.4Hz),7.63(s,1H),7.38(dd,1H,J=8.4,2.0Hz),7.24(d,1H,J=2.0Hz),5.73(br s,1H),4.13(m,2H),2.91-3.23(m,4H),1.93-2.32(m,4H),1.53(m,2H),1.08(s,6H).质谱(ESI,m/z):C26H30F3N5O2的理论值502.5(M+H),实测值502.2。
实施例91
N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-羟基-2,2,6,6-四甲基-1-(2,2,2-三氟-乙基)-哌啶-4-基]-苯基}-4-氰基-1H-咪唑-2-甲酰胺
a)2,2,6,6-四甲基-1-(2,2,2-三氟-乙基)-哌啶-4-酮
在0℃下,向2,2,6,6-四甲基-1-(2,2,2-三氟-乙基)-哌啶-4-醇(780mg,3.25mmol;J.Phys.Org.Chem.,16(3),175-182(2003))的DCM(50mL)溶液中分批加入戴斯-马丁氧化剂(1.6g,3.2mmol;Adv.Syn.Catalysis,346,111-124(2004))。将得到的混合物在室温下搅拌48h,用饱和NaHCO3(50mL)稀释,然后用DCM(3×25mL)萃取。将有机层合并,干燥(Na2SO4),真空浓缩。得到的油状物经硅胶层析(10-50%EtOAc/己烷)纯化,得到标题化合物309mg,40%。质谱(ESI,m/z):C11H18F3N的理论值238.1(M+H),实测值238.0。
b)N-{2-(4,4-二甲基-环己-1-烯基)-4-[4-羟基-2,2,6,6-四甲基-1-(2,2,2-三氟-乙基)-哌啶-4-基]-苯基}-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)中所述方法,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备)和2,2,6,6-四甲基-1-(2,2,2-三氟-乙基)-哌啶-4-酮(按以上制备)制备标题化合物。1H-NMR(CD3OD;400MHz):δ8.22(d,1H,J=8.4Hz),7.98(s,1H),7.43(dd,1H,J=8.4,2.0Hz),7.33(d,1H,J=2.0Hz),5.73(br s,1H),4.18(m,2H),2.28-2.36(m,4H),2.08(m,4H),1.73(s,6H),1.58(m,2H),1.42(m,6H),1.08(s,6H).质谱(ESI,m/z):C30H38F3N5O2的理论值558.3(M+H),实测值558.0。
实施例92
N-[2-(4,4-二甲基-环己-1-烯基)-4-(3-羟基-8-氧杂-双环[3.2.1]辛-3-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)中所述方法,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备)和8-氧杂-双环[3.2.1]辛-3-酮(Liebigs Annalen der Chemie,(1),1-5(1987))制备标题化合物。1H-NMR(CDCl3;400MHz):δ11.69(br s,1H),9.56(s,1H),8.36(d,1H,J=8.4Hz),7.70(s,1H),7.48(dd,1H,J=8.4,2.0Hz),7.30(d,1H,J=2.0Hz),5.79-5.74(m,1H),4.58-4.50(m,2H),2.48-2.41(m,2H),2.40-2.37(m,2H),2.32-2.25(m,2H),2.12-2.07(m,2H),2.05-1.96(m,2H),1.83-1.76(m,2H),1.57-1.53(m,2H),1.10(s,6H).质谱(ESI,m/z):C26H30N4O3的理论值447.2(M+H),实测值447.1。
实施例93
N-[2-(4,4-二甲基-环己-1-烯基)-4-(3-羟基-1,5-二甲基-8-氧杂-双环[3.2.1]辛-3-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例1步骤(h)中所述,用N-[4-溴-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例1步骤(g)制备)和1,5-二甲基-8-氧杂-双环[3.2.1]辛-3-酮(J.Org.Chem.,64(10),3398-3408(1999))制备标题化合物。1H-NMR(DMSO-d6;400MHz):δ14.25(bs,1H),9.72(s,1H),8.29(s,1H),7.90(d,1H,J=8.3Hz),7.33(dd,1H,J=2.3,8.6Hz),7.27(m,1H),5.65(m,1H),4.88(s,1H),2.42-2.37(m,2H),2.26-2.22(m,2H),1.95(m,2H),1.81-1.71(m,4H),1.53-1.47(m,4H),1.23(s,6H),1.00(s,6H).质谱(ESI,m/z):C28H34N4O3的理论值475.2(M+1),实测值475.1。
实施例94
N-[4-(3-氰基-1,5-二甲基-8-氧杂-双环[3.2.1]辛-3-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
在0℃下,向N-[2-(4,4-二甲基-环己-1-烯基)-4-(3-羟基-1,5-二甲基-8-氧杂-双环[3.2.1]辛-3-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(21mg,0.044mmol,按实施例93制备)的1mL DCM浆状物中依次加入TMSCN(25μL,0.19mmol)、SnCl4(4mg,0.01mmol)的0.08mL DCM溶液。使反应物升温至室温,再依次用25μL TMSCN、SnCl4(8mg,0.02mmol)的0.2mL DCM溶液处理。当反应物变为均相后,依次加入1mLMeOH、2mL水。将混合物搅拌5分钟,加入CHCl3(5mL),将各液层分离。将有机层干燥(Na2SO4),真空浓缩。残渣经制备TLC(依次为5%MeOH-CHCl3、50%EtOAc-己烷)纯化两次,得到标题化合物(6mg,28%)。1H-NMR(CD3OD;400MHz):δ8.09(d,1H,J=8.3Hz),7.70(s,1H),7.27-7.23(m,1H),7.16-7.12(m,1H),5.66-5.64(m,1H),2.80-2.56(m,4H),2.22-2.14(m,2H),2.02-1.97(m,2H),1.81-1.77(m,4H),1.51-1.46(m,2H),1.25(s,3H),1.25(s,1H),0.98(s,6H).质谱(ESI,m/z):C29H33N5O2的理论值484.2(M+1),实测值484.0。
实施例95
N-[4-(4-氰基-2,2,6,6-四甲基-四氢-吡喃-4-基)-2-(4,4-二甲基-环己-1-烯基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺
按实施例94中所述,用N-[2-(4,4-二甲基-环己-1-烯基)-4-(4-羟基-2,2,6,6-四甲基-四氢-吡喃-4-基)-苯基]-4-氰基-1H-咪唑-2-甲酰胺(按实施例88制备)制备标题化合物:1H-NMR(CD3OD;400MHz):δ8.47(d,1H,J=8.6Hz),8.00(s,1H),7.62(dd,1H,J=2.5,8.6Hz),7.52(m,1H),5.94(m,1H),2.53-2.49(m,4H),2.25(m,2H),2.02-1.99(m,2H),1.79-1.75(m,8H),1.45(s,6H),1.25(s,6H).质谱(ESI,m/z):C29H35N5O2的理论值486.2(M+H),实测值486.2。
IV.结果
荧光偏振竞争免疫测定
用自磷酸化、荧光偏振竞争免疫测定法测定选择的式I化合物对c-fms的抑制活性。在黑色96孔微量板(LJL BioSystems)中进行测定。所用的测定缓冲液是100mM 4-(2-羟乙基)哌嗪1-乙磺酸(HEPES),pH7.5,1mM 1,4-二硫-DL-苏糖醇(DTT),0.01%(v/v)吐温-20。在临测定前,将化合物用含4%二甲基亚砜(DMSO)的测定缓冲液稀释。向各孔中依次加入5μL化合物、3μL含33nM c-fms的混合液(Johnson &Johnson PRD)和溶于测定缓冲液的16.7mM MgCl2(Sigma)。通过加入2μL溶于测定缓冲液的5mM ATP(Sigma)引发激酶反应。测定终浓度为10nM c-fms,1mM ATP,5mM MgCl2,2%DMSO。在各板中进行对照反应:在阳性和阴性对照孔中,用测定缓冲液(制备为4%的DMSO溶液)代替化合物;另外,向阳性对照孔中加入1.2μL 50mM乙二胺四乙酸(EDTA)。
将各板在室温下温育45分钟。在温育结束时,将反应用1.2μL 50mM EDTA (此时不向阳性对照孔中加入EDTA;参见以上)淬灭。经过5分钟温育后,向各孔中分别加入10μL 1∶1∶3的抗磷酸酪氨酸抗体,10X,PTK绿色示踪物,10X(旋转),FP稀释缓冲液的混合物(均得自PanVera,cat.#P2837)。封板,在室温下温育30分钟,在Analyst上观测荧光偏振。仪器设置为:485nm激发光滤片;530nm发射滤片;Z高度:孔中线处;G因子:0.93。在这些条件下,阳性和阴性的荧光偏振值分别为约300和150,用它们定义对c-fms反应的100%和0%抑制。报道的IC50值为3次独立测量值的平均值。
CSF-1-驱动的小鼠骨髓衍生巨嗜细胞测定
通过在含有补充10%FCS和50ng/ml重组小鼠CSF-1的α-MEM的细菌培养皿中培养小鼠骨髓,衍生巨嗜细胞。在第6天,将巨嗜细胞与皿分离,漂洗,然后再悬浮于含10%FCS的α-MEM中至达到0.05百万细胞/ml浓度。将100μl细胞悬浮液分配到96孔培养板的各孔中。再向各孔中补加50μl含15ng/ml CSF-1、3μM吲哚美辛和3X稀释系列的试验化合物的培养基。在37℃和在5%CO2下,将细胞培养30小时。在最后6小时期间,向培养物中再补加30μl含1∶500稀释度的溴脱氧尿苷(BrDU)的培养基。在培养结束时,按1000RPM,将板离心1分钟,用吸管将130μl培养基除去,加入150μl固定液,在室温下保持1小时。然后将板中固定液除去,将板晾干。结合至固定、干细胞的BrDU用特异性ELISA定量。
表2列出本发明代表性化合物的测定结果。
表2
实施例# | 1nM c-fms;肽Pi测定IC-50(μM) | mCSF驱动的增殖BMDM(小鼠)IC-50(μM) | |
1 | 0.0007 | 0.004 | |
2 | 0.00042 | 0.0022 | |
3 | 0.0017 | N/A | |
4 | 0.0018 | 0.014 | |
5 | 0.0005 | 0.0024 | |
6 | 0.0016 | 0.015 | |
7 | 0.00067 | 0.011 | |
8 | 0.004 | 0.015 | |
9 | 0.0019 | 0.1 | |
10 | 0.0079 | >0.3 | |
11 | 0.0029 | 0.035 | |
12 | 0.0011 | 0.031 | |
13 | 0.0008 | 0.0081 |
14 | 0.0039 | 0.0095 | |
15 | 0.0029 | 0.014 | |
16 | 0.00067 | 0.046 | |
17 | 0.00056 | >0.3 | |
18 | 0.0036 | 0.3 | |
19 | 0.0018 | 0.019 | |
20 | 0.0018 | 0.02 | |
21 | 0.0016 | 0.0079 | |
22 | 0.0008 | >0.3 | |
23 | 0.0064 | >0.3 | |
24 | 0.0008 | 0.014 | |
25 | 0.00049 | 0.0065 | |
26 | 0.003 | 0.0053 | |
27 | 0.0029 | 0.0045 | |
28 | 0.0084 | 0.028 | |
29 | 0.0016 | 0.011 | |
30 | 0.0032 | 0.007 |
31 | 0.0014 | 0.003 | |
32 | 0.0032 | 0.019 | |
33 | 0.0037 | 0.033 | |
34 | 0.0015 | 0.0172 | |
35 | 0.0007 | 0.0058 | |
87 | 0.0011 | 0.0082 | |
88 | 0.0024 | 0.0064 | |
89 | 0.013 | 0.02 | |
90 | 0.0065 | 0.04 | |
91 | ~0.21 | 0.061 | |
92 | 0.0022 | 0.012 | |
93 | 0.0029 | 0.0089 | |
94 | 0.082 | >0.1 | |
95 | 0.026 | 0.029 |
虽然前述说明书教授了本发明原理,并且为举例说明目的提供了实施例,但可理解本发明实践包括在权利要求及其等价物范围内的所有普通改变、改进和/或修改。
以上说明书中公开的所有出版物通过引用全文结合到本文中。
Claims (21)
1.式I化合物或其药学上可接受的盐
其中:
W为
R2为
Z为H;
J为CH或N;
X为
其中R1为-ORa、-CN、-NA1A2、-SO2CH3、-COORa、-CO2CH3、-CH2-NA1A2、-CONA1A2、-CH2ORa、-NHCH2CH2CO2Ra、-NHCH2CH2ORa、-NRaCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2Ra或四唑基;
Rz和Ry独立为H或-C(1-4)烷基,其中两个Rz可具有顺式或反式立体化学;或者处于顺式关系的两个Rz可连接在一起形成-(CH2)n-,其中n为2或3;
R3为H、C(1-4)烷基、C(1-3)烷基-CF3、-COCH3、CONH2或CO2Ra;
A1为H或-C(1-4)烷基;
A2为H、-C(1-4)烷基、CORa或-CH2CH2ORa;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
其中Ra为H或C(1-4)烷基;
和
Rbb为H、-C(1-4)烷基、-CH2CO2H或-C(O)C(1-4)烷基。
2.权利要求1的化合物及其药学上可接受的盐,其中
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COORa、-CO2CH3、-CH2-NA1A2、-CONA1A2、-CH2ORa、-NHCH2CH2CO2Ra、-NHCH2CH2ORa、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2Ra或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
Ra为H或-C(1-4)烷基;
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-CH2CF3、-COCH3、-CH3、-CO2CH3、-CONH2或-CO2H。
3.权利要求2的化合物及其药学上可接受的盐,其中
R2为
X为
其中R1为-OH、-CN、-NA1A2、-SO2CH3、-COOH、-CO2CH3、-CH2-NA1A2、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2CO2CH3、-NHCH2CH2OCH3、-NHCH2CH2NA1A2、-OC(1-4)烷基NA1A2、-OCH2CO2H或四唑基;
A1为H或-CH3;
A2为H、-CH2CH2OCH3、-COCH3或-CH3;
或者,A1和A2可与它们连接的氮一起形成杂环,所述杂环选自以下杂环:
Rbb为H、-C(1-4)烷基、-CH2CO2H或-COCH3;
Ry为H或-CH3;
Rz为H、-CH3,或可连接在一起成为-CH2CH2-;
R3为H、-CH2CF3、-COCH3、-CH3、-CO2CH3、-CONH2或-CO2H。
4.权利要求3的化合物及其药学上可接受的盐,其中
R2为
5.权利要求4的化合物及其药学上可接受的盐,其中
W为
R2为
X为
其中R1为-OH、-NH2、-N(CH3)2、-SO2CH3、-COOH、-CO2CH3、-CH2-吗啉基、-CONH2、-CON(CH3)2、-CH2OH、-OCH2CH2N(CH3)2、-NHCH2CH2OCH3、-OCH2CO2H、吗啉基、哌嗪基、N-甲基哌嗪基、哌嗪基-CH2CO2H或四唑基;
Rz为H或-CH3;
R3为-COCH3、-CH2CF3或-CO2H。
6.一种化合物,所述化合物选自:
及其药学上可接受的盐。
7.权利要求6的化合物,所述化合物选自:
及其药学上可接受的盐。
8.一种化合物,所述化合物选自:
及其药学上可接受的盐。
9.一种药用组合物,所述组合物含有权利要求1的化合物和药学上可接受的载体。
10.一种药物剂量形式,所述剂量形式含有药学上可接受的载体和0.5mg-10g至少一种权利要求1的化合物。
11.权利要求10的剂量形式,所述剂量形式适合肠胃外或口服给药。
12.有效抑制量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于抑制蛋白酪氨酸激酶活性。
13.权利要求12的用途,其中所述蛋白酪氨酸激酶为c-fms。
14.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于在哺乳动物中治疗炎症。
15.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于在哺乳动物中治疗癌症。
16.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于在哺乳动物中治疗心血管病。
17.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于在哺乳动物中治疗含有炎性成分的疾病,所述疾病选自肾小球肾炎、炎性肠病、修复术失败、结节病、充血性阻塞性肺病、自发性肺纤维变性、哮喘、胰腺炎、HIV感染、银屑病、糖尿病、与肿瘤有关的血管发生、与年龄有关的黄斑变性、糖尿病性视网膜病、再狭窄、精神***症或阿耳茨海默痴呆。
18.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于在哺乳动物中治疗疼痛,所述疼痛选自由肿瘤转移或骨关节炎造成的骨骼疼痛,或内脏、炎性和神经原性疼痛。
19.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于治疗骨质疏松症、佩吉特病和其中由骨吸收介导发病的其它疾病,所述其它疾病选自类风湿性关节炎和其它形式的炎性关节炎、骨关节炎、修复术失败、溶骨肉瘤、骨髓瘤和转移至骨的肿瘤。
20.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于治疗和预防以下癌症转移:卵巢癌、子宫癌、乳腺癌、***癌、肺癌、结肠癌、胃癌和毛细胞白血病。
21.治疗有效量的至少一种权利要求1的化合物在制备药物中的用途,所述药物用于治疗自身免疫性疾病,所述疾病选自全身性红斑狼疮、类风湿性关节炎和其它形式的炎性关节炎、银屑病、斯耶格伦综合征、多发性硬化或葡萄膜炎。
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CN1411445A (zh) * | 2000-01-06 | 2003-04-16 | 阿方蒂农科股份有限公司 | 3-羟基吡啶甲酸衍生物的制备方法 |
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