CN103717591B - 作为选择性蛋白激酶(c-kit)抑制剂的噁唑和噻唑衍生物 - Google Patents
作为选择性蛋白激酶(c-kit)抑制剂的噁唑和噻唑衍生物 Download PDFInfo
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- CN103717591B CN103717591B CN201280037457.9A CN201280037457A CN103717591B CN 103717591 B CN103717591 B CN 103717591B CN 201280037457 A CN201280037457 A CN 201280037457A CN 103717591 B CN103717591 B CN 103717591B
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Abstract
本发明涉及式I的化合物或其药学上可接受的盐:其中R1、R2、R3、A、Q、W和X如说明书中所定义。这些化合物选择性地调整、调节和/或抑制由某些天然和/或突变的蛋白激酶介导的信号转导,所述蛋白激酶与多种人和动物疾病(例如细胞增殖病症、代谢病症、变应性病症和退行性病症)有关。更特别的是,这些化合物是强效且具有选择性的天然c‑kit抑制剂和/或突变c‑kit抑制剂。
Description
技术领域
本发明涉及式I的化合物或其药学上可接受的盐,所述化合物或其药学上可接受的盐选择性地调整(modulate)、调节(regulate)和/或抑制由某些天然和/或突变的蛋白激酶介导的信号转导,所述蛋白激酶与多种人和动物的疾病(如细胞增殖病症、代谢病症、变应性病症(allergic disorders)和退行性病症)有关。更特别的是,这些化合物是强效且具有选择性的天然c-kit抑制剂和/或突变c-kit抑制剂。
背景技术
蛋白激酶是受体型或非受体型蛋白,将ATP的末端磷酸根转移到蛋白的氨基酸残基上(如酪氨酸残基、苏氨酸残基、丝氨酸残基),由此使信号转导通路活化或失活。已知这些蛋白参与许多在被破坏的情况下导致病症(如异常的细胞增殖和迁移以及炎症)的细胞机制。
迄今为止,已知的蛋白激酶超过了500种。所包括在内的有众所周知的Abl、Akt1、Akt2、Akt3、ALK、Alk5、A-Raf、Axl、B-Raf、Brk、Btk、Cdk2、Cdk4、Cdk5、Cdk6、CHK1、c-Raf-1、Csk、EGFR、EphA1、EphA2、EphB2、EphB4、Erk2、Fak、Fes、Fer、FGFR1、FGFR2、FGFR3、FGFR4、Flt-3、Fms、Frk、Fyn、Gsk3α、Gsk3β、HCK、Her2/Erbb2、Her4/Erbb4、IGF1R、IKKβ、Irak4、Itk、Jak1、Jak2、Jak3、Jnk1、Jnk2、Jnk3、KDR、Kit、Lck、Lyn、MAP2K1、MAP2K2、MAP4K4、MAPKAPK2、Met、Mer、MNK1、MLK1、mTOR、p38、PDGFRα、PDGFRβ、PDPK1、PI3Kα、PI3Kβ、PI3Kδ、PI3Kγ、Pim1、Pim2、Pim3、PKCα、PKCβ、PKCθ、Plk1、Pyk2、Ret、ROCK1、ROCK2、RON、Src、Stk6、Syk、TEC、Tie2、TrkA、TrkB、Tyk2、VEGFR1/Flt-1、VEGFR2/Kdr、VEGFR3/Flt-4、Yes和Zap70。
由蛋白激酶介导的事件触发的异常细胞反应造成各种疾病。这些疾病包括自身免疫性疾病、炎性疾病、神经疾病和神经退行性疾病、癌症、心血管疾病、过敏症和哮喘、阿尔茨海默氏病以及激素相关的疾病。
酪氨酸激酶是受体型或非受体型蛋白,将ATP的末端磷酸根转移到蛋白的酪氨酸残基上,由此使信号转导通路活化或失活。已知这些蛋白参与许多在被破坏的情况下导致病症(如异常的细胞增殖和迁移以及炎症)的细胞机制。
迄今为止,有大约58种已知的受体酪氨酸激酶。所述受体酪氨酸激酶包括众所周知的VEGF受体(Kim等,Nature 362,第841-844页,1993年)、PDGF受体、c-kit、Flt-3和FLK族。这些受体可以将信号传输至其它酪氨酸激酶,所述酪氨酸激酶包括Src、Raf、Frk、Btk、Csk、Abl、Fes/Fps、Fak、Jak、Ack等。
在酪氨酸激酶受体中,c-kit引起了特别的兴趣。事实上,已证明c-kit是激活肥大细胞的关键受体,c-kit直接或间接地涉及多种疾病,为此,申请人提交了WO 03/004007、WO03/004006、WO 03/003006、WO 03/003004、WO 03/002114、WO 03/002109、WO 03/002108、WO03/002107、WO 03/002106、WO 03/002105、WO 03/039550、WO 03/035050、WO 03/035049、US60/359,652、US 60/359651以及US 60/449861、WO 04/080462、WO 05/039586、WO 06/135721、WO 07/089069、WO 07/124369、WO 08/137794、WO 08/063888、WO 08/011080、WO09/109071、WO 10/096395。
已经发现,存在于患者的组织中的肥大细胞涉及或促成疾病的成因,所述疾病如自身免疫性疾病(类风湿关节炎、炎性肠道疾病(IBD))、变应性疾病、骨质疏松、癌症(例如实体瘤、白血病和GIST)、肿瘤血管形成、炎性疾病、间质性膀胱炎、肥大细胞增多症、移植物-抗-宿主疾病、感染性疾病、代谢性疾病、纤维变性、糖尿病以及CNS疾病。在这些疾病中,已经表明肥大细胞通过释放不同蛋白酶和介质的混合物参与了组织的破坏,所述介质如组胺、中性蛋白酶、脂质衍生介质(前列腺素、血栓素和白细胞三烯)以及各种细胞因子(IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-8、TNF-α、GM-CSF、MIP-1a、MIP-1b、MIP-2和IFN-γ)。
c-Kit受体还可以通过突变被组成性地激活,导致异常的细胞增生和疾病的发展,所述疾病例如肥大细胞增多症(D816V突变)和各种癌症、如GIST(c-kitΔ27,近膜缺失)。
在患有AML的患者中,60%至70%具有表达c-kit的母细胞(blasts)和用于干细胞因子(SCF)的受体(Broudy,1997)。SCF促进造血祖细胞的生长,并作为存活因子用于AML母细胞。已经描述了在AML的某些情况下(1%-2%),在激酶结构域(Kit816)中保守残基的突变导致c-kit的组成性活化(Beghini等,2000年;Longley等,2001年)。在肥大细胞白血病细胞株以及来自肥大细胞增多症患者的样本中,已经识别到这种功能突变(Asp替换为Val/Tyr)的获得(Longley等,1996年)。初步结果显示,该突变在全身性肥大细胞增多症的多数情况下得到表达([-60%],P Dubreuil,AFIRMM,研究在约300名患者中进行)。
发明内容
发明目的
因此,本发明的主要目的是发现强效的选择性化合物,所述化合物能够抑制野生型和/或突变的蛋白激酶、尤其是野生型和/或突变的酪氨酸激酶、更尤其是野生型和/或突变的c-kit。
关于本发明,本发明人已经发现式I的化合物是某些蛋白激酶(例如野生型和/或突变的c-kit)的强效且具有选择性的抑制剂。这些化合物是用于治疗疾病(诸如自身免疫性疾病、炎性疾病、癌症和肥大细胞增多症)的良好候选物。
具体实施方式
对本发明的化合物进行筛选,考察其抑制蛋白激酶、尤其是酪氨酸激酶、更尤其是c-Kit和/或突变的c-Kit(特别是c-Kit D816V)的能力。
在第一实施方式中,本发明针对式I的化合物,所述式I的化合物可代表物质的游离碱形式或其药学上可接受的盐:
其中,
A是五元或六元杂环;
R1是氢、卤素(选自于F、Cl、Br或I)、硫代烷基、烷氧基或含有1至10个碳原子的烷基;
R2是卤素(选自于F、Cl、Br或I)、芳基、含有1至10个碳原子的烷基或卤代烷基,所述卤代烷基或烷基任选取代有至少一个杂原子(特别是硫、氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基或卤代烷基,该卤代烷基或烷基任选取代有增溶基团;以及烷氧基、硫代烷基或卤代烷氧基;以及-COOR、-NRR'、-NR-CO-R'、-CONRR'、-SO2NRR'或-NR-SO2-R'基团,其中R和R'各自独立地选自于氢、芳基、杂芳基、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团;
R3是氢、卤素(选自于F、Cl、Br或I)、氰基、烷氧基或含有1至10个碳原子的烷基;以及CF3、-NRR'、-NR-CO-R'、-CONRR'、-SO2NRR'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是硫、氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团;
Q是O或S;
W是N或CR4;
R4是氢、氰基、CF3、卤素(选自于F、Cl、Br或I)、硫代烷基、含有1至10个碳原子的烷基,所述烷基任选取代有至少一个杂原子(特别是硫、氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及烷氧基或卤代烷氧基、增溶基团、杂环、-CO-NRR'、-SO2-NRR'、-NRR'、NR-CO-R'或-NR-SO2R'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团或杂环基团;
X是N或CR5;
R5是氢、氰基、卤素(选自于F、Cl、Br或I)、含有1至10个碳原子的烷基、烷氧基、-CO-OR、-CO-NRR'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是硫、氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团或杂环基团。
在一个实施方式中,本发明涉及式I的化合物或其药学上可接受的盐,其中R2是卤素(选自于F、Cl、Br或I)、芳基、含有1至10个碳原子的卤代烷基或烷基,所述卤代烷基或烷基任选取代有至少一个杂原子(特别是硫、氧或氮),该杂原子上任选取代有含有1至10个碳原子的卤代烷基或烷基,该卤代烷基或烷基上任选取代有增溶基团;以及烷氧基、硫代烷基或卤代烷氧基;以及-NRR'、-NR-CO-R'、-CONRR'、-SO2NRR'或-NR-SO2-R'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团。
除非另外说明,本文所使用的下列术语的定义如下。
本文所使用的术语“烷基”意味着具有1至10个碳原子、优选1至6个碳原子、更优选1至4个碳原子的饱和的直链或支链非环状烃。具有代表性的饱和直链烷基包括甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、正壬基和正癸基;而饱和支链烷基包括异丙基、仲丁基、异丁基、叔丁基、异戊基、2-甲基丁基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基、3,3-二乙基己基等。包含在本发明化合物中的烷基可以任选取代有一个或多个取代基。包含在本发明化合物中的烷基可以任选取代有增溶基团。
本文所使用的术语“芳基”意味着含有碳原子和氢原子的单环或多环芳香族基团。合适的芳基的实例包括但不限于:苯基、甲苯基、蒽基、芴基、茚基、薁基和萘基;以及苯并稠合碳环部分,例如5,6,7,8-四氢萘基。芳基可以是未取代的,或取代有一个或多个取代基。包含在本发明化合物中的芳基可任选取代有增溶基团。
本文所使用的术语“烷氧基”是指通过氧原子连接至另一部分的、如上所定义的烷基。烷氧基的实例包括甲氧基、异丙氧基、乙氧基和叔丁氧基等。烷氧基基团可任选取代有一个或多个取代基。包含在本发明化合物中的烷氧基可以任选取代有增溶基团。
本文所使用的术语“硫代烷基”是指通过硫原子连接至另一部分的、如上所定义的烷基。硫代烷基基团可任选取代有一个或多个取代基。包含在本发明化合物中的硫代烷基可以任选取代有增溶基团。
本文所使用的术语“杂环”泛指杂环烷基和杂芳基。
本文所使用的术语“杂环烷基”意味着具有至少一个选自于O、N或S的杂原子的单环或多环基团,并且所述基团具有2至11个碳原子,其可以是饱和的或不饱和的,但不是芳香族的基团。杂环烷基的实例包括(但不限于):哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、4-哌啶酮基、吡咯烷基、乙内酰脲基、戊内酰氨基、氧杂环丙烷基、氧杂环丁基、四氢吡喃基、四氢噻喃基、四氢吡啶基、四氢嘧啶基、四氢噻喃基砜、四氢噻喃基亚砜、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜、1,3-二氧戊环、四氢呋喃基、二氢呋喃基-2-酮、四氢噻吩基以及四氢-1,1-二氧代噻吩基。通常,单环杂环烷基为3至7元环。优选的3至7元单环杂环烷基基团为具有5或6个环原子的基团。杂原子上可以取代有本领域普通技术人员已知的保护基团,例如,氮上的氢可以被叔丁氧基羰基取代。另外,杂环烷基基团可任选取代有一个或多个取代基。此外,杂环与另一基团的连接位点可以在杂环的碳原子或杂原子上。在本定义中只考虑该取代杂环基团稳定的异构体。
本文所使用的术语“杂芳基”或类似术语意味着单环或多环杂芳环,包括碳原子环成员以及一个或多个杂原子环成员(例如,如氧、硫或氮)。通常,杂芳基具有1至约5个杂原子环成员和1至约14个碳原子环成员。具有代表性的杂芳基基团包括吡啶基、1-氧代-吡啶基、呋喃基、苯并[1,3]二氧杂环戊烯、苯并[1,4]二氧杂环己二烯基、噻吩基、吡咯基、噁唑基、咪唑基、噻唑基、异噁唑基、喹啉基、吡唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、三唑基、噻二唑基、异喹啉基、吲唑基、苯并噁唑基、苯并呋喃基、吲嗪基、咪唑并吡啶基、四唑基、苯并咪唑基、苯并噻唑基、苯并噻二唑基、苯并噁二唑基、吲哚基、四氢吲哚基、氮杂吲哚基、咪唑并吡啶基、喹唑啉基、嘌呤基、吡咯并[2,3]嘧啶基、吡唑并[3,4]嘧啶基、咪唑并[1,2-a]吡啶基以及苯并(b)噻吩基。杂原子上可以取代有本领域普通技术人员已知的保护基团,例如,氮上的氢可以被叔丁氧基羰基取代。杂芳基基团可任选取代有一个或多个取代基。此外,氮或硫杂原子环成员可以被氧化。在一个实施方式中,杂芳环选自于5-8元单环杂芳环。杂芳环或杂芳香环与另一基团的连接位点可以在杂芳环或杂芳香环的碳原子或杂原子上。
本文所使用的术语“卤代烷基”意味着如上所定义的烷基中的一个或多个(包括全部)氢自由基被替换为卤素基团,其中各卤素基团独立地选自于-F、-Cl、-Br和-I。术语“卤甲基”意味着甲基中的1至3个氢自由基被替换为卤素基团。具有代表性的卤代烷基基团包括三氟甲基、溴甲基、1,2-二氯乙基、4-碘丁基和2-氟戊基等。卤代烷基基团可任选取代有一个或多个取代基。包含在本发明化合物中的卤代烷基基团可任选取代有增溶基团。
本文所使用的术语“卤代烷氧基”意味着如上所定义的烷氧基中的一个或多个(包括全部)氢自由基被替换为卤素基团,其中各卤素基团独立地选自于-F、-Cl、-Br和-I。具有代表性的卤代烷氧基基团包括三氟甲氧基、溴甲氧基、1,2-二氯乙氧基、4-碘丁氧基、2-氟戊氧基等。卤代烷氧基基团可任选取代有一个或多个取代基。包含在本发明化合物中的卤代烷氧基基团可任选取代有增溶基团。
本文所使用的术语“取代基”或“取代的”意味着化合物或基团中的氢自由基被替换为任何所期望的基团,所述所期望的基团以未受保护的形式或者在使用保护基团保护时,对于反应条件保持基本稳定。优选的取代基的实例为见于本文所公开的示例性化合物和实施方式中找基团、以及卤素、如上所定义的烷基、羟基、如上所定义的烷氧基、硝基、硫醇、如上所定义的硫代烷基、氰基、如上所定义的卤代烷基、如上所定义的卤代烷氧基、增溶基团或环烷基,所述环烷基可以是单环、或者稠合或非稠合的多环(例如,环丙基、环丁基、环戊基或环己基)。
本文所使用的术语“增溶”基团意味着相比于不含有该基团的类似化合物,具有足够亲水特性以改善或增加含有该基团的化合物的水溶性的基团。所述亲水特性可以通过任何手段来实现,例如通过包含在使用条件下电离以形成带电荷部分的官能团(例如,羧酸、磺酸、磷酸和胺等)、含有永久电荷的基团(例如,季铵基团)和/或杂原子或杂原子基团(如O、S、N、NH、N-(CH2)zR、N-(CH2)z-C(O)R、N-(CH2)z-C(O)OR、N-(CH2)z-S(O)2R、N-(CH2)z-S(O)2OR、N-(CH2)z-C(O)NRR',其中z是0至6的整数,R和R'各自独立地选自于氢、含有1至10个碳原子并且任选取代有一个或多个杂原子(如卤素(选自于F、Cl、Br或I)、氧和氮)的烷基、以及含有1至10个碳原子的烷氧基、以及芳基和杂芳基)。
在一些实施方式中,所述增溶基团是任选地包含1至5个取代基的杂环烷基,所述取代基本身可为增溶基团。
在特定的实施方式中,增溶基团为式:
其中,L选自于由CH和N所组成的组,M选自于由-CH(R)-、-CH2-、-O-、-S-、-NH-、-N(-(CH2)z-R)-、-N(-(CH2)z-C(O)R)-、-N(-(CH2)z-C(O)OR)-、-N(-(CH2)z-S(O)2R)-、-N(-(CH2)z-S(O)2OR)-和-N(-(CH2)z-C(O)NRR')-组成的组,其中z是0至6的整数,R和R'各自独立地选自于氢、含有1至10个碳原子并且任选取代有一个或多个杂原子(如卤素(选自于F、Cl、Br或I)、氧和氮)的烷基、以及含有1至10个碳原子的烷氧基、NRR'基团(其中R和R'各自独立地选自于氢、如上所定义的烷基,该烷基上任选取代有至少一个杂原子(特别是氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基基团,该烷基基团上任选地被取代)、以及芳基和杂芳基基团,但L和M不能同时分别为CH和CH2。
在另一具体实施方式中,所述增溶基团选自于由以下基团组成的组:吗啉基、哌啶基、N-(C1-C6)烷基哌啶基(特别是N-甲基哌啶基和N-乙基哌啶基)、N-(4-哌啶基)哌啶基、4-(1-哌啶基)哌啶基、1-吡咯烷基哌啶基、4-吗啉基哌啶基、4-(N-甲基-1-哌嗪基)哌啶基、哌嗪基,N-(C1-C6)烷基哌嗪基(特别是N-甲基哌嗪基和N-乙基哌嗪基)、N-(C3-C6)环烷基哌嗪基(特别是N-环己基哌嗪基)、吡咯烷基,N-(C1-C6)烷基吡咯烷基(特别是N-甲基吡咯烷基和N-乙基吡咯烷基)、二氮杂基、N-(C1-C6)烷基氮杂基(特别是N-甲基氮杂基和N-乙基氮杂基)、高哌嗪基、N-甲基高哌嗪基、N-乙基高哌嗪基和咪唑基等。
在式I的化合物中,其中环A如上面所描述,本发明涉及下式II的化合物:
其中,
A环是五元杂环;
R1是氢、卤素(选自于F、Cl、Br或I)、烷氧基或含有1至10个碳原子的烷基;
R2是卤素(选自于F、Cl、Br或I)、芳基、含有1至10个碳原子的烷基或卤代烷基,所述卤代烷基或烷基任选取代有至少一个杂原子(特别是氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基或卤代烷基,该卤代烷基或烷基任选取代有增溶基团;以及烷氧基或卤代烷氧基;以及-COOR、-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基团,其中R和R'各自独立地选自于氢、芳基、杂芳基、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团;
R3是氢、卤素(选自于F、Cl、Br或I)、氰基、烷氧基或含有1至10个碳原子的烷基;以及CF3、-NRR'、-NR-CO-R'、-CONRR'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团;
Q是O或S;
W是N或CR4;
R4是氢、氰基、CF3、卤素(选自于F、Cl、Br或I)、含有1至10个碳原子的烷基,所述烷基任选取代有至少一个杂原子(特别是氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及烷氧基或卤代烷氧基、增溶基团、杂环、-CO-NRR'、-SO2-NRR'、-NRR'、-NR-CO-R'或-NR-SO2R'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团或杂环基团;
X是N或CR5;
R5是氢、氰基、卤素(选自于F、Cl、Br或I)、烷氧基、含有1至10个碳原子的烷基、-CO-OR、-CO-NRR'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团或杂环基团;
M是C或N;
V是CH2、CR7或NR7;
R7是氢或含有1-10个碳原子的烷基,该烷基任选取代有增溶基团或杂环基团;
Y是N、CR8或CR8R9;
Z为N、NR8、CR8或CR8R9;
R8是氢、烷氧基或含有1至10个碳原子的烷基;
R9是氢或含有1至10个碳原子的烷基。
在一个实施方式中,本发明涉及式II的化合物或其药学上可接受的盐,其中R2是卤素(选自于F、Cl、Br或I)、芳基、含有1至10个碳原子的烷基或卤代烷基,所述卤代烷基或烷基任选取代有至少一个杂原子(特别是氧或氮),该杂原子上任选取代有含有1至10个碳原子的卤代烷基或烷基,该卤代烷基或烷基上任选取代有增溶基团;以及烷氧基或卤代烷氧基;以及-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团。
优选的上式化合物的实例如下表1所述:
表1
在式I的化合物中(其中环A如上所述),本发明涉及下式III的化合物:
其中,
A环是六元杂环;
R1是氢、卤素(选自于F、Cl、Br或I)、烷氧基或含有1至10个碳原子的烷基;
R2是卤素(选自于F、Cl、Br或I)、芳基、含有1至10个碳原子的烷基或卤代烷基,所述卤代烷基或烷基任选取代有至少一个杂原子(特别是氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基或卤代烷基,该卤代烷基或烷基任选取代有增溶基团;以及烷氧基或卤代烷氧基;以及-COOR、-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基团,其中R和R'各自独立地选自于氢、芳基、杂芳基、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团;
R3是氢、卤素(选自于F、Cl、Br或I)、氰基、烷氧基或含有1至10个碳原子的烷基;以及CF3、-NRR'、-NR-CO-R'、-CONRR'基团,其中R和R'各自独立地选自氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团;
Q是O或S;
W是N或CR4;
R4是氢、氰基、CF3、卤素(选自于F、Cl、Br或I)、含有1至10个碳原子的烷基,所述烷基任选取代有至少一个杂原子(特别是氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及烷氧基或卤代烷氧基、增溶基团、杂环、-CO-NRR'、-SO2-NRR'、-NRR'、-NR-CO-R'或-NR-SO2R'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团或杂环基团;
X是N或CR5;
R5是氢、氰基、卤素(选自于F、Cl、Br或I)、含有1至10个碳原子的烷基、烷氧基、-CO-OR、-CO-NRR'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团或杂环基团;
M是C或N;
V是N、CH2、CR7或NR7;
R7是氢、氰基或含有1-10个碳原子的烷基,该烷基任选取代有增溶基团或杂环基团;
Y是N、CR8或CR8R9;
Z是N、CR8或CR8R9;
T是N、C=O、CR8或CR8R9;
R8是氢、卤素(选自于F、Cl、Br或I)、羟基、烷氧基或含有1至10个碳原子的烷基;
R9是氢或含有1至10个碳原子的烷基。
在一个实施方式中,本发明涉及式III的化合物或其药学上可接受的盐,其中R2是卤素(选自于F、Cl、Br或I)、芳基、含有1至10个碳原子的烷基或卤代烷基,所述卤代烷基或烷基任选取代有至少一个杂原子(特别是氧或氮),该杂原子上任选取代有含有1至10个碳原子的烷基或卤代烷基,该卤代烷基或烷基上任选取代有增溶基团;以及烷氧基或卤代烷氧基;以及-NRR'、-NR-CO-R'、-CONRR'或-NR-SO2-R'基团,其中R和R'各自独立地选自于氢、任选取代有至少一个杂原子(特别是氧或氮)的烷基,该杂原子上任选取代有含有1至10个碳原子的烷基,该烷基上任选取代有增溶基团;以及杂环基团或增溶基团。
优选的上式化合物的实例如下表2所述:
表2
在可与本发明的其它实施方式相结合的一个实施方式中,本发明涉及式I的化合物或其药学上可接受的盐,其中:
R1是H或C1-C6烷基;
R2是H;
卤素;
COOH;
任选地被-NR10R11、OH或C1-C4烷氧基取代的C1-C6烷基,所述C1-C4烷氧基任选地被OH取代,其中R10和R11各自独立地为H或任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基的C1-C4烷基;或R10和R11与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉;
任选地被OH、C1-C4烷氧基或NR12R13取代的C1-C6烷氧基,其中R12和R13各自独立地为H或C1-C4烷基;或R12和R13与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;
-OR14基团,其中R14为五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;
-CONR15R16基团,其中R15和R16各自独立地为H或C1-C4烷基,所述C1-C4烷基任选取代有C1-C4烷氧基,或取代有含有1或2个选自于O、S和N的杂原子的五元或六元杂环烷基,特别是吗啉;或R15和R16与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉;
-NR17R18基团,其中R17是H或C1-C4烷基,R18是H、任选取代有C1-C4烷氧基的C1-C4烷基、或含有1至3个选自于O、S和N的杂原子的五元或六元杂芳基,特别是吡啶、嘧啶和噻唑;
-NR19COR20基团,其中R19是H或C1-C4烷基,R20是H或任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基的C1-C4烷基、或含有1或2个选自于O、S和N的杂原子的五元或六元杂环烷基,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;或
含有1或2个选自于O和N的杂原子的五元或六元杂环烷基或杂芳基,特别是哌啶和呋喃,所述杂环烷基或杂芳基任选取代有氧代基团或C1-C4烷基,该C1-C4烷基任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基;
R3是H、氰基、CF3、卤素、C1-C4烷基或C1-C4烷氧基;
Q是O或S,优选地,Q是O;
W是N或CR21,其中R21是
H;
卤素;
CN;
CF3;
OCF3;
任选取代有五元或六元杂环烷基的C1-C4烷基,所述杂环烷基含有1或2个选自于O和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉;
C1-C4烷氧基;
-O(CH2)nR22基团,其中n是0、1、2或3,R22是H、C1-C4烷氧基、-NR22aR22b基团(其中R22a和R22b各自独立地为H或C1-C4烷基)、或含有1或2个选自于O和N的杂原子的五元或六元杂环烷基,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;
-NR23R24基团,其中R23和R24各自独立地为H或任选取代有C1-C4烷氧基的C1-C4烷基;R24还可以表示-SO2(C1-C4)烷基;或R23和R24与它们所键合的氮原子一起形成五元或六元杂环烷基或杂芳基,所述杂环烷基或杂芳基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪、吗啉和吡唑,所述杂环烷基任选取代有1至3个C1-C4烷基;
X是N或CR25,其中R25是H、CN、C1-C4烷基或-COO(C1-C4)烷基基团;并且
A是含有1至3个选自于O和N的杂原子的五元或六元杂环烷基或杂芳基,特别是哌啶、哌嗪、吡咯烷、吗啉、咪唑烷、二氢咪唑、三唑、二氢吡啶和四氢吡啶,所述杂环烷基或杂芳基任选取代有1至3个取代基,所述取代基选自于:氧代基团、卤素、C1-C4烷基以及C1-C4烷氧基,所述C1-C4烷基任选取代有氨基、C1-C4烷基氨基、二(C1-C4)烷基氨基或含有1个或2个选自于O和N的杂原子的五元或六元杂环烷基,特别是哌啶。
在该族化合物中,优选R2、R3和W如下所定义的化合物:
R2是H;
卤素;
任选地被-NR10R11或C1-C4烷氧基取代的C1-C6烷基,所述C1-C4烷氧基任选地被OH取代,其中R10和R11各自独立地为H或任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基的C1-C4烷基;或R10和R11与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉;
任选地被OH、C1-C4烷氧基或-NR12R13基团取代的C1-C6烷氧基,其中R12和R13各自独立地为H或C1-C4烷基;或R12和R13与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;
-OR14基团,其中R14为五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;
-CONR15R16基团,其中R15和R16各自独立地为H或C1-C4烷基,所述C1-C4烷基任选取代有C1-C4烷氧基;或R15和R16与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉;
-NR17R18基团,其中R17是H或C1-C4烷基,R18是H、任选取代有C1-C4烷氧基的C1-C4烷基、或含有1至3个选自于O和N的杂原子的五元或六元杂芳基,特别是吡啶;
-NR19COR20基团,其中R19是H或C1-C4烷基,R20是H或任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基的C1-C4烷基,或含有1或2个选自于O、S和N的杂原子的五元或六元杂环烷基,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;或
含有1或2个选自于O和N的杂原子的五元或六元杂环烷基或杂芳基,特别是哌啶和呋喃,所述杂环烷基或杂芳基任选取代有氧代基团或C1-C4烷基,该C1-C4烷基任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基;
R3是H、CF3、卤素、C1-C4烷基或C1-C4烷氧基;
W是N或CR21,其中R21是
H;
卤素;
CN;
CF3;
OCF3;
任选取代有五元或六元杂环烷基的C1-C4烷基,所述杂环烷基含有1或2个选自于O和N的杂原子,特别是吡咯烷、哌啶、哌嗪和吗啉;
C1-C4烷氧基;
-O(CH2)nR22基团,其中n是0、1或2,R22是含有1或2个选自于O和N的杂原子的五元或六元杂环烷基,特别是吡咯烷、哌啶、哌嗪和吗啉,所述杂环烷基任选取代有1至3个C1-C4烷基;
-NR23R24基团,其中R23和R24各自独立地为H或任选取代有C1-C4烷氧基的C1-C4烷基;或R23和R24与它们所键合的氮原子一起形成五元或六元杂环烷基或杂芳基,所述杂环烷基或杂芳基含有1或2个选自于O、S和N的杂原子,特别是吡咯烷、哌啶、哌嗪、吗啉和吡唑,所述杂环烷基任选取代有1至3个C1-C4烷基。
在可与本发明的其它实施方式相结合的另一个实施方式中,式I的化合物或其药学上可接受的盐也在考虑之列,其中:
R1是H或C1-C4烷基;
R2是H、任选地被C1-C4烷氧基取代的C1-C4烷基、任选地被OH、-NR12R13基团或-CONR15R16基团(其中R15和R16各自独立地为H或C1-C4烷基)取代的C1-C4烷氧基,其中R12和R13各自独立地为H或C1-C4烷基,或R12和R13与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O和N的杂原子,特别是吗啉;
R3是H或C1-C4烷基;
Q是O;
W是N或CR21,其中R21是H、OCF3、C1-C4烷基、C1-C4烷氧基或-O(CH2)nR22基团,其中n是0、1或2,优选地n是2,R22是含有1或2个选自于O和N的杂原子的五元或六元杂环烷基,特别是吗啉;
X是N或CH;并且
A是含有1或2个氮原子的五元或六元杂环烷基或杂芳基,特别是咪唑烷和二氢吡啶,所述杂环烷基或杂芳基任选取代有1至3个C1-C4烷基。
本发明优选的化合物选自于实例1至225的化合物和其药学上可接受的盐。
特别优选下列化合物:
1-{4-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-吡啶-2-基}-咪唑烷-2-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-4,4-二甲基-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-5-甲基-苯基)-咪唑烷-2-酮;
1-(4-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-(4-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-{4-[2-((5-甲氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-吡啶-2-基}-4-甲基-咪唑烷-2-酮;
4-甲基-1-(4-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-(3-甲基-5-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-苯基)-咪唑烷-2-酮;
1-(4-{2-[2-甲基-5-(3-吗啉-4-基-丙氧基)-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-咪唑烷-2-酮;
1-(3-甲氧基-5-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-苯基)-咪唑烷-2-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-4-甲基-咪唑烷-2-酮;
1-{3-叔丁氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-苯基}-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-5-甲氧基-苯基)-咪唑烷-2-酮;
1-(3-甲氧基-5-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-苯基)-4-甲基-咪唑烷-2-酮;
1-{3-异丙氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-苯基}-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-5-异丙氧基-苯基)-咪唑烷-2-酮;
1-(3-异丙氧基-5-{2-[5-(2-甲氧基-乙基)-2-甲基-苯基氨基]-噁唑-5-基}-苯基)-咪唑烷-2-酮;
1-(3-(2-(2-甲基-5-(2-吗啉基乙氧基)苯基氨基)噁唑-5-基)-5-(三氟甲氧基)苯基)-咪唑烷-2-酮;
1-(3-(2-(5-甲氧基-2-甲基苯基氨基)噁唑-5-基)-5-(三氟甲氧基)苯基)-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基甲基)-2-甲基-苯基氨基]-噁唑-5-基}-5-甲基-苯基)-咪唑烷-2-酮;
3-{5-[3-异丙氧基-5-(2-氧代-咪唑烷-1-基)-苯基]-噁唑-2-基氨基}-N-(2-甲氧基-乙基)-4-甲基-苯甲酰胺;
1-(3-(2-(5-(乙氧基甲基)-2-甲基苯基氨基)噁唑-5-基)-5-(三氟甲氧基)苯基)-咪唑烷-2-酮;
3-{3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-三氟甲氧基-苯基}-4-甲基-1H-吡啶-2-酮;
3-{3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-1H-吡啶-2-酮;
3-{3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-异丙氧基-苯基}-4-甲基-1H-吡啶-2-酮;
4-[2-(5-(乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-4'-甲基-1'H-[2,3']联吡啶-2'-酮;
3-[3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-(2-吗啉-4-基-乙氧基)-苯基]-4-甲基-1H-吡啶-2-酮;
4'-甲基-4-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-1'H-[2,3']联吡啶-2'-酮;
4-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-4'-甲基-6-(2-吗啉-4-基-乙氧基)-1'H-[2,3']联吡啶-2'-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-异丙氧基-苯基}-咪唑烷-2-酮;
4'-甲基-4-{2-[2-甲基-5-(3-吗啉-4-基-丙氧基)-苯基氨基]-噁唑-5-基}-1'H-[2,3']联吡啶-2'-酮;以及
上述化合物在药学上可接受的盐。
可使用如下通用的实验方案来制备本发明的化合物。
氨基噁唑衍生物的合成经如下步骤:首先,运用Van Leusen等(TetrahedronLett.,1972,23,2369)的方法,使芳香醛I与对甲苯磺酰基甲基异腈(TosMIC)反应,制备相应的芳基取代噁唑衍生物II(反应方案1)。运用文献方法来制备非商品化的醛,使用有机金属试剂和DMF由相应的溴化芳香化合物引入醛基,或根据Frey等的方法氧化相应的甲苯来引入醛基(Tetrahedron Lett.,2001,39,6815)。
其次,通过适当的有机碱使噁唑部分去质子化将化合物II进一步官能化,随后用亲电氯化来制备2-氯噁唑化合物III。在适当的溶剂(如醇)的存在下,于高温中加热,由苯胺化合物IV(其中R'是氢)直接发生亲核取代反应,通常应得到最终目标化合物V。还可以通过使化合物IV(其中R'是乙酰基基团)和化合物III在氢化钠的存在下,在适当的溶剂(如四氢呋喃或二甲基甲酰胺)中反应得到化合物V(WO 2007/131953)。
反应方案2描述了氨基噻唑衍生物VIII的合成,所述合成经如下步骤:首先,运用由Iwao等(J.Org.Chem.,2009,74,8143)所述的Wittig反应,使芳香醛I与(甲氧基甲基)三苯基氯化鏻反应来制备相应的芳基取代的烯醇醚衍生物VI;其次,运用Zhao等(Tetrahedron Lett.,2001,42,2101)所述的方法使烯醇醚VI、硫脲衍生物VII和N-溴代琥珀酰亚胺(NBS)成环。
接下来,通过代表当前优选实施方式的实例对本发明加以阐明,所述实例构成了本发明的一部分,但决非用以限定本发明的范围。
化合物合成的实施例
通过参考下述制备实例将更全面地理解本发明,但不应将所述制备实例视为对本发明的范围的限定。
通用内容:所有使用的化学品都是商品试剂级产品。溶剂为干燥的商品级,并且无需进一步纯化而直接使用。通过使用预涂硅胶60F 254(Merck TLC板)的薄层色谱对反应进程进行监测,在UV光下加以可视化。1H NMR光谱中的多重性表示为单峰(s)、宽单峰(br s)、双峰(d)、三重峰(t)、四重峰(q)以及多重峰(m),NMR谱在Bruker Avance 300、360或400MHz光谱仪中进行。通过电喷雾电离质谱法(ESI MS)以正离子模式、或通过大气压化学电离质谱法(APCI MS)以正离子模式进行质谱。
LCMS方法:方法1:在连接至TQD质谱仪的超高效液相色谱(UPLC)ACQUITY Waters仪器上运行这一方法。使用的梯度为:在t=0.0min时以处于水+0.1%甲酸中的5%CH3CN+0.1%甲酸起始,直至t=0.5min;然后,从t=0.5min至t=7.0min以线性梯度达到100%CH3CN+0.1%甲酸;然后,从t=7.0min至t=10.0min保持这一状态。使用的柱为Waters HSSC18 1.8μm,2.1×50mm。使用的检测仪器为使用ESI正离子模式的三重四极质谱仪(TQD)。
方法2:在连接至ZMD质谱仪的HPLC 2695 Alliance Waters仪器上运行这一方法。使用的梯度为:在t=0.0min以处于水中的0%CH3CN+0.04%甲酸(10mM)起始;然后,以线性梯度在t=3.1min时达到100%CH3CN+0.04%甲酸;然后,保持这一状态至t=3.8min,至t=4.8min时降低至水中含0%CH3CN+0.04%甲酸。使用的柱是Sunfire 2.1×50mm dp:3.5μm。
缩写:
AcCl 乙酰氯
Al2O3 氧化铝凝胶
APCI MS 大气压化学电离质谱
BINAP 2,2'-双(二苯基膦)-1,1'-联萘
nBuLi 正丁基锂
tBuONO 亚硝酸叔丁酯
C2Cl6 六氯乙烷
CDCl3 氘代氯仿
CH3I 碘甲烷
mCPBA 3-氯过氧苯甲酸
Davephos 2-二环己基膦-2′-(N,N-二甲基氨基)联苯
DCM 二氯甲烷
DCE 1,2-二氯乙烷
DMF N,N-二甲基甲酰胺
DMSO-d6 六氘代二甲基亚砜
EDCI 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
EI-MS 电子轰击电离质谱
ES-MS 电喷雾质谱
Et2O 二乙醚
EtOAc 乙酸乙酯
EtOH 乙醇
h 小时
H2O2 过氧化氢
HOBT N-羟基苯并三唑
K2CO3 碳酸钾
K3PO4 磷酸三钾
KOtBu 叔丁醇钾
KSCN 硫氰酸钾
LiHMDS 双(三甲基硅烷基)锂酰胺
MeOH 甲醇
MgSO4 硫酸镁
min 分钟
NaH 氢化钠
NaHCO3 碳酸氢钠
NaI 碘化钠
NaOH 氢氧化钠
NaOtBu 叔丁醇钠
NaOEt 乙醇钠
NaOMe 甲醇钠
NBS N-溴代丁二酰亚胺
NEt3 三乙胺
Pd2(dba)3 三(二亚苄基丙酮)钯(0)
Pd(PPh3)4 四(三苯基膦)钯(0)
iPrOH 2-丙醇
SiO2 硅胶
SnCl2.2H2O 氯化锡(II)二水合物
TosMIC 对甲苯磺酰基甲基异腈
THF 四氢呋喃
Xantphos 4,5-双(二苯基膦)-9,9-二甲基呫吨
实例214
实例214的合成途径:
中间体I-e的合成途径:
中间体I-a的合成:1,3-二溴-5-异丙氧基苯
在0℃、惰性气氛下,向60%分散于矿物油的NaH(1.89g,47.25mmol)的干燥DMF溶液(20mL)中,滴加i-PrOH(3.62mL,47.25mmol)。混合物在0℃下搅拌15分钟。然后,在0℃下,滴加1,3-二溴-5-氟-苯(1.98mL,15.75mmol)的干燥DMF溶液(20mL)。反应混合物在室温下搅拌16小时。滴加饱和NaHCO3溶液,粗产物用Et2O萃取(2次),有机层用饱和NaHCO3溶液洗涤(3次),然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩,以定量的收率得到I-a,黄色油状物。1H NMR(300MHz,CDCl3)7.21(t,J=1.4Hz,1H),6.97(d,J=1.5Hz,2H),4.61-4.40(m,1H),1.32(d,J=6.0Hz,6H)。
中间体I-b的合成:3-溴-5-异丙氧基-苯甲醛
在-78℃、惰性气氛下,向I-a(4.630g,15.75mmol)的干燥Et2O溶液(60mL)中滴加正丁基锂的干燥Et2O溶液(6.3mL,15.75mmol)。反应混合物在-78℃下搅拌0.5小时。然后,在-78℃下滴加干燥DMF(1.35mL),用1.5小时升温至-40℃。加入HCl溶液(3N),粗产物用Et2O萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩,以82%的收率得到I-b,黄色油状物。1H NMR(300MHz,CDCl3)9.89(s,1H),7.54(m,1H),7.29(m,2H),4.60(dt,J=12.1,6.0Hz,1H),1.36(t,J=6.0Hz,6H)。
中间体I-c的合成:5-(3-溴-5-异丙氧基-苯基)-噁唑
向I-b(6.925g,28.50mmol)的MeOH溶液(125mL)中依次加入K2CO3(11.811g,85.50mmol)和TosMIC(6.674g,34.20mmol)。反应混合物在室温下搅拌16小时。然后,在减压下除去溶剂,加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用5%至30%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以86%的收率得到I-c,黄色油状物。1H NMR(300MHz,CDCl3)7.90(s,1H),7.34(m,2H),7.09(m,1H),7.00(m,1H),4.56(dt,J=12.1,6.0Hz,1H),1.49-1.26(m,6H)。
中间体I-d的合成:5-(3-溴-5-异丙氧基-苯基)-2-氯-噁唑
在-78℃、惰性气氛下,向I-c(6.921g,24.50mmol)的干燥THF溶液(130mL)中滴加LiHMDS的干燥THF溶液(29mL,29.00mmol)。反应混合物在-78℃下搅拌0.5小时。然后,在-78℃下加入C2Cl6(8.712g,36.75mmol),反应混合物在室温下搅拌16小时。加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至20%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以92%的收率得到I-d,黄色油状物。1H NMR(300MHz,CDCl3)δ7.29(t,J=1.5Hz,1H),7.27(s,1H),7.02(d,J=1.4Hz,2H),4.57(dt,J=12.1,6.0Hz,1H),1.36(s,3H),1.34(s,3H)。
中间体I-f的合成:[5-(3-溴-5-异丙氧基-苯基)-噁唑-2-基]–((5-乙氧基甲基)-2-甲基-苯基)-胺
在惰性气氛下,向I-d(1.556g,4.915mmol)和I-e(0.812g,4.915mmol)的i-PrOH溶液(45mL)中滴加HCl的干燥Et2O溶液(0.98mL,0.98mmol)。反应混合物在80℃下搅拌16小时。然后,在减压下除去溶剂,加入NaOH溶液(2.5N)。粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至30%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以64%的收率得到I-f,白色固体。1H NMR(300MHz,DMSO-d6)9.30(s,1H),7.81(s,1H),7.56(s,1H),7.30(s,1H),7.16(d,J=7.7Hz,1H),7.09(d,J=1.4Hz,1H),7.00(d,J=1.7Hz,1H),6.94(d,J=7.8Hz,1H),4.69(dt,J=12.0,5.9Hz,1H),4.41(s,2H),3.47(q,J=7.0Hz,2H),2.27(s,3H),1.39(s,3H),1.27(d,J=6.0Hz,6H),1.14(t,J=7.0Hz,3H)。
中间体I-g的合成:4-乙氧基甲基-1-甲基-2-硝基-苯
在惰性气氛下,向NaOEt的干燥EtOH溶液(45mL,114.90mmol)中加入4-氯甲基-1-甲基-2-硝基-苯(7.0g,38.30mmol)。反应混合物在室温下搅拌16小时。加入水,在减压下除去乙醇。粗产物用DCM萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩,以96%的收率得到I-g,棕色油状物。1H NMR(300MHz,CDCl3)δ7.95(s,1H),7.48(d,J=7.8Hz,1H),7.31(d,J=7.9Hz,1H),4.52(s,2H),3.56(q,J=7.0Hz,2H),2.57(d,J=10.1Hz,3H),1.26(t,J=7.0Hz,3H)。
中间体I-e的合成:5-乙氧基甲基-2-甲基-苯胺
向I-g(7.21g,36.93mmol)的EtOH溶液(238mL)溶液中依次加入Pd/C(2.432g)以及一水合肼(4.84mL,99.71mmol),一水合肼在0℃下滴加。反应混合物在80℃下搅拌2小时。然后,热的混合物经硅藻土垫过滤,用EtOH洗涤。滤液在减压下浓缩,以定量的收率得到I-e,黄色油状物。1H NMR(300MHz,CDCl3)δ6.99(d,J=7.6Hz,1H),6.67(d,J=7.5Hz,2H),4.41(s,2H),3.52(q,J=7.0Hz,3H),2.18(s,3H),1.04(t,J=8.5Hz,3H)。
实例214的合成:1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-异丙氧基-苯基}-咪唑烷-2-酮
在密封管中,向I-f(872mg,1.56mmol)的干燥二氧六环(13mL)溶液中依次加入咪唑烷-2-酮(674mg,7.84mmol)、碳酸铯(1.595g,4.90mmol)、Pd2(dba)3(113mg,0.20mmol)和Xantphos(54mg,0.06mmol)。反应混合物在110℃下搅拌16小时。加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用50%至100%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以50%的收率得到化合物214,白色固体。1H NMR(300MHz,DMSO-d6)δ9.26(s,1H),7.81(s,1H),7.40(s,1H),7.29(s,1H),7.15(d,J=7.7Hz,1H),7.11(t,J=2.0Hz,1H),7.01(s,1H),6.92(d,J=7.7Hz,1H),6.78(s,1H),4.62(dt,J=12.1,6.0Hz,1H),4.41(s,2H),3.92–3.81(m,2H),3.53–3.34(m,4H),2.27(s,3H),1.29(s,3H),1.27(s,3H),1.14(t,J=7.0Hz,3H)。
(ESI+)m/z 451.2(M+H)+。
保留时间=3.52min(方法2)。
实例215
实例215的合成途径:
中间体II-a的合成:2-溴-吡啶-4-甲醛肟
在-10℃、惰性气氛下,向2-溴-4-甲基吡啶(10.0g,58.13mmol)的干燥THF溶液(60mL)中,依次滴加亚硝酸叔丁酯(12.5mL,104.63mmol)和KOtBu的干燥THF溶液(88mL,87.20mmol)。反应混合物在-10℃下搅拌3小时。然后,加入饱和NH4Cl溶液,加入HCl溶液(4N)直至pH=6-7。粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩,以90%的收率得到II-a,黄色油状物。粗产物直接投入下一步。1H NMR(300MHz,DMSO-d6)δ12.47(s,1H),8.49(d,J=5.1Hz,1H),8.12(s,1H),7.90(dd,J=5.1,1.0Hz,1H),7.55(s,1H)。
中间体II-b的合成:2-溴-吡啶-4-甲醛
在-10℃下,向II-a(10.5g,52.23mmol)的水悬浮液(50mL)中滴加浓HCl溶液(50mL)和甲醛(50mL)的水溶液(37%w/w)。反应混合物在-10℃下搅拌4小时。然后,加入NaOH溶液(2N)直至pH=6-7。粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩,以97%的收率得到II-b,褐色油状物。1H NMR(300MHz,DMSO-d6)δ10.03(s,1H),8.68(d,J=4.9Hz,1H),8.07(s,1H),7.84(d,J=4.9Hz,1H)。
中间体II-c的合成:2-溴-4-噁唑-5-基-吡啶
向II-b(9.4g,50.53mmol)的MeOH溶液(100mL)中依次加入K2CO3(13.97g,101.06mmol)和TosMIC(14.80g,75.8mmol)。反应混合物在室温下搅拌16小时。然后,在减压下除去溶剂,加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。将深棕色固体在冷的乙醚中研磨,过滤并用更多的乙醚洗涤,以73%的收率得到终产物II-c,浅棕色固体。1H NMR(300MHz,CDCl3)δ8.42(d,J=5.2Hz,1H),8.02(s,1H),7.73(s,1H),7.60(s,1H),7.48(dd,J=5.2,1.3Hz,1H)。
中间体II-d的合成:2-甲基磺酰-1H-咪唑
向2-巯基咪唑(5.0g,49.93mmol)的水溶液(200mL)中加入NaOH(2.4g,59.91mmol)。反应混合物在室温下搅拌0.5小时。然后,加入丙酮(200mL)和MeI(3.4mL,54.92mmol)。反应混合物在室温下搅拌16小时。然后,在减压下除去溶剂,加入水,粗产物用EtOAc萃取(5次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。用石油醚将橙色固体研磨数次并过滤,以88%的收率得到化合物II-d,浅棕色固体。1H NMR(300MHz,DMSO-d6)δ12.16(s,1H),7.14(s,1H),6.91(s,1H),2.50(s,3H)。
中间体II-e的合成:2-(2-甲基磺酰-咪唑-1-基)-4-噁唑-5-基-吡啶
在密封管中,将II-d(1.98g,17.33mmol)、II-c(3.0g,13.33mmol)、K2CO3(3.87g,27.99mmol)、CuI(253mg,1.33mmol)、N,N'-二甲基环己烷-1,2-二胺(420μL,2.66mmol)加入干燥甲苯溶液(19mL)。反应混合物在110℃下搅拌4天。然后,加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。将棕色固体在冷的乙醚中研磨,过滤并用更多乙醚洗涤,以70%的收率得到终产物II-e,浅棕色固体。1H NMR(300MHz,DMSO-d6)δ8.67(s,1H),8.60(d,J=5.2Hz,1H),8.13(s,1H),7.97(s,1H),7.96(s,1H),7.70(dd,J=5.2,1.4Hz,1H),7.15(d,J=1.5Hz,1H),2.52(s,3H)。
中间体II-f的合成:2-(2-甲磺酰-咪唑-1-基)-4-噁唑-5-基-吡啶
向II-e(2.17g,7.83mmol)的DCM溶液(260mg)中加入mCPBA(2.97g,17.23mmol)。混合物在室温下搅拌16小时。然后,加入饱和NaHCO3溶液,粗产物用DCM萃取(2次),有机层用饱和NaHCO3溶液洗涤(3次),用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用5%至10%的MeOH/EtOAc作为洗脱剂,经硅胶柱层析纯化终产物,以84%的收率得到II-f,固体。1H NMR(300MHz,DMSO-d6)δ8.69(m,2H),8.14(s,1H),8.06(d,J=0.7Hz,1H),8.00(d,J=1.2Hz,1H),7.89(dd,J=5.2,1.5Hz,1H),7.38(d,J=1.2Hz,1H),3.53(s,3H)。
中间体II-g的合成:2-(2-甲氧基-咪唑-1-基)-4-噁唑-5-基-吡啶
在0℃下,向II-f(600mg,2.07mmol)的干燥MeOH/THF溶液(1/1,6mL)中加入NaOMe的MeOH溶液(6.2mL,3.10mmol)。反应混合物在50℃下搅拌16小时。加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩,以98%的收率得到化合物II-g,浅棕色固体。1H NMR(300MHz,DMSO-d6)δ8.66(s,1H),8.58(d,J=5.3Hz,1H),8.11(s,1H),8.03(s,1H),7.68(dd,J=5.2,1.4Hz,1H),7.51(d,J=1.9Hz,1H),6.70(d,J=1.9Hz,1H),4.09(s,3H)。
中间体II-h的合成:4-(2-氯-噁唑-5-基)-2-(2-甲氧基-咪唑-1-基)-吡啶
在-78℃、惰性气氛下,向中间体II-g(366mg,1.51mmol)的干燥THF溶液(15mL)中滴加LiHMDS的干燥THF溶液(2.3mL,2.27mmol)。反应混合物在-78℃下搅拌0.5小时。然后,在-78℃下加入C2Cl6(537mg,2.27mmol),反应混合物在室温下搅拌16小时。加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至10%的MeOH/EtOAc作为洗脱剂,经硅胶柱层析纯化终产物,以74%的收率得到中间体II-h,白色固体。1H NMR(300MHz,CDCl3)δ8.51(dd,J=5.2,0.8Hz,1H),7.95(dd,J=1.4,0.8Hz,1H),7.55(s,1H),7.52(d,J=1.9Hz,1H),7.33(dd,J=5.2,1.5Hz,1H),6.75(d,J=2.0Hz,1H),4.21(s,3H)。
中间体II-l的合成:4-甲氧基甲基-1-甲基-2硝基-苯
在惰性气氛下,向NaOMe(1.6g,29.63mmol)的干燥MeOH溶液(40mL)中加入4-氯甲基-1-甲基-2-硝基-苯(5.0g,26.94mmol)。反应混合物在室温下搅拌16小时。加入水,在减压下除去EtOH。粗产物用DCM萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩,得到中间体II-l,黄色油状物。1H NMR(300MHz,CDCl3)δ7.94(s,1H),7.47(d,J=7.8Hz,1H),7.32(d,J=7.8Hz,1H),4.48(s,2H),3.41(s,3H),2.58(s,3H)。
中间体II-m的合成:5-甲氧基甲基-2-甲基-苯胺
向中间体II-l(4.77g,26.32mmol)的EtOH/H2O溶液(9/1,150mL)中依次滴加SnCl2.2H2O(29.70g,131.60mmol)和37%的盐酸(15mL)。反应混合物在室温下搅拌16小时。在减压下除去EtOH。向所得的水溶液中加入NaOH溶液(10N)直至pH=6-7。然后,粗产物用DCM萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至30%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,得到中间体II-m,黄色油状物。1H NMR(300MHz,DMSO-d6)δ6.88(d,J=7.5Hz,1H),6.58(s,J=17.6Hz,1H),6.41(d,J=7.5Hz,1H),4.80(s,2H),4.24(s,2H),3.23(s,3H),2.03(s,3H)。
中间体II-i的合成:N-(5-甲氧基甲基-2-甲基-苯基)-乙酰胺
向II-m(2.0g,13.23mmol)的干燥DCM溶液(45mL)中依次加入干燥NEt3(2.3mL,15.88mmol)和AcCl(1.0mL,14.55mmol),AcCl在0℃下滴加。反应混合物在室温下搅拌2小时。加入水,粗产物用DCM萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用50%至80%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,得到中间体II-i,浅黄色固体,三步总收率为88%。1H NMR(300MHz,DMSO-d6)δ9.27(s,1H),7.36(s,1H),7.16(d,J=7.7Hz,1H),7.00(d,J=7.6Hz,1H),4.34(s,2H),3.26(s,3H),2.18(s,3H),2.05(s,4H)。
中间体II-j的合成:{5-[2-(2-甲氧基-咪唑-1-基)-吡啶-4-基]-噁唑-2-基}-(5-甲氧基甲基-2-甲基-苯基)-胺
在0℃下,向60%分散于矿物油的NaH(237mg,6.16mmol)的干燥DMF溶液(20mL)中,滴加中间体II-i(595mg,3.08mmol)的干燥DMF溶液(20mL)。反应混合物在室温下搅拌1小时,在0℃下滴加中间体II-h(852mg,3.08mmol)的干燥DMF溶液(20mL)。反应混合物在0℃下搅拌3小时。加入水,粗产物用EtOAc萃取(2次),有机层用饱和NaHCO3溶液洗涤(3次),然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至20%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以44%的收率得到中间体II-j,白色固体。1H NMR(300MHz,DMSO-d6)δ9.65(s,1H),8.45(d,J=5.3Hz,1H),7.86(s,1H),7.79(s,1H),7.72(s,1H),7.46(dd,J=5.1,3.6Hz,2H),7.21(d,J=7.7Hz,1H),7.00(d,J=7.7Hz,1H),6.68(d,J=1.8Hz,1H),4.38(s,2H),4.05(s,3H),3.28(s,3H),2.29(s,3H)。
实例215的合成:1-{4-[2-((5-甲氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-吡啶-2-基}-1,3-二氢-咪唑-2-酮盐酸盐
在0℃下,向II-j(100mg,0.26mmol)的干燥二氧六环溶液(4mL)中滴加HCl的干燥乙醚溶液(546μL,0.55mmol)。反应混合物在60℃下搅拌2小时,再在室温下搅拌16小时。然后,在减压下除去溶剂,将粗产物用乙醚研磨并过滤,以57%的收率得到化合物215,白色固体。1H NMR(300MHz,CD3OD)δ10.04–9.95(m,1H),9.46(s,1H),9.15(s,1H),9.03(d,J=4.6Hz,1H),8.95–8.87(m,1H),8.78(d,J=7.8Hz,1H),8.19(d,J=3.2Hz,1H),6.04(s,2H),4.97(s,3H),3.91(s,3H)。
实例216
化合物216的合成途径:
中间体III-a的合成:1-溴-3-(2-甲氧基-乙烯基)-苯
在0℃、惰性气氛下,向(甲氧基甲基)三苯基氯化鏻(5.56g,16.21mmol)的干燥THF溶液(13mL)中,滴加nBuLi的干燥THF溶液(22mL,21.62mmol)。反应混合物在室温下搅拌1小时。然后,在0℃下,滴加3-溴苯甲醛(2.0g,10.81mmol)的干燥THF溶液(20mL)。反应混合物在室温下搅拌16小时。加入饱和NH4Cl溶液,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用10%至15%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以66%的收率得到III-a,黄色油状物。1H NMR(300MHz,CDCl3)δ7.79(s,J=1.5Hz,1H),7.48–7.24(m,5H),7.20–7.12(m,2H),7.06(d,J=13.0Hz,1H),6.19(d,J=7.0Hz,1H),5.75(d,J=13.0Hz,1H),5.17(d,J=7.0Hz,1H),3.82(s,3H),3.71(s,3H)。
中间体III-b的合成:(5-甲氧基-2-甲基-苯基)-硫脲
在室温下,向KSCN(780mg,8.02mmol)的丙酮溶液(10mL)中滴加AcCl(900μL,8.02mmol)的丙酮溶液(10mL)。反应混合物在50℃下搅拌15分钟。然后,加入5-甲氧基-2-甲基苯胺(1.0g,7.29mmol)的丙酮溶液(10mL),反应混合物在50℃下搅拌15分钟。加入水,过滤固体,用更多的水和乙醚洗涤以得到白色固体。后者与K2CO3(2.0g,14.58mmol)的MeOH溶液(20mL)在室温下搅拌3小时。在减压下除去MeOH,固体用水和乙醚洗涤,以78%的收率得到III-b,白色固体。1H NMR(300MHz,DMSO-d6)δ9.20(s,1H),7.13(d,J=8.4Hz,1H),6.81(d,J=2.4Hz,1H),6.75(dd,J=8.3,2.6Hz,1H),3.71(s,3H),2.10(s,3H)。
中间体III-c的合成:[5-(3-溴-苯基)-噻唑-2-基]-(5-甲氧基-2-甲基-苯基)-胺
向III-a(300mg,1.41mmol)的二氧六环/水溶液(1/1,6mL)中加入NBS(276mg,1.55mmol)。反应混合物在室温下搅拌1小时。然后,加入III-b(277mg,1.41mmol),反应混合物在80℃下搅拌16小时。加入水,随后加入饱和NH4Cl溶液,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至35%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以69%的收率得到III-c,浅黄色固体。1H NMR(300MHz,DMSO-d6)δ9.48(s,1H),7.77–7.69(m,2H),7.54(d,J=2.1Hz,1H),7.46(dd,J=7.6,0.9Hz,1H),7.40(dd,J=7.9,1.0Hz,1H),7.30(t,J=7.9Hz,1H),7.11(d,J=8.3Hz,1H),6.60(dd,J=8.3,2.5Hz,1H),3.71(s,3H),2.19(s,3H)。
实例216的合成:1-{3-[2-(5-甲氧基-2-甲基-苯基氨基)-噻唑-5-基]-苯基}-咪唑烷-2-酮
在密封管中,向III-c(200mg,0.53mmol)的干燥二氧六环溶液(10mL)中依次加入2-咪唑烷酮(275mg,3.20mmol)、碳酸铯(432mg,1.33mmol)、Pd2(dba)3(46mg,0.05mmol)、4,5-Xantphos(61mg,0.11mmol)。反应混合物在110℃下搅拌16小时。加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至30%的MeOH/EtOAc作为洗脱剂,经硅胶柱层析纯化终产物,以41%的收率得到化合物216,黄色固体。1H NMR(300MHz,DMSO-d6)δ9.36(s,1H),7.75(s,1H),7.63–7.56(m,2H),7.37(d,J=8.2Hz,1H),7.29(t,J=7.9Hz,1H),7.15(d,J=7.5Hz,1H),7.11(d,J=8.4Hz,1H),7.01(s,1H),6.59(dd,J=8.3,2.6Hz,1H),3.93–3.83(m,2H),3.72(s,3H),3.44–3.37(m,2H),2.20(s,3H)。
实例217
实例217的合成途径:
中间体IV-a的合成途径:
中间体IV-c的合成:1-乙酰基-3-(4-甲基-3-硝基-苯基)-硫脲
向硫氰酸铵(1.05g,13.85mmol)的丙酮溶液(21mL)中,滴加乙酰氯(0.90mL,12.70mmol)。反应混合物在40℃下搅拌30分钟。然后,加入4-甲基-3-硝基苯胺(1.76g,11.54mmol)的丙酮溶液(7mL)。反应混合物在室温下搅拌4小时。将反应混合物倒入冰水中,过滤出沉淀,用更多的水和环己烷洗涤,以50%的收率得到化合物IV-c,棕色固体。1H NMR(300MHz,DMSO)δ12.45(s,1H),11.53(s,1H),8.38(d,J=2.0Hz,1H),7.69(dd,J=8.3,2.0Hz,1H),7.43(d,J=8.3Hz,1H),2.44(s,3H),2.09(s,3H)。
中间体IV-d的合成:(4-甲基-3-硝基-苯基)-硫脲
向IV-c(873mg,3.45mmol)的甲醇溶液(5mL)中加入K2CO3(953mg,6.90mmol)。反应混合物在室温下搅拌16小时。然后,在减压下除去溶剂,加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至50%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以60%的收率得到化合物IV-d,黄色固体。1HNMR(300MHz,DMSO)δ9.95(s,1H),8.28(d,J=2.1Hz,1H),8.00-7.70(m,3H),7.42(d,J=8.3Hz,1H),2.47(s,3H)。
中间体IV-e的合成:(4-甲基-3-硝基-苯基)-噻唑-2-基-胺
向IV-d(377mg,1.79mmol)的EtOH悬浮液(7mL)中加入氯乙醛(1.41g,17.93mmol)的水溶液(50%w/w)和KHCO3(539mg,5.37mmol)。反应混合物在70℃下搅拌16小时。然后,在减压下除去溶剂,加入水,粗产物用EtOAc萃取(3次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至70%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以40%的收率得到化合物IV-e,黄色固体。1H NMR(300MHz,DMSO)δ10.58(s,1H),8.55(d,J=2.4Hz,1H),7.69(dd,J=8.4,2.4Hz,1H),7.41(d,J=8.5Hz,1H),7.33(d,J=3.7Hz,1H),7.00(d,J=3.7Hz,1H),2.45(s,3H)。
中间体IV-f的合成:4-甲基-N1-噻唑-2-基-苯-1,3-二胺
向IV-e(737mg,3.13mmol)的EtOH/DCM溶液(30/13mL)中依次滴加SnCl2·2H2O(3.54g,15.65mmol)和37%的盐酸(3mL)。反应混合物在室温下搅拌16小时。在减压下除去EtOH,向所得水溶液中加入NaOH溶液(10N)直至pH=6-7。然后,粗产物用DCM萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至30%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以95%的收率得到中间体IV-f,黄色油状物。1HNMR(300MHz,DMSO)δ9.74(s,1H),7.18(d,J=3.7Hz,1H),6.90(d,J=2.0Hz,1H),6.85-6.77(m,2H),6.66(dd,J=8.0,2.0Hz,1H),4.83(brs,2H),1.99(s,3H)。
中间体IV-a的合成:N-[5-(乙酰基-噻唑-2-基-氨基)-2-甲基-苯基]-乙酰胺
在0℃下,向IV-f(610mg,2.97mmol)和NaHCO3(2.50g,29.71mmol)的干燥DCE溶液(10mL)中滴加乙酰氯(0.634mL,8.91mmol)。反应混合物在50℃下搅拌5小时。然后,加入水,粗产物用DCM萃取(3次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用30%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以75%的收率得到中间体IV-a,黄色固体。1H NMR(300MHz,DMSO)δ9.39(s,1H),7.54(d,J=1.7Hz,1H),7.40-7.32(m,2H),7.29(d,J=3.6Hz,1H),7.13(dd,J=7.9,1.9Hz,1H),2.28(s,3H),2.07(s,3H),1.99(s,3H)。
中间体IV-b的合成:N-{3-[5-(3-溴-5-异丙氧基-苯基)-噁唑-2-基氨基]-4-甲基-苯基}-N-噻唑-2-基-乙酰胺
在0℃下,向60%分散于矿物油的NaH(83mg,2.08mmol)的干燥DMF溶液(3mL)中,滴加中间体IV-a(300mg,1.04mmol)的干燥DMF溶液(3mL)。反应混合物在室温下搅拌1小时,在0℃下,滴加中间体I-d(328mg,1.04mmol)的干燥DMF溶液(3mL)。反应混合物在室温下搅拌16小时。加入水,粗产物用EtOAc萃取(2次),有机层用饱和NaHCO3溶液洗涤(3次),然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用0至35%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以46%的收率得到中间体IV-b,米黄色固体。1H NMR(300MHz,DMSO)δ9.63(s,1H),8.08(d,J=2.1Hz,1H),7.65(s,1H),7.47(d,J=2.2Hz,1H),7.45(d,J=2.5Hz,1H),7.42–7.38(m,2H),7.19(t,J=2.0Hz,1H),7.15(dd,J=7.9,2.2Hz,1H),7.11(t,J=2.0Hz,1H),4.78(septuplet,J=5.8Hz,1H),2.49(s,3H),2.14(s,3H),1.37(d,J=6.0Hz,6H)。
实例217的合成:1-(3-异丙氧基-5-{2-[2-甲基-5-(噻唑-2-基氨基)-苯基氨基]-噁唑-5-基}-苯基)-咪唑烷-2-酮
在密封管中,向IV-b(219mg,0.42mmol)的干燥二氧六环溶液(5mL)中依次加入咪唑烷-2-酮(286mg,3.36mmol)、碳酸铯(162mg,0.50mmol)、Pd2(dba)3(11mg,0.01mmol)和Xantphos(24mg,0.04mmol)。反应混合物在110℃下搅拌16小时。加入水,粗产物用EtOAc萃取(2次),有机层用水洗涤,然后用饱和NaCl溶液洗涤,用MgSO4干燥并浓缩。使用50%至100%的EtOAc/环己烷作为洗脱剂,经硅胶柱层析纯化终产物,以49%的收率得到化合物217,米黄色固体。1H NMR(300MHz,DMSO)δ10.12(brs,1H),9.25(s,1H),8.04(d,J=2.1Hz,1H),7.42(s,1H),7.38(dd,J=8.3,2.1Hz,1H),7.25(brs,1H),7.19(d,J=3.7Hz,1H),7.15(t,J=1.9Hz,1H),7.10(d,J=8.4Hz,1H),7.01(s,1H),6.85(d,J=3.6Hz,1H),6.81(s,1H),4.61(m,1H),3.84(m,2H),3.38(m,2H),2.23(s,3H),1.27(d,J=6.0Hz,6H)。
(ESI+)m/z 491(M+H)+。
保留时间=3.13分钟(方法2)。
实例218
实例218的合成途径:
中间体V-g的合成途径:
中间体V-a的合成:4-甲基-吡啶-2-醇
运用Adger等在J.Chem.Soc.Perkin Trans.1,1988,第2791-2796页所述的方法制备中间体V-a。将含有水(240mL)的1L的烧瓶用浓H2SO4(32mL)处理并冷却至0℃,一次加入2-氨基-4-甲基吡啶(30g,277mmol)进行处理。用1小时滴加NaNO2(20.6g,299mmol)的水溶液(40mL),使得内部温度不超过5℃。反应混合物在0℃下搅拌1小时,然后加热至95℃,在该温度下保持15分钟,冷却至室温。用50%的NaOH溶液将反应溶液的pH调至6-7(放热),趁热用EtOAc萃取(4×120mL)。合并有机层并干燥(MgSO4),过滤,蒸馏以获得中间体V-a(24.5g,81%),米黄色结晶固体。1H NMR(300MHz,DMSO-d6)δ11.31(s,1H),7.23(d,J=6.7Hz,1H),6.10(s,1H),6.00(dd,J=6.7,1.2Hz,1H),2.10(s,3H)。
中间体V-b的合成:3-溴-4-甲基-吡啶-2-醇
用NBS(37.4g,210mmol)处理4-甲基-吡啶-2-醇V-a(25g,229mmol)的冰醋酸(350mL)和EtOAc(680mL)溶液,在室温下搅拌30分钟。用氨水将混合物的pH调至8,用EtOAc萃取。分离得到的有机层用1:1的H2O/盐水洗涤并干燥(MgSO4),过滤,蒸馏,用硅胶柱层析(1-4%的EtOH/DCM)纯化,以获得所期望的产物V-b(8.66g),白色固体。1H NMR(300MHz,DMSO)δ11.90(s,1H),7.32(d,J=6.6Hz,1H),6.19(d,J=6.6Hz,1H),2.25(s,3H)。
中间体V-c的合成:3-溴-2-甲氧基-4-甲基-吡啶
用MeI(7.29mL,117mmol)和Ag2CO3(6.47g,23.5mmol)处理3-溴-4-甲基-2-吡啶酮V-b(2.20g,11.7mmol)的DCM溶液(80mL)。塞住烧瓶,在氩气下搅拌6天。将混合物过滤,用柱层析(SiO2,二氧六环中含10%的EtOAc)纯化,以获得所期望的产物V-c(1.83g,80%),澄清流动的油状物。1H NMR(300MHz,CDCl3)δ7.94(d,J=5.0Hz,1H),6.77(d,J=5.1Hz,1H),4.00(s,3H),2.39(s,3H)。
中间体V-d的合成:2-甲氧基-4-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶
在氩气下,向干燥的密封管中加入3-溴-2-甲氧基-4-甲基吡啶V-c(813mg,4.02mmol)、双(频哪醇)二硼(1.12g,4.41mmol)、PdCl2(dppf):DCM(146mg,0.20mmol)、KOAc(1.18g,12.0mmol)和干燥DMF(10mL)。在100℃下反应1.5小时后,将混合物冷却至室温,进一步加入大量催化剂(75mg,0.092mmol)。将管密封,混合物在100℃下搅拌过夜。将混合物冷却,蒸馏溶剂,将混合物溶于DCM,用水洗涤。干燥(MgSO4)分离得到的有机物,过滤并蒸馏,用柱层析(SiO2,环己烷中含10%至20%的EtOAc)纯化,以获得中间体V-d(2.14g,51%),流动的黄色油状物。1H NMR(300MHz,CDCl3)δ8.00(d,J=5.3Hz,1H),6.65(d,J=5.3Hz,1H),3.89(s,3H),2.33(s,3H),1.40(d,J=11.1Hz,12H)。
中间体V-e的合成:2'-甲氧基-4'-甲基-4-噁唑-5-基-[2,3']联吡啶
在氩气下,向烘干的烧瓶中加入2-溴-4-噁唑-5基-吡啶(中间体II-c,461mg,2.07mmol)、2-甲氧基-4-甲基-3-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-吡啶V-d(510mg,2.07mmol)、K3PO4(2.82g,13.3mmol)、Pd(OAc)2(51mg,0.225mmol)、Davephos(89mg,0.225mmol)、iPrOH(5mL)和水(3mL)。在100℃下反应40分钟后,将混合物冷却至室温,用水稀释,用EtOAc萃取,然后用盐水洗涤。干燥(MgSO4)有机物,过滤并蒸馏,用柱层析(SiO2,环己烷中含30%至100%的EtOAc)纯化,以获得所期望的产物V-e(240mg,43%),灰白色固体。1H NMR(300MHz,CDCl3)δ8.78(d,J=4.8Hz,1H),8.10(d,J=4.8Hz,1H),8.01(s,1H),7.59(d,J=4.9Hz,2H),7.51(d,J=4.9Hz,1H),6.86(d,J=4.9Hz,1H),3.88(s,3H),2.16(s,3H)。
中间体V-f的合成:4-(2-氯-噁唑-5-基)-4'-甲基-1'H-[2,3']联吡啶-2'-酮
如制备I-d的方法,使用LiHMDS(1M的THF溶液,2.62mL,2.62mmol)和C2Cl6(496mg,2.10mmol)的干燥THF溶液,由4'-甲基-4-噁唑-5-基-[2,3']联吡啶-2'-酮V-e制备4-(2-氯-噁唑-5-基)-4'-甲基-1'H-[2,3']联吡啶-2'-酮V-f。用柱层析(SiO2,用含有30%至50%EtOAc的环己烷洗脱)纯化粗产物,以获得中间体V-f(261mg,50%),白色固体。1H NMR(300MHz,DMSO-d6)δ8.76(d,J=5.3Hz,1H),8.12(d,J=4.4Hz,2H),7.70(s,1H),7.64(dd,J=5.2,1.7Hz,1H),7.00(d,J=5.2Hz,1H),3.78(s,3H),2.06(s,3H)。
中间体V-h的合成:4-(3-溴-丙氧基)-1-甲基-2-硝基-苯
用K2CO3(0.903g,6.53mmol)和1,3-二溴丙烷(6.63mL,65.3mmol)处理4-甲基-3-硝基苯酚(1.00g,6.53mmol)的DMF溶液(6mL),加热至100℃反应2.5小时。用水稀释冷却的混合物,用DCM萃取。干燥(MgSO4)合并的有机物,过滤并蒸馏,用柱层析(SiO2,使用含有20%EtOAc的环己烷洗脱)纯化,以获得所期望的产物V-h(1.05g,59%),流动的黄色油状物。1HNMR(300MHz,CDCl3)δ7.52(d,J=2.7Hz,1H),7.23(d,J=8.5Hz,1H),7.06(dd,J=8.5,2.7Hz,1H),4.14(t,J=5.8Hz,2H),3.60(t,J=6.4Hz,2H),2.53(s,3H),2.40–2.24(m,2H)。
中间体V-i的合成:4-[3-(4-甲基-3-硝基-苯氧基)-丙基]-吗啉
用K2CO3(1.01g,7.28mmol)和吗啉(319μl,3.65mmol)处理4-(3-溴-丙氧基)-1-甲基-2-硝基苯V-h(500mg,1.82mmol)的干燥二氧六环溶液(30mL),加热至100℃反应6小时。用水稀释冷却的混合物,用DCM萃取。干燥(MgSO4)合并的有机物,过滤并蒸馏,用柱层析(SiO2,使用含有2%EtOH的DCM洗脱)纯化,以获得所期望的产物V-i(356mg,70%),橙黄色油状物。1H NMR(300MHz,CDCl3)δ7.51(d,J=2.7Hz,1H),7.21(d,J=8.5Hz,1H),7.05(dd,J=8.5,2.7Hz,1H),4.06(t,J=6.3Hz,2H),3.79–3.66(m,4H),2.49(dt,J=9.0,5.1Hz,9H),2.07–1.88(m,2H)。
中间体V-g的合成:2-甲基-5-(3-吗啉-4-基-丙氧基)-苯胺
用SnCl2·H2O(1.58g,6.24mmol)和浓HCl(1.04mL,12.5mmol)处理4-[3-(4-甲基-3-硝基-苯氧基)-丙基]-吗啉V-i(350mg,1.25mmol)的90%EtOH溶液(15mL),加热回流1小时。在减压下将冷却的溶液浓缩,用饱和NaHCO3溶液将pH调至8,用EtOAc萃取。干燥(MgSO4)合并的有机物,过滤并蒸馏,以获得所期望的产物V-g(306mg,98%),粘稠黄色油状物。1HNMR(300MHz,CDCl3)δ6.92(d,J=8.8Hz,1H),6.30–6.24(m,2H),3.96(t,J=6.3Hz,2H),3.76–3.69(m,4H),3.58(s,2H),2.57–2.42(m,6H),2.09(s,3H),1.93(dt,J=13.3,6.5Hz,3H)。
实例218的合成:4'-甲基-4-{2-[2-甲基-5-(3-吗啉-4-基-丙氧基)-苯基氨基]-噁唑-5-基}-1'H-[2,3']联吡啶-2'-酮
用2-甲基-5-(3-吗啉-4-基-丙氧基)-苯胺V-g(48mg,0.191mmol)和HCl(2M的乙醚溶液,120μL,0.240mmol)处理4-(2-氯-噁唑-5-基)-4'-甲基-1'H-[2,3']联吡啶-2'-酮V-f(50mg,0.159mmol)的iPrOH溶液(4mL),加热回流18小时。该溶液进一步用150μL的HCl(2M的乙醚溶液,150μL,0.300mmol)处理,继续加热2小时。将混合物冷却至室温,然后在减压下蒸馏。用乙醚处理残留物,将白色沉淀物过滤,以获得化合物218(31mg,39%)。1H NMR(300MHz,DMSO)δ11.62(s,1H),9.40(s,1H),8.55(d,J=5.3Hz,1H),7.73(s,1H),7.55–7.48(m,2H),7.38(dd,J=5.2,1.7Hz,1H),7.29(d,J=6.7Hz,1H),7.03(d,J=8.8Hz,1H),6.52(dd,J=8.3,2.5Hz,1H),6.13(d,J=6.7Hz,1H),3.92(t,J=6.4Hz,2H),3.56–3.44(m,4H),2.40–2.25(m,6H),2.16(s,3H),1.98(s,3H),1.86–1.75(m,2H)。ESI+MS m/z 502(M+H)+。保留时间=1.76min(方法1)。
实例219
实例219的合成途径:
中间体VI-a的合成:5-(3-溴-苯基)-噁唑
如制备中间体I-c的方法,使用3-溴-苯甲醛(10g,54mmol)、TosMIC(12.7g,65mmol)和K2CO3(8.97g)在MeOH中制备5-(3-溴-苯基)-噁唑VI-a,得到所期望的中间体VI-a(12.1g,100%),褐色固体。1H NMR(300MHz,CDCl3)δ7.92(s,1H),7.80(s,1H),7.57(d,J=7.7Hz,1H),7.46(d,J=8.0Hz,1H),7.37(s,1H),7.29(d,J=7.9Hz,1H)。
中间体VI-b的合成:2-甲氧基-3-(3-噁唑-5-基-苯基)-1,2-二氢-吡啶
将5-(3-溴-苯基)-噁唑VI-a(1.33g,5.94mmol)、2-甲氧基-3-吡啶基硼酸(1.00g,6.53mmol)、Pd(PPh3)4和K2CO3(1.81g,13.1mmol)溶于THF(20mL)和水(10mL)中,加热回流4小时。将混合物冷却,用水稀释,用EtOAc萃取。干燥(MgSO4)合并的有机物,过滤,残留物经柱层析(SiO2,用含有30%EtOAc的环己烷洗脱)纯化,得到所期望的产物VI-b,棕色油状物,静置结晶(1.37g,91%)。1H NMR(300MHz,CDCl3)δ8.18(dd,J=1.8,5.0Hz,1H),7.91(s,1H),7.81(s,1H),7.64(d,J=6.9Hz,2H),7.53-7.44(m,2H),7.37(s,1H),6.99(dd,J=5.0,7.2Hz,1H),3.97(s,3H)。
中间体VI-c的合成:3-[3-(2-氯-噁唑-5-基)-苯基]-2-甲氧基-1,2-二氢-吡啶
如制备中间体I-d的方法,由2-甲氧基-3-(3-噁唑-5-基-苯基)-吡啶(1.37g,5.43mmol)、LiHMDS(1M的THF溶液,5.97mL,5.97mmol)和C2Cl6(1.54g,6.52mmol)在干燥THF(50mL)中制备3-[3-(2-氯-噁唑-5-基)-苯基]-2-甲氧基-吡啶VI-c,经柱层析(SiO2,用含有10%至30%EtOAc的环己烷洗脱)纯化后,得到所期望的化合物VI-c(1.24g,84%),白色固体。1H NMR(400MHz,CDCl3)δ8.20(dd,J=5.0,1.9Hz,1H),7.76(t,J=1.6Hz,1H),7.63(dd,J=7.3,2.0Hz,1H),7.59–7.45(m,3H),7.31(s,1H),6.99(dd,J=7.3,5.0Hz,1H),3.99(s,3H)。
实例219的合成:3-{3-[2-(3,5-二甲氧基-苯基氨基)-噁唑-5-基]-苯基}-1H-吡啶-2-酮
如制备中间体I-f的方法,由3-[3-(2-氯-噁唑-5-基)-苯基]-2-甲氧基-吡啶VI-c(40mg,0.150mmol)与3,5-二甲氧基苯胺(29mg,0.190mmol)和HCl(2M的乙醚溶液,120μL,0.23mmol)在iPrOH(4mL)中制备3-{3-[2-(3,5-二甲氧基-苯基氨基)-噁唑-5-基]-苯基}-1H-吡啶-2-酮219。粗的反应混合物在减压下蒸馏,用饱和NaHCO3溶液和EtOAc处理残留物。在两相混合物中形成沉淀,过滤并干燥,得到化合物219(19mg,33%),米黄色固体。1H NMR(300MHz,DMSO-d6)δ11.86(s,1H),10.35(s,1H),7.96(s,1H),7.70(dd,J=2.0,6.9Hz,1H),7.60-7.41(m,5H),6.89(d,J=2.0Hz,2H),6.32(t,J=6.7Hz,1H),6.13(s,1H),3.73(s,6H)。ESI+MS m/z 390(M+H)+。保留时间=3.45min(方法1)。
实例220
实例220的合成途径:
中间体VII-a的合成:2-氟-4-甲酰基-苯甲腈
在-10℃、氩气下,向4-溴-2-氟苯甲腈(5.00g,25mmol)的干燥THF溶液(50mL)中滴加异丙基氯化镁(2M的THF溶液,15.0mL,30.0mmol),在该温度下搅拌3小时。滴加N-甲酰基哌啶(3.89g,35.0mmol)的干燥THF溶液(15mL),加热混合物至室温,搅拌1.5小时。用4M的HCl水溶液(250mL每次)处理所得到的溶液,用EtOAc萃取有机物。干燥(MgSO4)合并的有机物,过滤,蒸馏,残留物经柱层析(SiO2,用含有30%至50%EtOAc的环己烷洗脱)纯化,得到2-氟-4-甲酰基-苯甲腈VII-a(2.73g,73%),浅黄色固体。1H NMR(300MHz,CDCl3)δ10.07(d,J=1.7Hz,1H),7.90–7.79(m,2H),7.74(dd,J=8.5,0.8Hz,1H)。
中间体VII-b的合成:2-氟-4-噁唑-5-基-苯甲腈
如制备中间体I-c的方法,由2-氟-4-甲酰基-苯甲腈VII-a(2g,13.43mmol)、TosMIC(2.85g、14.77mmol)和K2CO3(2.41g,1.86mmol)在MeOH(40mL)中制备2-氟-4-噁唑-5-基-苯甲腈VII-b,得到所期望的中间体VII-b(1.46g,58%),黄色固体。1H NMR(300MHz,CDCl3)δ7.94(s,1H),7.62(dd,J=8.0,6.5Hz,1H),7.52–7.37(m,3H)。
中间体VII-c的合成:2-(3-甲基-2-氧代-2H-吡啶-1-基)-4-噁唑-5-基-苯甲腈
用KOH(735mg,13.1mmol)处理3-甲基-1H-吡啶-2-酮(1.43g,13.1mmol)的无水EtOH溶液(100mL),加热至回流,强力搅拌2小时,冷却至室温,在减压下蒸馏除去溶剂。将橙色固体残留物加入干燥DMF(100mL)中,用2-氟-4-噁唑-5-基-苯甲腈VII-b(2.24g,11.9mmol)处理,在100℃下搅拌3小时。在减压下蒸馏除去溶剂,用饱和NaHCO3溶液处理残留物,用DCM萃取。干燥(MgSO4)合并的有机物,过滤,蒸馏,残留物经柱层析(SiO2,用含有50%EtOAc的环己烷洗脱)纯化,得到所期望的中间体VII-c(2.55g,77%),灰白色固体。1HNMR(300MHz,DMSO-d6)δ8.62(s,1H),8.15(d,J=8.1Hz,1H),8.04(s,2H),7.99(dd,J=8.1,1.6Hz,1H),7.62(dd,J=6.9,1.1Hz,1H),7.49(d,J=6.6Hz,1H),6.34(t,J=6.8Hz,1H),2.07(s,3H)。
中间体VII-d的合成:4-(2-氯-噁唑-5-基)-2-(3-甲基-2-氧代-2H-吡啶-1-基)-苯甲腈
在-78℃、氩气下,滴加LiHMDS(1M的THF溶液,11.0mL,11.0mmol)处理2-(3-甲基-2-氧代-2H-吡啶-1-基)-4-噁唑-5-基-苯甲腈VII-c(2.55g,9.19mmol)的干燥新蒸THF溶液(160mL),得到不透明黄色浆液。在该温度下反应1小时,一次加入C2Cl6(3.26g,13.8mmol),加热混合物至室温。用水处理混合物,用DCM萃取。干燥(MgSO4)合并的有机物,过滤,蒸馏,残留物经柱层析(SiO2,用含有50%EtOAc的环己烷洗脱)纯化,得到所期望的产物VII-d(1.51g,52%),粉红色固体。1H NMR(300MHz,DMSO-d6)δ8.16(d,J=8.2Hz,1H),8.10(s,1H),8.02(d,J=1.4Hz,1H),7.96(dd,J=8.1,1.5Hz,1H),7.61(d,J=6.9Hz,1H),7.49(d,J=6.7Hz,1H),6.35(t,J=6.8Hz,1H),2.07(s,3H)。
中间体VII-e的合成:N-(5-乙氧基甲基-2-甲基-苯基)-乙酰胺
如制备中间体II-i的方法,用5-乙氧基甲基-2-甲基-苯胺I-e(5g,30.26mmol)、干燥三乙胺(12.23mL)、DCM(60mL)和AcCl(4.32mL)制备N-(5-乙氧基甲基-2-甲基-苯基)-乙酰胺VII-e,得到所期望的中间体VII-e(5.39g,86%),白色固体。1H NMR(300MHz,CDCl3)δ7.69(s,1H),7.15(d,J=7.7Hz,1H),7.07(d,J=8.2Hz,1H),4.46(s,2H),3.53(q,J=7.0Hz,2H),2.23(s,3H),2.18(s,3H),1.23(t,J=7.0Hz,3H)。
实例220的合成:4-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-2-(3-甲基-2-氧代-2H-吡啶-1-基)-苯甲腈
在氩气下,将N-(5-乙氧基甲基-2-甲基-苯基)-乙酰胺VII-e(74mg,0.361mmol)、干燥THF(3mL)和NaH(60%油分散液,29mg,0.722mmol)的混合物在室温下搅拌1小时。在0℃下,滴加4-(2-氯-噁唑-5-基)-2-(3-甲基-2-氧代-2H-吡啶-1-基)-苯甲腈VII-d(75mg,0.241mmol)的干燥THF悬浮液(3mL),用2小时将温度升至室温。用水处理混合物,用EtOAc萃取。干燥(MgSO4)合并的有机物,过滤,蒸馏,残留物经柱层析(SiO2,用含有50%EtOAc的环己烷洗脱)纯化,得到所期望的产物220(61mg,56%),粉红色固体。1H NMR(300MHz,DMSO-d6)δ9.55(s,1H),8.05(d,J=8.0Hz,1H),7.83–7.68(m,4H),7.61(d,J=6.7Hz,1H),7.48(d,J=6.6Hz,1H),7.18(d,J=7.8Hz,1H),6.97(d,J=7.4Hz,1H),6.33(t,J=6.8Hz,1H),4.41(s,2H),3.46(q,J=7.0Hz,2H),2.27(s,3H),2.06(d,J=7.1Hz,3H),1.12(t,J=7.0Hz,3H)。
实例221
实例221的合成途径:
中间体VIII-a的合成:3-溴-5-噁唑-5-基-吡啶
如制备中间体I-c所述的方法,使用2-5-溴-吡啶-3-甲醛(0.260g,1.4mmol)、TosMIC(0.273g,1.54mmol)和K2CO3(0.580g,4.2mmol)在MeOH(15mL)中制备3-溴-5-噁唑-5-基-吡啶VIII-a,得到所期望的中间体VIII-a(0.16g,50%),米黄色固体。1H NMR(300MHz,DMSO)δ8.95(s,1H),8.70(s,1H),8.59(s,1H),8.43(s,1H),7.95(s,1H)。
中间体VIII-b的合成:5'-噁唑-5-基-[1,3']联吡啶-2-酮
向烘干的、含有3-溴-5-噁唑-5-基-吡啶VIII-a(1.00g,4.44mol)的脱气1,4-二氧六环溶液(20mL)的密封管中加入2-羟基吡啶(507mg,5.33mmol)、K2CO3(1.23g,1.78mmol)、CuI(169mg,0.899mmol)和外消旋-反式-N,N’–二甲基环己烷二胺(280μL,1.78mmol)。用氩气对管进行换气,密封,在油浴中加热至120℃反应过夜。冷却至室温后,将混合物过滤,用1,4-二氧六环洗涤滤饼。将混合物蒸馏,残留物经柱层析(在DCM中含有2%至5%的EtOH)纯化,得到所期望的产物VIII-b(752mg,71%),米黄色固体。1H NMR(300MHz,DMSO-d6)δ9.06(s,1H),8.68(s,1H),8.60(s,1H),8.29(s,1H),7.95(s,1H),7.80(dd,J=6.8,1.6Hz,1H),7.57(ddd,J=8.8,6.6,1.9Hz,1H),6.54(d,J=9.2Hz,1H),6.39(t,J=6.7Hz,1H)。
中间体VIII-c的合成:5'-(2-氯-噁唑-5-基)-[1,3']联吡啶-2-酮
如制备中间体I-d所述的方法,使用LiHMDS(1M的THF溶液,4.64mL,4.64mmol)和C2Cl6(1.10g,4.64mmol),由5'-噁唑-5-基-[1,3']联吡啶-2-酮VIII-d(740mg,3.09mmol)在干燥THF中制备5'-(2-氯-噁唑-5-基)-[1,3']联吡啶-2-酮VIII-c。粗产物经柱层析(SiO2,用含有2%至5%EtOH的DCM洗脱)纯化,得到所期望的产物VIII-c(393mg,47%),白色固体。1H NMR(300MHz,CDCl3)δ8.91(s,1H),8.61(s,1H),8.06(t,J=2.2Hz,1H),7.50–7.42(m,2H),7.35(dd,J=6.9,1.9Hz,1H),6.70(d,J=9.3Hz,1H),6.34(td,J=6.8,1.2Hz,1H)。
实例221的合成:5'-[2-(5-甲氧基-2-甲基-苯基氨基)-噁唑-5-基]-[1,3']联吡啶-2-酮
如上述制备I-f所述的方法,由5'-(2-氯-噁唑-5-基)-[1,3']联吡啶-2-酮VIII-c(68mg,0.250mmol)和5-甲氧基-2-甲基苯胺(35mg,0.250mmol)在iPrOH(3mL)中制备5'-[2-(5-甲氧基-2-甲基-苯基氨基)-噁唑-5-基]-[1,3']联吡啶-2-酮221,经柱层析(SiO2,用含有2%至5%EtOH的DCM洗脱)纯化后,得到标题化合物221(28mg,30%),橙色固体。1H NMR(300MHz,CDCl3)δ8.83(d,J=1.9Hz,1H),8.45(d,J=2.3Hz,1H),7.93(t,J=2.1Hz,1H),7.73(d,J=2.4Hz,1H),7.41(m,1H),7.34(m,1H),7.30(s,1H),7.07(d,J=8.3Hz,1H),6.78(s,1H),6.68(d,J=9.3Hz,1H),6.55(dd,J=8.3,2.5Hz,1H),6.30(t,J=5.6Hz,1H),3.81(s,3H),2.25(s,3H)。ESI+MS m/z 375(M+H)+。保留时间=2.99min(方法1)。
实例222
实例222的合成:3-{3-[2-(3,5-二甲氧基-苯基氨基)-噁唑-5-基]-苯基}-1-(2-二甲基氨基-乙基)-1H-吡啶-2-酮
将3-{3-[2-(3,5-二甲氧基-苯基氨基)-噁唑-5-基]-苯基}-1H-吡啶-2-酮219(39mg,0.10mmol)、(2-氯-乙基)-二甲基-胺盐酸盐(17.5mg,0.11mmol)、K2CO3(31mg,0.22mmol)和碘化钾(19mg,0.11mmol)的混合物在DMF(4mL)中加热至50℃,反应16小时。蒸馏除去DMF后,用水处理混合物,用EtOAc萃取。干燥(MgSO4)合并的有机物,过滤,蒸馏,残留物经柱层析(Al2O3,用含有1%EtOH的DCM洗脱)纯化,得到所期望的产物222(23mg,50%),黄色固体。1H NMR(300MHz,DMSO)δ10.32(s,1H),7.95(s,1H),7.72(d,J=6.7Hz,1H),7.66(dd,J=6.9,1.6Hz,1H),7.58–7.31(m,4H),6.90(s,1H),6.89(s,1H),6.35(t,J=6.8Hz,1H),6.13(s,1H),4.07(t,J=6.3Hz,2H),3.73(s,6H),2.55(t,J=6.3Hz,2H),2.20(s,6H)。ESI+MS m/z 461(M+H)+。保留时间=2.90min(方法1)。
实例223
实例223的合成途径:
中间体IX-a的合成:2-溴-4-(2-氯-噁唑-5-基)-吡啶
如制备实例I-d的方法,用2-溴-4-噁唑-5-基-吡啶(450mg,2mmol)、LiHMDS(2.2mL,2.2mmol)和C2Cl6(568mg,2.4mmol)在THF中制备2-溴-4-(2-氯-噁唑-5-基)-吡啶IX-a,得到中间体IX-a(465mg,90%),橙黄色固体。1H NMR(300MHz,CDCl3)δ8.43(d,J=5.1Hz,1H),7.68(s,1H),7.53(s,1H),7.46–7.36(m,1H)。
中间体IX-b的合成:[5-(2-溴-吡啶-4-基)-噁唑-2-基]-(5-乙氧基甲基-2-甲基-苯基)-胺
如制备实例220的方法,用中间体VII-e(169mg,0.65mmol)、N-(5-乙氧基甲基-2-甲基-苯基)-乙酰胺(162mg,0.78mmol)和NaH(65mg,1.6mmol)在DMF中制备[5-(2-溴-吡啶-4-基)-噁唑-2-基]-(5-乙氧基甲基-2-甲基-苯基)-胺IX-b,得到中间体IX-b(162mg,64%),黄色固体。1H NMR(300MHz,CDCl3)δ8.32(d,J=5.1Hz,1H),7.94(s,1H),7.56(s,1H),7.42(s,1H),7.32(d,J=5.2Hz,1H),7.21(d,J=7.6Hz,1H),7.06(d,J=7.7Hz,1H),6.91(s,1H),4.54(s,2H),3.58(q,J=7.0Hz,2H),2.34(s,3H),1.27(t,J=7.0Hz,3H)。
实例223的合成:4'-[2-(5-乙氧基甲基-2-甲基-苯基氨基)-噁唑-5-基]-3,4,5,6-四氢-[1,2']联吡啶-2-酮
将中间体IX-b(51mg,0.13mmol)、δ-戊内酰胺(16mg,0.16mmol)、碳酸铯(60mg,0.18mmol)、Pd2(dba)3(4mg,0.004mmol)和XantPhos(7mg,0.012mmol)的混合物在二氧六环(2.5mL)中回流1小时,直至起始原料反应完毕(用TLC监测反应)。然后将反应混合物蒸馏,粗品油状物直接经层析(SiO2,用含有1%至10%EtOH的DCM洗脱)分离得到实例223(22mg,42%),黄色固体。1H NMR(300MHz,CDCl3)δ8.39(d,J=5.3Hz,1H),7.99(s,1H),7.94(s,1H),7.39(s,1H),7.25–7.12(m,3H),7.05(d,J=7.6Hz,1H),4.54(s,2H),4.02–3.89(m,2H),3.57(q,J=6.9Hz,2H),2.69–2.56(m,2H),2.34(s,3H),2.02–1.89(m,4H),1.26(t,J=7.0Hz,3H)。ESI+MS m/z 407(M+H)+。保留时间=3.48min(方法1)。
实例224
实例224的合成:1-{4-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-吡啶-2-基}-四氢-嘧啶-2-酮
将中间体IX-b(50mg,0.13mmol)、N,N’-伸丙脲(130mg,1.3mmol)、碳酸铯(46mg,0.14mmol)、Pd2(dba)3(4mg,0.004mmol)和XantPhos(7mg,0.012mmol)的混合物在二氧六环(2.5mL)中回流反应1小时30分钟。然后,将反应混合物蒸馏,残留物溶解于乙酸乙酯,用水洗涤数次,经MgSO4干燥并浓缩。粗品油状物直接经层析(SiO2,用含有1%至10%EtOH的DCM洗脱)分离得到实例224(16mg,31%),橙黄色固体。1H NMR(300MHz,DMSO-d6)δ9.54(s,1H),8.28(d,J=5.2Hz,1H),7.99(s,1H),7.79(s,1H),7.66(s,1H),7.24–7.10(m,2H),7.00–6.86(m,2H),4.41(s,2H),3.92–3.80(m,2H),3.47(q,J=6.9Hz,2H),3.26–3.19(m,2H),2.27(s,3H),2.03–1.80(m,2H),1.14(t,J=7.0Hz,3H)。
实例225
实例225的合成途径:
中间体X-a的合成:5-(3-硝基-苯基)-噁唑
如制备实例I-c的方法,用3-硝基苯甲醛(4g,26mmol)、TosMIC(5.7g,29mmol)和K2CO3(4.4g,32mmol)在MeOH中制备中间体X-a,得到中间体X-a(4.7g,93%),黄色固体。1HNMR(400MHz,DMSO-d6)δ8.56(s,1H),8.50(t,J=1.9Hz,1H),8.21(ddd,J=8.2,2.3,1.0Hz,1H),8.17(ddd,J=7.8,1.6,1.0Hz,1H),7.99(s,1H),7.78(t,J=8.0Hz,1H)。
中间体X-b的合成:2-氯-5-(3-硝基-苯基)-噁唑
如制备实例I-d的方法,用中间体X-a(3.2g,17mmol)、LiHMDS(20.2mL,20mmol)和C2Cl6(4.78g,20mmol)在THF中制备中间体X-b,得到所期望的中间体X-b(3.13g,82%),黄色固体。1H NMR(400MHz,DMSO-d6)δ8.48(d,J=1.5Hz,1H),8.24(d,J=8.2Hz,1H),8.14(d,J=7.8Hz,1H),8.09(d,J=1.9Hz,1H),7.80(td,J=8.1,1.9Hz,1H)。
中间体X-c的合成:4-甲基-N3-[5-(3-硝基-苯基)-噁唑-2-基]-苯-1,3-二胺
如制备实例220的方法,用中间体X-b(448mg,2mmol)、N-(5-氨基-2-甲基-苯基)-乙酰胺(394mg,2.4mmol)和NaH(160mg,4mmol)在THF中制备中间体X-c,得到中间体X-c(236mg,64%),橙色固体。1H NMR(300MHz,DMSO-d6)δ9.17(s,1H),8.32(s,1H),8.07(d,J=7.5Hz,1H),8.00(d,J=7.7Hz,1H),7.72(m,2H),7.11(s,1H),6.82(d,J=8.0Hz,1H),6.24(d,J=7.4Hz,1H),4.91(s,2H),2.11(s,3H)。
中间体X-d的合成:N-{4-甲基-3-[5-(3-硝基-苯基)-噁唑-2-基氨基]-苯基}-2-吡咯烷-1-基-乙酰胺
在室温下,将中间体X-c(226mg,0.72mmol)、1-吡咯烷基乙酸盐酸盐(158mg,0.94mmol)、1-羟基苯并三唑水合物(148mg,1.1mmol)、N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(252mg,1.3mmol)和NEt3(360μL,2.6mmol)的混合物在DMF(15mL)中搅拌过夜。将反应混合物蒸馏,用乙酸乙酯稀释,用水洗涤,用MgSO4干燥,浓缩至最小体积以进行结晶。通过过滤收集标题化合物,得到中间体X-d(224mg,72%),黄色固体。1H NMR(300MHz,DMSO-d6)δ9.66(s,1H),9.43(s,1H),8.35(s,1H),8.03(d,J=7.3Hz,1H),7.89(d,J=7.9Hz,1H),7.70(m,2H),7.04(s,1H),6.89(d,J=8.1Hz,1H),6.26(d,J=7.5Hz,1H),3.24(s,2H),2.63-2.54(m,4H),2.22(s,3H),1.76–1.69(m,4H)。
中间体X-e的合成:N-{3-[5-(3-氨基-苯基)-噁唑-2-基氨基]-4-甲基-苯基}-2-吡咯烷-1-基-乙酰胺
在40℃下,将中间体X-d(220mg,0.52mmol)、SnCl2·2H2O(590mg,2.6mmol)和浓盐酸(735μL,5.2mmol)的混合物在乙醇/水混合溶剂(9mL/1mL)中搅拌4小时。然后,将反应混合物蒸馏,用乙酸乙酯和NaOH水溶液稀释。水层用乙酸乙酯萃取两次,然后用水洗涤合并的有机层,经MgSO4干燥并浓缩。粗品油状物经层析(Al2O3,用含有0.5%EtOH的DCM洗脱)分离得到中间体X-e(147mg,72%),黄色-米黄色固体。1H NMR(300MHz,DMSO-d6)δ9.68(s,1H),9.40(s,1H),8.21(s,1H),7.95(d,J=7.8Hz,1H),7.88(d,J=7.3Hz,1H),7.56(s,1H),7.32(s,1H),7.05(s,1H),6.91(d,J=7.3Hz,1H),6.19(d,J=7.6Hz,1H),4.85(s,2H),3.28(s,2H),2.67-2.56(m,4H),2.23(s,3H),1.78–1.68(m,4H)。
实例225的合成:N-(3-{5-[3-(2,6-二氧代-哌啶-1-基)-苯基]-噁唑-2-基氨基}-4-甲基-苯基)-2-吡咯烷-1-基-乙酰胺
在0℃、氩气下,向中间体X-e(70mg,0.18mmol)的无水THF溶液(4mL)中分批加入戊二酐(20mg,0.18mmol)。混合物在环境温度下搅拌1小时,然后回流过夜。通过过滤收集所形成的固体,然后用THF和二乙醚洗涤固体,得到白色固体(52mg),在无水1,2-二氯乙烷(8mL)中用SOCl2(30μL,0.4mmol)处理10分钟。混合物回流至少4小时,直至起始原料反应完毕,然后用DCM稀释,用NaHCO3水溶液和水洗涤,经MgSO4干燥并浓缩。残留物经层析(Al2O3,用含有0.5%至1%EtOH的DCM洗脱)分离得到化合物225(23mg,45%),米黄色固体。1H NMR(300MHz,DMSO-d6)δ9.96(s,1H),9.64(s,1H),9.27(d,J=12.2Hz,1H),8.03(d,J=10.9Hz,1H),7.94(s,1H),7.54–7.46(m,1H),7.35–7.27(m,3H),7.10(d,J=8.2Hz,1H),3.23(s,2H),2.69(t,J=6.5Hz,4H),2.63–2.56(m,4H),2.23(s,3H),2.12(m,2H),1.74(s,4H)。
在另一个实施方式中,本发明涉及包含上述化合物的药物组合物。
以合适的剂量、使用本领域公知的药学上可接受的载体,可将此类药物配制成适于口服给药的药物组合物形式。此类载体使得药物组合物能够配制成如下制剂用于患者摄取:片剂、丸剂、糖衣剂(dragees)、胶囊剂、液体剂、凝胶剂、糖浆剂、膏剂(slurries)和悬浮液剂等。除活性成分外,这些药物组合物还可含有合适的药学上可接受的载体(包括赋形剂和助剂),所述载体有助于将活性化合物加工成为可在药学上使用的制剂。在最新版的Remington’s Pharmaceutical Sciences中可找到配制和给予技术的进一步详情(MaackPublishing Co.,Easton,Pa.)。
本发明的组合物还可采取用于局部给予的药物组合物或化妆品组合物的形式。
此类组合物可以如下形式呈现:凝胶剂;糊剂;软膏剂(ointment);霜剂;乳液剂;液态水性悬浮液剂;水醇溶液或者油性溶液;或者serum型或乳液剂的分散剂;或者干燥凝胶剂或亲脂凝胶剂;或者通过将脂相分散入水相中或反之得到的、奶型(milk type)的液态或半固态稠度的乳剂;或者霜剂或凝胶型的、软质半固体稠度的乳剂或悬浮液剂;或者可选地,针对离子型和/或非离子型的囊泡分散剂(vesicular dispersions)、微颗粒剂、微胶囊剂或微乳剂。根据标准方法制备这些组合物。
本发明所述的组合物包含任何通常用于皮肤病学和化妆品中的成分。该组合物可包含选自如下成分中的至少一种:亲水胶凝剂或亲脂胶凝剂、亲水活化剂或亲脂活化剂、防腐剂、软化剂、粘度增强聚合物、保湿剂、表面活性剂、防腐剂、抗氧化剂、溶剂、以及填料、抗氧化剂、溶剂、香料、填料、掩蔽剂、杀菌剂、吸味剂和着色剂。
作为可用于本发明中的油可提及:矿物油(液体石蜡)、植物油(牛油树脂的液体部分、葵花油)、动物油、合成油、硅油(环甲硅油)和氟化油。还可将脂肪醇、脂肪酸(硬脂酸)和蜡(石蜡、棕榈蜡(carnauba)、蜂蜡)用作脂类物质。
作为可用于本发明中的乳化剂可提及:甘油、聚山梨醇酯、甘油酯和聚乙二醇。
作为亲水胶凝剂,可提及羧乙烯聚合物(卡波姆)、丙烯酸共聚物(如丙烯酸酯/烷基丙烯酸酯共聚物)、聚丙烯酰胺、多糖(如羟丙基纤维素)、粘土和天然胶;作为亲脂胶凝剂,可提及改性粘土(如有机皂土)、脂肪酸的金属盐(如硬脂酸铝)和疏水性二氧化硅、或者乙基纤维素和聚乙烯。
作为亲水活化剂可使用:蛋白或蛋白水解物、氨基酸、多元醇、尿素、尿囊素、糖和糖衍生物、维生素、淀粉和植物提取物(特别是芦荟(Aloe vera)的提取物)。
作为亲脂活化剂可使用:视黄醇(维生素A)及其衍生物、生育酚(维生素E)及其衍生物、必需脂肪酸、神经酰胺和精油(essential oil)。这些试剂在使用时增添了额外的保湿或软化皮肤的特征。
另外,组合物中可包含表面活性剂,以便对能够去除肥大细胞的化合物(如酪氨酸激酶抑制剂,优选c-kit抑制剂)提供更深的穿透(penetration)。
在所考虑的成分中,本发明包括:穿透增强剂,选自例如由矿物油、水、乙醇、三醋精、甘油和丙二醇所组成的组;凝聚剂(cohesion agent),选自例如由聚异丁烯、聚乙酸乙烯酯和聚乙烯醇组成的组;以及增稠剂。
增强药物局部吸收的化学方法是本领域公知的。例如,具有穿透增强特性的化合物包括十二烷基硫酸钠(Dugard,P.H.和Sheuplein,R.J.,"Effects of IonicSurfactants on the Permeability of Human Epidermis:An Electrometric Study",J.Ivest.Dermatol.,V.60,pp.263-69,1973)、十二烷基胺氧化物(Johnson等,US 4,411,893)、氮酮(Rajadhyaksha,US 4,405,616和3,989,816)和癸甲基亚砜(Sekura,D.L.和Scala,J.,"The Percutaneous Absorption of Alkylmethyl Sulfides",Pharmacologyof the Skin,Advances In Biolocy of Skin,(Appleton-Century Craft)V.12,pp.257-69,1972)。已观察到,提高两性分子中头部基团的极性使其穿透增强特性增加,但要以增加其皮肤刺激特性为代价(Cooper,E.R.和Berner,B.,"Interaction of Surfactants withEpidermal Tissues:Physiochemical Aspects",Surfactant Science Series,V.16,Reiger,M.M.编著,(Marcel Dekker,Inc.),pp.195-210,1987)。
第二类化学增强剂通常称为共溶剂。这些材料相对易于通过各种机制进行局部吸收,对于一些药物而言实现渗透增强。在显示出使得各种化合物的吸收得以增强的能力方面,乙醇(Gale等,美国专利号4,615,699和Campbell等,美国专利号4,460,372和4,379,454)、二甲亚砜(US 3,740,420和US 3,743,727以及US 4,575,515)和甘油衍生物(US 4,322,433)为这类化合物的几个实例。
本发明的药物组合物还可旨在用于以气雾制剂给予至患者呼吸道的目标区域。
在US 5,906,202中公开了用于递送药物制剂气雾喷射(aerosolized bursts)的装置和方法学。制剂优选为溶液,例如水溶液、乙酸溶液、水/乙酸溶液、盐水溶液、胶态悬浮液和微晶悬浮液。例如,气雾颗粒包含上文所述活性成分和载体(例如,药学上活性的呼吸药物和载体),所述气雾颗粒通过推动制剂通过喷嘴而形成,所述喷嘴优选为柔性多孔膜的形式。所述颗粒具有足够小的尺寸,使得颗粒形成时仍然在空气中悬浮足够长的时间,从而使患者可将颗粒吸入患者的肺内。
本发明涵盖了在US 5,556,611中描述的体系:
-处于压力容器中的液气体系(将液化气体用作推进气体(例如,低沸点的FCHC或丙烷、丁烷);
-悬浮气雾剂(活性物质颗粒以固态形式悬浮在液态推进相中);
-加压的气体体系(使用压缩气体,如氮气、二氧化碳、一氧化二氮、空气)。
因此,根据本发明所述,通过如下步骤制成药物制剂:将活性物质溶于或分散在合适的无毒介质中,并将所述溶液或分散液雾化成气雾剂,即,极其细微地分布在载气中。这在技术上是可行的,例如为如下形式:气雾剂推进气体包;泵送气雾剂;或本身已知用于液体成雾和固体雾化的其它装置,尤其是允许精确个体用量的装置。
因此,本发明还针对包含如上所定义的化合物和此类制剂的气雾剂装置,优选具有计量的给药阀。
本发明的药物组合物还可旨在用于鼻内给予。
关于这一点,本领域普通技术人员将容易地明白用于向鼻粘膜表面给予化合物的药学上可接受的载体。在Remington’s Pharmaceutical Sciences,第16版,1980,ArthurOsol编著中描述了这些载体,以引用的方式将其公开内容并入本文。
对适当载体的选择取决于所考虑的特定给予类型。为了通过上呼吸道进行给予,可将所述组合物配制成溶液,例如,缓冲或无缓冲的水或等渗盐水;或配制成悬浮液,以滴剂或喷雾剂用于鼻内给予。优选地,此类溶液或悬浮液相对于鼻部分泌物而言是等渗的、并且具有相同的pH,例如约pH4.0-约pH7.4或pH6.0-pH7.0。缓冲液应该是生理上相容的,仅举一例来说包括磷酸盐缓冲液。例如,代表性的鼻减充血剂描述为缓冲至pH约6.2(Remington’s,同前,第1445页)。当然,对于鼻部和/或上呼吸道给予而言,本领域普通技术人员能够容易地确定无害的水性载体合适的pH和盐水含量。
还可将粘度例如约10-约3000cps或约2500-6500cps以上的常见鼻内载体(包括鼻部凝胶剂、霜剂、糊剂或软膏剂)用于提供与鼻粘膜表面的更持久接触。仅以举例的方式来说,此类载体粘性制剂可基于本领域公知烷基纤维素和/或其它高粘度的生物相容载体(参见例如,上文所引用的Remington’s)。优选烷基纤维素例如,浓度为每100ml载体约5mg-约1000mg以上的甲基纤维素。仅以举例的方式来说,更优选的甲基纤维素浓度是每100ml载体约25mg-大约mg。
还可包含其它成分对制剂提供额外的粘度、保湿性和合意的质地和气味,所述其它成分例如本领域已知的防腐剂、着色剂、润滑或粘性的矿物油或植物油、香料、天然或合成的植物提取物(例如芳香油)、以及保湿剂和粘度增强剂(例如甘油)。对于本发明所述的溶液或悬浮液的鼻部给予,可利用本领域用于生成液滴(drops)、雾滴(droplets)和喷雾(sprays)的各种装置。
本发明的另一目的是,将含有滴量器(dropper)或喷雾装置的预先测定单位剂量分配器制成包含一个或多个剂量的待给予药物,所述滴量器或喷雾装置含有作为液滴或作为喷雾进行递送的溶液或悬浮液。本发明还包括准备通过添加适量水制成溶液或悬浮液的试剂盒,所述试剂盒含有一个或多个单位脱水剂量的化合物以及任何所需的盐和/或缓冲剂、防腐剂和着色剂等。
本发明另一方面针对所述化合物在制造药物方面的用途。换句话说,本发明包括用于对与c-kit转导失调(unregulated)相关的疾病进行治疗的方法,所述方法包括向需要该治疗的哺乳动物给予治疗强效量的如上所定义的化合物。
具体而言,本发明旨在针对用于治疗疾病的方法,所述方法包括向需要该治疗的哺乳动物给予强效量的上述化合物,所述疾病选自于由如下疾病所组成的组:自身免疫疾病、变应性疾病、骨丢失(bone loss)、癌症(如白血病和GIST)、肿瘤血管发生、病毒感染、炎性疾病、炎性肠病(IBD)、间质性膀胱炎、肥大细胞病、感染性疾病、代谢病症、纤维症、糖尿病和CNS病症。
上述化合物可用于制造对与c-kit转导失调相关的疾病进行治疗的药物,所述疾病包括但不限于:
-肿瘤性疾病,如肥大细胞病、犬肥大细胞瘤、实体瘤、人胃肠道间质瘤(GIST)、小细胞肺癌、非小细胞肺癌、急性骨髓性白血病、急性成淋巴细胞性白血病、骨髓增生异常综合征、慢性髓系白血病(chronic myelogenous leukemia)、结肠直肠癌、胃癌、胃肠道间质瘤、睾丸癌、胶质母细胞瘤、实体瘤和星形细胞瘤;
-肿瘤血管生成;
-代谢疾病,如糖尿病及其慢性并发症、肥胖症、II型糖尿病、高脂血症和血脂异常、动脉粥样硬化、高血压和心血管疾病;
-变应性疾病,如哮喘、变应性鼻炎、变应性窦炎、变应性综合征(anaphylacticsyndrome)、荨麻疹、血管性水肿、特应性皮炎、变应性接触性皮炎、结节性红斑、多形性红斑、皮肤坏死性小静脉炎(cutaneous necrotizing venulitis)和虫咬性皮肤炎症以及吸血寄生虫感染;
-间质性膀胱炎;
-骨丢失(骨质疏松症);
-炎性疾病,如类风湿性关节炎、结膜炎、类风湿性脊椎炎、骨关节炎、痛风性关节炎及其他关节炎病情;
-自身免疫性疾病,如多发性硬化、牛皮癣、肠道炎性疾病、溃疡性结肠炎、克罗恩氏病、类风湿性关节炎和多发性关节炎、局部和全身性硬皮病、全身性红斑狼疮、盘状红斑狼疮、皮肤狼疮(cutaneous lupus)、皮肌炎、多发性肌炎、斯耶格伦氏综合征、结节性全身动脉炎、自身免疫性肠病以及增生性肾小球肾炎;
-在任何器官移植(包括肾、胰腺、肝、心脏、肺和骨髓)中的移植物排斥或移植物抗宿主疾病;
-本发明的慢性活动性肝炎和慢性疲劳综合征所包含的其它自身免疫性疾病;
-表皮下起泡病症(subepidermal blistering disorders),如天疱疮;
-血管炎;
-HIV感染;
-黑色素细胞功能异常相关疾病,如由黑色素细胞功能异常引起的过度黑素沉着(hypermelanosis),包括着色斑(lentigines)、日光性着色斑和衰老性着色斑、Dubreuilh黑变病、痣和恶性黑色素瘤。关于这一点,本发明包含上述定义的化合物在制造用于使人类皮肤变白的药物或化妆品组合物方面的用途;
-CNS病症,如精神病症、偏头痛、疼痛、记忆丧失和神经细胞退化。具体而言,将本发明所述方法用于治疗下述病症:抑郁症,包括心境恶劣障碍、循环情感性障碍、两极型忧郁症、重度抑郁或“忧郁质”抑郁、非典型性抑郁、难治性抑郁、季节性抑郁;厌食症;贪食症;经期前综合征;绝经后综合征(post-menopause syndrome);其它综合征,如精神迟钝(mental slowing)和注意力不集中;悲观忧虑(pessimistic worry);激动;自我贬损(self-deprecation);性欲降低;疼痛,包括急性疼痛、术后疼痛、慢性疼痛、伤害感受性疼痛、癌性疼痛、神经性疼痛、心因性疼痛综合征;焦虑病症,包括与换气过度和心率失常相关的焦虑、恐怖症、强迫症、创伤后应激障碍、急性应激障碍、泛化性焦虑症;诸如惊恐发作(panic attacks)的精神病急症,包括精神异常、妄想性障碍、转换障碍(conversiondisorders)、恐惧症、躁狂症、谵妄(delirium);解离型发作(dissociative episode),包括解离型健忘症、解离型神游症和解离型认同症、人格解体、紧张症、癫痫(seizures);重度精神病急症,包括自杀行为、自我忽视、暴力或攻击性行为、创伤、边缘型人格和急性精神异常;精神分裂症,包括类偏狂型精神分裂症、错乱型精神分裂症、紧张型精神分裂症和混合型精神分裂症;
-神经退行性疾病,包括阿尔茨海默氏病、帕金森氏病、亨廷顿氏病、朊病毒病、运动神经元病(MND)和肌萎缩性侧索硬化症(ALS);
-本文所提到的物质使用障碍,包括但不限于药物成瘾、药物滥用、药物习惯性、药物依赖性、戒断综合征和服药过量;
-脑缺血;
-纤维症;
-Duchenne肌营养不良。
关于肥大细胞增多症,本发明考虑将如上定义的化合物用于治疗不同类别的用途,所述类别可如下分类:
类别I由两个子类(IA和IB)构成。类别IA由肥大细胞浸润作用严格局限于皮肤的疾病构成。该类别的表现为该疾病最常见的形式,包括:i)色素性荨麻疹,色素性荨麻疹是皮肤肥大细胞增多症、尤其在儿童中遇到的最常见的形式;ii)弥漫性皮肤肥大细胞增多症;iii)孤立性肥大细胞瘤;以及iv)一些罕见的亚型,如大疱、红皮病型和毛细管扩张(teleangiectatic)肥大细胞增多症。这些形式的特征是其与儿童自发缓解和成人病程非常缓慢的过程中良好的预后。这种疾病形式长期存在,通常如同正常人群,并且转化成肥大细胞增多症的另一种形式是罕见的。类别IB代表了涉及或不涉及皮肤的惰性全身性疾病(SM)。相比于儿童,这些形式在成人中更为常见。本病的病程通常进展缓慢,但有时可能发生攻击性或恶性肥大细胞增多症的迹象,导致渐进地损害器官功能。
类别II包括伴有相关血液病的肥大细胞增多症,所述血液病例如骨髓增生性或骨髓增生异常综合征、或急性白血病。这些恶性肥大细胞增多症通常不涉及皮肤。该疾病的病程通常取决于制约其预后的相关血液疾病的类型。
类别III代表了攻击性全身性肥大细胞增多症,其常见多个器官被异常肥大细胞大量浸润。在伴有这种攻击性临床病程的患者中,骨髓增生性病症的外周血特点更为突出。该疾病的病程可以非常迅速,类似于急性白血病,或者某些病人可以表现出更长的存活时间。
最后,肥大细胞增多症的类别IV包括肥大细胞白血病,其特征在于循环肥大细胞和肥大细胞祖细胞的存在占白细胞的10%以上。这个实体可能代表了人体白血病最罕见的类型,并具有非常差的预后,类似于恶性肥大细胞增多症的发展迅速的变体。肥大细胞白血病可以更始发生,或作为色素性荨麻疹或全身性肥大细胞增多症的最终阶段。
本发明还考虑将所述方法用于治疗复发性细菌感染、无症状期间(如细菌性膀胱炎)后复发感染。更具体而言,本发明可以用于治疗FimH表达的细菌感染,如包括大肠杆菌、肺炎杆菌(Klebsiella pneumoniae)、粘质沙雷氏菌(Serratia marcescens)、弗氏柠檬酸杆菌(Citrobactor freudii)和鼠伤寒沙门氏菌(Salmonella typhimurium)在内的革兰氏阴性肠杆菌。
在这种用于治疗细菌感染的方法中,有益的是单独地、顺序或伴随地给予至少一种抗生素,所述抗生素选自于杆菌肽、头孢菌素类、青霉素类、氨基糖苷类、四环素、链霉素的和大环内酯抗生素(如红霉素)、氟喹诺酮类、放线菌素、磺胺类药物以及甲氧苄啶。
在一个优选的实施方式中,本发明涉及用于治疗肿瘤性疾病的方法,所述肿瘤性疾病如肥大细胞增多症、犬肥大细胞瘤、实体瘤、人胃肠道间质瘤(“GIST”)、小细胞肺癌、非小细胞肺癌、急性髓细胞白血病、急性淋巴细胞性白血病、骨髓增生异常综合征、慢性骨髓性白血病、结肠直肠癌、胃癌、胃肠道间质瘤、睾丸癌、成胶质细胞瘤以及星形细胞瘤,所述方法包括向需要这种治疗的人或哺乳动物(特别是狗和猫)给予如本文所定义的化合物。
在另一个优选的实施方式中,本发明涉及用于治疗变应性疾病的方法,所述变应性疾病例如哮喘、过敏性鼻炎、过敏性鼻窦炎、变应性综合征、荨麻疹、血管性水肿、特应性皮炎、变应性接触性皮炎、结节性红斑、多形性红斑、皮肤坏死性静脉炎和昆虫叮咬皮肤炎症、以及吸血寄生虫感染,所述方法包括向需要这种治疗的人或哺乳动物(特别是狗和猫)给予如本文所定义的化合物。
在又一个优选的实施方式中,本发明涉及用于治疗炎性疾病的方法,所述炎性疾病例如类风湿性关节炎、结膜炎、类风湿性脊椎炎、骨关节炎、痛风性关节炎以及其它关节炎症状,所述方法包括向需要这种治疗的人给予如本文所定义的化合物。
在又一个优选的实施方式中,本发明涉及用于治疗自身免疫性疾病的方法,所述自身免疫性疾病例如多发性硬化症、银屑病、肠道炎性疾病、溃疡性结肠炎、克罗恩氏病、类风湿关节炎和多关节炎、局部和全身性硬皮病、全身性红斑狼疮、盘状红斑狼疮性狼疮、皮肤狼疮、皮肌炎、多发性肌炎、干燥综合征、结节性全动脉炎、自身免疫性肠病变以及增生性肾小球肾炎,所述方法包括向需要这种治疗的人给予如本文所定义的化合物。
在又一个优选的实施方式中,本发明涉及用于治疗移植物抗宿主病或任何器官移植排斥反应的方法,所述器官包括肾脏、胰脏、肝脏、心脏、肺以及骨髓,所述方法包括向需要这种治疗的人给予如本文所定义的化合物。
在又一个实施方式中,可将本发明的化合物或其药学上可接受的盐以足够提供治疗效果的量、与一种或多种其它活性药剂联合给药。在一个实施方式中,本发明的化合物与其它药剂同时给药。在另一个实施方式中,本发明的化合物与其它药剂相继给药。在进一步的实施方式中,本发明的化合物与其它药剂的给药间隔一段时间。
体外TK抑制试验的实施例
过程
c-kit WT和突变c-kit(D816V)试验
增殖试验
对BaF3 Kit WT或Kit D816细胞系、以及人和鼠肥大细胞和肥大细胞白血病细胞系进行比色细胞增殖和存活力试验(CellTiter-Blue试剂购于Promega cat N G8081)。
总共将2×104细胞/50μl接种于96孔板的各孔中。通过向其中加入从0μM至10μM的1/2系列稀释的2X药物溶液,开始进行处理。使细胞在37℃下生长48h,向每孔中加入10μL的CellTiter-Blue试剂1/2稀释液,将板放回孵育箱中继续孵育4小时。来自CellTiter-Blue试剂的荧光强度与活细胞的数量成比例,使用POLARstar OMEGA酶标仪(BMG LabteckSarl)记录数据(544Ex/590Em)。使用无细胞的本底对照作为空白。试验的阳性对照对应于未经药物处理而获得的细胞增殖(100%增殖)。将每个样品一式三份。将结果表示为占不进行处理时得到的增殖作用的百分比。
将所有药物均制成处于DMSO中的20mM储备溶液,并于-80℃下保存。在每次实验前,于培养基中新制成药物稀释液。每次试验中包含DMSO对照。
细胞
人Kit WT和人Kit D816V源自鼠IL-3依赖性Ba/F3 proB淋巴样细胞。尽管用250ng/ml的重组鼠SCF对Ba/F3 Kit WT进行了刺激,但表达Kit D816V的细胞在生长方面不依赖于细胞因子。FMA3和P815细胞系是表达Kit内源性突变形式的肥大细胞瘤细胞,即,在受体-密码子573至579(FMA3)的鼠近膜编码区域发生框缺失(frame deletion)并激活激酶结构域(P815)中D814Y突变。人白血病MC系HMC-1在c-Kit基因中表达两个单点突变,在近膜结构域表达V560G并在激酶结构域表达D816V。
免疫沉淀试验和western印迹分析:
对于各试验,按照描述(Beslu等,1996),将5×106Ba/F3细胞和Ba/F3-衍生细胞(表达多种c-kit突变)进行细胞溶解和免疫沉淀。简单而言,使用针对抗鼠KIT(Rottapel等,1991年)或抗人KIT(Santa Cruz)胞质区的兔免疫血清将细胞溶解物免疫沉淀。将Western印迹与4G10抗磷酸酪氨酸抗体(UBI)、相应的抗KIT兔免疫血清或针对信号分子的抗体杂交。然后,将膜与HRP缀合的山羊抗小鼠IgG抗体或与HRP缀合的山羊抗兔IgG抗体(Immunotech)进行孵育,通过与ECL试剂(Amersham)进行孵育,使所感兴趣的蛋白可见。
实验结果
在表3中列出了使用上述实验方案的各种本发明化合物的实验结果。
表3:各化合物对c-kit WT和c-kit D816V的体外抑制作用。
本发明人观察到了本发明式I化合物类对蛋白激酶、尤其是天然和/或突变的c-kit极其有效的抑制作用。表3列出的化合物很好地代表了这类式I化合物。
Claims (15)
1.式I的化合物或其药学上可接受的盐:
其中,
R1是H或C1-C6烷基;
R2是H;
卤素;
COOH;
任选地被-NR10R11、OH或C1-C4烷氧基取代的C1-C6烷基,所述C1-C4烷氧基任选地被OH取代,其中R10和R11各自独立地为H或任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基的C1-C4烷基;或R10和R11与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子;
任选地被OH、C1-C4烷氧基或-NR12R13基团取代的C1-C6烷氧基,其中R12和R13各自独立地为H或C1-C4烷基;或R12和R13与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,所述杂环烷基任选取代有1至3个C1-C4烷基;
-OR14基团,其中R14为五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O、S和N的杂原子,所述杂环烷基任选取代有1至3个C1-C4烷基;
-CONR15R16基团,其中R15和R16各自独立地为H或C1-C4烷基,所述C1-C4烷基任选取代有C1-C4烷氧基、或取代有含有1或2个选自于O、S和N的杂原子的五元或六元杂环烷基;或R15和R16与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环含有1或2个选自于O、S和N的杂原子;
-NR17R18基团,其中R17是H或C1-C4烷基,R18是H、任选取代有C1-C4烷氧基的C1-C4烷基、或含有1至3个选自于O、S和N的杂原子的五元或六元杂芳基;
-NR19COR20基团,其中R19是H或C1-C4烷基,R20是H或任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基的C1-C4烷基,或含有1或2个选自于O、S和N的杂原子的五元或六元杂环烷基,所述杂环烷基任选取代有1至3个C1-C4烷基;或含有1或2个选自于O和N的杂原子的五元或六元杂环烷基或杂芳基,所述杂环烷基或杂芳基任选取代有氧代基团或C1-C4烷基,该C1-C4烷基任选取代有氨基、C1-C4烷基氨基或二(C1-C4)烷基氨基;
R3是H、氰基、CF3、卤素、C1-C4烷基或C1-C4烷氧基;
Q是O或S;
W是N或CR21,其中R21是
H;
卤素;
CN;
CF3;
OCF3;
任选取代有五元或六元杂环烷基的C1-C4烷基,所述杂环烷基含有1或2个选自于O和N的杂原子;
C1-C4烷氧基;
-O(CH2)nR22基团,其中n是0、1、2或3,R22是:H;C1-C4烷氧基;-NR22aR22b基团,其中R22a和R22b各自独立地为H或C1-C4烷基;或含有1个或2个选自于O和N的杂原子的五元或六元杂环烷基,所述杂环烷基任选取代有1至3个C1-C4烷基;
-NR23R24基团,其中R23和R24各自独立地为H或任选取代有C1-C4烷氧基的C1-C4烷基;R24还可以表示-SO2(C1-C4)烷基;或R23和R24与它们所键合的氮原子一起形成五元或六元杂环烷基或杂芳基,所述杂环烷基或杂芳基含有1或2个选自于O、S和N的杂原子,所述杂环烷基任选取代有1至3个C1-C4烷基;
X是N或CR25,其中R25是H、CN、C1-C4烷基或-COO(C1-C4)烷基基团;并且
A是含有1至3个选自于O和N的杂原子的五元或六元杂环烷基或杂芳基,所述杂环烷基或杂芳基任选取代有1至3个取代基,所述取代基选自于:氧代基团;卤素;C1-C4烷基,所述C1-C4烷基任选取代有氨基、C1-C4烷基氨基、二(C1-C4)烷基氨基或含有1或2个选自于O和N的杂原子的五元或六元杂环烷基;以及C1-C4烷氧基。
2.如权利要求1所述的化合物或其药学上可接受的盐,其中,
R1是H或C1-C4烷基;
R2是H;任选地被C1-C4烷氧基取代的C1-C4烷基;任选地被OH或-NR12R13基团取代的C1-C4烷氧基,其中R12和R13各自独立地为H或C1-C4烷基,或R12和R13与它们所键合的氮原子一起形成五元或六元杂环烷基,所述杂环烷基含有1或2个选自于O和N的杂原子;或-CONR15R16基团,其中R15和R16各自独立地为H或C1-C4烷基;
R3是H或C1-C4烷基;
Q是O;
W是N或CR21,其中R21是H、OCF3、C1-C4烷基、C1-C4烷氧基或-O(CH2)nR22基团,其中n是0、1或2,R22是含有1或2个选自于O和N的杂原子的五元或六元杂环烷基;
X是N或CH;并且
A是含有1或2个氮原子的五元或六元杂环烷基或杂芳基,所述杂环烷基或杂芳基任选取代有1至3个C1-C4烷基。
3.如权利要求1所述的化合物或其药学上可接受的盐,其中,Q是O。
4.如权利要求1所述的化合物或其药学上可接受的盐,所述化合物或其药学上可接受的盐选自于:
1-{4-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-吡啶-2-基}-咪唑烷-2-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-4,4-二甲基-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-5-甲基-苯基)-咪唑烷-2-酮;
1-(4-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-(4-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-{4-[2-((5-甲氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-吡啶-2-基}-4-甲基-咪唑烷-2-酮;
4-甲基-1-(4-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-(3-甲基-5-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-苯基)-咪唑烷-2-酮;
1-(4-{2-[2-甲基-5-(3-吗啉-4-基-丙氧基)-苯基氨基]-噁唑-5-基}-吡啶-2-基)-咪唑烷-2-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-咪唑烷-2-酮;
1-(3-甲氧基-5-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-苯基)-咪唑烷-2-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-4-甲基-咪唑烷-2-酮;
1-{3-叔丁氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-苯基}-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-5-甲氧基-苯基)-咪唑烷-2-酮;
1-(3-甲氧基-5-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-苯基)-4-甲基-咪唑烷-2-酮;
1-{3-异丙氧基-5-[2-((5-甲氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-苯基}-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基)-2-甲基-苯基氨基]-噁唑-5-基}-5-异丙氧基-苯基)-咪唑烷-2-酮;
1-(3-异丙氧基-5-{2-[5-(2-甲氧基-乙基)-2-甲基-苯基氨基]-噁唑-5-基}-苯基)-咪唑烷-2-酮;
1-(3-(2-(2-甲基-5-(2-吗啉基乙氧基)苯基氨基)噁唑-5-基)-5-(三氟甲氧基)苯基)-咪唑烷-2-酮;
1-(3-(2-(5-甲氧基-2-甲基苯基氨基)噁唑-5-基)-5-(三氟甲氧基)苯基)-咪唑烷-2-酮;
1-(3-{2-[5-(2-羟基-乙氧基甲基)-2-甲基-苯基氨基]-噁唑-5-基}-5-甲基-苯基)-咪唑烷-2-酮;
3-{5-[3-异丙氧基-5-(2-氧代-咪唑烷-1-基)-苯基]-噁唑-2-基氨基}-N-(2-甲氧基-乙基)-4-甲基-苯甲酰胺;
1-(3-(2-(5-(乙氧基甲基)-2-甲基苯基氨基)噁唑-5-基)-5-(三氟甲氧基)苯基)-咪唑烷-2-酮;
3-{3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-三氟甲氧基-苯基}-4-甲基-1H-吡啶-2-酮;
3-{3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-甲氧基-苯基}-1H-吡啶-2-酮;
3-{3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-异丙氧基-苯基}-4-甲基-1H-吡啶-2-酮;
4-[2-(5-(乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-4'-甲基-1'H-[2,3']联吡啶-2'-酮;
3-[3-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-5-(2-吗啉-4-基-乙氧基)-苯基]-4-甲基-1H-吡啶-2-酮;
4'-甲基-4-{2-[2-甲基-5-(2-吗啉-4-基-乙氧基)-苯基氨基]-噁唑-5-基}-1'H-[2,3']联吡啶-2'-酮;
4-[2-(3,5-二甲基-苯基氨基)-噁唑-5-基]-4'-甲基-6-(2-吗啉-4-基-乙氧基)-1'H-[2,3']联吡啶-2'-酮;
1-{3-[2-((5-乙氧基甲基)-2-甲基-苯基氨基)-噁唑-5-基]-5-异丙氧基-苯基}-咪唑烷-2-酮;
4'-甲基-4-{2-[2-甲基-5-(3-吗啉-4-基-丙氧基)-苯基氨基]-噁唑-5-基}-1'H-[2,3']联吡啶-2'-酮;以及
上述化合物药学上可接受的盐。
5.一种药物组合物,所述药物组合物包含权利要求1-4中任一项所述的化合物或其药学上可接受的盐。
6.一种用于局部给予的化妆品组合物,所述化妆品组合物包含权利要求1-4中任一项所述的化合物或其药学上可接受的盐。
7.权利要求1-4中任一项所述的化合物或其药学上可接受的盐在制造用于治疗肥大细胞增多症的药物中的用途。
8.权利要求1-4中任一项所述的化合物或其药学上可接受的盐在制造用于治疗恶性血液病、骨髓增生性病症、自身免疫性病症、炎性疾病、变应性疾病或神经疾病的药物中的用途。
9.如权利要求8所述的用途,其中,所述恶性血液病为急性骨髓性白血病、骨髓增生异常综合征、急性成淋巴母细胞性白血病、慢性骨髓性白血病或嗜酸细胞增多综合征。
10.如权利要求8所述的用途,其中,所述增生性病症是癌症。
11.如权利要求8所述的用途,其中,所述自身免疫性病症是多发性硬化、牛皮癣、肠道炎性疾病、溃疡性结肠炎、克罗恩氏病、类风湿性关节炎和多发性关节炎、局部和全身性硬皮病、全身性红斑狼疮、盘状红斑狼疮、皮肌炎、多发性肌炎、斯耶格伦氏综合征、结节性全身动脉炎、自身免疫性肠病、特应性皮炎或增生性肾小球肾炎。
12.如权利要求8所述的用途,其中,所述自身免疫性病症是皮肤狼疮。
13.如权利要求8所述的用途,其中,所述变应性疾病是哮喘、变应性鼻炎、变应性窦炎、过敏性综合征、荨麻疹、血管性水肿、特应性皮炎、变应性接触性皮炎、结节性红斑、多形性红斑、皮肤坏死性小静脉炎和虫咬性皮肤炎症或吸血寄生虫感染。
14.如权利要求8所述的用途,其中,所述神经疾病是亨廷顿氏病、精神分裂症、帕金森氏病或阿尔茨海默氏病。
15.权利要求1-4中任一项所述的化合物或其药学上可接受的盐在制造蛋白激酶抑制剂中的用途,其中,所述蛋白激酶是天然和/或突变的c-kit。
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AR087354A1 (es) | 2014-03-19 |
EP2736904A1 (en) | 2014-06-04 |
US9168245B2 (en) | 2015-10-27 |
AU2012288900B2 (en) | 2016-10-06 |
ES2573831T3 (es) | 2016-06-10 |
CA2840029A1 (en) | 2013-01-31 |
JP2014521624A (ja) | 2014-08-28 |
RU2014107463A (ru) | 2015-09-10 |
TW201311676A (zh) | 2013-03-16 |
ZA201400465B (en) | 2015-04-29 |
AU2012288900A1 (en) | 2014-01-16 |
IL230504A0 (en) | 2014-03-31 |
BR112014001977A2 (pt) | 2017-02-21 |
RU2612972C2 (ru) | 2017-03-14 |
CL2014000007A1 (es) | 2014-09-05 |
CA2840029C (en) | 2021-07-20 |
KR20140041609A (ko) | 2014-04-04 |
MX2014001079A (es) | 2014-09-12 |
JP5944503B2 (ja) | 2016-07-05 |
NZ618953A (en) | 2015-05-29 |
US20140179698A1 (en) | 2014-06-26 |
EP2736904B1 (en) | 2016-03-16 |
CN103717591A (zh) | 2014-04-09 |
WO2013014170A1 (en) | 2013-01-31 |
KR101924247B1 (ko) | 2019-02-22 |
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