CN102119156A - 取代的吡咯及其使用方法 - Google Patents
取代的吡咯及其使用方法 Download PDFInfo
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- CN102119156A CN102119156A CN2009801311880A CN200980131188A CN102119156A CN 102119156 A CN102119156 A CN 102119156A CN 2009801311880 A CN2009801311880 A CN 2009801311880A CN 200980131188 A CN200980131188 A CN 200980131188A CN 102119156 A CN102119156 A CN 102119156A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及式(I)的取代的吡咯化合物,其用作为激酶抑制剂,更具体地,其用作检测点激酶1(chk1)抑制剂,因此用作癌症治疗药物。本发明还涉及组合物,更具体地,涉及包含这些化合物的药物组合物,以及使用其治疗多种形式的癌症和过度增殖性疾病的方法,以及涉及使用所述化合物用于体外、原位和体内诊断或治疗哺乳动物细胞或相关病理学病症的方法。
Description
本申请要求2008年6月11日提交的美国临时申请61/060,752号的权益和2008年10月10日提交的美国临时申请61/104,618号的权益,将两者整体并入本文作为参考。
技术领域
本发明涉及取代的吡咯化合物,其可用作为激酶抑制剂,更具体地,其可用作检测点激酶1(checkpoint kinase 1,chk1)抑制剂,因此可用作癌症治疗药物。本发明还涉及组合物,更具体地,涉及包含这些化合物的药物组合物,以及使用其治疗多种形式的癌症和过度增殖性疾病(hyperproliferative disorder)的方法,以及使用所述化合物用于体外、原位和体内诊断或治疗哺乳动物细胞或相关病理学病症的方法。
背景技术
个体细胞通过制备它们染色体的精确副本,然后将这些染色体和它们的副本分离成单独的细胞来复制。这种DNA复制、染色体分离和分裂的周期由细胞内维持所述步骤的顺序以及确保各步骤精确进行的机制调节。牵涉在这些过程中的是细胞周期检测点(Hartwell et al.,Science,Nov.3,1989,246(4930):629-34),其中细胞可停滞,以确保在继续通过所述周期进入有丝分裂之前,DNA修复机制有时间运行。在细胞周期中有两个检测点,即由p53调节的G1/S检测点和由丝氨酸/苏氨酸激酶检测点激酶1(chk1)监测的G2/M检测点。
chk1和chk2为应答遗传毒性刺激时而被活化的、结构上不相关但功能上重叠的丝氨酸/苏氨酸激酶(在Bartek et al.,Nat.Rev.Mol.Cell Biol.2001,vol.2,pp.877-886中综述)。chk1和chk2中继来自ATM和ATR的检测点信号,所述信号使它们磷酸化和活化。chk2是在整个细胞周期中被表达的稳定蛋白,其主要由ATM应答双链DNA断裂(DSBs)时而被活化。不同的是,chk1蛋白的表达大部分受限于S和G2期。在应答DNA损伤时,ChK1被ATM/ATR磷酸化和活化,导致细胞周期停滞在S和G2/M期,从而允许DNA损伤修复(在Cancer Cell,Bartek and Lukas,Volume 3,Issue 5,May 2003,Pages421-429中综述)。已经证明,对chk1的抑制取消了细胞周期停滞,导致了在DNA被一定范围的化疗损伤之后肿瘤细胞死亡增强。缺少完整G1检测点的细胞特别依赖于S和G2/M检测点,并因此预期其在chk1抑制剂存在下对化疗治疗更敏感,而预测具有功能性G1检测点的正常细胞经历更少细胞死亡。
发明内容
本发明大体涉及具有酶抑制活性,更具体地具有chk1抑制活性的式(I)的取代的吡咯化合物(和/或其溶剂化物、水合物和/或盐)。本发明的化合物还可用于糖原合成酶激酶3(GSK-3)、KDR激酶和FMS样酪氨酸激酶3(FLT3)的抑制剂。因此,本发明化合物及其组合物可用于治疗过度增殖性疾病,如癌症。
(I)
R1为苯基或杂芳基,其中所述苯基和杂芳基任选取代有一至五个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8S O2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;
R2为H、氯、氟或CN;
R3A和R3B独立地为H、烷基、环烷基或杂环基,其中所述烷基、环烷基和杂环基任选取代有一至五个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;
R3A和R3B任选与所连接N原子一起形成具有额外0-2个选自O、S和N的杂原子的4-10元单环或二环,所述环任选取代有一至五个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;
X为O或N(R6);
R6为H、CN或C1-C2烷基,其中所述烷基任选取代有一个或多个基团,所述基团选自OH、O(C1-C2烷基)、氟和环丙基;
R4为H、C1-C3烷基、C3-C5环烷基或-(CH2)0-1-4-5元杂环基,其中所述烷基任选取代有一个或多个基团,所述基团选自OH、O(C1-C2烷基)、氟和C3-C5环烷基,且所述环烷基任选取代有OH;
R5为H、氯、氟或CN;
每个p独立地为0、1或2;
R7和R8每次出现时独立地为H、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R10基团;
R7和R8任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的4-7元环,所述环任选取代有一至五个R10基团;
R9独立地为烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R10基团;
每个R10独立地为卤素、CN、CF3、-OCF3、-NO2、-C(O)OR11、-C(O)NR11R12、-NR11R12、-OR11、-S(O)pR11、-NR12C(O)R11、-NR12C(O)OR11、-NR12C(O)NR11R12、-NR12SO2R11、-OC(O)R11、-OC(O)NR11R12、-S(O)2NR11R12或R13;
R11和R12每次出现时独立地选自H、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R14基团;
R11和R12任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的5-6元环,所述环任选取代有一至五个R14基团;
R13独立地为烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R14基团;
每个R14独立地为卤素、CN、CF3、-OCF3、-NO2、-C(O)OR15、-C(O)NR15R16、-NR15R16、-OR15、-S(O)pR15、-NR16C(O)R15、-NR16C(O)OR15、-NR16C(O)NR15R16、-NR16SO2R15、-OC(O)R15、-OC(O)NR15R16、-S(O)2NR15R16或R17;
R15和R16每次出现时独立地为H、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至四个基团,所述基团选自卤素、-CN、-OCF3、-CF3、-NO2、-C1-C6烷基、-OH、氧代、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-SO2(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)(C1-C6烷基)、-NHC(O)(C1-C6烷基)、-NHSO2(C1-C6烷基)、-N(C1-C6烷基)SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-OC(O)NH2、-OC(O)NH(C1-C6烷基)、-OC(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)NH(C1-C6烷基)、-N(C1-C6烷基)C(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-NHC(O)O(C1-C6烷基)和-N(C1-C6烷基)C(O)O(C1-C6烷基);
R15和R16任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的5-6元环,所述环任选取代有一至四个基团,所述基团选自卤素、-CN、-OCF3、-CF3、-NO2、-C1-C6烷基、-OH、氧代、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-SO2(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)(C1-C6烷基)、-NHC(O)(C1-C6烷基)、-NHSO2(C1-C6烷基)、-N(C1-C6烷基)SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-OC(O)NH2、-OC(O)NH(C1-C6烷基)、-OC(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)NH(C1-C6烷基)、-N(C1-C6烷基)C(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-NHC(O)O(C1-C6烷基)和-N(C1-C6烷基)C(O)O(C1-C6烷基);和
R17为烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至四个基团,所述基团选自卤素、-CN、-OCF3、-CF3、-NO2、-C1-C6烷基、-OH、氧代、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-SO2(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)(C1-C6烷基)、-NHC(O)(C1-C6烷基)、-NHSO2(C1-C6烷基)、-N(C1-C6烷基)SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-OC(O)NH2、-OC(O)NH(C1-C6烷基)、-OC(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)NH(C1-C6烷基)、-N(C1-C6烷基)C(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-NHC(O)O(C1-C6烷基)和-N(C1-C6烷基)C(O)O(C1-C6烷基)。
本发明包括包含式(I)化合物(和/或其溶剂化物、水合物和/或盐)和载体(可药用载体)的组合物(如药物组合物)。本发明还包括包含式(I)化合物(和/或其溶剂化物、水合物和/或盐)和载体(可药用载体)以及包含另一种化学治疗药物的组合物(如药物组合物)。因此,本发明组合物可用于在哺乳动物(例如人)中抑制异常细胞生长或治疗过度增殖性疾病,如癌症。
本发明包括在哺乳动物(例如人)中抑制异常细胞生长或治疗过度增殖性疾病(如癌症)的方法,所述方法包括将治疗有效量的式(I)化合物(和/或其溶剂化物、水合物和盐)或包含其的组合物单独或与另一种化学治疗药物一起给予所述哺乳动物。
本发明包括使用本发明化合物用于体外、原位和体内诊断或治疗哺乳动物细胞、器官或相关病理学病症的方法。
现详细说明本发明的某些实施方案即所附结构和化学式所显示的实施例。虽然本发明是用所列举的实施方案描述的,应该理解它们并非意为将本发明局限于那些实施方案。相反地,本发明旨在涵盖可包括在如权利要求所定义的本发明范围内的所有变更、修改和等价形式。本领域技术人员会认识到与本申请描述的那些方法和物质类似或等价的多种方法和物质,这些方法和物质可用于本发明的实践中。本发明决不限于所描述的方法和物质。如果一篇或多篇引入的文献、专利和类似材料与本申请(包括但不限于所定义的术语、术语的用法、所描述的技术等)不同或矛盾,以本申请为准。
本申请所定义的术语″烷基″是指由一至十二个碳原子组成的饱和直链或支链单价烃基。烷基的实例包括但不限于甲基(Me,-CH3)、乙基(Et,-CH2CH3)、1-丙基(n-Pr,正丙基,-CH2CH2CH3)、2-丙基(i-Pr,异丙基,-CH(CH3)2)、1-丁基(n-Bu,正丁基,-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu,异丁基,-CH2CH(CH3)2)、2-丁基(s-Bu,仲丁基,-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu,叔丁基,-C(CH3)3)、1-戊基(正戊基,-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3、1-庚基、1-辛基等。
术语″烯基″是指由两至十二个碳原子组成的具有至少一个不饱和位点即碳碳sp2双键的直链或支链单价烃基,其中所述烯基包括具有“顺式”和“反式”取向(或者″E″和″Z″取向)的基团。实例包括但不限于乙烯基(ethylenyl或vinyl)(-CH=CH2)、烯丙基(-CH2CH=CH2)等。
术语″炔基″是指由两至十二个碳原子组成的具有至少一个不饱和位点即碳碳sp三键的直链或支链单价烃基。实例包括但不限于乙炔基(-C≡CH)、丙炔基(炔丙基、-CH2C≡CH)等。
术语″环烃基(cycloalkyl)″是指具有3至12个碳原子作为单环或6至12个碳原子作为二环的单价非芳香性饱和或部分饱和的环。具有6至12个原子的二环碳环可排列为例如二环[4,5]、[5,5]、[5,6]或[6,6]系统,具有9或12个环原子的二环碳环可排列为二环[5,6]或[6,6]系统,或排列为桥接系统(bridged system)如二环[2.2.1]庚烷、二环[2.2.2]辛烷和二环[3.2.2]壬烷。单环碳环的实例包括但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基等。
″芳基″表示通过从母体芳族环系统中的单个碳原子除去一个氢原子得到的由6-14个碳原子组成的单价芳族烃基。在示例性结构中一些芳基被表示为″Ar″。芳基包括含有与饱和、部分饱和的环或芳族碳环或杂环稠合的芳族环的二环基团。典型的芳基包括但不限于由苯(苯基)、取代的苯、萘、蒽、茚基(indenyl)、茚满基(indanyl)、1,2-二氢萘、1,2,3,4-四氢萘基等得到的基团。
术语″杂环(heterocycle)″、″杂环基(heterocyclyl)″和″杂环(heterocyclic ring)″在本申请中可交换使用,是指由3至14个环原子组成的饱和或部分不饱和(即在环中具有一个或多个双键)的碳环基团,其中至少一个环原子为选自氮、氧和硫的杂原子,其余环原子为C,其中一个或多个环原子任选独立地被一个或多个如下所述的取代基取代。杂环可以是具有3至7个环成员(2至6个碳原子以及选自N、O和S的1至4个杂原子)的单环或具有6至10个环成员(4至9个碳原子以及选自N、O、P和S的1至6个杂原子)的二环,例如二环[4,5]、[5,5]、[5,6]或[6,6]系统或桥接的[2.1.1]、[2.2.1]、[2.2.2]或[3.2.2]系统。杂环描述在Paquette,Leo A.;″Principles of Modern HeterocyclicChemistry″(W.A.Benjamin,New York,1968)(特别是第1、3、4、6、7和9章);″The Chemistry of Heterocyclic Compounds,A series ofMonographs″(John Wiley & Sons,New York,1950to present)(特别是第13、14、16、19和28卷);以及J.Am.Chem.Soc.(1960)82:5566中。″杂环基″还包括杂环基团与饱和、部分不饱和的环或芳族碳环或杂环稠合的基团。杂环的实例包括但不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫吗啉基、硫杂氧杂环己基(thioxanyl)、哌嗪基、高哌嗪基(homopiperazinyl)、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基(homopiperidinyl)、氧杂环庚烷基(oxepanyl)、硫杂环庚烷基(thiepanyl)、氧杂基(oxazepinyl)、二氮杂基(diazepinyl)、硫杂基(thiazepinyl)、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己烷基、1,3-二氧杂环戊基、吡唑啉基、二硫杂环己基(dithianyl)、二硫杂环戊基(dithiolanyl)、二氢吡喃基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基和氮杂二环[2.2.2]己烷基。螺部分也包括在本定义的范围内。环原子被氧代(=O)部分取代的杂环基的实例为嘧啶酮基(pyrimidinonyl)和1,1-二氧代-硫吗啉基。
术语″杂芳基″是指由5或6元环组成的单价芳族基团,以及包括由5-16个原子组成的稠环系统(其中至少一个环是芳族的),其含有独立地选自氮、氧和硫的一个或多个杂原子。杂芳基的实例为吡啶基(包括例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(包括例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异唑基、噻唑基、唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、二唑基、三唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯开唑基、喹唑啉基、喹啉基、二氮杂萘基和呋喃并吡啶基。
杂环或杂芳基在适当连接时可以是碳(碳联的)或(氮联的)连接的。通过举例而非限制,碳键合的杂环或杂芳基在以下位置键合:吡啶的2、3、4、5或6位,哒嗪的3、4、5或6位,嘧啶的2、4、5或6位,吡嗪的2、3、5或6位,呋喃、四氢呋喃、四氢噻吩、噻吩、吡咯或吡咯烷的2、3、4或5位,唑、咪唑或噻唑的2、4或5位,异唑、吡唑或异噻唑的3、4或5位,氮丙啶的2或3位,氮杂环丁烷的2、3或4位,喹啉的2、3、4、5、6、7或8位,或异喹啉的1、3、4、5、6、7或8位。
通过举例而非限制,氮键合的杂环或杂芳基在以下位置键合:氮丙啶、氮杂环丁烷、吡咯、吡咯烷、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、二氢吲哚、1H-吲唑、2-氧代-1,2-二氢吡啶或4-氧代-1,4-二氢吡啶的1位,异吲哚或异二氢吲哚的2位,吗啉的4位,和咔唑或β-咔啉的9位。
术语“卤素”是指F、Cl、Br或I。杂芳基或杂环基中存在的杂原子包括氧化形式如N+→O-、S(O)和S(O)2。
术语“治疗(treating)”或“治疗(treatment)”是指治疗性处置和预防性措施,其中目的是预防或减缓(减轻)不期望的生理学变化或障碍如癌的发展或扩散。出于本发明的目的,有益的或期望的临床结果包括但不限于缓解症状、减小病变程度、稳定(即不是恶化)疾病状态、延迟或减缓疾病进展、改善或缓和疾病状态以及好转(部分好转或完全好转),无论这些结果是可检测的还是不可检测的。“治疗(treating)”还可表示与未接受治疗的预期存活相比延长的存活。需要治疗的对象包括已经患有病症或障碍的对象以及易患所述病症或障碍的对象或所述病症或障碍应该被预防的对象。
短语“治疗有效量”表示(i)治疗或预防本申请描述的具体疾病、病症或障碍的本发明化合物的量,(ii)削弱、改善或消除本申请描述的具体疾病、病症或障碍的一种或多种症状的本发明化合物的量,或(iii)预防或延迟本申请描述的具体疾病、病症或障碍的一种或多种症状的发作的本发明化合物的量。在癌症的情况中,治疗有效量的药物可降低癌细胞的数量;减小肿瘤尺寸;抑制(即在一定程度上减慢以及优选停止)癌细胞渗入周围器官中;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解与癌症相关的一种或多种症状。如果药物可预防癌细胞的生长和/或杀死现存的癌细胞,其可能是细胞生长抑制性的(cytostatic)和/或细胞毒性的。对于癌症治疗而言,可例如通过评价疾病进展时间(TTP)和/或确定应答率(RR)来测量功效。
术语″异常细胞生长″和″过度增殖性疾病″在本申请中可交换使用。除非另有说明,本申请使用的″异常细胞生长″是指不依赖于正常调节机制的细胞生长。这包括例如以下细胞的异常生长:(1)通过表达突变的酪氨酸激酶或过度表达受体酪氨酸激酶而增殖的肿瘤细胞(肿瘤);(2)出现异常酪氨酸激酶活化的其它增殖性疾病中的良性和恶性细胞;(3)其增殖受受体酪氨酸激酶影响的任何肿瘤;(4)其增殖受异常丝氨酸/苏氨酸激酶活化影响的任何肿瘤;以及(5)出现异常丝氨酸/苏氨酸激酶活化的其它增殖性疾病中的良性和恶性细胞。
术语″癌症(cancer)″和″癌的(cancerous)″是指或描述哺乳动物中特征典型为未调节的细胞生长的生理学情况。″肿瘤″包含一种或多种癌细胞。肿瘤包括实体瘤和液体瘤(liquid tumor)。癌症的实例包括但不限于癌瘤(carcinoma)、淋巴瘤、母细胞瘤、肉瘤、骨髓瘤以及淋巴或淋巴样恶性肿瘤。所述癌症的更具体的实例包括鳞状细胞癌(例如上皮鳞状细胞癌),肺癌,包括小细胞肺癌、非小细胞肺癌(″NSCLC″)、肺腺癌(adenocarcinoma of the lung)和肺鳞状细胞癌(squamouscarcinoma of the lung)、腹膜癌、肝细胞癌、胃癌(gastric or stomachcancer),包括胃肠癌、胰腺癌、成胶质细胞瘤、子宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝细胞瘤(hepatoma)、乳癌(breast cancer)、结肠癌、直肠癌、结肠直肠癌、恶性脑肿瘤、黑色素瘤、子宫内膜癌或子宫癌、唾液腺癌、肾癌或肾脏癌、前列腺癌、外阴癌(vulval cancer)、甲状腺癌、肝脏癌(hepatic carcinoma)、肛门癌、阴茎癌、头/和颈癌以及急性髓细胞性白血病(acute myelogenous leukemia,AML)。
″化学治疗药物″是可用于治疗癌症的化学化合物。化学治疗药物的实例包括Erlotinib(Genentech/OSI Pharm.)、硼替佐米(Bortezomib)(Millennium Pharm.)、氟维司群(AstraZeneca)、Sutent(SU11248,Pfizer)、来曲唑(Novartis)、甲磺酸伊马替尼(Novartis)、PTK787/ZK 222584(Novartis)、奥沙利铂(Sanofi、甲酰四氢叶酸(Leucovorin)、雷帕霉素(Sirolimus,Wyeth)、拉帕替尼(Lapatinib)(GSK572016,Glaxo Smith Kline)、Lonafarnib(SCH 66336)、索拉非尼(Sorafenib,BAY43-9006,Bayer Labs)和Gefitinib(AstraZeneca)、AG1478、AG1571(SU 5271;Sugen);磺酸烷基酯(alkyl sulfonate)如白消安、英丙舒凡和哌泊舒凡(piposulfan);氮丙啶如benzodopa、卡波醌、meturedopa和uredopa;乙撑亚胺(ethylenimine)和甲基氨基吖啶(methylamelamine),包括六甲密胺、三亚胺嗪(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫化磷酰胺(triethylenethiophosphoramide)和trimethylomelamine;番荔枝内酯(acetogenin)(尤其是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成性类似物);cryptophycins(特别是cryptophycin 1和cryptophycin 8);多拉司他汀(dolastatin);duocarmycin(包括合成性类似物KW-2189和CB1-TM1);eleutherobin;pancratistatin;sarcodictyin;spongistatin;叶酸类似物如二甲叶酸、甲氨喋呤、喋罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物如氟达拉滨(fludarabine)、6-巯嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮鸟苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素如卡普睾酮(calusterone)、丙酸甲雄烷酮(dromostanolonepropionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺素(anti-adrenal)如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂(folic acid replenisher)如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);bestrabucil;比生群(bisantrene);伊达曲杀(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptiniumacetate);埃坡霉素(epothilone);依托格鲁(etoglucid);硝酸镓(galliumnitrate);香菇多糖(lentinan);氯尼达明(lonidainine);美登醇(maytansinoid)如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);mopidanmol;根瘤菌剂(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基肼;丙卡巴肼(procarbazine);多糖复合物(JHS NaturalProducts,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonicacid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺;单端孢菌毒素(trichothecene)(尤其是T-2毒素、verracurin A、杆孢菌素A和anguidine);长春地辛;达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(″Ara-C″);chloranmbucil;6-硫代鸟嘌呤;巯嘌呤;异环磷酰胺;米托蒽醌;诺消灵(novantrone);伊达曲杀(edatrexate);柔红霉素;氨基喋呤;卡培他滨伊班膦酸盐(ibandronate);CPT-11;二氟甲基鸟氨酸(difluoromethylornithine)(DMFO);以及上述任何物质的可药用盐、酸和衍生物。
以下物质也包括在″化学治疗药物″的定义中:(i)用于调节或抑制激素对肿瘤的作用的抗激素药物,如抗雌激素药物(anti-estrogen)和选择性雌激素受体调节剂(selective estrogen receptor modulator,SERM),包括例如他莫昔芬(包括枸橼酸他莫昔芬)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、雷洛西芬(keoxifene)、LY117018、奥那司酮(onapristone)和(枸橼酸托米芬(toremifine citrate));(ii)抑制芳香酶(调节肾上腺中雌激素产生)的芳香酶抑制剂,例如4(5)-咪唑、氨鲁米特、(醋酸甲地孕酮(megestrol acetate))、(依西美坦(exemestane);Pfizer)、formestanie、法倔唑(fadrozole)、(伏氯唑(vorozole))、(来曲唑;Novartis)和(阿那曲唑(anastrozole);AstraZeneca);(iii)抗雄激素药物(anti-androgen),如氟他胺、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、醋酸亮丙瑞林(leuprolide)和戈舍瑞林(goserelin)以及曲沙他滨(troxacitabine)(1,3-二氧杂环戊烷核苷胞嘧啶类似物);(iv)蛋白激酶抑制剂;(v)脂激酶抑制剂;(vi)反义寡核苷酸,特别是抑制异常细胞增殖中所涉及的信号转导途径中的基因表达的那些反义寡核苷酸,例如PKC-α、Ralf和H-Ras;(vii)核酶如VEGF表达抑制剂(例如)和HER2表达抑制剂;(viii)疫苗如基因治疗疫苗,例如和rIL-2;拓扑异构酶1抑制剂如rmRH;(ix)抗血管生成药物如贝伐单抗(Genentech);以及(x)上述任何物质的可药用盐、酸和衍生物。
可与本发明化合物联用的“化学治疗药物”的其它实例包括MEK(MAP激酶激酶)抑制剂,如XL518(Exelixis,Inc.)和AZD6244(Astrazeneca);Raf抑制剂,如XL281(Exelixis、Inc.)、PLX4032(Plexxikon)和ISIS5132(Isis Pharmaceuticals);mTor(雷帕霉素的哺乳动物靶(mammalian target of rapamycin))抑制剂,如雷帕霉素(rapamycin)、AP23573(Ariad Pharmaceuticals)、temsirolimus(WyethPharmaceuticals)和RAD001(Novartis);PI3K(磷酸肌醇-3激酶)抑制剂,如SF-1126(PI3K抑制剂,Semafore Pharmaceuticals)、BEZ-235(PI3K抑制剂,Novartis)、XL-147(PI3K抑制剂,Exelixis,Inc.)和GDC-0941(Genentech,Inc.);cMet抑制剂,如PHA665752(Pfizer)、XL-880(Exelixis,Inc.)、ARQ-197(ArQule)和CE-355621;以及上述任何物质的可药用盐、酸和衍生物。
“化学治疗药物”的实例还包括DNA损伤剂(DNA damagingagent),如塞替派(thiotepa)和环磷酰胺;烷化剂(例如顺铂;卡铂;环磷酰胺、氮芥如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(chlorophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);白消安(busulphan);硝基脲(nitrosourea)如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫斯汀(nimustine)和雷莫司汀(ranimnustine);以及莫替唑胺(temozolomide));抗代谢物(例如,抗叶酸剂(antifolates)如氟嘧啶(fluoropyrimidine),如5-氟尿嘧啶(5-FU)和替加氟(tegafur)、雷替曲塞(raltitrexed)、甲氨蝶呤(methotrexate)、阿糖胞苷(cytosine arabinoside)、羟基脲(hydroxyurea)和(吉西他滨(gemcitabine));抗肿瘤抗生素,如如烯二炔(enediyne)抗生素(例如刺孢霉素(calicheamicin)尤其是刺孢霉素γ1I和刺孢霉素ωI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);蒽环类抗生素(anthracycline)如阿霉素(adriamycin);蒽环类抗生素(dynemicin),包括dynemicin A;二膦酸盐(bisphosphonate)如氯膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新抑癌蛋白生色团(neocarzinostatin chromophore)和相关色蛋白烯二炔抗生素生色团(enediyne antibiotic chromophore))、aclacinomysin、放线菌素(actinomycin)、authramycin、偶氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、去甲柔红霉素(carminomycin)、嗜癌素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地拖比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、(多柔比星)、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星和去氧多柔比星、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)如丝裂霉素C、麦考酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌罗霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗有丝分裂剂(例如长春花生物碱如长春新碱、长春碱、vindestine和(长春瑞滨)和紫杉烷类如紫杉烷,例如(紫杉醇;Bristol-Myers Squibb Oncology,Princeton,N.J.)、ABRAXANETM(Cremophor-free)、紫杉醇的白蛋白工程化纳米微粒制剂(albumin-engineered nanoparticle formulations ofpaclitaxel)(American Pharmaceutical Partners,SChaumberg,Illinois)和(doxetaxel;-Poulenc Rorer,Antony,France);拓扑异构酶抑制剂(例如RFS 2000,鬼臼乙叉苷(epipodophyllotoxins)如依托泊苷(etoposide)和替尼泊苷(teniposide),安吖啶(amsacrine),喜树碱(camptothecin)(包括合成类似物托泊替康(topotecan))和伊立替康(irinotecan)和SN-38)和细胞分化剂(例如类视黄醇(retinoid)如全反视黄酸(all-trans retinoic acid)、13-顺视黄酸(13-cis retinoic acid)和芬维A胺(fenretinide));以及上述任何物质的可药用盐、酸和衍生物。
“化学治疗药物”还可包括调节细胞凋亡应答的试剂,包括IAP(细胞凋亡蛋白抑制剂)如AEG40826(Aegera Therapeutics);和bcl-2抑制剂如GX15-070(Gemin×Biotechnologies)、CNDO103(Apogossypol;Coronado Biosciences)、HA14-1(2-氨基-6-溴-4-(1-氰基-2-乙氧基-2-氧代乙基)-4H-色烯-3-羧酸乙酯)、AT101(Ascenta Therapeutics)、ABT-737和ABT-263(Abbott);以及上述任何物质的可药用盐、酸和衍生物。
本申请使用的术语″前药″是指能够经酶或水解活化或转化为更具活性的母体形式的本发明化合物的前体或衍生物形式。参见例如Wilman,″Prodrugs in Cancer Chemotherapy″Biochemical SocietyTransactions,14,pp.375-382,615th Meeting Belfast(1986)以及Stella etal.,″Prodrugs:A Chemical Approach to Targeted Drug Delivery,″Directed Drug Delivery,Borchardt et al.,(ed.),pp.247-267,HumanaPress(1985)。本发明的前药包括但不限于含酯的前药、含磷酸酯的前药、含硫代磷酸酯的前药、含硫酸酯的前药、含肽的前药、D-氨基酸修饰的前药、糖基化的前药、含β-内酰胺的前药、含任选取代的苯氧基乙酰胺的前药、含任选取代的苯基乙酰胺的前药、5-氟胞嘧啶和其它5-氟尿嘧啶前药,这些前药可转化为更具活性的无细胞毒性的药物。可衍生为用于本发明的前药形式的细胞毒性药物的实例包括但不限于本发明化合物和如上所述的化学治疗药物。
″代谢物″是通过具体化合物或其盐在体内的代谢而产生的产物。可使用本领域已知的常规技术鉴定化合物的代谢物,并使用如本申请所述的试验确定它们的活性。所述产物可起因于例如所给药的化合物的氧化、羟基化、还原、水解、酰胺化、脱酰胺化、酯化、脱酯化、酶法裂解等。因此,本发明包括本发明化合物的代谢物,包括由以下方法产生的化合物,所述方法包括使本发明化合物与哺乳动物接触足以产生其代谢产物的时间。
″脂质体″是由各种类型的脂类、磷脂和/或表面活性剂组成的小囊泡,其可用于将药物(如本申请公开的chk抑制剂和任选的化学治疗药物)递送至哺乳动物。与生物膜的脂排列类似,脂质体的组分通常以双层形式排列。
术语″包装说明书(package insert)″是指通常包括在治疗产品的市售包装中的说明书,其含有关于适应症、用法、剂量、给药、禁忌症和/或告诫事项的信息,这些信息涉及上述治疗产品的使用。
术语″手性″是指具有镜像配偶体(mirror image partner)不可重叠性质的分子,而术语″非手性″是指可与其镜像配偶体重叠的分子。
术语″立体异构体″是指具有相同化学组成和连结情况但它们原子的取向在空间上不同因此不能通过围绕单键旋转而相互转化的化合物。
″非对映异构体″是指具有两个或更多手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体的混合物可通过高拆分分析操作如结晶、电泳和色谱来分离。
″对映异构体″是指互为不可重叠镜像的化合物的两种立体异构体。
本申请使用的立体化学定义和常规通常按照S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill BookCompany,New York以及Eliel,E.and Wilen,S.,″Stereochemistry ofOrganic Compounds″,John Wiley&Sons,Inc.,New York,1994。本发明化合物可含有不对称或手性中心,因此以不同立体异构形式存在。预期的是,本发明化合物的所有立体异构形式,包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomers)及它们的混合物如外消旋混合物,形成了本发明的部分。多种有机化合物以光学活性形式存在,即它们具有旋转平面偏振光的平面的能力。在描述有光学活性的化合物时,使用前缀D和L或者R和S来表示分子围绕其一个或多个手性中心的绝对构型。前缀d和l或者(+)和(-)用于指定平面偏振光由化合物引起的旋转的符号,其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。对于给定的化学结构而言,除了这些立体异构体互为镜像外,这些立体异构体是相同的。具体的立体异构体也可称为对映异构体,所述异构体的混合物通常称作对映异构混合物。对映异构体的50∶50混合物称为外消旋混合物或外消旋体,当化学反应或方法中没有立体选择性或立体专一性时可出现这种情况。术语″外消旋混合物″和″外消旋体″是指两种对映异构体物质的等摩尔混合物,其没有光学活性。
术语″互变异构体″或″互变异构形式″是指可通过低能垒(lowenergy barrier)互相转化的不同能量的结构异构体。例如,质子互变异构体(proton tautomer)(也称为质子迁移互变异构体(prototropictautomer))包括通过质子迁移进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价互变异构体(valence tautomer)包括通过一些成键电子的重组进行的互相转化。例如,任何对2-羟基吡啶结构的提及包括其互变异构体2-氧代-1,2-二羟基吡啶(亦称作2-吡啶酮),反之亦然。
本申请使用的短语″可药用盐″是指本发明化合物的可药用有机或无机盐。示例性盐包括但不限于硫酸盐、枸橼酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式枸橼酸盐、酒石酸盐、油酸盐、鞣酸盐(tannate)、泛酸盐(pantothenate)、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖质酸盐(saccharate)、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐(甲磺酸盐(mesylate))、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、扑酸盐(即1,1’-亚甲基-二-(2-羟基-3-萘甲酸盐))、碱金属(例如钠和钾)盐、碱土金属(例如镁)盐以及铵盐。可药用盐可涉及另一种分子如乙酸根离子、琥珀酸根离子或其它抗衡离子的包合物(inclusion)。抗衡离子可以是稳定母体化合物电荷的任何有机或无机部分。此外,可药用盐可在其结构中具有多于一个带电原子。多个带电原子为可药用盐的部分的情况可具有多个抗衡离子。因此,可药用盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
若本发明化合物为碱,则期望的可药用盐可通过本领域可得的任何合适方法来制备,例如用无机酸(如盐酸、氢溴酸、硫酸、硝酸、磷酸等)或用有机酸(如乙酸、甲磺酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、羟乙酸、水杨酸、吡喃糖基酸(pyranosidylacid)如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如枸橼酸或酒石酸、氨基酸如天冬氨酸或谷氨酸、芳族酸如苯甲酸或肉桂酸、磺酸如对甲苯磺酸或乙磺酸等)处理游离碱。
若本发明化合物为酸,则期望的可药用盐可通过本领域可获得的任何合适方法来制备,例如用无机或有机碱(如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等)处理游离酸。合适盐的示例性实例包括但不限于从以下物质得到的有机盐:氨基酸如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺以及环状胺如哌啶、吗啉和哌嗪;以及从以下物质得到的无机盐:钠、钙、钾、镁、锰、铁、铜、锌、铝和锂。
短语″可药用的″表示所述物质或组合物必须与制剂包含的其它成分和/或用其治疗的哺乳动物在化学上和/或毒理学上是相容的。
″溶剂化物″是指一种或多种溶剂分子与本发明化合物的结合或络合。形成溶剂化物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语″水合物″是指当溶剂分子是水时的络合物。
术语″保护基″是指通常用于在化合物上的其它官能团发生反应时阻止或保护具体官能团的取代基。例如,″氨基保护基″为与氨基相连的阻止或保护化合物中氨基官能度的取代基。合适的氨基保护基包括乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苄基氧基羰基(CBZ)、2-(三甲基甲硅烷基)乙氧基甲基(SEM)和9-芴基甲氧基羰基(Fmoc)。类似地,″羟基保护基″是指阻止或保护羟基官能度的羟基的取代基。合适的保护基包括乙酰基和叔丁基二甲基甲硅烷基。″羧基保护基″是指阻止或保护羧基官能度的羧基的取代基。常见的羧基保护基包括苯基磺酰基乙基、氰基乙基、2-(三甲基甲硅烷基)乙基、2-(三甲基甲硅烷基)乙氧基甲基、2-(对甲苯磺酰基)乙基、2-(对硝基苯基磺酰基)乙基、2-(二苯基膦基)-乙基、硝基乙基等。针对保护基的一般描述及其用途,参见T.W.Greene,Protective Groups in Organic Synthesis,JohnWiley&Sons,New York,1991。
除非另有说明,术语″本发明化合物(compound of this invention)″和″本发明化合物(compounds of the present invention)″和“式(I)化合物”,除非另有说明,包括式(I)化合物及其立体异构体、几何异构体、互变异构体、溶剂化物、代谢物、盐(例如可药用盐)和前药。除非另行说明,本文中描述的结构还意为包括仅因存在一个或多个富含放射性同位素(isotopically enriched)的原子而存在差异的化合物。例如,其中一个或多个氢原子由氘或氚原子替换,或者一个或多个碳原子由富含13C-或14C的碳原子替换的式(I)化合物落在本发明的保护范围内。
本发明提供了如上所述具有激酶抑制活性,如chk1、chk2、GSK-3、KDR和/或FLT3抑制活性的式(I)的取代的吡咯化合物。本发明化合物具体而言可用作chk1激酶抑制剂。
在本发明的一些实施方案中,R1为取代有一至三个基团的苯基,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;并且所有其它变量如式(I)中所定义。在本发明的一些实施方案中,R1为取代有一至三个基团的苯基,所述基团独立地选自卤素、CN和CF3;并且所有其它变量如式(I)中所定义。
在本发明的一些实施方案中,R2为H;并且其它变量如式(I)中所定义或如上述任一实施方案中所定义.
在本发明的一些实施方案中,R3A为H;并且其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,R3B为H、环烷基或杂环基,其中所述环烷基和杂环基任选取代有一至三个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,R3B为任选取代有一至三个基团的环烷基,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。在本发明的一些实施方案中,R3B为任选取代有-NR7R8的环烷基;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,R3B为4-7元单环饱和杂环基或8-10元二环饱和杂环基,其中所述杂环基任选取代有一至三个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,R3B为哌啶基、吡咯烷基、氮杂环庚烷基或氮杂环丁烷基,其中所述哌啶基、吡咯烷基、氮杂环庚烷基或氮杂环丁烷基任选取代有一至三个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。在本发明的一些实施方案中,R3B为哌啶基;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,R3A和R3B任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的4-10元单环或二环,所述环任选取代有一至五个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,X为O;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。在本发明的一些实施方案中,X为N(R6),以及R6为H或CN;并且其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,R4为H、CH3、CH2CH3、正丙基、异丙基、CH2CH2OH、CH2CH2OCH3、CH2CH2CH2OH、CH2CH2CH2OCH3、环丙基、CH2-环丙基、CH2CH2F、CH2CHF2或CH2CF3;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。在本发明的一些实施方案中,R4为环丁基、N-3-氧杂环丁烷基、(氧杂环丁烷-2-基)甲基、(氧杂环丁烷-3-基)甲基、(四氢呋喃-2-基)甲基或(四氢呋喃-3-基)甲基;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。
在本发明的一些实施方案中,R5为H;并且所有其它变量如式(I)中所定义或如上述任一实施方案中所定义。
本发明的另一个实施方案包括在实施例1-21中描述的标题化合物。
根据在下面方案中所述的方法或通过本领域已知方法制备本发明化合物。起始物质可从商业性来源获得,从商购的化合物制备或使用公知的合成方法制备。
例如,可使用方案1-4所示的合成路线来制备式(1-9)、(2-6)、(3-3)或(4-12)的N-芳基吡咯化合物。
方案1
式(1-1)化合物可从商业性来源获得,从商购的化合物制备或使用公知的合成方法制备。在合适的溶剂(如THF、乙腈或N,N-二甲基甲酰胺)中,在室温至65℃的温度,在碱(如三乙胺或N,N-二异丙基胺)存在下,在任选添加相转移催化剂(如叔丁基碘化铵)的条件下,它们可与α-卤代乙酸酯(如溴乙酸叔丁酯)反应,得到式(1-2)化合物。
在合适的溶剂(如甲苯)中,在室温至120℃的温度,在碱(如1,8-二氮杂二环[5.4.0]十一-7-烯)存在下,可通过与烷氧基丙烯基腈(如(乙氧基亚甲基)氰基乙酸乙酯)反应将式(1-2)化合物转化为式(1-3)化合物。
在室温至溶剂回流温度的温度,在任选添加合适的溶剂(如二氯甲烷)的条件下,可通过式(1-3)化合物与三氟乙酸反应来获得式(1-4)化合物。可选择地,在合适的溶剂(如1,4-二噁烷)中,在室温至溶剂回流温度,可通过式(1-3)化合物与酸(如0.5-6.0N盐酸)反应来获得式(1-4)化合物。
在合适的溶剂(如四氢呋喃、N,N-二甲基甲酰胺或二氯甲烷)中,在0℃至室温的温度,可通过式(1-4)化合物与异氰酸三氯乙酰基酯反应来获得式(1-5)化合物。
在合适的溶剂(如甲醇)中,在0℃至室温的温度,中间体式(1-5)可与胺(1-6)(如氨)反应以获得式(1-7)化合物。
在惰性溶剂(如四氢呋喃)中,在室温至65℃的温度,在路易斯酸(如三甲基铝)存在下,式(VI)(1-7)化合物可与胺(1-8)(如(S)-(+)-3-氨基-1-Boc-哌啶)反应。应当理解的是,如果式(1-7)或(1-8)化合物含有保护基,则可能有必要将所得产物脱保护以得到式(1-9)化合物或其盐,然后可通过标准方法将其转化为相应的游离碱或其它可药用盐。
可使用方案2中所示的合成路线来制备式(2-6)的N-芳基吡咯化合物。
方案2
可使用方案1中所示的合成路线来制备式(2-1)化合物和中间体式(2-2)。
在合适的溶剂(如THF或乙醚)中,在0℃至室温的温度,可通过用异氰酸烷基酯(2-3)处理中间体(2-2)来制备中间体式(2-4)。
在惰性溶剂(如四氢呋喃)中,在室温至65℃的温度,在路易斯酸(如三甲基铝)存在下,式(2-4)化合物可与胺(2-5)(如(S)-(+)-3-氨基-1-Boc-哌啶)反应。可能需要对所得的产物脱保护以得到式(2-6)化合物或其药用盐。
可使用方案3中所示的合成路线来制备式(3-3)的N-芳基吡咯。
方案3
在合适的高沸点溶剂(如甲苯)中,在100至150℃的温度,在酸(如乙酸)存在下,中间体式(3-1)可与胺(3-2)(如2-甲氧基乙基胺或环丙烷甲基胺)反应。可能需要对所得的产物脱保护以得到式(3-3)化合物或其药用盐。
可使用方案4中所示的合成路线来制备式(4-13)的N-芳基吡咯。
方案4
式(4-1)化合物可从商业性来源获得,从商购的化合物制备或使用公知的合成方法制备。在合适的溶剂(如甲醇或乙醇)中,在室温至85℃的温度,可通过式(4-1)化合物与碱(如氢氧化钠或氢氧化钾)反应来制备式(4-2)化合物。
在合适的溶剂(如乙腈或THF)中,在室温至50℃的温度,可通过与脱水剂(如N,N′-二环己基碳二亚胺)反应将式(4-2)化合物转化为式(4-3)化合物。
在合适的溶剂(如乙腈或THF)中,在室温至溶剂回流温度的温度,可通过式(4-3)化合物与三甲基甲硅烷基叠氮化物反应来获得式(4-4)化合物。
在合适的溶剂(如二噁烷或THF)中,在任选添加共溶剂(如N,N-二甲基甲酰胺)的条件下,在室温至溶剂回流温度的温度,可通过与氨反应将式(4-4)化合物转化为式(4-5)化合物。
在合适的溶剂(如含甲醇的THF)中,在室温至溶剂回流温度的温度,可通过式(4-5)化合物与三甲基甲硅烷基重氮甲烷反应获得式(4-6)化合物。
可使用上述标准的脱保护方法将式(4-6)化合物(其中R1A为PG(保护基))转化为式(4-6)化合物(其中R1A为H,R5=H)。在合适的溶剂(如N,N-二甲基甲酰胺或甲苯)中,在室温至溶剂回流温度的温度,在合适的催化剂(如溴化亚铜(I)或碘化亚铜(I))存在下,在任选使用配体(如反式-N,N′-二甲基-1,2-环己二胺或1,10-菲咯啉)的条件下,在合适的碱(如磷酸钾)存在下,可通过与芳基卤化物或杂芳基卤化物(4-7)反应将式(4-6)化合物(其中R1A=H)转化为式(4-8)化合物。
在惰性溶剂(如四氢呋喃)中,在室温至65℃的温度,在路易斯酸(如三甲基铝)存在下,可通过式(4-6)化合物(其中R1A是R1)或式(4-8)化合物与胺(4-9)(如(S)-(+)-3-氨基-1-Boc-哌啶)反应来获得式(4-10)化合物。
在合适的高沸点溶剂(如甲苯)中,在100至150℃的温度,在酸(如乙酸)存在下,中间体式(4-10)可与胺(4-11)反应。可能需要对所得的产物脱保护以得到式(4-12)化合物或其可药用盐。
应当理解的是,当存在合适的官能团时,可通过一个或多个标准合成方法采用取代、氧化、还原或裂解反应将式(1-9)、(2-6)、(3-3)或(4-12)的化合物或用于其制备的任意中间体进行进一步衍生化。具体的取代方法包括常规的烷基化、芳基化、杂芳基化、酰化、磺酰化、卤化、硝化、甲酰化和偶联方法。
在另一个实例中,在溶剂例如卤化烃例如1,2-二氯乙烷或醇例如乙醇中,以及如果需要,在酸例如乙酸存在下在约环境温度,使用还原性烷基化方法采用醛或酮和硼氢化物例如三乙酰氧基硼氢化钠或氰基硼氢化钠可将伯胺(-NH2)基团烷基化。可采用醛将仲胺(-NH-)基团类似地烷基化。
在另一个实例中,通过酰化可将伯胺或仲胺转化成酰胺基团(-NHCOR’或-NRCOR’)。在碱例如三乙胺存在下在合适溶剂例如二氯甲烷中,通过与合适的酰氯反应实现酰化,或者在合适的偶联剂例如HATU(O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基六氟磷酸盐)存在下在合适溶剂例如二氯甲烷中通过与合适的羧酸反应实现酰化。类似地,在合适碱例如三乙胺存在下,在合适溶剂例如二氯甲烷中,可通过将胺基团与合适的磺酰氯反应而将其转化成磺酰氨基团(-NHSO2R’或-NR”SO2R’)。在合适碱例如三乙胺存在下,在合适溶剂例如二氯甲烷中,可通过将伯胺或仲胺基团与合适的异氰酸酯(盐)反应而将其转化成脲基团(-NHCONR’R”或-NRCONR’R”)。
通过还原硝基(-NO2)可得到胺(-NH2),例如通过催化氢化,在溶剂例如乙酸乙酯或醇例如甲醇中,在金属催化剂例如在负载(例如炭)上的钯存在下使用氢气。可选择地,在酸例如盐酸存在下使用例如金属例如锡或铁通过化学还原反应进行所述转化。
在另一个实例中,通过还原腈基团(-CN)得到胺基团(-CH2NH2),例如通过催化氢化反应,该反应在溶剂例如醚(例如环醚如四氢呋喃)中和在-78℃至溶剂的回流温度的温度,在金属催化剂例如在负载(例如炭)上的钯或阮内镍存在下使用例如氢气。
在另一个实例中,可通过转化成相应的酰基叠氮化物基团(-CON3)、库尔修斯重排(Curtius)和所得异氰酸酯(-N=C=O)的水解由羧酸基团得到胺(-NH2)基团。
在溶剂例如卤化烃例如二氯甲烷或醇例如乙醇中,以及如果需要在酸例如乙酸存在下和在约环境温度,通过还原氨化反应采用胺和硼氢化物例如三乙酰氧基硼氢化钠或氰基硼氢化钠可将醛基团(-CHO)转化成胺基团(-CH2NR’R”))。
在另一个实例中,在本领域技术人员已知的标准条件下,通过使用维蒂希反应(Witting)或Wadsworth-Emmons反应使用合适的膦烷或膦酸酯(盐)可将醛基团转化成烯基(-CH=CHR’)。
在合适溶剂例如甲苯中,通过使用氢化二异丁基铝还原酯基(例如-CO2Et)或腈基(-CN)可得到醛基团。可选择地,通过使用本领域技术人员已知的任意合适氧化剂可将醇氧化得到醛基。
根据R的性质,通过酸-或碱-催化的水解反应可将酯基(-CO2R’)转化为相应的酸基(-CO2H)。如果R是叔丁基,可通过例如在含水溶剂中用有机酸例如三氟乙酸处理实现酸催化的水解反应,或者在含水溶剂中通过用无机酸例如盐酸处理实现酸催化的水解反应。
在合适的溶剂例如二氯甲烷中,在合适的偶联剂例如HATU存在下,可通过将羧酸基团(-CO2H)与合适的胺反应而将其转化成酰胺(-CONHR’或-CONR’R”)。
在另一个实例中,通过转化成相应的酰氯(-COCl)然后通过阿恩特-艾斯特合成反应(Arndt-Eistert synthesis)将羧酸经一个碳同系化(即,-CO2H至-CH2CO2H)。
在另一个实例中,在如下条件下通过还原反应可由相应的酯(例如-CO2R’)或醛(-CHO)产生-OH基团:使用例如于乙醚或四氢呋喃中的复合金属氢化物例如氢化铝锂或使用在溶剂例如甲醇中的硼氢化钠。可选择地,可在如下条件下通过还原相应的酸(-CO2H)制备醇:在溶剂例如四氢呋喃中使用例如氢化铝锂,或使用在溶剂例如四氢呋喃中的硼烷。
使用本领域技术人员已知的条件可将醇基团转化成相应的离去基团,例如卤素原子或磺酰氧基例如烷基磺酰氧基例如三氟甲基磺酰氧基或芳基磺酰氧基例如对苯磺酰氧基。例如,在卤化烃(例如二氯甲烷)中,醇可与亚硫酰氯反应得到相应的氯化物。在所述反应中也可使用碱(例如,三乙胺)。
在另一个实例中,在溶剂例如四氢呋喃中在膦例如三苯基膦和活化剂例如偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯或偶氮二甲酸二甲酯存在下通过使酚或酰胺与醇偶联而将醇、酚或酰胺烷基化。可选择地,通过使用合适的碱例如氢化钠去质子然后加入烷基化剂例如烷基卤化物而实现烷基化。
在如下条件下,化合物中的芳族卤素取代基可经受卤素-金属交换:任选在低温例如约-78℃和在溶剂例如四氢呋喃中,用碱例如锂碱例如正丁基锂或叔丁基锂处理,然后用亲电试剂淬灭以引入所需取代基。因此,例如,通过使用N,N-二甲基甲酰胺作为亲电试剂可引入甲酰基。可选择地,芳族卤素取代基可经受金属(例如钯或酮)催化的反应以引入例如酸、酯、氰基、酰胺、芳基、杂芳基、烯基、炔基、硫代-或氨基取代基。可采用的合适方法包括由Heck、Suzuki、Stille、Buchwald或Hartwig描述的那些方法。
在与合适的亲核试剂例如胺或醇反应后,芳族卤素取代基也可经历亲核置换。有利地,所述反应可在微波辐射存在下在高温进行。
如下所述,测试了本发明化合物抑制chk1活性和活化的能力(第一测定)及其对生长细胞的生物学作用(第二测定)。以下化合物可用作chk1抑制剂:所述化合物在实施例i的chk1活性和活化测定中具有小于10μM(更优选小于5μM,甚至更优选小于1μM,最优选小于0.5μM)的IC50,在实施例ii的细胞测定中具有小于10μM(更优选小于5μM,最优选小于1μM)的EC50。
本发明包括含有式(I)化合物(和/或其溶剂化物、水合物和/或其盐)和载体(可药用载体)的组合物(例如药物组合物)。本发明还包括含有式(I)化合物(和/或其溶剂化物、水合物和/或其盐)和载体(可药用载体)以及还含有如本申请描述的另一种化学治疗药物的组合物(如药物组合物)。本发明还包括含有式(I)化合物(和/或其溶剂化物、水合物和/或其盐)和载体(可药用载体)以及还含有如本申请描述的另一种化学治疗药物(如DNA损伤剂,包括本文中所述的那些)的组合物(如药物组合物)。本发明组合物可用于在哺乳动物(例如人)中抑制异常细胞生长或治疗过度增殖性疾病(如癌症)。例如,本发明化合物和组合物可用于在哺乳动物(例如人)中治疗乳腺癌、结肠直肠癌、卵巢癌、非小细胞肺癌、恶性脑肿瘤、肉瘤、黑色素瘤、淋巴瘤、骨髓瘤和/或白血病。
本发明包括在哺乳动物(例如人)中抑制异常细胞生长或治疗过度增殖性疾病(如癌症)的方法,包括给予所述哺乳动物治疗有效量的式(I)化合物(和/或其溶剂化物、水合物和/或其盐)或其组合物。例如,本发明包括在哺乳动物(例如人)中治疗乳腺癌、结肠直肠癌、卵巢癌、非小细胞肺癌、恶性脑肿瘤、肉瘤、黑色素瘤、淋巴瘤、骨髓瘤和/或白血病的方法,包括给予所述哺乳动物治疗有效量的式(I)化合物(和/或其溶剂化物、水合物和/或其盐)或其组合物。
本发明包括在哺乳动物(例如人)中抑制异常细胞生长或治疗过度增殖性疾病(如癌症)的方法,包括给予所述哺乳动物治疗有效量的式(I)化合物(和/或其溶剂化物、水合物和/或其盐)或其组合物,与另一种如本文中所述的那些化学治疗药物的组合。本发明还包括在哺乳动物(例如人)中抑制异常细胞生长或治疗过度增殖性疾病(如癌症)的方法,包括给予所述哺乳动物治疗有效量的式(I)化合物(和/或其溶剂化物、水合物和/或其盐)或其组合物,与另一种化学治疗药物(如DNA损伤剂,包括本文中所述的那些)的组合。例如,本发明包括在哺乳动物(例如人)中治疗乳腺癌、结肠直肠癌、卵巢癌、非小细胞肺癌、恶性脑肿瘤、肉瘤、黑色素瘤、淋巴瘤、骨髓瘤和/或白血病的方法,包括给予所述哺乳动物治疗有效量的式(I)化合物(和/或其溶剂化物、水合物和/或其盐)或其组合物,与另一种如本文中所述的那些化学治疗药物的组合。本发明包括在哺乳动物(例如人)中治疗乳腺癌、结肠直肠癌、卵巢癌、非小细胞肺癌、恶性脑肿瘤、肉瘤、黑色素瘤、淋巴瘤、骨髓瘤和/或白血病的方法,包括给予所述哺乳动物治疗有效量的式(I)化合物(和/或其溶剂化物、水合物和/或其盐)或其组合物,与另一种化学治疗药物(如DNA损伤剂,包括本文中所述的那些)的组合。
本发明还包括使用本发明化合物用于体外、原位和体内诊断或治疗哺乳动物细胞、生物或相关病理学病症的方法。
本发明化合物(下文称为″活性化合物″)的给药可通过能够递送所述化合物至作用位点的任何方法进行。这些方法包括口服途径、十二指肠内途径、肠胃外注射(包括静脉内、皮下、肌内、血管内或输注)、局部、吸入和直肠给药。
所给药的活性化合物的量可取决于所治疗的受试者、疾病或病症的严重度、给药速率、化合物的体内沉积(disposition)和主治医师的判断。然而,有效剂量的范围为约0.001至约100mg/千克体重/天,优选约1至约35mg/kg/天,其为单一剂量或分份剂量。对于70kg的人而言,有效剂量可总计为约0.05至7g/天,优选约0.05至约2.5g/天。在一些情况下,低于上述范围的下限的剂量水平可以是远远足够的,而在其它情况下,可使用更大的剂量而不引起任何有害的副作用,条件是首先将所述更大的剂量分成若干小剂量用于在一天中给药。
活性化合物可用作单独治疗,或与一种或多种化学治疗药物例如本申请描述的那些药物联用。所述联合治疗可通过同时、先后或分开给予各治疗组分来实现。
药物组合物可例如呈适于口服给药的形式,其为片剂、胶囊剂、丸剂、粉末剂、持续释放制剂、溶液剂、混悬剂;适于肠胃外注射的形式,其为无菌溶液剂、混悬剂或乳剂;适于局部给药的形式,其为软膏剂或乳膏剂;或适于直肠给药的形式,其为栓剂。药物组合物可呈适于单次给药精确剂量的单位剂量形式。药物组合物可包含常规的药物载体或赋形剂,以及包含作为活性成分的本发明化合物。此外,其可包含其它医药试剂、载体、辅料等。
示例性的肠胃外给药形式包括活性化合物于无菌水溶液(例如丙二醇水溶液或右旋糖水溶液)中的溶液剂或混悬剂。如果期望,可对上述剂型进行适当的缓冲。
合适的药物载体包括惰性稀释剂或充填剂、水和各种有机溶剂。如果期望,药物组合物可含有额外的成分,如矫味剂、粘合剂、赋形剂等。由此,对于口服给药而言,含有各种赋形剂如枸橼酸的片剂可与各种崩解剂(如淀粉、海藻酸和某些复合硅酸盐(complex silicate))以及粘合剂(如蔗糖、明胶和阿拉伯胶)一起使用。此外,润滑剂(如硬脂酸镁、十二烷基硫酸钠和滑石)通常可用于片剂目的。相似类型的固体组合物也可按软填充明胶胶囊剂和硬填充明胶胶囊剂的形式使用。因此,优选的物质包括乳糖(lactose或milk sugar)和高分子量聚乙二醇。当含水混悬剂或酏剂期望用于口服给药时,可将其中的活性化合物与以下物质混合:各种甜味剂或矫味剂、着色剂或染料,和乳化剂或助悬剂(如果期望),以及稀释剂如水、乙醇、丙二醇、甘油或它们的组合。
对本领域技术人员而言,制备含有具体量的活性化合物的各种药物组合物的方法是已知的或是显而易见的。例如,参见Remington’sPharmaceutical SCiences,Mack Publishing Company,Ester,Pa.,15.sup.th Edition(1975)。
实施例
缩写
ATP 腺苷-5′-三磷酸
DCM 二氯甲烷
DIPEA 二异丙基乙基胺
DMF 二甲基甲酰胺
DMSO 二甲亚砜
DMSO-D6 氘化二甲亚砜
Eq. 当量
EtOAc 乙酸乙酯
h 小时
HCl 盐酸
有机样品
mmol 毫摩尔
mol 摩尔
LCMS 液相色谱质谱法
MeOH 甲醇
MeOH-D4 氘化甲醇
MeCN 乙腈
N 当量(浓度)
NMR 核磁共振
NaHCO3 碳酸氢钠
TBAI 叔丁基碘化铵
TLC 薄层色谱
TFA 三氟乙酸
THF 四氢呋喃
罗谢尔(Rochelle)盐L-酒石酸钾钠四水合物
一般实验条件
在环境温度,使用带有三重共振5mm探头的Varian UnityInova(400MHz)光谱仪或具有二重共振5mm探头的Bruker AvanceDPX(300MHz)光谱仪记录1H NMR光谱。化学位移表示为相对于四甲基甲硅烷的ppm。使用以下缩写:br=宽信号,s=单峰,d=二重峰,dd=双二重峰,t=三重峰,q=四重峰,m=多重峰。
使用下列方法之一进行高压液相色谱-质谱(LCMS)实验以确定保留时间(RT)和相关质量离子(mass ion)。
方法A:在与带有二极管阵列检测器的Hewlett Packard HP1100LC系统相连的Waters Micromass ZQ四极杆质谱仪上进行实验。该系统使用Higgins Clipeus 5微米C18100×3.0mm柱和1ml/分钟的流速。起始溶剂系统在开始的1分钟内为95%含有0.1%甲酸的水(溶剂A)和5%含有0.1%甲酸的乙腈(溶剂B),接着再历时14分钟梯度升至5%溶剂A和95%溶剂B。最终溶剂系统保持恒定再持续5分钟。
方法B:在与带有二极管阵列检测器和100位自动进样器的Hewlett Packard HP1100LC系统相连的Waters Platform LC四极杆质谱仪上进行实验,使用Phenomenex Luna C18(2)30×4.6mm柱和2ml/分钟的流速。溶剂系统在开始的0.50分钟内为95%含有0.1%甲酸的水(溶剂A)和5%含有0.1%甲酸的乙腈(溶剂B),接着再历时4分钟梯度升至5%溶剂A和95%溶剂B。最终溶剂系统保持恒定再持续0.50分钟。
使用Biotage Initiator 60TM进行微波实验,所述装置使用单模共振器和动力场调谐(dynamic field tuning)。可实现40-250℃的温度,并且可达到高至30巴的压力。
实施例i chk1和chk2测定(chk初级测定)
将组氨酸标记的并在昆虫细胞中表达的全长人突变重组蛋白用作酶活性源(Invitrogen,来自产物PV3982的chk1和来自产物PV3983的chk2)。
在10μM ATP存在下,使用生物物素化的Akt底物-1肽(CellSignalling Technology,product#1065)作为底物进行chk1AlphaScreen测定30分钟。使用AlphaScreen技术对底物的磷酸化进行检测和量化。其由抗-磷酸化-Akt底物-1抗体(Cell Signalling technology Product#9611)和两个AlphaScreen珠子(Perkin Elmer)组成,一个产物(产物6760137)涂覆有蛋白A(结合抗体Ig链),而一个产物(产物6760002)涂覆有抗生物素蛋白链菌素(在生物素化Akt底物肽-1上结合生物素)。chk1活性导致生成磷酸化的Akt底物肽-1,这是一个在抗体存在下造成两种珠子非常相似的事件,导致生成荧光,在Perkin Elmer读数器(Fusion)上检测所述荧光。
通过以下方式进行所述ATP Radiometric ChK1测定:在10μMATP(每个样品含有0.3μCi33P-ATP)存在下培育30分钟并使用ChKTide(肽序列为:KKKVSRSGLYRSPSMPENLNRPR)作为底物。然后用1%磷酸酸化并洗涤以除去未结合的ATP,通过使用PerkinElmer Topcount测量结合的放射性对底物的磷酸化进行检测和量化。
在30μM ATP存在下,使用生物素化的酪氨酸羟化酶(ser 40)肽(Cell Signalling Technology,product#1132)作为底物进行chk2AlphaScreen测定30分钟。使用AlphaScreen技术对底物的磷酸化进行检测和量化。其由抗-磷酸化-酪氨酸羟化酶(ser 40)肽抗体(CellSignalling technology Product#2791)和两个AlphaScreen珠子(PerkinElmer)组成,一个产物(Product 6760137)涂覆有蛋白A(结合抗体Ig链),而一个产物(Product 6760002)涂覆有抗生物素蛋白链菌素(在生物素化的酪氨酸羟化酶(ser 40)肽上结合生物素)。chk2活性导致生成磷酸化的酪氨酸羟化酶肽,这是一个在抗体存在下造成两种珠子非常相似的事件,导致生成荧光,在Perkin Elmer读数器(Fusion)上检测所述荧光。
通过以下方式进行所述ATP Radiometric ChK2测定:在30μMATP(每个样品含有0.3μCi33P-ATP)存在下培育30分钟并使用ChKTide(肽序列为:KKKVSRSGLYRSPSMPENLNRPR)作为底物。然后用1%磷酸酸化并洗涤以除去未结合的ATP,通过使用PerkinElmer Topcount测量结合的放射性对底物的磷酸化进行检测和量化。
在将试验化合物加至测定缓冲液之前将其稀释在DMSO中,测定中的最终DMSO浓度为1%。
将IC50定义为给定试验化合物对所控制的疾病实现50%抑制的浓度。使用XLfit软件包(2.0.5版本)计算IC50值。
所测试的实施例1-21的标题化合物在实施例i描述的抗chk1测定中显示小于5μM的IC50。
实施例ii细胞测定(检测点废除)
在细胞测定中使用源自细胞系HT-29(ATCC HTB-38)的人结肠直肠腺癌测试化合物。
在37℃和在5%CO2湿加培养箱中,将所述细胞系保持在DMEM/F12(1∶1)培养基(Invitrogengibco,#31331)(补充有10%FCS)中。
将细胞以30,000细胞/孔接种在96-孔板上,24小时后,使它们暴露于浓度为20nM的SN-38于0.4%DMSO中。将每个板的一列8个孔用于产生最大信号对照。这些细胞用不含SN-38的0.4%DMSO处理。使细胞再生长16小时,然后除去含有DMSO(添加SN-38或缺少SN-38)的培养基并替换为只含有300nM诺考达唑(nocodazole)(以确定基线)的培养基或替换为与十种浓度的chk1抑制剂(最终DMSO浓度为0.4%)结合的培养基。使细胞再生长24小时。除去培养基并替换为50μl溶胞缓冲液(含有蛋白酶抑制剂和磷酸酶抑制剂)。该缓冲液含有洗涤剂以使细胞破碎。然后细胞完全破碎,将25μl溶胞产物转移到涂覆有抗组蛋白H3(MesoScale Discovery(MSD)ProductK110EWA-3)的抗体的MesoScale 96孔4-点斑板上,所述板已经预先用3%于三羟甲基氨基甲烷缓冲盐水中的牛血清白蛋白阻滞(blcok)。然后将溶胞产物转移到MSD板上,通过在室温培育2小时将于所述溶胞产物中的组蛋白H3捕捉到被涂覆的抗体上。在所述捕捉步骤后,洗涤所述板,然后与抗磷酸化组蛋白H3的抗体培育,所述磷酸化组蛋白H3结合有Sulfo-标签。当该标签靠近MSD板底物的电极时,其给出信号。标记的抗体与捕获的蛋白的结合能够在MSD读数器上检测。
将EC50定义为:与由300nM诺考达唑单独产生的信号相比,在正常S形剂量应答曲线范围内,给定化合物实现将磷酸-组蛋白H3测量水平减少50%的浓度。使用XLfit软件包(2.0.5版本)或GraphpadPrism(3.03版本),使S形曲线与可变斜率拟合来计算EC50值。
在实施例ii所描述的测定中,所测试的实施例1-21的标题化合物显示小于10μM的EC50。
吡咯的合成
一般方法1:(4-芳基氨基)-乙酸叔丁酯的制备
向苯胺(10.4-90.1mmol,1.0当量)、TBAI(0.20当量)和DIPEA(1.05当量)在无水THF中的溶液中加入溴乙酸叔丁酯(1.01-1.05当量)。在室温至65℃的温度和在氮气气氛中,将反应混合物搅拌16至65小时。然后将反应混合物在EtOAc或DCM和水之间分配。有机相用水、盐水洗涤,干燥并浓缩。然后将所得的残余物通过快速色谱纯化(硅胶,40-330g柱,ISCO,0-40%EtOAc于戊烷/环己烷中的溶液),得到标题化合物。
(3-氟苯基氨基)-乙酸叔丁酯
遵循一般方法1,使用3-氟苯胺获得标题化合物,其为黄色油状物(19.3g,95%):1H NMR(CDCl3,300MHz);δ7.10(dt,J=6.7,8.2Hz,1H),6.42(m,1H),6.36(m,1H),6.27(dt,J=11.4,2.3Hz,1H),4.4(br.s,1H),3.77(s,2H),1.49(s,9H)。
(4-三氟甲基苯基氨基)-乙酸叔丁酯
遵循一般方法1,使用4-三氟甲基苯胺获得标题化合物,其为灰白色固体(4.36g,53%):1H NMR(CDCl3,300MHz):δ7.42(d,J=8.5Hz,2H),6.59(d,J=8.5Hz,2H),4.60(br.s,1H),3.82(d,J=5.2Hz,2H),1.50(s,9H)。
(4-氰基苯基氨基)-乙酸叔丁酯
遵循一般方法1,使用4-氰基苯胺获得标题化合物,其为灰白色固体(6.38g,67%);1H NMR(CDCl3,300MHz):δ7.44(d,J=8.7Hz,2H),6.55(d,J=8.8Hz,2H),4.81(br.s,1H),3.82(d,J=5.0Hz,2H),1.50(s,9H)。
(4-氯-3-氟苯基氨基)-乙酸叔丁酯
遵循一般方法1,使用4-氯-3-氟苯胺获得标题化合物,其为灰白色固体(4.76g,92%);1H NMR(CDCl3,300MHz):δ7.17-7.09(m,1H),6.38-6.28(m,2H),4.45(br.s,1H),3.75(s,2H),1.49(s,8H)。
(3-氟-4-三氟甲基苯基氨基)-乙酸叔丁酯
遵循一般方法1,使用4-氨基-2-氟三氟甲苯获得标题化合物,其为灰白色固体(1.92g,44%);1H NMR(CDCl3,300MHz):δ7.34(t,J=8.4Hz,1H),6.38-6.26(m,2H),4.65(br.s,1H),3.79(s,2H),1.50(s,9H)。
(3-氯-4-三氟甲基苯基氨基)-乙酸叔丁酯
遵循一般方法1,使用4-氨基-2-氯三氟甲苯获得标题化合物,其为灰白色固体(6.65g,84%);1H NMR(CDCl3,300MHz):δ7.44(d,J=8.7Hz,1H),6.63(d,J=2.4Hz,1H),6.46(dd,J=8.7,2.3Hz,1H),4.45(br.s,1H),3.80(s,2H),1.50(s,9H)。
一般方法2:3-氨基-1-(芳基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯的制备
向N-芳基甘氨酸叔丁酯(3.8-85.8mmol,1当量)于甲苯中的溶液中加入DBU(2.0-3.0当量)和(乙氧基亚甲基)氰基乙酸乙酯(2.0-3.0当量)。在110至120℃和在氮气气氛中,将反应混合物搅拌3-18小时。然后将反应混合物冷却,用饱和氯化铵水溶液处理,并在EtOAc或DCM和水之间分配。水层进一步用EtOAc或DCM萃取。合并的有机层用饱和碳酸氢钠溶液、盐水洗涤,干燥并浓缩。然后将粗残余物通过快速色谱法纯化(硅胶,80-330g柱,ISCO,0-40%EtOAc于戊烷/己烷中的溶液或0-100%DCM于戊烷中的溶液)以获得标题化合物。
3-氨基-1-(3-氟苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯
遵循一般方法2,使用(3-氟苯基氨基)-乙酸叔丁酯获得标题化合物,其为浅黄色固体(9.5g,32%);LCMS(方法B):RT=4.22分钟,M+H+=349;1H NMR(CDCl3,300MHz):δ7.36(dt,J=8.2,6.2Hz,1H),7.18(s,1H),7.14-7.04(m,2H),7.00(dt,J=9.3,2.2Hz,1H),5.82(s,2H),4.29(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H),1.30(s,9H)。
3-氨基-1-(4-三氟甲基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯
遵循一般方法2,使用(4-三氟甲基苯基氨基)-乙酸叔丁酯获得标题化合物,其为灰白色固体(1.86g,41%);LCMS(方法B):RT=4.59分钟,M+H+=399;1H NMR(CDCl3,400MHz):δ7.67(d,J=8.3Hz,2H),7.39(d,J=8.2Hz,2H),7.19(s,1H),5.82(br.s,2H),4.30(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H),1.29(s,9H)。
3-氨基-1-(4-氰基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯
遵循一般方法2,使用(4-氰基苯基氨基)-乙酸叔丁酯获得标题化合物,其为白色固体(6.26g,65%);LCMS(方法B):RT=3.98分钟,M+H+=356;1H NMR(CDCl3,300MHz):δ7.71(d,J=8.3Hz,2H),7.38(d,J=8.4Hz,2H),7.21(s,1H),5.84(s,2H),4.30(q,J=7.1Hz,2H),1.37-1.31(m,12H)。
3-氨基-1-(4-氯-3-氟苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯
遵循一般方法2,使用(4-氯-3-氟苯基氨基)-乙酸叔丁酯获得标题化合物,其为白色固体(2.20g,31%);LCMS(方法B):RT=4.42分钟,M+H+=383;1H NMR(CDCl3,300MHz):δ7.43(t,J=8.2Hz,1H),7.17(s,1H),7.10(dd,J=9.3,2.4Hz,1H),7.03(ddd,J=8.5,2.4,1.2Hz,1H),4.30(q,J=7.1Hz,2H),1.38-1.29(m,12H)。
3-氨基-1-(3-氟-4-三氟甲基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯
遵循一般方法2,使用(3-氟-4-三氟甲基苯基氨基)乙酸叔丁酯获得标题化合物,其为灰白色固体(1.68g,62%);LCMS(方法B):RT=4.43分钟,M+H+=417;1H NMR(CDCl3,300MHz):δ7.65(t,J=8.1Hz,1H),7.22(s,1H),7.21-7.13(m,2H),4.31(q,J=7.1Hz,2H),1.39-1.30(m,12H)。
3-氨基-1-(3-氯-4-三氟甲基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯
遵循一般方法2,使用(3-氯-4-三氟甲基苯基氨基)乙酸叔丁酯获得标题化合物,其为黄色固体(5.30g,57%);1H NMR(DMSO-D6,300MHz):δ7.93(d,J=8.5Hz,1H),7.83(d,J=2.0Hz,1H),7.64(s,1H),7.57(dd,J=8.4,2.0Hz,1H),5.96(s,2H),4.23(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H),1.23(s,9H)。
一般方法3:1-(芳基)-4-脲基-1H-吡咯-3-羧酸乙酯的制备
向3-氨基-1-(芳基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯(0.15-4.63mmol,1.0当量)中加入TFA(5.0-23mL,40当量)。将反应混合物在室温搅拌1-3小时,然后蒸干。氮气气氛中,向所得的残余物中加入无水THF,然后滴加异氰酸三氯乙酰酯(1.1当量)。将反应混合物在室温搅拌1-3小时,然后蒸干。向所得的残余物添加2N氨的甲醇溶液(10当量),并将反应混合物在室温搅拌2-16小时。此后,真空除去溶剂以得到粗残余物。当需要纯化时,将所得残余物负载在H-MN上,然后通过快速色谱法纯化(硅胶,40-120g柱,ISCO,0-100%EtOAc于DCM中的溶液或0-10%MeOH于DCM中的溶液)纯化以得到标题化合物。
1-(3-氟苯基)-4-脲基-1H-吡咯-3-羧酸乙酯
遵循一般方法3,使用3-氨基-1-(3-氟苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯获得标题化合物,其为橙色油状物(0.99g,74%);LCMS(方法B):RT=3.21分钟,M+H+=292;1H NMR(CDCl3,300MHz):δ8.50(s,1H),7.62(d,J=2.7Hz,1H),7.46(d,J=2.7Hz,1H),7.40(dt,J=8.2,6.2Hz,1H),7.23(ddd,J=8.2,2.2,0.9Hz,1H),7.16(dt,J=9.8,2.2Hz,1H),6.99(tdd,J=8.2,2.2,0.9Hz,1H),4.76(s,2H),4.31(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H)。
1-(4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯
遵循一般方法3,使用3-氨基-1-(4-三氟甲基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯获得标题化合物,其为灰白色固体(0.50g,58%);LCMS(方法B):RT=3.52分钟,M+H+=342;1H NMR(DMSO-D6,400MHz):δ8.34(s,1H),7.96(d,J=2.8Hz,1H),7.87(d,J=8.7Hz,2H),7.82(d,J=8.7Hz,2H),7.70(d,J=2.7Hz,1H),6.42(br.s,2H),4.29(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H)。
1-(4-氰基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯
遵循一般方法3,使用3-氨基-1-(4-氰基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯获得标题化合物,其为灰白色固体(0.226g,61%);LCMS(方法B):RT=3.02分钟,M+H+=299;1H NMR(CDCl3,300MHz):δ8.49(s,1H),7.76-7.71(m,2H),7.69(d,J=2.7Hz,1H),7.58-7.52(m,3H),4.66(s,2H),4.33(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H)。
1-(4-氯-3-氟苯基)-4-脲基-1H-吡咯-3-羧酸乙酯
遵循一般方法3,使用3-氨基-1-(4-氯-3-氟苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯,获得标题化合物,其为灰白色固体(0.998g,100%);LCMS(方法B):RT=3.44分钟,M+H+=326;1H NMR(DMSO-D6,300MHz):δ8.33(s,1H),7.92(d,J=2.7Hz,1H),7.88(dd,J=11.0,2.6Hz,1H),7.69-7.61(m,2H),7.55-7.50(m,1H),6.43(s,2H),4.28(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H)。
1-(3-氟-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯
遵循一般方法3,使用3-氨基-1-(3-氟-4-三氟甲基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯获得标题化合物,其为黄色固体(1.38g,96%);LCMS(方法B):RT=3.53分钟,M+H+=360;1H NMR(CDCl3,300MHz):δ8.49(s,1H),7.71-7.64(m,2H),7.51(d,J=2.7Hz,1H),7.35-7.27(m,2H),4.67(br.s,2H),4.33(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H)。
1-(3-氯-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯
遵循一般方法3,使用3-氨基-1-(3-氯-4-三氟甲基苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯,获得标题化合物,其为黄色固体(1.73g,100%);LCMS(方法B):RT=3.70分钟,M+H+=376;1HNMR(DMSO-D6,300MHz):δ8.42(s,2H),8.36(s,1H),8.30(s,2H),8.14(d,J=2.2Hz,1H),8.09(d,J=2.3Hz,1H),7.90(d,J=8.8Hz,1H),7.80(dd,J=8.7,2.2Hz,1H),7.73(d,J=2.8Hz,1H),6.46(s,2H),4.29(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H)。
一般方法4:4-(3-烷基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羧酸乙酯的制备
向3-氨基-1-(芳基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯(0.82-0.86mmol,1.0当量)中加入TFA(2.4-3.0mL)。将反应混合物在室温搅拌1-3小时,然后蒸干。氮气气氛中,向所得的残余物中添加无水THF,然后滴加异氰酸烷基酯(2.0当量)。将反应混合物在室温搅拌1-16小时,然后蒸干。将所得的残余物溶解于DCM中,然后过滤通过快速NH2柱,用MeOH进一步洗脱。然后将合并的有机洗涤物负载在H-MN上,并真空浓缩,通过快速色谱法纯化(硅胶,40-120g柱,ISCO,0-50%EtOAc于DCM中的溶液或0-30%EtOAc于戊烷中的溶液;或者硅胶,10-50g Si-SPE柱,Isolute,50%DCM于戊烷中的溶液,DCM,然后20%MeOH于DCM中的溶液)以获得标题化合物。
1-(3-氟苯基)-4-(3-甲基-脲基)-1H-吡咯-3-羧酸乙酯
遵循一般方法4,使用3-氨基-1-(3-氟苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯和异氰酸甲酯获得标题化合物,其为白色固体(194mg,74%);LCMS(方法B):RT=3.38分钟,M+H+=306;1HNMR(CDCl3,300MHz):δ8.42(s,1H),7.64(d,J=2.7Hz,1H),7.46(d,J=2.7Hz,1H),7.39(dt,J=8.2,6.2Hz,1H),7.24-7.20(m,1H),7.15(dt,J=9.9,2.3Hz,1H),6.99(tdd,J=8.3,2.40.9Hz,1H),4.71-4.65(m,1H),4.31(q,J=7.1Hz,2H),2.90(d,J=4.9Hz,3H),1.37(t,J=7.1Hz,3H)。
4-(3-乙基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羧酸乙酯
遵循一般方法4,使用3-氨基-1-(3-氟苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯和异氰酸乙酯,获得标题化合物,其为乳色固体(0.192g,73%);LCMS(方法B):RT=3.61分钟,M+H+=320;1HNMR(CDCl3,300MHz):δ8.41(s,1H),7.62(d,J=2.7Hz,1H),7.44(d,J=2.7Hz,1H),7.38(dt,J=8.2,6.2Hz,1H),7.21(dd,J=8.2,2.4Hz,1H),7.14(dt,J=9.9,2.4Hz,1H),6.98(td,J=8.2,2.4Hz,1H),4.73(s,1H),4.31(q,J=7.1Hz,2H),3.35-3.26(m,2H),1.37(t,J=7.1Hz,3H),1.21(t,J=7.1Hz,3H)。
1-(3-氟苯基)-4-(3-异丙基-脲基)-1H-吡咯-3-羧酸乙酯
遵循一般方法4,使用3-氨基-1-(3-氟苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯和异氰酸异丙酯获得标题化合物,其为灰白色固体(0.150g,55%);LCMS(方法B):RT=3.77分钟,M+H+=334;1HNMR(CDCl3,300MHz):δ8.35(s,1H),7.62(d,J=2.7Hz,1H),7.45(d,J=2.7Hz,1H),7.38(dt,J=8.2,6.2Hz,1H),7.22(ddd,J=8.2,2.3,0.9Hz,1H),7.15(dt,J=9.9,2.3Hz,1H),6.98(tdd,J=8.2,2.3,0.9Hz,1H),4.52(br.s,1H),4.31(q,J=7.1Hz,2H),3.94(br.s,1H),1.37(t,J=7.1Hz,3H),1.22(d,J=6.5Hz,6H)。
1-(4-氯-3-氟-苯基)-4-(3-乙基-脲基)-1H-吡咯-3-羧酸乙酯
遵循一般方法4,使用3-氨基-1-(4-氯-3-氟-苯基)-1H-吡咯-2,4-二羧酸·2-叔丁酯4-乙酯和异氰酸乙酯获得标题化合物,其为黄色固体(0.65g,76%);LCMS(方法B):RT=3.87分钟,M+H+=354;1HNMR(DMSO-D6,400MHz):δ8.27(s,1H),7.91(d,J=2.7Hz,1H),7.86(dd,J=10.9,2.6Hz,1H),7.68-7.63(m,2H),7.54-7.50(m,1H),7.23(t,J=5.3Hz,1H),4.28(q,J=7.1Hz,2H),3.13-3.05(m,2H),1.31(t,J=7.1Hz,3H),1.05(t,J=7.2Hz,3H)。
一般方法5:(S)-3-{[1-(3-芳基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯的制备
氮气气氛中,向(S)-3-氨基-1-Boc-哌啶(0.8-1.5当量)于THF中的溶液中添加2N三甲基铝的己烷溶液(2.0-3.3当量),使反应混合物在室温搅拌0.25至2小时。此后,添加1-(芳基)-4-脲基-1H-吡咯-3-羧酸乙酯(0.59-3.26mmol,1.0当量)的THF溶液,并将反应混合物在65至77℃加热3.5至24小时。此后,使反应混合物冷却,然后通过添加罗谢尔盐的饱和溶液淬灭。0.25至0.5小时之后,用EtOAc或DCM萃取混合物,并用水、盐水洗涤有机层,干燥并浓缩。然后将所得的残余物通过快速色谱法纯化(硅胶,12-120g柱,ISCO,0-100%EtOAc于DCM中的溶液)以得到标题化合物。
(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(3-氟苯基)-4-脲基-1H-吡咯-3-羧酸乙酯获得标题化合物,其为橙色固体(0.51g,35%);LCMS(方法B):RT=3.38分钟,M+H+=446;1H NMR(CDCl3,300MHz):δ9.15(s,1H),7.61(d,J=2.5Hz,1H),7.35(dt,J=8.2,6.2Hz,1H),7.25(br.s,1H),7.15(ddd,J=8.2,2.2,0.9Hz,1H),7.07(dt,J=9.9,2.2Hz,1H),6.95(tdd,J=8.2,2.5,0.9Hz,1H),6.36(br.s,1H),4.92(s,2H),4.02(m,1H),3.62(dd,J=13.3,3.5Hz,1H),3.49-3.33(m,3H),1.93-1.52(m,4H),1.46(s,9H)。
(S)-3-{[1-(4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯获得标题化合物,其为灰白色固体(0.08g,40%);LCMS(方法B):RT=3.65分钟,M+H+=496;1H NMR(CDCl3,400MHz):δ9.15(s,1H),7.70-7.64(m,3H),7.48(d,J=8.4Hz,2H),7.29-7.25(m,1H),4.74(s,2H),4.09-4.02(m,1H),3.58-3.49(m,3H),3.38-3.26(m,1H),1.89-1.82(m,2H),1.79-1.66(m,1H),1.64-1.52(m,1H),1.47(s,9H)。
(S)-3-{[1-(4-氰基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(4-氰基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯获得标题化合物,其为灰白色固体(0.105g,23%);LCMS(方法B):RT=3.16分钟,M+H+=453;1H NMR(CDCl3,300MHz):δ9.17(s,1H),7.73-7.63(m,3H),7.44(d,J=8.3Hz,2H),7.34-7.30(m,1H),6.47(br.s,1H),4.97(s,2H),4.09-3.96(m,1H),3.51-3.32(m,3H),1.95-1.64(m,3H),1.64-1.50(m,1H),1.46(s,9H)。
(S)-3-{[1-(4-氯-3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(4-氯-3-氟苯基)-4-脲基-1H-吡咯-3-羧酸乙酯获得标题化合物,其为浅黄色玻璃状物(212mg,25%):LCMS(方法B);RT=3.57分钟,M+H+=480;1H NMR(CDCl3,300MHz):δ9.15(s,1H),7.55(d,J=2.5Hz,1H),7.39(t,J=8.3Hz,1H),7.34-7.22(m,1H),7.15(dd,J=9.9,2.6Hz,1H),7.11-7.05(m,1H),6.50(br.s,1H),5.07(s,2H),4.07-3.94(m,1H),3.72-3.58(m,1H),3.48-3.27(m,3H),1.95-1.82(m,1H),1.81-1.63(m,2H),1.62-1.50(s,1H),1.46(s,9H)。
(S)-3-{[1-(3-氟-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(3-氟-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯获得标题化合物,其为淡黄色玻璃状物(117mg,13%);LCMS(方法B):RT=3.67分钟,M+H+=514;1H NMR(CDCl3,300MHz):δ9.16(s,1H),7.67-7.55(m,2H),7.40-7.30(m,1H),7.27-7.14(m,2H),6.53(s,1H),5.03(s,2H),4.08-3.96(m,1H),3.70-3.57(m,1H),3.49-3.32(m,3H),1.92-1.64(m,3H),1.63-1.52(m,1H),1.47(s,9H)。
(S)-3-{[1-(3-氯-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(3-氯-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸乙酯获得标题化合物,其为灰白色固体(220mg,31%);LCMS(方法B):RT=3.80分钟,M+H+=530。
(S)-3-{[1-(3-氟苯基)-4-(3-甲基-脲基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(3-氟苯基)-4-(3-甲基-脲基)-1H-吡咯-3-羧酸乙酯获得标题化合物,其为玻璃状物(171mg,27%);LCMS(方法B):RT=3.54分钟,M+H+=460;1H NMR(CDCl3,300MHz):δ8.42(s,1H),7.64(d,J=2.7Hz,1H),7.46(d,J=2.7Hz,1H),7.39(dt,J=8.2,6.2Hz,1H),7.24-7.20(m,1H),7.15(dt,J=9.9,2.3Hz,1H),6.99(tdd,J=8.3,2.4,0.9Hz,1H),4.71-4.65(m,1H),4.31(q,J=7.1Hz,2H),2.90(d,J=4.9Hz,3H),1.37(t,J=7.1Hz,3H)。
(S)-3-{[4-(3-乙基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用4-(3-乙基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羧酸乙酯获得标题化合物,其为灰白色玻璃状物(257mg,46%);LCMS(方法B):RT=3.69分钟,M+H+=474;1H NMR(CDCl3,300MHz):δ9.03(s,1H),7.65(d,J=2.4Hz,1H),7.36(dt,J=8.2,6.2Hz,1H),7.21-7.15(m,2H),7.11(dt,J=9.9,2.4Hz,1H),6.97(ddt,J=8.2,2.4,0.7Hz,1H),4.55(m,1H),4.07(m,1H),3.65-3.41(m,3H),3.36-3.26(m,2H),1.94-1.80(m,2H),1.77-1.65(m,2H),1.47(s,9H),1.19(t,3H)。
(S)-3-{[1-(3-氟苯基)-4-(3-异丙基-脲基)-1H-吡咯-3-羰基]-氨基-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(3-氟苯基)-4-(3-异丙基-脲基)-1H-吡咯-3-羧酸乙酯获得标题化合物,其为黄色固体(78mg,59%):LCMS(方法B):RT=3.88分钟,M+H+=488;1H NMR(CDCl3,300MHz):δ8.99(s,1H),7.64(s,1H),7.37(q,J=7.6Hz,1H),7.21-7.15(m,2H),7.11(dd,J=10.0,2.4Hz,1H),6.96(t,J=8.4Hz,1H),6.20(br.s,1H),4.46(d,J=7.6Hz,1H),4.07(m,1H),3.94(m,1H),3.65-3.43(m,3H),3.32(s,1H),1.93-1.80(m,2H),1.73(m,1H),1.58(m,1H),1.47(s,9H),1.21(d,J=6.5Hz,6H)。
(S)-3-{[1-(4-氯-3-氟-苯基)-4-(3-乙基-脲基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法5,使用1-(4-氯-3-氟-苯基)-4-(3-乙基-脲基)-1H-吡咯-3-羧酸乙酯获得标题化合物,其为黄色泡沫状物(220mg,42%);LCMS(方法B):RT=3.94分钟,M+H+=508。
一般方法6:用常规加热方法制备(S)-3-{[1-(3-氟苯基)-4-(3-取代的-脲基)-1H-吡咯-3-羰基]-氨基-哌啶-1-羧酸叔丁酯
氮气气氛中,向(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯(90-100mg,0.20-0.23mmol,1.0当量)和胺(1.0当量)于甲苯中的溶液中添加乙酸(0.8当量),将反应混合物在110℃加热24-72小时。此后,使反应混合物冷却,并在DSM和水之间分配。使DCM层通过疏水玻璃料(hydrophobic frit),然后蒸发得到标题化合物,其为粗制残余物。
一般方法7:用微波辐射方法制备(S)-3-{[1-(3-氟苯基)-4-(3-取代的-脲基)-1H-吡咯-3-羰基]-氨基-哌啶-1-羧酸叔丁酯。
氮气气氛中,向(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯(75-100mg,0.17-0.23mmol,1.0当量)和胺(1.5当量)于甲苯中的溶液中添加乙酸(0.8当量),将反应混合物在微波辐射下在150℃加热1小时。使反应混合物冷却,并在DCM和水之间分配。使DCM层通过疏水玻璃料,然后蒸发得到标题化合物,其为粗制残余物。
(S)-3-{[4-(3-环丙基甲基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法6,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和环丙烷甲基胺获得粗制标题化合物,其为橙色泡沫状物(114mg);LCMS(方法B):RT=3.94分钟,M+H+=500。该粗物质不经进一步纯化即用于下一步骤。
(S)-3-({1-(3-氟苯基)-4-[3-(2-甲氧基-乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯
遵循一般方法6,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和2-甲氧基乙基胺获得粗制标题化合物,其为橙色泡沫状物(109mg);LCMS(方法B):RT=3.69分钟,M+H+=504。该粗物质不经进一步纯化即用于下一步骤。
(S)-3-{[4-(3-环丙基脲基)-1-(3-氟-苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法7,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和环丙基胺获得粗制所需化合物。通过柱色谱法(硅胶,12g柱,ISCO,0-50%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(64mg,78%);LCMS(方法B):RT=3.70分钟,M+H+=486。
(S)-3-({1-(3-氟苯基)-4-[3-(2-羟基-乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯
遵循一般方法6,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和2-氨基-乙醇获得粗制所需产物。通过柱色谱法(硅胶,12g柱,ISCO,0-100%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(60mg,55%);LCMS(方法B):RT=3.25分钟,M+H+=490。
1-(3-氟苯基)-4-(3-丙基-脲基)-1H-吡咯-3-羧酸(S)-哌啶-3-基酰胺
遵循一般方法6,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和丙基胺获得粗的所需产物。通过柱色谱法(硅胶,12g柱,ISCO,0-50%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(100mg,65%);LCMS(方法B):RT=3.89分钟,M+H+=488。
(S)-3-({1-(3-氟苯基)-4-[3-(3-羟基-丙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯
遵循一般方法6,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和3-氨基-丙烷-1-醇获得粗制所需产物。通过柱色谱法(硅胶,12g柱,ISCO,0-100%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(70mg,60%);LCMS(方法B):RT=3.37分钟,M+H+=504。
(S)-3-({1-(3-氟苯基)-4-[3-(3-甲氧基-丙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯
遵循一般方法6,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和3-甲氧基-丙基胺获得粗制所需产物。通过柱色谱法(硅胶,12g柱,ISCO,0-60%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(100mg,71%)。LCMS(方法B):RT=3.67分钟,M+H+=518。
(S)-3-{[4-[3-(2-氟乙基)-脲基]-1-(3-氟-苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法7,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和2-氟乙基胺盐酸盐获得粗制所需产物(注:将0.34mmol无水乙酸钠添加至反应混合物中以中和所述胺)。通过柱色谱法(硅胶,12g柱,ISCO,0-100%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(80mg,95%)。LCMS(方法B):RT=3.68分钟,M+H+=492。
(S)-3-{[4-[3-(2,2-二氟乙基)-脲基]-1-(3-氟-苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯
遵循一般方法7,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和2,2-二氟乙基胺获得粗制所需产物。通过色谱法(硅胶,12g柱,ISCO,0-50%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(100mg,57%)。LCMS(方法B):RT=3.81分钟,M+H+=510。
(S)-3-({1-(3-氟苯基)-4-[3-(2,2,2-三氟-乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯
遵循一般方法7,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和2,2,2-三氟乙基胺获得粗制所需产物。用色谱法(硅胶,12g柱,ISCO,0-100%乙酸乙酯于DCM中的溶液)获得标题化合物,其为玻璃状物(70mg,39%)。LCMS(方法B):RT=4.00分钟,M+H+=528。
一般方法8:制备1-(芳基)-4-脲基-1H-吡咯-3-羧酸(S)-哌啶-3-基酰胺
向(S)-3-{[1-(3-芳基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯(0.07-1.14mmol,1.0当量)中添加TFA(0.2-3.4mL,40当量)。将反应混合物在室温搅拌1-3小时,然后蒸干。使用下述方法之一纯化所得粗制残余物以得到标题化合物。
A=将粗制残余物负载在H-MN上,然后通过快速色谱法纯化(硅胶,12-40g柱,ISCO,0-30%MeOH于DCM中的溶液);
B=反相HPLC(Phenomenex Gemini C18,20mM三乙胺于水中/5-95%MeCN的梯度)
D=溶解于DCM中,并过滤通过5g快速NH2柱,先后用10%MeOH于DCM中的溶液、20%MeOH于DCM中的溶液和MeOH洗涤所述柱,真空浓缩滤液,并通过快速色谱法纯化残余物(硅胶,12-40g柱,ISCO,0-30%MeOH于DCM中的溶液)。
E=用乙腈研磨
实施例1:1-(3-氟苯基)-4-脲基-1H-吡咯-3-羧酸(S)-哌啶-3-基酰胺
遵循一般方法8,使用(S)-3-{[1-(3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法B获得标题化合物,其为乳白色固体(237mg,60%);LCMS(方法A),RT=5.18分钟,M+H+=346;1H NMR(CD3OD,300MHz):δ7.80(d,J=2.6Hz,1H),7.53-7.44(m,2H),7.33-7.24(m,2H),7.04(m,1H),3.98(m,1H),3.16(m,1H),2.93(m,1H),2.59-2.49(m,2H),1.98(m,1H),1.79(m,1H),1.61-1.51(m,2H)。
实施例2:1-(4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸(S)-哌啶-3-
基酰胺-TFA
遵循一般方法8,使用(S)-3-{[1-(4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法A获得标题化合物,其为灰白色固体(70mg,100%);LCMS(方法A),RT=6.09分钟,M+H+=396;1H NMR(DMSO-D6,300MHz):δ8.86(s,1H),8.71(br.s,2H),8.09(d,J=2.7Hz,1H),8.03(d,J=7.30Hz,1H),7.87(d,J=8.6Hz,2H),7.72(d,J=8.5Hz,2H),7.66(d,J=2.6Hz,1H),6.35(br.s,2H),4.14-4.07(m,1H),3.43-3.31(m,1H),3.28-3.18(m,1H),2.94-2.75(m,2H),1.99-1.88(m,2H),1.77-1.64(m,1H),1.63-1.51(m,1H)。
实施例3:1-(4-氰基苯基)-4-脲基-1H-吡咯-3-羧酸(S)-哌啶-3-基酰
胺-TFA
遵循一般方法8,使用(S)-3-{[1-(4-氰基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法A获得标题化合物,其为灰白色固体(66mg,67%);LCMS(方法A),RT=4.96分钟,M+H+=353;1H NMR(DMSO-D6,300MHz):δ8.86(s,1H),8.66(s,2H),8.11(d,J=2.6Hz,1H),8.04(d,J=7.3Hz,1H),8.01-7.94(m,2H),7.71-7.64(m,3H),6.39(br.s,2H),4.17-4.02(m,1H),3.27-3.13(m,2H),2.84-2.74(m,2H),2.02-1.84(m,2H),1.79-1.48(m,2H)。
实施例4:1-(4-氯-3-氟苯基)-4-脲基-1H-吡咯-3-羧酸(S)-哌啶-3-
基酰胺-TFA
遵循一般方法8,使用(S)-3-{[1-(4-氯-3-氟苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法A获得标题化合物,其为白色固体(146mg,68%);LCMS(方法A),RT=5.88分钟,M+H+=380;1H NMR(DMSO-D6,300MHz):δ8.84(s,1H),8.78(s,2H),8.01(d,J=3.7Hz,2H),7.74-7.61(m,2H),7.59(d,J=2.6Hz,1H),7.40(dd,J=8.8,2.5Hz,1H),6.36(br.s,2H),4.18-4.03(m,1H),3.29-3.12(m,2H),2.92-2.75(m,2H),1.97-1.88(m,2H),1.79-1.48(m,2H)。
实施例5:1-(3-氟-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸(S)-
哌啶-3-基酰胺-TFA
遵循一般方法8,使用(S)-3-{[1-(3-氟-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法A获得标题化合物,其为白色固体(120mg,100%);LCMS(方法A),RT=6.36分钟,M+H+=414;1H NMR(DMSO-D6,300MHz):δ8.85(s,1H),8.79(s,2H),8.13(d,J=2.6Hz,1H),8.08(d,J=7.3Hz,1H),7.90(t,J=8.4Hz,1H),7.79-7.71(m,1H),7.69(d,J=2.6Hz,1H),7.58-7.51(m,1H),6.40(br.s,2H),4.18-4.03(m,1H),3.28-3.15(m,2H),2.98-2.70(m,2H),2.02-1.87(m,2H),1.79-1.47(m,2H)。
实施例6:1-(3-氯-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羧酸(S)-
哌啶-3-基酰胺-TFA
遵循一般方法8,使用(S)-3-{[1-(3-氯-4-三氟甲基苯基)-4-脲基-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法A获得标题化合物,其为灰白色固体(115mg,51%);LCMS(方法A),RT=6.61分钟,M+H+=430;1H NMR(DMSO-D6,300MHz):δ8.88(s,1H),8.14(d,J=2.7Hz,1H),8.03(d,J=7.4Hz,1H),7.96(d,J=8.8Hz,1H),7.89(d,J=2.1Hz,1H),7.70-7.65(m,2H),6.40(br.s,2H),4.16-4.00(m,1H),3.22-3.13(m,2H),2.89-2.68(m,2H),2.00-1.83(m,2H),1.75-1.47(m,2H)。
实施例7:1-(3-氟苯基)-4-(3-甲基-脲基)-1H-吡咯-3-羧酸(S)-哌啶
-3-基酰胺
遵循一般方法8,使用(S)-3-{[1-(3-氟苯基)-4-(3-甲基-脲基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和先后使用纯化方法D和E获得标题化合物,其为白色固体(105mg,79%);LCMS(方法A),RT=5.10分钟,M+H+=360;1H NMR(CDCl3,300MHz):δ9.15(s,1H),7.63(d,J=2.5Hz,1H),7.42-7.31(m,2H),7.23-7.09(m,2H),6.95(td,J=8.3,2.4Hz,1H),6.74(d,J=8.4Hz,1H),4.92-4.82(m,1H),4.20-4.09(m,1H),3.06(dd,J=12.0,3.2Hz,1H),2.91-2.74(m,6H),1.85-1.67(m,3H),1.65-1.50(m,1H)。
实施例8:4-(3-乙基-脲基)-1-(3-氟苯基)1H-吡咯-3-羧酸(S)-哌啶
-3-基酰胺-TFA
遵循一般方法8,使用(S)-3-{[4-(3-乙基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和先后使用纯化方法D和E获得标题化合物,其为白色固体(144mg,71%);LCMS(方法A),RT=5.85分钟,M+H+=374;1H NMR(CD3OD,300MHz):δ7.78(d,J=2.1Hz,1H),7.54-7.46(m,2H),7.34-7.24(m,2H),7.07-7.05(m,1H),4.21(m,1H),3.52(m,1H),3.35(m,1H),3.22(q,J=7.2Hz,2H),3.09-2.84(m,2H),2.16-1.98(m,2H),1.94-1.62(m,2H),1.17(t,J=7.2Hz,3H)。
实施例9:1-(3-氟苯基)-4-(3-异丙基-脲基)-1H-吡咯-3-羧酸(S)-哌
啶-3-基酰胺-TFA
遵循一般方法8,使用(S)-3-{[1-(3-氟苯基)-4-(3-异丙基-脲基)-1H-吡咯-3-羰基]-氨基-哌啶-1-羧酸叔丁酯和纯化方法A获得标题化合物,其为乳白色固体(80mg,100%);LCMS(方法A),RT=6.17分钟,M+H+=388;1H NMR(CDCl3,300MHz):δ9.51-9.22(m,2H),9.09(m,1H),7.80(m,1H),7.67(s,1H),7.49(d,J=2.4Hz,1H),7.34(m,1H),7.20-7.04(m,2H),6.95(td,J=8.3,2.4Hz,1H),4.47(m,1H),3.83(m,1H),3.35-3.09(m,3H),2.98(m,1H),2.13(m,1H),1.98-1.74(m,3H),1.22(d,J=6.3Hz,6H)。
实施例10:4-(3-环丙基甲基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羧酸
(S)-哌啶-3-基酰胺
遵循一般方法8,使用(S)-3-{[4-(3-环丙基甲基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法B获得标题化合物,其为白色固体(40mg,两个步骤的收率为50%);LCMS(方法A),RT=6.43分钟,M+H+=400;1H NMR(CDCl3,300MHz):δ9.07(s,1H),7.60(s,1H),7.49(s,1H),7.35-7.26(m,1H),7.15(d,J=8.7Hz,2H),6.90(t,J=8.3Hz,1H),5.32(s,1H),4.88-4.24(br.s,1H),4.24-4.09(m,1H),3.09-2.97(m,3H),2.96-2.66(m,3H),1.91-1.49(m,4H),1.04-0.90(m,1H),0.51-0.39(m,2H),0.22-0.11(m,2H)。
实施例11:1-(3-氟苯基)-4-[3-(2-甲氧基-乙基)-脲基]-1H-吡咯-3-
羧酸(S)-哌啶-3-基酰胺
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-(2-甲氧基-乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯和纯化方法B获得标题化合物,其为白色固体(38mg,两个步骤的收率为47%);LCMS(方法A),RT=5.83分钟,M+H+=404;1H NMR(CDCl3,300MHz):δ9.13(s,1H),7.60(d,J=2.5Hz,1H),7.46(d,J=2.5Hz,1H),7.38-7.24(m,1H),7.19-7.14(m,1H),7.14-7.08(m,1H),6.97-6.89(m,2H),5.45(s,1H),4.21-4.07(m,1H),3.58-3.40(m,4H),3.35(s,3H),3.12-3.00(m,1H),2.88-2.76(m,3H),1.87-1.69(m,3H),1.63-1.50(m,1H)。
实施例12:4-(3-环丙基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羧酸(S)-
哌啶-3-基酰胺
遵循一般方法8,使用(S)-3-{[4-(3-环丙基-脲基)-1-(3-氟苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯(94mg,0.19mmol)和先后使用纯化方法D和E获得标题化合物,其为白色固体(19mg,26%);LCMS(方法A),RT=5.83分钟,M+H+=386;1H NMR(CD3OD,300MHz):δ7.83(d,J=2.6Hz,1H),7.56(d,J=2.6Hz,1H),7.52-7.43(m,1H),7.34-7.29(m,1H),7.28(dt,J=10.2,2.3Hz,1H),7.07-7.01(m,1H),4.02-3.93(m,1H),3.14(dd,J=12.2,3.9Hz,1H),2.92(dt,J=12.7,3.7Hz,1H),2.62-2.49(m,3H),2.04-1.96(m,1H),1.83-1.73(m,1H),1.67-1.51(m,2H),0.83(d,J=6.7Hz,2H),0.63-0.54(m,2H)。
实施例13:1-(3-氟苯基)-4-[3-(2-羟基乙基)-脲基]-1H-吡咯-3-羧
酸(S)-哌
啶-3-基酰胺TFA
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-(2-羟基乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯(60mg,0.12mmol)和纯化方法A获得标题化合物,其为白色固体(23mg,48%);LCMS(方法A),RT=2.12分钟,M+H+=390;1H NMR(CD3OD,400MHz):δ7.81-7.79(m,1H),7.54-7.42(m,1H),7.32-7.29(m,1H),7.26(dt,J=10.2,2.3Hz,1H),7.04(tdd,J=8.3,2.4,0.8Hz,1H),4.24(tt,J=10.2,3.9Hz,1H),3.64(t,J=5.7Hz,2H),3.51(dd,J=12.3,4.0Hz,1H),3.32-3.29(m,3H),3.03-2.90(m,2H),2.11-2.03(m,2H),1.92-1.78(m,1H),1.77-1.66(m,1H)。
实施例14:1-(3-氟苯基)-4-(3-丙基-脲基)-1H-吡咯-3-羧酸(S)-哌
啶-3-基酰胺TFA
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-丙基脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯(100mg,0.20mmol)和纯化方法A获得标题化合物,其为白色固体(60mg,76%);LCMS(方法A),RT=2.31分钟,M+H+=388;1H NMR(CD3OD,400MHz):δ7.80(t,J=2.9Hz,1H),7.51-7.42(m,2H),7.31-7.22(m,2H),7.03(tdd,J=8.3,2.4,0.8Hz,1H),4.29-4.20(m,1H),3.55-3.49(m,1H),3.33-3.30(m,1H),3.16(t,J=7.0Hz,2H),3.05-2.93(m,2H),2.12-2.04(m,2H),1.93-1.79(m,1H),1.79-1.67(m,1H),1.62-1.51(m,2H),0.97(t,J=7.4Hz,3H)。
实施例15:1-(3-氟苯基)-4-[3-(3-羟基丙基)-脲基]-1H-吡咯-3-羧
酸(S)-哌啶-3-基酰胺TFA
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-(3-羟基丙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯(70mg,0.14mmol)和纯化方法A获得标题化合物,其为白色固体(18mg,32%);LCMS(方法A),RT=2.11分钟,M+H+=404;1H NMR(CD3OD,400MHz):δ7.80-7.79(m,1H),7.53(d,J=2.5Hz,1H),7.48(td,J=8.2,6.2Hz,1H),7.32-7.29(m,1H),7.26(dt,J=10.2,2.3Hz,1H),7.04(tdd,J=8.3,2.4,0.8Hz,1H),4.24(tt,J=10.2,3.9Hz,1H),3.64(t,J=6.3Hz,2H),3.51(dd,J=12.3,4.0Hz,1H),3.32-3.29(m,2H),3.31-3.26(m,2H),3.08-2.89(m,2H),2.11-2.02(m,2H),1.93-1.79(m,1H),1.76(t,J=6.5Hz,2H).
实施例16:1-(3-氟苯基)-4-[3-(3-甲氧基-丙基)-脲基]-1H-吡咯-3-
羧酸(S)-哌啶-3-基酰胺TFA
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-(3-甲氧基丙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯(100mg,0.19mmol)和纯化方法A获得标题化合物,其为白色固体(75mg,92%);LCMS(方法A),RT=2.21分钟,M+H+=418;1H NMR(CDCl3,300MHz):δ9.52(s,1H),9.21(s,1H),8.97(s,1H),7.61-7.54(m,2H),7.34(td,J=8.2,6.2Hz,1H),7.23-7.16(m,1H),7.14(dt,J=9.9,2.3Hz,1H),6.94(td,J=8.2,2.4Hz,1H),5.80(s,1H),4.43(s,1H),3.45(t,J=6.0Hz,2H),3.38-3.30(m,3H),3.29(s,3H),3.02(t,J=10.6Hz,1H),2.90(q,J=10.5Hz,1H),2.30-2.12(m,3H),1.97-1.82(m,1H),1.85-1.75(m,3H)。
实施例17:4-[3-(2-氟乙基)-脲基]-1-(3-氟-苯基)-1H-吡咯-3-羧酸
(S)-哌啶-3-基酰胺TFA
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-(2-氟乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯(80mg,0.16mmol)和纯化方法A获得标题化合物,其为白色固体(45mg,70%);LCMS(方法A),RT=2.20分钟,M+H+=392;1H NMR(CD3OD,300MHz):δ7.78(s,1H),7.56-7.46(m,2H),7.35-7.26(m,2H),7.06(tdd,J=8.3,2.4,0.9Hz,1H),4.49-4.38(m,2H),4.28-4.18(m,1H),3.56-3.49(m,2H),3.46(t,J=5.0Hz,1H),3.37-3.31(m,1H),3.04-2.88(m,2H),2.13-2.04(m,2H),1.91-1.78(m,1H),1.77-1.66(m,1H)。
实施例18:4-[3-(2,2-二氟乙基)-脲基]-1-(3-氟-苯基)-1H-吡咯-3-
羧酸(S)-哌啶-3-基酰胺TFA
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-(2,2-二氟乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯(100mg,0.20mmol)和纯化方法A获得标题化合物,其为白色固体(55mg,68%);LCMS(方法A),RT=2.24分钟,M+H+=410;1H NMR(DMSO-d6,400MHz):δ9.04(s,1H),8.72(s,2H),8.03-7.96(m,2H),7.71(t,J=5.9Hz,1H),7.61(d,J=2.5Hz,1H),7.59-7.51(m,1H),7.43-7.35(m,2H),7.15(td,J=8.4,2.4Hz,1H),6.02(tt,J=56.0,3.8Hz,1H),4.15-4.06(m,1H),3.54-3.41(m,2H),3.38-3.29(m,1H),3.28-3.17(m,1H),2.98-2.70(m,2H),1.99-1.89(m,2H),1.76-1.63(m,1H),1.64-1.54(m,1H)。
实施例19:1-(3-氟苯基)-4-[3-(2,2,2-三氟乙基)-脲基]-1H-吡咯-3-
羧酸(S)-哌啶-3-基酰胺-TFA
遵循一般方法8,使用(S)-3-({1-(3-氟苯基)-4-[3-(2,2,2-三氟乙基)-脲基]-1H-吡咯-3-羰基}-氨基)-哌啶-1-羧酸叔丁酯(70mg,0.13mmol)和纯化方法A获得标题化合物,其为白色固体(25mg,44%);LCMS(方法A),RT=2.37分钟,M+H+=428;1H NMR(400MHz,DMSO-d6):δ9.13(s,1H),8.71(s,2H),8.04-7.97(m,3H),7.62(d,J=2.5Hz,1H),7.59-7.51(m,1H),7.44-7.36(m,2H),7.16(td,J=8.4,2.4Hz,1H),4.16-4.06(m,1H),3.96-3.84(m,2H),3.38-3.29(m,1H),3.23(d,J=12.2Hz,1H),2.94-2.74(m,2H),1.97-1.88(m,2H),1.75-1.66(m,1H),1.62-1.54(m,1H)。
实施例20:1-(4-氯-3-氟-苯基)-4-(3-乙基-脲基)-1H-吡咯-3-羧酸
(S)-哌啶-3-基酰胺
遵循一般方法8,使用(S)-3-{[4-(3-乙基-脲基)-1-(4-氯-3-氟苯基)-1H-吡咯-3-羰基]-氨基}-哌啶-1-羧酸叔丁酯和纯化方法D获得标题化合物,其为白色固体(70mg,40%);LCMS(方法A),RT=6.49分钟,M+H+=408;1H NMR(DMSO-D6,400MHz):δ8.96(s,1H),8.04(d,J=2.6Hz,1H),7.74-7.62(m,3H),7.58(d,J=2.6Hz,1H),7.41-7.37(m,1H),7.15(t,J=5.5Hz,1H),3.85-3.74(m,1H),3.12-2.98(m,3H),2.83(dt,J=12.1,3.3Hz,1H),2.48-2.44(m,1H),2.40(dd,J=11.9,9.5Hz,1H),1.90-1.83(m,1H),1.72-1.64(m,1H),1.48-1.38(m,2H),1.03(t,J=7.2Hz,3H)。
实施例21:1-(3-氟苯基)-4-脲基-1H-吡咯-3-羧酸((S)-1-甲基-哌啶
-3-基)-酰胺
氮气气氛中,向(S)-1-甲基-哌啶-3-基胺(120mg,1.05mmol)于THF中的溶液(8.0mL)中添加2N三甲基铝的己烷溶液(1.0mL,2.0mmol),将反应混合物在室温搅拌1.5小时。此后,添加1-(3-氟苯基)-4-脲基-1H-吡咯-3-羧酸乙酯(291mg,1.0mmol)的THF(5.0mL)溶液,将反应混合物在65-70℃加热18小时。此后,使反应混合物冷却至室温,然后通过添加罗谢尔盐的饱和溶液淬灭。0.5小时之后,将混合物用DCM(3×10mL)和EtOAc(1×10mL)萃取。干燥(MgSO4)合并的有机层并并真空浓缩。然后通过快速色谱法纯化所得的残余物(硅胶,5g柱,Isolute,0-20%MeOH于DCM中的溶液)得到标题化合物(60mg,0.17mmol,17%)。LCMS(方法A),RT=5.13分钟,M+H+=360;1HNMR(DMSO-D6,400MHz):δ8.97(s,1H),8.05(d,J=2.6Hz,1H),7.68(d,J=7.8Hz,1H),7.56(d,J=2.6Hz,1H),7.55-7.48(m,1H),7.39(dt,J=10.6,2.3Hz,1H),7.36-7.33(m,1H),7.12(td,J=8.5,2.4Hz,1H),6.29(s,2H),3.95-3.88(m,1H),2.85-2.77(m,1H),2.65-2.57(m,1H),2.18(s,3H),1.92-1.73(m,3H),1.74-1.67(m,1H),1.58-1.46(m,1H),1.33-1.19(m,1H)。
Claims (19)
1.式(I)化合物:
(I)
R1是苯基或杂芳基,其中所述苯基和杂芳基任选取代有一至五个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;
R2为H、氯、氟或CN;
R3A和R3B独立地为H、烷基、环烷基或杂环基,其中所述烷基、环烷基和杂环基任选取代有一至五个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;
R3A和R3B任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的4-10元单环或二环,所述环任选取代有一至五个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9;
X为O或N(R6);
R6为H、CN或C1-C2烷基,其中所述烷基任选取代有一个或多个基团,所述基团选自OH、O(C1-C2烷基)、氟和环丙基;
R4为H、C1-C3烷基、C3-C5环烷基或-(CH2)0-1-4-5元杂环基,其中所述烷基任选取代有一个或多个基团,所述基团选自OH、O(C1-C2烷基)、氟和C3-C5环烷基,并且所述环烷基任选取代有OH;
R5为H、氯、氟或CN;
每个p独立地为0、1或2;
R7和R8每次出现时独立地为H、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R10基团;
R7和R8任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的4-7元环,所述环任选取代有一至五个R10基团;
R9独立地为烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R10基团;
每个R10独立地为卤素、CN、CF3、-OCF3、-NO2、-C(O)OR11、-C(O)NR11R12、-NR11R12、-OR11、-S(O)pR11、-NR12C(O)R11、-NR12C(O)OR11、-NR12C(O)NR11R12、-NR12SO2R11、-OC(O)R11、-OC(O)NR11R12、-S(O)2NR11R12或R13;
R11和R12每次出现时独立地选自H、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R14基团;
R11和R12任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的5-6元环,所述环任选取代有一至五个R14基团;
R13独立地为烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至五个R14基团;
每个R14独立地为卤素、CN、CF3、-OCF3、-NO2、-C(O)OR15、-C(O)NR15R16、-NR15R16、-OR15、-S(O)pR15、-NR16C(O)R15、-NR16C(O)OR15、-NR16C(O)NR15R16、-NR16SO2R15、-OC(O)R15、-OC(O)NR15R16、-S(O)2NR15R16或R17;
R15和R16每次出现时独立地为H、烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至四个基团,所述基团选自卤素、-CN、-OCF3、-CF3、-NO2、-C1-C6烷基、-OH、氧代、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-SO2(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)(C1-C6烷基)、-NHC(O)(C1-C6烷基)、-NHSO2(C1-C6烷基)、-N(C1-C6烷基)SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-OC(O)NH2、-OC(O)NH(C1-C6烷基)、-OC(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)NH(C1-C6烷基)、-N(C1-C6烷基)C(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-NHC(O)O(C1-C6烷基)和-N(C1-C6烷基)C(O)O(C1-C6烷基);
R15和R16任选与所连接的N原子一起形成具有额外0-2个选自O、S和N的杂原子的5-6元环,所述环任选取代有一至四个基团,所述基团选自卤素、-CN、-OCF3、-CF3、-NO2、-C1-C6烷基、-OH、氧代、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-SO2(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)(C1-C6烷基)、-NHC(O)(C1-C6烷基)、-NHSO2(C1-C6烷基)、-N(C1-C6烷基)SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-OC(O)NH2、-OC(O)NH(C1-C6烷基)、-OC(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)NH(C1-C6烷基)、-N(C1-C6烷基)C(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-NHC(O)O(C1-C6烷基)和-N(C1-C6烷基)C(O)O(C1-C6烷基);和
R17为烷基、环烷基、杂环基、芳基或杂芳基,其中所述烷基、环烷基、杂环基、芳基和杂芳基任选取代有一至四个基团,所述基团选自卤素、-CN、-OCF3、-CF3、-NO2、-C1-C6烷基、-OH、氧代、-SH、-O(C1-C6烷基)、-S(C1-C6烷基)、-NH2、-NH(C1-C6烷基)、-N(C1-C6烷基)2、-SO2(C1-C6烷基)、-CO2H、-CO2(C1-C6烷基)、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)(C1-C6烷基)、-NHC(O)(C1-C6烷基)、-NHSO2(C1-C6烷基)、-N(C1-C6烷基)SO2(C1-C6烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2N(C1-C6烷基)2、-OC(O)NH2、-OC(O)NH(C1-C6烷基)、-OC(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-N(C1-C6烷基)C(O)NH(C1-C6烷基)、-N(C1-C6烷基)C(O)N(C1-C6烷基)2、-NHC(O)NH(C1-C6烷基)、-NHC(O)N(C1-C6烷基)2、-NHC(O)O(C1-C6烷基)和-N(C1-C6烷基)C(O)O(C1-C6烷基)。
2.权利要求1的化合物,其中R1为取代有一至三个基团的苯基,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9。
3.权利要求2的化合物,其中R1为取代有一至三个独立地选自卤素、CN和CF3的基团的苯基。
4.权利要求2或3的化合物,其中R2为H。
5.权利要求4的化合物,其中R3A为H。
6.权利要求5的化合物,其中R3B为H、环烷基或杂环基,其中所述环烷基和杂环基任选取代有一至三个基团,所述基团独立地选自卤素、CN、CF3、-OCF3、-NO2、-C(O)OR7、-C(O)NR7R8、-NR7R8、-OR7、-S(O)pR7、-NR8C(O)R7、-NR8C(O)OR7、-NR8C(O)NR7R8、-NR8SO2R7、-OC(O)R7、-OC(O)NR7R8、-S(O)2NR7R8和R9。
7.权利要求6的化合物,其中R3B是4-7元单环饱和杂环基或8-10元二环饱和杂环基。
8.权利要求7的化合物,其中R3B是哌啶基。
9.权利要求6-8中任一项的化合物,其中X是O。
10.权利要求9的化合物,其中R4为H、CH3、CH2CH3、正丙基、异丙基、CH2CH2OH、CH2CH2OCH3、CH2CH2CH2OH、CH2CH2CH2OCH3、环丙基、CH2-环丙基、CH2CH2F、CH2CHF2或CH2CF3。
11.权利要求10的化合物,其中R5为H。
12.权利要求1的化合物,所述化合物选自实施例1-11的标题化合物。
13.一种药物组合物,其包含权利要求1-12中任一项的化合物和可药用载体。
14.权利要求13的药物组合物,其还包含另一种化学治疗药物。
15.权利要求14的药物组合物,其中所述另一种化学治疗药物是DNA损伤剂。
16.一种在哺乳动物中抑制异常细胞生长或治疗过度增殖性疾病的方法,包括给予所述哺乳动物治疗有效量的权利要求13-15中任一项的药物组合物。
17.一种在哺乳动物中治疗癌症的方法,包括给予所述哺乳动物治疗有效量的权利要求13-15中任一项的药物组合物。
18.权利要求17的方法,其中所述癌症选自乳腺癌、结肠直肠癌、卵巢癌、非小细胞肺癌、恶性脑肿瘤、肉瘤、黑色素瘤、淋巴瘤、骨髓瘤和白血病。
19.权利要求16-18中任一项的方法,其中将所述另一种化学治疗药物顺序或连续给予所述哺乳动物。
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