CN107108614A - 作为布罗莫结构域抑制剂的取代的吡咯并吡啶 - Google Patents
作为布罗莫结构域抑制剂的取代的吡咯并吡啶 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract
本发明涉及式(I)化合物及其盐及其组合物和用途,其中R1、R2和Q具有说明书中所定义的任何值。所述化合物可用作布罗莫结构域的抑制剂。本发明还包括包含式(I)化合物或其药用盐的药物组合物及使用此类化合物及其盐用于治疗各种由布罗莫结构域介导的病症的方法。
Description
对相关申请的交叉引用
本专利申请要求2014年11月10日提交的美国申请62/077,707的优先权,通过引用的方式将该申请并入本文。
技术领域
本发明涉及可用作布罗莫结构域(bromodomain)的抑制剂的化合物。
背景技术
染色质是构成染色体的DNA和蛋白质的复杂组合。其被发现在真核细胞的细胞核内且分为异染色质(缩合)和常染色质(延伸)形式。染色质的主要组分是DNA和蛋白质。组蛋白是染色质的主要蛋白质组分,其作为DNA缠绕的轴。染色质的功能是将DNA包裹到较小的体积中以适应细胞、使DNA得以强化以允许有丝分裂和减数分裂并用作控制表达和DNA复制的机制。染色质结构受控于对组蛋白蛋白的一系列翻译后修饰,特别是组蛋白H3和H4且最常见的是在延伸超出核心核小体结构的“组蛋白尾部”中。组蛋白尾部趋于发生蛋白质-蛋白质相互作用且也是组蛋白最易于翻译后修饰的部分。这些修饰包括乙酰化、甲基化、磷酸化、泛素化和SUMO化。这些后天性标志物被特异性酶所写入和擦除,所述酶将标签置于组蛋白尾部的特定残基上,从而形成后天性密码,其然后由细胞解释以允许对染色质结构进行基因特异性调节并由此转录。
组蛋白在所有类别的蛋白质中是最易于接受翻译后修饰的。组蛋白修饰是动态的,这是因为其可响应于特定刺激而被添加或去除且这些修饰既引导对染色质的结构变化,又引导基因转录的改变。不同类别的酶即组蛋白乙酰转移酶(HAT)和组蛋白去乙酰酶(HDAC)使特异性组蛋白赖氨酸残基发生乙酰化或去乙酰化(Struhl K.,Genes Dev.,1989,12,5,599-606)。
长度为约110个氨基酸的布罗莫结构域在很多种染色质相关蛋白中被发现且已在约70种通常与其它蛋白质基序相邻的人类蛋白质中被鉴定(Jeanmougin F.等人,TrendsBiochem.Sci.,1997,22,5,151-153;和Tamkun J.W.等人,Cell,1992,7,3,561-572)。布罗莫结构域与经修饰的组蛋白之间的相互作用可能是引起染色质结构变化和基因调节的重要机制。在包括癌症、炎症和病毒复制在内的疾病过程中已经涉及含有布罗莫结构域的蛋白质。参见例如Prinjha等人,Trends Pharm.Sci.,33(3):146-153(2012)和Muller等人,Expert Rev.,13(29):1-20(2011年9月)。
细胞类型特异性和适当的组织功能性需要对受其环境密切影响的不同转录程序进行严格控制。该转录稳态的改变与多种疾病状态直接相关,特别是癌症、免疫炎症、神经病症和代谢疾病。布罗莫结构域位于对独特的与疾病相关的转录途径进行控制的关键的染色质修饰复合物中。这被以下观察结果所强调:含有布罗莫结构域的蛋白质的突变与癌症及免疫和神经功能障碍是相关的。最近的发现还已经证实对BRD4的布罗莫结构域的小分子抑制可在从自身免疫到心脏肥大的多种人类疾病中具有临床实用性。这可能是因为潜在的机制存在于转录调节中。因此,对所述家族范围内的布罗莫结构域进行的选择性抑制提供了作为人类功能障碍的新颖治疗剂的各种机会。
需要对癌症、免疫病症和其它布罗莫结构域相关疾病的治疗。
发明内容
一个方面包括式(I)化合物或其盐:
其中
R1为H、甲基或乙基;
R2为H、C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基,其中R2中的每个C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基任选取代有一个或多个基团Rb;且
Q为5元杂芳基,其任选取代有一个或多个基团Rc,或Q为:
其中环A任选取代有一个或多个基团Rc,或环A任选与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg;
X1、X2和X3各自独立选自CRc和N,条件是X1、X2和X3中的至少一个不为N;且当环A任选与碳环基或杂环基稠合以形成多环基时,X1、X2和X3中的每个可为C且可为稠合点;
每个Rb独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-O-C(O)-O-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-O-C(O)-N(Rw)2、-N(Rw)-C(O)-ORw、-N(Rw)-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw、-N(Rw)-S(O)-N(Rw)2和-N(Rw)-S(O)2-N(Rw)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;
每个Rc独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有一个或多个C1-6烷基;
Re为氢、-F、-Cl、-Br、-I、-CN、-O-Rx、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Rx)2、-CN、-C(O)-N(Rx)2、-S(O)-N(Rx)2、-S(O)2-N(Rx)2、-O-Rx、-S-Rx、-O-C(O)-Rx、-O-C(O)-O-Rx、-C(O)-Rx、-C(O)-O-Rx、-S(O)-Rx、-S(O)2-Rx、-O-C(O)-N(Rx)2、-N(Rx)-C(O)-ORx、-N(Rx)-C(O)-N(Rx)2-N(Rx)-C(O)-Rx、-N(Rx)-S(O)-Rx、-N(Rx)-S(O)2-Rx、-N(Rx)-S(O)-N(Rx)2和-N(Rx)-S(O)2-N(Rx)2;
Rf为氢、-F、-Cl、-Br、-I、-CN、-O-Ry、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2和-N(Ry)-S(O)2-N(Ry)2;
每个Rg独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-O-C(O)-O-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-O-C(O)-N(Rz)2、-N(Rz)-C(O)-ORz、-N(Rz)-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、-N(Rz)-S(O)-N(Rz)2和-N(Rz)-S(O)2-N(Rz)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基;
每个Rv独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rva)2、羟基、氰基、C1-C6烷氧基、碳环基、杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rv与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代、-N(Rva)2和卤素的基团的C1-3烷基;
每个Rw独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rwa)2、羟基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rw与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rx独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Ry独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Rz独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氰基、-N(Rza)2、C1-C6烷氧基、碳环基、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rz与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rva独立为氢或C1-6烷基,或两个Rva与和它们所连接的氮一起形成杂环基;
每个Rwa独立为氢或C1-6烷基,或两个Rwa与和它们所连接的氮一起形成杂环基;且
每个Rza独立为氢或C1-6烷基,或两个Rza与和它们所连接的氮一起形成杂环基。
另一个方面包括组合物,其包含式(I)化合物或其药用盐和药用辅料、载体或媒介物。
另一个方面包括治疗动物中由布罗莫结构域介导的病症的方法,所述方法包括向所述动物施用式(I)化合物或其药用盐。
另一个方面包括式(I)化合物或其药用盐,其用于医学疗法。
另一个方面包括式(I)化合物或其药用盐,其用于预防性或治疗性处置由布罗莫结构域介导的病症。
另一个方面包括式(I)化合物或其药用盐在制备用于治疗动物(例如哺乳动物例如人类)中由布罗莫结构域介导的病症的药物中的用途。
另一个方面包括用于研究布罗莫结构域的化合物。
另一个方面包括本文公开的可用于制备式(I)化合物或其盐的合成中间体和合成方法。
发明内容
化合物和定义
下文更详细地对定义和术语进行描述。化学元素按照元素周期表,CAS版本,Handbook of Chemistry and Physics,第75版确定。
除非另有说明,式I化合物包括给定结构的对映异构、非对映异构和几何异构(或构象)形式。例如,包括针对每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构、非对映异构和几何异构(或构象)混合物。除非另有说明,包括本文描述的结构的所有互变异构形式。另外,除非另有说明,本文描述的结构还意在包括区别仅在于存在一个或多个同位素富集原子的化合物。例如,包括以下式I化合物,其中一个或多个氢被氘或氚、一个或多个碳被13C或14C碳、一个或多个氮被15N氮、一个或多个硫被33S、34S或36S硫或一个或多个氧被17O或18O氧所独立置换或富集。此类化合物可用作例如分析工具、生物学测定探针或治疗剂。
当描述具体的对映异构体时,其在某些实施方案中可被提供为基本上不含相应的对映异构体且也可被称为“光学富集”。本文使用的“光学富集”意指对映异构体的混合物由显著较大比例的一种对映异构体构成且可通过对映异构体过量(ee%)描述。在某些实施方案中,对映异构体的混合物由至少约90重量%的给定对映异构体构成(约90%ee)。在其它实施方案中,对映异构体的混合物由至少约95重量%、98重量%或99重量%的给定对映异构体构成(约95%、98%或99%ee)。对映异构体和非对映异构体可通过本领域技术人员已知的任何方法自外消旋混合物中分离,包括自其中一种立体异构体比另一种立体异构体较易溶解的溶剂中重结晶、手性高压液相色谱(HPLC)、超临界流体色谱(SFC)、形成手性盐且使其结晶且然后通过任何上述方法分离或通过不对称合成进行制备且任选进一步富集。参见例如Jacques等人,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Wilen等人,Tetrahedron 33:2725(1977);Eliel,E.L.Stereochemistryof Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agentsand Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,NotreDame,IN 1972)。
术语“杂原子”意指任何以下原子,其独立选自不是碳或氢的原子,例如氧、硫、氮、磷或硅中的一种或多种(包括氮、硫、磷或硅的任何氧化形式及任何氮的季铵化形式)。
本文使用的术语“卤代”和“卤素”是指选自氟(氟代、-F),氯(氯代、-Cl),溴(溴代、-Br)和碘(碘代、-I)的原子。
术语“氧代”意指=O或(=O)2。
本文使用的术语“不饱和”意指基团具有一个或多个不饱和单元。
单独或作为较大基团的一部分使用的术语“碳环基”是指具有3至20个碳原子的饱和、部分不饱和或芳族环系。在一个实施方案中,碳环基包含3至12碳原子(C3-C12)。在另一个实施方案中,碳环基包括C3-C8、C3-C10或C5-C10。在其它实施方案中,碳环基作为单环包括C3-C8、C3-C6或C5-C6。在另一个实施方案中,碳环基作为二环包括C7-C12。在另一个实施方案中,碳环基作为螺环系统包括C5-C12。单环碳环基的实例包括环丙基、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、全氘代环己基、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、苯基和环十二烷基;具有7至12个环原子的二环碳环基包括[4,3]、[4,4]、[4,5]、[5,5]、[5,6]或[6,6]环系统,例如二环[2.2.1]庚烷、二环[2.2.2]辛烷、萘和二环[3.2.2]壬烷;且螺环碳环基包括螺[2.2]戊烷、螺[2.3]己烷、螺[2.4庚烷、螺[2.5]辛烷和螺[4.5]癸烷。术语“碳环基”包括如本文所定义的芳基环系。术语“碳环基”还包括环烷基环(例如饱和或部分不饱和的单环、二环或螺环碳环)。
本文使用的术语“烷基”是指饱和直链或支链一价烃基。在一个实施方案中,烷基具有一个至十八个碳原子(C1-C18)。在其它实施方案中,烷基为C0-C6、C0-C5、C0-C3、C1-C12、C1-C10、C1-C8、C1-C6、C1-C5、C1-C4或C1-C3。C0烷基是指键。烷基的实例包括甲基(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)、庚基、辛基、壬基、癸基、十一烷基和十二烷基。
本文使用的术语“烯基”表示具有至少一个碳-碳双键的直链或支链一价烃基。烯基包括具有“顺式”和“反式”取向或“E”和“Z”取向的基团。在一个实例中,烯基具有2至18个碳原子(C2-C18)。在其它实例中,烯基为C2-C12、C2-C10、C2-C8、C2-C6或C2-C3。实例包括但不限于乙烯基(-CH=CH2)、丙-1-烯基(-CH=CHCH3)、丙-2-烯基(-CH2CH=CH2)、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯基、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基。
本文使用的术语“炔基”是指具有至少一个碳-碳叁键的直链或支链一价烃基。在一个实例中,炔基具有2至18个碳原子(C2-C18)。在其它实例中,炔基为C2-C12、C2-C10、C2-C8、C2-C6或C2-C3。实例包括但不限于乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH3)、丙-2-炔基(炔丙基、-CH2C≡CH)、丁-1-炔基、丁-2-炔基和丁-3-炔基。
术语“烷氧基”是指由式-OR表示的直链或支链一价基团,其中R为烷基、烯基、炔基或碳环基。烷氧基包括甲氧基、乙氧基、丙氧基、异丙氧基和环丙氧基。
本文使用的术语“卤代烷基”是指取代有一个或多个(例如1、2、3或4个)卤素基团的本文所定义的烷基。
单独或作为较大基团(例如“芳基烷基”、“芳基烷氧基”或“芳基氧基烷基”)的一部分使用的术语“芳基”是指单环、二环或三环碳环系统,其包括稠环,其中系统中的至少一个环为芳族的。术语“芳基”可与术语“芳基环”互换使用。在一个实施方案中,芳基包括具有6-18个碳原子的基团。在另一个实施方案中,芳基包括具有6-10个碳原子的基团。芳基的实例包括苯基、萘基、蒽基、联苯、菲基、并四苯基、1,2,3,4-四氢萘基、1H-茚基、2,3-二氢-1H-茚基等,其可被一个或多个本文所述的取代基取代或独立取代。具体的芳基为苯基。在另一个实施方案中,芳基包括与一个或多个碳环稠合的芳基环,例如茚满基或四氢萘基等,其中连接基或连接点在芳族环上。
单独或作为较大基团(例如“杂芳基烷基”或“杂芳基烷氧基”)的一部分使用的术语“杂芳基”是指具有5至14个环原子的单环、二环或三环系统,其中至少一个环是芳族的且含有至少一个杂原子。在一个实施方案中,杂芳基包括4-6元单环芳族基团,其中一个或多个环原子是独立任选取代的氮、硫或氧。在另一个实施方案中,杂芳基包括5-6元单环芳族基团,其中一个或多个环原子是独立任选取代的氮、硫或氧。杂芳基的实例包括噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、四唑基、硫杂三唑基、氧杂三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、四嗪基、四唑[1,5-b]哒嗪基、咪唑并[1,2-a]嘧啶基、嘌呤基、苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并三唑基、苯并咪唑基、吲哚基、1,3-噻唑-2-基、1,3,4-三唑-5-基、1,3-噁唑-2-基、1,3,4-噁二唑-5-基、1,2,4-噁二唑-5-基、1,3,4-噻二唑-5-基、1H-四唑-5-基、1,2,3-三唑-5-基和吡啶-2-基N-氧化物。术语“杂芳基”还包括以下基团,其中杂芳基与一个或多个芳基、碳环基或杂环基环稠合,其中连接基或连接点在杂芳基环上。非限制性实例包括吲哚基、异吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、喹喔啉基、4H-喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、四氢喹啉基、四氢异喹啉基和吡啶并[2,3-b]1,4-噁嗪-3(4H)-酮。杂芳基可为单环、二环或三环的。
本文使用的术语“杂环基”是指如本文所定义的“碳环基”,其中一个或多个(例如1、2、3或4个)碳原子已经被杂原子(例如O、N或S)替换。在一些实施方案中,杂环基是指饱和环系,例如3至12元饱和杂环基环系。在一些实施方案中,杂环基是指杂芳基环系,例如5-14元杂芳基环系。杂环基可任选取代有一个或多个独立选自本文所定义的那些取代基的取代基。术语“杂环基”还包括C3-C8杂环烷基,其是包含3-8个碳和一个或多个(例如1、2、3或4个)杂原子的饱和或部分不饱和的单环、二环或螺环系统。
在一个实例中,杂环基具有3-12个环原子且包括单环、二环、三环和螺环系统,其中环原子为碳且一个至五个环原子为选自氮、硫或氧的杂原子,其独立任选被一个或多个基团取代。在一个实例中,杂环基包含1至4个杂原子。在另一个实例中,杂环基包括具有一个或多个选自氮、硫或氧的杂原子的3元至7元单环。在另一个实例中,杂环基包括具有一个或多个选自氮、硫或氧的杂原子的4元至6元单环。在另一个实例中,杂环基包括3元单环。在另一个实例中,杂环基包括4元单环。在另一个实例中,杂环基包括5-6元单环。在一个实例中,杂环基包含0至3个双键。任何氮或硫杂原子可任选被氧化(例如NO、SO、SO2)且任何氮杂原子可任选被季铵化(例如[NR4]+Cl-、[NR4]+OH-)。示例性杂环基包括环氧乙烷基、氮杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁烷基、1,3-二硫杂环丁烷基、吡咯烷基、二氢-1H-吡咯基、二氢呋喃基、四氢呋喃基、二氢噻吩基、四氢噻吩基、咪唑烷基、哌啶基、哌嗪基、吗啉基、硫吗啉基、1,1-二氧代-硫吗啉基、二氢吡喃基、四氢吡喃基、六氢噻喃基、六氢嘧啶基、噁嗪烷基、噻嗪烷基、硫氧杂环己烷基、高哌嗪基、高哌啶基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、氧氮杂环庚烷基、二氮杂环庚烷基、1,4-二氮杂环庚烷基、二氮杂基、硫氮杂基、硫氮杂环庚烷基、四氢噻喃基、噁唑烷基、噻唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷酮基、噁唑烷酮基、咪唑烷酮基、4,5,6,7-四氢[2H]吲唑基、四氢苯并咪唑基、4,5,6,7-四氢苯并[d]咪唑基、1,6-二咪唑并[4,5-d]吡唑并[2,3-b]吡啶基、噻嗪基、噁嗪基、噻二嗪基、噁二嗪基、二噻嗪基、二噁嗪基、氧杂噻嗪基、硫杂三嗪基、氧杂三嗪基、二噻二嗪基、咪唑啉基、二氢嘧啶基、四氢嘧啶基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、噻喃基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧杂环戊烷基、吡唑啉基、吡唑烷基、二噻烷基、二硫杂环戊烷基、嘧啶酮基、嘧啶二酮基、嘧啶-2,4-二酮基、哌嗪酮基、哌嗪二酮基、吡唑烷基、咪唑啉基、3-氮杂二环[3.1.0]己烷基、3,6-二氮杂二环[3.1.1]庚烷基、6-氮杂二环[3.1.1]庚烷基、3-氮杂二环[3.1.1]庚烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、2-氮杂二环[3.2.1]辛烷基、8-氮杂二环[3.2.1]辛烷基、2-氮杂二环[2.2.2]辛烷基、8-氮杂二环[2.2.2]辛烷基、7-氧杂二环[2.2.1]庚烷、氮杂螺[3.5]壬烷基、氮杂螺[2.5]辛烷基、氮杂螺[4.5]癸烷基、1-氮杂螺[4.5]癸-2-酮基、氮杂螺[5.5]十一烷基、四氢吲哚基、八氢吲哚基、四氢异吲哚基、四氢吲唑基、1,1-二氧代六氢噻喃基。含有硫或氧原子和一个至三个氮原子的5元杂环基的实例为噻唑基,包括噻唑-2-基和噻唑-2-基N-氧化物;噻二唑基,包括1,3,4-噻二唑-5-基和1,2,4-噻二唑-5-基;噁唑基,例如噁唑-2-基;和噁二唑基,例如1,3,4-噁二唑-5-基和1,2,4-噁二唑-5-基。含有2至4个氮原子的5元杂环基的实例包括咪唑基,例如咪唑-2-基;三唑基,例如1,3,4-三唑-5-基、1,2,3-三唑-5-基、1,2,4-三唑-5-基;和四唑基,例如1H-四唑-5-基。与苯稠合的5元杂环基的实例为苯并噁唑-2-基、苯并噻唑-2-基和苯并咪唑-2-基。示例性6元杂环基含有一个至三个氮原子和任选的硫或氧原子,例如吡啶基,例如吡啶-3-基和吡啶-4-基;嘧啶基,例如嘧啶-2-基和嘧啶-4-基;三嗪基,例如1,3,4-三嗪-2-基和1,3,5-三嗪-4-基;哒嗪基,具体为哒嗪-3-基;和吡嗪基。其它示例性杂环基为吡啶N-氧化物和哒嗪N-氧化物及吡啶基、嘧啶-2-基、嘧啶-4-基、哒嗪基和1,3,4-三嗪-2-基。
本文使用的术语“部分不饱和”是指以下环部分,其在环原子之间包含至少一个双键或叁键,但是所述环部分不是芳族的。
本文使用的术语“多环”是指具有两个或更多个(例如2、3、4或5个)环的环系,其可为稠合、桥接或螺接关系。
本文使用的术语“抑制剂”是指以可测量的亲和力和活性结合并抑制布罗莫结构域的化合物。在某些实施方案中,抑制剂具有小于约50μM、小于约1μM、小于约500nM、小于约100nM或小于约10nM的IC50或结合常数。
本文使用的术语“可测量的亲和力”和“可测量地抑制”是指布罗莫结构域的活性在以下(i)和(ii)之间的降低是可测量的:(i)包含式I化合物或其组合物和此布罗莫结构域的样品;和(ii)在不存在所述化合物或其组合物的情况下包含此布罗莫结构域的等效样品。
“药用盐”包括酸和碱加成盐。应理解的是,当将本文中的化合物或实施例显示为具体的盐时,涵盖相应的游离碱及相应游离碱的其它盐(包括相应游离碱的药用盐)。
“药用酸加成盐”是指以下那些与无机酸和有机酸形成的盐,其保留游离碱的生物学有效性和性质且在生物学上或在其它方面不是不期望的,所述无机酸为例如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等,所述有机酸可选自脂族、环脂族、芳族、芳脂族、杂环、羧酸和磺酸类有机酸,例如甲酸、乙酸、丙酸、乙醇酸、葡糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨苯甲酸、苯甲酸、肉桂酸、扁桃酸、扑酸、苯乙酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、水杨酸等。
“药用碱加成盐”包括那些衍生自无机碱的盐,例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。具体的碱加成盐为铵、钾、钠、钙和镁盐。衍生自药用有机无毒碱的盐包括以下物质的盐:伯胺、仲胺和叔胺、经取代的胺(包括天然存在的经取代的胺)、环状胺和碱性离子交换树脂,例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基氨基乙醇、氨丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。具体的有机无毒碱为异丙胺、二乙胺、乙醇胺、氨丁三醇、二环己胺、胆碱和咖啡因。
术语“互变异构体”或“互变异构形式”是指具有不同能量的结构异构体,其可经由低的能垒相互转化。例如,质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移相互转化,例如酮-烯醇和亚胺-烯胺异构化。价态互变异构体包括通过重组一些成键电子相互转化。
“溶剂化物”是指一个或多个溶剂分子与本发明化合物的缔合物或络合物。溶剂的实例包括水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指其中溶剂分子为水的络合物。
“治疗有效量”是指本发明化合物的以下量,其(i)治疗特定疾病、病状或病症,(ii)减轻、改善或消除特定疾病、病状或病症的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、病状或病症的一种或多种症状的发作。对应癌症,药物的治疗有效量可减小癌细胞数目;减小肿瘤尺寸;抑制(即在一定程度上减慢且优选停止)癌细胞浸润到周围器官中;抑制(即在一定程度上减慢且优选停止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解一种或多种与癌症相关的症状。对于癌症疗法,效力可例如通过评估疾病进展时间(TTP)和/或确定响应率(RR)来测量。对于免疫病症,治疗有效量为以下量,其足以减轻或改善变应性病症、自身免疫性和/或炎性疾病的症状或急性炎性反应(例如哮喘)的症状。在一些实施方案中,治疗有效量为本文所述的化学实体的以下量,其足以显著降低耐药性或耐药持续性癌细胞的活性或数目。
“治疗”是指试图改变所治疗的个体或细胞的自然过程且可用于预防或在临床病理过程中实施的临床干预。治疗的期望效果包括以下一种或多种:预防疾病发生或复发,改善症状,减轻疾病的任何直接或间接病理后果,使疾病状态得以稳定(即不恶化),防止转移,降低疾病进展速度,改善或缓解疾病状态,使生存期与在不接受治疗和缓解或改善预后的情况下所预期的生存期相比得以延长。在某些实施方案中,式I化合物用于延迟疾病或病症发展或减缓疾病或病症进展。那些需要治疗的个体包括那些已经患有所述病状或病症的个体及那些易患所述病状或病症的个体(例如由于遗传突变或基因或蛋白质的异常表达)或那些其中所述病状或病症有待预防的个体。
除非另有明确说明,本文使用的“一个/种”意指一个/种或多个/种。本文使用的“另一个/种”意指至少另一个/种或更多个/种。
示例性值
一个实施方案提供式(I)化合物或其盐,其中
R1为H、甲基或乙基;
R2为H、C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基,其中R2中的每个C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基任选取代有一个或多个基团Rb;且
Q为5元杂芳基,其任选取代有一个或多个基团Rc,或Q为:
其中环A任选取代有一个或多个基团Rc,或环A任选与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg;
X1、X2和X3各自独立选自CRc和N,条件是X1、X2和X3中的至少一个不为N;且当环A任选与碳环基或杂环基稠合以形成多环基时,X1、X2和X3中的每个可为C且可为稠合点;
每个Rb独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-O-C(O)-O-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-O-C(O)-N(Rw)2、-N(Rw)-C(O)-ORw、-N(Rw)-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw、-N(Rw)-S(O)-N(Rw)2和-N(Rw)-S(O)2-N(Rw)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;
每个Rc独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有一个或多个C1-6烷基;
Re为氢、-F、-Cl、-Br、-I、-CN、-O-Rx、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Rx)2、-CN、-C(O)-N(Rx)2、-S(O)-N(Rx)2、-S(O)2-N(Rx)2、-O-Rx、-S-Rx、-O-C(O)-Rx、-O-C(O)-O-Rx、-C(O)-Rx、-C(O)-O-Rx、-S(O)-Rx、-S(O)2-Rx、-O-C(O)-N(Rx)2、-N(Rx)-C(O)-ORx、-N(Rx)-C(O)-N(Rx)2-N(Rx)-C(O)-Rx、-N(Rx)-S(O)-Rx、-N(Rx)-S(O)2-Rx、-N(Rx)-S(O)-N(Rx)2和-N(Rx)-S(O)2-N(Rx)2;
Rf为氢、-F、-Cl、-Br、-I、-CN、-O-Ry、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2和-N(Ry)-S(O)2-N(Ry)2;
每个Rg独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-O-C(O)-O-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-O-C(O)-N(Rz)2、-N(Rz)-C(O)-ORz、-N(Rz)-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、-N(Rz)-S(O)-N(Rz)2和-N(Rz)-S(O)2-N(Rz)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基;
每个Rv独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rva)2、羟基、氰基、C1-C6烷氧基、碳环基、杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rv与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代、-N(Rva)2和卤素的基团的C1-3烷基;
每个Rw独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rwa)2、羟基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rw与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rx独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Ry独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Rz独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氰基、-N(Rza)2、C1-C6烷氧基、碳环基、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rz与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rva独立为氢或C1-6烷基,或两个Rva与和它们所连接的氮一起形成杂环基;
每个Rwa独立为氢或C1-6烷基,或两个Rwa与和它们所连接的氮一起形成杂环基;且
每个Rza独立为氢或C1-6烷基,或两个Rza与和它们所连接的氮一起形成杂环基。
一个实施方案提供式(I)化合物或其盐,其中
R1为H、甲基或乙基;
R2为H、C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基,其中R2中的每个C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基任选取代有一个或多个基团Rb;且
Q为5元杂芳基,其任选取代有一个或多个基团Rc,或Q为:
其中环A任选取代有一个或多个基团Rc,或环A任选与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg;
X1、X2和X3各自独立选自CRc和N,条件是X1、X2和X3中的至少一个不为N;且当环A任选与碳环基或杂环基稠合以形成多环基时,X1、X2和X3中的每个可为C且可为稠合点;
每个Rb独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-O-C(O)-O-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-O-C(O)-N(Rw)2、-N(Rw)-C(O)-ORw、-N(Rw)-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw、-N(Rw)-S(O)-N(Rw)2和-N(Rw)-S(O)2-N(Rw)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;
每个Rc独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;
Re为氢、-F、-Cl、-Br、-I、-CN、-O-Rx、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Rx)2、-CN、-C(O)-N(Rx)2、-S(O)-N(Rx)2、-S(O)2-N(Rx)2、-O-Rx、-S-Rx、-O-C(O)-Rx、-O-C(O)-O-Rx、-C(O)-Rx、-C(O)-O-Rx、-S(O)-Rx、-S(O)2-Rx、-O-C(O)-N(Rx)2、-N(Rx)-C(O)-ORx、-N(Rx)-C(O)-N(Rx)2-N(Rx)-C(O)-Rx、-N(Rx)-S(O)-Rx、-N(Rx)-S(O)2-Rx、-N(Rx)-S(O)-N(Rx)2和-N(Rx)-S(O)2-N(Rx)2;
Rf为氢、-F、-Cl、-Br、-I、-CN、-O-Ry、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2和-N(Ry)-S(O)2-N(Ry)2;
每个Rg独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-O-C(O)-O-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-O-C(O)-N(Rz)2、-N(Rz)-C(O)-ORz、-N(Rz)-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、-N(Rz)-S(O)-N(Rz)2和-N(Rz)-S(O)2-N(Rz)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基;
每个Rv独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rva)2、羟基、碳环基、杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rv与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rw独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rwa)2、羟基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rw与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rx独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Ry独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Rz独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氰基、-N(Rza)2、C1-C6烷氧基、碳环基、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rz与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rva独立为氢或C1-6烷基,或两个Rva与和它们所连接的氮一起形成杂环基;
每个Rwa独立为氢或C1-6烷基,或两个Rwa与和它们所连接的氮一起形成杂环基;且
每个Rza独立为氢或C1-6烷基,或两个Rza与和它们所连接的氮一起形成杂环基。
对于上述针对式(I)的实施方案,提供以下示例性值。应理解的是,可将本文提供的两个或更多个实施方案组合起来。
在某些实施方案中,R1为H。
在某些实施方案中,R1为甲基。
在某些实施方案中,R1为乙基。
在某些实施方案中,R2为H。
在某些实施方案中,R2为甲基。
在某些实施方案中,Q为5元杂芳基,其任选取代有一个或多个基团Rc。
在某些实施方案中,Q为苯基,其任选取代有一个或多个基团Rc。
在某些实施方案中,Q为苯基,其在所述苯基的3、4、5或6位任选取代有一个或多个基团Rc。
在某些实施方案中,Q为苯基,其在所述苯基的3、4或5位任选取代有一个或多个基团Rc。
在某些实施方案中,Q为呋喃基、噻吩基、吡咯基、咪唑基、噻唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基,其任选取代有一个或多个基团Rc。
在某些实施方案中,Q为:
其中环A任选取代有一个或多个基团Rc。
在某些实施方案中,Q为:
其中环A取代有一个或多个独立选自以下的基团Rc:C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基。
在某些实施方案中,Q为:
其中环A与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
在某些实施方案中,Q为:
其中环A任选取代有一个或多个基团Rc,或环A任选与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
在某些实施方案中,X1为CRc,X2为CRc且X3为CRc。
在某些实施方案中,X1为N,X2为CRc且X3为CRc。
在某些实施方案中,X1为CRc,X2为N且X3为CRc。
在某些实施方案中,X1为N,X2为N且X3为CRc。
在某些实施方案中,X1为N,X2为CRc且X3为N。
在某些实施方案中,Re为氢。
在某些实施方案中,Re和Rf各自为氢。
在某些实施方案中,环A与碳环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
在某些实施方案中,环A与杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
在某些实施方案中,每个Rc独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基。
在某些实施方案中,每个Rc独立选自氢、C1-6烷基、杂环基、-F、-Cl、-N(Rv)2、-CN、-C(O)-N(Rv)2、-O-Rv、-C(O)-O-Rv、-N(Rv)-C(O)-ORv和-N(Rv)-C(O)-Rv,其中任何C1-6烷基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有C1-6烷基。
在某些实施方案中,每个Rc独立选自氢、C1-6烷基、杂环基、-CN、-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv和-N(Rv)-C(O)-Rv,其中任何C1-6烷基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有C1-6烷基。
在某些实施方案中,每个Rc独立选自氢、C1-6烷基、杂环基、-CN、-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv和-N(Rv)-C(O)-Rv,其中任何C1-6烷基或杂环基任选取代有一个或多个独立选自以下的基团:-O-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有C1-6烷基。
在某些实施方案中,每个Rg独立选自氧代、C1-6烷基、碳环基、杂环基、-F、-Cl、-N(Rz)2、-CN、-C(O)-N(Rz)2、-O-Rz、-C(O)-Rz、-C(O)-O-Rz、-N(Rz)-C(O)-ORz和-N(Rz)-C(O)-,其中任何C1-6烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基。
在某些实施方案中,每个Rg独立选自氧代、C1-6烷基、碳环基、杂环基和-C(O)-O-Rz,其中任何C1-6烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基。
在某些实施方案中,每个Rg独立选自氧代、C1-6烷基、碳环基、杂环基和-C(O)-O-Rz,其中任何C1-6烷基、碳环基或杂环基任选取代有一个或多个-O-Rz基团。
在某些实施方案中,Q选自苯基、2-氧代吲哚啉-5-基、1-叔丁氧基羰基-3,4-二氢-2H-喹啉-6-基、2,3,3a,5-四氢吡咯并[1,2-a]喹喔啉-1,4-二酮-8-基、3-甲基-3,4-二氢-1H-喹喔啉-2-酮-6-基、1,3,4,5-四氢-4-甲基-1,5-苯并二氮杂-2-酮-7-基、5,7,7a,8,9,10-六氢吡咯并[2,1-d][1,5]苯并二氮杂-6-酮-2-基、4-(2-噻吩基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮-7-基、3-氨基羰基苯基、3-氰基苯基、4-羟基甲基苯基、4-(3-氟氮杂环丁烷-1-基羰基)苯基、4-(1-吡咯烷基羰基)苯基、4-(4-甲基哌啶-1-基羰基)苯基、4-(4-乙酰基哌嗪-1-基羰基)苯基、4-(4-(氨基羰基)哌啶-1-基羰基)苯基、4-(N-(吡啶-3-基)氨基羰基)苯基、4-(2-苯基丙酰基)苯基、4-(N-甲基-N-(氰基甲基)氨基羰基)苯基、4-(N-(2-甲氧基乙基)氨基羰基)苯基、1-叔丁氧基羰基-3,4-二氢-2H-喹啉-7-基、4-(叔丁氧基羰基氨基)苯基、1,3,4,5-四氢-1,5-苯并二氮杂-2-酮-7-基、3-(N,N-二甲基氨基羰基)苯基、4-(1-羟基-1-甲基乙基)苯基、4-(1-甲基哌啶-4-基)苯基、4-(1-甲基哌啶-4-基甲基)苯基、4-(N-(2-甲氧基乙基羰基)氨基)苯基、2-甲基-4H-1,4-苯并噁嗪-3-酮-7-基、4-(N,N-二甲基氨基羰基)苯基、4-(4-甲基-3-氧代-哌嗪-1-基羰基)苯基、4-(3,3-二氟氮杂环丁烷-1-基羰基)苯基、4-(N-苯基氨基羰基)苯基、2-甲基-3,4-二氢-1H-异喹啉-6-基、3-(N-甲基氨基羰基)苯基、4-(吗啉代羰基)苯基、3-(N-苄基氨基羰基)苯基、3-(1-甲基哌啶-4-基)苯基、3-(1-甲基哌啶-4-基甲基)苯基和3-(2-羟基乙基)-3-苯基茚满-5-基。
在某些实施方案中,所述化合物选自:
6-甲基-4-苯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6-甲基-4-(2-氧代吲哚啉-5-基)-1H-吡咯并[2,3-c]吡啶-7-酮;
N-(2-甲氧基乙基)-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
6-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-3,4-二氢-2H-喹啉-1-甲酸叔丁酯;
7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-3,4-二氢-2H-喹啉-1-甲酸叔丁酯;
N-[4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯基]氨基甲酸叔丁酯;
3-甲氧基-N-[4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯基]丙酰胺;
4-(3-(2-羟基乙基)-3-苯基-2,3-二氢-1H-茚-5-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
8-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3,3a-二氢吡咯并[1,2-a]喹喔啉-1,4(2H,5H)-二酮;
3-甲基-6-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-3,4-二氢-1H-喹喔啉-2-酮;
3-甲基-7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
4-甲基-7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
3-异丙基-6-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1H-喹喔啉-2-酮;
2-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-5,7,7a,8,9,10-六氢吡咯并[2,1-d][1,5]苯并二氮杂-6-酮;
2-甲基-7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-4H-1,4-苯并噁嗪-3-酮;
7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-4-(2-噻吩基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
N,N-二甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
N,N-二甲基-3-(7-氧代-6-丙基-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
3-(6-乙基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N,N-二甲基-苯甲酰胺;
3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
N,N-二甲基-3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲腈;
N-甲基-3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
4-[4-(羟基甲基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-(4-(4-甲基-3-氧代哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-[4-(3-氟氮杂环丁烷-1-羰基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
4-[4-(3,3-二氟氮杂环丁烷-1-羰基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-(吡咯烷-1-羰基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-(吗啉-4-羰基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-(4-甲基哌啶-1-羰基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
4-[4-(4-乙酰基哌嗪-1-羰基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮,
1-[4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰基]哌啶-4-甲酰胺;
4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N-(3-吡啶基)苯甲酰胺;
4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N-苯基-苯甲酰胺;
N-甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N-苯基-苯甲酰胺;
N-苄基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
N-(氰基甲基)-N-甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
4-[4-(1-羟基-1-甲基-乙基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
4-[4-(1-羟基-1-甲基-乙基)苯基]-6-异丙基-1H-吡咯并[2,3-c]吡啶-7-酮;
6-环丙基-4-(4-(2-羟基丙-2-基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6-甲基-4-[4-(1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[3-(1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-(2-甲基-3,4-二氢-1H-异喹啉-6-基)-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-[(1-甲基-4-哌啶基)甲基]苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[3-[(1-甲基-4-哌啶基)甲基]苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;和
3-(2,6-二甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N,N-二甲基-苯甲酰胺;
及其盐。
在某些实施方案中,所述化合物选自:
N,N-二甲基-3-(7-氧代-6-丙基-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
4-[4-(1-羟基-1-甲基-乙基)苯基]-6-异丙基-1H-吡咯并[2,3-c]吡啶-7-酮;和
6-环丙基-4-(4-(2-羟基丙-2-基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
及其盐。
在某些实施方案中,所述化合物选自:
及其盐。
在针对式(I)化合物的某些实施方案中:
当R1为甲基且R2为乙氧基羰基时,A不为2-氟-5-(乙基磺酰基)苯基;
当R1为甲基且R2为氢时,A不为2-(2,2-二甲基丙-1-基氧基)-5-氨基苯基;
当R1为甲基且R2为氢时,A不为2-(2,2-二甲基丙-1-基氧基)-5-硝基苯基;
当R1为甲基且R2为氢时,A不为3-(乙基磺酰基)-6-氟苯基;
当R1为甲基且R2为氢时,A不为2-乙氧基-5-(甲基磺酰基)苯基;
当R1为甲基且R2为氢时,A不为4-溴-2-甲氧基苯基;
当R1为甲基且R2为氢时,A不为2-(2-叔丁氧基-1-甲基乙氧基-)-5-甲基磺酰基苯基;
当R1为甲基且R2为氢时,A不为2-异丁氧基-5-甲基磺酰基苯基;且
当R1为甲基且R2为氢时,A不为2-(2-甲基丙氧基)-5-乙基磺酰基氨基苯基。
在针对式(I)化合物的某些实施方案中:
当R1为甲基且R2为氢时,A不为2-异丙氧基-5-甲基磺酰基苯基。
在一些实施方案中,式(I)化合物不包括WO2013/097052的任何化合物。在一些实施方案中,式(I)化合物不包括WO2013/097601的任何化合物。
在某些实施方案中,本发明提供如实施例48和50所述的化合物1000及其盐。本发明还提供通过如实施例50所述那样监测化合物1000与TAF1-BD2靶标的结合来评价化合物抑制TAF1-BD2的能力的方法。
在某些实施方案中,本发明提供如实施例49和50所述的化合物1001及其盐。本发明还提供通过如实施例50所述那样监测化合物1001与CECR2靶标的结合来评价化合物抑制CECR2的能力的方法。
一个实施方案提供组合物,其包含本文公开的化合物或其药用盐和药用辅料、载体或媒介物。
一个实施方案提供治疗动物中由布罗莫结构域介导的病症的方法,其包括向所述动物施用本文公开的化合物或其药用盐。
一个实施方案提供本文公开的化合物或其药用盐,其用于医学疗法。
一个实施方案提供本文公开的化合物或其药用盐,其用于预防性或治疗性处置由布罗莫结构域介导的病症。
一个实施方案提供本文公开的化合物或其药用盐在制备用于治疗动物(例如哺乳动物例如人类)中由布罗莫结构域介导的病症的药物中的用途。
一个实施方案提供可用于制备本文公开的化合物或其盐的本文公开的合成中间体和合成方法。
用途、制剂和施用
药用组合物
另一个方面包括药物组合物,其包含式(I)化合物或其药用盐或本文公开的化合物或其药用盐。在一个实施方案中,所述组合物还包含药用载体、辅料或媒介物。在另一个实施方案中,所述组合物还包含以下量的所述化合物,其可有效地对布罗莫结构域产生可测量的抑制。在某些实施方案中,将所述组合物配制成用于施用至有此需要的患者。
本文使用的术语“患者”或“个体”是指动物,例如哺乳动物,例如人类。在一个实施方案中,患者或个人是指人类。
术语“药用载体、辅料或媒介物”是指不破坏所配制的化合物的药理学活性的无毒载体、辅料或媒介物。可用于本发明组合物的药用载体、辅料或媒介物包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白例如人血清白蛋白、缓冲物质例如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁,聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
包含式I化合物或其盐的组合物可口服、胃肠外、通过吸入喷雾、局部、经皮、经直肠、经鼻、含服、舌下、经阴道、腹膜内、肺内、皮内、硬膜外或经由植入储库施用。本文使用的术语“胃肠外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。
在一个实施方案中,将包含式I化合物或其盐或本文公开的化合物或其药用盐的组合物配制成用于口服施用的固体剂型。用于口服施用的固体剂型包括胶囊剂、片剂、丸剂、粉剂和颗粒剂。在某些实施方案中,包含式(I)化合物或其盐或本文公开的化合物或其药用盐的固体口服剂型还包含以下一种或多种:(i)惰性药用赋形剂或载体,例如柠檬酸钠或磷酸二钙;(ii)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇或硅酸;(iii)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖或阿拉伯胶;(iv)保湿剂,例如甘油;(v)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐或碳酸钠;(vi)溶出阻断剂,例如石蜡;(vii)吸收促进剂,例如季铵盐;(viii)润湿剂,例如鲸蜡醇或单硬脂酸甘油酯;(ix)吸附剂,例如高岭土或膨润土;和(x)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、聚乙二醇或月桂基硫酸钠。在某些实施方案中,将固体口服剂型配制成胶囊剂、片剂或丸剂。在某些实施方案中,固体口服剂型还包含缓冲剂。在某些实施方案中,可将用于固体口服剂型的此类组合物配制成在软和硬填充明胶胶囊中的包含一种或多种赋形剂例如乳糖、聚乙二醇等的填充物。
在某些实施方案中,包含式I化合物或其盐或本文公开的化合物或其药用盐的组合物的片剂、锭剂、胶囊剂、丸剂和颗粒剂任选包含包衣或外壳,例如肠溶衣。其可任选包含遮光剂且还可具有使其仅或优先在肠道的某一部分中任选以延迟方式释放活性成分的组分。包埋组分的实例包括聚合物和蜡,其也可用作在软和硬填充明胶胶囊中的包含赋形剂例如乳糖及高分子量聚乙二醇等的填充物。
在另一个实施方案中,组合物包含经微胶囊化的式(I)化合物或其盐或本文公开的化合物或其盐且任选还包含一种或多种赋形剂。
在另一个实施方案中,组合物包括含有式I化合物或其盐的用于口服施用的液体制剂且任选还包括一种或多种药用乳剂、微乳剂、溶液剂、混悬液、糖浆剂和酏剂。在某些实施方案中,液体剂型任选还包含一种或多种惰性稀释剂,例如水或其它溶剂;增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体为棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇或脱水山梨醇的脂肪酸酯及其混合物。在某些实施方案中,液体口服组合物任选还包含一种或多种辅料,例如润湿剂、助悬剂、甜味剂、矫味剂和芳香剂。
注射用制剂例如无菌注射用水性或油性混悬剂可根据已知技术使用合适的分散剂或润湿剂和助悬剂配制。无菌注射用制剂还可为在无毒的胃肠外可接受的稀释剂或溶剂中的无菌注射用溶液剂、混悬剂或乳剂,例如在1,3-丁二醇中的溶液剂。可使用的可接受的媒介物和溶剂为水、林格溶液、U.S.P.和等渗氯化钠溶液。另外,无菌不挥发性油通常用作溶剂或混悬介质。出于该目的,可使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。另外,脂肪酸例如油酸可用于制备注射剂。
注射用制剂可例如如下灭菌:过滤通过使细菌得以截留的过滤器或加入灭菌剂呈无菌固体组合物形式,其可在使用前溶解或分散在无菌水或其它无菌注射用介质中。
为了延长式(I)化合物或本文公开的化合物的作用,通常需要减缓化合物在皮下或肌内注射后的吸收。这可通过使用具有差的水溶性的结晶性或无定形材料的液体混悬剂来实现。然后化合物的吸收速率取决于其溶出速率,而所述溶出速率可取决于晶体尺寸和结晶形式。可选择地,胃肠外施用的化合物形式的延迟吸收通过将化合物溶解或混悬于油媒介物中来实现。注射用贮库形式通过在可生物降解的聚合物例如聚丙交酯-聚乙交酯中形成化合物的微胶囊基质来制备。取决于化合物与聚合物的比例和所使用的具体聚合物的性质,可控制化合物的释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。贮库型注射用制剂还通过将化合物包埋在与身体组织相容的脂质体或微乳液中来制备。
在某些实施方案中,将用于直肠或阴道施用的组合物配制成栓剂,其可如下制备:使式(I)化合物或其盐或本文公开的化合物或其盐与合适的无刺激性的赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡例如那些在环境温度为固体但在体温为液体并因此在直肠或阴道腔中融化并释放式(I)化合物或本文公开的化合物的赋形剂或载体混合。
用于局部或透皮施用式(I)化合物或本文公开的化合物的示例性剂型包括软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、粉剂、溶液剂、喷雾剂、吸入剂或贴剂。使式(I)化合物或其盐或本文公开的化合物或其盐在无菌条件下与药用载体及任选的防腐剂或缓冲剂混合。额外的制剂实例包括眼用制剂、滴耳剂、滴眼剂、透皮贴剂。透皮剂型可如下制备:将式(I)化合物或其盐溶解或分配于介质中,例如乙醇或二甲基亚砜。吸收增强剂也可用于增加化合物透过皮肤的通量。速率可通过提供速率控制膜或将化合物分散于聚合物基质或凝胶中来控制。
可将式(I)化合物或其盐或本文公开的化合物或其盐的鼻气雾剂或吸入剂制备成在盐水中的溶液,其中使用苄醇或其它合适的防腐剂、用于提高生物利用度的吸收促进剂、碳氟化合物和/或其它常规增溶剂或分散剂。
在某些实施方案中,药物组合物可与或不与食物一起施用。在某些实施方案中,药用组合物不与食物一起施用。在某些实施方案中,本发明的药用组合物与食物一起施用。
针对任何特定患者的具体剂量和治疗方案将取决于多种因素,包括年龄、体重、一般健康状况、性别、饮食、给药时间、排泄速率、药物联用、治疗医师的判断和所治疗的具体疾病的严重程度。所提供的式I化合物或其盐在组合物中的量还将取决于组合物中的具体化合物。
在一个实施方案中,每剂胃肠外施用的本发明化合物的治疗有效量将在每天约0.01-100mg/kg患者体重或每天约0.1-20mg/kg患者体重的范围内,其中所用化合物的典型初始范围为0.3至15mg/kg/天。在另一个实施方案中,口服单位剂型例如片剂和胶囊剂含有约5至约100mg本发明化合物。
示例性片剂口服剂型包含约2mg、5mg、25mg、50mg、100mg、250mg或500mg式(I)化合物或其盐且还包含约5-30mg无水乳糖,约5-40mg交联羧甲基纤维素钠、约5-30mg聚乙烯吡咯烷酮(PVP)K30和约1-10mg硬脂酸镁。配制片剂的方法包括将粉末状成分混合在一起并进一步与PVP溶液混合。可将所得组合物干燥,制粒,与硬脂酸镁混合并使用常规设备压制成片剂形式。气雾剂的实例可如下制备:将约2-500mg式I化合物或其盐溶解于合适的缓冲溶液例如磷酸盐缓冲液中且按需添加张力剂例如盐例如氯化钠。可例如使用0.2微米过滤器对溶液进行过滤以去除杂质和污染物。
化合物和药用组合物的用途
另一个方面包括式(I)化合物或其盐或本文公开的化合物或其盐用于(体外或体内)抑制布罗莫结构域的用途。
另一个实施方案包括治疗动物中由布罗莫结构域介导的病症的方法,其包括向所述动物施用式(I)化合物或其药用盐或本文公开的化合物或其药用盐。由布罗莫结构域介导的病症包括但不限于本文所述的那些病症。
另一个实施方案包括在动物中提高包含细胞毒剂的癌症治疗的效力的方法,其包括向所述动物施用有效量的式(I)化合物或其药用盐或本文公开的化合物或其药用盐。
另一个实施方案包括在动物中延迟或预防发展对细胞毒剂的癌症抗性的方法,其包括向所述动物施用式(I)化合物或其药用盐或本文公开的化合物或其药用盐。
另一个实施方案包括在动物中延长对癌症疗法的响应的持续时间的方法,其包括向接受癌症疗法的动物施用式(I)化合物或其药用盐或本文公开的化合物或其药用盐,其中当施用式(I)化合物或其药用盐或本文公开的化合物或其药用盐时对癌症疗法的响应的持续时间延长超过在不施用式(I)化合物或其药用盐或本文公开的化合物或其药用盐的情况下对癌症疗法的响应的持续时间。
另一个实施方案包括在个体中治疗癌症的方法,其包括向所述个体施用(a)式(I)化合物或其药用盐或本文公开的化合物或其药用盐和(b)细胞毒剂。在一个实施方案中,所述细胞毒剂选自抗微管剂、铂配位络合物、烷化剂、抗生素、拓扑异构酶II抑制剂、抗代谢剂、拓扑异构酶I抑制剂、激素和激素类似物、信号转导途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂、脂肪酸生物合成抑制剂、细胞周期信号传导抑制剂、HDAC抑制剂、蛋白酶体抑制剂和癌症代谢抑制剂。在一个实施方案中,所述细胞毒剂为紫杉烷类。在一个实施方案中,所述紫杉烷类为紫杉醇或多西紫杉醇。在一个实施方案中,所述细胞毒剂为铂剂。在一个实施方案中,所述细胞毒剂为EGFR拮抗剂。在一个实施方案中,所述EGFR拮抗剂为N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺或其药用盐(例如厄洛替尼)。在一个实施方案中,所述细胞毒剂为RAF抑制剂。在一个实施方案中,所述RAF抑制剂为BRAF或CRAF抑制剂。在一个实施方案中,所述RAF抑制剂为威罗菲尼。在一个实施方案中,所述细胞毒剂为PI3K抑制剂。
在某些实施方案中,治疗可在一个或多个症状已经发展后施用。在其它实施方案中,治疗可在没有症状的情况下施用。例如,治疗可在症状发作前向易感个体施用(例如鉴于症状历史和/或遗传或其它易感因素)。治疗也可在症状已经解决后继续以例如预防或延迟其复发。
由布罗莫结构域介导的病症
“由布罗莫结构域介导的病症”的特征在于一种或多种布罗莫结构域(例如BRD4)参与病症的起始、一种或多种症状或疾病标志物的出现、严重程度或进展。布罗莫结构域包括但不限于ASH1L、ATAD2、ATAD2B、BAZ1A、BAZ1B、BAZ2A、BAZ2B、BPTF、BRD1、BRD2、BRD3、BRD4、BRD7、BRD8、BRD9、BRDT、BRPF1、BRPF3、BRWD1、BRWD3、CECR2、CREBBP(aka、CBP)、EP300、GCN5L2、KIAA2026、MLL、MLL4、PBRM、PCAF、PHIP、SMARCA2、SMARCA4、SP100、SP110、SP140、SP140L、TAF1、TAF1L、TRIM24、TRIM28、TRIM33、TRIM66、ZMYND8和ZMYND11。
由布罗莫结构域介导的病症包括癌症,包括但不限于听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病(单核细胞性、成髓细胞性、腺癌、血管肉瘤、星形细胞瘤、骨髓单核细胞性和早幼粒细胞性)、急性T细胞性白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、子宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性(粒细胞性)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥散性大B细胞淋巴瘤、异常增殖性变化(发育异常和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因肿瘤、纤维肉瘤、滤泡淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、胶质肉瘤、重链疾病、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、淋巴管内皮肉瘤、淋巴管肉瘤、成淋巴细胞性白血病、淋巴瘤(霍奇金和非霍奇金)、膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增殖性病症、T细胞或B细胞源性淋巴恶性肿瘤、髓质癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、成骨肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体肿瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和威尔姆斯肿瘤。
在某些实施方案中,所述癌症为肺癌、乳腺癌、胰腺癌、结直肠癌和/或黑素瘤。在某些实施方案中,所述癌症为肺癌。在某些实施方案中,所述肺癌为NSCLC。在某些实施方案中,所述癌症为乳腺癌。在某些实施方案中,所述癌症为黑素瘤。
由布罗莫结构域介导的病症还包括炎性疾病、炎性病状和自身免疫性疾病,包括但不限于艾迪生病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、贝切特病、大疱性皮肤病、慢性阻塞性肺病(COPD)、克罗恩病、皮炎、湿疹、巨细胞性动脉炎、肾小球性肾炎、肝炎、垂体炎、炎性肠病、川崎病、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆汁性肝硬化、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、系统性红斑狼疮、多发性大动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、血管炎和韦格纳肉芽肿。
由布罗莫结构域介导的病症还包括AIDS;慢性肾脏疾病,包括但不限于糖尿病性肾病、高血压性肾病、HIV相关肾病、肾小球性肾炎、狼疮肾炎、IgA肾病、病灶性节段性肾小球硬化、膜性肾小球性肾炎、微小变化疾病、多囊肾病和肾小管间质性肾炎;急性肾脏损伤或疾病或病状,包括但不限于由缺血-再灌注诱导的、由心脏大手术诱导的、由经皮冠状动脉介入术诱导的、由放射性对比剂诱导的、由败血症诱导的、由肺炎诱导的和由药物毒性诱导的急性肾脏损伤或疾病或病状;肥胖症;血脂异常;高胆固醇血症;阿尔茨海默病;代谢综合征;肝脂肪变性;II型糖尿病;胰岛素抵抗;和糖尿病性视网膜病变。
布罗莫结构域抑制剂还可用于提供男性节育。
化合物和其它药剂的共同施用
式(I)化合物或其盐或本文公开的化合物或其药用盐可单独使用或与其它药物组合使用。例如,药物组合制剂或给药方案的第二药剂可具有与式(I)化合物互补的活性,使得它们不会不利地相互影响。化合物可以一体药物组合物一起给药或分开给药。在一个实施方案中,化合物或药用盐可与细胞毒剂共同施用以治疗增殖性疾病和癌症。
术语“共同施用”是指同时施用或任何方式的分开依序施用式(I)化合物或其盐或本文公开的化合物或其药用盐及额外的一种或多种活性药物成分,包括细胞毒剂和放射治疗。若不是同时施用,则化合物在彼此接近的时间内施用。另外,化合物是否以相同的剂型施用并不重要,例如,一种化合物可局部施用,另一种化合物可口服施用。
通常,可共同施用具有针对所治疗的疾病或病状的活性的任何药剂。此类药剂的实例可在Cancer Principles and Practice of Oncology by V.T.Devita andS.Hellman(editors),6th edition(February 15,2001),Lippincott Williams&WilkinsPublishers中找到。本领域普通技术人员将能够基于所涉及的药物和疾病的具体特征来辨别哪些药剂组合将是有用的。
在一个实施方案中,所述治疗方法包括共同施用式(I)化合物或其药用盐和至少一种细胞毒剂。本文使用的术语“细胞毒剂”是指抑制或防止细胞功能和/或引起细胞死亡或破坏的物质。细胞毒剂包括但不限于放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素);化学治疗剂;生长抑制剂;酶及其片段例如核分解酶;和毒素,例如细菌、真菌、植物或动物来源的小分子毒素或酶活性毒素,包括其片段和/或变体。
示例性细胞毒剂可选自抗微管剂、铂配位络合物、烷化剂、抗生素、拓扑异构酶II抑制剂、抗代谢剂、拓扑异构酶I抑制剂、激素和激素类似物、信号转导途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂;脂肪酸生物合成抑制剂;细胞周期信号传导抑制剂;HDAC抑制剂、蛋白酶体抑制剂;和癌症代谢抑制剂。
“化学治疗剂”包括可用于治疗癌症的化合物。化学治疗剂的实例包括厄洛替尼(erlotinib)(Genentech/OSI Pharm.)、硼替佐米(bortezomib)(Millennium Pharm.)、双硫仑(disulfiram)、表没食子儿茶素没食子酸酯(epigallocatechin gallate)、salinosporamide A、卡非佐米(carfilzomib)、17-AAG(格尔德霉素(geldanamycin))、根赤壳菌素(radicicol)、乳酸脱氢酶A(LDH-A)、氟维司群(fulvestrant)(AstraZeneca)、舒尼替尼(sunitib)(Pfizer/Sugen)、来曲唑(letrozole)(Novartis)、甲磺酸伊马替尼(imatinibmesylate)(Novartis)、finasunate(Novartis)、奥沙利铂(oxaliplatin)(Sanofi)、5-FU(5-氟尿嘧啶)、甲酰四氢叶酸(leucovorin)、雷帕霉素(Rapamycin)(Sirolimus,Wyeth)、拉帕替尼(lapatinib)(GSK572016,Glaxo Smith Kline)、Lonafamib(SCH 66336)、索拉非尼(sorafenib)(Bayer Labs)、吉非替尼(gefitinib)(AstraZeneca)、AG1478、烷化剂例如塞替派(thiotepa)和环磷酰胺;烷基磺酸酯类例如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridine)例如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(trietylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylomelamine);番荔枝内酯类(acetogenins)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(camptothecin)(包括托泊替康(topotecan)和伊立替康(irinotecan));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)合成类似物);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);肾上腺皮质类固醇(包括泼尼松(prednisone)和泼尼松龙(prednisolone));乙酸环丙氯地孕酮(cyproteroneacetate);5α-还原酶,包括非那雄胺(finasteride)和度他雄胺(dutasteride);伏立诺他(vorinostat)、罗米地辛(romidepsin)、帕比司他(panobinostat)、丙戊酸(valproicacid)、mocetinostat、多拉司他丁(dolastatin);阿地白介素(aldesleukin)、滑石(talc)、倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);软珊瑚醇(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥类(nitrogenmustards),例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、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(melphalan)、新氮芥(novembichin)、苯芥胆固醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝基脲类(nitrosureas),例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素类,例如烯二炔类(enediyne)抗生素(例如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ω1I(Angew、Chem.Intl.Ed.Engl.1994 33:183-186);达内霉素(dynemicin),包括达内霉素A;二膦酸盐类(bisphosphonates),例如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);及新制癌菌素(neocarzinostatin)生色团和相关色蛋白烯二炔类抗生素生色团)、阿克拉霉素类(aclacinomysins)、放线菌素(actinomycin)、氨茴霉素(authramycin)、重氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycin)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、(多柔比星(doxorubicin))、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、依达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)例如丝裂霉素C、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(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);抗代谢剂类,例如甲氨喋呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸(denopterin)、甲氨喋呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤;嘧啶类似物,例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,例如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺类,例如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,例如亚叶酸;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);氨苯吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);defofamine;地美可辛(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elfomithine,eflornithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);氯尼达明(lonidamine);美登木素生物碱类(maytansinoids),例如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);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-乙基酰肼;丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,Oreg.);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺;单端孢菌烯类(trichothecenes)(尤其是T-2毒素、verracurin A、杆孢菌素(roridin)A和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);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");环磷酰胺;噻替哌(thiotepa);类紫杉醇(taxoids),例如TAXOL(紫杉醇(paclitaxel);Bristol-Myers Squibb Oncology,Princeton,NJ)、(不含克列莫佛(Cremophor))、紫杉醇的白蛋白工程化纳米颗粒制剂(American PharmaceuticalPartners,Schaumberg,Ill.)和(多西他塞(docetaxel,doxetaxel);Sanofi-Aventis)、苯丁酸氮芥(chloranmbucil);(吉西他滨(gemcitabine));6-硫鸟嘌呤;巯基嘌呤;甲氨喋呤;铂类似物,例如顺铂和卡铂;长春碱(vinblastine);依托泊苷(etoposide)(VP-16);异环磷酰胺;米托蒽醌(mitoxantrone);长春新碱(vincristine);(长春瑞滨(vinorelbine));能灭瘤(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤;卡培他滨(capecitabine)伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(difluoromethylornithine)(DMFO);类视黄醇,例如视黄酸;及上述任何物质的药用盐、酸和衍生物。
化学治疗剂还包括:(i)作用为调节或抑制激素对肿瘤的作用的抗激素剂,例如抗雌激素类和选择性雌激素受体调节物(SERM),包括例如他莫昔芬(tamoxifen)(包括枸橼酸他莫昔芬)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、iodoxyfene、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、keoxifene、LY117018、奥那司酮(onapristone)和(枸橼酸托瑞米芬(toremifene citrate));(ii)抑制调节肾上腺中雌激素生成的酶芳香酶的芳香酶抑制剂,例如例如4(5)-咪唑、氨鲁米特(aminoglutethimide)、(醋酸甲地孕酮(megestrol acetate))、(依西美坦(exemestane);Pfizer)、福美坦(formestane)、法倔唑(fadrozole)、(伏氯唑(vorozole))、(来曲唑(letrozole);Novartis)和(阿那曲唑(anastrozole);AstraZeneca);(iii)抗雄激素类,例如氟他米特(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);布舍瑞林(buserelin)、曲普瑞林(tripterelin)、醋酸甲羟孕酮(medroxyprogesterone acetate)、己烯雌酚(diethylstilbestrol)、普雷马林(premarin)、氟甲睾酮(fluoxymesterone)、全反式维甲酸、芬维A胺(fenretinide)及曲沙他滨(troxacitabine)(一种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)脂质激酶抑制剂;(vi)反义寡核苷酸,具体为抑制牵涉异常细胞增殖的信号传导途径中的基因表达的那些,例如例如PKC-α、Ralf和H-Ras;(vii)核酶例如VEGF表达抑制剂(例如)和HER2表达抑制剂;(viii)疫苗例如基因疗法疫苗,例如和rIL-2;拓扑异构酶1抑制剂例如 rmRH;和(ix)上述任何物质的药用盐、酸和衍生物。
化学治疗剂还包括抗体,如阿仑单抗(alemtuzumab)(Campath)、贝伐单抗(bevacizumab)(Genentech);西妥昔单抗(cetuximab)(Imclone);帕尼单抗(panitumumab)(Amgen)、利妥昔单抗(rituximab)(Genentech/Biogen Idec)、培妥珠单抗(pertuzumab)(2C4,Genentech)、曲妥珠单抗(trastuzumab)(Genentech)、托西莫单抗(tositumomab)(Bexxar、Corixia)和抗体药物缀合物吉妥珠单抗奥佐米星(gemtuzumabozogamicin)(Wyeth)。与本发明化合物组合的、具有作为化疗剂的治疗潜力的其它人源化单克隆抗体包括:阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、atlizumab、巴品珠单抗(bapineuzumab)、bivatuzumab mertansine、cantuzumabmertansine、西利珠单抗(cedelizumab)、赛妥珠单抗(certolizumab pegol)、cidfusituzumab、cidtuzumab、达克珠单抗(daclizumab)、依库利珠单抗(eculizumab)、依法利珠单抗(efalizumab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、泛维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)、吉妥珠单抗奥佐米星、inotuzumabozogamicin、易普利单抗(ipilimumab)、拉贝珠单抗(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单抗(matuzumab)、美泊利单抗(mepolizumab)、莫维珠单抗(motavizumab)、motovizumab、那他珠单抗(natalizumab)、尼妥珠单抗(nimotuzumab)、nolovizumab、numavizumab、ocrelizumab、奥玛珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕考珠单抗(pascolizumab)、pecfusituzumab、pectuzumab、培克珠单抗(pexelizumab)、ralivizumab、兰尼单抗(ranibizumab)、reslivizumab、瑞利珠单抗(reslizumab)、resyvizumab、罗维珠单抗(rovelizumab)、鲁利单抗(ruplizumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)、索土珠单抗(sontuzumab)、tacatuzumabtetraxetan、tadocizumab、他利珠单抗(talizumab)、tefibazumab、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、tucotuzumab celmoleukin、tucusituzumab、umavizumab、乌珠单抗(urtoxazumab)、ustekinumab、维西珠单抗(visilizumab)和抗白细胞介素-12(ABT-874/J695,Wyeth Research and Abbott Laboratories),其为排他性地为重组的人序列、全长IgG1λ抗体,经遗传修饰识别白细胞介素-12p40蛋白质。
化学治疗剂还包括“EGFR抑制剂”,其是指结合或以其它方式与EGFR直接相互作用并防止或降低其信号传导活性的化合物,或称为“EGFR拮抗剂”。此类药剂的实例包括结合EGFR的抗体和小分子。结合EGFR的抗体的实例包括MAb 579(ATCC CRL HB 8506)、MAb 455(ATCC CRL HB8507)、MAb 225(ATCC CRL 8508)、MAb 528(ATCC CRL 8509)(参见美国专利第4,943,533号,Mendelsohn等人)及其变体,例如嵌合的225(C225或西妥昔单抗;)和重构的人225(H225)(参见WO96/40210,Imclone Systems Inc.);完全人类EGFR靶向抗体IMC-11F8(Imclone);结合II型突变EGFR的抗体(美国专利第5,212,290号);如美国专利第5,891,996号中所述结合EGFR的人源化和嵌合抗体;和结合EGFR的人抗体,例如ABX-EGF或Panitumumab(参见WO98/50433,Abgenix/Amgen);EMD 55900(Stragliotto等人Eur.J.Cancer 32A:636-640(1996));针对EGFR与EGF和TGF-α两者竞争EGFR结合的人源化EGFR抗体EMD7200(matuzumab)(EMD/Merck);人EGFR抗体,HuMax-EGFR(GenMab);称为E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3和E7.6.3并述于US 6,235,883的完全人抗体;MDX-447(Medarex Inc);和mAb 806或人源化mAb 806(Johns等人,J.Biol.Chem.279(29):30375-30384(2004))。抗EGFR抗体可与细胞毒剂缀合,从而产生免疫缀合物(参见例如,EP659,439A2,Merck Patent GmbH)。EGFR拮抗剂包括小分子,例如美国专利第5,616,582、5,457,105、5,475,001、5,654,307、5,679,683、6,084,095、6,265,410、6,455,534、6,521,620、6,596,726、6,713,484、5,770,599、6,140,332、5,866,572、6,399,602、6,344,459、6,602,863、6,391,874、6,344,455、5,760,041、6,002,008和5,747,498号及以下PCT公开:WO98/14451、WO98/50038、WO99/09016和WO99/24037。具体的小分子EGFR拮抗剂包括OSI-774(CP-358774,厄洛替尼,Genentech/OSIPharmaceuticals);PD 183805(CI 1033,2-丙烯酰胺,N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(4-吗啉基)丙氧基]-6-喹唑啉基]-,二盐酸盐,Pfizer Inc.);ZD1839,吉非替尼4-(3’-氯-4’-氟苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉,AstraZeneca);ZM 105180((6-氨基-4-(3-甲基苯基-氨基)-喹唑啉,Zeneca);BIBX-1382(N8-(3-氯-4-氟-苯基)-N2-(1-甲基-哌啶-4-基)-嘧啶并[5,4-d]嘧啶-2,8-二胺,Boehringer Ingelheim);PKI-166((R)-4-[4-[(1-苯基乙基)氨基]-1H-吡唑并[2,3-d]嘧啶-6-基]苯酚);(R)-6-(4-羟基苯基)-4-[(1-苯基乙基)氨基]-7H-吡唑并[2,3-d]嘧啶);CL-387785(N-[4-[(3-溴苯基)氨基]-6-喹唑啉基]-2-丁炔酰胺(butynamide));EKB-569(N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲基氨基)-2-丁烯酰胺)(Wyeth);AG1478(Pfizer);AG1571(SU 5271;Pfizer);双重EGFR/HER2酪氨酸激酶抑制剂例如拉帕替尼(GSK572016或N-[3-氯-4-[(3-氟苯基)甲氧基]苯基]-6[5[[[2-甲基磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺)。
化学治疗剂还包括前面段落所述的EGFR靶向药物的“酪氨酸激酶抑制剂”;小分子HER2酪氨酸激酶抑制剂例如可自Takeda获得的TAK165;CP-724,714,ErbB2受体酪氨酸激酶的口服选择性抑制剂(Pfizer and OSI);双HER抑制剂例如EKB-569(可自Wyeth获得),其优先结合EGFR但抑制HER2和EGFR过表达细胞;拉帕替尼(GSK572016;可得自Glaxo-SmithKline),口服HER2和EGFR酪氨酸激酶抑制剂;PKI-166(可得自Novartis);pan-HER抑制剂,例如canertinib(CI-1033;Pharmacia);Raf-1抑制剂,例如可得自ISISPharmaceuticals的反义剂ISIS-5132,其抑制Raf-1信号传导的;非HER靶向TK抑制剂,例如甲磺酸伊马替尼(可得自Glaxo SmithKline);多靶点酪氨酸激酶抑制剂例如舒尼替尼(可得自Pfizer);VEGF受体酪氨酸激酶抑制剂例如瓦他拉尼(vatalanib)(PTK787/ZK222584,可得自Novartis/Schering AG);MAPK细胞外调节激酶I抑制剂CI-1040(可得自Pharmacia);喹唑啉类,例如PD 153035,4-(3-氯苯胺基)喹唑啉;吡啶并嘧啶类;嘧啶并嘧啶类;吡唑并嘧啶类,例如CGP 59326、CGP 60261和CGP 62706;吡唑并嘧啶类,4-(苯基氨基)-7H-吡唑并[2,3-d]嘧啶类;姜黄素(curcumin)(姜黄素(diferuloylmethane),4,5-二(4-氟苯胺基)邻苯二甲酰亚胺);含有硝基噻吩部分的酪氨酸磷酸酯类(tyrphostines);PD-0183805(Warner-Lamber);反义分子(例如结合编码HER的核酸的那些);喹喔啉类(美国专利第5,804,396号);tryphostins(美国专利第5,804,396号);ZD6474(Astra Zeneca);PTK-787(Novartis/Schering AG);泛-HER抑制剂人CI-1033(Pfizer);Affinitac(ISIS 3521;Isis/Lilly);甲磺酸伊马替尼PKI 166(Novartis);GW2016(Glaxo SmithKline);CI-1033(Pfizer);EKB-569(Wyeth);Semaxinib(Pfizer);ZD6474(AstraZeneca);PTK-787(Novartis/Schering AG);INC-1C11(Imclone),雷帕霉素(sirolimus,);或述于任一以下专利公开中的那些:美国专利第5,804,396号;WO1999/09016(American Cyanamid);WO1998/43960(American Cyanamid);WO1997/38983(Warner Lambert);WO1999/06378(Warner Lambert);WO1999/06396(WarnerLambert);WO1996/30347(Pfizer,Inc);WO1996/33978(Zeneca);WO1996/3397(Zeneca)和WO1996/33980(Zeneca)。
化学治疗剂还包括地塞米松(dexamethasone)、干扰素、秋水仙碱(colchicine)、美托品(metoprine)、环孢菌素(cyclosporine)、两性霉素(amphotericin)、甲硝唑(metronidazole)、阿仑单抗(alemtuzumab)、阿利维A酸(alitretinoin)、别嘌呤醇(allopurinol)、氨磷汀(amifostine)、三氧化二砷(arsenic trioxide)、天冬酰胺酶(asparaginase)、活卡介苗(BCG live)、贝伐珠单抗(bevacuzimab)、贝沙罗汀(bexarotene)、克拉屈滨(cladribine)、氯法巴明(clofarabine)、达比泊汀α(darbepoetinalfa)、地尼白介素(denileukin)、右雷佐生(dexrazoxane)、阿法依泊汀(epoetin alfa)、厄洛替尼(elotinib)、非格司亭(filgrastim)、乙酸组氨瑞林(histrelin acetate)、替伊莫单抗(ibritumomab)、干扰素α-2a、干扰素α-2b、来那度胺(lenalidomide)、左旋咪唑(levamisole)、美司钠(mesna)、甲氧沙林(methoxsalen)、诺龙(nandrolone)、奈拉滨(nelarabine)、诺菲妥珠单抗(nofetumomab)、奥普瑞白介素(oprelvekin)、帕利夫明(palifermin)、帕米膦酸盐(pamidronate)、培加酶(pegademase)、培门冬酶(pegaspargase)、培非格司亭(pegfilgrastim)、培美曲塞二钠(pemetrexed disodium)、普拉霉素(plicamycin)、卟吩姆钠(porfimer sodium)、奎纳克林(quinacrine)、拉布立酶(rasburicase)、沙莫司亭(sargramostim)、替莫唑胺(temozolomide)、VM-26、6-TG、托瑞米芬(toremifene)、维A酸(tretinoin)、ATRA、戊柔比星(valrubicin)、唑来膦酸盐(zoledronate)和唑来膦酸及其药用盐。
化学治疗剂还包括氢化可的松、乙酸氢化可的松、乙酸可的松、替可的松匹伐酯(tixocortol pivalate)、曲安奈德(triamcinolone acetonide)、triamcinolonealcohol、莫米松(mometasone)、安西奈德(amcinonide)、布地奈德(budesonide)、地奈德(desonide)、氟轻松(fluocinonide)、氟西奈德(fluocinolone acetonide)、倍他米松(betamethasone)、倍他米松磷酸钠、地塞米松、地塞米松磷酸钠、氟可龙(fluocortolone)、氢化可的松-17-丁酸酯、氢化可的松-17-戊酸酯、二丙酸阿氯米松(aclometasonedipropionate)、戊酸倍他米松、二丙酸倍他米松、泼尼卡酯(prednicarbate)、氯倍他松-17-丁酸酯、氯倍他松-17-丙酸酯、己酸氟可龙、特戊酸氟可龙和乙酸氟泼尼定(fluprednidene acetate);免疫选择性抗炎肽(ImSAID)例如苯丙氨酸-谷氨酰胺-甘氨酸(FEG)及其D-异构体形式(feG)(IMULAN BioTherapeutics,LLC);抗风湿药物例如硫唑嘌呤(azathioprine)、环孢菌素(ciclosporin)(环孢霉素(cyclosporine)A)、D-青霉胺、金盐、羟氯喹(hydroxychloroquine),来氟米特(leflunomide)、米诺环素(minocycline)、柳氮磺吡啶(sulfasalazine)、肿瘤坏死因子α(TNFα)阻断剂例如依那西普(etanercept)(Enbrel)、英夫利昔单抗(infliximab)(Remicade)、阿达木单抗(adalimumab)(Humira)、赛妥珠单抗(certolizumab pegol)(Cimzia)、戈利木单抗(golimumab)(Simponi)、白细胞介素1(IL-1)阻断剂例如阿那白滞素(anakinra)(Kineret)、T细胞共刺激阻断剂例如阿巴西普(abatacept)(Orencia)、白细胞介素6(IL-6)阻断剂例如托珠单抗(tocilizumab)白细胞介素13(IL-13)阻断剂例如雷贝珠单抗(lebrikizumab);干扰素α(IFN)阻断剂例如罗利珠单抗(Rontalizumab);β7整合素阻断剂例如rhuMAb Beta7;IgE途径阻断剂例如抗M1引物(prime);分泌的同源三聚体LTa3和膜结合异源三聚体LTa1/β2阻断剂例如抗淋巴毒素α(LTa);放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素);各种研究性药剂例如thioplatin、PS-341、苯丁酸盐(phenylbutyrate)、ET-18-OCH3或法尼基转移酶抑制剂(L-739749、L-744832);多酚,例如槲皮素(quercetin)、白藜芦醇(resveratrol)、白皮杉醇(piceatannol)、表没食子儿茶素没食子酸酯(epigallocatechine gallate)、茶黄素(theaflavin)、黄烷醇(flavanol)、原花青素(procyanidin)、桦木酸(betulinic acid)及其衍生物;自噬抑制剂例如氯喹(chloroquine);δ-9-四氢大麻酚(屈大麻酚(dronabinol),);β-拉帕醌(lapachone);拉帕醇(lapachol);秋水仙碱(colchicine);桦木酸;乙酰喜树碱(乙酰基camptothecin)、莨菪亭(scopolectin)和9-氨基喜树碱;鬼臼毒素(podophyllotoxin);替加氟(tegafur)贝沙罗汀(bexarotene)二膦酸盐例如氯膦酸盐(例如或)、依替膦酸盐(etidronate)NE-58095、唑来膦酸/唑来膦酸盐阿仑膦酸盐帕米膦酸盐替鲁膦酸或利塞膦酸盐和表皮生长因子受体(EGF-R);疫苗例如疫苗;哌立福辛(perifosine)、COX-2抑制剂(例如塞来昔布(celecoxib)或依托考昔(etoricoxib))、蛋白酶体抑制剂(例如PS341);CCI-779;替吡法尼(tipifarnib)(R11577);奥拉非尼(orafenib)、ABT510;Bcl-2抑制剂,例如奥美林钠(oblimersen sodium)吡虫啉酮(pixantrone);法尼基转移酶抑制剂,例如拉那非尼(lonafarnib)(SCH 6636,SARASARTM);和任何上述药剂的药用盐、酸或衍生物;及上述两种或更多种药剂的组合,例如CHOP,即环磷酰胺、多柔比星、长春新碱和泼尼松龙组合疗法的缩写;和FOLFOX,即奥沙利铂(ELOXATINTM)与5-FU和亚叶酸组合的治疗方案的缩写。
化学治疗剂还包括具有镇痛、解热和抗炎作用的非甾体抗炎药。NSAID包括酶环加氧酶的非选择性抑制剂。NSAID的具体实例包括阿司匹林;丙酸衍生物例如布洛芬(ibuprofen)、非诺洛芬(fenoprofen)、酮洛芬(ketoprofen)、氟比洛芬(flurbiprofen)、奥沙普嗪(oxaprozin)和萘普生(naproxen);乙酸衍生物例如吲哚美辛(indomethacin)、舒林酸(sulindac)、依托度酸(etodolac)、双氯芬酸(diclofenac);烯醇酸衍生物例如吡罗昔康(piroxicam)、美洛昔康(meloxicam)、替诺昔康(tenoxicam)、屈噁昔康(droxicam)、氯诺昔康(lornoxicam)和依索昔康(isoxicam);芬那酸衍生物例如甲芬那酸(mefenamic acid)、甲氯芬那酸(meclofenamic acid)、氟芬那酸(flufenamic acid)、托芬那酸(tolfenamicacid);及COX-2抑制剂例如塞来昔布(celecoxib)、依托考昔(etoricoxib)、鲁米考昔(lumiracoxib)、帕瑞考昔(parecoxib)、罗非考昔(rofecoxib)、罗非考昔(rofecoxib)和伐地考昔(valdecoxib)。NSAID可适用于症状缓解,例如类风湿性关节炎、骨关节炎、炎性关节病、强直性脊柱炎、牛皮癣性关节炎、赖特综合征、急性痛风、痛经、转移性骨痛、头痛和偏头痛、术后疼痛、由于炎症和组织损伤引起的轻度至中度疼痛、发热、肠梗阻和肾绞痛。
化学治疗剂还包括阿尔茨海默病的治疗,例如盐酸多奈哌齐(donepezilhydrochloride)和利伐斯的明(rivastigmine);帕金森病的治疗,例如L-DOPA/卡比多巴(carbidopa)、恩他卡朋(entacapone)、罗吡尼洛(ropinrole)、普拉克索(pramipexole)、溴隐亭(bromocriptine)、培高利特(pergolide)、trihexephendyl和金刚烷胺(amantadine);用于治疗多发性硬化(MS)的药剂,例如β干扰素(例如和)、乙酸格拉默(glatiramer acetate)和米托蒽醌(mitoxantrone);哮喘的治疗,例如沙丁胺醇(albuterol)和孟鲁司特钠(montelukast sodium);用于治疗精神分裂症的药剂,例如再普乐(zyprexa),利培酮(risperdal)、思瑞康(seroquel)和氟哌啶醇(haloperidol);抗炎剂,例如皮质类固醇、TNF阻断剂、IL-1RA、硫唑嘌呤、环磷酰胺和柳氮磺吡啶;免疫调节剂和免疫抑制剂,例如环孢菌素、他克莫司(tacrolimus)、雷帕霉素、吗替麦考酚酯(mycophenolate mofetil)、干扰素、皮质类固醇、环磷酰胺、硫唑嘌呤和柳氮磺胺吡啶;神经营养因子,例如乙酰胆碱酯酶抑制剂、MAO抑制剂、干扰素、抗惊厥剂、离子通道阻断剂、利鲁唑(riluzole)和抗帕金森病剂;用于治疗心血管疾病的药剂,例如β-阻断剂、ACE抑制剂、利尿剂、硝酸酯(nitrate)、钙通道阻断剂和他汀类;治疗肝病的药剂,例如皮质类固醇、考来烯胺(cholestyramine)、干扰素和抗病毒剂;用于治疗血液病症的药剂,例如皮质类固醇、抗白血病剂和生长因子;和用于治疗免疫缺陷病症的药剂,例如γ球蛋白。
另外,化学治疗剂包括本文所述的任何化学治疗剂的药用盐、酸或衍生物及它们中的两种或更多种的组合。
为了治疗炎性疾病或自身免疫性疾病,可与甲氨蝶呤、托法替尼(tofacitinib)、6-巯基嘌呤、硫唑嘌呤、柳氮磺胺吡啶、美沙拉嗪(mesalazine)、奥沙拉嗪(olsalazine)、氯喹/羟氯喹、青霉胺、金硫苹果酸盐(肌内和口服)、硫唑嘌呤、秋水仙碱、皮质类固醇(口服、吸入和局部注射)、β-2肾上腺素受体激动剂(沙丁胺醇、特布他林、salmeteral)、黄嘌呤(茶碱、氨茶碱)、色甘酸盐(cromoglycate)、奈多罗米(nedocromil)、酮替芬(ketotifen)、异丙托铵(ipratropium)和氧托品(oxitropium)、环孢菌素、FK506、雷帕霉素、吗替麦考酚酯、来氟米特、NSAID(例如布洛芬)、皮质类固醇(例如泼尼松龙)、磷酸二酯酶抑制剂、adensosine激动剂、抗血栓形成剂、补体抑制剂、肾上腺素能剂、通过促炎细胞因子例如TNF或IL-1(例如NIK、IKK、p38或MAP激酶抑制剂)干扰信号传导的药剂、IL-1转换酶抑制剂,T-细胞信号传导抑制剂(例如激酶抑制剂)、金属蛋白酶抑制剂、柳氮磺吡啶、6-巯基嘌呤、血管紧张素转化酶抑制剂、可溶性细胞因子受体(例如可溶性p55或p75TNF受体和衍生物p75TNFRigG(依那西普)和p55TNFRigG(来那西普(Lenercept))、siL-1RI、siL-1RII、siL-6R)、抗炎细胞因子(例如IL-4、IL-l 0、IL-11、IL-13和TGF)、塞来昔布、叶酸、硫酸羟氯喹、罗非考昔、依那西普、英夫利昔单抗、阿达木单抗、赛妥珠单抗、托珠单抗、阿巴西普、萘普生、伐地考昔、柳氮磺吡啶、甲泼尼龙(methylprednisolone)、美洛昔康、乙酸甲泼尼龙、金硫苹果酸钠、阿司匹林、曲安奈德、萘磺酸丙氧酚(propoxyphene napsylate)/对乙酰氨基酚(apap)、叶酸(folate)、萘丁美酮(nabumetone)、双氯芬酸、吡罗昔康、依托度酸、双氯芬酸钠、奥沙普嗪、盐酸羟考酮(oxycodone HCl)、重酒石酸氢可酮(hydrocodone bitartrate)/对乙酰氨基酚、双氯芬酸钠/米索前列醇(misoprostol)、芬太尼(fentanyl)、阿那白滞素、盐酸曲马多(tramadol HCl)、双水杨酯(salsalate)、舒林酸、氰钴胺(cyanocobalamin)/fa/吡多辛(pyridoxine)、对乙酰氨基酚(acetaminophen)、阿仑膦酸钠(alendronate sodium)、泼尼松龙、可的松、倍他米松、硫酸吗啡、盐酸利多卡因(lidocaine hydrochloride)、吲哚美辛、硫酸葡萄糖胺(glucosamine sulf)/软骨素(chondroitin)、盐酸阿米替林(amitriptylineHCl)、磺胺嘧啶(sulfadiazine)、盐酸羟考酮/对乙酰氨基酚、盐酸奥洛他定(olopatadineHCl)、米索前列醇、萘普生钠、奥美拉唑(omeprazole)、环磷酰胺、利妥昔单抗、IL-l TRAP、MRA、CTLA4-IG、IL-18BP、抗IL-12、抗-ILlS、BIRB-796、SCI0-469、VX-702、AMG-548、VX-740、罗氟司特(Roflumilast)、IC-485、CDC-801、SlPl激动剂(例如FTY720)、PKC家族抑制剂(例如鲁伯斯塔(Ruboxistaurin)或AEB-071)或Mesopram。在某些实施方案中,式(I)化合物或其药用盐可与甲氨蝶呤或来氟米特共同施用。在中度或重度类风湿关节炎病例中,式(I)化合物或其药用盐可与上述环孢菌素和抗TNF抗体共同施用。式(I)化合物或其药用盐还可与以下药剂共同施用:布地奈德(budenoside);表皮生长因子;皮质类固醇;环孢菌素(cyclosporin)、柳氮磺吡啶;对氨基水杨酸盐;6-巯基嘌呤;硫唑嘌呤;甲硝唑;脂氧合酶抑制剂;美沙拉嗪;奥沙拉嗪;巴柳氮;抗氧化剂;凝血噁烷(thromboxane)抑制剂;IL-l受体拮抗剂;抗IL-l单克隆抗体;抗IL-6单克隆抗体;生长因子;弹性蛋白酶抑制剂;吡啶基-咪唑化合物;针对其它人细胞因子或生长因子(例如TNF、LT、IL-l、IL-2、IL-6、IL-7、IL-8、IL-12、IL-15、IL-16、IL-23、EMAP-II、GM-CSF、FGF和PDGF)的抗体或它们的拮抗剂;细胞表面分子(例如CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69或CD90或它们的配体);甲氨蝶呤;环孢菌素;FK506;雷帕霉素;吗替麦考酚酯;来氟米特;NSAID(例如布洛芬);皮质类固醇(例如泼尼松龙);磷酸二酯酶抑制剂;腺苷激动剂;抗血栓形成剂;补体抑制剂;肾上腺素能剂;通过促炎细胞因子干扰信号传导的药剂,例如TNF 5或IL-l(例如NIK、IKK或MAP激酶抑制剂);IL-l转化酶抑制剂;TNF转化酶抑制剂;T-细胞信号传导抑制剂例如激酶抑制剂;金属蛋白酶抑制剂;柳氮磺吡啶;硫唑嘌呤;6-巯基嘌呤;血管紧张素转化酶抑制剂;可溶性细胞因子受体(例如可溶性p55或p75TNF受体、siL-lRI、siL-lRII、siL-6R)和抗炎性细胞因子(例如IL-4、IL-l 0、IL-11、IL-13或TGF)。
为了治疗克罗恩病,式(I)化合物或其药用盐可与以下药剂共同施用:TNF拮抗剂(例如抗TNF抗体)、D2E7(阿达木单抗)、CA2(英夫利昔单抗)、CDP 571、TNFR-Ig构建体、(p75TNFRigG(依那西普))、p55TNFRigG(LENERCEPTTM)抑制剂或PDE4抑制剂。
为了治疗炎性肠病,式(I)化合物或其药用盐可与以下药剂共同施用:皮质类固醇(例如布地奈德或地塞米松);柳氮磺吡啶、5-氨基水杨酸;奥沙拉嗪;干扰促炎细胞因子例如IL-l(例如IL-l转化酶抑制剂或IL-lra)的合成或作用的药剂;T细胞信号传导抑制剂(例如酪氨酸激酶抑制剂);6-巯基嘌呤;IL-11;美沙拉嗪;泼尼松;硫唑嘌呤;巯基嘌呤;英夫利昔单抗;甲泼尼龙琥珀酸钠;地诺芬酯(diphenoxylate)/硫酸阿托品(atrop sulfate);盐酸洛哌丁胺(loperamide hydrochloride);甲氨蝶呤;奥美拉唑;叶酸;环丙沙星(ciprofloxacin)/葡萄糖-水;重酒石酸氢可酮/对乙酰氨基酚;盐酸四环素(tetracyclinehydrochloride);氟轻松;甲硝唑;硫柳汞(thimerosal)/硼酸;考来烯胺/蔗糖;盐酸环丙沙星;硫酸莨菪碱;盐酸哌替啶(meperidine hydrochloride);盐酸咪达唑仑(midazolamhydrochloride);盐酸羟考酮/对乙酰氨基酚;盐酸异丙嗪(promethazinehydrochloride);磷酸钠;磺胺甲噁唑/甲氧苄啶;塞来昔布;聚卡波非;萘磺酸丙氧酚;氢化可的松;多种维生素剂(multivitamin);巴柳氮二钠;磷酸可待因(codeine phosphate)/对乙酰氨基酚;盐酸考来维仑(colesevelam HCl);氰钴胺;叶酸;左氧氟沙星(levofloxacin);甲泼尼龙;那他珠单抗或干扰素-γ。
为了治疗多发性硬化,式(I)化合物或其药用盐可与以下药剂共同施用:皮质类固醇;泼尼松龙;甲泼尼龙;硫唑嘌呤;环磷酰胺;环孢菌素;甲氨蝶呤;4-氨基吡啶;替扎尼定(tizanidine);干扰素-la(Biogen);干扰素-lb(Chiron/Berlex);干扰素-n3)(Interferon Sciences/Fujimoto),干扰素-(Alfa Wassermann/J&J)、干扰素lA-IF(Serono/Inhale Therapeutics)、聚乙二醇化干扰素2b(Enzon/Schering-Plough)、共聚物1(Cop-1;Teva Pharmaceutical Industries,Inc.);高压氧;静脉注射免疫球蛋白;克拉屈滨;针对其它人细胞因子或生长因子及其受体(例如TNF、LT、IL-l、IL-2、IL-6、IL-7、IL-8、IL-12、IL-23、IL-15、IL-16、EMAP-II、GM-CSF、FGF或PDGF)的抗体或它们的拮抗剂
为了治疗AIDS,式(I)化合物或其药用盐可与针对以下的抗体共同施用:细胞表面分子例如CD2、CD3、CD4、CD8、CD19、CD20、CD25、CD28、CD30、CD40、CD45、CD69、CD80、CD86、CD90或它们的配体。式(I)化合物或其药用盐还可与以下药剂共同施用:甲氨蝶呤、环孢菌素、FK506、雷帕霉素、吗替麦考酚酯、来氟米特、SlPl激动剂、NSAID(例如布洛芬)、皮质类固醇(例如泼尼松龙)、磷酸二酯酶抑制剂、腺苷激动剂、抗血栓形成剂、补体抑制剂、肾上腺素能剂、通过促炎细胞因子例如TNF或IL-l(例如NIK、IKK、p38或MAP激酶抑制剂)干扰信号传导的药剂、IL-l转化酶抑制剂、TACE抑制剂、T-细胞信号传导抑制剂(例如激酶抑制剂)、金属蛋白酶抑制剂、柳氮磺吡啶、硫唑嘌呤、6-巯基嘌呤、血管紧张素转化酶抑制剂、可溶性细胞因子受体(例如可溶性p55或p75TNF受体、siL-lRI、siL-lRII或siL-6R)或抗炎性细胞因子(例如IL-4、IL-l 0、IL-13或TGF)。
式(I)化合物或其药用盐还可与以下药剂共同施用:例如阿仑单抗、屈大麻酚、达克珠单抗、米托蒽醌、盐酸扎利罗登(xaliproden hydrochloride)、氨吡啶(fampridine)、乙酸格拉默、那他珠单抗、sinnabidol、免疫因子(immunokine)NNS03、ABR-215062、AnergiX.MS、趋化因子受体拮抗剂、BBR-2778、calagualine、CPI-1189、LEM(脂质体包囊的米托蒽醌)、THC.CBD(大麻素激动剂)、MBP-8298、mesopram(PDE4抑制剂)、MNA-715、抗IL-6受体抗体、neurovax、吡非尼酮(pirfenidone)allotrap 1258(RDP-1258)、sTNF-Rl、他仑帕奈(talampanel)、特立氟胺(teriflunomide)、TGF-β2、替利莫肽(tiplimotide)、VLA-4拮抗剂(例如TR-14035、VLA4Ultrahaler或Antegran-ELAN/Biogen)、干扰素γ拮抗剂或IL-4激动剂。
用于治疗强直性脊柱炎,式(I)化合物或其药用盐可与以下药剂共同施用:布洛芬、双氯芬酸、米索前列醇、萘普生、美洛昔康、吲哚美辛、双氯芬酸、塞来昔布、罗非考昔、柳氮磺吡啶、甲氨蝶呤、硫唑嘌呤、米诺环素、泼尼松、抗TNF抗体、D2E7CA2(英夫利昔单抗)、CDP 571、TNFR-Ig构建体、(p75TNFRigG或p55TNFRigG
为了治疗哮喘,式(I)化合物或其药用盐可与以下药剂共同施用:沙丁胺醇、沙美特罗(salmeterol)/氟替卡松(fluticasone)、孟鲁司特钠、丙酸氟替卡松、布地奈德、泼尼松、昔萘酸沙美特罗、盐酸左旋沙丁胺醇(levalbuterol HCl)、硫酸沙丁胺醇/异丙托铵、泼尼松龙磷酸钠、曲安奈德、二丙酸倍氯米松、异丙托溴铵、阿奇霉素(azithromycin)、乙酸吡布特罗(pirbuterol acetate)、泼尼松龙、无水茶碱、甲泼尼龙琥珀酸钠、克拉霉素(clarithromycin)、扎鲁司特(zafirlukast)、富马酸福莫特罗(formoterol fumarate)、流感病毒疫苗、阿莫西林三水合物(amoxicillin trihydrate)、氟尼缩松(flunisolide)、色甘酸钠、盐酸非索非那定(fexofenadine hydrochloride)、氟尼缩松/薄荷醇(menthol)、阿莫西林/克拉维酸盐(clavulanate)、左氧氟沙星、愈创木酚甘油醚(guaifenesin)、地塞米松磷酸钠、盐酸莫西沙星(moxifloxacin HCl)、盐酸多西环素(doxycycline hyclate)、愈创木酚甘油醚/d-甲吗喃(methorphan)、p-麻黄碱/cod/-氯苯那敏(chlorphenir)、加替沙星(gatifloxacin)、盐酸西替利嗪(cetirizine hydrochloride)、糠酸莫米松(mometasonefuroate)、昔萘酸沙美特罗、苯佐那酯(benzonatate)、头孢氨苄(cephalexin)、pe/氢可酮/氯苯那敏、盐酸西替利嗪/伪麻黄碱(pseudoephed)、去氧肾上腺素(phenylephrine)/cod/异丙嗪、可待因/异丙嗪、头孢丙烯(cefprozil)、地塞米松、愈创木酚甘油醚/伪麻黄碱、氯苯那敏(chlorpheniramine)/氢可酮、奈多罗米钠(nedocromil sodium)、硫酸特布他林、肾上腺素(epinephrine)、甲泼尼龙、抗IL-13抗体或硫酸间羟异丙肾上腺素(metaproterenolsulfate)。
为了治疗COPD,式(I)化合物或其药用盐可与以下药剂共同施用:硫酸沙丁胺醇/异丙托铵、异丙托溴铵、沙美特罗/氟替卡松、沙丁胺醇、昔萘酸沙美特罗、丙酸氟替卡松、泼尼松、无水茶碱、甲泼尼龙琥珀酸钠、孟鲁司特钠、布地奈德、富马酸福莫特罗、曲安奈德、左氧氟沙星、愈创木酚甘油醚、阿奇霉素、二丙酸倍氯米松、盐酸左旋沙丁胺醇、氟尼缩松、头孢曲松钠(ceftriaxone sodium)、阿莫西林三水合物、加替沙星、扎鲁司特、阿莫西林/克拉维酸盐、氟尼缩松/薄荷醇、氯苯那敏/氢可酮、硫酸间羟异丙肾上腺素、甲泼尼龙、糠酸莫米松、p-麻黄碱/cod/氯苯那敏、乙酸吡布特罗、p-麻黄碱/氯雷他定(loratadine)、硫酸特布他林、噻托溴铵(tiotropium bromide)、(R,R)-福莫特罗、TgAAT、西洛司特(cilomilast)或罗氟司特。
为了治疗牛皮癣,式(I)化合物或其药用盐可与以下药剂共同施用:卡泊三烯(calcipotriene)、丙酸氯倍他索(clobetasol propionate)、曲安奈德、丙酸卤倍他索(halobetasol propionate)、他扎罗汀(tazarotene)、甲氨蝶呤、氟轻松、二丙酸倍他米松增强型(betamethasone diprop augmented)、氟西奈德、阿维A(acitretin)、焦油香波(tarshampoo)、戊酸倍他米松、糠酸莫米松、酮康唑(ketoconazole)、普莫卡因(pramoxine)/氟新诺龙(fluocinolone)、戊酸氢化可的松、氟氢缩松(flurandrenolide)、脲、倍他米松、丙酸氯倍他索/emoll、丙酸氟替卡松、阿奇霉素、氢化可的松、保湿配方、叶酸、地奈德、吡美莫司(pimecrolimus)、煤焦油、二乙酸二氟拉松(diflorasone diacetate)、依那西普叶酸、乳酸、甲氧沙林、he/碱式没食子酸铋(bismuth subgal)/znox/resor、乙酸甲泼尼龙、泼尼松、防晒霜(sunscreen)、氯氟舒松(halcinonide)、水杨酸、地蒽酚(anthralin)、特戊酸氯可托龙、煤提取物、煤焦油/水杨酸、煤焦油/水杨酸/硫、去羟米松(desoximetasone)、地西泮(diazepam)、emollient、氟轻松/emollient、矿物油/蓖麻油/na lact、矿物油/花生油、石油/肉豆蔻酸异丙酯、补骨脂素(psoralen)、水杨酸、皂/三溴沙仑(tribromsalan)、硫柳汞/硼酸、塞来昔布、英夫利昔单抗、环孢菌素、alefacept、依法利珠单抗、他克莫司、吡美莫司、PUVA、UVB、柳氮磺吡啶、ABT-874或ustekinamab。
为了治疗牛皮癣性关节炎,式(I)化合物或其药用盐可与以下药剂共同施用:甲氨蝶呤、依那西普、罗非考昔、塞来昔布、叶酸、柳氮磺吡啶、萘普生、来氟米特、乙酸甲泼尼龙、吲哚美辛、硫酸羟氯喹、泼尼松、舒林酸、二丙酸倍他米松增强型、英夫利昔单抗、甲氨蝶呤、叶酸、曲安奈德、双氯芬酸、二甲基亚砜、吡罗昔康、双氯芬酸钠、酮洛芬、美洛昔康、甲泼尼龙、萘丁美酮、托美汀钠(tolmetin sodium)、卡泊三烯、环孢菌素、双氯芬酸钠/米索前列醇、氟轻松、硫酸葡萄糖胺、金硫苹果酸钠、重酒石酸氢可酮/对乙酰氨基酚、布洛芬、利塞膦酸钠(risedronate sodium)、磺胺嘧啶、硫鸟嘌呤、伐地考昔、alefacept、D2E7(阿达木单抗)或依法利珠单抗。
为了治疗狼疮,式(I)化合物或其药用盐可与以下药剂共同施用:NSAID(例如双氯芬酸、萘普生、布洛芬、吡罗昔康或吲哚美辛);COX2抑制剂(例如塞来昔布、罗非考昔或伐地考昔);抗疟剂(例如羟氯喹);类固醇(例如泼尼松、泼尼松龙、布地奈德或地塞米松);细胞毒剂(例如硫唑嘌呤、环磷酰胺、吗替麦考酚酯或甲氨蝶呤);PDE4的抑制剂或嘌呤合成抑制剂(例如)。例如,式(I)化合物或其药用盐可与以下药剂共同施用:柳氮磺吡啶、5-氨基水杨酸、奥沙拉嗪、(一种干扰促炎细胞因子(例如IL-l)的合成、产生或作用的药剂)或半胱天冬酶(caspase)抑制剂(例如IL-l转化酶抑制剂或IL-lra)。
式(I)化合物或其药用盐还可与以下药剂共同施用:T细胞信号传导抑制剂(例如酪氨酸激酶抑制剂),或靶向T细胞活化的分子(例如CTLA-4-IgG、抗B7家族抗体或抗PD-1家族抗体)。
式(I)化合物或其药用盐还可与以下药剂共同施用:IL-11抗体、抗细胞因子抗体(例如fonotolizumab(抗IFNg抗体))或抗受体受体抗体(例如抗IL-6受体抗体或针对B细胞表面分子的抗体)。
式(I)化合物或其药用盐还可与以下药剂共同施用:LJP 394(阿贝莫司(abetimus))、可消耗或灭活B细胞的药剂(例如利妥昔单抗(抗CD20抗体)或lymphostat-B(抗BlyS抗体))、TNF拮抗剂(例如抗TNF抗体)、D2E7(阿达木单抗)、CA2(英夫利昔单抗)、CDP571、TNFR-Ig构建体、(p75TNFRigG(依那西普)或p55TNFRigG(LENERCEPTTM)。
式(I)化合物或其药用盐还可与一种或多种用于预防或治疗AIDS的药剂共同施用:HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、免疫调节剂或其它逆转录病毒药物。逆转录酶抑制剂的实例包括但不限于阿巴卡韦(abacavir)、阿德福韦(adefovir)、去羟肌苷(didanosine)、地拉夫啶二匹酯(dipivoxil delavirdine)、依法韦仑(efavirenz)、恩曲他滨(emtricitabine)、拉米夫定(lamivudine)、奈韦拉平(nevirapine)、利匹韦林(rilpivirine)、司他夫定(stavudine)、替诺福韦(tenofovir)、扎西他宾(zalcitabine)和齐多夫定(zidovudine)。蛋白酶抑制剂的实例包括但不限于安普那韦(amprenavir)、阿扎那韦(atazanavir)、达瑞那韦(darunavir)、茚地那韦(indinavir)、福沙那韦(fosamprenavir)、洛匹那韦(lopinavir)、奈非那韦(nelfinavir)、利托那韦(ritonavir)、沙奎那韦(saquinavir)和替拉诺韦(tipranavir)。其它逆转录病毒药物的实例包括但不限于,埃替格韦(elvitegravir)、恩夫韦肽(enfuvirtide)、马拉维若(maraviroc)和雷特格韦(raltegravir)。
为了治疗II型糖尿病、肝脂肪变性、胰岛素抵抗、代谢综合征或相关疾病,式(I)化合物或其药用盐可与以下药剂共同施用:胰岛素或经修饰以改善在体内的作用持续时间的胰岛素;刺激胰岛素分泌的药剂,例如乙酰己胺(acetohexamide)、氯丙酰胺(chlorpropamide)、格列本脲(glyburide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列齐特(glicazide)、格列吡脲(glycopyramide)、格列喹酮(gliquidone)、瑞格列奈(rapaglinide)、那格列奈(nataglinide)、妥拉磺脲(tolazamide)或甲苯磺丁脲(tolbutamide);作为胰高血糖素样肽激动剂的药剂,例如艾塞那肽(exanatide)、利拉鲁肽(liraglutide)或他司鲁泰(taspoglutide);抑制二肽基肽酶IV的药剂,例如维格列汀(vildagliptin)、西格列汀(sitagliptin)、沙格列汀(saxagliptin)、利格列汀(linagliptin)、allogliptin或septagliptin;结合过氧化物酶体增殖物激活受体γ的药剂,例如罗格列酮(rosiglitazone)或吡格列酮(pioglitazone);减少胰岛素抵抗的药剂,例如二甲双胍(metformin);或降低小肠中葡萄糖吸收的药剂,例如阿卡波糖(acarbose)、米格列醇(miglitol)或伏格列波糖(voglibose)。
为了治疗急性肾病或慢性肾病,式(I)化合物或其药用盐可与以下药剂共同施用:多巴胺(dopamine)、利尿剂(例如呋塞米(furosemide))、布美他尼(bumetanide)、噻嗪类(thiazide)、甘露醇、葡糖酸钙、碳酸氢钠、沙丁胺醇、帕立骨化醇(paricalcitol)、度骨化醇(doxercalciferol)、西那卡塞(cinacalcet)或bardoxalone methyl。
可与载体材料组合以产生单一剂型的式(I)化合物或其盐或本文公开的化合物或其盐和额外的药剂(在包含如上所述的额外的治疗剂的那些组合物中)的量将取决于所治疗的宿主和具体施用方式。在某些实施方案中,配制本发明的组合物使得可施用本发明的0.01-100mg/kg体重/天的剂量。
额外的治疗剂和式(I)化合物或本文公开的化合物可协同作用。因此,此类组合物中额外的治疗剂的量可小于仅使用该治疗剂的单一疗法中所需的量,或在使用较低剂量时可能对患者的副作用较少。在某些实施方案中,在此类组合物中,可施用0.01-1,000μg/kg体重/天的额外的治疗剂的剂量。
本文提供延长具有癌症的个体中对细胞毒剂的响应的持续时间的方法,其包括向所述个体施用(a)有效量的式(I)化合物或其药用盐或本文公开的化合物或其药用盐和(b)有效量的细胞毒剂。
在任一方法的某些实施方案中,所述细胞毒剂为靶向疗法。在某些实施方案中,所述靶向疗法为EGFR拮抗剂、RAF抑制剂和/或PI3K抑制剂中的一种或多种。
在任一方法的某些实施方案中,所述靶向疗法为EGFR拮抗剂。在任一方法的某些实施方案中,所述EGFR拮抗剂为N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)-4-喹唑啉胺和/或其药用盐。在某些实施方案中,所述EGFR拮抗剂为N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)-4-喹唑啉胺。在某些实施方案中,所述EGFR拮抗剂为N-(4-(3-氟苄基氧基)-3-氯苯基)-6-(5-((2-(甲基磺酰基)乙基氨基)甲基)呋喃-2-基)喹唑啉-4-胺,二4-甲基苯磺酸盐或其药用盐(例如拉帕替尼)。
在任一方法的某些实施方案中,靶向疗法为RAF抑制剂。在某些实施方案中,所述RAF抑制剂为BRAF抑制剂。在某些实施方案中,所述RAF抑制剂为CRAF抑制剂。在某些实施方案中,所述BRAF抑制剂为威罗菲尼。在某些实施方案中,所述RAF抑制剂为3-(2-氰基丙-2-基)-N-(4-甲基-3-(3-甲基-4-氧代-3,4-二氢喹唑啉-6-基氨基)苯基)苯甲酰胺或其药用盐(例如AZ628(CAS#878739-06-1))。
在任一方法的某些实施方案中,所述靶向疗法为PI3K抑制剂。
在任一方法的某些实施方案中,所述细胞毒剂为化学疗法。在任一方法的某些实施方案中,所述化学疗法为紫杉烷。在某些实施方案中,所述紫杉烷为紫杉醇。在某些实施方案中,所述紫杉烷为多西他赛。
在任一方法的某些实施方案中,所述细胞毒剂为铂剂。在某些实施方案中,所述铂剂为卡铂。在某些实施方案中,所述铂剂为顺铂。在任一方法的某些实施方案中,所述细胞毒剂为紫杉烷和铂剂。在某些实施方案中,所述紫杉烷为紫杉醇。在某些实施方案中,所述紫杉烷为多西他赛。在某些实施方案中,所述铂剂为卡铂。在某些实施方案中,所述铂剂为顺铂。
在任一方法的某些实施方案中,所述细胞毒剂为长春花生物碱。在某些实施方案中,所述长春花生物碱为长春瑞滨。在任一方法的某些实施方案中,所述化学疗法为核苷类似物。在某些实施方案中,所述核苷类似物为吉西他滨。
在任一方法的某些实施方案中,所述细胞毒剂为放射疗法。
在任一方法的某些实施方案中,所述式(I)化合物或其药用盐或本文公开的化合物或其药用盐与细胞毒剂(例如靶向疗法、化学疗法和/或放射疗法)同时(concomitantly)施用。在某些实施方案中,所述式(I)化合物或其药用盐在细胞毒剂(例如靶向疗法、化学疗法和/或放射疗法)之前和/或与其同时(concurrently)施用。
实施例
如下文实施例中所述,在某些示例性实施方案中,根据以下通用操作制备化合物。应理解的是,虽然通用方法描述了本发明的某些化合物的合成,但是以下通用方法和本领域普通技术人员已知的其它方法可应用于如本文所述的所有化合物及这些化合物中的每一种的亚类和种类。
通用方案A
(实施例1-7、19-27、44-48)
根据上述方案制备式(I)的代表性化合物。
中间体B(如中间体的通用合成中所述制备)在Pd催化条件下与经取代的芳基硼酸偶联以形成联芳基中间体,在水解条件下自其中除去甲苯磺酰基,得到式(I)化合物。
通用方案B
(实施例9-17)
根据上述方案制备式(I)的代表性化合物。
在包含水作为共溶剂的溶剂混合物中在升高的温度将4-(3-氟-4-硝基苯基)-6-甲基-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(根据通用方案A自中间体A和(3-氟-4-硝基苯基)硼酸制备)用氨基酸或氨基酯和碱处理。粗反应产物的硝基基团用元素铁在乙酸中在升高的温度还原,得到相应苯胺,其接受分子内环化,得到式(I)化合物。
通用方案C
(实施例28-40)
根据上述方案制备式(I)的代表性化合物。
使中间体D(如中间体的通用合成中所述制备)与各种胺偶联,形成式(I)化合物。
通用方案D
(实施例41-42)
根据上述方案制备式(I)的代表性化合物。
在溶剂例如DMF或乙腈中在升高的温度将中间体A(如中间体的通用合成中所述制备)用烷基化剂和碱处理,得到相应的经N-R1取代的溴化物。将这些产物在水解条件下脱保护,然后与2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-醇(其如下制备:将1,4-二溴苯用丁基锂处理并用丙酮淬灭,接着进行硼化)偶联,形成式(I)化合物。
制备中间体A的通用操作
步骤1:2-甲氧基-4-甲基-3-硝基吡啶
将2-氯-4-甲基-3-硝基吡啶(250g,1.45mol)于甲醇(1.0L)中的溶液逐滴添加(2h)至搅拌和冷却的(0℃)甲醇钠(250g,4.63mol)于甲醇(850mL)中的溶液。添加后,将混合物加热至回流且保持23h,此时TLC指示反应已经完成。减压浓缩混合物至约900mL的体积并通过添加水(1.5L)淬灭。通过过滤收集所得固体,用水洗涤并减压干燥,得到标题化合物(250g,100%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ8.22(d,J=5.2Hz,1H),7.10(d,J=5.6Hz,1H),3.92(s,3H),2.26(s,3H)。
步骤2:5-溴-2-甲氧基-4-甲基-3-硝基吡啶
在环境温度将乙酸钠(365g,5.37mol)添加至搅拌的2-甲氧基-4-甲基-3-硝基吡啶(250g,1.49mol)于乙酸(1.5L)中的溶液,然后逐滴添加(30min)Br2(639g,4.00mol)。添加后,将混合物在80℃加热12h,此时TLC指示反应已经完成。将混合物冷却(0℃)并通过依序添加10%亚硫酸钠水溶液(1.5L)和饱和亚硫酸钠水溶液(1.5L)淬灭。通过过滤收集所得固体,用水洗涤并减压干燥,得到标题化合物(302g,82.2%产率),其为浅黄色固体。1H NMR(400MHz,DMSO-d6):δ8.25(s,1H),3.94(s,3H),2.29(s,3H)。
步骤3:(E)-2-(5-溴-2-甲氧基-3-硝基-4-吡啶基)-N,N-二甲基-乙烯胺
将DMF-DMA(600mL)缓慢添加至搅拌和加热的(80℃)5-溴-2-甲氧基-4-甲基-3-硝基吡啶(134g,0.54mol)于DMF(1.1L)中的溶液。添加后,将混合物在95℃加热5h,此时TLC指示反应已经完成。将混合物冷却至室温并倒入冰冷的水(3L)中。通过过滤收集所得红色固体,用水洗涤并减压干燥,得到标题化合物(167g,100%产率),其为红色固体。1H NMR(400MHz,DMSO-d6):δ8.24(s,1H),7.05(d,J=13.6Hz,1H),7.05(d,J=13.6Hz,1H),4.80(d,J=13.2Hz,1H),3.88(s,3H),2.90(s,6H)。
步骤4:4-溴-7-甲氧基-1H-吡咯并[2,3-c]吡啶
将2-(5-溴-2-甲氧基-3-硝基吡啶-4-基)-N,N-二甲基乙烯胺(50.0g,165mmol)、Fe(50.0g,893mmol)和NH4Cl(50.0g,943mmol)于甲醇/水(1900/250mL)中的混合物加热回流7h,此时LCMS指示反应已经完成。将混合物趁热过滤并用甲醇(3×200mL)洗涤滤饼。减压浓缩合并的滤液并通过硅胶色谱(石油醚:乙酸乙酯=5:1)纯化所得残余物,得到粗产物。用乙腈研磨该粗物质,得到标题化合物(37.4g,99.5%产率),其为浅棕色固体。LCMS m/z(M+H)226.7,228.7。
步骤5:4-溴-7-甲氧基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶
将4-溴-7-甲氧基-1H-吡咯并[2,3-c]吡啶(34.3g,0.15mol)于四氢呋喃(700mL)中的溶液逐滴添加至搅拌和冷却的(0℃)氢化钠(60%,19.2g,0.48mol)于THF(700mL)中的溶液。添加后,将混合物在室温搅拌1h,然后再次冷却至0℃。逐滴添加于THF(700mL)中的甲苯磺酰氯(38.0g,0.20mol)并将所得混合物在环境温度搅拌2h。通过添加饱和氯化铵水溶液(1.0L)淬灭反应混合物,然后用乙酸乙酯(3×600mL)萃取。将合并的有机萃取物用硫酸钠干燥并减压浓缩。用乙腈研磨残余物,得到标题化合物(51.2g,88.9%产率),其为棕色固体。该粗物质未经进一步纯化即用于下一步。
步骤6:4-溴-1-(对甲苯基磺酰基)-6H-吡咯并[2,3-c]吡啶-7-酮
将溴化氢(40%水溶液,1.1L)添加至4-溴-7-甲氧基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶(102.5g,0.27mol)于乙醇(200mL)中的溶液。添加后,将混合物在90℃加热2h,此时TLC指示反应已经完成。将混合物冷却至0℃并通过过滤收集所得白色固体。将该固体用水洗涤并真空干燥,得到标题化合物(中间体A)(87.5g,88.6%产率),其为浅棕色固体。1H NMR(400MHz,DMSO-d6):δ11.48(s,1H),8.01(d,J=3.6Hz,1H),8.90(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.32(s,1H),6.57(d,J=3.2Hz,1H),2.34(s,3H)。
制备中间体B和C的通用操作
步骤1:4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
将碘甲烷(24.5g,172.8mmol)逐滴添加至搅拌的4-溴-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(中间体A)(16.7g,45.5mmol)和碳酸铯(17.8g,54.6mmol)于1,4-二噁烷(250mL)中的混悬液。添加后,将反应混合物在室温搅拌18h,此时LCMS指示反应已经完成。减压蒸发溶剂并用水(200mL)稀释残余物。混合物用乙酸乙酯(3×200mL)萃取。将合并的有机萃取物用硫酸钠干燥并减压浓缩。通过硅胶色谱(石油醚/乙酸乙酯=3:1)纯化残余物,得到标题化合物(中间体B)(14.0g,81.4%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ8.03(d,J=3.6Hz,1H),7.92(d,J=8.4Hz,2H),7.78(s,1H),7.39(d,J=8.4Hz,2H),6.57(d,J=3.6Hz,1H),3.35(s,3H),2.35(s,3H)。
步骤2:6-甲基-1-(对甲苯基磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[2,3-c]吡啶-7-酮
在100℃在氮气气氛下将4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(3.0g,7.89mmol)和4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-联(1,3,2-二氧杂硼杂环戊烷)(2.4g,9.47mmol)于1,4-二噁烷(50mL)中的混合物用乙酸钾(1.4g,14.27mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(300mg,0.39mmol)处理3h。冷却后,将混合物在水(50mL)与二氯甲烷(100mL)之间分配。分离的有机层用硫酸钠干燥并减压浓缩。通过硅胶色谱(石油醚:乙酸乙酯=1:1)纯化粗产物,得到标题化合物(中间体C,1.3g,38.5%产率),其为黄色固体。LCMS m/z(M+H)429.1
制备中间体D的通用操作
步骤1:4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酸甲酯
在氮气气氛下将4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(5.0g,13.0mmol)、(4-(甲氧基羰基)苯基)硼酸(4.5g,26.0mmol)、碳酸钾(5.5g,4.0mmol)和乙酸钯(500mg)于乙醇(100mL)中的混合物在110℃加热10h。冷却后,将反应混合物用水(50mL)稀释,然后用乙酸乙酯(3×100mL)萃取。将合并的有机萃取物用盐水(2×20mL)洗涤,用硫酸钠干燥并减压浓缩。通过硅胶色谱(石油醚/乙酸乙酯=3:1)纯化残余物,得到标题化合物(2.5g,64%产率),其为棕色固体。LCMS m/z(M+H)282.9。
步骤2:4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酸
将氢氧化钠(1.2g,29.7mmol)按份添加至搅拌的4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酸甲酯(2.0g,6.8mmol)于甲醇/水(50mL/10mL)中的溶液。添加后,将所得混合物在80℃加热2h,此时LCMS指示反应已经完成。减压浓缩混合物并用水(50mL)稀释残余物。将含水混合物用乙酸乙酯(3×50mL)洗涤,然后使用1N盐酸酸化至pH 3。通过过滤收集所得析出物并干燥,得到标题化合物(中间体D)(1.4g,77.8%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ12.21-12.18(s,1H),8.02(d,J=8.0Hz,2H),7.73(d,J=7.6Hz,2H),7.53(s,1H),7.38(s,1H),6.52-6.48(s,1H),3.60(s,3H)。
制备中间体E的通用操作
步骤1:5-溴-2-甲氧基-3-硝基吡啶
将甲醇钠(17.2g,318.4mmol)添加至搅拌的5-溴-2-氯-3-硝基吡啶(15.0g,64.2mmol)于甲醇(125mL)中的溶液。添加后,将反应混合物加热回流2h,此时TLC指示反应已经完成。减压浓缩混合物并用水(200mL)稀释残余物。通过过滤收集所得析出物,用水洗涤并减压干燥,得到标题化合物(12.0g,81.5%产率),其为棕色固体。1H NMR(400MHz、CDCl3):δ8.43(d,J=2.4Hz,1H),8.38(d,J=2.0Hz,1H),4.09(s,3H)。
步骤2:4-溴-7-甲氧基-2-甲基-1H-吡咯并[2,3-c]吡啶
将异丙烯基溴化镁(0.5M于THF中,105.0mL,55.0mmol)逐滴添加至搅拌和冷却的(-78℃)5-溴-2-甲氧基-3-硝基吡啶(4.0g,17.1mmol)于THF(40mL)中的溶液。添加后,将所得混合物逐渐温热至室温并再搅拌3h。通过添加1M氯化铵水溶液(150mL)淬灭反应混合物,然后用乙酸乙酯(3×100mL)萃取。将合并的有机萃取物用硫酸钠干燥并减压浓缩。通过硅胶色谱(石油醚:乙酸乙酯=10:1)纯化残余物,得到标题化合物(1.65g,39.9%产率),其为棕色油状物。LCMS m/z(M+H)240.1,242.1。
步骤3:4-溴-2-甲基-1,6-二氢吡咯并[2,3-c]吡啶-7-酮
将溴化氢(40%水溶液,20mL)添加至4-溴-7-甲氧基-2-甲基-1H-吡咯并[2,3-c]吡啶(1.65g,6.8mmol)于乙醇(10mL)中的溶液。添加后,将反应混合物在90℃加热15h,此时TLC指示反应已经完成。将混合物冷却至0℃并通过过滤收集所得固体。将该固体用水洗涤并干燥,得到标题化合物(中间体E)(0.9g,57.9%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ12.06(s,1H),11.00(s,1H),7.03(s,1H),5.97(s,1H),2.29(s,3H)。LCMS m/z(M+H)226.8,228.8
实施例1
6-甲基-4-苯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
小瓶装入4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(中间体B,50mg,0.13mmol)、苯基硼酸(32.0mg,0.26mmol)、乙酸钯(2.94mg,0.013mmol)、二环己基(2’,6’-二甲氧基联苯-2-基)膦(10.77mg,0.026mmol)、碳酸钾(36.3mg,0.26mmol)和4:1二噁烷:水(3mL)。将混合物在90℃搅拌1h,然后使用乙酸乙酯淋洗过滤。减压浓缩滤液,然后添加甲醇(5mL)和氢氧化钾(36.8mg,0.66mmol)。将反应混合物在室温搅拌18h。将混合物用水稀释并进行反相HPLC(乙腈/水/0.1%三氟乙酸),得到呈白色无定形固体形式的标题化合物(17%),接着自二噁烷冻干。1H NMR(400MHz,DMSO-d6)δ12.02-12.24(m,1H),7.59(d,J=7.06Hz,2H),7.46(s,3H),7.37(s,1H),7.34(d,J=2.70Hz,2H),6.48-6.60(m,1H),6.41-6.46(m,1H),3.58(s,3H)。LCMSm/z(M+H)225。
以与实施例1类似的方式制备以下化合物:
实施例2-7
实施例8
4-(3-(2-羟基乙基)-3-苯基-2,3-二氢-1H-茚-5-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
步骤1:5-溴-3-苯基-1H-茚
在氩气气氛下向6-溴-2,3-二氢-1H-茚-1-酮(2.80g,13.27mmol)于THF(10mL)中的溶液中逐滴添加冷却的(0℃)苯基溴化镁(1M于THF中,19.90mL,19.90mmol)于THF(26mL)中的溶液。将反应混合物在室温搅拌过夜并用1N HCl(200mL)淬灭。混合物用乙酸乙酯(3×100mL)萃取。将合并的有机萃取物用盐水洗涤,用硫酸镁干燥并减压浓缩,得到叔醇,将其溶于THF(50mL)并用4-甲基苯磺酸(0.46g,2.65mmol)处理。将该反应混合物在室温搅拌6h,然后用水(200mL)稀释。用二氯甲烷(3×100mL)萃取混合物并减压浓缩合并的萃取物。通过硅胶色谱(己烷/乙酸乙酯20:1)纯化残余物,得到5-溴-3-苯基-1H-茚(300mg,11%),其为无色油状物。该物质未经进一步纯化即用于下一步。LCMS m/z(M+H)271。
步骤2:6-溴-1-苯基-2,3-二氢-1H-茚
在氮气气氛下将2,2,2-三氟乙酸(6.4mL,83mmol)添加至冷却的(0℃)5-溴-3-苯基-1H-茚(5.63g,20.7mmol)和三乙基甲硅烷(9.95mL,62.3mmol)于二氯甲烷(50mL)中的溶液。将反应混合物温热至室温并继续搅拌过夜。将反应混合物用饱和碳酸氢钠水溶液小心淬灭,然后用二氯甲烷(3×100mL)萃取。将合并的有机萃取物用硫酸镁干燥并减压浓缩。通过硅胶色谱(己烷/乙酸乙酯20:1)纯化残余物,得到6-溴-1-苯基-2,3-二氢-1H-茚(5.57g,98%产率)。LCMS m/z(M+H)273。
步骤3:2-(6-溴-1-苯基-2,3-二氢-1H-茚-1-基)乙醇
在氩气气氛下将二甲基亚砜(1.4mL,20.1mmol)添加至氢化钠(60%于矿物油中,0.24g,6.04mmol)于THF(5mL)中的混合物。将混合物在搅拌下加热至65℃且保持1.5h,然后冷却至10℃。添加6-溴-1-苯基-2,3-二氢-1H-茚(0.55g,2.01mmol)于THF(0.5mL)中的溶液,然后添加(2-溴乙氧基)(叔丁基)二甲基甲硅烷(0.86mL,4.03mmol)并将反应混合物在室温搅拌1h。然后将混合物用水(25mL)淬灭并用二氯甲烷(50mL)萃取。将有机萃取物用硫酸镁干燥并减压浓缩,得到(2-(6-溴-1-苯基-2,3-二氢-1H-茚-1-基)乙氧基)(叔丁基)二甲基甲硅烷,其为无色油状物。将该物质立即溶于甲醇(20mL)并用4N氯化氢/二噁烷(2mL)处理。将该混合物在室温搅拌1h,然后减压浓缩。经由硅胶色谱(己烷/乙酸乙酯5:1)纯化残余物,得到2-(6-溴-1-苯基-2,3-二氢-1H-茚-1-基)乙醇(518mg,73%)。LCMS m/z(M+Na)341。
步骤4:4-[3-(2-羟基乙基)-3-苯基-茚满-5-基]-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
将2-(6-溴-1-苯基-2,3-二氢-1H-茚-1-基)乙醇(476mg,1.5mmol)、碳酸钾(518mg,3.75mmol)、6-甲基-1-(对甲苯基磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[2,3-c]吡啶-7-酮(中间体C,642mg,1.5mmol)和四(三苯基膦)钯(0)(173mg,0.15mmol)于1,4-二噁烷(7.5mL)和水(1.5mL)中的混合物在氮气气氛下清洗并置于氮气气氛下。将反应混合物加热至95℃且保持4h,然后冷却至室温。将混合物直接加载于硅胶柱上,用乙酸乙酯/己烷(1:1)洗脱,得到标题化合物(487mg,54%)。LCMS m/z(M+H)539。
步骤5:4-(3-(2-羟基乙基)-3-苯基-2,3-二氢-1H-茚-5-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
将氢氧化钾(25mg,0.45mmol)添加至4-[3-(2-羟基乙基)-3-苯基-茚满-5-基]-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(240mg,0.45mmol)于甲醇(2mL)中的溶液。将反应混合物在室温搅拌1h,然后预吸附于硅胶(5g)上。该混合物接受使用二氯甲烷/甲醇(10:1)的硅胶色谱,得到4-(3-(2-羟基乙基)-3-苯基-2,3-二氢-1H-茚-5-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(107mg,56%)。1H NMR(400MHz,DMSO-d6)δ12.11(br.s.,1H)7.41-7.26(m,9H),7.16(t,1H)6.33(t,1H)3.58(s,3H),3.36-3.32(m,2H),2.94-2.80(m,2H),2.46-2.43(m,2H),2.34-2.29(m,1H)2.25-2.18(m,1H)。LCMS m/z(M+H)385。
实施例9
8-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3,3a-二氢吡咯并[1,2-a]喹喔啉-1,4(2H,5H)-二酮
步骤1:4-(3-氟-4-硝基-苯基)-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
通过实施例1中描述的Suzuki方法自中间体B和(3-氟-4-硝基苯基)硼酸制备标题化合物。
步骤2:8-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3,3a-二氢吡咯并[1,2-a]喹喔啉-1,4(2H,5H)-二酮
将4-(3-氟-4-硝基-苯基)-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(0.059g,0.13mmol)、2-氨基戊二酸(0.044g,0.27mmol)和碳酸钾(0.037g,0.27mmol)于水(0.05mL)和二甲基亚砜(6mL)中的混合物在室温搅拌2h。将混合物用乙酸乙酯稀释并经使用甲醇淋洗的硅藻土过滤。减压浓缩合并的滤液,得到粗中间体,其直接用于下一步。
将粗中间体1-(5-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-2-硝基苯基)-5-氧代吡咯烷-2-甲酸(0.053g,0.13mmol)溶于乙醇(5mL)和乙酸(0.15ml,2.68mmol)。添加铁(0.060g,1.07mmol)并将混悬液在110℃加热1.5h。冷却后,将混合物用乙酸乙酯稀释并经使用乙酸乙酯淋洗的硅藻土过滤混合物。减压浓缩合并的滤液并通过制备型HPLC(乙腈/水/0.1%三氟乙酸)纯化残余物,得到标题化合物(3.7mg,6%),其为白色固体。1H NMR(400MHz,DMSO-d6)δ12.01-12.23(m,1H),10.76(s,1H),8.26(d,J=1.87Hz,1H),7.21-7.39(m,2H),7.06(d,J=8.10Hz,1H),6.41-6.58(m,1H),4.53(s,1H),3.50-3.61(m,3H),2.54-2.72(m,1H),2.10-2.48(m,3H)。LCMS m/z(M+H)349。
以与实施例9类似的方式制备以下化合物:
实施例10-17
实施例18
N,N-二甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺
步骤1:N,N-二甲基-4-[6-甲基-7-氧代-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-4-基]苯甲酰胺
向4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(中间体B,30mg,0.08mmol)、[4-(二甲基氨甲酰基)苯基]硼酸(20mg,0.1mmol)于乙腈(0.5mL)和1M碳酸钾水溶液(0.5mL)中的混合物中添加[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(6mg,0.008mmol)。将反应混合物在微波辐射下在120℃搅拌10分钟。将反应混合物用水(5mL)稀释,然后用乙酸乙酯(3×5mL)萃取.将合并的有机萃取物用硫酸钠干燥并减压浓缩,得到标题化合物(60mg,100%产率)。该粗物质未经进一步纯化即用于下一步。LCMS m/z(M+H)450.4。
步骤2:N,N-二甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺
将N,N-二甲基-4-[6-甲基-7-氧代-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-4-基]苯甲酰胺(60mg,0.1mmol)于甲醇(1mL)和10M氢氧化钾水溶液(0.1mL)中的混合物在45℃搅拌2h。减压浓缩混合物并将残余物溶于水(10mL)。混合物用乙酸乙酯(3×10mL)萃取。将合并的有机萃取物用硫酸钠干燥并减压浓缩。通过制备型HPLC(5-50%ACN/(0.1%NH4OH/H2O))纯化残余物,得到标题化合物(11mg,30%产率),其为白色固体。1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.68-7.62(m,2H),7.52-7.48(m,2H),7.45(s,1H),7.36(t,J=2.8Hz,1H),6.48(q,J=2.0Hz,1H),3.59(s,3H),2.99(s,6H)。LCMS m/z(M+H)296.2。
实施例19
N,N-二甲基-3-(7-氧代-6-丙基-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺
步骤1:4-溴-6-丙基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
以与中间体B类似的方式制备4-溴-6-丙基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(210mg,100%)。LCMS m/z(M+H)409/411。
步骤2:N,N-二甲基-3-[7-氧代-6-丙基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-4-基]苯甲酰胺
向4-溴-6-丙基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(210mg,0.51mmol)和[3-(二甲基氨甲酰基)苯基]硼酸(110mg,0.56mmol)于乙腈(2mL)和1M碳酸钾水溶液(2mL)中的混合物中添加[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(38mg,0.051mmol)。使反应混合物在100℃接受微波辐射10分钟。通过使用乙酸乙酯(30mL)淋洗的硅藻土垫过滤混合物。将滤液用盐水(10mL)洗涤,用硫酸钠干燥并减压浓缩,得到标题化合物(240mg,98%产率),其为黄色固体。该粗物质未经进一步纯化即用于下一步。LCMS m/z(M+H)478。
步骤3:N,N-二甲基-3-(7-氧代-6-丙基-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺
将N,N-二甲基-3-[7-氧代-6-丙基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-4-基]苯甲酰胺(240mg,0.50mmol)于甲醇(2mL)和10M氢氧化钾水溶液(0.4mL)中的混合物在50℃搅拌1h。冷却后,减压浓缩反应混合物。将残余物溶于水(5mL)并用乙酸乙酯(3×10mL)萃取。将合并的有机萃取物用硫酸钠干燥并减压浓缩。通过制备型HPLC(25-35%ACN/(0.1%NH4OH/H2O))纯化残余物,得到标题化合物(17.3mg,10%产率),其为白色固体。1HNMR(400MHz,DMSO-d6)δ7.68(dt,J=7.9,1.4Hz,1H),7.60-7.48(m,2H),7.42(s,1H),7.40-7.29(m,2H),6.43(t,J=2.3Hz,1H),4.00(dd,J=8.0,6.6Hz,2H),2.99(d,J=13.3Hz,6H),1.72(m,J=7.3Hz,2H),0.91(m,J=7.4Hz,3H)。LCMS m/z(M+H)324。
以与实施例19类似的方式制备以下化合物:
实施例20-25
实施例26
6-甲基-4-(4-(4-甲基-3-氧代哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
将HATU(184mg,0.48mmol)添加至搅拌的4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酸(中间体D)(100mg,0.37mmol)、1-甲基哌嗪-2-酮(63mg,0.56mmol)和二异丙基乙基胺(168mg,1.30mmol)于DMF(5mL)中的混合物。将反应混合物在室温搅拌8h,此时LCMS指示反应已经完成。将反应混合物在乙酸乙酯(20mL)与水(15mL)之间分配。将分离的有机溶液用盐水(2×10mL)洗涤,用硫酸钠干燥并减压浓缩。通过制备型HPLC(乙腈:水(10nM碳酸氢铵)35%-65%)纯化残余物,得到标题化合物(47.9mg,15.8%产率),其为白色固体。1H NMR(400MHz,DMSO-d6):δ12.14(s,1H),7.66(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),7.45(s,1H),7.35(s,1H),6.47(d,J=2.0Hz,1H),4.12-4.09(m,4H),3.56-3.50(m,2H),3.47(s,3H),2.85(s,3H)。LCMSm/z(M+H)365.1。
以与实施例26类似的方式制备以下化合物:
实施例27-38
实施例39
4-[4-(1-羟基-1-甲基-乙基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮
步骤1:2-(4-溴苯基)丙-2-醇
将正丁基锂(6.8mL,17.0mmol)逐滴添加至搅拌和冷却的(-78℃)1,4-二溴苯(4.0g,16.9mmol)于THF(50mL)中的溶液。添加后,继续在-78℃搅拌1h并逐滴添加丙酮(3.0g,51.7mmol)。将所得混合物温热至0℃并再搅拌3h,然后通过添加饱和氯化铵水溶液(40mL)淬灭。用75%乙酸乙酯/石油醚(3×50mL)萃取混合物。将合并的有机萃取物用盐水(50mL)洗涤,用硫酸钠干燥并减压浓缩,得到标题化合物(1.8g,50%产率),其为无色油状物。LCMS m/z[M-OH+]197.0。
步骤2:2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-醇
将乙酸钾(1.4g,13.9mmol)、4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-联(1,3,2-二氧杂硼杂环戊烷)(2.2g,8.4mmol)、2-(4-溴苯基)丙-2-醇(1.5g,7.0mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(0.15g,0.2mmol)于二噁烷(15mL)中的混合物脱气30min,然后在氮气下在80℃加热12h。冷却后,通过使用乙酸乙酯淋洗的硅藻土垫过滤反应混合物。蒸发滤液并通过硅胶色谱(石油醚:乙酸乙酯1:1)纯化残余物,得到标题化合物(1.1g,68.7%产率),其为无色油状物。
步骤3:4-溴-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮
将氢氧化钠(0.94g,23.6mmol)于水(4mL)中的溶液缓慢添加至4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(中间体B,1.8g,4.7mmol)于甲醇(40mL)中的溶液。将所得混合物在80℃加热2h。冷却后,减压浓缩混合物并用水(30mL)稀释含水残余物。通过过滤收集所得析出物,用水(2×30mL)洗涤并减压浓缩,得到标题化合物(0.9g,84%产率),其为白色固体。LCMS m/z(M+1)227。
步骤4:6-甲基-4-(4-(2-羟基丙-2-基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
在氮气下将4-溴-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮(步骤3,200mg,0.88mmol)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-醇(步骤2,277mg,1.1mmol)、碳酸铯(574mg,1.8mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(0.02g,0.03mmol)于二噁烷(6mL)和水(1mL)中的混合物在90℃加热3h。冷却后,通过使用乙酸乙酯淋洗的硅藻土过滤混合物。减压浓缩滤液并通过硅胶色谱(石油醚:乙酸乙酯=1:1)纯化残余物,得到标题化合物(38.5mg,16%产率),其为白色固体。1H NMR(400MHz,DMSO-d6):δ12.13(s,1H),7.55-7.50(m,4H),7.34-7.33(m,2H),6.44-6.43(m,1H),5.04(s,1H),3.57(s,3H),1.46(s,6H)。LCMS m/z(M+H)282.8
以与实施例39类似的方式自2-碘丙烷制备实施例40。
实施例41
6-环丙基-4-(4-(2-羟基丙-2-基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
步骤1:4-溴-6-环丙基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
向4-溴-1-(对甲苯基磺酰基)-6H-吡咯并[2,3-c]吡啶-7-酮(中间体A)(1.0g,2.7mmol)、环丙基硼酸(480mg,5.6mol)和Cu(OAc)2(500mg,2.7mmol)于二氯乙烷(30mL)中的混合物中添加2,2’-联吡啶(421mg,2.7mmol),随后添加碳酸氢钠(600mg,5.7mmol)。将所得混合物在70℃加热12h。冷却后,通过使用乙酸乙酯淋洗的小硅藻土垫过滤混合物。减压浓缩滤液并通过硅胶色谱(石油醚:乙酸乙酯10:1至3:1)纯化残余物,得到标题化合物(0.6g,54.5%产率),其为浅黄色固体。LCMS m/z(M+1)408.7。
步骤2:4-溴-6-环丙基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
将氢氧化钠(0.3g,7.5mmol)于水(1.5mL)中的溶液缓慢添加至4-溴-6-环丙基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮(0.6g,1.5mmol)于MeOH(15mL)和水(1.5mL)中的溶液。将所得混合物在80℃加热3h。冷却后,减压部分浓缩混合物并用水(30mL)稀释含水残余物。通过过滤收集所得析出物,得到标题化合物(307mg,81.2%产率),其为白色固体。该粗物质未经进一步纯化即用于下一步。LCMS m/z(M+1)252.6。
步骤3:6-环丙基-4-(4-(2-羟基丙-2-基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
在氮气保护下将4-溴-6-环丙基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(252mg,1.0mmol)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-醇(315mg,1.2mmol)、碳酸铯(652mg,2.0mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(73mg,0.1mmol)于二噁烷(10mL)和水(2mL)中的混合物在90℃加热3h。冷却后,通过使用乙酸乙酯淋洗的小硅藻土垫过滤混合物。减压浓缩滤液并通过制备型HPLC(乙腈:水(10nM碳酸氢铵),55%-85%)纯化残余物,得到标题化合物(38.9mg,12.7%产率),其为白色固体。1HNMR(400MHz,DMSO-d6):δ12.10(s,1H),7.55-7.50(m,4H),7.35-7.33(t,J=2.8Hz,1H),7.07(s,1H),6.41(d,J=2.4Hz,1H),5.02(s,1H),3.41-3.36(m,1H),1.46(s,6H),1.05-1.00(m,2H),0.99-0.92(m,2H)。LCMS m/z(M+H)308.9。
实施例42
6-甲基-4-[4-(1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮
步骤1:4-(4-溴苯基)-1-甲基哌啶
将4-(4-溴苯基)哌啶(200mg,0.84mmol)和甲醛(35-40%水溶液,1mL)于甲醇(15mL)中的混合物在30℃搅拌5h。按份添加硼氢化钠(80mg,2.12mmol)。添加后,继续搅拌30min,此时TLC指示反应已经完成。通过添加饱和氯化铵水溶液(10mL)淬灭反应混合物,然后通过添加饱和碳酸氢钠水溶液调节至pH 8-9。用乙酸乙酯(3×20mL)萃取所得混合物。将合并的有机萃取物用硫酸钠干燥并减压浓缩。通过制备型TLC(二氯甲烷:甲醇10:1)纯化残余物,得到标题化合物(120mg,56.7%产率),其为白色固体。LCMS m/z(M+H)255.3。
步骤2:6-甲基-4-[4-(1-甲基-4-哌啶基)苯基]-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
使4-(4-溴苯基)-1-甲基哌啶(180mg,0.72mmol)、6-甲基-1-(对甲苯基磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[2,3-c]吡啶-7-酮(中间体C)(200mg,0.47mmol)、碳酸铯(520mg,1.60mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(10mg,0.01mmol)于二噁烷(1.5mL)和水(0.5mL)中的混合物在110℃接受微波辐射0.5h。冷却后,将反应混合物在水(15mL)与乙酸乙酯(30mL)之间分配。分离的有机溶液用硫酸钠干燥并减压浓缩。通过制备型TLC(二氯甲烷:甲醇10:1)纯化残余物,得到标题化合物(130mg,58.3%产率),其为黄色固体。LCMS m/z(M+H)476.2。
步骤3:6-甲基-4-[4-(1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮
将6-甲基-4-[4-(1-甲基-哌啶-4-基)-苯基]-1-(甲苯-4-磺酰基)-1,6-二氢-吡咯并[2,3-c]吡啶-7-酮(130mg,0.27mmol)于二噁烷(10mL)和氢氧化钠水溶液(2.5N,2mL)中的溶液在100℃加热1h。冷却后,使用2N盐酸将混合物调节至pH=7.0,然后减压浓缩。通过制备型HPLC(乙腈:水(10nM氨)35%-65%)纯化残余物,得到标题化合物(16.6mg,18.9%产率),其为白色固体。1H NMR(400MHz,CD3OD):δ7.55(d,J=8.0Hz,2H),7.40-7.36(m,3H),7.26(s,1H),6.54(d,J=2.8Hz,1H),3.72(s,3H),3.05-3.02(m,2H),2.65-2.63(m,1H),2.36(s,3H),2.23-2.18(m,2H),1.90-1.84(m,4H)。LCMS m/z(M+H)322.1。
以与实施例42类似的方式制备以下化合物。
实施例45
6-甲基-4-[4-[(1-甲基-4-哌啶基)甲基]苯基]-1H-吡咯并[2,3-c]吡啶-7-酮
步骤1:4-(4-溴苄基)哌啶-1-甲酸叔丁酯
将4-甲酰基哌啶-1-甲酸叔丁酯(500mg,2.34mmol)和甲苯磺酰基肼(436mg,2.34mmol)于二噁烷(15mL)中的混合物在80℃加热1.5h。冷却后,添加(4-溴苯基)硼酸(500mg,2.49mmol)和碳酸钾(486mg,2.49mmol)。将所得混合物在100℃加热3h。减压浓缩混合物并用水(25mL)稀释残余物。然后用乙酸乙酯(3×40mL)萃取混合物。将合并的有机萃取物用硫酸钠干燥并减压浓缩。通过制备型TLC(石油醚:乙酸乙酯3:1)纯化残余物,得到标题化合物(200mg,36.4%产率),其为白色固体。LCMS m/z(M+H)255.3。
步骤2:4-(4-溴苄基)-1-甲基哌啶
将4-(4-溴苄基)哌啶-1-甲酸叔丁酯(200mg,0.57mmol)于乙酸乙酯(15mL)中的溶液在室温用HCl(2N于乙酸乙酯中,1mL)处理1h。减压浓缩混合物并将残余物与甲醛(35-40%水溶液,1mL)和甲醇(5mL)合并。将所得混合物在室温搅拌5h,然后按份添加硼氢化钠(100mg,2.64mmol)。添加后,继续搅拌30min。通过添加饱和氯化铵水溶液(5mL)淬灭反应混合物并通过添加饱和碳酸氢钠水溶液将混合物调节至pH 8-9。然后用乙酸乙酯(3×30mL)萃取混合物。将合并的有机萃取物用硫酸钠干燥并减压浓缩。通过制备型TLC(二氯甲烷:甲醇10:1)纯化残余物,得到标题化合物(50mg,历经2步32.9%),其为白色固体。LCMS m/z(M+H)267.2。
步骤3:6-甲基-4-[4-[(1-甲基-4-哌啶基)甲基]苯基]-1H-吡咯并[2,3-c]吡啶-7-酮
使4-(4-溴苄基)-1-甲基哌啶(50mg,0.19mmol)、6-甲基-1-(对甲苯基磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[2,3-c]吡啶-7-酮(中间体C)(95mg,0.22mmol)、碳酸铯(125mg,0.38mmol)和[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(15mg,0.02mmol)于二噁烷(2mL)和水(0.5mL)中的混合物在110℃接受微波辐射0.5h。冷却后,将反应混合物在水(5mL)与乙酸乙酯(20mL)之间分配。分离的有机溶液用硫酸钠干燥并减压浓缩。通过制备型TLC(二氯甲烷:甲醇10:1)纯化残余物,得到所期望的中间体(约80mg,70%纯度)。将物质溶于二噁烷(5mL)和2.5N氢氧化钠水溶液(1mL)。将混合物在100℃加热1h。冷却后,使用2N HCl调节混合物至pH=7.0,然后减压浓缩。通过制备型HPLC(乙腈:水(10nM氨)34%-64%)纯化残余物,得到标题化合物(7.0mg,历经2步10.9%),其为白色固体。1H NMR(400MHz,CD3OD):δ7.53(d,J=8.0Hz,2H),7.39(s,1H),7.29-7.25(m,3H),6.55(d,J=2.8Hz,1H),3.72(s,3H),2.90-2.87(m,2H),2.63-2.62(m,2H),2.27(s,3H),2.03-2.00(m,2H),1.73-1.62(m,3H),1.37-1.34(m,2H)。LCMS m/z(M+H)336.2。
以与实施例45类似的方式制备实施例46。
实施例47
3-(2,6-二甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N,N-二甲基-苯甲酰胺
步骤1:4-溴-2,6-二甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮
在室温将碘甲烷(112mg,0.79mmol)逐滴添加搅拌的4-溴-2-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(中间体E)(300mg,1.32mmol)和碳酸钾(274mg,1.98mmol)于DMF(15mL)中的混合物。添加后,将混合物在70℃搅拌15h。通过添加水(25mL)淬灭所得混合物并用乙酸乙酯(20mL×2)萃取。合并的有机层用硫酸钠干燥并减压浓缩。通过制备型TLC(甲醇/二氯甲烷=1/15)纯化粗产物,得到标题化合物,其为棕色固体(82mg,26%)。1H NMR(400MHz,CD3OD):δ7.33(s,1H),6.07(s,1H),3.58(s,3H),2.39(s,3H)。
步骤2:3-(2,6-二甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-N,N-二甲基苯甲酰胺
在氮气气氛下向4-溴-2,6-二甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(步骤1,82mg,0.34mmol)、(3-(二甲基氨甲酰基)苯基)硼酸(66mg,0.34mmol)、碳酸铯(227mg,0.70mmol)于二噁烷/水(3.5mL,6:1)中的混合物中添加[1,1’-二(二苯基膦基)二茂铁]二氯化钯(II)(10mg,0.013mmol)。然后将反应混合物在110℃在氮气下加热18h。将反应混合物冷却至室温,然后通过硅藻土过滤混合物。减压浓缩滤液,然后通过制备型HPLC(乙腈:水(0.3%甲酸)25%-55%)纯化残余物,得到标题化合物,其为棕色固体(6.9mg,6.5%)。1HNMR(400MHz,CD3OD):δ7.73-7.72(m,1H),7.65(s,1H),7.55-7.59(m,1H),7.2(d,J=7.6Hz,1H),7.32(s,1H),6.28(s,1H),3.72(s,3H),3.16(s,3H),3.09(s,3H),2.45(s,3H)。LCMS m/z(M+H)310.1
实施例48
用于下述TAF测定的生物素化探针化合物(1000)的合成。
步骤1:2-甲氧基-4-甲基-3-硝基吡啶
将2-氯-4-甲基-3-硝基吡啶(250g,1.45mol)于甲醇(1.0L)中的溶液逐滴添加(2h)至搅拌和冷却的(0℃)甲醇钠(250g,4.63mol)于甲醇(850mL)中的溶液。添加后,将混合物加热至回流且保持23h,此时TLC指示反应已经完成。减压浓缩混合物至约900mL的体积并通过添加水(1.5L)淬灭。通过过滤收集所得固体,用水洗涤并减压干燥,得到标题化合物(250g,100%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ8.22(d,J=5.2Hz,1H),7.10(d,J=5.6Hz,1H),3.92(s,3H),2.26(s,3H)。
步骤2:5-溴-2-甲氧基-4-甲基-3-硝基吡啶
在环境温度将乙酸钠(365g,5.37mol)添加至搅拌的2-甲氧基-4-甲基-3-硝基吡啶(250g,1.49mol)于乙酸(1.5L)中的溶液,然后逐滴添加(30min)Br2(639g,4.00mol)。添加后,将混合物在80℃加热12h,此时TLC指示反应已经完成。将混合物冷却(0℃)并通过依序添加10%Na2SO3水溶液(1.5L)和饱和Na2SO3水溶液(1.5L)淬灭。通过过滤收集所得固体,用水洗涤并减压干燥,得到标题化合物(302g,82.2%产率),其为浅黄色固体。1H NMR(400MHz,DMSO-d6):δ8.25(s,1H),3.94(s,3H),2.29(s,3H)。
步骤3:(E)-2-(5-溴-2-甲氧基-3-硝基-4-吡啶基)-N,N-二甲基-乙烯胺
将DMF-DMA(600mL)缓慢添加至搅拌和加热的(80℃)5-溴-2-甲氧基-4-甲基-3-硝基吡啶(134g,0.54mol)于DMF(1.1L)中的溶液。添加后,将混合物在95℃加热5h,此时TLC指示反应已经完成。将混合物冷却至室温并倒入冰冷的水(3L)中。通过过滤收集所得红色固体,用水洗涤并减压干燥,得到标题化合物(167g,100%产率),其为红色固体。1H NMR(400MHz,DMSO-d6):δ8.24(s,1H),7.05(d,J=13.6Hz,1H),7.05(d,J=13.6Hz,1H),4.80(d,J=13.2Hz,1H),3.88(s,3H),2.90(s,6H)。
步骤4:4-溴-7-甲氧基-1H-吡咯并[2,3-c]吡啶
将2-(5-溴-2-甲氧基-3-硝基吡啶-4-基)-N,N-二甲基乙烯胺(50.0g,165mmol)、Fe(50.0g,893mmol)和NH4Cl(50.0g,943mmol)于甲醇/H2O(1900/250mL)中的混合物加热回流7h,此时LCMS指示反应已经完成。将混合物趁热过滤并用甲醇(3×200mL)洗涤滤饼。减压浓缩合并的滤液并通过硅胶色谱(石油醚:乙酸乙酯=5:1)纯化所得残余物,得到粗产物。用乙腈研磨该粗物质,得到标题化合物(37.4g,99.5%产率),其为浅棕色固体。LCMS m/z(M+H)226.7,228.7。
步骤5:4-溴-7-甲氧基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶
将4-溴-7-甲氧基-1H-吡咯并[2,3-c]吡啶(34.3g,0.15mol)于THF(700mL)中的溶液逐滴添加至搅拌和冷却的(0℃)氢化钠(60%,19.2g,0.48mol)于THF(700mL)中的溶液。添加后,将混合物在室温搅拌1h,然后再次冷却至0℃。逐滴添加甲苯磺酰氯(38.0g,0.20mol)于THF(700mL)中的溶液并将所得混合物在环境温度搅拌2h。通过添加饱和氯化铵水溶液(1.0L)淬灭反应混合物,然后用乙酸乙酯(3×600mL)萃取。合并的有机萃取物用Na2SO4干燥并减压浓缩。用乙腈研磨残余物,得到标题化合物(51.2g,88.9%产率),其为棕色固体。该粗物质未经进一步纯化即用于下一步。
步骤6:4-溴-1-(对甲苯基磺酰基)-6H-吡咯并[2,3-c]吡啶-7-酮
将HBr(40%水溶液,1.1L)添加至4-溴-7-甲氧基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶(102.5g,0.27mol)于乙醇(200mL)中的溶液。添加后,将混合物在90℃加热2h,此时TLC指示反应已经完成。将混合物冷却至0℃并通过过滤收集所得白色固体。该固体用水洗涤并真空干燥,得到标题化合物(87.5g,88.6%产率),其为浅棕色固体。1H NMR(400MHz,DMSO-d6):δ11.48(s,1H),8.01(d,J=3.6Hz,1H),8.90(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.32(s,1H),6.57(d,J=3.2Hz,1H),2.34(s,3H)。
步骤7:4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
将碘甲烷(24.5g,172.8mmol)逐滴添加至搅拌的4-溴-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(中间体A)(16.7g,45.5mmol)和碳酸铯(17.8g,54.6mmol)于二噁烷(250mL)中的混悬液。添加后,将反应混合物在室温搅拌18h,此时LCMS指示反应已经完成。减压蒸发溶剂并用水(200mL)稀释残余物。用EtOAc(3×200mL)萃取混合物。合并的有机萃取物用硫酸钠干燥,过滤并减压浓缩。通过硅胶色谱(石油醚/乙酸乙酯=3:1)纯化残余物,得到标题化合物(14.0g,81.4%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ8.03(d,J=3.6Hz,1H),7.92(d,J=8.4Hz,2H),7.78(s,1H),7.39(d,J=8.4Hz,2H),6.57(d,J=3.6Hz,1H),3.35(s,3H),2.35(s,3H)。
步骤8:
50mL小瓶装入磁力搅拌棒、4-溴-6-甲基-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(0.281g,0.737mmol)、1,4-二噁烷(3.69ml,0.737mmol)、水(0.5ml,27.8mmol)、K2CO3(0.306g,2.211mmol)、4-(叔丁氧基羰基氨基)苯基硼酸(0.227g,0.958mmol)和Pd(PPh3)4(0.085g,0.074mmol)。将小瓶在氮气气氛下冲洗,置于氮气气氛下并在搅拌下加热至95℃且保持12h,然后冷却至室温。然后用水(20ml)稀释反应混合物。使用布氏漏斗经由真空过滤收集所形成的析出物。固体用额外的水(2×25mL)洗涤,干燥并收集。将该物质混悬于甲醇(约5mL)并用KOH(200mg)处理。2h后,真空除去MeOH并将粗物质混悬于水(约20mL)且使用布氏漏斗经由真空过滤收集所得固体。固体用额外的水洗涤,收集并真空干燥,得到4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基氨基甲酸叔丁酯(362mg,0.907mmol),其为浅黄色固体。LCMS m/z(M+H)494。
步骤9:
50mL圆底烧瓶装入磁力搅拌棒、4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基氨基甲酸叔丁酯(350mg,1.031mmol)、MeOH(2.062mL,1.031mmol)和HCl(1.031mL,4.12mmol)(4N于二噁烷中)。然后将反应混合物在室温搅拌4h,然后用二噁烷(25mL)稀释。使用布氏漏斗经由真空过滤收集所形成的析出物,用额外的二噁烷洗涤并真空干燥,得到4-(4-氨基苯基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(188mg,0.786mmol,76%产率),其为白色固体。LCMS m/z(M+H)240。
步骤10:
25mL小瓶装入磁力搅拌棒、4-(4-氨基苯基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(0.038g,0.159mmol)、无水DMF(0.794ml,0.159mmol)、DIPEA(0.139ml,0.794mmol)、17-氧代-21-((3aS,4S,6aR)-2-氧代-六氢-1H-噻吩并[3,4-d]咪唑-4-基)-4,7,10,13-四氧杂-16-氮杂二十一烷-1-酸(0.078g,0.159mmol)和HATU(0.075g,0.199mmol)。经由反相HPLC直接纯化粗反应混合物,得到N-(4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-1-(5-((3aS,4S,6aR)-2-氧代-六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酰氨基)-3,6,9,12-四氧杂十五烷-15-酰胺(31mg,0.041mmol,26.0%产率)。LCMS m/z(M+2H)/2 357。
实施例49
用于下述CECR2测定的生物素化探针化合物(1001)的合成。
步骤1:2-甲氧基-4-甲基-3-硝基吡啶
将2-氯-4-甲基-3-硝基吡啶(250g,1.45mol)于甲醇(1.0L)中的溶液逐滴添加(2h)至搅拌和冷却的(0℃)甲醇钠(250g,4.63mol)于甲醇(850mL)中的溶液。添加后,将混合物加热至回流且保持23h,此时TLC指示反应已经完成。减压浓缩混合物至约900mL的体积并通过添加水(1.5L)淬灭。通过过滤收集所得固体,用水洗涤并减压干燥,得到标题化合物(250g,100%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ8.22(d,J=5.2Hz,1H),7.10(d,J=5.6Hz,1H),3.92(s,3H),2.26(s,3H)。
步骤2:5-溴-2-甲氧基-4-甲基-3-硝基吡啶
在环境温度将乙酸钠(365g,5.37mol)添加至搅拌的2-甲氧基-4-甲基-3-硝基吡啶(250g,1.49mol)于乙酸(1.5L)中的溶液,然后逐滴添加(30min)Br2(639g,4.00mol)。添加后,将混合物在80℃加热12h,此时TLC指示反应已经完成。将混合物冷却(0℃)并通过依序添加10%Na2SO3水溶液(1.5L)和饱和Na2SO3水溶液(1.5L)淬灭。通过过滤收集所得固体,用水洗涤并减压干燥,得到标题化合物(302g,82.2%产率),其为浅黄色固体。1H NMR(400MHz,DMSO-d6):δ8.25(s,1H),3.94(s,3H),2.29(s,3H)。
步骤3:(E)-2-(5-溴-2-甲氧基-3-硝基-4-吡啶基)-N,N-二甲基-乙烯胺
将DMF-DMA(600mL)缓慢添加至搅拌和加热的(80℃)5-溴-2-甲氧基-4-甲基-3-硝基吡啶(134g,0.54mol)于DMF(1.1L)中的溶液。添加后,将混合物在95℃加热5h,此时TLC指示反应已经完成。将混合物冷却至室温并倒入冰冷的水(3L)中。通过过滤收集所得红色固体,用水洗涤并减压干燥,得到标题化合物(167g,100%产率),其为红色固体。1H NMR(400MHz,DMSO-d6):δ8.24(s,1H),7.05(d,J=13.6Hz,1H),7.05(d,J=13.6Hz,1H),4.80(d,J=13.2Hz,1H),3.88(s,3H),2.90(s,6H)。
步骤4:4-溴-7-甲氧基-1H-吡咯并[2,3-c]吡啶
将2-(5-溴-2-甲氧基-3-硝基吡啶-4-基)-N,N-二甲基乙烯胺(50.0g,165mmol)、Fe(50.0g,893mmol)和NH4Cl(50.0g,943mmol)于甲醇/H2O(1900/250mL)中的混合物加热回流7h,此时LCMS指示反应已经完成。将混合物趁热过滤并用甲醇(3×200mL)洗涤滤饼。减压浓缩合并的滤液并通过硅胶色谱(石油醚:乙酸乙酯=5:1)纯化所得残余物,得到粗产物。用乙腈研磨该粗物质,得到标题化合物(37.4g,99.5%产率),其为浅棕色固体。LCMS m/z(M+H)226.7,228.7。
步骤5:4-溴-7-甲氧基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶
将4-溴-7-甲氧基-1H-吡咯并[2,3-c]吡啶(34.3g,0.15mol)于THF(700mL)中的溶液逐滴添加至搅拌和冷却的(0℃)氢化钠(60%,19.2g,0.48mol)于THF(700mL)中的溶液。添加后,将混合物在室温搅拌1h,然后再次冷却至0℃。逐滴添加甲苯磺酰氯(38.0g,0.20mol)于THF(700mL)中的溶液并将所得混合物在环境温度搅拌2h。通过添加饱和氯化铵水溶液(1.0L)淬灭反应混合物,然后用乙酸乙酯(3×600mL)萃取。合并的有机萃取物用Na2SO4干燥并减压浓缩。用乙腈研磨残余物,得到标题化合物(51.2g,88.9%产率),其为棕色固体。该粗物质未经进一步纯化即用于下一步。
步骤6:4-溴-1-(对甲苯基磺酰基)-6H-吡咯并[2,3-c]吡啶-7-酮
将HBr(40%水溶液,1.1L)添加至4-溴-7-甲氧基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶(102.5g,0.27mol)于乙醇(200mL)中的溶液。添加后,将混合物在90℃加热2h,此时TLC指示反应已经完成。将混合物冷却至0℃并通过过滤收集所得白色固体。该固体用水洗涤并真空干燥,得到标题化合物(87.5g,88.6%产率),其为浅棕色固体。1H NMR(400MHz,DMSO-d6):δ11.48(s,1H),8.01(d,J=3.6Hz,1H),8.90(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.32(s,1H),6.57(d,J=3.2Hz,1H),2.34(s,3H)。
步骤7:4-溴-6-甲基-1-(对甲苯基磺酰基)吡咯并[2,3-c]吡啶-7-酮
将碘甲烷(24.5g,172.8mmol)逐滴添加至搅拌的4-溴-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(中间体A)(16.7g,45.5mmol)和碳酸铯(17.8g,54.6mmol)于二噁烷(250mL)中的混悬液。添加后,将反应混合物在室温搅拌18h,此时LCMS指示反应已经完成。减压蒸发溶剂并用水(200mL)稀释残余物。用EtOAc(3×200mL)萃取混合物。合并的有机萃取物用硫酸钠干燥,过滤并减压浓缩。通过硅胶色谱(石油醚/乙酸乙酯=3:1)纯化残余物,得到标题化合物(14.0g,81.4%产率),其为棕色固体。1H NMR(400MHz,DMSO-d6):δ8.03(d,J=3.6Hz,1H),7.92(d,J=8.4Hz,2H),7.78(s,1H),7.39(d,J=8.4Hz,2H),6.57(d,J=3.6Hz,1H),3.35(s,3H),2.35(s,3H)。
步骤8:
50mL小瓶装入磁力搅拌棒、4-溴-6-甲基-1-甲苯磺酰基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(0.281g,0.737mmol)、1,4-二噁烷(3.69ml,0.737mmol)、水(0.5ml,27.8mmol)、K2CO3(0.306g,2.211mmol)、4-(叔丁氧基羰基氨基)苯基硼酸(0.227g,0.958mmol)和Pd(PPh3)4(0.085g,0.074mmol)。将小瓶在氮气气氛下冲洗,置于氮气气氛下并在搅拌下加热至95℃且保持12h,然后冷却至室温。然后用水(20ml)稀释反应混合物。使用布氏漏斗经由真空过滤收集所形成的析出物。固体用额外的水(2×25mL)洗涤,干燥并收集。将该物质混悬于甲醇(约5mL)并用KOH(200mg)处理。2h后,真空除去MeOH并将粗物质混悬于水(约20mL)且使用布氏漏斗经由真空过滤收集所得固体。固体用额外的水洗涤,收集并真空干燥,得到4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基氨基甲酸叔丁酯(362mg,0.907mmol),其为浅黄色固体。LCMS m/z(M+H)494。
步骤9:
50mL圆底烧瓶装入磁力搅拌棒、4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基氨基甲酸叔丁酯(350mg,1.031mmol)、MeOH(2.062mL,1.031mmol)和HCl(1.031mL,4.12mmol)(4N于二噁烷中)。然后将反应混合物在室温搅拌4h,然后用二噁烷(25mL)稀释。使用布氏漏斗经由真空过滤收集所形成的析出物,用额外的二噁烷洗涤并真空干燥,得到4-(4-氨基苯基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(188mg,0.786mmol,76%产率),其为白色固体。LCMS m/z(M+H)240。
步骤10:
25mL小瓶装入磁力搅拌棒、4-(4-氨基苯基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(0.038g,0.159mmol)、无水DMF(0.794ml,0.159mmol)、DIPEA(0.139ml,0.794mmol)、17-氧代-21-((3aS,4S,6aR)-2-氧代-六氢-1H-噻吩并[3,4-d]咪唑-4-基)-4,7,10,13-四氧杂-16-氮杂二十一烷-1-酸(0.078g,0.159mmol)和HATU(0.075g,0.199mmol)。经由反相HPLC直接纯化粗反应混合物,得到N-(4-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)苯基)-1-(5-((3aS,4S,6aR)-2-氧代-六氢-1H-噻吩并[3,4-d]咪唑-4-基)戊酰氨基)-3,6,9,12-四氧杂十五烷-15-酰胺(31mg,0.041mmol,26.0%产率)。LCMS m/z(M+2H)/2 357。
实施例50
代表性化合物对布罗莫结构域的抑制活性可使用已知方法或使用以下测定方案之一进行评价。
使用BRD4AlphaLisa结合测定对抑制剂进行IC50测量
将经His/Flag表位标记的BRD4BD142-168克隆,表达并纯化至均质。通过使用AlphaLisa技术(Perkin-Elmer)监测生物素化H4-四乙酰基肽(New England Peptide,NEP2069-1/13)与靶标的接合来评估BRD4结合和抑制。具体地,在384孔ProxiPlate中在DMSO(最终1.2%DMSO)或化合物在DMSO中的系列稀释液存在下在40mM HEPES(pH 7.0)、40mM NaCl、1mM DTT、0.01%(w/v)BSA和0.008%(w/v)Brij-35中将BRD4(BD1)(最终30nM)与肽(最终200nM)组合。在室温培育20分钟后,添加AlphaLisa链霉亲和素供体珠子和AlphaLisa抗Flag受体珠子至最终浓度各自为10μg/mL。平衡3小时后,在Envision仪器上读取板并使用四参数非线性曲线拟合计算IC50。
使用BRD9AlphaLisa结合测定对抑制剂进行IC50测量
将经His/Flag表位标记的BRD9134-239克隆,表达并纯化至均质。通过使用AlphaLisa技术(Perkin-Elmer)监测生物素化H4-四乙酰基肽(New England Peptide,NEP2069-11/13)与靶标的接合来评估BRD9结合和抑制。具体地,在384孔ProxiPlate中在DMSO(最终0.8%DMSO)或化合物在DMSO中的系列稀释液存在下在50mM HEPES(pH 7.5)、150mM NaCl、1mM TCEP、0.01%(w/v)BSA和0.008%(w/v)Brij-35中将BRD9(最终50nM)与肽(最终3nM)组合。在室温培育20分钟后,添加AlphaLisa链霉亲和素受体珠子(Perkin-AL125C)和AlphaLisa镍供体珠子(Perkin AS 10ID)至最终浓度各自为15μg/mL。平衡90分钟后,在Envision仪器上读取板并使用四参数非线性曲线拟合计算IC50。
使用TAF1-BD2TR-FRET结合测定对抑制剂进行IC50测量
将经His/Flag表位标记的TAF1-BD21504-1635克隆,表达并纯化至均质。通过使用TR-FRET测定技术(Perkin-Elmer)监测生物素化小分子化合物1000(实施例48)与靶标的接合来评估TAF1-BD2结合和抑制。具体地,在384孔ProxiPlate中在DMSO(最终0.2%DMSO)或化合物在DMSO中的系列稀释液存在下在50mM HEPES(pH 7.5)、50mM NaCl、1mM TCEP、0.01%(w/v)BSA和0.008%(w/v)Brij-35中将TAF1-BD2(最终6nM)与生物素-配体(最终50nM)组合。在室温培育10分钟后,添加混合物Eu-W1024抗6×His抗体(Perkin Elmer AD0110)和SureLightTM别藻蓝蛋白-链霉亲和素(APC-SA,Perkin Elmer CR130-100)至最终浓度各自为0.2nM抗体和25nM APC-SA。平衡20分钟后,在Envision仪器上读取板并使用四参数非线性曲线拟合计算IC50。新颖的化合物1000和上述TAF1-BD2TR-FRET结合测定表示本发明额外的实施方案。
使用CECR2TR-FRET结合测定对抑制剂进行IC50测量
将经His/Flag表位标记的CECR2424-538克隆,表达并纯化至均质。通过使用TR-FRET测定技术(Perkin-Elmer)监测生物素化小分子化合物1001(实施例49)与靶标的接合来评估CECR2结合和抑制。具体地,在384孔ProxiPlate中在DMSO(最终0.2%DMSO)或化合物在DMSO中的系列稀释液存在下在50mM HEPES(pH 7.5)、50mM NaCl、1mM TCEP、0.01%(w/v)BSA和0.008%(w/v)Brij-35中将CECR2(最终1.5nM)与生物素-配体(最终25nM)组合。在室温培育15分钟后,添加混合物Eu-W1024抗6×His抗体(Perkin Elmer AD0110)和SureLightTM别藻蓝蛋白-链霉亲和素(APC-SA,Perkin Elmer CR130-100)至最终浓度各自为0.2nM抗体和12.5nM APC-SA。平衡40分钟后,在Envision仪器上读取板并使用四参数非线性曲线拟合计算IC50。新颖的化合物1001和上述CECR2TR-FRET结合测定表示本发明额外的实施方案。
代表性式(I)化合物(和本文提供的其它化合物)的来自上述四种测定的数据提供在下表中。
虽然已经描述了多种实施方案,但是可改变这些实施例以提供使用本文所述的化合物和方法的其它实施方案。因此,本发明的范围由所附权利要求书而非示例性具体实施方案来限定。
Claims (57)
1.式(I)化合物或其盐:
其中
R1为H、甲基或乙基;
R2为H、C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基,其中R2中的每个C1-12烷基、C2-12烯基、C2-12炔基、碳环基或杂环基任选取代有一个或多个基团Rb;且
Q为5元杂芳基,其任选取代有一个或多个基团Rc,或Q为:
其中环A任选取代有一个或多个基团Rc,或环A任选与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg;
X1、X2和X3各自独立选自CRc和N,条件是X1、X2和X3中的至少一个不为N;且当环A任选与碳环基或杂环基稠合以形成多环基时,X1、X2和X3中的每个可为C且可为稠合点;
每个Rb独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-O-C(O)-O-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-O-C(O)-N(Rw)2、-N(Rw)-C(O)-ORw、-N(Rw)-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw、-N(Rw)-S(O)-N(Rw)2和-N(Rw)-S(O)2-N(Rw)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rw)2、-CN、-C(O)-N(Rw)2、-S(O)-N(Rw)2、-S(O)2-N(Rw)2、-O-Rw、-S-Rw、-O-C(O)-Rw、-C(O)-Rw、-C(O)-O-Rw、-S(O)-Rw、-S(O)2-Rw、-C(O)-N(Rw)2、-N(Rw)-C(O)-Rw、-N(Rw)-S(O)-Rw、-N(Rw)-S(O)2-Rw和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;
每个Rc独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有一个或多个C1-6烷基;
Re为氢、-F、-Cl、-Br、-I、-CN、-O-Rx、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Rx)2、-CN、-C(O)-N(Rx)2、-S(O)-N(Rx)2、-S(O)2-N(Rx)2、-O-Rx、-S-Rx、-O-C(O)-Rx、-O-C(O)-O-Rx、-C(O)-Rx、-C(O)-O-Rx、-S(O)-Rx、-S(O)2-Rx、-O-C(O)-N(Rx)2、-N(Rx)-C(O)-ORx、-N(Rx)-C(O)-N(Rx)2-N(Rx)-C(O)-Rx、-N(Rx)-S(O)-Rx、-N(Rx)-S(O)2-Rx、-N(Rx)-S(O)-N(Rx)2和-N(Rx)-S(O)2-N(Rx)2;
Rf为氢、-F、-Cl、-Br、-I、-CN、-O-Ry、C1-6烷基、C2-6烯基或C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、-F、-Cl、-Br、-I、-NO2、-N(Ry)2、-CN、-C(O)-N(Ry)2、-S(O)-N(Ry)2、-S(O)2-N(Ry)2、-O-Ry、-S-Ry、-O-C(O)-Ry、-O-C(O)-O-Ry、-C(O)-Ry、-C(O)-O-Ry、-S(O)-Ry、-S(O)2-Ry、-O-C(O)-N(Ry)2、-N(Ry)-C(O)-ORy、-N(Ry)-C(O)-N(Ry)2、-N(Ry)-C(O)-Ry、-N(Ry)-S(O)-Ry、-N(Ry)-S(O)2-Ry、-N(Ry)-S(O)-N(Ry)2和-N(Ry)-S(O)2-N(Ry)2;
每个Rg独立选自氧代、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-O-C(O)-O-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-O-C(O)-N(Rz)2、-N(Rz)-C(O)-ORz、-N(Rz)-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、-N(Rz)-S(O)-N(Rz)2和-N(Rz)-S(O)2-N(Rz)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基;
每个Rv独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rva)2、羟基、氰基、C1-C6烷氧基、碳环基、杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rv与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代、-N(Rva)2和卤素的基团的C1-3烷基;
每个Rw独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rwa)2、羟基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rw与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rx独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Ry独立选自氢、C1-6烷基、C2-6烯基和C2-6炔基,其中每个C1-6烷基、C2-6烯基或C2-6炔基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氨基、羟基和C1-C6烷基;
每个Rz独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、碳环基和杂环基,其中每个C1-6烷基、C2-6烯基、C2-6炔基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、氰基、-N(Rza)2、C1-C6烷氧基、碳环基、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基;或两个Rz与和它们所连接的氮一起形成杂环基,所述杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-N(Rza)2、-C(O)-N(Rza)2、-O-Rza、-O-C(O)-Rza、-C(O)-O-Rza、-N(Rza)-C(O)-Rza和任选取代有一个或多个独立选自氧代和卤素的基团的C1-3烷基;
每个Rva独立为氢或C1-6烷基,或两个Rva与和它们所连接的氮一起形成杂环基;
每个Rwa独立为氢或C1-6烷基,或两个Rwa与和它们所连接的氮一起形成杂环基;且
每个Rza独立为氢或C1-6烷基,或两个Rza与和它们所连接的氮一起形成杂环基;
条件是当R1为甲基且R2为乙氧基羰基时,A不为2-氟-5-(乙基磺酰基)苯基;
且条件是当R1为甲基且R2为氢时,A不为2-(2,2-二甲基丙-1-基氧基)-5-氨基苯基;
且条件是当R1为甲基且R2为氢时,A不为2-(2,2-二甲基丙-1-基氧基)-5-硝基苯基;
且条件是当R1为甲基且R2为氢时,A不为3-(乙基磺酰基)-6-氟苯基;
且条件是当R1为甲基且R2为氢时,A不为2-乙氧基-5-(甲基磺酰基)苯基;
且条件是当R1为甲基且R2为氢时,A不为4-溴-2-甲氧基苯基;
且条件是当R1为甲基且R2为氢时,A不为2-(2-叔丁氧基-1-甲基乙氧基-)-5-甲基磺酰基苯基;
且条件是当R1为甲基且R2为氢时,A不为2-异丁氧基-5-甲基磺酰基苯基;
且条件是当R1为甲基且R2为氢时,A不为2-(2-甲基丙氧基)-5-乙基磺酰基氨基苯基。
2.权利要求1的化合物,其中R1为H。
3.权利要求1的化合物,其中R1为甲基。
4.权利要求1的化合物,其中R1为乙基。
5.权利要求1-4中任一项的化合物,其中R2为H。
6.权利要求1-4中任一项的化合物,其中R2为甲基。
7.权利要求1-6中任一项的化合物,其中Q为5元杂芳基,其任选取代有一个或多个基团Rc。
8.权利要求1-6中任一项的化合物,其中Q为呋喃基、噻吩基、吡咯基、咪唑基、噻唑基、噁唑基、异噁唑基、噻唑基、异噻唑基或三唑基,其任选取代有一个或多个基团Rc。
9.权利要求1-6中任一项的化合物,其中Q为:
其中环A任选取代有一个或多个基团Rc,或环A任选与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
10.权利要求1-6中任一项的化合物,其中Q为:
其中环A任选取代有一个或多个基团Rc。
11.权利要求1-6中任一项的化合物,其中Q为:
其中环A与碳环基或杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
12.权利要求1-6或9-11中任一项的化合物,其中X1为N,X2为CRc且X3为CRc。
13.权利要求1-6或9-11中任一项的化合物,其中X1为CRc,X2为N且X3为CRc。
14.权利要求1-6或9-11中任一项的化合物,其中X1为N,X2为N且X3为CRc。
15.权利要求1-6或9-11中任一项的化合物,其中X1为N,X2为CRc且X3为N。
16.权利要求1-6或9-11中任一项的化合物,其中X1为CRc,X2为CRc且X3为CRc。
17.权利要求1-6或9-16中任一项的化合物,其中Re为氢。
18.权利要求1-6或9-16中任一项的化合物,其中Re和Rf各自为氢。
19.权利要求1-6或9-18中任一项的化合物,其中每个Rc独立选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基、杂环基、-F、-Cl、-Br、-I、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-O-C(O)-O-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-O-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv、-N(Rv)-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、-N(Rv)-S(O)-N(Rv)2和-N(Rv)-S(O)2-N(Rv)2,其中任何C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基。
20.权利要求1-6或9-18中任一项的化合物,其中每个Rc独立选自氢、C1-6烷基、杂环基、-F、-Cl、-N(Rv)2、-CN、-C(O)-N(Rv)2、-O-Rv、-C(O)-O-Rv、-N(Rv)-C(O)-ORv和-N(Rv)-C(O)-Rv,其中任何C1-6烷基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有C1-6烷基。
21.权利要求1-6或9-18中任一项的化合物,其中每个Rc独立选自氢、C1-6烷基、杂环基、-CN、-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv和-N(Rv)-C(O)-Rv,其中任何C1-6烷基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rv)2、-CN、-C(O)-N(Rv)2、-S(O)-N(Rv)2、-S(O)2-N(Rv)2、-O-Rv、-S-Rv、-O-C(O)-Rv、-C(O)-Rv、-C(O)-O-Rv、-S(O)-Rv、-S(O)2-Rv、-C(O)-N(Rv)2、-N(Rv)-C(O)-Rv、-N(Rv)-S(O)-Rv、-N(Rv)-S(O)2-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有C1-6烷基。
22.权利要求1-6或9-18中任一项的化合物,其中每个Rc独立选自氢、C1-6烷基、杂环基、-CN、-C(O)-N(Rv)2、-N(Rv)-C(O)-ORv和-N(Rv)-C(O)-Rv,其中任何C1-6烷基或杂环基任选取代有一个或多个独立选自以下的基团:-O-Rv、6元单环杂环基和任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基,其中所述6元单环杂环基任选取代有C1-6烷基。
23.权利要求1-6或12-18中任一项的化合物,其中环A与碳环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
24.权利要求1-6或12-18中任一项的化合物,其中环A与杂环基稠合以形成多环基,所述多环基任选取代有一个或多个基团Rg。
25.权利要求1-6、23或24中任一项的化合物,其中每个Rg独立选自氧代、C1-6烷基、碳环基、杂环基、-F、-Cl、-N(Rz)2、-CN、-C(O)-N(Rz)2、-O-Rz、-C(O)-Rz、-C(O)-O-Rz、-N(Rz)-C(O)-ORz和-N(Rz)-C(O)-,其中任何C1-6烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基。
26.权利要求1-6、23或24中任一项的化合物,其中每个Rg独立选自氧代、C1-6烷基、碳环基、杂环基和-C(O)-O-Rz,其中任何C1-6烷基、碳环基或杂环基任选取代有一个或多个独立选自以下的基团:氧代、卤素、-NO2、-N(Rz)2、-CN、-C(O)-N(Rz)2、-S(O)-N(Rz)2、-S(O)2-N(Rz)2、-O-Rz、-S-Rz、-O-C(O)-Rz、-C(O)-Rz、-C(O)-O-Rz、-S(O)-Rz、-S(O)2-Rz、-C(O)-N(Rz)2、-N(Rz)-C(O)-Rz、-N(Rz)-S(O)-Rz、-N(Rz)-S(O)2-Rz、任选取代有一个或多个独立选自氧代和卤素的基团的C1-6烷基和任选取代有一个或多个独立选自氧代、卤素和C1-6烷基的基团的杂环基。
27.权利要求1-6、23或24中任一项的化合物,其中每个Rg独立选自氧代、C1-6烷基、碳环基、杂环基和-C(O)-O-Rz,其中任何C1-6烷基、碳环基或杂环基任选取代有一个或多个-O-Rz基团。
28.权利要求1-6中任一项的化合物,其中Q选自:
苯基、2-氧代吲哚啉-5-基、1-叔丁氧基羰基-3,4-二氢-2H-喹啉-6-基、2,3,3a,5-四氢吡咯并[1,2-a]喹喔啉-1,4-二酮-8-基、3-甲基-3,4-二氢-1H-喹喔啉-2-酮-6-基、1,3,4,5-四氢-4-甲基-1,5-苯并二氮杂-2-酮-7-基、5,7,7a,8,9,10-六氢吡咯并[2,1-d][1,5]苯并二氮杂-6-酮-2-基、4-(2-噻吩基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮-7-基、3-氨基羰基苯基、3-氰基苯基、4-羟基甲基苯基、4-(3-氟氮杂环丁烷-1-基羰基)苯基、4-(1-吡咯烷基羰基)苯基、4-(4-甲基哌啶-1-基羰基)苯基、4-(4-乙酰基哌嗪-1-基羰基)苯基、4-(4-(氨基羰基)哌啶-1-基羰基)苯基、4-(N-(吡啶-3-基)氨基羰基)苯基、4-(2-苯基丙酰基)苯基、4-(N-甲基-N-(氰基甲基)氨基羰基)苯基、4-(N-(2-甲氧基乙基)氨基羰基)苯基、1-叔丁氧基羰基-3,4-二氢-2H-喹啉-7-基、4-(叔丁氧基羰基氨基)苯基、1,3,4,5-四氢-1,5-苯并二氮杂-2-酮-7-基、3-(N,N-二甲基氨基羰基)苯基、4-(1-羟基-1-甲基乙基)苯基、4-(1-甲基哌啶-4-基)苯基、4-(1-甲基哌啶-4-基甲基)苯基、4-(N-(2-甲氧基乙基羰基)氨基)苯基、2-甲基-4H-1,4-苯并噁嗪-3-酮-7-基、4-(N,N-二甲基氨基羰基)苯基、4-(4-甲基-3-氧代-哌嗪-1-基羰基)苯基、4-(3,3-二氟氮杂环丁烷-1-基羰基)苯基、4-(N-苯基氨基羰基)苯基、2-甲基-3,4-二氢-1H-异喹啉-6-基、3-(N-甲基氨基羰基)苯基、4-(吗啉代羰基)苯基、3-(N-苄基氨基羰基)苯基、3-(1-甲基哌啶-4-基)苯基、3-(1-甲基哌啶-4-基甲基)苯基和3-(2-羟基乙基)-3-苯基茚满-5-基。
29.权利要求1的化合物及其盐,所述化合物选自:
6-甲基-4-苯基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6-甲基-4-(2-氧代吲哚啉-5-基)-1H-吡咯并[2,3-c]吡啶-7-酮;
N-(2-甲氧基乙基)-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
6-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-3,4-二氢-2H-喹啉-1-甲酸叔丁酯;
7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-3,4-二氢-2H-喹啉-1-甲酸叔丁酯;
N-[4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯基]氨基甲酸叔丁酯;
3-甲氧基-N-[4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯基]丙酰胺;
4-(3-(2-羟基乙基)-3-苯基-2,3-二氢-1H-茚-5-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
8-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3,3a-二氢吡咯并[1,2-a]喹喔啉-1,4(2H,5H)-二酮;
3-甲基-6-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-3,4-二氢-1H-喹喔啉-2-酮;
3-甲基-7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
4-甲基-7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
3-异丙基-6-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-1H-喹喔啉-2-酮;
2-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-5,7,7a,8,9,10-六氢吡咯并[2,1-d][1,5]苯并二氮杂-6-酮;
2-甲基-7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-4H-1,4-苯并噁嗪-3-酮;
7-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-4-(2-噻吩基)-1,3,4,5-四氢-1,5-苯并二氮杂-2-酮;
N,N-二甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
3-(6-乙基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N,N-二甲基-苯甲酰胺;
3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
N,N-二甲基-3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲腈;
N-甲基-3-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
4-[4-(羟基甲基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-(4-(4-甲基-3-氧代哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4-[4-(3-氟氮杂环丁烷-1-羰基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
4-[4-(3,3-二氟氮杂环丁烷-1-羰基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-(吡咯烷-1-羰基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-(吗啉-4-羰基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-(4-甲基哌啶-1-羰基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
4-[4-(4-乙酰基哌嗪-1-羰基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮,
1-[4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰基]哌啶-4-甲酰胺;
4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N-(3-吡啶基)苯甲酰胺;
4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N-苯基-苯甲酰胺;
N-甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N-苯基-苯甲酰胺;
N-苄基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
N-(氰基甲基)-N-甲基-4-(6-甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
4-[4-(1-羟基-1-甲基-乙基)苯基]-6-甲基-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-(1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[3-(1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-(2-甲基-3,4-二氢-1H-异喹啉-6-基)-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[4-[(1-甲基-4-哌啶基)甲基]苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;
6-甲基-4-[3-[(1-甲基-4-哌啶基)甲基]苯基]-1H-吡咯并[2,3-c]吡啶-7-酮;和
3-(2,6-二甲基-7-氧代-1H-吡咯并[2,3-c]吡啶-4-基)-N,N-二甲基-苯甲酰胺。
30.一种化合物及其盐,所述化合物选自:
N,N-二甲基-3-(7-氧代-6-丙基-1H-吡咯并[2,3-c]吡啶-4-基)苯甲酰胺;
4-[4-(1-羟基-1-甲基-乙基)苯基]-6-异丙基-1H-吡咯并[2,3-c]吡啶-7-酮;和
6-环丙基-4-(4-(2-羟基丙-2-基)苯基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮。
31.一种组合物,其包含权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐和药用辅料、载体或媒介物。
32.权利要求31的组合物,其与额外的治疗剂组合。
33.权利要求32的组合物,其中所述额外的治疗剂为化学治疗剂。
34.治疗动物中由布罗莫结构域介导的病症的方法,其包括向所述动物施用权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐。
35.权利要求34的方法,其中所述病症为癌症、炎性病症或自身免疫性疾病。
36.权利要求35的方法,其中所述病症为癌症且所述癌症选自听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性T细胞性白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、子宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥散性大B细胞淋巴瘤、异常增殖性变化、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因肿瘤、纤维肉瘤、滤泡淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、胶质肉瘤、重链疾病、头颈癌、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感性前列腺癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、淋巴管内皮肉瘤、淋巴管肉瘤、成淋巴细胞性白血病、淋巴瘤、T细胞或B细胞源性淋巴恶性肿瘤、髓质癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、成骨肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体肿瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和威尔姆斯肿瘤。
37.权利要求35的方法,其中所述病症为癌症且所述癌症选自肺癌、乳腺癌、胰腺癌、结直肠癌和黑素瘤。
38.权利要求35的方法,其中所述病症为炎性病症或自身免疫性疾病且所述炎性病症或自身免疫性疾病选自艾迪生病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、贝切特病、大疱性皮肤病、慢性阻塞性肺病、克罗恩病、皮炎、湿疹、巨细胞性动脉炎、纤维化、肾小球性肾炎、肝血管闭塞、肝炎、垂体炎、免疫缺陷综合征、炎性肠病、川崎病、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆汁性肝硬化、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、系统性红斑狼疮、多发性大动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、血管炎和韦格纳肉芽肿。
39.权利要求34的方法,其中所述布罗莫结构域选自ASH1L、ATAD2、ATAD2B、BAZ1A、BAZ1B、BAZ2A、BAZ2B、BPTF、BRD1、BRD2、BRD3、BRD4、BRD7、BRD8、BRD9、BRDT、BRPF1、BRPF3、BRWD1、BRWD3、CECR2、CREBBP(aka、CBP)、EP300、GCN5L2、KIAA2026、MLL、MLL4、PBRM、PCAF、PHIP、SMARCA2、SMARCA4、SP100、SP110、SP140、SP140L、TAF1、TAF1L、TRIM24、TRIM28、TRIM33、TRIM66、ZMYND8和ZMYND11。
40.权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐,其用于医学疗法。
41.权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐,其用于预防性或治疗性处置由布罗莫结构域介导的病症。
42.权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐在制备用于治疗动物中由布罗莫结构域介导的病症的药物中的用途。
43.在动物中提高包含细胞毒剂的癌症治疗的效力的方法,其包括向所述动物施用有效量的权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐。
44.权利要求43的方法,还包括向所述动物施用细胞毒剂。
45.在动物中延迟或预防发展对细胞毒剂的癌症抗性的方法,其包括向所述动物施用权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐。
46.在动物中延长对癌症疗法的响应的持续时间的方法,其包括向接受癌症疗法的动物施用权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐,其中当施用式(I)化合物或权利要求30的化合物或其药用盐时对癌症疗法的响应的持续时间延长超过在不施用式(I)化合物或权利要求30的化合物或其药用盐的情况下对癌症疗法的响应的持续时间。
47.在个体中治疗癌症的方法,其包括向所述个体施用(a)权利要求1-29中任一项的式(I)化合物或其药用盐或权利要求30的化合物或其药用盐和(b)细胞毒剂。
48.权利要求47的方法,其中所述细胞毒剂选自抗微管剂、铂配位络合物、烷化剂、抗生素、拓扑异构酶II抑制剂、抗代谢剂、拓扑异构酶I抑制剂、激素和激素类似物、信号转导途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂、脂肪酸生物合成抑制剂、细胞周期信号传导抑制剂、HDAC抑制剂、蛋白酶体抑制剂和癌症代谢抑制剂。
49.权利要求47的方法,其中所述细胞毒剂为紫杉烷类。
50.权利要求49的方法,其中所述紫杉烷类为紫杉醇或多西他赛。
51.权利要求47的方法,其中所述细胞毒剂为铂剂。
52.权利要求47的方法,其中所述细胞毒剂为EGFR拮抗剂。
53.权利要求52的方法,其中所述EGFR拮抗剂为N-(3-乙炔基苯
基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺或其药用盐。
54.权利要求47的方法,其中所述细胞毒剂为RAF抑制剂。
55.权利要求54的方法,其中所述RAF抑制剂为BRAF或CRAF抑制剂。
56.权利要求54的方法,其中所述RAF抑制剂为威罗菲尼。
57.权利要求47的方法,其中所述细胞毒剂为PI3K抑制剂。
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CN111712496A (zh) * | 2017-12-20 | 2020-09-25 | 贝达药业股份有限公司 | 作为溴结构域蛋白质抑制剂的化合物和组合物 |
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WO2020007322A1 (zh) * | 2018-07-04 | 2020-01-09 | 清华大学 | 一种靶向降解bet蛋白的化合物及其应用 |
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CN112625036A (zh) * | 2019-10-08 | 2021-04-09 | 上海海和药物研究开发股份有限公司 | 一类具有brd4抑制活性的化合物、其制备方法及用途 |
CN114401964A (zh) * | 2019-10-08 | 2022-04-26 | 上海海和药物研究开发股份有限公司 | 一类具有brd4抑制活性的化合物、其制备方法及用途 |
CN115611890A (zh) * | 2021-07-15 | 2023-01-17 | 成都苑东生物制药股份有限公司 | 一种新型噻吩类bet溴结构域抑制剂、其制备方法及医药用途 |
CN115611890B (zh) * | 2021-07-15 | 2024-05-31 | 成都硕德药业有限公司 | 一种新型噻吩类bet溴结构域抑制剂、其制备方法及医药用途 |
Also Published As
Publication number | Publication date |
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EP3218374B1 (en) | 2021-12-29 |
EP3218374A1 (en) | 2017-09-20 |
JP2017533249A (ja) | 2017-11-09 |
US10150767B2 (en) | 2018-12-11 |
US20170342067A1 (en) | 2017-11-30 |
HK1243076A1 (zh) | 2018-07-06 |
MA40940A (fr) | 2017-09-19 |
JP6669745B2 (ja) | 2020-03-18 |
WO2016077380A1 (en) | 2016-05-19 |
CN107108614B (zh) | 2021-06-01 |
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