CN112812118A - 一类蛋白受体激酶抑制剂的制备和应用 - Google Patents
一类蛋白受体激酶抑制剂的制备和应用 Download PDFInfo
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- CN112812118A CN112812118A CN201911130029.0A CN201911130029A CN112812118A CN 112812118 A CN112812118 A CN 112812118A CN 201911130029 A CN201911130029 A CN 201911130029A CN 112812118 A CN112812118 A CN 112812118A
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- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
本发明提供了一种蛋白受体激酶抑制剂的制备方法。具体地，本发明公开了一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐，其中，各基团的定义如说明书中所述。本发明还公开了上述化合物作为TRK激酶抑制剂的用途。
Description
技术领域
本发明涉及医药技术领域，更具体而言，涉及一种蛋白受体激酶抑制剂。
背景技术
原肌球蛋白受体激酶(tropomyosin-receptor kinase,TRK)是一类神经生长因子受体，隶属于受体酪氨酸激酶家族，主要包括高度同源的TRKA、TRKB和TRKC三个成员，分别由NTRK1、NTRK2和NTRK3三个基因编码而成。这些受体酪氨酸激酶主要在神经组织中表达，并通过神经营养因子NTs(neurotrophins)的激活在神经系统的发育和生理功能中发挥重要作用。TRK作为酪氨酸激酶受体，每个TRK都有与其相对应的配体结合并激活其下游的信号通路。NGF(nerve growth factor)特异性结合并激活TRKA；TRKB的配体包括有BDGF(brain-derived growth factor)和NT-4/5(neurotrophin-4/5)；NT-3特异性结合并激活TRKC。三种TRK受体均含有用于配体结合的细胞外结构域、跨膜结构域和具有激酶活性的胞内结构域。
当特定配体与相应受体的胞外结构域相结合，会引发受体的寡聚化和胞质内激酶结构域中特定酪氨酸残基的磷酸化，从而引起下游信号通路如Ras/MAPK、PLCγ/PKC和PI3K/AKT信号通路的激活，进而调控神经细胞的增殖、分化和存活等一系列生理过程。TRK信号通路通常被精确调控，而它的异常激活则与肿瘤发生密切相关。研究结果表明，引起TRK通路异常激活的机制有很多，包括基因融合、蛋白质过度表达和单核苷酸突变，这些异常与肿瘤的发病机制密切相关，特别是NTRK基因融合已被证实是导致多种肿瘤发生的重要因素，且不依赖于肿瘤的组织来源和类型。在当前二代测序技术和精准医疗的迅猛发展下，越来越多的NTRK融合基因被发现，例如ETV6-NTRK3、MPRIP–NTRK1、CD74–NTRK1等。近年来的临床试验结果表明，这些融合基因是非常有效的抗癌靶点，且含有NTRK融合基因的肿瘤对TRK抑制剂有非常显著的响应率。
因此，越来越多的TRK靶点抑制剂被报道，如(WO2010048314、WO2011146336、WO2017004342)。同时，在临床试验阶段，已经发现有部分接受治疗的患者出现了耐药现象，并被证实是由酶活区域的部分碱基突变引起，例如NTRK1 G595R或G667C突变，NTRK3的G623R或G696A突变。因此，本领域仍然需要开发新一代TRK激酶抑制剂，以解决上述问题。
发明内容
本发明的目的在于提供一类新的TRK激酶抑制剂及其制备方法和用途。
本发明第一方面，提供了一种式I所示的化合物，或其立体异构体或外消旋体，或其药学上可接受的盐：
其中，
L1选自下组：-NH-、-CH＝CH-、-NH(CHR)-、-NHC(O)NH-、-CH2-O-、-CH2-S-、-NHS(O)2-、-S(O)2-、-S(O)-；R选自下组：H、C1-C4烷基、卤素；
L2选自下组：取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括并环、桥环、螺环)；
或所述的L1和L2共同形成选自下组的基团：取代或未取代的10-12元二环含氮杂芳基，或取代或未取代的10-12元二环含氮杂环基；其中，所述的杂芳基或杂环基具有1-3个选自N、S和O的杂原子；
Rc为取代或未取代的4-6元的杂环基(优选为饱和或不饱和的氮杂环基)、取代或未取代的5-10元杂芳基；其中，所述的杂芳基或杂环基具有1-3个选自N、S和O的杂原子；
RA为
其中，
X1、X2、X3各自独立地为CR6或N；R6为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
n为1、2或3；
各个R3各自独立地为氢、氘、羟基、卤素、三氟甲基，氰基，氨基，酰胺基，取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
或者n为2且两个R3共同形成-O-(CH2)m-O-；m为1-4的整数；
RB为取代或未取代的4-7元杂环(所述杂环含有1-3个选自氮原子、氧原子和硫原子的杂原子)；-(CH2)m1-、-O-(CH2)m2-O-；其中，m1、m2各自独立地为1-4的整数；
或者RB为-取代或未取代的-C1-C10亚烷基-X2-(其中，X2为NH、O、S或S(O)2)、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：氘、卤素、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O)2NH2、氧代(＝O)、-CN、羟基、-NH2、羧基、C1-C6酰胺基(-C(＝O)-N(Rd)2或-NH-C(＝O)(Rd)，Rd为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
或取代或未取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-12元杂环基、-(CH2)-C6-C10芳基、-(CH2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH2、-OH、C6-C10芳基、C1-C6胺基、-S(＝O)2CH3、-S(＝O)2NH2、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
虚线表示化学键或无。
在另一优选例中，所述的Rc为未取代的，或者被选自下组的一个或多个取代基取代：甲基砜基、-S(＝O)2NH2、氧代(＝O)、-CN、羟基、-NH2、羧基、C1-C6酰胺基(-C(＝O)-N(Rd)2或-NH-C(＝O)(Rd)，Rd为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
或取代或未取代的选自下组的基团：C1-C6烷基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-6元杂环基，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH2、-OH、-S(＝O)2CH3。
在另一优选例中，L1为-CH＝CH-。
在另一优选例中，RA选自下组：
各式中，X1、X2定义同前；
芳香环上，n为1、2或3；且R3为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；或者n为2且两个R3共同形成-O-(CH2)m-O-；m为1-4的整数；
其它位置的R3、R4、R5各自独立地为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基。
在另一优选例中，RA为
其中，X1为CR6或N；X2、X3各自独立地为CR6；
n为1、2或3；且R3为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；或者n为2且两个R3共同形成-O-(CH2)m-O-；m为1-4的整数。
在另一优选例中，所述的式I化合物具有如下式所示的结构：
在另一优选例中，所述的L1和L2共同形成选自下组的取代或未取代的基团：
在另一优选例中，所述的式I化合物具有如下式所示的结构：
在另一优选例中，所述的式I化合物具有如下式所示的结构：
在另一优选例中，所述的化合物选自下组：
本发明的第二方面，提供了一种药物组合物，其包含治疗有效量的如本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，或如本发明第二方面所述的药物组合物的用途，其用于预防和治疗与TRK相关的疾病的药物中的用途。
在另一优选例中，所述TRK相关的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒，炎症相关疾病，骨相关的疾病。
在另一优选例中，所述的癌症选自TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的癌症(包括但不仅限于)：神经母细胞瘤，前列腺癌，甲状腺癌，肺癌卵巢癌，胰腺癌、结直肠癌症、非小细胞肺癌、纤维肉瘤等。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如本发明第二方面所述的药物组合物的用途，其用于制备预防和/或治疗与TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的疾病的药物组合物。
在另一优选例中，所述的药物组合物可以与其他治疗剂进行联合用药。
在另一优选例中，所述的药物组合包括但不仅限于其他靶点的激酶抑制剂、免疫调节剂(肿瘤免疫检查点抑制剂)、细胞分裂阻滞剂等常规一线化疗药物。
在另一优选例中，所述的疾病选自下组：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒。
在另一优选例中，所述的癌症选自TRK功能异常(TRK基因扩增、或者过表达、或者突变、或者基因融合导致的功能异常激活)相关的癌症(包括但不仅限于)：神经母细胞瘤，前列腺癌，甲状腺癌，肺癌卵巢癌，胰腺癌、结直肠癌症、非小细胞肺癌、纤维肉瘤等。
本发明的第五方面，提供了一种TRK抑制剂，所述抑制剂包含如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
在另一优选例中，所述的TRK抑制剂选择性抑制选自下组的一种或多种TRK激酶：TRKA、TRKB或TRKC。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次发现了一类新颖、有效的TRK激酶小分子抑制剂。在此基础上完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
在本申请中，作为基团或是其它基团的一部分，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“C1-C6烷基”指含有1至6个碳原子的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“6-10元芳环”意指具有6-10个环原子的芳环，所述环原子为碳原子。所述芳环可以单环或双环。例如苯环、萘环等类似基团。
在本申请中，作为基团或是其它基团的一部分，术语“5-10元杂芳环”意指具有5-10个环原子的杂芳环，所述环原子至少有1个(可以是1个、2个或3个)是选自氮、氧和硫的杂原子。所述杂芳环可以单环或双环。例如，嘧啶并吡唑环、吡嗪并咪唑环、吡啶并吡唑环、吡啶并咪唑环、吡啶并嘧啶环、吡啶并吡啶环。
本发明化合物
本发明的化合物为式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐。
本发明的化合物可能含有一个或多个手性碳原子，因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
制备方法
下列反应方案示例性的说明了制备式I所示化合物或其立体异构体或外消旋体或其药学上可接受的盐的方法，其中各基团均如在上所述。应理解在下列反应方案中，所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合物时才是可允许的。还应理解其他的通式可由有机化学领域的技术人员通过本文公开的方法(通过应用适当取代的起始材料并利用本领域技术人员公知的方法根据需要修改合成参数)或已知方法进行制备。
当L1为-CH＝CH-时，所述方法包括步骤：
当L1为-NH(CHR)-时，所述方法包括步骤：
其他化合物可以通过替换相应的原料片段，根据本领域通用方法制备。
当本发明的各个化合物具有取代基时，上述的方法还可以包括对于化合物进行取代基修饰的步骤，所述的取代基也可以通过选择对应的起始原料从而制备得到。在本发明公开了骨架结构的构建方法后，这样的修饰是显而易见的。
在另一优选例中，当化合物中还含有保护基团(例如，氨基保护基或羟基保护基等)，则该步骤中还含有脱保护基的步骤。
应用
本发明的化合物具有优异的TRK(例如TRKA、TRKB、TRKC)抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗与TRK激酶活性或表达量相关的疾病(例如，癌症)。
在本申请中，术语“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，术语“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在本申请中，术语“肿瘤”包括但不限于神经胶质瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
在本申请中，术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
在本申请中，术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
在本申请中，术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
在本申请中，术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
在本申请中，术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
与现有技术相比，本发明的主要优点在于：
1.本发明化合物具有优异的药代动力学性质。
2.本发明化合物能够在荷瘤小鼠中有效抑制肿瘤生长。
3.本发明化合物能够有效的抑制KM12-LUC细胞的增殖。
4.本发明化合物能够在细胞学水平有效抑制TRKA、TRKB和TRKC的磷酸化水平。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganiSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
实施例
中间体A的合成
(R,E)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺
将2，5-二氟苯甲醛(5g，35.2mmol)与(R)-2-甲基丙烷-2-亚磺酰胺(4.47g，36.9mmol)溶于二氯甲烷(50mL)中，室温下加入碳酸铯(8.0g，24.6mmol)，然后升温至50℃反应3小时，TLC显示反应完毕，过滤，滤饼用二氯甲烷洗涤，滤液用盐水洗涤，无水硫酸钠干燥，旋干得黄色油状液体(9g)。
(R)-N-((R)-1-(2，5-二氟苯基)-3-(1，3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺
将镁屑(2g，83.3mmol)溶于四氢呋喃(72mL)中，氮气保护，于40℃下将二异丁基氢化铝的四氢呋喃溶液(0.1mL，1.5M，0.15mmol)滴加入体系，40℃反应0.5h，然后将2-(2-溴乙基)-1，3-二噁烷(14.3g，73.47mmol)的四氢呋喃(40mL)溶液缓慢滴加入体系并控制温度在40-50℃，滴完后保持40℃搅拌1h。撤掉加热，将反应体系冷却至-30℃，然后将(R，E)-N-(2，5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺(9g，36.73mmol)的四氢呋喃(40mL)溶液滴加入体系，控制其温度在-30℃-20℃，滴完后，于-30℃搅拌2h，TLC显示反应完毕，用10％的柠檬酸水溶液淬灭并控制温度在10℃，用二氯甲烷萃取，有机相用饱盐水洗涤，无水硫酸钠干燥，旋干得无色油状液体(15.8g)。
(R)-2-(2，5-二氟苯基)吡咯烷
室温下将(R)-N-((R)-1-(2，5-二氟苯基)-3-(1，3-二噁烷-2-基)丙基)-2-甲基丙烷-2-亚磺酰胺(15.8g，43.76mmol)加入到三氟乙酸(32mL)与水(8mL)的混合溶液中，室温搅拌1h，然后将三氟乙酸(60mL)加入到体系，三乙基硅烷(15.2g，131.1mmol)滴加入体系，反应室温过夜，LCMS监测反应完毕，旋掉大部分三氟乙酸，剩余溶于盐酸(1N，100mL)并搅拌0.5h，用甲基叔丁基醚萃取，有机相用盐酸(1N，50mL)洗涤，合并水相，水相用40％氢氧化钠水溶液调节pH＝11，然后用二氯甲烷萃取，合并有机相，饱盐水洗涤，无水硫酸钠干燥，旋干得油状液体(6.7g)。
中间体B的合成
(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺
将(R)-N-(2,5-二氟苯亚甲基)-2-甲基丙烷-2-亚磺酰胺(30g,122.45mmol)于室温下加入到饱和溴化钠(480mL)的水溶液中,加入In(42g,367.35mmol),然后加入烯丙基溴化镁(42mL,489.8mmol),室温反应6小时,TLC监测反应完毕，用饱和碳酸氢钠溶液淬灭，过滤，滤液用乙酸乙酯萃取，饱盐水洗涤，无水硫酸钠干燥，旋干得(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺,黄色固体(35g).
(S)-N-((1S)-1-(2,5-二氟苯基)-2-(环氧乙烷-2-基)乙基)-2-甲基丙烷-2-亚磺酰胺
将(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺(35g,121.95mmol)溶于二氯甲烷(800mL)中,于室温下分批加入间氯过氧苯甲酸(80g,365.85mmol),室温搅拌过夜，TLC监测反应完毕，反应液用饱和碳酸氢钠与饱和硫代硫酸钠溶液洗涤，饱盐水洗涤，无水硫酸钠干燥，旋干得(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺，黄色固体(31g,收率：79％).
(3R，5R)-1-(叔丁基磺酰基)-5-(2,5-二氟苯基)吡咯烷-3-醇
将(S)-N-((S)-1-(2,5-二氟苯基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺(31g,97.18mmol)溶于N,N-二甲基甲酰胺(300mL)中，室温下加入碳酸钾(40g,291.53mmol),碘化钾(16g,97.18mmol),加热至100℃反应1小时，TLC监测反应完毕，待反应液冷却至室温，过滤，滤液打入水中，用乙酸乙酯萃取，合并有机相，饱盐水洗涤，无水硫酸钠干燥，旋干过柱纯化(石油醚/乙酸乙酯＝10/1—5/1)得到化合物(3R，5R)-1-(叔丁基磺酰基)-5-(2,5-二氟苯基)吡咯烷-3-醇(7.5g)。
(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷
将(3R，5R)-1-(叔丁基磺酰基)-5-(2,5-二氟苯基)吡咯烷-3-醇(2.0g,6.27mmol)溶于二氯甲烷(50ml)中，冷却至零下60℃，将DAST(2ml)滴加入体系，然后自然升至室温并搅拌过夜，LCMS监测反应完毕，反应液加入二氯甲烷稀释，将其缓慢倒入冰水中，分液，有机相用饱盐水洗涤，无水硫酸钠干燥，旋干过柱纯化(石油醚/乙酸乙酯＝10/1)得到(2R，4S)-1-(叔丁基磺酰基)-2-(2,5-二氟苯基)-4-氟，黄色固体(1.2g,收率：60％)。
(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷
向(2R，4S)-1-(叔丁基磺酰基)-2-(2,5-二氟苯基)-4-氟(500mg，1.55mmol)的二氯甲烷溶液(20mL)中加入三氟甲磺酸(0.7mL)，反应2小时，溶剂旋干，用2M的氢氧化钠溶液洗涤，加入乙酸乙酯萃取，分液，有机相用饱盐水洗涤，无水硫酸钠干燥，旋干过柱纯化(石油醚/乙酸乙酯＝4/1)得到(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷，黄色固体(305mg,收率：99％)。
中间体C的合成
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-3-硝基咪唑并[1,2-b]哒嗪
向(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(150mg,0.75mmol),6-氯-3-硝基咪唑并[1,2-b]哒嗪(222mg,1.12mmol)的二甲基亚砜(2mL)溶液中加入三乙胺(151mg,1.5mmol).反应液100℃搅拌16小时。LCMS显示大部分原料消失。反应液通过制备型高效液相色谱纯化获得黄色固体(150mg,55％)。
MS(ESI):m/z＝364[M+H]+.
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-胺
向6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)-3-硝基咪唑并[1,2-b]哒嗪(60mg,0.16mmol)的甲醇(20mL)溶液中加入钯碳(15mg).反应液通过水泵用氢气球置换三次后室温搅拌8小时。LCMS显示大部分原料消失。反应液通过硅藻土过滤，并用二氯甲烷(20mL)冲洗。滤液浓缩后通过制备型高效液相色谱纯化获得黄色固体(30mg，收率57％)。
MS(ESI):m/z＝334[M+H]+.
中间体D的合成：
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-甲醛
乙基6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-羧酸酯
向一封管中依次加入乙基6-氯咪唑并[1,2-b]哒嗪-3-羧酸酯(400mg,1.78mmol),(2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷(393mg,1.95mmol)，氟化钾(206mg,3.56mmol)和二甲亚砜(4mL)，加热到120℃反应16个小时，冷却到室温，倒入水中，加入乙酸乙酯，有机相分离，干燥，旋干过柱纯化(石油醚/乙酸乙酯＝1/1)得到白色固体(475mg,收率：68％)。
MS(ESI):m/z＝391[M+H]+.
(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)甲醇
将乙基6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-羧酸酯(476mg,1.22mmol)加入到四氢呋喃(8mL)中，冷却到0℃。滴加四氢铝锂四氢呋喃溶液(1.8mL，1M)。反应3个小时，依次加入水，15％氢氧化钠溶液，水淬灭反应，产生固体过滤，滤液旋干过柱纯化(乙酸乙酯/甲醇＝30/1)得到白色固体(380mg,收率：90％)。
MS(ESI):m/z＝349[M+H]+.
6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-甲醛
将(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)甲醇(120mg,0.34mmol),二氧化锰(1.5g,17.20mmol)和四氢呋喃(10mL)混合，加热到45℃反应16个小时，冷却到室温，把固体过滤掉，滤饼用乙酸乙酯洗涤，有机相旋干，得到粗产品(200mg)。
MS(ESI):m/z＝347[M+H]+.
实施例1：
(S)-1-(6-((E)-2-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙烯基)吡啶-3-基)吡咯烷-3-醇
((5-溴吡啶-2-基)甲基)三苯基磷氯化物
将5-溴-2-(氯甲基)吡啶(2.3g,8.68mmol)，三苯基膦(2.5g,9.55mmol)和乙腈(16mL)混合，加热到50℃反应16个小时，反应完毕后，将溶剂旋干，得到固体用石油醚/乙酸乙酯＝10:1打浆，得到粉红色固体(3.5g,收率98％)。
MS(ESI):m/z＝432[M+H]+.
3-((E)-2-(5-溴吡啶-2-基)乙烯基)-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪
将((5-溴吡啶-2-基)甲基)三苯基磷氯化物(168mg,0.39mmol)和四氢呋喃(5mL)混合，冷却到0℃，加入氢化钠(15mg,0.39mmol)，在此温度下反应半个小时，将6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-甲醛(90mg,0.26mmol)溶解在四氢呋喃(5mL)中，滴加到上述溶液中，室温下反应16个小时，加入水淬灭反应，反应液用乙酸乙酯萃取，有机相分离，干燥，旋干过柱纯化(石油醚/乙酸乙酯＝1/2)得到黄色固体(108mg,收率：83％)。
MS(ESI):m/z＝349[M+H]+.
(S)-1-(6-((E)-2-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙烯基)吡啶-3-基)吡咯烷-3-醇
将3-((E)-2-(5-溴吡啶-2-基)乙烯基)-6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪(108mg,0.22mmol),(S)-吡咯烷-3-醇(92mg,1.08mmol),三(二亚苄基丙酮)二钯(39mg,0.04mmol)，2-二环己基磷-2',4',6'-三异丙基联苯(41mg,0.08mmol)，碳酸铯(176mg,0.54mmol)和甲苯(10mL)混合，加热到110℃反应16个小时，反应完毕后，加入水和二氯甲烷萃取，有机相分离，干燥，旋干过柱纯化(乙酸乙酯/甲醇＝5/1)得到黄色固体(45mg,收率：41％)。
MS(ESI):m/z＝507[M+H]+.
1H NMR(400MHz,DMSO-d6)δ7.94(d,J＝2.8Hz,1H),7.82(d,J＝10.0Hz,1H),7.73(s,1H),7.36–7.20(m,5H),7.08–7.03(m,,1H),6.90(dd,J＝2.8,8.8Hz,1H),6.78(d,J＝10.0Hz,1H),5.52(d,J＝53.2Hz,1H),5.40(t,J＝8.4Hz,1H),4.98(d,J＝4.0Hz,1H),4.41(s,1H),4.23–4.02(m,2H),3.48-3.42(m,3H),3.16-3.13(m,1H),2.87–2.77(m,1H),2.29-2.15(m,1H),2.15–1.99(m,1H),1.92–1.87(m,1H).
实施例2
4-(6-((E)-2-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙烯基)吡啶-3-基)吗啉
采用类似于实施例1的条件，替换相应的起始原料,得4-(6-((E)-2-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙烯基)吡啶-3-基)吗啉(35mg,收率65％)，为黄色固体。
MS(ESI):m/z＝507[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝2.8Hz,1H),7.85(d,J＝10.0Hz,1H),7.77(s,1H),7.46–7.20(m,6H),7.08–7.03(m,,1H),6.80(d,J＝10.0Hz,1H),5.66(d,J＝52.8Hz,1H),5.40(t,J＝8.8Hz,1H),4.23–4.02(m,2H),3.75-3.73(m,4H),3.21-3.18(m,4H),2.87–2.77(m,1H),2.29-2.15(m,1H).
实施例3
(S)-1-(2-((E)-2-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙烯基)嘧啶-5-基)吡咯烷-3-醇
采用类似于实施例1的条件，替换相应的起始原料,得(S)-1-(2-((E)-2-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)乙烯基)嘧啶-5-基)吡咯烷-3-醇(19mg,收率15％)，为黄色固体。
MS(ESI):m/z＝508[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.16(s,2H),7.89(s,1H),7.86(d,J＝9.6Hz,1H),7.68(d,J＝16.0Hz,1H),7.40(d,J＝16.0Hz,1H),7.31–7.26(m,2H),7.11–7.07(m,,1H),6.76(d,J＝10.0Hz,1H),5.58(d,J＝52.4Hz,1H),5.40(t,J＝8.0Hz,1H),5.05(d,J＝3.6Hz,1H),4.46(s,1H),4.26–4.10(m,2H),3.53-3.36(m,3H),3.26-3.22(m,1H),2.92–2.81(m,1H),2.07-2.04(m,1H),1.97–1.94(m,1H).
实施例5
(S)-1-(6-(((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)氨基)甲基)吡啶-3-基)吡咯烷-3-醇
(S)-5-(3-羟基吡咯烷-1-基)甲基吡啶醛
向5-氟吡啶-2-醛(200mg,1.60mmol)和(S)-3-吡咯烷醇(139mg,1.6mmol)的乙腈(10mL)溶液中加入碳酸钾(442mg,3.2mmol)。反应液加热到80℃，并搅拌24小时。加入水(50mL),用乙酸乙酯(50mL*2)萃取.有机相,干燥,过滤，浓缩，柱层析(乙酸乙酯)得到黄色固体(217mg,收率70.6％)。
MS(ESI):m/z＝193[M+H]+.
(S)-1-(6-(((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)氨基)甲基)吡啶-3-基)吡咯烷-3-醇
向6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-胺(60mg,0.18mmol)和(S)-5-(3-羟基吡咯烷-1-基)甲基吡啶醛(104mg,0.54mmol)的甲醇(5mL)溶液中加入醋酸(0.05mL)。反应液加热到40℃，搅拌过夜。把反应液降到室温，加入氰基硼氢化钠(34mg,0.54mmol)后，室温搅拌1小时。加入水(50mL),用二氯甲烷/甲醇＝10/1(50mL*2)萃取.有机相,干燥,浓缩，制备得到标题黄色固体(16.4mg,收率17.9％)。
MS(ESI):m/z＝510[M+H]+.
1H NMR(400MHz,DMSO-d6)δ7.82(d,J＝2.7Hz,1H),7.55(d,J＝9.7Hz,1H),7.29–7.15(m,2H),7.19-7.09(m,2H),6.81(dd,J＝8.5,2.9Hz,1H),6.68(s,1H),6.39(d,J＝9.7Hz,1H),5.55(s,1H),5.42(s,1H),5.33–5.26(m,1H),5.26-5.20(m,1H),4.94(d,J＝3.8Hz,1H),4.40-4.32(m,1H),4.22(d,J＝6.3Hz,2H),4.05(d,J＝30.9Hz,2H),3.37(dd,J＝10.1,4.9Hz,1H),3.27-3.22(m,1H),3.05(d,J＝8.7Hz,1H),2.81–2.68(m,1H),2.31–2.10(m,2H),2.03-1.93(m,1H),1.90-1.80(m,1H).
实施例6
(3S)-1-(6-(1-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)氨基)-2,2,2-三氟乙基)吡啶-3-基)吡咯烷-3-醇
2,2,2-三氟-1-(5-氟吡啶-2-基)乙烷-1-醇
将5-氟吡啶-2-醛(1.0g,8.0mmol)溶解在四氢呋喃(15mL)里面，冷却到0℃，氮气保护下缓慢加入三氟甲基三甲基硅烷(1.7g,12.0mmol)。反应液在0℃搅拌15分钟，滴加四丁基氟化胺四氢呋喃溶液(20mL，1.0M)，反应升到室温，搅拌16小时。反应完毕后加入水和乙酸乙酯，分离有机相，干燥，浓缩，柱层析(石油醚/乙酸乙酯＝4/1)得到棕色油状物(1.16g,收率74％)。
2,2,2-三氟-1-(5-氟吡啶-2-基)乙烷-1-酮
将2,2,2-三氟-1-(5-氟吡啶-2-基)乙烷-1-醇(1.16g,5.9mmol),戴斯-马丁氧化剂(3.0g,7.1mmol)和二氯甲烷(25mL)混合，室温搅拌16个小时，过滤掉固体，滤液依次用饱和碳酸钠，饱和硫代硫酸钠洗涤，干燥，浓缩，柱层析(石油醚/乙酸乙酯＝4/1)得到棕色油状物(350mg,收率46％)。
MS(ESI):m/z＝196[M+H]+.
(S)-2,2,2-三氟-1-(5-(3-羟基吡咯烷-1-基)吡啶-2-基)乙烷-1-酮
将2,2,2-三氟-1-(5-氟吡啶-2-基)乙烷-1-酮(200mg,1.0mmol)，(S)-3-吡咯烷醇(170mg,2.0mmol)，N,N'-二异丙基乙胺(250mg,2.0mmol)和N-甲基吡咯烷酮(4mL)混合，加热到60℃搅拌2个小时，反应完毕后，冷却到室温，反应液用反向制备纯化，得到棕色固体(252mg,收率97％)。
MS(ESI):m/z＝194[M+H]+.
(3S)-1-(6-(1-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)氨基)-2,2,2-三氟乙基)吡啶-3-基)吡咯烷-3-醇
将6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-胺(104mg,0.4mmol)，(S)-2,2,2-三氟-1-(5-(3-羟基吡咯烷-1-基)吡啶-2-基)乙烷-1-酮(132mg,0.4mmol)和二氯甲烷混合，向此混合物中加入三甲基铝的甲苯溶液(0.6mL,1M)，此反应液在30℃下搅拌3天。再加入硼烷二甲硫醚的四氢呋喃溶液(1.0mL,2M)，在30℃下搅拌2天。加入20％氢氧化钠溶液淬灭反应，用二氯甲烷萃取，有机相分离，干燥，浓缩，反向制备得到白色固体(8.0mg,收率3.5％)。
MS(ESI):m/z＝578[M+H]+.
1H NMR(400MHz,DMSO-d6)δ7.85(dd,J＝2.7,52.1Hz,1H),7.64–7.58(m,1H),7.30–7.03(m,4H),6.97–6.81(m,2H),6.58–6.49(m,1H),5.78–5.40(m,2H),5.40–5.18(m,2H),4.99–4.93(m,1H),4.37(s,1H),4.20–3.90(m,2H),3.43–3.34(m,1H),3.13–3.03(m,1H),2.84–2.70(m,1H),2.03–1.82(m,2H).
实施例7
(S)-1-(6-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)氨基)吡啶-3-基)吡咯烷-3-醇
(S)-1-(6-氯吡啶-3-基)吡咯烷-3-醇
向2-氯-5-氟吡啶(200mg,1.52mmol)和(S)-吡咯烷-3-醇(132mg,1.52mmol)的N-甲基吡咯烷酮(4mL)溶液中加入N,N-二异丙基乙胺(590mg,4.56mmol)后,加热到100℃反应40小时。反应液反相制备得到白色固体(88mg,收率29.1％)，为白色固体。
MS(ESI):m/z＝199[M+H]+.
(S)-1-(6-((6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)氨基)吡啶-3-基)吡咯烷-3-醇
向6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-胺(100mg,0.30mmol)，(S)-1-(6-氯吡啶-3-基)吡咯烷-3-醇(72mg,0.36mmol)和碳酸铯(196mg,0.60mmol)的甲苯(10mL)溶液中加入三(二亚苄基丙酮)二钯(55mg,0.06mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(70mg,0.12mmol)。反应液升温至120℃，搅拌过夜。加入水(50mL),用二氯甲烷/甲醇＝10/1(50mL*2)萃取.合并有机相,干燥,过滤，浓缩，制备得到黄色固体(20mg,13.5％)。
MS(ESI):m/z＝496[M+H]+.
1H NMR(400MHz,CD3OD)δ8.30(s,1H),7.65(d,J＝9.8Hz,1H),7.53(s,1H),7.38(d,J＝2.7Hz,1H),7.09–6.95(m,3H),6.93-6.85(m,1H),6.74(d,J＝10.0Hz,1H),6.70(d,J＝9.2Hz,1H),5.49-5.32(m,2H),4.57–4.48(m,1H),4.11(s,1H),4.09–3.97(m,1H),3.50–3.36(m,2H),3.32-3.28(m,1H),3.16(d,J＝9.6Hz,1H),2.87–2.74(m,1H),2.28–2.09(m,2H),2.06-1.97(m,1H).
实施例8
1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)-3-(5-((S)-3-羟基吡咯烷-1-基)吡啶-2-基)脲
(S)-1-(6-硝基吡啶-3-基)吡咯烷-3-醇
向5-氟-2-硝基吡啶(200mg,1.41mmol)和(S)-3-吡咯烷醇(184mg,2.11mmol)的N-甲基吡咯烷酮(4mL)溶液中加入N,N-二异丙基乙胺(547mg,4.23mmol)。反应液加热到100℃，并搅拌过夜。反应液浓缩，反相制备得到黄色固体(230mg,收率78.0％)。
MS(ESI):m/z＝209[M+H]+.
(S)-1-(6-氨基吡啶-3-基)吡咯烷-3-醇
向(S)-1-(6-硝基吡啶-3-基)吡咯烷-3-醇(230mg,1.1mmol)的甲醇(8mL)溶液中加入10％钯炭(100mg)。反应液氢气置换三次，在氢气球下室温搅拌2小时。反应液过滤，浓缩，得到粉色固体(190mg,收率96.4％)。
MS(ESI):m/z＝180[M+H]+.
1-(6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-基)-3-(5-((S)-3-羟基吡咯烷-1-基)吡啶-2-基)脲
在0℃时向三光气(18mg,0.06mmol)的二氯甲烷(3mL)溶液中滴加6-((2R,4S)-2-(2,5-二氟苯基)-4-氟吡咯烷-1-基)咪唑并[1,2-b]哒嗪-3-胺(40mg,0.12mmol)的二氯甲烷(1mL)溶液，以及三乙胺(24mg,0.24mmol)。混合物在0℃下半个小时，滴加(S)-1-(6-氨基吡啶-3-基)吡咯烷-3-醇(32mg,0.18mmol)的二氯甲烷(2mL)和N,N-二甲基甲酰胺(1mL)混合溶液，室温搅拌1个小时。加入甲醇(2mL)，浓缩，反向制备得到黄色固体(15mg,收率23％)。
MS(ESI):m/z＝539[M+H]+.
1H NMR(400MHz,CD3OD)δ7.68(d,J＝2.5Hz,1H),7.60–7.55(m,2H),7.12-7.07(m,1H),7.06–6.90(m,4H),6.56(d,J＝9.8Hz,1H),5.57-5.40(m,2H),4.62-4.54(m,1H),4.59-4.30(m,1H),4.23–4.09(m,1H),3.54–3.42(m,2H),3.40-3.32(m,1H),3.22(d,J＝10.0Hz,1H),2.97-2.86(m,1H),2.37–2.22(m,1H),2.22–2.13(m,1H),2.08-1.99(m,1H).
生物测试例1TRKA，TRKB，TRKC激酶体外活性测试
实验材料
重组人源TRKA，TRKB，TRKC蛋白购自Carna Biosciences。HTRF kinEASE TK kit购自CisbioBioassays。使用BioTek酶标仪Synergy Neo 2读板。
实验方法
将测试化合物进行3倍浓度梯度稀释，终浓度为1μM到0.05nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
TRKA酶反应：
0.2ng/μl TRKA蛋白激酶，1μM TK Substrate-biotin多肽底物，14.68μM ATP，1×enzymatic buffer，5mM MgCl2，1mM DTT。检测板为White Proxiplate384-Plus plate(PerkinElmer)，室温反应40分钟，反应体系为10μl。
TRKB酶反应：
0.037ng/μl TRKB蛋白激酶，1μM TK Substrate-biotin多肽底物，4.77μM ATP，1×enzymatic buffer，5mM MgCl2，1mMMnCl2，1mM DTT。检测板为White Proxiplate384-Plusplate(PerkinElmer)，室温反应50分钟，反应体系为10μl。
TRKC酶反应：
0.037ng/μl TRKC蛋白激酶，1μM TK Substrate-biotin多肽底物，25.64μM ATP，1×enzymatic buffer，5mM MgCl2，1mM DTT。检测板为White Proxiplate 384-Plus plate(PerkinElmer)，室温反应40分钟，反应体系为10μl。
反应检测：
加入10μl的检测试剂至反应板中，含终浓度0.125μM SA-XL665和5μl1×TK-Antibody，室温孵育过夜，Synergy Neo 2读板。
数据分析
将665/620Ratio数值通过下列公式将读数转化成抑制率(％)＝(1-Ratiotest/Ratiomax)×100％。Ratiomax为不含检测化合物的阳性对照，Ratiotest为不同化合物各浓度的检测值。4参数曲线拟合测得IC50(nM)数据，具体见表1。
表1
| Compound | TRKA(nm) | TRKB(nm) | TRKC(nm) |
| 实施例1 | <10 | <10 | <10 |
| 实施例4 | <10 | <10 | <10 |
| 实施例5 | <10 | <100 | <100 |
| 实施例7 | <10 | <10 | <10 |
| 实施例8 | <10 | <10 | <10 |
生物测试例2:KM12-LUC细胞增殖实验
含有TPM3-NTRK1融合基因的的人结肠癌细胞株KM12-LUC(LUC,稳定表达Luciferace)用于待测化合物细胞学水平药效评估的模型。KM12-LUC细胞中的TRK融合基因使其不依赖于胞外生长因子的刺激，可以持续自发激活并激活其下游信号通路MAPK-ERK、PI3K-AKT等与细胞增殖密切相关的信号通路。因此，在KM12-LUC细胞中抑制TRK活性可显著抑制细胞的增殖。方法如下：第一天，在384孔板中接种细胞，2000细胞/孔；第二天加不同浓度的待测化合物；第五天，加CellTiter-Glo(Promega)检测细胞活性，计算细胞72小时增殖抑制率。用prism5来进行统计分析并得出待测化合物的IC50值。
结果显示，本发明化合物能够有效的抑制KM12-LUC细胞的增殖,具体见表2
表2
生物测试例3突变的TRKA(G595R),TRKA(G667C)and TRKC(G623R)激酶体外活性测试
实验材料
重组人源TRKA(G595R)，TRKA(G667C)，TRKC(G623R)蛋白购自SignalChem。HTRFkinEASE TK kit购自CisbioBioassays。使用BioTek酶标仪Synergy Neo 2读板。
实验方法
将测试化合物进行4倍浓度梯度稀释，终浓度为1μM到0.004nM 10个浓度，每个浓度两个复孔；DMSO在检测反应中的含量为1％。
TRKA(G595R)酶反应：
0.12ng/μlTRKA(G595R)蛋白激酶，1μM TK Substrate-biotin多肽底物，4.5μMATP，1×enzymatic buffer，5mM MgCl2，1mM DTT。检测板为White Proxiplate384-Plusplate(PerkinElmer)，室温反应30分钟，反应体系为10μl。
TRKA(G667C)酶反应：
0.026ng/μlTRKA(G667C)蛋白激酶，1μM TK Substrate-biotin多肽底物，5.5μMATP，1×enzymatic buffer，5mM MgCl2，1mM DTT。检测板为White Proxiplate 384-Plusplate(PerkinElmer)，室温反应30分钟，反应体系为10μl。
TRKC(G623R)酶反应：
1.0ng/μlTRKC(G623R)蛋白激酶，1μM TK Substrate-biotin多肽底物，62.9μMATP，1×enzymatic buffer，5mM MgCl2，1mM DTT。检测板为White Proxiplate 384-Plusplate(PerkinElmer)，室温反应50分钟，反应体系为10μl。
反应检测：
加入10μl的检测试剂至反应板中，含终浓度0.125μM SA-XL665和5μl1×TK-Antibody，室温孵育过夜，Synergy Neo 2读板。
数据分析
将665/620Ratio数值减去不含酶的阴性对照孔数值后通过下列公式将读数转化成抑制率(％)＝(1-Ratiotest/Ratiomax)×100％。Ratiomax为不含检测化合物的阳性对照，Ratiotest为不同化合物各浓度的检测值。4参数曲线拟合测得IC50(nM)数据，具体见表3。
表3
生物测试例4：本发明中小分子抑制剂小鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予ICR小鼠测试化合物，于不同时间点采集血样，LC-MS/MS测定小鼠血浆中受试物的浓度并计算相关参数。具体如下：取所需量供试品，溶于5％DMSO+10％Solutol+85％注射用水中，配成所需浓度的溶液，用于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间：给药后0.083h，0.25h，0.5h，1h，2h，4h，8h和24h。口服采血时间：给药后0.25h，0.5h，1h，2h，4h，6h，8h和24h。建立生物样品分析方法及样品检测方法。收集不同时间点的血药浓度数据，运用Phoenix WinNonlin 7.0软件计算药代动力学参数，如AUC(0-t)，AUC(0-∞)，T1/2，Cmax，Tmax和MRT等。
生物测试例5：本发明中小分子抑制剂大鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予SD大鼠测试化合物，于不同时间点采集血样，LC-MS/MS测定大鼠血浆中受试物的浓度并计算相关参数。具体如下：取所需量供试品，溶于5％DMSO+10％Solutol+85％注射用水中，配成所需浓度的溶液，用于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间：给药后0.083h，0.25h，0.5h，1h，2h，4h，8h和24h。口服采血时间：给药后0.25h，0.5h，1h，2h，4h，6h，8h和24h。建立生物样品分析方法及样品检测方法。过不同时间点的血药浓度数据，运用Phoenix WinNonlin 7.0软件计算药代动力学参数，如AUC(0-t)，AUC(0-∞)，T1/2，Cmax，Tmax和MRT等。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种式I所示的化合物或其立体异构体或外消旋体或其药学上可接受的盐：
其中，
L1选自下组：-NH-、-CH＝CH-、-NH(CHR)-、-NHC(O)NH-、-CH2-O-、-CH2-S-、-NHS(O)2-、-S(O)2-、-S(O)-；R选自下组：H、C1-C4烷基、卤素；
L2选自下组：取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-12元杂环基(包括并环、桥环、螺环)；
或所述的L1和L2共同形成选自下组的基团：取代或未取代的10-12元二环含氮杂芳基，或取代或未取代的10-12元二环含氮杂环基；其中，所述的杂芳基或杂环基具有1-3个选自N、S和O的杂原子；
Rc为取代或未取代的4-6元的杂环基(优选为饱和或不饱和的氮杂环基)、取代或未取代的5-10元杂芳基；其中，所述的杂芳基或杂环基具有1-3个选自N、S和O的杂原子；
RA为
其中，
X1、X2、X3各自独立地为CR6或N；R6为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
n为1、2或3；
各个R3各自独立地为氢、氘、羟基、卤素、三氟甲基，氰基，氨基，酰胺基，取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；
或者n为2且两个R3共同形成-O-(CH2)m-O-；m为1-4的整数；
RB为取代或未取代的4-7元杂环(所述杂环含有1-3个选自氮原子、氧原子和硫原子的杂原子)；-(CH2)m1-、-O-(CH2)m2-O-；其中，m1、m2各自独立地为1-4的整数；
或者RB为-取代或未取代的-C1-C10亚烷基-X2-(其中，X2为NH、O、S或S(O)2)、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基；除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：氘、卤素、卤代的C1-C6烷基、卤代的C1-C6烷氧基、卤代的C3-C8环烷基、甲基砜基、-S(＝O)2NH2、氧代(＝O)、-CN、羟基、-NH2、羧基、C1-C6酰胺基(-C(＝O)-N(Rd)2或-NH-C(＝O)(Rd)，Rd为H或C1-C5的烷基)、C1-C6烷基-(C1-C6酰胺基)、
或取代或未取代的选自下组的基团：C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、C1-C6胺基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-12元杂环基、-(CH2)-C6-C10芳基、-(CH2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)，且所述的取代基选自下组：卤素、C1-C6烷基、C1-C6烷氧基、氧代、-CN、-NH2、-OH、C6-C10芳基、C1-C6胺基、-S(＝O)2CH3、-S(＝O)2NH2、具有1-3个选自N、S和O的杂原子的5-10元杂芳基；
虚线表示化学键或无。
2.如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，L1为-CH＝CH-。
3.如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，RA选自下组：
各式中，X1、X2定义同前；
芳香环上，n为1、2或3；且R3为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；或者n为2且两个R3共同形成-O-(CH2)m-O-；m为1-4的整数；
其它位置的R3、R4、R5各自独立地为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基。
4.如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，RA为
其中，X1为CR6或N；X2、X3各自独立地为CR6；
n为1、2或3；且R3为氢、氘、羟基、卤素、取代或未取代的C1-C6烷基、或取代或未取代的C1-C6烷氧基；或者n为2且两个R3共同形成-O-(CH2)m-O-；m为1-4的整数。
5.如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，所述的式I化合物具有如下式所示的结构：
6.如权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐：其特征在于，选自下组：
7.一种药物组合物，其包含治疗有效量的权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐，以及药学上可接受的赋形剂。
8.权利要求1所述的化合物或其立体异构体或外消旋体或其药学上可接受的盐或权利要求7所述的药物组合物的用途，其特征在于，用于预防和治疗与TRK功能异常相关的疾病的药物中的用途。
9.一种TRK抑制剂，其特征在于，所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
10.如权利要求9所述的TRK抑制剂，其特征在于，所述的抑制剂用于治疗选自下组的疾病：癌症，增生性疾病，疼痛，皮肤病或病症，代谢疾病，肌肉疾病，神经性疾病，自身免疫疾病，皮炎引起的瘙痒，炎症相关疾病，骨相关的疾病。
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Inventor after: Zhang Shuyun Inventor after: Xu Yuan Inventor after: Zhang Yi Inventor after: Zhang Yuxing Inventor after: Feng Zhiyong Inventor after: Jiang Lei Inventor after: Jin Xian Inventor after: Qiao Zhi Inventor after: Shou Jianyong Inventor after: Shang Ke Inventor after: Wu Danyi Inventor after: Xu Lingling Inventor before: Zhang Shuyun Inventor before: Xu Yuan Inventor before: Zhang Yi Inventor before: Zhang Yuxing Inventor before: Feng Zhiyong Inventor before: Jiang Lei Inventor before: Jin Xian Inventor before: Qiao Zhi Inventor before: Shou Jianyong Inventor before: Shang Ke Inventor before: Wu Danyi Inventor before: Xu Lingling |
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Application publication date: 20210518 |