CN110831596A - 作为蛋白激酶抑制剂的氨基噻唑化合物 - Google Patents
作为蛋白激酶抑制剂的氨基噻唑化合物 Download PDFInfo
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- CN110831596A CN110831596A CN201880039827.XA CN201880039827A CN110831596A CN 110831596 A CN110831596 A CN 110831596A CN 201880039827 A CN201880039827 A CN 201880039827A CN 110831596 A CN110831596 A CN 110831596A
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Abstract
本发明公开了下示式(I)的氨基噻唑化合物及含有这些化合物中的一者的药物组合物。本发明还公开了利用氨基噻唑化合物中的一者抑制酪氨酸激酶和治疗与酪氨酸激酶相关的癌症的方法。
Description
背景技术
蛋白激酶在调节各种细胞功能的细胞信号通路中是重要的，包括分化、增殖、迁移和凋亡。蛋白激酶的失调涉及癌症和许多其他疾病。
酪氨酸激酶为蛋白激酶的一种亚类，其通过将磷酸根从ATP中转移至目标蛋白酪氨酸的羟基基团来调节目标蛋白功能。FMS样酪氨酸激酶3(FMS-like tyrosine kinase 3，“FLT3”)、血管内皮生长因子受体(vascular endothelial growth factor receptor，“VEGFR”)和酪氨酸蛋白激酶Kit(tyrosine-protein kinase Kit，“c-Kit”)是作为癌症治疗中引人注目的治疗靶标而已被研究的三种酪氨酸激酶。
FLT3为一种受体酪氨酸激酶，其突变可以导致癌症的发展，例如急性髓细胞白血病(acute myeloid leukemia)。参见Pratz等人,Current Drug Targets,2010,11(7),781-9。
血管内皮生长因子是一种信号蛋白，通过结合至VEGFR和经由转磷酸作用(transphosphorylation)活化血管内皮生长因子，其刺激新血管的生长。VEGFR已被确认为肿瘤血管新生(angiogenesis)的主要调节因子。参见Hicklin等人,J Clin Oncol.,2005,23,1011-1027。
c-Kit也是一种受体酪氨酸激酶，其参与细胞内信号传导(intracellularsignaling)。c-Kit的突变形式在一些癌症的发生中起到关键作用。已证实抑制c-Kit可以有效治疗胃肠间质瘤(gastrointestinal stromal tumor)、急性髓细胞白血病和黑色素瘤。参见Babaei等人,Drug Des Devel Ther.,2016 10,2443-2459。
作为有效的酪氨酸激酶抑制剂，已经对氨基噻唑化合物进行了广泛的探索，其作为候选药物存在若干挑战。它们具有差的激酶选择性，在毒性研究中经常引起动物死亡，并且通常缺乏为了在临床前或临床研究中发挥所需功效的足够的体内暴露(in vivoexposure)。
有需要开发新的氨基噻唑化合物，其特异性地抑制特定酪氨酸激酶，展现出期望的安全性，并且在治疗目标癌症中发挥足够的体内功效。
发明内容
本发明基于意想不到的发现：特定氨基噻唑化合物有效地抑制多种酪氨酸激酶，例如FLT3、VEGFR和c-Kit。
在一个方面中，本发明涉及式(I)的氨基噻唑化合物：
其中R1为C1-6烷基或C1-6硫代烷基；X为O或NRa，其中Ra为H或C1-6烷基；Y为CRbRc或NRd，其中Rb和Rc各自独立地为H、卤素、C1-6烷基、C1-6烷氧基或氨基，或者Rb与Ra、键接到Rb的碳原子和键接到Ra的氮原子一起为C3-10杂环烷基，并且Rd为H或C1-6烷基，或者Rd与Ra和键接到Rd和Ra的氮原子一起为C3-10杂环烷基；R2为-CH2CH2Re或NRfRg，其中Re为H、卤素、C1-6烷基或ORh，并且Rf和Rg各自独立地为C1-6烷基或C3-8环烷基，Rh为H或C1-6烷基，或者Rh与Rd、键接到Rh的氧原子和键接到Rd的氮原子一起为C3-10杂环烷基；并且R3为杂芳基。
本文中的术语“烷基”是指饱和的直链或支链烃部分(moiety)，诸如-CH3或支链的-C3H7。术语“环烷基”是指非芳族的单环、双环、三环或四环的烃部分，诸如环己基、环己烯-3-基或金刚烷基(adamantyl)。术语“烷氧基”是指-O-烷基基团。烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。术语“硫代烷基”是指-S-烷基基团。硫代烷基的实例包括但不限于甲硫醇、乙硫醇和苄硫醇(benzylthiol)。术语“杂环烷基”是指具有一个或多个环杂原子(例如N、O或S)的非芳族的单环、双环、三环、或四环的部分。杂环烷基的实例包括但不限于4-吗啉基(4-morpholinyl)、1-哌嗪基(1-piperazinyl)、4-四氢吡喃基(4-tetrahydropyranyl)和4-吡喃基(4-pyranyl)。术语“杂芳基”是指具有含有至少一个杂原子(例如N、O或S)的一个或多个芳族环的部分。杂芳基部分的实例包括呋喃基(furyl)、亚呋喃基(furylene)、芴基(fluorenyl)、吡咯基(pyrrolyl)、噻吩基(thienyl)、噁唑基(oxazolyl)、咪唑基(imidazolyl)、噻唑基(thiazolyl)、吡啶基(pyridyl)、嘧啶基(pyrimidinyl)、喹唑啉基(quinazolinyl)、喹啉基(quinolyl)、异喹啉基(isoquinolyl)和吲哚基(indolyl)。
除非另有说明，本文提及的烷基、硫代烷基、烷氧基、环烷基、杂环烷基和杂芳基包括经取代的和未经取代的部分两者。环烷基、杂环烷基和杂芳基上可能的取代基包括C1-10烷基、C2-10烯基、C2-10炔基、C3-20环烷基、C3-20环烯基、C1-20杂环烷基、C1-20杂环烯基、C1-10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、C1-10烷基氨基、C1-20二烷基氨基、芳基氨基、二芳基氨基、羟基、卤素、硫代(thio)、C1-10烷硫基(alkylthio)、芳硫基(arylthio)、C1-10烷基磺酰基(alkylsulfonyl)、芳基磺酰基(arylsulfonyl)、酰氨基(acylamino)、氨酰基(aminoacyl)、氨基硫代酰基(aminothioacyl)、脒基(amidino)、胍(guanidine)、脲基(ureido)、氰基、硝基、酰基、硫酰基(thioacyl)、酰氧基(acyloxy)、羧基和羧酸酯(carboxylic ester)。另一方面，烷基上可能的取代基包括除C1-10烷基、C2-10烯基和C2-10炔基以外的所有上述取代基。环烷基、杂环烷基、芳基和杂芳基也可以彼此稠合。
如果适用，上述氨基噻唑化合物包括化合物本身，以及它们的盐、前药和溶剂化物。例如，可以在阴离子与氨基噻唑化合物上带正电的基团(如氨基)之间形成盐。合适的阴离子包含氯、溴、碘、硫酸根、硝酸根、磷酸根、柠檬酸根(citrate)、甲磺酸根(methanesulfonate)、三氟乙酸根(trifluoroacetate)、乙酸根、苹果酸根(malate)、甲苯磺酸根(tosylate)、酒石酸根(tartrate)、延胡索酸根(fumurate)、谷氨酸根(glutamate)、葡萄糖醛酸根(glucuronate)、乳酸根(lactate)、戊二酸根(glutarate)和马来酸根(maleate)。同样地，也可以在阳离子和氨基噻唑化合物上带负电的基团(如羧酸根)之间形成盐。合适的阳离子包含钠离子、钾离子、镁离子、钙离子和铵阳离子诸如四甲基铵离子。氨基噻唑化合物也包括含有季氮原子的那些盐。前药的实例包括酯类和其他药用衍生物，其在施用至受试者时能够提供活性氨基噻唑化合物。溶剂化物是指在活性氨基噻唑化合物和药用溶剂之间形成的复合物。药用溶剂的实例包括水、乙醇、异丙醇、乙酸乙酯、乙酸和乙醇胺。
在另一个方面中，本发明涉及一种抑制酪氨酸激酶(例如FLT3、VEGFR和c-Kit)的方法。该方法包括使酪氨酸激酶与有效量的一种或多种上述氨基噻唑化合物接触。
治疗与酪氨酸激酶相关的癌症的方法也在本发明的范围内。该方法包括向有需要的受试者施用有效量的一种或多种上述式(I)的氨基噻唑化合物。
与癌症相关的酪氨酸激酶可以是野生型或突变体。酪氨酸激酶的实例包括但不限于FLT3、FLT4、VEGFR、血小板衍生生长因子受体(platelet-derived growth factorreceptor，PDGFR)A、PDGFR B、c-Kit、c-Src(SRC)、酪氨酸蛋白激酶Lyn(tyrosine-proteinkinase Lyn，LYN)A、LYN B、在转染期间重排的酪氨酸激酶(rearranged duringtransfection tyrosine kinase，RET)、淋巴细胞特异性蛋白质酪氨酸激酶(lymphocyte-specific protein tyrosine kinase)、加德纳-拉希德猫肉瘤病毒致癌基因同源物(Gardner-Rasheed feline sarcoma viral oncogene homolog)、盘状结构域受体1(discoidin domain receptor 1)、激酶插入结构域受体(kinase insert domainreceptor)、B淋巴细胞激酶(B lymphocyte kinase)、酪氨酸蛋白激酶Yes(tyrosine-protein kinase Yes)、爱柏森鼠类白血病病毒致癌基因同源物1(Abelson murineleukemia viral oncogene homolog 1，ABL1)、酪氨酸蛋白激酶Tek(tyrosine-proteinkinase Tek)、RET V804L、RET Y791F、FLT3 D835Y、PDGFR A V561D或ABL1 T315I。
在一个示例性方法中，式(I)的氨基噻唑化合物用于治疗与FLT3、VEGFR或c-Kit相关的癌症。
癌症的实例包括急性髓细胞白血病(acute myeloid leukemia)、绿色瘤(chloroma)、慢性骨髓性白血病(chronic myelogenous leukemia)、急性淋巴母细胞性白血病(acute lymphoblastic leukemia)、慢性淋巴细胞性白血病(chronic lymphocyticleukemia)、霍奇金病(Hodgkin’s disease)、非霍奇金淋巴瘤(non-Hodgkin’s lymphoma)、B细胞淋巴瘤(B-cell lymphoma)、多发性骨髓瘤(multiple myeloma)、瓦尔登斯特伦巨球蛋白血症(Waldenstrom’s macroglobulinemia)、骨髓增生异常综合征(myelodysplasticsyndrome)、胰腺癌(pancreatic cancer)、膀胱癌(bladder cancer)、结直肠癌(colorectal cancer)、乳癌(breast cancer)、男性生殖道癌(male genital tractcancer)、肾癌(renal cancer)、肝细胞癌(hepatocellular cancer)、肺癌(lung cancer)、卵巢癌(ovarian cancer)、宫颈癌(cervical cancer)、子宫癌(uterus cancer)、妊娠滋养细胞疾病(gestational trophoblastic disease)、胃癌(gastric cancer)、胆管癌(bileduct cancer)、胆囊癌(gallbladder cancer)、小肠癌(small intestine cancer)、食管癌(esophageal cancer)、口咽癌(oropharyngeal cancer)、下咽癌(hypopharyngealcancer)、眼癌(eye cancer)、神经癌(nerve cancer)、头颈癌(head and neck cancer)、黑色素瘤(melanoma)、浆细胞瘤(plasmacytoma)、内分泌腺肿瘤(endocrine glandneoplasm)、神经内分泌癌(neuroendocrine cancer)、脑瘤(brain tumor)、骨癌(bonecancer)和肉瘤(sarcoma)(例如胃肠间质瘤(gastrointestinal stromal tumor或GIST))。
含有一种或多种上述式(I)的氨基噻唑化合物的药物组合物也在本发明的范围内。该药物组合物可以用于治疗癌症。
本发明还包括一种或多种上述式(I)的氨基噻唑化合物用于制备治疗癌症的药物的用途。
术语“治疗”(treating或treatment)是指将一种或多种氨基噻唑化合物施用至受试者，该受试者患有上述疾病(即癌症)、具有这样的疾病的症状或具有易患这样的疾病的倾向，目的是给予治愈效果，例如治愈、缓解、改变、影响、改善或预防上述疾病、其症状或易患其的倾向。术语“有效量”是指给予治疗效果所需的活性化合物的量。如本领域技术人员所认识到的，有效剂量将依据治疗疾病的类型、施用途径、赋形剂用法以及与其他治疗性治疗共同使用的可能性而变化。
为了实施本发明的方法，具有一种或多种上述氨基噻唑化合物的组合物可以肠胃外、口服、经鼻、直肠、局部或经颊施用。本文所使用的术语“肠胃外”是指皮下、皮内、静脉内、腹膜内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内或颅内注射，以及任何合适的灌注技术。
无菌可注射组合物可以是在无毒的肠胃外可接受的稀释剂或溶剂中的溶液或悬浮液，例如在1,3-丁二醇中的溶液。其中可以使用的可接受的载体和溶剂为甘露醇、水、林格氏溶液(Ringer’s solution)和等渗氯化钠溶液。此外，不挥发性油(fixed oils)通常用作溶剂或悬浮介质(例如合成的单或双甘油酯)。脂肪酸如油酸及其甘油酯衍生物可用于注射剂的制备，天然药用油如橄榄油、蓖麻油，特别是它们的聚氧乙烯化(polyoxyethylated)形式，也可用于注射剂的制备。这些油溶液或悬浮液也可以含有长链醇稀释剂或分散剂、羧甲基纤维素或类似的分散剂。为了配制的目的，还可以使用其他常用的表面活性剂，例如吐温类(Tweens)和司盘类(Spans)或其他类似的乳化剂或生物利用度增强剂，其通常用于制备药用固体、液体或其他剂型。
用于口服施用的组合物可以是任何口服可接受的剂型，包括胶囊、片剂、乳剂以及水性悬浮液、分散体和溶液。在片剂的情况下，常用的载体包括乳糖和玉米淀粉。通常也添加润滑剂，例如硬脂酸镁。对于以胶囊形式的口服施用，可用的稀释剂包括乳糖和干燥玉米淀粉。当口服施用水性悬浮液或乳剂时，活性成分可以悬浮或溶解在与乳化剂或悬浮剂结合的油相中。如有需要，可以添加某些甜味剂、调味剂或着色剂。
可以根据药物制剂领域公知的技术制备鼻用气雾剂或吸入剂组合物。例如，采用苯甲醇或其他合适的防腐剂、增强生物利用度的吸收促进剂、碳氟化合物(fluorocarbon)和/或本领域已知的其他增溶剂或分散剂，这样的组合物可以制备成盐水中的溶液。
具有一种或多种上述氨基噻唑化合物的组合物也可以以用于直肠施用的栓剂形式施用。
药物组合物中的载体必须是“可接受的”，在此意义上，其与组合物的活性成分相容(并且优选地能够稳定该活形成分)，并且对待治疗的受试者无害。一种或多种增溶剂可以用作药物赋形剂，用来递送活性的1,5-二苯基-戊-1,4-二烯-3-酮化合物。其他载体的实例包括胶体二氧化硅、硬脂酸镁、纤维素、十二烷基硫酸钠和D&C黄色#10(D&C Yellow#10)。
在下面的描述中阐述了本发明的一个或多个实施方案的细节。本发明的其他特征、目的和优点根据说明书和权利要求书将是显而易见的。
发明详述
详细公开了式(I)的氨基噻唑化合物：
其中变量R1、R2、R3、X和Y如在上述发明内容部分中定义的。
通常，式(I)的化合物具有的R3为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者式(I)的化合物具有的R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自由H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基组成的组。示例性化合物具有的R3为独立地被一个或多个(CH2)nZ部分取代的6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基。R3的两个实例为吡啶基或嘧啶基。
一组上述新颖氨基噻唑化合物为式(II)的化合物：
其中R1为C1-6烷基。
在一个子集中，式(II)的化合物具有的X为O，Y为NRd，并且R2为-CH2CH2Re，其中Re为ORh，Rh与Rd、键接到Rh的氧原子和键接到Rd的氮原子一起为C3-10杂环烷基。该子集的化合物可以具有R3，其为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基。例如，R3可以是吡啶基或嘧啶基。示例性化合物包括但不限于以下化合物：
在另一个子集中，式(II)的化合物具有的X为NRa，并且Y为CRbRc或NRd，其中Ra与Rb、键接到Ra的氮原子和键接到Rb的碳原子一起为C3-10杂环烷基；Rc为H、卤素、C1-6烷基、C1-6烷氧基或氨基；并且Rd与Ra和键接到Ra和Rd的氮原子一起为C3-10杂环烷基。
值得注意的是，这些化合物可以具有的X为NRa，Y为CRbRc，并且R2为NRfRg，其中Ra与Rb、键接到Ra的氮原子和键接到Rb的碳原子一起为C3-10杂环烷基；Rc为H、卤素、C1-6烷基、C1-6烷氧基或氨基；并且Rf和Rg各自为C1-6烷基。它们通常具有的R3为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基。R3可以是吡啶基或嘧啶基。示例性化合物包括但不限于以下化合物：
另一方面，该子集中的化合物可以具有的X为NRa，Y为NRd，并且R2为-CH2CH2Re，其中Ra与Rd和键接到Ra和Rd的氮原子一起为C3-10杂环烷基；并且Re为H、卤素或ORh，Rh为H或C1-6烷基。通常，这些化合物具有的R3为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基。例如，R3为吡啶基或嘧啶基。示例性化合物包括但不限于以下化合物：
另一组上述新颖氨基噻唑化合物为式(III)的化合物：
其中R1为C1-6烷基。
示例性的式(III)的化合物为
下面列出的是本发明的示例性化合物，每个化合物分配一个化合物编号。
用于治疗癌症的含有一种或多种式(I)的氨基噻唑化合物的药物组合物也在本发明的范围内。
本发明还涵盖一种治疗癌症的方法，该方法包括向有需要的受试者施用有效量的式(I)的化合物。
用于合成式(I)的化合物的合成化学转化和保护基团方法(保护和去保护)为本领域公知的。参见例如R.Larock,Comprehensive Organic Transformations(第2版，VCHPublishers 1999)；P.G.M.Wuts和T.W.Greene,Greene’s Protective Groups in OrganicSynthesis(第4版，John Wiley and Sons 2007)；L.Fieser和M.Fieser,Fieser andFieser’s Reagents for Organic Synthesis(John Wiley and Sons 1994)；L.Paquette编，Encyclopedia of Reagents for Organic Synthesis(第2版，John Wiley and Sons2009)；以及G.J.Yu等人，J.Med.Chem.2008,51,6044-6054。
如此制备的式(I)的化合物可以使用生化测定(例如以下实施例2-4中描述的激酶测定)或细胞测定(例如以下实施例5中描述的体外抗癌活性测定)来初步筛选它们在抑制酪氨酸激酶或抑制表达特定酪氨酸激酶的癌细胞的生长的潜力。随后可以使用体内测定(例如异种移植动物模型测定)来评价它们在哺乳动物中抑制肿瘤生长的活性。可以进一步测试所选择的化合物以验证它们在治疗癌症中的功效。例如，可以将化合物施用至患有癌症的动物(例如小鼠)，然后评价其治疗效果。基于结果，可以研究和确定适当的剂量范围和施用途径。
不需要进一步说明，相信本领域技术人员可以基于以上描述最大程度地利用本发明。因此，以下的具体实施例应被解释为仅仅是说明性的，而不以任何方式限制本公开的其余部分。本文引用的所有出版物均通过引用整体结合于此。
以下实施例1示出了13种示例性式(I)化合物的合成和表征。由此制备的化合物的分析数据也列在实施例1中，并且测试这些化合物的程序在以下实施例2-5中描述。
所有化学品和溶剂从商业供货商购买，并且按原样使用。所有反应在干燥氮气气氛下进行。通过使用Merck 60F254硅胶玻璃背板(5x 10cm)的TLC监测反应；并且在紫外线照射下(254nm)或通过喷洒磷钼酸试剂(Aldrich)接着在80℃下加热来目视检测区域。所有快速柱层析使用Merck Kieselgel 60,No.9385,230-400目ASTM硅胶作为固定相进行。质子(1H)核磁共振光谱在Varian Mercury-300或Varian Mercury-400光谱仪上测量。相对于溶剂峰的共振，在δ量度上以每百万分之几(ppm)纪录化学位移。以下缩写用于描述耦合：s＝单峰；d＝双重峰；t＝三重峰；q＝四重峰；quin＝五重峰；br＝宽；以及m＝多重峰。LCMS数据在Agilent MSD-1100ESI-MS/MS、Agilent 1200系列LC/MSD VL和Waters Acquity UPLC-ESI-MS/MS系统上测量。
实施例1：化合物1-13的合成
根据以下流程1所示的合成路线制备化合物1-13。在所列出的试剂中，TEA为三乙胺，KOAc为乙酸钾，Pd(PPh3)4为四(三苯基膦)钯(0)，DMAc为N,N-二甲基乙酰胺，CsF为氟化铯，HCl为盐酸，NaHCO3为碳酸氢钠，NaH为氢化钠，NMP为1-甲基-2-吡咯烷酮，KOH为氢氧化钾，并且DMSO为二甲亚砜。
流程1.试剂和条件：(a)TEA，CH2Cl2，0℃至室温；(b)KOAc，Pd(PPh3)4，DMAc，150℃(对于Py＝吡啶-2-基，用CsF替代KOAc)；(c)12N HCl，H2O，回流；(d)NaHCO3，H2O，室温；(e)NaH，NMP，0℃；(f)DMSO，RH，100℃，或二甘醇二甲醚，KOH，160℃(对于RH＝4-(2-羟乙基)-吗啉；以及(g)6N HCl，0℃。
步骤I.2,2-二甲基-N-噻唑-2-基-丙酰胺B的合成
在0℃向2-氨基噻唑A(300mmol)和三乙胺(330mmol)在无水CH2Cl2(250mL)中的混合物中加入三甲基乙酰氯(310mmol)，并且将混合物在氩气气氛下在室温搅拌1小时。将混合物用6N HCl(60mL)洗涤，并且分离有机层，用硫酸镁(MgSO4)干燥，并且在减压下浓缩。残余物通过硅胶上的层析纯化(20％EtOAc/己烷)，以得到标题产物B，其为灰白色固体(72％)。1H NMR(300MHz,DMSO-d6)：δ11.75(s,1H),7.46(d,J＝6.0Hz,1H),7.17(d,J＝6.0Hz,1H),1.22(s,9H)；MS(ES+)m/z C8H12N2OS计算值：184.07；实测值：185.1(M+H+)。
步骤II.化合物C的合成(Py＝吡啶-3-基、吡啶-4-基和嘧啶-5-基)
将2,2-二甲基-N-噻唑-2-基-丙酰胺B(30mmol)、氯吡啶(30mmol)、乙酸钾(120mmol)和四(三苯基膦)钯(0)(1.5mmol)在N,N-二甲基乙酰胺(60mL)中的混合物在氩气气氛下在150℃加热24小时。通过蒸馏(120℃/160mm Hg)移除大部分溶剂，并且将残余物用水(250mL)洗涤。通过过滤收集沉淀，再溶解于CH3OH/CH2Cl2(200mL)中，并且通过硅藻土(Celite)垫过滤。将滤液在减压下浓缩，并且通过硅胶上的层析纯化(1％MeOH/CH2Cl2)，以得到所需产物，其为灰白色固体(40-85％)。
步骤II.化合物C的合成(Py＝吡啶-2-基)
将2,2-二甲基-N-噻唑-2-基-丙酰胺B(10mmol)、氯吡啶(10mmol)、氟化铯(20mmol)和四(三苯基膦)钯(0)(0.5mmol)在二甲亚砜(20mL)中的混合物在氩气气氛下在160℃加热16小时。所得混合物用0.5N HCl(150mL)和CH2Cl2(150mL)分配。将有机层分离，用MgSO4干燥，在减压下浓缩，并且通过硅胶上的层析纯化(3％丙酮/CH2Cl2)，以得到所需产物，其为淡棕色固体(20％)。
仅选择C中的一个来示出其NMR光谱和质谱。
2,2-二甲基-N-(5-吡啶-4-基-噻唑-2-基)-丙酰胺。1H NMR(400MHz,CDCl3)：δ9.28(bs,1H),8.61(dd,J＝4.8,1.6Hz,2H),7.84(s,1H),7.42(dd,J＝4.8,1.6Hz,2H),1.38(s,9H)；MS(ES+)m/z C13H15N3OS计算值：261.09；实测值：262.1(M+H+)。
步骤III.化合物D的合成
将C(5mmol)和12N HCl(5mL)在水(5mL)中的混合物加热至回流达2小时。在减压下移除大部分溶剂，并且用CH3OH(15mL)稀释残余物。通过蒸馏移除大部分溶剂，并且将残余物在真空下干燥，以得到D盐酸盐，其为淡棕色固体。
在室温下将上述固体在水(30mL)中的搅拌悬浮液用碳酸氢钠调整至pH＝7，并且将混合物在50℃搅拌2小时。通过过滤收集沉淀，并且在真空下干燥，以得到所需产物D，其为淡棕色固体(85-90％)。
仅选择D中的一个来示出其NMR光谱和质谱。
5-吡啶-4-基-噻唑-2-基胺。1H NMR(300MHz,DMSO-d6)：δ8.41(dd,J＝4.8,1.5Hz,2H),7.73(s,1H),7.48(s,2H),7.35(dd,J＝4.8,1.5Hz,2H)；MS(ES+)m/z C8H7N3S计算值：177.04；实测值：178.1(M+H+)。
步骤IV.化合物E的合成
在0℃向D或市售的4-吡啶-3-基-噻唑-2-基胺(4mmol)和4,6-二氯-2-甲基嘧啶(8mmol)在1-甲基-2-吡咯烷酮(20mL)中的混合物中加入氢化钠(在油中的60％，10mmol)，并且将混合物在氩气气氛下在0℃搅拌1小时。在0℃用水(100mL)猝灭反应，并且将反应用6N HCl调整至pH＝2。将浆料用碳酸氢钠调整至pH＝7，并且通过过滤收集沉淀，用水(50mL)洗涤，并且在真空下干燥。将残余物通过硅胶上的层析纯化(20％EtOAc/CH2Cl2，然后是5％至10％MeOH/CH2Cl2梯度)，以得到所需产物E，其为棕色固体(45-60％)。
仅选择E中的一个来示出其NMR光谱和质谱。
(6-氯-2-甲基-嘧啶-4-基)-(5-吡啶-4-基-噻唑-2-基)-胺。1H NMR(300MHz,DMSO-d6)：δ12.15(s,1H),8.53(dd,J＝4.5,1.5Hz,2H),8.18(s,1H),7.59(dd,J＝4.5,1.5Hz,2H),6.90(s,1H),2.59(s,3H)；MS(ES+)m/zC13H10ClN5S计算值：303.03；实测值：304.1(M+H+)。
步骤V.化合物1-4和7-13的合成
将化合物E(2mmol)和1-乙基哌嗪(8mmol)在二甲亚砜(2mL)中的混合物在100℃加热1小时。在冷却至室温后，将混合物用水(50mL)稀释。通过过滤收集沉淀，用水(10mL)洗涤并且在真空下干燥。将残余物通过氧化铝上的层析纯化(0.5％至1.5％MeOH/CH2Cl2梯度)，以得到每个化合物1-4和7-13的游离碱，其为灰白色固体。
在0℃向搅拌的6N HCl(10mL)中加入上述固体，并且将溶液通过0.45μm PVDF膜过滤。在1小时的过程中向搅拌的滤液中逐滴加入丙酮(40mL)，并且在0℃搅拌另外1小时。通过过滤收集沉淀，用丙酮(15mL)洗涤，并且在真空下干燥，以得到每个化合物1-4和7-13的盐酸盐，其为黄色固体(90-95％)。
[6-(4-乙基-哌嗪-1-基)-2-甲基-嘧啶-4-基]-(5-吡啶-4-基-噻唑-2-基)-胺盐酸盐。1H NMR(400MHz,DMSO-d6)：δ11.55(bs,1H),8.72(d,J＝5.6Hz,2H),8.61(s,1H),8.14(d,J＝5.2Hz,2H),6.27(s,1H),4.35(d,J＝13.2Hz,2H),3.55(d,J＝12.0Hz,2H),3.45(t,J＝13.0Hz,2H),3.13(t,J＝5.8Hz,2H),3.02(q,J＝10.0Hz,2H),2.50(s,3H),1.28(t,J＝6.8Hz,3H)；MS(ES+)m/z C19H23N7S计算值：381.17；实测值：382.2(M+H+)。
{6-[4-(2-氟-乙基)-哌嗪-1-基]-2-甲基-嘧啶-4-基}-(5-吡啶-4-基-噻唑-2-基)-胺盐酸盐(化合物2)。1H NMR(300MHz,DMSO-d6)：δ11.89(bs,1H),8.73(d,J＝6.3Hz,2H),8.62(s,1H),8.15(d,J＝5.7Hz,2H),6.26(s,1H),4.95(d,J＝47.4Hz,2H),4.38(s,2H,与水峰重叠),3.70-3.35(m,6H),3.18(bs,2H),2.50(s,3H)；MS(ES+)m/z C19H22FN7S计算值：399.16；实测值：400.1(M+H+)。
2-{4-[2-甲基-6-(5-吡啶-4-基-噻唑-2-基氨基)-嘧啶-4-基]-哌嗪-1-基}-乙醇盐酸盐(化合物3)。1H NMR(400MHz,DMSO-d6)：δ11.03(s,1H),8.73(d,J＝7.2Hz,2H),8.63(s,1H),8.15(d,J＝7.2Hz,2H),6.26(s,1H),4.34(d,J＝12.4Hz,2H),3.82(t,J＝5.2Hz,2H),3.62(d,J＝12.0Hz,2H),3.43(t,J＝12.4Hz,2H),3.30-3.09(m,4H),2.49(s,3H)；MS(ES+)m/z C19H23N7OS计算值：397.17；实测值：398.1(M+H+)。
[6-(4-二甲基氨基-哌啶-1-基)-2-甲基-嘧啶-4-基]-(5-吡啶-4-基-噻唑-2-基)-胺盐酸盐(化合物4)。1H NMR(300MHz,DMSO-d6)：δ11.07(s,1H),8.73(d,J＝6.9Hz,2H),8.62(s,1H),8.15(d,J＝6.9Hz,2H),6.25(s,1H),4.43(d,J＝12.9Hz,2H),3.44(quin,J＝5.2Hz,1H),2.94(t,J＝12.5Hz,2H),2.69(d,J＝4.5Hz,6H),2.49(s,3H),2.15(d,J＝10.5Hz,2H),1.60(q,J＝11.0Hz,2H)；MS(ES+)m/z C20H25N7S计算值：395.19；实测值：396.1(M+H+)。
[6-(4-乙基-哌嗪-1-基)-2-甲基-嘧啶-4-基]-(5-吡啶-3-基-噻唑-2-基)-胺盐酸盐(化合物7)。1H NMR(400MHz,DMSO-d6)：δ11.23(bs,1H),9.15(s,1H),8.68(d,J＝5.2Hz,1H),8.60(d,J＝8.0Hz,1H),8.19(s,1H),7.93(t,J＝6.2Hz,1H),6.21(s,1H),4.35(d,J＝14.4Hz,2H),3.55(d,J＝11.6Hz,2H),3.40(t,J＝13.2Hz,2H),3.13(t,J＝5.8Hz,2H),3.01(q,J＝6.9Hz,2H),2.50(s,3H),1.28(t,J＝6.6Hz,3H)；MS(ES+)m/z C19H23N7S计算值：381.17；实测值：382.2(M+H+)。
{6-[4-(2-氟-乙基)-哌嗪-1-基]-2-甲基-嘧啶-4-基}-(5-吡啶-3-基-噻唑-2-基)-胺盐酸盐(化合物8)。1H NMR(400MHz,DMSO-d6)：δ11.80(bs,1H),9.16(s,1H),8.68(d,J＝5.6Hz,1H),8.62(d,J＝8.0Hz,1H),8.20(s,1H),7.95(t,J＝6.8Hz,1H),6.22(s,1H),4.98(d,J＝46.8Hz,2H),4.34(bs,2H),3.70-3.35(m,6H),3.16(bs,2H),2.49(s,3H)；MS(ES+)m/z C19H22FN7S计算值：399.16；实测值：400.1(M+H+)。
2-{4-[2-甲基-6-(5-吡啶-3-基-噻唑-2-基氨基)-嘧啶-4-基]-哌嗪-1-基}-乙醇盐酸盐(化合物9)。1H NMR(400MHz,DMSO-d6)：δ11.02(bs,1H),9.18(s,1H),8.69(s,1H),8.64(d,J＝7.6Hz,1H),8.22(s,1H),7.96(d,J＝5.2Hz,1H),6.25(s,1H),4.33(d,J＝11.2Hz,2H),3.80(s,1H),3.60(d,J＝11.6Hz,2H),3.19(s,2H),3.13(s,2H),2.48(s,3H)；MS(ES+)m/z C19H23N7OS计算值：397.17；实测值：398.1(M+H+)。
[6-(4-二甲基氨基-哌啶-1-基)-2-甲基-嘧啶-4-基]-(5-吡啶-3-基-噻唑-2-基)-胺盐酸盐(化合物10)。1H NMR(400MHz,DMSO-d6)：δ11.27(bs,1H),9.18(s,1H),8.69(d,J＝5.2Hz,1H),8.64(d,J＝8.0Hz,1H),8.23(s,1H),7.97(t,J＝6.8Hz,1H),6.36(bs,1H),4.42(d,J＝8.8Hz,2H),3.43(bs,1H),2.99(t,J＝12.4Hz,2H),2.68(s,3H),2.67(s,3H),2.55(s,3H),2.17(d,J＝10.8Hz,2H),1.64(q,J＝9.2Hz,2H)；MS(ES+)m/z C20H25N7S计算值：395.19；实测值：396.2(M+H+)。
[6-(4-乙基-哌嗪-1-基)-2-甲基-嘧啶-4-基]-(5-吡啶-2-基-噻唑-2-基)-胺盐酸盐(化合物11)。1H NMR(300MHz,DMSO-d6)：δ11.34(s,1H),8.54(d,J＝4.8Hz,1H),8.32(s,1H),8.01-7.96(m,2H),7.40-7.34(m,1H),6.31(s,1H),4.37(d,J＝13.2Hz,2H),3.62-3.38(m,4H),3.20-2.90(m,4H),2.47(s,3H),1.26(t,J＝7.4Hz,3H)；MS(ES+)m/z C19H23N7S计算值：381.17；实测值：382.2(M+H+)。
[6-(4-乙基-哌嗪-1-基)-2-甲基-嘧啶-4-基]-(5-嘧啶-5-基-噻唑-2-基)-胺盐酸盐(化合物12)。1H NMR(400MHz,DMSO-d6)：δ11.35(bs,1H),9.20-9.03(m,3H),8.09(s,1H),6.28(s,1H),4.40(s,2H),3.56(d,J＝12.4Hz,2H),3.44(d,J＝7.4Hz,2H),3.13(bs,2H),3.02(d,J＝8.0Hz,2H),1.28(bs,3H)；MS(ES+)m/z C18H22N8S计算值：382.17；实测值：383.3(M+H+)。
[6-(4-乙基-哌嗪-1-基)-2-甲基-嘧啶-4-基]-(4-吡啶-3-基-噻唑-2-基)-胺盐酸盐(化合物13)。1H NMR(400MHz,DMSO-d6)：δ11.80(bs,1H),11.54(bs,1H),9.28(s,1H),8.94(d,J＝8.4Hz,1H),8.84(d,J＝5.2Hz,1H),8.15-8.07(m,2H),6.31(bs,2H),4.35(d,J＝14.0Hz,2H),3.55(d,J＝12.0Hz,2H),3.45(t,J＝13.0Hz,2H),3.15-3.07(m,2H),3.00(q,J＝10.0Hz,2H),2.49(s,3H),1.27(t,J＝7.4Hz,3H)；MS(ES+)m/z C19H23N7S计算值：381.17；实测值：382.1(M+H+)。
步骤V.化合物5和6的合成
在100℃向化合物E(1mmol)和4-(2-羟乙基)-吗啉(4mmol)在二甘醇二甲醚(1mL)中的混合物中加入氢氧化钾(10mmol)，并且将混合物在氩气气氛下在160℃搅拌10分钟。将反应在0℃用水(20mL)猝灭，并且用6N HCl调整至pH＝2。用碳酸氢钠将浆料调整至pH＝7，并且通过过滤收集沉淀，用水(10mL)洗涤并且在真空下干燥。将残余物通过氧化铝上的层析纯化(0.5％至1.5％MeOH/CH2Cl2梯度)，以得到化合物6的游离碱，其为灰白色固体。
在0℃在搅拌下向上述固体在MeOH(10mL)中的悬浮液中加入6N HCl(1mL)。在减压下移除大部分溶剂，并且将残余物用EtOH(10mL)处理。通过过滤收集沉淀，用丙酮(10mL)洗涤并且在真空下干燥，以得到每个化合物5-6的盐酸盐，其为黄色固体(45-50％)。
[2-甲基-6-(2-吗啉-4-基-乙氧基)-嘧啶-4-基]-(5-吡啶-4-基-噻唑-2-基)-胺盐酸盐(化合物5)。1H NMR(400MHz,DMSO-d6)：δ11.61(s,1H),8.74(d,J＝5.2Hz,2H),8.64(s,1H),8.17(d,J＝5.2Hz,2H),6.37(s,1H),4.72(s,2H),4.00-3.80(m,4H),3.64-3.42(m,4H),3.16(bs,2H),2.59(s,3H)；MS(ES+)m/z C19H22N6O2S计算值：398.15；实测值：399.2(M+H+)。
[2-甲基-6-(2-吗啉-4-基-乙氧基)-嘧啶-4-基]-(5-吡啶-3-基-噻唑-2-基)-胺盐酸盐(化合物6)。1H NMR(400MHz,DMSO-d6)：δ11.51(bs,1H),9.20(s,1H),8.71(d,J＝5.6Hz,1H),8.66(d,J＝8.4Hz,1H),8.24(s,1H),7.98(dd,J＝8.0,5.6Hz,1H),6.35(s,1H),4.72(t,J＝4.8Hz,2H),3.96(d,J＝10.8Hz,2H),3.85(t,J＝12.0Hz,2H),3.55(bs,2H),3.47(d,J＝12.4Hz,2H),3.19(bs,2H),2.59(s,3H)；MS(ES+)m/z C19H22N6O2S计算值：398.15；实测值：399.1(M+H+)。
实施例2：抑制FLT3活性
如下进行研究以在抑制FLT3活性方面对根据实施例1制备的特定化合物进行测试。
将含有FLT3激酶催化结构域(残基Y567-S993)的GST-FLT3-KDWT在转染了含有pBac-PAK8-GST-FLT3-KD质粒的杆状病毒的Sf9昆虫细胞中表达。FLT3WT激酶-Glo测定在96孔板中在30℃下进行4小时以测试化合物，最终体积为50μl，包含以下组分：75ng GST-FLT3-KDWT蛋白、25mM HEPES，pH 7.4、4mM MnCl2、10mM MgCl2、2mM DTT、0.02％Triton X-100、0.1mg/ml牛血清白蛋白、25μM Her2肽底物、0.5mM Na3VO4和1μM ATP。温育后，向每个孔中加入50μl激酶-Glo Plus试剂(Promega,Madison,WI,USA)，并且将混合物在25℃温育20分钟。将每个反应混合物的70-μL等分试样转移至黑色微量滴定板中，并且在WallacVector 1420多标记计数器(PerkinElmer,Shelton,CT,USA)上测量荧光。
测试了多种化合物。出乎意料地，化合物1-11显示出低于100nM的IC50(响应减少一半时抑制剂的浓度)值。
实施例3：抑制VEGFR2活性
如下进行研究以在抑制VEGFR2活性方面对根据实施例1制备的特定化合物进行测试。请注意VEGFR2为VEGFR的三种主要亚型之一。
含有激酶结构域的重组GST-VEGFR2(残基V789-V1356)在Sf9昆虫细胞中表达。激酶测定在具有测试化合物的96孔板中在30℃进行120分钟，最终体积为50μl反应，具有以下组分：25mM HEPES pH 7.4、10mM MgCl2、4mM MnCl2、0.5mM Na3VO4、2mM DTT、0.02％TritonX100、0.01％BSA、1μM ATP、2μM聚Glu4:Tyr肽、50～100ng重组VEGFR2。温育后，向每个孔中加入50μl激酶-Glo Plus试剂(Promega,Madison,WI,USA)，并且将混合物在25℃温育20分钟。将每个反应混合物的70-μL等分试样转移至黑色微量滴定板中，并且在Wallac Vector1420多标记计数器(PerkinElmer,Shelton,CT,USA)上测量荧光。
在VEGFR2测定中测试了多种化合物。化合物1、9和10出乎意料地显示出低于30nM的IC50值。
实施例4：抑制c-Kit活性
如下进行研究以在抑制c-Kit活性方面对根据实施例1制备的特定化合物进行测试。
纯化在Sf9杆状病毒-昆虫细胞表达系统中表达的N-末端His-标记的人类c-KIT(残基T544-V976)重组蛋白，以用于c-KIT ADP激酶-Glo测定。c-Kit-ADP激酶-Glo测定在96孔板中在30℃下进行150分钟，最终体积为10μl，包含40mM Tris pH 7.4、20mM MgCl2、2mMMnCl2、2mM DTT、0.01％BSA、20μM ATP、20μM聚(Glu,Tyr)4:1肽、0.1mM Na3VO4、250ng的重组c-Kit蛋白和指定浓度的测试化合物。在25℃，在40分钟温育的情况下，通过加入5μl ADP-GloTM试剂(Promega,Madison,WI,USA)终止反应，然后加入10μl的激酶检测试剂温育另外30分钟。最后，将每个反应混合物的30μl等分试样转移至黑色微量滴定板中，并且在WallacVector1420多标记计数器(Perkin-Elmer,Shelton,CT,USA)上测量荧光。
测试了多种化合物。出乎意料地，化合物1-7和11-12显示出低于100nM的IC50值。
实施例5：体外抗癌活性
如下进行研究以使用细胞系和MTS细胞存活测定(MTS代表3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑鎓)评价根据实施例1制备的特定化合物的体外抗癌活性。
白血病细胞系MOLM-13、MV4:11和Kasumin-1购自美国模式培养物保藏中心(American Type Culture Collection)(ATCC,Manassas,VA,USA)。人类胃肠间质瘤GIST-T1细胞系购自Cosmo Bio Co.,LTD(Tokyo，日本)。在37℃和5％CO2下，将所有白血病细胞系维持在补充有10％胎牛血清(FBS)、10U/ml青霉素(penicillin)和10g/ml链霉素(streptomycin)的RPMI1640培养基中。细胞系GIST-T1在补充有10％FBS、0.01％非必需氨基酸、10U/ml青霉素和10g/ml链霉素的DMEM培养基中培养。
GIST882、GIST48和GIST430细胞均在维持在37℃和5％CO2的培养箱中培养。GIST882在补充有20％胎牛血清(FBS)的RPMI-1640中培养。GIST48在补充有20％胎牛血清(FBS)、0.5％Mito、血清增充剂(serum extender)(BD Bioscience,355006)和1％牛垂体提取物(BD Bioscience354123)的F10中培养。GIST430在补充有20％FBS的IMDM中培养。GIST882、GIST430和GIST48细胞由Jonathan A.Fletcher博士(哈佛医学院(HarvardMedical School)，US)提供。
MOLM-13、MV4:11和Kasumin-1MTS测定
将细胞以1×104个细胞/100μl/孔的密度一式三份地接种在96孔培养板中，并且用范围为1nM至10μM的指定浓度的测试化合物处理72小时。比色法的CellTiter
Aqueous One Solution细胞增殖测定(MTS测定；Promega,Madison,WI,USA)用于测定细胞毒性。使用微孔板光度计(Victor2；Perkin-Elmer,Waltham,MA,USA)测量在492nm处的光密度。当细胞用测试化合物处理72小时时，通过MTS测定确定IC50值并且使用GraphPad Prism6进行计算。每个实验重复三次。
GIST-T1 MTS测定
将GIST-T1细胞以8000个细胞/100μl/孔的密度一式三份地接种在96孔培养板中，并且用范围为1nM至10μM的指定浓度的测试化合物处理72小时。比色法的CellTiter
Aqueous One Solution细胞增殖测定(MTS测定；Promega,Madison,WI,USA)用于测定细胞毒性。使用微孔板光度计(Victor2；Perkin-Elmer,Waltham,MA,USA)测量在492nm处的光密度。当细胞用测试化合物处理72小时时，通过MTS测定确定IC50值并且使用GraphPad Prism6进行计算。每个实验重复三次。
GIST882、GIST48和GIST430 MTS测定
将GIST细胞(4X 104)用不同剂量的化合物处理。在37℃在5％CO2中，将处理过的GIST882细胞培养144小时，并且将GIST48和GIST430细胞培养120小时。通过将细胞与亚甲蓝(Clontech,CA,US)温育1小时来测定细胞增殖。使用SpectraMax M5微孔板读数器(Molecular Devices,US)在450nm处测量吸光度。
特定式(I)化合物的GI50(细胞增殖的最大抑制的50％处的浓度)值显示于下表：
ND：未测量
其他实施方案
本说明书公开的所有特征可以以任何组合方式结合。本说明书公开的各个特征可以被具有相同、等价或相似目的的替代特征代替。因此，除非以其他方式明确指明，所公开的各个特征仅为一系列等价或相似特征的实例。
另外，根据前述描述，本领域技术人员能够容易地确定本发明的基本特征，且在不偏离本发明的精神及范围的情况下，本领域技术人员能够对本发明做出各种改变和修饰，以使其适应各种用途及情况。因此，其他实施方案也在以下权利要求书的范围中。
Claims (26)
1.一种下式(I)的化合物或其药用盐：
其中，
R1为C1-6烷基或C1-6硫代烷基；
X为O或NRa，其中Ra为H或C1-6烷基；
Y为CRbRc或NRd，其中Rb和Rc各自独立地为H、卤素、C1-6烷基、C1-6烷氧基或氨基，或者Rb与Ra、键接到Rb的碳原子和键接到Ra的氮原子一起为C3-10杂环烷基；并且Rd为H或C1-6烷基，或者Rd与Ra和键接到Rd和Ra的氮原子一起为C3-10杂环烷基；
R2为-CH2CH2Re或NRfRg，其中Re为H、卤素、C1-6烷基或ORh，并且Rf和Rg各自独立地为C1-6烷基或C3-8环烷基，Rh为H或C1-6烷基，或者Rh与Rd、键接到Rh的氧原子和键接到Rd的氮原子一起为C3-10杂环烷基；并且
R3为杂芳基。
2.根据权利要求1所述的化合物或盐，其中所述化合物为式(II)的化合物：
其中R1为C1-6烷基。
3.根据权利要求2所述的化合物或盐，其中X为O，Y为NRd，并且R2为-CH2CH2Re，其中Re为ORh，Rh与Rd、键接到Rh的氧原子和键接到Rd的氮原子一起为C3-10杂环烷基。
4.根据权利要求2所述的化合物或盐，其中X为NRa，并且Y为CRbRc或NRd，其中Ra与Rb、键接到Ra的氮原子和键接到Rb的碳原子一起为C3-10杂环烷基；Rc为H、卤素、C1-6烷基、C1-6烷氧基或氨基；并且Rd与Ra和键接到Ra和Rd的氮原子一起为C3-10杂环烷基。
5.根据权利要求4所述的化合物或盐，其中X为NRa，Y为CRbRc，并且R2为NRfRg，其中Ra与Rb、键接到Ra的氮原子和键接到Rb的碳原子一起为C3-10杂环烷基；Rc为H、卤素、C1-6烷基、C1-6烷氧基或氨基；并且Rf和Rg各自为C1-6烷基。
6.根据权利要求4所述的化合物或盐，其中X为NRa，Y为NRd，并且R2为-CH2CH2Re，其中Ra与Rd和键接到Ra和Rd的氮原子一起为C3-10杂环烷基；并且Re为H、卤素或ORh，Rh为H或C1-6烷基。
7.根据权利要求1所述的化合物或盐，其中R3为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自由H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基组成的组。
8.根据权利要求7所述的化合物或盐，其中R3为独立地被一个或多个(CH2)nZ部分取代的6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基。
9.根据权利要求8所述的化合物或盐，其中R3为吡啶基或嘧啶基。
10.根据权利要求3所述的化合物或盐，其中R3为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自由H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基组成的组。
11.根据权利要求10所述的化合物或盐，其中R3为吡啶基或嘧啶基。
12.根据权利要求11所述的化合物或盐，其中所述化合物为
13.根据权利要求5所述的化合物或盐，其中R3为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自由H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基组成的组。
14.根据权利要求13所述的化合物或盐，其中R3为吡啶基或嘧啶基。
15.根据权利要求14所述的化合物或盐，其中所述化合物为
16.根据权利要求6所述的化合物或盐，其中R3为独立地被一个或多个(CH2)nZ部分取代的5-或6-元杂芳基，其中n为0或1，并且Z为H、卤素、CN、OH、CF3、C1-6烷基或C1-6烷氧基；或者R3为与被一个或多个取代基取代的苯环稠合的5-或6-元杂芳基，所述取代基独立地选自由H、卤素、CN、OH、CF3、C1-6烷基和C1-6烷氧基组成的组。
17.根据权利要求16所述的化合物或盐，其中R3为吡啶基或嘧啶基。
18.根据权利要求17所述的化合物或盐，其中所述化合物为以下化合物中的一者：
19.根据权利要求1所述的化合物或盐，其中所述化合物为以下化合物中的一者：
20.根据权利要求1所述的化合物或盐，其中所述化合物为式(III)的化合物：
其中R1为C1-6烷基。
21.一种药物组合物，所述药物组合物包含药用载体以及根据权利要求1所述的化合物或盐。
22.一种抑制酪氨酸激酶的方法，所述方法包括使所述酪氨酸激酶与有效量的根据权利要求1所述的化合物或盐接触。
23.一种治疗与酪氨酸激酶相关的癌症的方法，所述方法包括向有需要的受试者施用有效量的根据权利要求1所述的化合物或盐。
24.根据权利要求23所述的方法，其中所述酪氨酸激酶为FMS样酪氨酸激酶3(FLT3)、FMS样酪氨酸激酶4、血管内皮生长因子受体(VEGFR)、集落刺激因子1受体(CSF1R)、血小板衍生生长因子受体(PDGFR)A、PDGFR B、酪氨酸蛋白激酶Kit(c-KIT)、c-Src(SRC)、酪氨酸蛋白激酶Lyn(LYN)A、LYN B、在转染期间重排的酪氨酸激酶(RET)、淋巴细胞特异性蛋白质酪氨酸激酶、加德纳-拉希德猫肉瘤病毒致癌基因同源物、盘状结构域受体1、激酶插入结构域受体、B淋巴细胞激酶、酪氨酸蛋白激酶Yes、爱柏森鼠类白血病病毒致癌基因同源物1(ABL1)、酪氨酸受体激酶TRKA、TRKB、TRKC、ZAK/MLTK、IRAK4、RET V804L、RET Y791F、FLT3D835Y、PDGFR A V561D、或ABL1 T315I。
25.根据权利要求24所述的方法，其中所述酪氨酸激酶为FLT3、VEGFR或c-KIT。
26.根据权利要求25所述的方法，其中所述癌症为急性髓细胞白血病、绿色瘤、慢性骨髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、霍奇金病、非霍奇金淋巴瘤、B细胞淋巴瘤、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症、骨髓增生异常综合征、胰腺癌、膀胱癌、结直肠癌、乳癌、男性生殖道癌、肾癌、肝细胞癌、肺癌、卵巢癌、宫颈癌、子宫癌、妊娠滋养细胞疾病、胃癌、胆管癌、胆囊癌、小肠癌、食管癌、口咽癌、下咽癌、眼癌、神经癌、头颈癌、黑色素瘤、浆细胞瘤、内分泌腺肿瘤、神经内分泌癌、脑瘤、骨癌或肉瘤。
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| BR112019026577A2 (pt) | 2020-06-23 |
| NZ759327A (en) | 2021-08-27 |
| MY201291A (en) | 2024-02-15 |
| WO2018231910A1 (en) | 2018-12-20 |
| AU2018284249B2 (en) | 2021-06-24 |
| ZA202000107B (en) | 2020-12-23 |
| MX2019014845A (es) | 2020-08-06 |
| JP2020523348A (ja) | 2020-08-06 |
| KR20200014350A (ko) | 2020-02-10 |
| EP3638237A1 (en) | 2020-04-22 |
| CA3064081C (en) | 2023-03-21 |
| US20180353509A1 (en) | 2018-12-13 |
| ES2949616T3 (es) | 2023-10-02 |
| EP3638237B1 (en) | 2023-04-19 |
| KR102372288B1 (ko) | 2022-03-08 |
| RU2019137573A (ru) | 2021-05-24 |
| JP6979595B2 (ja) | 2021-12-15 |
| BR112019026577A8 (pt) | 2023-04-11 |
| US10300061B2 (en) | 2019-05-28 |
| TWI667236B (zh) | 2019-08-01 |
| RU2019137573A3 (zh) | 2021-07-23 |
| CA3064081A1 (en) | 2018-12-20 |
| TW201906836A (zh) | 2019-02-16 |
| AU2018284249A1 (en) | 2019-12-12 |
| EP3638237A4 (en) | 2021-01-13 |
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