CN115151534A - 白细胞介素-1受体相关激酶(irak)/fms样受体酪氨酸激酶(flt3)的抑制剂、其药物产品及其方法 - Google Patents
白细胞介素-1受体相关激酶(irak)/fms样受体酪氨酸激酶(flt3)的抑制剂、其药物产品及其方法 Download PDFInfo
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- CN115151534A CN115151534A CN202180012966.5A CN202180012966A CN115151534A CN 115151534 A CN115151534 A CN 115151534A CN 202180012966 A CN202180012966 A CN 202180012966A CN 115151534 A CN115151534 A CN 115151534A
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- pyridin
- pyrimidin
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- diazaspiro
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Abstract
呈任意结晶形式或无定形形式的具有式(I)的白细胞介素‑1受体相关激酶(IRAK)/FMS样受体酪氨酸激酶(FLT3)抑制剂,其药学上可接受的盐、酯、前药、复合物、溶剂化物、水合物或异构体。式(I)中,X、X1、X2选自N和C;且U、V和W基团彼此独立地为非氢单价基团。还提供了包含IRAK抑制剂以及预防和/或治疗炎症性疾病、自身免疫性疾病和增殖性疾病等的药物产品。上面提到的白细胞介素‑1受体相关激酶(IRAK)可以是IRAK4。
Description
技术领域
本公开总体上涉及白细胞介素-1受体相关激酶(IRAK)/FMS样受体酪氨酸激酶(FLT3)的抑制剂、其药物产品、其生产及其应用。尽管将通过一类化合物在预防和/或治疗炎症性疾病、自身免疫性疾病和/或增殖性疾病中的应用来说明、解释和举例说明本公开,但是应当理解,本公开还可以包括所述化合物及其衍生物在预防和/或治疗与IRAK/FLT3相关或由其介导的或与IRAK/FLT3活性异常相关的广泛病症或疾病,例如炎症性疾病、感染如病毒、细菌、真菌和寄生虫感染、HIV-1感染、败血症、自身免疫性病症或疾病如类风湿性关节炎和多发性硬化症、痛风、幼年特发性关节炎、Muckle-Wells病、家族性地中海热、白塞病、成人斯蒂尔病(adult onset Still’s disease)、增殖性疾病如癌症、增生、再狭窄、心脏肥大、白血病、血管内凝血、骨病、代谢疾病、神经和神经退行性疾病、心血管疾病、纤维化和过敏性疾病、哮喘、特应性皮炎、阿尔茨海默病、激素相关疾病、外伤(手术)、血液透析、缺血性疾病(心肌梗塞)、非感染性肝炎、紫外线辐射、闭合性头部损伤、胰腺炎、牙周炎、移植物抗宿主病、移植排斥等中的应用。上文提到的白细胞介素-1受体相关激酶(IRAK)可以是IRAK4。
背景技术
激酶是开发用于预防和/或治疗各种疾病和病症的药物的非常重要的靶标,这仅仅是因为激酶参与细胞生理学的许多基本过程,例如蛋白质磷酸化。特别是,蛋白激酶和脂质激酶参与细胞的活化、生长、分化和存活。蛋白激酶可分为那些优先使酪氨酸残基磷酸化的和那些优先使丝氨酸和/或苏氨酸残基磷酸化的。
特别地,IRAK激酶,更特别地IRAK-4,已被鉴定为在炎症和自身免疫性疾病中起作用。IRAK在许多细胞类型中表达并介导来自各种细胞受体,包括白细胞介素-1(IL-1)和toll样受体(TLR)的信号。IL-1R和Toll样受体具有保守的Toll/IL-1R结构域,在先天免疫学中起着至关重要的作用。与LPS或细胞因子结合后,Toll/IL-1受体通过TIR结构域募集适体(adaptor)分子MyD88,启动下游蛋白复合物组装和磷酸化级联反应,导致炎症细胞因子和趋化因子如TNF-α、IL-1β、IL-6和IL-8的诱导。通过MyD88依赖性途径,IL-1R相关激酶(IRAK)家族在支架(scaffold)和激酶功能中都发挥着重要作用。IL-1R相关激酶(IRAK)家族由四个成员组成,即IRAK1、IRAK2、IRAKM和IRAK4。IRAK1和IRAK4是活性激酶,而其他两个不是。然而,它们都调节核因子-κB(NF-κB)和丝裂原活化蛋白激酶(MAPK)途径。
在IRAK家族中,IRAK4代表有吸引力的治疗靶标。IRAK4是由460个氨基酸组成的苏氨酸/丝氨酸蛋白激酶,包含激酶结构域和死亡结构域。通常,在激酶结构域中可以找到N末端叶(lobe)和C末端叶,它们会聚在一起形成ATP结合位点。死亡结构域的存在是为了在蛋白质募集过程中结合MyD88并与之相互作用。此外,蛋白质上存在三个参与反式磷酸化的磷酸化位点。IRAK4被认为是IL-1受体和TLR下游的早期激活的关键蛋白激酶,通过快速激活IRAK1和IRAK2启动信号传导,导致先天免疫反应。此外,其他白细胞介素,如IL-18和IL-33,依赖IRAK4进行信号传导。因此,这些细胞因子参与致病过程(例如,纤维化)的疾病和特应性皮炎是IRAK4抑制剂治疗的潜在目标疾病。
在表达失活的IRAK4突变体而不是野生型的小鼠中,观察到对由几种TLR激动剂引发的脓毒性休克的完全耐药以及对IL-1的反应受损。此外,表达失活的IRAK4突变体而不是野生型的小鼠在几种自身免疫性疾病(例如类风湿性关节炎和多发性硬化症)模型中得到部分保护。有趣的是,类风湿性关节炎和系统性红斑狼疮患者的血清已显示以IRAK4依赖性方式激活浆细胞样树突状细胞。最后,在患有导致IRAK4无活性的遗传缺陷的儿童中观察到复发性化脓性细菌感染。
此外,IRAK4被认为是“主IRAK(Master IRAK)”,因为它充当信号传导通路中的中心组分。作为支架蛋白,IRAK4用死亡结构域结合MyD88,募集IRAK1和IRAK2,以形成MyD88-IRAK4-IRAK2复合物或所谓的“myddosome”。晶体结构揭示它由6个MyD88、4个IRAK4和4个IRAK2死亡结构域组成,表现为左旋螺旋寡聚体。作为激酶,IRAK4使myddosome中的IRAK1或IRAK2磷酸化,导致TNF受体相关因子6(TRAF6)的募集,引发NF-κB介导的转录激活的信号转导事件的启动。
因此,IRAK4对于先天免疫很重要。对于IRAK4缺陷儿童,他们的全血细胞或PBMC在IL-6分泌方面对IL-1β没有反应或在IFN-γ产生方面对IL-18没有反应。此外,刺激TLR1/2、TLR2/6、TLR3、TLR4、TLR5和TLR9不会诱导主要炎症细胞因子(TNF-α、IL-6和IL-12)和生长因子(G-CSF和GM-CSF)在全血细胞和PBMC中的产生。然而,有缺陷的成年患者不易发生慢性感染,这表明可能存在一些绕过TLR信号传导缺陷的某些机制。最近的研究发现,在没有IRAK4激酶活性的情况下,myddosome形成保持稳定,这表明这种功能对于myddosome组装以及NF-κB和MAPK途径的激活是可有可无的,但对于MyD88依赖性炎症细胞因子的产生至关重要。因此,抑制IRAK4可能成为自身免疫性疾病的潜在治疗策略,这些自身免疫性疾病具有过度活跃的TLR信号传导,而免疫的抗感染功能仍然可以保持。
由于IRAK4调节的下游途径,IRAK4也与癌症有关。活化的B细胞样弥漫性大B细胞淋巴瘤(ABC DLBCL)中的致癌活性MyD88突变的发现揭示了癌症对IRAK信号传导的特异性依赖性。大量肿瘤活检中MyD88编码区的序列分析表明,29%的ABC DLBCL肿瘤在MyD88 TIR结构域内具有L265P单氨基酸取代,而其他DLBCL亚型中不存在这种取代。L265P MyD88突变体通过包含IRAK1和IRAK4的蛋白质信号传导复合物的自发组装来促进细胞存活,从而导致IRAK4激酶激活、IRAK1磷酸化和激活的JAK-STAT和NF-κB信号传导。此外,MyD88的常见体细胞L265P突变发生在91%的巨球蛋白血症患者中,这是一种淋巴细胞性血液系统恶性肿瘤。
几种癌症类型已显示依赖于MYD88的活化形式,MYD88是TLR和IL-1R下游的适体分子,可激活IRAK4。已在例如弥漫性大B细胞淋巴瘤(DLBCL)和Waldenstrom巨球蛋白血症中鉴定出激活MYD88突变。有报告支持IRAK4在肿瘤学领域,特别是在T细胞急性淋巴细胞白血病(T-ALL)中的作用。已显示IRAK-4的药理学抑制可增强T-ALL对化疗剂的敏感性。IL-33已被证明在纤维化和过敏性疾病,特别是哮喘和特应性皮炎的进展中发挥作用。由于这种细胞因子通过IRAK4依赖性途径进行信号传导,因此这些疾病也可能代表IRAK4抑制剂的靶标。此外,一些自身炎症性疾病已被证明依赖于IL-1活性,因此,阻断IL-1的生物制剂对这些患者显示出一些益处。痛风、幼年特发性关节炎、Muckle-Wells病、家族性地中海热、白塞病、成人斯蒂尔病是此类自身炎症性疾病的实例。
所有证据都支持抑制IRAK4介导的信号传导将是一种有希望的治疗方法。因此,选择性IRAK4抑制剂的开发一直是许多药物研究人员关注的焦点。迄今为止,已有多家公司参与了该领域的竞争。辉瑞已完成临床化合物PF-06650833对类风湿性关节炎的Ⅱ期研究(NCT 02996500),其在临床前研究中表现优异。Aurigene/Curis也发现了一种针对血液系统恶性肿瘤的小分子IRAK4抑制剂。其CA-4948正在进行Ⅰ期研究(NCT03328078)。此外,拜耳已经开发了一系列与Curis的化合物具有相似核心的化合物,用于炎症治疗,并完成了多项I期研究。
然而,现有技术的状态并不令人满意,并且仍然需要鉴定具有新结构的小分子,其可用于预防和/或治疗IRAK4相关的病症和疾病,例如炎症性疾病、自身免疫性疾病和/或增殖性疾病等。
此外,现有技术已经证明在用FLT3i处理FLT3突变的AML细胞后先天免疫应激反应途径的激活,并表明通过白细胞介素-1受体相关激酶1和4(IRAK1/4)复合物的先天免疫途径激活有助于FLT3突变的AML细胞的适应性耐药。同时抑制FLT3和IRAK1/4激酶的小分子可能有效克服这种适应性耐药机制。
发明内容
本公开的一个方面提供了呈任意结晶形式或无定形形式的由式(I)表示的化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、水合物或异构体。式(I)中,X、X1、X2选自N和C;且U、V和W基团彼此独立地为非氢单价基团。
本公开的另一方面提供了药物组合物、试剂盒或包装的药物产品,其包含治疗有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物,以及药学上可接受的载体或赋形剂。
本公开的又一方面提供了抑制白细胞介素-1受体相关激酶(IRAK)例如白细胞介素-1受体相关激酶-4(IRAK4)的方法。所述方法包括使IRAK例如IRAK4与有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
本公开的又一方面提供了改变基因表达或改变转录的方法,其包括使体外或受试者中的细胞与有效量的呈任意结晶形式或无定形形式的式(I)或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
本公开的又一方面提供了用于预防和/或治疗由IRAK(例如IRAK4)介导的或与异常IRAK(例如IRAK4)活性相关的病症或疾病的方法,其包括向有需要的受试者施用治疗有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物;或其药物组合物。
本公开的又一方面提供了抑制FMS样受体酪氨酸激酶(FLT3)的方法。所述方法包括使FLT3与有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
本公开的另一方面提供了用于预防和/或治疗由FLT3介导的或与异常FLT3活性相关的病症或疾病的方法,其包括向有需要的受试者施用治疗有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物;或其药物组合物。
本公开的上述特征和优点以及其他特征和优点从以下结合附图对实施本公开的最佳方式的详细描述中显而易见。
具体实施方式
在以下描述中,出于解释的目的,阐述了许多具体细节以便提供对本公开的透彻理解。然而,对于本领域技术人员显而易见的是,本公开可以在没有这些具体细节的情况下或通过等同设置来实践。
在本说明书中的不同位置,本公开的化合物的取代基以组或范围公开。本公开具体旨在包括此类组和范围的成员的每一个单独的子组合。例如,术语“C1-6烷基”具体旨在包括C1烷基(甲基)、C2烷基(乙基)、C3烷基、C4烷基、C5烷基和C6烷基。在本文公开数值范围的情况下,除非另有说明,否则该范围是连续的,包括该范围的最小值和最大值两者以及该最小值和最大值之间的每个值。更进一步,在范围指整数的情况下,仅包括从该范围的最小值到包括最大值的整数。此外,在提供多个范围来描述特征或特性的情况下,可以组合这些范围。
本公开提供了式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物或水合物。
式(I)中,X、X1、X2选自N和C;且U、V和W基团彼此独立地为非氢单价基团。如本文所用,术语“非氢单价基团”可以包括但不限于以下8类中的基团。
第(1)类:卤代或卤素基团,即-F、-Cl、-Br或-I;-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OR、-ONR2、-NR2、-NR3 +X-、-N(OR)R、-SH、-SR、-SSR、-C(=O)R、-CO2H、-CHO、-C(OR)2、-CO2R、-OC(=O)R、-OCO2R、-C(=O)NR2、-OC(=O)NR2、-NRC(=O)R、-NRCO2R、-NRC(=O)NR2、-C(=NR)R、-C(=NR)OR、-OC(=NR)R、-OC(=NR)OR、-C(=NR)NR2、-OC(=NR)NR2、-NRC(=NR)NR2、-C(=O)NRSO2R、-NRSO2R、-SO2NR2、-SO2R、-SO2OR、-OSO2R、-S(=O)R、-OS(=O)R、-SiR3、-OSiR3、-C(=S)NR2、-C(=O)SR、-C(=S)SR、-SC(=S)SR、-SC(=O)SR、-OC(=O)SR、-SC(=O)OR、-SC(=O)R、-P(=O)2R、-OP(=O)2R、-P(=O)R2、-OP(=O)R2、-OP(=O)(OR)2、-P(=O)NR2、-OP(=O)2NR2、-P(=O)(NR)2、-OP(=O)(NR)2、-NRP(=O)(OR)2、-NRP(=O)(NR)2、-PR2、-PR3、-OPR2、-OPR3、-BR2、-B(OR)2、-BR(OR)等。R彼此独立地是任何合适的基团,例如烷基。例如,-OR可以是烷氧基,即-O-烷基。术语C1-6烷氧基是-O-(C1-6烷基)基团。烷氧基的实例包括甲氧基、乙氧基、丙氧基(例如,正丙氧基和异丙氧基)、叔丁氧基等。烷氧基任选地可以被1个或多个(例如1至5个)合适的取代基取代。
第(2)类:烷基,即饱和脂肪烃,包括直链和支链。在一些实施方案中,烷基具有1至20个碳原子、1至10个碳原子、1至6个碳原子或1至4个碳原子。例如,术语“C1-6烷基”是指1至6个碳原子的直链或支链基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)。烷基任选地可以被一个或多个(例如1至5个)合适的取代基取代。
第(3)类:烯基,即具有至少一个碳-碳双键的脂肪烃,包括具有至少一个碳-碳双键的直链和支链。在一些实施方案中,烯基具有2至20个碳原子、2至10个碳原子、2至6个碳原子、3至6个碳原子或2至4个碳原子。例如,术语“C2-6烯基”包括2至6个碳原子的直链或支链不饱和基团(具有至少一个碳-碳双键),包括但不限于乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。烯基任选地可以被一个或多个(例如1至5个)合适的取代基取代。烯基可以以纯E型、纯Z型或其任意混合物存在。
第(4)类:炔基,即具有至少一个碳-碳三键的脂肪烃,包括具有至少一个碳-碳三键的直链和支链。在一些实施方案中,炔基具有2至20、2至10、2至6或3至6个碳原子。例如,“C2-6炔基”包括具有2至6个碳原子的如上定义的直链或支链烃链炔基。炔基任选地可以被一个或多个(例如1至5个)合适的取代基取代。
第(5)类:环烷基可以是饱和或不饱和的、非芳族的、单环或多环的(例如双环的)烃环(例如单环,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基,或双环,包括螺环、稠合或桥接体系(例如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢萘基等)。环烷基具有3至15个碳原子。在一些实施方案中,环烷基可以任选地包含一个、两个或更多个非累积的非芳族双键或三键和/或一至三个氧代基团。在一些实施方案中,双环烷基具有6至14个碳原子。例如,“C3-14环烷基”包括具有3至14个成环碳原子的饱和或不饱和的、非芳族的、单环或多环的(例如双环的)烃环(例如环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基或环癸基)。环烷基任选地可以被1个或多个(例如1至5个)合适的取代基取代。
第(6)类:芳基,即具有共轭π电子体系的全碳单环或稠环多环芳族基团。芳基在环中可以具有6个或10个碳原子。最常见的是,芳基在环中具有6个碳原子。例如,C6-10芳基是含有6至10个碳原子的芳族基团,例如苯基或萘基。芳基任选地可以被1个或多个(例如1至5个)合适的取代基取代。
第(7)类:杂芳基,即在至少一个环中具有一个或多个杂原子环成员(成环原子)的单环或稠环多环芳族杂环基团,所述杂原子环成员(成环原子)各自独立地选自O、S和N。杂芳基具有5至14个成环原子,包括1至13个碳原子,以及1至8个选自O、S和N的杂原子。在一些实施方案中,杂芳基具有5至10个成环原子,包括1至4个杂原子。杂芳基还可以包含1至3个氧代或硫代(即,=S)基团。在一些实施方案中,杂芳基具有5至8个成环原子,包括一个、两个或三个杂原子。例如,5元杂芳基是在单环杂芳基环中具有5个成环原子的如上定义的单环杂芳基;6元杂芳基是在单环杂芳基环中具有6个成环原子的如上定义的单环杂芳基;5~10元杂芳基是在单环或双环杂芳基环中具有5、6、7、8、9或10个成环原子的如上定义的单环或双环杂芳基。杂芳基任选地可以被1个或多个(例如1至5个)合适的取代基取代。单环杂芳基的实例包括具有5个成环原子(包括1至3个杂原子)的那些,或具有6个成环原子(包括1、2或3个氮杂原子)的那些。稠合双环杂芳基的实例包括两个稠合的5元和/或6元单环,包括1至4个杂原子。杂芳基的实例包括吡啶基、吡嗪基、嘧啶基、哒嗪基、噻吩基、呋喃基、咪唑基、吡咯基、噁唑基(例如1,3-噁唑基、1,2-噁唑基)、噻唑基(例如1,2-噻唑基、1,3-噻唑基)、吡唑基(例如吡唑-1-基、吡唑-3-基、吡唑-4-基)、四唑基、三唑基(例如1,2,3-三唑基、1,2,4-三唑基)、噁二唑基(oxadiazolyl)(例如1,2,3-噁二唑基)、噻二唑基(例如1,3,4-噻二唑基)、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、吲哚基、1H-咪唑并[4,5-c]吡啶基、咪唑并[1,2-a]吡啶基、1H-吡咯并[3,2-c]吡啶基、咪唑并[1,2-a]吡嗪基、咪唑并[2,1-c][1,2,4]三嗪基、咪唑并[1,5-a]吡嗪基、咪唑并[1,2-a]嘧啶基、1H-吲唑基、9H-嘌呤基、咪唑并[1,2-a]嘧啶基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[4,3-b]哒嗪基、异噁唑并[5,4-c]哒嗪基、异噁唑并[3,4-c]哒嗪基、吡啶酮、嘧啶酮、吡嗪酮、嘧啶酮、1H-咪唑-2(3H)-酮、1H-吡咯-2,5-二酮、3-氧代-2H-哒嗪基、1H-2-氧代-嘧啶基、1H-2-氧代-吡啶基、2,4(1H,3H)-二氧代-嘧啶基、1H-2-氧代-吡嗪基等。
第(8)类:杂环烷基,即单环或多环的(包括稠合在一起的2个或更多个环,包括螺环、稠合或桥接体系,例如双环体系)、饱和或不饱和的、非芳族的4元至15元环系统,包括1至14个成环碳原子和1至10个各自独立地选自O、S、N、P和B的成环杂原子。杂环烷基还可以任选地包含一个或多个氧代(即,=O)或硫代(即,=S)基团。例如,4元至12元杂环烷基是单环或多环的、饱和或不饱和的、非芳族的4元至12元环系统,其包含一个或多个成环杂原子。此类杂环烷基环的实例包括:氮杂环丁烷基(azetidinyl)、四氢呋喃基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫代吗啉基、四氢噻嗪基、四氢噻二嗪基、吗啉基、氧杂环丁烷基(oxetanyl)、四氢二嗪基(tetrahydrodiazinyl)、噁嗪基(oxazinyl)、噁噻嗪基(oxathiazinyl)、喹宁环基(quinuclidinyl)、色满基(chromanyl)、异色满基、苯并噁嗪基(benzoxazinyl)、2-氧杂螺[3.3]庚基{例如2-氧杂螺[3.3]庚-6-基}、7-氮杂双环[2.2.1]庚烷-1-基、7-氮杂双环[2.2.1]庚烷-2-基、7-氮杂双环[2.2.1]庚烷-7-基、2-氮杂双环[2.2.1]庚烷-3-酮-2-基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基等。杂环烷基环的其它实例包括四氢呋喃-2-基、四氢呋喃-3-基、四氢吡喃基(例如四氢-2H-吡喃-4-基)、咪唑啉-1-基、咪唑啉-2-基、咪唑啉-4-基、吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、哌嗪-1-基、哌嗪-2-基、1,3-噁唑烷-3-基、1,4-噁唑烷-1-基、异噻唑烷基、1,3-噻唑烷-3-基、1,2-吡唑烷-2-基、1,2-四氢噻嗪-2-基、1,3-噻嗪烷-3-基(1,3-thiazinan-3-yl)、1,2-四氢二嗪-2-基、1,3-四氢二嗪-1-基、1,4-噁嗪-4-基、噁唑烷酮基(oxazolidinonyl)、2-氧代-哌啶基(例如,2-氧代-哌啶-1-基)、2-氧代氮杂环庚烷-3-基(2-oxoazepan-3-yl)等。芳族稠合杂环烷基的一些实例包括二氢吲哚基、异二氢吲哚基、异二氢吲哚-1-酮-3-基、5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基、6,7-二氢-5H-吡咯并[3,4-d]嘧啶-6-基、4,5,6,7-四氢噻吩并[2,3-c]吡啶-5-基、5,6-二氢噻吩并[2,3-c]吡啶-7(4H)-酮-5-基、1,4,5,6-四氢吡咯并[3,4-c]吡唑-5-基和3,4-二氢异喹啉-1(2H)-酮-3-基基团。杂环烷基任选地被1个或多个(例如1至5个)合适的取代基取代。杂环烷基的实例包括5元或6元单环和9元或10元稠合双环。
术语“非氢单价基团”可以包括选自上述8类的任意数量的基团的组合。两个基团的组合是指一个基团(G1)被另一个基团(G2)取代,形成新基团-G1-G2。三个基团的组合是指第一基团(G1)被第二基团(G2)取代,第二基团(G2)被第三基团(G3)取代,形成新基团-G1-G2-G3。例如,第(2)-(8)类的基团可以被第(1)类的基团取代:(i)卤代烷基,例如氟代烷基,即具有一个或多个卤素取代基(例如F)的烷基(直至全卤代烷基,即烷基的每个氢原子都被卤素原子取代)。例如,C1-6卤代烷基是具有一个或多个卤素取代基的C1-6烷基(直至全卤代烷基,即烷基的每个氢原子都被卤素原子取代)。C1卤代烷基是具有一个、两个或三个卤素取代基的甲基。(ii)羟烷基,即具有一个或多个(例如,1、2或3个)OH取代基的烷基。(iii)氰基烷基,即具有一个或多个(例如,1、2或3个)-CN取代基的烷基。第(1)类的一个基团可以被第(1)类的另一个基团取代,例如卤代烷氧基,如氟代烷氧基,即-O-卤代烷基。C1-6卤代烷氧基是指-O-(C1-6卤代烷基)基团。
术语“非氢单价基团”也可以是选自上述8类的任意基团以及选自上述8类的任意数量的基团的组合,其被一个或多个二价基团取代,即同一个原子上的两个原始氢被基团例如=O、=S、=NNR2、=NNRC(=O)R、=NNRC(=O)OR、=NNRS(=O)2R、=NR、=NOR等取代。
在优选的实施方案中,式(I)中的U可以选自苯基;吡啶基氨基;哌啶-4-亚基甲基(piperidin-4-ylidenemethyl);(四氢-2H-吡喃-4-基)氧基;(1,1-二氧化四氢-2H-噻喃-4-基)氨基;五元或六元环烷基非芳族基团;含有1-2个杂原子(例如N、O或S)的五元杂环非芳族基团;含有1-2个杂原子(例如N、O、S或2N)的六元杂环非芳族基团;含有1-2个杂原子(例如1N、1S、2N或1N1O)的五元杂环芳族基团;含有1-2个杂原子(例如N、O或S)的六元杂环芳族基团;双环基团,其含有具有0-2个成员杂原子的4元、5元或6元环,该环与另一个具有0-2个成员杂原子的4元、5元或6元环稠合;以及双环基团,其含有具有0-1个成员N原子的4元、5元或6元环,该环与另一个具有0-1个成员N原子的4元、5元或6元环螺旋扭曲。
式(I)中U的一个或多个非芳族部分(如果有的话)可以是饱和的或不饱和的(例如包括双键或三键)。基团U可以是未取代的,或被一个或多个选自以下的基团取代:-OH、-NH2、-NHCH3、-CN、-F、-Cl、-CH3、-OCH3、-CH2CH3、-CF3、-OCF3、=O、C(=O)NHCH3、吗啉基磺酰基、甲基磺酰基、叔丁氧羰基哌嗪基、四氢呋喃基、甲基哌啶基、叔丁氧羰基哌啶基、环丁砜基(sulfolanyl)、乙氧羰基、N-(甲基)氨基羰基、甲基羰基、
通常,非氢单价基团(式(I)中的U、V和W)的连接点可以来自任何合适的位置。例如,哌啶基可以是哌啶-1-基(通过哌啶基的N原子连接)、哌啶-2-基(通过哌啶基2位上的C原子连接)、哌啶-3-基(通过哌啶基3位上的C原子)或哌啶-4-基(通过哌啶基4位上的C原子连接)。又例如,吡啶基可以是2-吡啶基(或吡啶-2-基)、3-吡啶基(或吡啶-3-基)或4-吡啶基(或吡啶-4-基)。可以指定非氢单价基团的连接点以指示非氢单价基团与另一个部分连接的位置。例如,“-C1-2烷基-(C3-4环烷基)”表示连接点出现在“C1-2烷基”部分。又例如,“(C3-4环烷基)-C1-2烷基-”也表示连接点出现在“C1-2烷基”部分。当与取代基键合的键显示为与连接一个环中的两个原子的键交叉时,则该取代基可以键合到该环中可被取代的任意成环原子(即一个或多个氢原子),除非从上下文中以其他方式指定或以其他方式隐含。
在本公开的具体但仍是示例性的实施方案中,式(I)的基团U可以选自:
在本公开的优选实施方案中,式(I)中的基团V可以选自-Cl;-OH;-N(CH3)2;N-(四氢吡喃基)氨基;N-(甲基羰基哌嗪基乙基)氨基;叔丁氧基羰基8-氮杂螺[4,5]癸基氨基;含有1个杂原子的四元杂环基;含有1个杂原子的四元杂环芳族基团(例如1N氮杂环丁烷基);含有1-2个杂原子(例如1O、1N、1S、1N1O、2N)的六元杂环非芳族基团;含有1-2个杂原子(例如2N)的六元杂环芳族基团;含有包括4-6个C原子和2个N原子的桥环的双环基团;含有1-2个杂原子(例如1N)的六元杂环芳族基团;双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环螺旋扭曲;以及双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环稠合。
V的一个或多个非芳族部分(如果有的话)可以是饱和的或不饱和的。式(I)中的基团V可以是未取代的,或被一个或多个选自以下的基团取代:-NH2、-OH、-OCH3、-CN、-F、-Cl、-甲基、=O、-C(=O)CH3、-C(=O)CH2OH、-C(=O)CH2NH2、羟甲基、甲氧基乙基、N-(甲基羰基)氨基、N-(环丙基羰基)氨基、N-甲基氨基羰基、甲基羰基、羟基羰基、甲氧基羰基、乙氧基羰基、叔丁氧羰基、N-(甲基羰基)氨基乙基、甲基羰基苯基、叔丁氧羰基哌啶基、N-(叔丁氧羰基)氨基、二氧化-硫代吗啉基、哌啶基、甲基羰基哌啶基、吗啉基、氧杂环丁烷基和甲基磺酰基。
在本公开的具体但仍是示例性的实施方案中,式(I)的基团V可以选自-Cl、-OH、
在本公开的优选实施方案中,式(I)中的基团W可以选自-Cl、吡啶基和-NHR1,其中R1选自-Cl、吡啶基和-NHR1,其中R1选自苯基;环己基;含有1-2个杂原子(例如1N、2N、1N1O、1N1S)的五元杂环芳族或非芳族基团;含有1-2个杂原子(例如1N、2N)的六元杂环芳族或非芳族基团;以及双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环稠合。
R1中的一个或多个非芳族部分(如果有的话)可以是饱和的或不饱和的。作为W基团的吡啶基和W基团中的R1可以未被取代或被一个或多个选自以下的基团取代:-Cl、-F、-OH、-SCH3、-CN、甲基、乙基、-CF3、=O、叔丁基、-OCH(CH3)2、-OCF3、-OCHF2、-CH(OCH3)2、-CH(CH3)2、-CH2CH(CH3)2、-N(CH3)2、甲氧基、乙氧基、羟甲基、叔丁基、环丙氧基、环戊基、环丁氧基、N-甲氨基、甲基哌嗪基、
在本公开的优选实施方案中,式(I)可以是式(Ia-1)或式(Ia-2):
其中R2选自-Cl、-F、-OH、-SCH3、-CN、甲基、乙基、-CF3、=O、叔丁基、-OCH(CH3)2、-OCF3、-OCHF2、-CH(OCH3)2、-CH(CH3)2、-CH2CH(CH3)2、-N(CH3)2、甲氧基、乙氧基、羟甲基、叔丁基、环丙氧基、环戊基、环丁氧基、N-甲氨基、甲基哌嗪基、且
其中V和U与前面提到的定义相同。
在本公开的具体但仍是示例性的实施方案中,式(I)化合物可以选自以下:
1-(2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#215),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#210),
1-(2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#212),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#147),
2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(#214),
5-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮(#152),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#18),
2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#180),
2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#156),
1-(2-(2-(4-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#151),
N-甲基-2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#166),
2-(6-((4-氰基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#179),
N-甲基-2-(6-((4-(甲硫基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#198),
1-(2-(2-(1-(甲基磺酰基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#121),
2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#186),
8-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(#223),
2-(吡啶-3-基)-6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#50),
N-(4-甲氧基吡啶-2-基)-6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-胺(#227),
N-甲基-2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#141),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-甲酰胺(#30),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#79-1),
2-甲基-8-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#224),
1-(2-(2-(1-甲基哌啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#125),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-醇(#61),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#90),
2-(6-((4-环丁氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#195),
1-(2-(2-(6-(甲基磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#119),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-胺盐酸盐(#68),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-甲酰胺(#31),
N-甲基-2-(2-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#114),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-硫杂-2-氮杂螺[3.5]壬烷-7,7-二氧化物(#51),
2-(6-((4-(羟甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#175),
6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#229),
1-(2-(2-(1-甲基-1H-吡唑-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#153),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#71),
2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#110),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#71-1),
N-甲基-2-(2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#117),
3-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺(#218),
1-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-基)乙烷-1-酮(#24),
2-(6-((4-(叔丁基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#187),
1-(2-(2-(噻吩-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#129),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#176),
N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)乙酰胺(#36),
1-(2-(2-(3,3-二氟吡咯烷-1-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#124),
甲基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#87),
1-(2-(2-(1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#130),
2-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#4),
2-(吡啶-3-基)-6-(6-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#43),
2-(6-((4-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#170),
3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-胺盐酸盐(#69),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#79),
2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#84),
1-(2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#213),
N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)乙酰胺(#28),
6-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(#47),
2-((6-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(#226),
N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#216),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#3),
1-(2-(2-(1-甲基-1,2,5,6-四氢吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#126),
2-(6-((4-乙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#189),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺盐酸盐(#75),
甲基2-(2-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#116),
6-(7-(甲基磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#55),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-7-酮(#41),
2-(6-((1H-吡咯并[3,2-c]吡啶-6-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#196),
9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,9-二氮杂螺[5.5]十一烷-2-酮(#9),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#160),
1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-基)乙烷-1-酮(#22),
1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)乙烷-1-酮(#37),
2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(#161),
1-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(#6),
N-(3-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#221),
9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-1-酮(#2),
2-(6-((4-环丙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#207),
6-(3-吗啉代氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#57),
1-(2-(2-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#127),
2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#84-1),
1-(2-(2-(1-甲基-1H-吡唑-5-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#154),
2-(6-((4-氟吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#199),
1-(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(#59),
3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺(#219),
9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-硫杂-9-氮杂螺[5.5]十一烷3,3-二氧化物(#11),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-基)乙烷-1-酮(#39),
1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-基)乙烷-1-酮(#21),
N-甲基-2-(2-(6-(甲氨基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#102),
2-甲基-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-1-酮(#44),
N-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氮杂螺[4.5]癸烷-2-基)乙酰胺(#27),
2-(6-((4-(二甲氧基甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#194),
1-(2-(2-(吡啶-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-[3.5]-7-基)乙烷-1-酮(#131),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺(#73-1),
2-((6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(#228),
4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)硫代吗啉1,1-二氧化物(#42),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#86),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(#89),
7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-硫杂-7-氮杂螺[4.4]壬烷-2,2-二氧化物(#53),
2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#163),
6-(3-(哌啶-4-基)氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#92),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-3-酮(#10),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-基)乙烷-1-酮(#34),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-基)乙烷-1-酮(#33),
2-(2-(3-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#139),
(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-氮杂螺[3.5]壬烷-2-基)甲醇(#49),
N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)乙酰胺(#29),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-酮(#13),
8-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(#225),
(7S)-N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#313),
叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)氨基甲酸酯(#74),
N-甲基-2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#137),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(#52),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-硫杂-2-氮杂螺[4.5]癸烷8,8-二氧化物(#54),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氧杂-2,5-二氮杂螺[3.5]壬烷-6-酮(#46),
N-甲基-2-(6-((4-(甲氨基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#197),
1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-基)乙烷-1-酮(#35),
2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#173),
6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺(#81-1),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(#5),
2-(吡啶-3-基)-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#12),
N-(6-(8-氨基-3-氮杂螺[5.5]十一烷-3-基)-2-(吡啶-3-基)嘧啶-4-基)-5-(叔丁基)异噻唑-3-胺(#222),
2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(#174),
N-甲基-2-(6-((5-甲基-1H-吡唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#204),
叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)氨基甲酸酯(#72),
1-(4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-基)乙烷-1-酮(#48),
N-甲基-2-(6-(吡啶-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#193),
6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺盐酸盐(#81),
N-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)乙酰胺(#58),
乙基2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#142),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺(#75-1),
1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(4-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#128),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#77-1),
1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(6-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#123),
N-甲基-2-(6-(吡嗪-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#200),
N-甲基-2-(2-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#132),
(S)-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢-3H-噁唑[3,4-a]吡嗪-3-酮(#7),
6-(4-(2-甲氧基乙基)哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#19),
2-(6-((6-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#167),
1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(5-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#122),
(7R)-N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#312),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸酯(#78),
叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)氨基甲酸酯(#63),
N-(2-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)乙基)乙酰胺(#26),
6-吗啉代-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#16),2-(6-((5-氯-4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#203),
N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)乙酰胺(#38),
2-(2-(3-氰基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#143),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#60),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#77),
N-甲基-2-(2-(2-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#145),
(R)-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(#8),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(#40),
乙基2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#111),
1-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)乙烷-1-酮(#56),
2-(6-((4-氯-5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#205),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺盐酸盐(#73),
2-(6-((1H-吡唑[3,4-c]吡啶-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#191),
2-(吡啶-3-基)-6-(2-氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#14),
6-(2-(甲基磺酰基)-2,9-二氮杂螺[5.5]十一烷-9-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#23),
1-(4-(2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙烷-1-酮(#25),
N-甲基-2-(6-((5-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#169),
1-(2-(2-(3,5-二甲基异噁唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#155),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-羧酸酯(#70),
2-(6-((4-乙炔基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#209),
叔丁基8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸酯(#67),
乙基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#88),
N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)环丙烷甲酰胺(#20),
叔丁基(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)氨基甲酸酯(#64),
2-(6-((5-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#177),
叔丁基4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-羧酸酯(#91),
2-(6-((4,5-二甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#202),
2-(吡啶-3-基)-N4-(四氢-2H-吡喃-4-基)-N6-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4,6-二胺(#17),
叔丁基4-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(#148),
叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸酯(#65),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-羧酸酯(#83),
2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)异烟腈(#236),
2-甲基-8-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#101),
2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-醇(#2-1),
N-(3-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#220),
2-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#162),
N-(3-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#217),
2-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#159),
N-甲基-2-(6-((3-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#164),
N-甲基-2-(6-((6-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#165),
2-(6-((3-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#168),
6-(哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#15),
N-甲基-2-(6-((1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#171),
2-(6-((5-氯-1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#172),
2-(6-((4-氰基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#178),
2-(6-((3-(叔丁基)-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#181),
2-(6-((4-羟基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#182),
2-(6-((3-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#183),
2-(6-((3-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#184),
2-(6-((4-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#185),
2-(6-((4-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#188),
叔丁基2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)-8-氮杂螺[4.5]癸烷-8-羧酸酯(#62),
6-氯-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#1),
2-(6-((5-甲氧基吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#190),
N-甲基-2-(6-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#192),
叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸酯(#66),
N-甲基-2-(4-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#93),
N-甲基-2-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#98),
N-甲基-2-(2-(吡啶-3-基)-6-(嘧啶-4-基氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#201),
叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-羧酸酯(#76),
叔丁基(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)氨基甲酸酯(#80),
叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-羧酸酯(#82),
N-甲基-2-(6-((4-甲基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#206),
乙基2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#109),
N-甲基-2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#108),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#85),
1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(#32),
乙基2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#107),
N-甲基-2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#105),
N-甲基-2-(6-((5-甲基异噁唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#208),
乙基2-(2-(5-(吗啉代磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#113),
N-甲基-2-(2-(5-(吗啉代磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#112),
乙基2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#138),
乙基2-(2-(6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#150),
叔丁基4-(5-(4-(7-(甲基氨甲酰基)-2-氮杂螺[4.5]癸烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)吡啶-2-基)哌嗪-1-羧酸酯(#149),
1-(3-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)苯基)乙烷-1-酮(#45),
1-(2-(6-(吡啶-3-基)-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#233),
1-(2-(6'-((4-(三氟甲氧基)吡啶-2-基)氨基)-[3,4'-联吡啶]-2'-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#230),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#316),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#317),
1-(2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#318),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#319),
1-(2-(2-(1-(二氟甲基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#320),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#321),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#322),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-甲基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#323),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#324),
1-(2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#325),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡咯-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#326),
1-(2-(6-((4-(二氟甲基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#327),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#328),
1-(2-(6-((4-氟吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#329),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#330),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#331),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#332),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#333),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(3-乙基-1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#334),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-甲基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#335),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-乙基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#336),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#337),
1-(2-(2-(1-((1,1-二氧化四氢-2H-噻喃-4-基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#338),
1-(2-(2-(1-(1,1-二氧化四氢-2H-噻喃-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#339),
1-(2-(2-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#340),
1-(2-(2-(1-(氧杂环丁烷-3-基甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#341),
1-(2-(2-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#342),
1-(2-(2-(1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#343),
1-(2-(2-(1-(2-(甲基磺酰基)乙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#344),
1-(2-(2-(1-((3,3-二氟环丁基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#345),
1-(2-(2-(4-吗啉代苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#346),
1-(2-(2-(4-(甲基磺酰基)苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#347),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#349),
1-(2-(2-((1,1-二氧化四氢-2H-噻喃-4-基)氨基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#350),
1-(2-(2-((四氢-2H-吡喃-4-基)氧基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#352),
1-(5,5-二氟-2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#357),
1-(2-(2-(1-(2-甲基-2-硝基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#361),
1-(2-(2-(1-(2-氨基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#362),
2-甲基-1-(4-(4-(7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)丙烷-2-醇(#365),
环丙基(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)甲酮(#370),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(3,6-二氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#372),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(四氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#373),
4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-3,6-二氢-2H-噻喃1,1-二氧化物(#376),
4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)四氢-2H-噻喃1,1-二氧化物(#377),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1,3-二甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#378),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-甲氧基-2-甲基丙烷-2-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#379),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(2,3-二甲基-2H-吲唑-5-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#380),
1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#381),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-异丙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#382),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-乙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#383),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(二氟甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#384),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#385),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#386),
2-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)乙酰胺(#387),
1-(2-(2-(1-(2,2-二氟乙基)-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#388),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(氟甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#389),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(哌啶-4-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#392),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-(甲基磺酰基)乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#393),
1-(2-(2-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#394),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#395),
1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-(哒嗪-3-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#396),
1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#397),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-(二甲基氨基)乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#398),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#399),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#400),
1-(2-(6-((1H-吡咯并[2,3-b]吡啶-6-基)氨基)-2-(1-环丙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#401),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(4,5,6,7-四氢吡唑[1,5-a]吡嗪-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#402),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(吡咯烷-2-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#403),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(哌啶-4-亚基甲基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#404),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丙基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#405),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(4-(甲基磺酰基)环己-1-烯-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#406),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丁基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#408),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(吡咯烷-3-基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#409),
1-(2-(6-((4-环丙基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#410),
1-(2-(6-((4-环己基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#411),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-(噻唑-2-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#412),
1-(2-(6-(异噻唑-3-基氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#413),
1-(2-(6-((4-乙氧基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#414),
4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲基)吡啶-2-基)氨基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(#415),
1-(2-(6-((4-环丙氧基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#416),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(3-羟基-3-甲基丁基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#417),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#421),
1-(2-(6-((4-(3-氟氮杂环丁烷-1-基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#422),
1-(2-(6-((4-(二甲基氨基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#423),
1-(2-(2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#424),
1-(2-(6-((4-(二氟甲基)吡啶-2-基)氨基)-2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#425),
3-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)氨基)吡啶-2(1H)-酮(#426),
1-(2-(2-(1-乙基-1H-吡唑-4-基)-6-(异噻唑-3-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#427),
6-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)氨基)哒嗪-3(2H)-酮(#428),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((3-甲氧基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#429),
1-(2-(2-(5-氨基-1-甲基-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#430),
1,1'-((6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2,4-二基)双(2,7-二氮杂螺[3.5]壬烷-2,7-二基))双(乙烷-1-酮)(#431),
4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(#432),
1-(2-(4-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)-1,3,5-三嗪-2-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#433),
1-(2-(2-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(4-甲基-1H-吡唑-1-基)吡啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#434),
1-(2-(3-((4-(二氟甲氧基)吡啶-2-基)氨基)-5-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)苯基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#435),
6-(3-甲氧基氮杂环丁烷-1-基)-2-(1-甲基-1H-吡唑-4-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#436),
N4-(4-甲氧基吡啶-2-基)-N6,N6-二甲基-2-(1-甲基-1H-吡唑-4-基)嘧啶-4,6-二胺(#437),
1-(2-(2-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#438),
1-(2-(4-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#439),
2-氨基-1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#440),
4-(4-((4-(二氟甲基)吡啶-2-基)氨基)-6-(7-甘氨酰基-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(#441),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)-2-羟基乙烷-1-酮(#442),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-羟基-4,5,6,7-四氢吡唑[1,5-a]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#443)和
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丙氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#444)。
本公开可以包括所有药学上可接受的同位素标记的式(I)化合物或其盐,其中一个或多个原子被具有相同原子序数但原子质量或质量序数不同于该原子在自然界中占主导地位的原子质量或质量数的原子取代。适合包含在本公开的化合物中的同位素的实例包括氢的同位素,例如2H和3H,碳的同位素,例如11C、13C和14C,氯的同位素,例如36Cl,氟的同位素,例如18F,碘的同位素,例如123I和125I,氮的同位素,例如13N和15N,氧的同位素,例如15O、17O和18O,磷的同位素,例如32P,和硫的同位素,例如35S。某些同位素标记的式(I)化合物,例如掺入放射性同位素的化合物,可用于药物和/或底物组织分布研究。放射性同位素氚(即3H)和碳-14(即14C)由于易于掺入和检测而特别适用于此目的。用较重的同位素(例如氘,即2H)进行取代可能会带来某些治疗优势,这些优势源于更高的代谢稳定性,例如体内半衰期增加或剂量要求降低,因此在某些情况下可能是优选的。用正电子发射同位素(例如11C、18F、15O和13N)进行取代可用于正电子发射地形图(Positron Emission Topography,PET)研究,以检查底物受体的占有。同位素标记的式(I)化合物通常可以通过本领域技术人员已知的常规技术使用合适的同位素标记试剂代替先前使用的未标记试剂来制备。
关于异构体,一些式(I)化合物可以包括立体异构体和互变异构体,所有这些都包括在本公开的范围内。式(I)的立体异构体包括式(I)化合物的顺式和反式异构体、旋光异构体例如R和S对映异构体、非对映异构体、几何异构体、旋转异构体、阻转异构体和构象异构体,包括表现出多于一种类型的异构现象的化合物;及其混合物(例如外消旋体和非对映异构对)。
式(I)化合物可以以药学上可接受的盐的形式存在,例如其酸加成盐和/或碱盐。合适的酸加成盐由形成无毒盐例如盐酸盐/氯化物的酸形成。合适的碱盐由形成无毒盐例如钙盐和钠盐的碱形成。也可以形成酸和碱的半盐,例如半硫酸盐和半钙盐。
式(I)化合物或其药学上可接受的盐包括式(I)化合物或其药学上的盐的所有形式,包括水合物、溶剂化物、异构体(例如旋转立体异构体)、结晶和非结晶形式、同晶型体(isomorph)、多晶型、代谢物及其前药。式(I)化合物可以以非溶剂化和溶剂化形式存在。当溶剂或水紧密结合时,复合物将具有明确的化学计量,不受湿度影响。然而,当溶剂或水的结合较弱时,如在通道溶剂化物和吸湿性化合物中,水/溶剂含量将取决于湿度和干燥条件。
式(I)化合物可以以从完全无定形到完全结晶的固态的连续体存在。术语“无定形”是指材料在分子水平上缺乏长程有序的状态,并且取决于温度,可能表现出固体或液体的物理性质。通常,此类材料不会给出独特的X射线衍射图案,并且虽然表现出固体的特性,但更正式地被描述为液体。加热时,会发生从表观固体到具有液体特性的材料的变化,其特征在于状态变化,通常是二级(“玻璃化转变”)。术语“结晶”是指一种固相,其中材料在分子水平上具有规则有序的内部结构,并给出具有明确峰的独特的X射线衍射图案。这种材料在充分加热时也会表现出液体的特性,但从固体到液体的变化以相变为特征,通常是一级(“熔点”)。当经受合适的条件时,本公开的化合物还可以以介晶状态(中间相或液晶)存在。介晶状态介于真正的结晶状态和真正的液态(熔体或溶液)之间。
本公开还涉及式(I)化合物的前药。一些式(I)化合物本身可能具有很少药理活性或没有药理活性,但是当将它们施用到身体内或身体上时,它们可以例如通过水解裂解转化为具有所需活性的式(I)化合物。此类衍生物被称为“前药”。根据本公开的前药可以例如通过用本领域技术人员已知为“前部分(pro-moieties)”的某些部分替换式(I)化合物中存在的适当官能团来产生。在一些实施方案中,某些式(I)化合物本身可以充当其他式(I)化合物的前药。药物施用后在体内形成的式(I)化合物的代谢物也包括在本公开的范围内。
化合物制备
可用于制备本公开的化合物的起始材料和中间体可从化学供应商获得或可根据化学领域中描述的方法制备。
本公开的化合物(包括化合物的盐)可以使用已知的有机合成技术来制备并且可以根据许多可能的合成路线中的任意一种来合成。用于制备本公开的化合物的反应可以在合适的溶剂中进行,有机合成领域的技术人员可以容易地选择这些溶剂。合适的溶剂可以在反应进行的温度下与起始材料(反应物)、中间体或产物基本上不反应,例如,温度范围可以从溶剂的凝固温度到溶剂的沸腾温度。给定的反应可以在一种溶剂或多于一种溶剂的混合物中进行。取决于特定的反应步骤,本领域技术人员可以选择用于特定反应步骤的合适溶剂。
本公开的化合物的制备可以涉及各种化学基团的保护和去保护。本领域技术人员可以容易地确定保护和去保护的需要以及适当保护基团的选择。例如,-CN基团可以水解得到酰胺基团;羧酸可以转化为酰胺;羧酸可以转化为酯,酯又可以还原为醇,醇又可以进一步改性。对于另一个实例,可以将OH基团转化为更好的离去基团,例如甲磺酸酯,其又适合于亲核取代,例如通过氰离子。对于另一个实例,-S-可以被氧化成-S(=O)-和/或-S(=O)2-。对于又一个实例,不饱和键例如C-C双键或C-C三键可以通过氢化来还原为饱和键。
如果合适和/或需要的话,可以在合成方案的过程中保护/去保护官能性(反应性)基团。例如,可以用苄基、甲基或乙酰基保护OH基团,这些基团可以在合成过程的后期去保护并转化回OH基团。对于另一个实例,可以用苄氧羰基(Cbz)或BOC基团保护NH2基团;转化回NH2基团可以在合成过程的后期通过去保护进行。
可以根据本领域已知的任何合适的方法监测反应。例如,可以通过光谱方法例如核磁共振光谱(例如,1H或13C)、红外光谱、分光光度法(例如,UV-可见)、质谱法或通过色谱方法例如高效液相色谱(HPLC)或薄层色谱(TLC)来监测产物形成。
在一些实施方案中,化合物可以作为立体异构体例如阻转异构体、外消旋体、对映异构体或非对映异构体存在。用于制备/分离各个对映异构体的常规技术包括从合适的光学纯前体手性合成或使用例如手性高效液相色谱(HPLC)分离外消旋体。或者,外消旋体(或外消旋体前体)可以与合适的光学活性化合物(例如醇)反应,或者在化合物含有酸性或碱性部分的情况下,与酸或碱(例如酒石酸或1-苯乙胺)反应。所得非对映异构体混合物可以通过色谱法和/或分级结晶进行分离,并且通过本领域技术人员熟知的方法将一种或两种非对映异构体转化为相应的纯对映异构体。手性化合物(及其手性前体)可以在不对称树脂上使用色谱法(通常为HPLC)以对映异构体富集的形式获得,其中流动相由烃(通常为庚烷或己烷)组成,含有0%至50%的2-丙醇,通常为2%至20%,和0%至5%的烷基胺,通常为0.1%的二乙胺。洗脱液的浓缩提供了富集的混合物。立体异构体聚集体可以通过本领域技术人员已知的常规技术分离。合适的立体选择性技术为本领域普通技术人员所熟知。对于含有烯基或亚烯基的式(I)化合物,几何顺式/反式(或Z/E)异构体是可能的。顺式/反式异构体可以通过本领域技术人员熟知的常规技术(例如色谱法和分级结晶)分离。
药物组合物和施用
本公开还提供了药物组合物,其包含治疗有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物,药学上可接受的载体或赋形剂,并且任选地包含至少一种另外的药物或药剂。
所述药学上可接受的载体或赋形剂可以包括任何常规的药物载体或赋形剂。合适的药物载体包括惰性稀释剂或填充剂、水和各种有机溶剂如水合物和溶剂化物。如果需要,药物组合物可以包含另外的成分,例如调味剂、粘合剂、赋形剂等。
如本文所用,术语“治疗有效量”是指所施用的化合物(包括其药学上可接受的盐)将在一定程度上缓解所治疗的病症的一种或多种症状的量。关于预防和/或治疗由IRAK(例如IRAK4)介导的或与异常IRAK(例如IRAK4)活性相关的病症或疾病,治疗有效量是指具有在一定程度上缓解或消除与IRAK4(例如IRAK4)介导的疾病或病症相关的一种或多种症状的作用的量。关于预防和/或治疗由FLT3介导的或与异常FLT3活性相关的病症或疾病,治疗有效量是指具有在一定程度上缓解或消除与FLT3介导的疾病或病症相关的一种或多种症状的作用的量。如本文所用,除非另有说明,否则术语“治疗”是指逆转、减轻、抑制进展、或预防该术语所适用的病症或病况或该病症或病况的一种或多种症状。术语“治疗”还包括受试者的辅助和新辅助治疗。
式(I)化合物(包括其盐)的施用可以通过能够将化合物递送至作用位点的任意方法来实现。这些方法包括例如肠内途径(例如,口服途径、口腔途径、唇下途径和舌下途径)、口服途径、鼻内途径、吸入途径、十二指肠内途径、肠胃外注射(包括静脉内、皮下、肌肉内、血管内或输注)、鞘内途径、硬膜外途径、脑内途径、脑室内(intracerbroventricular)途径、局部和直肠施用。在本公开的一个实施方案中,式(I)化合物可以通过肠胃外注射途径(例如,静脉内注射途径)施用/起作用。在本公开的一个实施方案中,式(I)化合物可以通过口服途径施用或起作用。
可以调整式(I)化合物的剂量以提供所需的反应。需要注意的是,剂量值可能会随着要缓解的病况的类型和严重程度而变化,并且可能包括单剂量或多剂量。
试剂盒或包装的药物产品
本公开提供了试剂盒或包装的药物产品,其包含呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物,及其使用说明。
所述试剂盒(例如,药物包装)可以包括提供的药物组合物或化合物和容器(例如,小瓶、安瓿、瓶子、注射器和/或分配器包装,或其他合适的容器)。在一些实施方案中,所述试剂盒可任选地进一步包括第二容器,所述第二容器包含用于稀释或悬浮药物组合物或化合物的药物赋形剂。在一些实施方案中,在两个容器中提供药物组合物或化合物,并且当需要时,将两个容器中的内容物组合以形成一个单位剂型。
应用
本公开提供了一种抑制白细胞介素-1受体相关激酶(IRAK)例如白细胞介素-1受体相关激酶-4(IRAK4)的方法,其包括:使IRAK例如IRAK4与有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
本公开还提供了一种抑制FMS样受体酪氨酸激酶(FLT3)的方法,其包括:使FLT3与有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
抑制步骤可以在体外或体内进行。“体外”是指在人工环境中(例如但不限于在试管或培养基中)进行的程序。“体内”是指在活的有机体(例如但不限于人、小鼠、狗、大鼠或兔)中进行的程序。
如本文所用,术语“IC50”是指抑制剂在抑制生物学或生物化学功能中的半数最大抑制浓度。这种定量测量表明需要多少特定抑制剂才能将给定的生物过程(或过程的组成部分,即酶、细胞、细胞受体或微生物)抑制一半。换言之,它是物质的半数最大(50%)抑制浓度(IC)(50%IC,或IC50)。EC50是指获得50%的体内最大效果所需的血浆浓度。
在一些实施方案中,本公开的方法使用的式(I)的IRAK(例如IRAK4)或FLT3抑制剂的IC50值为约或小于预定值,如在体外测定中确定的。在一些实施方案中,所述抑制剂抑制IRAK(例如IRAK4)或FLT3的IC50值为约10nM或更小、20nM或更小、30nM或更小、40nM或更小、50nM或更小、60nM或更小、70nM或更小、80nM或更小、90nM或更小、100nM或更小、150nM或更小、200nM或更小、300nM或更小、400nM或更小、500nM或更小、600nM或更小、700nM或更小、800nM或更小、900nM或更小、1000nM或更小或>1000nM、1500nM或更小、2000nM或更小、或2500nM或更小(或由上述的两个数字限定并包括该数字的范围内的数字)。
本公开提供了一种改变基因表达或改变转录的方法,其包括使体外或受试者中的细胞与有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。在某些实施方案中,所述细胞在体外培养。在某些实施方案中,所述细胞在动物(例如人)中。在某些实施方案中,所述细胞在需要治疗的受试者中。
在一些实施方案中,式(I)化合物可用于体细胞重编程,例如将体细胞重编程为干细胞。在一些实施方案中,式(I)化合物可用于生殖细胞发育,因此设想可用于生殖技术和再生医学领域。
本公开提供了一种用于预防和/或治疗由IRAK(例如IRAK4)介导的或与异常IRAK(例如IRAK4)活性相关的病症或疾病的方法,其包括向有需要的受试者施用治疗有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物;或其药物组合物。
如本文所用,术语“IRAK(例如IRAK4)介导的病症”是指已知IRAK(例如IRAK4)在其中起作用的任何疾病、病症或其他病理状况。因此,在一些实施方案中,本公开涉及治疗已知IRAK(例如IRAK4)在其中起作用的一种或多种疾病或减轻其严重程度。本公开的方法可用于治疗与IRAK(例如IRAK4)相关的疾病状况。任何由IRAK(例如IRAK4)的异常活性或表达水平直接或间接导致的疾病状况都可以是预期的疾病状况。已经报道了与IRAK(例如IRAK4)相关的不同疾病状况。
本公开还提供了一种用于预防和/或治疗由FLT3介导的或与异常FLT3活性相关的病症或疾病的方法,其包括向有需要的受试者施用治疗有效量的呈任意结晶形式或无定形形式的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物;或其药物组合物。
如本文所用,术语“FLT3介导的病症”是指已知FLT3在其中起作用的任何疾病、病症或其他病理状况。因此,在一些实施方案中,本公开涉及治疗已知FLT3在其中起作用的一种或多种疾病或减轻其严重程度。本公开的方法可用于治疗与FLT3相关的疾病状况。任何由FLT3的异常活性或表达水平直接或间接导致的疾病状况都可以是预期的疾病状况。已经报道了与FLT3相关的不同疾病状况。
所述病症或疾病包括炎症性疾病、感染如病毒、细菌、真菌和寄生虫感染、HIV-1感染、败血症、自身免疫性病症或疾病如类风湿性关节炎和多发性硬化症、痛风、幼年特发性关节炎、Muckle-Wells病、家族性地中海热、白塞病、成人斯蒂尔病、增殖性疾病如癌症、增生、再狭窄、心脏肥大、白血病、血管内凝血、骨病、代谢疾病、神经和神经退行性疾病、心血管疾病、纤维化和过敏性疾病、哮喘、特应性皮炎、阿尔茨海默病、激素相关疾病、外伤(手术)、血液透析、缺血性疾病(心肌梗塞)、非感染性肝炎、紫外线辐射、闭合性头部损伤、胰腺炎、牙周炎、移植物抗宿主病和/或移植排斥。
式(I)化合物以及包含它们的药物组合物可以单独或与医学疗法组合施用以治疗任何所述疾病。医学疗法包括例如手术和放射疗法(例如伽马射线、中子束放射疗法、电子束放射疗法、质子疗法、近距离放射疗法、全身放射性同位素)。
将通过具体实施例更详细地描述本公开。提供以下实施例用于说明目的,并不旨在以任何方式限制本公开。本领域技术人员将容易地认识到可以改变或修改的各种非关键参数以产生基本相同的结果。可以使用这些实施例中说明的方法单独或与本领域通常已知的技术组合来制备本公开的范围内的其他化合物。
实施例
下面说明本公开的各种化合物的合成。可以使用这些实施例中说明的方法单独或与本领域通常已知的技术组合来制备本公开的范围内的其他化合物。
实施例1:9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-1-酮(IRAK-052)(#2)
步骤1:6-氯-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-061)(#1)
在冰水浴温度下,向4,6-二氯-2-(吡啶-3-基)嘧啶(2.26g,10.0mmol,1.0eq.)和4-(三氟甲氧基)吡啶-2-胺(1.78g,10.0mmol,1.0eq.)在THF(20mL)中的搅拌溶液中加入NaHMD在THF(2M,10mL,20.0mmoL,2.0eq.)中的溶液,并将所得混合物在室温下搅拌2小时。反应混合物用冷水(30mL)淬灭,并用EtOAc萃取。有机相用盐水洗涤,经Na2SO4干燥,并浓缩至干。粗物质通过柱色谱法(Biotage Rening Flash 45g,EtOAc/n-Hep=20%~50%)纯化,得到淡黄色固体(2.45g,66.8%产率)。LC-MS(m/z):368.5[M+H]+。
步骤2:9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-1-酮(IRAK-052)(#2)
将6-氯-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(50.00mg,0.13mmol,1.0eq.)、2,9-二氮杂螺[5.5]十一烷-1-酮(53.30mg,0.26mmol,2.0eq.)、Pd2(dba)3(11.90mg,0.01mmol,0.1eq.)、BINAP(16.17mg,0.26mmol,0.2eq.)和CS2CO3(127.14mg,0.39mmol,3.0eq.)的混合物悬浮在1,4-二噁烷(3.0mL)中,并将所得混合物在氮气气氛下加热至90℃保持10小时。反应溶液通过柱色谱法(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化,得到白色固体。1H NMR(400MHz,氯仿-d)δ9.56(d,1H),8.66(d,3H),8.22(d,1H),8.11(s,1H),7.48(brs,1H),6.72(d,1H),6.41(s,1H),4.15-4.11(m,2H),3.64(m,2H),3.30(m,2H),2.25-2.19(m,2H),1.81-1.61(m,6H);LC-MS(m/z):500[M+H]+。
2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-醇(IRAK-062)(#2-1)
在化合物#2的制备过程中可以观察到由于水解导致的副产物,其也可以在色谱过程中作为白色粉末状固体获得。LC-MS(m/z):349.08[M+H]+。
实施例2:8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-037)(#3)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-037)。1HNMR(400MHz,氯仿-d)δ9.59(s,1H),8.70-8.62(m,2H),8.28(d,1H),7.89(s,1H),7.82(s,1H),7.40(dd,1H),6.76(s,1H),6.51(s,1H),6.02(s,1H),4.36(d,2H),3.42-3.39(m,4H),2.18-2.15(m,2H),2.06-2.00(m,2H),1.62-1.59(m,2H);LC-MS(m/z):486[M+H]+。
实施例3:2-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-027)(#4)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-027)。1H NMR(400MHz,氯仿-d)δ9.57(s,1H),8.68(d,1H),8.60(d,1H),8.28(d,1H),7.83(d,1H),7.82(s,1H),7.38(dd,1H),6.75(d,1H),6.49(s,1H),4.36(d,2H),3.40-3.36(m,4H),2.89(s,3H),2.07-1.97(m,4H),1.56-1.52(m,2H);LC-MS(m/z):500[M+H]+。
实施例4:8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(IRAK-050)(#5)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(IRAK-050)。1HNMR(400MHz,氯仿-d)δ9.56(s,1H),8.69(d,1H),8.58(d,1H),8.28-8.21(m,2H),7.80(d,1H),7.81(s,1H),7.38(dd,1H),6.74(t,1H),6.58(s,1H),3.79(d,4H),2.51-2.47(m,2H),2.06-2.02(m,2H),1.80-1.77(m,4H);LC-MS(m/z):486[M+H]+。
实施例5:1-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(IRAK-028)(#6)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(IRAK-028)。1HNMR(400MHz,DMSO-d6)δ10.16(s,1H),9.46(d,1H),8.77-8.73(m,2H),8.40(d,1H),7.97(d,1H),7.69(dd,1H),7.01(s,1H),6.97(d,1H),4.47(s,2H),3.14-3.08(m,2H),2.60(s,3H),2.32-2.29(m,2H),2.06-2.03(m,2H),1.91-1.84(m,2H),1.55-1.51(m,2H);LC-MS(m/z):500[M+H]+。
实施例6:(S)-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢-3H-噁唑[3,4-a]吡嗪-3-酮(IRAK-025)(#7)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体(S)-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢-3H-噁唑[3,4-a]吡嗪-3-酮(IRAK-025)。1HNMR(400MHz,氯仿-d)δ9.57(s,1H),8.73(d,1H),8.62(d,1H),8.33(d,2H),7.62(d,1H),7.43-7.40(m,1H),6.81-6.78(m,1H),4.58-4.52(m,1H),4.42-4.39(m,1H),4.14-4.10(m,1H),3.97(d,1H),3.21-3.12(m,2H),2.95-2.89(m,1H);LC-MS(m/z):474[M+H]+。
实施例7:(R)-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(IRAK-091)(#8)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体(R)-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(IRAK-091)。1HNMR(400MHz,氯仿-d)δ9.59(s,1H),8.72(d,1H),8.62(d,1H),8.33(d,1H),7.68(d,1H),7.53(d,1H),7.43-7.40(m,1H),6.80(d,1H),6.71(d,1H),4.88-4.84(m,1H),4.50-4.47(m,1H),4.18-4.17(m,1H),3.72-3.70(m,1H),3.53-3.50(m,3H),3.02-2.92(m,1H),2.74-2.68(m,1H),2.53-2.49(m,2H),2.36-2.31(m,2H);LC-MS(m/z):472[M+H]+。
实施例8:9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,9-二氮杂螺[5.5]十一烷-2-酮(IRAK-054)(#9)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,9-二氮杂螺[5.5]十一烷-2-酮(IRAK-054)。1HNMR(400MHz,氯仿-d)δ9.59(s,1H),8.70-8.62(m,3H),8.22(d,1H),8.12(d,1H),7.42-7.30(m,1H),6.73(d,1H),6.41(s,1H),4.15-4.11(m,2H),3.65-3.60(m,2H),3.0(t,2H),2.25-2.19(m,2H),1.81-1.61(m,6H);LC-MS(m/z):500[M+H]+。
实施例9:8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-3-酮(IRAK-051)(#10)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-3-酮(#10)。1HNMR(400MHz,氯仿-d)δ9.57(s,1H),8.70(d,1H),8.62(d,1H),8.30(d,1H),7.80(d,1H),7.42-7.39(m,1H),6.78(d,1H),6.60(s,1H),6.01(s,1H),3.92-3.89(m,2H),3.64-3.61(m,2H),3.51(s,2H),3.30(d,2H),2.36(s,2H),1.80(s,2H);LC-MS(m/z):486[M+H]+。
实施例10:9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-硫杂-9-氮杂螺[5.5]十一烷3,3-二氧化物(IRAK-029)(#11)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-硫杂-9-氮杂螺[5.5]十一烷3,3-二氧化物(IRAK-029)。1HNMR(400MHz,氯仿-d)δ9.58(s,1H),8.70(d,1H),8.62(d,1H),8.30(d,1H),7.73(d,2H),7.42-7.38(m,1H),6.67(d,1H),6.60(s,1H),3.74(s,4H),3.07-3.04(m,4H),2.13-2.10(m,4H),1.79-1.68(m,4H);LC-MS(m/z):535[M+H]+。
实施例11:2-(吡啶-3-基)-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-058)(#12)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-058)。1HNMR(400MHz,氯仿-d)δ9.59(s,1H),8.71-8.70(m,2H),8.30(d,1H),7.78(d,2H),7.46-7.40(m,2H),6.77(d,1H),6.56(s,1H),4.54(s,3H),3.71-3.68(m,3H),2.01-1.98(m,3H),1.62(s,3H);LC-MS(m/z):459[M+H]+。
实施例12:8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-酮(IRAK-053)(#13)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-酮(IRAK-053)。1H NMR(400MHz,氯仿-d)δ9.59(dd,J=2.2,0.9Hz,1H),8.83–8.69(m,1H),8.62(dt,J=8.0,2.0Hz,1H),8.31(d,J=5.7Hz,1H),7.72(d,J=35.2Hz,2H),7.40(d,J=8.0Hz,1H),6.77(ddt,J=5.6,2.2,1.1Hz,1H),6.56(s,1H),4.21-4.10(m,5H),3.53-3.47(m,2H),1.93-1.88(m,2H),1.74-1.68(m,3H);LC-MS(m/z):487[M+H]+。
实施例13:2-(吡啶-3-基)-6-(2-氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-026)(#14)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(2-氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-026)。1H NMR(400MHz,氯仿-d)δ9.63(d,J=2.1Hz,1H),8.73–8.61(m,2H),8.30(d,J=5.7Hz,1H),7.86(d,J=19.7Hz,2H),7.39(dd,J=8.0,4.8Hz,1H),6.75(d,J=5.8Hz,1H),6.13(s,1H),3.84–3.16(m,4H),1.89(s,3H),1.54-1.53(m,9H);LC-MS(m/z):472[M+H]+。
实施例14:6-(哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-024)(#15)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体6-(哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#15)。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.1Hz,1H),8.86–8.53(m,2H),8.30(d,J=5.7Hz,1H),7.86(s,1H),7.61(s,1H),7.40(d,J=7.9Hz,1H),6.76(d,J=5.8Hz,1H),6.43(s,1H),3.73(t,J=5.3Hz,4H),1.91–1.48(m,6H);LC-MS(m/z):417[M+H]+。
实施例15:6-吗啉代-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-059)(#16)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体6-吗啉代-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-059)。1H NMR(400MHz,氯仿-d)δ9.59(s,1H),8.72(s,1H),8.63(d,J=8.4Hz,1H),8.32(s,1H),7.74(s,1H),7.53–7.37(m,2H),6.79(d,J=5.8Hz,1H),6.59(s,1H),3.99–3.83(m,4H),3.76-3.75(m,4H);LC-MS(m/z):419[M+H]+。
实施例16:2-(吡啶-3-基)-N4-(四氢-2H-吡喃-4-基)-N6-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4,6-二胺(IRAK-060)(#17)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(吡啶-3-基)-N4-(四氢-2H-吡喃-4-基)-N6-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4,6-二胺(IRAK-060)。1H NMR(400MHz,氯仿-d)δ9.57(dd,J=2.2,0.9Hz,1H),8.71(dd,J=4.8,1.7Hz,1H),8.60(dt,J=7.9,1.9Hz,1H),8.30(d,J=5.7Hz,1H),7.64(s,1H),7.51(s,1H),7.41(d,J=8.0,Hz,1H),6.83–6.73(m,1H),6.47(s,1H),4.90(s,1H),4.17–3.94(m,3H),3.61(td,J=11.6,2.2Hz,2H),2.12(dd,J=12.3,3.8Hz,2H),1.68-1.58(m,2H);LC-MS(m/z):433[M+H]+。
实施例17:1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-071)(#18)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-071)。1H NMR(400MHz,氯仿-d)δ9.58(d,J=2.3Hz,1H),8.70(dd,J=4.8,1.8Hz,1H),8.63(dt,J=8.0,2.0Hz,1H),8.30(d,J=5.7Hz,1H),7.70(s,1H),7.54(s,1H),7.40(dd,J=8.0,4.8Hz,1H),6.78(d,J=5.7Hz,1H),6.25(s,1H),3.94(s,4H),3.64(t,J=5.5Hz,2H),3.49(t,J=5.6Hz,2H),2.15(s,3H),1.88(dt,J=17.8,5.7Hz,4H);LC-MS(m/z):500[M+H]+。
实施例18:6-(4-(2-甲氧基乙基)哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-077)(#19)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体6-(4-(2-甲氧基乙基)哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-077)。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.44(dd,J=2.2,0.8Hz,1H),8.67(dd,J=4.8,1.7Hz,1H),8.56(dt,J=8.0,2.0Hz,1H),8.38(d,J=5.7Hz,1H),8.05(t,J=1.9Hz,1H),7.52(dd,J=8.0Hz,1H),6.94(dd,J=5.7Hz,1H),6.87(s,1H),4.40(d,J=13.0Hz,2H),3.38(t,J=6.4Hz,2H),3.23(s,3H),2.94(td,J=12.8,2.6Hz,2H),1.84–1.73(m,2H),1.72-1.66(m,1H),1.47(q,J=6.5Hz,2H),1.14(qd,J=12.4,4.1Hz,2H);LC-MS(m/z):475[M+H]+。
实施例19:N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)环丙烷甲酰胺(IRAK-094)(#20)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)环丙烷甲酰胺(IRAK-094)。1H NMR(400MHz,氯仿-d)δ9.58(s,1H),8.77–8.67(m,1H),8.63(dt,J=8.0,2.0Hz,1H),8.29(dd,J=5.9,2.7Hz,1H),7.83(s,1H),7.59–7.51(m,1H),7.40(dd,J=8.0,4.7Hz,1H),6.76(t,J=3.7Hz,1H),6.46(d,J=2.8Hz,1H),5.48(d,J=8.2Hz,1H),4.06–3.88(m,1H),2.19–1.99(m,4H),1.60(d,J=77.5Hz,8H),1.41–1.20(m,5H),1.20–0.64(m,13H);LC-MS(m/z):569[M+H]+。
实施例20:1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-基)乙烷-1-酮(IRAK-093)(#21)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-基)乙烷-1-酮(IRAK-093)。1H NMR(400MHz,氯仿-d)δ9.57(s,1H),8.69(d,J=5.2Hz,1H),8.63(d,J=8.1Hz,1H),8.30(t,J=5.6Hz,1H),7.81(d,J=2.0Hz,1H),7.40(q,J=6.1Hz,2H),6.76(d,J=6.2Hz,1H),6.49(s,1H),3.68–3.43(m,7H),2.16(s,3H),2.16-1.18(m,9H);LC-MS(m/z):528[M+H]+。
实施例21:1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-基)乙烷-1-酮(IRAK-086)(#22)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-基)乙烷-1-酮(IRAK-086)。1H NMR(400MHz,氯仿-d)δ10.08(s,1H),9.44(d,J=2.2Hz,1H),8.68(dd,J=4.7,1.8Hz,1H),8.56(dt,J=8.0,2.0Hz,1H),8.38(d,J=5.7Hz,1H),8.04(s,1H),7.52(dd,J=8.0,4.9Hz,1H),7.00–6.92(m,1H),6.89(s,1H),3.67(s,4H),3.44(dt,J=17.7,5.9Hz,5H),1.99(s,3H),1.65–1.36(m,7H);LC-MS(m/z):528[M+H]+。
实施例22:6-(2-(甲基磺酰基)-2,9-二氮杂螺[5.5]十一烷-9-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-134)(#23)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体6-(2-(甲基磺酰基)-2,9-二氮杂螺[5.5]十一烷-9-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-134)。LC-MS(m/z):564[M+H]+。
实施例23:1-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-基)乙烷-1-酮(IRAK-125)(#24)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-基)乙烷-1-酮(IRAK-125)。1H NMR(400MHz,DMSO-d6)δ10.09(d,J=3.2Hz,1H),9.44(s,1H),8.68(d,J=4.7Hz,1H),8.57(dd,J=7.9,2.2Hz,1H),8.39(d,J=5.7Hz,1H),8.05(s,1H),7.53(dd,J=7.9,4.8Hz,1H),7.03–6.93(m,1H),6.90(d,J=5.0Hz,1H),3.74-3.64(m,5H),3.53(t,J=7.0Hz,1H),3.38(d,J=8.3Hz,2H),3.25(s,1H),1.95(s,3H),1.86(t,J=7.1Hz,1H),1.78(t,J=7.2Hz,1H),1.60(s,3H);LC-MS(m/z):514[M+H]+。
实施例24:1-(4-(2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙烷-1-酮(IRAK-084)(#25)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(4-(2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙烷-1-酮(IRAK-084)。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.43(d,J=2.1Hz,1H),8.67(dd,J=4.7,1.7Hz,1H),8.55(dt,J=8.1,2.0Hz,1H),8.36(d,J=5.8Hz,1H),7.87(s,1H),7.53(dd,J=8.0,4.8Hz,1H),7.35(s,1H),6.93(d,J=5.7Hz,1H),6.76(s,1H),3.45-3.37(m,8H),2.56(t,J=6.7Hz,2H),2.47(t,J=4.9Hz,1H),2.41(t,J=5.2Hz,2H),1.98(s,3H)..LC-MS(m/z):503[M+H]+。
实施例25:N-(2-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)乙基)乙酰胺(IRAK-085)(#26)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(2-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)乙基)乙酰胺(IRAK-085)。1H NMR(400MHz,DMSO-d6)10.06(s,1H),9.54–9.38(m,1H),8.68(d,J=4.8Hz,1H),8.57(d,J=8.0Hz,1H),8.39(d,J=5.8Hz,1H),8.05(s,1H),7.83(t,J=5.5Hz,1H),7.52(dd,J=7.9,4.8Hz,1H),6.95(d,J=5.7Hz,1H),6.87(s,1H),4.41(d,J=12.5Hz,2H),3.10(q,J=6.7Hz,2H),2.94(t,J=12.6Hz,2H),1.80(s,5H),1.61(d,J=11.4Hz,1H),1.37(q,J=7.0Hz,2H),1.13(q,J=13.1,11.8Hz,2H);LC-MS(m/z):502[M+H]+。
实施例26:N-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氮杂螺[4.5]癸烷-2-基)乙酰胺(IRAK-087)(#27)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氮杂螺[4.5]癸烷-2-基)乙酰胺(IRAK-087)。1H NMR(400MHz,氯仿-d)δ9.65(s,1H),8.70(d,J=4.8Hz,1H),8.63(d,J=8.0Hz,1H),8.30(d,J=5.8Hz,1H),7.82(s,1H),7.58(s,1H),7.40(dd,J=8.0,4.8Hz,1H),6.77(d,J=5.6Hz,1H),6.48(s,1H),5.52(d,J=7.6Hz,1H),4.35(p,J=7.7Hz,1H),3.92–3.57(m,4H),2.17(dt,J=12.5,7.7Hz,2H),2.00(s,3H),1.85–1.44(m,6H),1.39–1.21(m,2H);LC-MS(m/z):528[M+H]+。
实施例27:N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)乙酰胺(IRAK-088)(#28)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)乙酰胺(IRAK-088)。1H NMR(400MHz,氯仿-d)δ9.75(s,1H),8.70(d,J=4.8Hz,1H),8.67–8.57(m,1H),8.30(d,J=5.7Hz,1H),7.80(s,2H),7.56(s,1H),7.40(dt,J=8.2,4.3Hz,1H),6.76(d,J=5.6Hz,1H),6.21(s,1H),3.97–3.08(m,5H),2.03(s,3H),2.01(s,1H),1.98-1.93(m,1H),1.74-1.70(m,5H),1.45–1.22(m,3H);LC-MS(m/z):528[M+H]+。
实施例28:N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)乙酰胺(IRAK-090)(#29)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)乙酰胺(IRAK-090)。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.44(dd,J=2.2,0.9Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),8.57(d,J=8.1Hz,1H),8.38(d,J=5.7Hz,1H),8.05(t,J=2.1Hz,1H),7.73(d,J=7.7Hz,1H),7.52(d,J=8.0Hz,1H),6.95(d,J=5.8Hz,1H),6.86(s,1H),3.65(s,4H),3.58–3.48(m,1),1.79(s,3H),1.76–1.50(m,6H),1.48–1.11(m,6H);LC-MS(m/z):542[M+H]+。
实施例29:N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-甲酰胺(IRAK-089)(#30)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-甲酰胺(IRAK-089)。1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.43(d,J=2.1Hz,1H),8.67(dd,J=4.8,1.8Hz,1H),8.55(d,J=8.0Hz,1H),8.38(d,J=5.7Hz,1H),7.92(s,1H),7.69(q,J=4.5Hz,1H),7.52(dd,J=8.0,4.8Hz,1H),7.00–6.88(m,1H),6.55(s,1H),3.80-3.73(m,4H),2.57(d,J=4.5Hz,3H),2.15–2.03(m,1H),1.97-1.94(m,2H),1.68-1.65(m,2H),1.58–1.34(m,4H)...LC-MS(m/z):514[M+H]+。
实施例30:N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-甲酰胺(IRAK-092)(#31)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-甲酰胺(IRAK-092)。1H NMR(400MHz,氯仿-d)δ9.60(s,1H),8.69(dd,J=4.8,1.7Hz,1H),8.64(d,J=8.0Hz,1H),8.30(d,J=5.7Hz,1H),7.82(s,1H),7.54(s,1H),7.40(dd,J=8.0,4.8Hz,1H),6.82–6.71(m,1H),6.19(s,1H),5.55(d,J=5.5Hz,1H),2.85(d,J=4.8Hz,3H),2.23–2.08(m,1H),2.00(s,2H),1.94–1.72(m,3H),1.70(s,6H),1.58–1.40(m,2H);LC-MS(m/z):528[M+H]+。
实施例31:1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(IRAK-147)(#32)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(IRAK-147)。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.46(d,J=2.1Hz,1H),8.69(d,J=4.7Hz,1H),8.58(d,J=7.9Hz,1H),8.39(d,J=5.7Hz,1H),8.07(s,1H),7.54(dd,J=8.0,4.8Hz,1H),6.96(d,J=5.8Hz,1H),6.91(s,1H),3.73–3.46(m,8H),3.12(s,4H),1.76(s,3H);LC-MS(m/z):500[M+H]+。
实施例32:1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-基)乙烷-1-酮(IRAK-149)(#33)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-基)乙烷-1-酮(IRAK-149)。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.43(dd,J=6.0,2.1Hz,1H),8.68(dd,J=4.8,1.6Hz,1H),8.55(dd,J=7.8,4.9Hz,1H),8.38(d,J=5.7Hz,1H),7.93(s,1H),7.52(dd,J=8.0,4.8Hz,1H),6.95(d,J=5.7Hz,1H),6.56(d,J=16.8Hz,1H),3.69(dd,J=45.8,12.7Hz,6H),3.00(s,2H),2.05(d,J=8.3Hz,3H),1.91(s,2H),1.85(t,J=5.8Hz,2H);LC-MS(m/z):500[M+H]+。
实施例33:1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-基)乙烷-1-酮(IRAK-144)(#34)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-基)乙烷-1-酮(IRAK-144)。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.43(s,1H),8.68(d,J=4.7Hz,1H),8.55(d,J=8.0Hz,1H),8.37(d,J=5.7Hz,1H),7.94(s,1H),7.53(dd,J=8.0,4.8Hz,1H),6.95(d,J=5.6Hz,1H),6.58(d,J=5.4Hz,1H),4.19–3.93(m,4H),3.78–3.48(m,4H),2.21(t,J=6.8Hz,1H),2.11(t,J=7.0Hz,1H),1.95(s,3H);LC-MS(m/z):486[M+H]+。
实施例34:1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-基)乙烷-1-酮(IRAK-143)(#35)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-基)乙烷-1-酮(IRAK-143)。1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.47(d,J=2.1Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),8.59(dt,J=8.0,2.0Hz,1H),8.39(d,J=5.7Hz,1H),7.99(s,1H),7.53(dd,J=8.0,4.7Hz,1H),7.00–6.89(m,1H),6.66(s,1H),4.17(d,J=8.5Hz,1H),4.08(d,J=8.4Hz,1H),3.93–3.78(m,2H),3.64(s,2H),2.22(s,2H),1.78(s,3H),1.24(s,2H);LC-MS(m/z):486[M+H]+。
实施例35:N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)乙酰胺(IRAK-142)(#36)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)乙酰胺(IRAK-142)。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.42(d,J=2.2Hz,1H),8.68(dd,J=4.8,1.8Hz,1H),8.54(d,J=8.0Hz,1H),8.38(d,J=5.7Hz,1H),8.05–7.86(m,2H),7.53(dd,J=8.0,4.7Hz,1H),7.06–6.90(m,1H),6.53(s,1H),4.23–3.83(m,4H),3.62(s,1H),3.14(s,1H),2.21(dd,J=13.3,7.7Hz,1H),2.05–1.82(m,2H),1.80(s,3H),1.74(dd,J=13.3,6.7Hz,1H),1.54–1.38(m,1H);LC-MS(m/z):500[M+H]+。
实施例36:1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)乙烷-1-酮(IRAK-135)(#37)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)乙烷-1-酮(IRAK-135)。1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.42(d,J=2.1Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),8.54(d,J=8.0Hz,1H),8.38(d,J=5.7Hz,1H),7.96(s,1H),7.53(dd,J=8.0,4.8Hz,1H),7.05–6.88(m,1H),6.54(s,1H),4.33(s,2H),4.24(s,4H),4.06(s,2H),1.76(s,3H);LC-MS(m/z):472[M+H]+。
实施例37:N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)乙酰胺(IRAK-141)(#38)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)乙酰胺(IRAK-141)。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.42(d,J=2.1Hz,1H),8.68(dd,J=4.8,1.8Hz,1H),8.54(d,J=8.0Hz,1H),8.38(d,J=5.7Hz,1H),8.12(d,J=7.4Hz,1H),7.95(s,1H),7.53(dd,J=8.0,4.8Hz,1H),6.95(dd,J=5.9,2.1Hz,1H),6.50(s,1H),4.35–3.94(m,5H),2.58–2.52(m,2H),2.13(td,J=8.8,3.0Hz,2H),1.78(s,3H);LC-MS(m/z):486[M+H]+。
实施例38:1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-基)乙烷-1-酮(IRAK-140)(#39)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-基)乙烷-1-酮(IRAK-140)。1H NMR(400MHz,DMSO-d6)δ10.07(d,J=6.7Hz,1H),9.45(d,J=2.1Hz,1H),8.67(d,J=4.7Hz,1H),8.56(dd,J=6.1,4.0Hz,1H),8.38(d,J=5.7Hz,1H),8.03(s,1H),7.53(d,J=7.7Hz,1H),6.94(d,J=5.7Hz,1H),6.58(d,J=21.7Hz,1H),3.55(s,6H),3.16–2.92(m,4H),2.05(s,2H),1.91(d,J=5.5Hz,3H),1.79–1.42(m,2H);LC-MS(m/z):514[M+H]+。
实施例39:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(IRAK-151)(#40)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(IRAK-151)。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.45(s,1H),8.68(d,J=4.6Hz,1H),8.58(d,J=8.0Hz,1H),8.38(d,J=5.7Hz,1H),8.00(s,1H),7.56–7.49(m,1H),6.95(s,1H),6.61(s,1H),2.51(p,J=1.9Hz,4H),2.23(s,1H),1.87(d,J=39.3Hz,3H),1.64(s,2H),1.34(d,J=79.6Hz,3H),0.85(d,J=7.2Hz,2H);LC-MS(m/z):515[M+H]+。
实施例40:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-7-酮(IRAK-174)(#41)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-7-酮(IRAK-174)。1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),9.55–9.37(m,1H),8.68(dd,J=4.7,1.7Hz,1H),8.54(d,J=8.0Hz,1H),8.37(d,J=5.7Hz,1H),7.95(s,1H),7.69(s,1H),7.53(d,J=7.9Hz,1H),6.95(d,J=5.7Hz,1H),6.55(s,1H),4.08(s,4H),3.53(s,2H),2.56(s,2H);LC-MS(m/z):458[M+H]+。
实施例41:4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)硫代吗啉1,1-二氧化物(IRAK-176)(#42)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)硫代吗啉1,1-二氧化物(IRAK-176)。1H NMR(400MHz,氯仿-d)δ9.66–9.55(m,1H),8.71(dd,J=4.8,1.7Hz,1H),8.62(d,J=8.0Hz,1H),8.31(d,J=5.7Hz,1H),7.68(s,1H),7.49–7.36(m,2H),6.84–6.76(m,1H),6.28(s,1H),4.28(t,J=7.8Hz,2H),4.02(t,J=7.1Hz,2H),3.69–3.60(m,1H),3.15(t,J=5.2Hz,4H),3.01(dd,J=7.2,3.6Hz,4H);LC-MS(m/z):522[M+H]+。
实施例42:2-(吡啶-3-基)-6-(6-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-177)(#43)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(6-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-177)。1H NMR(400MHz,氯仿-d)δ9.59(d,J=2.1Hz,1H),8.70(dd,J=4.8,1.7Hz,1H),8.63(dt,J=7.9,2.0Hz,1H),8.30(d,J=5.7Hz,1H),7.73(s,1H),7.48(s,1H),7.40(dd,J=7.9,4.8Hz,1H),6.77(d,J=5.7Hz,1H),6.19(s,1H),3.94(d,J=8.5Hz,2H),3.81(d,J=27.7Hz,4H),3.69(t,J=5.1Hz,2H),1.93(t,J=6.0Hz,2H),1.67(d,J=10.3Hz,2H);LC-MS(m/z):459[M+H]+。
实施例43:2-甲基-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-1-酮(IRAK-190)(#44)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-甲基-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-1-酮(IRAK-190)。LC-MS(m/z):486[M+H]+。
实施例44:1-(3-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)苯基)乙烷-1-酮(IRAK-191)(#45)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(3-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)苯基)乙烷-1-酮(IRAK-191)。1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.52–9.44(m,1H),8.69(dd,J=4.8,1.7Hz,1H),8.60(d,J=8.0Hz,1H),8.40(d,J=5.7Hz,1H),8.06(s,1H),7.92–7.76(m,2H),7.63–7.41(m,3H),7.03–6.89(m,2H),4.61(d,J=12.9Hz,2H),3.04(d,J=37.0Hz,3H),2.58(s,3H),1.96(d,J=12.8Hz,2H),1.81–1.60(m,2H);LC-MS(m/z):535[M+H]+。
实施例45:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氧杂-2,5-二氮杂螺[3.5]壬烷-6-酮(IRAK-192)(#46)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氧杂-2,5-二氮杂螺[3.5]壬烷-6-酮(IRAK-192)。1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.44(dd,J=2.2,0.8Hz,1H),8.83(s,1H),8.69(dd,J=4.8,1.8Hz,1H),8.56(dt,J=8.0,2.0Hz,1H),8.39(d,J=5.7Hz,1H),7.94(s,1H),7.54(d,J=8.0Hz,1H),6.97(d,J=5.8Hz,1H),6.60(s,1H),4.16(d,J=8.8Hz,2H),4.10–3.91(m,5H);LC-MS(m/z):474[M+H]+。
实施例46:6-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(IRAK-193)(#47)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体6-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(IRAK-193)。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.46–9.40(m,1H),8.68(dd,J=4.8,1.7Hz,1H),8.54(dt,J=8.0,2.0Hz,1H),8.37(d,J=5.7Hz,1H),7.95(t,J=1.9Hz,1H),7.53(d,J=8.0Hz,1H),6.96(d,J=5.7Hz,1H),6.56(s,1H),4.15(d,J=8.4Hz,2H),4.03(d,J=8.3Hz,2H),3.32(d,J=7.0Hz,2H),2.51(p,J=1.9Hz,3H),2.40(t,J=6.8Hz,2H);LC-MS(m/z):472[M+H]+。
实施例47:1-(4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-基)乙烷-1-酮(IRAK-195)(#48)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-基)乙烷-1-酮(IRAK-195)。1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.43(d,J=2.2Hz,1H),8.68(dd,J=4.7,1.7Hz,1H),8.55(dt,J=7.9,2.0Hz,1H),8.38(d,J=5.6Hz,1H),7.94(s,1H),7.53(dd,J=7.9,4.7Hz,1H),6.95(dd,J=5.7,2.1Hz,1H),6.53(s,1H),4.40(d,J=13.0Hz,1H),4.13(t,J=8.4Hz,2H),3.91–3.79(m,3H),3.61(p,J=6.7Hz,1H),3.14(q,J=7.4Hz,2H),2.00(s,3H),1.81–1.62(m,3H);LC-MS(m/z):514[M+H]+。
实施例48:(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-氮杂螺[3.5]壬烷-2-基)甲醇(IRAK-196)(#49)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-氮杂螺[3.5]壬烷-2-基)甲醇(IRAK-196)。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.43(d,J=2.1Hz,1H),8.68(dd,J=4.8,1.8Hz,1H),8.56(dt,J=7.9,2.0Hz,1H),8.38(d,J=5.7Hz,1H),8.13–7.99(m,1H),7.52(ddd,J=8.0,4.8,0.8Hz,1H),6.94(ddd,J=5.7,2.3,1.0Hz,1H),6.87(s,1H),4.48(t,J=5.3Hz,1H),3.59(dt,J=32.1,5.6Hz,4H),3.39(t,J=5.8Hz,2H),2.38(p,J=7.2Hz,1H),1.94–1.78(m,2H),1.65(t,J=5.7Hz,2H),1.60–1.42(m,3H);LC-MS(m/z):487[M+H]+。
实施例49:2-(吡啶-3-基)-6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-197)(#50)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-197)。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.43(d,J=2.3Hz,1H),8.68(dt,J=4.4,2.2Hz,1H),8.55(dt,J=8.0,2.1Hz,1H),8.38(d,J=4.5Hz,1H),7.93(s,1H),7.53(dd,J=8.0,4.7Hz,1H),7.00–6.90(m,1H),6.56(d,J=2.7Hz,1H),3.86(s,4H),3.57(d,J=5.4Hz,4H),1.78(t,J=5.3Hz,4H)。LC-MS(m/z):459[M+H]+。
实施例50:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-硫杂-2-氮杂螺[3.5]壬烷-7,7-二氧化物(IRAK-198)(#51)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-硫杂-2-氮杂螺[3.5]壬烷-7,7-二氧化物(IRAK-198)。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.43(dd,J=2.2,0.8Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),8.54(dt,J=7.9,2.0Hz,1H),8.37(d,J=5.7Hz,1H),7.93(s,1H),7.53(d,J=8.0Hz,1H),6.96(d,J=5.7Hz,1H),6.57(s,1H),3.92(s,4H),3.16(t,J=5.9Hz,4H),2.27(d,J=6.6Hz,4H)。LC-MS(m/z):507[M+H]+。
实施例51:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(IRAK-214)(#52)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(IRAK-214)。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.43(dd,J=2.2,0.8Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),8.55(d,J=8.0Hz,1H),8.38(d,J=5.7Hz,1H),7.96(d,J=2.4Hz,1H),7.88(s,1H),7.57–7.49(m,1H),6.96(d,J=5.7Hz,1H),6.56(s,1H),4.15(d,J=8.2Hz,2H),4.03(d,J=8.3Hz,2H),3.22(t,J=6.7Hz,2H),2.43(t,J=6.7Hz,2H);LC-MS(m/z):458[M+H]+。
实施例52:7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-硫杂-7-氮杂螺[4.4]壬烷-2,2-二氧化物(IRAK-215)(#53)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-硫杂-7-氮杂螺[4.4]壬烷-2,2-二氧化物(IRAK-215)。LC-MS(m/z):507[M+H]+。
实施例53:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-硫杂-2-氮杂螺[4.5]癸烷8,8-二氧化物(IRAK-216)(#54)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-硫杂-2-氮杂螺[4.5]癸烷8,8-二氧化物(IRAK-216)。1H NMR(400MHz,氯仿-d)δ9.61(t,J=3.0Hz,1H),8.78–8.69(m,1H),8.64(d,J=9.9Hz,1H),8.32(t,J=5.7Hz,1H),7.72(s,1H),7.48(d,J=4.7Hz,1H),7.42(dd,J=7.9,5.0Hz,1H),6.79(d,J=5.7Hz,1H),6.36(d,J=5.3Hz,1H),3.12(t,J=5.9Hz,4H),2.23(d,J=6.1Hz,4H),2.08(q,J=6.6Hz,2H),1.63(s,4H)。LC-MS(m/z):521[M+H]+。
实施例54:6-(7-(甲基磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-220)(#55)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体6-(7-(甲基磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-220)。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.43(dd,J=2.2,0.9Hz,1H),8.68(dd,J=4.7,1.7Hz,1H),8.55(dt,J=8.0,2.0Hz,1H),8.38(d,J=5.7Hz,1H),7.92(s,1H),7.53(ddd,J=8.0,4.8,0.9Hz,1H),6.96(ddd,J=5.8,2.3,1.1Hz,1H),6.58(s,1H),3.86(s,4H),3.15(t,J=5.5Hz,4H),2.88(s,3H),1.89(t,J=5.5Hz,4H);LC-MS(m/z):536[M+H]+。
实施例55:1-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)乙烷-1-酮(IRAK-221)(#56)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)乙烷-1-酮(IRAK-221)。1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.43(dd,J=2.2,0.9Hz,1H),8.69(dd,J=4.8,1.7Hz,1H),8.55(dt,J=7.9,2.0Hz,1H),8.39(d,J=5.7Hz,1H),7.97(s,1H),7.54(ddd,J=7.9,4.7,0.9Hz,1H),6.98(ddd,J=5.7,2.2,1.0Hz,1H),6.69(s,1H),4.56(s,2H),4.06(t,J=12.7Hz,1H),3.89(d,J=13.4Hz,1H),3.65(d,J=11.7Hz,1H),3.46(d,J=13.3Hz,1H),2.76(q,J=7.1Hz,1H),1.88(s,3H),1.64(d,J=8.6Hz,1H);LC-MS(m/z):472[M+H]+。
实施例56:6-(3-吗啉代氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-222)(#57)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体6-(3-吗啉代氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-222)。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.56–9.33(m,1H),8.68(dd,J=4.8,1.7Hz,1H),8.60–8.52(m,1H),8.38(d,J=5.7Hz,1H),7.94(s,1H),7.53(ddd,J=8.0,4.8,0.9Hz,1H),6.95(ddd,J=5.6,2.3,1.1Hz,1H),6.55(s,1H),4.13(t,J=7.9Hz,2H),3.98–3.83(m,3H),3.62(t,J=4.6Hz,4H),2.39(s,4H);LC-MS(m/z):474[M+H]+。
实施例57:N-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)乙酰胺(IRAK-145)(#58)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体N-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)乙酰胺(IRAK-145)。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.45(d,J=2.1Hz,1H),8.67(dd,J=4.8,1.7Hz,1H),8.58(d,J=8.0Hz,1H),8.38(d,J=5.7Hz,1H),8.12(d,J=7.8Hz,1H),8.00(s,1H),7.52(dd,J=8.0,4.8Hz,1H),6.94(dd,J=5.7,2.1Hz,1H),6.56(s,1H),3.69(s,2H),3.12(s,2H),2.58(s,2H),2.19–1.97(m,1H),1.97–1.67(m,7H)。LC-MS(m/z):500[M+H]+。
实施例58:1-(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(IRAK-171)(#59)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体1-(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(IRAK-171)。LC-MS(m/z):500[M+H]+。
实施例59:2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-172)(#60)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-172)。LC-MS(m/z):457.2[M+H]+。
实施例60:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-醇(IRAK-173)(#61)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-醇(IRAK-173)。1H NMR(400MHz,氯仿-d)δ9.59(dd,J=2.2,0.8Hz,1H),8.70(dd,J=4.8,1.7Hz,1H),8.64(dt,J=8.0,2.0Hz,1H),8.30(d,J=5.7Hz,1H),7.73(s,1H),7.46–7.36(m,2H),6.77(d,J=5.7Hz,1H),6.18(s,1H),3.87(d,J=12.3Hz,3H),2.12–1.99(m,2H),1.98–1.85(m,2H),1.75–1.56(m,4H),1.48(q,J=8.8,7.6Hz,2H);LC-MS(m/z):473[M+H]+。
实施例61:叔丁基2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)-8-氮杂螺[4.5]癸烷-8-羧酸酯(IRAK-055)(#62)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)-8-氮杂螺[4.5]癸烷-8-羧酸酯(IRAK-055)。LC-MS(m/z):585.3[M+H]+。
实施例62:叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)氨基甲酸酯(IRAK-056)(#63)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)氨基甲酸酯(IRAK-056)。LC-MS(m/z):585.3[M+H]+。
实施例63:叔丁基(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)氨基甲酸酯(IRAK-057)(#64)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)氨基甲酸酯(IRAK-057)。LC-MS(m/z):599.3[M+H]+。
实施例64:叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸酯(IRAK-072)(#65)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸酯(IRAK-072)。LC-MS(m/z):585.3[M+H]+。
实施例65:叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸酯(IRAK-073)(#66)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸酯(IRAK-073)。LC-MS(m/z):527.2[M+H]+。
实施例66:叔丁基8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸酯(IRAK-074)(#67)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸酯(IRAK-074)。LC-MS(m/z):571.2[M+H]+。
实施例67:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-胺盐酸盐(IRAK-075)(#68)
在冰水浴温度下,向叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)氨基甲酸酯(15mg,0.026mmol,1.0eq.)在EtOAc(2mL)中的搅拌溶液中逐滴加入HCl在1,4-二噁烷(4M,0.26ml,40.0eq)中的溶液,并将所得混合物在室温下搅拌过夜。将反应混合物浓缩至干,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-胺盐酸盐(IRAK-075)。LC-MS(m/z):485.2[M+H]+。
实施例68:3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-胺盐酸盐(IRAK-076)(#69)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-胺盐酸盐(IRAK-076)。LC-MS(m/z):499.2[M+H]+。
实施例69:叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-103)(#70)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-103)。LC-MS(m/z):571.2[M+H]+。
实施例70:2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(IRAK-105)(#71)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(IRAK-105)。LC-MS(m/z):471.2[M+H]+。
2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-104)(#71-1)
通过用饱和碳酸钠水溶液中和2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#71),得到2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-104)。LC-MS(m/z):471.2[M+H]+。
实施例71:叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)氨基甲酸酯(IRAK-106)(#72)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)氨基甲酸酯(IRAK-106)。LC-MS(m/z):543.2[M+H]+。
实施例72:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺盐酸盐(IRAK-108)(#73)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺盐酸盐(IRAK-108)。LC-MS(m/z):443.2[M+H]+。
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺(IRAK-107)(#73-1)
通过用饱和碳酸钠水溶液中和2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺盐酸盐(#73),得到2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺(IRAK-107)。LC-MS(m/z):443.2[M+H]+。
实施例73:叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)氨基甲酸酯(IRAK-109)(#74)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)氨基甲酸酯(IRAK-109)。LC-MS(m/z):557.2[M+H]+。
实施例74:2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺盐酸盐(IRAK-111)(#75)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺盐酸盐(IRAK-111)。LC-MS(m/z):457.2[M+H]+。
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺(IRAK-110)(#75-1)
通过用饱和碳酸钠水溶液中和2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺盐酸盐(#75),得到2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺(IRAK-110)。LC-MS(m/z):457.2[M+H]+。
实施例75:叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-羧酸酯(IRAK-112)(#76)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-羧酸酯(IRAK-112)。LC-MS(m/z):543.2[M+H]+。
实施例76:2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(IRAK-114)(#77)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(IRAK-114)。LC-MS(m/z):443.2[M+H]+。
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-113)(#77-1)
通过用饱和碳酸钠水溶液中和2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#77),得到2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-113)。LC-MS(m/z):443.2[M+H]+。
实施例77:叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸酯(IRAK-115)(#78)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸酯(IRAK-115)。LC-MS(m/z):543.2[M+H]+。
实施例78:2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(IRAK-117)(#79)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(IRAK-117)。LC-MS(m/z):443.2[M+H]+。
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-116)(#79-1)
通过用饱和碳酸钠水溶液中和2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#79),得到2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#79-1)。LC-MS(m/z):443.2[M+H]+。
实施例79:叔丁基(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)氨基甲酸酯(IRAK-118)(#80)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)氨基甲酸酯(#80)。LC-MS(m/z):557.2[M+H]+.
实施例80:6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺盐酸盐(IRAK-120)(#81)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺盐酸盐(#81)。LC-MS(m/z):457.2[M+H]+。
6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺(IRAK-119)(#81-1)
通过用饱和碳酸钠水溶液中和6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺盐酸盐(#81),得到6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺(#81-1)。LC-MS(m/z):457.2[M+H]+。
实施例81:叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-羧酸酯(IRAK-121)(#82)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-羧酸酯。LC-MS(m/z):557.2[M+H]+。
实施例82:叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-羧酸酯(IRAK-122)(#83)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-羧酸酯(#83)。LC-MS(m/z):557.2[M+H]+。
实施例83:2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(IRAK-124)(#84)
使用类似于实施例67中化合物#68的合成方法,得到白色粉末状固体2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#84)。LC-MS(m/z):485.2[M+H]+。
2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-123)(#84-1)
用饱和碳酸钠水溶液中和2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#84),得到2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#84-1)。LC-MS(m/z):485.2[M+H]+。
实施例84:2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-146)(#85)
使用类似于实施例67中化合物#68的合成方法得到化合物#82的水解产物,在用饱和NaHCO3溶液中和后,得到白色粉末状固体2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#85)。LC-MS(m/z):457.2[M+H]+。
实施例85:2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-148)(#86)
使用类似于实施例67中化合物#68的合成方法得到化合物#83的水解产物,在用饱和NaHCO3溶液中和后,得到白色粉末状固体2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#86)。LC-MS(m/z):457.2[M+H]+。
实施例86:甲基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-150)(#87)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体甲基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#87)。LC-MS(m/z):528.2[M+H]+。
实施例87:乙基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-152)(#88)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体乙基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#88)。LC-MS(m/z):542.2[M+H]+。
实施例88:叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(IRAK-178)(#89)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(#89)。LC-MS(m/z):557.2[M+H]+.
实施例89:2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-189)(#90)
使用类似于实施例67中化合物#68的合成方法得到化合物#89的水解产物,在用饱和NaHCO3溶液中和后,得到白色粉末状固体2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#90)。LC-MS(m/z):457.2[M+H]+。
实施例90:叔丁基4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-羧酸酯(IRAK-175)(#91)
使用类似于实施例1中化合物#2的合成方法,得到白色粉末状固体叔丁基4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-羧酸酯(#91)。LC-MS(m/z):571.2[M+H]+。
实施例91:6-(3-(哌啶-4-基)氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-194)(#92)
使用类似于实施例67中化合物#68的合成方法得到化合物#91的水解产物,在用饱和NaHCO3溶液中和后,得到白色粉末状固体6-(3-(哌啶-4-基)氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#92)。LC-MS(m/z):471.2[M+H]+。
实施例92:N-甲基-2-(4-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-080)(#93)
步骤1:叔丁基7-(甲基氨基甲酰基)-2-氮杂螺[4.5]癸烷-2-羧酸酯(#94)
在冰水浴温度下,向2-(叔丁氧基羰基)-2-氮杂螺[4.5]癸烷-7-羧酸(2.21g,7.80mmol,1.0eq.)在DMF(15mL)中的搅拌溶液中加入三乙胺(2.16mL,15.60mmol,2.0eq.)和HATU(3.56g,9.36mmol,1.2eq.)。将所得混合物在0℃下搅拌半小时,然后加入甲胺盐酸盐(632.55mg,9.36mmol,1.2eq.),并将所得混合物在室温下搅拌过夜。反应混合物用水和EtOAc处理,并分离有机相。有机相用水洗涤,经Na2SO4干燥,并浓缩至干。粗物质通过柱色谱法(Biotage Rening Flash 80g,EtOAc/n-Hep=20%~50%)纯化,得到透明蜡(2.45g,产率>100%)。LC-MS(m/z):296.4[M+H]+。
步骤2:N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#95)
在冰水浴温度下,向叔丁基7-(甲基氨基甲酰基)-2-氮杂螺[4.5]癸烷-2-甲酸酯(2.45g,8.28mmol,1.0eq.)在EtOAc(10mL)中的搅拌溶液中加入HCl在1,4-二噁烷(4M,20mL,80.00mmol,9.66eq.)中的溶液,并将所得混合物在室温下搅拌过夜。粗物质不经进一步纯化直接用于下一步骤。LC-MS(m/z):196.3[M+H]+。
步骤3:2,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#96)
在冰水浴温度下,向2,4,6-三氯嘧啶(9.17g,54.53mmol,1.0eq.)在THF(50mL)中的搅拌溶液中加入NaHMD在THF(2M,37.50mL,81.80mmol,1.5eq.)的溶液中,保持10分钟。逐滴加入4-(三氟甲氧基)吡啶-2-胺(9.70g,54.53mmol,1.0eq.),将得到的混合物在冰水浴温度下搅拌2小时。加入饱和氯化铵溶液(50mL),混合物用EtOAc(100mL)萃取。将有机相干燥并浓缩至干。粗物质通过柱色谱法纯化,得到淡黄色固体(6.77g,56%产率)。LC-MS(m/z):326[M+H]+。
步骤4:2-氯-6-(吡啶-4-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#97)
向2,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(325mg,1mmol)和吡啶-4-基硼酸(184mg,1.5mmol)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,1.5mL,3mmol)和Pd(dppf)Cl2(0.1mol),并将所得混合物在氮气气氛下加热至90℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(300mg,81.7%产率)。LC-MS(m/z):368[M+H]+。
步骤5:N-甲基-2-(4-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#93)
向(2-氯-6-(吡啶-4-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(0.1g,0.27mmol)在THF(15mL)的搅拌溶液中加入N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(0.1g,0.54mmol)、DIPEA(0.5mL)、BINAP(0.03mmol)和Pd2(dba)3(0.03mmol),并将所得混合物在氮气气氛下加热至110℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(20mg,14.0%产率)。1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.76–8.68(m,2H),8.45(s,1H),8.40(d,J=5.6Hz,1H),7.89(d,J=6.0Hz,2H),7.72(s,1H),7.08(s,1H),7.00(d,J=4.8Hz,1H),4.13(d,J=5.28Hz,2H),2.54(d,J=4.5Hz,3H),2.33(d,J=1.9Hz,1H),1.90(d,J=4.5Hz,2H),1.75–1.58(m,4H),1.50–1.22(m,6H);LC-MS(m/z):328[M+H]+。
实施例93:N-甲基-2-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-083)(#98)
步骤1:6-氯-2-苯基-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#99)
在冰水浴温度下,向4,6-二氯-2-苯基嘧啶(2.23g,1mmol)在THF(50mL)中的搅拌溶液中加入NaHMD在THF中的溶液(2M,1mL,2mmol),保持10分钟。逐滴加入4-(三氟甲氧基)吡啶-2-胺(3.56g,2mmol),将得到的混合物在冰水浴温度下搅拌2小时。加入饱和氯化铵溶液(50mL),混合物用EtOAc(100mL)萃取。将有机相干燥并浓缩至干。粗物质通过柱色谱法纯化,得到淡黄色固体(3.0g,81.7%产率);LC-MS(m/z):367[M+H]+。
步骤2:乙基2-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#100)
向6-氯-2-苯基-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(0.1g,0.27mmol)在THF(15mL)中的搅拌溶液中加入乙基2-氮杂螺[4.5]癸烷-7-羧酸酯(0.1g,0.540mmol)、DIPEA(0.5mL)、BINAP(0.03mmol)和Pd(dba)2(0.03mmol),将所得混合物在氮气气氛下加热至110℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(50mg,34.2%产率);LC-MS(m/z):542[M+H]+。
步骤3:N-甲基-2-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#98)
向乙基2-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg)在甲醇(2mL)中的搅拌溶液加入甲胺在乙醇(5mL)中的溶液。将所得混合物加热至120℃保持12小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(15mg)。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.35(dd,J=12.9,4.8Hz,2H),8.12(s,1H),7.74(s,1H),7.48(s,2H),6.93(s,1H),6.51(s,1H),5.82(s,1H),4.13(d,J=5.28Hz,2H),2.54(d,J=4.5Hz,3H),2.33(d,J=1.9Hz,1H),1.90(d,J=4.5Hz,2H),1.75–1.58(m,4H),1.50–1.22(m,6H);LC-MS(m/z):527[M+H]+。
实施例94:2-甲基-8-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-082)(#101)
步骤1:2-甲基-8-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#101)
向6-氯-2-苯基-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(0.1g,0.27mmol)在THF(15mL)中的搅拌溶液中加入2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(0.09g,0.540mmol)、DIPEA(0.5mL)、BINAP(0.03mmol)和Pd(dba)2(0.03mmol),并且将所得混合物在氮气气氛下加热至110℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(20mg,15.0%产率)。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.38(d,J=5.7Hz,1H),8.32(dd,J=6.6,3.2Hz,2H),8.16(s,1H),7.50(d,J=2.1Hz,3H),6.96–6.92(m,1H),6.82(s,1H),4.28(d,J=11.4Hz,2H),3.35(s,1H),3.32(s,1H),3.25–3.16(m,2H),2.75(s,3H),2.03(t,J=6.9Hz,2H),1.70(td,J=13.1,4.2Hz,2H),1.48(d,J=13.3Hz,2H);LC-MS(m/z):499[M+H]+。
实施例95:N-甲基-2-(2-(6-(甲氨基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-137)(#102)
步骤1:乙基2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#103)
向2,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(3.25g,10mmol)和乙基2-氮杂螺[4.5]癸烷-7-羧酸酯(2.11g,10mmol)在NMP中的搅拌溶液中加入DIPEA(3.0mL,30mmol),并将所得混合物用微波加热至140℃保持3小时。反应混合物用水和EtOAc处理。将有机相浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(1.0g,20.0%产率);LC-MS(m/z):500/502[M+H]+。
步骤2:乙基2-(2-(6-(甲氨基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#104)
向乙基2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg,0.1mmol)和(6-(甲氨基)吡啶-3-基)硼酸(30mg,0.2mmol)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,0.3mL,0.6mmol)和Pd(dppf)Cl2(0.01mol),并将所得混合物在氮气气氛下加热至90℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(30mg,52.7%产率);LC-MS(m/z):570[M+H]+。
步骤3:N-甲基-2-(2-(6-(甲氨基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#102)
向乙基2-(2-(6-(甲氨基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg)在甲醇(2mL)中的搅拌溶液中加入甲胺在乙醇中的溶液(5mL)。将所得混合物加热至120℃保持12小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(15mg)。1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.95(d,J=2.0Hz,1H),8.35(d,J=5.7Hz,1H),8.22(dd,J=8.8,2.1Hz,1H),8.09(s,1H),7.70(d,J=4.7Hz,1H),6.95–6.88(m,2H),6.49(d,J=8.9Hz,1H),6.37(s,1H),3.17(d,J=5.2Hz,1H),2.84(d,J=4.8Hz,2H),2.58–2.54(m,3H),2.36–2.23(m,2H),1.89(s,2H),1.75–1.54(m,4H),1.49–1.39(m,2H),1.30(dd,J=28.0,13.8Hz,4H);LC-MS(m/z):556[M+H]+。
实施例96:N-甲基-2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-154)(#105)
步骤1:乙基2-(4-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#106)
向2,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(1.0g,2.7mmol)在NMP(5mL)中的搅拌溶液中加入乙基2-氮杂螺[4.5]癸烷-7-羧酸酯(1.0g,5.4mmol)和DIPEA(0.5mL)。用微波将所得混合物加热至140℃保持3小时。将反应混合物用水和EtOAc处理,将有机相浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(50mg);LC-MS(m/z):500[M+H]+。
步骤2:乙基2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-153)(#107)
向乙基2-(4-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg,0.1mmol)和吡啶-3-基硼酸(30mg,0.2mmol)在二噁烷中的搅拌溶液中加入磷酸钾H2O溶液(2M,0.3mL,0.6mmol)和Pd(dppf)Cl2(0.01mol),然后将所得混合物在氮气气氛下加热至90℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(30mg)。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.14(s,1H),8.70–8.66(m,1H),8.47(s,1H),8.39(d,J=5.6Hz,1H),8.30(d,J=8.2Hz,1H),7.55(dd,J=7.8,4.8Hz,1H),7.05–6.95(m,2H),4.05(q,J=7.0Hz,2H),3.68(s,2H),3.44(s,1H),3.34(s,3H),1.87(d,J=33.9Hz,4H),1.66(s,2H),1.55–1.40(m,2H),1.32(dd,J=29.7,19.8Hz,2H),1.17(t,J=7.1Hz,3H);LC-MS(m/z):543[M+H]+。
步骤3:N-甲基-2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#105)
向乙基2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(30mg)在甲醇(2mL)中的搅拌溶液中加入甲胺在乙醇(5mL)中溶液。将所得混合物加热至120℃保持12小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(15mg)。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.14(s,1H),8.68(d,J=4.6Hz,1H),8.48(s,1H),8.40(d,J=5.6Hz,1H),8.29(t,J=6.7Hz,1H),7.73(s,1H),7.55(dd,J=7.7,4.9Hz,1H),7.01(s,1H),3.69(s,2H),3.41(s,1H),2.54(d,J=4.5Hz,3H),2.38–2.25(m,1H),1.90(s,2H),1.76–1.58(m,4H),1.36(ddd,J=44.0,26.8,15.7Hz,4H);LC-MS(m/z):528[M+H]+。
实施例97:N-甲基-2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-139)(#108)
步骤1:乙基2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-138)(#109)
向乙基2-(4-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg,0.1mmol)和(4-甲基吡啶-3-基)硼酸(30mg,0.2mmol)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,0.3mL,0.6mmol)和Pd(dppf)Cl2(0.01mol),并将所得混合物在氮气气氛下加热至90℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(30mg,53.8%产率)。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.58–8.42(m,3H),8.38(d,J=5.3Hz,1H),7.34(d,J=4.3Hz,1H),6.98(d,J=3.5Hz,1H),6.62(s,1H),4.04(d,J=6.8Hz,2H),3.60(s,2H),2.43(s,3H),1.86(d,J=28.0Hz,5H),1.65(s,2H),1.47(d,J=12.9Hz,2H),1.36–1.21(m,2H),1.17(t,J=6.9Hz,3H);LC-MS(m/z):557[M+H]+。
步骤2:N-甲基-2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#108)
向乙基2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(30mg)在甲醇(2mL)中的搅拌溶液中加入甲胺在乙醇(5mL)中的溶液。将所得混合物加热至120℃保持12小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(15mg)。1H NMR(400MHz,DMSO-d6)δ10.23(d,J=48.7Hz,1H),8.59–8.45(m,2H),8.32(dd,J=47.4,5.4Hz,1H),7.70(s,1H),7.34(d,J=4.8Hz,1H),6.99(s,1H),6.62(s,1H),3.62(s,2H),2.54(d,J=4.3Hz,3H),2.43(s,3H),2.36–2.23(m,1H),1.88(s,2H),1.65(s,3H),1.42(d,J=12.0Hz,2H),1.27(d,J=19.8Hz,3H),1.11(s,2H);LC-MS(m/z):542[M+H]+。
实施例98:2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-159)(#110)
步骤1:乙基2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-158)(#111)
向乙基2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg,0.1mmol)和(6-氨基吡啶-3-基)硼酸(30mg,0.2mmol)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,0.3mL,0.6mmol)和Pd(dppf)Cl2(0.01mol),并将所得混合物在氮气气氛下加热至90℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(30mg,52.4%产率)。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.88(d,J=2.1Hz,1H),8.35(d,J=5.7Hz,1H),8.21(dd,J=8.7,2.3Hz,1H),8.15(s,1H),6.91(d,J=5.7Hz,1H),6.48(d,J=8.7Hz,1H),6.41(s,2H),6.32(s,1H),4.05(q,J=7.1Hz,2H),1.91(d,J=6.0Hz,3H),1.79(d,J=11.6Hz,1H),1.67(d,J=13.0Hz,2H),1.51(dd,J=27.4,14.7Hz,4H),1.38–1.21(m,5H),1.17(t,J=7.1Hz,3H);LC-MS(m/z):572[M+H]+。
步骤2:2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#110)
向乙基2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯在甲醇(2mL)中的搅拌溶液中加入甲胺在乙醇(5mL)中的溶液。将所得混合物加热至120℃保持12小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(15mg)。1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.88(d,J=1.8Hz,1H),8.35(d,J=5.6Hz,1H),8.21(dd,J=8.7,2.2Hz,1H),8.15(s,1H),7.72(d,J=3.7Hz,1H),6.91(d,J=5.1Hz,1H),6.48(d,J=8.7Hz,1H),6.41(s,2H),6.32(s,1H),5.77(s,1H),2.54(d,J=4.5Hz,3H),1.89(s,2H),1.75–1.53(m,4H),1.50–1.34(m,3H),1.34–1.21(m,6H);LC-MS(m/z):557[M+H]+。
实施例99:N-甲基-2-(2-(5-(吗啉代磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-161)(#112)
步骤1:乙基2-(2-(5-(吗啉代磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-160)(#113)
使用类似于实施例97的合成方法,用(5-(吗啉代磺酰基)吡啶-3-基)硼酸代替(4-甲基吡啶-3-基)硼酸,得到白色固体(25mg,36.1%产率)。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.73(d,J=1.9Hz,1H),9.02(d,J=2.2Hz,1H),8.83(s,1H),8.40(d,J=5.7Hz,1H),7.75(s,1H),6.96(dd,J=5.7,1.1Hz,1H),6.86(s,1H),4.06(q,J=7.1Hz,2H),3.71–3.62(m,4H),3.47(d,J=25.8Hz,2H),3.16(s,1H),3.05–2.96(m,4H),1.89(d,J=10.8Hz,3H),1.79(s,1H),1.71–1.23(m,8H),1.18(t,J=7.1Hz,3H);LC-MS(m/z):692[M+H]+。
步骤2:N-甲基-2-(2-(5-(吗啉代磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#112)
使用类似于实施例97中的合成方法得到白色固体(5mg,20.4%产率)。1HNMR(400MHz,DMSO-d6)δ10.18(s,1H),9.73(d,J=1.8Hz,1H),9.02(d,J=2.2Hz,1H),8.83(s,1H),8.40(d,J=5.6Hz,1H),7.79–7.70(m,2H),6.96(d,J=4.8Hz,1H),6.88(s,1H),3.71–3.61(m,4H),3.14(s,1H),2.99(s,4H),2.54(d,J=4.5Hz,3H),1.95(d,J=45.2Hz,3H),1.67(dd,J=28.8,12.3Hz,5H),1.54–1.39(m,3H),1.39–1.19(m,4H);LC-MS(m/z):677[M+H]+。
实施例100:N-甲基-2-(2-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-163)(#114)
步骤1:甲基2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#115)
使用类似于实施例96中的合成方法,用甲基2-氮杂螺[4.5]癸烷-7-羧酸酯代替乙基2-氮杂螺[4.5]癸烷-7-羧酸酯,得到白色固体(1.0g);LC-MS(m/z):486[M+H]+。
步骤2:甲基2-(2-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-162)(#116)
使用类似于实施例96中的合成方法,用(1-(四氢呋喃-3-基)-1H-吡唑-4-基)硼酸代替吡啶-3-基硼酸,得到白色固体(20mg,33.3%产率)。1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.88(d,J=1.8Hz,1H),8.35(d,J=5.6Hz,1H),8.21(dd,J=8.7,2.2Hz,1H),8.15(s,1H),7.72(d,J=3.7Hz,1H),6.91(d,J=5.1Hz,1H),6.48(d,J=8.7Hz,1H),6.41(s,2H),6.32(s,1H),5.77(s,1H),3.39(s,1H),2.54(d,J=4.5Hz,3H),2.36–2.23(m,2H),1.89(s,2H),1.75–1.57(m,4H),1.51–1.25(m,6H);LC-MS(m/z):588[M+H]+。
步骤3:N-甲基-2-(2-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#114)
使用类似于实施例96中的合成方法得到白色固体(5mg,26.3%产率)。1HNMR(400MHz,DMSO-d6)δ9.89(s,1H),8.34(d,J=5.7Hz,1H),8.18(s,1H),8.07(s,1H),7.93(s,1H),7.70(d,J=4.6Hz,1H),6.90(dd,J=5.7,1.2Hz,1H),6.38(s,1H),5.15–5.04(m,1H),4.00(m,2H),3.93(dd,J=9.5,3.6Hz,1H),3.84(m,1H),3.39(s,1H),2.55(d,J=4.6Hz,3H),2.41(dd,J=14.2,7.1Hz,2H),2.34–2.24(m,2H),1.88(s,2H),1.75–1.53(m,4H),1.36(m,6H);LC-MS(m/z):587[M+H]+。
实施例101:N-甲基-2-(2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-170)(#117)
步骤1:乙基2-(2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#118)
使用类似于实施例97中的合成方法,用(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)硼酸代替(4-甲基吡啶-3-基)硼酸,得到白色固体(20mg,31.7%产率);LC-MS(m/z):629[M+H]+。
步骤2:N-甲基-2-(2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#117)
使用类似于实施例97中的合成方法得到白色固体(5mg,25.6%产率)。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.34(d,J=5.2Hz,1H),8.18(s,1H),8.07(s,1H),7.93(s,1H),7.74(s,1H),7.68(s,1H),6.90(s,1H),4.32(s,1H),3.11(s,3H),2.13(s,4H),2.02–1.82(m,4H),1.62(d,J=18.0Hz,6H),1.49–1.32(m,6H),1.23-1.25(m,5H);LC-MS(m/z):614[M+H]+。
实施例102:1-(2-(2-(6-(甲基磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-180)(#119)
步骤1:1-(2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#120)
向2,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(3.0g,9mmol)和1-(2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮盐酸盐(3.0g,13mmol)在DMA(50mL)中的搅拌溶液中加入DIPEA,并将所得混合物加热至80℃保持3小时。将反应混合物用水和EtOAc处理,并分离有机相。有机相用水洗涤,用Na2SO4干燥,并浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(1.0g,23.6%产率);LC-MS(m/z):457/459[M+H]+。
步骤2:1-(2-(2-(6-(甲基磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#119)
向1-(2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(45mg,0.1mmol)和(6-(甲基磺酰基)吡啶-3-基)硼酸(40mg,0.2mmol)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,0.3mL,0.6mmol)和Pd(dppf)Cl2(0.01mol),并将所得混合物在氮气气氛下加热至90℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(30mg,51.9%产率)。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.53(d,J=1.1Hz,1H),8.85(dd,J=8.2,1.8Hz,1H),8.39(d,J=5.7Hz,1H),8.21(d,J=8.2Hz,1H),7.75(s,1H),6.97(d,J=4.8Hz,1H),6.75(s,1H),3.88(s,4H),3.51–3.39(m,4H),3.35(s,3H),2.02(s,3H),1.81(s,2H),1.71(s,2H)。LC-MS(m/z):578[M+H]+。
实施例103:1-(2-(2-(1-(甲基磺酰基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-181)(#121)
使用类似于实施例102中的合成方法得到白色固体(10mg,17.6%产率)。1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.52(s,1H),8.36(d,J=5.6Hz,1H),8.30(s,1H),7.95(s,1H),6.94(d,J=4.2Hz,1H),6.45(s,1H),3.82(s,4H),3.65(s,3H),3.42(s,4H),2.01(s,3H),1.78(s,2H),1.69(s,2H);LC-MS(m/z):567[M+H]+。
实施例104:1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(5-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-188)(#122)
使用类似于实施例102中的合成方法得到白色固体(10mg,17.6%产率)。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.69(d,J=1.3Hz,1H),9.11(d,J=1.3Hz,1H),8.79(s,1H),8.39(d,J=5.7Hz,1H),7.90(s,1H),6.97(d,J=4.7Hz,1H),6.59(s,1H),3.88(s,4H),3.51–3.39(m,4H),2.02(s,3H),1.80(s,2H),1.73–1.67(m,2H);LC-MS(m/z):568[M+H]+。
实施例105:1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(6-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-206)(#123)
使用类似于实施例102中的合成方法得到白色固体(15mg,26.4%产率)。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.54(s,1H),8.79(dd,J=8.2,1.5Hz,1H),8.39(d,J=5.7Hz,1H),8.07(d,J=8.2Hz,1H),7.78(s,1H),7.00–6.91(m,1H),6.72(s,1H),3.87(s,4H),3.52–3.38(m,4H),2.02(s,3H),1.80(d,J=5.1Hz,2H),1.75–1.67(m,2H);LC-MS(m/z):568[M+H]+。
实施例106:1-(2-(2-(3,3-二氟吡咯烷-1-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-207)(#124)
向1-(2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(45mg,0.1mmol)和3,3-二氟吡咯烷(40mg,0.2mmol)在二噁烷中的搅拌溶液中加入CS2CO3(77mg,0.2mmol)、BINAP(10%mmol)、Pd(dba)2(5%mmol),并将所得混合物在氮气气氛下加热至110℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(10mg,18.9%产率)。LC-MS(m/z):528[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.30(d,J=5.6Hz,1H),8.18(s,1H),6.87(dd,J=5.6,1.4Hz,1H),5.74–5.73(m,1H),3.84(t,J=13.3Hz,2H),3.74–3.61(m,6H),3.47–3.36(m,4H),2.55(d,J=7.2Hz,1H),2.46(d,J=7.3Hz,1H),2.00(s,3H),1.74(s,2H),1.68–1.60(m,2H);LC-MS(m/z):528[M+H]+。
实施例107:1-(2-(2-(1-甲基哌啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-209)(#125)
步骤1:1-(2-(2-(1-甲基-1,2,5,6-四氢吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-208)(#126)
使用类似于实施例102中的合成方法得到白色固体(10mg,17.5%产率)。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.34(d,J=5.7Hz,1H),7.97(s,1H),7.11(s,1H),6.92(d,J=5.7Hz,1H),6.33(s,1H),3.76(s,4H),3.57(s,2H),3.48–3.37(m,4H),2.77(s,2H),2.44(s,3H),1.99(d,J=9.8Hz,3H),1.76(s,2H),1.63(s,2H);LC-MS(m/z):518[M+H]+。
步骤2:1-(2-(2-(1-甲基哌啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-209)(#125)
向1-(2-(2-(1-甲基-1,2,5,6-四氢吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮在DCM(10mL)中的搅拌溶液中加入10%Pd/C,并将所得混合物在氢气气氛下反应5小时。将反应混合物浓缩至干,得到白色固体(8mg,80%产率)。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.35(d,J=5.7Hz,1H),7.79(s,1H),6.92(d,J=4.6Hz,1H),6.47(s,1H),3.75(s,4H),3.49–3.36(m,4H),3.09(s,2H),2.79–2.66(m,2H),2.08(s,1H),2.01(s,3H),1.99(d,J=9.8Hz,3H),1.88(s,1H),1.76(s,2H),1.67(s,2H);LC-MS(m/z):520[M+H]+。
实施例108:1-(2-(2-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-210)(#127)
使用类似于实施例106中的合成方法,用2-甲基-2,6-二氮杂-螺[3.3]庚烷二盐酸盐代替3,3-二氟吡咯烷,得到白色固体(20mg,37.5%产率)。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.28(d,J=5.6Hz,1H),8.16(s,1H),7.84–7.76(m,1H),7.47(s,1H),6.85(d,J=4.2Hz,1H),3.98(s,4H),3.65(s,4H),3.40(s,4H),3.24(s,4H),2.18(s,3H),2.00(s,3H),1.73(s,2H),1.63(s,2H);LC-MS(m/z):533[M+H]+。
实施例109:1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(4-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-218)(#128)
使用类似于实施例102中的合成方法,用(4-(三氟甲基)吡啶-3-基)硼酸代替(6-(甲基磺酰基)吡啶-3-基)硼酸,得到白色固体(15mg,26.4%产率)。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.99(s,1H),8.92(d,J=5.1Hz,1H),8.36(d,J=5.7Hz,1H),7.87(d,J=5.2Hz,1H),7.77(s,1H),6.93(d,J=4.7Hz,1H),6.64(s,1H),3.80(s,4H),3.48–3.37(m,4H),2.00(s,3H),1.78(s,2H),1.69(s,2H);LC-MS(m/z):568[M+H]+。
实施例110:1-(2-(2-(噻吩-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-219)(#129)
使用类似于实施例102中的合成方法,用噻吩-3-基硼酸代替(6-(甲基磺酰基)吡啶-3-基)硼酸,得到白色固体(10mg,19.8%产率)。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.36(d,J=5.7Hz,1H),8.14(dd,J=3.1,1.1Hz,1H),7.95(s,1H),7.72(dd,J=5.0,1.1Hz,1H),7.62(dd,J=5.0,3.1Hz,1H),6.93(dd,J=5.7,1.2Hz,1H),6.46(s,1H),3.82(s,4H),3.48–3.36(m,4H),2.01(s,3H),1.84–1.74(m,2H),1.73–1.66(m,2H);LC-MS(m/z):505[M+H]+。
实施例111:1-(2-(2-(1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-223)(#130)
使用类似于实施例102中的合成方法,用1H-吡唑-4-硼酸代替(6-(甲基磺酰基)吡啶-3-基)硼酸,得到白色固体(10mg,20.4%产率)。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.36(d,J=5.7Hz,1H),7.95(s,1H),7.68(s,1H),6.94(d,J=5.7Hz,1H),6.77(s,1H),6.43(s,1H),3.83(s,4H),2.01(s,3H),1.80(d,J=5.6Hz,2H),1.70(t,J=5.6Hz,2H);LC-MS(m/z):489[M+H]+。
实施例112:1-(2-(2-(吡啶-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-224)(#131)
使用类似于实施例102中的合成方法,用吡啶-2-硼酸代替(6-(甲基磺酰基)吡啶-3-基)硼酸,得到白色固体(10mg,20.0%产率)。1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.83(d,J=6.7Hz,2H),8.61(d,J=8.0Hz,1H),8.29(t,J=7.9Hz,1H),7.91(s,1H),7.25(d,J=6.6Hz,1H),7.12(s,1H),6.02(s,1H),3.91(s,4H),2.02(s,3H),1.84(s,2H),1.74(s,2H);LC-MS(m/z):500[M+H]+。
实施例113:N-甲基-2-(2-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-136)(#132)
步骤1:乙基2-氮杂螺[4.5]癸烷-7-羧酸酯(#133)
在冰水浴温度下,向2-(叔丁基)7-乙基2-氮杂螺[4.5]癸烷-2,7-二羧酸酯(5.00g,16.06mmol,1.0eq.)在EtOAc(20mL)中的搅拌溶液中逐滴加入HCl在1,4-二噁烷中的溶液(4M,10mL,40.00mmoL,2.5eq.),并将所得混合物在室温下搅拌过夜。将反应混合物浓缩至干。粗物质(3.1g,91.1%产率)不经进一步纯化直接用于下一步骤。LC-MS(m/z):212.42[M+H]+。
步骤2:2,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#134)
在冰水浴温度下,向2,4,6-三氯嘧啶(3.62g,2mmol,1.0eq.)在THF(50mL)中的搅拌溶液中加入NaHMD在THF(2M,2mL,4mmol,2.0eq.)中的溶液,保持10分钟。逐滴加入4-(三氟甲氧基)吡啶-2-胺(3.56g,2mmol,1.0eq.),并将得到的混合物在冰水浴温度下搅拌2小时。加入饱和氯化铵溶液(50mL),混合物用EtOAc(100mL)萃取。将有机相干燥并浓缩至干。粗物质通过柱色谱法纯化,得到淡黄色固体(3.0g,46.2%产率)。LC-MS(m/z):326[M+H]+。
步骤3:乙基2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#135)
向2,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(3.00g,9.23mmol,1.0eq.)和乙基2-氮杂螺[4.5]癸烷-7-羧酸酯(2.93g,13.85mmol,1.5eq.)在NMP(10mL)中的搅拌溶液中加入DIPEA(3.58g,27.70mmol,3.0eq.),并将所得混合物用微波加热至140℃保持3小时。将反应混合物用水和EtOAc处理,并将有机相浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(1.5g,32.5%产率)。
步骤4:乙基2-(2-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#136)
向2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg,0.10mmol,1.0eq.)和吡啶-4-硼酸(14.76mg,0.12mmol,1.2eq.)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,0.2mL,0.4mmol,4.0eq.)和Pd(dppf)Cl2(0.01mol),并将所得混合物在氮气气氛下加热至90℃保持6小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(20mg,37%产率)。
步骤5:N-甲基-2-(2-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#132)
向乙基2-(2-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(20.00mg,0.03mmol,1.0eq.)在甲醇(2mL)中的搅拌溶液中加入甲胺在乙醇(5mL)中的溶液。将所得混合物加热至120℃保持12小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(5mg,17.2%产率)。1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.71-8.72(d,2H),8.3—8.38(d,1H),8.16-8.17(d,2H),7.94(s,1H),7.68(s,1H),6.93(m,1H),6.69(s,1H),3.57(m,2H),3.19(m,2H),2.54(d,3H),2.29(m,1H),1.91(m,2H),1.62-1.69(m,4H),1.31–1.44(m,2H),1.23(m,2H);LC-MS(m/z):528[M+H]+。
实施例114:N-甲基-2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-165)(#137)
步骤1:乙基2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-164)(#138)
向乙基2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(50mg,0.10mmol,1.0eq.)和4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(25.94mg,0.12mmol,1.2eq.)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,0.2mL,0.4mmol,4.0eq.)和Pd(dppf)Cl2(0.01mol),并将所得混合物在氮气气氛下加热至90℃保持6小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(22mg,39.5%产率)。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.91(s,1H),8.44-8.46(d,1H),8.35-8.37(d,1H),7.30-7.32(d,1H),6.90-6.91(dd,1H),6.65(s,1H),4.04-4.05(m,2H),3.57(m,2H),3.19(m,2H),2.58(d,3H),2.29(m,1H),1.91(m,4H),1.62-1.69(m,4H),1.41–1.44(m,2H),1.36(t,3H);LC-MS(m/z):557[M+H]+。
步骤2:N-甲基-2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#137)
向乙基2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(22.00mg,0.03mmol,1.0eq.)在甲醇(2mL)中的搅拌溶液中加入甲胺在乙醇(5mL)中的溶液。将所得混合物加热至120℃保持12小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(5mg,23.8%产率)。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.91(s,1H),8.44-8.46(d,1H),8.35-8.36(d,1H),7.88(s,1H),7.30-7.31(d,1H),6.90-6.91(dd,1H),6.64(s,1H),,3.57(m,2H),3.19(m,2H),2.58(d,3H),2.53-2.54(d,3H),2.29(m,1H),1.91(m,4H),1.62-1.69(m,4H),1.41–1.44(m,2H);LC-MS(m/z):543[M+H]+。
实施例115:2-(2-(3-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-166)(#139)
步骤1:乙基2-(2-(3-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#140)
使用类似于实施例114中的合成方法,用3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺代替4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶,得到白色固体(25mg,44.8%产率)。LC-MS(m/z):557[M+H]+。
步骤2:2-(2-(3-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#139)
使用类似于实施例114中的合成方法得到白色固体(5mg,20.8%产率)。1HNMR(400MHz,DMSO-d6)δ9.94(s,1H),8.32-8.35(m,1H),7.70-7.71(m,1H),7.56(s,1H),7.48-7.49(d,1H),7.06-7.10(t,1H),6.90-6.91(dd,1H),6.65-6.67(d,1H),6.49(s,1H),5.11(s,2H),3.57(m,2H),3.19(m,2H),2.54(d,3H),2.29(m,1H),1.91(m,2H),1.62-1.69(m,4H),1.31–1.44(m,2H),1.23(m,2H);LC-MS(m/z):542[M+H]+。
实施例116:N-甲基-2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-168)(#141)
步骤1:乙基2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-167)(#142)
使用类似于实施例114中的合成方法,用1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑代替4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶,得到白色固体(20mg,36.6%产率)。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.33-8.34(d,1H),8.12(s,1H),8.06(s,1H),7.87(s,1H),6.89-6.90(m,1H),6.37(s,1H),4.02-4.06(m,2H),3.89(s,3H),3.57(m,2H),3.19(m,2H),2.29(m,1H),1.91(m,4H),1.62-1.69(m,2H),1.46–1.59(m,4H),1.45(t,3H);LC-MS(m/z):546[M+H]+。
步骤2:N-甲基-2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#141)
使用类似于实施例114中的合成方法得到白色固体(5mg,26.3%产率)。1HNMR(400MHz,DMSO-d6)δ10.03(s,1H),8.38(d,1H),8.18(s,1H),7.92(s,1H),7.67(d,1H),6.94(s,1H),6.33(s,1H),3.91(s,3H),3.35(m,2H),3.19(m,2H),2.55(d,2H),2.29(m,1H),1.91(m,4H),1.62-1.69(m,2H),1.40–1.59(m,4H);LC-MS(m/z):531[M+H]+。
实施例117:2-(2-(3-氰基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-169)(#143)
步骤1:乙基2-(2-(3-氰基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#144)
使用类似于实施例114中的合成方法,用3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)腈苯代替4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶,得到白色固体(20mg,35.2%产率);LC-MS(m/z):567[M+H]+。
步骤2:2-(2-(3-氰基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#143)
使用类似于实施例114中的合成方法得到白色固体(6mg,31%产率)。1HNMR(400MHz,DMSO-d6)δ10.07(s,1H),8.61-8.62(m,2H),8.37-8.38(d,1H),8.02(s,1H),7.70-7.74(t,1H),7.65-7.66(d,1H),6.93-6.94(d,1H),6.57(s,1H),3.57(m,2H),3.19(m,2H),2.54(d,3H),2.26(m,1H),1.91(m,2H),1.62-1.69(m,4H),1.38–1.50(m,4H);LC-MS(m/z):552[M+H]+。
实施例118:N-甲基-2-(2-(2-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-179)(#145)
步骤1:乙基2-(2-(2-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#146)
使用类似于实施例114中的合成方法,用2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶代替4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶,得到白色固体(20mg,35.2%产率);LC-MS(m/z):567[M+H]+。
步骤2:N-甲基-2-(2-(2-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#145)
使用类似于实施例114中的合成方法得到白色固体(5mg,31%产率)。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.49-8.50(dd,1H),8.35-8.36(d,1H),8.09-8.11(d,1H),7.88(s,1H),7.67-7.68(d,1H),7.30-7.33(m,1H),6.90-6.91(d,1H),6.64(s,1H),3.57(m,2H),3.19(m,2H),2.73(s,3H),2.54(d,3H),2.25-2.28(m,1H),1.89(m,2H),1.62-1.69(m,4H),1.36–1.43(m,4H);LC-MS(m/z):552[M+H]+。
实施例119:1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-182)(#147)
向1-(2-(2-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(45.00mg,0.10mmol,1.0eq.)和3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)四氢噻吩1,1-二氧化物(46.80mg,0.15mmol,1.5eq.)在二噁烷中的搅拌溶液中加入磷酸钾水溶液(2M,0.15mL,0.3mmol,3.0eq.)和Pd(dppf)Cl2(0.01mol),并将所得混合物在氮气气氛下加热至90℃保持10小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到白色固体(10mg,16.5%产率)。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.33-8.36(d,1H),8.29(s,1H),7.98(s,1H),7.93(s,1H),6.91-6.92(d,1H),6.40(s,1H),5.30-5.36(m,1H),3.71-3.83(m,4H),3.39-3.53(m,6H),3.26-3.29(m,2H),2.66-2.72(m,2H),2.53-2.55(m,2H),2.00(s,3H),1.78(s,2H),1.69(s,2H)。LC-MS(m/z):607[M+H]+。
实施例120:叔丁基4-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(IRAK-183)(#148)
使用类似于实施例119中的合成方法,用叔丁基4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯代替3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)四氢噻吩1,1-二氧化物,得到白色固体(8mg,11.9%产率)。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.33-8.36(d,1H),8.17(s,1H),8.02(s,1H),7.91(s,1H),6.92-6.93(d,1H),6.29(s,1H),4.43-4.46(m,1H),4.05-4.07(m,2H),3.78(m,4H),3.40-3.44(m,4H),2.91(s,2H),2.06(m,2H),2.01(s,3H),1.77-1.81(m,4H),1.68(s,2H),1.42(s,9H);LC-MS(m/z):672[M+H]+。
实施例121:叔丁基4-(5-(4-(7-(甲基氨甲酰基)-2-氮杂螺[4.5]癸烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)吡啶-2-基)哌嗪-1-羧酸酯(IRAK-185)(#149)
步骤1:乙基2-(2-(6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(IRAK-184)(#150)
使用类似于实施例114中的合成方法,用叔丁基4-(5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-基)哌嗪-1-羧酸酯代替4-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶,得到白色固体(25mg,34.4%产率)。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.01(s,1H),8.34-8.40(m,2H),7.93(s,1H),6.93-6.94(d,2H),6.44(s,1H),4.02-4.08(m,2H),3.57(m,6H),3.19(m,4H),2.29(m,1H),1.91(m,4H),1.62-1.69(m,4H),1.43(s,9H),1.32–1.38(m,4H),1.28(t,3H)。LC-MS(m/z):727[M+H]+。
步骤2:叔丁基4-(5-(4-(7-(甲基氨甲酰基)-2-氮杂螺[4.5]癸烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)吡啶-2-基)哌嗪-1-羧酸酯(IRAK-185)(#149)
使用类似于实施例114中的合成方法得到白色固体(6mg,22.2%产率)。1HNMR(400MHz,DMSO-d6)δ10.00(s,1H),9.02(s,1H),8.33-8.37(m,2H),7.97(s,1H),7.67-7.68(d,1H),6.92-6.93(d,2H),6.43(s,1H),3.57(m,6H),3.19(m,4H),2.53-2.55(d,3H),2.29(m,1H),1.91(m,4H),1.62-1.69(m,4H),1.43(s,9H),1.24–1.32(m,4H)。LC-MS(m/z):772[M+H]+。
实施例122:1-(2-(2-(4-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-186)(#151)
使用类似于实施例119中的合成方法,用4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯胺代替3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)四氢噻吩1,1-二氧化物,得到白色固体(6mg,11.6%产率)。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.36-8.37(d,1H),8.07-8.12(m,1H),8.00-8.12(d,2H),6.94(s,1H),6.60-6.63(d,2H),6.17(s,1H),3.81(m,4H),3.41-3.45(m,4H),2.01(s,3H),1.78(s,2H),1.69(s,2H);LC-MS(m/z):514[M+H]+。
实施例123:5-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮(IRAK-187)(#152)
使用类似于实施例119中的合成方法,用5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮代替3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)四氢噻吩1,1-二氧化物,得到白色固体(6mg,10.8%产率)。1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.99(s,1H),8.35-8.37(d,1H),8.32(s,1H),7.97(s,1H),6.93-6.94(d,1H),6.44(s,1H),3.83(m,4H),3.64(s,2H),3.41-3.45(m,4H),2.01(s,3H),1.79(s,2H),1.69(s,2H);LC-MS(m/z):555[M+H]+。
实施例124:1-(2-(2-(1-甲基-1H-吡唑-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-211)(#153)
使用类似于实施例119中的合成方法,用1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑代替3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)四氢噻吩1,1-二氧化物,得到白色固体(5mg,9.9%产率)。1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.33-8.34(d,1H),8.02(s,1H),7.74(s,1H),6.89-6.91(d,1H),6.74(s,1H),6.50(s,1H),3.90(s,3H),3.79(m,4H),3.41-3.45(m,4H),2.01(s,3H),1.78(s,2H),1.68(s,2H);LC-MS(m/z):503[M+H]+。
实施例125:1-(2-(2-(1-甲基-1H-吡唑-5-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-212)(#154)
使用类似于实施例119中的合成方法,用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑代替3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)四氢噻吩1,1-二氧化物,得到白色固体(5mg,9.9%产率)。1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.36-8.37(d,1H),7.81(s,1H),7.48(s,1H),6.93-6.95(d,1H),6.82(s,1H),6.55(s,1H),4.25(s,3H),3.82(m,4H),3.41-3.45(m,4H),2.01(s,3H),1.79(s,2H),1.70(s,2H);LC-MS(m/z):503[M+H]+。
实施例126:1-(2-(2-(3,5-二甲基异噁唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-213)(#155)
使用类似于实施例119中的合成方法,用3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异噁唑代替3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)四氢噻吩1,1-二氧化物,得到白色固体(6mg,11.6%产率)。1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.34-8.36(d,1H),7.55(s,1H),6.91-6.92(d,1H),6.67(s,1H),3.79(m,4H),3.41-3.45(m,4H),2.74(s,3H),2.49(s,3H),1.99(s,3H),1.77(s,2H),1.68(s,2H);LC-MS(m/z):518[M+H]+
实施例127:2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-033)(#156)
步骤1:叔丁基7-(甲基氨基甲酰基)-2-氮杂螺[4.5]癸烷-2-羧酸酯(#157)
在冰水浴温度下,向2-(叔丁氧基羰基)-2-氮杂螺[4.5]癸烷-7-羧酸(2.21g,7.80mmol,1.0eq.)在DMF(15mL)中的搅拌溶液中加入三乙胺(2.16ml,15.60mmol,2.0eq.)和HATU(3.56g,9.36mmol,1.2eq.)。将所得混合物在0℃下搅拌半小时,然后加入甲胺盐酸盐(632.55mg,9.36mmol,1.2eq.),并将所得混合物在室温下搅拌过夜。将反应混合物用水和EtOAc处理,并分离有机相。有机相用水洗涤,用Na2SO4干燥,浓缩至干。粗物质通过柱色谱法(Biotage Rening Flash 80g,EtOAc/n-Hep=20%~50%)纯化,得到透明蜡(2.45g,产率>100%)。LC-MS(m/z):296.4[M+H]+。
步骤2:N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#158)
在冰水浴温度下,向叔丁基7-(甲基氨基甲酰基)-2-氮杂螺[4.5]癸烷-2-羧酸酯(2.45g,8.28mmol,1.0eq.)在EtOAc(10mL)中的搅拌溶液中加入HCl在1,4-二噁烷中的溶液(4M,20mL,80.00mmol,9.66eq.),并将所得混合物在室温下搅拌过夜。粗物质不经进一步纯化直接用于下一步骤。LC-MS(m/z):196.3[M+H]+。
步骤3:2-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-008)(#159)
在冰水浴温度下,向N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(1.92g,8.28mmol,1.2eq.)在THF(15mL)中的搅拌溶液中逐滴加入4,6-二氯-2-(吡啶-3-基)嘧啶(2.65g,6.90mmol,1.0eq.)和DIPEA(5mL,30.7mmol,4.45eq.)。将所得混合物在室温下搅拌过夜。将反应混合物用水和EtOAc处理,并分离有机相。有机相用水洗涤,用Na2SO4干燥,并浓缩至干。粗物质通过柱色谱法(Biotage Rening Flash 80g,EtOAc/n-Hep=50%~100%)纯化,得到淡黄色片状松软固体(2.30g,86.8%产率)。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.70(dd,J=4.8,1.7Hz,1H),8.56(dt,J=8.0,1.9Hz,1H),7.68(t,J=5.0Hz,1H),7.53(ddd,J=8.0,4.8,0.9Hz,1H),6.57(d,J=4.5Hz,1H),3.70-3.83(m,1H),2.55(d,J=4.6Hz,3H),1.97–1.81(m,3H),1.73-1.55(m,5H),1.51–1.21(m,6H)。LC-MS(m/z):385.9[M+H]+。
步骤4:2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#156)
向2-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(50.00mg,0.13mmol,1.0eq.)、4-甲氧基吡啶-2-胺(23.56mg,0.19mmol,1.5eq.)和叔丁醇钠(24.96mg,0.26mmol,2.0eq.)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入t-BuXPhos-Pd-G3在THF中的溶液(10mM,0.65mL,0.0065mmol,0.05eq.)。将所得混合物在氮气气氛下加热至90℃保持10小时。(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化,得到透明固体(35mg,57%产率)。1H NMR(400MHz,氯仿-d)δ9.62–9.56(m,1H),8.67–8.60(m,2H),8.17(s,1H),8.10(d,J=5.9Hz,1H),7.44(s,1H),7.39–7.33(m,1H),6.50(dd,J=5.9,2.3Hz,1H),6.24(s,1H),5.81(d,J=5.4Hz,1H),3.91(s,3H),2.82(d,J=4.8Hz,3H),2.32-2.27(m,1H),1.92–1.61(m,7H),1.55–1.27(m,5H);LC-MS(m/z):473.6[M+H]+。
实施例128:N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-004)(#160)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.45(d,J=2.2Hz,1H),8.67(dd,J=4.8,1.8Hz,1H),8.58(dt,J=8.0,2.0Hz,1H),8.38(d,J=5.7Hz,1H),8.00(s,1H),7.68(d,J=4.8Hz,1H),7.52(dd,J=7.9,4.8Hz,1H),6.94(dd,J=5.3,2.1Hz,1H),6.60(s,1H),2.55(d,J=4.6Hz,3H),2.28(d,J=12.3Hz,1H),1.95–1.64(m,6H),1.62–1.27(m,8H)。LC-MS(m/z):527.2[M+H]+。
实施例129:2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(IRAK-016)(#161)
将N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(8.00mg,0.02mmol,1.0eq.)在NaOH的甲醇溶液(5%,1mL)中在90℃下搅拌12小时。用柠檬酸溶液将pH调节至中性,反应混合物用DCM萃取两次。将所得混合物浓缩至干。粗物质通过反相柱纯化(5mg,50%产率)。1H NMR(400MHz,氯仿-d)δ9.51(s,1H),8.49(s,2H),7.95(s,1H),7.19(d,J=7.9Hz,1H),6.37(s,1H),3.82(s,3H),1.97–1.31(m,14H)。LC-MS(m/z):460.2[M+H]+。
实施例130:2-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-005)(#162)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.38(s,1H),8.71(d,J=4.8Hz,1H),8.53(d,J=7.9Hz,1H),7.68(s,1H),7.56(dd,J=8.0,4.7Hz,1H),6.83(s,2H),6.61(d,J=7.1Hz,1H),5.17(s,1H),2.92(t,J=8.1Hz,1H),2.85(t,J=8.0Hz,1H),2.55(d,J=4.5Hz,3H),1.99–1.83(m,8H),1.74–1.58(m,14H)。LC-MS(m/z):500.3[M+H]+。
实施例131:2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-017)(#163)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.58(d,J=2.1Hz,1H),8.69–8.57(m,2H),8.02(d,J=3.0Hz,1H),7.68(s,1H),7.57(d,J=9.0Hz,1H),7.41–7.34(m,1H),7.28(dd,J=4,J=12,1H),6.27(s,1H),5.83(q,J=4.9Hz,1H),3.86(s,3H),2.81(d,J=4.8Hz,3H),2.31-2.25(m,1H),2.01–1.53(m,8H),1.48-1.29(m,5H);LC-MS(m/z):473.6[M+H]+。
实施例132:N-甲基-2-(6-((3-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-018)(#164)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((3-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.59(d,J=2.1Hz,1H),8.68–8.63(m,2H),8.27–8.20(m,1H),7.46(dd,J=7.5,1.9Hz,1H),7.41(s,1H),7.38(dd,J=7.9,4.9Hz,1H),7.11(s,1H),6.86(dd,J=7.3,4.9Hz,1H),5.63(d,J=6.6Hz,1H),2.82(d,J=4.8Hz,3H),2.37(s,3H),2.33–2.24(m,1H),2.05–1.67(m,9H),1.56–1.24(m,5H);LC-MS(m/z):457.6[M+H]+。
实施例133:N-甲基-2-(6-((6-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-019)(#165)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((6-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.1Hz,1H),8.67-8.62(m,2H),7.55(t,J=7.8Hz,2H),7.40–7.30(m,2H),6.77(d,J=7.4Hz,1H),6.58(s,1H),5.71(d,J=6.3Hz,1H),2.82(d,J=4.8Hz,3H),2.50(s,3H),2.28(m,1H),2.05–1.56(m,9H),1.50-1.27(m,5H).;LC-MS(m/z):457.6[M+H]+。
实施例134:N-甲基-2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-020)(#166)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.59(d,J=2.2Hz,1H),8.69–8.60(m,2H),8.18(d,J=5.2Hz,1H),7.68(s,1H),7.37(dd,J=7.9,4.8Hz,1H),7.33(s,1H),6.77–6.72(m,1H),6.56(s,1H),5.75(q,J=4.9Hz,1H),2.82(d,J=4.8Hz,3H),2.37(s,3H),2.31–2.25(m,1H),2.10–1.61(m,8H),1.53–1.22(m,5H);LC-MS(m/z):457.6[M+H]+。
实施例135:2-(6-((6-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-021)(#167)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((6-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.59(d,J=2.1Hz,1H),8.69–8.59(m,2H),7.52(t,J=7.9Hz,1H),7.42–7.33(m,2H),6.87(s,1H),6.76(d,J=7.8Hz,1H),6.35(d,J=8.0Hz,1H),5.74(d,J=5.3Hz,1H),3.98(s,3H),2.82(d,J=4.8Hz,3H),2.33–2.24(m,1H),1.96–1.62(m,9H),1.53-1.27(m,5H);LC-MS(m/z):473.6[M+H]+。
实施例136:2-(6-((3-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-022)(#168)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((3-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.0Hz,1H),8.69–8.61(m,2H),7.93(d,J=5.0Hz,1H),7.86(s,1H),7.53(s,1H),7.40–7.34(m,1H),7.06(dd,J=8.0,1.5Hz,1H),6.85(dd,J=7.9,5.0Hz,1H),5.68(d,J=5.6Hz,1H),3.95(s,3H),2.82(d,J=4.8Hz,3H),2.33-2.25(m,1H),2.02–1.59(m,9H),1.54–1.25(m,5H).LC-MS(m/z):473.6[M+H]+。
实施例137:N-甲基-2-(6-((5-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-023)(#169)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((5-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.58(d,J=2.1Hz,1H),8.64-8.60(m,2H),8.14(s,1H),7.84(s,1H),7.52–7.44(m,2H),7.35(dd,J=7.9,4.8Hz,1H),6.36(s,1H),5.93(d,J=5.0Hz,1H),2.81(d,J=4.7Hz,3H),2.29(s,4H),2.02–1.56(m,9H),1.50–1.24(m,5H);LC-MS(m/z):457.6[M+H]+。
实施例138:2-(6-((4-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-030)(#170)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.61(s,1H),8.69(s,1H),8.65(dd,J=7.9,2.2Hz,1H),8.20(d,J=5.6Hz,1H),7.81(d,J=1.8Hz,1H),7.41(dd,J=10.0,6.5Hz,2H),6.93(dd,J=5.4,1.9Hz,1H),6.36(s,1H),5.57(s,1H),2.83(d,J=4.7Hz,3H),2.32-2.22(m,1H),2.01–1.71(m,9H),1.50-1.28(m,5H);LC-MS(m/z):478.0[M+H]+。
实施例139:N-甲基-2-(6-((1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-031)(#171)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.62–9.58(m,1H),8.69–8.62(m,3H),7.87(s,1H),7.42–7.37(m,1H),6.91(dd,J=6.8,1.8Hz,1H),6.34(t,J=7.2Hz,1H),5.71(d,J=5.2Hz,1H),5.56(s,1H),3.65(s,3H),2.82(d,J=4.9Hz,3H),2.32-2.25(m,1H),1.93–1.62(m,9H),1.50–1.26(m,5H);LC-MS(m/z):473.6[M+H]+。
实施例140:2-(6-((5-氯-1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-032)(#172)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((5-氯-1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.59(s,1H),8.72(d,J=2.6Hz,1H),8.71–8.66(m,1H),8.63(dt,J=8.0,1.9Hz,1H),7.85(s,1H),7.42(dd,J=7.9,4.8Hz,1H),6.94(d,J=2.6Hz,1H),5.71(d,J=5.3Hz,1H),5.56(s,1H),3.62(s,3H),2.82(d,J=4.8Hz,3H),2.32-2.26(m,1H),1.91–1.64(m,9H),1.51–1.26(m,5H);LC-MS(m/z):508.0[M+H]+。
实施例141:2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-034)(#173)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60–9.57(m,1H),8.66(dd,J=4.8,1.7Hz,1H),8.63(dt,J=8.0,1.9Hz,1H),8.01(s,1H),7.39–7.34(m,1H),6.85(s,1H),6.79(s,1H),5.65(d,J=5.4Hz,1H),2.83(d,J=4.8Hz,3H),2.33–2.25(m,1H),1.91–1.64(m,9H),1.51-1.27(m,5H).;LC-MS(m/z):505.7[M+H]+。
实施例142:2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(IRAK-015)(#174)
向2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(20.00mg,0.04mmol,1.0eq.)在1,4-二噁烷(1mL)中的搅拌溶液中逐滴加入HCl的水溶液(1.2M,0.12mL),在90℃下保持12小时。用饱和碳酸氢钠水溶液将pH调节至中性,并用DCM萃取反应混合物。将所得混合物浓缩至干。粗物质用反相柱纯化(3mg,15.2%产率)。LC-MS(m/z):492.2[M+H]+。
实施例143:2-(6-((4-(羟甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-035)(#175)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-(羟甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.53(d,J=2.1Hz,1H),8.61–8.54(m,2H),8.21(d,J=5.2Hz,1H),8.03–7.96(m,1H),7.87(s,1H),7.31(dd,J=8.0,4.9Hz,1H),6.83(dd,J=5.2,1.3Hz,1H),6.21(s,1H),6.03(d,J=5.0Hz,1H),4.73(s,2H),4.63(s,1H),2.80(d,J=4.7Hz,3H),2.24(m,1H),1.93–1.25(m,14H);LC-MS(m/z):473.6[M+H]+。
实施例144:N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-036)(#176)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.62–9.58(m,1H),8.69(dd,J=4.8,1.8Hz,1H),8.64(dt,J=8.0,1.9Hz,1H),8.45(d,J=5.2Hz,1H),8.18(s,1H),7.83(s,1H),7.41–7.36(m,1H),7.11(dd,J=5.4,1.5Hz,1H),6.25(s,1H),5.70(d,J=4.9Hz,1H),2.83(d,J=4.8Hz,3H),2.33–2.25(m,1H),1.96–1.64(m,9H),1.57–1.25(m,5H);LC-MS(m/z):511.6[M+H]+。
实施例145:2-(6-((5-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-038)(#177)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((5-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(s,1H),8.75(d,J=4.8Hz,1H),8.70(s,1H),8.64(d,J=7.9Hz,1H),8.23(s,1H),7.39(d,J=6.8Hz,1H),7.25(s,1H),7.18(d,J=4.7Hz,1H),5.58(d,J=5.4Hz,1H),2.83(d,J=4.8Hz,3H),2.35–2.26(m,1H),2.04–1.69(m,9H),1.58–1.25(m,5H);LC-MS(m/z):478.0[M+H]+。
实施例146:2-(6-((4-氰基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-039)(#178)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-氰基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.58(d,J=2.2Hz,1H),8.67(dd,J=4.8,1.7Hz,1H),8.62(dt,J=7.9,1.9Hz,1H),8.25(d,J=2.3Hz,1H),7.72(s,1H),7.63(dd,J=4.1,1.7Hz,1H),7.38(dd,J=8.0,4.8Hz,1H),6.33(s,1H),5.72(d,J=5.3Hz,1H),2.83(d,J=4.8Hz,3H),2.33-2.25(m,1H),1.99–1.63(m,9H),1.57–1.22(m,5H);LC-MS(m/z):469.6[M+H]+。
实施例147:2-(6-((4-氰基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-040)(#179)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-氰基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.62–9.57(m,1H),8.72–8.67(m,1H),8.63–8.59(m,1H),8.43(d,J=5.1Hz,1H),8.05(s,1H),7.69(s,1H),7.42(dd,J=8.0,4.8Hz,1H),7.10(dd,J=5.1,1.3Hz,1H),6.32(s,1H),5.61(d,J=5.3Hz,1H),2.84(d,J=4.8Hz,3H),2.34-2.27(m,1H),1.94–1.65(m,9H),1.53–1.23(m,5H);LC-MS(m/z):468.6[M+H]+。
实施例148:2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-041)(#180)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.0Hz,1H),8.69–8.62(m,2H),8.20(d,J=5.2Hz,1H),7.65(s,1H),7.42–7.34(m,2H),6.78(dd,J=5.3,1.5Hz,1H),6.54(s,1H),5.68(d,J=5.5Hz,1H),2.82(d,J=4.8Hz,3H),2.68(q,J=7.6Hz,2H),2.32-2.25(m,1H),2.00–1.58(m,9H),1.51-1.38(m,4H),1.31(t,J=7.6Hz,3H),1.27–1.25(m,1H);LC-MS(m/z):471.6[M+H]+。
实施例149:2-(6-((3-(叔丁基)-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-042)(#181)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((3-(叔丁基)-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60–9.57(m,1H),8.66(dd,J=4.8,1.7Hz,1H),8.62(dt,J=7.9,1.9Hz,1H),7.41–7.34(m,2H),6.14(s,1H),6.03(s,1H),5.74(s,1H),2.82(d,J=4.8Hz,3H),2.27-2.20(m,1H),1.92–1.60(m,9H),1.41-1.27(m,13H);LC-MS(m/z):488.6[M+H]+。
实施例150:2-(6-((4-羟基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-043)(#182)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-羟基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,DMSO-d6)δ9.50(d,J=2.1Hz,2H),8.66(dd,J=4.8,1.8Hz,1H),8.62(dt,J=7.9,2.0Hz,1H),7.96(d,J=5.7Hz,1H),7.69(q,J=4.5Hz,1H),7.54–7.49(m,1H),6.40–6.34(m,1H),5.86(d,J=6.2Hz,1H),5.67(d,J=19.8Hz,2H),2.55(d,J=4.5Hz,3H),2.33-2.25(m,1H),1.96–1.54(m,7H),1.52–1.16(m,6H);LC-MS(m/z):459.6[M+H]+。
实施例151:2-(6-((3-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-044)(#183)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((3-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1HNMR(400MHz,氯仿-d)δ9.54(dd,J=4.7,2.1Hz,1H),8.65–8.62(m,1H),8.59(m,1H),7.34(dd,J=7.9,4.8Hz,1H),5.62(d,J=6.9Hz,1H),5.11(s,1H),4.92(d,J=8.0Hz,1H),3.85(dq,J=9.7,5.1,4.6Hz,1H),2.82(d,J=4.8Hz,3H),2.36(d,J=12.3Hz,1H),2.30-2.26(m,1H),1.94–1.62(m,14H),1.51–1.26(m,8H);LC-MS(m/z):464.6[M+H]+。
实施例152:2-(6-((3-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-045)(#184)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((3-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1HNMR(400MHz,氯仿-d)δ9.60(d,J=2.0Hz,1H),8.69–8.61(m,2H),7.37(dd,J=7.9,4.7Hz,1H),7.29(t,J=8.0Hz,1H),7.02(t,J=2.2Hz,1H),6.94(dd,J=8.1,2.1Hz,1H),6.72–6.64(m,2H),5.68(s,1H),5.59(d,J=4.9Hz,1H),3.85(s,3H),2.82(m,3H),2.31–2.22(m,1H),1.91–1.63(m,9H),1.53–1.25(m,5H);LC-MS(m/z):472.6[M+H]+。
实施例153:2-(6-((4-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-046)(#185)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1HNMR(400MHz,氯仿-d)δ9.58(d,J=2.1Hz,1H),8.68–8.60(m,2H),7.37(dd,J=7.9,4.8Hz,1H),7.29(s,1H),7.27(s,1H),6.96(s,1H),6.94(s,1H),6.50(s,1H),5.57(d,J=5.1Hz,1H),5.41(s,1H),3.86(s,3H),2.82(d,J=4.8Hz,3H),2.29-2.22(m,1H),1.86–1.60(m,9H),1.49–1.28(m,5H);LC-MS(m/z):472.6[M+H]+。
实施例154:2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-047)(#186)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.61(s,1H),8.70(dd,J=4.8,1.7Hz,1H),8.67–8.63(m,1H),8.25(d,J=5.7Hz,1H),7.73(s,1H),7.44–7.35(m,2H),6.71(t,J=72Hz,1H),6.68(dd,J=5.8,2.2Hz,1H),6.20(s,1H),5.51(s,1H),2.84(d,J=4.8Hz,3H),2.32-2.26(m,1H),1.99–1.68(m,9H),1.50–1.31(m,5H);LC-MS(m/z):509.6[M+H]+。
实施例155:2-(6-((4-(叔丁基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-048)(#187)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-(叔丁基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.63(d,J=2.0Hz,1H),8.70–8.64(m,2H),8.23(d,J=5.5Hz,1H),7.62(s,1H),7.56(s,1H),7.37(m,1H),6.94(dd,J=5.5,1.7Hz,1H),6.51(s,1H),5.64(d,J=5.2Hz,1H),2.83(d,J=4.8Hz,3H),2.34–2.24(m,1H),1.94–1.63(m,9H),1.45(m,5H),1.36(s,9H);LC-MS(m/z):499.6[M+H]+。
实施例156:2-(6-((4-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-049)(#188)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1HNMR(400MHz,氯仿-d)δ9.54(d,J=2.2Hz,1H),8.64(dd,J=4.8,1.8Hz,1H),8.59(dt,J=7.9,2.0Hz,1H),7.35(dd,J=8.0,4.8Hz,1H),5.57(d,J=5.1Hz,1H),5.12(s,1H),4.63(d,J=7.9Hz,1H),3.72(tt,J=10.3,4.2Hz,2H),2.82(d,J=4.8Hz,3H),2.32-2.25(m,1H),2.21–2.05(m,4H),1.93(m,4H),1.77–1.26(m,14H);LC-MS(m/z):464.6[M+H]+。
实施例157:2-(6-((4-乙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-063)(#189)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-乙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.61(d,J=2.0Hz,1H),8.66(dd,J=4.8,1.7Hz,1H),8.65–8.60(m,1H),8.11(t,J=6.5Hz,1H),7.90–7.79(m,1H),7.38–7.34(m,1H),7.27–7.21(m,1H),6.49(m,1H),6.37(s,1H),6.26(dd,J=6.0,2.2Hz,1H),4.15(q,J=6.9Hz,2H),2.82(d,J=4.8,3H),2.28(m,1H),1.99–1.38(m,17H),1.27(d,J=2.1Hz,1H);LC-MS(m/z):487.6[M+H]+。
实施例158:2-(6-((5-甲氧基吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-064)(#190)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((5-甲氧基吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.62–9.58(m,1H),8.68(dd,J=4.8,1.8Hz,1H),8.64(dt,J=7.9,1.9Hz,1H),8.26(d,J=2.1Hz,1H),8.05(d,J=2.6Hz,1H),7.71(d,J=2.4Hz,1H),7.38(m,1H),6.81(s,1H),5.61(d,J=7.0Hz,1H),5.58(s,1H),3.92(s,3H),2.83(d,J=4.8Hz,3H),2.32–2.22(m,1H),1.94–1.63(m,9H),1.50–1.28(m,5H);LC-MS(m/z):473.6[M+H]+。
实施例159:2-(6-((1H-吡唑[3,4-c]吡啶-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-065)(#191)
使用类似于实施例127中化合物#156的合成方法,得到淡绿色粉末状固体2-(6-((1H-吡唑[3,4-c]吡啶-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.67(s,1H),8.80(s,1H),8.72–8.66(m,2H),8.21(s,1H),8.15(d,J=1.0Hz,1H),7.50(s,1H),7.42(dd,J=7.9,4.9Hz,1H),5.99(s,1H),5.58(s,1H),2.84(d,J=4.8Hz,3H),2.33-2.25(m,1H),1.94–1.63(m,10H),1.53–1.28(m,4H);LC-MS(m/z):483.6[M+H]+。
实施例160:N-甲基-2-(6-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-066)(#192)
使用类似于实施例127中化合物#156的合成方法,得到淡棕色粉末状固体N-甲基-2-(6-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.1Hz,1H),8.69–8.61(m,2H),8.02(d,J=3.0Hz,1H),7.51(d,J=9.0Hz,1H),7.46–7.31(m,3H),6.33(s,1H),5.67(s,1H),3.19(t,J=5.0Hz,4H),2.82(d,J=4.7Hz,3H),2.62(t,J=5.0Hz,4H),2.38(s,3H),2.31-2.24(m,1H),1.96–1.57(m,9H),1.55–1.25(m,5H);LC-MS(m/z):541.7[M+H]+。
实施例161:N-甲基-2-(6-(吡啶-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-067)(#193)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-(吡啶-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.61(d,J=2.1Hz,1H),8.70–8.62(m,2H),8.35–8.28(m,1H),7.68(ddd,J=9.0,7.2,1.9Hz,1H),7.57(d,J=8.3Hz,1H),7.39(dd,J=8.0,4.8Hz,2H),6.93(ddd,J=7.2,5.0,1.0Hz,1H),6.54(s,1H),5.53(s,1H),2.83(d,J=4.8Hz,2H),2.33-2.25(m,1H),1.95–1.67(m,9H),1.54–1.29(m,5H);LC-MS(m/z):443.6[M+H]+。
实施例162:2-(6-((4-(二甲氧基甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-068)(#194)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-(二甲氧基甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.64(d,J=2.0Hz,1H),8.71–8.65(m,2H),8.31(d,J=5.2Hz,1H),7.87(s,1H),7.47–7.36(m,2H),7.03–6.96(m,1H),6.46(s,1H),5.52(s,1H),5.45(s,1H),3.41(s,6H),2.83(d,J=4.8Hz,3H),2.34–2.23(m,1H),1.94–1.65(m,9H),1.52–1.29(m,5H);LC-MS(m/z):517.6[M+H]+。
实施例163:2-(6-((4-环丁氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-069)(#195)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-环丁氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.61(d,J=2.1Hz,1H),8.70–8.61(m,2H),8.10(d,J=5.9Hz,1H),7.60(s,1H),7.38(ddd,J=8.0,4.8,0.9Hz,1H),7.11(s,1H),6.43(dd,J=5.9,2.2Hz,1H),6.39(s,1H),5.66–5.60(m,1H),4.77(p,J=7.1Hz,1H),2.83(d,J=4.9Hz,3H),2.54–2.44(m,2H),2.34–2.15(m,3H),2.02–1.65(m,11H),1.52–1.26(m,5H);LC-MS(m/z):513.6[M+H]+。
实施例164:2-(6-((1H-吡咯并[3,2-c]吡啶-6-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-078)(#196)
使用类似于实施例127中化合物#156的合成方法,得到淡棕色粉末状固体2-(6-((1H-吡咯并[3,2-c]吡啶-6-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.81–9.50(m,2H),8.61(d,J=21.2Hz,2H),8.37(d,J=28.9Hz,2H),7.40(s,1H),6.66–6.45(m,2H),5.75(d,J=18.5Hz,2H),2.82(s,3H),2.44–1.84(m,9H),1.50–1.17(m,6H);LC-MS(m/z):482.6[M+H]+。
实施例165:N-甲基-2-(6-((4-(甲氨基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-095)(#197)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((4-(甲氨基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.58(d,J=2.0Hz,1H),8.68–8.61(m,2H),7.82(d,J=6.5Hz,1H),7.43(s,1H),7.37(dt,J=8.0,3.1Hz,1H),6.27(dd,J=6.5,2.5Hz,1H),6.18(s,1H),5.67(s,1H),4.87(s,2H),3.13(s,3H),2.83(d,J=4.8Hz,3H),2.32–2.26(m,1H),2.01–1.62(m,9H),1.51–1.26(m,5H);LC-MS(m/z):472.6[M+H]+。
实施例166:N-甲基-2-(6-((4-(甲硫基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-096)(#198)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((4-(甲硫基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.2Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),8.64(dt,J=8.0,2.0Hz,1H),8.09(d,J=5.5Hz,1H),7.52(s,1H),7.47(s,1H),7.38(dd,J=7.9,4.8Hz,1H),6.77(dd,J=5.5,1.7Hz,1H),6.39(s,1H),5.61(s,1H),2.83(d,J=4.8Hz,3H),2.55(s,3H),2.33–2.24(m,1H),2.01–1.65(m,9H),1.52–1.27(m,5H);LC-MS(m/z):489.6[M+H]+。
实施例167:2-(6-((4-氟吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-097)(#199)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-氟吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.1Hz,1H),8.69(dd,J=4.9,1.7Hz,1H),8.64(dt,J=8.0,2.0Hz,1H),8.26(dd,J=8.9,5.7Hz,1H),7.59(dd,J=11.3,2.2Hz,2H),7.41(dd,J=8.1,4.8Hz,1H),6.71-6.67(m,1H),6.26(s,1H),5.60(s,1H),2.83(d,J=4.8Hz,3H),2.32-2.26(m,1H),1.86–1.65(m,9H),1.47(m,5H);LC-MS(m/z):461.6[M+H]+。
实施例168:N-甲基-2-(6-(吡嗪-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-098)(#200)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-(吡嗪-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.62(s,1H),8.94(s,1H),8.69(d,J=4.5Hz,1H),8.66(dd,J=8.0,1.9Hz,1H),8.25(s,1H),8.18(s,1H),7.45–7.37(m,2H),6.57(s,1H),5.56(s,1H),2.83(d,J=4Hz,3H),2.33-2.23(m,1H),1.96-1.69(m,9H),1.55–1.28(m,5H);LC-MS(m/z):444.5[M+H]+。
实施例169:N-甲基-2-(2-(吡啶-3-基)-6-(嘧啶-4-基氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-099)(#201)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(2-(吡啶-3-基)-6-(嘧啶-4-基氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.1Hz,1H),8.86(s,1H),8.70(dd,J=4.8,1.8Hz,1H),8.64(dt,J=7.9,2.0Hz,1H),8.52(d,J=5.9Hz,1H),7.69–7.58(m,2H),7.41(dd,J=8.1,4.8Hz,1H),6.52(s,1H),5.57(s,1H),2.84(d,J=4.8Hz,3H),2.34–2.25(m,1H),2.07–1.71(m,8H),1.66-1.63(m,1H),1.55–1.28(m,5H);LC-MS(m/z):444.5[M+H]+。
实施例170:2-(6-((4,5-二甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-100)(#202)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4,5-二甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.60(d,J=2.9Hz,1H),8.71–8.61(m,2H),7.83(d,J=7.1Hz,1H),7.59(s,1H),7.50(s,1H),7.37(dd,J=8.0,4.8Hz,1H),6.21(s,1H),6.07(s,1H),4.42(s,1H),4.02(s,3H),3.94(s,3H),2.83(d,J=4.9,3H),2.31-2.24(m,1H),2.03–1.63(m,9H),1.55–1.27(m,5H);LC-MS(m/z):503.6[M+H]+。
实施例171:2-(6-((5-氯-4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-101)(#203)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((5-氯-4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.63–9.58(m,1H),8.68(d,J=4.3Hz,1H),8.62-8.66(m,1H),8.14(d,J=5.9Hz,1H),7.67(s,1H),7.38(dd,J=8.0,4.8Hz,1H),6.11(s,1H),5.63(s,1H),4.05(s,3H),2.83(dd,J=4.8,1.7Hz,3H),2.33-2.22(m,1H),1.94-1.68(m,9H),1.52–1.27(m,5H);LC-MS(m/z):508.0[M+H]+。
实施例172:N-甲基-2-(6-((5-甲基-1H-吡唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-102)(#204)
使用类似于实施例127中化合物#156的合成方法,得到棕色粉末状固体N-甲基-2-(6-((5-甲基-1H-吡唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.57(d,J=1.9Hz,1H),8.67(dd,J=4.9,1.7Hz,1H),8.61(d,J=8.1Hz,1H),7.38(dd,J=7.9,4.8Hz,1H),7.21(s,1H),6.09(s,1H),6.01(s,1H),5.65(s,1H),2.83(d,J=4.7Hz,3H),2.34(s,3H),2.29–2.23(m,1H),1.84–1.63(m,9H),1.46-1.35(m,5H);LC-MS(m/z):446.6[M+H]+。
实施例173:2-(6-((4-氯-5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-126)(#205)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-氯-5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.61(s,1H),8.69(d,J=4.6Hz,1H),8.65(d,J=8.1Hz,1H),7.99(s,1H),7.86(s,1H),7.41(dd,J=7.9,4.8Hz,1H),7.16(s,1H),6.26(s,1H),5.52(s,1H),3.99(s,3H),2.83(d,J=4.8Hz,3H),2.33-2.26(m,1H),1.95-1.66(m,9H),1.48(m,5H);LC-MS(m/z):508.0[M+H]+。
实施例174:N-甲基-2-(6-((4-甲基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-127)(#206)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-甲基-2-(6-((4-甲基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.65–9.55(m,1H),8.70–8.62(m,2H),8.40(d,J=5.1Hz,1H),7.90(s,1H),7.43(s,1H),7.39(dd,J=7.9,4.8Hz,1H),6.75(d,J=5.1Hz,1H),5.62(s,1H),2.96(s,3H),2.83(d,J=4.8Hz,3H),2.02–1.74(m,8H),1.55–1.25(m,6H);LC-MS(m/z):458.6[M+H]+。
实施例175:2-(6-((4-环丙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-155)(#207)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体2-(6-((4-环丙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.63–9.57(m,1H),8.66(d,J=10.4Hz,2H),8.11(d,J=6.0Hz,1H),7.49(s,1H),7.38(t,J=6.6Hz,1H),6.61(d,J=5.6Hz,1H),6.37(s,1H),5.53(s,1H),5.39–5.34(m,1H),3.90–3.84(m,1H),2.83(d,J=4.8Hz,3H),2.34–2.20(m,5H),1.98–1.82(m,8H),1.54–1.41(m,6H);LC-MS(m/z):499.6[M+H]+。
实施例176:N-甲基-2-(6-((5-甲基异噁唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-156)(#208)
使用类似于实施例127中化合物#156的合成方法,得到淡绿色粉末状固体N-甲基-2-(6-((5-甲基异噁唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺。1H NMR(400MHz,氯仿-d)δ9.76(d,J=2.3Hz,1H),9.03(d,J=8.1Hz,1H),8.80(dd,J=4.8,1.7Hz,1H),7.51(dd,J=8.1,4.8Hz,1H),6.22(s,1H),5.49(s,2H),2.84(d,J=4.8Hz,3H),2.33(s,3H),2.02-1.76(m,9H),1.54-1.38(m,5H);LC-MS(m/z):447.5[M+H]+。
实施例177:2-(6-((4-乙炔基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-157)(#209)
使用类似于实施例127中化合物#156的合成方法,得到淡黄色粉末状固体2-(6-((4-乙炔基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺。LC-MS(m/z):467.2[M+H]+。
实施例178:1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-128)(#210)
步骤1:1-(2-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#211)
使用类似于实施例127中化合物#159的合成方法,制得白色粉末状固体1-(2-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮。LC-MS(m/z):357.8[M+H]+。
步骤2:1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#210)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮。1H NMR(400MHz,氯仿-d)δ9.59(s,1H),8.69(dd,J=4.8,1.8Hz,1H),8.64(dt,J=8.0,1.9Hz,1H),8.12(d,J=6.0Hz,1H),7.39(dd,J=8.0,4.8Hz,1H),7.25(s,1H),6.55(dd,J=6.0,2.3Hz,1H),6.40(s,1H),3.95(s,4H),3.93(s,3H),3.67–3.61(m,2H),3.49(t,J=5.6Hz,2H),2.15(s,3H),1.88(dt,J=17.6,5.7Hz,4H);LC-MS(m/z):445.5[M+H]+。
实施例179:1-(2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-129)(#212)
使用类似于实施例178中化合物#210的合成方法,得到白色粉末状固体1-(2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮。1H NMR(400MHz,氯仿-d)δ9.57(s,1H),8.70(s,1H),8.63(dt,J=8.2,1.9Hz,1H),8.17(d,J=5.3Hz,1H),7.41(dd,J=8.0,4.8Hz,1H),6.84–6.76(m,1H),6.65(s,1H),3.95(s,4H),3.64(t,J=5.6Hz,2H),3.48(t,J=5.6Hz,2H),2.40(s,3H),2.15(s,3H),1.87(dt,J=17.6,5.7Hz,4H);LC-MS(m/z):429.5[M+H]+。
实施例180:1-(2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-130)(#213)
使用类似于实施例178中化合物#210的合成方法,得到白色粉末状固体1-(2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮。1H NMR(400MHz,氯仿-d)δ9.60–9.57(m,1H),8.68(dd,J=4.8,1.7Hz,1H),8.63(dt,J=7.9,1.9Hz,1H),8.03(d,J=3.0Hz,1H),7.79(d,J=3.0Hz,1H),7.48(d,J=8.9Hz,1H),7.32–7.29(m,1H),7.12(dd,J=8.8,3.0Hz,1H),6.37(s,1H),3.92(s,4H),3.88(s,3H),3.63(t,J=5.6Hz,2H),3.48(t,J=5.6Hz,2H),2.14(s,3H),1.87(dt,J=17.6,5.7Hz,5H);LC-MS(m/z):445.5[M+H]+。
实施例181:2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(IRAK-200)(#214)
使用类似于实施例178中化合物#210的合成方法,得到黄色粉末状固体2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈。1H NMR(400MHz,氯仿-d)δ9.59(s,1H),8.71(d,J=4.8Hz,1H),8.61(d,J=8.0Hz,1H),8.45(d,J=5.2Hz,1H),7.91(s,1H),7.73(s,1H),7.42(dd,J=8.0,4.8Hz,1H),7.11(d,J=5.1Hz,1H),6.39(s,1H),3.95(s,4H),3.65(s,2H),3.50(d,J=5.7Hz,2H),2.15(s,3H),1.85(d,J=5.8Hz,4H).;LC-MS(m/z):440.2[M+H]+。
实施例182:1-(2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-202)(#215)
使用类似于实施例178中化合物#210的合成方法,得到白色粉末状固体1-(2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮。1H NMR(400MHz,氯仿-d)δ9.59(d,J=2.4Hz,1H),8.69(dd,J=4.8,1.7Hz,1H),8.64(dt,J=8.0,2.0Hz,1H),8.21(d,J=5.2Hz,1H),7.62(s,1H),7.38(dd,J=8.0,4.8Hz,1H),7.27(s,1H),6.80(dd,J=5.3,1.4Hz,1H),6.62(s,1H),3.94(s,4H),3.64(t,J=5.7Hz,2H),3.48(t,J=5.5Hz,2H),2.68(q,J=7.6Hz,2H),2.15(s,3H),1.87(dt,J=17.5,5.7Hz,4H),1.30(t,J=7.6Hz,3H).LC-MS(m/z):443.2[M+H]+。
实施例183:N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(IRAK-001)(#216)
步骤1:N-(3-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(IRAK-007)(#217)
使用类似于实施例127中化合物#159的合成方法,得到淡黄色粉末状固体N-(3-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.39(dd,J=2.2,0.9Hz,1H),8.70(dd,J=4.8,1.7Hz,1H),8.56(dt,J=8.0,1.9Hz,1H),7.69(d,J=7.8Hz,1H),7.53(ddd,J=8.0,4.8,0.9Hz,1H),6.94(s,1H),3.91–3.63(m,4H),1.85(s,2H),1.77(s,3H),1.71(d,J=13.3Hz,1H),1.63–1.32(m,7H),1.10–0.99(m,2H)。LC-MS(m/z):399.2[M+H]+。
步骤2:N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#216)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.44(dd,J=2.2,0.9Hz,1H),8.68(dd,J=4.7,1.7Hz,1H),8.57(dt,J=8.1,1.9Hz,1H),8.38(d,J=5.7Hz,1H),8.07–8.01(m,1H),7.70(d,J=7.8Hz,1H),7.53(ddd,J=8.0,4.8,0.9Hz,1H),6.95(dq,J=5.7,1.1Hz,1H),6.86(s,1H),3.65(s,4H),1.84(d,J=12.5Hz,2H),1.77(s,3H),1.71(d,J=13.3Hz,1H),1.66–1.33(m,8H),1.23(s,2H)。LC-MS(m/z):541.2[M+H]+。
实施例184:3-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺(IRAK-009)(#218)
使用类似于实施例129中化合物#161的合成方法,得到白色粉末状固体3-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺。1H NMR(400MHz,氯仿-d)δ9.61(dd,J=2.2,0.9Hz,1H),8.68(dd,J=4.8,1.8Hz,1H),8.65(dt,J=7.9,2.0Hz,1H),8.10(d,J=5.9Hz,1H),7.56(d,J=12.9Hz,1H),7.43(d,J=2.3Hz,1H),7.41–7.37(m,1H),6.59(s,1H),6.52(dd,J=5.9,2.3Hz,1H),3.94(s,3H),2.92–2.84(m,1H),2.09–1.88(m,6H),1.57–1.41(m,6H)。LC-MS(m/z):445.3[M+H]+。
实施例185:3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺(IRAK-010)(#219)
使用类似于实施例142中的合成方法,得到白色粉末状固体3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺。1H NMR(400MHz,氯仿-d)δ9.59(dd,J=2.2,0.9Hz,1H),8.69(dd,J=4.9,1.7Hz,1H),8.63(dt,J=8.0,1.9Hz,1H),8.29(d,J=5.7Hz,1H),7.85(q,J=1.7Hz,1H),7.57(s,1H),7.40(ddd,J=8.0,4.8,0.9Hz,1H),6.76(ddt,J=5.7,2.2,1.1Hz,1H),6.45(s,1H),2.92–2.83(m,1H),1.92(d,J=11.3Hz,6H),1.69–1.49(m,10H)。LC-MS(m/z):499.2[M+H]+。
实施例186:N-(3-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(IRAK-002)(#220)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-(3-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.38(dd,J=10.7,2.2Hz,1H),8.71(td,J=5.1,1.7Hz,1H),8.54(ddt,J=10.2,8.2,2.0Hz,1H),7.71(dd,J=8.0,2.3Hz,1H),7.54(ddd,J=12.6,7.9,4.8Hz,1H),6.92(d,J=11.7Hz,1H),6.82(s,1H),5.17(s,1H),3.72(s,4H),2.93(dt,J=14.4,7.3Hz,1H),2.87–2.82(m,1H),1.77(s,3H),1.73–1.43(m,20H)。LC-MS(m/z):514.3[M+H]+。
实施例187:N-(3-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(IRAK-003)(#221)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-(3-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.45(dd,J=2.2,0.9Hz,1H),8.66(dd,J=4.8,1.7Hz,1H),8.58(dt,J=8.0,2.0Hz,1H),7.69(d,J=7.7Hz,1H),7.52(ddd,J=8.0,4.7,0.9Hz,1H),7.25(s,1H),7.10(s,1H),3.78–3.70(m,1H),3.64(s,4H),1.83(d,J=11.4Hz,2H),1.77(s,3H),1.70(s,1H),1.66–1.41(m,6H),1.39(s,9H)。LC-MS(m/z):519.3[M+H]+。
实施例188:N-(6-(8-氨基-3-氮杂螺[5.5]十一烷-3-基)-2-(吡啶-3-基)嘧啶-4-基)-5-(叔丁基)异噻唑-3-胺(IRAK-011)(#222)
使用类似于实施例142中的合成方法,得到白色粉末状固体N-(6-(8-氨基-3-氮杂螺[5.5]十一烷-3-基)-2-(吡啶-3-基)嘧啶-4-基)-5-(叔丁基)异噻唑-3-胺。1H NMR(400MHz,氯仿-d)δ9.59–9.56(m,1H),8.67(dd,J=4.8,1.7Hz,1H),8.62(dt,J=8.0,2.0Hz,1H),7.81(s,1H),7.37(dd,J=8.0,4.8Hz,1H),7.13(s,1H),6.85(s,1H),2.94–2.86(m,1H),1.98-1.93(m,3H),1.74–1.46(m,11H)。LC-MS(m/z):477.3[M+H]+。
实施例189:8-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-131)(#223)
步骤1:8-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮
使用类似于实施例127中化合物#159的合成方法,得到白色粉末状固体8-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮。LC-MS(m/z):357.8[M+H]+。
步骤2:8-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(#223)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体8-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮。1H NMR(400MHz,氯仿-d)δ9.62–9.59(m,1H),8.68(dd,J=4.8,1.7Hz,1H),8.64(dt,J=8.0,2.0Hz,1H),8.12(d,J=5.9Hz,1H),7.42–7.35(m,2H),6.66(s,1H),6.53(dd,J=5.9,2.3Hz,1H),4.38(d,J=13.2Hz,2H),3.94(s,3H),3.42–3.31(m,4H),2.91(s,3H),2.10–1.97(m,4H),1.59-1.53(m,2H);LC-MS(m/z):445.5[M+H]+。
实施例190:2-甲基-8-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-132)(#224)
使用类似于实施例189中化合物#223的合成方法,得到白色粉末状固体2-甲基-8-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮。1H NMR(400MHz,氯仿-d)δ9.59(d,J=2.2Hz,1H),8.69(dd,J=4.8,1.7Hz,1H),8.63(dt,J=8.0,2.0Hz,1H),8.18(d,J=5.2Hz,1H),7.39(dd,J=8.0,4.8Hz,1H),7.32(s,1H),6.98(s,1H),6.77(d,J=5.2Hz,1H),4.40(d,J=13.3Hz,2H),3.41–3.32(m,4H),2.90(s,3H),2.39(s,3H),2.09–1.99(m,4H),1.59-1.54(m,2H);LC-MS(m/z):429.5[M+H]+。
实施例191:8-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(IRAK-133)(#225)
使用类似于实施例189中化合物#223的合成方法,得到白色粉末状固体8-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮。1H NMR(400MHz,氯仿-d)δ9.62–9.56(m,1H),8.69(dd,J=4.8,1.7Hz,1H),8.62(dt,J=7.9,2.0Hz,1H),8.02(d,J=3.0Hz,1H),7.59(d,J=9.0Hz,1H),7.39(dd,J=8.0,4.8Hz,1H),7.31(dd,J=9.0,3.1Hz,1H),6.67(s,1H),4.38(d,J=13.2Hz,2H),3.88(s,3H),3.42–3.29(m,4H),2.90(s,3H),2.10–1.97(m,4H),1.60–1.53(m,2H);LC-MS(m/z):445.5[M+H]+。
实施例192:2-((6-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(IRAK-201)(#226)
使用类似于实施例189中化合物#223的合成方法,得到黄色粉末状固体2-((6-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈。1HNMR(400MHz,氯仿-d)δ9.58(d,J=2.2Hz,1H),8.70(d,J=4.8Hz,1H),8.62–8.56(m,1H),8.42(d,J=5.1Hz,1H),8.07(s,1H),7.70(s,1H),7.42(dd,J=8.0,4.8Hz,1H),7.10(d,J=5.1Hz,1H),6.65(s,1H),4.38(d,J=13.3Hz,2H),3.42-3.38(m,4H),2.91(s,3H),2.09-2.02(m,4H),1.60–1.53(m,2H).;LC-MS(m/z):440.2[M+H]+。
实施例193:N-(4-甲氧基吡啶-2-基)-6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-胺(IRAK-203)(#227)
步骤1:4-氯-6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶
使用类似于实施例127中化合物#159的合成方法,得到白色粉末状固体4-氯-6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶。LC-MS(m/z):331.1[M+H]+。
步骤2:N-(4-甲氧基吡啶-2-基)-6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-胺(#227)
使用类似于实施例127中化合物#156的合成方法,得到白色粉末状固体N-(4-甲氧基吡啶-2-基)-6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-胺。1H NMR(400MHz,氯仿-d)δ9.59(s,1H),8.68(d,J=4.8Hz,1H),8.63(d,J=7.9Hz,1H),8.12(d,J=5.9Hz,1H),7.99–7.86(m,1H),7.38(dd,J=8.0,4.9Hz,1H),7.28(d,J=4.1Hz,1H),6.72(s,1H),6.53(dd,J=6.0,2.3Hz,1H),4.71(dt,J=17.0,6.4Hz,4H),3.91(s,3H),3.80(t,J=5.0Hz,4H),3.56(p,J=6.4Hz,1H),2.46(t,J=5.0Hz,4H).;LC-MS(m/z):419.2[M+H]+。
实施例194:2-((6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(IRAK-204)(#228)
使用类似于实施例193中化合物#227的合成方法,得到黄色粉末状固体2-((6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈。LC-MS(m/z):414.2[M+H]+。
实施例195:6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-205)(#229)
使用类似于实施例193中化合物#227的合成方法,得到白色粉末状固体6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺。1H NMR(400MHz,氯仿-d)δ9.59(d,J=2.2Hz,1H),8.71(dd,J=4.9,1.7Hz,1H),8.62(dt,J=7.9,2.0Hz,1H),8.30(d,J=5.7Hz,1H),7.75(s,1H),7.59(s,1H),7.41(dd,J=8.0,4.7Hz,1H),6.78(d,J=5.7Hz,1H),6.57(s,1H),4.72(dt,J=17.0,6.4Hz,4H),3.81(t,J=5.0Hz,4H),3.57(p,J=6.4Hz,1H),2.48(t,J=5.0Hz,4H);LC-MS(m/z):473.2[M+H]+。
实施例196:1-(2-(6'-((4-(三氟甲氧基)吡啶-2-基)氨基)-[3,4'-联吡啶]-2'-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-225)(#230)
步骤1:2',6'-二氯-3,4'-联吡啶(#231)
将2,6-二氯-4-碘吡啶(150.00mg,0.55mmol,1.0eq.)、3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(281.88mg,1.37mmol,2.5eq.)、PdCl2(dppf)(40.26mg,0.06mmol)和无水磷酸钾(349.80mg,1.65mmol,3.0eq.)在1,4-二噁烷(2mL)中的混合物在90℃下搅拌过夜。将反应混合物浓缩至干,并将得到的残余物通过柱色谱法(BiotageRening Flash 10g,EtOAc/n-Hep=10%~20%)纯化,得到2',6'-二氯-3,4'-联吡啶(105mg,85%产率)。LC-MS(m/z):224.0[M+H]+。
步骤2:1-(2-(6'-氯-[3,4'-联吡啶]-2'-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#232)
在室温下向2',6'-二氯-3,4'-联吡啶(100.00mg,0.44mmol,1.0eq.)和1-(2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-酮盐酸盐(98.74mg,0.48mmol,1.1eq.)在DMAC(2mL)中的搅拌溶液中逐滴加入DIPEA(223mg,1.76mmol,4.0eq),所得混合物在80℃下搅拌1小时。用饱和盐水和EtOAc处理反应混合物,分离有机相。粗物质通过柱色谱法(Biotage ReningFlash 10g,EtOAc/n-Hep=50%~100%)纯化,得到1-(2-(6'-氯-[3,4'-联吡啶]-2'-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(130mg,83%产率)。LC-MS(m/z):356.1[M+H]+。
步骤3:1-(2-(6'-((4-(三氟甲氧基)吡啶-2-基)氨基)-[3,4'-联吡啶]-2'-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#230)
向1-(2-(6'-氯-[3,4'-联吡啶]-2'-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(100.00mg,0.28mmol,1.0eq.)、4-(三氟甲氧基)吡啶-2-胺(75.00mg,0.42mmol,1.5eq.)、叔丁醇钠(40.32mg,0.42mmol,1.5eq.)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入t-BuXPhos-Pd-G3在THF中的溶液(10mM,1.4mL,0.014mmol,0.05eq.)。将所得混合物在氮气气氛下加热至90℃保持10小时。将反应溶液通过柱色谱法(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=20%)纯化,得到淡黄色固体(45mg,32%产率)。1HNMR(400MHz,氯仿-d)δ8.87(d,J=2.3Hz,1H),8.69–8.65(m,1H),8.26–8.20(m,2H),7.89(dt,J=8.1,2.1Hz,1H),7.54(s,1H),7.41(dd,J=8.0,4.6Hz,1H),6.73–6.67(m,1H),6.51(s,1H),6.04(d,J=1.2Hz,1H),3.88(s,4H),3.63(t,J=5.9Hz,2H),3.48(t,J=5.9Hz,2H),2.15(s,3H),1.89(dt,J=21.0,5.6Hz,4H);LC-MS(m/z):498.2[M+H]+。
实施例197:1-(2-(6-(吡啶-3-基)-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-199)(#233)
步骤1:4,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-2-胺(#234)
在实施例92的步骤3中作为副产物获得了4,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-2-胺。LC-MS(m/z):324.0[M+H]+。
步骤2:1-(2-(6-氯-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#235)
在室温下,向4,6-二氯-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-2-胺(72.4mg,0.22mmol,1.0eq.)在DMAC(1mL)中的搅拌溶液中逐滴加入1-(2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮盐酸盐(50.00mg,0.24mmol,1.1eq.)、DIPEA(0.20ml,1.11mmol,5.0eq)。将所得混合物在80℃下搅拌1小时。用饱和盐水和EtOAc处理反应混合物,并分离有机相。粗物质通过柱色谱法纯化,得到1-(2-(6-氯-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(50mg,49.8%产率)。LC-MS(m/z):456.1[M+H]+。
步骤3:1-(2-(6-(吡啶-3-基)-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#233)
将1-(2-(6-氯-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(25.00mg,0.05mmol,1.0eq.)、3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(25.60mg,0.125mmol,2.5eq.)、Pd(dppf)Cl2(3.65mg,0.005mmol,0.1eq)和无水磷酸钾(31.80mg,0.15mmol,3.0eq.)在1,4-二噁烷(2.0mL)中的混合物在氮气气氛下在90℃搅拌过夜。将反应混合物浓缩至干,并将得到的残余物通过柱色谱法(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化,得到淡黄色固体(12mg,48%产率)。1H NMR(400MHz,氯仿-d)δ9.17(d,J=1.6Hz,1H),8.71–8.72(m,1H),8.58(s,1H),8.30–8.33(m,2H),8.13(s,1H),7.43(dd,J=8.0,4.6Hz,1H),6.73(d,1H),6.25(s,1H),3.95(s,4H),3.64(t,J=5.9Hz,2H),3.49(t,J=5.9Hz,2H),2.15(s,3H),1.89(dt,J=21.0,5.6Hz,4H)。LC-MS(m/z):499.2[M+H]+。
实施例198:2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)异烟腈(IRAK-217)(#236)
步骤1:2-((2,6-二氯嘧啶-4-基)氨基)异烟腈(#237)
在冰水浴温度下,向2,4,6-三氯嘧啶(2.50g,13.66mmol,1.0eq.)在THF(25mL)中的搅拌溶液中加入NaHMD在THF中的溶液(2M,7.51mL,15.03mmol,1.1eq.),保持10分钟。逐滴加入2-氨基异烟腈(1.79g,15.03mmol,1.1eq.),将得到的混合物在冰水浴温度下搅拌2小时。加入饱和氯化铵溶液(50mL),混合物用EtOAc(100mL)萃取。将有机相干燥并浓缩至干。粗物质通过柱色谱法纯化,得到淡黄色固体(350mg,10%产率)。LC-MS(m/z):264.99[M+H]+.
步骤2:2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-氯嘧啶-4-基)氨基)异烟腈(#238)
在室温下,向2-((2,6-二氯嘧啶-4-基)氨基)异烟腈(120mg,0.45mmol,1.0eq.)和1-(2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮盐酸盐(110.16mg,0.54mmol,1.2eq.)在DMAC(5mL)中的搅拌溶液中逐滴加入DIPEA(0.20ml,1.11mmol,5.0eq)。将所得混合物在80℃下搅拌1小时。用饱和盐水和EtOAc处理反应混合物,并分离有机相。粗物质通过柱色谱法纯化,得到白色固体(43mg,24.06%产率)。LC-MS(m/z):497.14[M+H]+。
步骤3:2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)异烟腈(#236)
将2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-氯嘧啶-4-基)氨基)异烟腈(25.00mg,0.06mmol,1.0eq.)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(31.20mg,0.15mmol,2.5eq.)、Pd(dppf)Cl2(4.39mg,0.006mmol,0.1eq.)和无水磷酸钾(38.16mg,0.18mmol,3.0eq.)在1,4-二噁烷(2.0mL)中的混合物在氮气气氛下在90℃搅拌过夜。将反应混合物浓缩至干,并将得到的残余物通过柱色谱法(Biotage ReningFlash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化,得到淡黄色固体(5mg,18.8%产率)。1H NMR(400MHz,氯仿-d)δ8.64(s,1H),8.41(d,J=5.1Hz,1H),7.95(d,J=2.6Hz,2H),7.52(s,1H),7.13(dd,J=5.0,1.4Hz,1H),6.39(s,1H),4.03-3.93(m,7H),3.64(s,2H),3.48(d,J=5.9Hz,2H),2.15(s,3H),1.88(dt,J=22.5,5.6Hz,4H);LC-MS(m/z):443.22[M+H]+。
实施例199:(7R)-N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-012)/(#312)和(7S)-N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(IRAK-013)/(#313)
化合物(IRAK-012)/(#312)和(IRAK-013)/(#313)通过化合物(IRAK-004)(#160)的正相色谱通过以下方法获得:仪器:Shimadzu LC-20AT;柱:Daicel ChiralPakIC,250×4.6mm I.D.,5μm,工作温度为37℃;流动相:A为己烷,B为乙醇,A:B=80:20(v/v),流速1.0mL/min;波长:220nm;样品制备:将2mg溶于约1ml乙醇中,每次进样15μl。第一种化合物的保留时间为12.181分钟,第二种化合物的保留时间为13.082分钟。分别收集各部分并冻干,得到白色粉末,为化合物(IRAK-012)/(#312)和(IRAK-013)/(#313)。尚未确定绝对构型。LC-MS(m/z):527.2[M+H]+。
实施例200:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-231)(#316)
步骤1:1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#314)
在室温下向4,6-二氯-2-碘-嘧啶(2.70g,9.82mmol,1.0eq.)在THF(25mL)中的搅拌溶液中逐滴加入1-(2,7-二氮杂螺[3.5]壬烷-7-基)乙酮盐酸盐(2.01g,9.82mmol,1.0eq.)和TEA(2.73mL,19.64mmol,2.0eq.)。使混合物反应2小时并逐渐形成白色固体。过滤后,用THF和EtOAc洗涤白色固体。干燥得到目标产物。LC-MS(m/z):406.65[M+H]+。
步骤2:1-(2-(6-氯-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#315)
向1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(500.00mg,1.23mmol,1.0eq.)和2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙烷-2-醇(490.86mg,1.84mmol,1.5eq.)在二噁烷中的搅拌溶液中加入磷酸钾(521.33mg,2.46mmol,2.0eq.)和Pd(dppf)Cl2(87.72mg,0.12mmol,0.1eq.),将所得混合物在氮气气氛下加热至90℃保持16小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到标题化合物(390mg,75.7%产率)。LC-MS(m/z):418.92[M+H]+。
步骤3:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-231)(#316)
向1-(2-(6-氯-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(220.00mg,0.52mmol,1.0eq.)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入4-(三氟甲氧基)吡啶-2-胺(112.24mg,0.63mmol,1.2eq.)、叔丁醇钠(100.83mg,1.05mmol,2.0eq.)和t-BuXPhos-Pd-G3(41.70mg,0.052mmol,0.1eq.)。将所得混合物在氮气气氛下加热至90℃保持16小时。将反应溶液干燥并通过柱色谱法(BiotageRening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化,得到标题化合物。1HNMR(400MHz,氯仿-d)δ8.28(d,J=5.7Hz,1H),8.17(s,1H),8.06(s,1H),7.78(s,1H),7.60(s,1H),6.78–6.71(m,1H),6.02(s,1H),4.12(s,2H),3.88(s,4H),3.62(t,J=5.5Hz,2H),3.53–3.43(m,2H),2.14(s,3H),1.85(dt,J=18.3,5.6Hz,4H),1.22(s,6H)。LC-MS(m/z):560.78[M+H]+。
实施例201:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-249)(#317)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,氯仿-d)δ8.23(d,J=5.7Hz,1H),8.18(s,1H),8.09(s,1H),7.69(d,J=2.2Hz,1H),7.57(s,1H),6.88(s,0H),6.70(t,J=72Hz,1H),6.67(dd,J=5.7,2.2Hz,1H),6.52(s,0H),6.02(s,1H),4.12(s,2H),3.88(s,4H),3.67–3.59(m,2H),3.47(t,J=5.6Hz,2H),2.14(s,3H),1.88(t,J=5.5Hz,2H),1.83(t,J=5.7Hz,2H),1.22(s,6H).LC-MS(m/z):542.58[M+H]+。
实施例202:1-(2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-238)(#318)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,氯仿-d)δ8.27(d,J=5.7Hz,1H),8.11(s,1H),8.02(s,1H),7.81(s,1H),6.75(d,J=5.7Hz,1H),6.01(s,1H),3.97(s,3H),3.89(s,4H),3.63(t,J=5.6Hz,2H),3.47(t,J=5.6Hz,2H),2.14(s,3H),1.88(t,J=5.7Hz,2H),1.84(t,J=5.7Hz,2H)。LC-MS(m/z):502.49[M+H]+。
实施例203:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-242)(#319)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,氯仿-d)δ8.22(d,J=5.8Hz,1H),8.11(s,1H),8.02(s,1H),7.71(d,J=5.5Hz,2H),6.69(t,J=72Hz,1H),6.65(dd,J=5.8,2.2Hz,1H),5.99(s,1H),3.96(s,3H),3.87(s,4H),3.62(t,J=5.4Hz,2H),3.46(t,J=5.3Hz,2H),2.14(s,3H),1.88–1.85(m,2H),1.82(t,J=5.6Hz,2H)。LC-MS(m/z):484.9[M+H]+。
实施例204:1-(2-(2-(1-(二氟甲基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-241)(#320)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.45(s,1H),8.26(s,1H),8.10(d,J=5.9Hz,1H),7.64(s,1H),7.24(d,J=64Hz,1H),7.19(d,J=2.3Hz,1H),6.53(dd,J=5.9,2.3Hz,1H),6.33(s,1H),3.91(s,4H),3.90(s,3H),3.63(s,2H),3.48(t,J=5.6Hz,2H),2.15(s,3H),1.88(t,J=5.6Hz,2H),1.84(t,J=5.7Hz,2H)。LC-MS(m/z):484.5[M+H]+。
实施例205:1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-243)(#321)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.09(d,J=10.3Hz,2H),8.02(s,1H),7.66(s,1H),7.26(d,J=2.3Hz,1H),6.51(dd,J=5.9,2.3Hz,1H),6.24(s,1H),3.97(s,3H),3.92(s,3H),3.90(s,4H),3.63(s,2H),3.47(t,J=5.6Hz,2H),2.14(s,3H),1.88(d,J=5.7Hz,2H),1.83(t,J=5.7Hz,2H)。LC-MS(m/z):448.5[M+H]+。
实施例206:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-244)(#322)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.17(s,1H),8.13–8.06(m,2H),7.61(s,1H),7.20(s,1H),6.55–6.49(m,1H),6.27(s,1H),4.12(s,2H),3.91(s,3H),3.89(s,4H),3.62(s,2H),3.46(t,J=5.2Hz,2H),2.14(s,3H),1.87(t,J=5.2Hz,2H),1.82(t,J=5.2Hz,2H),1.22(s,6H)。LC-MS(m/z):506.61[M+H]+。
实施例207:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-甲基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-245)(#323)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,氯仿-d)δ8.17(d,J=6.0Hz,2H),8.09(s,1H),7.19(s,1H),6.76(d,J=5.1Hz,1H),6.56(s,1H),4.13(s,2H),3.91(s,4H),3.63(s,2H),3.47(t,J=5.5Hz,2H),2.37(s,3H),2.14(s,3H),1.88(t,J=5.6Hz,2H),1.84(t,J=5.7Hz,2H),1.22(s,6H)。LC-MS(m/z):490.61[M+H]+。
实施例208:1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-246)(#324)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.27(s,1H),8.20(s,1H),8.10(d,J=5.9Hz,1H),7.22(d,J=2.2Hz,1H),6.52(dd,J=5.9,2.2Hz,1H),6.28(s,1H),5.51(p,J=6.9Hz,1H),5.10(d,J=6.9Hz,4H),3.91(s,3H),3.89(s,4H),3.63(t,J=5.6Hz,2H),3.47(t,J=5.6Hz,2H),2.14(s,3H),1.85(dt,J=18.3,5.7Hz,4H)。LC-MS(m/z):490.57[M+H]+。
实施例209:1-(2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-253)(#325)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ9.09(d,J=2.3Hz,1H),8.41(dd,J=8.6,2.3Hz,1H),8.28(d,J=5.7Hz,1H),7.76(s,1H),7.51(s,1H),6.76(d,J=5.4Hz,1H),6.57(d,J=8.5Hz,1H),6.10(s,1H),4.82–4.73(m,2H),3.91(s,4H),3.63(d,J=6.1Hz,2H),3.47(t,J=5.6Hz,2H),2.15(s,3H),1.89(t,J=5.6Hz,2H),1.84(t,J=5.7Hz,2H)。LC-MS(m/z):514.73[M+H]+。
实施例210:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡咯-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-259)(#326)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.21(d,J=5.7Hz,1H),7.81(s,1H),7.43(s,1H),6.80(dd,J=2.8,1.7Hz,1H),6.71(t,J=72Hz,1H),6.66–6.61(m,2H),5.90(s,1H),3.88(s,4H),3.72(s,3H),3.62(s,2H),3.46(t,J=5.6Hz,2H),2.14(s,3H),1.88(d,J=5.7Hz,2H),1.83(t,J=5.7Hz,2H)。LC-MS(m/z):483.5[M+H]+。
实施例211:1-(2-(6-((4-(二氟甲基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-261)(#327)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.39(d,J=5.2Hz,1H),8.17(s,1H),8.08(s,1H),7.96(s,1H),7.70(s,1H),7.00(d,J=5.2Hz,1H),6.65(t,J=56Hz,1H),6.17(s,1H),4.12(s,2H),3.88(s,5H),3.62(t,J=5.4Hz,2H),3.46(t,J=5.5Hz,2H),2.14(s,3H),1.88-1.82(m,4H)。LC-MS(m/z):526.6[M+H]+。
实施例212:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-267)(#328)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.43(d,J=5.2Hz,1H),8.24(s,1H),8.17(s,1H),8.07(s,1H),7.64(s,1H),7.11(dd,J=5.2,1.4Hz,1H),6.03(s,1H),4.12(s,2H),3.89(s,4H),3.62(d,J=5.8Hz,2H),3.47(t,J=5.6Hz,2H),2.14(s,3H),1.88(t,J=5.6Hz,2H),1.84(t,J=5.6Hz,2H),1.22(s,6H)。LC-MS(m/z):544.6[M+H]+。
实施例213:1-(2-(6-((4-氟吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-268)(#329)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.24(dd,J=8.9,5.7Hz,1H),8.18(s,1H),8.06(s,1H),7.73(s,1H),7.48(dd,J=11.3,2.2Hz,1H),6.69-6.65(m,1H),6.15(s,1H),4.12(s,2H),3.88(s,4H),3.62(t,J=5.6Hz,2H),3.46(t,J=5.5Hz,2H),2.14(s,3H),1.87(t,J=5.6Hz,2H),1.82(t,J=5.7Hz,2H),1.21(s,6H)。LC-MS(m/z):494.6[M+H]+。
实施例214:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-262)(#330)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.20(d,J=5.7Hz,1H),8.12(s,1H),8.09(s,1H),7.72(s,1H),7.70(s,1H),6.70(t,J=72Hz,1H),6.65(dd,J=5.7,2.2Hz,1H),5.97(s,1H),4.29(dd,J=5.6,4.0Hz,2H),4.04(dd,J=5.5,4.0Hz,2H),3.85(s,4H),3.60(t,J=5.6Hz,2H),3.45(t,J=5.5Hz,2H),2.13(s,3H),1.86(t,J=5.6Hz,2H),1.81(t,J=5.7Hz,2H)。LC-MS(m/z):514.5[M+H]+。
实施例215:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-264)(#331)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.22(d,J=5.7Hz,1H),8.16(d,J=0.5Hz,1H),8.13(s,1H),7.71(d,J=2.1Hz,1H),7.56(s,1H),6.69(t,J=72Hz,1H),6.66(dd,J=5.7,2.2Hz,1H),5.99(s,1H),3.88(s,4H),3.85(s,2H),3.62(t,J=5.6Hz,2H),3.47(t,J=5.6Hz,2H),2.14(s,3H),1.87(t,J=5.6Hz,2H),1.83(t,J=5.7Hz,2H),1.61(s,6H)。LC-MS(m/z):542.6[M+H]+。
实施例216:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-265)(#332)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.23(d,J=5.7Hz,1H),7.59(s,1H),7.29(s,1H),6.64(dd,J=5.8,2.1Hz,1H),6.63(t,J=72Hz,1H),6.22(s,1H),3.88(s,4H),3.77(s,3H),3.62(t,J=5.7Hz,2H),3.50–3.44(m,2H),2.61(s,3H),2.55(s,3H),2.14(s,3H),1.88(d,J=5.6Hz,2H),1.84(d,J=7.5Hz,2H)。LC-MS(m/z):512.6[M+H]+。
实施例217:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-266)(#333)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.23(d,J=5.7Hz,1H),8.15(s,1H),7.68(d,J=2.2Hz,1H),7.33(s,1H),6.68(t,J=72Hz,1H),6.66(dd,J=5.7,2.1Hz,1H),5.98(s,1H),4.21(t,J=7.3Hz,2H),3.87(s,4H),3.63(t,J=5.7Hz,2H),3.48(t,J=5.5Hz,2H),3.25(t,J=7.4Hz,2H),2.69(p,J=7.4Hz,2H),2.15(s,3H),1.88(t,J=5.6Hz,2H),1.84(t,J=5.7Hz,2H)。LC-MS(m/z):510.6[M+H]+。
实施例218:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(3-乙基-1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-269)(#334)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.23(d,J=5.7Hz,1H),8.00(s,1H),7.68(d,J=2.2Hz,1H),7.26(s,1H),6.69(t,J=72Hz,1H),6.66(dd,J=5.7,2.2Hz,1H),5.94(s,1H),3.90(s,3H),3.87(s,4H),3.63(t,J=5.7Hz,2H),3.48(t,J=5.6Hz,2H),3.13(q,J=7.5Hz,2H),2.15(s,3H),1.89(t,J=5.5Hz,2H),1.84(t,J=5.7Hz,2H),1.33(t,J=7.5Hz,3H)。LC-MS(m/z):512.6[M+H]+。
实施例219:1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-甲基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-226)(#335)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.18-8.16(m,2H),8.15(s,1H),7.13(s,1H),6.76(d,J=5.2Hz,1H),6.60(s,1H),5.15(p,J=7.3Hz,1H),3.90(s,4H),3.70-3.61(m,4H),3.58-3.51(m,1H),3.47(t,J=5Hz,2H),3.26-3.19(m,1H),2.77(q,J=7.4Hz,2H),2.37(s,3H),2.14(s,3H),1.85(dt,J=18.4,5.7Hz,4H)。LC-MS(m/z):536.66[M+H]+。
实施例220:1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-乙基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-227)(#336)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,氯仿-d)δ8.20(d,J=5.2Hz,1H),8.18(s,1H),8.15(s,1H),7.44(s,1H),7.17(s,1H),6.79(dd,J=5.3,1.4Hz,1H),6.57(s,1H),5.14(p,J=7.4Hz,1H),3.90(s,4H),3.70–3.61(m,4H),3.58-3.51(m,1H),3.47(t,J=5.6Hz,2H),3.28–3.19(m,1H),2.77(q,J=7.4Hz,2H),2.67(q,J=7.6Hz,2H),2.14(s,3H),1.88(t,J=5.7Hz,2H),1.83(t,J=5.8Hz,2H)。LC-MS(m/z):550.68[M+H]+。
实施例221:1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-228)(#337)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.17(s,1H),8.15(s,1H),8.12(d,J=6.0Hz,1H),7.09(d,J=2.2Hz,1H),6.52(dd,J=5.9,2.3Hz,1H),6.34(s,1H),5.15(p,J=7.3Hz,1H),3.90(s,3H),3.88(s,3H),3.69–3.60(m,4H),3.54(dt,J=13.2,7.6Hz,1H),3.47(t,J=5.6Hz,2H),3.26-3.19(m,1H),2.77(q,J=7.3Hz,2H),2.14(s,3H),1.85(dt,J=18.4,5.7Hz,4H)。LC-MS(m/z):552.65[M+H]+。
实施例222:1-(2-(2-(1-((1,1-二氧化四氢-2H-噻喃-4-基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-229)(#338)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.28(d,J=5.7Hz,1H),8.16(s,1H),8.00(s,1H),7.80(s,1H),7.40(s,1H),6.78–6.74(m,1H),6.00(s,1H),4.10(d,J=7.2Hz,2H),3.89(s,4H),3.63(s,2H),3.47(t,J=5.2Hz,2H),3.12–3.04(m,2H),2.98(td,J=13.3,4.1Hz,2H),2.33-2.27(m,1H),2.15(s,3H),2.07-2.00(m,2H),1.98-1.94(m,2H),1.86(dt,J=18.4,5.8Hz,4H)。LC-MS(m/z):634.68[M+H]+。
实施例223:1-(2-(2-(1-(1,1-二氧化四氢-2H-噻喃-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-230)(#339)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.29(d,J=5.7Hz,1H),8.14(s,1H),7.79–7.48(m,3H),6.78(s,1H),6.05(s,1H),4.53(s,1H),3.92(s,4H),3.64(s,2H),3.48(t,J=5.7Hz,4H),3.18-3.12(m,2H),2.74–2.60(m,4H),2.15(s,3H),1.91-1.84(m,4H)。LC-MS(m/z):620.65[M+H]+。
实施例224:1-(2-(2-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-232)(#340)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.28(d,J=5.8Hz,2H),8.21(s,1H),7.79(s,1H),6.77(d,J=5.7Hz,1H),6.06(s,1H),5.52(p,J=6.9Hz,1H),5.11(d,J=6.9Hz,4H),3.90(s,4H),3.63(s,2H),3.47(d,J=5.8Hz,2H),2.15(s,3H),1.87(dt,J=18.4,5.8Hz,5H)。LC-MS(m/z):544.54[M+H]+。
实施例225:1-(2-(2-(1-(氧杂环丁烷-3-基甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-233)(#341)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.28(d,J=5.7Hz,1H),8.12(s,1H),8.04(s,1H),7.76(s,1H),6.79–6.74(m,1H),6.04(s,1H),4.89–4.83(m,2H),4.56(t,J=6.2Hz,2H),4.50(d,J=7.5Hz,2H),3.90(s,4H),3.66–3.56(m,3H),3.47(t,J=5.2Hz,2H),2.15(s,3H),1.86(dt,J=17.9,5.7Hz,4H)。LC-MS(m/z):558.57[M+H]+。
实施例226:1-(2-(2-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-234)(#342)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.27(d,J=5.7Hz,1H),8.14(s,1H),8.10(s,1H),7.83(s,1H),6.77–6.74(m,1H),6.00(s,1H),4.44-4.36(m,1H),4.17–4.12(m,2H),3.91(s,4H),3.65–3.54(m,4H),3.47(t,J=5.6Hz,2H),2.20–2.15(m,2H),2.14(s,3H),2.14–2.09(m,2H),1.88(t,J=5.6Hz,2H),1.83(t,J=5.7Hz,2H)。LC-MS(m/z):572.59[M+H]+。
实施例227:1-(2-(2-(1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-235)(#343)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.28(d,J=5.8Hz,1H),8.14(s,1H),8.03(s,1H),7.79(d,J=9.4Hz,1H),6.76(d,J=5.6Hz,1H),6.02(s,1H),4.12–3.94(m,6H),3.90(s,4H),3.63(s,2H),3.47(t,J=5.5Hz,2H),3.41-3.35(m,2H),2.27–2.19(m,2H),2.15(s,3H),1.89(t,J=5.6Hz,2H),1.83(t,J=5.5Hz,2H),1.54(d,J=13.0Hz,2H)。LC-MS(m/z):586.62[M+H]+。
实施例228:1-(2-(2-(1-(2-(甲基磺酰基)乙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-236)(#344)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.28(d,J=5.7Hz,1H),8.19(d,J=1.3Hz,2H),7.69(s,1H),6.79–6.74(m,1H),6.13(s,1H),4.67(t,J=6.0Hz,2H),3.89(s,4H),3.71(t,J=6.1Hz,2H),3.63(s,2H),3.47(t,J=5.6Hz,2H),2.56(s,3H),2.14(s,3H),1.88(t,J=5.6Hz,2H),1.83(t,J=5.7Hz,2H)。LC-MS(m/z):594.61[M+H]+。
实施例229:1-(2-(2-(1-((3,3-二氟环丁基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-237)(#345)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.27(d,J=5.7Hz,1H),8.14(s,1H),8.11(s,1H),7.78(s,1H),6.77(d,J=5.2Hz,1H),6.13(s,1H),4.28(d,J=6.56Hz,2H),3.91(s,4H),3.63(s,2H),3.48(t,J=5.3Hz,2H),2.78-2.68(m,3H),2.47-2.37(m,2H),2.15(s,3H),1.89(t,J=5.4Hz,2H),1.84(t,J=5.4Hz,2H)。LC-MS(m/z):592.58[M+H]+。
实施例230:1-(2-(2-(4-吗啉代苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-239)(#346)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.32(d,J=8.5Hz,2H),8.28(d,J=5.6Hz,1H),7.90(s,1H),6.96(d,J=9.2Hz,2H),6.75(d,J=5.7Hz,1H),6.00(s,1H),3.94–3.88(m,8H),3.63(t,J=5.7Hz,2H),3.47(t,J=5.6Hz,2H),3.29(dd,J=5.9,3.7Hz,4H),2.14(s,3H),1.86(dt,J=17.0,5.6Hz,4H)。LC-MS(m/z):583.62[M+H]+。
实施例231:1-(2-(2-(4-(甲基磺酰基)苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-240)(#347)
使用类似于实施例119中化合物#147的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.59(d,J=8.6Hz,2H),8.31(d,J=5.7Hz,1H),8.04(d,J=8.6Hz,2H),7.71(s,1H),7.47(s,1H),6.80-6.78(m,1H),6.26(s,1H),3.95(s,4H),3.65(s,2H),3.50(t,J=5.5Hz,2H),3.12(s,3H),2.15(s,3H),1.89(dt,J=17.8,5.7Hz,4H)。LC-MS(m/z):576.6[M+H]+。
实施例232:1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-247)(#349)
步骤1:1-(2-(6-氯-2-(4-甲基哌嗪-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#348)
向1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(100mg,0.24mmol,1eq)在二噁烷(2mL)中的搅拌溶液中加入1-甲基哌嗪(27.09mg,0.27mmol,1.1eq)、Pd2(dba)3(19.5mg,0.024mmol,0.1eq)、BINAP(15.3mg,0.024mmol,0.1eq)和Cs2CO3(80.12mg,0.24mmol,2.0eq)。将所得混合物在氮气气氛下加热至90℃保持5小时。将反应溶液干燥并通过柱色谱法(EA:MeOH/EA=1:10)纯化,得到标题化合物(90mg,产率96.6%)。LC-MS(m/z):378.91[M+H]+。
步骤2:1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-247)(#349)
向1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(93.00mg,0.24mmol,1.0eq.)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入4-(三氟甲氧基)吡啶-2-胺(45.71mg,0.37mmol,1.2eq.)、叔丁醇钠(35.34mg,0.37mmol,2.0eq.)和t-BuXPhos-Pd-G3(19.49mg,0.024mmol,0.1eq.)。将所得混合物在氮气气氛下加热至90℃保持16小时。将反应溶液干燥并通过反相柱色谱法(MeCN/H2O=30%)纯化,得到标题化合物,为白色固体(30mg,26.2%产率)。1H NMR(400MHz,氯仿-d)δ8.06(d,J=5.9Hz,1H),7.42(d,J=2.4Hz,1H),7.09(s,1H),6.46(dd,J=5.8,2.3Hz,1H),5.46(s,1H),3.86-3.82(m,7H),3.78(s,4H),3.60(t,J=5.6Hz,2H),3.44(t,J=5.4Hz 2H),2.47(t,J=5.1Hz,4H),2.36(s,3H),2.13(s,3H),1.84(t,J=5.2Hz2H),1.79(t,J=5.7Hz,2H)。LC-MS(m/z):466.59[M+H]+。
实施例233:1-(2-(2-((1,1-二氧化四氢-2H-噻喃-4-基)氨基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-250)(#350)
使用类似于实施例232中化合物#349的合成方法,得到标题化合物。1H NMR(400MHz,氯仿-d)δ8.48(s,1H),8.28(d,J=5.8Hz,1H),7.54–7.33(m,2H),6.79(d,J=5.2Hz,1H),4.15(s,1H),3.85(s,4H),3.62(s,2H),3.47(t,J=5.6Hz,2H),3.26-3.07(m,4H),2.47-2.31(m,4H),2.14(s,3H),1.88-1.81(m,4H)。LC-MS(m/z):569.6[M+H]+。
实施例234:1-(2-(2-((四氢-2H-吡喃-4-基)氧基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-251)(#352)
步骤1:1-(2-(6-氯-2-((四氢-2H-吡喃-4-基)氧基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#351)
向1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(80mg,0.20mmol,1.0eq)和四氢-2H-吡喃-4-醇(24.48mg,0.24mmol,1.2eq)在DMAC中的搅拌溶液中加入叔丁醇钾(44.8mg,0.4mmol,2.0eq)并在微波下将所得混合物加热至130℃保持1h。反应混合物用盐水洗涤并用乙酸乙酯萃取。将合并的有机层浓缩至干。粗物质通过柱色谱法(EA作为洗脱液)纯化,得到标题化合物。LC-MS(m/z):380.87[M+H]+。
步骤2:1-(2-(2-((四氢-2H-吡喃-4-基)氧基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-251)(#352)
向1-(2-(6-氯-2-((四氢-2H-吡喃-4-基)氧基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(40.00mg,0.10mmol,1.0eq.)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入4-(三氟甲氧基)吡啶-2-胺(20.63mg,0.12mmol,1.2eq.)、Pd2dba3(4.82mg,5.26μmol,0.05eq)、BINAP(6.56mg,10.53μmol,0.1eq)、Cs2CO3(51.46mg,157.94μmol,1.5eq)。将所得混合物在氮气气氛下加热至90℃保持3小时。将反应溶液干燥并通过柱色谱法(BiotageRening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)然后反相柱色谱法(40%MeCN/水溶液)纯化,得到标题化合物(54.9mg,78.3%产率)。1H NMR(400MHz,氯仿-d)δ8.28(d,J=5.7Hz,1H),7.54(d,J=2.0Hz,1H),7.39(s,1H),6.77(dq,J=5.8,1.6Hz,1H),5.87(s,1H),5.14(tt,J=8.8,4.2Hz,1H),4.05(dt,J=11.8,4.3Hz,2H),3.85(s,4H),3.59(ddd,J=12.0,9.7,2.8Hz,4H),3.44(t,J=5.5Hz,2H),2.13(s,5H),1.91(td,J=9.4,4.0Hz,2H),1.85(t,J=5.4Hz,2H),1.81(t,J=5.7Hz,2H)。LC-MS(m/z):523.27[M+H]+。
实施例235:1-(5,5-二氟-2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-248)(#357)
步骤1:叔丁基2-(6-氯-2-碘嘧啶-4-基)-5,5-二氟-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(#353)
在0℃下,向4,6-二氯-2-碘-嘧啶(300mg,1.09mmol,1.0eq)和叔丁基5,5-二氟-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(314.90mg,1.20mmol,1.1eq)的搅拌溶液中逐滴加入DIPEA(282.11mg,2.18mmol,2.0eq)。将所得混合物保持在0℃并搅拌3小时。混合物用盐水洗涤并用乙酸乙酯萃取。将合并的有机层浓缩至干。粗产物通过快速柱色谱法(EA/庚烷=30%)纯化,得到标题化合物(230mg,42.09%产率)。LC-MS(m/z):500.71[M+H]+。
步骤2:叔丁基2-(6-氯-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-5,5-二氟-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(#354)
向叔丁基-5,5-二氟-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(80mg,0.16mmol,1.0eq)在二噁烷中的溶液中加入1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑(66.49mg,0.32mmol,2.0eq)、Pd(dppf)Cl2(11.70mg,0.016mmol,0,1)和K3PO4(67.74mg,15.98mmil,0.1eq)。将所得混合物加热至90℃并搅拌5小时。将反应浓缩至干并用快速柱色谱法(EA/庚烷=50%)纯化,得到标题化合物(65mg,89.43%产率)。LC-MS(m/z):454.91[M+H]+。
步骤3:叔丁基5,5-二氟-2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(#355)
向叔丁基2-[6-氯-2-(1-甲基吡唑-4-基)嘧啶-4-基]-5,5-二氟-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(40mg,0.09mmol,1.0eq)和4-甲氧基吡啶-2-胺(16.37mg,0.13mmol,1.5eq)在二噁烷(2mL)中的搅拌溶液中加入tBuXantPhos Pd G3(6.98mg,8.79μmol,0.1eq)和叔丁醇钠(12.66mg,0.13mmol,2.0eq)。将所得混合物加热至90℃并搅拌16小时。将混合物浓缩至干。粗产物用柱色谱法(EA:MeOH/EA=10%)纯化,得到标题化合物(47.71mg,67.07%产率)。LC-MS(m/z):542.59[M+H]+。
步骤4:6-(5,5-二氟-2,7-二氮杂螺[3.5]壬烷-2-基)-N-(4-甲氧基吡啶-2-基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺(#356)
在0℃下,向叔丁基5,5-二氟-2-[6-[(4-甲氧基-2-吡啶基)氨基]-2-(1-甲基吡唑-4-基)嘧啶-4-基]-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(32mg,58.98μmol,1.0eq)在乙酸乙酯(2mL)中的搅拌溶液中逐滴加入HCl的EA溶液(4M,147.25μL,10eq)。将反应温度升至25℃并将混合物搅拌12小时。将混合物浓缩至干,得到粗产物,为白色固体,其可直接用于下一步骤。LC-MS(m/z):442.47[M+H]+。
步骤5:1-(5,5-二氟-2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-248)(#357)
向乙酸(5.29mg,88.14μmol,1.5eq)在DCM(5mL)中的搅拌溶液中分别加入DIPEA(22.78mg,176.29μmol,3.0eq)和HATU(33.51mg,88.14μmol,1.5eq)。将所得混合物在25℃下搅拌30分钟。然后是6-(5,5-二氟-2,7-二氮杂螺[3.5]壬烷-2-基)-N-(4-甲氧基-2-吡啶基)-2-(1-甲基吡唑-4-基)嘧啶-4-胺(26mg,58.76μmol,1.0eq)。将混合物再搅拌2小时。将混合物浓缩至干并通过柱色谱法纯化,得到标题化合物(18.5mg,64.98%产率)。1H NMR(400MHz,氯仿-d)δ8.08(s,1H),8.06(d,J=5.2Hz,2H),7.25(s,1H),6.55(d,J=6.0Hz,1H),6.22(s,1H),4.36–4.26(m,2H),3.99(s,3H),3.92(s,3H),3.88(d,J=8.8Hz,2H),3.67(t,J=10.4Hz,2H),2.21–2.13(m,5H),2.08(T,J=5.2Hz,2H)。LC-MS(m/z):484.51[M+H]+。
实施例236:1-(2-(2-(1-(2-氨基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-254)(#362)
步骤1:2-甲基-2-硝基丙基三氟甲磺酸酯(#358)
在冰浴中,向2-甲基-2-硝基-丙烷-1-醇(1g,8.39mmol,1.0eq)和TEA(1.27g,12.59mmol,1.5eq)在DCM(10mL)中的搅拌溶液中逐滴加入三氟甲磺酸酐(2.84g,10.07mmol,1.2eq)。将反应在25℃下搅拌3小时。混合物用盐水洗涤并用DCM萃取。将合并的有机层浓缩至干。粗产物通过快速柱色谱法(EA/庚烷=20%)纯化,得到标题化合物,为黄色油状物(1.9g,90.10%产率)。LC-MS(m/z):251.2[M+H]+。
步骤2:1-(2-甲基-2-硝基丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(#359)
在0℃下,向4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(200mg,1.03mmol,1.0eq)在THF(5mL)中的搅拌溶液中加入NaH(29.68mg,1.24mmol,1.2eq)。将所得混合物搅拌10分钟,然后加入2-甲基-2-硝基丙基三氟甲磺酸酯(310.68mg,1.24mmol,1.2eq)。将反应在25℃下再搅拌5小时。用水淬灭,用EA萃取。将有机层浓缩至干。粗产物通过快速柱色谱法(EA/庚烷=10%~30%)纯化,得到标题化合物,为白色固体(120mg,39.45%产率)。LC-MS(m/z):295.2[M+H]+。
步骤3:1-(2-(6-氯-2-(1-(2-甲基-2-硝基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#360)
向1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(70.00mg,0.17mmol,1.0eq.)和1-(2-甲基-2-硝基丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(76.39mg,0.26mmol,1.5eq.)在二噁烷中的搅拌溶液中加入磷酸钾(73.16mg,0.34mmol,2.0eq.)和Pd(dppf)Cl2(12.63mg,0.02mmol,0.1eq.),并将所得混合物在氮气气氛下加热至90℃保持16小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到标题化合物(77.12mg,77.80%产率)。LC-MS(m/z):447.92[M+H]+。
步骤4:1-(2-(2-(1-(2-甲基-2-硝基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-252)(#361)
向1-(2-(6-氯-2-(1-(2-甲基-2-硝基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(60.00mg,0.13mmol,1.0eq)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入4-(三氟甲氧基)吡啶-2-胺(28.69mg,0.16mmol,1.2eq)、Pd2dba3(6.15mg,6.71μmol,0.05eq)、BINAP(8.36mg,13.42μmol,0.1eq)、Cs2CO3(87.48mg,268.50μmol,2.0eq)。将所得混合物在氮气气氛下加热至90℃保持5小时。将反应溶液干燥并通过柱色谱法(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)然后反相柱色谱法(50%MeCN水溶液)纯化,得到标题化合物(30mg,38.0%产率)。1H NMR(400MHz,氯仿-d)δ8.27(d,J=5.7Hz,1H),8.12(s,1H),7.99(s,1H),7.73(s,1H),7.63(s,1H),6.75(d,J=5.6Hz,1H),6.04(s,1H),4.68(s,2H),3.87(s,4H),3.63(s,2H),3.47(t,J=5.4Hz,2H),2.14(s,3H),1.88(d,J=4.9Hz,2H),1.84(d,J=5.6Hz,2H),1.66(s,6H)。LC-MS(m/z):590.37[M+H]+。
步骤5:1-(2-(2-(1-(2-氨基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-254)(#362)
向1-[2-[2-[1-(2-甲基-2-硝基-丙基)吡唑-4-基]-6-[[4-(三氟甲氧基)-2-吡啶基]氨基]嘧啶-4-基]-2-氮杂螺[3.5]壬烷-7-基]乙酮(30mg,50.97μmol,1.0eq)在CH3OH(5mL)中的搅拌溶液中加入Raney Ni(1g)。将所得混合物在H2气氛下搅拌2小时。过滤混合物并浓缩至干。粗产物通过反相色谱法(MeCN/水=40%)纯化,得到标题化合物,为白色固体(5mg,17.56%)。1H NMR(400MHz,氯仿-d)δ8.25(d,J=5.7Hz,1H),8.13(s,1H),8.06(s,1H),7.81(s,1H),7.43(s,1H),7.26(s,3H),6.73(d,J=5.5Hz,1H),5.98(s,1H),4.65(s,2H),4.05(s,2H),3.87(s,4H),3.74(s,2H),3.61(s,2H),3.46(d,J=5.6Hz,2H),2.12(s,3H),1.83(dd,J=13.4,8.1Hz,4H),1.17(s,6H)。LC-MS(m/z):560.11[M+H]+。
实施例237:2-甲基-1-(4-(4-(7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)丙烷-2-醇(IRAK-255)(#365)
步骤1:1-(4-(4,6-二氯嘧啶-2-基)-1H-吡唑-1-基)-2-甲基丙烷-2-醇(#363)
向4,6-二氯-2-碘嘧啶(0.10g,0.36mmol,1.0eq.)和2-甲基-1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑-1-基]丙烷-2-醇(145.24mg,0.54mmol,1.5eq.)在二噁烷中的搅拌溶液中加入磷酸钾(154.25mg,0.73mmol,2.0eq.)和Pd(dppf)Cl2(26.63mg,36.38μmol,0.1eq.),并将所得混合物在氮气气氛下加热至90℃保持2小时。将反应混合物浓缩至干。粗物质通过柱色谱法(EA)纯化,得到标题化合物(60.00mg,57.4%产率)。LC-MS(m/z):287.14[M+H]+。
步骤2:1-(4-(4-氯-6-(7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-2-基)-1H-吡唑-1-基)-2-甲基丙烷-2-醇(#364)
在冰浴下,向1-(4-(4,6-二氯嘧啶-2-基)-1H-吡唑-1-基)-2-甲基丙烷-2-醇(40.00mg,0.14mmol,1.0eq)和7-甲基-2,7-二氮杂螺[3.5]壬烷盐酸盐(24.62mg,0.14mmol,1.0eq)在THF(5mL)中的搅拌溶液中逐滴加入TEA(42.42mg,0.42mmol,3.0eq)。将所得混合物在室温下搅拌3小时。过程中形成白色固体。过滤并用EA洗涤,收集残余物并鉴定为标题化合物(50mg,91.82%产率)。LC-MS(m/z):390.92[M+H]+。
步骤3:2-甲基-1-(4-(4-(7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)丙烷-2-醇(IRAK-255)(#365)
向1-(4-(4-氯-6-(7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-2-基)-1H-吡唑-1-基)-2-甲基乙烷-2-醇(40.00mg,0.10mmol,1.0eq)在1,4-二噁烷(3.0mL)中的搅拌溶液中加入4-(三氟甲氧基)吡啶-2-胺(21.87mg,0.12mmol,1.2eq)、Pd2dba3(4.69mg,5.12μmol,0.05eq)、BINAP(6.37mg,10.23μmol,0.1eq)、Cs2CO3(66.68mg,0.20mmol,2.0eq)。将所得混合物在氮气气氛下加热至90℃保持5小时。将反应溶液干燥并通过反相柱色谱法(50%MeCN/水溶液)纯化,得到标题化合物(20mg,37.6%产率)。1H NMR(400MHz,氯仿-d)δ8.27(d,J=5.7Hz,1H),8.17(s,1H),8.06(s,1H),7.82(d,J=1.7Hz,1H),7.41(s,1H),6.75-6.73(m,1H),5.95(s,1H),4.12(s,2H),3.82(s,4H),2.40(s,4H),2.30(s,3H),1.89(t,J=5.4Hz,4H),1.23(s,6H)。LC-MS(m/z):532.57[M+H]+。
实施例238:环丙基(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)甲酮(IRAK-263)(#370)
步骤1:叔丁基7-(环丙烷羰基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸酯(#366)
向环丙烷羧酸(128.95mg,1.50mmol,1.5eq)在DCM(10mL)中的搅拌溶液中分别加入DIPEA(258.12mg,2.00mmol,2.0eq)和HATU(569.55mg,1.50mmol,1.5eq)。搅拌30分钟。然后将叔丁基2,7-二氮杂螺[3.5]壬烷-2-羧酸酯(226mg,1.00mmol,1.0eq)加入混合物中并在25℃下搅拌16小时。将该溶液用水洗涤并用乙酸乙酯萃取。将合并的有机层浓缩至干。粗产物通过色谱柱法(EA/庚烷=30%)纯化,得到标题化合物,为透明蜡(280mg,95.24%)。LC-MS(m/z):294.4[M+H]+。
步骤2:环丙基(2,7-二氮杂螺[3.5]壬烷-7-基)甲酮(#367)
在冰浴下,向叔丁基7-(环丙烷羰基)-2,7-二氮杂螺[3.5]壬烷-2-羧酸酯(280mg,0.95mmol,1.0eq)在CH3OH(5mL)中的搅拌溶液中逐滴加入HCl的CH3OH溶液(4M,2.3mL,10.0eq)。升至室温,将混合物搅拌5小时。混合物用饱和NaHCO3水溶液中和并用乙酸乙酯萃取。将有机层浓缩至干。粗产物不经进一步纯化直接用于下一步骤(160mg,86.59%产率)。
步骤3:(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)(环丙基)甲酮(#368)
在冰浴下,向4,6-二氯-2-碘-嘧啶(237.00mg,0.86mmol,1.0eq)和环丙基(2,7-二氮杂螺[3.5]壬烷-7-基)甲酮(167.50mg,0.86mmol,1.0eq)在THF(5mL)中的搅拌溶液中逐滴加入TEA(261.74mg,2.59mmol,3.0eq)。将所得混合物在0℃下搅拌3小时。反应混合物用盐水洗涤并用乙酸乙酯萃取。将有机层浓缩至干。粗产物通过快速柱色谱法(EA/庚烷=90%)纯化,得到标题化合物,为黄色油状物(167mg,44.76%产率)。LC-MS(m/z):432.69[M+H]+。
步骤4:(2-(6-氯-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)(环丙基)甲酮(#369)
向(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)(环丙基)甲酮(50.00mg,0.11mmol,1.0eq)和1-甲基-4-(4,4,5,5-四甲基-1,3-二氧戊环-2-基)吡唑(29.16mg,0.14mmol,1.2eq.)在二噁烷中的搅拌溶液中加入磷酸钾(49.00mg,0.23mmol,2.0eq.)和Pd(ppf)Cl2(8.46mg,0.01mmol,0.1eq.),并将所得混合物在氮气气氛下加热至90℃保持16小时。将反应混合物浓缩至干。粗物质通过柱色谱法(MeOH/EA=10%)纯化,得到标题化合物(22.00mg,49.21%产率)。LC-MS(m/z):386.9[M+H]+。
步骤5:环丙基(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)甲酮(IRAK-263)(#370)
向(2-(6-氯-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)(环丙基)甲酮(22.00mg,0.06mmol,1.0eq)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入4-(二氟甲氧基)吡啶-2-胺(10.93mg,0.06mmol,1.2eq)、Pd2dba3(2.59mg,2.84μmol,0.05eq)、BINAP(3.54mg,5.69μmol,0.1eq)、Cs2CO3(37.06mg,113.73μmol,2.0eq)。将所得混合物在氮气气氛下加热至90℃保持16小时。将反应溶液干燥并通过柱色谱法(BiotageRening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)然后反相柱色谱法(40%MeCN/水溶液)纯化,得到标题化合物(11mg,37.89%产率)。1H NMR(400MHz,氯仿-d)δ8.23(d,J=5.7Hz,1H),8.12(s,1H),8.03(s,1H),7.73(d,J=2.1Hz,1H),7.44(s,1H),6.70(t,J=72Hz,1H),6.66(dd,J=5.7,2.2Hz,1H),5.98(s,1H),3.97(s,3H),3.89(s,4H),3.68(s,4H),1.88(d,J=26.3Hz,4H),1.81–1.76(m,1H),1.01(m,2H),0.82–0.77(m,2H)。LC-MS(m/z):510.6[M+H]+。
实施例239:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(四氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-257)(#373)
步骤1:1-(2-(6-氯-2-(3,6-二氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#371)
向1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(60.00mg,0.15mmol,1.0eq.)和2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷(31.00mg,0.15mmol,1.0eq.)在二噁烷中的搅拌溶液中加入磷酸钾(62.56mg,0.30mmol,2.0eq.)和Pd(dppf)Cl2(10.80mg,14.75μmol,0.1eq.),并在氮气气氛下将所得混合物加热至90℃保持16小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到标题化合物(53.54mg,85.9%产率)。步骤2:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(3,6-二氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-256)(#372)
向1-(2-(6-氯-2-(3,6-二氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(46.00mg,0.13mmol,1.0eq.)在1,4-二噁烷(1.0mL)中的搅拌溶液中加入4-(二氟甲氧基)吡啶-2-胺(20.03mg,0.13mmol,1.0eq.)、Pd2dba3(5.94mg,6.50μmol,0.05eq)、BINAP(8.09mg,13.00μmol,0.1eq)、Cs2CO3(63.38mg,0.20μmol,1.5eq)。将所得混合物在氮气气氛下加热至90℃保持16小时。将反应溶液干燥并通过柱色谱法(BiotageRening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)然后反相柱色谱法(40%MeCN水溶液)纯化,得到标题化合物(25mg,40.5%产率)。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.23(d,J=5.7Hz,1H),7.79(d,J=2.2Hz,1H),7.42(t,J=72Hz,1H),7.04(s,1H),6.74(dd,J=5.7,2.3Hz,1H),6.34(s,1H),4.27(d,J=3.1Hz,2H),3.80-3.75(m,6H),3.47–3.39(m,4H),2.51(t,J=1.9Hz,2H),2.00(s,3H),1.76(t,J=5.4Hz,2H),1.66(t,J=5.8Hz,2H)。LC-MS(m/z):486.5[M+H]+。步骤3:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(四氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-257)(#373)
向1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(3,6-二氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(30mg,61.66μmol,1.0eq.)在CH3OH(5mL)中的搅拌溶液中加入Pd/C(1g)。将所得混合物在H2气氛下搅拌4小时。过滤混合物并浓缩至干。粗产物通过反相色谱法(MeCN/水=40%)纯化,得到标题化合物,为白色固体(15mg,30.7%)。1H NMR(400MHz,氯仿-d)δ8.21(d,J=5.7Hz,1H),7.62(d,J=2.1Hz,1H),7.41(s,1H),6.68(t,J=72Hz,1H),6.65(dd,J=5.7,2.2Hz,1H),6.05(s,1H),4.12-4.06(m,2H),3.84(s,4H),3.61(t,J=5.7Hz,2H),3.55(td,J=11.4,2.9Hz,2H),3.46(t,J=5.6Hz,2H),2.88-2.80(m,1H),2.14(s,3H),2.05–1.93(m,4H),1.87(t,J=5.7Hz,2H),1.83(d,J=5.7Hz,2H)。LC-MS(m/z):488.5[M+H]+。
实施例240:4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)四氢-2H-噻喃1,1-二氧化物(IRAK-260)(#377)
步骤1:4,6-二氯-2-(1-甲基-1H-吡唑-4-基)嘧啶(#374)
向4,6-二氯-2-碘嘧啶(0.50g,1.82mmol,1.0eq.)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(567.71mg,2.73mmol,1.5eq.)在二噁烷中的搅拌溶液中加入磷酸钾(771.26mg,3.64mmol,2.0eq.)和Pd(dppf)Cl2(133.15mg,181.90μmol,0.1eq.),并将所得混合物在氮气气氛下加热至90℃保持16小时。将反应混合物浓缩至干。粗物质通过柱色谱法(EA/庚烷=30~50%)纯化,得到标题化合物(260.00mg,62.4%产率)。LC-MS(m/z):229.06[M+H]+。步骤2:6-氯-N-(4-(二氟甲氧基)吡啶-2-基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺(#375)
在冰水浴温度下,向4,6-二氯-2-(1-甲基-1H-吡唑-4-基)嘧啶(200mg,0.87mmol,1.0eq.)和4-(二氟甲氧基)吡啶-2-胺(167.76mg,1.05mmol,1.2eq.)在THF(20mL)中的搅拌溶液中加入NaHMD在THF中的溶液(2M,0.65mL,1.31mmoL,1.5eq.),并将所得混合物在室温下搅拌3小时。反应混合物用冷水(30mL)淬灭,并用EtOAc萃取。有机相用盐水洗涤,经Na2SO4干燥,并浓缩至干。粗物质通过柱色谱法(Biotage Rening Flash 24g,EtOAc/n-Hep=50~510%)纯化,得到淡黄色固体(140.00mg,45.5%产率)。LC-MS(m/z):352.7[M+H]+。
步骤3:4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-3,6-二氢-2H-噻喃1,1-二氧化物(IRAK-258)(#376)
向6-氯-N-(4-(二氟甲氧基)吡啶-2-基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-胺(40mg,0.11mmol,1.0eq.)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢-2H-噻喃1,1-二氧化物(43.91mg,0.17mmol,1.5eq.)在二噁烷中的搅拌溶液中加入磷酸钾(48.08mg,0.22mmol,2.0eq.)和Pd(dppf)Cl2(8.30mg,11.34μmol,0.1eq.),并将所得混合物在氮气气氛下加热至90℃保持16小时。将反应混合物浓缩至干。粗物质通过柱色谱法(MeOH/EA=10%)然后反相色谱法(MeCN/H2O=40%)纯化,得到标题化合物(300.00mg,66.9%产率)。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.36–8.28(m,2H),8.06–8.00(m,2H),7.52(t,J=72Hz,1H),7.36(s,1H),6.88-6.83(m,1H),4.03(s,2H),3.92(s,3H),3.44–3.39(m,2H),3.08(t,J=6.4Hz,2H)。LC-MS(m/z):448.4[M+H]+。
步骤4:4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)四氢-2H-噻喃1,1-二氧化物(IRAK-260)(#377)
向4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-3,6-二氢-2H-噻喃1,1-二氧化物(15mg,33.45μmol,1.0eq)在CH3OH(5mL)中的搅拌溶液中加入Pd/C(1g)。将所得混合物在H2气氛下搅拌4小时。过滤混合物并浓缩至干。粗产物通过反相色谱法(MeCN/水=35%)纯化,得到标题化合物,为白色固体(8.00mg,53.1%)。1HNMR(400MHz,DMSO-d6)δ10.31(s,1H),8.31(d,J=5.7Hz,1H),8.26(s,1H),7.96(d,J=4.5Hz,2H),7.50(t,J=72Hz,1H),7.17(s,1H),6.85(dd,J=5.7,2.3Hz,1H),3.91(s,3H),3.20–3.12(m,2H),2.96(p,J=7.8,7.3Hz,1H),2.24-2.18(m,4H)。LC-MS(m/z):450.5[M+H]+。
实施例241:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1,3-二甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-270)(#378)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,DMSO-d6)δ9.77(s,1H),8.26(d,J=5.6Hz,1H),8.06(s,1H),7.64(s,1H),7.45(s,1H),6.78(s,1H),6.31(s,1H),3.84–3.75(m,7H),3.48–3.39(m,4H),3.30(s,3H),2.01(s,3H),1.79(s,2H),1.69(s,2H),LC-MS(m/z):499.2[M+H]+。
实施例242:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-甲氧基-2-甲基丙烷-2-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-271)(#379)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,DMSO-d6)δ9.81(s,1H),8.24(d,J=5.7Hz,1H),8.13(s,1H),7.98–7.89(m,1H),7.84(s,1H),6.75(dd,J=5.7,2.3Hz,1H),6.58(s,1H),6.24(s,1H),3.79(s,4H),3.58(s,2H),3.43(d,J=13.1Hz,4H),3.19(s,3H),2.01(s,3H),1.79(d,J=5.6Hz,2H),1.69(d,J=5.7Hz,2H),1.55(s,6H),LC-MS(m/z):558.3[M+H]+。
实施例243:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(2,3-二甲基-2H-吲唑-5-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-272)(#380)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,DMSO-d6)δ9.93(s,1H),8.65(s,1H),8.31–8.20(m,2H),7.89(s,1H),7.57–7.48(m,2H),7.35(m,1H),6.79(dd,J=5.7,2.3Hz,1H),6.42(s,1H),4.08(s,3H),3.86(s,4H),3.53–3.41(m,4H),2.67(s,3H),2.02(s,3H),1.81(d,J=6.3Hz,2H),1.75–1.65(m,2H),LC-MS(m/z):549.3[M+H]+。
实施例244:1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-273)(#381)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.24(d,J=5.7Hz,1H),8.16(s,1H),7.89(d,J=0.7Hz,1H),7.84(s,1H),7.49(s,1H),6.75(dd,J=5.7,2.3Hz,1H),6.30(s,1H),3.84–3.75(m,5H),3.48–3.39(m,4H),2.01(s,3H),1.78(s,2H),1.69(s,2H),1.09(q,J=4.2Hz,2H),1.03–0.97(m,2H),LC-MS(m/z):511.2[M+H]+。
实施例245:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-异丙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-274)(#382)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,DMSO-d6)δ9.82(s,1H),8.24(d,J=5.5Hz,1H),8.16(s,1H),7.93(s,1H),7.87(s,1H),6.76(s,1H),6.30(s,1H),4.56(s,2H),3.78(s,4H),3.43(s,4H),2.02(s,3H),1.78(s,2H),1.69(s,2H),1.46(d,J=6.7Hz,6H),LC-MS(m/z):513.3[M+H]+。
实施例246:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-乙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-275)(#383)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.24(d,J=5.7Hz,1H),8.15(s,1H),7.92(s,1H),7.48(s,1H),7.82(s,1H),6.75(dd,J=5.7,2.3Hz,1H),6.32(s,1H),4.19(q,J=7.2Hz,2H),3.78(s,4H),3.43(d,J=13.9Hz,4H),2.01(s,3H),1.78(s,2H),1.69(s,2H),1.41(t,J=7.3Hz,3H),LC-MS(m/z):499.2[M+H]+。
实施例247:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(二氟甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-277)(#384)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.59(s,1H),8.25(d,J=5.7Hz,1H),8.21(s,1H),7.89(d,J=5.1Hz,1H),7.74(t,J=3.1Hz,1H),7.50(d,J=9.3Hz,1H),6.77(dd,J=5.7,2.3Hz,1H),6.45(s,1H),3.81(s,4H),3.48–3.39(m,4H),2.02(s,3H),1.79(s,2H),1.69(s,2H),LC-MS(m/z):521.2[M+H]+。
实施例248:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-278)(#385)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.32(s,1H),8.26(d,J=5.8Hz,1H),8.04(s,1H),7.69(s,1H),7.46(s,1H),6.77(dd,J=5.7,2.3Hz,1H),6.43(s,1H),5.23(q,J=9.0Hz,2H),3.80(s,4H),3.49–3.39(m,4H),2.01(s,3H),1.79(s,2H),1.69(s,2H),LC-MS(m/z):553.2[M+H]+。
实施例249:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-279)(#386)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR 1HNMR(400MHz,DMSO-d6)δ9.80(s,1H),8.24(d,J=5.8Hz,1H),8.17(s,1H),7.94(s,1H),7.82(s,1H),7.38(s,2H),6.75(dd,J=5.7,2.3Hz,1H),6.32(s,1H),4.23(m,2H),3.78(s,4H),3.41(d,J=7.1Hz,4H),3.30(s,3H),2.76(m,2H),2.05(s,2H),2.01(s,3H),1.78(s,2H),1.67(d,J=10.6Hz,2H),LC-MS(m/z):568.3[M+H]+。
实施例250:2-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)乙酰胺(IRAK-280)(#387)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ8.30(d,J=5.8Hz,1H),8.22(s,1H),7.97(s,1H),7.60(s,1H),7.47(s,1H),7.29(d,J=4.1Hz,1H),6.81(d,J=5.7Hz,1H),6.37(s,1H),4.85(s,2H),3.82(m,4H),3.48-3.42(m,6H),2.01(s,3H),1.79(s,2H),1.69(s,2H),LC-MS(m/z):528.2[M+H]+。
实施例251:1-(2-(2-(1-(2,2-二氟乙基)-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-281)(#388)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.28–8.21(m,2H),7.99(s,1H),7.73(s,1H),7.46(s,1H),6.76(dd,J=5.7,2.3Hz,1H),6.41(d,J=3.8Hz,2H),4.71(td,J=15.1,3.7Hz,2H),3.79(s,4H),3.42(dd,J=13.5,7.2Hz,4H),2.01(s,3H),1.78(d,J=6.1Hz,2H),1.70(d,J=5.6Hz,2H),LC-MS(m/z):535.2[M+H]+。
实施例252:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(氟甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-282)(#389)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.50(s,1H),8.25(d,J=5.7Hz,1H),8.11(s,1H),7.89(d,J=5.8Hz,1H),7.71(s,1H),7.48(d,J=17.2Hz,1H),6.77-6.75(m,1H),6.46(d,J=2.9Hz,1H),6.15(d,J=2.9Hz,1H),3.80(s,4H),3.48–3.39(m,4H),2.01(s,3H),1.79(s,2H),1.69(s,2H),LC-MS(m/z):503.2[M+H]+。
实施例253:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(哌啶-4-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-283)(#392)
步骤1:叔丁基4-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-氯嘧啶-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(#390)
向1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(200.00mg,0.49mmol,1.0eq.)和叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)哌啶-1-羧酸酯(185.56mg,0.49mmol,1.0eq.)在二噁烷(9.0mL)和H2O(3.0mL)中的搅拌溶液中加入K2CO3(139.95mg,0.98mmol,2.0eq.)和Pd(dppf)Cl2(40.15mg,0.049mmol,0.1eq.),并将所得混合物在氮气气氛下加热至85℃保持8小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到标题化合物(110mg,42.2%产率)。LC-MS(m/z):531.1[M+H]+。
步骤2:叔丁基4-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(#391)
向叔丁基4-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-氯嘧啶-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(110.00mg,0.20mmol,1.0eq.)在1,4-二噁烷(6.0mL)中的搅拌溶液中加入4-(二氟甲氧基)吡啶-2-胺(50.0mg,0.31mmol,1.5eq.)、Cs2CO3(146.5mg,0.41mmol,2.0eq.)、Xant-Phos(12.0mg,0.02mmol,0.1eq.)和Pd2(dba)3(19.0mg,0.02mmol,0.1eq.)。将所得混合物在氮气气氛下加热至95℃保持8小时。将反应溶液干燥,并通过柱色谱法(Biotage Rening Flash 10g,DCM=100%~甲醇/DCM=5%)纯化,得到标题化合物(120mg,88.5%产率),LC-MS(m/z):654.7[M+H]+。
步骤3:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(哌啶-4-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-283)(#392)
在叔丁基4-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(120.0mg,0.18mmol,1.0eq.)在MeOH(5.0mL)中的搅拌溶液中加入4M HCl/二噁烷(5.0mL)。将所得混合物在室温下搅拌3小时。将反应混合物浓缩至干并用饱和碳酸钾溶液中和。粗物质通过柱色谱法纯化,得到标题化合物(80.9mg,79.59%产率)。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.78(s,1H),8.24(d,J=5.7Hz,1H),8.16(s,1H),7.98(s,1H),7.79(s,1H),7.47(s,1H),6.76(dd,J=5.7,2.3Hz,1H),6.36(s,1H),4.62–4.51(m,1H),3.78(s,4H),3.46–3.38(m,6H),3.13–3.03(m,2H),2.28–2.09(m,4H),2.02(s,3H),1.79(d,J=6.0Hz,2H),1.69(s,2H),LC-MS(m/z):554.3[M+H]+。
实施例254:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-(甲基磺酰基)乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-284)(#393)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.29–8.21(m,2H),7.98(d,J=0.7Hz,1H),7.74(s,1H),7.46(s,1H),6.76(dd,J=5.7,2.3Hz,1H),6.40(s,1H),4.62(t,J=6.7Hz,2H),3.81–3.70(m,6H),3.42(dd,J=12.8,6.7Hz,4H),2.90(s,3H),2.01(s,3H),1.78(s,2H),1.69(s,2H),LC-MS(m/z):577.2[M+H]+。
实施例255:1-(2-(2-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-285)(#394)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.94(s,1H),8.31(s,1H),8.25(d,J=5.7Hz,1H),8.12(s,1H),7.80(d,J=2.2Hz,1H),7.48(s,1H),6.77(dd,J=5.7,2.3Hz,1H),6.36(s,1H),5.48(p,J=7.6Hz,1H),4.42–4.29(m,4H),3.78(s,4H),3.43(d,J=16.8Hz,4H),2.02(s,3H),1.78(t,J=5.6Hz,2H),1.68(d,J=6.0Hz,2H),LC-MS(m/z):525.2[M+H]。
实施例256:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-286)(#395)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),9.79(s,2H),8.86(d,J=7.6Hz,1H),8.28(d,J=4.3Hz,1H),8.12(s,1H),7.77(s,1H),7.50(s,1H),7.20(s,1H),6.78(s,1H),6.38(s,1H),3.86(s,4H),3.45(s,4H),2.03(s,3H),1.82(s,2H),1.73(s,2H),LC-MS(m/z):521.5[M+H]+。
实施例257:1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-(哒嗪-3-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-287)(#396)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.80(dd,J=4.6,1.4Hz,1H),8.21(s,1H),8.12(dd,J=9.1,1.4Hz,1H),7.92(d,J=0.7Hz,1H),7.60(dd,J=9.1,4.6Hz,1H),6.49(s,1H),3.88–3.74(m,5H),3.49–3.40(m,4H),2.02(s,3H),1.79(s,2H),1.68(d,J=6.2Hz,2H),1.15–1.07(m,2H),1.03–0.96(m,2H),LC-MS(m/z):446.2[M+H]+。
实施例258:1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-288)(#397)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.21(s,1H),7.91(d,J=5.7Hz,2H),7.42(s,1H),5.26(s,1H),3.84(s,4H),3.73(s,4H),3.49–3.38(m,4H),2.01(s,3H),1.76(t,J=5.4Hz,2H),1.70–1.62(m,2H),1.14–1.06(m,2H),1.00(dt,J=7.5,3.6Hz,2H),LC-MS(m/z):448.2[M+H]+。
实施例259:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-(二甲基氨基)乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-289)(#398)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.24(d,J=5.7Hz,1H),8.18(s,1H),7.92(s,1H),7.81(s,1H),6.76(dd,J=5.7,2.3Hz,1H),6.33(s,1H),4.30(s,1H),3.78(s,4H),3.41(s,4H),2.27(s,6H),2.01(s,3H),1.78(s,2H),1.69(s,2H),LC-MS(m/z):542.3[M+H]+。
实施例260:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-290)(#399)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),9.81(s,1H),8.63(dd,J=9.8,2.9Hz,1H),8.33–8.22(m,1H),7.65(d,J=13.0Hz,1H),7.49(s,1H),7.37(d,J=13.7Hz,1H),7.19(s,1H),7.07(s,1H),6.78(dd,J=5.8,2.3Hz,1H),3.86(s,4H),3.45(s,4H),2.02(s,3H),1.82(s,2H),1.73(s,2H),LC-MS(m/z):539.2[M+H]+。
实施例261:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-291)(#400)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),9.83(s,1H),8.44(s,1H),8.28(s,1H),8.09(s,1H),8.04(d,J=2.9Hz,1H),7.81(s,2H),7.40(s,1H),7.20(s,1H),6.79(s,1H),6.32(s,1H),3.88(m,4H),3.68(m,3H),3.36(m,4H),2.02(s,3H),1.83(s,2H),1.73(s,2H),LC-MS(m/z):551.5[M+H]+。
实施例262:1-(2-(6-((1H-吡咯并[2,3-b]吡啶-6-基)氨基)-2-(1-环丙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-293)(#401)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR 1HNMR(400MHz,DMSO-d6)δ8.39(s,1H),8.16(d,J=3.9Hz,1H),7.99(s,1H),7.85(s,1H),7.67(d,J=8.4Hz,1H),6.50–6.38(m,2H),6.07(s,2H),3.93(s,4H),3.82(m,1H),3.51–3.42(m,4H),2.03(s,3H),1.83(s,2H),1.74(s,2H),1.16–1.08(m,2H),1.05–0.95(m,2H),LC-MS(m/z):484.3[M+H]+。
实施例263:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(4,5,6,7-四氢吡唑[1,5-a]吡嗪-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-294)(#402)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.24(d,J=5.7Hz,1H),7.93(s,1H),7.70(d,J=2.1Hz,1H),6.76(dd,J=5.7,2.3Hz,1H),6.38(s,1H),4.37(s,2H),4.09(s,2H),3.78(s,4H),3.49–3.41(m,6H),3.22(s,2H),2.02(s,3H),1.79(s,2H),1.69(s,2H),LC-MS(m/z):526.2[M+H]+。
实施例264:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(吡咯烷-2-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-295)(#403)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.06(s,1H),8.26(d,J=5.7Hz,1H),7.49–7.43(m,1H),6.79(dd,J=5.8,2.2Hz,1H),6.62(s,1H),4.50(t,J=7.5Hz,1H),3.80(s,4H),3.53–3.39(m,5H),3.26(dd,J=11.2,7.1Hz,2H),2.37(dq,J=14.0,7.0Hz,1H),2.14–1.89(m,6H),1.78(t,J=5.5Hz,2H),1.68(t,J=5.5Hz,2H),LC-MS(m/z):474.2[M+H]+。
实施例265:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(哌啶-4-亚基甲基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-299)(#404)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.71(s,1H),8.24(d,J=5.8Hz,1H),7.47(d,J=2.2Hz,1H),6.76(dd,J=5.8,2.3Hz,1H),6.52(s,1H),6.18(s,1H),3.74(m,4H),3.41(m,8H),3.16(dt,J=27.2,6.0Hz,4H),2.52(m,1H),2.01(s,3H),1.77(s,2H),1.67(s,2H),LC-MS(m/z):500.2[M+H]+。
实施例266:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丙基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-300)(#405)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.51(d,J=2.8Hz,1H),8.17–8.09(m,2H),7.90(dd,J=4.5,0.7Hz,1H),7.65(s,1H),6.86–6.75(m,1H),6.56(d,J=12.9Hz,1H),4.76(d,J=1.4Hz,1H),4.07(s,2H),3.78(s,4H),3.43(dd,J=13.1,7.0Hz,4H),2.89-2.82(m,1H),2.01(s,3H),1.78(s,2H),1.68(t,J=5.9Hz,2H),1.23(d,J=6.9Hz,6H),1.09(s,6H),LC-MS(m/z):519.3[M+H]+。
实施例267:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(4-(甲基磺酰基)环己-1-烯-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-301)(#406)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.22(d,J=5.72,1H),7.77(s,1H),7.44(s,1H),7.04(s,1H),6.37(s,1H),3.93-3.92(d,J=2.72Hz,2H),4,3.76(m,4H),3.43(dd,J=13.1,7.0Hz,4H),3.23(m,4H),2.95(s,3H),2.70(m,2H),2.01(s,3H),1.78(s,2H),1.68(t,J=5.9Hz,2H),LC-MS(m/z):563.2[M+H]+。
实施例268:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丁基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-302)(#408)
步骤1:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(2-甲基丙-1-烯-1-基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#407)
向1-(2-(6-氯-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(200.00mg,0.48mmol,1.0eq.)在1,4-二噁烷(6.0mL)中的搅拌溶液中加入4-(2-甲基丙-1-烯-1-基)吡啶-2-胺(106.1mg,0.72mmol,1.5eq.)、Cs2CO3(311.1mg,0.95mmol,2.0eq.)、Xant-Phos(27.6.0mg,0.048mmol,0.1eq.)和Pd2(dba)3(43.7mg,0.048mmol,0.1eq.)。将所得混合物在氮气气氛下加热至95℃保持8小时。将反应溶液干燥,并通过柱色谱法(Biotage Rening Flash 10g,DCM=100%~甲醇/DCM=5%)纯化,得到标题化合物(150mg,59.2%产率),LC-MS(m/z):531.3[M+H]+。
步骤2:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丁基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-302)(#408)
向1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(2-甲基丙-1-烯-1-基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(150.00mg,0.48mmol,1.0eq.)在EtOH(6.0mL)中的搅拌溶液中加入10%Pd/C(w/w:10%,0.1g)。将所得混合物在氢气气氛下在室温下搅拌24小时。过滤反应溶液,滤液浓缩至干,并通过柱色谱法(Biotage Rening Flash 10g,DCM=100%~甲醇/DCM=5%)纯化,得到标题化合物(71mg,47.16%产率)。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.16–8.10(m,2H),7.89(d,J=0.6Hz,1H),7.55(s,1H),6.75(dd,J=5.1,1.4Hz,1H),6.56(s,1H),4.77(s,1H),4.07(s,2H),3.78(s,4H),3.42(dd,J=12.9,7.0Hz,4H),2.44(d,J=7.2Hz,2H),2.01(s,3H),1.94–1.88(m,1H),1.78(s,2H),1.68(s,2H),1.09(s,6H),0.91(d,J=6.6Hz,6H),LC-MS(m/z):533.3[M+H]+。
实施例269:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(吡咯烷-3-基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-303)(#409)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.46(s,2H),8.24(s,1H),8.18(s,1H),7.93(s,1H),7.69(d,J=5.1Hz,1H),6.98(s,1H),6.48(s,1H),4.84(s,1H),4.11(s,2H),3.80(s,4H),3.66(s,2H),3.50–3.41(m,6H),3.30–3.22(m,2H)3.15–3.02(m,1H),2.41(m,1H),2.01(s,3H),1.95(m,1H),1.69(d,J=5.7Hz,2H),1.09(s,6H),LC-MS(m/z):546.3[M+H]+。
实施例270:1-(2-(6-((4-环丙基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-304)(#410)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),8.21(s,2H),7.98(s,1H),7.33(s,2H),6.74(s,2H),4.80(s,1H),4.10(s,2H),3.90–3.72(m,4H),3.42(s,4H),2.01(m,4H),1.78(t,J=5.5Hz,2H),1.69(t,J=5.3Hz,2H),1.09(s,7H),0.82(s,2H),LC-MS(m/z):517.3[M+H]+。
实施例271:1-(2-(6-((4-环己基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-305)(#411)
使用类似于实施例268中化合物#408的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.22(s,2H),7.98(s,1H),7.53(s,1H),6.91(s,1H),6.41(s,1H),4.80(s,1H),4.09(s,2H),3.82(s,4H),3.49–3.40(m,5H),2.01(s,3H),1.90–1.65(m,9H),1.46–1.34(m,4H),1.32–1.20(m,1H),1.09(s,6H),LC-MS(m/z):559.3[M+H]+。
实施例272:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-(噻唑-2-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-306)(#412)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.25(d,J=0.7Hz,1H),8.05(d,J=0.6Hz,1H),7.39(d,J=3.6Hz,1H),7.08(d,J=3.6Hz,1H),5.65(s,1H),4.77(s,1H),4.10(s,2H),3.78(s,4H),3.43(d,J=14.3Hz,4H),2.01(s,3H),1.78(s,2H),1.68(t,J=5.6Hz,2H),1.10(s,6H),LC-MS(m/z):483.2[M+H]+。
实施例273:1-(2-(6-(异噻唑-3-基氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-307)(#413)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ8.93(d,J=4.7Hz,1H),8.18(s,1H),7.84(d,J=0.7Hz,1H),7.60(d,J=4.9Hz,1H),7.07(s,1H),3.90(s,3H),3.82(s,4H),3.42(m,4H),2.01(s,3H),1.78(s,2H),1.68(s,2H),LC-MS(m/z):425.2[M+H]+。
实施例274:1-(2-(6-((4-乙氧基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-309)(#414)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.12(d,J=0.6Hz,1H),8.04(d,J=5.8Hz,1H),7.88(d,J=0.6Hz,1H),7.34(s,1H),6.56(s,1H),6.52(dd,J=5.8,2.3Hz,1H),4.77(s,1H),4.11(q,J=7.0Hz,2H),4.06(s,2H),3.77(s,4H),3.42(m,4H),2.01(s,3H),1.77(s,2H),1.68(t,J=5.8Hz,2H),1.37(t,J=7.0Hz,3H),1.08(s,6H),LC-MS(m/z):521.3[M+H]+。
实施例275:4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲基)吡啶-2-基)氨基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(IRAK-311)(#415)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.41–8.36(m,1H),8.21(s,1H),8.15(q,J=4.5Hz,1H),7.46(d,J=1.8Hz,1H),7.27(d,J=1.9Hz,1H),7.13(s,1H),7.07–7.04(m,1H),6.31(s,1H),3.89(s,3H),3.78(s,4H),3.42(m,4H),2.72(d,J=4.6Hz,3H),2.01(s,3H),1.83–1.75(m,2H),1.69(t,J=5.5Hz,2H),LC-MS(m/z):525.3[M+H]+。
实施例276:1-(2-(6-((4-环丙氧基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-312)(#416)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.14–8.10(m,1H),8.06(d,J=5.8Hz,1H),7.88(d,J=0.6Hz,1H),7.51(s,1H),6.61(dd,J=5.8,2.3Hz,1H),6.56(s,1H),4.76(s,1H),4.05(s,2H),3.94(dq,J=6.1,3.0Hz,1H),3.77(s,4H),3.42(dd,J=m,4H),2.01(s,3H),1.77(s,2H),1.68(t,J=5.7Hz,2H),1.07(s,6H),0.82(h,J=6.4Hz,2H),0.76–0.68(m,2H),LC-MS(m/z):533.3[M+H]+。
实施例277:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(3-羟基-3-甲基丁基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-313)(#417)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.23(d,J=5.7Hz,1H),8.15(s,1H),7.90(s,1H),7.83(s,1H),7.48(s,1H),6.75(dd,J=5.7,2.3Hz,1H),6.30(s,1H),4.47(s,1H),4.23(dd,J=9.2,6.4Hz,2H),3.77(s,4H),3.42(m,4H),2.01(s,3H),1.96–1.89(m,2H),1.78(s,2H),1.68(s,2H),1.13(s,6H),LC-MS(m/z):557.3[M+H]+。
实施例278:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-315)(#421)
步骤1:1-(2-(6-氯-2-(1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#418)
向1-(2-(6-氯-2-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(4.00g,9.84mmol,1.0eq.)和4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(1.91g,9.84mmol,1.0eq.)在二噁烷(30mL)和H2O(5mL)中的搅拌溶液中加入Na2CO3(2.09,19.67mmol,2.0eq.)和Pd(dppf)Cl2(0.71g,0.98mmol,0.1eq.),在氮气气氛下将所得混合物加热至85℃保持8小时。将反应混合物浓缩至干。粗物质通过柱色谱法纯化,得到标题化合物(3.00g,87.94%产率)。LC-MS(m/z):347.8[M+H]+。
步骤2:1-(2-(6-氯-2-(1-((1-((四氢-2H-吡喃-2-基)氧基)环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#419)
向1-(2-(6-氯-2-(1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(1.00g,2.88mmol,1.0eq.)在DMF(10.0mL)中的搅拌溶液中加入NaH(69.2mg,2.88mmol,1.0eq.),将所得混合物在氮气气氛下搅拌10分钟,然后加入2-(1-((乙基磺酰基)甲基)环丙氧基)四氢-2H-吡喃(0.92g,3.46mmol,1.2eq.)并在氮气气氛下搅拌1小时。反应混合物用MeOH淬灭,然后浓缩至干。粗物质通过柱色谱法纯化,得到标题化合物(1.00g,69.2%产率)。LC-MS(m/z):502.1[M+H]+。
步骤3:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-((1-((四氢-2H-吡喃-2-基)氧基)环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#420)
向1-(2-(6-氯-2-(1-((1-((四氢-2H-吡喃-2-基)氧基)环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(375.0mg,0.75mmol,1.0eq.)在1,4-二噁烷(10.0mL)中的搅拌溶液中加入4-(二氟甲氧基)吡啶-2-胺(131.8mg,0.0.82mmol,1.1eq.)、Cs2CO3(731.6mg,2.25mmol,3.0eq.)、Xant-Phos(43.3mg,0.075mmol,0.1eq.)和Pd2(dba)3(68.5mg,0.075mmol,0.1eq.)。将所得混合物在氮气气氛下加热至95℃保持8小时。将反应溶液浓缩至干,并通过柱色谱法(Biotage Rening Flash 10g,DCM=100%~甲醇/DCM=5%)纯化,得到标题化合物(400mg,85.69%产率),LC-MS(m/z):625.7[M+H]+。
步骤4:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-315)(#421)
向1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-((1-((四氢-2H-吡喃-2-基)氧基)环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(400.0mg,0.64mmol,1.0eq.)在MeOH(5.0mL)中的搅拌溶液中加入4MHCl/二噁烷溶液,并在氮气气氛下在20℃下搅拌1小时。将反应溶液浓缩至干并通过柱色谱法(BiotageRening Flash 10g,DCM=100%~甲醇/DCM=5%)纯化,得到标题化合物(116mg,33.52%产率)。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.24(d,J=5.7Hz,1H),8.20(s,1H),7.92(s,1H),7.74(s,1H),7.46(s,1H),6.76(dd,J=5.7,2.3Hz,1H),6.39(s,1H),5.60(s,1H),4.21(s,2H),3.78(m,4H),3.42(m,4H),2.00(d,J=6.5Hz,3H),1.78(t,J=5.7Hz,2H),1.68(t,J=5.6Hz,2H),0.69(dt,J=5.8,1.9Hz,4H),LC-MS(m/z):541.2[M+H]+。
实施例279:1-(2-(6-((4-(3-氟氮杂环丁烷-1-基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-317)(#422)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ14.39–14.26(m,1H),11.19(s,1H),8.30(s,1H),8.21(s,1H),8.10(s,1H),6.42(s,1H),6.14(s,1H),5.67-5.64(m,1H),5.52-5.49(m,1H),4.82(s,1H),4.48(s,2H),4.37–4.17(m,2H),4.10(s,2H),3.82(s,4H),3.55–3.39(m,4H),2.01(s,3H),1.78(s,2H),1.69(s,2H),1.09(s,6H),LC-MS(m/z):550.3[M+H]+。
实施例280:1-(2-(6-((4-(二甲基氨基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-318)(#423)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ14.21(s,1H),δ11.15(s,1H),8.31(s,1H),8.20(s,1H),8.13(s,1H),6.75(s,1H),6.37(s,1H),5.64(s,1H),4.85–4.79(m,1H),4.10(s,2H),3.83(s,4H),3.42(m,4H),3.14(s,6H),2.01(s,3H),1.79(s,2H),1.69(s,2H),1.10(s,6H),LC-MS(m/z):520.3[M+H]+。
实施例281:1-(2-(2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-319)(#424)
使用类似于实施例278中化合物#421的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),8.59–8.52(m,1H),8.50(s,1H),8.16(s,1H),7.49–7.39(m,1H),7.13(d,J=5.6Hz,1H),6.38(s,1H),4.28(s,2H),3.96(s,4H),3.41(m,5H),2.01(s,3H),1.80(t,J=5.2Hz,2H),1.72(d,J=5.4Hz,2H),0.79–0.64(m,4H),LC-MS(m/z):559.2[M+H]+。
实施例282:1-(2-(6-((4-(二氟甲基)吡啶-2-基)氨基)-2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-320)(#425)
使用类似于实施例278中化合物#421的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),8.59(d,J=5.3Hz,1H),8.51(s,1H),8.18(s,1H),8.18(s,1H),7.29(d,J=7.4Hz,1H),7.16-7.13(m,1H),6.41(s,1H),4.29(s,2H),3.97(s,4H),3.63(m,5H),2.02(s,3H),1.81(t,J=5.4Hz,2H),1.72(t,J=5.6Hz,2H),0.72(dt,J=13.9,1.9Hz,4H),LC-MS(m/z):525.2[M+H]+。
实施例283:3-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)氨基)吡啶-2(1H)-酮(IRAK-322)(#426)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.54(dd,J=7.4,1.8Hz,1H),8.32(s,1H),8.15(s,1H),7.94(s,1H),6.97(t,J=5.8Hz,1H),6.30(t,J=6.9Hz,1H),5.93(s,1H),4.78(s,1H),4.08(s,2H),3.74(m,4H),3.49–3.38(m,4H),2.01(s,3H),1.77(s,2H),1.67(s,2H),1.08(s,6H),LC-MS(m/z):493.3[M+H]+。
实施例284:1-(2-(2-(1-乙基-1H-吡唑-4-基)-6-(异噻唑-3-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-323)(#427)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.89(d,J=4.7Hz,1H),8.15(s,1H),7.90(s,1H),7.31(d,J=4.7Hz,1H),6.71(s,1H),4.23–4.13(m,2H),3.79(m,4H),3.49–3.38(m,4H),2.01(s,3H),1.78(m,2H),1.67(m,2H),1.40(t,J=7.3Hz,3H),LC-MS(m/z):439.2[M+H]+。
实施例285:6-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)氨基)哒嗪-3(2H)-酮(IRAK-329)(#428)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),9.55(s,1H),8.10(d,J=0.6Hz,1H),7.87(d,J=0.6Hz,1H),7.65(d,J=10.0Hz,1H),6.90(dd,J=10.0,2.1Hz,1H),6.33(s,1H),4.77(s,1H),4.06(s,2H),3.77(m,4H),3.43(m,4H),2.00(s,3H),1.78(d,J=6.2Hz,2H),1.67(d,J=11.2Hz,2H),1.07(s,6H),LC-MS(m/z):494.6[M+H]+。
实施例286:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((3-甲氧基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-330)(#429)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),δ11.34(s,1H),9.51(s,1H),9.17(s,1H),8.21(s,1H),7.89(s,1H),5.41(d,J=24.8Hz,2H),4.78(s,1H),4.06(s,2H),3.75(m,7H),3.41(dd,J=12.6,7.1Hz,4H),2.00(s,3H),1.80–1.71(m,2H),1.66(t,J=5.5Hz,2H),1.08(s,6H),LC-MS(m/z):496.2[M+H]+。
实施例287:1-(2-(2-(5-氨基-1-甲基-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-333)(#430)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.89(d,J=4.7Hz,1H),8.15(s,1H),7.90(s,1H),7.39(s,1H),7.31(d,J=4.7Hz,1H),6.71(s,1H),4.27–4.14(m,2H),3.79(m,4H),3.48–3.38(m,4H),3.32(s,3H),2.01(s,3H),1.78(m,2H),1.67(m,2H),LC-MS(m/z):500.2[M+H]+。
实施例288:1,1'-((6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2,4-二基)双(2,7-二氮杂螺[3.5]壬烷-2,7-二基))双(乙烷-1-酮)(IRAK-292)(#431)
使用类似于实施例232中化合物#349的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.18(d,J=5.7Hz,1H),8.00(s,1H),7.40(s,1H),6.68(dd,J=5.7,2.3Hz,1H),5.70(s,1H),3.69(d,J=27.9Hz,8H),3.41(d,J=14.9Hz,8H),2.03–1.97(m,6H),1.74(s,4H),1.64(s,4H),LC-MS(m/z):571.3[M+H]+。
实施例289:4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(IRAK-297)(#432)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.24(d,J=5.7Hz,1H),8.12(d,J=5.0Hz,1H),7.83(s,1H),7.51–7.44(m,2H),7.33–7.24(m,1H),6.75(dd,J=5.7,2.2Hz,1H),6.28(s,1H),3.88(s,3H),3.78(M,4H),3.43(d,J=14.0Hz,4H),2.72(d,J=4.5Hz,3H),2.02(s,3H),1.79(s,2H),1.70(s,2H).,LC-MS(m/z):541.6[M+H]+。
实施例290:1-(2-(4-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)-1,3,5-三嗪-2-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-298)(#433)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.89(s,1H),8.34–8.23(m,3H),7.97(d,J=0.7Hz,1H),7.50(s,1H),6.85(dd,J=5.6,2.3Hz,1H),3.90(d,J=8.9Hz,7H),3.49-3.40(m,4H),2.02(s,3H),1.80(s,2H),1.70(d,J=6.1Hz,2H).,LC-MS(m/z):486.5[M+H]+。
实施例291:1-(2-(2-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(4-甲基-1H-吡唑-1-基)吡啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-321)(#434)
使用类似于实施例232中化合物#349的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.25–8.17(m,2H),7.81(d,J=2.2Hz,1H),7.49(s,1H),6.70(dd,J=5.7,2.3Hz,1H),6.46(d,J=1.8Hz,1H),6.37(d,J=1.8Hz,1H),3.73(s,4H),3.42(dd,J=12.7,7.3Hz,4H),2.10(s,3H),2.01(s,3H),1.78(s,2H),1.69(t,J=5.6Hz,2H).,LC-MS(m/z):485.5[M+H]+。
实施例292:1-(2-(3-((4-(二氟甲氧基)吡啶-2-基)氨基)-5-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)苯基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-324)(#435)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.14(d,J=5.7Hz,1H),7.95(s,1H),7.72(s,1H),7.39(s,1H),7.06(s,1H),6.71(s,1H),6.62–6.49(m,2H),6.22(s,1H),4.75(s,1H),4.03(s,2H),3.61(m,4H),3.43(m,4H),2.01(s,3H),1.77(s,2H),1.68(s,2H),1.08(s,6H).,LC-MS(m/z):541.6[M+H]+。
实施例293:6-(3-甲氧基氮杂环丁烷-1-基)-2-(1-甲基-1H-吡唑-4-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(IRAK-325)(#436)
使用类似于实施例198中化合物#236的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.35(d,J=5.7Hz,1H),8.12(s,1H),8.00(s,1H),7.88(s,1H),6.92(dd,J=5.6,2.0Hz,1H),6.32(s,1H),4.35(dq,J=6.3,3.9,3.2Hz,1H),4.22(dd,J=9.2,6.3Hz,2H),3.90(s,3H),3.83(dd,J=9.4,3.9Hz,2H),3.27(s,3H),LC-MS(m/z):422.4[M+H]+。
实施例294:N4-(4-甲氧基吡啶-2-基)-N6,N6-二甲基-2-(1-甲基-1H-吡唑-4-基)嘧啶-4,6-二胺(IRAK-326)(#437)
使用类似于实施例198中化合物#236的合成方法,得到标题化合物d。1H NMR(400MHz,DMSO-d6)δ8.26(d,J=30.4Hz,3H),8.01(s,1H),7.32(s,1H),6.69(s,1H),6.48(s,1H),3.90(m,6H),3.09(s,6H),LC-MS(m/z):326.4[M+H]+。
实施例295:1-(2-(2-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-328)(#438)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.17(d,J=5.8Hz,1H),8.12(s,1H),8.05(s,1H),7.90(s,1H),7.46(s,1H),6.66(s,1H),6.29(d,J=15.7Hz,2H),3.87(s,3H),3.68(s,4H),3.44(s,4H),2.01(s,3H),1.78(m,2H),1.68(m,2H),LC-MS(m/z):484.5[M+H]+。
实施例296:1-(2-(4-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-331)(#439)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.24(d,J=5.8Hz,1H),8.03(s,1H),7.76(d,J=0.8Hz,1H),7.43(s,1H),7.03(d,J=1.6Hz,1H),6.72(d,J=1.7Hz,1H),6.69(dd,J=5.8,2.2Hz,1H),6.61(d,J=2.2Hz,1H),3.87(s,3H),3.70(d,J=1.7Hz,4H),3.44(dd,J=9.8,4.5Hz,4H),2.01(s,3H),1.77(t,J=5.2Hz,2H),1.71–1.58(m,3H),LC-MS(m/z):484.5[M+H]+。
实施例297:2-氨基-1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-308)(#440)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.24(d,J=5.6Hz,1H),8.13(s,1H),7.91(s,1H),7.71(d,J=2.2Hz,1H),7.45(s,1H),6.76(dd,J=5.7,2.3Hz,1H),6.42(s,1H),4.77(s,1H),4.07(s,2H),3.80(s,4H),3.70(s,2H),3.52(m,4H),3.44(s,2H),1.80(d,J=5.5Hz,2H),1.73(s,2H),1.09(s,6H).,LC-MS(m/z):558.6[M+H]+。
实施例298:4-(4-((4-(二氟甲基)吡啶-2-基)氨基)-6-(7-甘氨酰基-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(IRAK-310)(#441)
使用类似于实施例253中化合物#392的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.32(s,1H),8.08(t,J=5.7Hz,3H),7.71(s,1H),7.31(d,J=6.7Hz,2H),7.24(s,1H),7.17(s,1H),6.27(s,1H),3.92(m,9H),3.53(m,4H),2.74(d,J=4.5Hz,3H),1.85(d,J=6.1Hz,2H),1.77(d,J=8.1Hz,2H),LC-MS(m/z):540.6[M+H]+。
实施例299:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)-2-羟基乙烷-1-酮(IRAK-316)(#442)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.24(d,J=5.7Hz,1H),8.13(s,1H),7.90(d,J=0.6Hz,1H),7.72(s,1H),7.45(s,1H),6.75(dd,J=5.7,2.3Hz,1H),6.40(s,1H),4.77(s,1H),4.52(t,J=5.4Hz,1H),4.09(d,J=5.5Hz,2H),4.06(s,2H),3.79(m,5H),3.49(m,4H),1.77(s,2H),1.72(s,2H),1.08(s,6H).,LC-MS(m/z):559.6[M+H]+。
实施例300:1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-羟基-4,5,6,7-四氢吡唑[1,5-a]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-327)(#443)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1HNMR(400MHz,DMSO-d6)δ9.83(s,1H),8.29(s,1H),7.96(s,1H),7.46(s,1H),6.80(s,1H),6.27(s,1H),5.11(s,1H),4.16(dt,J=17.7,6.7Hz,3H),3.82(m,4H),3.45–3.25(m,6H),3.20(d,J=22.0Hz,2H),2.01(s,4H),1.79(t,J=5.4Hz,2H),1.70(t,J=5.7Hz,2H).,LC-MS(m/z):541.6[M+H]+。
实施例301:1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丙氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(IRAK-314)(#444)
使用类似于实施例200中化合物#316的合成方法,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ9.51(d,J=2.8Hz,1H),8.17–8.09(m,2H),7.90(dd,J=4.5,0.7Hz,1H),7.65(s,1H),6.86–6.75(m,1H),6.56(d,J=12.9Hz,1H),4.76(d,J=1.4Hz,1H),4.07(s,2H),3.78(m,5H),3.43(dd,J=13.1,7.0Hz,4H),2.89-2.82(m,1H),2.01(s,3H),1.78(s,2H),1.68(t,J=5.9Hz,2H),1.23(d,J=6.9Hz,6H),1.09(s,6H),LC-MS(m/z):535.6[M+H]+。
实施例302:IRAK4生化抑制测定
在昆虫细胞/杆状病毒表达系统中共表达的IL-1R相关激酶(IRAK4)购自SinoBiological Inc.(中国北京)。生物素标记的肽底物(生物素化的AGAGRDKYKTLRQIR,ERM-肽)购自金斯瑞(中国南京)。抗磷酸化一抗Phospho-Ezrin(Thr567)/Radixin(Thr564)/Moesin(Thr558)(48G2)兔单克隆抗体(#3726S)购自Cell Signaling Technology(Danvers,MA)。与一抗结合的二抗PAb Anti Rabbit IgG-Eu穴状化合物(#61PARTAA)、链霉亲和素-XL665(#610SAXLA)和测试缓冲液检测缓冲液(#62SDBRDD)购自Cisbio Bioassays(Codolet,法国)。二硫苏糖醇(DTT)、氯化镁、三磷酸腺苷(ATP)、Tween-20、二甲基亚砜(DMSO)和HEPES缓冲液均从Sigma获得,最高纯度。
IRAK4酶抑制测定的一般程序
在由20mM HEPES、pH 7.5、5mM MgCl2组成的缓冲液中进行测定,其中在测定之前添加0.01%Tween 20和1mM DTT。将2.5μL的化合物在测定缓冲液(含4%DMSO)中的溶液和5μL的IRAK4/ERM-肽混合物在测定缓冲液中的溶液加入到白色低容量384孔微量滴定板中,通过向测定缓冲液中加入2.5μLATP溶液来引发磷酸化。IRAK4、生物素标记的肽底物ERM肽、ATP和DMSO的终浓度为1nM、200nM、600μM和1%。使反应在室温下在黑暗中进行60分钟,然后将来自制造商的检测缓冲液中的2.5μL一抗、2.5μL二抗和5μL链霉亲和素-XL665添加到反应混合物中,然后孵育60分钟。链霉亲和素-XL665的最终浓度为50nM,一抗和二抗均以制造商提供的终浓度稀释。在Tecan Spark(瑞士)的多模式读板器上读取板,检测两组的时间分辨荧光强度,其中激发波长为320nm,发射波长为665nm和620nm。通过计算每个孔的665nm/620nm信号的比率,通过使用Prism 7(La Jolla,15CA)在S型剂量反应曲线(可变斜率,四个参数)中拟合比率与抑制剂浓度,获得抑制剂的IC50值。本文所述的代表性化合物的结果如表1所示。
表1
实施例303:FLT3生化抑制测定
材料
使用杆状病毒表达系统将人FLT3细胞质结构域[登录号NP_004110.2的564-993(末端)氨基酸]表达为N末端GST融合蛋白(77kDa)。通过使用谷胱甘肽琼脂糖色谱纯化GST-FLT3。FLT3购自Carna Biosciences,Inc.(日本,CK)。TK底物-生物素、TK抗体-穴状化合物、链霉亲和素-XL665和5×酶促缓冲液、检测缓冲液(含EDTA)购自Cisbio(Codolet,法国)。ATP、DTT、MgCl2、MnCl2和二甲基亚砜(DMSO)从Sigma获得,最高纯度。
FLT3 TK-HTRF酶抑制测定的一般程序
在由5×酶促缓冲液、5mM MgCl2、1mM MnCl2和1mM DTT组成的缓冲液(1x)中进行测定,所述组分在测定之前添加。将2μL的化合物在测定缓冲液(含5%DMSO)中的溶液和4μl的FLT3酶、4μl的TK底物-生物素/ATP混合在测定缓冲液中的溶液加入白色低容量384孔微量滴定板中。FLT3、TK底物-生物素、ATP、DMSO的终浓度分别为0.2ng/ul、1uM、20μM和1%。使反应在室温下进行1小时。1h后,将10μl TK抗体-穴状化合物(1x终浓度)/链霉亲和素-XL665(62.50nM终浓度)在检测缓冲液中的混合溶液添加到混合物中,然后孵育1h。在来自TECAN(瑞士)的SPARK多模读板器上读取板,激发波长为320nm,发射波长为665nm和620nm。通过使用Prism 7(La Jolla,CA)在S型剂量反应曲线(可变斜率,四个参数)中拟合荧光强度与抑制剂浓度,获得抑制剂的IC50值。本文所述的代表性化合物的结果如表2所示。
表2
化合物 | IC50(nM) |
#316 | 0.9 |
#319 | 14.4 |
#317 | 9.1 |
#421 | 10.7 |
#430 | 20.2 |
实施例304:细胞增殖抑制测定
材料和细胞系
HL60、MV4-11和Molm13细胞购自中国科学院(中国上海)。亲代BaF3、BaF3-FLT-ITD和BaF3-FLT3-ITD-F691L来自上海交通大学医学院瑞金医院。Iscove改良Dulbecco培养基(IMDM)、RPMI培养基1640基础、青霉素-链霉素和0.5%胰蛋白酶-EDTA(10X)购自ThermoFisher(Waltham,MA,USA)。经认证的胎牛血清(FBS)购自Biological Industries(BI)。康宁96和384孔细胞培养板购自美国康宁。Cell-Titer购自PromegaCorporation(Madison,WI,USA)。
为了评估合成的化合物对急性髓细胞白血病HL60细胞增殖的抑制能力,将指数生长的细胞接种在含有10%FBS和1%青霉素-链霉素的RPMI培养基1640基础培养基中,在384孔板中浓度为2000个细胞/ml,每孔20ul,在37℃、5%CO2培养箱中孵育过夜。将化合物制备为在DMSO中的从2mM开始的12个点、3倍系列稀释液。将来自化合物储备板的1μl DMSO溶液添加到99ul细胞培养基中(测定中化合物的最高终浓度为10uM,DMSO的终浓度为0.5%)。在HL60细胞板的每个孔中加入20μL培养基中的化合物溶液。加入化合物溶液后,将测定板在37℃、5%CO2下孵育3天。使用来自Promega(Madison,WI,USA)的CellTiter-Glo测定试剂盒通过定量细胞培养物中存在的ATP来测量细胞活力。用来自TECAN(瑞士)的SPARK多板读数器孵育20分钟后读取发光。使用Prism 7(La Jolla,CA)中的S型剂量反应模型(可变斜率,四个参数)确定抑制细胞活力50%的化合物浓度(IC50值)。
为了评估合成的化合物对小鼠原代B细胞亲代BaF3增殖的抑制能力,将指数生长的细胞接种在含有10%FBS和1%青霉素-链霉素的RPMI培养基1640基础培养基中,在384孔板中浓度为1000个细胞/ml,每孔20ul,在37℃、5%CO2培养箱中孵育过夜。将化合物制备为在DMSO中的从2mM开始的12个点、3倍系列稀释液。将来自化合物储备板的1μl DMSO溶液添加到99ul细胞培养基中(测定中化合物的最高终浓度为10uM,DMSO的终浓度为0.5%)。在亲代BaF3细胞板的每个孔中加入20μL培养基中的化合物溶液。加入化合物溶液后,将测定板在37℃、5%CO2下孵育3天。使用来自Promega(Madison,WI,USA)的CellTiter-Glo测定试剂盒通过定量细胞培养物中存在的ATP来测量细胞活力。用来自TECAN(瑞士)的SPARK多板读数器孵育20分钟后读取发光。使用Prism 7(La Jolla,CA)中的S型剂量反应模型(可变斜率,四个参数)确定抑制细胞活力50%的化合物浓度(IC50值)。
为了评估合成的化合物对小鼠原代B细胞BaF3-FLT3-ITD增殖的抑制能力,将指数生长的细胞接种在含有10%FBS和1%青霉素-链霉素的RPMI培养基1640基础培养基中,在384孔板中浓度为1000个细胞/ml,每孔20ul,在37℃、5%CO2培养箱中孵育过夜。将化合物制备为在DMSO中的从2mM开始的12个点、3倍系列稀释液。将来自化合物储备板的1μl DMSO溶液添加到99ul细胞培养基中(测定中化合物的最高终浓度为10uM,DMSO的终浓度为0.5%)。在BaF3-FLT3-ITD细胞板的每个孔中加入20μL培养基中的化合物溶液。加入化合物溶液后,将测定板在37℃、5%CO2下孵育3天。使用来自Promega(Madison,WI,USA)的CellTiter-Glo测定试剂盒通过定量细胞培养物中存在的ATP来测量细胞活力。用来自TECAN(瑞士)的SPARK多板读数器孵育20分钟后读取发光。使用Prism 7(La Jolla,CA)中的S型剂量反应模型(可变斜率,四个参数)确定抑制细胞活力50%的化合物浓度(IC50值)。
为了评估合成的化合物对小鼠原代B细胞BaF3-FLT3-ITD-F691L增殖的抑制能力,将指数生长的细胞接种在含有10%FBS和1%青霉素-链霉素的RPMI培养基1640基础培养基中,在384孔板中浓度为1000个细胞/ml,每孔20ul,在37℃、5%CO2培养箱中孵育过夜。将化合物制备为在DMSO中的从2mM开始的12个点、3倍系列稀释液。将来自化合物储备板的1μlDMSO溶液添加到99ul细胞培养基中(测定中化合物的最高终浓度为10uM,DMSO的终浓度为0.5%)。在BaF3-FLT3-ITD-F691L细胞板的每个孔中加入20μL培养基中的化合物溶液。加入化合物溶液后,将测定板在37℃、5%CO2下孵育3天。使用来自Promega(Madison,WI,USA)的CellTiter-Glo测定试剂盒通过定量细胞培养物中存在的ATP来测量细胞活力。用来自TECAN(瑞士)的SPARK多板读数器孵育20分钟后读取发光。使用Prism 7(La Jolla,CA)中的S型剂量反应模型(可变斜率,四个参数)确定抑制细胞活力50%的化合物浓度(IC50值)。
为了评估合成的化合物对人急性髓细胞白血病细胞Molm13细胞增殖的抑制能力,将指数生长的细胞接种在含有20%FBS和1%青霉素-链霉素的RPMI培养基1640基础培养基中,在384孔板中浓度为2000个细胞/ml,每孔20ul,在37℃、5%CO2培养箱中孵育过夜。将化合物制备为在DMSO中的从2mM开始的12个点、3倍系列稀释液。将来自化合物储备板的1μlDMSO溶液添加到99ul细胞培养基中(测定中化合物的最高终浓度为10uM,DMSO的终浓度为0.5%)。在Molm13细胞板的每个孔中加入20μL培养基中的化合物溶液。加入化合物溶液后,将测定板在37℃、5%CO2下孵育3天。使用来自Promega(Madison,WI,USA)的CellTiter-Glo测定试剂盒通过定量细胞培养物中存在的ATP来测量细胞活力。用来自TECAN(瑞士)的SPARK多板读数器孵育20分钟后读取发光。使用Prism 7(La Jolla,CA)中的S型剂量反应模型(可变斜率,四个参数)确定抑制细胞活力50%的化合物浓度(IC50值)。
为了评估合成的化合物对人骨髓单核细胞白血病细胞MV4-11增殖的抑制能力,将指数生长的细胞接种在含有10%FBS和1%青霉素-链霉素的Iscove改良Dulbecco培养基中,在384孔板中浓度为1000个细胞/ml,每孔20ul,在37℃、5%CO2培养箱中孵育过夜。将化合物制备为在DMSO中的从2mM开始的12个点、3倍系列稀释液。将来自化合物储备板的1μlDMSO溶液添加到99ul细胞培养基中(测定中化合物的最高终浓度为10uM,DMSO的终浓度为0.5%)。在MV4-11细胞板的每个孔中加入20μL培养基中的化合物溶液。加入化合物溶液后,将测定板在37℃、5%CO2下孵育3天。使用来自Promega(Madison,WI,USA)的CellTiter-Glo测定试剂盒通过定量细胞培养物中存在的ATP来测量细胞活力。用来自TECAN(瑞士)的SPARK多板读数器孵育20分钟后读取发光。使用Prism 7(La Jolla,CA)中的S型剂量反应模型(可变斜率,四个参数)确定抑制细胞活力50%的化合物浓度(IC50值)。
本文所述的代表性化合物的结果如表3所示。
表3
在前述说明书中,已经参考许多具体细节描述了本公开的实施方案,这些具体细节可能因实施方式而异。因此,说明书和附图被认为是说明性的而不是限制性的。本公开的范围的唯一和排他性指示物,以及申请人打算成为本公开的范围的内容,是从本申请得出的一组权利要求的字面和等同范围,其具体形式为此类权利要求所要求的,包括任何后续更正。
Claims (24)
2.根据权利要求1所述的化合物,其中U选自苯基;吡啶基氨基;哌啶-4-亚基甲基;(四氢-2H-吡喃-4-基)氧基;(1,1-二氧化四氢-2H-噻喃-4-基)氨基;五元或六元环烷基非芳族基团;含有1-2个杂原子(例如N、O或S)的五元杂环非芳族基团;含有1-2个杂原子(例如N、O、S或2N)的六元杂环非芳族基团;含有1-2个杂原子(例如1N、1S、2N或1N1O)的五元杂环芳族基团;含有1-2个杂原子(例如N、O或S)的六元杂环芳族基团;双环基团,其含有具有0-2个成员杂原子的4元、5元或6元环,该环与另一个具有0-2个成员杂原子的4元、5元或6元环稠合;以及双环基团,其含有具有0-1个成员N原子的4元、5元或6元环,该环与另一个具有0-1个成员N原子的4元、5元或6元环螺旋扭曲;
其中U的非芳族部分(如果有的话)是饱和的或不饱和的;且
其中U是未取代的或取代的。
5.根据权利要求1所述的化合物,其中V选自-Cl;-OH;-N(CH3)2;N-(四氢吡喃基)氨基;N-(甲基羰基哌嗪基乙基)氨基;叔丁氧基羰基8-氮杂螺[4,5]癸基氨基;含有1个杂原子的四元杂环基;含有1个杂原子的四元杂环芳族基团(例如1N氮杂环丁烷基);含有1-2个杂原子(例如1O、1N、1S、1N1O、2N)的六元杂环非芳族基团;含有1-2个杂原子(例如2N)的六元杂环芳族基团;含有包括4-6个C原子和2个N原子的桥环的双环基团;含有1-2个杂原子(例如1N)的六元杂环芳族基团;双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环螺旋扭曲;以及双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环且,该环另一个具有0-2个杂原子的4元、5元、6元或7元环稠合;
其中V的非芳族部分(如果有的话)是饱和的或不饱和的;且
其中V是未取代的或取代的。
8.根据权利要求1所述的化合物,其中W选自-Cl、吡啶基和-NHR1,其中R1选自苯基;环己基;含有1-2个杂原子(例如1N、2N、1N1O、1N1S)的五元杂环芳族或非芳族基团、含有1-2个杂原子(例如1N、2N)的六元杂环芳族或非芳族基团;以及双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环稠合;
其中R1的非芳族部分(如果有的话)是饱和的或不饱和的;且
其中所述吡啶基和R1是未取代的或取代的。
11.根据权利要求1所述的化合物,其中式(I)是式(Ia-1):
其中R2选自-Cl、-F、-OH、-SCH3、-CN、甲基、乙基、-CF3、=O、叔丁基、-OCH(CH3)2、-OCF3、-OCHF2、-CH(OCH3)2、-CH(CH3)2、-CH2CH(CH3)2、-N(CH3)2、甲氧基、乙氧基、羟甲基、叔丁基、环丙氧基、环戊基、环丁氧基、N-甲氨基、甲基哌嗪基、且
其中U选自苯基;吡啶基氨基;哌啶-4-亚基甲基;(四氢-2H-吡喃-4-基)氧基;(1,1-二氧化四氢-2H-噻喃-4-基)氨基;五元或六元环烷基非芳族基团;含有1-2个杂原子(例如N、O或S)的五元杂环非芳族基团;含有1-2个杂原子(例如N、O、S或2N)的六元杂环非芳族基团;含有1-2个杂原子(例如1N、1S、2N或1N1O)的五元杂环芳族基团;含有1-2个杂原子(例如N、O或S)的六元杂环芳族基团;双环基团,其含有具有0-2个成员杂原子的4元、5元或6元环,该环与另一个具有0-2个成员杂原子的4元、5元或6元环稠合;以及双环基团,其含有具有0-1个成员N原子的4元、5元或6元环,该环与另一个具有0-1个成员N原子的4元、5元或6元环螺旋扭曲;
其中U的非芳族部分(如果有的话)是饱和的或不饱和的;且
其中U未被取代或被一个或多个选自以下的基团取代:-OH、-NH2、-NHCH3、-CN、-F、-Cl、-CH3、-OCH3、-CH2CH3、-CF3、-OCF3、=O、C(=O)NHCH3、吗啉基磺酰基、甲基磺酰基、叔丁氧羰基哌嗪基、四氢呋喃基、甲基哌啶基、叔丁氧羰基哌啶基、环丁砜基、乙氧羰基、N-(甲基)氨基羰基、甲基羰基、 且
其中V选自-Cl;-OH;-N(CH3)2;N-(四氢吡喃基)氨基;N-(甲基羰基哌嗪基乙基)氨基;叔丁氧基羰基8-氮杂螺[4,5]癸基氨基;含有1个杂原子的四元杂环基;含有1个杂原子的四元杂环芳族基团(例如1N氮杂环丁烷基);含有1-2个杂原子(例如1O、1N、1S、1N1O、2N)的六元杂环非芳族基团;含有1-2个杂原子(例如2N)的六元杂环芳族基团;含有包括4-6个C原子和2个N原子的桥环的双环基团;含有1-2个杂原子(例如1N)的六元杂环芳族基团;双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环螺旋扭曲;以及双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环稠合;
其中V的非芳族部分(如果有的话)是饱和的或不饱和的;且
13.根据权利要求1所述的化合物,其选自:
1-(2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#215),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#210),
1-(2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#212),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#147),
2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(#214),
5-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮(#152),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#18),
2-(6-((4-乙基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#180),
2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#156),
1-(2-(2-(4-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#151),
N-甲基-2-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#166),
2-(6-((4-氰基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#179),
N-甲基-2-(6-((4-(甲硫基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#198),
1-(2-(2-(1-(甲基磺酰基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#121),
2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#186),
8-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(#223),
2-(吡啶-3-基)-6-(7-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#50),
N-(4-甲氧基吡啶-2-基)-6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-胺(#227),
N-甲基-2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#141),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-甲酰胺(#30),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#79-1),
2-甲基-8-(6-((4-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#224),
1-(2-(2-(1-甲基哌啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#125),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.5]壬烷-7-醇(#61),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#90),
2-(6-((4-环丁氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#195),
1-(2-(2-(6-(甲基磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#119),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-胺盐酸盐(#68),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-甲酰胺(#31),
N-甲基-2-(2-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#114),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-硫杂-2-氮杂螺[3.5]壬烷-7,7-二氧化物(#51),
2-(6-((4-(羟甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#175),
6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#229),
1-(2-(2-(1-甲基-1H-吡唑-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#153),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#71),
2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#110),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#71-1),
N-甲基-2-(2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#117),
3-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺(#218),
1-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-基)乙烷-1-酮(#24),
2-(6-((4-(叔丁基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#187),
1-(2-(2-(噻吩-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#129),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#176),
N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)乙酰胺(#36),
1-(2-(2-(3,3-二氟吡咯烷-1-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#124),
甲基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#87),
1-(2-(2-(1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#130),
2-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#4),
2-(吡啶-3-基)-6-(6-氧杂-2-氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#43),
2-(6-((4-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#170),
3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-胺盐酸盐(#69),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#79),
2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#84),
1-(2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#213),
N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)乙酰胺(#28),
6-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(#47),
2-((6-(2-甲基-1-氧代-2,8-二氮杂螺[4.5]癸烷-8-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(#226),
N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#216),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#3),
1-(2-(2-(1-甲基-1,2,5,6-四氢吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#126),
2-(6-((4-乙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#189),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺盐酸盐(#75),
甲基2-(2-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#116),
6-(7-(甲基磺酰基)-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#55),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-7-酮(#41),
2-(6-((1H-吡咯并[3,2-c]吡啶-6-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#196),
9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,9-二氮杂螺[5.5]十一烷-2-酮(#9),
N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#160),
1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-基)乙烷-1-酮(#22),
1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.3]庚烷-2-基)乙烷-1-酮(#37),
2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(#161),
1-甲基-8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(#6),
N-(3-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#221),
9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-1-酮(#2),
2-(6-((4-环丙氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#207),
6-(3-吗啉代氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#57),
1-(2-(2-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#127),
2-(吡啶-3-基)-6-(2,9-二氮杂螺[5.5]十一烷-9-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#84-1),
1-(2-(2-(1-甲基-1H-吡唑-5-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#154),
2-(6-((4-氟吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#199),
1-(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(#59),
3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-胺(#219),
9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-硫杂-9-氮杂螺[5.5]十一烷3,3-二氧化物(#11),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-基)乙烷-1-酮(#39),
1-(9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-基)乙烷-1-酮(#21),
N-甲基-2-(2-(6-(甲氨基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#102),
2-甲基-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-1-酮(#44),
N-(8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氮杂螺[4.5]癸烷-2-基)乙酰胺(#27),
2-(6-((4-(二甲氧基甲基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#194),
1-(2-(2-(吡啶-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-[3.5]-7-基)乙烷-1-酮(#131),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺(#73-1),
2-((6-(4-(氧杂环丁烷-3-基)哌嗪-1-基)-2-(吡啶-3-基)嘧啶-4-基)氨基)异烟腈(#228),
4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)硫代吗啉1,1-二氧化物(#42),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#86),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸酯(#89),
7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-硫杂-7-氮杂螺[4.4]壬烷-2,2-二氧化物(#53),
2-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#163),
6-(3-(哌啶-4-基)氮杂环丁烷-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#92),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-3-酮(#10),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-基)乙烷-1-酮(#34),
1-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-基)乙烷-1-酮(#33),
2-(2-(3-氨基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#139),
(7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-7-氮杂螺[3.5]壬烷-2-基)甲醇(#49),
N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)乙酰胺(#29),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-酮(#13),
8-(6-((5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-甲基-2,8-二氮杂螺[4.5]癸烷-1-酮(#225),
(7S)-N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#313),
叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-基)氨基甲酸酯(#74),
N-甲基-2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#137),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-5-酮(#52),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-硫杂-2-氮杂螺[4.5]癸烷8,8-二氧化物(#54),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-8-氧杂-2,5-二氮杂螺[3.5]壬烷-6-酮(#46),
N-甲基-2-(6-((4-(甲氨基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#197),
1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-基)乙烷-1-酮(#35),
2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#173),
6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺(#81-1),
8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-1,8-二氮杂螺[4.5]癸烷-2-酮(#5),
2-(吡啶-3-基)-6-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#12),
N-(6-(8-氨基-3-氮杂螺[5.5]十一烷-3-基)-2-(吡啶-3-基)嘧啶-4-基)-5-(叔丁基)异噻唑-3-胺(#222),
2-(6-((5-(叔丁基)异噻唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(#174),
N-甲基-2-(6-((5-甲基-1H-吡唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#204),
叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)氨基甲酸酯(#72),
1-(4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-基)乙烷-1-酮(#48),
N-甲基-2-(6-(吡啶-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#193),
6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-胺盐酸盐(#81),
N-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)乙酰胺(#58),
乙基2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#142),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.4]辛烷-6-胺(#75-1),
1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(4-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#128),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#77-1),
1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(6-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#123),
N-甲基-2-(6-(吡嗪-2-基氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#200),
N-甲基-2-(2-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#132),
(S)-7-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢-3H-噁唑[3,4-a]吡嗪-3-酮(#7),
6-(4-(2-甲氧基乙基)哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#19),
2-(6-((6-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#167),
1-(2-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)-2-(5-(三氟甲基)吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#122),
(7R)-N-甲基-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#312),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-6-羧酸酯(#78),
叔丁基(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-8-基)氨基甲酸酯(#63),
N-(2-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)乙基)乙酰胺(#26),
6-吗啉代-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#16),
2-(6-((5-氯-4-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#203),
N-(2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-基)乙酰胺(#38),
2-(2-(3-氰基苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#143),
2-(吡啶-3-基)-6-(2,7-二氮杂螺[3.5]壬烷-7-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#60),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.4]辛烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺盐酸盐(#77),
N-甲基-2-(2-(2-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#145),
(R)-2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)六氢吡咯并[1,2-a]吡嗪-6(2H)-酮(#8),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸(#40),
乙基2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#111),
1-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)乙烷-1-酮(#56),
2-(6-((4-氯-5-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#205),
2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[3.3]庚烷-6-胺盐酸盐(#73),
2-(6-((1H-吡唑[3,4-c]吡啶-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#191),
2-(吡啶-3-基)-6-(2-氮杂螺[4.5]癸烷-2-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#14),
6-(2-(甲基磺酰基)-2,9-二氮杂螺[5.5]十一烷-9-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#23),
1-(4-(2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)乙基)哌嗪-1-基)乙烷-1-酮(#25),
N-甲基-2-(6-((5-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#169),
1-(2-(2-(3,5-二甲基异噁唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#155),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[4.5]癸烷-7-羧酸酯(#70),
2-(6-((4-乙炔基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#209),
叔丁基8-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-羧酸酯(#67),
乙基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#88),
N-(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)环丙烷甲酰胺(#20),
叔丁基(3-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-9-基)氨基甲酸酯(#64),
2-(6-((5-氯吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#177),
叔丁基4-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)哌啶-1-羧酸酯(#91),
2-(6-((4,5-二甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#202),
2-(吡啶-3-基)-N4-(四氢-2H-吡喃-4-基)-N6-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4,6-二胺(#17),
叔丁基4-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)哌啶-1-羧酸酯(#148),
叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,9-二氮杂螺[5.5]十一烷-2-羧酸酯(#65),
叔丁基2-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-6-羧酸酯(#83),
2-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)异烟腈(#236),
2-甲基-8-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,8-二氮杂螺[4.5]癸烷-1-酮(#101),
2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-醇(#2-1),
N-(3-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#220),
2-(6-((3-环戊基-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#162),
N-(3-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-3-氮杂螺[5.5]十一烷-8-基)乙酰胺(#217),
2-(6-氯-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#159),
N-甲基-2-(6-((3-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#164),
N-甲基-2-(6-((6-甲基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#165),
2-(6-((3-甲氧基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#168),
6-(哌啶-1-基)-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#15),
N-甲基-2-(6-((1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#171),
2-(6-((5-氯-1-甲基-2-氧代-1,2-二氢吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#172),
2-(6-((4-氰基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#178),
2-(6-((3-(叔丁基)-1H-吡唑-5-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#181),
2-(6-((4-羟基吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#182),
2-(6-((3-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#183),
2-(6-((3-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#184),
2-(6-((4-甲氧基苯基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#185),
2-(6-((4-羟基环己基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#188),
叔丁基2-((2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)氨基)-8-氮杂螺[4.5]癸烷-8-羧酸酯(#62),
6-氯-2-(吡啶-3-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#1),
2-(6-((5-甲氧基吡啶-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-N-甲基-2-氮杂螺[4.5]癸烷-7-甲酰胺(#190),
N-甲基-2-(6-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#192),
叔丁基9-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸酯(#66),
N-甲基-2-(4-(吡啶-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#93),
N-甲基-2-(2-苯基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#98),
N-甲基-2-(2-(吡啶-3-基)-6-(嘧啶-4-基氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#201),
叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.4]辛烷-2-羧酸酯(#76),
叔丁基(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-6-氮杂螺[3.4]辛烷-1-基)氨基甲酸酯(#80),
叔丁基6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-羧酸酯(#82),
N-甲基-2-(6-((4-甲基嘧啶-2-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#206),
乙基2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#109),
N-甲基-2-(4-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#108),
2-(吡啶-3-基)-6-(2,6-二氮杂螺[3.5]壬烷-6-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#85),
1-(6-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,6-二氮杂螺[3.5]壬烷-2-基)乙烷-1-酮(#32),
乙基2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#107),
N-甲基-2-(4-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#105),
N-甲基-2-(6-((5-甲基异噁唑-3-基)氨基)-2-(吡啶-3-基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#208),
乙基2-(2-(5-(吗啉代磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#113),
N-甲基-2-(2-(5-(吗啉代磺酰基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-甲酰胺(#112),
乙基2-(2-(4-甲基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#138),
乙基2-(2-(6-(4-(叔丁氧基羰基)哌嗪-1-基)吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2-氮杂螺[4.5]癸烷-7-羧酸酯(#150),
叔丁基4-(5-(4-(7-(甲基氨甲酰基)-2-氮杂螺[4.5]癸烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)吡啶-2-基)哌嗪-1-羧酸酯(#149),
1-(3-(1-(2-(吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)哌啶-4-基)苯基)乙烷-1-酮(#45),
1-(2-(6-(吡啶-3-基)-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#233),
1-(2-(6'-((4-(三氟甲氧基)吡啶-2-基)氨基)-[3,4'-联吡啶]-2'-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#230),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#316),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#317),
1-(2-(2-(1-甲基-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#318),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#319),
1-(2-(2-(1-(二氟甲基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#320),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#321),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#322),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-甲基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#323),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#324),
1-(2-(2-(6-氨基吡啶-3-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#325),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡咯-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#326),
1-(2-(6-((4-(二氟甲基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#327),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#328),
1-(2-(6-((4-氟吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#329),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#330),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#331),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1,3,5-三甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#332),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#333),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(3-乙基-1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#334),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-甲基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#335),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-乙基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#336),
1-(2-(2-(1-(1,1-二氧化四氢噻吩-3-基)-1H-吡唑-4-基)-6-((4-甲氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#337),
1-(2-(2-(1-((1,1-二氧化四氢-2H-噻喃-4-基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#338),
1-(2-(2-(1-(1,1-二氧化四氢-2H-噻喃-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#339),
1-(2-(2-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#340),
1-(2-(2-(1-(氧杂环丁烷-3-基甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#341),
1-(2-(2-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#342),
1-(2-(2-(1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#343),
1-(2-(2-(1-(2-(甲基磺酰基)乙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#344),
1-(2-(2-(1-((3,3-二氟环丁基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#345),
1-(2-(2-(4-吗啉代苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#346),
1-(2-(2-(4-(甲基磺酰基)苯基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#347),
1-(2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#349),
1-(2-(2-((1,1-二氧化四氢-2H-噻喃-4-基)氨基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#350),
1-(2-(2-((四氢-2H-吡喃-4-基)氧基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#352),
1-(5,5-二氟-2-(6-((4-甲氧基吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#357),
1-(2-(2-(1-(2-甲基-2-硝基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#361),
1-(2-(2-(1-(2-氨基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#362),
2-甲基-1-(4-(4-(7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)丙烷-2-醇(#365),
环丙基(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)甲酮(#370),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(3,6-二氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#372),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(四氢-2H-吡喃-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#373),
4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-3,6-二氢-2H-噻喃1,1-二氧化物(#376),
4-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)四氢-2H-噻喃1,1-二氧化物(#377),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1,3-二甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#378),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-甲氧基-2-甲基丙烷-2-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#379),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(2,3-二甲基-2H-吲唑-5-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#380),
1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#381),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-异丙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#382),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-乙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#383),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(二氟甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#384),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#385),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#386),
2-(4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)乙酰胺(#387),
1-(2-(2-(1-(2,2-二氟乙基)-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#388),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(氟甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#389),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(哌啶-4-基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#392),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-(甲基磺酰基)乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#393),
1-(2-(2-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#394),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#395),
1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-(哒嗪-3-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#396),
1-(2-(2-(1-环丙基-1H-吡唑-4-基)-6-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#397),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-(二甲基氨基)乙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#398),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#399),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#400),
1-(2-(6-((1H-吡咯并[2,3-b]吡啶-6-基)氨基)-2-(1-环丙基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#401),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(4,5,6,7-四氢吡唑[1,5-a]吡嗪-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#402),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(吡咯烷-2-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#403),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(哌啶-4-亚基甲基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#404),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丙基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#405),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(4-(甲基磺酰基)环己-1-烯-1-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#406),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丁基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#408),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-(吡咯烷-3-基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#409),
1-(2-(6-((4-环丙基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#410),
1-(2-(6-((4-环己基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#411),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-(噻唑-2-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#412),
1-(2-(6-(异噻唑-3-基氨基)-2-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#413),
1-(2-(6-((4-乙氧基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#414),
4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲基)吡啶-2-基)氨基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(#415),
1-(2-(6-((4-环丙氧基吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#416),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(3-羟基-3-甲基丁基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#417),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#421),
1-(2-(6-((4-(3-氟氮杂环丁烷-1-基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#422),
1-(2-(6-((4-(二甲基氨基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#423),
1-(2-(2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)-6-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#424),
1-(2-(6-((4-(二氟甲基)吡啶-2-基)氨基)-2-(1-((1-羟基环丙基)甲基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#425),
3-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)氨基)吡啶-2(1H)-酮(#426),
1-(2-(2-(1-乙基-1H-吡唑-4-基)-6-(异噻唑-3-基氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#427),
6-((6-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)氨基)哒嗪-3(2H)-酮(#428),
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((3-甲氧基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#429),
1-(2-(2-(5-氨基-1-甲基-1H-吡唑-4-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#430),
1,1'-((6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2,4-二基)双(2,7-二氮杂螺[3.5]壬烷-2,7-二基))双(乙烷-1-酮)(#431),
4-(4-(7-乙酰基-2,7-二氮杂螺[3.5]壬烷-2-基)-6-((4-(二氟甲氧基)吡啶-2-基)氨基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(#432),
1-(2-(4-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)-1,3,5-三嗪-2-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#433),
1-(2-(2-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(4-甲基-1H-吡唑-1-基)吡啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#434),
1-(2-(3-((4-(二氟甲氧基)吡啶-2-基)氨基)-5-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)苯基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#435),
6-(3-甲氧基氮杂环丁烷-1-基)-2-(1-甲基-1H-吡唑-4-基)-N-(4-(三氟甲氧基)吡啶-2-基)嘧啶-4-胺(#436),
N4-(4-甲氧基吡啶-2-基)-N6,N6-二甲基-2-(1-甲基-1H-吡唑-4-基)嘧啶-4,6-二胺(#437),
1-(2-(2-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)吡啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#438),
1-(2-(4-((4-(二氟甲氧基)吡啶-2-基)氨基)-6-(1-甲基-1H-吡唑-4-基)吡啶-2-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#439),
2-氨基-1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#440),
4-(4-((4-(二氟甲基)吡啶-2-基)氨基)-6-(7-甘氨酰基-2,7-二氮杂螺[3.5]壬烷-2-基)嘧啶-2-基)-N,1-二甲基-1H-吡咯-2-甲酰胺(#441),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)-2-羟基乙烷-1-酮(#442),
1-(2-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-2-(5-羟基-4,5,6,7-四氢吡唑[1,5-a]吡啶-3-基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#443)和
1-(2-(2-(1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基)-6-((4-异丙氧基吡啶-2-基)氨基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)乙烷-1-酮(#444)。
14.一种药物组合物、试剂盒或包装的药物产品,其包含治疗有效量的呈任意结晶形式或无定形形式的根据权利要求1所述的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物,以及药学上可接受的载体或赋形剂。
15.根据权利要求14所述的药物组合物、试剂盒或包装的药物产品,其中式(I)的U选自苯基;吡啶基氨基;哌啶-4-亚基甲基;(四氢-2H-吡喃-4-基)氧基;(1,1-二氧化四氢-2H-噻喃-4-基)氨基;五元或六元环烷基非芳族基团;含有1-2个杂原子(例如N、O或S)的五元杂环非芳族基团;含有1-2个杂原子(例如N、O、S或2N)的六元杂环非芳族基团;含有1-2个杂原子(例如1N、1S、2N或1N1O)的五元杂环芳族基团;含有1-2个杂原子(例如N、O或S)的六元杂环芳族基团;双环基团,其含有具有0-2个成员杂原子的4元、5元或6元环,该环与另一个具有0-2个成员杂原子的4元、5元或6元环稠合;以及双环基团,其含有具有0-1个成员N原子的4元、5元或6元环,该环与另一个具有0-1个成员N原子的4元、5元或6元环螺旋扭曲;
其中U的非芳族部分(如果有的话)是饱和的或不饱和的;且
16.根据权利要求14所述的药物组合物、试剂盒或包装的药物产品,其中式(I)的V选自-Cl;-OH;-N(CH3)2;N-(四氢吡喃基)氨基;N-(甲基羰基哌嗪基乙基)氨基;叔丁氧基羰基8-氮杂螺[4,5]癸基氨基;含有1个杂原子的四元杂环基;含有1个杂原子的四元杂环芳族基团(例如1N氮杂环丁烷基);含有1-2个杂原子(例如1O、1N、1S、1N1O、2N)的六元杂环非芳族基团;含有1-2个杂原子(例如2N)的六元杂环芳族基团;含有包括4-6个C原子和2个N原子的桥环的双环基团;含有1-2个杂原子(例如1N)的六元杂环芳族基团;双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环螺旋扭曲;以及双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环稠合;
其中V的非芳族部分(如果有的话)是饱和的或不饱和的;且
17.根据权利要求14所述的药物组合物、试剂盒或包装的药物产品,其中式(I)的W选自-Cl、吡啶基和-NHR1,其中R1选自苯基;环己基;含有1-2个杂原子(例如1N、2N、1N1O、1N1S)的五元杂环芳族或非芳族基团;含有1-2个杂原子(例如1N、2N)的六元杂环芳族或非芳族基团;以及双环基团,其含有具有0-2个杂原子的4元、5元、6元或7元环,该环与另一个具有0-2个杂原子的4元、5元、6元或7元环稠合;
其中R1的非芳族部分(如果有的话)是饱和的或不饱和的;且
18.一种抑制白细胞介素-1受体相关激酶(IRAK)例如白细胞介素-1受体相关激酶-4(IRAK4)的方法,其包括:使IRAK例如IRAK4与有效量的呈任意结晶形式或无定形形式的根据权利要求1所述的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
19.一种改变基因表达或改变转录的方法,其包括使体外或受试者中的细胞与有效量的呈任意结晶形式或无定形形式的根据权利要求1所述的式(I)或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
20.一种用于预防和/或治疗由IRAK例如IRAK4介导的或与异常IRAK例如IRAK4活性相关的病症或疾病的方法,其包括向有需要的受试者施用治疗有效量的呈任意结晶形式或无定形形式的根据权利要求1所述的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物;或其药物组合物。
21.根据权利要求20所述的方法,其中所述病症或疾病选自炎症性疾病、感染如病毒、细菌、真菌和寄生虫感染、HIV-1感染、败血症、自身免疫性病症或疾病如类风湿性关节炎和多发性硬化症、痛风、幼年特发性关节炎、Muckle-Wells病、家族性地中海热、白塞病、成人斯蒂尔病、增殖性疾病如癌症、增生、再狭窄、心脏肥大、白血病、血管内凝血、骨病、代谢疾病、神经和神经退行性疾病、心血管疾病、纤维化和过敏性疾病、哮喘、特应性皮炎、阿尔茨海默病、激素相关疾病、外伤(手术)、血液透析、缺血性疾病(心肌梗塞)、非感染性肝炎、紫外线辐射、闭合性头部损伤、胰腺炎、牙周炎、移植物抗宿主病和/或移植排斥。
22.一种抑制FMS样受体酪氨酸激酶(FLT3)的方法,其包括使FLT3与有效量的呈任意结晶形式或无定形形式的根据权利要求1所述的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物接触。
23.一种用于预防和/或治疗由FLT3介导的或与异常FLT3活性相关的病症或疾病的方法,其包括向有需要的受试者施用治疗有效量的呈任意结晶形式或无定形形式的根据权利要求1所述的式(I)化合物或其药学上可接受的盐、酯、前药、复合物、溶剂化物、异构体或水合物;或其药物组合物。
24.根据权利要求23所述的方法,其中所述病症或疾病选自炎症性疾病、感染如病毒、细菌、真菌和寄生虫感染、HIV-1感染、败血症、自身免疫性病症或疾病如类风湿性关节炎和多发性硬化症、痛风、幼年特发性关节炎、Muckle-Wells病、家族性地中海热、白塞病、成人斯蒂尔病、增殖性疾病如癌症、增生、再狭窄、心脏肥大、白血病、血管内凝血、骨病、代谢疾病、神经和神经退行性疾病、心血管疾病、纤维化和过敏性疾病、哮喘、特应性皮炎、阿尔茨海默病、激素相关疾病、外伤(手术)、血液透析、缺血性疾病(心肌梗塞)、非感染性肝炎、紫外线辐射、闭合性头部损伤、胰腺炎、牙周炎、移植物抗宿主病和/或移植排斥。
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