CN111499612A - 一种作为irak抑制剂的化合物及其制备方法和用途 - Google Patents
一种作为irak抑制剂的化合物及其制备方法和用途 Download PDFInfo
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- CN111499612A CN111499612A CN202010049702.4A CN202010049702A CN111499612A CN 111499612 A CN111499612 A CN 111499612A CN 202010049702 A CN202010049702 A CN 202010049702A CN 111499612 A CN111499612 A CN 111499612A
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- alkyl
- compound
- cycloalkyl
- radical
- membered heterocyclyl
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 108060006633 protein kinase Proteins 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005551 pyridylene group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
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- 238000005070 sampling Methods 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 125000005556 thienylene group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
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Abstract
本发明属于IRAK抑制剂领域,具体涉及适用于治疗癌症和与白细胞介素‑1受体相关激酶(IRAK)相关的炎性疾病的式(I)所示的化合物。实验表明,本发明中所披露的化合物对IRAK4激酶有良好的抑制作用,并且对其他激酶具有良好的选择性;部分化合物在动物体内显示出良好的暴露量和滞留时间;在LPS诱导的人PBMC中细胞因子TNF‑α显示了良好的抑制作用;在LPS诱导的Balb/c雌性小鼠释放TNF‑a的体内模型中也显示出良好的效果。
Description
本申请要求享有2019年1月30日向中国国家知识产权局提交的,专利申请号为201910093660.1,发明名称为“一种作为IRAK抑制剂的化合物及其制备方法和用途”的中国发明专利在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于IRAK抑制剂领域,具体涉及适用于治疗癌症和与白细胞介素-1受体相关激酶(IRAK)相关的炎性疾病的化合物,并且更具体地是一种作为IRAK抑制剂的化合物及其制备方法和用途。
背景技术
白细胞介素-1受体相关激酶(IRAK)是存在于细胞内的一类丝/苏氨酸蛋白激酶家族,有四个成员:IRAK1,IRAK2,IRAK-M和IRAK4。这四者共同特征是具有典型的N-末端死亡结构域,该结构域介导与MyD88-家族衔接蛋白和位于中心的激酶结构域之间的相互作用,其中IRAK1和 IRAK4具有激酶活性。IRAK4是Toll样受体(TLR)/白介素-1受体(IL-1R)介导的炎症信号转导通路下游的关键因子。TLR细胞外部分识别病原特异性分子(如脂多糖,多肽,病毒DNA等),与配体结合后,细胞内部分招募MyD88等形成复合体,激活IRAK1自磷酸化,进而活化下游丝氨酸/ 苏氨酸激酶TAK1,激活NF-κB及MAPK信号通路,随后产生促炎细胞因子、趋化因子和破坏性酶,最终导致产生炎症反应,介导先天性免疫。IL-1R参与宿主防御和造血,是连接先天免疫和获得性免疫的桥梁(Flannery,et.al.Biochem.Pharmacol.,2010,80(12):1981-1991)。
类风湿性关节炎(rheumatoid arthritis,RA)是一种慢性、炎性、系统性的自身免疫性疾病,以关节和关节组织非化脓性炎症为主要特征,主要表现为关节滑膜炎,终致关节的软骨、韧带、肌腱等各种组织以及多脏器损害。研究显示,在RA患者中有多种免疫细胞参与并介导了自身免疫性炎症,其中包括T/B淋巴细胞、巨噬细胞、中性粒细胞等。同时也有大量研究证明细胞因子与RA疾病直接关联,如白介素类(IL-1/IL-6等),TNF-α等。
研究表明,在LPS或CpG诱导的人白细胞中,IRAK4抑制剂能够有效地阻断促炎细胞因子肿瘤坏死因子(TNF)的产生;在胶原蛋白诱导关节炎的小鼠模型中,IRAK4抑制剂能够显著抑制TNF 的释放,从而控制疾病的进程;在MyD88依赖性炎症性痛风小鼠模型中,IRAK4抑制剂能够剂量依赖性地阻断白细胞浸润(Priscilla N,et.al.J.Exp.Med.,2015,13(212):2189-2201)。
因此可以认为,IRAK4依赖性的TLR/IL-1R信号通路的过度激活与类风湿性关节炎发生发展密切相关。另外多项研究也证实,IRAK4酶活化与以下疾病的发生发展密切相关,如肿瘤、痛风、系统性红斑狼疮、多发性硬化症、代谢综合症、动脉粥样硬化、心肌梗死、脓血症、炎症性肠病、哮喘和过敏等疾病(Chaudhary D,et.al.,J.Med.Chem.2015,58(1):96-110)。
有必要开发药理活性或其相关性能得到改善的IRAK4抑制剂。
发明内容
为了改善上述问题,本发明提供如下式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或其药学上可接受的盐,
其中,R1选自H、卤素、氰基、羟基、氨基、无取代或任选被一个、两个或更多个Ra取代的下列基团:C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基、-COOC1-40烷基、-COC1-40烷基、-NHC1-40烷基或-N(C1-40烷基)2;
Ra选自=O、羟基、氨基、氰基、无取代或任选被一个、两个或更多个Rb取代的下列基团:C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基、-COOC1-40烷基或-COC1-40烷基;
Rb选自=O、C1-40烷基、-COOC1-40烷基或-COC1-40烷基;
m选自1-3的数;
R2选自无取代或任选被一个、两个或更多个Rc取代的下列基团:C1-40烷基、C3-20环烷基、3-20 元杂环基、C6-20芳基或5-20元杂芳基;
Rc选自卤素、羟基、氨基、无取代或任选被一个、两个或更多个Rd取代的下列基团:C1-40烷基、 C1-40烷氧基、C3-20环烷基、3-20元杂环基、-COOC1-40烷基、-COC1-40烷基、-NHC1-40烷基、-N(C1-40烷基)2、-NHC3-20环烷基或-NH(3-20元杂环基);
Rd选自卤素、C1-40烷基、C3-20环烷基或3-20元杂环基;
R3选自H、无取代或任选被一个、两个或更多个Re取代的下列基团:C1-40烷基、C3-20环烷基、3-20元杂环基、-C1-40烷基-C3-20环烷基、-C1-40烷基-3-20元杂环基、C6-20芳基或5-20元杂芳基;
Re选自卤素、氰基、羟基、氨基、无取代或任选被一个、两个或更多个Rf取代的下列基团:C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基;
Rf选自=O、氰基、-C1-40烷基-氰基、羟基、-C1-40烷基-羟基、-COOC1-40烷基、-COC1-40烷基、 -NHC1-40烷基、-N(C1-40烷基)2、-SO2C1-40烷基、C1-40烷基、C3-20环烷基或3-20元杂环基。
根据本发明优选的实施方案,R1选自H、无取代或任选被一个、两个或更多个=O、羟基、氰基、 C1-12烷基、C3-12环烷基或-COC1-12烷基取代的下列基团:C1-12烷基、C1-12烷氧基、-C1-12烷氧基-3-12 元杂环基、3-12元杂环基、C6-12芳基、5-12元杂芳基或-N(C1-12烷基)2;
m选自1-3的数;
R2选自无取代或任选被一个、两个或更多个如下基团取代的C6-12芳基或5-12元杂芳基:卤素、氨基、C1-12烷基、卤代C1-12烷基、C3-12环烷基、3-12元杂环基、-NHC1-12烷基、-NHC3-12环烷基或 -NH(3-12元杂环基);
R3选自被一个、两个或更多个如下基团取代的C1-12烷基、C3-20环烷基、-C1-12烷基-C3-12环烷基或-C1-12烷基-3-12元杂环基:羟基、氰基、-C1-12烷基-氰基、C1-12烷基、-C1-12烷基-羟基、C3-12环烷基、3-12元杂环基;
所述C1-12烷基、C3-12环烷基、3-12元杂环基可进一步被一个、两个或更多个如下基团取代:=O、氰基、-C1-12烷基-氰基、C1-12烷基、-COC1-12烷基或-SO2C1-12烷基。
根据本发明的实施方案,当-C1-40烷基-C3-20环烷基或-C1-40烷基-3-20元杂环基被氰基或-C1-40烷基氰基取代时,所述氰基或-C1-40烷基-氰基优选取代在-C1-40烷基-C3-20环烷基或-C1-40烷基-3-20元杂环基中与C1-40烷基键合的C3-20环烷基或3-20元杂环基的成环原子上,例如碳原子上。
优选地,R1选自如下基团:甲氧基、
优选地,R2选自如下基团:
优选地,R3选自如下基团:
作为实例,式(I)所示的化合物选自如下化合物:
本发明还提供如上式(I)所示化合物的制备方法,包括下列步骤中的一种:
方法一:
L选自离去基团;R1、R2、R3、m具有如上所述的定义;
式(II)所示的化合物与化合物R3-L反应生成式(I)所示的化合物;
或者,
方法二:
式(II)所示的化合物与化合物R3’(Rp)n发生加成反应生成式(I)所示的化合物;
其中,R3’(Rp)n表示R3H脱去相邻的两个H原子形成双键后的化合物。
优选地,方法一中,L选自卤素或OTs。
优选地,方法二中,每一个Rp相同或不同,彼此独立地选自H或上述Re所述的定义;优选地,每一个Rp相同或不同,彼此独立地选自H、氰基、C1-12烷基、C3-12环烷基、3-12元杂环基;
优选地,n选自1、2或更多个的整数,例如选自2或3。
作为实例,R3’选自C2-40烷基、C3-20环烷基、3-20元杂环基脱去相邻的两个H原子形成碳碳双键后的基团;优选地,R3’是具有一个碳碳双键的上述基团,例如选自C2-40烯基、C3-40环烯基或不饱和的3-20元杂环基;
优选地,R3'选自C2-12烯基、C3-12环烯基或不饱和的3-12元杂环基。
本发明还提供一种药物组合物,其包含式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或其药学上可接受的盐。
优选地,所述药物组合物还包括药学上可接受的载体。
优选地,所述药物组合物为IRAK4抑制剂。
优选地,所述IRAK4抑制剂用于预防和/或治疗肿瘤、痛风、系统性红斑狼疮、多发性硬化症、代谢综合症、动脉粥样硬化、心肌梗死、脓血症、炎症性肠病、哮喘和过敏等疾病。
本发明还提供式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或其药学上可接受的盐在制备治疗和/或预防与白细胞介素-1受体相关激酶的疾病或病症的药物中的用途。
优选地,所述与白细胞介素-1受体相关激酶的疾病或病症选自肿瘤、痛风、系统性红斑狼疮、多发性硬化症、代谢综合症、动脉粥样硬化、心肌梗死、脓血症、炎症性肠病、哮喘、类风湿性关节炎、败血症、自身免疫性疾病和过敏等疾病。
本发明还提供一种与白细胞介素-1受体相关疾病的预防和/或治疗方法,包括向有此需要的个体施用治疗有效量的上述药物组合物。
有益效果
本发明提供了对白细胞介素-1受体相关激酶-4(IRAK4)具有抑制作用的新化合物。实验表明,本发明中所披露的化合物对IRAK4激酶有良好的抑制作用,并且对其他激酶具有良好的选择性;部分化合物在动物体内显示出良好的暴露量和滞留时间;在LPS诱导的人PBMC中细胞因子TNF-α显示了良好的抑制作用;在LPS诱导的Balb/c雌性小鼠释放TNF-a的体内模型中也显示出良好的效果。
术语定义和说明
除非另有定义,否则本文所有科技术语具有的含义与权利要求主题所属领域技术人员通常理解的含义相同。
本申请说明书和权利要求书记载的数值范围,当该数值范围被定义为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“0~10的整数”应当理解为记载了0、1、 2、3、4、5、6、7、8、9和10的每一个整数。当该数值范围被定义为“数”时,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。“更多个”表示三个或三个以上。
应当理解,可在参考文献(包括Carey and Sundberg"ADVANCED ORGANICCHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,CH2O 等同于OCH2。
术语“卤素”包括F、Cl、Br或I。
术语“C1-40烷基”应理解为表示具有1~40个碳原子的直链或支链饱和一价烃基,优选为C1-10烷基。“C1-10烷基”应理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2、3、4、5、6、个碳原子(“C1-6烷基”),例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基,更特别地,所述基团具有1、2或3个碳原子(“C1-3烷基”),例如甲基、乙基、正丙基或异丙基。
术语“C3-20环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~20个碳原子,优选“C3-10环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3、4、5、6、7、8、 9或10个碳原子。所述C3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和或不饱和的一价单环或双环烃环,其包含1-5个独立选自N、O 和S的杂原子,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个,优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个、两个或更多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4] 噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基、1,3-苯并噁唑基、1,3-苯并二氧杂环戊烯基。根据本发明,所述杂环基是无芳香性的。
术语“C6-20芳基”应理解为表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C6-14芳基”。术语“C6-14芳基”应理解为表示具有6、7、8、9、10、11、12、13或 14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”),特别是具有6 个碳原子的环(“C6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C13芳基”),例如芴基,或者是具有14个碳原子的环(“C14芳基”),例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14 个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3各独立选自N、O和S 的杂原子并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻 -4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3- 基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩 -3-基和亚噻吩-3-基。
上述对术语“烷基”,如“C1-40烷基”的定义同样适用于含有“C1-40烷基”的其他术语,例如术语“C1-40烷氧基”。。
本文所用的有关术语“个体”是指患有疾病、病症或病况等的个体,包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员:人,非人的灵长类动物(例如黑猩猩和其它猿类和猴);家畜,例如牛、马、绵羊、山羊、猪;家养动物,例如兔、狗和猫;实验室动物,包括啮齿类动物,例如大鼠、小鼠和豚鼠等。非人哺乳动物的实施例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方式中,所述哺乳动物为人。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状,预防其它症状,改善或预防导致症状的潜在代谢原因,抑制疾病或病症,例如阻止疾病或病症的发展,缓解疾病或病症,使疾病或病症好转,缓解由疾病或病症导致的症状,或者中止疾病或病症的症状,此外,该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外,对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果,例如尽管患者可能仍然受到潜在疾病的影响,但观察到患者情况改善。就预防效果而言,可向具有患特定疾病风险的患者施用所述组合物,或者即便尚未做出疾病诊断,但向出现该疾病的一个、两个或更多个生理症状的患者施用所述组合物。
本文所使用术语“治疗有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个、两个或更多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/ 或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“施用”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,The PharmacologicalBasis of Therapeutics,current ed.; Pergamon;and Remington's,PharmaceuticalSciences(current edition),Mack Publishing Co.,Easton,Pa 中讨论的那些。在优选的实施方式中,本文讨论的化合物和组合物通过口服施用。
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
本文所用术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质(如辅料,例如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
所述药学上可接受的辅料包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/ 或赋形剂。
本文所用术语“载体”是指相对无毒的化学化合物或试剂,其有助于将化合物引入到细胞或组织中。
本文所用术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力,并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学上可以接受的盐,例如硝酸盐、盐酸盐、硫酸盐或磷酸盐等。药学上可接受的盐是指把母体化合物中的碱基基团转换成盐的形式。药学上可接受的盐包括,但不仅限于,碱基基团例如胺(氨)基的无机或有机酸盐类。本申请药学上可接受的盐可以由母体化合物合成,即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remingtong’sPharmaceutical Scicences,17thed.,Mack Publishing Company, Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中,例如盐酸盐。
除特别指示外,本申请中的盐指用有机酸/无机酸形成的酸式盐,以及用有机碱/无机碱形成的碱式盐。另外,当式(I)化合物的碱性官能团是吡啶或咪唑(但不限制于吡啶或咪唑),酸性官能团是羧酸(但不限制于羧酸)时就会形成两性离子(内盐),内盐也包括在本申请中的盐内。
本文所使用的术语“同位素标记物”是指有同位素标记的本申请化合物。
本文使用的“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。式(I) 化合物含有不对称或手性中心,因此,存在不同的立体异构形式。式(I)的所有立体结构和混合物一样,包括外消旋混合物,作为目前申请的一部分。非对映体混合物能够分离成单独的非对映体,基于它们不同的物理化学性质,采用众所周知的手段,例如,对映异构体的拆分可通过与适当的光学活性物质(例如手性醇或Mosher`s莫氏酰氯)反应转换为非对映异构体,将其分离并转化(如水解)为相对应的单一的异构体。式(I)中的一些化合物可能是阻转异构体(如取代芳基)也是本申请中的一部分。对映异构体也可利用手性色谱柱分离。式(I)中的化合物可能存在着不同的互变异构形式,这些形式都包含在本申请范围内。例如,酮-烯醇和亚胺-烯胺形式的化合物。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
以下实施例中所提到的化合物1a、化合物1b等均指代相应实施例中反应流程式中使用该代码标示的化合物。
实施例1
目标化合物001的制备步骤如下:
1.中间体1c的合成
室温下将中间体1a(500mg,7.24mmol)溶解在30毫升四氢呋喃中,在-30℃下将LDA(7.24 mmol)慢慢滴加到溶液中,在此温度下搅拌30分钟,然后慢慢将中间体1b(2.07g,8.69mmol) 滴加到反应液中(-30℃),继续在此温度下搅拌2小时。反应液加饱和氯化铵溶液淬灭,然后经过二氯甲烷萃取,合并的有机相经过水洗后用无水硫酸钠干燥,过滤浓缩。残留物经过硅胶柱纯化 (石油醚:乙酸乙酯=50:1)得到无色油状物1.3g。
1H NMR(400MHz,CDCl3):δ3.82(t,J=6.8Hz,2H),1.77(t,J=6.8Hz,2H),1.38(s,6H),0.89(s, 9H),0.07(s,6H).
2.中间体1d的合成
室温下将中间体1c(650mg,2.86mmol)溶解到8毫升四氢呋喃中,在-10℃下将TBAF的四氢呋喃溶液(5.72mL,5.72mmol,1M/THF)慢慢滴入溶液中,在此温度下搅拌2小时。反应液加饱和氯化铵溶液淬灭,然后经过二氯甲烷萃取,合并的有机相经过水洗后用无水硫酸钠干燥,过滤浓缩,残留物经过硅胶柱纯化(石油醚:乙酸乙酯=2:1)得到淡黄色油状物290mg。
1H NMR(400MHz,CDCl3):δ3.89(t,J=6.8Hz,2H),1.83(t,J=6.8Hz,2H),1.40(s,6H).
3.中间体1e的合成
室温下依次将中间体1d(290mg,2.56mmol),TsCl(655mg,3.33mmol),DMAP(410mg,3.33mmol)和三乙胺(0.7mL,5.13mmol)加入到10mL二氯甲烷中。加完后混合体系室温下搅拌过夜。反应液浓缩至干。残留物经过硅胶柱纯化(石油醚:乙酸乙酯=2:1)得到黄色固体480mg。
1H NMR(400MHz,CDCl3):δ7.81(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),4.21(t,J=7.2Hz, 2H),2.46(s,3H),1.95(t,J=6.8Hz,2H),1.36(s,6H).
4.目标化合物001的合成
将中间体1f(150mg,0.446mmol),中间体1e(135mg,0.491mmol)和碳酸铯(292.5mg,0.892 mmol)依次加入到DMF(5mL)中,90℃搅拌过夜。反应液冷却,加入水淬灭,乙酸乙酯萃取。合并的有机相水洗,减压浓缩,残留物用高效液相制备色谱柱(CH3CN:H2O(0.1%NH4HCO3)=5-95%, UV:214nm,Flowrate:15ml/min)纯化得到白色固体(目标化合物001):34mg。
1H NMR(400MHz,CDCl3):δ10.70(s,1H),8.82(s,1H),8.50(d,J=8Hz,1H),8.12(t,J=8Hz, 1H),7.89(s,1H),7.87(d,J=7.6Hz,1H),7.04(s,1H),4.56(t,J=8Hz,2H),4.03(s,3H),2.30(t,J=8 Hz,2H),1.40(s,6H)。LCMS:Rt=4.090min,[M+H]+=432.2.
实施例2
目标化合物018的制备步骤如下:
1.中间体18c的合成
0℃下向NaH(0.63g,0.016mmol)的10mL THF中滴加中间体18b(2.78g,0.016mmol)的 10mL THF溶液,室温下搅拌两小时后,再滴加中间体18a(1g,0.014mmol)的10mL THF溶液,室温下搅拌过夜,反应结束后,水洗,乙酸乙酯萃取后,合并的有机相浓缩,残余物经硅胶柱纯化 (石油醚:乙酸乙酯=5:1)得到无色油状产物(化合物18c)0.45g。
1H NMR(400MHz,CDCl3):δ5.12-5.09(m,1H),3.00-2.94(m,2H),2.89-2.83(m,2H),2.14-2.04 (m,2H).
2.目标化合物018的合成
将中间体18c(125mg,1.34mmol),中间体1f(150mg,0.45mmol),DBU(68mg,0.45mmol) 和DIPEA(173mg,1.34mmol)依次加入到甲苯(20mL)中,110℃氮气保护下搅拌3天。反应液冷却,加入水淬灭,乙酸乙酯萃取。合并的有机相水洗,减压浓缩,残留物用高效液相制备色谱柱 (CH3CN:H2O(0.1%NH4HCO3)=5-95%,UV:214nm,Flowrate:15ml/min)纯化得到白色固体37mg。
1H NMR(400MHz,CDCl3):δ10.71(s,1H),8.84(s,1H),8.50(d,J=8.0Hz,1H),8.12(t,J=8.0 Hz,1H),8.01(s,1H),7.86(d,J=7.2Hz,1H),7.05(s,1H),4.03(s,3H),3.21(s,2H),2.94-2.85(m,2H), 2.66-2.59(m,2H),2.15-2.09(m,2H)。LCMS:Rt=4.275min,[M+H]+=430.1。
实施例3
目标化合物021制备步骤如下:
25℃下将碳酸铯(362mg,1.11mmol)加到中间体1f(150mg,0.44mmol)和21a(98mg,0.67 mmol)的DMF(10mL)溶液中,反应液80℃搅拌3h。冷却加入水(15mL),乙酸乙酯萃取(10mL*4),有机相减压浓缩,残留物通过高效液相制备色谱柱(CH3CN:H2O(0.1%NH4HCO3)=5-95%, UV:214nm,Flowrate:15ml/min)纯化得到白色固体产品(化合物021)50mg。
1H NMR(400MHz,CDCl3):δ10.70(s,1H),8.82(s,1H),8.49(d,J=8.0Hz,1H),8.12(t,J=8.0 Hz,1H),7.88-7.85(m,2H),7.04(s,1H),4.51(t,J=6.0Hz,2H),4.04(s,3H),2.40-2.34(m,4H).LCMS: Rt=3.238min,[M+H]+=404.1.
实施例4
目标化合物002制备步骤如下:
15℃下依次将化合物1f(170.4mg,0.5mmol),化合物2a(147.3mg,0.557mmol)和碳酸铯 (416.2mg,1.267mmol)加入到10mL DMF中。加完后混合体系90℃搅拌18小时,向反应液中加入10mL水淬灭反应,然后用20mL乙酸乙酯萃取两次。合并有机相用无水硫酸钠干燥后浓缩蒸干,残留物用高效液相制备色谱(CH3CN:H2O(0.1%NH4HCO3)=25-70%,UV:214nm,Flowrate:15 ml/min)纯化得到白色固体39mg,收率18%。
1H NMR(400MHz,CDCl3):δ10.69(s,1H),8.83(s,1H),8.51(d,J=7.6Hz,1H),8.12(t,J=8Hz, 1H),7.96(s,1H),7.87(d,J=7.6Hz,1H),7.02(s,1H),4.60(t,J=6.8Hz,2H),4.03(s,3H),2.18(t,J= 6.8Hz,2H),1.10-1.07(m,2H),0.56-0.53(m,2H).LCMS:Rt=3.562min,[M+H]+=430.2.
实施例5
目标化合物013制备步骤如下:
1.中间体13c(结构如下所示)的合成
0℃下将NaH(0.23g,5.85mmol)加入到50mL THF中,滴加化合物13b(1.24g,7.02mmol) 的20mL THF溶液,5℃下搅拌2小时后再滴加化合物13a(1g,5.85mmol)的20mLTHF溶液, 5℃下搅拌16小时,加入100mL水中,用乙酸乙酯萃取(20mL*3)三次,有机相减压浓缩后过硅胶柱纯化(PE/EA=5/1)得到0.92g白色固体,收率81.4%。
1H NMR(400MHz,CDCl3):δ5.40-5.37(m,1H),4.72-4.70(m,2H),4.63-4.61(m,2H),7.46(s, 9H).
2.中间体13d的合成
15℃下依次将化合物13c(416mg,2.14mmol),化合物1f(600mg,1.78mmol),DBU(353 mg,2.32mmol)和DIPEA(691mg,5.36mmol)加入到60mL甲苯中,反应液氮气保护下110℃搅拌18小时。将反应液旋干,残留物用高效液相制备色谱(CH3CN:H2O(0.1%NH4HCO3)=55-80%, UV:214nm,Flowrate:15ml/min)得到白色固体370mg,收率39.1%。
1H NMR(400MHz,CDCl3):δ10.73(s,1H),8.85(s,1H),8.50(d,J=7.6Hz,1H),8.13(t,J=7.6 Hz,1H),8.03(s,1H),7.87(d,J=7.2Hz,1H),7.02(s,1H),4.59(d,J=9.6Hz,2H),4.34(d,J=9.6Hz, 2H),4.04(s,3H),3.36(s,2H),1.45(s,9H).
3.目标化合物013和副产物13e的合成
15℃下将化合物13d(370mg,0.7mmol),加入到DCM(20mL)和TFA(1mL)的混合溶液中搅拌18小时。反应液浓缩蒸干,残留物用高效液相制备色谱 (CH3CN:H2O(0.1%NH4HCO3)=30-95%,UV:214nm,Flowrate:15ml/min)得到化合物013(30mg,白色固体,收率10%)和副产物13e(80mg,白色固体,收率26%)。
化合物013:1H NMR(400MHz,CDCl3):δ10.72(s,1H),8.84(s,1H),8.50(d,J=8.0Hz,1H), 8.13(t,J=8.0Hz,1H),8.02(s,1H),7.86(d,J=8.0Hz,1H),7.03(s,1H),4.34(d,J=9.2Hz,2H),4.04 (s,3H),3.94(d,J=9.2Hz,2H),3.46(s,2H).LCMS:Rt=3.507min,[M+H]+=431.1。
化合物13e:1H NMR(400MHz,CDCl3):δ10.69(s,1H),8.82(s,1H),8.49(d,J=8.0Hz,1H), 8.13(t,J=8.0Hz,2H),7.92(d,J=8.0Hz,1H),7.02(s,1H),5.79(s,1H),5.14(s,1H),4.29(d,J=8.8 Hz,2H),4.13(d,J=9.2Hz,2H),4.03(s,3H),3.33(s,2H).LCMS:Rt=3.280min,[M+H]+=449.1。
实施例6
目标化合物014制备步骤如下:
1.中间体14a的合成
将化合物13e(20mg,0.045mmol),醋酸酐(9mg,0.089mmol),三乙胺(13mg,0.13mmol) 溶于DCM(5mL)中,反应液25℃搅拌16h。反应结束后有机相减压浓缩,残留物用制备色谱纯化(CH3CN:H2O(0.1%NH4HCO3)=20-60%,UV:214nm,Flowrate:15ml/min)得到白色固体10mg,收率45%。
1H NMR(400MHz,CDCl3):δ10.52(s,1H),8.69(s,1H),8.48-8.39(m,3H),8.22(d,J=6.4Hz, 1H),7.42(s,1H),7.19(s,1H),6.90(s,1H),4.73(d,J=9.6Hz,1H),4.64(d,J=9.2Hz,1H),4.37(q,J= 10.0Hz,2H),3.99(s,3H),3.17(s,2H),1.82(s,3H).
2.目标化合物014的合成
依次将化合物14a(55mg,0.11mmol),TFAA(47mg,0.22mmol),吡啶(40mg,0.51mmol) 溶解在10mL的THF溶液中。加完后混合体系氮气保护下65℃搅拌16小时,将反应液浓缩蒸干,残留物用高效液相制备色谱(CH3CN:H2O(0.1%NH4HCO3)=5-95%,UV:214nm,Flowrate:15ml/min) 纯化得到浅黄色固体产品35mg,收率66%。
1H NMR(400MHz,CDCl3):δ10.73(s,1H),8.85(s,1H),8.49(d,J=8.0Hz,1H),8.13(t,J=8.0 Hz,1H),8.04(s,1H),7.87(d,J=7.6Hz,1H),7.01(s,1H),4.83(d,J=9.2Hz,1H),4.67(d,J=10.4Hz, 1H),4.55(d,J=9.2Hz,1H),4.45(d,J=10.4Hz,1H),4.05(s,3H),3.36(d,J=5.6Hz,2H),1.98(s, 3H).LCMS:Rt=3.607min,[M+H]+=473.1.
实施例7
目标化合物015制备步骤如下:
1.中间体15a的合成
将化合物13e(50mg,0.11mmol),MsCl(19mg,0.17mmol)和TEA(34mg,0.33mmol) 溶于DCM(10mL)溶液中,反应液15℃搅拌16h。反应结束后用制备色谱纯化(CH3CN:H2O(0.1%NH4HCO3)=5-95%,UV:214nm,Flowrate:15ml/min)得到白色固体产品50mg,收率61%。LCMS:Rt =1.47min,[M+H]+=527.0。
2.目标化合物015的合成
将化合物15a(40mg,0.076mmol),TFAA(32mg,0.15mmol),吡啶(27mg,0.34mmol)溶解在15mL的THF中。加完后混合体系65℃搅拌16小时,将反应液浓缩蒸干,残留物用高效液相制备色谱(CH3CN:H2O(0.1%NH4HCO3)=30-95%,UV:214nm,Flowrate:15ml/min)纯化得到白色固体产品34mg,收率87%。
1H NMR(400MHz,CDCl3):δ10.74(s,1H),8.85(s,1H),8.50(d,J=7.6Hz,1H),8.14(t,J=8.0 Hz,1H),8.05(s,1H),7.87(d,J=7.6Hz,1H),7.01(s,1H),4.66(d,J=7.6Hz,2H),4.31(d,J=7.2Hz, 2H),4.05(s,3H),3.45(s,2H),3.00(s,3H).
LCMS:Rt=2.698min,[M+H]+=509.1.
实施例8
目标化合物017制备步骤如下:
1.中间体17b的合成
0℃下向NaH(1.0g,27mmol)的200mL THF中滴加化合物2(4.4g,25mmol)的10mLTHF 溶液,室温下搅拌两小时后,再滴加化合物17a(1.5g,20mmol)的10mL THF溶液,室温下搅拌过夜,反应结束后,加入冰水(300mL),乙酸乙酯(200mL*4)萃取后,合并的有机相浓缩,残余物经硅胶柱纯化(石油醚:乙酸乙酯=3:1)得白色固体1.3g,收率65%。
1H NMR(400MHz,CDCl3):δ5.39-5.36(m,2H),5.30-5.29(m,2H),5.28-5.24(m,1H).
2.目标化合物017的合成
将化合物17b(212mg,2.2mmol),化合物1f(150mg,0.44mmol),DBU(340mg,2.2mmol) 和DIPEA(288mg,2.2mmol)依次加入到甲苯(24mL)中,100℃下微波反应2小时。反应液冷却,加入水(100mL),乙酸乙酯(50mL*4)萃取。合并的有机相水洗,减压浓缩,残留物用高效液相制备色谱柱(CH3CN:H2O(0.1%NH4HCO3)=20-60%,UV:214nm,Flowrate:15ml/min)纯化得到黄色固体54mg,收率:28%。
1H NMR(400MHz,CDCl3):δ10.73(s,1H),8.86(s,1H),8.50(d,J=8.0Hz,1H),8.13(t,J=16 Hz,1H),8.04(s,1H),7.87(d,J=8Hz,1H),7.02(s,1H),5.25(d,J=8Hz,2H),4.91(d,J=8Hz,2H), 4.04(s,3H),3.49(s,2H).LCMS:Rt=3.195min,[M+H]+=432.2。
实施例9
目标化合物022制备步骤如下:
10℃下将DIPEA(276mg,2.14mmol)加到化合物1f(120mg,0.36mmol)和化合物22a(278 mg,5.35mmol)的甲苯(8mL)溶液中,反应液120℃搅拌48h。冷却反应液减压浓缩,残留物通过高效液相制备色谱柱(CH3CN:H2O(0.1%NH4HCO3)=5-95%,UV:214nm,Flowrate:15ml/min)纯化得到白色固体产品50mg,收率36%。
1H NMR(400MHz,DMSO-d6):δ10.50(s,1H),8.71(s,1H),8.46-8.40(m,3H),8.22(d,J=6.0Hz, 1H),7.18(s,1H),4.65(s,2H),4.00(s,3H),3.21(s,2H).LCMS:Rt=3.832min,[M+H]+=390.1.
实施例10
目标化合物025的制备步骤如下:
1.中间体25b和25c的合成
15℃下依次将化合物25a(240mg,1.92mmol),TsCl(490.8mg,2.496mmol),DMAP(307 mg,2.496mmol)和三乙胺(388.5mg,3.84mmol)加入到10mL的二氯甲烷中,15℃搅拌18小时。反应液中加入5mL水淬灭,然后用10mL的二氯甲烷萃取两次,合并有机相,水洗并用无水硫酸钠干燥。浓缩蒸干,残留物用硅胶柱纯化(石油醚:乙酸乙酯=6:1)得到白色固体25b(240mg) 和25c(210mg)。
化合物25b:1H NMR(400MHz,CDCl3):δ7.80(d,J=8.4Hz,2H),7.35(d,J=8.0Hz,2H), 4.64-4.60(m,1H),2.64-2.59(m,1H),2.45(s,3H),2.01-1.87(m,4H),1.77-1.67(m,4H).
化合物25c:1H NMR(400MHz,CDCl3):δ7.79(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H), 4.60-4.58(m,1H),2.70-2.69(m,1H),2.45(s,3H),2.06-1.94(m,2H),1.92-1.89(m,2H),1.71-1.66(m, 4H).
2.目标化合物025的合成
室温下依次将化合物1f(169mg,0.5mmol),化合物25b(210mg,0.75mmol)和碳酸铯(410 mg,1.25mmol)加入到DMF(10mL)中,加完后混合体系加热到90℃并搅拌18小时。反应液加 5mL水淬灭,并用20mL乙酸乙酯萃取三次,合并有机相浓缩蒸干,残留物用高效液相制备色谱 (CH3CN:H2O(0.1%NH4HCO3)=5-95%,UV:214nm,Flowrate:15ml/min)得到白色固体16mg,收率 6.4%。
1H NMR(400MHz,CDCl3):δ10.70(s,1H),8.81(s,1H),8.49(d,J=7.6Hz,1H),8.11(t,J=8Hz, 1H),7.86(d,J=9.6Hz,1H),7.84(s,1H),7.04(s,1H),4.39-4.34(m,1H),4.02(s,3H),2.63-2.56(m, 1H),2.36-2.33(m,4H),2.10-2.01(m,2H),1.89-1.79(m,2H).LCMS:Rt=3.260min,[M+H]+=444.2.
实施例11
目标化合物026制备步骤如下:
室温下依次将化合物1f(169mg,0.5mmol),化合物25c(210mg,0.75mmol)和碳酸铯(410 mg,1.25mmol)加入到DMF(10mL)中,加完后混合体系加热到90℃并搅拌18小时。反应液浓缩蒸干,残留物用高效液相制备色谱(CH3CN:H2O(0.1%NH4HCO3)=5-95%,UV:214nm,Flowrate:15ml/min)得到白色固体32mg,收率14.5%。
1H NMR(400MHz,CDCl3):δ10.70(s,1H),8.83(s,1H),8.50(d,J=8.0Hz,1H),8.12(t,J=7.6 Hz,1H),7.91(s,1H),7.84(d,J=7.6Hz,1H),7.06(s,1H),4.42-4.35(m,1H),4.03(s,3H),3.06-3.05(m, 1H),2.34-2.23(m,6H),1.87-1.79(m,2H).LCMS:Rt=3.163min,[M+H]+=444.2。
实施例12
目标化合物028的制备步骤如下:
10℃下将化合物28a(3.0g,8.24mmol),化合物1e(6.6g,24.73mmol)和碳酸铯(5.32g,41.20 mmol)加入到甲苯(30mL)中,加完后混合体系加热到130℃并搅拌62小时。反应完毕后减压浓缩,残留物用硅胶色谱柱纯化(石油醚:乙酸乙酯=2:1)得到粗品2.8g。粗品再次用高效液相制备色谱(CH3CN:H2O(0.1%NH4HCO3)=40-80%,UV:254nm,Flowrate:15ml/min)得到白色固体2.12 g,收率51%。
1H NMR(400MHz,CDCl3):δ12.28(s,1H),8.85(s,1H),8.49(d,J=8.0Hz,1H),8.10(t,J=8.0 Hz,1H),7.93(s,1H),7.83(d,J=7.6Hz,1H),7.69(s,1H),4.59(t,J=7.8Hz,2H),2.37(s,1H),2.31(t, J=7.8Hz,2H),1.79(s,6H),1.39(s,6H).LCMS:Rt=3.249min,[M+H]+=460.2。
实施例13
目标化合物040的制备步骤如下:
1.中间体40c的合成
25℃下将碳酸铯(2.2g,6.7mmol)加入到化合物40a(500mg,2.7mmol)和化合物40b(3.7g, 54mmol)的DMSO(15mL)溶液中,反应液在120℃条件下搅拌16h,冷却,加水20mL,乙酸乙酯萃取(20mL*4),合并的有机相减压浓缩。残留物用硅胶色谱柱纯化(PE/EA=2/1)得到黄色固体产品410mg,收率65%。
1H NMR(400MHz,DMSO-d6):δ13.86(s,1H),8.62(s,1H),8.41(s,1H),8.34(s,1H),7.86(s,1H), 7.74(s,1H),6.56(s,1H).
2.中间体40d的合成
25℃下将19mg的Pd/C加入到化合物40c(190mg,0.83mmol)的乙酸乙酯(20mL)溶液中,反应液在氢气球下25℃搅拌16小时。过滤,滤液减压浓缩得到黄色固体产品174mg,收率100%。
1H NMR(400MHz,CDCl3):δ7.92(s,1H),7.80(d,J=4Hz,1H),7.73(s,1H),7.32(s,1H),7.11 (s,1H),6.48(s,1H).
3.中间体40f的合成
将EDCI(244mg,1.2mmol)加入到化合物40d(169mg,0.84mmol)和化合物40e(178mg, 0.93mmol)的3mL吡啶溶液中。加完后混合体系25℃搅拌16小时。反应液浓缩旋干,得粗品为黄色油状液体315mg,收率100%,直接用于下一步的合成。
4.目标化合物040的合成
25℃下将碳酸铯(690mg,2.1mmol)加到化合物40f(315mg,0.84mmol)和化合物1e(271mg, 1.0mmol)的DMF(5mL)溶液中,反应液90℃搅拌16h。冷却加入水(80mL),乙酸乙酯萃取(40mL*4),有机相减压浓缩,残留物用高效液相制备色谱柱(CH3CN:H2O(0.1%NH4HCO3)= 5-95%,UV:214nm,Flowrate:15ml/min)纯化得到白色固体产品52mg,产率13%。
1H NMR(400MHz,CDCl3):δ12.07(s,1H),9.04(s,1H),8.45(d,J=8Hz,1H),8.09-8.05(m,2H), 7.97(s,1H),7.85-7.81(m,2H),7.70(s,1H),6.56(s,1H),4.67-4.63(m,2H),2.36-2.32(m,2H),1.42(s, 6H).LCMS:Rt=4.290,[M+H]+=468.1.
实施例14
目标化合物068的制备步骤如下:
1.中间体68c的合成
将化合物68a(200mg,1.1mmol),化合物68b(906mg,11mmol),碳酸铯(1.8g,5.5mmol) 溶于DMSO(10mL)中,反应液在120℃搅拌40h。冷却至25℃,加入水(100mL),乙酸乙酯萃取(20mL*3),合并的有机相减压浓缩,残留物用硅胶柱纯化(DCM/CH3OH=100/1)得到红色固体300mg,收率89%。
1H NMR(400MHz,DMSO-d6):δ12.46(br s,1H),8.57(s,1H),8.38(s,1H),8.09(s,1H),7.80(s, 1H),7.55(s,1H),2.12(s,3H).
2.中间体68d的合成
将化合物68c(300mg,1.23mmol)与Pd/C(30mg)加到甲醇(20mL)溶液中,氢气保护下,反应液40℃搅拌16h。反应结束后过滤,滤液旋干得红色固体150mg,收率57%。
1H NMR(400MHz,CDCl3):δ7.91(s,1H),7.60(s,1H),7.52(s,1H),7.30(s,1H),7.10(s,1H), 2.18(s,3H).
3.中间体68f的合成
将化合物68d(95mg,0.045mmol),化合物40e(85mg,0.045mmol),EDCI(103mg,0.054 mmol)依次加入吡啶(10mL)中,反应液50℃搅拌16小时。反应结束后加入水(50mL),乙酸乙酯萃取(20mL*3),合并的有机相减压浓缩后过硅胶柱纯化(DCM/CH3OH=20/1)得到白色固体 170mg,收率99%。
1H NMR(400MHz,CDCl3):δ12.16(s,1H),9.15(s,1H),8.47(d,J=7.6Hz,1H),8.15(s,J=8.0 Hz,1H),8.09(t,J=8.0Hz,1H),7.83(d,J=7.6Hz,1H),7.78(s,1H),7.60(s,1H),7.48(s,1H),2.21(s, 3H).
4.目标化合物068的合成
将化合物68f(160mg,0.41mmol),化合物1e(111mg,0.44mmol),碳酸铯(162mg,0.5mmol) 溶解在25mL的DMF中。加完后混合体系90℃搅拌16小时,将反应液浓缩蒸干,残留物用高效液相制备色谱(CH3CN:H2O(0.1%NH4HCO3)=30-95%,UV:214nm,Flowrate:15ml/min)纯化得到白色固体产品30mg,收率15%。
1H NMR(400MHz,CDCl3):δ12.16(s,1H),9.04(s,1H),8.44(d,J=4.0Hz,1H),8.08(t,J=7.6 Hz,1H),8.04(s,1H),7.82(d,J=8.0Hz,1H),7.78(s,1H),7.66(s,1H),7.62(s,1H),4.64(t,J=7.6Hz, 2H),2.34(t,J=8.0Hz,2H),2.21(s,3H),1.42(s,6H).LCMS:Rt=3.753min,[M+H]+=482.2。
实施例15
目标化合物069可用化合物068类似的制备方法得到。
1H NMR(400MHz,DMSO-d6):δ11.03(s,1H),9.16(s,1H),8.82(s,1H),8.69(s,1H),8.37-8.42 (m,3H),8.17-8.19(m,1H),8.03(s,1H),4.67(t,J=8.0Hz,2H),2.30(t,J=8.0Hz,2H),1.38(s,6H). LCMS:Rt=3.291min,[M+H]+=493.2。
实施例16
目标化合物070可用化合物014类似的制备方法得到。
1H NMR(400MHz,CDCl3):δ12.33(s,1H),8.92(s,1H),8.50(d,J=7.6Hz,1H),8.12(t,J=8.0 Hz,1H),8.09(s,1H),7.85(d,J=7.2Hz,1H),7.71(s,1H),4.85(d,J=9.6Hz,1H),4.69(d,J=10.4Hz, 1H),4.57(d,J=8.8Hz,1H),4.69(d,J=10.8Hz,1H),3.38(d,J=4.8Hz,2H),2.27(s,1H),2.01(s, 3H),1.81(s,6H).
LCMS:Rt=3.349min,[M+H]+=501.2.
实施例17
目标化合物071可用化合物015类似的制备方法得到。
1H NMR(400MHz,CDCl3):δ12.32(s,1H),8.91(s,1H),8.50(d,J=7.6Hz,1H),8.11(t,J=7.2 Hz,2H),7.85(d,J=7.6Hz,1H),7.70(s,1H),4.67(d,J=9.2Hz,2H),4.33(d,J=9.6Hz,2H),3.46(s, 2H),2.99(s,3H),2.24(s,1H),1.81(s,6H).
LCMS:Rt=3.503min,[M+H]+=537.2.
实施例18
目标化合物072可用化合物014类似的制备方法得到。
1H NMR(400MHz,CDCl3):δ12.32(s,1H),8.91(s,1H),8.51(d,J=8.0Hz,1H),8.12(t,J=8.0 Hz,1H),8.09(s,1H),7.85(d,J=7.6Hz,1H),7.71(s,1H),4.82(d,J=8.8Hz,1H),4.69(d,J=11.2Hz, 1H),4.55(d,J=9.2Hz,1H),4.47(d,J=10.8Hz,1H),3.37(d,J=4.4Hz,2H),2.23(s,1H),2.22-2.17 (m,2H),1.81(s,6H),1.17(s,J=7.6Hz,3H).
LCMS:Rt=3.550min,[M+H]+=515.2.
实施例19
目标化合物073可用化合物015类似的制备方法得到。
1H NMR(400MHz,CDCl3):δ12.32(s,1H),8.92(s,1H),8.51(d,J=8.0Hz,1H),8.12(t,J=7.6 Hz,2H),7.85(d,J=7.6Hz,1H),7.71(s,1H),4.70(d,J=9.2Hz,2H),4.31(d,J=9.6Hz,2H),3.46(s, 2H),3.09(q,J=8.0Hz,2H),2.18(s,1H),1.82(s,6H),1.42(q,J=7.2Hz,3H).
LCMS:Rt=3.757min,[M+H]+=551.2.
实施例20
目标化合物074可用化合物002类似的制备方法得到。
1H NMR(400MHz,CDCl3):δ12.26(s,1H),8.87(s,1H),8.52(d,J=7.6Hz,1H),8.11(t,J=8.0 Hz,1H),8.01(s,1H),7.85(d,J=7.6Hz,1H),7.68(s,1H),4.64(t,J=6.8Hz,2H),2.22-2.18(m,3H), 1.80(s,6H),1.10-1.07(m,2H),0.55-0.52(m,2H).LCMS:Rt=10.179min,[M+H]+=458.1.
实施例21和实施例22
目标化合物075和076的制备步骤如下:
1.中间体75c的合成
25℃下依次将化合物75b(6.5g,105.6mmol)和对甲苯磺酸(60mg,0.35mmol)加到化合物75a(10g,70.4mmol)的150mL甲苯溶液中,反应液130℃搅拌16小时。反应液浓缩蒸干,残余物通过硅胶柱(PE:EA=1:1)纯化得到无色油状物11g,收率84%。
1H NMR(400MHz,CDCl3):δ4.18-4.12(m,2H),3.91-3.89(m,4H),2.89-2.85(m,1H),2.68-2.62 (m,2H),2.58-2.50(m,2H),1.26(t,J=7.2Hz,3H).
2.中间体75d的合成
-35℃下向化合物75c(10g,53.8mmol)的四氢呋喃溶液(200mL)中加入甲基溴化镁(90ml, 269mmol),并在25℃下搅拌反应18小时。反应完成后,用饱和氯化铵溶液淬灭,乙酸乙酯(100 mL×3)萃取,萃取液用饱和碳酸氢钠溶液(150mL×2),饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶色谱柱(石油醚:乙酸乙酯=2:1)纯化得到无色油状物8.5 g,收率92%。
1H NMR(400MHz,CDCl3):δ3.94-3.85(m,4H),2.32-2.23(m,4H),2.22-2.11(m,1H),1.74(s, 1H),1.15(s,6H)。
3.中间体75e的合成
将化合物75d(170mg,1mmol)溶于(4mL)二氧六环,(4mL)4M稀盐酸的混合溶液中,65℃下搅拌反应18小时。反应完毕后,反应液用饱和碳酸氢钠溶液中和,乙酸乙酯(100mL×3) 萃取,经饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物无须纯化得到无色油状物130mg,收率99%。
1H NMR(400MHz,CDCl3):δ3.13-3.06(m,2H),2.96-2.89(m,2H),2.45-2.41(m,1H),1.28(s, 6H)。
4.中间体75g的合成
0℃,氮气保护下将化合物75f(198mg,1.1mmol)的5mL四氢呋喃滴加到NaH(45mg,1.1 mmol)的5mL四氢呋喃中,25℃下搅拌2小时后再加入75e(130mg,1mmol)的5mL四氢呋喃溶液,反应16h。反应液用水淬灭,乙酸乙酯(100mL×3)萃取,经饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶色谱柱(石油醚:乙酸乙酯=2:1)纯化得到无色油状物70mg,收率46%。
1H NMR(400MHz,CDCl3):δ5.15(s,1H),2.19-2.88(m,2H),2.86-2.83(m,1H),2.77-2.73(m,1H), 2.45-2.39(m,1H),1.19(s,3H),1.17(s,3H).
5.目标化合物075和076的合成
25℃下依次向甲苯(40mL)中加入化合物75g(300mg,2mmol),化合物1f(445mg,1.32 mmol),DBU(403mg,2.65mmol),DIPEA(513mg,3.97mmol),氮气保护下,120℃搅拌反应4天,冷却到25℃加水(5mL)淬灭反应,用乙酸乙酯(10mL×3)萃取,萃取液用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用高效液相制备色谱 (CH3CN:H2O=30-65%,UV:214nm,Flowrate 15mL/min)纯化后得到Rt=8.77min的白色固体075 (29mg,收率5%),和Rt=10.68min的白色固体076(249mg,收率39%)。
化合物075:1H NMR(400MHz,CDCl3):δ10.71(s,1H),8.85(s,1H),8.50(d,J=7.6Hz,1H), 8.12(t,J=8.0Hz,2H),7.86(d,J=7.2Hz,1H),7.06(s,1H),4.04(s,3H),3.21(s,2H),2.92(t,J=9.2 Hz,2H),2.66(t,J=11.6Hz,2H),2.44-2.41(m,1H),1.19(s,6H).LCMS:Rt=3.179min,[M+H]+= 488.2。
化合物076:1H NMR(400MHz,CDCl3):δ10.69(s,1H),8.82(s,1H),8.49(d,J=8.0Hz,1H),8.11 (t,J=8.0Hz,1H),8.03(s,1H),7.85(d,J=7.6Hz,1H),7.04(s,1H),4.02(s,3H),3.23(s,2H),2.83(t,J =7.6Hz,2H),2.60(t,J=8.4Hz,2H),2.43-2.39(m,1H),1.18(s,6H).LCMS:Rt=3.691min,[M+H]+=488.2。
实施例23
目标化合物077的制备步骤如下:
1.中间体77b的合成
-30℃下将n-BuLi(1.34mL,3.34mmol)加入到二异丙基胺(376mg,3.73mmol)的8mL的THF 溶液中,反应在-30℃下搅拌1h后,-70℃下将乙腈(153mg,1.86mmol)慢慢滴加到反应液中在此温度下搅拌反应1h,化合物77a(500mg,1.86mmol)2mL的THF溶液中慢慢加入到反应液中,反应在-70℃下搅拌1h,-30℃下搅拌1h,30℃下搅拌2h后,用10mL的饱和氯化铵溶液淬灭,乙酸乙酯(15mL×3)萃取,有机相无水硫酸钠干燥,过滤,减压浓缩,残留物通过硅胶色谱柱 (PE/EA=1/1)得到黄色油状产物400mg,收率73%。
1H NMR(400MHz,CDCl3):δ7.80-7.74(m,2H),7.35-7.33(m,2H),4.46-4.38(m,1H),2.48(s, 2H),2.45(s,3H),2.21-1.67(m,6H),1.67-1.49(m,2H).LCMS:Rt=1.40min,[M+H]+=327.5.
2.目标化合物077的合成
将化合物77b(496mg,1.6mmol),化合物1f(450mg,1.3mmol)和碳酸铯(1g,3mmol)加入到NMP(50mL)中,置换氮气,90℃下搅拌16小时,冷却至室温,加水(300mL),乙酸乙酯(300mL×3)萃取,有机相用饱和氯化钠溶液(800×3mL)洗,无水硫酸钠干燥,过滤,减压浓缩,残留物高效液相制备色谱柱(CH3CN:H2O(0.1%NH4HCO3)=5-95%,UV:214nm,Flowrate:15mL /min)得到黄色固体(48mg,收率13%).
1H NMR(400MHz,CDCl3):δ10.71(s,1H),8.82(s,1H),8.49(d,J=8.0Hz,1H),8.12(t,J=16 Hz,1H),7.89-7.85(m,2H),7.08(s,1H),4.51-4.69(m,1H),4.04(s,3H),2.77(s,2H),2.31-2.22(m,4H), 2.12-2.07(m,2H),1.99(s,1H),1.85-1.79(m,2H).LCMS:Rt=3.702min,[M+H]+=474.1.
实施例24
目标化合物078的制备步骤如下:
1.中间体78b的合成
零下5℃将硝酸(50mL)和硫酸(50mL)混合溶液加到化合物78a(50g,284.09mmol)的硫酸(200mL)溶液中,在此温度下搅拌1小时。合并的反应液倒入1.5L冰水中,过滤,滤饼用 3L水淋洗,滤饼干燥得到黄色固体产品125g,收率99%。
1H NMR(400MHz,DMSO-d6):δ14.01(s,1H),8.71(s,1H),8.51(s,1H),7.98(s,1H),3.89(s, 3H).
2.中间体78c的合成
25℃下将8g的Pd/C加入到化合物78b(30g,135.7mmol)的甲醇(1200mL)溶液中,反应在一个氢气袋(760Torr)压力下搅拌16h,反应液过滤,减压浓缩,得到黄色固体产品23g,收率88%。
1H NMR(400MHz,DMSO-d6):δ12.82(s,1H),7.80(s,1H),7.85(s,1H),6.99(s,1H),6.01(s,2H), 3.85(s,3H).
3.中间体78d的合成
在25℃下向化合物78c(73g,382.2mmol)和化合物40e(73g,382.2mmol)的吡啶(750mL) 溶液中加入EDCI(110g,573.3mmol),加完后混合体系25℃搅拌16h。减压浓缩至干,残留物用水(1000mL)打浆,得到黄色固体138g,收率99%。
1H NMR(400MHz,DMSO-d6):δ13.45(s,1H),12.57(s,1H),9.15(s,1H),8.47(d,J=8.0Hz,1H), 8.39(t,J=8.0Hz,1H),8.30(s,1H),8.25(s,1H),8.20(d,J=7.6Hz,1H),3.98(s,3H).
4.中间体78e的合成
在-15℃下向化合物78d(30g,82.4mmol)的四氢呋喃(500mL)溶液中缓慢滴加甲基溴化镁 (192.3mL,576.9mmol,3M)的乙醚溶液,加完后混合体25℃下搅拌18小时,反应完毕后,冷却到0℃,用饱和氯化铵水溶液(100mL)淬灭反应,乙酸乙酯萃取(300mL×3),萃取液饱和盐水洗涤(200mL),无水硫酸钠干燥,减压浓缩,残留物用硅胶色谱柱纯化(二氯甲烷/甲醇=80/1) 得到黄色固体22g,收率47%。
1H NMR(400MHz,DMSO-d6):δ12.98(s,1H),12.33(s,1H),8.78(s,1H),8.49-8.44(m,1H),8.37 (t,J=7.6Hz,1H),8.6(d,J=7.6Hz,1H),8.06(s,1H),7.49(s,1H),6.00(s,1H),1.63(s,6H).
5.目标化合物078的合成
25℃下依次向NMP(10mL)中加入化合物78e(550mg,1.51mmol),化合物78f(700mg,2.26mmol),碳酸铯(943mg,2.87mmol),并在90度下搅拌反应18小时。冷却到25℃,加水(30mL)淬灭反应,用乙酸乙酯(30mL×3)萃取,萃取液用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残留物用高效液相制备色谱(CH3CN:H2O=5-95%,UV:214nm,Flowrate 15mL/min)纯化后再用制备板(石油醚:乙酸乙酯=1:1)纯化得到白固体28mg,收率4%。
1H NMR(400MHz,CDCl3):δ12.28(s,1H),8.85(s,1H),8.50(d,J=7.6Hz,1H),8.10(t,J=8.0 Hz,1H),7.93(s,1H),7.85(d,J=8.0Hz,1H),7.72(s,1H),4.54-4.50(m,1H),2.73(s,2H),2.33-2.18 (m,5H),2.08-2.04(m,3H),1.86-1.82(m,2H),1.80(s,6H).LCMS:Rt=3.631min,[M+H]+=502.2。
参考制备方法一或者制备方法二制备了如下表格化合物,其中化合物016参考制备方法二合成,其他化合物参考制备方法一合成,其表征结果如下表所示:
【生物学评价】
测试例1.测定本发明示例性的实施例化合物对人IRAK4激酶活性的抑制作用
主要试验材料
ATP(Sigma,货号:A7699-1G)
DMSO(Sigma,货号D2650)
EDTA(Sigma,货号:E5134)
HEPES(Sigma,货号:V900477-500G)
DTT(Sigma,货号:D0632-25g)
Brij-35(Sigma,货号:B4184)
96孔板(Corning,货号:3365)
384孔板(Corning,货号:3573)
实验步骤
化合物在ATP的Km浓度时对IRAK4抑制活性,在下文描述的IRAK4 MSA(Mobility-Shift Assay,微流体芯片技术的迁移率检测技术)中进行测量。
使用N-末端GST(谷胱甘肽-S-转移酶)和人IRAK4的重组融合蛋白作为酶(GST-IRAK4,激酶IRAK4(Carna,货号:09-145)),终浓度为1nM;ATP终浓度为37μM;用于激酶反应的底物为5-FAM(5-羧基荧光素)标记的多肽(5-FAM-IPTSPITTTYFFFKKK-COOH),底物肽FAM-P8 (GL Biochem,货号:112396),终浓度为5μM。
在该试验中,用100%DMSO配制成500μM的化合物溶液,并用100%DMSO 4倍稀释10个浓度梯度,再用化合物缓冲液(50mM HEPES,pH 7.5,0.00015%Brij-35)进一步稀释10倍,配成含10%DMSO的化合物中间稀释溶液,化合物终浓度在10μM-0.04nM范围内,转移5μL至黑色 384孔板中。
将激酶IRAK4用激酶缓冲液(50mM HEPES,pH 7.5,0.00015%Brij-35,2mM DTT)稀释成2.5nM的IRAK4溶液,并转移10μL至384孔板中,与化合物共孵育10-15分钟。
将底物和ATP分别用反应缓冲液(50mM HEPES,pH 7.5,0.00015%Brij-35,10mMMgCl2) 稀释成12.5μM和92.5μM。转移10μL至384孔板,起始反应,并于28℃反应1小时。转移25μL 50mM EDTA至384孔板,终止反应。
用Caliper EZ Reader(PerkinElmer)读取底物磷酸化的转化率,从而计算化合物对IRAK4的抑制率,用XL-fit软件计算IC50。检测结果如下表所示。
本发明化合物对人IRAK4激酶活性的抑制IC50值
化合物编号 | IC<sub>50</sub>(nM) | 化合物编号 | IC<sub>50</sub>(nM) |
001 | 3.6 | 028 | 8.6 |
002 | 6.8 | 040 | 7.8 |
013 | 28 | 041 | 23 |
014 | 7.6 | 068 | 4.4 |
015 | 5.6 | 069 | 6.7 |
017 | 10 | 070 | 4.8 |
018 | 14 | 071 | 10 |
019 | 80 | 072 | 8.4 |
020 | 59 | 073 | 14 |
021 | 22 | 074 | 35 |
022 | 9.7 | 075 | 5.8 |
025 | 1.0 | 077 | 0.89 |
026 | 2.1 | 078 | 3.0 |
027 | 260 | 076 | 5.9 |
并且,本发明其他实施例化合物对人IRAK4激酶活性的抑制IC50值优选为100nM以下,还优选80nM以下,更优选50nM以下。
结论:本发明化合物对人IRAK4活性具有明显的抑制作用。
测试例2.实施例化合物对LPS诱导的人PBMC中细胞因子TNF-α的抑制作用
主要试验材料
新鲜人PBMC(赛笠生物科技)
RPMI 1640培养基(Gibco,目录号A10491-01)
胎牛血清(Gibco,目录号10091-148)
青霉素/链霉素(Gibco,目录号15140-122)
LPS(Sigma,目录号L2630)
Human TNF-αELISA Kit(碧云天,目录号PT518)
DMSO(Sigma,目录号D8418)
实验步骤
体外LPS(脂多糖)诱导的人PBMC(外周血单核细胞)中细胞因子产生,考察发明的化合物对于人PBMC中诱导性细胞因子产生的功效。
新鲜的人PBMC购买自上海赛笠生物科技有限公司。收到PBMC后,立即在室温下450×g离心10分钟并弃去上清液,将PBMC重悬于完全培养基RPMI 1640(Gibco,目录号A10491-01), 10%胎牛血清(Gibco,目录号10091-148),100U/mL青霉素,100μg/mL链霉素(Gibco,目录号15140-122)中。
测定也是在完全培养基中进行。将PBMC以1×105个细胞/孔的细胞密度接种到96孔细胞培养板。将本发明化合物进行一系列稀释,稀释在等溶的100%DMSO中,并以20μM至0.002nM范围内的8个不同浓度应用于测定中,使得最终的DMSO浓度为0.25%DMSO。在实际刺激前,将细胞与配制的发明化合物在37℃预孵育30分钟。为了诱导细胞因子分泌,用0.1μg/mL LPS(Sigma, Escherichia coli O111:B4,目录号L2630)在37℃刺激细胞4小时。然后在室温下450×g离心10 分钟后移取细胞培养后的上清液。
细胞上清液中分泌的TNF-α的量使用Human TNF-αELISA Kit(碧云天,目录号PT518)按照制造商的说明书进行测定。
吸光度A450的读值用酶标仪SpectraMax i3x(Molecular Device)检测,从而计算化合物对的抑制率,用GraphPad Prism 7.0软件计算IC50。
结果表明本发明多个示例性化合物对LPS诱导的人PBMC中细胞因子TNF-α的抑制IC50值为 300nM以下,优选100nM以下,更优选90nM以下,还优选70nM以下,例如50nM以下。
测试例3.实施例化合物对大鼠的PK分析测试
本发明优选实施例的小鼠药物代谢动力学试验,采用雄性SPF级的SD大鼠(上海西普尔-必凯实验动物有限公司)进行。
给药方式:单次灌胃口服给药或单次静脉注射
取样点:给药后5min、0.25、0.5、1、2、4、6、8、24小时
样品处理:静脉采血0.2mL,血液样本采集后置于冰上,离心分离血浆(离心条件:8000转/ 分钟,6分钟,4℃)。收集的血浆分析前存放于-80℃。
内标工作液:吸取一定量的浓度为645,000ng/mL的甲苯磺丁脲内标储备液至一定体积的容量瓶中,用甲醇定容至刻度后混匀,制得浓度为50ng/mL的内标工作溶液。
样品前处理:取50μL血浆样品至1.5mL离心管中,加入250μL内标溶液(空白不加内标补加相同体积的甲醇),涡旋混匀,14000转/分钟离心5分钟,取200μL上清液加入到96孔进样板中,LC-MS/MS进样分析。
液相条件:
色谱柱:ACQUITY UPLC BEH C18 1.7μm(50mm×2.10mm)
移动相:A液为0.1%甲酸水溶液,B液为0.1%甲酸乙腈溶液
流速:0.5mL/min
数据处理系统为Analyst软件(美国应用生物系统公司,软件版本号1.5.5)。
结果表明,本发明实施例化合物具有令人满意的药代性能。
测试例4.实施例化合物对LPS诱导的Balb/c雌性小鼠释放TNF-α的抑制作用
将雌性Balb/c(17~19g,上海吉辉)小鼠随机分成若干组,每组4只,组别包括正常对照+溶媒组、模型+溶媒组、模型+阳性药组及其它模型+测试药组。正常对照组动物接受腹腔注射生理盐水 (10ml/kg),模型动物接收LPS刺激(Sigma货号L2630,腹腔注射,10mL/kg,0.2mg/kg)。实验中测试药依次加入DMSO,Solutol,10mM PBS制成所需给药浓度的溶液或浊液,溶媒各成分DMSO、 Solutol、10mM PBS的终体积比为5:15:80。各实验组按设定剂量在LPS(或saline)刺激前5h进行相应的灌胃给药(10ml/kg),各组动物在刺激后1.5h用CO2安乐死,进行心脏采血。所得全血不抗凝,于湿冰中静置1.5h后2000g,4℃离心10min分离血清。血清-80℃冻存备TNFα测定。TNFα的定量通过TNFαELISA试剂盒(碧云天,货号:PT512),按制造商的使用说明书完成测定。
化合物编号 | TNF-α的抑制率% | 化合物编号 | TNF-α的抑制率% |
001 | 77% | 021 | 68% |
002 | 69% | 026 | 76% |
013 | 70% | 028 | 93% |
014 | 81% | 040 | 61% |
015 | 87% | 072 | 79% |
017 | 74% | 074 | 90% |
018 | 77% |
检测结果表明本发明多个实施例化合物对TNF-α的抑制作用超过60%,优选超过70%,还优选超过80%。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或其药学上可接受的盐,
其中,R1选自H、卤素、氰基、羟基、氨基、无取代或任选被一个、两个或更多个Ra取代的下列基团:C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基、-COOC1-40烷基、-COC1-40烷基、-NHC1-40烷基或-N(C1-40烷基)2;
Ra选自=O、羟基、氨基、氰基、无取代或任选被一个、两个或更多个Rb取代的下列基团:C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基、-COOC1-40烷基或-COC1-40烷基;
Rb选自=O、C1-40烷基、-COOC1-40烷基或-COC1-40烷基;
m选自1-3的数;
R2选自无取代或任选被一个、两个或更多个Rc取代的下列基团:C1-40烷基、C3-20环烷基、3-20元杂环基、C6-20芳基或5-20元杂芳基;
Rc选自卤素、羟基、氨基、无取代或任选被一个、两个或更多个Rd取代的下列基团:C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基、-COOC1-40烷基、-COC1-40烷基、-NHC1-40烷基、-N(C1-40烷基)2、-NHC3-20环烷基或-NH(3-20元杂环基);
Rd选自卤素、C1-40烷基、C3-20环烷基或3-20元杂环基;
R3选自H、无取代或任选被一个、两个或更多个Re取代的下列基团:C1-40烷基、C3-20环烷基、3-20元杂环基、-C1-40烷基-C3-20环烷基、-C1-40烷基-3-20元杂环基、C6-20芳基或5-20元杂芳基;
Re选自卤素、氰基、羟基、氨基、无取代或任选被一个、两个或更多个Rf取代的下列基团:C1-40烷基、C1-40烷氧基、C3-20环烷基、3-20元杂环基;
Rf选自=O、氰基、-C1-40烷基-氰基、羟基、-C1-40烷基-羟基、-COOC1-40烷基、-COC1-40烷基、-NHC1-40烷基、-N(C1-40烷基)2、-SO2C1-40烷基、C1-40烷基、C3-20环烷基或3-20元杂环基。
2.根据权利要求1所述的化合物,其特征在于,R1选自H、无取代或任选被一个、两个或更多个=O、羟基、氰基、C1-12烷基、C3-12环烷基或-COC1-12烷基取代的下列基团:C1-12烷基、C1-12烷氧基、-C1-12烷氧基-3-12元杂环基、3-12元杂环基、C6-12芳基、5-12元杂芳基或-N(C1-12烷基)2;
m选自1-3的数;
R2选自无取代或任选被一个、两个或更多个如下基团取代的C6-12芳基或5-12元杂芳基:卤素、氨基、C1-12烷基、卤代C1-12烷基、C3-12环烷基、3-12元杂环基、-NHC1-12烷基、-NHC3-12环烷基或-NH(3-12元杂环基);
R3选自被一个、两个或更多个如下基团取代的C1-12烷基、C3-20环烷基、-C1-12烷基-C3-12环烷基或-C1-12烷基-3-12元杂环基:羟基、氰基、-C1-12烷基-氰基、C1-12烷基、-C1-12烷基-羟基、C3-12环烷基、3-12元杂环基;
所述C1-12烷基、C3-12环烷基、3-12元杂环基可进一步被一个、两个或更多个如下基团取代:=O、氰基、-C1-12烷基-氰基、C1-12烷基、-COC1-12烷基或-SO2C1-12烷基。
6.一种药物组合物,其特征在于,包含权利要求1-4任一项所述式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或其药学上可接受的盐。
7.根据权利要求6所述的药物组合物,其特征在于,所述药物组合物还包括药学上可接受的载体。
8.根据权利要求6或7所述的药物组合物,其特征在于,所述药物组合物为IRAK4抑制剂;
优选地,所述IRAK4抑制剂用于预防和/或治疗肿瘤、痛风、系统性红斑狼疮、多发性硬化症、代谢综合症、动脉粥样硬化、心肌梗死、脓血症、炎症性肠病、哮喘和过敏等疾病。
9.权利要求1-4任一项所述式(I)所示的化合物、其立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物或其药学上可接受的盐在制备治疗和/或预防与白细胞介素-1受体相关激酶的疾病或病症的药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述与白细胞介素-1受体相关激酶的疾病或病症选自肿瘤、痛风、系统性红斑狼疮、多发性硬化症、代谢综合症、动脉粥样硬化、心肌梗死、脓血症、炎症性肠病、哮喘、类风湿性关节炎、败血症、自身免疫性疾病和过敏等疾病。
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