CN117222634A - 用于治疗与sting活性有关的疾病的化合物和组合物 - Google Patents
用于治疗与sting活性有关的疾病的化合物和组合物 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本公开提供了抑制(例如拮抗)干扰素基因刺激物(STING)的化学实体(例如化合物或药学上可接受的盐和/或水合物和/或共晶体和/或化合物的药物组合)。所述化学实体可用于例如治疗其中STING活化(例如,STING信号转导)的增加(例如,过度)促进对象(例如人)的病状、疾病或病症(例如癌症)的病态/或症状和/或进展的病状、疾病或病症。本发明还提供了包含该化学实体的组合物以及使用和制备该组合物的方法。
Description
相关申请的交叉引用
本申请要求2020年12月16日提交的美国临时专利申请系列号63/126,332的权益,其公开内容通过引用全文纳入本文。
技术领域
本发明提供了抑制(例如拮抗)干扰素基因刺激物(STING)的化学实体(例如化合物或药学上可接受的盐和/或水合物和/或共晶体和/或化合物的药物组合)。所述化学实体可用于例如治疗其中STING活化(例如,STING信号转导)的增加(例如,过度)促进对象(例如人)的病状、疾病或病症(例如癌症)的病态/或症状和/或进展的病状、疾病或病症。本发明还提供了包含该化学实体的组合物以及使用和制备该组合物的方法。
背景技术
STING,也称为跨膜蛋白173(TMEM173)和MPYS/MITA/ERIS,是在人体中由TMEM173基因编码的蛋白质。STING已显示在先天免疫中起作用。当细胞感染细胞内病原体(例如病毒,分枝杆菌和细胞内寄生虫)时,STING会诱导I型干扰素产生。由STING介导的I型干扰素以自分泌和旁分泌方式保护感染的细胞和附近细胞免受局部感染。
STING途径在介导胞质DNA的识别中至关重要。在这种情况下,STING是一种定位于内质网(ER)的跨膜蛋白,它充当2’,3’环状GMP-AMP(以下简称cGAMP)的第二信使受体,由dsDNA结合后cGAS产生。此外,STING还可以用作细菌环状二核苷酸(CDN)和小分子激动剂的主要模式识别受体。内源性或原核CDN的识别通过STING的羧基末端结构域进行,其面向细胞质并产生由STING同型二聚体形成的V形结合袋。配体诱导的STING活化会触发其重新定位到高尔基体,这是促进STING与TBK1相互作用必不可少的过程。这种蛋白质复合物进而通过转录因子IRF-3发出信号,从而诱导I型干扰素(IFN)和其它共同调节的抗病毒因子。此外,显示STING会触发NF-κB和MAP激酶激活。在引发信号转导之后,STING迅速降解,这在终止炎症反应中很重要。
STING的过度活化与单基因自身炎性病症的子集(即所谓的I型干扰素病)有关。这些疾病的例子包括称为婴儿期发作的STING相关血管病(SAVI)的临床综合征,它是由TMEM173(STING的基因名称)中的功能获得性突变引起的。此外,STING参与了艾卡迪-古蒂雷斯综合征(Aicardi-Goutières Syndrome,AGS)的发病机制和遗传形式的狼疮。与SAVI不同,AGS中连续的先天免疫活化是核酸代谢失调的基础。除了这些遗传疾病外,新出现的证据表明STING在一系列与炎症相关的疾病(如系统性红斑狼疮,类风湿性关节炎和癌症)中具有更普遍的致病作用。因此,对STING信号通路的基于小分子的药理干预在治疗多种疾病方面具有巨大潜力。
发明内容
本发明提供了抑制(例如拮抗)干扰素基因刺激物(STING)的化学实体(例如化合物或药学上可接受的盐和/或水合物和/或共晶体和/或化合物的药物组合)。所述化学实体可用于例如治疗其中STING活化(例如,STING信号转导)的增加(例如,过度)促进对象(例如人)的病状、疾病或病症(例如癌症)的病态/或症状和/或进展的病状、疾病或病症。本发明还提供了包含该化学实体的组合物以及使用和制备该组合物的方法。
STING的“拮抗剂”包括在蛋白质水平上直接结合或修饰STING使得STING的活性降低的化合物,例如通过抑制、阻断或减弱激动剂介导的应答,改变分布或其它方式。STING拮抗剂包括干扰或抑制STING信号转导的化学实体。
一方面,本公开的特征在于式I的化合物或其药学上可接受的盐:
其中X1、X2、X3、Y1、Y2、Y3、R3、R4、R5、R6和m可以如本文任何位置处所定义。
一方面,本发明提供了药物组合物,其包括本文所述的化学实体(例如,本文一般或具体描述的化合物或其药学上可接受的盐或包含该化合物的组合物)和一种或多种药学上可接受的赋形剂。
一方面,本发明提供了抑制(例如拮抗)STING活性的方法,包括使STING与本文所述的化学实体(例如本文一般或具体描述的化合物或其药学上可接受的盐或包含该化合物的组合物)接触。方法包括体外方法,例如使包含一个或多个包含STING的细胞(例如先天免疫细胞,例如肥大细胞,巨噬细胞,树突状细胞(DC)和自然杀伤细胞)的样品与所述化学实体接触。方法还可以包括体内方法;例如,将所述化学实体给予患有疾病的对象(例如,人),所述疾病中STING信号转导增加(例如,过量)从而导致该疾病的病理和/或症状和/或进展。
在一方面,本发明提供了治疗病状、疾病或病症的方法,所述病状、疾病或病症通过拮抗STING而改善,其中,STING活化(例如,STING信号转导)的增加(例如,过量)促进对象(例如,人)的病状、疾病或病症的病态/或症状和/或进展。该方法包括向需要这种治疗的对象给予有效量的本文所述的化学实体(例如,本文一般或具体描述的化合物,其药学上可接受的盐或包含其的组合物)。
另一方面,本发明提供了治疗癌症的方法,包括向需要这种治疗的对象给予有效量的本文所述的化学实体(例如,本文一般或具体描述的化合物,其药学上可接受的盐或包含其的组合物)。
在另一方面,本发明提供了治疗其它与STING相关的疾病的方法,例如,I型干扰素病(例如,婴儿期发作的STING相关血管病(SAVI)),艾卡迪-古蒂雷斯综合征(Aicardi-Goutières Syndrome,AGS),遗传形式的狼疮,以及炎症相关疾病,例如系统性红斑狼疮和类风湿关节炎。该方法包括向需要这种治疗的对象给予有效量的本文所述的化学实体(例如,本文一般或具体描述的化合物,其药学上可接受的盐或包含其的组合物)。
在另一方面,本发明提供了抑制有需要的对象中STING依赖性I型干扰素产生的方法,包括给予对象有效量的本文所述的化学实体(例如,本文一般或具体描述的化合物,其药学上可接受的盐或包含其的组合物)。
在另一方面,本发明提供了治疗疾病的方法,其中STING活化(例如,STING信号转导)的增加(例如,过量)促进该疾病的病态/或症状和/或进展。该方法包括向需要这种治疗的对象给予有效量的本文所述的化学实体(例如,本文一般或具体描述的化合物,其药学上可接受的盐或包含其的组合物)。
在另一方面,本发明提供了治疗方法,包括给予对象有效量的本文所述的化学实体(例如,本文一般或具体描述的化合物或其药学上可接受的盐或包含其的组合物);其中,所述对象患有(或倾向于患有)其中STING活化(例如,STING信号转导)的增加(例如,过量)促进该疾病的病态/或症状和/或进展的疾病。
在另一方面,本发明提供了治疗方法,包括给予对象本文所述的化学实体(例如,本文一般或具体描述的化合物或其药学上可接受的盐或包含其的组合物),其中,所述化学实体以有效地治疗其中STING活化(例如,STING信号转导)的增加(例如,过量)促进该疾病的病态/或症状和/或进展的疾病的量给予,从而治疗所述疾病。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体,其用于治疗由STING抑制调节的疾病、病状或病症。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于治疗与增加的(例如过度的)STING活化相关的病状、疾病或病症。
在另一方面,是本文所述的用于治疗癌症的化合物或其药学上可接受的盐或互变异构体。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体,其用于治疗选自下组的癌症:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
在另一方面,是本文所述的用于治疗I型干扰素病的化合物或其药学上可接受的盐或互变异构体。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体,其用于治疗选自以下的I型干扰素病:婴儿期发作的STING-相关的血管病(SAVI),艾卡迪-古蒂雷斯综合征(Aicardi-Goutières Syndrome,AGS)、遗传形式的狼疮,以及炎症相关疾病,例如系统性红斑狼疮和类风湿关节炎。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于制备治疗与增加的(例如过度的)STING活化相关的病状、疾病或病症的药物。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于制备用于治疗癌症的药物。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于制备用于治疗选自下组的癌症的药物:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于制备用于治疗I型干扰素病的药物。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体在制备用于治疗选自下组的I型干扰素病的药物中的用途:婴儿期发作的STING-相关的血管病(SAVI),艾卡迪-古蒂雷斯综合征(Aicardi-Goutières Syndrome,AGS)、遗传形式的狼疮,以及炎症相关疾病,例如系统性红斑狼疮和类风湿关节炎。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体在治疗由STING抑制调节的疾病、病状或病症中的用途。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于治疗与增加的(例如过度的)STING活化相关的病状、疾病或病症的用途。
在另一方面,是本文所述的用于治疗癌症的化合物或其药学上可接受的盐或互变异构体的用途。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于治疗选自下组的癌症的用途:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
在另一方面,是本文所述的用于治疗I型干扰素病的化合物或其药学上可接受的盐或互变异构体的用途。
在另一方面,是本文所述的化合物或其药学上可接受的盐或互变异构体用于治疗选自以下的I型干扰素病的用途:婴儿期发作的STING-相关的血管病(SAVI),艾卡迪-古蒂雷斯综合征(Aicardi-Goutières Syndrome,AGS)、遗传形式的狼疮,以及炎症相关疾病,例如系统性红斑狼疮和类风湿关节炎。
实施方式可包括以下特性中的一项或多项。
该化学实体可以与一种或多种其它治疗剂和/或方案组合给予。例如,方法可以进一步包括给予一种或多种(例如,两种,三种,四种,五种,六种或更多种)其它药剂。
该化学实体可以与一种或多种可用于治疗其它与STING相关的疾病的其它治疗剂和/或方案组合给予,例如,I型干扰素病(例如,婴儿期发作的STING相关血管病(SAVI)),艾卡迪-古蒂雷斯综合征(Aicardi-Goutières Syndrome,AGS),遗传形式的狼疮,以及炎症相关疾病,例如系统性红斑狼疮和类风湿关节炎。
该化学实体可以与一种或多种另外的癌症疗法(例如手术,放疗,化学疗法,毒素疗法,免疫疗法,冷冻疗法或基因疗法,或其组合)组合给予;例如,包括给予一种或多种(例如,两种,三种,四种,五种,六种或更多种)其它化学治疗剂的化学疗法。其它化学治疗剂的非限制性示例选自:烷化剂(例如,顺铂,卡铂,氮芥,环磷酰胺,苯丁酸氮芥,异环磷酰胺和/或奥沙利铂);抗代谢物(例如,硫唑嘌呤和/或巯基嘌呤);萜类化合物(例如,长春花生物碱(vincaalkaloid)和/或紫杉烷;例如长春新碱(vincristine)、长春碱(vinblastine)、长春瑞宾(vinorelbine)和/或长春地辛(vindesine),泰素(taxol),紫杉醇(paclitaxel)和/或多西他赛(docetaxel));拓扑异构酶(例如,I型拓扑异构酶和/或2型拓扑异构酶;例如喜树碱(camptothecin),例如伊立替康(irinotecan)和/或拓扑替康(topotecan);安吖啶(amsacrine),依托泊苷(etoposide),磷酸依托泊苷和/或替尼泊苷(teniposide));细胞毒性抗生素(例如,放线菌素,蒽环霉素(anthracycline),多柔比星,柔红霉素,伐柔比星(valrubicin),伊达比星,表柔比星(epirubicin),博莱霉素(bleomycin),普卡霉素(plicamycin)和/或丝裂霉素(mitomycin));激素(例如,促黄体激素释放的激素激动剂;例如亮丙瑞林(leuprolidine),戈舍瑞林(goserelin),曲普瑞林(triptorelin),组胺瑞林(histrelin),比卡鲁胺(bicalutamide),氟他胺(flutamide)和/或尼鲁米特);抗体(例如,阿昔单抗(Abciximab),阿达木单抗(Adalimumab),阿仑单抗(Alemtuzumab),阿利珠单抗(Atlizumab),巴利昔单抗(Basiliximab),贝利木单抗(Belimumab),贝伐珠单抗(Bevacizumab),本妥昔单抗(Brentuximab Vedotin),康纳单抗(Canakinumab),西妥昔单抗(Cetuximab),培舍珠单抗(Certolizumab pegol),达克珠单抗(Daclizumab),地舒单抗(Denosumab),依库珠单抗(Eculizumab),艾法珠单抗(Efalizumab),吉妥珠单抗(Gemtuzumab),戈利木单抗(Golimumab),替伊莫单抗(Ibritumomabtiuxetan),英利昔单抗(Infliximab),伊匹木单抗(Ipilimumab),莫罗单抗(Muromonab)-CD3,那他珠单抗(Natalizumab),奥伐木单抗(Ofatumumab),奥马珠单抗(Omalizumab),帕利珠单抗(Palivizumab),帕尼单抗(Panitumuab),雷珠单抗(Ranibizumab),利妥昔单抗(Rituximab),妥珠单抗(Tocilizumab),托西莫单抗(Tositumomab)和/或曲妥珠单抗(Trastuzumab);抗血管生成剂;细胞因子;血栓形成活性剂;生长抑制剂;抗蠕虫剂;及靶向选自以下的免疫检查点受体的免疫检查点抑制剂:CTLA-4,PD-1,PD-L1,PD-1–PD-L1,PD-1–PD-L2,白介素-2(IL-2),吲哚胺2,3-双加氧酶(IDO),IL-10,转化生长因子-β(TGFβ),T细胞免疫球蛋白及粘蛋白3(TIM3或HAVCR2),半乳凝素9-TIM3,磷脂酰丝氨酸-TIM3,淋巴细胞活化基因3蛋白(LAG3),MHC II类–LAG3,4-1BB–4-1BB配体,OX40–OX40配体,GITR,GITR配体–GITR,CD27,CD70-CD27,TNFRSF25,TNFRSF25–TL1A,CD40L,CD40–CD40配体,HVEM–LIGHT–LTA,HVEM,HVEM–BTLA,HVEM–CD160,HVEM–LIGHT,HVEM–BTLA–CD160,CD80,CD80–PDL-1,PDL2–CD80,CD244,CD48–CD244,CD244,ICOS,ICOS–ICOS配体,B7-H3,B7-H4,VISTA,TMIGD2,HHLA2–TMIGD2,嗜乳脂蛋白,包括BTNL2,Siglec家族,TIGIT和PVR家族成员,KIRs,ILTs和LIRs,NKG2D和NKG2A,MICA和MICB,CD244,CD28,CD86–CD28,CD86–CTLA,CD80–CD28,CD39,CD73腺苷–CD39–CD73,CXCR4–CXCL12,磷脂酰丝氨酸,TIM3,磷脂酰丝氨酸–TIM3,SIRPA–CD47,VEGF,神经毡蛋白(Neuropilin),CD160,CD30,和CD155(例如,CTLA-4或PD1或PD-L1)。
对象可能患有癌症;例如,对象已经历和/或正在经历和/或将经历一种或多种癌症治疗。
癌症的非限制性示例包括:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合症,多发性骨髓瘤,移行细胞癌,成神经细胞瘤,浆细胞瘤,威尔姆氏肿瘤或肝细胞癌。在一些实施方式中,癌症可以是难治性癌症。
化学实体可以瘤内给予。
该方法可以进一步包括识别对象。
其它实施方式包括在具体实施方式和/或权利要求中描述的内容。
其它定义
为了促进对本文阐述的公开的理解,下面定义了多个其它术语。通常,本文所用的命名法和本文所述的有机化学、药物化学和药理学的实验室程序是本领域众所周知的和常用的。除非另外定义,否则,本文中所使用的所有技术和科学术语都具有本文所属领域普通技术人员通常所理解的含义。整个说明书中提到的每篇专利、申请、公开的申请和其它出版物以及所附的附录均通过引用全文并入本文。
如本文所用,术语“STING”旨在包括但不限于核酸,多核苷酸,寡核苷酸,有义和反义多核苷酸链,互补序列,肽,多肽,蛋白质,同源和/或直系STING分子,同种型,前体,突变体,变体,衍生物,剪接变体,等位基因,不同物种及其活性片段。
如本文所用,就制剂、组合物或成分而言,术语“可接受的”是指对所治疗的对象的总体健康没有持续的有害影响。
“API”是指活性药物成分。
如本文所用,术语“有效量”或“治疗有效量”是指足以在某种程度上缓解所治疗疾病或病症的一种或多种症状的化学实体的量。结果包括减少和/或减轻疾病的体征、症状、或疾病原因,或生物系统的任何其它所需改变。例如,用于治疗用途的“有效量”是包含本文公开的化合物以提供临床上显著减轻疾病症状所需的量。在任何情况下,都可以使用任何适当的技术(例如剂量递增研究)来确定合适的“有效”量。
术语“赋形剂”或“药学上可接受的赋形剂”是指药学上可接受的材料、组合物或载剂,例如液体或固体填充剂、稀释剂、载体、溶剂或包封材料。在一个实施方式中,每种组分在与药物制剂的其他成分相容的意义上是“药学上可接受的”,并且适合与人和动物的组织或器官接触而没有过度的毒性、刺激性、过敏反应、免疫原性或其他问题或并发症,与合理的获益/风险比相称。例如,参见《雷明顿药物科学与实践》(Remington:The Science andPractice of Pharmacy),第21版;LWW出版公司(Lippincott Williams&Wilkins):宾夕法尼亚州费城,2005;《药物赋形剂手册》(Handbook of Pharmaceutical Excipients),第6版;Rowe等编,药学出版社和美国药学会(The Pharmaceutical Press and the AmericanPharmaceutical Association):2009:《药物添加剂手册》(Handbook of PharmaceuticalAdditives),第3版;Ash和Ash编著,高尔出版公司(Gower Publishing Company):2007;《药物预制剂和制剂》(Pharmaceutical Preformulation and Formulation),第2版,Gibson编,CRC出版有限公司(CRC Press LLC):佛罗里达州博卡拉顿,2009)。
术语“药学上可接受的盐”是指化合物的制剂,其不会对其施用的生物造成明显的刺激并且不会消除该化合物的生物学活性和特性。在一些情况下,药学上可接受的盐是通过使本文所述的化合物与酸,例如盐酸、氢溴酸、硫酸、硝酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等反应获得的。在一些情况下,通过使本文所述的具有酸性基团的化合物与碱反应形成盐,例如铵盐,碱金属盐,例如钠或钾盐,碱土金属盐,例如钙盐或镁盐,有机碱的盐,例如二环己胺,N-甲基-D-葡萄糖胺,三(羟甲基)甲胺,以及与氨基酸形成的盐,例如精氨酸,赖氨酸等,或通过先前确定的其它方法。对药学上可接受的盐没有特别限制,只要其可以用于药物即可。本文所述化合物与碱形成的盐的示例包括如下:与无机碱形成的盐,例如钠、钾、镁、钙和铝;与有机碱(例如甲胺、乙胺和乙醇胺)形成的盐;与赖氨酸和鸟氨酸等碱性氨基酸形成的盐;以及铵盐。所述盐可以是酸加成盐,其具体例子为以下酸加成盐:无机酸,如盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸:有机酸,如甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸和乙磺酸;酸性氨基酸,如天冬氨酸和谷氨酸。
术语“药物组合物”是指本文所述的化合物与其它化学组分(本文统称为“赋形剂”)的混合物,所述化学组分例如为载体、稳定剂、稀释剂、分散剂、助悬剂和/或增稠剂。药物组合物促进化合物向生物体的给药。本领域存在多种施用化合物的技术,包括但不限于:直肠、口服、静脉内、气溶胶、胃肠外、眼、肺部和局部给药。
术语“对象”可以指动物,包括但不限于灵长类动物(例如人)、猴、牛、猪、绵羊、山羊、马、狗、猫、兔、大鼠或小鼠。术语“对象”和“患者”在本文中可互换使用,例如指哺乳动物对象,例如人对象。
在治疗疾病、病症或病状的上下文中,术语“治疗”、“处理”和“疗法”旨在包括减轻或消除疾病、病症或病状或与疾病,疾病或状况有关的一种或多种症状;或减慢疾病、病症或病状或其一种或多种症状的进展、扩散或恶化。“癌症治疗”是指以下作用中的一或多个:(1)在一定程度上抑制肿瘤生长,包括(i)减缓及(ii)完全的生长阻止;(2)减少肿瘤细胞数目;(3)维持肿瘤尺寸;(4)减小肿瘤尺寸;(5)抑制,包括(i)减少、(ii)减缓或(iii)完全防止肿瘤细胞浸润于周边器官中;(6)抑制,包括(i)减少、(ii)减缓或(iii)完全防止癌转移;(7)增强抗肿瘤免疫反应,其可(i)维持肿瘤尺寸,(ii)减小肿瘤尺寸,(iii)减缓肿瘤生长,(iv)减少、减缓或防止侵袭和/或(8)在一定程度上减轻与障碍相关的一或多种症状的严重性或数目。
术语“卤(素)”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“烷基”是指可以是直链或支链的无环饱和烃链,其包含所示数目的碳原子。例如,C1-10表示该基团中可以具有1至10个(含)碳原子。烷基可以是未取代的或被一个或多个取代基取代。非限制性示例包括甲基、乙基、异丙基、叔丁基、正己基。在本文中使用的术语“”饱和“”是指仅存在于组成碳原子和由氢和/或本文定义的其他取代基占据的其他可用价之间的单键。
术语“卤代烷基”是指其中一个或多个氢原子被独立选择的卤素取代的烷基。
术语“烷氧基”是指-O-烷基(例如,-OCH3)。
术语“亚烷基”是指二价烷基(例如,-CH2-)。
术语“烯基”是指可以是具有一个或多个碳-碳双键的直链或支链的无环烃链。烯基部分包含指定数目的碳原子。例如,C2-6表示该基团中可以具有2至6个(含)碳原子。烯基可以是未取代的或被一个或多个取代基取代。
术语“炔基”是指可以是具有一个或多个碳-碳三键的直链或支链的无环烃链。炔基部分包含指定数目的碳原子。例如,C2-6表示该基团中可以具有2至6个(含)碳原子。炔基可以是未取代的或被一个或多个取代基取代。
术语“芳基”是指6-20个碳的单环、双环、三环或多环基团,其中系统中的至少一个环是芳族的(例如6-碳单环,10-碳双环或14-碳三环芳族环系统);以及其中每个环的0、1、2、3或4个原子可以被取代基取代。芳基的实例还包括苯基、萘基、四氢萘基、二氢-1H-茚基等。
本文所用的术语“环烷基”是指具有例如3至20个环碳,优选3至16个环碳,并且更优选3至12个环碳或3-10个环碳或3-6个环碳的环状饱和烃基,其中环烷基可以任选地被取代。环烷基的实例包括但不限于环丙基,环丁基,环戊基,环己基,环庚基和环辛基。环烷基可包括多个稠合和/或桥环。稠合/桥接环烷基的非限制性示例包括:双环[1.1.0]丁烷基,双环[2.1.0]戊烷基,双环[1.1.1]戊烷基,双环[3.1.0]己烷基,双环[2.1.1]己烷基,双环[3.2.0]庚烷基,双环[4.1.0]庚烷基,双环[2.2.1]庚烷基,双环[3.1.1]庚烷基,双环[4.2.0]辛烷基,双环[3.2.1]辛烷基,双环[2.2.2]辛烷基,等等。环烷基还包括螺环(例如,螺环双环,其中两个环仅通过一个原子连接)。螺环环烷基的非限制性示例包括:螺[2.2]戊基、螺[2.5]辛基、螺[3.5]壬基、螺[3.5]壬基、螺[3.5]壬基、螺[4.4]壬基、螺[2.6]壬基、螺[4.5]癸基、螺[3.6]癸基、螺[5.5]十一烷基等。在本文中使用的术语“饱和”是指仅存在于组成碳原子之间的单键。
本文所用的术语“环烯基”表示具有3至20个环碳,优选3至16个环碳,并且更优选3至12个环碳或3-10个环碳或3-6个环碳的部分不饱和环烃基,其中环烯基可以任选地被取代。环烯基的实例包括但不限于环戊烯基,环己烯基,环庚烯基和环辛烯基。作为部分不饱和的环状烃基,环烯基可以具有任何程度的不饱和度,条件是环中存在一个或多个双键,环系统中的环都不是芳族的,并且环烯基总体上不完全饱和。环烯基可包括多个稠环和/或桥环和/或螺环。
本文所用,术语“杂芳基”是指具有5至20个环原子,或者5、6、9、10或14个环原子的单,双,三或多环基团;并且在环状阵列中共享6、10或14个π电子;其中系统中的至少一个环是芳族的,并且系统中的至少一个环包含一个或多个独立地选自N、O和S的杂原子(但不必是包含杂原子的环,例如四氢异喹啉基,例如四氢喹啉基)。杂芳基基团可以是未取代的或被一个或多个取代基取代。杂芳基的实例包括:噻吩基、吡啶基、呋喃基、噁唑基、噁二唑基、吡咯基、咪唑基、三唑基、噻二唑基(thiodiazolyl)、吡唑基、异噁唑基、噻重氮基(thiadiazolyl)、吡喃基、吡嗪基、嘧啶基、哒嗪基、三嗪基、噻唑基苯并噻吩基、苯并噁二唑基、苯并呋喃基、苯并咪唑基、苯并三唑基、噌啉基、吲唑基、吲哚基、异喹啉基、异噻唑基、萘啶基、嘌呤基、噻吩并吡啶基、吡啶并[2,3-d]嘧啶基、吡咯并[2,3-b]吡啶基、喹唑啉基、喹啉基、噻吩并[2,3-c]吡啶基、吡唑并[3,4-b]吡啶基、吡唑并[3,4-c]吡啶基、吡唑并[4,3-c]吡啶、吡唑并[4,3-b]吡啶基、四唑基、色原烷、2,3-二氢苯并[b][1,4]二氧杂环己烯、苯并[d][1,3]间二氧杂环戊烯、苯并[d]噻唑基2,3-二氢苯并呋喃、四氢喹啉、2,3-二氢苯并[b][1,4]氧硫杂环己二烯(oxathiine)、吲哚啉基、异吲哚啉基等。在一些实施方式中,杂芳基选自:噻吩基、吡啶基、呋喃基、吡唑基、咪唑基、异吲哚基、吡喃基、吡嗪基和嘧啶基。
术语“杂环基”是指具有3-16个环原子(例如5-8元单环,8-12元双环或11-14元三环的单环,双环,三环或多环饱和环系统),具有1-3个杂原子(如果是单环的话),1-6个杂原子(如果是双环的话)或1-9个杂原子(如果是三环或多环的话),所述杂原子选自O,N或S(例如,如果分别为单环,双环或三环,具有碳原子和1-3、1-6或1-9个选自N、O或S的杂原子),其中每个环的0、1、2或3个原子可以被取代基取代。杂环基的实例包括哌嗪基,吡咯烷基,二噁烷基,吗啉基,四氢呋喃基等。杂环基可包括多个稠合和/或桥环。稠合/桥接的杂环基的非限制性示例包括:2-氮杂双环[1.1.0]丁基、2-氮杂双环[2.1.0]戊基、2-氮杂双环[1.1.1]戊基、3-氮杂双环[3.1.0]己基、5-氮杂双环[2.1.1]己基、3-氮杂双环[3.2.0]庚基、八氢环戊[c]吡咯基、3-氮杂双环[4.1.0]庚基、7-氮杂双环[2.2.1]庚基、6-氮杂双环[3.1.1]庚基、7-氮杂双环[4.2.0]辛基、2-氮杂双环[2.2.2]辛基、3-氮杂双环[3.2.1]辛基、2-氧杂双环[1.1.0]丁基、2-氧杂双环[2.1.0]戊基、2-氧杂双环[1.1.1]戊基、3-氧杂双环[3.1.0]己基、5-氧杂双环[2.1.1]己基、3-氧杂双环[3.2.0]庚基、3-氧杂双环[4.1.0]庚基、7-氧杂双环[2.2.1]庚基、6-氧杂双环[3.1.1]庚基、7-氧杂双环[4.2.0]辛基、2-氧杂双环[2.2.2]辛基、3-氧杂双环[3.2.1]辛基等。杂环基还包括螺环(例如,螺环双环,其中两个环仅通过一个原子连接)。螺环杂环基的非限制性示例包括:2-氮杂螺[2.2]戊基、4-氮杂螺[2.5]辛基、1-氮杂螺[3.5]壬基、2-氮杂螺[3.5]壬基、7-氮杂螺[3.5]壬基、2-氮杂螺[4.4]壬基、6-氮杂螺[2.6]壬基、1,7-二氮杂螺[4.5]]癸基、7-氮杂螺[4.5]]癸基、2,5-二氮杂螺[3.6]]癸基、3-氮杂螺[5.5]十一烷基、2-氧杂螺[2.2]戊基、4-氧杂螺[2.5]辛基、1-氧杂螺[3.5]壬基、2-氧杂螺[3.5]壬基、7-氧杂螺[3.5]壬基、2-氧杂螺[4.4]壬基、6-氧杂螺[2.6]壬基、1,7-二氧杂螺[4.5]癸基、2,5-二氧杂螺[3.6]癸基、1-氧杂螺[5.5]十一烷基、3-氧杂螺[5.5]十一烷基、3-氧杂-9-氮杂螺[5.5]十一烷基等。在本文中使用的术语“饱和”是指仅存在于组成环原子和由氢和/或本文定义的其他取代基占据的其他可用价之间的单键。
文中所用的术语“杂环烯基”是指具有3-16个环原子的部分不饱和环体系(例如5-8元单环,8-12元双环或11-14元三环体系),如果是单环则具有1-3个杂原子,如果是双环则具有1-6个杂原子,或者如果是三环或多环则具有1-9个杂原子),所述杂原子选自O,N或S(例如,碳原子和分别对应单环、双环或三环的1-3、1-6或1-9个N,O或S的杂原子),其中每个环的0、1、2或3个原子可以被取代基取代。杂环烯基的实例包括但不限于四氢吡啶基、二氢吡嗪基、二氢吡啶基、二氢吡咯基、二氢呋喃基、二氢噻吩基。作为部分不饱和的环状基团,杂环烯基可以具有任何程度的不饱和度,条件是环中存在一个或多个双键,环系统中的环都不是芳族的,并且杂环烯基总体上不完全饱和。杂环烯基可包括多个稠环和/或桥环和/或螺环。
如本文所用,当环被描述为“芳(香)族”时,意味着所述环具有连续的、离域的π-电子系统。通常,平面外π电子的数量对应于Hückel规则(4n+2)。这类环的实例包括:苯、吡啶、嘧啶、吡嗪、哒嗪、吡啶酮、吡咯、吡唑、噁唑、噻唑、异噁唑、异噻唑等。
如本文所用,当环被描述为“部分不饱和”时,意味着所述环具有一个或多个额外的不饱和度(除了归因于环本身的不饱和度外另外具有的;例如,构成环的原子之间的一个或多个双键或三键),前提是该环不是芳族的。这类环的实例包括:环戊烯、环己烯、环庚烯、二氢吡啶、四氢吡啶、二氢吡咯、二氢呋喃、二氢噻吩等。
为避免疑义,除非另有说明,环和环状基团(例如,本文所述的芳基、杂芳基、杂环基、杂环烯基、环烯基、环烷基等)含有足够数量的环原子以形成双环或更高级的环系统(例如,三环、多环系统),应理解此类环和环状基团包括具有稠合环的那些,包括以下情况:(i)稠合位点位于相邻环原子上(例如,[x.x.0]环系统,其中0表示零原子桥(例如);(ii)稠合位点位于单个环原子(螺稠环系统)(例如/>),或(iii)稠合位点位于连续的环原子阵列(所有桥长>0的桥环系统)(例如/>)。
另外,构成本实施方式的化合物的原子旨在包括此类原子的所有同位素形式。本文所用的同位素包括具有相同原子序数但质量数不同的那些原子。作为一般示例而非限制,氢的同位素包括氚和氘,而碳的同位素包括13C和14C。
另外,本文一般或具体公开的化合物旨在包括所有互变异构形式。因此,例如,包含部分的化合物涵盖包含/>部分的互变异构形式。类似地,描述为任选地被羟基取代的吡啶基或嘧啶基部分包括吡啶酮或嘧啶酮互变异构形式。
附图和以下说明进一步详细说明了本发明的一种或多种实施方式。从本文说明、附图以及权利要求书还可清楚地看出本发明的其它特征、目的和优势。
具体实施方式
本发明提供了抑制(例如拮抗)干扰素基因刺激物(STING)的化学实体(例如化合物或药学上可接受的盐和/或水合物和/或共晶体和/或化合物的药物组合)。所述化学实体可用于例如治疗其中STING活化(例如,STING信号转导)的增加(例如,过度)促进对象(例如人)的病状、疾病或病症(例如癌症)的病态/或症状和/或进展的病状、疾病或病症。本发明还提供了包含该化学实体的组合物以及使用和制备该组合物的方法。
式I的化合物
一方面,本发明提供式I的化合物或其药学上可接受的盐或互变异构体:
其中:
R4和R5根据(AA)或(BB)定义:
(AA)
R4选自下组:
·任选地被1-6个Ra取代的C1-15烷基;和
·-(YA1)n-YA2,其中:
οn是0或1;
οYA1是任选地被1-3个Ra个取代的C1-3亚烷基;和
οYA2选自下组:
·C3-10环烷基或C3-10环烯基,其各自任选地被1-6个RY取代;
·具有3-10个环原子的杂环基或杂环烯基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂环基或杂环烯基任选地被1-6个RY取代;
·具有5-10个环原子的杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的C6-10芳基;
每次出现的RY独立地选自下组:氧代、Rc、Rb和-(Lb)b-Rb;
条件是当YA2是苯基或单环杂芳基,其各自任选地被1-4个RY取代,那么每次出现的RY独立地选自下组:-Rc、Rb和-(Lb)b-Rb;
R5是H或Rd;或
(BB)
R4和R5与其各自连接的氮原子形成4-12个环原子的饱和、部分不饱和或芳环,其中0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb;
M是0、1、2或3;
每次出现的R6独立地选自:Rc、Rb和-(Lb)b-Rb;
R3选自下组:H和Rd;
Y1选自下组:CR1a和N;
Y2选自下组:CR1b和N;
Y3选自下组:CR1c和N;
X1选自下组:CR1d、N、N(R2)、O和S;
X2选自下组:CR1e、N、N(R2)、O和S;
X3选自下组:CR1f、N、N(R2)、O和S,
条件是X1、X2和X3中的1-3个独立地选自下组:N、N(R2)、O和S;
各独立地为单键或双键,条件是包含X1、X2和X3的五元环是芳族的,并且包含Y1、Y2和Y3的六元环是芳族的;
R1a、R1b和R1c各自独立地选自:H、-(Lb)b-Rb、Rb和Rc;
R1d、R1e和R1f各自独立地选自下组:H、-Lb-Rb、Rb和Rc;
每次出现的R2独立地选自:H、Rd、-(Lb)b-Rb和Rb;
每次出现的Ra独立地选自下组:–OH;-卤素;–NReRf;C1-4烷氧基;C1-4卤代烷氧基;-C(=O)O(C1-4烷基);-C(=O)(C1-4烷基);-C(=O)OH;-CONR’R”;-S(O)1-2NR’R”;-S(O)1-2(C1-4烷基);和氰基;
每次出现的Rb独立地选自下组:
·C3-10环烷基或C3-10环烯基,其各自任选地被1-4个Rc取代;
·具有3-10个环原子的杂环基或杂环烯基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且所述杂环基或杂环烯基任选地被1-4个Rc取代;
·具有5-10个环原子的杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-4个Rc取代;和
·任选地被1-4个Rc取代的C6-10芳基;
每次出现的Lb独立地选自下组:-O-、-NH-、-NRd、-S(O)0-2、C(O)和任选地被1-3个Ra取代的C1-3亚烷基;
每次出现的b独立地是1、2或3;
每次出现的Rc独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代,C2-6烯基;C2-6炔基;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-S(O)(=NH)(C1-4烷基);-NReRf;–OH;-S(O)1- 2NR’R”;-C1-4硫代烷氧基;-C1-4硫代卤代烷氧基;-NO2;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;-C(=O)NR’R”;和–SF5;
每次出现的Rd独立地选自下组:任选地被1-3个独立选择的Ra取代的C1-6烷基;-C(O)(C1-4烷基);-C(O)O(C1-4烷基);-CONR’R”;-S(O)1-2NR’R”;-S(O)1-2(C1-4烷基);-OH;和C1-4烷氧基;
每次出现的Re和Rf独立地选自下组:H;任选地被各自独立地选自下组的1-3个取代基取代的C1-6烷基:NR’R”、-OH、卤素、C1-4烷氧基和C1-4卤代烷氧基;-C(O)R”’;-C(O)OR”’;-CONR’R”;-C(=O)C(=O)R”’;-S(O)1-2NR’R”;-S(O)1-2R”’;-OH;和C1-4烷氧基;
每次出现的R’和R”独立地选自下组:H;-OH;和C1-4烷基,其任选地被各自独立地选自下组的1-3个取代基取代:卤素、氰基、C1-4烷氧基、C1-4卤代烷氧基和–OH;和
R”’选自下组:H;和C1-4烷基,其任选地被各自独立地选自下组的1-3个取代基取代:卤素、氰基、C1-4烷氧基、C1-4卤代烷氧基和–OH。
在一些实施方式中,条件是当所述化合物是具有式
的化合物时,R1f不是/>其中Rd2是H或Rd。
在一些实施方式中,化合物不是具有式 的化合物。在一些实施方式中,Rf不是/>其中Rd2是H或Rd。
在一些实施方式中,化合物不是:
在一些实施方式中,化合物不是2020年6月12日提交的PCT/US2020/037403中公开的化学实体,其全文通过引用并入本文。在一些实施方式中,化合物不是2020年6月12日提交的PCT/US2020/037403的表C1中描绘的化学物,其全文通过引用并入本文。
在这些实施方式中的某些中,化合物不是:
在一些实施方式中,式(I)化合物是式(I-a)化合物或其药学上可接受的盐:
在这些实施方式的某些中,式(I)化合物是式(I-a1)化合物或其药学上可接受的盐:
变量m
在式(I)、(I-a)或(I-a1)的一些实施方式中,m是1、2或3。在这些实施方式的某些中,m是1或2。例如,m可以是1。
在某些实施方式中,式(I)的化合物是式(I-a1-a)的化合物或其药学上可接受的盐:
其中:
m1是0或1。
在式(I-a1-a)的某些实施方式中,m1是0。
变量R4和R5
R4和R5根据(AA)定义的实施方式:
变量R4
在(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中式、R4和R5根据(AA)定义。
在这些实施方式的某些中,R4是-(YA1)n-YA2。
在某些前述实施方式中,n是0。
在某些实施方式中(当R4是-(YA1)n-YA2时),YA2选自下组:
·具有5-10个环原子的杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的C6-10芳基。
在这些实施方式的某些中,YA2选自下组:
·具有5-6个环原子的单环杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
在某些实施方式中,YA2选自下组:
·具有6个环原子的单环杂芳基,其中1-3个环原子是环氮原子,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
作为前述实施方式的非限制性示例,YA2可以是苯基或吡啶基,其各自被1-3个RY取代。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的某些实施方式中,YA2是苯基,其被1-3个RY取代。
在这些实施方式的某些中,YA2选自下组:
在式(I)、(I-a)、(I-a1)或(I-a1-a)的某些实施方式中,YA2是吡啶基,其被1-3个RY取代。
在这些实施方式的某些中,YA2是3-吡啶基,其被1-2个RY取代。
在某些前述的实施方式中,YA2选自下组:
在式(I)、(I-a)、(I-a1)或(I-a1-a)的某些实施方式中,YA2选自下组:
·具有8-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C8-10芳基。
在这些实施方式的某些中,YA2选自下组:
·具有9-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C9-10芳基。
在某些前述实施方式中,YA2是其中,环B是具有5-6个环原子的芳族或部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代;和m2是0或1。
在某些实施方式中(当YA2是时),环B是具有5-6个环原子的芳环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中环B任选地被1-3个RY取代。
在某些实施方式中,环B是具有5-6个环原子的芳环,其中,1-2个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中环B任选地被1-3个RY取代。
作为非限制的示例(当YA2是时),YA2可以选自下组:
在某些实施方式中(当YA2是时),环B连同与稠合苯环共有的sp2碳原子是具有5-6个环原子的部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代。/>
为了避免疑问,当YA2是且环B连同与稠合苯环共有的sp2碳原子是部分不饱和环,其旨在涵盖YA2环系统,例如下述:/>
作为前述实施方式的非限制性示例,YA2可以选自下组:
变量R5
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,R5是H。
R4和R5根据(BB)定义的实施方式:
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中式、R4和R5根据(BB)定义。
在这些实施方式的某些中,R4和R5与其各自连接的氮原子形成4-12个环原子的饱和环,其中,0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb。
在前述实施方式的某些中,R4和R5与其各自连接的氮原子形成4-8个环原子的饱和环,其中,0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb。
在某些实施方式中,R4和R5与其各自连接的氮原子形成:其中Z1选自下组:N(Rd);-O-;和C(RZ)2、其中,各RZ独立地选自下组:H、Rc、Rb和-(Lb)b-Rb。
在某些实施方式中,R4和R5与其各自连接的氮原子形成:其中,RZ选自下组:任选地被1-6个独立选择的卤素取代的C1-6烷基;C1-4烷氧基;C1-4卤代烷氧基;Rb;和-O-Rb(例如,–O-苯基,其中,苯基任选地被1-2个Rc取代)。/>
在某些实施方式中,R4和R5与其各自连接的氮原子形成:其中,各RZ独立地选自下组:卤素(例如,–F);和任选地被1-6个独立选择的卤素取代的C1-6烷基。
在某些实施方式中,R4和R5与其各自连接的氮原子形成:其中,Rd是任选地被1-3个独立选择的Ra取代的C1-6烷基。
变量RY
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中、各RY是独立选择的Rc。
在这些实施方式的某些中,各RY独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”。
在某些前述的实施方式中,各RY独立地选自下组::卤素(例如,–F或–Cl);氰基;C1-6烷基(例如,甲基、乙基、异丙基或叔丁基);被1-6个独立选择的卤素取代的C1-6烷基(例如,CF3或CH2CF3);C1-4烷氧基(例如,甲氧基);C1-4卤代烷氧基(例如,OCF3、OCF2H或OCH2CF3);和-C(=O)NR’R”(例如,–C(=O)NHCH3)。
变量R6
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,每次出现的R6是独立选择的Rc。
在这些实施方式的某些中,每次出现的R6独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”。
在某些实施方式中,一次出现的R6是氰基。
在某些实施方式中,一次出现的R6是卤素。
在某些实施方式中,一次出现的R6是C1-10烷基,其任选地被1-6个独立选择的Ra取代。例如,一次出现的R6可以是C1-6烷基,其任选地被1-6个独立选择的卤素取代。
在某些实施方式中,一次出现的R6选自下组:任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1- 2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”。
变量Y1、Y2、Y3、X1、X2和X3
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,Y1是CR1a。
在这些实施方式的某些中,R1a是H。
在某些实施方式中(当Y1是CR1a),R1a选自下组:-(Lb)b-Rb、Rb和Rc。在这些实施方式的某些中,R1a是Rc。例如,R1a可以是卤素(例如,-Cl)。
在某些实施方式中(当Y1是CR1a),R1a是Rb。在某些实施方式中(当Y1是CR1a)、R1a是-(Lb)b-Rb。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,Y2是CR1b。在这些实施方式的某些中,Y2是CH。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,Y3是CR1c。在这些实施方式的某些中,Y3是CH。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的某些实施方式中,Y1是CH;Y2是CH;且Y3是CH。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,Y1是CR1a,其中,R1a选自下组:-(Lb)b-Rb、Rb和Rc;Y2是CH;并且Y3是CH。在这些实施方式的某些中,R1a是Rc。例如,R1a可以是卤素(例如,-Cl)。在某些实施方式中,R1a是-(Lb)b-Rb或Rb。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,X1是N(R2)。在这些实施方式的某些中,X1是N(H)。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,X2是CR1e。在这些实施方式的某些中,X2是CH。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,X3是CR1f。
在这些实施方式的某些中,X3是CH。
在某些实施方式中,R1f选自下组:-Lb-Rb、Rb和Rc。在这些实施方式的某些中,R1f是Rc。在某些实施方式中,R1f是–Lb-Rb或–Rb。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的某些实施方式中,X1是N(H);X2是CH;且X3是CH。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的某些实施方式中,X1是N(H);X2是CH;且X3是CR1f,其中,R1f选自下组:-Lb-Rb、Rb和Rc。在这些实施方式的某些中,R1f是Rc。在某些实施方式中,R1f是–Lb-Rb或Rb。
在式(I)、(I-a)、(I-a1)或(I-a1-a)的某些实施方式中,所述部分是/>
在这些实施方式的某些中,R2是H。
在的某些实施方式中,R1a是H;且R1f是H。在这些实施方式的某些中,R2是H。/>
在的某些实施方式中,R1a是卤素(例如,-Cl);且R1f是H。在这些实施方式的某些中,R2是H。
在的某些实施方式中,R1a是H;且R1f选自下组:-Lb-Rb、Rb和Rc。例如,R1f是Rc。在这些实施方式的某些中,R2是H。
在的某些实施方式中,R1a选自下组:-(Lb)b-Rb、Rb和Rc;和R1f是H。在这些实施方式的某些中,R2是H。
在的某些实施方式中,R1a选自下组:-(Lb)b-Rb、Rb和Rc;且R1f选自下组:-Lb-Rb、Rb和Rc。例如,R1a和R1f各自可以是独立选择的Rc。在这些实施方式的某些中,R2是H。
变量R3
在式(I)、(I-a)、(I-a1)或(I-a1-a)的一些实施方式中,R3是H。
非限制性组合
在某些实施方式中,式(I)的化合物是式(I-a1-a1)的化合物或其药学上可接受的盐:
式(I-a1-a1),
其中:
m1是0或1;和
R4是-YA2,其中YA2选自下组:
·具有5-6个环原子的单环杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
在式(I-a1-a1)的某些实施方式中,R4选自下组:
·具有6个环原子的单环杂芳基,其中1-3个环原子是环氮原子,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
在这些实施方式的某些中,R4是苯基或吡啶基,其各自被1-3个RY取代。
在式(I-a1-a1)的某些实施方式中,YA2选自下组:
在某些实施方式中,式(I)的化合物是式(I-a1-a2)的化合物或其药学上可接受的盐:
其中:
m1是0或1;和
R4是-YA2,其中YA2选自下组:
·具有9-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C9-10芳基。
在式(I-a1-a2)的某些实施方式中,R4是其中,环B是具有5-6个环原子的芳族或部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代;和m2是0或1。
在这些实施方式的某些中,环B是具有5-6个环原子的芳环,其中,1-2个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中环B任选地被1-4个RY取代。
作为前述实施方式的非限制性示例,R4可以选自下组:
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在式(I-a1-a2)的某些实施方式中,R4是其中,环B连同与稠合苯环共有的sp2碳原子是具有5-6个环原子的部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代。
为了避免疑问,当YA2是且环B连同与稠合苯环共有的sp2碳原子是部分不饱和环,其旨在涵盖环系统,例如下述:/>
作为前述实施方式的非限制性示例,R4可以选自下组:
在式(I-a1-a1)或(I-a1-a2)的某些实施方式中,各RY是独立选择的Rc。
在式(I-a1-a1)或(I-a1-a2)的某些实施方式中,各RY独立地选自下组:卤素(例如,–F或–Cl);氰基;C1-6烷基(例如,甲基、乙基、异丙基或叔丁基);被1-6个独立选择的卤素取代的C1-6烷基(例如,CF3或CH2CF3);C1-4烷氧基(例如,甲氧基);C1-4卤代烷氧基(例如,OCF3、OCF2H或OCH2CF3);和-C(=O)NR’R”(例如,–C(=O)NHCH3)。
在某些实施方式中,式(I)的化合物是式(I-a1-a3)的化合物或其药学上可接受的盐:
其中:
m1是0或1;和
R4和R5与其各自连接的氮原子形成4-8个环原子的饱和环,其中0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb。
在式(I-a1-a3)的某些实施方式中,R4和R5与其各自连接的氮原子形成:其中Z1选自下组:N(Rd);-O-;和C(RZ)2、其中,各RZ独立地选自下组:H、Rc、Rb和-(Lb)b-Rb。
在式(I-a1-a3)的某些实施方式中,R4和R5与其各自连接的氮原子形成:其中,RZ选自下组:任选地被1-6个独立选择的卤素取代的C1-6烷基;C1-4烷氧基;C1-4卤代烷氧基;Rb;和-O-Rb(例如,–O-苯基,其中,苯基任选地被1-2个Rc取代)。
在式(I-a1-a3)的某些实施方式中,R4和R5与其各自连接的氮原子形成:其中,各RZ独立地选自下组:卤素(例如,–F)和任选地被1-6个独立选择的卤素取代的C1-6烷基。
在式(I-a1-a3)的某些实施方式中,R4和R5与其各自连接的氮原子形成: 其中,Rd是任选地被1-3个独立选择的Ra取代的C1-6烷基。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,m1是0。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,每次出现的R6是独立选择的Rc。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,每次出现的R6独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,一次出现的R6是氰基。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,m1是0;且R6是氰基。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,R2是H。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,R1a是H;且R1f是H。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,R1a是H;且R1f选自下组:-Lb-Rb、Rb和Rc。在这些实施方式的某些中,R1f是Rc。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,R1a选自下组:-(Lb)b-Rb、Rb和Rc;且R1f是H。在这些实施方式的某些中,R1a是Rc。例如,R1a可以是卤素(例如,–Cl)。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,R1a选自下组:-(Lb)b-Rb、Rb和Rc;且R1f选自下组:-Lb-Rb、Rb和Rc。例如,R1a和R1f可以是独立选择的Rc。
在式(I-a1-a1)、(I-a1-a2)或(I-a1-a3)的某些实施方式中,R3是H。
非限制性示例性化合物
在一些实施方式中,化合物选自表C1中描述的化合物或其药学上可接受的盐。
表C1
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药物组合物和给药
概述
在一些实施方式中,将化学实体(例如,抑制(例如,拮抗)STING的化合物,或其药学上可接受的盐,和/或水合物,和/或共晶,和/或它们的药物组合)作为包含该化学实体和一种或多种药学上可接受的赋形剂,以及任选地一种或多种本文所述的其它治疗剂的药物组合物给予。
在一些实施方式中,化学实体可以与一种或多种常规药物赋形剂组合给药。药学上可接受的赋形剂包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,自乳化药物递送系统(SEDDS),例如d-α-生育酚聚乙二醇1000琥珀酸酯,药物剂型中使用的表面活性剂,例如吐温(Tweens)、泊洛沙姆或其它类似的聚合物递送基质,血清蛋白,例如人血清白蛋白,缓冲物质,例如磷酸盐,三羟甲基氨基甲烷(tris),甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电介质,例如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶体二氧化硅,三硅酸镁,聚乙烯基吡咯烷酮,基于纤维素的物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜡,聚乙烯-聚氧化丙烯-嵌段聚合物,以及羊毛脂。环糊精如á-、β和-环糊精,或化学改性的衍生物如羟烷基环糊精,包括2-和3-羟丙基-β-环糊精,或其它溶液化的衍生物也可用于提供文中所述的化合物的递送。可制备包含0.005%-100%范围内的本文所述化学实体的剂型或组合物,余量由非毒性赋形剂补足。所考虑的组合物可包含0.001%-100%的本文提供的化学实体,在一个实施方式中为0.1-95%,在另一个实施方式中为75-85%,在又一个实施方式中为20-80%。制备这种剂型的实际方法是已知的,或是本领域技术人员所明白的;例如参见《雷明顿:药物科学和实践》(Remington:TheScience and Practice of Pharmacy),第22版(英国伦敦的药物出版社(PharmaceuticalPress),2012)。
给药途径和组合物组分
在一些实施方式中,本文所述的化学实体或其药物组合物可以通过任何可接受的给药途径给予有需要的对象。可接受的给药途径包括但不限于:含服,经皮,宫颈内,鼻窦内,气管内,肠内,硬膜上(epidural),间质,腹腔内,动脉内,支气管内,囊内(intrabursal),脑内,脑池内,冠状动脉内,真皮内,导管内,十二指肠内,硬脑膜内,表皮内,食道内,胃内,牙龈内,回肠内,淋巴管内,髓内,脑膜内,肌肉内,卵巢内,腹膜内,前列腺内,肺内,窦内,脊髓内,滑膜内,睾丸内,鞘内,肾小管内,肿瘤内,子宫内,血管内,静脉内,鼻,鼻胃,口服,胃肠外,经皮,硬膜外(peridural),直肠,呼吸(吸入),皮下,舌下,粘膜下,局部,透皮,经粘膜,经气管,输尿管,尿道和阴道。在一些实施方式中,优选的给药途径是胃肠外的(例如肿瘤内的)。
组合物可以配制用于胃肠外给药,例如配制用于通过静脉内,肌肉内,皮下或甚至腹膜内途径注射。通常,这种组合物可以制成注射剂,以液体溶液形式或悬浮液形式;也可以制备适合用于在注射前加入液体制备溶液或悬浮液的固体形式;并且,制剂也可以经乳化。根据本公开,此类制剂的制备对于本领域技术人员而言是已知的。
适于注射使用的药物形式包括无菌水溶液或分散液;包括芝麻油,花生油或丙二醇水溶液制剂;和用于临时制备无菌可注射溶液或分散液的无菌粉末。在所有情况下,该形式必须是无菌的,并且必须为易于注射的程度的流体。其也应该在制造和储存条件下稳定,并且必须在保存过程中能够抵抗微生物如细菌和真菌的污染作用。
载体也可以是包含例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)及其合适的混合物以及植物油的溶剂或分散介质。可维持合适的流动性,例如通过使用诸如卵磷脂的包衣、分散情况下通过保持所需粒度以及通过使用表面活性剂来实现。可以通过各种抗菌剂和抗真菌剂来预防微生物的作用,例如对羟基苯甲酸酯类、氯丁醇、苯酚、山梨酸、硫柳汞等。在很多情况中,优选包括等渗剂,例如糖类或氯化钠。可通过将延迟吸收的试剂例如单硬脂酸铝和明胶用于组合物中来延长可注射组合物的吸收。
通过将合适溶剂中所需量的活性化合物掺入不同的其它上述组分后根据需要过滤灭菌制得无菌注射液。通常,将各种经过灭菌的活性成分纳入含有碱性分散介质和上述其它所需成分的无菌载体中来制备分散液。当制备无菌注射液制备所需的无菌粉末时,优选的制备方法是真空干燥和冷冻干燥技术,由之前无菌过滤的溶液得到活性组分和任何其它所需组分的粉末。
瘤内注射例如参见Lammers等人,“瘤内注射对基于HPMA共聚物的药物递送系统的生物分布和治疗潜力的影响”(“Effect of Intratumoral Injection on theBiodistribution and the Therapeutic Potential of HPMACopolymer-Based DrugDelivery Systems”)Neoplasia.2006,10,788–795。
在直肠组合物中可用作凝胶、乳膏、灌肠或直肠栓剂的药学上可接受的赋形剂包括但不限于下列物质中的一种或多种:可可脂甘油酯,合成聚合物(如聚乙烯吡咯烷酮,PEG(如PEG软膏)),甘油,甘油明胶,氢化植物油,泊洛沙姆,各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物,凡士林,无水羊毛脂,鲨鱼肝油,糖精钠,薄荷醇,甜杏仁油,山梨糖醇,苯甲酸钠,Anoxid SBN,香草香精油,气雾剂,苯氧乙醇中的对羟基苯甲酸酯,对氧苯甲酸甲酯钠,对氧苯甲酸丙酯钠,二乙胺,卡波姆,卡波普,甲氧苯甲酸甲酯,聚乙二醇鲸蜡硬脂基醚,椰油酸辛酸癸酯,异丙醇,丙二醇,液体石蜡,黄原胶,羧基-焦亚硫酸盐,乙二胺四乙酸钠,苯甲酸钠,焦亚硫酸钾,葡萄柚籽提取物,甲基磺酰基甲烷(MSM),乳酸,甘氨酸,维生素(例如维生素A和E)和乙酸钾。
在一些实施方式中,可以通过将本文所述的化学实体与合适的无刺激性的赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合来制备栓剂,所述赋形剂或载体在环境温度下为固体,但在体温下为液体,因此在直肠融化并释放活性化合物。在其它实施方式中,用于直肠给药的组合物为灌肠剂形式。
在其它实施方式中,本文所述的化合物或其药物组合物适于通过口服给药(例如,固体或液体剂型)局部递送至消化道或胃肠道。
用于口服给予的固体剂型包括胶囊、片剂、丸剂、粉末剂和颗粒剂。在这些固体剂型中,将化学实体与一种或多种药学上可接受的赋形剂(例如柠檬酸钠或磷酸二钙)和/或以下物质混合:a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;b)粘结剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶(acacia);c)保湿剂,例如甘油;d)崩解剂,例如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些复合硅酸盐和碳酸钠;e)溶液缓凝剂,例如石蜡;f)吸收促进剂,例如季铵化合物;g)润湿剂,例如乙酰基醇和单硬脂酸甘油酯;h)吸附剂,例如高岭土和膨润土;以及i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。就胶囊、片剂和丸剂而言,剂型中还可含有缓冲剂。相似类型的固体组合物也可作为填充剂用于软填充和硬填充明胶胶囊中,其使用例如乳糖或乳糖分以及高分子量聚乙二醇等赋形剂。
在一个实施方式中,组合物可采取诸如丸剂或片剂等单位剂型形式,因此该组合物除本文提供的化学实体外还可包含:稀释剂如乳糖、蔗糖、磷酸二钙等;润滑剂如硬脂酸镁等;粘合剂如淀粉、阿拉伯胶、聚乙烯吡咯烷酮、明胶、纤维素、纤维素衍生物等。在另一种固体剂型中,粉末、药丸、溶液或混悬液(例如在碳酸亚丙酯、植物油、PEG剂、泊洛沙姆124或甘油三酸酯中)被包封在胶囊内(明胶或纤维素基胶囊)。也可以考虑其中本文提供的一种或多种化学实体或其它活性剂物理上隔开的单位剂型,例如包含各药物颗粒的胶囊(或胶囊中的片剂);双层片剂;双室凝胶胶囊等。也考虑肠溶包衣或延迟释放的口服剂型。
其它生理学上可接受的化合物包括润湿剂、乳化剂、分散剂或防腐剂,防腐剂对于避免微生物生长或作用特别有用。各种防腐剂是众所周知的,包括例如苯酚和抗坏血酸。
在某些实施方式中,赋形剂是无菌的并且通常不含不希望的物质。可以通过常规的、众所周知的灭菌技术对组合物进行灭菌。对于各种口服剂型赋形剂,例如片剂和胶囊剂,不需要无菌。USP/NF标准通常就足够了。
在一些实施方式中,固体口服剂型可进一步包括一种或多种组分,所述组分在化学上和/或在结构上使所述组合物易于将化学实体递送至胃或下GI;例如,升结肠和/或横结肠和/或远端结肠和/或小肠。示例性的配制技术参见例如Filipski,K.J.等人,CurrentTopics in Medicinal Chemistry,2013,13,776-802,其通过引用整体并入本文。
示例包括上GI靶向技术,例如手风琴药丸(Accordion Pill)(Intec Pharma公司),浮动胶囊和能够粘附在粘膜壁上的材料。
其它例子包括下GI靶向技术。为了靶向肠道的各个区域,可以使用几种肠溶/pH响应性包衣和赋形剂。这些材料通常是被设计为在特定pH范围内溶解或溶蚀的聚合物,基于所需药物释放的GI区进行选择。在活性成分可能刺激上GI的情况下,这些材料还起到保护酸不稳定药物免受胃液侵蚀或限制暴露的作用(例如,羟丙基甲基纤维素邻苯二甲酸酯系列,Coateric(邻苯二甲酸乙酸乙烯酯),乙酸邻苯二甲酸纤维素,乙酸琥珀酸羟丙基甲基纤维素,Eudragit系列(甲基丙烯酸-甲基丙烯酸甲酯共聚物)和Marcoat。其它技术包括响应胃肠道局部菌群的剂型,压力控制的结肠递送胶囊和Pulsincap。
眼科组合物可以包含但不限于以下任意一种或多种:粘胶原(viscogens)(例如,羧甲基纤维素,甘油,聚乙烯吡咯烷酮,聚乙二醇);稳定剂(例如Pluronic(三嵌段共聚物),环糊精);防腐剂(例如苯扎氯铵,ETDA,SofZia(硼酸,丙二醇,山梨糖醇和氯化锌;爱尔康实验有限公司(Alcon Laboratories Inc.)),Purite(稳定的氧化氯络合物;艾尔建有限公司(Allergan,Inc.))。
局部用组合物可包括软膏剂和乳膏剂。软膏剂是半固体制剂,通常基于凡士林或其它石油衍生物。含有所选活性剂的乳膏通常是粘性液体或半固体乳液,通常是水包油或油包水。乳膏基质通常是可水洗的,并且包含油相、乳化剂和水相。油相有时也称为“内”相,通常由凡士林和脂肪醇(如鲸蜡醇或硬脂醇)组成;尽管不一定,水相通常超过油相的体积,并且通常包含湿润剂。乳膏制剂中的乳化剂通常是非离子,阴离子,阳离子或两性表面活性剂。与其它载体或载剂一样,软膏基质应是惰性的,稳定的,无刺激性和不敏感的。
在任何前述实施方式中,本文所述的药物组合物可包含以下物质中的一种或多种:脂质,双层间交联的多层囊泡,可生物降解的聚(D,L-乳酸-共-乙醇酸)[PLGA]基或聚酸酐基纳米颗粒或微粒,以及纳米多孔颗粒支持的脂质双层。
剂量
剂量可以根据患者的需要,所治疗疾病的严重程度和所使用的特定化合物而变化。对于特定情况的合适剂量的确定可以由医学领域的技术人员确定。可以将每日总剂量分开,并在一整天内或通过提供连续递送的方式分次给药。
在一些实施方式中,本文所述的化合物以下述剂量给予:约0.001mg/Kg-约500mg/Kg(例如,约0.01mg/Kg-约100mg/Kg;约0.01mg/Kg-约10mg/Kg;约0.01mg/Kg-约1mg/Kg;约0.01mg/Kg-约0.1mg/Kg;约0.1mg/Kg-约100mg/Kg;约0.1mg/Kg-约10mg/Kg)。
给药方案
前述剂量可以每天(例如,作为单剂量或作为两个或更多个分剂量)或非每天给予(例如,每隔一天,每两天,每三天,每周一次,每周两次,每两周一次,每月一次)。
在一些实施方式中,本文所述化合物的给药时间为1天,2天,3天,4天,5天,6天,7天,8天,9天,10天,11天,12天,13天,14天,3周,4周,5周,6周,7周,8周,9周,10周,11周,12周,4个月,5个月,6个月,7个月,8个月,9个月,10个月,11个月,12个月或更长时间。在另一个实施方式中,给药停止时间为1天,2天,3天,4天,5天,6天,7天,8天,9天,10天,11天,12天,13天,14天,3周,4周,5周,6周,7周,8周,9周,10周,11周,12周,4个月,5个月,6个月,7个月,8个月,9个月,10个月,11个月,12个月或更长时间。在一个实施方式中,给予个体治疗化合物一段时间,然后是分开的时间段。在另一个实施方式中,在第一段时间给予治疗化合物,在第一段时间之后的第二段年时间停止给药,然后在第三段时间重新开始给予治疗化合物,再然后在第三段时间之后的第四段时间停止给药。在该实施方式的一方面,在确定的或未确定的时间段内重复治疗化合物的给药时间段和随后的停止给药的时间段。在另一个实施方式中,给药时间为1天,2天,3天,4天,5天,6天,7天,8天,9天,10天,11天,12天,13天,14天,3周,4周,5周,6周,7周,8周,9周,10周,11周,12周,4个月,5个月,6个月,7个月,8个月,9个月,10个月,11个月,12个月或更长时间。在另一个实施方式中,停止给药的时间为1天,2天,3天,4天,5天,6天,7天,8天,9天,10天,11天,12天,13天,14天,3周,4周,5周,6周,7周,8周,9周,10周,11周,12周,4个月,5个月,6个月,7个月,8月,9个月,10个月,11个月,12个月或更长时间。
治疗方法
在一些实施方式中,提供了用于治疗患有病状、疾病或病症的对象的方法,其中增加(例如,过量)的STING活性(例如,STING信号转导)有助于所述病状、疾病或病症(例如,免疫病症,癌症)的病态/或症状和/或进展。
适应症
在一些实施方式中,所述病状、疾病或病症是癌症。癌症的非限制性示例包括:黑色素瘤,癌,淋巴瘤,母细胞瘤,肉瘤和白血病或淋巴样恶性肿瘤。这类癌症的更具体例子包括:乳腺癌,结肠癌,直肠癌,大肠癌,肾癌,透明细胞癌肺癌,包括小细胞肺癌,非小细胞肺癌,肺腺癌和肺鳞癌,鳞状细胞癌(例如上皮鳞状细胞癌),宫颈癌,卵巢癌,前列腺癌,前列腺肿瘤,肝脏癌症,膀胱癌,腹膜癌,肝细胞癌,胃癌,包括胃肠道癌,胃肠道间质瘤,胰腺癌,头颈癌,胶质母细胞瘤,视网膜母细胞瘤,星形细胞瘤,卵泡膜细胞瘤,肾母细胞瘤,肝癌(hepatoma),血液系统恶性肿瘤,包括非霍奇金淋巴瘤(NHL),多发性骨髓瘤,骨髓增生异常,骨髓增值疾病,慢性粒细胞性白血病,和急性血液系统恶性肿瘤,子宫内膜癌或子宫癌,子宫内膜异位症,子宫内膜间质肉瘤,纤维肉瘤,绒毛膜癌,唾液腺癌,外阴癌,甲状腺癌,食道癌,肝癌(hepatic carcinoma),肛门癌,阴茎癌,鼻咽癌,喉癌,卡波西氏肉瘤,肥大细胞肉瘤,卵巢肉瘤,子宫肉瘤,黑色素瘤,恶性间皮瘤,皮肤癌,神经鞘瘤(Schwannoma),神经胶质瘤,神经母细胞瘤,神经外胚层肿瘤,横纹肌肉瘤,成骨肉瘤,平滑肌肉瘤,尤因肉瘤,外周原始神经外胚层肿瘤,尿路癌,甲状腺癌,威尔姆氏瘤以及与吞噬相关的异常血管增生,水肿(例如与脑肿瘤有关的水肿)和梅格斯综合症。在一些情况下,癌症是黑色素瘤。
在一些实施方式中,所述病状、疾病或病症是神经系统疾病,其包括涉及中枢神经系统(脑,脑干和小脑),周围神经系统(包括颅神经)和植物神经系统(其部分位于中枢和周围神经系统中)的疾病。该神经障碍的非限制性示例包括:获得性癫痫样失语;急性播散性脑脊髓炎;肾上腺白质营养不良;年龄相关性黄斑变性;胼胝体发育不全;失认症;艾卡迪综合征(Aicardi syndrome);亚历山大病(Alexander disease);阿尔珀斯病(Alpers'disease);交替性偏瘫;阿尔茨海默病;血管性痴呆;肌萎缩性侧索硬化;无脑畸形;安格曼综合征(Angelman syndrome);血管瘤病;缺氧;失语症;失用症;蛛网膜囊肿;蛛网膜炎;阿-蔡二氏畸形(Anronl-Chiari malformation);动静脉畸形;艾斯伯格综合征(Aspergersyndrome);共济失调性毛细血管扩张症;注意缺陷多动障碍;自闭症;自主神经功能障碍;背疼;白特病(Batten disease);白塞病(Behcet's disease);贝尔麻痹(Bell's palsy);良性本质性眼睑痉挛;良性局部肌萎缩;颅内良性高血压;宾斯旺格病(Binswanger'sdisease);眼睑痉挛;布洛克-苏兹贝克综合征(Bloch Sulzberger syndrome);臂丛神经损伤;脑脓肿;脑损伤;脑肿瘤(包括多形性胶质母细胞瘤);脊柱肿瘤;布朗-赛卡尔综合征(Brown-Sequard syndrome);卡那万病(Canavan disease);腕管综合征;灼性神经痛(causalgia);中枢性疼痛综合征;脑桥中央髓鞘溶解;头痛;脑动脉瘤;脑动脉硬化;脑萎缩;脑性巨人症;脑瘫;夏-马-图三氏病(Charcot-Marie-Tooth);化疗引起的神经病和神经性疼痛;恰里畸形(Chiari malformation);舞蹈症;慢性炎性脱髓鞘性多发性神经病;慢性疼痛;慢性局部疼痛综合征;科-勒二氏综合征(Coffin Lowry syndrome);昏迷,包括持续的植物状态;先天性面部瘫痪;皮质基底变性;颅动脉炎;颅骨前突;克雅病(Creutzfeldt-Jakob disease);累积性创伤疾病;库欣综合征;巨细胞包涵体疾病;巨细胞病毒感染;跳舞眼舞足综合征;丹迪-沃克综合征(Dandy-Walker syndrome);道森病(Dawson disease);德莫西耶综合征(De Morsier's syndrome);杰杰琳-克鲁克麻痹(Dejerine-Klumke palsy);痴呆;皮肌炎;糖尿病性神经病;弥漫性硬化;自主神经异常;书写困难(dysgraphia);阅读障碍;肌张力障碍;婴幼儿早期癫痫性脑病;空蝶鞍综合征;脑炎;脑膨出;脑三叉神经血管瘤病(encephalotrigeminal angiomatosis);癫痫;厄布麻痹(Erb's palsy);特发性震颤;法布里氏病(Fabry's disease);法尔氏综合症(Fahr's syndrome);晕倒;家族性痉挛性麻痹;高热惊厥;费舍尔综合征(Fisher syndrome);弗里德里希共济失调(Friedreich'sataxia);额颞痴呆症及其它“tau病变(tauopathies)”;高雪氏病(Gaucher's disease);格斯曼综合征(Gerstmann's syndrome);巨细胞动脉炎;巨细胞包涵体病;球状细胞白质营养不良;格林巴利综合征(Guillain-Barre syndrome);HTLV-1相关性脊髓病;Hallervorden-Spatz病;头部受伤;头痛;面肌痉挛;遗传性痉挛性截瘫;遗传性共济失调性多发性神经炎样病(heredopathia atactica polyneuritiformis);耳带状疱疹;带状疱疹;平山综合症(Hirayama syndrome);HIV相关的痴呆和神经病(也是AIDS的神经系统表现);全前脑畸形(holoprosencephaly);亨廷顿氏病和其它多聚谷氨酰胺重复病;积水性无脑畸形(hydranencephaly);脑积水;皮质醇过多症;缺氧;免疫介导的脑脊髓炎;包涵体肌炎;色素失禁(incontinentia pigmenti);婴儿植酸贮积病;婴儿雷夫叙姆病(infantile refsumdisease);婴儿痉挛;炎性肌病;颅内囊肿;颅内高压;乔伯特综合征(Joubert syndrome);Kearns-Sayre综合征;肯尼迪病(Kennedy disease)金斯本综合征(Kinsbournesyndrome);Klippel Feil综合征;克拉伯病(Krabbe disease);库戈尔贝格-维兰德病(Kugelberg-Welander disease);库鲁病(kuru);拉福拉病(Lafora disease);朗伯-伊顿肌无力综合征(Lambert-Eaton myasthenic syndrome);兰达-克莱夫纳综合征(Landau-Kleffner syndrome);外侧延髓(Wallenberg)综合征;学习障碍;利氏病(Leigh'sdisease);伦诺克斯-加斯托综合征(Lennox-Gustaut syndrome);莱-萘二氏综合征(Lesch-Nyhan syndrome);白质营养不良;路易体痴呆;平脑症(Lissencephaly);闭锁综合征;路格里格氏病(Lou Gehrig's disease)(即运动神经元病或肌萎缩性侧索硬化症);腰椎间盘疾病;莱姆病-神经后遗症;马查多-约瑟夫病(Machado-Joseph disease);大脑畸形(macrencephaly);巨脑畸形(megalencephaly);梅尔森-罗森塔尔综合征(Melkersson-Rosenthal syndrome);梅尼埃病(Menieres disease);脑膜炎;Menkes病;异染性脑白质营养不良(metachromatic leukodystrophy);小头畸形;偏头痛;米勒·费舍综合症(MillerFisher syndrome);小中风;线粒体肌病;莫比乌斯综合征(Mobius syndrome);单体肌萎缩;运动神经元病;脑底异常血管网病;黏多糖贮积症(mucopolysaccharidoses);多梗塞性痴呆;多灶性运动神经病;多发性硬化症和其它脱髓鞘疾病;多系统萎缩伴体位性低血压;p肌营养不良;重症肌无力;骨髓碎裂性弥漫性硬化症;婴儿肌阵挛性脑病;肌阵挛;肌病;先天性肌强直;发作性睡病;神经纤维瘤病;神经阻滞剂恶性综合征(neuroleptic malignantsyndrome);AIDS的神经系统表现;狼疮的神经系统后遗症;神经肌强直;神经元蜡样脂褐质沉积症(neuronal ceroid lipofuscinosis);神经元迁移障碍;尼曼-皮克病(Niemann-Pick disease);奥沙利文-麦克劳德综合征(O'Sullivan-McLeod syndrome);枕神经痛;隐性脊柱神经管闭合不全序列征(occult spinal dysraphism sequence);大田原综合征(Ohtahara syndrome);橄榄脑桥小脑萎缩(olivopontocerebellaratrophy);眼球阵挛-肌阵挛(opsoclonus myoclonus);视神经炎;体位性低血压;过度使用综合征;感觉异常;帕金森氏病;先天性肌强直;副肿瘤性疾病;阵发性发作;帕里隆伯格综合征(Parry Rombergsyndrome);比利牛斯-默兹巴赫病(Pelizaeus-Merzbacher disease);周期性麻痹;周围神经病;疼痛性神经病和神经性疼痛;持续的植物人状态;普遍性发育障碍;强光喷嚏反射(photic sneeze reflex);植酸贮积病;皮克病;捏神经;垂体瘤;多发性肌炎;脑穿通畸形(porencephaly);后脊髓灰质炎综合征(post-polio syndrome);疱疹后神经痛;感染后脑脊髓炎;体位性低血压;普拉德-威利综合征(Prader-Willi syndrome);原发性侧索硬化;朊病毒病;进行性半面部萎缩;进行性多灶性白质脑病;进行性硬化性脊髓灰质炎;进行性核上性麻痹;假性脑瘤;Ramsay-Hunt综合征(I型和II型);拉斯穆森脑炎(Rasmussen'sencephalitis);反射性交感神经营养不良综合征;雷夫叙姆病(Refsum disease);重复性运动障碍;重复性压力伤害;不安腿综合征;逆转录病毒相关性脊髓病;雷特综合征(Rettsyndrome);雷伊综合征(Reye's syndrome);圣维特舞蹈(Saint Vitus dance);桑霍夫病(Sandhoff disease);希尔德氏病(Schilder's disease);精神分裂症;视隔发育不全(septo-optic dysplasia);婴儿摇动综合征;带状疱疹病(shingles);Shy-Drager综合征;干燥综合征(syndrome);睡眠呼吸暂停;索托综合征(Soto's syndrome);痉挛;脊柱裂;脊髓损伤;脊髓肿瘤;脊髓性肌萎缩;僵人综合征(Stiff-Person syndrome);中风;斯特奇-韦伯综合征(Sturge-Weber syndrome);亚急性硬化性全脑炎;皮质下动脉硬化性脑病;薛登汉氏舞蹈症(Sydenham chorea);昏厥;脊髓空洞症;迟发性运动障碍;Tay-Sachs病;颞动脉炎;脊髓拴系综合征;汤姆森病(Thomsen disease);胸廓出口综合征;痛性痉挛(Tic Douloureux);托德瘫痪(Todd's paralysis);抽动秽语综合征(Tourettesyndrome);短暂性脑缺血发作;传染性海绵状脑病;横贯性脊髓炎;创伤性脑损伤;震颤;三叉神经痛;热带痉挛性轻瘫;结节性硬化;血管性痴呆(多发性梗塞性痴呆);血管炎包括颞动脉炎;冯·希佩尔·林道病(Von Hippel-Lindau disease);瓦伦堡综合征(Wallenberg's syndrome);韦德尼格-霍夫曼病(Werdnig-Hoffman disease);韦斯特综合征(Westsyndrome);鞭打(whiplash);威廉姆斯综合征(Williams syndrome);怀尔顿氏病(Wildon's disease);肌萎缩性侧索硬化症和泽尔韦格氏综合征(Zellweger syndrome)。
在一些实施方案中,所述病状、疾病或病症是与STING相关的病状,例如,I型干扰素病(例如,婴儿期发作的STING相关血管病(SAVI)),心型-门蒂综合征(Aicardi-Goutières Syndrome,AGS),遗传形式的狼疮和炎症相关疾病,例如系统性红斑狼疮和类风湿关节炎。在一些实施方式中,所述病状、疾病或病症是自身免疫疾病(例如,细胞质DNA触发的自身炎性疾病)。非限制性示例包括:类风湿性关节炎,系统性红斑狼疮,多发性硬化,包括克罗恩病(CD)和溃疡性结肠炎(UC)的炎性肠病(IBD),其是具有多基因易感性的慢性炎性疾病。在一些实施方式中,所述病症是炎性肠病。在一些实施方式中,所述病状是克罗恩病,自身免疫性结肠炎,医源性自身免疫性结肠炎,溃疡性结肠炎,由一种或多种化学治疗剂诱导的结肠炎,通过过继细胞疗法治疗诱导的结肠炎,与一种或多种同种免疫疾病(例如移植物抗宿主疾病,例如急性移植物抗宿主病和慢性移植物抗宿主病)相关的结肠炎,放射性肠炎,胶原性结肠炎,淋巴细胞性结肠炎,显微镜性结肠炎和放射性肠炎。这些实施方式的某些中,病状是同种免疫疾病(例如移植物抗宿主病,例如急性移植物抗宿主病和慢性移植物抗宿主病),腹腔疾病,肠易激综合症,类风湿性关节炎,狼疮,硬皮病,牛皮癣,皮肤T细胞淋巴瘤,葡萄膜炎和粘膜炎(例如口腔粘膜炎,食道粘膜炎或肠粘膜炎)。
在一些实施方式中,通过STING调节免疫系统提供了疾病的治疗,包括由外来因子引起的疾病。可以通过本发明的方法治疗和/或预防的外来因子的示例性感染包括:细菌(例如革兰氏阳性或革兰氏阴性细菌)的感染,真菌感染,寄生虫感染,以及病毒感染。在本发明的一个实施方式中,感染是细菌感染(例如,大肠杆菌,肺炎克雷伯菌(Klebsiellapneumonia),铜绿假单胞菌(Pseudomonas aeruginosa),沙门氏菌(Salmonella spp.),金黄色葡萄球菌(Staphylococcus aureus),链球菌或耐万古霉素肠球菌的感染)或败血症。在另一个实施方式中,感染是真菌感染(例如,霉菌,酵母或高等真菌感染)。在另一个实施方式中,感染是寄生虫感染(例如,由单细胞或多细胞寄生虫导致的感染,包括十二指肠贾第虫(Giardia duodenalis),小隐孢子虫(Cryptosporidium parvum),圆孢子虫(Cyclospora cayetanensis)和弓形虫(Toxoplasma gondiz))。在又一个实施方式中,感染是病毒感染(例如,与AIDS相关的病毒感染,禽流感,水痘,唇疱疹,普通感冒,肠胃炎,腺热,流感,麻疹,腮腺炎,咽炎,肺炎,风疹,SARS,以及下呼吸道感染或上呼吸道感染(例如呼吸道合胞病毒)。
在一些实施方式中,所述病状、疾病或病症是乙型肝炎(参见,例如,WO 2015/061294)。
在一些实施方式中,所述病状、疾病或病症选自心血管疾病(包括例如心肌梗塞)。
在一些实施方式中,所述病状、疾病或病症是与年龄有关的黄斑变性。
在一些实施方式中,所述病状、疾病或病症是粘膜炎,也称为口腔炎,其可以由于单独或组合使用的化学疗法或放射疗法而发生,以及由于在放射疗法范围之外暴露于放射线造成的损害导致。
在一些实施方式中,所述病状、疾病或病症是葡萄膜炎,其是葡萄膜的炎症(例如,前葡萄膜炎,例如虹膜睫状体炎或虹膜炎;中间葡萄膜炎(也称为睫状体平坦部炎(parsplanitis));后葡萄膜炎;或脉络膜视网膜炎,例如,泛-葡萄膜炎)。
在一些实施方式中,所述病状、疾病或病症选自下组:癌症,神经系统疾病,自身免疫疾病,乙型肝炎,葡萄膜炎,心血管疾病,年龄相关性黄斑变性和粘膜炎。
其它示例可以包括在本文以及下文中在预期的联合治疗方案中讨论的那些适应症。
组合疗法
本公开内容涵盖单一疗法方案以及联合疗法方案。
在一些实施方式中,本文描述的方法可以进一步包括与本文描述的化合物联合给予一种或多种另外的疗法(例如,一种或多种另外的治疗剂和/或一种或多种治疗方案)。
在一些实施方式中,本文所述的方法可以进一步包括给予一种或多种另外的癌症疗法。
一种或多种另外的癌症疗法可以包括但不限于:手术,放射疗法,化学疗法,毒素疗法,免疫疗法,冷冻疗法,癌症疫苗(例如,HPV疫苗,乙型肝炎疫苗,Oncophage,普罗文奇疫苗(Provenge))和基因疗法,以及它们的组合。免疫疗法,包括但不限于过继细胞疗法,干细胞和/或树突状细胞的衍生,输血,灌洗和/或其它疗法,包括但不限于冷冻肿瘤。
在一些实施方式中,所述一种或多种另外的癌症疗法是化学疗法,其可以包括给予一种或多种另外的化学疗法药剂。
在一些实施方式中,其它化学治疗剂是免疫调节分子,例如免疫检查点抑制剂。在这些实施方式的一些中,免疫检查点抑制剂靶向选自以下的免疫检查点受体:CTLA-4,PD-1,PD-L1,PD-1–PD-L1,PD-1–PD-L2,白介素-2(IL-2),吲哚胺2,3-二加氧酶(IDO),IL-10,转化生长因子-β(TGFβ),T细胞免疫球蛋白和粘蛋白3(TIM3或HAVCR2),半乳凝素9–TIM3,磷脂酰丝氨酸–TIM3,淋巴细胞活化基因3蛋白(LAG3),MHC II类–LAG3,4-1BB–4-1BB配体,OX40–OX40配体,GITR,GITR配体–GITR,CD27,CD70-CD27,TNFRSF25,TNFRSF25–TL1A,CD40L,CD40–CD40配体,HVEM–LIGHT–LTA,HVEM,HVEM–BTLA,HVEM–CD160,HVEM–LIGHT,HVEM–BTLA–CD160,CD80,CD80–PDL-1,PDL2–CD80,CD244,CD48–CD244,CD244,ICOS,ICOS–ICOS配体,B7-H3,B7-H4,VISTA,TMIGD2,HHLA2–TMIGD2,嗜乳脂蛋白(Butyrophilins),包括BTNL2,Siglec家族,TIGIT和PVR家族成员,KIRs,ILTs和LIRs,NKG2D和NKG2A,MICA和MICB,CD244,CD28,CD86–CD28,CD86–CTLA,CD80–CD28,CD39,CD73腺苷–CD39–CD73,CXCR4–CXCL12,磷脂酰丝氨酸,TIM3,磷脂酰丝氨酸–TIM3,SIRPA–CD47,VEGF,神经菌毛素(Neuropilin),CD160,CD30,和CD155;例如,CTLA-4或PD1或PD-L1)。例如参见,Postow,M.J.Clin.Oncol.2015,33,1。
在这些实施方案的一些中,免疫检查点抑制剂选自:乌鲁单抗(Urelumab),PF-05082566,MEDI6469,TRX518,伐立鲁单抗(Varlilumab),CP-870893,派姆单抗(Pembrolizumab)(PD1),纳武单抗(Nivolumab)(PD1),阿特朱单抗(Atezolizumab)(过去称为MPDL3280A)(PDL1),MEDI4736(PD-L1),阿维鲁单抗(Avelumab)(PD-L1),PDR001(PD1),BMS-986016,MGA271,利鲁单抗(Lirilumab),IPH2201,尹玛克妥珠单抗(Emactuzumab),INCB024360,高鲁尼替(Galunisertib),乌克普鲁单抗(Ulocuplumab),BKT140,巴维昔单抗(Bavituximab),CC-90002,贝伐单抗(Bevacizumab),MNRP1685A,和MGA271。
在一些实施方式中,其它化学治疗剂是烷化剂。烷基化剂之所以被命名是因为它们能够在细胞(包括但不限于癌细胞)中存在的条件下将许多亲核官能团烷基化。在另一个实施方式中,烷基化剂包括但不限于:顺铂,卡铂,甲乙胺,环磷酰胺,苯丁酸氮芥,异环磷酰胺和/或奥沙利铂。在一个实施方式中,烷基化剂可通过与生物学上重要的分子中的氨基,羧基,巯基和磷酸基团形成共价键来破坏细胞功能而起作用,或者它们可通过修饰细胞的DNA而起作用。在另一个实施方式中,烷基化剂是合成的、半合成的或衍生物。
在一些实施方式中,其它化学治疗剂是抗代谢物。抗代谢物会伪装成嘌呤或嘧啶,它们是DNA的基本组成部分,通常会阻止这些物质在“S”期(细胞周期)内掺入DNA,从而阻止正常发育和分裂。抗代谢物也会影响RNA合成。在一个实施方式中,抗代谢物包括但不限于:硫唑嘌呤和/或巯基嘌呤。在另一个实施方式中,抗代谢物是合成的,半合成的或衍生物。
在一些实施方式中,其它化学治疗剂是植物生物碱和/或萜类。这些生物碱通常来自植物并通过防止微管功能阻止细胞分裂。在一个实施方式中,植物生物碱和/或萜类化合物是长春花生物碱,鬼臼毒素和/或紫杉烷。通常,长春花生物碱结合微管蛋白上的特定位点,通常在细胞周期的M期,抑制微管蛋白组装成微管。在一个实施方式中,长春花生物碱不限于:马达加斯加长春花(Madagascar periwinkle),常春花(Catharanthus roseus)(过去称为蔓长春花(Vinca rosea))。在一个实施方式中,长春花生物碱包括但不限于:长春新碱,长春碱,长春瑞滨和/或长春地辛。在一个实施方式中,紫杉烷包括但不限于:Taxol,紫杉醇和/或多西紫杉醇。在另一个实施方式中,植物生物碱或萜类生物是合成的,半合成的或衍生物。在另一个实施方式中,鬼臼毒素是但不限于依托泊苷和/或替尼泊苷。在一个实施方式中,紫杉烷是但不限于多西紫杉醇和/或奥塔紫杉醇。[021]在一个实施方式中,癌症治疗剂是拓扑异构酶。拓扑异构酶是维持DNA拓扑结构的必需酶。I型或II型拓扑异构酶的抑制通过破坏适当的DNA超螺旋而干扰DNA的转录和复制。在另一个实施方式中,拓扑异构酶是但不限于I型拓扑异构酶抑制剂或II型拓扑异构酶抑制剂。在一个实施方式中,I型拓扑异构酶抑制剂是但不限于喜树碱。在另一个实施方式中,喜树碱是但不限于依喜替康(exatecan),伊立替康,鲁托替康,托泊替康,BNP 1350,CKD 602,DB 67(AR67)和/或ST1481。在一个实施方式中,II型拓扑异构酶抑制剂为但不限于表鬼臼毒素。在另一个实施方式中,表鬼臼毒素是但不限于氨曲林(amsacrine),依托泊苷,磷酸依托泊苷和/或替尼泊苷。在另一个实施方式中,拓扑异构酶是合成的,半合成的或衍生物,包括在自然界中发现的那些,例如但不限于表鬼臼毒素,其是天然存在于北美五月果(American Mayapple)(美洲鬼臼(Podophyllum peltatum))的根中的物质。
在一些实施方式中,其它化学治疗剂是芪类。在进一步的实施方式中,芪类包括但不限于:白藜芦醇,白皮杉醇(Piceatannol),赤松素(Pinosylvin),紫檀芪(Pterostilbene),α-葡萄素(Alpha-Viniferin),蛇葡萄素(Ampelopsin)A,蛇葡萄素E,地吲哚肌酮(Diptoindonesin)C,地吲哚肌酮F,ε-葡萄素(Epsilon-Vinferin),弗莱索尔(Flexuosol)A,葛萘宁(Gnetinins)D,席尔瓦酚(Hopeaphenol),反式-地吲哚肌酮B,阿曲汀(Astringin),云杉新苷(Piceid)和地吲哚肌酮A。在另一个实施方式中,芪类是合成的、半合成的或衍生物。
在一些实施方式中,其它化学治疗剂是细胞毒性抗生素。在一个实施方式中,细胞毒性抗生素是但不限于:放线菌素,蒽二酮,蒽环类,沙利度胺,二氯乙酸,烟酸,2-脱氧葡萄糖和/或氯氟嗪明(chlofazimine)。在一个实施方案中,放线菌素是但不限于:放线菌素D,杆菌肽,粘菌素(colistin)(多粘菌素E)和/或多粘菌素B。在另一个实施方案中,蒽醌类是但不限于米托蒽醌和/或匹克生琼(pixantrone)。在另一个实施方式中,蒽环类药物是但不限于博来霉素,阿霉素(亚德里亚霉素(Adriamycin)),柔红霉素(道诺霉素),表柔比星,伊达比星,丝裂霉素,普霉素和/或缬沙星。在另一个实施方式中,细胞毒性抗生素是合成的,半合成的或衍生物。
在一些实施方案中,所述另外的化学治疗剂选自:内皮抑素,血管生成素,血管抑制素,趋化因子,促血管生成素休息素(angioarrestin),血管抑制素(纤溶酶原片段),基底膜胶原衍生的抗血管生成因子(肿瘤抑素(tumstatin),坎他汀(canstatin)或抑制蛋白(arrestin)),抗血管生成抗凝血酶III,信号转导抑制剂,软骨衍生抑制剂(CDI),CD59补体片段,纤连蛋白片段,gro-β,肝素酶,肝素六糖片段,人绒毛膜促性腺激素(hCG),干扰素α/β/γ,干扰素诱导蛋白(IP-10),白介素12,kringle5(血纤维蛋白溶酶原片段),金属蛋白酶抑制剂(TIMP),2-甲氧基雌二醇,胎盘核糖核酸酶抑制剂,纤溶酶原活化物抑制剂,血小板因子-4(PF4),催乳素16kD片段,与增殖蛋白相关的蛋白(PRP),各种类维生素A,四氢皮质醇-S,血小板反应蛋白1(TSP-1),转化生长因子-β(TGF-β),血管抑素(vasculostatin),血管抑制因子(vasostatin)(钙网蛋白片段)等等。
在一些实施方式中,所述其它化学治疗剂选自:乙酸阿比特龙,六甲蜜胺(altretamine),脱水长春碱(anhydrovinblastine),澳瑞他汀(auristatin),贝沙罗汀(bexarotene),比卡鲁胺(bicalutamide),BMS184476,2,3,4,5,6-五氟-N-(3-氟-4-甲氧基苯基)苯磺酰胺,博来霉素,N,N-二甲基-L-缬氨酰-L-缬氨酰-N-甲基-L-缬氨酰-L-脯氨酰-1-L脯氨酸-叔丁酰胺,恶病质素(cachectin),西马多丁(cemadotin),苯丁酸氮芥,环磷酰胺,酒石酸长春瑞滨(3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine),多西紫杉醇,多西他赛(doxetaxel),环磷酰胺,卡铂,卡莫司汀(carmustine),顺铂,隐藻霉素(cryptophycin),环磷酰胺,阿糖胞苷,达卡巴嗪(DTIC),放线菌素,柔红霉素,地西他滨(decitabine)尾海兔素(dolastatin),多柔比星(阿霉素),依托泊苷,5-氟尿嘧啶,非那雄胺,氟他胺,羟基脲和羟基脲胺紫杉烷类,异环磷酰胺(ifosfamide),利拉唑(liarozole),氯尼达明(lonidamine),洛莫司汀(lomustine)(CCNU),MDV3100,甲草胺(氮芥),美法仑,羟乙磺酸羟色胺(mivobulin isethionate),根瘤菌素(rhizoxin),舍替尼(sertenef),链球菌素(streptozocin),丝裂霉素,甲氨蝶呤,紫杉烷类,尼鲁米特(nilutamide),奥那司酮(onapristone),紫杉醇,泼尼氮芥(prednimustine),甲基苄肼(procarbazine),RPR109881,磷酸雌莫司汀(stramustine phosphate),他莫昔芬,他索纳明(tasonermin),紫杉醇,维甲酸,长春碱,长春新碱,硫酸长春地辛和长春氟宁。
在一些实施方式中,所述其它化学治疗剂是铂,顺铂,卡铂,奥沙利铂,甲氯乙胺,环磷酰胺,苯丁酸氮芥,硫唑嘌呤,巯基嘌呤,长春新碱,长春碱,长春瑞滨,长春地辛,依托泊苷和替尼泊苷,紫杉醇,多西紫杉醇,伊立替康,托泊替康,氨氯林(amsacrine),依托泊苷,磷酸依托泊苷,替尼泊苷,5-氟尿嘧啶,亚叶酸钙,氨甲蝶呤,吉西他滨,紫杉烷,亚叶酸,丝裂霉素C,替加福-尿嘧啶(tegafur-uracil),伊达比星,氟达拉滨,米托蒽醌,异环磷酰胺和阿霉素。其它试剂包括mTOR(雷帕霉素的哺乳动物靶标)抑制剂,包括但不限于雷帕霉素,依维莫司(everolimus),替西罗莫司(temsirolimus)和地福莫司(deforolimus)。
在另一些实施方式中,其它化学治疗剂可以选自美国专利7,927,613中描述的那些,该专利通过引用整体并入本文。
在一些实施方案中,所述另外的治疗剂和/或方案可以用于治疗其它STING相关病症,例如I型干扰素病,例如,婴儿期发作的STING相关血管病(SAVI),心型-门蒂综合征(AGS),遗传形式的狼疮,炎症相关病症,例如系统性红斑狼疮,以及类风湿关节炎,等等。
用于治疗类风湿性关节炎的另外的治疗剂和/或治疗方案的非限制性示例包括:非甾体抗炎药(NSAID;例如布洛芬和萘普生),皮质类固醇(例如泼尼松),缓解疾病的抗风湿药(DMARD;例如,甲氨蝶呤 来氟米特羟基氯喹(Plaquenil),PF-06650833,艾拉妥莫德(iguratimod),托法替尼(tofacitinib)/>ABBV-599,依伏溴替尼(evobrutinib)和柳氮磺吡啶(sulfasalazine)/>以及生物制剂(例如,阿巴西普(abatacept)/>阿达木单抗(adalimumab)/>阿那白滞素(anakinra)/>塞妥珠单抗(certolizumab)/>依那西普(etanercept)/>戈利木单抗(golimumab)英夫利昔单抗(infliximab)/>利妥昔单抗(rituximab)托珠单抗(tocilizumab)/>沃巴利单抗(vobarilizumab),撒利鲁单抗(sarilumab)/>苏金单抗(secukinumab),ABP 501,CHS-0214,ABC-3373,和托珠单抗(tocilizumab)/>)。
用于治疗狼疮的另外的治疗剂和/或治疗方案的非限制性例子包括:类固醇,局部免疫调节剂(例如,他克莫司软膏和吡美莫司乳膏/>),沙利度胺非甾体类抗炎药药物(NSAID;例如布洛芬和萘普生),抗疟疾药物(例如,羟氯喹(Plaquenil)),皮质类固醇(例如泼尼松),免疫调节剂(例如,依伏溴替尼(evobrutinib),伊贝多胺(iberdomide),沃氯普辛(voclosporin),西立莫德(cenerimod),硫唑嘌呤(azathioprine)/>环磷酰胺/> 环孢菌素(Neoral,/>),霉酚酸酯),巴瑞克替尼(baricitinb),艾拉妥莫德(iguratimod),非洛替尼(filogotinib),GS-9876,雷帕霉素,和PF-06650833),生物制剂(例如,贝利木单抗(belimumab)/>阿氟洛单抗(anifrolumab),普来鲁单抗(prezalumab),MEDI0700,奥滨尤妥珠单抗(obinutuzumab),沃巴利单抗(vobarilizumab),鲁利珠单抗(lulizumab),阿塞西普(atacicept),PF-06823859,和鲁皮唑尔(lupizor),利妥昔单抗(rituximab),BT063,BI655064,BIIB059,阿地白介素(aldesleukin)达匹罗单抗(dapirolizumab),依屈肽(edratide),IFN-α-kinoid,OMS721,RC18,RSLV-132,赛利左单抗(theralizumab),XmAb5871,和尤特克单抗(ustekinumab))。例如,系统性红斑狼疮的非限制性治疗方法包括:非甾体抗炎药(NSAID;例如布洛芬和萘普生),抗疟药(例如羟氯喹(Plaquenil)),皮质类固醇(例如强的松)和免疫调节剂((例如,伊贝多胺(iberdomide),沃氯普辛(voclosporin),硫唑嘌呤(azathioprine)环磷酰胺/>和环孢菌素(Neoral,),和霉酚酸酯,巴瑞克替尼(baricitinb),非洛替尼(filogotinib),和PF-06650833),以及生物制剂(例如,贝利木单抗(belimumab)阿氟洛单抗(anifrolumab),普来鲁单抗(prezalumab),MEDI0700,沃巴利单抗(vobarilizumab),鲁利珠单抗(lulizumab),阿塞西普(atacicept),PF-06823859,鲁皮唑尔(lupizor),利妥昔单抗(rituximab),BT063,BI655064,BIIB059,阿地白介素(aldesleukin)/>达匹罗单抗(dapirolizumab),依屈肽(edratide),IFN-α-kinoid,RC18,RSLV-132,赛利左单抗(theralizumab),XmAb5871,和尤特克单抗(ustekinumab)/>)。作为另一个例子,用于皮肤狼疮的治疗的非限制性例子包括:类固醇,免疫调节剂(例如他克莫司软膏/>和吡美莫司乳膏/>),GS-9876,非洛替尼(filogotinib)和沙利度胺/>也可以给予用于治疗药物诱发的和/或新生儿的狼疮的药剂和方案。
用于治疗婴儿期发作的STING相关血管病(SAVI)的另外的治疗剂和/或治疗方案的非限制性示例包括JAK抑制剂(例如托法替尼(tofacitinib),鲁索替尼(ruxolitinib),菲格替尼(filgotinib)和巴利替尼(baricitinib))。
用于治疗艾卡迪-古蒂雷斯综合征(AGS)的另外的治疗剂和/或治疗方案的非限制性示例包括:物理疗法,呼吸道并发症治疗,癫痫发作的抗惊厥疗法,管饲,核苷逆转录酶抑制剂(例如,恩曲他滨(emtricitabine)(例如),替诺福韦(tenofovir)(例如),恩曲他滨/替诺福韦(emtricitabine/tenofovir)(例如/>),齐多夫定(zidovudine),拉米夫定(lamivudine)和阿巴卡韦(abacavir)),和JAK抑制剂(例如,托法替尼(tofacitinib),鲁索替尼(ruxolitinib),菲格替尼(filgotinib)和巴利替尼(baricitinib))。
用于治疗IBD的另外的治疗剂和/或治疗方案的非限制性示例包括:6-巯基嘌呤,AbGn-168H,ABX464,ABT-494,阿达木单抗(Adalimumab),AJM300,阿利卡单抗(alicaforsen),AMG139,安鲁金珠单抗(anrukinzumab),阿普斯特(apremilast),ATR-107(PF0530900),自体CD34选择的外周血干细胞移植,硫唑嘌呤(azathioprine),贝蒂单抗(bertilimumab),BI 655066,BMS-936557,塞妥珠单抗(certolizumab pegol)昔比莫德(cobitolimod),皮质类固醇(例如,强的松,甲泼尼龙,强的松),CP-690,550,CT-P13,环孢霉素,DIMS0150,E6007,E6011,埃曲西莫特(etrasimod),埃特罗珠单抗(etrolizumab),粪便微生物移植,费洛替尼(figlotinib),芬戈莫德(fingolimod),非拉司特(firategrast)(SB-683699)(过去称为T-0047),GED0301,GLPG0634,GLPG0974,古塞库单抗(guselkumab),戈利木单抗(golimumab),GSK1399686,HMPL-004(穿心莲提(Andrographis paniculata)提取物),IMU-838,英夫利昔单抗(infliximab),白介素2(IL-2),Janus激酶(JAK)抑制剂,拉喹莫德(laquinimod),马赛替尼(masitinib)(AB1010),基质金属蛋白酶9(MMP 9)抑制剂(例如,GS-5745),MEDI2070,美沙拉敏(mesalamine),甲氨蝶呤,米立单抗(mirikizumab)(LY3074828),那他珠单抗(natalizumab),NNC 0142-0000-0002,NNC0114-0006,奥扎尼莫德(ozanimod),培非替尼(peficitinib)(JNJ-54781532),PF-00547659,PF-04236921,PF-06687234,QAX576,RHB-104,利福昔明(rifaximin),利赛唑单抗(risankizumab),RPC1063,SB012,SHP647,柳氮磺吡啶(sulfasalazine),TD-1473,沙利度胺,替拉珠单抗(tildrakizumab)(MK 3222),TJ301,/>托法替尼(tofacitinib),曲妥单抗(tralokinumab),TRK-170,阿帕西替尼(upadacitinib),尤特克单抗(ustekinumab),UTTR1147A,V565,伐利珠单抗(vatelizumab),VB-201,维多珠单抗(vedolizumab),和维多氟地姆(vidofludimus)。
用于治疗肠易激综合症的其它治疗剂和/或治疗方案的非限制性例子包括:阿洛司琼(alosetron),胆汁酸螯合剂(例如,消胆胺(cholestyramine),降胆宁(celestipol),考来维仑(colesevelam),氯离子通道活化剂(例如,鲁比前列酮(lubiprostone)),包衣的薄荷油胶囊,地昔帕明(desipramine),双环胺(dicyclomine),依巴斯汀(ebastine),依法度林(eluxadoline),法尼醇X受体激动剂(例如,奥贝胆酸),粪便微生物移植,氟西汀(fluoxetine),加巴喷丁(gabapentin),鸟苷酸环化酶C激动剂(例如,利那洛肽(linaclotide),普卡那肽(plecanatide),依博度他(ibodutant),丙咪嗪(imipramine),JCM-16021,洛哌丁胺(loperamide),鲁比前列酮(lubiprostone),去甲替林(nortriptyline),恩丹西酮(ondansetron),阿片类药物,帕罗西汀(paroxetine),匹维溴铵(pinaverium),聚乙二醇,普瑞巴林(pregabalin),益生菌,雷莫司琼(ramosetron),利福昔明(rifaximin)和坦帕诺尔(tanpanor)。
用于治疗硬皮病的另外的治疗剂和/或治疗方案的非限制性例子包括:非甾体抗炎药(NSAID;例如布洛芬和萘普生),皮质类固醇(例如泼尼松),免疫调节剂(例如硫唑嘌呤,甲氨蝶呤环磷酰胺/>和环孢菌素/>抗胸腺细胞球蛋白,霉酚酸酯,静脉注射免疫球蛋白,利妥昔单抗,西罗莫司和阿法西普(alefacept)),钙通道阻滞剂(例如硝苯地平),α阻滞剂,血清素受体拮抗剂,血管紧张素II受体抑制剂,他汀类药物,局部硝酸盐,伊洛前列素(iloprost),磷酸二酯酶5抑制剂(例如西地那非),波生坦(bosentan),四环素抗生素,内皮素受体拮抗剂,前列腺素,和酪氨酸激酶抑制剂(例如伊马替尼,尼洛替尼和达沙替尼)。
用于治疗克罗恩氏病(CD)的另外的治疗剂和/或治疗方案的非限制性例子包括:阿达木单抗,自体CD34选择的外周血干细胞移植,6-巯基嘌呤,硫唑嘌呤,聚乙二醇赛妥珠单抗皮质类固醇(例如泼尼松),埃特罗珠单抗(etrolizumab),E6011,粪便微生物移植,费洛替尼(figlotinib),古塞库单抗(guselkumab),英利昔单抗(Infliximab),IL-2,JAK抑制剂,基质金属蛋白酶9(MMP 9)抑制剂(例如GS-5745),MEDI2070,美沙拉敏,甲氨蝶呤,那他珠单抗,奥扎尼莫德(ozanimod),RHB-104,利福昔明(rifaximin),利赛唑单抗(risankizumab),SHP647,柳氮磺吡啶,沙利度胺,阿帕西替尼(upadacitinib),V565和维多珠单抗(vedolizumab)。
用于治疗UC的另外的治疗剂和/或治疗方案的非限制性例子包括:AbGn-168H,ABT-494,ABX464,阿普斯特(apremilast),PF-00547659,PF-06687234、6-巯基嘌呤,阿达木单抗,硫唑嘌呤,贝利替单抗,布拉迪单抗(brazikumab)(MEDI2070),古比托莫德(cobitolimod),聚乙二醇塞妥珠单抗CP-690,550,皮质类固醇(例如,多功能布地奈德(multimax budesonide),甲基强的松龙(Methylprednisolone)),环孢菌素,E6007,埃曲西莫德,埃特罗珠单抗,粪便微生物移植,菲洛替尼,古塞库单抗(guselkumab),戈利木单抗,IL-2,IMU-838,英夫利昔单抗,基质金属蛋白酶9(MMP9)抑制剂(例如GS-5745),美沙拉敏,美沙拉敏,米立单抗(mirikizumab)(LY3074828),RPC1063,利桑木单抗(risankizumab)(BI 6555066),SHP647,柳氮磺吡啶,TD-1473,TJ301,蒂达珠单抗(tildrakizumab)(MK 3222),托法替尼(tofacitinib),托法替尼(Tofacitinib),尤特克单抗(ustekinumab),UTTR1147A和维多珠单抗(vedolizumab)。
用于治疗自身免疫性结肠炎的其它治疗剂和/或治疗方案的非限制性例子包括:皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,二丙酸倍氯米松),苯海拉索/阿托品,英夫利昔单抗,洛哌丁胺(loperamide),美沙拉敏,TIP60抑制剂(参见,例如,美国专利申请公开号2012/0202848)和维多珠单抗。
用于治疗医源性自身免疫性结肠炎的另外的治疗剂和/或治疗方案的非限制性例子包括:皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,二丙酸倍氯米松),苯海拉索/阿托品,英夫利昔单抗,洛哌丁胺(loperamide),TIP60抑制剂(参见,例如,美国专利申请公开号2012/0202848)和维多珠单抗。
用于治疗由一种或多种化学治疗剂诱导的结肠炎的另外的治疗剂和/或治疗方案的非限制性例子包括:皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,二丙酸倍氯米松),苯海拉索/阿托品,英夫利昔单抗,洛哌丁胺(loperamide),美沙拉敏,TIP60抑制剂(参见,例如,美国专利申请公开号2012/0202848)和维多珠单抗。
用于治疗由过继细胞疗法引起的结肠炎的另外的治疗剂和/或治疗方案的非限制性例子包括:皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,二丙酸倍氯米松),苯海拉索/阿托品,英夫利昔单抗,洛哌丁胺(loperamide),TIP60抑制剂(参见,例如,美国专利申请公开号2012/0202848)和维多珠单抗。
用于治疗与一种或多种同种异体免疫疾病相关的结肠炎的另外的治疗剂和/或治疗方案的非限制性示例包括:皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,倍氯米松二丙酸酯),柳氮磺吡啶和二十碳五烯酸。
用于治疗放射性肠炎的另外的治疗剂和/或治疗方案的非限制性示例包括:替度鲁肽(teduglutide),氨磷汀(amifostine),血管紧张素转化酶(ACE)抑制剂(例如贝那普利(benazepril),卡托普利(captopril),依那普利(enalapril),福辛普利(fosinopril),赖诺普利(lisinopril),莫西普利(moexipril),培哚普利(perindopril),喹那普利(quinapril),雷米普利(ramipril)和川地普利(trandolapril)),益生菌,补充硒,他汀类药物(例如,阿托伐他汀,氟伐他汀,洛伐他汀,普伐他汀,罗苏伐他汀(rosuvastatin),辛伐他汀(simvastatin)和匹伐他汀),硫糖铝(sucralfate)和维生素E。
用于治疗胶原性结肠炎的另外的治疗剂和/或治疗方案的非限制性实例包括:6-巯基嘌呤,氮杂扎普林(azathaioprine),碱式铋(bismuth subsalicate),齿叶乳香(Boswellia serrata)提取物,消胆胺(cholestyramine),胆甾醇(colestipol),皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,倍氯米松双丙酸酯),美沙拉敏,甲氨蝶呤,益生菌和柳氮磺吡啶。
用于治疗淋巴细胞性结肠炎的另外的治疗剂和/或治疗方案的非限制性实例包括:6-巯基嘌呤,氮杂扎普林(azathaioprine),次水杨酸铋(bismuth subsalicylate),消胆胺(cholestyramine),胆甾醇(colestipol),皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,倍氯米松双丙酸酯),美沙拉敏,甲氨蝶呤和柳氮磺吡啶。
用于治疗微生物结肠炎的另外的治疗剂和/或治疗方案的非限制性实例包括:6-巯基嘌呤,硫唑嘌呤(azathioprine),碱式铋(bismuth subsalicate),齿叶乳香(Boswellia serrata)提取物,消胆胺(cholestyramine),降胆宁(colestipol),皮质类固醇(例如布地奈德,泼尼松,泼尼松龙,倍氯米松双丙酸酯),粪便微生物移植,洛哌丁胺(loperamide),美沙拉敏,甲氨蝶呤,益生菌和柳氮磺吡啶。
用于治疗同种异体免疫疾病的另外的治疗剂和/或治疗方案的非限制性实例包括:子宫内血小板输注,静脉注射免疫球蛋白,母体类固醇,阿巴西普(abatacept),阿仑单抗(alemtuzumab),α1-抗胰蛋白酶,AMG592,抗胸腺细胞球蛋白,巴瑞替尼(barcitinib),巴利昔单抗(basiliximab),硼替佐米(bortezomib),本妥昔单抗(brentuximab),大麻二酚(cannabidiol),皮质类固醇(例如甲基泼尼松,泼尼松),环孢菌素,达西单抗(dacilzumab),去纤苷(defribrotide),地尼白介素-毒素连接物(denileukin diftitox),格拉吉布(glasdegib),依鲁替尼(ibrutinib),IL-2,英利昔单抗,伊他替尼(itacitinib),LBH589,马拉维若(maraviroc),霉酚酸酯,那他珠单抗,奈珠单抗(neihulizumab),喷司他丁,培伐他汀(pevonedistat),光生物调节,光采血,鲁索替尼(ruxolitinib),西罗莫司(sirolimus),索尼德吉(sonidegib),他克莫司,塔西单抗(tocilizumab)和维莫德吉(vismodegib)。
用于治疗多发性硬化症(MS)的另外的治疗剂和/或治疗方案的非限制性示例包括:阿仑单抗ALKS 8700,阿米洛利(amiloride),ATX-MS-1467,硫唑嘌呤,巴氯芬(baclofen)/>β干扰素(例如IFN-β-1a,IFN-β-1b),克拉屈滨(cladribine),皮质类固醇(例如甲基泼尼松龙),达克珠单抗(daclizumab),富马酸二甲酯芬戈莫德(fingolimod)/>氟西汀(fluoxetine),醋酸格拉替雷(glatiramer acetate)/>羟氯喹,异丁司特(ibudilast),艾地苯醌(idebenone),拉喹莫德(laquinimod),硫辛酸,氯沙坦(losartan),马赛替尼(masitinib),MD1003(生物素),米托蒽醌,孟鲁司特(montelukast),那他珠单抗/>,NeuroVaxTM,奥瑞珠单抗(ocrelizumab),奥法木单抗(ofatumumab),吡格列酮(pioglitazone)和RPC1063。
用于治疗移植物抗宿主病的另外的治疗剂和/或治疗方案的非限制性实例包括:阿巴西普(abatacept),阿仑单抗(alemtuzumab),α1-抗胰蛋白酶,AMG592,抗胸腺细胞球蛋白,巴瑞替尼(barcitinib),巴利昔单抗(basiliximab),硼替佐米(bortezomib),本妥昔单抗(brentuximab),大麻二酚(cannabidiol),皮质类固醇(例如甲基泼尼松,泼尼松),环孢菌素,达西单抗(dacilzumab),去纤苷(defribrotide),地尼白介素-毒素连接物(denileukin diftitox),格拉吉布(glasdegib),依鲁替尼(ibrutinib),IL-2,伊马替尼(imatinib),英利昔单抗,伊他替尼(itacitinib),LBH589,马拉维若(maraviroc),霉酚酸酯,那他珠单抗,奈珠单抗(neihulizumab),喷司他丁,培伐他汀(pevonedistat),光生物调节,光采血,鲁索替尼(ruxolitinib),西罗莫司(sirolimus),索尼德吉(sonidegib),他克莫司,塔西单抗(tocilizumab)和维莫德吉(vismodegib)。
用于治疗急性移植物抗宿主病的另外的治疗剂和/或治疗方案的非限制性实例包括:阿仑单抗(alemtuzumab),α1-抗胰蛋白酶,抗胸腺细胞球蛋白,巴利昔单抗(basiliximab),本妥昔单抗(brentuximab),皮质类固醇(例如甲基泼尼松,泼尼松),环孢菌素,达西单抗(dacilzumab),去纤苷(defribrotide),地尼白介素-毒素连接物(denileukin diftitox),依鲁替尼(ibrutinib),英利昔单抗,伊他替尼(itacitinib),LBH589,霉酚酸酯,那他珠单抗,奈珠单抗(neihulizumab),喷司他丁,光溶血,鲁索替尼(ruxolitinib),西罗莫司(sirolimus),他克莫司和塔西单抗(tocilizumab)。
用于治疗慢性移植物抗宿主病的另外的治疗剂和/或治疗方案的非限制性实例包括:阿巴西普(abatacept),阿仑单抗(alemtuzumab),AMG592,抗胸腺细胞球蛋白,巴利昔单抗(basiliximab),硼替佐米(bortezomib),皮质类固醇(例如甲基泼尼松,泼尼松),环孢菌素,达西单抗(dacilzumab),地尼白介素-毒素连接物(denileukin diftitox),格拉吉布(glasdegib),依鲁替尼(ibrutinib),IL-2,伊马替尼(imatinib),英利昔单抗,霉酚酸酯,喷司他丁,光生物调节,光溶血,鲁索替尼(ruxolitinib),西罗莫司(sirolimus),索尼德吉(sonidegib),他克莫司,塔西单抗(tocilizumab)和维莫德吉(vismodegib)。
用于治疗乳糜泻的另外的治疗剂和/或治疗方案的非限制性示例包括:AMG 714,AMY01,黑曲霉(Aspergillus niger)脯氨酰内切蛋白酶,BL-7010,CALY-002,GBR 830,Hu-Mik-Beta-1,IMGX003,KumaMax,醋酸拉拉唑肽(Larazotide Acetate),胰脂肪酶,TIMP-GLIA,维多珠单抗和ZED1227。
用于治疗银屑病的另外的治疗剂和/或方案的非限制性实例包括:局部皮质类固醇,局部克立硼罗(crisaborole)/AN2728,局部SNA-120,局部SAN021,局部苯烯莫德(tapinarof),局部托卡非尼(tocafinib),局部IDP-118,局部M518101,局部卡泊三烯(calcipotriene)和二丙酸倍他米松(例如,MC2-01乳膏和),局部P-3073,局部LEO 90100/>局部使用二丙酸倍他米松/>丙酸倍他索尔/>维生素D类似物(例如,卡泊三烯/>和骨化三醇/>),蒽林(anthralin)(例如,/>和/>),局部类维生素A(例如,他扎罗汀(tazarotene)(例如,/>和/>)),钙调神经磷酸酶抑制剂(例如,他克莫司/>和吡美莫司/>),水杨酸,焦油(coal tar),保湿剂,光疗(例如,暴露在阳光下,UVB光疗,窄带UVB光疗,戈克曼疗法(Goeckerman therapy),补骨脂素加紫外线A(PUVA)疗法和准分子激光(excimer laser)),类维生素A(例如,阿维A(acitretin)/>甲氨蝶呤Apo805K1,巴利替尼(baricitinib),FP187,KD025,普鲁索尔(prurisol),VTP-43742,XP23829,ZPL-389,CF101(匹利诺生(piclidenoson)),LAS41008,VPD-737(塞罗匹他(servopitant)),阿帕西替尼(upadacitinib)(ABT-494),阿普司特(aprmilast),托法替宾(tofacitibin),环孢霉素生物制剂(例如,依那西普/>依那西普-szzs/>英利昔单抗/>阿达木单抗/>阿达木单抗-adbm尤特克单抗(ustekinumab)/>戈利木单抗/>阿普斯特(apremilast)/>苏金单抗(secukinumab)/>聚乙二醇西妥昔单抗,苏金单抗(secukinumab),替拉珠单抗(tildrakizumab)-asmn,英利昔单抗-dyyb,阿巴西普(abatacept),依克珠单抗(ixekizumab)/>ABP 710,BCD-057,BI695501,比美珠单抗(bimekizumab)(UCB4940),CHS-1420,GP2017,古塞库单抗(guselkumab)(CNTO 1959),HD203,M923,MSB11022,米立珠单抗(Mirikizumab)(LY3074828),PF-06410293,PF-06438179,利赛唑单抗(risankizumab)(BI655066),SB2,SB4,SB5,siliq(布罗鲁单抗(brodalumab)),那美芦单抗(namilumab)(MT203,替拉珠单抗(tildrakizumab)(MK-3222),和依克珠单抗(ixekizumab)/>),硫鸟嘌呤,和羟基脲(例如,/>和/>)。
用于治疗皮肤T细胞淋巴瘤的另外的治疗剂和/或治疗方案的非限制性示例包括:光疗(例如,暴露于阳光下,UVB光疗,窄带UVB光疗,戈克曼疗法,补骨脂素加紫外线A(PUVA)疗法疗和准分子激光),体外光穿刺术(extracorporeal photopheresis),放射疗法(例如,点辐射和全身皮肤电子束疗法),干细胞移植,皮质类固醇,咪喹莫特,贝沙罗汀(bexarotene)凝胶,局部双氯乙基-硝基脲,甲氧乙胺凝胶,伏立诺他(vorinostat)罗米地辛(romidepsin)/>普拉拉特(pralatrexate)/>生物制剂(例如,阿仑单抗(alemtuzumab)/>维多地布伦妥昔单抗(brentuximabvedotin)(SGN-35),莫加单抗(mogamulizumab)和IPH4102)。
用于治疗葡萄膜炎的另外的治疗剂和/或方案的非限制性实例包括:皮质类固醇(例如玻璃体内曲安奈德注射液),抗生素,抗病毒药(例如无环鸟苷),地塞米松,免疫调节剂(例如,他克莫司,来氟米特,环磷酰胺和环孢菌素苯丁酸氮芥(chlorambucil),硫唑嘌呤,甲氨蝶呤,和霉酚酸酯),生物制剂(例如,英利昔单抗/>阿达木单抗/>依那西普/>戈利木单抗/>赛妥珠单抗(certolizumab)/>利妥昔单抗/>阿巴西普/>巴利昔单抗/>阿那白滞素(anakinra)/>康纳单抗(Canakinumab)/>戈沃需单抗(gevokixumab)(XOMA052),托珠单抗(tocilizumab)/>阿仑单抗/>艾法珠单抗(Efalizumab)
LFG316,西罗莫司/>阿巴西普,撒利鲁单抗(sarilumab)和达克珠单抗(daclizumab)/>),细胞毒性药物,外科植入物(例如氟轻松插片),和玻璃体切除术。
用于治疗粘膜炎的另外的治疗剂和/或治疗方案的非限制性示例包括:AG013,SGX942(达舒奎肽(dusquetide)),氨磷汀冷冻疗法,思必乐(cepacol)锭剂(lonzenges),辣椒素锭剂(capsaicin lozenges),粘膜胶粘剂(例如,/>),口服苯海拉明(例如,/>酏剂),口服生物粘附剂(例如,聚乙烯吡咯烷酮-透明质酸钠凝胶/>),口服润滑剂(例如,Oral/>),康普舒(caphosol),母菊(chamomillarecutita)漱口水,食用葡萄植物外来体,杀菌漱口水(例如,葡萄糖酸氯己定(例如,或/>),局部止痛药(例如,利多卡因,苯佐卡因,盐酸达克罗宁,二甲苯卡因(例如,粘性二甲苯卡因2%),和/>(0.6%苯酚),皮质类固醇(例如,强的松),止痛药(例如,布洛芬,萘普生,对乙酰氨基酚,和阿片类药物),GC4419,帕利夫明(palifermin)(角质形成细胞生长因子;/>),ATL-104,可乐定(clonidine)劳里亚德(lauriad),IZN-6N4,SGX942,瑞巴派特(rebamipide),奈匹德明(nepidermin),可溶性β-1,3/1,6葡聚糖,P276,LP-0004-09,CR-3294,ALD-518,IZN-6N4,槲皮素,含欧洲越橘(vaccinium myrtillus)提取物的颗粒,博落回(macleaya cordata)生物碱和紫锥菊(echinacea angustifolia)提取物(例如,/>),和胃肠道混合物(一种酸还原剂,例如氢氧化铝和氢氧化镁(例如,Maalox),抗真菌药(例如,制霉菌素(nystatin)),和止痛药(例如,飓风液体(hurricane liquid))。例如,用于治疗口腔粘膜炎的另外的治疗剂和/或治疗方案的非限制性示例包括:AG013,氨磷汀/>冷冻疗法,思必乐(cepacol)锭剂(lonzenges),粘膜胶粘剂(例如,/>),口服苯海拉明(例如,/>酏剂),口服生物粘附剂(例如,聚乙烯吡咯烷酮-透明质酸钠凝胶/>),口服润滑剂(例如,Oral/>),康普舒(caphosol),母菊(chamomilla recutita)漱口水,食用葡萄植物外来体,杀菌漱口水(例如,葡萄糖酸氯己定(例如,/>或/>),局部止痛药(例如,利多卡因,苯佐卡因,盐酸达克罗宁,二甲苯卡因(例如,粘性二甲苯卡因2%),和(0.6%苯酚),皮质类固醇(例如,强的松),止痛药(例如,布洛芬,萘普生,对乙酰氨基酚,和阿片类药物),GC4419,帕利夫明(palifermin)(角质形成细胞生长因子;),ATL-104,可乐定(clonidine)劳里亚德(lauriad),IZN-6N4,SGX942,瑞巴派特(rebamipide),奈匹德明(nepidermin),可溶性β-1,3/1,6葡聚糖,P276,LP-0004-09,CR-3294,ALD-518,IZN-6N4,槲皮素,和胃肠道混合物(一种酸还原剂,例如氢氧化铝和氢氧化镁(例如,Maalox),抗真菌药(例如,制霉菌素(nystatin)),和止痛药(例如,飓风液体(hurricane liquid))。作为另一个例子,食道粘膜炎的治疗的非限制性示例包括:二甲苯卡因(例如,凝胶粘性二甲苯卡因2%)。作为另一个例子,肠粘膜炎的治疗,改变肠粘膜炎的治疗以及肠粘膜炎的体征和症状的治疗包括:胃肠道混合物(一种酸还原剂,例如氢氧化铝和氢氧化镁(例如,Maalox),抗真菌剂(例如,制霉菌素),和止痛药(例如飓风液体)。
在一些实施方式中,在与化学实体接触或给予化学实体之前(例如,在约一小时前,或约6小时前,或约12小时前或约24小时前,或大约48小时之前,大约1周之前或大约1个月之前)给予对象第二治疗剂或方案。
在其它实施方式中,在与化学实体接触或给予化学实体的大约相同时间给予对象第二治疗剂或方案。举例来说,第二治疗剂或方案和化学实体以相同的剂型同时提供给对象。作为另一个例子,第二治疗剂或方案和化学实体以分开的剂型同时提供给对象。
在其它实施方式中,在与化学实体接触或给予化学实体之后(例如,在约一小时后,或约6小时后,或约12小时后,或约24小时后,或约48小时后,约1周后或约1个月后)给予对象第二治疗剂或方案。
患者选择
在一些实施方式中,本文所述的方法进一步包括鉴定需要这种治疗的对象(例如患者)的步骤(例如,通过活检,内窥镜检查,或本领域已知的其它常规方法)。在一些实施方式中,STING蛋白可以用作一些类型的癌症例如结肠癌和前列腺癌的生物标记。在其它实施方式中,鉴定对象可以包括分析患者(例如患有一个或多个冷肿瘤(cold tumor))的患者的肿瘤微环境中是否存在T细胞和/或是否存在耗尽的T细胞。这样的患者可以包括对使用检查点抑制剂治疗有耐受性的患者。在一些实施方式中,可以用本文的化学实体治疗这类患者,例如以将T细胞募集到肿瘤中,并且在一些情况下,例如一旦T细胞耗尽时,用一种或多种检查点抑制剂进一步治疗。
在一些实施方式中,可以将本文所述的化学实体,方法和组合物施用给一些对治疗有耐受性的患者群体(例如,对检查点抑制剂有耐受性的患者;例如,具有一种或多种冷肿瘤(例如,缺乏T细胞或T细胞耗尽的肿瘤)的患者)。
化合物制备
如本领域技术人员可以理解的,合成本文所述式的化合物的方法对于本领域普通技术人员将是显而易见的。可用于合成本文所述化合物的合成化学转化和保护基方法(保护和脱保护)是本领域已知的,并且包括例如在R.Larock,《综合有机转化》(ComprehensiveOrganic Transformations),VCH出版社(1989);T.W.Greene和RGM.Wuts,《有机合成中的保护基团》,第2版,约翰威利父子公司(John Wiley and Sons)(1991);L.Fieser和M.Fieser,《Fieser和Fieser的有机合成试剂》,约翰威利父子公司(1994);L.Paquette编,《有机合成试剂百科全书》,约翰威利父子公司(1995),及其后续版本中描述的那些。用于制备本发明化合物的原料是已知的,可通过已知方法制备的,或者可市售获得。本领域技术人员还将认识到,本文所述的条件和试剂可以与替代的本领域公认的等同物互换。例如,在许多反应中,三乙胺可与其它碱,例如非亲核碱(例如二异丙胺,1,8-二氮杂双环十一碳-7-烯,2,6-二叔丁基吡啶,或四丁基磷腈)互换。
技术人员将认识到可用于表征本文描述的化合物的多种分析方法,包括例如1HNMR,异核NMR,质谱,液相色谱和红外光谱。前述列表是本领域技术人员可用的表征方法的子集,并且无意于进行限制。
为了进一步说明上述内容,包括以下非限制性示例性合成方案。在权利要求范围内的这些实施例的变化形式在本领域技术人员的知识范围内,应认为落在所描述要求保护的本发明的范围内。读者将认识到,本领域技术人员在本公开的基础上能够准备和使用本发明,而无需详尽的示例。
以下缩写具有所示含义:
ACN=乙腈
DCM=二氯甲烷
t-AmOH=叔戊醇
THF=四氢呋喃
TEA=三乙胺
TMSCN=三甲基甲硅烷
Sphos Pd G3=(2-二环己基膦基-2',6'-二甲氧基联苯基)[2-(2'-氨基-1,1'-联苯基)]钯(II)甲磺酸盐
Brettphos Pd G3=甲烷磺酸(2-二环己基膦基-3,6-二甲氧基-2’,4’,6’-三异丙基-1,1’-联苯基)(2’-氨基-1,1’-联苯基-2-yl)钯(II)
Ruphos Pd G3=甲烷磺酸(2-二环己基膦基-2,6-二异丙氧基-1,1-联苯基)(2-氨基-1,1-联苯基-2-yl)钯(II)
PEPSSIPd TPentCl=[1,3-双[2,6-双(1-丙基丁基)苯基]-4,5-二氯-咪唑-2-亚基]-二氯-(3-氯吡啶-1-鎓-1-yl)钯
Xantphos=4,5-双(二苯基膦基)-9,9-二甲基呫吨
Pd2(dba)3=三(二亚苄基-丙酮)二钯(0)
DMAP=4-二甲氨基吡啶
m-CPBA=3-苯甲酸
K3PO4=磷酸钾
Cs2CO3=碳酸铯
NaHCO3=碳酸氢钠
Na2SO4=硫酸钠
Na2SO4=硫酸钠
HPLC=高效液相色谱
LCMS=液相色谱-质谱
MeOH=甲醇
H2O=水
NMR=核磁共振
EtOAc=乙酸乙酯
FA=甲酸
SpeedVac=Savant SC250EXP SpeedVac浓缩器
实施例
LCMS分析条件
方法A
仪器:配备DAD和ELSD检测器的安捷伦(Agilent)LCMS系统
离子模式:阳性
柱:Waters X-Bridge C18,50*2.1mm*5μm或同等规格
流动相A:H2O(0.04% TFA);流动相B:CH3CN(0.02% TFA)
梯度:4.5分钟梯度法,实际方法取决于化合物的clogP。
流速:0.6mL/分钟或0.8mL/分钟
柱温:40℃或50℃
UV:220nm
方法B
仪器:配备DAD和ELSD检测器的安捷伦(Agilent)LCMS系统
离子模式:阳性
柱:Waters X-Bridge ShieldRP18,50*2.1mm*5μm或同等规格
流动相A:H2O(0.05% NH3·H2O)或10mM碳酸氢氨;流动相B:CH3CN
梯度:4.5分钟梯度法;实际方法取决于化合物的clogP
流速:0.6mL/分钟或0.8mL/分钟
柱温:40℃
UV:220nm
制备型HPLC条件
仪器:
1.GILSON 281和岛津(Shimadzu)LCMS2010A
2.GILSON 215和岛津LC-20AP
3.GILSON 215
流动相:
A:NH4OH/H2O=0.05%v/v;B:ACN
A:FA/H2O=0.225%v/v;B:ACN
柱:
Xtimate C18 150*25mm*5μm
流速:25mL/分钟或30mL/分钟
监测波长:220&254nm
梯度:实际方法取决于化合物的clogP
探测器:MS触发或UV
中间体制备:6-[(4-氯-6-氰基-2-吡啶基)氨基]吲哚-1-羧酸叔丁酯的合成
步骤1:2-氨基-4-氯吡啶1-氧化物的合成
将4-氯吡啶-2-胺(20g,155.57mmol,1当量)溶解在DCM(500mL)中。m-CPBA(36.91g,171.13mmol,80%纯度,1.1当量)在0℃添加。反应混合物在0-30℃下搅拌4小时。然后将反应混合物过滤。将滤液用2M水性Na2SO3溶液和2M水性NaHCO3溶液洗涤,以得到白色固体的4-氯-1-氧化-吡啶-1-鎓-2-胺(35g,121.06mmol,77.82%产率,50%纯度)。
步骤2:6-氨基-4-氯皮考啉腈(chloropicolinonitrile)的合成
4-氯-1-氧化-吡啶-1-鎓-2-胺(35g,121.06mmol,50%纯度,1当量)溶解在ACN(500mL)中。然后添加TEA(1.94mol,269.60mL,16当量)和TMSCN(192.16g,1.94mol,242.32mL,16当量)。将混合物在90℃下加热16小时,然后冷却至室温并在减压下浓缩以去除CAN。通过逐滴添加2M水性NaHCO3溶液将混合物调整到pH 8,并添加水(300mL),并用DCM(3x100 mL)萃取。合并的有机层用300mL H2O洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到粗产物。粗产物通过快速硅胶色谱(220g/>硅胶快速柱,洗脱液为0~28%EtOAc/石油醚,梯度为80mL/分钟)纯化,以得到黄色固体的6-氨基-4-氯-吡啶-2-腈(8g,49.49mmol,40.88%产率,95%纯度)。
步骤3:6-溴-1H-吲哚-1-羧酸叔丁酯的合成
将6-溴-1H-吲哚(25g,127.52mmol,1当量)溶解在THF(300mL)中,然后添加(Boc)2O(41.75g,191.28mmol,43.94mL,1.5当量)和DMAP(31.16g,255.05mmol,2当量)。反应混合物在20℃下搅拌4小时。反应混合物在减压下浓缩以去除THF。粗产物在30℃下用MeOH(50mL)和H2O(100mL)研磨30分钟。收集固体以得到6-溴吲哚-1-羧酸叔丁酯(32g,92.92mmol,72.87%产率,86%纯度)。
步骤4:6-((4-氯-6-氰基吡啶-2-yl)氨基)-1H-吲哚-1-羧酸叔丁酯的合成
将6-氨基-4-氯-吡啶-2-腈(8g,49.49mmol,95%纯度,1当量)和6-溴吲哚-1-羧酸叔丁酯(20.45g,59.39mmol,86%纯度,1.2当量)溶解在二噁烷(400mL)中。然后,在氮气气氛下添加Cs2CO3(32.25g,98.98mmol,2当量)、Xantphos(2.86g,4.95mmol,0.1当量)和Pd2(dba)3(2.27g,2.47mmol,0.05当量)。反应混合物在100℃下加热16小时,然后在减压下浓缩,以去除二噁烷。将水(300mL)添加到残余物,并用300mL DCM萃取。合并的有机层用90mLH2O洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到粗产物。粗产物通过快速硅胶色谱(240g/>硅胶快速柱,洗脱液为0~15% EtOAc/石油醚,梯度为80mL/分钟)纯化,以得到黄色油状的6-[(4-氯-6-氰基-2-吡啶基)氨基]吲哚-1-羧酸叔丁酯(10.5g,25.62mmol,51.77%产率,90%纯度)。MS-ESI,369.1[M+H+]。
中间体制备:4-氯-6-[(4-氯-6-氰基-2-吡啶基)氨基]吲哚-1-羧酸叔丁酯的合成
步骤1:2-氨基-4-氯吡啶1-氧化物的合成
将4-氯吡啶-2-胺(20g,155.57mmol,1当量)溶解于DCM(500mL)中。然后,将m-CPBA(36.91g,171.13mmol,80%纯度,1.1当量)在0℃下添加。将反应混合物在30℃下搅拌16小时。然后将反应混合物过滤,以得到残余物。将残余物用2M水性Na2SO3溶液和2M水性NaHCO3溶液洗涤,以得到白色固体的2-氨基-4-氯吡啶1-氧化物(35g,121.06mmol,77.82%产率,50%纯度)。
步骤2:6-氨基-4-氯皮考啉腈的合成
4-氯-1-氧化-吡啶-1-鎓-2-胺(35g,121.06mmol,50%纯度,1.0当量)溶解于ACN(500mL)中。然后添加TEA(269.60mL,1.94mol,16当量)和TMSCN(192.16g,242.32mL,1.94mol,16当量)。混合物在90℃下加热16小时,然后在减压下浓缩,以去除ACN。通过逐滴添加2M水性NaHCO3溶液将混合物调整至pH=8。向残余物添加300mL H2O,并用DCM萃取。合并的有机层用300mL H2O洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到残余物。残余物通过快速硅胶色谱(220g/>硅胶快速柱,洗脱液为0~28%石油醚/乙酸乙酯,梯度为@80mL/分钟)纯化,以得到黄色固体的6-氨基-4-氯皮考啉腈(8g,49.49mmol,40.88%产率,95%纯度)。
步骤3:6-溴-4-氯-吲哚-1-羧酸叔丁酯的合成
向6-溴-4-氯-1H-吲哚(10g,43.39mmol,1.0当量)的THF(300mL)溶液中添加焦碳酸二-叔丁酯(14.20g,14.95mL,65.08mmol,1.5当量)和DMAP(10.60g,86.77mmol,2.0当量)。将混合物在20℃下搅拌4小时。反应混合物在减压下浓缩以去除THF。粗产物在20℃下用MeOH(50mL)和H2O(100mL)研磨30分钟。收集固体,以得到白色固体的6-溴-4-氯-吲哚-1-羧酸叔丁酯(15g,36.30mmol,83.66%产率,80%纯度)。
步骤4:4-氯-6-[(4-氯-6-氰基-2-吡啶基)氨基]吲哚-1-羧酸叔丁酯的合成
向溶解在二噁烷(300mL)中的6-溴-4-氯-吲哚-1-羧酸叔丁酯(6g,14.52mmol,80%纯度,1当量)和6-氨基-4-氯皮考啉腈(2.35g,14.52mmol,95%纯度,1当量)添加Cs2CO3(14.19g,43.56mmol,3当量)和Xantphos(840.09mg,1.45mmol,0.1当量)和Pd2(dba)3(664.76mg,725.94umol,0.05当量)。混合物在100℃下加热16小时,然后在减压下浓缩,以去除二噁烷。向残余物添加200mL H2O,并用300mL DCM萃取。合并的有机层用300mL H2O洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到残余物。残余物通过快速硅胶色谱(240g/>硅胶快速柱,洗脱液为0~15%石油醚/乙酸乙酯,梯度为80mL/分钟)纯化,以得到黄色固体的4-氯-6-[(4-氯-6-氰基-2-吡啶基)氨基]吲哚-1-羧酸叔丁酯(2g,4.46mmol,30.74%产率,90%纯度)。
实施例1:6-((1H-吲哚-6-基)氨基)-4-((2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)皮考啉腈(化合物143)的合成
步骤1:6-((6-氰基-4-((2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯的合成
将6-((4-氯-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(110.4mg,0.3mmol,1.0当量)和2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英(dioxin)-6-胺(133.8mg,0.6mmol,2.0当量)溶解在t-AmOH(3.0mL)中。然后在氮气气氛下添加K3PO4(190.8mg,0.9mmol,3.0当量)和BrettPhos Pd G3(13.59mg,0.015mmol,0.05当量)。将混合物在120℃下加热3小时。向反应混合物添加10mL H2O,然后用EtOAc萃取。收集合并的有机层,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到粗制6-((6-氰基-4-((2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯,将其用于下一步,无需进一步纯化。
步骤2:6-((1H-吲哚-6-基)氨基)-4-((2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)皮考啉腈的合成
将6-((6-氰基-4-((2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(166.5mg,70%纯度)溶解于1.5mL二噁烷中。然后添加1.5H2O mL。将反应混合物在100℃下加热16小时。所得混合物在真空下浓缩并通过制备型HPLC纯化,以得到6-((1H-吲哚-6-基)氨基)-4-((2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)皮考啉腈。MS-ESI,456.1[M+H+]。1H NMR(400MHz,DMSO-d6)δppm10.98(s,1H),9.13(s,1H),9.04(s,1H),7.87(s,1H),7.54–7.38(m,2H),7.29(d,1H),7.25–7.18(m,1H),7.13(dd,1H),6.96(dd,1H),6.83(d,1H),6.62(d,1H),6.33(t,1H)。
实施例5:4-[(5-叔丁基吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈(化合物115)的合成
步骤1:6-((4-((5-(叔丁基)吡啶-3-基)氨基)-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯的合成
将6-((4-氯-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(110.4mg,0.3mmol,1.0当量)和5-(叔丁基)吡啶-3-胺(90.1mg,0.6mmol,2.0当量)溶解在t-AmOH(3.0mL)中。然后在氮气气氛下添加K3PO4(190.8mg,0.9mmol,3.0当量)和BrettPhos Pd G3(13.59mg,0.015mmol,0.05当量)。将混合物在120℃下加热3小时。向反应混合物添加10mLH2O,然后用EtOAc萃取。收集合并的有机层,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到粗制6-((4-((5-(叔丁基)吡啶-3-基)氨基)-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(144.7mg,70%纯度),将其用于下一步,无需进一步纯化。
步骤2:4-[(5-叔丁基吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈的合成
将6-((4-((5-(叔丁基)吡啶-3-基)氨基)-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(144.7mg,70%纯度)溶解于1.5mL二噁烷中。然后添加1.5mL的H2O。将反应混合物在100℃下加热16小时。将反应混合物在真空下浓缩并通过制备型HPLC纯化,以得到4-[(5-叔丁基吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈。MS-ESI,383.1.1[M+H+].1H NMR(400MHz,DMSO-d6)δppm 10.97(s,1H),8.99(d,2H),8.37(d,1H),8.34(d,1H),7.80(s,1H),7.51(t,1H),7.41(d,1H),7.22–7.20(m,1H),6.94(dd,1H),6.57(d,1H),6.34–6.32(m,1H),2.07(s,1H),1.29(s,9H)。下表实施例2-4和6-20中所述的化合物使用类似于上述实施例1和5中所述的程序制备。
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实施例21:6-((1H-吲哚-6-基)氨基)-4-((3-氯-4-氟苯基)氨基)皮考啉腈(化合物140)的合成
类似于实施例1合成。在步骤1,不使用BrettPhos Pd G3,而是利用Sphos Pd G3。1H NMR(400MHz,DMSO-d6)δppm 10.97(s,1H),9.00(d,2H),7.84(s,1H),7.48–7.35(m,3H),7.26–7.17(m,2H),6.95(dd,1H),6.77(d,1H),6.54(d,1H),6.33(t,1H)。
实施例22:6-((1H-吲哚-6-基)氨基)-4-((5-氯吡啶-3-基)氨基)皮考啉腈(化合物109)的合成
步骤1:6-((4-((3-氯-4-氟苯基)氨基)-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯的合成
将6-((4-氯-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(110.4mg,0.3mmol,1.0当量)和5-氯吡啶-3-胺(76.8mg,0.6mmol,2.0当量)溶解在t-AmOH(3.0mL)中。然后在氮气气氛下添加K3PO4(190.8mg,0.9mmol,3.0当量)和SPhos Pd G3(13.12mg,0.015mmol,0.05当量)。将混合物在100℃下加热3小时。向反应混合物添加10mL H2O,然后用EtOAc萃取。收集合并的有机层,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到粗制6-((4-((3-氯-4-氟苯基)氨基)-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(138.0mg,70%纯度),将其用于下一步,无需进一步纯化。
步骤2:4-[(5-氯吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈的合成
将6-((4-((3-氯-4-氟苯基)氨基)-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸酯(138.0mg,70%纯度)溶解于1.5mL二噁烷中。然后添加1.5mL H2O。将反应混合物在100℃下加热16小时。将反应混合物在真空下浓缩并通过制备型HPLC纯化,以得到4-[(5-氯吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈。MS-ESI,361.1[M+H+]。1H NMR(400MHz,DMSO-d6)δppm 10.98(s,1H),9.24(s,1H),9.09(s,1H),8.42(d,1H),8.29–8.28(d,1H),7.87(s,1H),7.76-7.50(t,1H),7.44–7.42(d,1H),7.22–7.20(t,1H),6.98(dd,1H),6.89–6.88(d,1H),6.67(d,1H),6.34–6.33(s,1H).
使用类似于上述实施例21和22中所述的程序制备下表中实施例23-36中所述的化合物。
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实施例37:6-((1H-吲哚-6-基)氨基)-4-(4-甲基哌嗪-1-基)皮考啉腈(化合物121)的合成
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类似于实施例1合成。在步骤1,不使用BrettPhos Pd G3,而是利用Ruphos Pd G3。MS-ESI,333.2[M+H+]。1H NMR(400MHz,DMSO-d6)δppm 10.95(br s,1H),8.90(s,1H),7.88(s,1H),7.40(d,1H),7.23–7.16(m,1H),7.04(d,1H),6.94(dd,1H),6.37–6.28(m,2H),3.34(br s,4H),2.44–2.36(m,4H),2.21(s,3H)。
实施例38:6-((1H-吲哚-6-基)氨基)-4-(4-甲基哌嗪-1-基)皮考啉腈(化合物103)的合成
步骤1:6-((6-氰基-4-(4-甲氧基哌啶-1-基)吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯的合成
将6-((4-氯-6-氰基吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(110.4mg,0.3mmol,1.0当量)和1-甲基哌嗪(69.1mg,0.6mmol,2.0当量)溶解在t-AmOH(3.0mL)中。然后在氮气气氛下添加K3PO4(190.8mg,0.9mmol,3.0当量)和RuPhos Pd G3(12.54mg,0.015mmol,0.05当量)。将混合物在100℃下加热3小时。向反应混合物添加10mL H2O,然后用EtOAc萃取。收集合并的有机层,用无水Na2SO4干燥,过滤并在减压下浓缩,以得到粗制6-((6-氰基-4-(4-甲氧基哌啶-1-基)吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(268.3mg,70%纯度),将其用于下一步,无需进一步纯化。
步骤2:6-[(1H-吲哚-6-基)氨基]-4-(4-甲氧基哌啶-1-基)吡啶-2-腈的合成
将6-((6-氰基-4-(4-甲氧基哌啶-1-基)吡啶-2-基)氨基)-1H-吲哚-1-羧酸叔丁酯(268.3mg,70%纯度)溶解于1.5mL二噁烷中。然后添加1.5mL的H2O。将反应混合物在100℃下加热16小时。将反应混合物在真空下浓缩并通过制备型HPLC纯化,以得到6-[(1H-吲哚-6-基)氨基]-4-(4-甲氧基哌啶-1-基)吡啶-2-腈。MS-ESI,348.2[M+H+]。1H NMR(400MHz,DMSO-d6)δppm 10.94(s,1H),8.85(s,1H),7.88(s,1H),7.41–7.38(d,1H),7.19–7.18(t,1H),7.03(d,1H),6.95-6.92(dd,1H),6.34–6.31(m,2H),3.61–3.56(m,2H),3.42(m,1H),3.13(s,3H),3.11–3.08(m,2H),1.89–1.86(m,2H),1.47–1.44(m,2H)。使用类似于上述实施例37和38中所述的程序制备下表中实施例39-44中所述的化合物。
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实施例45:4-((5-(叔丁基)吡啶-3-基)氨基)-6-((4-氯-1H-吲哚-6-基)氨基)皮考啉腈(化合物163)的合成
将4-氯-6-[(4-氯-6-氰基-2-吡啶基)氨基]吲哚-1-羧酸叔丁酯(90.1mg,0.3mmol,1.0当量)和5-(叔丁基)吡啶-3-胺(67.5mg,0.45mmol,1.5当量)溶解在t-AmOH(3.0mL)中。然后在氮气气氛下添加K3PO4(190.8mg,0.9mmol,3.0当量)和BrettPhos Pd G3(13.4mg,0.015mmol,0.05当量)。将混合物在80℃下加热16小时。向反应混合物添加10mLH2O,然后用EtOAc萃取。收集合并的有机层,用无水Na2SO4干燥,过滤并在减压下通过Speedvac浓缩以得到残余物。残余物通过制备型HPLC纯化,以得到4-((5-(叔丁基)吡啶-3-基)氨基)-6-((4-氯-1H-吲哚-6-基)氨基)皮考啉腈(8.92mg,0.02mmol)。MS-ESI,417.2[M+H+]。1H NMR(400MHz,DMSO-d6)δppm 11.30(br s,1H),9.18–9.02(m,2H),8.47–8.33(m,2H),7.84(s,1H),7.53(s,1H),7.31(t,1H),7.13(s,1H),6.83(s,1H),6.57(s,1H),6.36(br s,1H),1.31(s,9H)。
使用类似于上述实施例45中所述的程序制备下表中实施例46-80中所述的化合物。
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实施例81:6-((4-氯-1H-吲哚-6-基)氨基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)皮考啉腈(化合物148)的合成
将4-氯-6-[(4-氯-6-氰基-2-吡啶基)氨基]吲哚-1-羧酸叔丁酯(90.1mg,0.3mmol,1.0当量)和1-(2,2,2-三氟乙基)哌嗪(75.6mg,0.45mmol,1.5当量)溶解在t-AmOH(3.0mL)中。然后在氮气气氛下添加K3PO4(190.8mg,0.9mmol,3.0当量)和PEPSSIPd TPentCl(14.6mg,0.015mmol,0.05当量)。将混合物在80℃下加热16小时。向反应混合物添加10mLH2O,然后用EtOAc萃取。收集合并的有机层,用无水Na2SO4干燥,过滤并在减压下通过Speedvac浓缩以得到残余物。将残余物通过制备型HPLC纯化,以得到6-((4-氯-1H-吲哚-6-基)氨基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)皮考啉腈(17.36mg,0.04mmol)。MS-ESI,435.2[M+H+]。1H NMR(400MHz,DMSO-d6)δppm11.28(br s,1H),9.09(s,1H),7.88(s,1H),7.31–7.28(m,1H),7.12(dd,2H),6.38–6.29(m,2H),3.25(q,4H),2.76–2.68(m,4H),1.29–1.10(m,1H),0.88–0.75(m,1H)。
使用类似于上述实施例81中所述的程序制备下表中实施例82-89中所述的化合物。
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生物检测
使用THP1-Dual TM细胞(KO-IFNAR2)测量本文所述化合物对STING途径的活化。
THP1-DualTMKO-IFNAR2细胞(从活体来源获得)保存在RPMI,10%FCS,5ml P/S,2mML-glut,10mM Hepes和1mM丙酮酸钠中。用Echo在空的384孔组织培养板(Greiner 781182)中发现化合物,最终浓度为0.0017-100μM。将细胞以每孔40μL、2×10E6个细胞/mL接种到TC板中。为了用STING配体激活,在Optimem培养基中制备了2'3'cGAMP(MW 718.38,从英杰公司(Invivogen)获得)。
为每个1×384板制备以下溶液:
ο溶液A:2mL Optimem,具有以下刺激物之一:
·60uL的10mM 2'3'cGAMP→150ìM储液
ο溶液B:2mL Optimem与60ìL Lipofectamine 2000→在室温下孵育5分钟
将2mL溶液A和2mL溶液B混合并在室温(RT)下孵育20分钟。将20μL转染溶液(A+B)添加到铺板细胞的顶部,最终2'3'cGAMP浓度为15μM。然后将板立即以340g离心1分钟,然后在37℃、5%CO2、>98%湿度下孵育24小时。然后测量荧光素酶报道分子活性。通过使用本领域已知的标准方法计算EC50值。
荧光素酶报道分子检测:将10μL来自检测的上清液转移到具有平底和方形孔的白色384板中。将一袋QUANTI-LucTMPlus溶于25mL水中。每25mL QUANTI-LucTMPlus溶液添加100μL QLC稳定剂。然后每孔加入50μL QUANTI-LucTMPlus/QLC溶液。在读板仪(例如,Spectramax I3X(Molecular Devices GF3637001))上测量发光。
然后测量荧光素酶报道分子活性。通过使用本领域已知的标准方法计算EC50值。
表BA显示了化合物在STING报道分子检测中的活性:<0.008μM=“++++++”;≥0.008和<0.04μM=“+++++”;≥0.04和<0.2μM=“++++”;≥0.2和<1μM=“+++”;≥1和<5μM=“++”;≥5和<100μM=“+”。
表BA
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编号条款
本文所述的化合物、组合物、方法和其他主题在以下编号的条款中进一步描述:
1.一种式(I)的化合物或其药学上可接受的盐:
其中:
R4和R5根据(AA)或(BB)定义:
(AA)
R4选自下组:
·任选地被1-6个Ra取代的C1-15烷基;和
·-(YA1)n-YA2,其中:
οn是0或1;
οYA1是任选地被1-3个Ra个取代的C1-3亚烷基;和
οYA2选自下组:
·C3-10环烷基或C3-10环烯基,其各自任选地被1-6个RY取代;
·具有3-10个环原子的杂环基或杂环烯基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂环基或杂环烯基任选地被1-6个RY取代;
·具有5-10个环原子的杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的C6-10芳基;
每次出现的RY独立地选自下组:氧代、Rc、Rb和–(Lb)b-Rb;
条件是当YA2是苯基或单环杂芳基,其各自任选地被1-4个RY取代,那么每次出现的RY独立地选自下组:-Rc,-Rb,和–(Lb)b-Rb;
R5是H或Rd;或
(BB)
R4和R5与其各自连接的氮原子一起形成4-12个环原子的饱和环、部分饱环和或芳环,其中0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和–(Lb)b-Rb;
M是0、1、2或3;
每次出现的R6独立地选自:Rc、Rb和-(Lb)b-Rb;
R3选自下组:H和Rd;
Y1选自下组:CR1a和N;
Y2选自下组:CR1b和N;
Y3选自下组:CR1c和N;
X1选自下组:CR1d、N、N(R2)、O和S;
X2选自下组:CR1e、N、N(R2)、O和S;
X3选自下组:CR1f、N、N(R2)、O和S,
条件是X1、X2和X3中的1-3个独立地选自下组:N、N(R2)、O和S;
各独立地为单键或双键,条件是包含X1、X2和X3的五元环是芳族的,并且包含Y1、Y2和Y3的六元环是芳族的;
R1a、R1b和R1c各自独立地选自:H、-(Lb)b-Rb、Rb和Rc;
R1d、R1e和R1f各自独立地选自下组:H、-Lb-Rb、Rb和Rc;
每次出现的R2独立地选自:H、Rd、-(Lb)b-Rb和Rb;
每次出现的Ra独立地选自下组:–OH;-卤素;–NReRf;C1-4烷氧基;C1-4卤代烷氧基;-C(=O)O(C1-4烷基);-C(=O)(C1-4烷基);-C(=O)OH;-CONR’R”;-S(O)1-2NR’R”;-S(O)1-2(C1-4烷基);和氰基;
每次出现的Rb独立地选自下组:
·C3-10环烷基或C3-10环烯基,其各自任选地被1-4个Rc取代;
·具有3-10个环原子的杂环基或杂环烯基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且所述杂环基或杂环烯基任选地被1-4个Rc取代;
·具有5-10个环原子的杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-4个Rc取代;和
·任选地被1-4个Rc取代的C6-10芳基;
每次出现的Lb独立地选自下组:-O-、-NH-、-NRd、-S(O)0-2、C(O)和任选地被1-3个Ra取代的C1-3亚烷基;
每次出现的b独立地是1、2或3;
每次出现的Rc独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代,C2-6烯基;C2-6炔基;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-S(O)(=NH)(C1-4烷基);-NReRf;–OH;-S(O)1- 2NR’R”;-C1-4硫代烷氧基;-C1-4硫代卤代烷氧基;-NO2;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;-C(=O)NR’R”;和–SF5;
每次出现的Rd独立地选自下组:任选地被1-3个独立选择的Ra取代的C1-6烷基;-C(O)(C1-4烷基);-C(O)O(C1-4烷基);-CONR’R”;-S(O)1-2NR’R”;-S(O)1-2(C1-4烷基);-OH;和C1-4烷氧基;
每次出现的Re和Rf独立地选自下组:H;任选地被各自独立地选自下组的1-3个取代基取代的C1-6烷基:NR’R”、-OH、卤素、C1-4烷氧基和C1-4卤代烷氧基;-C(O)R”’;-C(O)OR”’;-CONR’R”;-C(=O)C(=O)R”’;-S(O)1-2NR’R”;-S(O)1-2R”’;-OH;和C1-4烷氧基;
每次出现的R’和R”独立地选自下组:H;-OH;和C1-4烷基,其任选地被各自独立地选自下组的1-3个取代基取代:卤素、氰基、C1-4烷氧基、C1-4卤代烷氧基和–OH;和
R”’选自下组:H;和C1-4烷基,其任选地被各自独立地选自下组的1-3个取代基取代:卤素、氰基、C1-4烷氧基、C1-4卤代烷氧基和–OH;
条件是:
(i)当所述化合物是具有式 的化合物时,R1f不是/>其中Rd2是H或Rd;和
(ii)所述化合物不是:
2.如条款1所述的化合物,其中,所述化合物是式(I-a)的化合物或其药学上可接受的盐:
3.如条款1-2中任一项所述的化合物,其中所述化合物是式(I-a1)的化合物或其药学上可接受的盐:
4.如条款1-3中任一项所述的化合物,其中,m是1、2或3。
5.如条款1-4中任一项所述的化合物,其中,m是1或2。
6.如条款1-5中任一项所述的化合物,其中,m是1。
7.如条款1-4中任一项所述的化合物,其中,所述化合物是式(I-a1-a)的化合物或其药学上可接受的盐:
其中:
m1是0或1。
8.如条款7所述的化合物,其中,m1是0。
9.如条款1-8中任一项所述的化合物,其中,R4和R5根据(AA)定义。
10.如条款1-9中任一项所述的化合物,其中,R4是-(YA1)n-YA2。
11.如条款1-10中任一项所述的化合物,其中,n是0。
12.如条款1-11中任一项所述的化合物,其中,YA2选自下组:
·具有5-10个环原子的杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的C6-10芳基。
13.如条款1-12中任一项所述的化合物,其中,YA2选自下组:
·具有5-6个环原子的单环杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
14.如条款1-13中任一项所述的化合物,其中,YA2选自下组:
·具有6个环原子的单环杂芳基,其中1-3个环原子是环氮原子,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
15.如条款1-14中任一项所述的化合物,其中,其中,YA2是苯基或吡啶基,其各自被1-3个RY取代。
16.如条款1-15中任一项所述的化合物,其中,其中,YA2是苯基,其被1-3个RY取代。
17.如条款1-16中任一项所述的化合物,其中,YA2选自下组:
18.如条款1-15中任一项所述的化合物,其中,其中,YA2是吡啶基,其被1-3个RY取代。
19.如条款1-15或18中任一项所述的化合物,其中,其中,YA2是3-吡啶基,其被1-2个RY取代。
20.如条款1-15或18-19中任一项所述的化合物,其中,YA2选自下组:
21.如条款1-12中任一项所述的化合物,其中,YA2选自下组:
·具有8-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C8-10芳基。
22.如条款1-12或21中任一项所述的化合物,其中,YA2选自下组:
·具有9-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C9-10芳基。
23.如条款1-12或21-22中任一项所述的化合物,其中,YA2是其中,环B是具有5-6个环原子的芳族或部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代;和m2是0或1。
24.如条款23所述的化合物,其中,环B是具有5-6个环原子的芳环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中环B任选地被1-3个RY取代。
25.如条款23或24所述的化合物,其中,环B是具有5-6个环原子的芳环,其中,1-2个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中环B任选地被1-3个RY取代。
26.如条款1-12或21-25中任一项所述的化合物,其中,YA2选自下组:
27.如条款23所述的化合物,其中,环B连同与稠合苯环共有的sp2碳原子是具有5-6个环原子的部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代。
28.如条款1-12、21-23或27中任一项所述的化合物,其中,YA2选自下组:
29.如条款1-28中任一项所述的化合物,其中,各RY是独立选择的Rc。
30.如条款1-29中任一项所述的化合物,其中,各RY独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”,例如:
其中各RY独立地选自下组:卤素,例如–F或-Cl;氰基;C1-6烷基,例如甲基、乙基、异丙基或叔丁基;被1-6个独立选择的卤素取代的C1-6烷基,例如CF3或CH2CF3;C1-4烷氧基,例如甲氧基;C1-4卤代烷氧基,例如OCF3、OCF2H或OCH2CF3;和-C(=O)NR’R”,例如–C(=O)NHCH3。
31.如条款1-30中任一项所述的化合物,其中,R5是H。
32.如条款1-8中任一项所述的化合物,其中,R4和R5根据(BB)定义。
33.如条款1-8或32中任一项所述的化合物,其中,R4和R5与其各自连接的氮原子形成4-12个环原子的饱和环,其中,0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb。
34.如条款1-8或32-33中任一项所述的化合物,其中,R4和R5与其各自连接的氮原子形成4-8个环原子的饱和环,其中,0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb。
35.如条款1-8或32-34中任一项所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,Z1选自下组:N(Rd);-O-;和C(RZ)2,其中,各RZ独立地选自下组:H、Rc、Rb和-(Lb)b-Rb。
36.如条款1-8或32-35中任一项所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,RZ选自下组:任选地被1-6个独立选择的卤素取代的C1-6烷基;C1-4烷氧基;C1-4卤代烷氧基;Rb;和–O-Rb,例如–O-苯基,其中,苯基任选地被1-2个Rc取代。
37.如条款1-8或32-35中任一项所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,各RZ独立地选自下组:卤素,例如–F;和任选地被1-6个独立选择的卤素取代的C1-6烷基。
38.如条款1-8或32-35中任一项所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,Rd是任选地被1-3个独立选择的Ra取代的C1-6烷基。
39.如条款1-38中任一项所述的化合物,其中,每次出现的R6是独立选择的Rc。
40.如条款1-39中任一项所述的化合物,其中,每次出现的R6独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1- 2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”。
41.如条款1-40中任一项所述的化合物,其中,一次出现的R6是氰基。
42.如条款1-40中任一项所述的化合物,其中,一次出现的R6是卤素。
43.如条款1-40中任一项所述的化合物,其中,一次出现的R6是C1-10烷基,其任选地被1-6个独立选择的Ra取代。
44.如条款1-40或43中任一项所述的化合物,其中,一次出现的R6是C1-6烷基,其任选地被1-6个独立选择的卤素取代。
45.如条款1-40中任一项所述的化合物,其中,一次出现的R6选自下组:任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”。
46.如条款1-45中任一项所述的化合物,其中,Y1是CR1a。
47.如条款1-46中任一项所述的化合物,其中,R1a是H。
48.如条款1-46中任一项所述的化合物,其中,R1a选自下组:-(Lb)b-Rb、Rb和Rc。
49.如条款1-46或48中任一项所述的化合物,其中,R1a是Rc。
50.如条款1-46或48-49中任一项所述的化合物,其中,R1a是卤素,例如-Cl。
51.如条款1-46或48中任一项所述的化合物,其中,R1a是Rb。
52.如条款1-46或48中任一项所述的化合物,其中,R1a是-(Lb)b-Rb。
53.如条款1-52中任一项所述的化合物,其中,Y2是CR1b。
54.如条款1-53中任一项所述的化合物,其中,Y2是CH。
55.如条款1-54中任一项所述的化合物,其中,Y3是CR1c。
56.如条款1-55中任一项所述的化合物,其中,Y3是CH。
57.如条款1-45中任一项所述的化合物,其中,Y1是CH;Y2是CH;且Y3是CH。
58.如条款1-45中任一项所述的化合物,其中,Y1是CR1a,其中,R1a选自下组:-(Lb)b-Rb、Rb和Rc;Y2是CH;并且Y3是CH。
59.如条款58所述的化合物,其中,R1a是Rc。
60.如条款58所述的化合物,其中,R1a是-(Lb)b-Rb或Rb。
61.如条款1-60中任一项所述的化合物,其中,X1是N(R2)。
62.如条款1-61中任一项所述的化合物,其中,X1是N(H)。
63.如条款1-62中任一项所述的化合物,其中,X2是CR1e。
64.如条款1-63中任一项所述的化合物,其中,X2是CH。
65.如条款1-64中任一项所述的化合物,其中,X3是CR1f。
66.如条款1-65中任一项所述的化合物,其中,R1f是CH。
67.如条款1-65中任一项所述的化合物,其中,R1f选自下组:-Lb-Rb、Rb和Rc。
68.如条款1-65或67中任一项所述的化合物,其中,R1f是Rc。
69.如条款1-65或67中任一项所述的化合物,其中,R1f是–Lb-Rb或–Rb。
70.如条款1-60中任一项所述的化合物,其中,X1是N(H);X2是CH;且X3是CH。
71.如条款1-60中任一项所述的化合物,其中,X1是N(H);X2是CH;且X3是CR1f,其中,R1f选自下组:-Lb-Rb、Rb和Rc。
72.如条款71所述的化合物,其中,R1f是Rc。
73.如条款71所述的化合物,其中,R1f是–Lb-Rb或Rb。
74.如条款1-45中任一项所述的化合物,其中所述部分是/>
75.如条款74所述的化合物,其中,R2是H。
76.如条款74或75所述的化合物,其中,R1a是H或Cl;且R1f是H。
77.如条款74或75所述的化合物,其中,R1a是H或Cl;且R1f选自下组:-Lb-Rb、Rb和Rc。
78.如条款77所述的化合物,其中,R1f是Rc。
79.如条款74或75所述的化合物,其中,R1a选自下组:-(Lb)b-Rb,Rb和Rc;且R1f是H。
80.如条款79所述的化合物,其中,R1a是Rc。
81.如条款74或75所述的化合物,其中,R1a选自下组:-(Lb)b-Rb,Rb和Rc;且R1f选自下组:-Lb-Rb、Rb和Rc。
82.如条款1所述的化合物,其中,所述化合物是式(I-a1-a1)的化合物或其药学上可接受的盐:
其中:
m1是0或1;和
R4是–YA2,其中YA2选自下组:
·具有5-6个环原子的单环杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
83.如条款82所述的化合物,其中R4选自下组:
·具有6个环原子的单环杂芳基,其中1-3个环原子是环氮原子,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基。
84.如条款82或83所述的化合物,其中,其中,R4是苯基或吡啶基,其各自被1-3个RY取代。
85.如条款82-84中任一项所述的化合物,其中,YA2选自下组:
86.如条款1所述的化合物,其中,所述化合物是式(I-a1-a2)的化合物或其药学上可接受的盐:
其中:
m1是0或1;和
R4是–YA2,其中YA2选自下组:
·具有9-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C9-10芳基。
87.如条款86所述的化合物,其中,R4是其中,环B是具有5-6个环原子的芳族或部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代;和m2是0或1。
88.如条款87所述的化合物,其中,环B是具有5-6个环原子的芳环,其中,1-2个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S,并且其中环B任选地被1-4个RY取代。
89.如条款86-88中任一项所述的化合物,其中R4选自下组:
90.如条款87所述的化合物,其中,环B连同与稠合苯环共有的sp2碳原子是具有5-6个环原子的部分不饱和环,其中,0-3个环原子是杂原子,各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中环B任选地被1-4个RY取代。
91.如条款86-87或90中任一项所述的化合物,其中,R4选自下组:
92.如条款82-91中任一项所述的化合物,其中,各RY是独立选择的Rc。
93.如条款82-92中任一项所述的化合物,其中,各RY独立地选自下组:卤素,例如–F或-Cl;氰基;C1-6烷基,例如甲基、乙基、异丙基或叔丁基;被1-6个独立选择的卤素取代的C1-6烷基,例如CF3或CH2CF3;C1-4烷氧基,例如甲氧基;C1-4卤代烷氧基,例如OCF3、OCF2H或OCH2CF3;和-C(=O)NR’R”,例如
–C(=O)NHCH3。
94.如条款1所述的化合物,其中,所述化合物是式(I-a1-a3)的化合物或其药学上可接受的盐:
其中:
m1是0或1;和
R4和R5与其各自连接的氮原子形成4-8个环原子的饱和环,其中0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb。
95.如条款94所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,Z1选自下组:N(Rd);-O-;和C(RZ)2,其中,各RZ独立地选自下组:H、Rc、Rb和-(Lb)b-Rb。
96.如条款94或95所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,RZ选自下组:任选地被1-6个独立选择的卤素取代的C1-6烷基;C1-4烷氧基;C1-4卤代烷氧基;Rb;和–O-Rb,例如–O-苯基,其中,苯基任选地被1-2个Rc取代。
97.如条款94或95所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,各RZ独立地选自下组:卤素,例如–F;和任选地被1-6个独立选择的卤素取代的C1-6烷基。
98.如条款94或95所述的化合物,其中,R4和R5与其各自连接的氮原子形成:其中,Rd是任选地被1-3个独立选择的Ra取代的C1-6烷基。/>
99.如条款82-98中任一项所述的化合物,其中,m1是0。
100.如条款82-99中任一项所述的化合物,其中,每次出现的R6是独立选择的Rc。
101.如条款82-100中任一项所述的化合物,其中,每次出现的R6独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”。
102.如条款82-101中任一项所述的化合物,其中,一次出现的R6是氰基。
103.如条款82-102中任一项所述的化合物,其中,m1是0;且R6是氰基。
104.如条款82-103中任一项所述的化合物,其中,R2是H。
105.如条款82-104中任一项所述的化合物,其中,R1a是H;且R1f是H。
106.如条款82-104中任一项所述的化合物,其中,R1a是H;且R1f选自下组:-Lb-Rb、Rb和Rc。
107.如条款106所述的化合物,其中,R1f是Rc。
108.如条款82-104中任一项所述的化合物,其中,R1a选自下组:-(Lb)b-Rb,Rb和Rc;且R1f是H。
109.如条款108所述的化合物,其中,R1a是Rc。
110.如条款108或109所述的化合物,其中,R1a是卤素,例如–Cl。
111.如条款82-104中任一项所述的化合物,其中,R1a选自下组:-(Lb)b-Rb,Rb和Rc;且R1f选自下组:-Lb-Rb、Rb和Rc。
112.如条款82-104或111中任一项所述的化合物,其中,R1a和R1f是独立选择的Rc。
113.如条款1-112中任一项所述的化合物,其中,R3是H。
114.如条款1所述的化合物,其中,所述化合物是选自表C1中描述的化合物或其药学上可接受的盐。
115.如条款1所述的化合物,其中,所述化合物选自下组:
6-((1H-吲哚-6-基)氨基)-4-((2,2,3,3-四氟-2,3-二氢苯并[b][1,4]二噁英-6-基)氨基)皮考啉腈;
4-[(2,3-二氢-1,4-苯并二噁英-6-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(2,3-二氢-1H-茚-5-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-{[5-(三氟甲基)吡啶-3-基]氨基}吡啶-2-腈;
4-[(5-叔丁基吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[(6-甲氧基吡啶-3-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[(6-甲基吡啶-3-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-{[6-(三氟甲基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-{[6-(2,2,2-三氟乙氧基)吡啶-3-基]氨基}吡啶-2-腈;
4-[(6-乙基吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-{[6-(二氟甲氧基)吡啶-3-基]氨基}-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-{[6-(三氟甲氧基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-{[5-(丙-2-基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[(2-氧代-2,3-二氢-1H-吲哚-5-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[(3-氧代-2,3-二氢-1H-异吲哚-5-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[(2-甲基-1,3-苯并噻唑-6-基)氨基]吡啶-2-腈;
4-[(3,3-二甲基-2-氧代-2,3-二氢-1H-吲哚-6-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[(2-甲基-1,3-苯并噻唑-5-基)氨基]吡啶-2-腈;
4-[(2,2-二氟-2H-1,3-苯并二氧戊环-5-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(1,3-二甲基-1H-吲唑-5-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-((1H-吲哚-6-基)氨基)-4-((3-氯-4-氟苯基)氨基)皮考啉腈;
4-[(5-氯吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(4-氯-3-氟苯基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(3,4-二氟苯基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(3,4-二氯苯基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(3,5-二氟苯基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-{[3-氟-5-(三氟甲基)苯基]氨基}-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(3,5-二氯苯基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(3-氯-5-甲氧基苯基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-[(3-氯-5-氰基苯基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-{[3-氯-5-(三氟甲氧基)苯基]氨基}-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-{[3-氟-4-(三氟甲基)苯基]氨基}-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-{[3-氯-4-(三氟甲基)苯基]氨基}-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
4-({2-氰基-6-[(1H-吲哚-6-基)氨基]吡啶-4-基}氨基)-2-氟-N-甲基苯甲酰胺;
4-[(5-氟吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-((1H-吲哚-6-基)氨基)-4-(4-甲基哌嗪-1-基)皮考啉腈;
4-[(6-氯-5-甲氧基吡啶-3-基)氨基]-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-(4-甲氧基哌啶-1-基)吡啶-2-腈;
4-(4,4-二氟哌啶-1-基)-6-[(1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[4-(三氟甲基)哌啶-1-基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[4-(2,2,2-三氟乙基)哌嗪-1-基]吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-(吗啉-4-基)吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-(4-苯氧基哌啶-1-基)吡啶-2-腈;
6-[(1H-吲哚-6-基)氨基]-4-[4-(2-甲基丙基)哌嗪-1-基]吡啶-2-腈;
4-[(5-叔丁基吡啶-3-基)氨基]-6-[(4-氯-1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(2,3-二氢-1,4-苯并二噁英-6-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(2,2,3,3-四氟-2,3-二氢-1,4-苯并二噁英-6-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(2,3-二氢-1H-茚-5-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(5-氯吡啶-3-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[5-(三氟甲基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3-氯-4-氟苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(4-氯-3-氟苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3,4-二氟苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3,4-二氯苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3,5-二氟苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[3-氟-5(三氟甲基)苯基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3-氯-5-氟苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3,5-二氯苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3-氯-5-甲氧基苯基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[3-氯-5-(三氟甲氧基)苯基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[3-氟-4-(三氟甲基)苯基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[3-氯-4-(三氟甲基)苯基]氨基}吡啶-2-腈;
4-({2-[(4-氯-1H-吲哚-6-基)氨基]-6-氰基吡啶-4-基}氨基)-2-氟-N-甲基苯甲酰胺;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(6-甲氧基吡啶-3-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(6-甲基吡啶-3-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[6-(三氟甲基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(5-氟吡啶-3-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(6-氯-5-甲氧基吡啶-3-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[6-(2,2,2-三氟乙氧基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(6-乙基吡啶-3-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[6-(二氟甲氧基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{[5-(丙-2-基)吡啶-3-基]氨基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(2-氧代-2,3-二氢-1H-吲哚-5-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3-氧代-2,3-二氢-1H-异吲哚-5-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(2-甲基-1,3-苯并噻唑-6-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(3,3-二甲基-2-氧代-2,3-二氢-1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(2-甲基-1,3-苯并噻唑-5-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(2,2-二氟-2H-1,3-苯并二氧戊环-5-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[(1,3-二甲基-1H-吲唑-5-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-(4-甲基哌嗪-1-基)吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[4-(2,2,2-三氟乙基)哌嗪-1-基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-(4-甲氧基哌啶-1-基)吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-{4-[(4-氟苯基)甲基]哌啶-1-基}吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[4-(三氟甲基)哌啶-1-基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-(吗啉-4-基)吡啶-2-腈;
4-(4-苄基哌啶-1-基)-6-[(4-氯-1H-吲哚-6-基)氨基]吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-(4-苯氧基哌啶-1-基)吡啶-2-腈;
6-[(4-氯-1H-吲哚-6-基)氨基]-4-[4-(2-甲基丙基)哌嗪-1-基]吡啶-2-腈;和
6-[(4-氯-1H-吲哚-6-基)氨基]-4-(4,4-二甲基哌啶-1-基)吡啶-2-腈。
116.一种药物组合物,其包含如条款1-115中任一项所述的化合物和一种或多种药学上可接受的赋形剂。
117.一种抑制STING活性的方法,所述方法包括使STING与如条款1-115中任一项所述的化合物或其药学上可接受的盐接触;或与如条款116所述的药物组合物接触。
118.如条款117所述的方法,其中,所述抑制包括拮抗STING。
119.如条款117-118中任一项所述的方法,所述方法在体外进行。
120.如条款119所述的方法,其中,所述方法包括使包含含有STING的一个或多个细胞的样品与所述化合物接触。
121.如条款119或120所述的方法,其中,所述一种或多种细胞是一种或多种癌细胞。
122.如条款120或121所述的方法,其中,所述样品还包含一个或多个癌细胞,所述癌选自下组:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
123.如条款117或118所述的方法,所述方法在体内进行。
124.如条款123所述的方法,其中,所述方法包括将所述化合物给予患有其中增加(例如,过量)的STING信号转导导致所述疾病的病理和/或症状和/或进展的疾病的对象。
125.如条款124所述的方法,其中,所述对象是人。
126.如条款125所述的方法,所述疾病是癌症。
127.如条款126所述的方法,其中,所述癌症选自下组:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
128.如条款126或127所述的方法,其中,所述癌症是难治性癌症。
129.如条款124所述的方法,其中,所述化合物与一种或多种另外的癌症疗法组合给予。
130.如条款129所述的方法,其中,所述一种或多种另外的癌症疗法包括:手术,放射疗法,化学疗法,毒素疗法,免疫疗法,冷冻疗法或基因疗法,或其组合。
131.如条款130所述的方法,其中,所述化学疗法包括给予一种或多种其它化学治疗剂。
132.如条款131所述的方法,其中,所述一种或多种其它化学治疗剂选自:烷化剂(例如,顺铂,卡铂,氮芥,环磷酰胺,苯丁酸氮芥,异环磷酰胺和/或奥沙利铂);抗代谢物(例如,硫唑嘌呤和/或巯基嘌呤);萜类化合物(例如,长春花生物碱和/或紫杉烷;例如长春新碱、长春碱、长春瑞宾和/或长春地辛,泰素,紫杉醇和/或多西他赛);拓扑异构酶(例如,I型拓扑异构酶和/或2型拓扑异构酶;例如喜树碱,例如伊立替康和/或拓扑替康;安吖啶,依托泊苷,磷酸依托泊苷和/或替尼泊苷);细胞毒性抗生素(例如,放线菌素,蒽环霉素,多柔比星,柔红霉素,伐柔比星,伊达比星,表柔比星,博莱霉素,普卡霉素和/或丝裂霉素);激素(例如,促黄体激素释放的激素激动剂;例如亮丙瑞林,戈舍瑞林,曲普瑞林,组胺瑞林,比卡鲁胺,氟他胺和/或尼鲁米特);抗体(例如,阿昔单抗,阿达木单抗,阿仑单抗,阿利珠单抗,巴利昔单抗,贝利木单抗,贝伐珠单抗,本妥昔单抗,康纳单抗,西妥昔单抗,培舍珠单抗,达克珠单抗,地舒单抗,依库珠单抗,艾法珠单抗,吉妥珠单抗,戈利木单抗,替伊莫单抗,英利昔单抗,伊匹木单抗,莫罗单抗-CD3,那他珠单抗,奥伐木单抗,奥马珠单抗,帕利珠单抗,帕尼单抗,雷珠单抗,利妥昔单抗,妥珠单抗,托西莫单抗和/或曲妥珠单抗);抗血管生成剂;细胞因子;血栓形成活性剂;生长抑制剂;抗蠕虫剂;及靶向选自下组的免疫检查点受体的免疫检查点抑制剂:CTLA-4,PD-1,PD-L1,PD-1–PD-L1,PD-1–PD-L2,白介素-2(IL-2),吲哚胺2,3-双加氧酶(IDO),IL-10,转化生长因子-β(TGFβ),T细胞免疫球蛋白及粘蛋白3(TIM3或HAVCR2),半乳凝素9-TIM3,磷脂酰丝氨酸-TIM3,淋巴细胞活化基因3蛋白(LAG3),MHC II类–LAG3,4-1BB–4-1BB配体,OX40–OX40配体,GITR,GITR配体–GITR,CD27,CD70-CD27,TNFRSF25,TNFRSF25–TL1A,CD40L,CD40–CD40配体,HVEM–LIGHT–LTA,HVEM,HVEM–BTLA,HVEM–CD160,HVEM–LIGHT,HVEM–BTLA–CD160,CD80,CD80–PDL-1,PDL2–CD80,CD244,CD48–CD244,CD244,ICOS,ICOS–ICOS配体,B7-H3,B7-H4,VISTA,TMIGD2,HHLA2–TMIGD2,嗜乳脂蛋白,包括BTNL2,Siglec家族,TIGIT和PVR家族成员,KIRs,ILTs和LIRs,NKG2D和NKG2A,MICA和MICB,CD244,CD28,CD86–CD28,CD86–CTLA,CD80–CD28,CD39,CD73腺苷–CD39–CD73,CXCR4–CXCL12,磷脂酰丝氨酸,TIM3,磷脂酰丝氨酸–TIM3,SIRPA–CD47,VEGF,神经毡蛋白,CD160,CD30,和CD155(例如,CTLA-4或PD1或PD-L1)。
133.如条款124-132中任一项所述的方法,其中,所述化合物是肿瘤内施用的。
134.一种治疗癌症的方法,包括对需要这种治疗的对象给予有效量的根据条款1-115中任一项所述的化合物或根据条款116所述的药物组合物。
135.如条款134所述的方法,其中,所述癌症选自下组:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
136.如条款134或135所述的方法,其中,所述癌症是难治性癌症。
137.如条款134所述的方法,其中,所述化合物与一种或多种另外的癌症疗法组合给予。
138.如条款137所述的方法,其中,所述一种或多种另外的癌症疗法包括:手术,放射疗法,化学疗法,毒素疗法,免疫疗法,冷冻疗法或基因疗法,或其组合。
139.如条款138所述的方法,其中,所述化学疗法包括给予一种或多种其它化学治疗剂。
140.如条款139所述的方法,其中,所述一种或多种其它化学治疗剂选自:烷化剂(例如,顺铂,卡铂,氮芥,环磷酰胺,苯丁酸氮芥,异环磷酰胺和/或奥沙利铂);抗代谢物(例如,硫唑嘌呤和/或巯基嘌呤);萜类化合物(例如,长春花生物碱和/或紫杉烷;例如长春新碱、长春碱、长春瑞宾和/或长春地辛,泰素,紫杉醇和/或多西他赛);拓扑异构酶(例如,I型拓扑异构酶和/或2型拓扑异构酶;例如喜树碱,例如伊立替康和/或拓扑替康;安吖啶,依托泊苷,磷酸依托泊苷和/或替尼泊苷);细胞毒性抗生素(例如,放线菌素,蒽环霉素,多柔比星,柔红霉素,伐柔比星,伊达比星,表柔比星,博莱霉素,普卡霉素和/或丝裂霉素);激素(例如,促黄体激素释放的激素激动剂;例如亮丙瑞林,戈舍瑞林,曲普瑞林,组胺瑞林,比卡鲁胺,氟他胺和/或尼鲁米特);抗体(例如,阿昔单抗,阿达木单抗,阿仑单抗,阿利珠单抗,巴利昔单抗,贝利木单抗,贝伐珠单抗,本妥昔单抗,康纳单抗,西妥昔单抗,培舍珠单抗,达克珠单抗,地舒单抗,依库珠单抗,艾法珠单抗,吉妥珠单抗,戈利木单抗,替伊莫单抗,英利昔单抗,伊匹木单抗,莫罗单抗-CD3,那他珠单抗,奥伐木单抗,奥马珠单抗,帕利珠单抗,帕尼单抗,雷珠单抗,利妥昔单抗,妥珠单抗,托西莫单抗和/或曲妥珠单抗);抗血管生成剂;细胞因子;血栓形成活性剂;生长抑制剂;抗蠕虫剂;及靶向选自下组的免疫检查点受体的免疫检查点抑制剂:CTLA-4,PD-1,PD-L1,PD-1–PD-L1,PD-1–PD-L2,白介素-2(IL-2),吲哚胺2,3-双加氧酶(IDO),IL-10,转化生长因子-β(TGFβ),T细胞免疫球蛋白及粘蛋白3(TIM3或HAVCR2),半乳凝素9-TIM3,磷脂酰丝氨酸-TIM3,淋巴细胞活化基因3蛋白(LAG3),MHC II类–LAG3,4-1BB–4-1BB配体,OX40–OX40配体,GITR,GITR配体–GITR,CD27,CD70-CD27,TNFRSF25,TNFRSF25–TL1A,CD40L,CD40–CD40配体,HVEM–LIGHT–LTA,HVEM,HVEM–BTLA,HVEM–CD160,HVEM–LIGHT,HVEM–BTLA–CD160,CD80,CD80–PDL-1,PDL2–CD80,CD244,CD48–CD244,CD244,ICOS,ICOS–ICOS配体,B7-H3,B7-H4,VISTA,TMIGD2,HHLA2–TMIGD2,嗜乳脂蛋白,包括BTNL2,Siglec家族,TIGIT和PVR家族成员,KIRs,ILTs和LIRs,NKG2D和NKG2A,MICA和MICB,CD244,CD28,CD86–CD28,CD86–CTLA,CD80–CD28,CD39,CD73腺苷–CD39–CD73,CXCR4–CXCL12,磷脂酰丝氨酸,TIM3,磷脂酰丝氨酸–TIM3,SIRPA–CD47,VEGF,神经毡蛋白,CD160,CD30,和CD155(例如,CTLA-4或PD1或PD-L1)。
141.如条款134-140中任一项所述的方法,其中,所述化合物是肿瘤内施用的。
142.一种在有需要的对象中诱导免疫应答的方法,所述方法包括向所述对象给予有效量的根据条款1-115中任一项所述的化合物或根据条款116所述的药物组合物。
143.如条款142所述的方法,其中,所述对象患有癌症。
144.如条款143所述的方法,其中,所述对象已经历和/或正在经历和/或将经历一种或多种癌症疗法。
145.如条款143所述的方法,其中,所述癌症选自下组:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
146.如条款143-145中任一项所述的方法,其中,所述癌症是难治性癌症。
147.如条款142所述的方法,其中,所述免疫应答是先天免疫应答。
148.如条款147所述的方法,其中,所述至少一种或多种另外的癌症疗法包括:手术,放射疗法,化学疗法,毒素疗法,免疫疗法,冷冻疗法或基因疗法,或其组合。
149.如条款148所述的方法,其中,所述化学疗法包括给予一种或多种其它化学治疗剂。
150.如条款149所述的方法,其中,所述一种或多种其它化学治疗剂选自:烷化剂(例如,顺铂,卡铂,氮芥,环磷酰胺,苯丁酸氮芥,异环磷酰胺和/或奥沙利铂);抗代谢物(例如,硫唑嘌呤和/或巯基嘌呤);萜类化合物(例如,长春花生物碱和/或紫杉烷;例如长春新碱、长春碱、长春瑞宾和/或长春地辛,泰素,紫杉醇和/或多西他赛);拓扑异构酶(例如,I型拓扑异构酶和/或2型拓扑异构酶;例如喜树碱,例如伊立替康和/或拓扑替康;安吖啶,依托泊苷,磷酸依托泊苷和/或替尼泊苷);细胞毒性抗生素(例如,放线菌素,蒽环霉素,多柔比星,柔红霉素,伐柔比星,伊达比星,表柔比星,博莱霉素,普卡霉素和/或丝裂霉素);激素(例如,促黄体激素释放的激素激动剂;例如亮丙瑞林,戈舍瑞林,曲普瑞林,组胺瑞林,比卡鲁胺,氟他胺和/或尼鲁米特);抗体(例如,阿昔单抗,阿达木单抗,阿仑单抗,阿利珠单抗,巴利昔单抗,贝利木单抗,贝伐珠单抗,本妥昔单抗,康纳单抗,西妥昔单抗,培舍珠单抗,达克珠单抗,地舒单抗,依库珠单抗,艾法珠单抗,吉妥珠单抗,戈利木单抗,替伊莫单抗,英利昔单抗,伊匹木单抗,莫罗单抗-CD3,那他珠单抗,奥伐木单抗,奥马珠单抗,帕利珠单抗,帕尼单抗,雷珠单抗,利妥昔单抗,妥珠单抗,托西莫单抗和/或曲妥珠单抗);抗血管生成剂;细胞因子;血栓形成活性剂;生长抑制剂;抗蠕虫剂;及靶向选自下组的免疫检查点受体的免疫检查点抑制剂:CTLA-4,PD-1,PD-L1,PD-1–PD-L1,PD-1–PD-L2,白介素-2(IL-2),吲哚胺2,3-双加氧酶(IDO),IL-10,转化生长因子-β(TGFβ),T细胞免疫球蛋白及粘蛋白3(TIM3或HAVCR2),半乳凝素9-TIM3,磷脂酰丝氨酸-TIM3,淋巴细胞活化基因3蛋白(LAG3),MHC II类–LAG3,4-1BB–4-1BB配体,OX40–OX40配体,GITR,GITR配体–GITR,CD27,CD70-CD27,TNFRSF25,TNFRSF25–TL1A,CD40L,CD40–CD40配体,HVEM–LIGHT–LTA,HVEM,HVEM–BTLA,HVEM–CD160,HVEM–LIGHT,HVEM–BTLA–CD160,CD80,CD80–PDL-1,PDL2–CD80,CD244,CD48–CD244,CD244,ICOS,ICOS–ICOS配体,B7-H3,B7-H4,VISTA,TMIGD2,HHLA2–TMIGD2,嗜乳脂蛋白,包括BTNL2,Siglec家族,TIGIT和PVR家族成员,KIRs,ILTs和LIRs,NKG2D和NKG2A,MICA和MICB,CD244,CD28,CD86–CD28,CD86–CTLA,CD80–CD28,CD39,CD73腺苷–CD39–CD73,CXCR4–CXCL12,磷脂酰丝氨酸,TIM3,磷脂酰丝氨酸–TIM3,SIRPA–CD47,VEGF,神经毡蛋白,CD160,CD30,和CD155(例如,CTLA-4或PD1或PD-L1)。
151.一种治疗其中增加(例如,过量)的STING信号转导促进该疾病的病理和/或症状和/或进展的疾病的方法,所述方法包括向需要这种治疗的对象给予有效量的根据条款1-115中任一项所述的化合物或根据条款116所述的药物组合物。
152.一种治疗方法,包括给予患有其中增加(例如,过量)的STING信号转导促进该疾病的病理和/或症状和/或进展的疾病的对象有效量的根据条款1-115中任一项所述的化合物或根据条款116所述的药物组合物。
153.一种治疗方法,包括给予对象根据条款1-115中任一项所述的化合物或根据条款116所述的药物组合物,其中,所述化合物或组合物以有效量给予以治疗其中增加(例如,过量)的STING信号转导促进该疾病的病理和/或症状和/或进展的疾病,从而治疗疾病。
154.如条款151-153中任一项所述的方法,其中所述疾病是癌症。
155.如条款154所述的方法,其中,所述癌症选自下组:黑色素瘤,宫颈癌,乳腺癌,卵巢癌,前列腺癌,睾丸癌,尿路上皮癌,膀胱癌,非小细胞肺癌,小细胞肺癌,肉瘤,结直肠腺癌,胃肠道间质瘤,胃食管癌,结肠直肠癌,胰腺癌,肾癌,肝细胞癌,恶性间皮瘤,白血病,淋巴瘤,骨髓增生异常综合征,多发性骨髓瘤,移行细胞癌,神经母细胞瘤,浆细胞瘤,维尔姆斯瘤或肝细胞癌。
156.如条款154或155所述的方法,其中,所述癌症是难治性癌症。
157.如条款154-156中任一项所述的方法,其中,所述化合物与一种或多种另外的癌症疗法组合给予。
158.如条款157所述的方法,其中,所述一种或多种另外的癌症疗法包括:手术,放射疗法,化学疗法,毒素疗法,免疫疗法,冷冻疗法或基因疗法,或其组合。
159.如条款158所述的方法,其中,所述化学疗法包括给予一种或多种其它化学治疗剂。
160.如条款159所述的方法,其中,所述一种或多种其它化学治疗剂选自:烷化剂(例如,顺铂,卡铂,氮芥,环磷酰胺,苯丁酸氮芥,异环磷酰胺和/或奥沙利铂);抗代谢物(例如,硫唑嘌呤和/或巯基嘌呤);萜类化合物(例如,长春花生物碱和/或紫杉烷;例如长春新碱、长春碱、长春瑞宾和/或长春地辛,泰素,紫杉醇和/或多西他赛);拓扑异构酶(例如,I型拓扑异构酶和/或2型拓扑异构酶;例如喜树碱,例如伊立替康和/或拓扑替康;安吖啶,依托泊苷,磷酸依托泊苷和/或替尼泊苷);细胞毒性抗生素(例如,放线菌素,蒽环霉素,多柔比星,柔红霉素,伐柔比星,伊达比星,表柔比星,博莱霉素,普卡霉素和/或丝裂霉素);激素(例如,促黄体激素释放的激素激动剂;例如亮丙瑞林,戈舍瑞林,曲普瑞林,组胺瑞林,比卡鲁胺,氟他胺和/或尼鲁米特);抗体(例如,阿昔单抗,阿达木单抗,阿仑单抗,阿利珠单抗,巴利昔单抗,贝利木单抗,贝伐珠单抗,本妥昔单抗,康纳单抗,西妥昔单抗,培舍珠单抗,达克珠单抗,地舒单抗,依库珠单抗,艾法珠单抗,吉妥珠单抗,戈利木单抗,替伊莫单抗,英利昔单抗,伊匹木单抗,莫罗单抗-CD3,那他珠单抗,奥伐木单抗,奥马珠单抗,帕利珠单抗,帕尼单抗,雷珠单抗,利妥昔单抗,妥珠单抗,托西莫单抗和/或曲妥珠单抗);抗血管生成剂;细胞因子;血栓形成活性剂;生长抑制剂;抗蠕虫剂;及靶向选自下组的免疫检查点受体的免疫检查点抑制剂:CTLA-4,PD-1,PD-L1,PD-1–PD-L1,PD-1–PD-L2,白介素-2(IL-2),吲哚胺2,3-双加氧酶(IDO),IL-10,转化生长因子-β(TGFβ),T细胞免疫球蛋白及粘蛋白3(TIM3或HAVCR2),半乳凝素9-TIM3,磷脂酰丝氨酸-TIM3,淋巴细胞活化基因3蛋白(LAG3),MHC II类–LAG3,4-1BB–4-1BB配体,OX40–OX40配体,GITR,GITR配体–GITR,CD27,CD70-CD27,TNFRSF25,TNFRSF25–TL1A,CD40L,CD40–CD40配体,HVEM–LIGHT–LTA,HVEM,HVEM–BTLA,HVEM–CD160,HVEM–LIGHT,HVEM–BTLA–CD160,CD80,CD80–PDL-1,PDL2–CD80,CD244,CD48–CD244,CD244,ICOS,ICOS–ICOS配体,B7-H3,B7-H4,VISTA,TMIGD2,HHLA2–TMIGD2,嗜乳脂蛋白,包括BTNL2,Siglec家族,TIGIT和PVR家族成员,KIRs,ILTs和LIRs,NKG2D和NKG2A,MICA和MICB,CD244,CD28,CD86–CD28,CD86–CTLA,CD80–CD28,CD39,CD73腺苷–CD39–CD73,CXCR4–CXCL12,磷脂酰丝氨酸,TIM3,磷脂酰丝氨酸–TIM3,SIRPA–CD47,VEGF,神经毡蛋白,CD160,CD30,和CD155(例如,CTLA-4或PD1或PD-L1)。
161.如条款151-160中任一项所述的方法,其中,所述化合物是肿瘤内施用的。
162.一种治疗与STING有关的疾病、病症或病状的方法,包括对需要这种治疗的对象给予有效量的根据条款1-115中任一项所述的化合物或根据条款116所述的药物组合物。
163.如条款162所述的方法,其中所述疾病、病症或病状选自:I型干扰素病,艾卡迪-古蒂雷斯综合征(AGS),遗传形式的狼疮,炎症相关病症和类风湿性关节炎。
164.如条款163所述的方法,其中所述疾病、病症或病状是I型干扰素病(例如,婴儿期发作的STING相关血管病(SAVI))。
165.如条款164所述的方法,其中所述I型干扰素病是婴儿期发作的STING相关血管病(SAVI)。
166.如条款163所述的方法,其中,所述疾病、病症或病状是艾卡迪-古蒂雷斯综合征(AGS)。
167.如条款163所述的方法,其中所述疾病、病症或病状是遗传形式的狼疮。
168.如条款163所述的方法,其中,所述疾病、病症或病状是炎症相关的病症。
169.如条款168所述的方法,其中,所述与炎症相关的病症是系统性红斑狼疮。
170.一种组合,包含条款1-115中任一项所定义的化合物或其药学上可接受的盐或互变异构体,以及一种或多种治疗活性剂。
171.如条款1-115中任一项定义的化合物或其药学上可接受的盐或互变异构体,或条款116定义的药物组合物,用作药物。
172.如条款1-115中任一项定义的化合物或其药学上可接受的盐或互变异构体,或条款116定义的药物组合物,用于治疗由STING抑制调节的疾病、病症或病状。
173.如条款1-115中任一项定义的化合物或其药学上可接受的盐或互变异构体,或条款116中定义的药物组合物,用于治疗条款117-169中任一项所述的疾病(例如,条款122、126-128、135-136、143、145、146、151-156或162-169中的任一项)。
174.如条款1-115中任一项定义的化合物或其药学上可接受的盐或互变异构体,或条款116定义的药物组合物在制备用于治疗条款117-169中的任一项(例如,条款122、126-128、135-136、143、145、146、151-156或162-169中的任一项)所提及的疾病的药物中的用途。
Claims (20)
1.一种式(I)的化合物或其药学上可接受的盐:
其中:
R4和R5根据(AA)或(BB)定义:
(AA)
R4选自下组:
·任选地被1-6个Ra取代的C1-15烷基;和
·-(YA1)n-YA2,其中:
οn是0或1;
οYA1是任选地被1-3个Ra个取代的C1-3亚烷基;和
οYA2选自下组:
·C3-10环烷基或C3-10环烯基,其各自任选地被1-6个RY取代;
·具有3-10个环原子的杂环基或杂环烯基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂环基或杂环烯基任选地被1-6个RY取代;
·具有5-10个环原子的杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的C6-10芳基;
每次出现的RY独立地选自下组:氧代、Rc、Rb和-(Lb)b-Rb;
条件是当YA2是苯基或单环杂芳基,其各自任选地被1-6个RY取代,那么每次出现的RY独立地选自下组:-Rc、Rb和-(Lb)b-Rb;
R5是H或Rd;或
(BB)
R4和R5与其各自连接的氮原子一起形成4-12个环原子的饱和、部分饱和或芳环,其中0-2个环原子(除了与R4和R5连接的氮原子)是各自独立地选自下组的环杂原子:N、N(H)、N(Rd)、O和S(O)0-2,其中所述环被独立地选自下组的1-4个取代基取代:氧代、Rc、Rb和-(Lb)b-Rb;
M是0、1、2或3;
各R6独立地选自下组:Rc、Rb和-(Lb)b-Rb;
R3选自下组:H和Rd;
Y1选自下组:CR1a和N;
Y2选自下组:CR1b和N;
Y3选自下组:CR1c和N;
X1选自下组:CR1d、N、N(R2)、O和S;
X2选自下组:CR1e、N、N(R2)、O和S;
X3选自下组:CR1f、N、N(R2)、O和S,
条件是X1、X2和X3中的1-3个独立地选自下组:N、N(R2)、O和S;
各独立地为单键或双键,条件是包含X1、X2和X3的五元环是芳族的,并且包含Y1、Y2和Y3的六元环是芳族的;
每次出现的R1a、R1b和R1c各自独立地选自:H、-(Lb)b-Rb、Rb和Rc;
每次出现的R1d、R1e和R1f独立地选自下组:H、-Lb-Rb、Rb和Rc;
每次出现的R2独立地选自:H、Rd、-(Lb)b-Rb和Rb;
每次出现的Ra独立地选自下组:–OH;-卤素;–NReRf;C1-4烷氧基;C1-4卤代烷氧基;-C(=O)O(C1-4烷基);-C(=O)(C1-4烷基);-C(=O)OH;-CONR’R”;
-S(O)1-2NR’R”;-S(O)1-2(C1-4烷基);和氰基;
每次出现的Rb独立地选自下组:
·C3-10环烷基或C3-10环烯基,其各自任选地被1-4个Rc取代;
·具有3-10个环原子的杂环基或杂环烯基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且所述杂环基或杂环烯基任选地被1-4个Rc取代;
·具有5-10个环原子的杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-4个Rc取代;和
·任选地被1-4个Rc取代的C6-10芳基;
每次出现的Lb独立地选自下组:-O-、-NH-、-NRd、-S(O)0-2、C(O)和任选地被1-3个Ra取代的C1-3亚烷基;
每次出现的b独立地是1、2或3;
每次出现的Rc独立地选自下组:卤素;氰基;任选地被1-6个独立选择的Ra取代的C1-10烷基;C2-6烯基;C2-6炔基;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-S(O)(=NH)(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-NO2;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;-C(=O)NR’R”;和–SF5;
每次出现的Rd独立地选自下组:任选地被1-3个独立选择的Ra取代的C1-6烷基;-C(O)(C1-4烷基);-C(O)O(C1-4烷基);-CONR’R”;-S(O)1-2NR’R”;-S(O)1-2(C1-4烷基);-OH;和C1-4烷氧基;
每次出现的Re和Rf独立地选自下组:H;任选地被各自独立地选自下组的1-3个取代基取代的C1-6烷基:NR’R”、-OH、卤素、C1-4烷氧基和C1-4卤代烷氧基;
-C(O)R”’;-C(O)OR”’;-CONR’R”;-C(=O)C(=O)R”’;-S(O)1-2NR’R”;-S(O)1-2R”’;-OH;和C1-4烷氧基;
每次出现的R’和R”独立地选自下组:H;-OH;和C1-4烷基,其任选地被各自独立地选自下组的1-3个取代基取代:卤素、氰基、C1-4烷氧基、C1-4卤代烷氧基和–OH;和
R”’选自下组:H;和C1-4烷基,其任选地被各自独立地选自下组的1-3个取代基取代:卤素、氰基、C1-4烷氧基、C1-4卤代烷氧基和–OH;
条件是:
(iii)当所述化合物是具有式
的化合物时,R1f不是/>其中Rd2是H或Rd;和
(iv)所述化合物不是:
2.如权利要求1所述的化合物,其中,所述化合物是式(I-a)的化合物或其药学5上可接受的盐:
或者
其中,所述化合物是式(I-a1)的化合物或其药学上可接受的盐:
并且
任选地,其中式(I-a)或(I-a1)中的m是1或2,或任选地,其中m是1。
3.如权利要求1或2所述的化合物,其中,所述化合物是式(I-a1-a)的化合物或其药学上可接受的盐:
其中:
m1是0或1。
4.如权利要求1-3中任一项所述的化合物,其中,R4和R5根据(AA)限定。
5.如权利要求1-4中任一项所述的化合物,其中,R4是-(YA1)n-YA2,任选地,其中n是0,并且
YA2选自下组:
·具有5-10个环原子的杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的C6-10芳基;或
其中,YA2选自下组:
·具有5-6个环原子的单环杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基;或
其中,YA2选自下组:
·具有8-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C8-10芳基。
6.如权利要求1-5中任一项所述的化合物,其中,各RY独立地选自下组:素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”,或
各RY独立地选自下组:卤素;氰基;C1-6烷基;C1-6烷基,其被1-6个独立选择的卤素取代;C1-4烷氧基;C1-4卤代烷氧基;和-C(=O)NR’R”,例如-C(=O)NHCH3。
7.如权利要求1-6中任一项所述的化合物,其中,R5是H。
8.如权利要求1-3中任一项所述的化合物,其中,R4和R5根据(BB)限定。
9.如权利要求1-8中任一项所述的化合物,其中每次出现的R6是独立选择的Rc;
任选地,其中每次出现的R6独立地选自下组:卤素;氰基;C1-10烷基,其任选地被1-6个独立选择的Ra取代;任选地被–OH、NR’R”、C1-4烷氧基或C1-4卤代烷氧基取代的C1-4烷氧基;C1-4卤代烷氧基;-S(O)1-2(C1-4烷基);-NReRf;–OH;
-S(O)1-2NR’R”;-C1-4硫代烷氧基;-C(=O)(C1-10烷基);-C(=O)O(C1-4烷基);-C(=O)OH;和-C(=O)NR’R”;和
任选地其中,一次出现的R6是氰基。
10.如权利要求1-9中任一项所述的化合物,其中,Y1是CR1a;任选地,Y2是CR1b;并且任选地,Y3是CR1c。
11.如权利要求1-10中任一项所述的化合物,其中,Y1是CH;Y2是CH;并且Y3是CH;或
其中,Y1是CR1a,其中,R1a选自下组:-(Lb)b-Rb、Rb和Rc;Y2是CH;并且Y3是CH。
12.如权利要求1-11中任一项所述的化合物,其中,X1是N(R2);并且X2是CR1e,或者其中,X1是N(H);并且X2是CH。
13.如权利要求1-9中任一项所述的化合物,其中,所述部分是任选地,其中R2是H。
14.如权利要求1所述的化合物,其中,所述化合物是式(I-a1-a1)的化合物或其药学上可接受的盐:
其中:
m1是0或1;和
R4是-YA2,其中YA2选自下组:
·具有5-6个环原子的单环杂芳基,其中1-3个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-3个RY取代;和
·任选地被1-4个RY取代的苯基;
任选地其中,R2是H。
15.如权利要求1所述的化合物,其中,所述化合物是式(I-a1-a2)的化合物或其药学上可接受的盐:
其中:
m1是0或1;和
R4是-YA2,其中YA2选自下组:
·具有9-10个环原子的双环杂芳基,其中1-4个环原子是杂原子,其各自独立地选自下组:N、N(H)、N(Rd)、O和S(O)0-2,并且其中所述杂芳基任选地被1-6个RY取代;和
·任选地被1-6个RY取代的双环C9-10芳基;并且
任选地其中,R2是H。
16.如权利要求1所述的化合物,其中,所述化合物是选自表C1中描述的化合物或其药学上可接受的盐。
17.一种药物组合物,其包含如权利要求1-16中任一项所述的化合物和一种或多种药学上可接受的赋形剂。
18.一种抑制STING活性的方法,所述方法包括使STING与如权利要求1-16中任一项所述的化合物或其药学上可接受的盐;或如权利要求17所述的药物组合物接触。
19.一种在有需要的对象中诱导免疫应答的方法,所述方法包括向所述对象给予有效量的如权利要求1-16中任一项所述的化合物或其药学上可接受的盐;或如权利要求17所述的药物组合物。
20.一种治疗与STING相关的疾病、病症或症状的方法,例如其中增加的STING信号传导,例如过度的STING信号传导,促成疾病的病理和/或症状和/或进展的疾病、病症或症状,包括向需要这种治疗的对象给予有效量的如权利要求1-16中任一项所述的化合物或其药学上可接受的盐,或如权利要求17所述的药物组合物。
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