CN114072409B - 炔类衍生物及其制备方法和用途 - Google Patents
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Abstract
本发明涉及炔类衍生物、其制备方法及其在医药上的应用。具体而言,本发明涉及式(I)所示的炔类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是磷脂酰肌醇‑3‑激酶γ(PI3Kγ)抑制剂的用途,其中式(I)中各取代基的定义与说明书中的定义相同。
Description
交叉引用
本申请要求发明名称为“炔类衍生物及其制备方法和用途”于2019年7月8日提交到中国专利局的中国专利申请201910608212.0的优先权,其内容通过引用以整体并入本文。
技术领域
本发明涉及一种新的炔类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为磷脂酰肌醇-3-激酶γ(PI3Kγ)抑制剂的用途。
背景技术
磷酸肌醇3-激酶(PI3-激酶或PI3K)是一种胞内的磷脂酰激酶,与病毒癌基因相关,由其介导的PI3K-Akt-mTOR信号通路在肿瘤的发生发展中起着重要作用,可以调节肿瘤细胞生成、存活、增殖、迁移、代谢和凋亡。基于序列同源性和脂质底物特异性,PI3K家族分为I型、II型和III型。I型PI3K是研究的比较广泛的一种类型,也是众多药物研究的重要靶标。所有I型PI3K都是异二聚体蛋白质,每个包含小的调节结构域和大的110kDa催化结构域,其以四种亚型存在,分化为p110α,p110β,p110γ和p110δ。I型PI3K(p110α、p110β、p110δ或p110γ)通常由酪氨酸激酶或G-蛋白偶联受体活化以生成PIP3,所述PIP3接合下游效应物如Akt/PDK1通路、mTOR、Tec家族激酶和Rho家族GTP酶。II型和III型PI3K通过PI(3)P和PI(3,4)P2的合成在细胞内运输中起到关键作用。PI3K是控制细胞生长(mTORC1)或监测基因组完整性(ATM、ATR、DNA-PK和hSmg-1)的蛋白激酶。四种I型PI3K亚型在体内表现出特征性的表达模式。PI3Kα和PI3Kβ表达极其普遍,对于细胞生长、存活和增殖等发挥关键作用;抑制PI3Kα和PI3Kβ主要针对癌症的治疗;PI3Kγ在粒细胞、单核细胞和巨噬细胞中广泛表达,而PI3Kδ亚型也在B细胞和T细胞中发现。含有编码PI3Kδ或PI3Kγ的基因的敲除小鼠可存活,但在先天免疫和适应性反应中表现出明显的缺陷,因此,特异性PI3Kδ或PI3Kγ抑制剂可能对自身免疫疾病具有治疗益处,而不会干扰一般PI3K信号传导对其他细胞系统的正常功能。
目前多种针对PI3K的抑制剂已进入临床研究甚至上市,如BEZ235、GDC-0941、CAL-101等。近年来的研究发现PI3Kγ与自身免疫系统、炎性疾病、呼吸疾病等密切相关,因此PI3Kγ选择性抑制剂成为免疫治疗癌症、炎性疾病、骨障碍、呼吸疾病、自身免疫性疾病(Matthew W.D.等,Journal of Medicinal Chemistry(2019),62(10),4783-4814;Perrotta等,International Journal of Molecular Sciences(2016),17(11),1858/1-1858/9;Okkenhaug,Klaus等,Cancer Discovery(2016),6(10),1090-1105.;Hirsch E,等.Science(80-).2000;287:1049-1053.;Li Z.等,Science(80-).2000;287:1046-1049.;Kaneda MM等,Nature.2016;1-21)的热门靶点。PI3Kγ选择性抑制剂是潜在治疗癌症的药物,癌症包括血液肿瘤和实体瘤;其中所述的血液肿瘤选自急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、幼淋巴细胞白血病(PLL)、毛细胞白血病(HLL)、华氏巨球蛋白血症、(WM)、外周T细胞淋巴瘤(PTCL)、成人T细胞白血病/淋巴瘤(ATL)、皮肤T细胞淋巴瘤(CTCL)、大颗粒淋巴细胞白血病(LGL)、急性髓性白血病(AML)、霍奇金淋巴瘤(HL)、非霍奇金淋巴瘤(NHL)、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)、肥大细胞增多症、多发性骨髓瘤(MM)、骨髓增生异常综合征(MDS)或骨髓增生障碍(MPD);其中所述的实体瘤优选选自脑癌、皮肤癌、头颈癌、神经内分泌癌、胰腺癌、肺癌、乳腺癌、前列腺癌、睾丸癌、食道癌、肝癌、胃癌、结肠癌、结肠直肠癌、卵巢癌、宫颈癌、子宫癌、子宫内膜癌、膀胱癌、肾癌、病毒引起的癌症、成神经管细胞瘤、基底细胞癌、胶质瘤、肝细胞癌、胃肠道间质瘤(GIST)、黑素瘤、原始神经外胚层肿瘤(PNT)、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、淋巴血管内皮肉瘤、滑膜瘤、间皮瘤、平滑肌肉瘤、膀胱中的移行细胞癌、上皮癌、鳞状细胞癌、腺癌、支气管癌、肾细胞癌和类癌瘤。PI3Kγ抑制剂对于呼吸疾病也有治疗益处,包括哮喘、囊肿型纤维化、肺气肿、慢性阻塞性肺病(COPD)、慢性支气管炎、支气管扩张、急性呼吸窘迫综合征、呼吸道疾病、胸腔疾病和肺动脉高血压等。
目前唯一进入临床研究的PI3Kγ选择性抑制剂是Infinity公司的IPI-549,其可以逆转肿瘤对免疫检查点抑制剂(如PD-1抑制剂和PD-L1抑制剂)的抵抗,在肿瘤免疫治疗方面显示出潜力。IPI-549结构如下所示,专利申请WO2015051244A1公开了IPI-549的制备方法。
除此之外,现有技术还公开了一系列的PI3Kγ选择性抑制剂专利申请,其中包括WO2012052753、WO2011008302等。
尽管PI3Kγ选择性抑制剂的研究和应用已取得一定的进展,但是这类新型抑制剂尚未研究成熟,仍有很多问题需要解决,例如生物活性不够理想、选择性不够好、脱靶风险较大或者安全性和耐受性不够好等,其提升的空间仍然巨大,仍有必要继续研究和开发新的PI3Kγ选择性抑制剂。
发明内容
针对上述的技术问题,本发明提供了式(I)所示的炔类化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
X选自CH或N;
R1选自环烷基或杂环基,其中所述的环烷基或杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基或-NR5R6的取代基所取代;优选地,R1选自氧杂环丁烷基、环丙基、环丁基、环戊基或环己基;更优选为环丙基或氧杂环丁烷基;
R2和R3各自独立地选自氢原子、烷基、烷氧基、氰基或卤素,其中所述的烷基或烷氧基任选进一步被一个或多个卤素所取代;
R4相同或不同,各自独立地选自氢原子、烷基、烷氧基、氰基或卤素,其中所述的烷基或烷氧基任选进一步被一个或多个卤素所取代;
R5和R6各自独立地选自氢原子、烷基或环烷基,其中所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氰基、烷基、烷氧基、环烷基或杂环基的取代基所取代;且
m为0、1、2、3、4或5。
在本发明的优选方案中,R1优选为环丙基、环丁基、环戊基、环己基或氧杂环丁烷基;更优选为环丙基或氧杂环丁烷基。
在本发明的优选方案中,R2和R3各自独立地选自氢原子或卤素,所述卤素优选为氟。
在本发明的优选方案中,R4相同或不同,各自独立地选自氢原子、烷基或卤素,且m为0、1、2或3;优选地,R4为氢。
在本发明的优选方案中,X选自CH或N,R1选自环丙基和氧杂环丁烷基,R2和R3选自氢原子和F。
本发明的典型化合物包括,但不限于:
或其立体异构体、互变异构体或其可药用的盐。
更进一步,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
本发明提供了本发明所述的式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备用作磷脂酰肌醇-3-激酶γ抑制剂的药物中的用途。
本发明提供了式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备用于治疗由磷脂酰肌醇-3-激酶γ介导的疾病的药物中的用途,其中所述由磷脂酰肌醇-3-激酶γ介导的疾病优选为癌症、骨障碍、呼吸疾病、炎性疾病或自身免疫疾病;其中所述呼吸疾病优选为哮喘、囊肿型纤维化、肺气肿、慢性阻塞性肺病、慢性支气管炎、支气管扩张、急性呼吸窘迫综合征、呼吸道疾病、胸腔疾病和肺动脉高血压;其中所述癌症优选为血液肿瘤和实体瘤;其中所述血液肿瘤优选选自急性淋巴细胞性白血病、慢性淋巴细胞性白血病、幼淋巴细胞白血病、毛细胞白血病、华氏巨球蛋白血症、外周T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、皮肤T细胞淋巴瘤、大颗粒淋巴细胞白血病、急性髓性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、肥大细胞增多症、多发性骨髓瘤、骨髓增生异常综合征或骨髓增生障碍;其中所述实体瘤优选选自脑癌、皮肤癌、头颈癌、神经内分泌癌、胰腺癌、肺癌、乳腺癌、前列腺癌、睾丸癌、食道癌、肝癌、胃癌、结肠癌、结肠直肠癌、卵巢癌、宫颈癌、子宫癌、子宫内膜癌、膀胱癌、肾癌、病毒引起的癌症、成神经管细胞瘤、基底细胞癌、胶质瘤、肝细胞癌、胃肠道间质瘤、黑素瘤、原始神经外胚层肿瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、淋巴血管内皮肉瘤、滑膜瘤、间皮瘤、平滑肌肉瘤、膀胱中的移行细胞癌、上皮癌、鳞状细胞癌、腺癌、支气管癌、肾细胞癌和类癌瘤。
本发明还提供了式(I)所述的化合物或其立体异构体化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物与一种或多种第二治疗剂之联合在制备用于治疗由磷脂酰肌醇-3-激酶γ介导的疾病的药物中的用途,其中所述由磷脂酰肌醇-3-激酶γ介导的疾病优选为癌症、骨障碍、呼吸疾病、炎性疾病或自身免疫疾病;所述呼吸疾病优选为哮喘、囊肿型纤维化、肺气肿、慢性阻塞性肺病、慢性支气管炎、支气管扩张、急性呼吸窘迫综合征、呼吸道疾病、胸腔疾病和肺动脉高血压;所述癌症优选为血液肿瘤和实体瘤;所述血液肿瘤优选选自急性淋巴细胞性白血病、慢性淋巴细胞性白血病、幼淋巴细胞白血病、毛细胞白血病、华氏巨球蛋白血症、外周T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、皮肤T细胞淋巴瘤、大颗粒淋巴细胞白血病、急性髓性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、肥大细胞增多症、多发性骨髓瘤、骨髓增生异常综合征或骨髓增生障碍;所述实体瘤优选选自脑癌、皮肤癌、头颈癌、神经内分泌癌、胰腺癌、肺癌、乳腺癌、前列腺癌、睾丸癌、食道癌、肝癌、胃癌、结肠癌、结肠直肠癌、卵巢癌、宫颈癌、子宫癌、子宫内膜癌、膀胱癌、肾癌、病毒引起的癌症、成神经管细胞瘤、基底细胞癌、胶质瘤、肝细胞癌、胃肠道间质瘤、黑素瘤、原始神经外胚层肿瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、淋巴血管内皮肉瘤、滑膜瘤、间皮瘤、平滑肌肉瘤、膀胱中的移行细胞癌、上皮癌、鳞状细胞癌、腺癌、支气管癌、肾细胞癌和类癌瘤;其中所述的第二治疗剂选自PI3Kδ抑制剂、mTOR抑制剂、共刺激调节剂、免疫刺激剂、CXCL12/CXCR4抑制剂、HDAC抑制剂、蛋白酶体抑制剂、CD28抗体、CD30抗体、CD40抗体、GM-CSF、吉西他滨、环磷酰胺、多西紫杉醇、紫杉醇、5-FU、替莫唑胺、抗血管生成剂、阿昔替尼、PD-1抑制剂、PD-L1抑制剂或其混合物;优选为PD-1抑制剂或PD-L1抑制剂。
本发明提供了一种抑制磷脂酰肌醇-3-激酶γ活性的方法,其包括给予式(I)所述的化合物或其立体异构体化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物。
本发明提供了一种通过抑制磷脂酰肌醇-3-激酶γ活性来治疗癌症、骨障碍、呼吸疾病、炎性疾病或自身免疫疾病的病症的方法,其包括给予所需患者式(I)所述化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物;其中所述呼吸疾病优选选自哮喘、囊肿型纤维化、肺气肿、慢性阻塞性肺病、慢性支气管炎、支气管扩张、急性呼吸窘迫综合征、呼吸道疾病、胸腔疾病和肺动脉高血压;所述癌症优选为血液肿瘤和实体瘤;其中所述血液肿瘤优选选自急性淋巴细胞性白血病、慢性淋巴细胞性白血病、幼淋巴细胞白血病、毛细胞白血病、华氏巨球蛋白血症、外周T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、皮肤T细胞淋巴瘤、大颗粒淋巴细胞白血病、急性髓性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、肥大细胞增多症、多发性骨髓瘤、骨髓增生异常综合征或骨髓增生障碍;其中所述实体瘤优选选自脑癌、皮肤癌、头颈癌、神经内分泌癌、胰腺癌、肺癌、乳腺癌、前列腺癌、睾丸癌、食道癌、肝癌、胃癌、结肠癌、结肠直肠癌、卵巢癌、宫颈癌、子宫癌、子宫内膜癌、膀胱癌、肾癌、病毒引起的癌症、成神经管细胞瘤、基底细胞癌、胶质瘤、肝细胞癌、胃肠道间质瘤、黑素瘤、原始神经外胚层肿瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、淋巴血管内皮肉瘤、滑膜瘤、间皮瘤、平滑肌肉瘤、膀胱中的移行细胞癌、上皮癌、鳞状细胞癌、腺癌、支气管癌、肾细胞癌和类癌瘤。
在一些优选的实施方案中,上述治疗癌症、骨障碍、呼吸疾病、炎性疾病或自身免疫疾病的病症的方法还包括另外给予所述患者一种或多种第二治疗剂,其中所述呼吸疾病优选选自哮喘、囊肿型纤维化、肺气肿、慢性阻塞性肺病、慢性支气管炎、支气管扩张、急性呼吸窘迫综合征、呼吸道疾病、胸腔疾病和肺动脉高血压;其中所述癌症优选自血液肿瘤和实体瘤;其中所述血液肿瘤优选选自急性淋巴细胞性白血病、慢性淋巴细胞性白血病、幼淋巴细胞白血病、毛细胞白血病、华氏巨球蛋白血症、外周T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、皮肤T细胞淋巴瘤、大颗粒淋巴细胞白血病、急性髓性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、肥大细胞增多症、多发性骨髓瘤、骨髓增生异常综合征或骨髓增生障碍;其中所述实体瘤优选选自脑癌、皮肤癌、头颈癌、神经内分泌癌、胰腺癌、肺癌、乳腺癌、前列腺癌、睾丸癌、食道癌、肝癌、胃癌、结肠癌、结肠直肠癌、卵巢癌、宫颈癌、子宫癌、子宫内膜癌、膀胱癌、肾癌、病毒引起的癌症、成神经管细胞瘤、基底细胞癌、胶质瘤、肝细胞癌、胃肠道间质瘤、黑素瘤、原始神经外胚层肿瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、淋巴血管内皮肉瘤、滑膜瘤、间皮瘤、平滑肌肉瘤、膀胱中的移行细胞癌、上皮癌、鳞状细胞癌、腺癌、支气管癌、肾细胞癌和类癌瘤。其中所述第二治疗剂选自PI3Kδ抑制剂、mTOR抑制剂、共刺激调节剂、免疫刺激剂、CXCL12/CXCR4抑制剂、HDAC抑制剂、蛋白酶体抑制剂、CD28抗体、CD30抗体、CD40抗体、GM-CSF、吉西他滨、环磷酰胺、多西紫杉醇、紫杉醇、5-FU、替莫唑胺、抗血管生成剂、阿昔替尼、PD-1抑制剂、PD-L1抑制剂及其混合物;优选为PD-1抑制剂或PD-L1抑制剂。
发明的详细说明
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“烷基”当作一基团或一基团的一部分时是指包括C1-C20直链或者带有支链的脂肪烃基团。优选为C1-C10烷基,更优选为C1-C6烷基,以及C1-C4烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C3-C12环烷基,更优选为C3-C8环烷基,最优选为C3-C6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。所述环烷基环可以稠合于芳基、杂芳基或杂环基环上,其中与母体结构连接在一起的环为环烷基,非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或未取代的。
“杂环基”或“杂环”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮、硫原子等,包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双-或三环,其可以包含1、2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基,氧杂环丁烷基,硫代吗啉基,四氢吡喃基,1,1-二氧代-硫代吗啉基,哌啶基,2-氧代-哌啶基,吡咯烷基,2-氧代-吡咯烷基,哌嗪-2-酮,8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。
“芳基”是指含有一个或者两个环的碳环芳香系统,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基,更优选芳基为苯基和萘基,最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合,其中与母体结构连接在一起的为芳基环,非限制性实施例包括但不限于:
“杂芳基”是指芳香族5至6元单环或8至10元双环,其可以包含1、2、3或4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基,吡啶基,2-氧代-1,2-二氢吡啶基,哒嗪基,嘧啶基,吡嗪基,噻吩基,异噁唑基,噁唑基,噁二唑基,咪唑基,吡咯基,吡唑基,三唑基,四氮唑基,噻唑基,异噻唑基,1,2,3-噻二唑基,苯并间二氧杂环戊烯基,苯并噻吩基、苯并咪唑基,吲哚基,异吲哚基,1,3-二氧代-异吲哚基,喹啉基,吲唑基,苯并异噻唑基,苯并噁唑基和苯并异噁唑基。杂芳基可以是取代或未取代的。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6烷氧基或C1-C4烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴或碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“羧基”指-C(0)OH。
“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基,其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“Me”指甲基。
“Et”指乙基。
“TMS”指三甲基甲硅烷基。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1个、2个或3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个选自以下的基团取代:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、=O和-NR5R6的取代基所取代;
R5和R6各自独立地选自氢原子、烷基或环烷基,其中所述的烷基或环烷基任选进一步被一个或多个选自羟基、卤素、氰基、烷基、烷氧基、环烷基或杂环基的取代基所取代。特别优选地,R5和R6各自独立地选自氢原子。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的可药用的盐可以为与合适的酸形成的铵盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
在本发明中,用语“多个”表示数量上多于1个,例如2个、3个、4个或更多个。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。1H NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
在下列实施例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于Aldrich Chemical Company,ABCR GmbH&Co.KG,Acros Organics,广赞化工科技有限公司和景颜化工科技有限公司等处购买。
CD3OD:氘代甲醇。
CDCl3:氘代氯仿。
DMSO-d6:氘代二甲基亚砜。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用硅胶柱层析洗脱剂体系和薄层色谱法,其中洗脱剂体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷:乙酸乙酯;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行调节,如醋酸或三乙胺等。
实施例1
(S)-2-amino-N-(1-(8-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoq uinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
(S)-2-氨基-N-(1-(8-((1-环丙基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
第一步
(Z)-3-氨基-4,4,4-三氯-2-氰基丁-2-烯酸乙酯
将2-氰基乙酸乙酯1a(16.48g,0.1448mol)和2,2,2-三氯乙腈1b(40g,0.289mol)溶于50mL的乙醇中,冰浴下缓慢滴加三乙胺(1.1mL,7.9mmol),反应2小时。减压浓缩,得到(Z)-3-氨基-4,4,4-三氯-2-氰基丁-2-烯酸乙酯1c(37g,黄色固体),产率:100%。
MS m/z(ESI):258.8[M+H]
第二步
3,5-二氨基-1H-吡唑-4-羧酸乙酯
将(Z)-3-氨基-4,4,4-三氯-2-氰基丁-2-烯酸乙酯1c(37g,0.1448mmol)和水合肼(18g,0.362mol)溶于75mL的N,N-二甲基甲酰胺中,加热至100℃,反应3小时。减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:B体系),得到3,5-二氨基-1H-吡唑-4-羧酸乙酯1d(24.6g,黄色固体),产率:100%。
MS m/z(ESI):171.1[M+H]
第三步
2-氨基吡唑并[1,5-a]嘧啶-3-羧酸乙酯
将3,5-二氨基-1H-吡唑-4-羧酸乙酯1d(23.5g,0.138mol)和1,1,3,3-四甲基氧丙烷(24.9g,0.152mol)加入到140mL的2M盐酸中,加热至50℃,反应2小时。冷却至室温,以氨水调节pH=9,以二氯甲烷(200mL×3)萃取,合并有机相,减压浓缩,得到2-氨基吡唑并[1,5-a]嘧啶-3-羧酸乙酯1e(15.2g,黄色固体),产率:53.5%。
MS m/z(ESI):206.9[M+H]
第四步
2-氨基吡唑并[1,5-a]嘧啶-3-甲酸
将2-氨基吡唑并[1,5-a]嘧啶-3-羧酸乙酯1e(16.7g,0.081mol)和一水合氢氧化锂(14.98g,0.356mol)加入到150mL甲醇和水的混合溶剂(V/V=1∶4)中,加热至50℃,反应2小时。减压浓缩,以4M盐酸调节pH=6,固体洗出,过滤干燥,得到2-氨基吡唑并[1,5-a]嘧啶-3-甲酸1f(7.8g,黄色固体),产率:54%。
MS m/z(ESI):178.9[M+H]
第五步
1-环丙基-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑
氩气保护下,将1-环丙基-4-碘-1H-吡唑1k(28g,0.12mol,根据专利申请“WO2015134701”制备而得)溶于500mL四氢呋喃,加入双三苯基磷二氯化钯(4.2g,0.006mol)、碘化亚铜(2.28g,0.012mol)和0.6mL的三乙胺,温度控制在0℃,缓慢加入乙炔基三甲基硅烷(23.5g,0.24mol),室温反应过夜。过滤,滤液减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:A体系),得到1-环丙基-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑1l(20.5g,棕黑色液体),产率:83.7%。
MS m/z(ESI):205.1[M+H]
第六步
1-环丙基-4-乙炔基-1H-吡唑
将1-环丙基-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑1l(20.5g,0.1mol)溶于120mL的四氢呋喃中,温度控制在0℃,加入四丁基氟化铵四氢呋喃溶液(120mL,0.12mol,1mol/L),室温反应1小时。减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:A体系),得到1-环丙基-4-乙炔基-1H-吡唑1m(12g,淡黄色液体),产率:90.9%。
MS m/z(ESI):133.1[M+H]
第七步
2-氯-6-甲基-N-苯基苯甲酰胺
将2-氯-6-甲基苯甲酸1g(17g,0.1mol)溶于100mL的二氯甲烷中,滴加0.2mL的N,N-二甲基甲酰胺,冰浴下,缓慢滴加草酰氯(9.3mL,0.11mol),室温下反应3小时。减压浓缩,残留物溶于70mL的二氯甲烷中,冰浴下,缓慢滴加溶解有苯胺(9.76g,0.105mol)和三乙胺(30mL,0.210mol)的100mL二氯甲烷溶液,室温下反应2小时。加入100mL水和100mL二氯甲烷,以无水硫酸钠干燥,减压浓缩,加入20mL的乙酸乙酯和200mL的正己烷,搅拌,固体析出,过滤干燥。得到2-氯-6-甲基-N-苯基苯甲酰胺1h(18.9g,黄色固体),产率:77.14%。
MS m/z(ESI):246.0[M+H]
第八步
(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮
将2-氯-6-甲基-N-苯基苯甲酰胺1h(490mg,2mmol)加入到5mL的四氢呋喃中,温度控制在-30℃,缓慢滴加正丁基锂(2.5mL,5mmol),在此温度下反应半小时。同时将(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙基-2-基)氨基甲酸叔丁酯1i(696mg,3mmol,根据J.Med.Chem.2003,43,3434-3442自制)加入到5mL的四氢呋喃中,温度控制在-30℃,缓慢滴加异丙基氯化镁(1.65mL,3.3mmol),在此温度下反应0.5小时。温度控制在-15℃,将1i的反应液缓慢滴加入到1h的反应液中,反应1小时。加入1mL的水淬灭反应液,以浓盐酸调节pH=2,减压浓缩,残留物溶于10mL甲醇,加入5mL浓盐酸,加热回流1小时。减压浓缩,以200mL乙酸乙酯和石油醚的混合溶剂(乙V/V=1∶1)萃取2次,水相以氨水调节pH=10,以100mL二氯甲烷萃取,二氯甲烷层减压浓缩,残留物制备液相分离得到(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮1j(300mg,淡黄色固体),产率:50%。
MS m/z(ESI):299.0[M+H]
第九步
(S)-3-(1-氨基乙基)-8-((1-环丙基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮
氩气保护下,将(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮1j(200mg,0.67mmol)、双乙腈二氯化钯(34mg,0.132mmol)、碳酸铯(659mg,2.01mmol)、2-二环己基磷-2,4,6-三异丙基联苯(95mg,0.2mmol)和1-环丙基-4-乙炔基-1H-吡唑1m(174mg,1.32mmol)加入到10mL的乙腈中,加热至75℃,反应4小时。减压浓缩,加入二氯甲烷,硅藻土过滤,水洗,合并有机相,无水硫酸钠干燥,浓缩,薄层制备分离,得到(S)-3-(1-氨基乙基)-8-((1-环丙基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮1n(120mg,黄色固体),产率:45%。
MS m/z(ESI):394.9[M+H]
第十步
(S)-2-氨基-N-(1-(8-((1-环丙基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-l,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
氩气保护下,将(S)-3-(1-氨基乙基)-8-((1-环丙基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮1n(120mg,0.304mmol)、2-氨基吡唑并[1,5-a]嘧啶-3-甲酸1f(56.92mg,0.319mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(69.93mg,0.364mmol)、1-羟基苯并三唑(4mg,0.0304mmol)、N,N-二异丙基乙胺(0.16mL,0.912mmol)溶于3mL的N,N-二甲基甲酰胺中,室温反应过夜。缓慢加入冷的碳酸钾溶液(10mL,0.1mol),过滤,水洗,以无水硫酸钠干燥,滤液浓缩,薄层制备分离,得到(S)-2-氨基-N-(1-(8-((1-环丙基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺1(70mg),产率:41.6%。
MS m/z(ESI):554.9[M+H]
1H NMR(400MHz,DMSO-d6)δppm 8.93(d,J=6.7Hz,1H),8.55(d,J=4.6Hz,1H),8.09(s,1H),8.00(d,J=6.6Hz,1H),7.54-7.67(m,5H),7.43-7.53(m,3H),7.34-7.41(m,1H),7.02(dd,J=6.7,4.5Hz,1H),6.74(s,1H),6.43(brs,2H),4.55(t,J=6.7Hz,1H)3.72(dq,J=7.5,3.8Hz,1H),1.35(d,J=6.7Hz,3H),1.01-1.08(m,2H),0.90-0.98(m,2H).
实施例2
(S)-2-amino-N-(1-(5-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-3-phenyl-3,4-dihydroquin azolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
(S)-2-氨基-N-(1-(5-((1-环丙基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
第一步
(S)-2-(1-氨基乙基)-5-((1-环丙基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮
氩气保护下,将(S)-2-(1-氨基乙基)-5-氯-3-苯基喹唑啉-4(3H)-酮2a(5g,16.7mmol,根据US 20180105527自制)、双乙腈二氯化钯(217mg,0.835mmol)、碳酸铯(16.3g,50.1mmol)、2-二环己基磷-2,4,6-三异丙基联苯(796mg,1.67mmol)和1-环丙基-4-乙炔基-1H-吡唑1m(2.9g,21.7mmol)加入到100mL的乙腈中,加热至85℃,反应5小时。减压浓缩,加入二氯甲烷,硅藻土过滤,水洗,合并有机相,无水硫酸钠干燥,浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:B体系),得到(S)-2-(1-氨基乙基)-5-((1-环丙基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮2b(5.2g),产率:78.8%。
MS m/z(ESI):396.1[M+H]
第二步
(S)-2-氨基-N-(1-(5-((1-环丙基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
氩气保护下,将(S)-2-(1-氨基乙基)-5-((1-环丙基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮2b(25.6g,64.7mmol)、2-氨基吡唑并[1,5-a]嘧啶-3-甲酸1f(13.8g,77.5mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(18.6g,97.05mmol)、1-羟基苯并三唑(4.37g,32.3mmol)、N,N-二异丙基乙胺(17g,129.4mmol)溶于300mL的N,N-二甲基甲酰胺中,40℃反应3小时。减压浓缩,加水500mL,乙酸乙酯萃取(500mL×3),合并有机相,500mL饱和氯化钠溶液洗涤,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:B体系),得到(S)-2-氨基-N-(1-(5-((1-环丙基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺2(21.3g),产率:59.2%。
MS m/z(ESI):556.2[M+H]
1H NMR(400MHz,DMSO-d6)δppm 8.91(dd,J=6.7,1.0Hz,1H),8.71(d,J=7.4Hz,1H),8.64(d,J=4.5,1.6Hz,1H),8.11(s,1H),7.81(t,J=7.8Hz,1H),7.71(dd,J=8.1,1.3Hz,1H),7.56-7.66(m,6H),7.50-7.55(m,1H),7.02(dd,J=6.7,4.4Hz,1H),6.44(brs,2H),4.75(t,J=6.9Hz,1H),3.73(dt,J=7.3,3.6Hz,1H),1.33(d,J=6.6Hz,3H),1.01-1.08(m,2H),0.91-0.98(m,2H).
实施例3
(S)-2-amino-N-(1-(5-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-6-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
(S)-2-氨基-N-(1-(5-((1-环丙基-1H-吡唑-4-基)乙炔基)-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
第一步
(S)-(1-(5-氯-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯
氩气保护下,将6-氨基-2-氯-3-氟苯甲酸3a(95mg,0.5mmol)、三苯基氧膦(388mg,1.25mmol)和(叔丁氧羰基)-L-丙氨酸(95mg,0.5mmol)加到5mL吡啶中,加热至75℃,反应3小时。再加入苯胺(55μL,0.6mmol),反应4小时。减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:A体系),得到(S)-(1-(5-氯-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯3b(200mg),产率:96%。
MS m/z(ESI):418.1[M+H]
第二步
(S)-2-(1-氨基乙基)-5-氯-6-氟-3-苯基喹唑啉-4(3H)-酮
将(S)-(1-(5-氯-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯3b(200mg,0.479mmol)和三异丙基硅烷(294μL,1.436mmol)加到10mL的二氯甲烷中,再加入1.2mL的三氟乙酸,室温下反应3小时。减压浓缩,加入饱和碳酸氢钠溶液中和,以乙酸乙酯萃取(10mL×3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:A体系),得到(S)-2-(1-氨基乙基)-5-氯-6-氟-3-苯基喹唑啉-4(3H)-酮3c(174.7mg),产率:100%。
MS m/z(ESI):318.1[M+H]
第三步
(S)-2-氨基-N-(1-(5-氯-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-α]嘧啶-3-甲酰胺
氩气保护下,将(S)-2-(1-氨基乙基)-5-氯-6-氟-3-苯基喹唑啉-4(3H)-酮3c(174.7mg,0.479mmol)、2-氨基吡唑并[1,5-a]嘧啶-3-甲酸1f(102mg,0.575mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(139mg,0.719mmol)、1-羟基苯并三唑(32mg,0.24mmol)、N,N-二异丙基乙胺(237μL,1.437mmol)溶于5mL的N,N-二甲基甲酰胺中,35℃反应4小时。加入乙酸乙酯,以稀盐酸中和,分别以饱和碳酸氢钠和氯化钠溶液洗涤,合并有机相,无水硫酸钠干燥,减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:B体系),得到(S)-2-氨基-N-(1-(5-氯-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-α]嘧啶-3-甲酰胺3d(210mg),产率:92%。
MS m/z(ESI):478.1[M+H]
第四步
(S)-2-氨基-N-(1-(5-((1-环丙基-1H-吡唑-4-基)乙炔基)-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
氩气保护下,将(S)-2-氨基-N-(1-(5-氯-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-α]嘧啶-3-甲酰胺3d(210mg,0.440mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(35mg,0.044mmol)、碳酸铯(468mg,1.437mmol)、2-二环己基磷-2,4,6-三异丙基联苯(46mg,0.096mmol)和1-环丙基-4-乙炔基-1H-吡唑1m(96mg,0.719mmol)加入到20mL的1,4-二氧六环中,加热至100℃,反应过夜。硅藻土过滤,滤液减压浓缩,加入乙酸乙酯,以稀盐酸中和,分别以饱和碳酸氢钠和氯化钠溶液洗涤,合并有机相,无水硫酸钠干燥,减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:B体系),得到(S)-2-氨基-N-(1-(5-((1-环丙基-1H-吡唑-4-基)乙炔基)-6-氟-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺3(147.4mg),产率:58.4%。
MS m/z(ESI):574.2[M+H]
1H NMR(400MHz,DMSO-d6)δppm 8.92(d,J=6.7Hz,1H),8.69(d,J=7.4Hz,1H),8.64(d,J=4.5Hz,1H),8.16(s,1H),7.72-7.87(m,2H),7.49-7.67(m,6H),6.97-7.07(m,1H),6.44(s,2H),4.69-4.80(m,1H),3.69-3.79(m,1H),1.32(d,J=6.8Hz,3H),1.03-1.09(m,2H),0.90-0.99(m,2H).
实施例4
(S)-2-amino-N-(1-(8-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroiso quinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
(S)-2-氨基-N-(1-(8-((1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
第一步
4-碘-1-(氧杂环丁烷-3-基)-1H-吡唑
将4-碘-1H-吡唑4a(5g,25.78mmol)溶于20mL的N,N-二甲基甲酰胺中,温度控制在0℃,加入氢化钠(1.34g,33.52mmol),反应10分钟后再加入3-碘氧杂环丁烷(2.44mL,28.35mmol),加热至65℃,反应3小时。将反应液加入饱和氯化铵溶液中,以乙酸乙酯(30mL×2)萃取,合并有机相,水洗,以无水硫酸钠干燥,减压浓缩,得到4-碘-1-(氧杂环丁烷-3-基)-1H-吡唑4b(5.412g),产率:82.8%。
MS m/z(ESI):250.8[M+H]
第二步
1-(氧杂环丁烷-3-基)-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑
氩气保护下,将4-碘-1-(氧杂环丁烷-3-基)-1H-吡唑4b(5.412g,21.65mmol)溶于50mL四氢呋喃,加入双三苯基磷二氯化钯(758mg,1.08mmol)、碘化亚铜(410.4mg,2.16mmol)和14mL的三乙胺,温度控制在0℃,缓慢加入乙炔基三甲基硅烷(6.7mL,47.62mmol),室温反应5小时。加水10mL,以乙酸乙酯(10mL×3)萃取,合并有机相,水洗,以无水硫酸钠干燥,减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:A体系),得到1-(氧杂环丁烷-3-基)-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑4c(2.6g),产率:54.6%。
MS m/z(ESI):221.0[M+H]
第三步
4-乙炔基-1-(氧杂环丁烷-3-基)-1H-吡唑
氩气保护下,将1-(氧杂环丁烷-3-基)-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑4c(0.6g,2.73mmol)溶于5mL的四氢呋喃中,温度控制在0℃,加入四丁基氟化铵(855mg,3.27mmol),室温反应1小时。减压浓缩,得到的残留物通过硅胶柱层析进一步分析纯化(洗脱剂:A体系),得到4-乙炔基-1-(氧杂环丁烷-3-基)-1H-吡唑4d(0.236g),产率:58.6%。1HNMR(400MHz,CDCl3)δppm 7.73(s,1H),7.69(s,1H),5.42(p,J=6.9Hz,1H),4.99-5.07(m,4H),3.03(s,1H).
第四步
(S)-3-(1-氨基乙基)-8-((1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮
氩气保护下,将(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮1j(200mg,0.67mmol)、双乙腈二氯化钯(17mg,0.067mmol)、碳酸铯(659mg,2.01mmol)、2-二环己基磷-2,4,6-三异丙基联苯(95mg,0.2mmo1)和4-乙炔基-1-(氧杂环丁烷-3-基)-1H-吡唑4d(148mg,1.0mmol)加入到10mL的乙腈中,加热至75℃,反应4小时。减压浓缩,加入二氯甲烷,硅藻土过滤,水洗,合并有机相,无水硫酸钠干燥,浓缩,薄层制备分离,得到(S)-3-(1-氨基乙基)-8-((1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮4e(110mg),产率:40%。
1H NMR(400MHz,CDCl3)δppm 7.82(s,1H),7.74(s,1H),7.64(d,J=7.2Hz,1H),7.50-7.58(m,3H),7.42-7.50(m,2H),7.27-7.35(m,2H),6.75(s,1H),5.40(p,J=6.9Hz,1H),4.97-5.05(m,4H),3.71(q,J=6.5Hz,1H),2.00(brs,2H),1.28(d,J=6.5Hz,3H).
第五步
(S)-2-氨基-N-(1-(8-((1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺
氩气保护下,将(S)-3-(1-氨基乙基)-8-((1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮4e(110mg,0.268mmol)、2-氨基吡唑并[1,5-a]嘧啶-3-甲酸1f(50.1mg,0.28mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(61.6mg,0.32mmol)、1-羟基苯并三唑(3.6mg,0.0268mmol)、N,N-二异丙基乙胺(0.15mL,0.804mmol)溶于3mL的N,N-二甲基甲酰胺中,室温反应5小时。缓慢加入冷的碳酸钾溶液(10mL,0.1mol),加水15mL,乙酸乙酯萃取(15mL×3),合并有机相,30mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,薄层制备分离,得到(S)-2-氨基-N-(1-(8-((1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺4(110mg),产率:72%。
MS m/z(ESI):570.8[M+H]
1H NMR(400MHz,DMSO-d6)δppm 8.93(dd,J=6.7,1.6Hz,1H),8.55(dd,J=4.6,1.7Hz,1H),8.21(s,1H),8.00(d,J=6.7Hz,1H),7.76(s,1H),7.61-7.66(m,2H),7.54-7.60(m,2H),7.44-7.52(m,3H),7.36-7.40(m,1H),7.01(dd,J=6.8,4.5Hz,1H),6.75(s,1H),6.42(s,2H),5.55(q,J=6.9Hz,1H),4.83-4.92(m,4H),4.53-4.58(m,1H),1.35(d,J=6.7Hz,3H).
生物学评价
测试例1、本发明化合物对PI3K激酶抑制活性的测试
以下方法用于测定本发明化合物在体外条件下对重组人源PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ激酶活性的抑制程度。本方法使用Promega公司的ADP-GloTM Kinase Assay试剂盒(货号V9102)。上述试剂盒是一种发光法激酶检测试剂盒,用于检测激酶反应产生的ADP含量,ADP的含量与激酶活性正相关,通过测定ADP的含量,反映化合物对PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ激酶活性的抑制强弱。详细实验操作可参考试剂盒说明书。重组人源PI3Kα、PI3Kγ和PI3Kδ购于Invitrogen,PI3Kβ购自Promega(货号分别为PI3Kα:PV4788、PI3Kβ:V1751、PI3Kγ:PV4786和PI3Kδ:PV6451)。
将实验流程简述如下:受试化合物首先溶解于DMSO中制备为贮存液,随后按照试剂说明书中提供的缓冲液配方配置缓冲液(HEPES 50mM,MgCl2 3mM,EGTA 1mM,CHAPS0.03%,NaCl 100mM,pH7.5),使用该缓冲液进行梯度稀释,受试化合物在反应体系中的终浓度范围为1000nM~0.05nM。使用梯度稀释的ATP溶液(来自ADP-GloTM Kinase Assay试剂盒)测定PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ的ATP Km值,依据实验所得的ATP Km值,设定反应体系中的ATP浓度均为10μM。反应在384孔微孔板中进行,首先向孔中加入化合物和一定量的PI3Kα、PI3Kβ、PI3Kγ或PI3Kδ蛋白,并在室温下孵育15分钟,随后向反应液中加入ATP溶液及PIP2:3PS(终浓度为0.01mg/mL),并在室温下振荡孵育60分钟。随后向反应体系中加入5μL ADP-Glo Reagent(含有10mM MgCl2),并在室温下继续振荡孵育40分钟。之后向反应体系中加入10μL Kinase Detection Reagent,并在室温下继续振荡孵育40分钟。孵育结束后,在酶标仪以Luminescence模式测定各孔的化学发光强度值。通过与对照组(0.1%DMSO)的发光强度比值进行比较计算化合物在各浓度下的百分比抑制率,并通过GraphPad Prism5软件以化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC50值,见表1。
表1本发明实施例化合物和IPI-549对PI3K激酶活性抑制的IC50值
表2本发明实施例化合物和IPI-549的PI3Kγ激酶相对其他亚型的抑制活性的选择性
从表1和2可以看出,与IPI-549相比,本发明实施例1、实施例2和实施例3化合物对于PI3Kγ激酶具有显著的抑制活性,且对于PI3Kγ激酶的抑制活性显著优于对PI3Kα、PI3Kβ和PI3Kδ的抑制活性,本发明的化合物具有显著的PI3Kγ选择性抑制作用。
测试例2、本发明化合物对PI3K各亚型抑制的细胞活性测试
以下方法用于测定本发明化合物在不同细胞中对PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ激酶活性的抑制程度。本方法使用PE公司的AlphaLISA SureFire Ultra p-AKT1/2/3(pS473)试剂盒(#ALSU-PAKT-B500)。上述试剂盒使用AlphaLISA技术,利用供体和受体的微珠来进行检测生物分子的相互作用,用于检测p-AKT(pS473)的含量,反映化合物在细胞层面对PI3Kα、PI3Kβ、PI3Kγ和PI3Kδ激酶活性的抑制强弱。详细实验操作可参考试剂盒说明书。
将实验流程简述如下:该实验在384孔板中进行,使用Multidrop分液器(Thermo,#836-4049),针对不同PI3K亚型使用不同细胞(PI3Kα:C2C12细胞(成肌细胞);PI3Kβ:PC-3细胞(人前列腺癌细胞);PI3Kγ:Raw264.7细胞(单核巨噬细胞);PI3Kδ:Raji细胞(淋巴瘤细胞)),将6μL相应细胞移至384孔板孔中,500RPM离心30秒后放置37℃,5%C02培养箱内2小时;受试化合物首先溶解于DMSO中制备为10mM贮存液,使用DMSO进行4倍梯度稀释,利用Echo(Labcyte,#550)移取30nL至每孔(终浓度为10000nM-0.2nM),并孵育30分钟。而后针对PI3Kα亚型使用的C2C12细胞,加入2uL IGF-1(R&D,#291-G1-200,终浓度1200ng/mL)并孵育20分钟;针对PI3Kβ亚型使用的PC-3细胞,加入2μL LPA(Sigma,#L7260,终浓度15ug/mL)并孵育20分钟;针对PI3Kγ亚型使用的Raw264.7细胞,加入2uL C5α(Biotang,#RPR9899,终浓度80ng/mL)并孵育5分钟;针对PI3Kδ亚型使用的Raji细胞,加入2μL IgM(JacksonImmunoResearch,#109-006-129,终浓度3ug/mL)并孵育10分钟;待孵育结束后,使用AlphaLISA SureFire Ultra p-AKT1/2/3(pS473)试剂盒测定AlphaLISA信号。试剂盒测定方式简述如下:使用2μL Lysis Buffer裂解细胞10分钟,之后在384孔板中加入5uLacceptor mix和5uL donor mix,室温下振荡孵育2小时,使用Envision(PE,#2104)读取AlphaLISA信号。通过与对照组(0.5%DMSO)的信号强度比值进行比较计算化合物在各浓度下的百分比抑制率,并通过GraphPad Prism 5软件以化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC50值,见表3。
表3本发明实施例化合物对PI3K各亚型抑制的细胞活性的IC50值
表4本发明实施例化合物对于PI3Kγ相对其他亚型的细胞抑制活性的选择性
从表3和4可以看出,本发明实施例2化合物对于PI3Kγ亚型的细胞活性具有显著的抑制效果,且对于PI3Kγ亚型的细胞抑制活性显著优于对PI3Kα、PI3Kβ和PI3Kδ亚型的细胞抑制活性,因此本发明的化合物对于PI3Kγ亚型具有显著地选择性抑制作用。
测试例3、本发明化合物在小鼠肝微粒体中代谢稳定性研究
1.实验目的
本实验研究的目的是考察本发明化合物在小鼠肝微粒体中的代谢稳定性。
2.试剂信息(见表5)
表5实验所用试剂信息
名称 | 批号 | 供应商 |
人鼠肝微粒体 | 5118007 | 美国Coming公司 |
马来酸咪达唑仑 | 171265-201402 | 中国食品药品检定研究院 |
NADPH | 20595626 | 瑞士Roche公司 |
磷酸二氢钾 | 20150428 | 国药集团化学试剂有限公司 |
磷酸氢二钾 | 20150312 | 国药集团化学试剂有限公司 |
氯化镁(MgCl2) | F20090916 | 国药集团化学试剂有限公司 |
盐酸维拉帕米 | 100223-200102 | 中国食品药品检定研究院 |
格列本脲 | 100135-201105 | 中国食品药品检定研究院 |
DMSO | 1427C108 | 美国Amresco公司 |
甲醇 | QADG3H | 美国Honeywell公司 |
乙腈 | S13A1H | 美国Honeywell公司 |
甲酸 | A1819048 | 上海阿拉丁生化科技股份有限公司 |
3.实验方案
将受试化合物与人肝微粒体进行共孵育,加入辅酶NADPH启动反应。在0、5、15、30和60分钟取出20μL孵育液并转移至200μL含有内标的乙腈中终止反应。蛋白沉淀后,3,700rpm离心10分钟,取上清。上清液加水1∶1稀释后由LC-MS/MS方法分析。根据受试化合物在孵育体系中的清除半衰期算出体外内在清除率。咪达唑仑作为内部参考化合物,均平行孵育2份。孵育条件总结如下表6:
表6本发明实施例化合物与IPI-549、WO2015051244A1中的化合物21的孵育条件
4.数据分析
分析物/内标峰面积之比(Aanalyte/AIS)将由仪器得出,剩余百分比(%Control)由非零时间点样品与零时刻样品中Aanalyte/AIS之比计算出。将Ln(%Control)对孵育时间作图并进行线性拟合。受试化合物清除常数(k,min-1)、清除半衰期(T1/2,min)以及体外内在清除率(CLint,mL·min-1·mg-1proteins)由以下方程式计算得到。
k=-slope
T1/2=0.693/k
CLint=k/Cprotein
Cprotein(mg·mL-1)指孵育体系中的微粒体蛋白质浓度。
5.实验结果(见表7)
表7本发明实施例化合物与IPI-549、WO2015051244A1中的化合物21的人肝微粒体稳定性的相关参数
结论:与IPI-549以及WO2015051244A1中公开的化合物21相比,本发明实施例1、实施例2和实施例3化合物的半衰期明显延长,人肝微粒体稳定性显著提高。
专利申请WO2015051244A1中公开的化合物21结构如下:
测试例4、本发明化合物ICR小鼠口服药代动力学研究
1、实验目的
以ICR小鼠为受试动物,采用LC/MS/MS法测定小鼠灌胃给予本发明化合物,测定其不同时刻血浆中的药物浓度,研究本发明化合物在小鼠体内的药代动力学特征。
2、实验方案
2.1实验药品与动物
IPI-549、本发明实施例1化合物和实施例2化合物;
健康成年雄性ICR小鼠27只,购自维通利华实验动物技术有限公司,动物质量合格证号:1903040021。
2.2药物配制与给药
称取适量的待测化合物,加入0.5%羧甲基纤维素钠(含0.05%Tween80),涡旋振荡,超声使固体分散均匀,得到混悬液;吸取100μL×2制剂,装入1.5-mL EP管,2~8℃保存,制剂浓度为0.5mg/mL。
健康成年ICR雄性小鼠27只,禁食过夜后灌胃给药(给药剂量5mg/kg),给药4小时后进食。
2.3样品采集
于给药前和给药后0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时、12小时和24小时经眼眶静脉采血80uL采约0.08mL血液,置于EDTA-K2抗凝管。血液样本采集后置于冰上,离心分离血浆(离心条件:1500g,10分钟)。收集的血浆分析前存放于-40~-20℃。用LC-MS/MS法测定不同的化合物灌胃给药后ICR小鼠血浆中的待测化合物的含量。
3、药代动力学参数结果
本发明实施例化合物和阳性对照化合物IPI-549的药代动力学参数如下表8所示。
表8本发明实施例化合物与IPI-549的药代动力学参数
结论:与IPI-549相比,本发明实施例1和实施例2化合物在ICR小鼠中的血药浓度和曲线下面积显著增加,药代吸收良好,半衰期延长,生物利用度明显提高,具有较好的药代动力学性质。
测试例5、本发明化合物SD大鼠口服药代动力学研究
1、实验目的
以SD大鼠为受试动物,采用LC/MS/MS法测定灌胃给予本发明化合物,测定其不同时刻血浆中的药物浓度,研究本发明化合物在大鼠体内的药代动力学特征。
2、实验方案
2.1实验药品与动物
IPI-549、本发明实施例1和实施例2化合物;
健康成年Sprague Dawley(SD)雄性大鼠9只,购自维通利华实验动物技术有限公司,生产许可证号:11400700271077。
2.2药物配制与给药
口服灌胃组:
称取适量的待测化合物,加入0.5%羧甲基纤维素钠(含0.05%Tween80),涡旋振荡,超声使固体分散均匀,得到混悬液;吸取100μL×2过滤后制剂,装入1.5-mL EP管,2~8℃保存,制剂浓度为0.5mg/mL。
健康成年SD雄性大鼠9只,禁食过夜后灌胃给药(给药剂量5mg/kg),给药4小时后进食。
2.3样品采集
于给药前和给药后0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时、12小时和24小时经颈静脉采约0.2mL血液,肝素钠抗凝。血液样本采集后置于冰上,离心分离血浆(离心条件:1500g,10分钟)。收集的血浆分析前存放于-40~-20℃。用LC-MS/MS法测定不同的化合物灌胃给药后SD大鼠血浆中的待测化合物的含量。
3、药代动力学参数结果
本发明实施例化合物和阳性对照化合物IPI-549的药代动力学参数如下表9所示。
表9本发明实施例化合物与IPI-549的药代动力学参数
结论:与IPI-549相比,本发明实施例1和实施例2化合物在SD大鼠中药代吸收良好,半衰期延长,血药浓度、曲线下面积、生物利用度明显提高,具有较好的药代动力学性质。
测试例6、本发明化合物联合PD-L1单抗对CT26小鼠结肠癌细胞皮下移植瘤模的生长抑制作用的药效学测试
1.实验目的
评价实施例2化合物和PD-L1单抗之联合在CT26小鼠结肠癌细胞皮下移植瘤模型中的抗肿瘤作用。
2.受试物配制
2.1空白给药制剂配制:
空白对照组给予5%NMP(N-甲基吡咯烷酮)+95%PEG400,给药体积0.1mL/10g。
2.2实施例2化合物给药制剂配制
称量适量实施例2化合物至离心管中,加入5%NMP 95%PEG400,涡旋至全溶溶液,浓度为6mg/mL,涡旋至全溶溶液,现配现用。
2.3 PD-L1单抗配制
重组抗PD-L1全鼠源单克隆抗体(InVivoMAb anti-mouse PD-L1(B7-H1),购买于Bioxcell,Clone 10F.9G2,货号:BE0101,批号:720619F1),用PBS稀释,浓度为1mg/mL,现配现用。
3.实验动物
BALB/c小鼠,雌性,7-8周(肿瘤细胞接种时的小鼠周龄),体重18.4-19.1g,每组9只。购自浙江维通利华实验动物技术有限公司,许可证号:SCXK(浙)2019-0001。
4.CT26小鼠结肠癌培养
CT26小鼠结肠癌细胞培养在含10%胎牛血清、100U/mL青霉素和100μg/mL链霉素的RPMI-1640培养液中。收集指数生长期的CT26细胞,PBS重悬至适合浓度用于小鼠皮下肿瘤接种。
5.动物接种及分组
雌性BALB/c小鼠背部皮下接种2.5×105CT26细胞。待肿瘤平均体积约127mm3时,根据肿瘤大小随机分组,每组9只,分为4组,分组当天定义为第0天。
6.动物给药和观察
肿瘤接种后,常规监测包括了肿瘤生长及治疗对动物正常行为的影响,具体内容有实验动物的活动性,摄食和饮水情况,体重增加或降低情况,眼睛、被毛及其它异常情况。每周称重和测量肿瘤体积2次,给药周期21天,于第21天称量体重测量肿瘤体积后次日处死小鼠取瘤块称重,计算肿瘤体积(TV)、相对肿瘤体积(RTV)、相对肿瘤增殖率(T/C)、肿瘤抑制百分率(IR)和相对肿瘤抑制率(TGI),做统计学检测。计算公式如下:
(1)TV=1/2×a×b2,其中a、b分别表示肿瘤的长和宽;
(2)RTV=Vt/V0,其中V0为分组给药时(即d0)所测得的肿瘤体积,Vt为每一次测量时的肿瘤体积;
(3)TGI(%)=(1-T/C)×100%;其中,T/C%为相对肿瘤增殖率,在某一时间点,治疗组和对照组相对肿瘤体积的百分比值,T和C分别为治疗组和对照组某一特定时间点的相对肿瘤体积,T/C(%)=TRTV/CRTV×100%,其中TRTV为治疗组的RTV,CRTV为对照组的RTV;
(4)IR(%)=(1-TWt/TWc)×100%,其中TWt为治疗组瘤重,TWc为对照组瘤重。
7.结果
给药后第21天在CT26小鼠结肠癌模型中各组药效参数如下表10所示。
表10给药后第21天在CT26小鼠结肠癌模型中各组药效分析表
表11给药后第21天在CT26小鼠结肠癌模型各组小鼠肿瘤重量分析表
由表10和11可知,给药后第21天,在CT26小鼠结肠癌模型中,本发明实施例2化合物的60mg/kg单药治疗组、联合治疗组和Anti-PD-L1组的TGI分别为51.2%、77.3%和38.7%,IR分别为52.1%,79.0%和35.8%,体重均无明显变化,这表明本发明实施例2化合物的60mg/kg单药治疗组、联合治疗组均表现出显著有效的抑制肿瘤生长作用,联合治疗组抑制肿瘤生长作用更优于单药治疗组。
Claims (18)
1.式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
X选自CH或N;
R1选自C3-C6环烷基或氧杂环丁烷基,其中所述的C3-C6环烷基或氧杂环丁烷基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、C1-C6烷基、C1-C6烷氧基或-NR5R6的取代基所取代;
R2和R3各自独立地选自氢原子、C1-C6烷基、C1-C6烷氧基或卤素;
R4相同或不同,各自独立地选自氢原子、C1-C6烷基、C1-C6烷氧基;
R5和R6各自独立地选自氢原子、C1-C6烷基或C3-C6环烷基;且
m为0、1、2、3、4或5。
2.根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:R1为环丙基、环丁基、环戊基、环己基或氧杂环丁烷基。
3.根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:R1为环丙基或氧杂环丁烷基。
4.根据权利要求1~3中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:R2和R3各自独立地选自氢原子或卤素。
5.根据权利要求4所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中所述卤素为氟。
6.根据权利要求1~3中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:R4相同或不同,各自独立地选自氢原子或C1-C6烷基,且m为0、1、2或3。
7.根据权利要求6所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R4为氢原子。
8.根据权利要求1~3中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中所述的化合物选自:
9.一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
10.根据权利要求1~8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求9所述的药物组合物在制备用作磷脂酰肌醇-3-激酶γ抑制剂的药物中的用途。
11.根据权利要求1~8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求9所述的药物组合物在制备用于治疗由磷脂酰肌醇-3-激酶γ介导的疾病的药物中的用途。
12.根据权利要求11所述的用途,其中所述由磷脂酰肌醇-3-激酶γ介导的疾病为癌症、骨障碍、呼吸疾病、炎性疾病或自身免疫疾病。
13.根据权利要求12所述的用途,其中所述呼吸疾病为哮喘、囊肿型纤维化、肺气肿、慢性阻塞性肺病、慢性支气管炎、支气管扩张、急性呼吸窘迫综合征、呼吸道疾病、胸腔疾病或肺动脉高血压。
14.根据权利要求12所述的用途,其中所述癌症为血液肿瘤或实体瘤。
15.根据权利要求14所述的用途,其中所述血液肿瘤选自急性淋巴细胞性白血病、慢性淋巴细胞性白血病、幼淋巴细胞白血病、毛细胞白血病、华氏巨球蛋白血症、外周T细胞淋巴瘤、成人T细胞白血病/淋巴瘤、皮肤T细胞淋巴瘤、大颗粒淋巴细胞白血病、急性髓性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、肥大细胞增多症、多发性骨髓瘤、骨髓增生异常综合征或骨髓增生障碍。
16.根据权利要求14所述的用途,其中所述实体瘤选自脑癌、皮肤癌、头颈癌、神经内分泌癌、胰腺癌、肺癌、乳腺癌、前列腺癌、睾丸癌、食道癌、肝癌、胃癌、结肠癌、结肠直肠癌、卵巢癌、宫颈癌、子宫癌、子宫内膜癌、膀胱癌、肾癌、病毒引起的癌症、成神经管细胞瘤、基底细胞癌、胶质瘤、肝细胞癌、胃肠道间质瘤、黑素瘤、原始神经外胚层肿瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索瘤、内皮肉瘤、淋巴管肉瘤、淋巴血管内皮肉瘤、滑膜瘤、间皮瘤、平滑肌肉瘤、膀胱中的移行细胞癌、上皮癌、鳞状细胞癌、腺癌、支气管癌、肾细胞癌和类癌瘤。
17.根据权利要求11或14所述的用途,其中所述根据权利要求1~8中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求9所述的药物组合物与一种或多种第二治疗剂联合,其中所述第二治疗剂选自PI3Kδ抑制剂、mTOR抑制剂、共刺激调节剂、免疫刺激剂、CXCL12/CXCR4抑制剂、HDAC抑制剂、蛋白酶体抑制剂、CD28抗体、CD30抗体、CD40抗体、GM-CSF、吉西他滨、环磷酰胺、多西紫杉醇、紫杉醇、5-FU、替莫唑胺、抗血管生成剂、阿昔替尼、PD-1抑制剂、PD-L1抑制剂或其混合物。
18.根据权利要求17所述的用途,其中所述第二治疗剂为PD-1抑制剂或PD-L1抑制剂。
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