CN116768865A - Cd73抑制剂及其在医药上的应用 - Google Patents
Cd73抑制剂及其在医药上的应用 Download PDFInfo
- Publication number
- CN116768865A CN116768865A CN202310238661.7A CN202310238661A CN116768865A CN 116768865 A CN116768865 A CN 116768865A CN 202310238661 A CN202310238661 A CN 202310238661A CN 116768865 A CN116768865 A CN 116768865A
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- Prior art keywords
- alkylene
- pharmaceutically acceptable
- compound
- halogen
- substituted
- Prior art date
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- 229940127272 CD73 inhibitor Drugs 0.000 title description 4
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- 238000000034 method Methods 0.000 claims description 13
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- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明涉及一种新型化合物,其具有癌症治疗活性。本发明还涉及这些化合物的制备方法以及包含其的药物组合物。
Description
技术领域
本发明涉及一种可作为CD73抑制剂的化合物,其具有癌症治疗活性。本发明还涉及这些化合物的制备方法以及包含其的药物组合物。
背景技术
胞外5'-核苷酸酶(ecto-5'-nucleotidase,CD73)是一种细胞膜上的糖蛋白,在多种细胞类型的细胞膜表面存在,包括内皮细胞、淋巴细胞、基质细胞和肿瘤细胞等。CD73能够催化细胞外5'-磷酸腺苷(5'-AMP)生成腺苷,而腺苷可诱导免疫抑制效应,促进肿瘤增殖和/或转移。此外,CD73还能够以非免疫相关机制促进肿瘤生成,如促进肿瘤血管生成、促进肿瘤细胞对细胞外基质蛋白的粘附等。临床上,CD73高水平表达与多种癌症类型的淋巴结转移和不良预后相关,已发现CD73是前列腺癌和三阴性乳腺癌患者的独立预后因素。
靶向CD73的药物成为当前药物研发热点领域之一,已有品种进入临床阶段。在研品种既包括大分子抗体,也包括小分子药物。本发明将提供一种新型结构的小分子CD73抑制剂,具有良好的抗肿瘤活性。
发明内容
本发明提供一种通式(I)所示的化合物、其立体异构体、互变异构体、氘代物或药用盐:
其中,
X1、X2、X3、X4、X5各自独立地选自N、NRa、CRa或C(Ra)2;
R1各自独立地选自H、卤素、氰基、C1-3烷基、C1-3烷氧基或C1-3卤代烷基,优选为H;
R2选自H、卤素、氰基、取代或未取代的C1-3烷基、取代或未取代的C1-3烷氧基、取代或未取代的C2-4烯基、取代或未取代的C2-4炔基;
R3选自H、氰基、卤素、C1-6烷基、C1-6卤代烷基、-C0-6亚烷基-ORa、-C0-6亚烷基-OC(O)N(Ra)2、-C0-6亚烷基-N(Ra)2、-C0-6亚烷基-NRaC(O)Ra、-C0-6亚烷基-NRaC(O)N(Ra)2、-C0-6亚烷基-NRaS(O)Ra、-C0-6亚烷基-NRaS(O)2Ra、-C0-6亚烷基-S(=O)Ra、-C0-6亚烷基-S(=O)2Ra、-C0-6亚烷基-SRa、-C0-6亚烷基-S(Ra)5、-C0-6亚烷基-C(=O)Ra、-C0-6亚烷基-C(=O)ORa、-C0-6亚烷基-C(=O)N(Ra)2、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基),所述C1-6烷基、C2-6烯基、C2-6炔基、C0-6亚烷基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个Ra所取代;
R4为
R5选自H、卤素或甲基;
每个Ra各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6杂烷基、-C0-6亚烷基-C3-8环烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基,所述-C0-6亚烷基-C3-8环烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基任选地还可被1个或多个卤素、羟基或氨基所取代;m选自0、1、2或3;
n选自0、1或2。
一些实施例中,式(I)所述的化合物,或其立体异构体、互变异构体、氘代物或药用盐选自式(IA)或式(IA-1)化合物:
X1、X2、X3、X4、X5、R2、R3、R4和R5定义同式(I)所定义。
一些实施例中,式(I)中的R1选自H、卤素、氰基或C1-3烷基,优选为H。
一些实施例中,式(I)中的R2选自卤素、氰基、C1-3烷基或C1-3烷氧基,优选为氯、氰基、甲基或甲氧基。
一些实施例中,式(I)中的R3选自H或卤素。
一些实施例中,式(I)中的选自
一些实施例中,式(I)中的R5选自H、卤素或甲基,优选为H。
一些实施例中,式(I)中的化合物选自:
本发明还提供了一种药物组合物,其特征在于,所述药物组合物包含治疗有效量的至少一种式(I)所示的化合物或其药用盐和至少一种药学上可接受的辅料。
本发明进一步提供了一种药物组合物,其特征在于,所述的治疗有效量的至少一种式(I)所示的化合物或其药用盐和药学上可接受的辅料的质量百分比为0.0001:1-10。
本发明提供了结构式(I)所示化合物或其药用盐或含其的药物组合物在制备药物中的应用。
本发明进一步提供了所述应用的优选技术方案:
作为优选,所述应用为制备治疗和/或预防癌症药物中的应用。
作为优选,所述应用为制备用于治疗由CD73介导的疾病的药物的应用。作为优选,所述疾病是癌症。
作为优选,所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
本发明还提供了一种治疗和/或预防的疾病的方法,包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或其药用盐或含其的药物组合物。
本发明还提供了一种治疗和/或预防由CD73介导的疾病的方法,包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或其药用盐或含其的药物组合物。
本发明还提供了一种治疗癌症的方法,包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或其药用盐或含其的药物组合物。
作为优选,在上述方法中,所述CD73介导的疾病是癌症。
除非另有说明,所述结构通式中使用的一般化学术语具有通常的含义。
例如,除非另有说明,本发明所用的术语“卤素”是指氟、氯、溴或碘。
在本发明中,除非另有说明,“烷基”包括直链或支链的一价饱和烃基。例如,烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的,“基1-8烷基”中的“1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。
在本发明中,“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此,例如,包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。
术语“芳基”,在本发明中,除非另有说明,是指未取代或取代的包括碳环的原子的单环或稠环芳香基团,具有完全共轭的π电子体系。优选芳基为6到14元的单环或多环的芳香环基团。优选为苯基、萘基。最优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环。
术语“杂环基”,在本发明中,除非另有说明,是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的3-14元稳定环系统,其为饱和或部分不饱和单环或多环环状烃取代基,其包括3-14个碳原子,其中氮或硫杂原子可以选择性地被氧化,并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、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。
术语“杂芳基”,在本发明中,除非另有说明,是指未取代或取代的稳定的5元或6元单环芳族环系统或未取代或取代的9-14元苯并稠合杂芳族环系统或多环杂芳族环系统,其由碳原子和1-4个选自N、O或S的杂原子组成,并且其中所述氮或硫杂原子可以选择性地被氧化,所述氮杂原子可以选择性地被季铵化。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基腺嘌呤、喹啉基、异喹啉基或所述杂芳基可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。
术语“环烷基”是指具有至少一个环化烷基的环系统。优选C3-10环烷基,其中的“C3-10”是指环烷基可以具有3、4、5、6、7、8、9或10个成环原子。环烷基可以包括单环和多环(例如具有2、3或4个稠合环、螺环、桥环等)。一些实施例中环烷基包括但不限于环丙基、环丁基、环戊基等;所述环烷基还可以稠合于芳基、杂环基或杂芳基环上,其中与母体结构连接在一起的环为环烷基。
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于H、=CH2、=O、=S、酰基、氰基、卤素、硝基、C1-6烷基、C1-6卤代烷基、-C0-3亚烷基-ORb、-C0-3亚烷基-N(Rb)2、-C0-3亚烷基-S(=O)Rb、-C0-3亚烷基-S(=O)2Rb、-C0-3亚烷基-SRb、-C0-3亚烷基-S(Rb)5、-C0-3亚烷基-C(=O)Rb、-C0-3亚烷基-C(=O)ORb、-C0-3亚烷基-C(=O)N(Rb)2、C2-6烯基、C2-6炔基、取代或未取代的-C0-3亚烷基-C3-14环烷基、取代或未取代的-C0-3亚烷基-(3-14元杂环烷基)、取代或未取代的-C0-3亚烷基-C6-14芳基或取代或未取代的-C0-3亚烷基-(5-14元杂芳基),每个Rb独立地为H、C1-6烷基、C3-6环烷基或C1-6卤代烷基。在一些实施例中,取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH3、-SC2H5、甲醛基、-C(OCH3)、氰基、硝基、-CF3、-OCF3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。
取代烷基的实例包括但不限于2,3-二羟基丙基、2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基、苯基甲基、二恶茂基甲基和哌嗪基甲基。
取代烷氧基的实例包括但不限于2-羟基乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2-甲氧基乙氧基、2-氨基乙氧基、2,3-二羟基丙氧基、环丙基甲氧基、氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。
术语“药用盐”是指从药学上可接受的无毒的碱或酸制备的盐。
当本发明提供的化合物是酸时,可以从药学上可接受的无毒的碱,包括无机碱和有机碱,方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺,也包括环胺及含有取代基的胺,如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱,包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、异丙胺、赖氨酸,甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时,可以从药学上可接受的无毒的酸,包括无机酸和有机酸,方便制得其相应的盐。这样的酸包括,如,醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地,柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地,甲酸和盐酸。
由于式(I)所示化合物将作为药物应用,较优地,使用一定纯度,例如,至少为60%纯度,比较合适的纯度为至少75%,特别合适地纯度为至少98%(%是重量比)。
本发明化合物的药物前体包含在本发明的保护范围内。通常,所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如,本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物,其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。特别优选的衍生物或前药是在施用于患者时可以提高本申请化合物生物利用度的那些化合物(例如,可以使口服的化合物更易于被吸收到血液中),或者促进母体化合物向生物器官或作用位点(例如脑部或淋巴系统)递送的那些化合物。因此,本发明提供的治疗方法中的术语“给药”是指施用能治疗不同疾病的本发明公开的化合物,或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物的化合物。
本发明所述化合物可能含有一个或多个不对称中心,并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药用盐。
当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势,这是由于更大的代谢稳定性,例如增加体内半衰期或减少剂量要求。
当式(I)所示化合物及其药用盐存在溶剂化物或多晶型时,本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“组合物”,在本发明中,是指包括包含指定量的各指定成分的产品,以及直接或间接地由指定量的各指定成分的组合生产的任何产品。因此,含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药用盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下,最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
具体实施方式
为使上述内容更清楚、明确,本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式,以使本领域的技术人员能够理解本发明,但不用于限制本发明的保护范围。本发明的具体实施方式中,未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。
除非另有说明,本发明所有的一部分和百分比均按重量计算,所有温度均指摄氏度。
实施例中使用了下列缩略语:
PE:EA:石油醚和乙酸乙酯的比值;
Pd(dppf)Cl2:[1,1'-双(二苯基膦)二茂铁]二氯化钯;
Pre-TLC:薄层层析硅胶板;
DMSO:N,N-二甲基甲酰胺;
Ru(II)-(R)-Pheox:四(乙腈)[2-[(4R)-4,5-二氢-4-苯基-2-恶唑基-N]苯基]钌(II)六氟磷酸盐;
DCC:二环己基碳二亚胺;
DCM:二氯甲烷;
DMF:N,N-二甲基甲酰胺;
B2Pin2:联硼酸频那醇酯;
THF:四氢呋喃;
DIEA:N,N-二异丙基乙胺;
中间体M的合成:
步骤1:化合物M-1的合成
将乙醛酸(50%水溶液)(10g)加入60mL水中,65℃加热;将对甲苯磺酰肼(12.6g)加入2.5M盐酸(40mL)中,65℃预热,然后将该溶液滴加至乙醛酸溶液中,65℃反应1小时。反应液冷却至室温,将反应液于冰箱中放置过夜,抽滤,冷水洗涤滤饼,滤饼干燥,得白色粉末12.8g,即化合物M-1。1H NMR(500MHz,DMSO)δ12.28(s,1H),7.71(s,1H),7.54(s,1H),7.44(s,1H),7.37(s,1H),7.18(s,1H),2.38(s,3H)。
步骤2:化合物M的合成
将M-1(12.80g),N-羟基邻苯二甲酰亚胺(12.93g)加入100mL二氯甲烷中,氮气保护,冰浴下向反应液中滴加DCC(21.80g)的DCM溶液,滴加完毕,反应液于室温反应过夜,TLC监测反应完成。抽滤,滤液用饱和碳酸氢钠洗两遍,有机相浓缩。浓缩物经柱层析分离纯化(PE-DCM,60%DCM出峰)得淡黄色晶体12.0g,即化合物M。ESI-MS m/z:232[M+H]+。
实施例1:化合物5-(6-氯-5-((1S,2S)-2-(1-(2,2,2-三氟乙基)-1H-吲唑-6-基)环丙基)哒嗪-3-基)嘧啶-2,4(1H,3H)-二酮的合成
步骤1:化合物1-1的合成
将6-溴吲唑(5.0g),2,2,2-三氟乙基三氟甲烷磺酸酯(8.84g),碳酸钾(10.52g)依次加入DMF(50mL)中,N2保护,85℃反应2小时,LCMS监测反应完成。向反应液中加水淬灭,EA萃取两次,合并有机相,有机相蒸干。柱层析分离纯化(PE-EA,10%EA出峰)得白色晶体4.0g,即化合物1-1。1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.60-7.46(m,2H),7.27(dd,J=8.5,1.5Hz,1H),4.84(q,J=8.4Hz,2H)。ESI-MS m/z:279[M+H]+。
步骤2:化合物1-2的合成
将1-1(2.0g),乙烯三氟硼酸钾(1.01g),碳酸钾(2.18g),Pd(dppf)Cl2(0.58g)依次加入THF(40mL),H2O(4mL)中,氮气保护,65℃反应,LCMS监测反应完成。直接浓缩,浓缩物经柱层析分离纯化(PE-EA,5%EA出峰)得白色粉末1.3g,即化合物1-2。ESI-MS m/z:227[M+H]+。
步骤3:化合物1-3的合成
将1-2(0.8g),Ru(II)-(R)-Pheox(0.23g)依次加入DCM(50mL)中,氮气保护,反应液冰浴下反应10分钟,然后向反应液中缓慢滴加M(2.45g)的DCM(50mL)溶液,滴加完毕,继续反应1小时,LCMS监测反应完成。直接蒸干溶剂,柱层析分离纯化(PE-EA,30%EA出峰),得淡黄色粉末1.3g,即化合物1-3。ESI-MS m/z:430[M+H]+。
步骤4:化合物1-4的合成
将1-3(1.3g),联硼酸频那醇酯(1.54g),异烟酸乙酯(0.21mL)依次加入乙酸乙酯(20mL)中,氮气保护,80℃反应,LCMS监测反应完成。将反应液直接浓缩,柱层析分离纯化(PE-EA,10%EA出峰),得无色油状物0.36g,即化合物1-4。ESI-MS m/z:367[M+H]+。
步骤5:化合物1-5的合成
将化合物1-4(0.36g),4-溴-3,6-二氯哒嗪(0.27g),碳酸钾(0.27g),Pd(dppf)Cl2(0.08g)依次加入THF(10mL),H2O(2mL)中,氮气保护,65℃反应,LCMS监测反应完成。将反应液直接浓缩,柱层析分离纯化(PE-EA,20%EA出峰),得无色油状物0.3g,即化合物1-5。ESI-MS m/z:387[M+H]+。
步骤6:化合物1-6的合成
将1-5(0.30g),2,4-二甲氧基-5-嘧啶硼酯(0.23g),碳酸钠(0.12g),Pd(dppf)Cl2(0.06g)依次加入二氧六环(10mL),H2O(0.5mL)中,氮气保护,60℃反应,LCMS监测反应完成。将反应液直接浓缩,柱层析分离纯化(PE-EA,30%EA出峰),得白色粉末0.2g,即化合物1-6。ESI-MS m/z:491[M+H]+。
步骤7:化合物1的合成
将1-6(0.15g)溶解于THF(2mL)中,然后加入1M盐酸(2mL),50℃反应,LCMS监测反应完成。抽滤,滤饼分别用DCM和MeOH打浆,得白色粉末50mg,即化合物1。ESI-MS m/z:463[M+H]+。1H NMR(500MHz,DMSO)δ11.65–11.57(m,2H),8.35(d,J=6.2Hz,1H),8.16(s,1H),8.11(s,1H),7.76–7.69(m,2H),7.15(d,J=8.4Hz,1H),5.42(q,J=8.9Hz,2H),2.45-2.54(m,2H),1.85(dd,J=14.0,6.1Hz,1H),1.73(dd,J=14.2,5.7Hz,1H).
下述实施例采用上述实施例方法合成,或使用相应中间体的类似方法合成。
对比实施例1
按照WO2019168744A1实施例2的方法合成对比化合物1(D1),LCMS:[M+H]+=287。
药理实验
实施例1:细胞水平的酶学活性检测
将Calu-6细胞消化,使用TM buffer(25mM Tris,5mM MgCl2,pH 7.5)重悬细胞,按25000细胞、100μL/孔铺96孔板。TM buffer配制梯度浓度的化合物溶液,分别向各孔细胞中加入50μL各浓度的待测化合物DMSO溶液,化合物终浓度为20000、6666.7、2222.2、740.7、246.9、82.3、27.4、9.1、3.0、1.0、0.3、0nM(DMSO终浓度均为0.625%)。37℃恒温水平摇床预孵育30min,各孔中加入50μL 800μM AMP溶液,37℃恒温水平摇床继续孵育120min后,将96孔板离心,每孔转移50μL上清液至新的96孔板中,每孔中加入50μL 130μM ATP溶液和100μLCell-titer Glo工作液,震荡混匀后室温孵育10min,多功能酶标仪读取Luminescence发光值,将发光值读数转换为抑制百分数:
抑制百分数=(1-读数/最大值)*100。
“最大值”为DMSO对照。
用GraphPad Prism软件进行曲线拟合并得到IC50值。
实施例化合物在Calu-6细胞水平的酶学IC50数据参见表1。本发明的化合物具有较好活性。
表1
化合物名称 | IC50(nM) |
1 | 0.2 |
D1 | 49.1 |
虽然本发明已通过其实施方式进行了全面的描述,但是值得注意的是,各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。
Claims (11)
1.一种通式(I)所示的化合物,或其立体异构体、互变异构体、氘代物或药用盐:
其中,
X1、X2、X3、X4、X5各自独立地选自N、NRa、CRa或C(Ra)2;
R1各自独立地选自H、卤素、氰基、C1-3烷基、C1-3烷氧基或C1-3卤代烷基,优选为H;
R2选自H、卤素、氰基、取代或未取代的C1-3烷基、取代或未取代的C1-3烷氧基、取代或未取代的C2-4烯基、取代或未取代的C2-4炔基;
R3选自H、氰基、卤素、C1-6烷基、C1-6卤代烷基、-C0-6亚烷基-ORa、-C0-6亚烷基-OC(O)N(Ra)2、-C0-6亚烷基-N(Ra)2、-C0-6亚烷基-NRaC(O)Ra、-C0-6亚烷基-NRaC(O)N(Ra)2、-C0-6亚烷基-NRaS(O)Ra、-C0-6亚烷基-NRaS(O)2Ra、-C0-6亚烷基-S(=O)Ra、-C0-6亚烷基-S(=O)2Ra、-C0-6亚烷基-SRa、-C0-6亚烷基-S(Ra)5、-C0-6亚烷基-C(=O)Ra、-C0-6亚烷基-C(=O)ORa、-C0-6亚烷基-C(=O)N(Ra)2、C2-6烯基、C2-6炔基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基),所述C1-6烷基、C2-6烯基、C2-6炔基、C0-6亚烷基、-C0-6亚烷基-C3-14环烷基、-C0-6亚烷基-(3-14元杂环基)、-C0-6亚烷基-C6-14芳基或-C0-6亚烷基-(5-14元杂芳基)任选地还可被1个或多个Ra所取代;
R4为
R5选自H、卤素或甲基;
每个Ra各自独立地选自H、卤素、羟基、氨基、氧代基、硝基、氰基、羧基、C1-6烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6杂烷基、-C0-6亚烷基-C3-8环烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基,所述-C0-6亚烷基-C3-8环烷基、C3-8环烷基、3-8元杂环基、C6-14芳基或5-14元杂芳基任选地还可被1个或多个卤素、羟基或氨基所取代;m选自0、1、2或3;
n选自0、1或2。
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、氘代物或药用盐,其特征在于,选自式(IA)或式(IA-1)化合物:
X1、X2、X3、X4、X5、R2、R3、R4和R5定义同式(I)所定义。
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、氘代物或药用盐,其特征在于,R1选自H、卤素、氰基或C1-3烷基,优选为H。
4.根据权利要求1-3任一项所述的化合物,或其立体异构体、互变异构体、氘代物或药用盐,其特征在于,R2选自卤素、氰基、C1-3烷基或C1-3烷氧基,优选为氯、氰基、甲基或甲氧基。
5.根据权利要求1-4中任一项所述的化合物,或其立体异构体、互变异构体、氘代物或药用盐,其特征在于,R3选自H或卤素。
6.根据权利要求1-5中任一项所述的化合物,或其立体异构体、互变异构体、氘代物或药用盐,其特征在于,选自/>
7.根据权利要求1-6中所述的化合物,或其立体异构体、互变异构体、氘代物或药用盐,其特征在于,R5选自H、卤素或甲基,优选为H。
8.一种化合物,或其立体异构体、互变异构体、氘代物或药用盐,所述化合物选自:
9.一种药物组合物,其特征在于,所述药物组合物含有治疗有效量的权利要求1-8任一项所述的化合物和至少一种药学上可接受的辅料。
10.权利要求1-8任一项所述的化合物或权利要求9所述的药物组合物在制备药物中的应用。
11.一种治疗和/或预防疾病的方法,包括向治疗对象施用治疗有效量的权利要求1-8任一项所述的化合物或权利要求9所述的药物组合物。
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