CN116554057B - 降低促红细胞生长素(epo)生成的化合物及其用途 - Google Patents
降低促红细胞生长素(epo)生成的化合物及其用途 Download PDFInfo
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- CN116554057B CN116554057B CN202310508673.7A CN202310508673A CN116554057B CN 116554057 B CN116554057 B CN 116554057B CN 202310508673 A CN202310508673 A CN 202310508673A CN 116554057 B CN116554057 B CN 116554057B
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Abstract
本申请涉及降低促红细胞生长素(EPO)生成的化合物及其用途。具体地,本申请公开了如式(I)所示的化合物、或其药学上可接受的盐。本申请还涉及所述化合物在医学方面的应用。
Description
技术领域
本申请提供了一类具有药学活性的新颖化合物,所述化合物可用于降低促红细胞生长素(erythropoietin,EPO)的生成。本申请还涉及包含所述化合物的组合物,以及所述化合物和所述组合物在制备用于治疗与EPO相关的疾病或病症的药物中的用途。
背景技术
在正常的生理条件下,EPO(erythropoietin,促红细胞生长素)由肾小管周围***响应局部组织的缺氧而产生,然而在肾细胞癌中,EPO却在肿瘤细胞中产生。统计表明,有三分之二的肾细胞癌患者体内EPO较正常水平相比升高,而其中8%的患者会出现红细胞增多症(polycythemia)(Reviews in Urology.2002,4(4),163–170)。在这些患者中,血清红细胞的浓度升高被认为是由EPO介导的。而真性红细胞增多易导致静脉血栓形成、出血及血管神经***问题从而导致中风和心脏疾病;如果缺乏治疗,病人会有生命危险。现在已有的治疗包括长期的静脉放血、羟基尿和干扰素α等降细胞疗法、也有静脉注射放射性磷、百消安、以及JAK抑制剂如芦可替尼(ruxolitinib)等(中华血液学杂志Chin.J.Hematol.2022,vol 43,537-541)。
另外,在肾细胞癌中EPO水平普遍偏高,因此EPO可以作为一种潜在的肿瘤标志物。有文献表明,透明肾细胞癌症中EPO表达的缺失是一个独立的预测因素,对生存率有负面影响;亦即,EPO高的肾癌患者反而生存效果更佳(Kidney Cancer 2017,1(2),143-149)。当然,EPO作为治疗透明肾细胞癌患者的可能标志物,其使用还需要深入研究,从而了解EPO在肿瘤生物学中的作用。EPO水平较高的肾细胞癌患者可能对其EPO水平的高低更加敏感,因此降低EPO的水平是治疗红细胞增多症和肾细胞癌的一种潜在而有效的方法。
因此,期望开发出一种能够显著降低EPO水平的EPO抑制剂,从而实现在多种疾病,如红细胞增多症、肾细胞癌和其他癌症等的治疗中的应用。
发明内容
本发明提供了作为EPO抑制剂的式(I)所示的化合物,或其药学上可接受的盐,
其中,环A选自C5-C6环烷基或C5-C6环烯基,所述C5-C6环烷基或C5-C6环烯基任选被1、2、3或4个R取代;
环B选自C5-C6芳基或C5-C10苯并杂芳基,所述C5-C6芳基或C5-C10苯并杂芳基任选被1、2或3个R取代,并且所述C5-C10苯并杂芳基任选地含有1或2个N杂原子;
R1、R2、R3、R4分别独立地选自氢或卤素;
R5选自氢、卤素或羟基,优选为卤素或羟基;并且
R各自独立地选自氢、卤素、C1-C3烷基或氰基,或者R中的两个与其直接相连的碳原子共同形成环外烯基。
在根据本发明的一些实施方式中,所述化合物如式(Ⅱ)所示,
其中,环B选自C5-C6芳基或C5-C10苯并杂芳基;
R1、R2、R3、R4、R6和R7分别独立地选自氢或卤素,优选地,R1,R2,R3,R4为H或F;
R5为F或OH;
R8、R9分别独立地选自氢、卤素或C1-C3烷基,优选地,R8,R9为H、F或甲基,或者R8和R9与其直接相连的碳原子共同形成环外烯基。
优选地,所述式(II)化合物可以为如式(Ⅱ-1)或(Ⅱ-2)所示的化合物,
其中,R1-R9如上所定义;
R10、R11、R12分别独立地选自氢、卤素或氰基,优选地,R10、R11、R12为H、F或CN;并且
X、Y、Z分别独立地为C或N。
在根据本发明的一些实施方式中,所述化合物如式(Ⅲ)所示,
其中,CFC2为
R1-R7如上所定义;并且
R10、R11、R12分别独立地选自氢、卤素或氰基,优选地,R10、R11、R12为H、F或CN。
本申请的化合物可以以其药学上可接受的盐的形式存在。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地,该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。
所述药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于:乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于:铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。关于合适的盐的综述,参见Handbook of Pharmaceutical Salts:Properties,Selection and Use by Stahl andWermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
在本文中使用时,术语“被取代”是指环中的一个或多个(优选1至4个,更优选1至3个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时,术语“独立地”是指当取代基的个数超过一个时,这些取代基可以相同也可以不同。
在本文中使用时,术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如,一个基团“任选地被取代”表示:该基团可以是未被取代的,也可以是被取代的。
术语“卤素”是指-F,-Cl,-Br,或-I。
在本文中使用时,术语“烷基”是指饱和的脂族烃基,包括直链及支链。在一些实施方式中,烷基基团具有1-3个、或1-2个、或1个碳原子。例如,术语“C1-3烷基”是指具有1-3个碳原子的直链或支链原子团。术语“C1-3烷基”在其定义中包括术语“C1-2烷基”、“C1烷基”。烷基的实例包括但不限于甲基、乙基、丙基、异丙基等。烷基基团可任选地被一或多个(例如,1至5个)适当的取代基所取代,优选是未取代的。
在本文中使用时,术语“环外烯基”是指存在于环外的具有至少一个碳-碳双键的脂族烃,包括具有至少一个碳-碳双键的直链及支链。在一些实施方式中,环外烯基具有2-8个碳原子、2-6个碳原子、2-4个碳原子或2-3个碳原子。例如,术语“环外C2-8烯基”是指存在于环外的具有2-8个碳原子的直链或支链的不饱和原子团(具有至少一个碳-碳双键)。烯基包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-甲基-2-丙烯基、丁烯基、戊烯基、3-己烯基等。烯基基团可任选地被一或多个(例如,1至5个)适当的取代基所取代。作为示例性说明,在根据本发明的一些优选实施方式中,环外烯基可以具有如下结构
在本文中使用时,术语“C5-6环烷基”是指具有5-6个形成环的碳原子的环烷基。所述环烷基是单环环。环烷基的实例为,例如环戊基和环己基。环烷基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“C5-6环烯基”是指具有5-6个形成环的碳原子且具有至少一个环内烯基的环烃。所述环烯基是单环环。环烯基的实例为,例如环戊烯基和环己烯基。环烯基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“C5-6芳基”是指具有含5-6个碳原子的芳环的芳基,例如苯基。
在本文中使用时,术语“C5-10苯并杂芳基”是指具有含5-10个碳原子的苯环与杂芳环稠合形成的烃基。苯并杂芳基的实例为,例如苯并吡咯、苯并吡唑或苯并咪唑。
本文中,与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举,而范围仅是作为一种简化的表示法。例如:“C5-6”表示5个(C5)或6个(C6)碳原子;“C5-10”表示5个(C5)、6个(C6)、7个(C7)、8个(C8)、9个(C9)或10个碳原子(C10)。因此,与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围,且每一个子范围也视为被本文公开。
在一些实施方式中,本申请的化合物选自:
顺式-3-氟-5-(2,2,4-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
顺式-2-氟-4-(2,2,4-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
顺式-5-(2,2,4-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)间苯二腈
顺式-3-氟-5-(2,2,2a,4-四氟-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
3-(2,2-二氟-2a-羟基-4-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)-5-氟苯甲腈
3-(2,2-二氟-2a-羟基-4-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)-5-氟苯甲腈
3-(1,1-二氟-8a-羟基-1,2,8,8a-四氢苊-4-基)-5-氟苯甲腈
3-(1,1-二氟-8a-羟基-1,2,6,7,8,8a-六氢苊-4-基)-5-氟苯甲腈
3-氟-5-(2,2,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
3-氟-5-(1,1,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
反式-3-氟-5-(1,2,2,3,3,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
顺式-3-氟-5-(1,2,2,3,3,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
3-氟-5-(1,2,2,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈
2,2,4,4-四氟-6-(5-氟-1H-吲唑-1-基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇
1-(2,2,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)-1H-吲唑-6-甲腈
2,2,4,4-四氟-6-(5-氟-1H-吲哚-1-基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇
2,2,4,4-四氟-6-(6-氟-1H-吲哚-1-基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇
6-(1H-苯并[d]咪唑-1-基)-2,2,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇
本发明的通式(II)或(Ⅲ)的化合物可以用本领域技术人员所熟悉的多种方法合成。以下仅仅给出了一些示例性的合成方法,这些方法是本领域技术人员所公知的,并且可以通过对这些方法进行各种修改。如果需要,可使用常规技术(包括但不限于过滤、蒸馏、结晶或柱层析等相关技术)分离和纯化反应中的起始原料、中间体和最终产物。另外,本文的各个具体实施例也说明了合成本发明化合物的方法。
本发明的化合物主要采用以下技术方案来合成。
方案一:具有式(II-1)的化合物的通用合成:
通过化合物II-a与芳基硼酸或芳基硼酸频那醇酯II-b进行Suzuki偶联反应得到具有式(II-1)的化合物,其中R为B(OH)2或BPin,使用的Pd催化剂可以是Pd(dppf)Cl2或Pd(PPh3)4,碱可以是Na2CO3,K2CO3或Cs2CO3。
方案二:具有式(II-2)的化合物的通用合成:
通过化合物II-a与杂环化合物II-c进行Buchwald偶联反应得到具有式(II-2)的化合物,使用的Pd催化剂可以是Pd(OAc)2或Pd2(dba)3,碱可以是K2CO3,K3PO4或t-BuOK,膦配体可以是BINAP,XPhos,t-BuXPhos或Me4t-BuXPhos。
方案三:具有式(Ⅲ)的化合物的通用合成:
通过化合物Ⅲ-a与芳基硼酸或芳基硼酸频那醇酯Ⅲ-b进行Suzuki偶联反应得到具有式(Ⅲ)的化合物,其中R为B(OH)2或BPin,使用的Pd催化剂可以是Pd(dppf)Cl2或Pd(PPh3)4,碱可以是Na2CO3,K2CO3或Cs2CO3。
本申请的化合物可以抑制EPO的水平。例如,本申请的化合物可以用于选择性抑制细胞中或需要对EPO进行抑制的个体或患者中的EPO的活性,这是通过向该细胞、个体或患者施用抑制量的本申请的化合物实现的。
在一些实施方式中,本申请的化合物对EPO具有优异的抑制活性。
在第二个方面,本申请提供了一种药物组合物,其含有如上文所述的本申请的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体、佐剂或赋形剂。
本申请的药物组合物可以按制药领域中熟知的方式制备,并且可以通过多种途径施用,这取决于期望局部治疗还是全身性治疗并且取决于有待治疗的部位。给药可以是局部的(包括眼科的和至粘膜,包括鼻内、***和直肠递送)、肺部的(例如,通过吸入或吹入粉末或气溶胶,包括通过喷雾器;气管内、鼻内、表皮和经皮肤)、眼部的、经口的或肠胃外的。用于眼部递送的方法可以包括局部给药(滴眼剂),结膜下、眼周或玻璃体内注射或者通过用手术方法放置在结膜囊中的气囊式导管或眼科***件引入。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内(例如,鞘内或脑室内)给药。肠胃外给药可以处于单次推注剂量的形式,或者可以例如通过连续灌注泵。用于局部给药的医药组合物和配制物可以包括透皮贴剂、软膏剂、洗剂、乳膏剂、凝胶剂、滴剂、栓剂、喷雾剂、液体以及粉剂。
如果使用固体载剂,则该制剂可以成片,以粉末或颗粒形式置于硬质凝胶胶囊中,或以糖锭或锭剂形式。固体载剂可以包括常规的赋形剂,诸如粘合剂、填料、成片润滑剂、崩解剂、润湿剂等等。如果需要可以通过常规技术膜包衣该片剂。如果使用液体载剂,则该制剂可以是糖浆、乳液、膏剂、软凝胶胶囊、用于注射的无菌载体、水性或非水性液体悬浮液形式的,或者可以是在使用前用水或其他适当载体复原的干品。液体制剂可以包含常规添加剂,诸如悬浮剂、乳化剂、润湿剂、非水性载体(包括可食用油)、防腐剂以及香味剂和/或着色剂。为了胃肠外施予,通常载体至少大部分包括无菌水,但也可以使用盐水溶液、葡萄糖溶液等。也可以使用可注射悬浮液,在这种情况下,可以使用常规悬浮剂。常规防腐剂、缓冲试剂等也可以添加到胃肠外剂型中。药物组合物通过对包含适量的活性成分(即本申请的化合物)的所需制剂合适的常规技术制备。
适于非肠道注射的组合物可以包括生理学上可接受无菌水性或非水性溶液、分散液、悬浮液或乳液和用于无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、丙三醇等)、其合适的混合物、植物油(例如,橄榄油)和可注射有机酯(例如,油酸乙酯)。
这些组合物还可以包含各种赋形剂,例如,防腐剂、润湿剂、乳化剂和分散剂。可以通过各种抗菌剂和抗真菌剂(例如,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等)来确保对微生物的作用的抑制。还可以包括等渗剂,例如,糖、氯化钠等。可以通过使用延迟吸收试剂(例如,单硬脂酸铝和凝胶)来延长可注射药学剂型的吸收。
用于口服的固体剂型包括胶囊、药片、药丸、粉末和颗粒。在这种固体剂型中,将活性化合物与至少一种惰性赋型剂(或载体)(例如,柠檬酸钠或磷酸二钙)混合,其中还可以包括:(a)填料或混合剂(例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸);(b)粘结剂(例如,羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和***树胶);(c)保湿剂(例如,丙三醇);(d)崩解剂(例如,琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠);(e)溶液阻滞剂(例如,石蜡);(f)吸收促进剂(例如,季铵化合物);(I)润湿剂(例如,十六烷醇和单硬脂酸丙三醇酯);(h)吸附剂(例如,高岭土和斑脱土)和(i)润滑剂(例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
类似类型的固体组合物还可以在使用例如乳糖以及高分子量聚乙二醇等作为赋型剂的软填充和硬填充凝胶胶囊中作为填料。
固体剂型(例如,药片、糖衣丸、胶囊、药丸和颗粒)可以采用涂层和外壳(例如,肠道涂层和本领域已知的其它)来制备。它们可以包含遮光剂,它们还可以是以延迟方式在肠道的某一部分中释放活性化合物或各种活性化合物的组合物。可用的包埋组合物的实例是聚合物质和蜡。活性组分还可以以微胶囊化形式,如果适当的话,可以具有一种或更多种上述赋型剂。
用于口服的液体剂型包括药学上可接受乳液、溶液、分散液、糖浆和酏剂。除了活性化合物以外,液体剂型可以包含本领域中通常所用的惰性稀释剂(例如,水或其它溶剂)、增溶剂和乳化剂(例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3丁二醇、二甲基甲酰铵)、油(具体为,棉花子油、落花生油、玉米油、橄榄油、蓖麻油、芝麻油)、丙三醇、四氢呋喃醇、聚乙二醇和山梨聚糖的脂肪酸酯或这些物质的混合物等。
除了这些惰性稀释剂,组合物还可以包括,例如,润湿剂、乳化和悬浮剂、香化剂、调味剂和加香剂。
除了活性化合物,悬浮液可以包含悬浮剂,例如乙氧基化异十八烷醇、聚氧化乙烯山梨醇、山梨聚糖酯、微晶纤维、偏氢氧化铝、斑脱土、琼脂-琼脂和黄芪胶或这些物质的混合物等。
本申请的化合物的局部给药用剂型包括膏剂、粉末、喷雾和吸入剂。该活性组分在无菌条件下与生理学上可接受载体和任何所需要的防腐剂、缓冲剂或推进剂混合。眼用配方、眼药膏、粉末和溶液也包括在本申请的范围内。
本申请的化合物在药物组合物和剂型中的量可以由本领域技术人员根据需要适当地确定,例如本申请的化合物可以治疗有效量存在于药物组合物或剂型中。
本申请也提供了治疗与EPO相关的疾病或病症的方法,所述方法包括向有此需要的患者施用治疗有效量的本申请的化合物或其药学上可接受的盐,或如上文所述的药物组合物。其中,所述患者优选是哺乳动物,更优选是人类患者。其中给药途径可以是口服、外用(包括但不限于外敷、喷涂等)、胃肠外(包括皮下、肌肉、皮层和静脉)施予、支气管施予或鼻施予等。
在一些实施方案中,所述与EPO相关的疾病或病症是红细胞增多症、肾细胞癌和其他癌症。
示例性的其他癌症包括膀胱癌、乳腺癌、子***、结肠直肠癌、小肠癌、结肠癌、直肠癌、***癌、子宫内膜癌、头颈癌(例如,喉、喉咽、鼻咽、口咽、唇部和口腔的癌症)、肝癌(例如,肝细胞癌、胆管细胞癌)、肺癌(例如,腺癌、小细胞肺癌和非小细胞肺癌、小细胞癌和非小细胞癌、支气管癌、支气管腺瘤、胸膜肺母细胞瘤)、卵巢癌、***癌、睾丸癌、子宫癌、食管癌、胆囊癌、胰腺癌(例如外分泌胰腺癌)、甲状腺癌、副甲状腺癌、皮肤癌(例如,鳞状细胞癌、卡波西肉瘤、梅克尔(Merkel)细胞皮肤癌)以及脑癌(例如,星状细胞瘤、神经管胚细胞瘤、室管膜瘤、神经外胚层肿瘤、松果体肿瘤)。
在一些优选的实施方式中,所述与EPO相关的疾病或病症为红细胞增多症。
在一些优选的实施方式中,所述与EPO相关的疾病或病症为肾细胞癌。
下面结合具体实施例对本申请做进一步的说明和描述。
实施例
以下在本文中阐述的实施例仅仅为了说明目的,用以举例说明本发明的各个方面以及实施方式,并不意欲以任何方式限制本发明所要求保护的范围。
除非另有声明,所有反应物均从商业途径获得。合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。
实施例1:顺式-3-氟-5-(2,2,4-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物1)的制备
合成路线:
步骤a:中间体5,7-二溴-N-(3-甲氧基丙基)-2,3-二氢-1H-茚-1-亚胺(1-1)的制备
将5,7-二溴-1-茚酮(4.0g,13.79mmol),3-甲氧基丙胺(6.1g,68.95mmol)和三氟乙酸(319.2mg,2.8mmol)溶解于甲苯(50.0mL)中,分水器加热回流6h。LCMS显示反应完全后,冷却至室温,将反应液浓缩后得粗品产物1-1,直接投下一步。
步骤b:中间体5,7-二溴-2,2-二氟-2,3-二氢-1H-茚-1-酮(1-2)的制备
将中间体1-1溶解于无水乙腈(30.0mL)中,加入无水硫酸钠(5.9g,41.37mmol)和1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(Selectfluor)(14.7g,41.37mmol),80℃搅拌过夜。TLC显示反应完全后,冷却至室温,加入6M HCl(5.0mL),搅拌1h。加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得到产物1-2(1.9g)。
1H NMR(500MHz,Acetonitrile-d3)δ7.93(1H),7.77(1H),3.59(2H).
步骤c:中间体1-烯丙基-5,7-二溴-2,2-二氟-2,3-二氢-1H-茚-1-醇(1-3)的制备
将中间体1-2(800.0mg,2.45mmol)溶解于无水四氢呋喃(15.0mL)中,加入铟粉(562.6mg,4.9mmol)和(1S,2R)-2-氨基-1,2-二苯基乙醇(1.0g,4.9mmol),氮气置换。依次滴加吡啶(387.6mg,4.9mmol)和烯丙基溴(592.8mg,4.9mmol),室温下搅拌2h。TLC监测反应完全后,加入水淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得到产物1-3(950.0mg)。
1H NMR(500MHz,DMSO-d6)δ7.73(1H),7.52(1H),6.16(1H),5.63–5.53(1H),4.95(1H),4.92(1H),3.43–3.34(1H),3.27(1H),2.82–2.76(1H),2.65(1H).
步骤d:中间体6-溴-2,2-二氟-4-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(1-4)和中间体7-溴-2,2-二氟-1,2-二氢苊-2a(3H)-醇(1-5)的制备
将中间体1-3(860.0mg,2.35mmol)溶解于无水N,N-二甲基甲酰胺(30.0mL)中,加入1,1-双(二苯基膦)二荗铁二氯化钯(174.2mg,0.24mmol)和乙酸钾(706.6mg,7.2mmol),氮气置换,100℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得到产物1-4(200.0mg)和1-5(242.0mg)。
1-4:1H NMR(500MHz,DMSO-d6)δ7.65(1H),7.38(1H),6.21(1H),5.70(1H),5.30(1H),3.93(1H),3.33(1H),3.01(1H),2.73(1H).
1-5:1H NMR(500MHz,DMSO-d6)δ7.41(1H),7.36(1H),6.58(1H),6.12(1H),5.67(1H),3.61(1H),3.25(1H),2.58(2H).
步骤e:中间体6-溴-2,2-二氟-2a-羟基-1,2,2a,3-四氢-4H-环戊[cd]茚-4-酮(1-6)的制备
将中间体1-4(200.0mg,0.70mmol)溶解于二氯甲烷(5.0mL),乙腈(5.0mL)和水(1.0mL)中,冷却至0℃,加入三氯化钌(14.5mg,0.070mmol),再分批加入高碘酸钠(755.7mg,3.5mmol),维持0℃搅拌0.5h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得到产物1-6(140.0mg)。
ESI-MS m/z:333[M-H+HO2H]-;1H NMR(500MHz,DMSO-d6)δ7.84(1H),7.72(1H),6.69(1H),3.99(1H),3.41(1H),3.08(1H),2.73(1H).
步骤f:中间体反式-6-溴-2,2-二氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a,4-二醇(1-7)的制备
将中间体1-6(140.0mg,0.48mmol)溶解于甲醇(8.0mL)中,冷却至0℃,缓慢加入硼氢化钠(27.2mg,0.72mmol),维持0℃搅拌0.5h。TLC监测反应完全后,加入水淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得到产物1-7(134.0mg)。
ESI-MS m/z:335[M-H+HO2H]-。
步骤g:中间体顺式-6-溴-2,2,4-三氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(1-8)的制备
将中间体1-7(110.0mg,0.38mmol)溶解于无水二氯甲烷(5.0mL)中,氮气置换,冷却至-78℃,缓慢滴加二乙胺基三氟化硫(61.5mg,0.38mmol),维持-78℃搅拌1h。LCMS监测反应完全后,加入饱和碳酸氢钠淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得到产物1-8(74.5mg)。
1H NMR(500MHz,DMSO-d6)δ7.65(1H),7.55(1H),6.41(1H),5.99(1H),3.99(1H),3.35(1H),2.58(1H),2.31(1H).
步骤h:顺式-3-氟-5-(2,2,4-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物1)的制备
将中间体1-8(40.0mg,0.14mmol),3-氰基-5-氟苯硼酸(46.2mg,0.28mmol),1,1-双(二苯基膦)二荗铁二氯化钯(5.1mg,0.007mmol),碳酸钠(29.7mg,0.28mmol)溶解于1,4-二氧六环(3.0mL)和水(0.3mL)中,氮气置换,100℃搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物1(35.7mg)。
ESI-MS m/z:378[M-H+HCO2H]-;1H NMR(500MHz,Acetonitrile-d3)δ7.83(1H),7.69(1H),7.65(1H),7.57(1H),7.55–7.52(2H),6.01(1H),4.28(1H),4.07(1H),3.39(1H),2.73(1H),2.45–2.38(1H)。
实施例2:顺式-2-氟-5-(2,2,4-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物2)的制备
合成路线:
将中间体1-8(30.0mg,0.1mmol),3-氰基-4-氟苯硼酸(33.0mg,0.2mmol),1,1-双(二苯基膦)二荗铁二氯化钯(3.7mg,0.005mmol),碳酸钠(21.2mg,0.2mmol)溶解于1,4-二氧六环(3.0mL)和水(0.3mL)中,氮气置换,100℃搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物2(15.3mg)。
ESI-MS m/z:378[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.25(1H),8.07(1H),7.74(1H),7.64(1H),7.63(1H),6.40(1H),6.04(1H),4.05(1H),3.40–3.34(1H),2.62(1H),2.36(1H)。
实施例3:顺式-5-(2,2,4-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)间苯二腈(化合物3)的制备
合成路线:
将中间体1-8(16.0mg,0.06mmol),3,5-二氰基苯硼酸频哪醇酯(30.5mg,0.12mmol),1,1-双(二苯基膦)二荗铁二氯化钯(2.2mg,0.003mmol),碳酸钠(12.7mg,0.12mmol)溶解于1,4-二氧六环(2.0mL)和水(0.2mL)中,氮气置换,100℃搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物3(7.4mg)。
ESI-MS m/z:385[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.52(2H),8.47(1H),7.87(1H),7.76(1H),6.44(1H),6.04(1H),4.06(1H),3.37(1H),2.63(1H),2.37(1H)。
实施例4:顺式-3-氟-5-(2,2,2a,4-四氟-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物4)的制备
合成路线:
步骤a:中间体顺式-6-溴-2,2-二氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-4-基-4-硝基苯甲酸酯(4-1)的制备
将中间体1-7(150.0mg,0.52mmol),4-硝基苯甲酸(173.8mg,1.04mmol),三苯基膦(272.8mg,1.04mmol)溶解于无水四氢呋喃(8.0mL)中,氮气置换,冷却至0℃,加入偶氮二甲酸二乙酯(181.1mg,1.04mmol),室温反应过夜。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物4-1(192.0mg)。
ESI-MS m/z:484[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.38(2H),8.23(2H),7.61(1H),7.55(1H),6.47(1H),6.26(1H),4.07–3.95(1H),3.39(1H),2.76(1H),2.38(1H).
步骤b:中间体顺式-6-溴-2,2-二氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a,4-二醇(4-2)的制备
将中间体4-1(192.0mg,0.44mmol)溶解于四氢呋喃(5.0mL)和水(0.5mL)中,加入氢氧化锂(21.1mg,0.88mmol),室温下搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,得产物4-2(133.0mg)。
步骤c:中间体顺式-6-溴-2,2,2a,4-四氟-2,2a,3,4-四氢-1H-环戊[cd]茚(4-3)的制备
将中间体4-2(133.0mg,0.44mmol)溶解于无水二氯甲烷(5.0mL)中,冷却至-78℃,加入二乙胺基三氟化硫(212.8mg,1.32mmol),-78℃搅拌3h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,得产物4-3(133.0mg)。
步骤d:顺式-3-氟-5-(2,2,2a,4-四氟-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物4)的制备
将中间体4-3(133.0mg,0.44mmol),3-氰基-5-氟苯硼酸(145.1mg,0.88mmol),1,1-双(二苯基膦)二荗铁二氯化钯(16.1mg,0.022mmol),碳酸钠(93.3mg,0.88mmol)溶解于二氧六环(5.0mL)和水(0.5mL)中,氮气置换,100℃搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得目标化合物4(72.0mg)。
1H NMR(500MHz,DMSO-d6)δ8.11(1H),8.02–7.98(1H),7.91(1H),7.81(2H),7.02–6.84(1H),4.13(1H),3.60(1H),3.21(1H),2.61–2.51(1H).
实施例5:3-(2,2-二氟-2a-羟基-4-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)-5-氟苯甲腈(化合物5)的制备
合成路线:
将中间体1-4(70.0mg,0.24mmol),3-氰基-5-氟苯硼酸(79.2mg,0.48mmol),1,1-双(二苯基膦)二荗铁二氯化钯(8.8mg,0.012mmol),碳酸钠(50.9mg,0.48mmol)溶解于1,4-二氧六环(7.0mL)和水(0.7mL)中,氮气置换,100℃搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物5(65.1mg)。
ESI-MS m/z:371[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.07(1H),7.96(1H),7.86(1H),7.82(1H),7.57(1H),6.22(1H),5.73(1H),5.32(1H),4.06–3.94(1H),3.06(1H),2.79(1H)。
实施例6:3-(2,2-二氟-2a-羟基-4-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)-5-氟苯甲腈(化合物6)的制备
合成路线:
将化合物5(15.0mg,0.046mmol)溶解于甲醇(3.0mL)中,加入10%钯碳(1.5mg),在氢气氛围下搅拌1h。LCMS监测反应完全后,过滤,旋干,制备板分离得目标化合物6(2.6mg)。
ESI-MS m/z:374[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.03(1H),7.91(1H),7.83(1H),7.49(1H),7.46(1H),6.03(1H),4.03–3.89(2H),2.34(1H),1.90(1H)。
实施例7:3-(1,1-二氟-8a-羟基-1,2,8,8a-四氢苊-4-基)-5-氟苯甲腈(化合物7)的制备
合成路线:
将中间体1-5(30mg,0.1mmol),3-氰基-5-氟苯硼酸(33.0mg,0.2mmol),1,1-双(二苯基膦)二荗铁二氯化钯(3.7mg,0.005mmol),碳酸钠(21.2mg,0.2mmol)溶解于1,4-二氧六环(3.0mL)和水(0.3mL)中,氮气置换,100℃搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物7(30.9mg)。
ESI-MS m/z:371[M-H+HCO2H]-;1H NMR(500MHz,Acetonitrile-d3)δ7.86–7.84(1H),7.72–7.67(1H),7.53–7.50(1H),7.47(1H),7.40(1H),6.68–6.65(1H),6.18–6.13(1H),3.68(1H),3.62(1H),3.32(1H),2.79(1H),2.63(1H)。
实施例8:3-(1,1-二氟-8a-羟基-1,2,6,7,8,8a-六氢苊-4-基)-5-氟苯甲腈(化合物8)的制备
合成路线:
将化合物7(10.0mg,0.031mmol)溶解于甲醇(3.0mL)中,加入10%钯碳(1.0mg),在氢气氛围下搅拌1h。LCMS监测反应完全后,过滤,旋干,制备板分离得目标化合物8(11.0mg)。
ESI-MS m/z:374[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.03(1H),7.91(1H),7.83(1H),7.53(1H),7.47(1H),5.70(1H),3.68(1H),3.17(1H),2.88(1H),2.68–2.59(1H),2.23–2.12(1H),1.91(2H),1.70–1.62(1H)。
实施例9:3-氟-5-(2,2,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物9)的制备
合成路线:
步骤a:中间体3-(2,2-二氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)-5-氟苯甲腈(9-1)的制备
将中间体1-6(100mg,0.35mmol),3-氰基-5-氟苯硼酸(115.5mg,0.70mmol),1,1-双(二苯基膦)二荗铁二氯化钯(13.2mg,0.018mmol),碳酸钠(74.2mg,0.70mmol)溶解于1,4-二氧六环(5mL)和水(0.5mL)中,氮气置换,100℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物9-1(122.3mg)。
ESI-MS m/z:374[M-H+HCO2H]-。
步骤b:中间体6-(3-氰基-5-氟苯基)-2,2-二氟-4-氧代-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(9-2)的制备
将中间体9-1(120mg,0.36mmol)溶解于无水二氯甲烷(10mL)中,加入4-二甲氨基吡啶(4.4mg,0.036mmol)和三乙胺(91.1mg,0.9mmol),冷却至0℃,加入乙酸酐(73.5mg,0.72mmol),恢复至室温反应2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物9-2(120mg)。
步骤c:中间体6-(3-氰基-5-氟苯基)-2,2,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(9-3)的制备
将中间体9-2(20.0mg,0.05mmol)溶解于无水二氯甲烷(0.1mL)中,加入二乙胺基三氟化硫(241.8mg,1.5mmol),80℃搅拌5h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物9-3(21.4mg)。
1H NMR(500MHz,DMSO-d6)δ8.15(1H),8.04(1H),8.01(1H),7.95(1H),7.92(1H),4.13(1H),3.56(1H),3.47(1H),3.11(1H).
步骤d:3-氟-5-(2,2,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物9)的制备
将中间体9-3(18.0mg,0.05mmol)溶解于四氢呋喃(3mL)和水(0.3mL)中,加入氢氧化锂(3.6mg,0.15mmol),室温下搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物9(17.0mg)。
ESI-MS m/z:396[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.12(1H),8.03–7.99(1H),7.91–7.86(3H),6.74(1H),4.01(1H),3.39(1H),2.89–2.77(2H)。
实施例10:3-氟-5-(1,1,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物10)的制备
合成路线:
步骤a:中间体2,4,6-三溴苯甲醛(10-1)的制备
将1,3,5-三溴苯(100.0g,317.7mmol)溶解于无水四氢呋喃(1.0L)中,氮气置换,冷却至-78℃,滴加二异丙基氨基锂(190.0mL,381.2mmol),搅拌0.5h,滴加无水N,N-二甲基甲酰胺(27.9g,381.2mmol),-78℃搅拌2h。TLC监测反应完全后,加入饱和氯化铵淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干得粗品产物10-1(109.8g)。
步骤b:中间体1-(2,4,6-三溴苯基)丁-3-烯-1-醇(10-2)的制备
将中间体10-1(109.8g,317.7mmol)溶解于无水四氢呋喃(1.0L)中,氮气置换,冷却至0℃,滴加烯丙基溴化镁(476.6mL,476.6mmol),0℃搅拌2h。TLC监测反应完全后,加入饱和氯化铵淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物10-2(69.0g)。
步骤c:中间体5,7-二溴-3-亚甲基-2,3-二氢-1H-茚-1-醇(10-3)的制备
将中间体10-2(69.0g,179.3mmol),双三苯基膦二氯化钯(6.3g,9.0mmol)和乙酸钾(52.8g,537.9mmol)溶解于乙腈(700.0mL)中,氮气置换,80℃搅拌4h。TLC监测反应完全后,加入乙酸乙酯稀释,硅藻土过滤,滤液旋干,柱层析分离得产物10-3(19.0g)。
步骤d:中间体5,7-二溴-3-亚甲基-2,3-二氢-1H-茚-1-酮(10-4)的制备
将中间体10-3(14.0g,46.1mmol)溶解于无水二氯甲烷(200.0mL)中,冷却至0℃,加入戴斯-马丁氧化剂(39.1g,92.2mmol),维持0℃搅拌3h。TLC监测反应完全后,硅藻土过滤,二氯甲烷淋洗,滤液旋干,柱层析分离得粗品产物10-4(14.0g)。
步骤e:中间体1-烯丙基-5,7-二溴-3-亚甲基-2,3-二氢-1H-茚-1-醇(10-5)的制备
将中间体10-4(14.0g,46.1mmol),铟粉(10.6g,92.2mmol)和(1S,2R)-2-氨基-1,2-二苯基乙醇(19.7g,92.2mmol)溶解于无水四氢呋喃(150.0mL)中,氮气置换,加入吡啶(7.3g,92.2mmol)和烯丙基溴(11.1g,92.2mmol),室温搅拌2h。TLC监测反应完全后,加入水搅拌1h,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物10-5(6.8g)。
步骤f:中间体6-溴-1,4-二亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(10-6)的制备
将中间体10-5(6.8g,19.8mmol),双三苯基膦二氯化钯(0.7g,1.0mmol)和乙酸钾(5.8g,59.4mmol)溶解于乙腈(70.0mL)中,氮气置换,80℃搅拌4h。TLC监测反应完全后,加入乙酸乙酯稀释,硅藻土过滤,滤液旋干,柱层析分离得产物10-6(2.3g)。
步骤g:中间体3-氟-5-(2a-羟基-1,4-二亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(10-7)的制备
将中间体10-6(300.0mg,1.14mmol),3-氰基-5-氟苯硼酸(376.0mg,2.28mmol),1,1-双(二苯基膦)二荗铁二氯化钯(41.7mg,0.057mmol),碳酸钠(241.7mg,2.28mmol)溶解于1,4-二氧六环(8.0mL)和水(2.0mL)中,氮气置换,100℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物10-7(278.0mg)。
步骤h:中间体6-(3-氰基-5-氟苯基)-1,4-二亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(10-8)的制备
将中间体10-7(278.0mg,0.92mmol),4-二甲氨基吡啶(11.2mg,0.092mmol),三乙胺(232.7mg,2.3mmol)溶解于无水二氯甲烷(5.0mL)中,冷却至0℃,滴加乙酸酐(187.8mg,1.84mmol),0℃搅拌5h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物10-8(233.0mg)。
步骤i:中间体6-(3-氰基-5-氟苯基)-1,4-二氧代-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(10-9)的制备
将中间体10-8(233.0mg,0.67mmol)溶解于二氯甲烷(5.0mL),乙腈(5.0mL)和水(1.0mL)中,加入三氯化钌(13.9mg,0.067mmol),冷却至0℃,加入高碘酸钠(723.3mg,3.35mmol),0℃搅拌3h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物10-9(140.0mg)。
步骤j:中间体6-(3-氰基-5-氟苯基)-1,1,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(10-10)的制备
将中间体10-9(80.0mg,0.23mmol)溶解于无水二氯甲烷(1.0mL)中,加入二乙胺基三氟化硫(3.0g,18.4mmol),80℃搅拌10h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物10-10(34.0mg)。
步骤k:3-氟-5-(1,1,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物10)的制备
将中间体10-10(34.0mg,0.086mmol)溶解于四氢呋喃(2.0mL)和水(0.5mL)中,加入氢氧化锂(4.1mg,0.17mmol),室温下搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物10(20.0mg)。
ESI-MS m/z:396[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.21(1H),8.13(2H),8.09(1H),7.92–7.89(1H),6.18(1H),3.00–2.86(4H)。
实施例11:反式-3-氟-5-(1,2,2,3,3,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物11)和顺式-3-氟-5-(1,2,2,3,3,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物12)的制备
合成路线:
步骤a:中间体6-溴-2a-羟基-2a,3-二氢-1H-环戊[cd]茚-1,4(2H)-二酮(11-1)的制备
将中间体10-6(3.3g,12.5mmol)溶解于二氯甲烷(30.0mL),乙腈(30.0mL)和水(30.0mL)中,加入三氯化钌(269.6mg,1.3mmol),冷却至0℃,加入高碘酸钠(21.6g,100.0mmol),0℃搅拌1h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物11-1(2.1g)。
步骤b:中间体6-溴-1,4-双((3-甲氧基丙基)亚胺基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(11-2)的制备
将中间体11-1(1.0g,3.7mmol),3-甲氧基丙胺(2.6g,29.6mmol)和三氟乙酸(79.8mg,0.7mmol)溶解于甲苯(35.0mL)中,分水器加热回流3h。TLC监测反应完全后,旋干溶剂得粗品产物11-2。
ESI-MS m/z:409[M+H]+。
步骤c:中间体6-溴-2,2,3,3-四氟-2a-羟基-2a,3-二氢-1H-环戊[cd]茚-1,4(2H)-二酮(11-3)的制备
将中间体11-2(3.7mmol),1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(13.1g,37.0mmol)和无水硫酸钠(4.2g,29.6mmol)溶解于无水乙腈(30.0mL)中,氮气置换,80℃搅拌8h。TLC监测反应完全后,室温下加入浓盐酸(3.0mL),搅拌0.5h,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物11-3(465.0mg)。
步骤d:中间体6-溴-2,2,3,3-四氟-1,4-二氧代-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基苯甲酸酯(11-4)的制备
将中间体11-3(250.0mg,0.74mmol),三乙胺(303.6mg,3.0mmol)溶解于无水二氯甲烷(10.0mL)中,冷却至0℃,加入苯甲酰氯(267.1mg,1.9mmol),维持0℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物11-4(354.0mg)。
步骤e:中间体6-溴-2,2,3,3-四氟-1,4-二羟基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基苯甲酸酯(11-5)的制备
将中间体11-4(354.0mg,0.74mmol)溶解于甲醇(10.0mL)中,冷却至0℃,加入硼氢化钠(42.0mg,1.11mmol),0℃搅拌3h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物11-5(208.0mg)。
ESI-MS m/z:491[M-H+HCO2H]-;1H NMR(500MHz,Acetonitrile-d3)δ8.03(1H),8.02(1H),7.71–7.67(1H),7.56–7.51(4H),5.96–5.90(2H),4.48(2H).
步骤f:中间体顺式-6-溴-1,2,2,3,3-五氟-4-羟基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基苯甲酸酯(11-6)和中间体反式-6-溴-1,2,2,3,3-五氟-4-羟基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基苯甲酸酯(11-7)的制备
将中间体11-5(137.0g,0.31mmol)溶解于无水二氯甲烷(5.0mL)中,加入二乙胺基三氟化硫(499.7mg,3.1mmol),40℃搅拌1.5h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物11-6(30.0mg)和11-7(15.0mg)。
步骤g:中间体反式-6-溴-1,2,2,3,3,4-六氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基苯甲酸酯(11-8)的制备
将中间体11-6(30.0mg,0.067mmol)溶解于无水二氯甲烷(2.0mL)中,加入二乙胺基三氟化硫(108.0mg,0.67mmol),80℃搅拌2h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物11-8(17.0mg)。
步骤h:中间体反式-6-(3-氰基-5-氟苯基)-1,2,2,3,3,4-六氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基苯甲酸酯(11-9)的制备
将中间体11-8(17.0mg,0.038mmol),3-氰基-5-氟苯硼酸(12.5mg,0.076mmol),1,1-双(二苯基膦)二荗铁二氯化钯(1.4mg,0.0019mmol),碳酸钠(8.1mg,0.076mmol)溶解于1,4-二氧六环(1.0mL)和水(0.1mL)中,氮气置换,100℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物11-9(16.1mg)。
步骤i:反式-3-氟-5-(1,2,2,3,3,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物11)的制备
将中间体11-9(16.1mg,0.033mmol)溶解于甲醇(3.0mL),加入4M氢氧化钠溶液(0.08mL,0.33mmol),室温搅拌1.5h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备液相分离得目标化合物11(1.8mg)。
ESI-MS m/z:432[M-H+HCO2H]-;1H NMR(500MHz,Acetonitrile-d3)δ8.12(2H),7.89(1H),7.74(1H),7.61(1H),6.01–5.98(1H),5.91–5.87(1H),5.41(1H)。
步骤j:中间体顺式-6-溴-1,2,2,3,3,4-六氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基苯甲酸酯(11-10)的制备
将中间体11-7(15.0mg,0.033mmol)溶解于无水二氯甲烷(1.0mL)中,加入二乙胺基三氟化硫(53.2mg,0.33mmol),80℃搅拌2h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物11-10(15.0mg)。
步骤k:顺式-3-氟-5-(1,2,2,3,3,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物12)的制备
将中间体11-10(15.0mg,0.033mmol),3-氰基-5-氟苯硼酸(10.9mg,0.066mmol),1,1-双(二苯基膦)二荗铁二氯化钯(1.2mg,0.0017mmol),碳酸钠(7.0mg,0.066mmol)溶解于1,4-二氧六环(1.0mL)和水(0.1mL)中,氮气置换,100℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物12(25.2mg)。
ESI-MS m/z:432[M-H+HCO2H]-;1H NMR(500MHz,Acetonitrile-d3)δ7.91(1H),7.82(1H),7.79(1H),7.78–7.75(1H),7.61(1H),6.69(1H),5.92(1H),4.74(1H)。
实施例12:3-氟-5-(1,2,2,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物13)的制备
合成路线:
步骤a:中间体6-(3-氰基-5-氟苯基)-2,2,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(13-1)的制备
将中间体9-2(100.0mg,0.27mmol)溶解于无水二氯甲烷(0.5mL)中,加入二乙胺基三氟化硫(1.3g,8.1mmol),80℃搅拌5h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物13-1(89.7mg)。
步骤b:中间体1-溴-6-(3-氰基-5-氟苯基)-2,2,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(13-2)的制备
将中间体13-1(60mg,0.15mmol),N-溴代丁二酰亚胺(101.5mg,0.75mmol),偶氮二异丁腈(24.6mg,0.15mmol)溶解于四氯化碳(3.0mL)中,氮气置换,80℃搅拌48h。TLC监测反应完全后,,二氯甲烷萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物13-2(48.0mg)。
1H NMR(500MHz,DMSO-d6)δ8.22–8.20(2H),8.18(1H),8.09(1H),7.95(1H),6.02(1H),3.53(1H),3.18(1H),2.14(3H).
步骤c:中间体6-(3-氰基-5-氟苯基)-2,2,4,4-四氟-1-羟基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(13-3)的制备
将中间体13-2(40mg,0.085mmol),高碘酸钠(36.7mg,0.17mmol)溶解于无水N,N-二甲基甲酰胺(2.0mL)中,150℃搅拌48h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物13-3(10.0mg)。
步骤d:中间体6-(3-氰基-5-氟苯基)-1,2,2,4,4-五氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(13-4)的制备
将中间体13-3(8.0mg,0.02mmol)溶解于无水二氯甲烷(1.0mL)中,冷却至-78℃,加入二乙胺基三氟化硫(6.4mg,0.04mmol),-78℃搅拌1h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得产物13-4(6.9mg)。
步骤e:3-氟-5-(1,2,2,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)苯甲腈(化合物13)的制备
将中间体13-4(6.9mg,0.017mmol)溶解于四氢呋喃(2mL)和水(0.5mL)中,加入氢氧化锂(0.8mg,0.034mmol),室温下搅拌2h。TLC显示反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物13(4.0mg)。
ESI-MS m/z:414[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.18(1H),8.10–8.05(2H),7.95–7.92(2H),6.96(1H),5.95(1H),3.27–3.08(2H)。
实施例13:2,2,4,4-四氟-6-(5-氟-1H-吲唑-1-基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(化合物14)的制备
合成路线:
步骤a:中间体6-溴-2,2-二氟-4-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(14-1)的制备
将中间体1-4(8.3g,28.91mmol)溶解于无水二氯甲烷(80.0mL)中,加入4-二甲氨基吡啶(0.3g,2.89mmol)和三乙胺(7.3g,72.28mmol),冷却至0℃,滴加乙酸酐(5.9g,57.82mmol),室温搅拌12h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物14-1(8.6g)。
步骤b:中间体6-溴-2,2-二氟-4-氧代-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(14-2)的制备
将中间体14-1(2.0g,6.08mmol)和三氯化钌(126.5mg,0.61mmol)溶解于二氯甲烷(10.0mL),乙腈(10.0mL)和水(10.0mL)中,冷却至0℃,加入高碘酸钠(6.6g,30.40mmol),维持0℃搅拌1h。TLC监测反应完全后,加入水,二氯甲烷萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物14-2(1.4g)。
步骤c:中间体6-溴-2,2,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基乙酸酯(14-3)的制备
将中间体14-2(1.4g,4.23mmol)溶解于无水二氯甲烷(1.0mL)中,加入二乙胺基三氟化硫(27.3g,169.20mmol),80℃搅拌10h。TLC监测反应完全后,将反应液滴至饱和碳酸氢钠中淬灭,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物14-3(930.0mg)。
步骤d:中间体6-溴-2,2,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(14-4)的制备
将中间体14-3(557.0mg,1.58mmol)溶解于四氢呋喃(10.0mL)和水(2.0mL)中,加入氢氧化锂(113.5mg,4.74mmol),室温搅拌过夜。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得产物14-4(393.0mg)。
ESI-MS m/z:355[M-H+HCO2H]-。
步骤e:2,2,4,4-四氟-6-(5-氟-1H-吲唑-1-基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(化合物14)的制备
将中间体14-4(80.0mg,0.26mmol),5-氟吲唑(53.1mg,0.39mmol),三(二亚苄基丙酮)二钯(23.8mg,0.026mmol),2-二-叔丁膦基-2',4',6'-三异丙基联苯(22.1mg,0.052mmol)和叔丁醇钾(58.3mg,0.52mmol)溶解于甲苯(5.0mL)中,氮气置换,120℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,柱层析分离得目标化合物14(40.0mg)。
ESI-MS m/z:408[M+H+MeCN]+;1H NMR(500MHz,DMSO-d6)δ8.42(1H),7.91–7.87(2H),7.81(1H),7.71(1H),7.42(1H),6.78(1H),4.04(1H),3.48(1H),2.95–2.80(2H)。
实施例14:1-(2,2,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-6-基)-1H-吲唑-6-甲腈(化合物15)的制备
合成路线:
将中间体14-4(50.0mg,0.16mmol),6-氰基吲唑(34.4mg,0.24mmol),三(二亚苄基丙酮)二钯(14.7mg,0.016mmol),2-二-叔丁膦基-2',4',6'-三异丙基联苯(13.6mg,0.032mmol)和叔丁醇钾(35.9mg,0.32mmol)溶解于甲苯(3.0mL)中,氮气置换,120℃搅拌5h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物15(35.0mg)。
ESI-MS m/z:418[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.61(1H),8.51(1H),8.12(1H),7.94(1H),7.88(1H),7.65(1H),6.79(1H),4.05(1H),3.50(1H),2.95–2.81(2H)。
实施例15:2,2,4,4-四氟-6-(5-氟-1H-吲哚-1-基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(化合物16)的制备
合成路线:
将中间体14-4(50.0mg,0.16mmol),5-氟吲唑(32.4mg,0.24mmol),三(二亚苄基丙酮)二钯(23.8mg,0.016mmol),2-二环己基磷-2',4',6'-三异丙基联苯(24.8mg,0.052mmol)和叔丁醇钾(58.3mg,0.52mmol)溶解于甲苯(3.0mL)中,氮气置换,120℃搅拌3h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备液相分离得目标化合物16(15.0mg)。
ESI-MS m/z:410[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ7.80(1H),7.70(1H),7.67(1H),7.53(1H),7.44(1H),7.06(1H),6.76(1H),6.72(1H),4.03(1H),3.45(1H),2.95–2.79(2H)。
实施例16:2,2,4,4-四氟-6-(6-氟-1H-吲哚-1-基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(化合物17)的制备
合成路线:
将中间体14-4(20.0mg,0.064mmol),6-氟吲哚(13.0mg,0.096mmol),三(二亚苄基丙酮)二钯(5.9mg,0.0064mmol),2-二环己基磷-2',4',6'-三异丙基联苯(6.2mg,0.013mmol)和叔丁醇钾(14.6mg,0.13mmol)溶解于甲苯(1.0mL)中,氮气置换,100℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备液相分离得目标化合物17(3.0mg)。
ESI-MS m/z:410[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ7.73(1H),7.71(1H),7.69–7.65(2H),7.33(1H),7.05–7.00(1H),6.76(1H),6.75–6.74(1H),4.03(1H),3.46(1H),2.94–2.80(2H)。
实施例17:6-(1H-苯并[d]咪唑-1-基)-2,2,4,4-四氟-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(化合物18)的制备
合成路线:
将中间体14-4(55.0mg,0.18mmol),苯并咪唑(31.9mg,0.27mmol),三(二亚苄基丙酮)二钯(16.5mg,0.018mmol),2-二叔丁基磷-3,4,5,6-四甲基-2',4',6'-三异丙基联苯(17.3mg,0.036mmol)和磷酸三钾(76.4mg,0.36mmol)溶解于甲苯(5.0mL)中,氮气置换,120℃搅拌2h。TLC监测反应完全后,加入水,乙酸乙酯萃取,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干,制备板分离得目标化合物18(24.2mg)。
ESI-MS m/z:393[M-H+HCO2H]-;1H NMR(500MHz,DMSO-d6)δ8.54(1H),7.76–7.70(3H),7.56–7.54(1H),7.27(2H),6.74(1H),3.99(1H),3.41(1H),2.89–2.74(2H)。
生物学检测
用Hep3B细胞检测各化合物的EPO抑制率
以5×104/mL在板中铺上Hep3B细胞(中国科学院细胞库,TCHu106),于37℃,5%二氧化碳培养箱(Thermo Scientific BB150)中过夜。第二天将培养基更换为含0.5% FBS的培养基(VivaCell C04001-500)使细胞饥饿6小时,之后添加(6’-羟基-3’-(4-甲氧基苯基)-8’-氧代-8’H-螺[环戊烷-1,5’-吲嗪]-7’-羰基)甘氨酸或其类似物的DMSO溶液使其终浓度为30μM,将板继续置于37℃,5%二氧化碳培养箱中作用24小时后,再加入待测化合物的DMSO溶液使化合物终浓度分别为30000nM,7500nM,1875nM,469nM,117nM,29nM,7.3nM,1.8nM,0.5nM,0nM共10个浓度,持续作用48小时,收集细胞上清液用于EPO ELISA检测,按ELISA试剂盒(生工生物工程(上海)股份有限公司,D711311-0096)说明书步骤进行检测操作,于波长450nm(酶标仪,Thermo Scientific(Multiskan Go),511191200)处读取数值。化合物抑制率计算公式:化合物抑制率=1-100%*(给药孔EPO值-空白孔EPO值)/(Control孔EPO值-空白孔EPO值)。将抑制率进行线性拟合计算IC50值。其中Control孔:待测化合物浓度为0nM且终浓度为30μM(6’-羟基-3’-(4-甲氧基苯基)-8’-氧代-8’H-螺[环戊烷-1,5’-吲嗪]-7’-羰基)或类似物的DMSO溶液作用72h的含细胞的孔,以该孔EPO含量为100%;空白孔:不添加任何化合物的含细胞的孔。
某些实施例的IC50数据提供于表1中,其中,A表示IC50≤1μM,B表示1μM<IC50≤5μM,C表示IC50>5μM。
表1
实施例编号 | IC50(μM) | 实施例编号 | IC50(μM) |
实施例1 | B | 实施例10 | C |
实施例2 | B | 实施例11 | B |
实施例3 | B | 实施例12 | C |
实施例4 | A | 实施例13 | C |
实施例5 | B | 实施例14 | B |
实施例6 | C | 实施例15 | C |
实施例7 | C | 实施例16 | C |
实施例8 | A | 实施例17 | C |
实施例9 | B | 实施例18 | C |
测试的各实施例化合物对于EPO显示出优异的抑制活性。
虽然已经阐明并描述了本发明的特定实施方式,但并不意味着这些实施方式阐明了并描述了本发明的所有可能形式。更确切地,用在本说明书中的文字仅仅是描述性的文字并非限制性的。对于本领域技术人员明显的是,在不脱离本公开的一般范围的情况下,可以进行各种其他改变和修改。因此,在所附权利要求中,旨在包括在本发明范围内的所有这些改变和修改。
Claims (16)
1.一种式(I)所示的化合物:
其中,
环A选自C5-C6环烷基或C5-C6环烯基,所述C5-C6环烷基或C5-C6环烯基任选被1、2、3或4个R取代,
环B选自C5-C6芳基或C5-C10苯并杂芳基,所述C5-C6芳基或C5-C10苯并杂芳基任选被1、2或3个R取代,并且所述C5-C10苯并杂芳基任意地含有1或2个N杂原子,
R1、R2、R3、R4分别独立地选自氢或卤素,
R5选自氢、卤素或羟基,
R各自独立地选自氢、卤素、C1-C3烷基、或氰基,或者R中的两个与其直接相连的碳原子共同形成环外烯基,或
其药学上可接受的盐。
2.根据权利要求1所述的化合物或其药学上可接受盐,其特征在于,所述R5为卤素或羟基。
3.根据权利要求1所述的化合物,或药学上可接受的盐,其特征在于,所述化合物如式(II)所示,
其中,环B、R1、R2、R3、R4和R5如上所定义;
R6和R7分别独立地选自氢或卤素;
R8、R9分别独立地选自氢、卤素或C1-C3烷基,或者R8和R9与其直接相连的碳原子共同形成环外烯基。
4.根据权利要求3所述的化合物,或药学上可接受的盐,其特征在于,所述R1、R2、R3、R4分别独立地为H或F。
5.根据权利要求3所述的化合物,或药学上可接受的盐,其特征在于,所述R5为F或OH。
6.根据权利要求3所述的化合物,或药学上可接受的盐,其特征在于,所述R6、R7各自独立地为H,F或甲基。
7.根据权利要求3所述的化合物,或药学上可接受的盐,其特征在于,R8、R9分别独立地为H,F或甲基,或者R8和R9与其直接相连的碳原子共同形成环外乙烯基。
8.根据权利要求1-7中任意一项所述的化合物,或药学上可接受的盐,其特征在于,所述化合物如式(Ⅱ-1)或式(Ⅱ-2)所示,
其中,R1-R9如上所定义;
R10、R11、R12分别独立地选自氢、卤素或氰基;并且
X、Y、Z分别独立地为C或N。
9.根据权利要求8所述的化合物,或药学上可接受的盐,其特征在于,R10、R11、R12为H、F或CN。
10.根据权利要求1所述的化合物,或其药学上可接受的盐,其特征在于,所述化合物如式(Ⅲ)所示,
其中,为/>
R1-R5如上所定义;并且
R6和R7分别独立地选自氢或卤素;
R10、R11、R12分别独立地选自氢、卤素或氰基。
11.根据权利要求10所述的化合物,或药学上可接受的盐,其特征在于,所述R6、R7分别独立地为H。
12.根据权利要求10所述的化合物,或其药学上可接受的盐,其特征在于,R10、R11、R12各自独立地为H、F或CN。
13.根据权利要求1所述的化合物,或其药学上可接受的盐,其特征在于,所述化合物选自,
14.一种药物组合物,其包含根据权利要求1-13中任一项所述的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体、佐剂或赋形剂。
15.根据权利要求1-13中任一项所述的化合物或其药学上可接受的盐或者根据权利要求14所述的药物组合物在制备用于治疗与EPO相关的疾病或病症的药物中的用途。
16.根据权利要求15所述的用途,其中所述与EPO相关的疾病和病症选自:红细胞增多症、肾细胞癌、膀胱癌、乳腺癌、子***、结肠直肠癌、小肠癌、结肠癌、直肠癌、***癌、子宫内膜癌、头颈癌、肝癌、肺癌、卵巢癌、***癌、睾丸癌、子宫癌、食管癌、胆囊癌、胰腺癌、甲状腺癌、副甲状腺癌、皮肤癌以及脑癌。
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