CN116425670A - 作为tead抑制剂的新型杂环化合物 - Google Patents
作为tead抑制剂的新型杂环化合物 Download PDFInfo
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- CN116425670A CN116425670A CN202211209538.4A CN202211209538A CN116425670A CN 116425670 A CN116425670 A CN 116425670A CN 202211209538 A CN202211209538 A CN 202211209538A CN 116425670 A CN116425670 A CN 116425670A
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明提供了式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中环A、Y、Z1、Z2、Z3、R1和R2如本文所述,其可用作TEAD抑制剂,还提供了包含其的药物组合物及其在治疗TEAD相关疾病或病状例如癌症中的用途。
Description
相关申请的交叉引用
本申请要求于2022年7月15日提交的国际申请号为PCT/CN2022/106073,发明名称为“NOVEL HETEROCYCLIC COMPOUNDS AS TEAD INHIBITORS”的国际申请的优先权,在此通过引用将其全文并入本文。
技术领域
本发明涉及可用作TEAD抑制剂的新型杂环化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体。本发明还涉及包含一种或更多种此类化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体作为活性成分的药物组合物,以及此类化合物或其药学上可接受的盐、溶剂化物、立体异构体或其同位素变体在治疗TEAD相关疾病或病状(例如癌症)中的用途。
背景技术
近年来,Hippo通路已成为治疗过度增殖性病症和疾病,特别是癌症的目的靶标(S.A.Smith等人,J.Med.Chem.2019,62,1291-1305;K.C.Lin等人,Annu.Rev.CancerBiol.2018,2:59-79;C.-L.Kim等人,Cells(2019),8,468;K.F.Harvey等人,NatureReviews Cancer,Vol.13,246-257(2013))。Hippo通路调节细胞生长、增殖和迁移。据推测,在哺乳动物中,Hippo通路充当肿瘤抑制因子,并且在人癌症中经常观察到Hippo信号传导功能障碍。
由于Hippo通路在多种生物过程中发挥作用——如在干细胞和祖细胞的自我更新和分化、伤口愈合和组织再生、与其他信号传导通路(例如Wnt)的相互作用——其功能障碍也可能在人癌症以外的疾病中发挥作用(C.-L.Kim等人,Cells(2019),8,468;Y.Xiao等人,Genes&Development(2019)33:1491-1505;K.F.Harvey等人,Nature Reviews Cancer,Vol.13,246-257(2013))。
虽然通路活性和调控的几个方面仍有待进一步研究,已经确定在其“开启”状态下,Hippo通路涉及细胞质中的一系列激酶(包括Mst 1/2和Lats 1/2),导致两种转录共激活因子YAP的磷酸化(Yes相关蛋白)和TAZ(具有PDZ结合基序的转录共激活剂)。YAP/TAZ的磷酸化导致它们被隔离在细胞质中并最终导致它们的降解。相反,当Hippo通路“关闭”或功能障碍时,非磷酸化、激活的YAP/TAZ共激活剂被转移到细胞核中。它们的主要靶转录因子是转录增强相关结构域(TEAD)转录因子家族(TEAD1-4)的四种蛋白质。YAP或TAZ与TEAD(或其他转录因子)的结合和激活已显示诱导几种基因表达,其中许多基因介导细胞存活和增殖。因此,激活的、非磷酸化的YAP和TAZ可能充当癌基因,而激活的、开启的Hippo通路可能通过失活,即磷酸化YAP和TAZ来充当肿瘤抑制因子。
此外,Hippo通路还可能在癌细胞对肿瘤学和免疫肿瘤学治疗的耐药机制中发挥作用(R.Reggiani等人,Biochimica et Biophysica Acta(BBA)-Reviews on Cancer 1873(2020)188341,1-11)。
因此,Hippo通路作为肿瘤抑制因子的功能障碍或异常调节被认为是多种癌症类型和疾病发展中发挥着重要的作用。
因此,通过药物干预抑制YAP、TAZ、TEAD和YAP-TEAD或TAZ-TEAD蛋白质-蛋白质相互作用可作为一种潜在的、合理且有价值的策略来预防和/或治疗癌症和其他过度增殖性疾病和Hippo通路功能障碍相关的疾病的。
发明内容
本文公开了作为TEAD抑制剂的新型杂环化合物。因此,本发明的化合物特别适用于调节YAP-TEAD或TAZ-TEAD蛋白质-蛋白质相互作用,并因此可用于治疗TEAD相关疾病和病状,例如癌症。
在一方面,本发明涉及一种式(I)的化合物
或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中环A、Y、Z1、Z2、Z3、R1和R2如本文所述。
在另一方面,本发明涉及一种药物组合物,该药物组合物包含如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,以及药学上可接受的载体或辅料。
在还一方面,本发明涉及一种治疗有需要的受试者的TEAD相关疾病或病状例如癌症的方法,该方法包括向受试者施用治疗有效量的如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体。
在还一方面,本发明涉及如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体用于治疗TEAD相关疾病或病状,例如癌症。
在还一方面,本发明涉及如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体在制备用于治疗TEAD相关疾病或病状例如癌症的药物中的用途。
在还一方面,本发明涉及用于治疗TEAD相关疾病或病状例如癌症的试剂盒,该试剂盒包含:如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,或包含如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体和药学上可接受的载体或辅料的药物组合物,容器和任选的指示治疗的包装插页或标签。
具体实施方式
现在将详述某些实施方案,其实例在随附的具体实施方式中说明。虽然将描述列举的实施方案,但应理解它们并非旨在将本发明限制于这些实施方案。相反,本发明旨在涵盖所有可选方案、修改和等同方案,它们可以包括在由权利要求限定的本发明的范围内。本领域技术人员将认识到许多与本文所述的方法和材料相似或等同的方法和材料,它们可用于本发明的实践。本发明决不限于所描述的方法和材料。如果一个或更多个并入的文献和类似材料与本公开不同或相矛盾,包括但不限于定义的术语、术语用法、描述的技术等,以本公开为准。
可以理解,本发明的某些特征,为了清楚,在单独实施方案的背景下进行描述,也可以在单个实施方案中组合提供。相反,为了简洁,在单个实施方案的背景下描述的本发明的各种特征也可以单独提供或以任何合适的子组合提供。
本文提供以下内容。
项1.一种式(I)的化合物
或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
环A是6元芳环、6元杂芳环或吡啶-2-酮环,该环任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基、C3-10环烷基或-(CH2)n-RA组成的组的一个或更多个取代基取代;其中所述烷基、所述烷氧基和所述环烷基任选地还被一个或更多个卤素取代,RA是任选地被选自由卤素、C1-10烷基和C1-10烷氧基组成的组的一个或更多个取代基取代的苯基,并且n为0、1或2;
Y是CRY或N;
Z1、Z2和Z3各自独立地是C(RZ)2;
RY是H或C1-6烷基,其任选地被一个或更多个卤素取代;
RZ在每次出现时独立地是H、卤素或C1-10烷基,或两个RZ,连同它们所附接的相同碳原子一起,组合形成C3-10环烷烃环,该环任选地被选自由卤素、C1-10烷基和C1-10烷氧基组成的组的一个或更多个取代基取代;
R1是6元至10元芳基、5元至10元杂芳基、或3元至10元单环或双环环烷基或杂环基,其中所述芳基、所述杂芳基、所述环烷基和所述杂环基任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基和C3-10环烷基组成的组的一个或更多个取代基取代,其中所述C1-10烷基、C1-10烷氧基和C3-10环烷基任选地还被一个或更多个卤素取代,并且其中所述杂芳基和所述杂环基含有选自由N、O和S组成的组的至少一个杂原子环成员;
R2是-C(=O)R2A、-C(=O)OR2A、-C(=O)N(R2A)2、-NR2AC(=O)R2A、-NR2AS(=O)R2A、-NR2AS(=O)2R2A、-S(=O)R2A、-S(=O)2R2A、-S(=O)2OR2A或-S(=O)2N(R2A)2;
R2A在每次出现时独立地是H、C1-10烷基、C2-10烯基、C2-10炔基或-L-R2AA,其中所述烷基、所述烯基和所述炔基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;或两个R2A,连同它们所附接的氮原子,组合形成3元至10元杂环基,其任选地含有选自由N、O和S组成的组的一个另外的杂原子环成员,其中所述杂环基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;
L不存在或是任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代的C1-10烷基;以及
R2AA是C3-10环烷基、3元至10元杂环基、6元至10元芳基或5元至10元杂芳基,其中所述环烷基、所述杂环基、所述芳基和所述杂芳基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;
条件是排除以下化合物:
2-(甲基磺酰基)-5-苯基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚,
2-(乙基磺酰基)-6-氟-5-(2-氟苯基)-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚,
8-氟-5-(4-氟苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-羧酸甲酯,
8-氯-5-(4-氯苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-羧酸乙酯,和
8-甲氧基-5-(4-甲氧基苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-羧酸乙酯。
项2.根据项1的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
环A是苯、吡啶或吡啶-2-酮环,该环任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基、C3-10环烷基或-(CH2)n-RA组成的组的一个或更多个取代基取代;其中所述烷基、所述烷氧基和所述环烷基任选地还被一个或更多个卤素取代,RA是任选地被选自由卤素、C1-10烷基和C1-10烷氧基组成的组的一个或更多个取代基取代的苯基,并且n为0、1或2。
项3.根据项2的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
环A是
RX在每次出现时独立地是卤素、CN、C1-10烷基或C1-10烷氧基;
m为0、1、2、3或4。
项4.根据项3的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
环A是
项5.根据前述项中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
Y是CH、CCH3或N;
Z1、Z2和Z3各自独立地是C(RZ)2;以及
RZ在每次出现时独立地是H或C1-10烷基,或两个RZ,连同它们所附接的相同碳原子一起,组合形成环丙烷环。
项6.根据前述项中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
R1是苯基、吡啶基或5元至10元单环或双环环烷基或杂环基,其中所述苯基、所述吡啶基、所述环烷基和所述杂环基任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基和C3-10环烷基组成的组的一个、两个或三个取代基取代,其中所述C1-10烷基、C1-10烷氧基和C3-10环烷基任选地还被一个、两个或三个卤素取代,并且其中所述杂环基含有选自由N、O和S组成的组的一个或两个杂原子环成员。
项7.根据项6的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
R1是
项8.根据项7的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
R1是
项9.根据前述项中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
R2是-C(=O)R2A、-C(=O)OH、-C(=O)OR2A、-C(=O)NHR2A、-C(=O)N(R2A)2、-
NHC(=O)R2A、-S(=O)2R2A、-S(=O)2NHR2A或-S(=O)2N(R2A)2;
R2A在每次出现时独立地是C1-10烷基、C2-10烯基、C2-10炔基或-L-R2AA,其中所述烷基、所述烯基和所述炔基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;
L不存在或是C1-10烷基;以及
R2AA是C3-10环烷基、3元至10元杂环基、6元至10元芳基或5元至10元杂芳基,其中所述环烷基、所述杂环基、所述芳基和所述杂芳基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代。
项10.根据前述项中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
R2是
项11.根据项1的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中所述式(I)的化合物具有下式表示的结构:
项12.一种药物组合物,所述药物组合物包含根据项1至11中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,以及药学上可接受的载体或辅料。
项13.一种治疗有需要的受试者的癌症的方法,所述方法包括向受试者施用治疗有效量的根据项1至11中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体。
项14.根据项13的方法,其中所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
项15.根据项1至11中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体用于治疗癌症。
项16.根据项15的用于治疗癌症的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
项17.根据项1至11中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体在制备用于治疗癌症的药物中的用途。
项18.根据项17的用途,其中所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
项19.一种用于治疗癌症的试剂盒,所述试剂盒包括
根据项1至11中任一项的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,或根据项12的药物组合物;
容器;和
任选的指示治疗的包装插页或标签。
项20.根据项19的试剂盒,其中所所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
定义
本文使用但未定义的术语具有其通常含义,并且此类术语的含义在其每次出现时均是独立的。然而,除非另有说明,否则以下定义适用于整个说明书和权利要求。
如本文所用,除非另有明确说明,否则单数形式“a”、“an”和“the”包括复数指代对象。
如本文所用,术语“包含”和“包括”旨在指定存在所述特征、整体、组件或步骤,但它们不排除存在或添加一个或更多个其他特征、整体、组件、步骤或它们的组。
下文更详细地描述了特定官能团和化学术语的定义。出于本发明的目的,化学元素根据元素周期表,CAS版,化学和物理手册,第75版,内封面进行鉴定,并且特定官能团通常如其中所述定义。此外,有机化学的一般原理以及特定官能部分和反应性描述于OrganicChemistry,Thomas Sorrell,University Science Books,Sausalito,1999;Smith和March,March’s Advanced Organic Chemistry,第5版,John Wiley&Sons,Inc.,New York,2001;Larock,Comprehensive Organic Transformations,VCH Publishers,Inc.,NewYork,1989;Carruthers,Some Modem Methods of Organic Synthesis,第3版,CambridgeUniversity Press,Cambridge,1987。
除非另有明确说明,否则包含本文引用的所有范围。
当列出一系列值时,旨在涵盖该范围内的每个值和子范围。例如,“C1-6”旨在涵盖C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6。
当任何变量在任何成分中或在式(I)中或在描绘和描述本发明的化合物的任何其他式中出现多于一次时,它在每次出现时的定义均独立于它在每隔一次出现时的定义。此外,仅当此类组合产生稳定的化合物时,才允许使用取代基和/或变量的组合。
如本文所用,术语“烷基”是指直链或支链饱和烃基。术语“Ci-j烷基”是指具有i至j个碳原子的烷基。除非另有说明,否则烷基可以含有1至10个碳原子。在某些实施方案中,烷基含有1至6个碳原子,例如1至5个碳原子、1至4个碳原子、1至3个碳原子或1至2个碳原子。烷基的非限制性实例包括甲基、乙基、正丙基和异丙基、正丁基、仲丁基、异丁基和叔丁基、新戊基等。如本文所用,术语“亚烷基”是指二价取代基,其是具有一个氢原子被化合价取代的一价烷基。
如本文所用,术语“烯基”是指具有至少一个碳-碳双键的直链或支链烃基,并且包括具有“顺式”和“反式”取向的基团,或可选地,“E”和“Z”方向。除非另有说明,否则烯基可以含有2至10个碳原子。在某些实施方案中,烯基可以含有2至6个碳原子,例如2至5个碳原子、2至4个碳原子、2至3个碳原子。在某些实施方案中,烯基基团含有2个碳原子。烯基的非限制性实例包括亚乙基(乙烯基)、丙烯基、丁烯基、戊烯基、1-甲基-2-丁烯-1-基、5-己烯基等。
如本文所用,术语“炔基”是指具有至少一个碳-碳三键的直链或支链烃基。除非另有说明,否则炔基可以含有2至10个碳原子。在某些实施方案中,炔基基团含有2至8个碳原子、2至6个碳原子、2至4个碳原子、2至3个碳原子。在某些实施方案中,炔基基团含有2个碳原子。炔基的非限制性实例包括乙炔基、1-丙炔基、2-丙炔基等。
如本文所用,术语“烷氧基”是指基团-O-烷基,其中烷基具有如本文所定义的含义。
如本文所用,术语“环烷基”是指非芳族、饱和单环和多环环系统,其中所有成环原子均是碳。除非另有说明,否则环烷基基团可以含有3至10个成环碳原子(即C3-10环烷基)。在某些实施方案中,环烷基基团可以包含3至9个、3至8个、3至7个、3至6个、4至10个、4至9个、4至8个、4至7个、4至6个、4至5个、5至10个、5至9个、5至8个、5至7个、5至6个成环碳原子等。特别地,环烷基可以是单环或双环的。可选地,双环环烷基基团可以包括稠合、螺环和桥接环烷基结构。
在另一方面,还包括其中1、2或3个杂原子替换成环碳原子的环烷基环。此类基团被称为“杂环基”或“杂环”,其是指如上定义但带有选自N、O和S的至少一个杂原子作为成环原子的环烷基基团。除非另有说明,否则杂环基基团可以含有3至10个成环原子(即3至10元杂环基)。在某些实施方案中,杂环基基团可以含有3至9个、3至8个、3至7个、3至6个、4至10个、4至9个、4至8个、4至7个、4至6个、4至5个、5至10个、5至9个、5至8个、5至7个、5至6个成环原子等。特别地,杂环基基团可以是单环或双环的。可选地,双环杂环基基团可以包括稠合、螺环和桥接杂环基结构。杂环基基团的非限制性实例包括环氧乙烷基、吡咯烷基、哌啶基、四氢吡喃基、哌嗪基、吡咯烷基和吗啉基。杂环基基团还可以通过使用碳数来描述。例如,C3-6杂环基是指含有三至六个成环碳原子的杂环基基团,还可以含有至少一个杂原子,例如1、2或3个杂原子作为成环原子。在某些实施方案中,杂环基基团或杂环含有1或2个杂原子作为成环原子。在某些实施方案中,杂环基基团可以是单环或双环的,例如稠合双环和螺双环。在本发明的背景下,术语“杂环基”和“杂环”可以互换使用。
如本文所用,术语“芳基”或“芳环”是指具有至少一个芳环的单环、双环或多环碳环系统。除非另有说明,否则芳基可以是6至10元。在某些实施方案中,芳基基团可以含有6个成环碳原子。碳环芳基基团内的所有原子均是碳原子。芳基基团的非限制性实例包括苯基、萘基、1,2-二氢萘基、1,2,3,4-四氢萘基、芴基、茚满基、茚基等。在本发明的背景下,术语“芳基”和“芳环”可以互换使用。
如本文所用,术语“杂芳基”或“杂芳环”是指单环系统,或稠合或桥接的双环系统,其中环系含有一个、两个、三个或四个独立地选自由氮、氧和硫组成的组的杂原子;并且至少一个环是芳环。除非另有说明,否则杂芳基基团可以是5至10元。在某些实施方案中,杂芳基基团可以是5元或6元的。在某些实施方案中,杂芳基基团可以含有一个、两个或三个杂原子。在某些实施方案中,杂芳基基团可以含有一个或两个杂原子。杂芳基基团的非限制性实例包括苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、呋喃基、咪唑基、吲哚基、异吲唑基、异喹啉基、异噻唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、嘌呤基、吡咯基、吡啶基、吡嗪基、嘧啶基、喹啉基、喹啉基、噻二唑基、噻唑基、噻吩基、三唑基、四唑基、二氢吲哚基、四氢喹啉基、四氢异喹啉基等。杂芳基基团包括至少一个具有至少一个如上所述的杂原子的环和至少一个芳环。例如,具有至少一个杂原子的环可以稠合至一个、两个或三个碳环,例如芳基环、环己烷环、环己烯环、环戊烷环、环戊烯环或另一个单环杂环。稠合杂芳基基团的非限制性实例包括1,2,3,5,8,8a-六氢中氮茚、2,3-二氢苯并呋喃、2,3-二氢吲哚、2,3-二氢苯并噻吩等。在本发明的背景下,术语“杂芳基”和“杂芳环”可以互换使用。
如本文所用,术语“氧代”是指二价氧原子并且氧代的结构可以显示为=O。
如本文所用,术语“卤代”或“卤素”是指氟化物、氯化物、溴化物和碘化物。在某些实施方案中,卤代的非限制性实例包括氟化物、氯化物和溴化物,更特别地是氟化物和氯化物。
如本文所用,术语“杂原子”是指氮(N)、氧(O)和硫(S),并且可以包括氮和硫的任何氧化形式,以及碱性氮的任何季铵化形式,除非另有说明。
如本文所用,术语“取代的”在指化学基团时是指该化学基团具有一个或更多个氢原子,该氢原子被取代基除去和替换。如本文所用,术语“取代基”具有本领域已知的普通含义并且是指共价附接至母基团或如果合适,稠合至母基团的化学部分。可以理解,给定原子的取代受化合价的限制。应理解取代基可以被进一步取代。
当在式(I)或其任何实施方案中指出部分被“任选地”取代时,这表示式(I)或其实施方案涵盖在该部分上被所指出的取代基取代的化合物和在该部分上不含有所指出的取代基(即,其中该部分未被取代)的化合物。
参考通式和具体化合物描述本文提供的化合物。此外,本发明的化合物可以以多种不同的形式或衍生物存在,所有均在本发明的范围内。这些包括例如药学上可接受的盐、互变异构体、立体异构体、外消旋混合物、位置异构体、前药、溶剂化形式、不同晶型或多晶型物以及活性代谢物等。
如本文所用,除非另有说明,否则术语“药学上可接受的盐”包括保持特定化合物的游离酸/碱形式的生物学有效性并且在生物学或其他方面不是非期望的盐。药学上可接受的盐可以包括与无机碱或酸和有机碱或酸形成的盐。在本发明的化合物含有一个或更多个酸性或碱性基团的情况下,本发明还包括它们相应的药学上可接受的盐。因此,含有酸性基团(例如羧基基团)的本发明的化合物可以盐形式存在,并且可以根据本发明使用,例如,碱金属盐、碱土金属盐、铝盐或铵盐。此类盐的更多非限制性实例包括锂盐、钠盐、钾盐、钙盐、镁盐、钡盐或与氨或有机胺(例如乙胺、乙醇胺、二乙醇胺、三乙醇胺、哌啶、N-甲基谷氨酰胺、或氨基酸)的盐。例如,通过使具有酸性基团的化合物与合适的碱(例如氢氧化锂、氢氧化钠、丙醇钠、氢氧化钾、乙醇钾、氢氧化镁、氢氧化钙或氢氧化钡)反应,这些盐是容易获得的。本发明的化合物的其他碱盐包括但不限于铜(I)、铜(II)、铁(II)、铁(III)、锰(II)和锌盐。本发明的化合物含有一个或更多个碱性基团,例如可以质子化的基团,可以以盐的形式存在,并且可以根据本发明以它们与无机酸或有机酸的加成盐的形式使用。合适的酸的实例包括氯化氢、溴化氢、碘化氢、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、磺基乙酸、三氟乙酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、碳酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、丙二酸、马来酸、苹果酸、帕莫酸、扁桃酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸、牛磺胆酸、戊二酸、硬脂酸、谷氨酸或天冬氨酸,以及本领域技术人员已知的其他酸。所形成的盐尤其是盐酸盐、氯化物、氢溴酸盐、溴化物、碘化物、硫酸盐、磷酸盐、甲基磺酸盐(甲磺酸盐)、甲苯磺酸盐、碳酸盐、碳酸氢盐、甲酸盐、乙酸盐、磺基乙酸盐、三氟甲磺酸盐、草酸盐、丙二酸盐、马来酸盐、琥珀酸盐、酒石酸盐、苹果酸盐、帕莫酸盐、扁桃酸盐、富马酸盐、乳酸盐、柠檬酸盐、戊二酸盐、硬脂酸盐、天冬氨酸盐和谷氨酸盐。此外,由本发明的化合物形成的盐的化学计量可以是1的整数倍或非整数倍。
含有碱性含氮基团的本发明的化合物可以使用试剂例如C1-4卤代烷进行季铵化,例如,甲基、乙基、异丙基和叔丁基氯、溴和碘;二C1-4烷基硫酸盐,例如硫酸二甲酯、二乙酯和二戊酯;C10-18烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;以及芳基C1-4烷基卤化物,例如苄基氯和苯乙基溴。
如果本发明的化合物在分子中同时含有酸性基团和碱性基团,则除了上述盐形式外,本发明还包括内盐或甜菜碱(两性离子)。相应的盐可以通过本领域技术人员已知的常规方法获得,例如通过将它们与有机或无机酸或碱在溶剂或分散剂中接触,或通过与其他盐的阴离子交换或阳离子交换。本发明还包括本发明的化合物的所有盐,由于低生理相容性,它们不直接适用于药物,但可用于,例如,作为化学反应的中间体或用于制备药学上可接受的盐。有关更合适的盐的综述,参见Stahl和Wermuth,药用盐手册:特性、选择和使用(Wiley-VCH,2002)。
式(I)的化合物及其药学上可接受的盐可以以非溶剂化和溶剂化形式存在。如本文所用,术语“溶剂化物”是指包含式(I)的化合物或其药学上可接受的盐和一种或更多种药学上可接受的溶剂分子的分子复合物。例如,当溶剂是水时使用术语“水合物”。
式(I)的化合物可以具有一个或更多个手性(不对称)中心。本发明涵盖式(I)的化合物的所有立体异构形式。存在于式(I)的化合物中的不对称中心可以彼此独立地具有(R)或(S)构型。当至手性碳的键在本发明的结构式中被描述为直线时,或当化合物名称在没有手性碳的(R)或(S)手性名称的情况下被描述时,应当理解,每种此类手性碳的(R)和(S)构型以及因此每种对映异构体或非对映异构体及其混合物均包含在该式或名称中。特定立体异构体或其混合物的产生可以在获得此类立体异构体或混合物的实例中进行鉴定,但这绝不限制所有立体异构体及其混合物被包括在本发明的范围内。
本发明包括所有可能的对映异构体和非对映异构体以及两种或更多种立体异构体的混合物,例如所有比例的对映异构体和/或非对映异构体的混合物。因此,对映异构体是本发明主题的对映异构体纯形式(作为左旋和右旋对映体)、外消旋体形式和两种对映异构体以所有比例的混合物形式。在顺式/反式异构体的情况下,本发明包括顺式形式和反式形式以及这些形式的所有比例的混合物。如有需要,可以通过常规方法(例如通过色谱或结晶、通过使用立体化学均一的合成起始材料或通过立体选择性合成)分离混合物来制备单个立体异构体。任选地,可以在立体异构体分离之前进行衍生化。立体异构体混合物的分离可以在式(I)的化合物合成期间的中间步骤中进行,或者可以在最终外消旋产物上进行。绝对立体化学可以通过结晶产物或结晶中间体的X-射线晶体学来确定,如有需要,用含有已知构型的立体中心的试剂衍生这些结晶产物或结晶中间体。可选地,绝对立体化学可以通过振动圆二色性(VCD)光谱分析来确定。
除非另有说明,否则本文描述的结构还意在包括仅在存在一种或更多种同位素富集原子时不同的化合物,换言之,其中一个或更多个原子被具有相同原子序数的原子替换,但原子质量或质量序数不同于自然界中占优势的原子质量或质量序数的化合物。此类化合物被称为“同位素变体”。本发明旨在包括式(I)的化合物的所有药学上可接受的同位素变体。适合包括在本发明的化合物中的同位素的实例包括但不限于氢的同位素,例如2H(即,D)和3H;碳,例如11C、13C和14C;氯,例如36Cl;氟,例如18F;碘,例如123I和125I;氮,例如13N和15N;氧,例如15O、17O和18O;磷,例如32P;和硫,例如35S。式(I)的化合物的某些同位素变体,例如掺入放射性同位素的那些,可用于药物和/或底物组织分布研究。特别地,具有仅在用较重同位素替换(例如用氘(2H或D)替换氢)中不同的所描绘结构的化合物可以提供某些治疗优势,例如,由于更高的代谢稳定性、增加的体内半衰期或减少的剂量要求,因此可以在一些特定情况下使用。式(I)的化合物的同位素变体通常可以通过本领域技术人员已知的常规技术或通过与所附实施例中描述的那些类似的方法以及使用适当的同位素标记试剂代替先前采用的非标记试剂合成进行制备。
根据本发明的药学上可接受的溶剂化物可以包括其中结晶溶剂可以被同位素取代的那些,例如D2O、d6-丙酮、d6-DMSO。
实施本发明的一种方式是以前药的形式施用式(I)的化合物。因此,式(I)的化合物的某些衍生物可能本身具有很少或没有药理活性,当施用于体内或身体上时,例如通过水解切割,特别是由酯酶或肽酶促进的水解切割,其被转化成具有期望活性的式(I)的化合物。此类衍生物被称为“前药”。有关前药使用的更多信息可见于,例如,T.Higuchi和W.Stella,“Pro-drugs as Novel Delivery Systems”,Vol.14,ACS Symposium Series,和E.B.Roche(Ed.),“Bioreversible Carriers in Drug Design”,Pergamon Press,1987,American Pharmaceutical Association。还可以参考Nature Reviews/Drug Discovery,2008,7,355,和Current Opinion in Drug Discovery and Development,2007,10,550。
根据本发明的前药可以例如通过用本领域技术人员已知的某些部分替换式(I)的化合物中存在的适当官能团来制备,例如,H.Bundgaard,“Design of Prodrugs”,Elsevier,1985,以及Y.M.Choi-Sledeski和C.G.Wermuth,“Designing Prodrugs andBioprecursors”,Practice of Medicinal Chemistry,第4版,Chapter 28,657-696,Elsevier,2015中所述的“前部分”。因此,根据本发明的前药可以包括但不限于(a)式(I)的化合物中羧酸的酯或酰胺衍生物,如果有;(b)式(I)的化合物中氨基的酰胺、亚胺、氨基甲酸酯或胺衍生物;(c)式(I)的化合物中羰基的肟或亚胺衍生物,如果有;或(d)可以在式(I)的化合物中代谢氧化成羧酸的甲基、伯醇或醛基,如果有。
提及式(I)的化合物包括化合物本身及其前药。本发明包括此类式(I)的化合物以及此类化合物的药学上可接受的盐和所述化合物和盐的药学上可接受的溶剂化物。
使用和施用
本发明的化合物-或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,包括其所有比例的混合物-可用作药物。发现它们表现出抑制TEAD的药理活性。假设通过这种活性,本发明的化合物可以预防或逆转Hippo通路的功能障碍。通过预防其功能障碍,Hippo通路可能能够发挥其作为肿瘤抑制因子的作用。除了预防或逆转Hippo通路的功能障碍和独立于上游Hippo调节之外,本发明的化合物的药理活性还可用于抑制TEAD将是有益的其他病理生理情况。
因此,作为TEAD抑制剂的本发明的化合物特别适用于治疗过度增殖性疾病和癌症,特别是肿瘤,包括以下各项的实体瘤:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤、基底细胞癌。不希望承诺任何具体的理论或解释,可以假设这些化合物可能能够通过直接作用于癌细胞和/或间接地通过调节免疫系统对肿瘤的反应来实现这一目标。此外,本发明的化合物还可用于治疗非癌性病症和疾病,例如心血管疾病和纤维化(例如肝纤维化)。
本发明的化合物可以以有效治疗本文所述的疾病或病状的量施用。本发明的化合物可以作为化合物本身施用,或可选地,作为药学上可接受的盐施用。为了施用和给药目的,本发明的化合物本身或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体将被简称为本发明的化合物。
本发明的化合物通过任何合适的途径以适合这种途径的药物组合物的形式施用,并且以对预期治疗有效的剂量施用。本发明的化合物可以口服、直肠、阴道、肠胃外或外用施用。
如本文所用,术语“施用(administration和administer)”是指吸收、摄取、注射、吸入、植入或以其他方式引入本发明的化合物或其药物组合物。术语“治疗(treatment和treat)”是指逆转、减轻、延迟本文所述的“病理状况”(例如,疾病、病症或病状,或其一种或更多种体征或症状)的发作或抑制其进展。在某些实施方案中,可以在疾病或病状的一种或更多种体征或症状已经发展或已经观察到之后施用治疗。在其他实施方案中,可以在没有疾病或病状的体征或症状的情况下进行治疗。例如,可以在症状发作之前对易感个体进行治疗(例如,根据症状史和/或根据遗传或其他易感性因素)。在症状消退后也可以继续治疗,例如延迟或预防复发。如本文所用,术语“疾病”、“病症”、“病状”和“病理状况”可互换使用。
本领域技术人员可以通过常规实验确定施用的剂量水平。本发明的化合物和/或包含所述化合物的组合物的剂量方案基于多种因素,包括患者的类型、年龄、体重、性别和医疗状况;病状的严重程度;施用途径;和所用特定化合物的活性。因此,剂量方案可以有很大的不同。例如,本发明的化合物的剂量水平可以是每天约0.001至约100mg/kg(即mg/kg体重)。在某些实施方案中,以单次或分次施用的本发明的化合物的总日剂量可以为约0.001至约10mg/kg。本发明的化合物的施用可以在一天内重复多次的情况并不少见。
在某些实施方案中,本发明的化合物可以与一种或更多种另外的治疗剂联合施用。在某些实施方案中,另外的治疗剂的非限制性实例可以包括抗癌剂。可以在施用本发明的化合物之前、之后或同时施用另外的治疗剂。
如本文所用,术语“抗癌剂”是指为了治疗癌症而施用于患有癌症的受试者的任何药剂。常规手术或放疗或药物疗法可以与本发明的化合物联合用于癌症治疗。此类药物疗法,例如化疗或靶向疗法,可以包括一种或更多种,但优选一种以下抗癌剂:
烷化剂:例如六甲蜜胺、盐酸苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、盐酸氮芥、环磷酰胺、达卡巴嗪、异环磷酰胺、英丙舒凡(improsulfan)、舒他西林、洛莫司汀、盐酸美法仑、二溴甘露醇、二溴卫矛醇(mitolactol)、盐酸尼莫司汀、雷莫司汀(ranimustine)、替莫唑胺、塞替派、曲奥舒凡(treosulfan)、二氯甲基二乙胺(mechloretamine)、卡波醌(carboquone)、阿帕喹酮(apaziquone)、福莫司汀、葡磷酰胺(glufosfamide)、帕利伐米(palifosfamide)、哌泊溴烷(pipobroman)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uramustine)、艾伏磷酰胺(evofosfamide)、VAL-083。
铂类化合物:例如卡铂、顺铂、依铂(eptaplatin)、米铂(miriplatine hydrate)、奥沙利铂、洛铂、奈达铂、吡铂(picoplatin)、赛特铂(satraplatin)。
DNA改变剂:例如氨柔比星(amrubicin)、比生群(bisantrene)、地西他滨、盐酸米托蒽醌、盐酸丙卡巴肼、曲贝替定(trabectedin)、氯法拉滨(clofarabine)、安吖啶、溴他利星(brostallicin)、匹杉琼(pixantrone)、拉莫司汀(laromustine)。
拓扑异构酶抑制剂:例如依托泊苷、盐酸伊立替康、右雷佐生、索布佐生(sobuzoxane)、替尼泊苷、盐酸托泊替康、氨萘非特(amonafide)、贝洛替康(belotecan)、依利醋铵(elliptinium acetate)、伏瑞洛辛(voreloxin)。
微管调节剂:例如卡巴他赛(cabazitaxel)、多西他赛、艾立布林、伊沙匹隆(ixabepilone)、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁(vinflunine)、康普瑞汀磷酸二钠(fosbretabulin)、替司他赛(tesetaxel)。
抗代谢药:例如门冬酰胺酶、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨(enocitabine)、氟脲苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨(nelarabine)、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤(thioguanine)、卡莫氟、去氧氟尿苷、艾西拉滨(elacytarabine)、雷替曲塞、沙帕他滨(sapacitabine)、替加氟、三甲曲沙(trimetrexate)。
抗癌抗生素:例如博来霉素、放线菌素D、多柔比星、表柔比星、伊达比星、左旋咪唑、灭特复星(miltefosine)、丝裂霉素C(mitomycin C)、罗米地辛(romidepsin)、链脲霉素(streptozocin)、戊柔比星(valrubicin)、净司他丁(zinostatin)、佐柔比星(zorubicin)、柔红霉素(daunurobicin)、普卡霉素(plicamycin)、阿柔比星、匹来霉素(peplomycin)、吡柔比星。
激素/拮抗剂:例如阿巴瑞克(abarelix)、阿比特龙、比卡鲁胺、布舍瑞林(buserelin)、卡鲁睾酮(calusterone)、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙(fluocortolone)、氟甲睾酮(fluoxymesterone)、氟他胺、氟维司群、戈舍瑞林、组氨瑞林(histrelin)、亮丙瑞林、甲地孕酮、米托坦(mitotane)、那法瑞林(nafarelin)、诺龙、尼鲁米特(nilutamide)、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺素α(thyrotropinalfa)、托瑞米芬、曲洛司坦(trilostane)、曲普瑞林、已烯雌酚、阿考比芬(acolbifene)、达那唑、地洛瑞林(deslorelin)、环硫雄醇(epitiostanol)、orteronel、恩扎卢胺。
芳香酶抑制剂:例如氨鲁米特、阿那曲唑、依西美坦、法屈唑(fadrozole)、来曲唑、睾内酯(testolactone)、福美坦。
小分子激酶抑制剂:例如克唑替尼、达沙替尼、盐酸厄洛替尼、甲磺酸伊马替尼、甲苯磺酸拉帕替尼、尼洛替尼、培唑帕尼、瑞戈非尼、磷酸芦可替尼、甲苯磺酸索拉非尼、苹果酸舒尼替尼、凡德他尼(vandetanib)、维莫非尼、博舒替尼(bosutinib),吉非替尼、阿昔替尼、马来酸阿法替尼、阿立塞替(alisertib)、甲磺酸达拉非尼、达可替尼、dinaciclib、多韦替尼(dovitinib)、恩扎妥林(enzastaurin)、乙磺酸尼达尼、甲磺酸仑伐替尼、利尼伐尼(linifanib)、林西替尼(linsitinib)、马赛替尼(masitinib)、米哚妥林(midostaurin)、莫特沙尼(motesanib)、马来酸奈拉替尼、奥兰替尼(orantinib)、哌立福新(perifosine)、普纳替尼(ponatinib)、拉多替尼(radotinib)、瑞格色替(rigosertib)、特泊替尼(tepotinib)、替吡法尼(tipifarnib)、替万替尼(tivantinib)、替沃扎尼(tivozanib),曲美替尼、匹马赛替尼(pimasertib)、丙氨酸布立尼布(brivanib alaninate)、西地尼布(cediranib)、甲磺酸阿帕替尼、苹果酸卡博替尼(cabozantinib S-malate)、伊布替尼、盐酸埃克替尼、布帕尼西(buparlisib)、西帕替尼(cipatinib)、考比替尼(cobimetinib)、艾德拉尼(idelalisib)、菲卓替尼(fedratinib)、特伐替尼(tesevatinib)。
光敏剂:例如甲氧沙林、卟吩姆钠(porfimer sodium)、他拉泊芬(talaporfin)、替莫卟吩(temoporfin)。
抗体:例如阿仑单抗(alemtuzumab)、贝索单抗(besilesomab)、维布妥昔单抗、西妥昔单抗、地舒单抗、伊匹木单抗、奥法妥木单抗、帕尼单抗(panitumumab)、利妥昔单抗、托西莫单抗(tositumomab)、曲妥珠单抗、贝伐珠单抗、帕妥珠单抗、卡妥索单抗(catumaxomab)、埃罗妥珠单抗(elotuzumab)、依帕珠单抗(epratuzumab)、法妥组单抗(farletuzumab)、莫格利珠单抗(mogamulizumab)、耐昔妥珠单抗(necitumumab)、尼妥珠单抗、奥妥珠单抗、奥卡妥珠单抗(ocaratuzumab)、奥戈伏单抗(oregovomab)、雷莫西尤单抗、利妥木单抗(rilotumumab)、司妥昔单抗、托珠单抗、扎芦木单抗(zalutumumab)、扎木单抗(zanolimumab)、马妥珠单抗(matuzumab)、达罗托组单抗(dalotuzumab)、奥那妥组单抗(onartuzumab)、雷妥莫单抗(racotumomab)、他贝芦单抗(tabalumab)、EMD-525797、阿替利珠单抗、度伐利尤单抗、帕博利珠单抗、纳武利尤单抗。
细胞因子:例如阿地白介素(aldesleukin)、干扰素α2、干扰素α2a、干扰素α2b、西莫白介素(celmoleukin)、他索纳明(tasonermin)、替西白介素(teceleukin)、奥普瑞白介素(oprelvekin)、重组干扰素β-1a。
药物缀合物:例如地尼白介素(denileukin diftitox)、替伊莫单抗(ibritumomabtiuxetan)、碘苄胍I 123(iobenguane I 123)、泼尼莫司汀(prednimustine)、恩美曲妥珠单抗、雌莫司汀、吉妥单抗(gemtuzumab)、吉妥珠单抗(Ozogamicin)、阿柏西普、贝辛白介素(cintredekin besudotox)、依多曲肽(edotreotide)、奥加伊妥珠单抗、他那莫单抗(naptumomab estafenatox)、莫妥组单抗(oportuzumab monatox)、锝(99mTc)阿西莫单抗(technetium(99mTc)arcitumomab)、长春福肽(vintafolide)。
疫苗:例如西普鲁塞(sipuleucel)、维特斯朋(vitespen)、emepepimut-S、oncoVAX、rindopepimut、troVax、MGN-1601、MGN-1703。
其他:例如阿利维甲酸(alitretinoin)、贝沙罗汀(bexarotene)、硼替佐米、依维莫司、伊班膦酸(ibandronic acid)、咪喹莫特、来那度胺、香菇多糖、甲酪氨酸(metirosine)、米伐木肽(mifamurtide)、帕米膦酸(pamidronic acid)、培门冬酶、喷司他丁(pentostatin)、sipuleucel、西索菲兰(sizofiran)、他米巴罗汀(tamibarotene)、替西罗莫司(temsirolimus)、沙利度胺、维A酸、维莫德吉(vismodegib)、唑来膦酸、伏立诺他(vorinostat)、塞来昔布、西仑吉肽(cilengitide)、恩替诺特(entinostat)、依他硝唑(etanidazole)、ganetespib、idronoxil、伊尼帕利卜(iniparib)、枸橼酸伊沙佐米、氯尼达明(lonidamine)、尼莫拉唑(nimorazole)、帕比司他(panobinostat)、peretinoin、普拉泰(plitidepsin)、泊马度胺、丙考达唑(procodazol)、地磷莫司(ridaforolimus)、他喹莫德(tasquinimod)、telotristat、胸腺法新、替拉扎明(tirapazamine)、tosedostat、曲贝德生(trabedersen)、乌苯美司、伐司朴达(valspodar)、今又生(gendicine)、溶链菌(picibanil)、reolysin、瑞他霉素盐酸盐(retaspimycin hydrochloride)、曲巴尼布(trebananib)、维如利金(virulizin)、卡非佐米、血管内皮抑制素、immucothel、贝利司他(belinostat)。
PARP抑制剂:奥拉帕尼(Olaparib)、维利帕尼(Veliparib)。
MCT1抑制剂:AZD3965、BAY-8002。
药物组合物
在一些方面,本发明涉及药物组合物,其包含如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,以及至少一种药学上可接受的载体或辅料。
如本文所用,术语“药学上可接受的载体或辅料”是指可用于制备药物组合物的载体或辅料,其通常是安全的、无毒的并且在生物学上或其他方面均不是非期望的,并且包括可接受用于兽医用途以及人药物用途的载体或辅料。如本文所用的药学上可接受的载体或辅料包括一种和多于一种此类载体或辅料。使用的具体载体或辅料将取决于应用本发明的化合物的方式和目的。合适的载体和辅料是本领域技术人员所熟知,并详述于,例如,Ansel,Howard C等人,Ansel’s Pharmaceutical Dosage Forms and Drug DeliverySystems.Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.等人,Remington:The Science and Practice of Pharmacy.Philadelphia:Lippincott,Williams&Wilkins,2000;和Rowe,Raymond C.Handbook of PharmaceuticalExcipients.Chicago,Pharmaceutical Press,2005。还可以包括缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、混悬剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、甜味剂、加香剂、调味剂、稀释剂和其他已知的添加剂中的一种或更多种,以提供药物(即本文提供的化合物或药物组合物)的精致表现或有助于生产药物产品(即药物)。
本发明的组合物可以制剂成多种形式。这些包括,例如,液体、半固体和固体剂型,例如液体溶液(例如,可注射和可输注的溶液)、分散体或混悬剂、片剂、丸剂、粉剂、脂质体、栓剂等。形式取决于预期施用的方式和治疗应用。
本发明的药物组合物可以通过任何熟知的药学技术(例如有效制剂和施用程序)制备。上述关于有效制剂和施用程序的考虑是本领域熟知的,并且在标准教科书中有所描述。例如,在Hoover,John E.,Remington’s Pharmaceutical Sciences,Mack PublishingCo.,Easton,Pennsylvania,1975;Liberman等人,编辑,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980;和Kibbe等人,编辑,Handbook of PharmaceuticalExcipients,第3版,American Pharmaceutical Association,Washington,1999中讨论了药物产品的制剂。
在某些实施方案中,药物组合物包含如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或其同位素变体,联合一种或更多种另外的治疗剂(例如抗癌剂),以及至少一种药学上可接受的载体或辅料。
在还一方面,本发明涉及用于治疗TEAD相关疾病或病状的试剂盒,其包含如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或其同位素变体,或如本文提供的包含式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体的药物组合物,容器和任选的指示治疗的包装插页或标签。在某些实施方案中,该试剂盒可进一步包含一种或更多种另外的治疗剂,例如抗癌剂。
治疗方法
在还一方面,本发明涉及一种治疗有需要的受试者的TEAD相关疾病或病状例如癌症的方法,由于本发明的化合物的TEAD抑制活性,该方法包括向受试者施用治疗有效量的如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或其同位素变体。
如本文所用,术语“有需要的受试者”是患有TEAD相关疾病或病状的受试者,或相对于整个人群具有增加的发展TEAD相关疾病或病状的风险的受试者。在某些实施方案中,受试者是温血动物。在某些实施方案中,温血动物是哺乳动物。在某些实施方案中,温血动物是人。
如本文所用,术语“TEAD相关疾病或病状”是指TEAD的抑制将是有益的任何病理生理情况。在某些实施方案中,TEAD相关疾病或病状是癌症。在某些实施方案中,TEAD相关疾病或病状是选自由以下组成的组的癌症:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
如本文所述的治疗TEAD相关疾病或病状的方法可以用作单一疗法。如本文所用,术语“单一疗法”是指向有需要的受试者施用单一活性或治疗性化合物。在某些实施方案中,单一疗法将涉及向需要这种治疗的受试者施用治疗有效量的本发明的化合物中的一种或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体。
取决于待治疗的特定疾病或病状,本文描述的治疗TEAD相关疾病或病状的方法除了施用式(I)的化合物外,还包括一种或更多种另外的治疗剂,例如抗癌剂,的联合治疗。如本文所用,术语“联合疗法”是指联合施用多种活性治疗剂。在某些实施方案中,本发明的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体可以与一种或更多种另外的治疗剂的治疗同时、单独或序贯施用。例如,另外的治疗剂可以与本发明的化合物单独施用,作为多剂量方案的一部分。可选地,另外的治疗剂可以是单一剂型的一部分,与本发明的化合物在单一组合物中混合。
在还一方面,本发明涉及如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体用于治疗TEAD相关疾病或病状,例如癌症。
在还一方面,本发明涉及如本文提供的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体在制备用于治疗TEAD相关疾病或病状例如癌症的药物中的用途。
合成
本发明的化合物可以使用合成有机化学领域技术人员的公知常识,通过下文描述的一般和特定方法制备。这种公知常识可见于标准参考书,例如,Barton和Ollis(编辑),综合有机化学,Elsevier;Richard Larock,综合有机转化:官能团制备指南,John Wiley andSons;和有机合成方法纲要,I-XII卷,Wiley-Interscience。
下文描述的方案旨在提供用于制备本发明的化合物的方法的一般描述。本发明的一些化合物可以含有单个或多个具有立体化学名称(R)或(S)的手性中心。对本领域技术人员显而易见的是,无论材料是对映体富集的还是外消旋的,所有合成转化均可以以类似的方式进行。此外,期望的光学活性材料的解析可以使用公知的方法,例如本文和化学文献中描述的那些方法,在程序中的任何期望点进行。
实施例
为了更详细地描述本发明,提出以下实施例。本文描述的实施例用于说明本文提供的化合物、方法和组合物,并且不应以任何方式解释为限制它们的范围。
在合成过程中,可能需要和/或期望保护任何相关分子上的敏感或反应性基团。这可以通过常规保护基团来实现,例如在T.W.Greene和P.G.M.Wutts,有机合成中的保护基团,第4版,John Wiley and Sons中所述的那些。使用本领域熟知的方法在方便的后续阶段任选地去除保护基团。
本发明的化合物可以根据以下反应方案和实施例或其修改,使用容易获得的起始材料、试剂和常规合成程序容易地制备。在这些反应中,也可以使用本领域技术人员已知但未更详细提及的变体。此外,根据本文所述的反应方案和实施例,制备本发明的化合物的其他方法对于本领域技术人员将是显而易见的。除非另有说明,否则所有变量均如上定义。一般而言,化学程序中,所有试剂和起始材料均可购自商业供应商或可由本领域技术人员容易地制备。
示例性化合物如表1所示。
表1
中间体A的制备:
步骤1:
向4-氧代哌啶-1-甲酸叔丁酯(1.00g,5.02mmol)的AcOH(10mL)溶液中加入对甲苯肼(796mg,5.02mmol)。将混合物在65℃下搅拌5小时。将反应混合物用水(50mL)稀释并用EtOAc(30mL×3)萃取。合并的有机层用NaHCO3(150mL)洗涤,经无水硫酸钠干燥,过滤并减压浓缩,得到A-1。LCMS[M+H]+:287.3。
步骤2:
将A-1(50mg,174μmol)、1-碘-4-(三氟甲基)苯(142mg,523μmol,77.0μL)、CuI(16.6mg,87.3μmol)、K3PO4(111mg,523μmol)和(1R,2R)-N1,N2-二甲基环己烷-1,2-二胺(12.4mg,87.3μmol)在DMF(1.50mL)中的混合物脱气并用氮气置换3次。所得混合物在氮气保护下于90℃下搅拌反应3小时。反应完成后,反应混合物用EtOAc(30mL)稀释并过滤。滤液用水(100mL)稀释并用EtOAc(50mL×2)萃取。合并的有机层经无水硫酸钠干燥并过滤。将滤液浓缩并通过制备型TLC纯化得A-2。LCMS[M+H]+:431.3。
步骤3:
向A-2(100mg,0.232mmol)的DCM(3.0mL)溶液中加入TFA(1.0mL)。所得反应液在室温下搅拌1.5小时。完毕,减压浓缩反应混合物,得到中间体A。LCMS[M+H]+:331.2。
实施例1
6-甲基-9-(4-(三氟甲基)苯基)-2,3,4,9-四氢-1H-咔唑-3-羧酸的制备
根据以下程序制备标题化合物。
步骤1:
对甲苯基肼盐酸盐(1.50g,12.8mmol)和4-氧代环己烷-1-甲酸乙酯(2.15mL,13.5mmol)于AcOH(702μL,12.2mmol)中的的混合物在氮气保护下于80℃加热搅拌反应3小时。完毕,将反应混合物用水(50mL)稀释并用EtOAc(80mL×2)萃取。合并的有机层用盐水(20mL×2)洗涤,经无水硫酸钠干燥,过滤并浓缩得到1-1。LCMS[M+H]+:258.2。
步骤2:
向1-1(200mg,777μmol)和1-碘代-4-(三氟甲基)苯(211mg,777μmol,114μL)在DMF(10mL)的混合物中加入N,N'-二甲基乙烷-1,2-二胺(68.5mg,777.22μmol,83.65μL)、Cs2CO3(506mg,1.55mmol)和CuI(7.4mg,38.86μmol)并用氮气置换3次。所得混合物在氮气保护下于120℃搅拌反应10小时。完毕,将反应混合物用水(50mL)稀释并用EtOAc(80mL×2)萃取。合并的有机层用盐水(20mL×2)洗涤,经无水硫酸钠干燥并过滤。将滤液浓缩并通过硅胶色谱纯化,得到1-2。LCMS[M+H]+:402.2。
步骤3:
向1-2(50.0mg,125μmol)的THF(4mL)溶液中加入LiOH(15.8mg,377μmol)的水(1mL)溶液。所得混合物在25℃下搅拌4小时。将反应混合物用水(50mL)稀释并用EtOAc(80mL×2)萃取。合并的有机层用盐水(20mL×2)洗涤,经无水硫酸钠干燥并过滤。将滤液浓缩并通过制备型HPLC纯化,得到实施例1的化合物。1HNMR:(400MHz,CDCl3)δ7.77(d,J=8.3Hz,2H),7.49(d,J=8.2Hz,2H),7.33(s,1H),7.15(d,J=8.4Hz,1H),6.99(dd,J=8.5,1.7Hz,1H),3.17(dd,J=15.4,5.3Hz,1H),3.07–2.90(m,2H),2.79–2.69(m,2H),2.46(s,3H),2.41–2.29(m,1H),2.12–1.97(m,1H).LCMS[M+H]+:373.9。
实施例2
1-(8-甲基-5-(4-(三氟甲基)苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-基)丙-2-烯-1-酮的制备
根据以下程序制备标题化合物。
在0℃下,向中间体A(30.0mg,0.0910mmol)和NaHCO3(38.1mg,0.454mmol)在THF(2.00mL)和水(1.00mL)的溶液中加入2-烯酰氯(9.04mg,0.100mmol)。添加完成后,将反应在25℃下搅拌30分钟。完毕,将反应混合物用水(50mL)稀释并用DCM(30mL×3)萃取。合并的有机层用水(50mL)洗涤,经无水硫酸钠干燥并过滤。将滤液浓缩并通过制备型HPLC纯化,得到实施例2的化合物。1HNMR:(400MHz,CDCl3)δ7.81(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7.34(d,J=22.6Hz,1H),7.23(d,J=8.8Hz,1H),7.05(d,J=8.5Hz,1H),6.82–6.64(m,1H),6.38(dd,J=16.8,1.9Hz,1H),5.78(d,J=10.6Hz,1H),4.90(d,J=34.6Hz,2H),4.05(s,1H),3.90(s,1H),2.82(s,2H),2.50(s,3H).LCMS[M+H]+:385.3。
实施例3
2-氯-2-氟-1-(8-甲基-5-(4-(三氟甲基)苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-基)乙-1-酮的制备
根据以下程序制备标题化合物。
步骤1:
向2-氯-2-氟乙酸乙酯(2.00g,14.2mmol)中滴加NaOH的水溶液(5M,2.85mL,14.23mmol)。完毕,所得反应液在25℃下搅拌反应1小时。将反应混合物用水(30mL)稀释并用MTBE(20mL×3)萃取。合并的有机层用水(30mL)洗涤,经无水硫酸钠干燥,过滤并浓缩,得到3-1。
步骤2:
向3-1(100mg,0.303mmol)和中间体A(68mg,0.605mmol)在DCM(5mL)中的溶液加入DIEA(0.25mL,1.51mmol)和T3P(50wt%在EtOAc,0.070mL,2.11mmol)。所得反应液在室温下搅拌3小时。完毕,将反应混合物用水(50mL)稀释并用DCM(30mL×3)萃取。合并的有机层用水(50mL)洗涤,经无水硫酸钠干燥并过滤。将滤液浓缩并通过制备型HPLC纯化,得到实施例3的化合物。1HNMR:(400MHz,CDCl3)δ7.82(d,J=8.2Hz,2H),7.52(d,J=7.5Hz,2H),7.34(s,1H),7.23(dd,J=8.4,3.7Hz,1H),7.07(dd,J=8.8,4.0Hz,1H),6.62(dd,J=50.8,14.3Hz,1H),5.07–4.94(m,1H),4.85(dd,J=24.2,15.8Hz,1H),4.17(ddt,J=33.5,14.1,5.2Hz,1H),3.89(dddd,J=25.3,12.7,7.6,4.8Hz,1H),2.98–2.73(m,2H),2.50(d,J=4.8Hz,3H)。
实施例4
8-甲基-2-(甲基磺酰基)-5-(4-(三氟甲基)苯基)-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚的制备
根据以下程序制备标题化合物。
在0℃下,向中间体A(30mg,0.09mmol)和TEA(25μL,0.18mmol)的DCM(2.00mL)的溶液中加入甲磺酸酐(32mg,0.18mmol)。所得反应液在25℃下搅拌1小时。完毕,将反应混合物用水(50mL)稀释并用DCM(30mL×3)萃取。合并的有机层用水(50mL)洗涤,经无水硫酸钠干燥并过滤。将所得滤液浓缩并通过制备型HPLC纯化,得到实施例4的化合物。1HNMR:(400MHz,CDCl3)δ7.80(d,J=8.3Hz,2H),7.49(d,J=8.2Hz,2H),7.28(s,1H),7.20(d,J=8.4Hz,1H),7.04(dd,J=8.5,1.7Hz,1H),4.62(s,2H),3.68(t,J=5.7Hz,2H),2.92(s,3H),2.85(t,J=5.6Hz,2H),2.47(s,3H).LCMS[M+H]+:409.2。
实施例5
8-甲基-5-(4-(三氟甲基)苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-磺酰胺的制备
根据以下程序制备标题化合物。
在0℃下,向中间体A(100mg,0.303mmol)和NaHCO3(38.1mg,0.454mmol)的THF(2mL)和水(1mL)溶液中加入氮杂磺酰氯(104mg,0.908mmol)。所得反应液在25℃下搅拌1小时。将反应混合物用水(50mL)稀释并用DCM(30mL×3)萃取。合并的有机层用水(50mL)洗涤,经无水硫酸钠干燥并过滤。将滤液浓缩并通过制备型HPLC纯化,得到实施例5的化合物。1HNMR:(400MHz,CDCl3)δ7.82(d,J=8.3Hz,2H),7.51(d,J=8.2Hz,2H),7.30(s,1H),7.22(d,J=8.4Hz,1H),7.06(dd,J=8.4,1.3Hz,1H),4.60(s,2H),4.50(s,2H),3.66(t,J=5.7Hz,2H),2.94–2.87(m,2H),2.49(s,3H).LCMS[M+H]+:410.2。
实施例6
N,8-二甲基-5-(4-(三氟甲基)苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-磺酰胺的制备
根据以下程序制备标题化合物。
向中间体A(50mg,0.151mmol)的DCM(0.5mL)溶液中加入甲基氮杂磺酰氯(19.61mg,0.151mmol)和TEA(0.063mL,0.454mmol)。将反应在室温下搅拌过夜,然后用EtOAc和水洗脱。所得有机层用盐水洗涤后浓缩,并通过制备型HPLC纯化,得到实施例6的化合物。1H NMR(400MHz,CD3OD)δ7.77(d,J=8.4Hz,2H),7.51(d,J=8.3Hz,2H),7.18(s,1H),7.08(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),4.39(s,2H),3.51(t,J=5.6Hz,2H),2.74(t,J=5.6Hz,2H),2.57(s,3H),2.33(s,3H).LCMS[M+H]+:424.1。
生物活性评价
以下实施例证明了本发明的化合物的生物活性。
1.细胞生长测定
1.1细胞培养
RPMI1640培养基(Gibco,31800)+10%FBS(Biosera,FB-1058/500)用于NCI-H226细胞(来自ATCC)。
1.2试剂
CellTiter-Glo试剂(CTG试剂,Promega,G7573)。
1.3操作流程
(1)将细胞接种于384孔微孔板中(150个细胞/孔,50mL培养基/孔)。还接种额外的板作为第0天对照测量。将微孔板在37℃、5%CO2下温育过夜。
(2)化合物在DMSO中连续稀释3倍,最高终浓度为30mM,共10个浓度。0.3%DMSO作为溶媒对照。此外,将25mL/孔的CTG试剂加入额外的板中并在室温下温育30分钟,并使用EnVision(PerkinElmer,2104Mutilabel Reader)检测发光信号作为第0天对照。
(3)将其他化合物处理的板在37℃下再温育7天,向板中加入25mL/孔的CTG试剂,在室温下温育30分钟并检测发光信号。
1.4数据分析
(1)第0天发光信号用作阴性对照或基线。
信号第0天=第0天对照细胞的平均发光信号。
信号DMSO溶媒对照=第7天DMSO溶媒对照细胞的平均发光信号。
信号cpds处理=第7天化合物处理细胞的发光信号。
抑制%=1-(信号cpds处理–信号第0天)/(信号DMSO溶媒对照–信号第0天)*100。
(2)使用剂量效应曲线计算生长抑制50%(GI50)和最大抑制%。
表2
2.TEAD荧光素酶报告基因测定
2.1细胞培养
DMEM培养基(Gibco,10566-016)+10%FBS(Gibco,10099-141)用于HEK-293T细胞。将萤火虫荧光素酶报告质粒上游的TEAD结合元件的八个串联重复序列转染到HEK-293T细胞中,并建立稳定的TEAD报告基因单克隆细胞作为TEAD报告基因细胞系。
2.2试剂
2.3操作流程
(1)将20000个细胞/孔接种到96孔板(Corning,3603)中。将板在37℃、5%CO2下温育过夜。
(2)化合物在DMSO中连续稀释4倍,最高终浓度为30mM,共10个浓度。0.3%DMSO作为溶媒对照。然后将板在37℃、5%CO2下温育24小时。
(3)将75ml/孔Glo-试剂加入9孔板中。将板温育并振荡10分钟。通过使用Envision(PerkinElmer,2104Mutilabel Reader)检测萤火虫发光。
2.4数据分析
(1)空白培养基发光信号作为阴性对照。
信号阴性对照=阴性对照发光信号的平均值。
信号DMSO溶媒对照=DMSO对照的发光信号的平均值。
Signalcpds处理=化合物处理的发光信号。
抑制%=(1-(信号cpds处理–信号阴性对照)/(信号DMSO溶媒对照–信号阴性对照))*100。
(2)从非线性回归方程拟合IC50:
Y=底部+(顶部-底部)/(1+10^((logIC50-X)*Hill斜率))。
X:化合物浓度。
Y:抑制%。
顶部和底部:与Y相同单位的平台期。
logIC50:与X相同的对数单位。
Hill斜率:斜率系数或Hill斜率。
表3
前面的描述被认为仅是对本发明原理的说明。此外,由于对本领域技术人员而言许多修改和变化将是显而易见的,因此不希望将本发明限制于如上所述的确切构造和过程。因此,所有合适的修改和等同物均可以被认为落入由所附权利要求限定的本发明的范围内。
本文引用的所有出版物、专利和专利申请均通过引用以其全文并入本公开。
Claims (20)
1.一种式(I)的化合物
或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
环A是6元芳环、6元杂芳环或吡啶-2-酮环,该环任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基、C3-10环烷基或-(CH2)n-RA组成的组的一个或更多个取代基取代;其中所述烷基、所述烷氧基和所述环烷基任选地还被一个或更多个卤素取代,RA是任选地被选自由卤素、C1-10烷基和C1-10烷氧基组成的组的一个或更多个取代基取代的苯基,并且n为0、1或2;
Y是CRY或N;
Z1、Z2和Z3各自独立地是C(RZ)2;
RY是H或C1-6烷基,其任选地被一个或更多个卤素取代;
RZ在每次出现时独立地是H、卤素或C1-10烷基,或两个RZ,连同它们所附接的相同碳原子一起,组合形成C3-10环烷烃环,该环任选地被选自由卤素、C1-10烷基和C1-10烷氧基组成的组的一个或更多个取代基取代;
R1是6元至10元芳基、5元至10元杂芳基、或3元至10元单环或双环环烷基或杂环基,其中所述芳基、所述杂芳基、所述环烷基和所述杂环基任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基和C3-10环烷基组成的组的一个或更多个取代基取代,其中所述C1-10烷基、C1-10烷氧基和C3-10环烷基任选地还被一个或更多个卤素取代,并且其中所述杂芳基和所述杂环基含有选自由N、O和S组成的组的至少一个杂原子环成员;
R2是-C(=O)R2A、-C(=O)OR2A、-C(=O)N(R2A)2、-NR2AC(=O)R2A、-NR2AS(=O)R2A、-NR2AS(=O)2R2A、-S(=O)R2A、-S(=O)2R2A、-S(=O)2OR2A或-S(=O)2N(R2A)2;
R2A在每次出现时独立地是H、C1-10烷基、C2-10烯基、C2-10炔基或-L-R2AA,其中所述烷基、所述烯基和所述炔基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;或两个R2A,连同它们所附接的氮原子,组合形成3元至10元杂环基,其任选地含有选自由N、O和S组成的组的一个另外的杂原子环成员,其中所述杂环基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;
L不存在或是任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代的C1-10烷基;以及
R2AA是C3-10环烷基、3元至10元杂环基、6元至10元芳基或5元至10元杂芳基,其中所述环烷基、所述杂环基、所述芳基和所述杂芳基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;
条件是排除以下化合物:
2-(甲基磺酰基)-5-苯基-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚,
2-(乙基磺酰基)-6-氟-5-(2-氟苯基)-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚,
8-氟-5-(4-氟苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-羧酸甲酯,
8-氯-5-(4-氯苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-羧酸乙酯,和
8-甲氧基-5-(4-甲氧基苯基)-1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚-2-羧酸乙酯。
2.如权利要求1所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
环A是苯、吡啶或吡啶-2-酮环,该环任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基、C3-10环烷基或-(CH2)n-RA组成的组的一个或更多个取代基取代;其中所述烷基、所述烷氧基和所述环烷基任选地还被一个或更多个卤素取代,RA是任选地被选自由卤素、C1-10烷基和C1-10烷氧基组成的组的一个或更多个取代基取代的苯基,并且n为0、1或2。
5.如前述权利要求中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
Y是CH、CCH3或N;
Z1、Z2和Z3各自独立地是C(RZ)2;以及
RZ在每次出现时独立地是H或C1-10烷基,或两个RZ,连同它们所附接的相同碳原子一起,组合形成环丙烷环。
6.如前述权利要求中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
R1是苯基、吡啶基或5元至10元单环或双环环烷基或杂环基,其中所述苯基、所述吡啶基、所述环烷基和所述杂环基任选地被选自由卤素、CN、C1-10烷基、C1-10烷氧基和C3-10环烷基组成的组的一个、两个或三个取代基取代,其中所述C1-10烷基、C1-10烷氧基和C3-10环烷基任选地还被一个、两个或三个卤素取代,并且其中所述杂环基含有选自由N、O和S组成的组的一个或两个杂原子环成员。
9.如前述权利要求中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中
R2是-C(=O)R2A、-C(=O)OH、-C(=O)OR2A、-C(=O)NHR2A、-C(=O)N(R2A)2、-NHC(=O)R2A、-S(=O)2R2A、-S(=O)2NHR2A或-S(=O)2N(R2A)2;
R2A在每次出现时独立地是C1-10烷基、C2-10烯基、C2-10炔基或-L-R2AA,其中所述烷基、所述烯基和所述炔基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代;
L不存在或是C1-10烷基;以及
R2AA是C3-10环烷基、3元至10元杂环基、6元至10元芳基或5元至10元杂芳基,其中所述环烷基、所述杂环基、所述芳基和所述杂芳基任选地被选自由卤素、OH和NH2组成的组的一个或更多个取代基取代。
12.一种药物组合物,所述药物组合物包含如权利要求1至11中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,以及药学上可接受的载体或辅料。
13.一种治疗有需要的受试者的癌症的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1至11中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体。
14.如权利要求13所述的方法,其中所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
15.如权利要求1至11中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体用于治疗癌症。
16.如权利要求15所述的用于治疗癌症的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,其中所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
17.如权利要求1至11中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体在制备用于治疗癌症的药物中的用途。
18.如权利要求17所述的用途,其中所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
19.一种用于治疗癌症的试剂盒,所述试剂盒包括
如权利要求1至11中任一项所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、立体异构体或同位素变体,或如权利要求12所述的药物组合物;
容器;和
任选的指示治疗的包装插页或标签。
20.如权利要求19所述的试剂盒,其中所述癌症选自由以下组成的组:乳腺癌、肺癌、间皮瘤、上皮样血管内皮瘤、葡萄膜黑色素瘤、肝癌、卵巢癌、鳞状细胞癌、肾癌、胃癌、髓母细胞瘤、结肠癌、胰腺癌、神经鞘瘤、脑膜瘤、神经胶质瘤和基底细胞癌。
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