CN116261454A - 转录激活蛋白的咪唑并哌嗪抑制剂 - Google Patents
转录激活蛋白的咪唑并哌嗪抑制剂 Download PDFInfo
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Abstract
本披露涉及杂环化合物和方法,这些杂环化合物能够用作转录激活蛋白如CBP和P300的抑制剂用于治疗或预防疾病如增生性疾病、炎性障碍、自身免疫性疾病和纤维化疾病。
Description
本申请要求于2020年10月2日提交的美国临时申请号63/086,728的优先权权益,该美国临时申请出于所有目的通过引用并入本文。
本文披露了新的咪唑并哌嗪化合物和组合物以及它们作为药物用于治疗疾病的应用。还提供了在人或动物受试者中抑制转录激活蛋白如CBP和P300活性的方法用于治疗疾病如癌症。
染色质是在真核细胞核中发现的DNA和蛋白质的组合,其构成染色体。染色质可以分为异染色质(凝聚)和常染色质(伸展)形式。染色质的主要蛋白组分称为组蛋白,组蛋白作为支架,DNA在该支架上包装并被压紧成较小的体积以适合细胞核。组蛋白与有丝分裂和减数分裂过程有关,并被认为在DNA的表达和复制中起重要作用。重要的是,组蛋白在各个氨基酸位点发生翻译后修饰(“PTM”),这调节染色质结构并因而影响转录。这种修饰为“表观遗传学”提供了一种机制,或者提供了一种控制基因活性和表达的机制,而这种机制并非源自DNA序列的直接改变。
赖氨酸残基的乙酰化是一种与细胞信号传导(signaling)和疾病生物学广泛相关的PTM。在核大分子复合物中尤其广泛存在的赖氨酸乙酰化在染色质调控和转录控制中起关键作用。在细胞中,乙酰基-赖氨酸标记的主要“阅读者”是溴结构域(BRD),这些溴结构域是一系列不同的进化保守蛋白-蛋白相互作用模块,它们特异性识别并结合到乙酰化赖氨酸残基。溴结构域与在组蛋白和非组蛋白上“写入”(组蛋白乙酰基转移酶,HAT)和“擦除”(组蛋白脱乙酰基酶,HDAC)乙酰化赖氨酸残基的酶一起严格控制基因表达的调控,从而控制细胞表型,包括增殖、细胞分化和新陈代谢。除染色质外,许多其他蛋白如p53也经过翻译后修饰,它们也可能被溴结构域蛋白识别。由于染色质介导的过程通常在癌症中失控,因此靶向表观遗传阅读蛋白如BET(含双BRD4的蛋白)、CREBBP、ATAD2A、SMARCA2/4和含三联基元24(TRIM24))成为药物发现的有希望的目标。如通过对溴结构域的BET家族的选择性抑制剂的开发所证实,保守的BRD折叠代表了开发小的药物活性分子的有希望的途径。
组蛋白乙酰基转移酶旁系同源物即环状单磷酸腺苷反应元件结合蛋白、结合蛋白(CBP、CREBBP或CREB结合蛋白)和300kDa的腺病毒E1A结合蛋白(P300或EP300)是高度同源的,并且是既包含组蛋白乙酰基转移酶(HAT)又包含溴结构域的两个密切相关的多结构域转录激活蛋白,且在组蛋白乙酰化中具有重要作用。它们是对于许多细胞过程都必不可少的关键转录共激活因子,并且还与包括癌症在内的几种人类病理状况有关。
CBP和P300通过它们的溴结构域与染色质结合,一旦与染色质结合,此复合物就会募集额外的转录机制来调节基因表达,从而导致募集各种转录蛋白来调节基因表达。除了染色质外,还证实CBP/P300也结合非组蛋白蛋白;例如,已经描述了CBP识别DNA损伤后在K382处乙酰化的p53。几项研究已将CBP/P300与癌症和肿瘤免疫力的发生、维持和/或进展联系在一起,因此CBP/P300抑制剂是开发抗癌剂的当前努力的目标。特别地,已发现CBP调控在许多人类癌症中广泛上调的MYC(一种转录因子及癌基因)的表达,这提示针对多发性骨髓瘤和其他淋巴恶性肿瘤及实体瘤的潜在治疗策略。
另外,CBP和P300是已知的雄激素受体(AR)的共激活因子,并且与增强对雄激素的反应有关。与此一致,已经提出CBP/P300在前列腺癌中起致癌作用,并且已经在肿瘤中观察到两种蛋白的上调。CBP抑制剂选择性抑制谱系特异性肿瘤类型中的增殖,这些肿瘤类型包括几种血液恶性肿瘤和雄激素受体阳性前列腺癌。CBP抑制剂在雄激素敏感和去势抵抗性前列腺癌中均抑制雄激素受体转录程序,并在前列腺癌异种移植模型中抑制肿瘤生长。
CBP也与癌症免疫疗法有关,并且已经描述了CBP溴结构域抑制剂损害Treg分化和抑制功能的能力。这项活性可能构成一种新的增强对癌症免疫疗法的反应的小分子方法。
已经发现了多种化合物和药物组合物,其中某些已发现可结合并抑制CBP和P300的相互作用,以及合成和使用这些化合物的方法,包括通过施用这些化合物来治疗患者中的CBP和P300介导的疾病的方法。
附图说明
图1显示(a)肿瘤体积(纵轴,mm3)随时间(横轴,天数)的变化和(b)用(i)媒介物和(ii)实例1化合物处理DOHH2异种移植物后体重的%变化。
具体实施方式
本文提供了一种具有结构式I的化合物:
或其盐,其中:
X1是N并且X2是CH;
R1选自环丙基、四氢-2H-吡喃-4-基和2-氧杂二环[2.2.2]辛-4-基,它们中的任一个任选地被1或2个R5基团取代;
R2是甲基;
R3选自吡啶-3-基和噻唑-5-基,并且任选地被1或2个R7基团取代;
R4选自H和氟;
每个R5独立地选自烷基、烷氧基、氰基、羧基、卤代、卤代烷基、卤代烷氧基、羟基和氧代;
R7每次出现时独立地选自-C(O)NR8R9和烷基,并且
R8和R9独立地选自氢和烷基。
本文披露的某些化合物可以具有对CBP或P300的有用的抑制活性,并且可以用于治疗或预防CBP或P300在其中起积极作用的疾病或病症。因此,在广义上,某些实施例还提供了包含一种或多种本文披露的化合物以及药学上可接受的载体的药物组合物,以及制备和使用这些化合物和组合物的方法。某些实施例提供了用于抑制CBP或P300的方法。其他实施例提供了在需要这样的治疗的患者中治疗由CBP或P300介导的障碍的方法,这些方法包括向所述患者施用治疗有效量的根据本披露的化合物或组合物。还提供了本文披露的某些化合物用于制造用来治疗通过抑制CBP和P300而改善的疾病或病症的药物的用途。
在某些实施例中,R1选自环丙基、四氢-2H-吡喃-4-基、2-氧杂二环[2.2.2]辛-4-基。
在某些实施例中,R3选自吡啶-3-基和噻唑-5-基,并且任选地被1或2个R7基团取代。在某些实施例中,R3选自吡啶-3-基和噻唑-5-基,并且任选地被1个R7基团取代。在某些实施例中,R3选自6-(甲基氨甲酰基)吡啶-3-基、2-甲基噻唑-5-基、2,4-二甲基噻唑-5-基、6-甲基吡啶-3-基和2-(甲基氨甲酰基)噻唑-5-基。在某些实施例中,R3选自: 在某些实施例中,R3是
本文还提供了一种具有结构式I的化合物:
或其盐,其中:
X1是N并且X2是CH;
R1是任选地被1或2个R5基团取代的四氢-2H-吡喃-4-基;
R2是甲基;
R3是任选地被1或2个R7基团取代的噻唑-5-基;
R4选自H和氟;
每个R5独立地选自烷基、烷氧基、氰基、羧基、卤代、卤代烷基、卤代烷氧基、羟基和氧代;
R7每次出现时独立地选自-C(O)NR8R9和烷基,并且
R8和R9独立地选自氢和烷基。
本文还提供了一种具有结构式II的化合物:
或其盐,其中:
X1是N并且X2是CH;
R1是任选地被1或2个R5基团取代的四氢-2H-吡喃-4-基;
R2是甲基;
R3选自吡啶-3-基和噻唑-5-基,并且任选地被1或2个R7基团取代;
R4选自H或氟;
每个R5独立地选自烷基、烷氧基、氰基、羧基、卤代、卤代烷基、卤代烷氧基、羟基和氧代;
R7每次出现时独立地选自-C(O)NR8R9和烷基,并且
R8和R9独立地选自氢和烷基。
在某些实施例中,R1是四氢-2H-吡喃-4-基。
在某些实施例中,R2是甲基。
在某些实施例中,R3是噻唑-5-基,并且任选地被1个R7基团取代。在某些实施例中,R3选自2-甲基噻唑-5-基、2,4-二甲基噻唑-5-基、6-甲基吡啶-3-基和2-(甲基氨甲酰基)噻唑-5-基。在某些实施例中,R3选自:在某些实施例中,R3是
在某些实施例中,R7是-C(O)NR8R9。在某些另外的实施例中,R7是-C(O)NHCH3。
在某些实施例中,R7是C1-6烷基,在某些另外的实施例中,R7是甲基。
在某些实施例中,R8和R9独立地选自氢和C1-6烷基。在某些另外的实施例中,R8和R9独立地选自氢和甲基。
在某些实施例中,R8和R9中的至少一个是氢。在某些实施例中,R8和R9中的至多一个是氢。
还提供了其中可以将以上任何实施例与这些实施例中的任一个或多个组合的实施例,条件是该组合不互相排斥。
如本文所用,当一个实施例被定义为与另一个实施例不同时,两个实施例是“互相排斥的”。例如,其中两个基团组合形成环烷基的实施例与其中一个基团是乙基而另一个基团是氢的实施例是互相排斥的。类似地,其中一个基团是CH2的实施例与其中相同基团是NH的实施例是互相排斥的。
还提供了选自本文披露的实例的化合物。
本披露还涉及抑制CBP的至少一种功能的方法,该方法包括使CBP与如本文所述的化合物或其盐接触的步骤。可以监测细胞表型、细胞增殖、CBP活性、由活性CBP产生的生化输出的变化、CBP的表达或CBP与天然结合伴侣的结合。此类方法可以是疾病的治疗方式、生物学测定、细胞测定、生化测定等。
本披露还涉及抑制P300的至少一种功能的方法,该方法包括使P300与如本文所述的化合物或其盐接触的步骤。可以监测细胞表型、细胞增殖、P300的活性、由活性P300产生的生化输出的变化、P300的表达或P300与天然结合伴侣的结合。此类方法可以是疾病的治疗方式、生物学测定、细胞测定、生化测定等。
本文还提供了一种治疗CBP介导的疾病的方法,该方法包括向有需要的患者施用治疗有效量的如本文披露的化合物或其盐。
本文还提供了治疗P300介导的疾病的方法,该方法包括向有需要的患者施用治疗有效量的如本文披露的化合物或其盐。
在某些实施例中,该疾病是增生性疾病。
在某些实施例中,该疾病是癌症。
本文还提供了如本文披露的化合物或其盐,其用作药物。
本文还提供了如本文披露的化合物或其盐,其用作用于治疗CBP介导的疾病的药物。
本文还提供了如本文披露的化合物或其盐,其用作用于治疗P300介导的疾病的药物。
还提供了如本文披露的化合物或其盐作为药物的用途。
还提供了如本文披露的化合物或其盐作为用于治疗CBP介导的疾病的药物的用途。
还提供了如本文披露的化合物或其盐作为用于治疗P300介导的疾病的药物的用途。
还提供了如本文披露的化合物或其盐,用于在制造用于治疗CBP介导的疾病的药物中使用。
还提供了如本文披露的化合物或其盐,用于在制造用于治疗P300介导的疾病的药物中使用。
还提供了如本文披露的化合物或其盐用于治疗CBP介导的疾病的用途。
还提供了如本文披露的化合物或其盐用于治疗P300介导的疾病的用途。
本文还提供了抑制CBP的方法,该方法包括使CBP与如本文披露的化合物或其盐接触。
本文还提供了抑制P300的方法,该方法包括使P300与如本文披露的化合物或其盐接触。
本文还提供了用于在患者中实现效果的方法,该方法包括向患者施用治疗有效量的如本文披露的化合物或其盐,其中该效果选自认知增强。
在某些实施例中,CBP介导的疾病是癌症。
在某些实施例中,P300介导的疾病是癌症。
还提供了在受试者中调节CBP介导的功能的方法,该方法包括施用治疗有效量的如本文披露的化合物或其盐。
还提供了在受试者中调节P300介导的功能的方法,该方法包括施用治疗有效量的如本文披露的化合物或其盐。
还提供了药物组合物,其包含如本文披露的化合物或其盐以及药学上可接受的载体。
在某些实施例中,将药物组合物配制为用于口服施用。
在某些实施例中,将药物组合物配制为用于肠胃外施用。
在某些实施例中,口服药物组合物选自片剂和胶囊。
缩写和定义
如本文所用,以下术语具有所指出的含义。
当披露值范围以及使用符号“从n1…至n2”或“在n1…与n2之间”(其中n1和n2是数字)时,则除非另外说明,否则此符号旨在包括这些数字本身以及它们之间的范围。此范围可以是整的或在这些端值之间连续的并且包括这些端值。举例来说,“2至6个碳”的范围旨在包括两个、三个、四个、五个和六个碳,因为碳以整数单位出现。通过举例,将范围“从1至3μM(微摩尔)”(其旨在包括1μM、3μM和介于两者之间的所有数)与有效数字的任何数字(例如,1.255μM、2.1μM、2.9999μM等)进行比较。
如本文所用,术语“约”旨在限定它所修饰的数值,表示此值在误差界限内可变。当未列举特定误差界限(如图表或数据表中给出的平均值的标准差)时,术语“约”应被理解为意指涵盖所列举值的范围、和考虑到有效数字通过四舍五入到该数字而被包括的范围。
如本文单独或组合所用,术语“酰基”是指附接到烯基、烷基、芳基、环烷基、杂芳基、杂环或任何其他部分上的羰基,其中附接到羰基上的原子是碳。“乙酰基”基团是指–C(O)CH3基团。“烷基羰基”或“烷酰基”基团是指通过羰基基团附接到母体分子部分上的烷基基团。此类基团的实例包括甲基羰基和乙基羰基。酰基基团的实例包括甲酰基、烷酰基和芳酰基。
如本文单独或组合所用,术语“烯基”是指具有一个或多个双键并含有从2至20个碳原子的直链或支链烃基。在某些实施例中,所述烯基将包含2至6个碳原子。术语“亚烯基”是指附接在两个或多个位置处的碳-碳双键体系,如亚乙烯基[(-CH=CH-),(-C::C-)]。适合的烯基基团的实例包括乙烯基、丙烯基、2-甲基丙烯基、1,4-丁二烯基等。除非另外说明,否则术语“烯基”可以包括“亚烯基”基团。
如本文单独或组合所用,术语“烷氧基”是指烷基醚基团,其中术语烷基是如下所定义的。适合的烷基醚基团的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
如本文单独或组合所用,术语“烷基”是指含有1至20个碳原子的直链或支链烷基基团。在某些实施例中,所述烷基将包含1至10个碳原子。在另外的实施例中,所述烷基将包含1至8个碳原子。烷基基团可以如本文所限定任选地被取代。烷基基团的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、辛基、壬基等。如本文单独或组合所用,术语“亚烷基(alkylene)”是指衍生自附接在两个或更多个位置处的直链或支链饱和烃的饱和脂肪族基团,如亚甲基(-CH2-)。除非另外说明,否则术语“烷基”可以包括“亚烷基”基团。
如本文单独或组合所用,术语“烷基氨基”是指通过氨基基团附接到母体分子部分上的烷基基团。适合的烷基氨基基团可以是单烷基化的或二烷基化的形成的基团,例如像N-甲基氨基、N-乙基氨基、N,N-二甲基氨基、N,N-乙基甲基氨基等。
如本文单独或组合所用,术语“亚烷基(alkylidene)”是指烯基基团,其中碳-碳双键的一个碳原子属于烯基基团所附接的部分。
如本文单独或组合所用,术语“烷硫基”是指烷基硫醚(R–S–)基,其中术语烷基如上定义,并且其中硫可以是单氧化或双氧化的。适合的烷基硫醚基团的实例包括甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基、甲磺酰基、乙亚磺酰基等。
如本文单独或组合所用,术语“炔基”是指具有一个或多个三键并且含有2至20个碳原子的直链或支链烃基。在某些实施例中,所述炔基包含2至6个碳原子。在另外的实施例中,所述炔基包含2至4个碳原子。术语“亚炔基”是指附接在两个位置处的碳-碳三键,如亚乙炔基(-C:::C-,-C≡C-)。炔基基团的实例包括乙炔基、丙炔基、羟基丙炔基、丁炔-1-基、丁炔-2-基、戊炔-1-基、3-甲基丁炔-1-基、己炔-2-基等。除非另外说明,否则术语“炔基”可以包括“亚炔基”基团。
如本文单独或组合所用,术语“酰胺基”和“氨甲酰基”是指如下所述通过羰基基团附接到母体分子部分上的氨基基团,或反之亦然。如本文单独或组合所用,术语“C-酰胺基”是指-C(O)N(RR’)基团,其中R和R'是如本文所定义的或如通过所指定的特别枚举的“R”基团定义的。如本文单独或组合所用,术语“N-酰胺基”是指RC(O)N(R’)-基团,其中R和R'是如本文所定义的或如通过所指定的特别枚举的“R”基团定义的。如本文单独或组合所用,术语“酰基氨基”包括通过氨基基团附接到母体部分上的酰基基团。“酰基氨基”基团的实例是乙酰基氨基(CH3C(O)NH-)。
如本文单独或组合所用,术语“氨基”是指-NRR’,其中R和R’独立地选自氢、烷基、酰基、杂烷基、芳基、环烷基、杂芳基和杂环烷基,其中任一个可以本身任选地被取代。另外,R和R’可以组合形成杂环烷基,这两个中的任一个可以任选地被取代。
如本文单独或组合所用,术语“芳基”意指含有一个、两个或三个环的碳环芳香族系统,其中此类多环环系统稠合在一起。术语“芳基”包括芳香族基团,如苯基、萘基、蒽基和菲基。
如本文单独或组合所用,术语“芳基烯基”或“芳烯基”是指通过烯基基团附接到母体分子部分上的芳基基团。
如本文单独或组合所用,术语“芳基烷氧基”或“芳烷氧基”是指通过烷氧基基团附接到母体分子部分上的芳基基团。
如如本文单独或组合所用,术语“芳基烷基”或“芳烷基”是指通过烷基基团附接到母体分子部分上的芳基基团。
如本文单独或组合所用,术语“芳基炔基”或“芳炔基”是指通过炔基基团附接到母体分子部分上的芳基基团。
如本文单独或组合所用,术语“芳基烷酰基”或“芳烷酰基”或“芳酰基”是指衍生自经芳基取代的链烷羧酸的酰基基团,如苯甲酰基、萘甲酰基、苯乙酰基、3-苯基丙酰基(氢肉桂酰基)、4-苯基丁酰基、(2-萘基)乙酰基、4-氯氢肉桂酰基等。
如本文单独或组合所用,术语芳氧基是指通过氧基附接到母体分子部分上的芳基基团。
如本文单独或组合所用,术语“苯并(benzo)”和“苯并(benz)”是指衍生自苯的二价基团C6H4=。实例包括苯并噻吩和苯并咪唑。
如本文单独或组合所用,术语“氨基甲酸酯”是指氨基甲酸的酯(-NHCOO-),其可以从氮或酸端附接到母体分子部分上,并且其可以如本文所定义的那样任选地被取代。
如本文单独或组合所用,术语“O-氨甲酰基”是指-OC(O)NRR’基团,其中R和R'如本文所定义。
如本文单独或组合所用,术语“N-氨甲酰基”是指ROC(O)NR’基团,其中R和R’如本文所定义。
如本文所用,术语“羰基”当单独时包括甲酰基[-C(O)H],并且当组合时是-C(O)-基团。
如本文所用,术语“羧基(carboxyl)”或“羧基(carboxy)”是指-C(O)OH或对应的“羧酸根”阴离子,如在羧酸盐中。“O-羧基”基团是指RC(O)O-基团,其中R是如本文所定义的。“C-羧基”基团是指-C(O)OR基团,其中R是如本文所定义的。
如本文单独或组合所用,术语“氰基”是指-CN。
如本文单独或组合所用,术语“环烷基”或可替代地“碳环”是指饱和的或部分饱和的单环、双环或三环烷基基团,其中每个环部分含有3至12个碳原子环成员,并且可以任选地是如本文所定义的任选地被取代的苯并稠合环系统。在某些实施例中,所述环烷基将包含5至7个碳原子。此类环烷基基团的实例包括环丙基、环丁基、环戊基、环己基、环庚基、四氢萘基、茚满基、八氢萘基、2,3-二氢-1H-茚基、金刚烷基等。如本文所用,“双环”和“三环”旨在包括两个稠合环系统,如十氢萘、八氢萘以及多环(多中心)饱和的或部分不饱和的类型。后一种类型的异构体通常以双环[1,1,1]戊烷、樟脑、金刚烷和双环[3,2,1]辛烷为例。
如本文单独或组合所用,术语“酯”是指对在碳原子处附接的两个部分进行桥接的羧基基团。
如本文单独或组合所用,术语“醚”是指对在碳原子处附接的两个部分进行桥接的氧基基团。
如本文单独或组合所用,术语“卤代”或“卤素”是指氟、氯、溴或碘。
如本文单独或组合所用,术语“卤代烷氧基”是指通过氧原子附接到母体分子部分上的卤代烷基基团。
如本文单独或组合所用,术语“卤代烷基”是指具有如上所定义的含义的烷基基团,其中一个或多个氢被卤素代替。确切地包括单卤代烷基、双卤代烷基和多卤代烷基基团。举一个例子,单卤代烷基基团可以在该基团内具有碘、溴、氯或氟原子。双卤代和多卤代烷基基团可以具有两个或更多个相同的卤原子或具有不同的卤代基团的组合。卤代烷基基团的实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。“卤代亚烷基”是指附接在两个或更多个位置处的卤代烷基基团。实例包括氟亚甲基(-CFH-)、二氟亚甲基(-CF2-)、氯亚甲基(-CHCl-)等。
如本文单独或组合所用,术语“杂烷基”是指稳定的直链或支链、或其组合,其为完全饱和的或含有1至3个不饱和度,其由所述数量的碳原子和一至三个选自N、O和S的杂原子组成,并且其中可以将N和S原子任选地氧化并且可以将N杂原子任选地季铵化。一个或多个杂原子可以放置在杂烷基基团的任意内部位置处。多达两个杂原子可以是连续的,例如像-CH2-NH-OCH3。
如本文单独或组合所用,术语“杂芳基”是指3至15元不饱和杂单环或稠合的单环、双环或三环环系统,其中所有稠合环均是芳香族的,其包含至少一个选自N、O和S的原子。术语“杂芳基”因此涵盖例如吡啶、噻吩、喹啉和菲啶。因此,术语“杂芳基”不涵盖例如吲哚啉和2,3-二氢苯并呋喃。在某些实施例中,所述杂芳基将包含1至4个杂原子作为环成员。在另外的实施例中,所述杂芳基将包含1至2个杂原子作为环成员。在某些实施例中,所述杂芳基将包含5至7个原子。该术语还包括稠合的多环基团,其中杂环与芳基环稠合,并且其中杂芳基环与其他杂芳基环稠合。杂芳基基团的实例包括吡咯基、吡咯烷基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噁二唑基、噻唑基、噻二唑基、异噻唑基、吲哚基、异吲哚基、吲哚嗪基、苯并咪唑基、喹啉基、异喹啉基、喹喔啉基、喹唑啉基等。示例性三环杂环基团包括咔唑基、菲咯啉基、二苯并呋喃基、吖啶基、菲啶基等。
如本文单独或组合所用,术语“杂环烷基”和可互换地“杂环”分别是指饱和的、部分不饱和的或完全不饱和的(但不是完全芳香族的)单环、双环或三环杂环基团,其包含至少一个杂原子作为环成员,其中每个所述杂原子可以独立地选自氮、氧和硫。因此,术语“杂环烷基”不包括完全芳香族的环系统,如吡啶、嘧啶、喹啉和吖啶。因此,术语“杂环烷基”包括部分芳香族的双环环系统和较大的环系统,如1,2,3,4-四氢喹啉、5,6,7,8-四氢喹啉和吲哚啉。在某些实施例中,所述杂环烷基将包含1至4个杂原子作为环成员。在另外的实施例中,所述杂环烷基将包含1至2个杂原子作为环成员。在某些实施例中,所述杂环烷基将在每个环中包含3至8个环成员。在另外的实施例中,所述杂环烷基将在每个环中包含3至7个环成员。在又另外的实施例中,所述杂环烷基将在每个环中包含5至6个环成员。“杂环烷基”和“杂环”旨在包括砜、亚砜、具有叔氮环成员的N-氧化物以及碳环稠合环系统和苯并稠合环系统;另外,这两个术语还包括如下系统,其中杂环与如本文所定义的芳基基团或另外的杂环基团稠合。杂环基团的实例包括吖丙啶基、氮杂环丁烷基、1,3-苯并间二氧杂环戊烯基、二氢异吲哚基、二氢异喹啉基、二氢噌啉基、二氢苯并二噁英基、二氢[1,3]噁唑并[4,5-b]吡啶基、苯并噻唑基、二氢吲哚基、二氢吡啶基、1,3-二噁烷基、1,4-二噁烷基、1,3-二氧戊环基、异二氢吲哚基、吗啉基、哌嗪基、吡咯烷基、四氢吡啶基、哌啶基、硫代吗啉基等。除非明确地禁止,否则杂环基团可以任选地被取代。
本披露中的某些化合物可以包含二氮杂萘基团,其将被理解为萘的衍生物,其中两个非桥头CH基团被N代替。术语“二氮杂萘”涵盖苯并二嗪的四种异构体(其两个氮在同一环中)和萘啶的六种异构体(其氮在不同的环上)。
如本文单独或组合所用,术语“肼基”是指由单键连接的两个氨基基团,即-N-N-。
如本文单独或组合所用,术语“羟基”是指-OH。
如本文单独或组合所用,术语“羟基烷基”是指通过烷基基团附接到母体分子部分上的羟基基团。
如本文单独或组合所用,术语“亚氨基”是指=N-。
如本文单独或组合所用,术语“亚氨基羟基”是指=N(OH)和=N-O-。
短语“在主链中”是指起始于某基团与具有本文披露的任一式的化合物的附接点处的碳原子的最长连续链或相邻链。
术语“异氰酸基”是指-NCO基团。
术语“异硫氰酸基”是指-NCS基团。
短语“原子的线性链”是指原子的最长直链,这些原子独立地选自碳、氮、氧和硫。
如本文单独或组合所用,在没有另外明确定义的情况下,术语“低级”意指含有1至6个碳原子,并且包括6个碳原子(即,C1-C6烷基)。
如本文单独或组合所用,术语“低级芳基”意指苯基或萘基,其中的任一个可以如所提供的任选地被取代。
如本文单独或组合所用,术语“低级杂芳基”意指1)包含五个或六个环成员的单环杂芳基,其中一个至四个所述成员可以是选自N、O和S的杂原子,或2)双环杂芳基,其中每个稠合环包含五个或六个环成员,在它们之间包含一至四个选自N、O和S的杂原子。
如本文单独或组合所用,术语“低级环烷基”意指具有三至六个环成员的单环环烷基(即,C3-C6环烷基)。低级环烷基可以是不饱和的。低级环烷基的实例包括环丙基、环丁基、环戊基和环己基。
如本文单独或组合所用,术语“低级杂环烷基”意指具有三至六个环成员的单环杂环烷基,其中一至四个可以是选自N、O和S的杂原子(即,C3-C6杂环烷基)。低级杂环烷基的实例包括吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、哌嗪基和吗啉基。低级杂环烷基可以是不饱和的。
如本文单独或组合所用,术语“低级氨基”是指-NRR',其中R和R'独立地选自氢和低级烷基,这两个中的任一个可以任选地被取代。
如本文单独或组合所用,术语“巯基”是指RS-基团,其中R是如本文所定义的。
如本文单独或组合所用,术语“硝基”是指–NO2。
如本文单独或组合所用,术语“氧基”或“氧杂”是指–O–。
如本文单独或组合所用,术语“氧代”是指=O。
术语“全卤代烷氧基”是指烷氧基基团,其中所有的氢原子都被卤素原子代替。
如本文单独或组合所用,术语“全卤代烷基”是指烷基基团,其中所有的氢原子都被卤素原子代替。
如本文单独或组合所用,术语“磺酸酯”、“磺酸(sulfonic acid和sulfonic)”是指-SO3H基团并且其阴离子作为磺酸用于盐形成中。
如本文单独或组合所用,术语“硫烷基”是指-S-。
如本文单独或组合所用,术语“亚磺酰基”是指–S(O)–。
如本文单独或组合所用,术语“磺酰基”是指–S(O)2–。
术语“N-磺酰胺基”是指RS(=O)2NR’-基团,其中R和R'是如本文所定义的。
术语“S-磺酰胺基”是指-S(=O)2NRR’基团,其中R和R’是如本文所定义的。
如本文单独或组合所用,术语“硫杂”和“硫代”是指–S–基团或其中氧被硫替代的醚。硫代基团的被氧化的衍生物(即亚磺酰基和磺酰基)包括在硫杂和硫代的定义中。
如本文单独或组合所用,术语“硫醇”是指–SH基团。
如本文所用,术语“硫代羰基”当单独时包括硫代甲酰基–C(S)H,并且当组合时是–C(S)–基团。
术语“N-硫代氨甲酰基”是指ROC(S)NR’–基团,其中R和R’是如本文所定义的。
术语“O-硫代氨甲酰基”是指–OC(S)NRR’基团,其中R和R’是如本文所定义的。
术语“硫氰酸基”是指–CNS基团。
术语“三卤代甲磺酰胺基”是指X3CS(O)2NR–基团,其中X是卤素并且R如本文定义。
术语“三卤代甲磺酰基”是指X3CS(O)2–基团,其中X是卤素。
术语“三卤代甲氧基”是指X3CO–基团,其中X是卤素。
如本文单独或组合所用,术语“三取代的甲硅烷基”是指在其三个自由价处被本文在取代的氨基的定义下所列出的基团取代的有机硅基团。实例包括三甲基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基等。
本文的任何定义可以与任何其他定义结合使用以描述复合结构基团。按照惯例,任何此类定义的尾随元素是附接到母体部分上的元素。例如,复合基团烷基酰胺基表示通过酰胺基基团附接到母体分子上的烷基基团,并且术语烷氧基烷基表示通过烷基基团附接到母体分子上的烷氧基基团。
当基团被定义为“无(null)”时,意指所述基团是不存在的。
术语“任选地被取代的”意指前述基团可以被取代或不被取代。当被取代时,“任选地被取代的”基团的取代基可包括但不限于独立地选自以下基团或特定指定的一组基团(单独或组合)的一个或多个取代基:低级烷基、低级烯基、低级炔基、低级烷酰基、低级杂烷基、低级杂环烷基、低级卤代烷基、低级卤代烯基、低级卤代炔基、低级全卤代烷基、低级全卤代烷氧基、低级环烷基、苯基、芳基、芳氧基、低级烷氧基、低级卤代烷氧基、氧代、低级酰氧基、羰基、羧基、低级烷基羰基、低级羧酸酯、低级甲酰胺基、氰基、氢、卤素、羟基、氨基、低级烷基氨基、芳基氨基、酰胺基、硝基、硫醇、低级烷硫基、低级卤代烷硫基、低级全卤代烷硫基、芳硫基、磺酸酯、磺酸、三取代的甲硅烷基、N3、SH、SCH3、C(O)CH3、CO2CH3、CO2H、吡啶基、噻吩、呋喃基、低级氨基甲酸酯和低级脲。在结构上可行的情况下,可以将两个取代基连接在一起以形成由零至三个杂原子组成的稠合的五元、六元或七元碳环或杂环,例如形成亚甲二氧基或亚乙二氧基。任选取代的基团可以是未取代的(例如-CH2CH3)、完全取代的(例如-CF2CF3)、单取代的(例如-CH2CH2F)或以完全取代与单取代之间的任意水平取代(例如-CH2CF3)。在叙述取代基而未定性为取代的情况下,涵盖取代形式和未取代形式两者。在取代基被定性为“取代的”情况下,尤其意指取代形式。另外,对特定部分的不同组的任选取代基可以按需进行定义;在这些情况下,任选的取代将是如所定义的,通常紧跟在短语“任选地被取代”之后。
除非另有定义,否则术语R或术语R’(独自出现并且没有数字指定的情况下)是指选自以下的部分:氢、烷基、环烷基、杂烷基、芳基、杂芳基以及杂环烷基,这些基团中的任何基团可以任选地被取代。此类R和R’基团应理解为如本文所定义的那样任选地被取代。无论R基团是否具有数字指定,应当理解的是,每个R基团(包括R、R’和Rn,其中n=(1、2、3、……n))、每个取代基和每个术语就从组的选择而论是独立于所有其他的。如果任何变量、取代基或术语(例如,芳基、杂环、R等)在某式或通用结构中出现不止一次,则在每次出现时其定义应当独立于在其他每次出现时的定义。本领域的技术人员将进一步认识到,某些基团可以附接到母体分子上或可以在从如所写的任一端的元素的链中占据位置。例如,如-C(O)N(R)-的不对称基团可以在碳或氮处附接至母体部分。
不对称中心存在于本文披露的化合物中。这些中心由符号“R”或“S”指定,取决于手性碳原子周围的取代基的构型。应当理解,本披露涵盖所有立体化学异构体形式,包括非对映异构体、对映异构体和差向异构体形式,以及d-异构体和1-异构体,以及它们的混合物。化合物的单独立体异构体可以从可商购的含有手性中心的起始材料合成制备,或通过制备对映异构体的产物的混合物随后分离,如转化为非对映异构体的混合物随后分离或重结晶、色谱技术、在手性色谱柱上直接分离对映异构体,或本领域已知的任何其他适当的方法来制备。特定立体化学的起始化合物是可商购的,或可以通过本领域已知的技术进行制备并拆分。另外,本文披露的化合物可以作为几何异构体存在。本披露包括所有顺式、反式、同式、逆式、异侧(E)和同侧(Z)异构体,以及它们的适当混合物。另外,化合物可以作为互变异构体存在;本披露提供了所有互变异构体。另外,本文披露的化合物可以按非溶剂化形式以及与药学上可接受的溶剂如水、乙醇等的溶剂化形式存在。通常,认为溶剂化形式等效于非溶剂化形式。
当通过键连接的原子被认为是较大子结构的部分时,术语“键”是指在两个原子或两个部分之间的共价键。除非另外说明,否则键可以是单键、双键或三键。在分子图中,在两个原子之间的虚线指示另外的键在该位置可以存在或不存在。
如本文所用,术语“疾病”旨在通常与术语“障碍”、“综合征”和“病症”(如在医学病症中)同义并且可以与这些术语互换使用,因为所有这些都反映了人体或动物体的或其部位之一的损害了正常功能的异常情况,典型地表现为区别的体征和症状,并且使人或动物有减少的寿命期限或降低的生活质量。
术语“组合疗法”意指施用两种或更多种治疗剂来治疗本披露中所述的治疗的病症或障碍。这种施用涵盖以基本上同时的方式共同施用这些治疗剂,如以具有固定比率的活性成分的单个胶囊施用或以每种活性成分的多个分开的胶囊施用。此外,这种施用还涵盖以依次的方式使用每种类型的治疗剂。在任一情况下,治疗方案将在治疗本文所述的病症或障碍中提供药物组合的有益作用。
如本文所用,“CBP抑制剂”是指以可测量的亲和力和活性结合并抑制CBP的溴结构域的化合物。在某些实施例中,如在本文总体描述的CBP(测定法名称)中所测量的,CBP抑制剂相对于CBP活性表现出不超过约100μM,更典型地不超过约50μM的IC50。“IC50”是将CBP的溴结构域的活性降低至最大水平的一半的抑制剂浓度。已经发现本文披露的某些化合物表现出对CBP的抑制。在某些实施例中,化合物相对于CBP将表现出不超过约20μM的IC50;在另外的实施例中,化合物相对于CBP将表现出不超过约5μM的IC50;在另外的实施例中,化合物相对于CBP将表现出不超过约200nM的IC50;在另外的实施例中,化合物相对于CBP将表现出不超过约50nM的IC50;在另外的实施例中,化合物相对于CBP将表现出不超过约10nM的IC50;在另外的实施例中,如在本文所述的CBP测定法中所测量的,化合物相对于CBP将表现出不超过约2nM的IC50。
如本文所用,“P300抑制剂”是指以可测量的亲和力和活性结合并抑制P300的溴结构域的化合物。在某些实施例中,如在本文总体描述的P300(测定法名称)中所测量的,P300抑制剂相对于P300活性表现出不超过约100μM,更典型地不超过约50μM的IC50。“IC50”是将P300的溴结构域的活性降低至最大水平的一半的抑制剂浓度。已经发现本文披露的某些化合物表现出对P300的抑制。在某些实施例中,化合物相对于P300将表现出不超过约20μM的IC50;在另外的实施例中,化合物相对于P300将表现出不超过约5μM的IC50;在另外的实施例中,化合物相对于P300将表现出不超过约200nM的IC50;在另外的实施例中,化合物相对于P300将表现出不超过约50nM的IC50;在另外的实施例中,化合物相对于P300将表现出不超过约10nM的IC50;在另外的实施例中,如在本文所述的P300测定法中所测量的,化合物相对于P300将表现出不超过约2nM的IC50。
在一些实施例中,本文披露的某些化合物干扰CBP和/或EP300与组蛋白,特别是组蛋白中的乙酰化赖氨酸的缔合。在一些实施例中,本文披露的某些化合物抑制CBP和/或EP300与染色质(例如,组蛋白相关的DNA)的结合。在一些实施例中,本文披露的某些化合物抑制和/或减少CBP溴结构域和/或EP300溴结构域与染色质(例如,组蛋白相关的DNA)的结合。在一些实施例中,本文披露的某些化合物不影响CBP和/或EP300的其他结构域与染色质的缔合。在一些实施例中,本文披露的某些化合物主要(例如,仅)通过与CBP溴结构域和/或EP300溴结构域的接触和/或相互作用而与CBP和/或EP300结合。在一些实施例中,本文披露的某些化合物通过与CBP溴结构域和/或EP300溴结构域以及另外的CBP和/或EP300残基和/或结构域的接触和/或相互作用而与CBP和/或EP300结合。测定与染色质缔合的方法是本领域已知的,并且包括但不限于染色质分级分离、BRET测定法(普洛麦格公司(Promega))、FRAP测定法、染色质免疫沉淀(ChIP)、生物物理结合测定法和/或组蛋白缔合测定法。参见例如Das等人,BioTechniques[生物技术]37:961-969(2004)。
短语“治疗有效”旨在限制在疾病或障碍的治疗中或对临床终点产生效果使用的活性成分的量。
术语“治疗上可接受的”是指适用于与患者组织接触而不产生过度毒性、刺激和过敏反应的化合物(或盐、前药、互变异构体、两性离子形式等),这些化合物与合理受益/风险比相称,且对于其预定用途是有效的。
如本文所用,提及“治疗”患者旨在包括预防。治疗也可以是自然地抢占先机,即,它可以包括疾病的预防。疾病的预防可以涉及完全免受疾病,例如像在预防病原体感染的情况下,或可以涉及疾病进展的预防。例如,疾病的预防可以不意指完全圈定任何水平的与疾病相关的任何效果,而是可意指将疾病的症状预防至临床上显著的或可检测的水平。疾病的预防也可以意指预防疾病进展至疾病的更晚阶段。
术语“患者”通常与术语“受试者”同义,并且包括所有哺乳动物,包括人。患者的实例包括人、牲畜(如牛、山羊、绵羊、猪和兔)和宠物(如狗、猫、兔和马)。优选地,患者是人。
术语“前药”是指在体内变得更具活性的化合物。本文披露的某些化合物也可以作为前药存在,如Hydrolysis in Drug and Prodrug Metabolism:Chemistry,Biochemistry,and Enzymology[药物和前药代谢中的水解:化学、生物化学和酶学](Testa,Bernard和Mayer,Joachim M.Wiley-VHCA,Zurich,Switzerland[瑞士苏黎世威利-VHCA出版社]2003)中所述。本文所述化合物的前药是以下化合物的结构改良型:该化合物在生理条件下容易进行化学变化来提供该化合物。另外,在离体环境中,通过化学方法或生化方法可以将前药转变成该化合物。例如,当前药置于经皮贴片贮器内部时用合适的酶试剂或化学试剂可以将前药缓慢地转变成化合物。因为在一些情况下前药可以比化合物或母体药物更容易施用,所以它们经常是有用的。例如,它们可以是通过口服施用而生物可利用的,而母体药物却不行。前药还可以在药物组合物中具有改善的优于母体药物的溶解性。本领域已知多种前药衍生物,如依赖于前药的水解切割或氧化激活的那些。前药的实例是(但不限于)作为酯(该“前药”)施用的化合物,但是然后代谢水解为羧酸,即活性实体。另外的实例包括化合物的肽基衍生物。
本文披露的化合物可以作为治疗上可接受的盐存在。本披露包括以上以盐形式列出的化合物,该盐形式包括酸加成盐。合适的盐包括与有机酸和无机酸两者形成的盐。这种酸加成盐通常是药学上可接受的。然而,非药学上可接受的盐的盐可以在所讨论的化合物的制备和纯化中是有效用的。也可以形成碱加成盐,并且其是药学上可接受的。有关盐的制备和选择的更完整讨论,请参阅Pharmaceutical Salts:Properties,Selection,and Use[可药用盐:特性、选择与用途](Stahl,P.Heinrich.Wiley-VCHA,Zurich,Switzerland[瑞士苏黎世威利-VHCA出版社],2002)。
如本文所用,术语“治疗上可接受的盐”表示本文披露的化合物的盐或两性离子形式,其是水溶性的或油溶性的或可分散的并且是如本文所定义的治疗上可接受的。这些盐可以在化合物的最终分离和纯化期间制备,或者通过使游离碱形式的适当化合物与合适的酸反应来分别地制备。代表性的酸加成盐包括乙酸盐、己二酸盐、海藻酸盐、L-抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(benzenesulfonate,besylate)、重硫酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡萄糖酸盐、甲酸盐、延胡索酸盐、龙胆酸盐、戊二酸盐、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟乙磺酸盐(羟乙基磺酸盐)、乳酸盐、马来酸盐、丙二酸盐、DL-扁桃酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、焦谷氨酸盐、琥珀酸盐、磺酸盐、酒石酸盐、L-酒石酸盐、三氯乙酸盐、2,2,2-三氟乙酸盐=三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐(para-toluenesulfonate,p-tosylate)以及十一烷酸盐。并且,可以将本文披露的化合物中的碱性基团用甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;二甲基、二乙基、二丁基和二戊基的硫酸酯;癸基、月桂基、豆蔻基和甾醇基的氯化物、溴化物和碘化物;以及苯甲基和苯乙基的溴化物来季铵化。可以采用以形成治疗上可接受的加成盐的酸的实例包括无机酸(如盐酸、氢溴酸、硫酸和磷酸)以及有机酸(如草酸、马来酸、琥珀酸和柠檬酸)。盐还可以通过这些化合物与碱金属或碱土离子的配位形成。因此,本披露考虑了本文披露的化合物的钠、钾、镁和钙盐等。
碱加成盐可以在化合物最终的分离和纯化过程中,通过使羧基基团与合适的碱(如金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)或与氨或有机伯、仲或叔胺反应来制备。治疗上可接受的盐的阳离子包括锂、钠、钾、钙、镁和铝,以及无毒季胺阳离子如铵、四甲铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺、三丁胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、普鲁卡因、二苄胺、N,N-二苄基苯乙胺、1-二苯羟甲胺和N,N'-二苄基乙二胺。可用于形成碱加成盐的其他代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶和哌嗪。
药物组合物
虽然本披露的化合物可能作为原始化学物质施用,它们还可能作为药物配制品来提供。因此,本文提供了药物配制品,这些药物配制品包含本文披露的某些化合物中的一种或多种,或者其一种或多种药学上可接受的盐、酯、前药、酰胺或溶剂化物,以及一种或多种其药学上可接受的载体和任选地一种或多种其他治疗成分。在与配制品的其他成分相容并且对其接受者无害的意义上,一种或多种载体必须是“可接受的”。合适的配制品取决于所选择的施用途径。任何熟知的技术、载体和赋形剂均可以在适合时并且如本领域已知的那样使用。本文披露的药物组合物可以用本领域已知的任何方式制造,例如通过常规的混合、溶解、造粒、造糖衣丸、磨细、乳化、包囊、包埋或压片方法。
配制品包括适于口服、肠胃外(包括皮下、皮内、肌内、静脉内、关节内和髓内)、腹膜内、经粘膜、经皮、直肠和局部(包括皮肤、经颊、舌下和眼内)施用的那些,但最适合的途径可以取决于例如接受者的病症和障碍。配制品可以方便地以单位剂型存在并且可以通过药学领域熟知的任何方法制备。典型地,这些方法包括使本文披露的化合物或其药学上可接受的盐、酯、酰胺、前药或溶剂化物(“活性成分”)与构成一种或多种辅助成分的载体相关联的步骤。通常,通过将活性成分与液体载体或细碎固体载体或两者均匀且紧密地缔合来制备配制品,并且然后如果需要,使产物成形来制备希望的配制品。
口服施用
本披露的化合物可以口服施用,包括吞咽,使化合物进入胃肠道,或包括舌下或经颊施用,使化合物从口直接吸收到血流中。
用于口服施用的合适的组合物包括固体配制品如片剂、丸剂、扁囊剂、锭剂、和硬胶囊或软胶囊(其可含有液体、凝胶、粉末或颗粒)、水性液体或非水性液体中的溶液或悬浮液,或呈现为水包油液体乳液或油包水液体乳液。活性成分也可以大丸剂、药糖剂或糊剂呈现。
在片剂或胶囊剂型中,存在的药的量可为剂型的按重量计约0.05%至约95%,更典型地约2%至约50%。
此外,片剂或胶囊可以含有崩解剂,其占剂型的按重量计约0.5%至约35%,更典型地约2%至约25%。崩解剂的实例包括甲基纤维素、羧甲基纤维素钠或钙、交联羧甲基纤维素钠、聚乙烯吡咯烷酮、羟丙基纤维素、淀粉等。
用于片剂的合适的粘合剂包括明胶、聚乙二醇、糖、树胶、淀粉、羟丙基纤维素等。用于片剂的合适的稀释剂包括甘露糖醇、木糖醇、乳糖、右旋糖、蔗糖、山梨糖醇和淀粉。
用于片剂或胶囊的合适的表面活性剂和助流剂能以按重量计约0.1%至约3%的量存在,并且包括聚山梨酯80、十二烷基硫酸钠、滑石和二氧化硅。
用于片剂或胶囊的合适的润滑剂能以按重量计约0.1%至约5%的量存在,并且包括硬脂酸钙、硬脂酸锌或硬脂酸镁、硬脂酰富马酸钠等。
片剂可以通过压制或模制,任选地用一种或多种辅助成分制成。可以通过在适合的机器中压制处于自由流动形式(如粉末或颗粒)的活性成分来制备压制片,该活性成分任选地与粘合剂、惰性稀释剂或润滑剂、表面活性剂或分散剂混合。模制片可以通过在适合的机器中模制用液体稀释剂润湿的粉状化合物的混合物来制备。可以将染料或颜料添加到片剂中,以用于鉴别或表征活性化合物剂量的不同组合。
液体配制品可以包括乳液、溶液、糖浆、酏剂和悬浮液,它们可以用于软胶囊或硬胶囊。此类配制品可以包括药学上可接受的载体,例如水、乙醇、聚乙二醇、纤维素或油。配制品还可以包括一种或多种乳化剂和/或悬浮剂。
用于口服施用的组合物可以配制为即刻释放或缓释,包括延迟或持续释放,任选地具有肠溶包衣。
在另一个实施例中,药物组合物包含治疗有效量的具有式(I)的化合物或其药学上可接受的盐以及药学上可接受的载体。
可以口服使用的药物制剂包括片剂、由明胶制成的推入配合式(push-fit)胶囊、以及由明胶和增塑剂如甘油或山梨糖醇制成的密封的软胶囊。片剂可以通过压制或模制,任选地用一种或多种辅助成分制成。可以通过在适合的机器中压制处于自由流动形式(如粉末或颗粒)的活性成分来制备压制片,该活性成分任选地与粘合剂、惰性稀释剂或润滑剂、表面活性剂或分散剂混合。模制片可以通过在适合的机器中模制用惰性液体稀释剂润湿的粉状化合物的混合物来制备。片剂可以任选地被包衣或刻痕,并且可以被配制成实现其中的活性成分的缓慢或受控释放。所有用于口服施用的配制品应以适合于这种施用的剂量使用。推入配合式胶囊可以含有与填充剂如乳糖、粘合剂如淀粉和/或润滑剂如滑石或硬脂酸镁以及任选地稳定剂配混的活性成分。在软胶囊中,可以将活性化合物溶解或悬浮在合适的液体如脂肪油、液体石蜡或液体聚乙二醇中。此外,可以添加稳定剂。糖衣丸的芯具有合适的包衣。出于这个目的,可使用浓缩的糖溶液,这些糖溶液可任选地含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波姆胶、聚乙二醇和/或二氧化钛、漆溶液,以及适合的有机溶剂或溶剂混合物。可以将染料或颜料添加到片剂或糖衣丸包衣中,以用于鉴别或表征活性化合物剂量的不同组合。
肠胃外施用
本披露的化合物可以通过注射,例如通过推注或连续输注直接施用到血流、肌肉或内部器官中。用于肠胃外施用的合适的方式包括静脉内、肌内、皮下动脉内、腹膜内、鞘内、颅内等。用于肠胃外施用的合适的装置包括注射器(包括带针和无针注射器)和输注方法。配制品可以呈现在单位剂量或多剂量容器(例如密封的安瓿和小瓶)中。
大多数肠胃外配制品是含有赋形剂(包括盐、缓冲剂、悬浮剂、稳定剂和/或分散剂)、抗氧化剂、抑菌剂、防腐剂、和使配制品与预期接受者的血液等渗的溶质、和碳水化合物的水溶液。
肠胃外配制品也可以脱水形式制备(例如,通过冻干)或制备为无菌非水溶液。这些配制品可与合适的媒介物如无菌水一起使用。溶解性增强剂也可用于制备肠胃外溶液。用于肠胃外施用的组合物可以配制为即刻释放或缓释,包括延迟或持续释放。化合物还可以被配制为贮库(depot)制剂。此类长效配制品可以通过植入(例如,皮下或肌内)或通过肌内注射来施用。因此,例如,这些化合物可以与合适的聚合物或疏水性材料(例如,作为在可接受的油中的乳液)或离子交换树脂一起配制,或被配制成微溶性衍生物,例如被配制成微溶性盐。
化合物可以被配制为用于通过注射(例如通过推注或连续输注)进行肠胃外施用。用于注射的配制品可以以单位剂型而存在,例如在添加有防腐剂的安瓿中或在多剂量容器中。组合物可采取此类形式,如在油性或水性媒介物中的悬浮液、溶液或乳液,并且可含有配制剂,如悬浮剂、稳定剂和/或分散剂。配制品可以呈现在单位剂量或多剂量容器(例如密封的安瓿和小瓶)中,并且可以以粉末形式或于冷冻干燥(冻干)条件下储存,并且仅需要在即将使用之前添加无菌液体载体(例如生理盐水或无菌无热原水)。临时注射溶液和悬浮液可以由先前描述类型的无菌粉末、颗粒和片剂制备。
用于肠胃外施用的配制品包括活性化合物的水性和非水性(油性)无菌注射溶液,其可以包含抗氧化剂、缓冲液、抑菌剂和使配制品与预期接受者的血液等渗的溶质;以及水性和非水性无菌悬浮液,其可以包括悬浮剂和增稠剂。适合的亲脂性溶剂或媒介物包括脂肪油如芝麻油或合成的脂肪酸酯如油酸乙酯或甘油三酯,或者脂质体。水性注射悬浮液可以含有增加悬浮液的粘度的物质,如羧甲基纤维素钠、山梨糖醇或葡聚糖。任选地,悬浮液还可以含有合适的稳定剂或增加化合物的溶解性的药剂,以允许制备高度浓缩的溶液。
除了前述配制品之外,化合物还可以被配制为贮库制剂。此类长效配制品可以通过植入(例如,皮下或肌内)或通过肌内注射来施用。因此,例如,这些化合物可以与合适的聚合物或疏水性材料(例如,作为在可接受的油中的乳液)或离子交换树脂一起配制,或被配制成微溶性衍生物,例如被配制成微溶性盐。
局部施用
本披露的化合物可以局部施用(例如施用至皮肤、粘膜、耳朵、鼻子或眼睛)或经皮施用。用于局部施用的配制品可以包括但不限于洗剂、溶液、霜剂、凝胶剂、水凝胶、软膏剂、泡沫剂、植入剂、贴剂等。用于局部施用配制品的药学上可接受的载体可包括水、醇、矿物油、甘油、聚乙二醇等。局部施用还可以通过(例如)电穿孔、离子电渗疗法、超声透入疗法等进行。
典型地,局部施用的活性成分可占配制品的0.001%至10%w/w(按重量计)。在某些实施例中,活性成分可占配制品的多达10%w/w;少于5%w/w;2%w/w至5%w/w;或0.1%至1%w/w。
用于局部施用的组合物可以配制为即刻释放或缓释,包括延迟或持续释放。
本文披露的某些化合物可以局部地施用,即通过非全身施用。这包括将本文披露的化合物经外部施用至表皮或口腔以及将此种化合物滴注至耳朵、眼睛和鼻子中,使得该化合物不会大量进入血流。相比之下,全身施用是指口服、静脉内、腹膜内和肌内施用。
适于局部施用的配制品包括适于渗透通过皮肤至炎症部位的液体或半液体制剂,如凝胶剂、搽剂、洗剂、霜剂、软膏剂或糊剂,以及适于施用至眼睛、耳朵或鼻子的滴剂。局部施用的活性成分可占例如配制品的0.001%至10%w/w(按重量计)。在某些实施例中,活性成分可占多达10%w/w。在其他实施例中,它可占少于5%w/w。在某些实施例中,活性成分可占2%w/w至5%w/w。在其他实施例中,它可占配制品的0.1%至1%w/w。
直肠、经颊和舌下施用
用于本披露化合物的直肠施用的栓剂可通过将活性药剂与合适的无刺激性的赋形剂混合来制备,这些赋形剂例如是可可脂,合成的单-、二-、或三甘油酯,脂肪酸或聚乙二醇,它们在常温下是固体,但在直肠温度下为液体,并因此熔化于直肠和释放药物。
对于经颊或舌下施用,组合物可以采取以常规方式配制的片剂、锭剂、糖果锭剂、或凝胶的形式。此类组合物可以包含调味基质如蔗糖和阿拉伯树胶或黄芪胶中的活性成分。
这些化合物还可以被配制为直肠组合物,如栓剂或保留灌肠剂,例如含有常规栓剂基质,如可可脂、聚乙二醇、或其他甘油酯。
通过吸入施用
针对通过吸入施用,化合物可以方便地从吹入器、喷雾器加压包或其他递送气雾剂喷雾的方便的手段来递送。加压包可以包含合适的推进剂,如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体。在加压气雾剂的情况下,剂量单位可以通过提供用于递送一个计量量的阀门来确定。可替代地,对于通过吸入或吹入施用,根据本披露的化合物可以采用干燥的粉末组合物的形式,例如,该化合物与适合的粉末基质(如乳糖或淀粉)的粉末混合物。粉末组合物可以以单位剂型呈现在例如胶囊、药筒、明胶或泡罩包装中,粉末从中可以借助于吸入器或吹入器施用。
也可使用制药领域所公知的其他载体材料和施用方式。本披露的药物组合物可以通过任何药学上熟知的技术(如有效配制和施用程序)来制备。优选的单位剂量配制品是含有有效剂量的(如下文所叙述的)或其适当部分的活性成分的那些。
应当理解,除了上文特别提及的成分外,上述配制品还可以包括本领域中考虑到所讨论配制品的类型的其他常规试剂,例如适合于口服施用的那些配制品可以包括调味剂。
化合物可以经口服或经由注射以每天0.1至500mg/kg的剂量施用。成人的剂量范围通常为5mg至2g/天。以离散单位提供的片剂或其他呈现形式可以方便地包含一定量的一种或多种化合物,其以这种剂量或多个这种剂量有效,例如,含有5mg至500mg(通常为约10mg至200mg)的单位。
可以与载体材料组合产生单一剂型的活性成分的量将取决于所治疗的宿主和特定的施用方式而变化。
可以按多种方式施用化合物,例如口服、局部或通过注射。向患者施用的化合物的精确量是主治医生的职责。针对任何特定患者的特定剂量水平将取决于多种因素,包括所使用的特定化合物的活性、年龄、体重、一般健康情况、性别、饮食、施用时间、施用途径、排泄速率、药物组合、所治疗的确切的障碍以及所治疗的适应症或病症的严重程度。此外,施用途径可以根据病症及其严重程度而变化。关于有效配制和施用程序的上述考虑在本领域中是众所周知的,并且在标准教科书中有描述。
优选的单位剂量配制品是含有有效剂量的(如下文所叙述的)或其适当部分的活性成分的那些。
应当理解,除了上文特别提及的成分外,上述配制品还可以包括本领域中考虑到所讨论配制品的类型的其他常规试剂,例如适合于口服施用的那些配制品可以包括调味剂。
化合物可以经口服或经由注射以每天0.1至500mg/kg的剂量施用。成人的剂量范围通常为5mg至2g/天。以离散单位提供的片剂或其他呈现形式可以方便地包含一定量的一种或多种化合物,其以这种剂量或多个这种剂量有效,例如,含有5mg至500mg(通常为约10mg至200mg)的单位。
可以与载体材料组合产生单一剂型的活性成分的量将取决于所治疗的宿主和特定的施用方式而变化。
可以按多种方式施用化合物,例如口服、局部或通过注射。向患者施用的化合物的精确量是主治医生的职责。针对任何特定患者的特定剂量水平将取决于多种因素,包括所使用的特定化合物的活性、年龄、体重、一般健康情况、性别、饮食、施用时间、施用途径、排泄速率、药物组合、所治疗的确切的障碍以及所治疗的适应症或病症的严重程度。同样,施用途径可以根据病症及其严重程度而变化。
组合和组合疗法
在某些情况下,可能适当的是,将至少一种本文所述的化合物(或其药学上可接受的盐、酯或前药)与另一种治疗剂组合施用。仅通过举例,如果患者在接受本文中的一种化合物时经历的副作用之一是高血压,则将抗高血压剂与初始治疗剂组合施用可能是适当的。或者,仅通过举例,可以通过施用辅助剂来增强本文所述的化合物之一的治疗效果(即,辅助剂本身仅具有微弱的治疗益处,但是与另一种治疗剂组合时,对患者的总体治疗益处得到增强)。或者,仅通过举例,可以通过将本文所述的化合物之一与也具有治疗益处的另一种治疗剂(也包括治疗方案)一起施用来增加患者所经历的益处。仅通过举例,在涉及施用本文所述的化合物之一的糖尿病治疗中,还可以通过向患者提供另一种糖尿病治疗剂来增加治疗益处。在任何情况下,无论所治疗的疾病、障碍或病症如何,患者所经历的总体益处可能只是两种治疗剂的加和,或者患者可能经历协同益处。
可能的组合疗法的特定非限制性实例包括本发明的某些化合物与抗癌(化疗)药一起使用。抗癌药的类别包括但不限于:烷化剂、抗代谢药、抗有丝分裂剂、检查点抑制剂、植物生物碱和萜类化合物、拓扑异构酶抑制剂、细胞毒性抗生素、芳香酶抑制剂、血管生成抑制剂、抗类固醇和抗雄激素、mTOR抑制剂、酪氨酸激酶抑制剂等。
针对在癌症和肿瘤疾病中的使用,CBP/EP300抑制剂可以最优地与以下抗癌剂的非限制性实例中的一种或多种一起使用:
(1)烷化剂,包括但不限于卡莫司汀(carmustine)、苯丁酸氮芥(LEUKERAN)、顺铂(PLATIN)、卡铂(PARAPLATIN)、奥沙利铂(ELOXATIN)、链脲菌素(ZANOSAR)、白消安(MYLERAN)、达卡巴嗪、异环磷酰胺、洛莫司汀(CCNU)、美法仑(ALKERAN)、甲苄肼(MATULAN)、替莫唑胺(TEMODAR)、噻替哌和环磷酰胺(ENDOXAN);
(2)抗代谢药,包括但不限于克拉屈滨(LEUSTATIN)、巯基嘌呤(PURINETHOL)、硫鸟嘌呤、喷司他汀(NIPENT)、胞嘧啶阿拉伯糖苷(阿糖胞苷、ARA-C)、吉西他滨(GEMZAR)、氟尿嘧啶(5-FU、CARAC)、卡培他滨(XELODA)、亚叶酸(FUSILEV)、氨甲蝶呤(RHEUMATREX)、雷替曲塞;
(3)抗有丝分裂剂,其通常是植物生物碱和萜类化合物、或其衍生物,包括但不限于紫杉烷类,如多西他赛(TAXITERE)和紫杉醇(ABRAXANE,TAXOL);长春花生物碱,如长春新碱(ONCOVIN)、长春碱、长春地辛和长春瑞滨(NAVELBINE);
(4)检查点抑制剂,如抗PD-1或PD-L1抗体派姆单抗(KEYTRUDA)、纳武单抗(OPDIVO)、MEDI4736和MPDL3280A;抗CTLA-4抗体艾匹利木单抗(YERVOY);以及靶向LAG3(淋巴细胞活化基因3蛋白)、KIR(杀伤细胞免疫球蛋白样受体)、4-1BB(肿瘤坏死因子受体超家族成员9)、TIM3(含T细胞免疫球蛋白和粘蛋白结构域3)和OX40(肿瘤坏死因子受体超家族成员4)的那些;
(5)拓扑异构酶抑制剂,包括但不限于喜树碱(CTP)、伊立替康(CAMPTOSAR)、拓扑替康(HYCAMTIN)、替尼泊苷(VUMON)和依托泊苷(EPOSIN);
(6)细胞毒性抗生素,包括但不限于放线菌素D(更生霉素,COSMEGEN)、博来霉素(BLENOXANE)、阿霉素(ADRIAMYCIN)、柔红霉素(CERUBIDINE)、表柔比星(ELLENCE)、氟达拉滨(FLUDARA)、伊达比星、丝裂霉素(MITOSOL)、米托蒽醌(NOVANTRONE)、普卡霉素;
(7)芳香酶抑制剂,包括但不限于氨鲁米特、阿那曲唑(ARIMIDEX)、来曲唑(FEMARA)、伏氯唑(RIVIZOR)、依西美坦(AROMASIN);
(8)血管生成抑制剂,包括但不限于金雀异黄酮(genisten)、舒尼替尼(SUTENT)和贝伐单抗(AVASTIN);
(9)抗类固醇和抗雄激素,如氨鲁米特(CYTADREN)、比卡鲁胺(CASODEX)、环丙孕酮、氟他米特(EULEXIN)、尼鲁米特(NILANDRON);
(10)酪氨酸激酶抑制剂,包括但不限于伊马替尼(GLEEVEC)、埃罗替尼(TARCEVA)、拉帕替尼(TYKERB)、索拉非尼(NEXAVAR)和阿昔替尼(INLYTA);
(11)mTOR抑制剂,如依维莫司、坦西莫司(TORISEL)和西罗莫司;
(12)单克隆抗体,如曲妥珠单抗(HERCEPTIN)和利妥昔单抗(RITUXAN);
(13)其他药剂,如安吖啶;卡介苗(B-C-G);布舍瑞林(ETILAMIDE);氯喹(ARALEN);氯膦酸盐、帕米膦酸盐和其他双膦酸盐;秋水仙碱;去甲氧绿胶霉素(demethoxyviridin);二氯乙酸盐;雌莫司汀;非格司亭(NEUPOGEN);氟氢可的松(FLORINEF);戈舍瑞林(ZOLADEX);干扰素;亚叶酸;亮丙瑞林(LUPRON);左旋咪唑;氯尼达明;美斯纳;二甲双胍;米托坦(o,p'-DDD,LYSODREN);诺考达唑;奥曲肽(SANDOSTATIN);哌立福辛;卟吩姆钠(特别是与光疗和放射疗法组合使用);苏拉明;他莫昔芬;二氯二茂钛;维甲酸;合成代谢类固醇,如氟甲睾酮(HALOTESTIN);雌激素,如雌二醇、己烯雌酚(DES)和己二烯雌酚;孕激素,如醋酸甲羟孕酮(MPA)和甲地孕酮;以及睾酮。
当受试者正在遭受或具有遭受炎性病症的风险时,本文所述的CBP/EP300抑制剂化合物任选地与治疗炎性病症的一种或多种药剂或方法以任意组合一起使用。用于治疗自身免疫和/或炎性病症的治疗剂/治疗包括但不限于以下实例中的任一种:
(1)皮质类固醇,包括但不限于可的松、地塞米松和甲基泼尼松龙;
(2)非甾体类抗炎药(NSAID),包括但不限于布洛芬、萘普生、扑热息痛、阿司匹林、非诺洛芬(NALFON)、氟比洛芬(ANSAID)、酮洛芬、奥沙普秦(DAYPRO)、双氯芬酸钠(VOLTAREN)、双氯芬酸钾(CATAFLAM)、依托度酸(LODINE)、吲哚美辛(INDOCIN)、酮咯酸(TORADOL)、舒林酸(CLINORIL)、托美丁(TOLECTIN)、甲氯芬那酸(MECLOMEN)、甲芬那酸(PONSTEL)、萘丁美酮(RELAFEN)和吡罗昔康(FELDENE);
(3)免疫抑制剂,包括但不限于氨甲蝶呤(RHEUMATREX)、来氟米特(ARAVA)、硫唑嘌呤(IMURAN)、环孢菌素(NEORAL,SANDIMMUNE)、他克莫司和环磷酰胺(CYTOXAN);
(4)CD20阻断剂,包括但不限于利妥昔单抗(RITUXAN);
(5)肿瘤坏死因子(TNF)阻断剂,包括但不限于依那西普(ENBREL)、英利昔单抗(REMICADE)和阿达木单抗(HUMIRA);
(6)白介素-1受体拮抗剂,包括但不限于阿那白滞素(KINERET);
(7)白介素-6抑制剂,包括但不限于托珠单抗(ACTEMRA);
(8)白介素-17抑制剂,包括但不限于AIN457;
(9)Janus激酶抑制剂,包括但不限于托法替尼(tasocitinib);以及
(10)syk抑制剂,包括但不限于福他替尼(fostamatinib)。
在任何情况下,可以按任何顺序或甚至同时施用多种治疗剂(其中至少一种是本文披露的化合物)。如果同时施用,则多种治疗剂可以按单一、统一的形式或按多种形式(仅通过举例,作为单一丸剂或作为两种分开的丸剂)来提供。这些治疗剂中的一种可以按多个剂量给予,或者两种治疗剂都可以作为多个剂量而给予。如果不同时,则多个剂量之间的时间间隔可以是从几分钟到四周的任何持续时间。
因此,在另一方面,某些实施例提供了在需要这种治疗的人或动物受试者中治疗CBP介导的障碍的方法,该方法包括与至少一种另外的用于治疗所述障碍的本领域已知的药剂组合向所述受试者施用一定量的本文披露的化合物,该量的化合物有效减轻或预防该受试者的所述障碍。在一个相关方面,某些实施例提供了用于治疗CBP介导的障碍的治疗组合物,这些组合物包含至少一种本文披露的化合物与一种或多种另外的药剂的组合。
因此,在另一方面,某些实施例提供了在需要这种治疗的人或动物受试者中治疗P300介导的障碍的方法,该方法包括与至少一种另外的用于治疗所述障碍的本领域已知的药剂组合向所述受试者施用一定量的本文披露的化合物,该量的化合物有效减轻或预防该受试者的所述障碍。在一个相关方面,某些实施例提供了用于治疗P300介导的障碍的治疗组合物,这些组合物包含至少一种本文披露的化合物与一种或多种另外的药剂的组合。
本文披露的化合物、组合物和方法可用于治疗疾病。在某些实施例中,该疾病是一种细胞增殖失调,包括癌症。癌症可能是激素依赖性的或激素抵抗性的,如在乳腺癌的情况下。在某些实施例中,癌症是实体瘤。在其他实施例中,癌症是淋巴瘤或白血病。在某些实施例中,癌症是本文披露的或本领域已知的癌症的抗药性表型。肿瘤侵袭、肿瘤生长、肿瘤转移和血管生成也可以使用本文披露的组合物和方法进行治疗。还使用本文披露的组合物和方法治疗癌前瘤形成。
将通过本文披露的方法治疗的癌症包括结肠癌、乳腺癌、卵巢癌、肺癌和前列腺癌;口腔癌和咽癌(唇、舌、口、喉、咽)、食道癌、胃癌、小肠癌、大肠癌、结肠癌、直肠癌、肝癌和胆道癌;胰腺癌、骨癌、结缔组织癌、皮肤癌、宫颈癌、子宫癌、子宫内膜癌、睾丸癌、膀胱癌、肾癌和其他泌尿组织癌,包括肾细胞癌(RCC);眼癌、脑癌、脊髓癌和中枢神经系统及周围神经系统的其他组分的癌症以及相关结构(如脑膜)的癌症;以及甲状腺和其他内分泌腺的癌症。术语“癌症”还涵盖不一定形成实体瘤的癌症,包括霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤和造血系统恶性肿瘤,包括白血病(慢性淋巴细胞性白血病(CLL)、急性淋巴细胞性白血病(ALL)、慢性骨髓性白血病(CML)、急性骨髓性白血病(AML))以及淋巴瘤,包括淋巴细胞性、粒细胞性和单核细胞性淋巴瘤。可以使用本发明的化合物和方法治疗的其他类型的癌症包括但不限于腺癌、血管肉瘤、星形细胞瘤、听神经瘤、间变性星形细胞瘤、基底细胞癌、母细胞胶质瘤、软骨肉瘤、绒毛膜癌、脊索瘤、颅咽管瘤、皮肤黑色素瘤、囊腺癌、内皮肉瘤、胚胎性癌、室管膜瘤、尤因氏肿瘤、上皮癌、纤维肉瘤、胃部癌(gastric cancer)、泌尿生殖道癌、多形性成胶质细胞瘤、头颈癌、成血管细胞瘤、肝细胞癌、肝癌、卡波西肉瘤、大细胞癌、平滑肌肉瘤、白血病、脂肪肉瘤、淋巴系统癌、淋巴瘤、淋巴管肉瘤、淋巴管内皮细胞肉瘤、甲状腺髓样癌、髓母细胞瘤、脑膜瘤、间皮瘤、骨髓瘤、粘液肉瘤、神经母细胞瘤、神经纤维肉瘤、少突胶质细胞瘤、成骨性肉瘤、上皮性卵巢癌、乳头状癌、乳头状腺癌、副神经节瘤、甲状旁腺肿瘤、嗜铬细胞瘤、松果体瘤、浆细胞瘤、视网膜母细胞瘤、横纹肌肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、黑色素瘤、小细胞肺癌、非小细胞肺癌、鳞状细胞癌、汗腺癌、滑膜瘤、甲状腺癌、葡萄膜黑色素瘤和维尔姆斯瘤。
在某些实施例中,本文披露的组合物和方法可用于预防或减少肿瘤侵袭和肿瘤转移。
除了可用于人治疗之外,本文披露的某些化合物和配制品还可以用于宠物、野外动物和农场动物,包括哺乳动物、啮齿动物等的兽医治疗。更优选的动物包括马、狗和猫。
化合物合成
本披露的化合物可使用在一般合成方案和下面详细描述的实验程序中阐明的方法来制备。一般合成方案和实验程序是为了说明的目的,而不是旨在进行限制。用于制备本披露化合物的起始材料是可商购的或可以使用本领域已知的常规方法制备。
缩写列表
Ac2O=乙酸酐;AcCl=乙酰氯;AcOH=乙酸;AIBN=偶氮二异丁腈;aq.=水溶液;BPin2=双(频哪醇)二硼=4,4,4′,4′,5,5,5′,5′-八甲基-2,2'-双-1,3,2-二氧杂环戊硼烷;Brettphos=2-(二环己基膦基)3,6-二甲氧基-2′,4′,6′-三异丙基-1,1'-联苯;Bu3SnH=氢化三丁基锡;CBz=羧基苄基=PhCH2OC(=O)-;CBzCl=氯甲酸苄酯=PhCH2OC(=O)Cl;CD3OD=氘代甲醇;CDCl3=氘代氯仿;CDI=1,1′-羰基二咪唑;DAST=二乙基氨基三氟化硫;DBU=1,8-二氮杂双环[5.4.0]十一碳-7-烯;DCE=1,2-二氯乙烷;DCM=二氯甲烷;DEAD=偶氮二甲酸二乙酯;DIBAL-H=二异丁基氢化铝;DIEA=DIPEA=N,N-二异丙基乙胺;DMAP=4-二甲基氨基吡啶;DMF=N,N-二甲基甲酰胺;DMSO-d6=氘代二甲基亚砜;DMSO=二甲基亚砜;DPPA=叠氮磷酸二苯酯;dppe=1,2-双(二苯基膦基)乙烷;dppf=1,1'-双(二苯基膦基)二茂铁;EDC.HCl=EDCI.HCl=1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐;Et2O=二乙醚;EtOAc=乙酸乙酯;EtOH=乙醇;h=小时;HATU=2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸甲铵;HMDS=六甲基二硅氮烷;HOBT=1-羟基苯并三唑;iPr=i-Pr=异丙基=(CH3)2CH-;i-PrOH=异丙醇=(CH3)2CH-OH;LAH=LiAlH4=氢化铝锂;LiHMDS=LiN(TMS)2=双(三甲基甲硅烷基)酰胺锂;MeCN=乙腈;MeOH=甲醇;MP-碳酸酯树脂=大孔三乙基铵甲基聚苯乙烯碳酸酯树脂;MsCl=甲磺酰氯;MTBE=甲基叔丁基醚;MW=微波辐照;n-BuLi=正丁基锂;NaHMDS=双(三甲基甲硅烷基)酰胺钠;NaOMe=甲醇钠;NaOtBu=叔丁醇钠;NBS=N-溴代琥珀酰亚胺;NCS=N-氯代琥珀酰亚胺;NIS=N-碘代琥珀酰亚胺;NMP=N-甲基-2-吡咯烷酮;PdCl2(dppf)=Pd(dppf)Cl2=[1,1’-双(二苯基膦基)二茂铁]氯化钯(II);Pd(Ph3)4=四(三苯基膦)钯(0);Pd2(dba)3=三(二亚苄基丙酮)二钯(0);PdCl2(PPh3)2=双(三苯基膦)二氯化钯(II);PG=保护基团;制备型HPLC=制备型高效液相色谱;PyBop=六氟磷酸(苯并三唑-1-基氧基)三吡咯烷基磷;Pyr=吡啶;RT=室温;RuPhos=2-二环己基膦基-2′,6′-二异丙氧基联苯;sat.=饱和;ss=饱和溶液;tBu=t-Bu=叔丁基=(CH3)3C-;t-BuOH=叔丁醇=(CH3)3C-OH;T3P=丙基膦酸酐;TBS=TBDMS=叔丁基二甲基甲硅烷基;TBSCl=TBDMSCl=叔丁基二甲基氯硅烷;TEA=Et3N=三乙胺;TFA=三氟乙酸;TFAA=三氟乙酸酐;THF=四氢呋喃;Tol=甲苯;TsCl=甲苯磺酰氯;XPhos=2-二环己基膦基-2′,4′,6′-三异丙基联苯;Xphos Pd G2=氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1'-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(II)。
用于制备化合物的通用合成方法
以下方案可以用来实践本披露。
方案I
可以使用以下方案I中列出的通用合成程序来合成实例。咪唑I-02的合成始于乙二胺I-01,该乙二胺具有表示为(P)的合适的保护基团,如氨基甲酸根保护基团。使化合物I-01与乙二醛和醛R1-CHO反应。单碘化合物I-03通过两步过程形成,该过程包括合成4,5-二碘咪唑化合物(未示出),然后进行所得有机金属化物的选择性卤素/金属交换和H+淬灭。除去保护基团(例如,用HCl除去Boc基团),并与甲醛缩合,得到双环结构。可以用乙酰氯(或等效物,如乙酸酐)将氨基基团官能化以给出酰胺I-06。通过Pd(II)介导的I-06与芳基硼酸或酯的偶联完成合成以给出I-07。
方案II
可以使用方案II中列出的以下通用合成程序来合成其他实例。I-06与NBS的反应提供溴代-碘代中间体II-01,其可以在铃木(Suzuki)偶联条件下选择性反应两次,首先提供II-02,然后提供II-03。
方案III
其他实例可以使用方案III中所述的通用合成程序来合成。酸III-01与吡嗪-2-基甲胺的偶联提供酰胺III-02,将该酰胺环化以提供咪唑并吡嗪III-03。通过氢化将咪唑并吡嗪III-03还原为咪唑并哌嗪III-04。使咪唑并哌嗪III-04与乙酰氯(或等效物,如乙酸酐)反应,随后与碘反应,以提供酰胺III-05。通过Pd(II)介导的III-05与芳基硼酸酯或酸的偶联完成合成以分别给出III-06。
通过以下实例进一步说明本披露。
中间体“A”
1-(3-环丙基-1-碘-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙-1-酮
(2-(2-环丙基-1H-咪唑-1-基)乙基)氨基甲酸叔丁酯
在室温下向环丙甲醛(0.70g,10mmol)在MeOH(50ml)中的溶液添加(2-氨基乙基)氨基甲酸叔丁酯(1.60g,10mmol),然后添加NH4OAc(0.771g,10.0mmol)和40%乙二醛水溶液(1.451g,10.00mmol)。将混合物在室温下搅拌16h,然后减压浓缩。添加饱和NaHCO3水溶液(50mL),将水相用EtOAc(3x20mL)萃取,并将合并的有机层用饱和NaCl水溶液洗涤,经MgSO4干燥,过滤并减压浓缩,以给出呈黄色泡沫状固体的粗标题化合物(2.51g),其无需进一步纯化即可用于下一步。MS(ES+)C13H21N3O2要求:251,实测:252[M+H]+。
(2-(2-环丙基-4,5-二碘-1H-咪唑-1-基)乙基)氨基甲酸叔丁酯
向来自前一步骤的粗产物(2.51g,10.0mmol)在DMF(30ml)中的溶液中添加NIS(6.75g,30.0mmol)并将所得混合物在80℃下搅拌2h,然后使其冷却到RT。添加H2O(100mL)和饱和Na2S2O3水溶液(5ml)。将水相用EtOAc(3x50mL)萃取,并将合并的有机层用饱和NaCl水溶液洗涤,经MgSO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在己烷中的0%至50%EtOAc)纯化,以给出呈淡黄色泡沫状固体的标题化合物(2.41g,48%)。MS(ES+)C13H19I2N3O2要求:503,实测:504[M+H]+。
(2-(2-环丙基-4-碘-1H-咪唑-1-基)乙基)氨基甲酸叔丁酯
在-78℃下,向来自前一步骤的产物(2.40g,4.77mmol)在THF(20ml)中的溶液中添加在THF中的2.0M iPrMgCl(3.58ml,7.16mmol),并将所得混合物在-78℃下搅拌0.5h。添加饱和NH4Cl水溶液(50mL),并且将各层分离。将水相用EtOAc(3x30mL)萃取,并将合并的有机层用饱和NaCl水溶液洗涤,经MgSO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在己烷中的0%至60%EtOAc)纯化,以给出呈灰白色固体的标题化合物(1.45g,81%)。MS(ES+)C13H20IN3O2要求:377,实测:378[M+H]+。
1-(3-环丙基-1-碘-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙-1-酮
向HCl在MeOH中的溶液(通过向MeOH(10mL)逐滴添加AcCl(2mL)而制备)添加来自前一步骤的产物(700mg,1.86mmol),并将所得混合物在室温下搅拌1h。将混合物减压浓缩,并将残余物溶于EtOH(10ml)中。向所得混合物中添加50%HCHO水溶液(2.045ml,37.1mmol),并将混合物在100℃下搅拌3h,然后减压浓缩。将残余物溶于CH2Cl2(10ml)中,并将所得混合物冷却至0℃,然后用iPr2NEt(0.972ml,5.57mmol)和乙酰氯(0.198ml,2.78mmol)处理。将混合物在室温下搅拌1h,然后减压浓缩。将残余物用H2O(20mL)处理,用EtOAc(3x10mL)萃取,并将合并的有机层用饱和NaCl水溶液洗涤,经MgSO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至5%MeOH)纯化,以给出呈灰白色固体的标题化合物(355mg,58%)。MS(ES+)C11H14IN3O要求:331,实测:332[M+H]+。
中间体“B”
1-(1-碘-3-(四氢-2H-吡喃-4-基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙酮
2-(2-(四氢-2H-吡喃-4-基)-1H-咪唑-1-基)乙基氨基甲酸叔丁酯。
在0℃下向四氢-2H-吡喃-4-甲醛(2.80g,25mmol)和40%乙二醛水溶液(5.0g,34mmol)在MeOH(100mL)中的混合物中添加NH4OAc(3.8g,49mmol),随后逐滴添加2-氨基乙基氨基甲酸叔丁酯(3.94g,24.6mmol)。将混合物在室温下搅拌过夜,然后减压浓缩。将残余物用MeOH/CH2Cl2(1/10,400mL)稀释,并将混合物用饱和NH4Cl水溶液(200mL)洗涤,经Na2SO4干燥,过滤并减压浓缩,得到呈红色油状物的粗标题化合物(7.0g,96%)。MS(ES+)C15H25N3O3要求:295,实测:296[M+H]+。
2-(4,5-二碘-2-(四氢-2H-吡喃-4-基)-1H-咪唑-1-基)乙基氨基甲酸酯叔丁酯。
在0℃下向来自前一步骤的产物(7.0g,24mmol)在DMF(80mL)中的混合物分小部分添加NIS(16g,71mmol)。将混合物在室温下搅拌过夜,用H2O(800mL)稀释,并用EtOAc(300mL×3)萃取。将合并的有机层用饱和NH4Cl水溶液(200mL×4)洗涤,经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在石油醚中的0%至40%EtOAc)纯化,以给出呈棕褐色固体的标题化合物(4.3g,33%)。MS(ES+)C15H23I2N3O3要求:547,实测:548[M+H]+。
2-(4-碘-2-(四氢-2H-吡喃-4-基)-1H-咪唑-1-基)乙基氨基甲酸叔丁酯。
在-50℃下向来自前一步骤的产物(4.3g,7.9mmol)在THF(100mL)中的混合物中逐滴添加在THF中的1.0M EtMgBr(31.6mL,31.6mmol)。将混合物在-50℃下搅拌3h,用饱和NH4Cl水溶液(10mL)在低温下处理,用H2O(200mL)稀释,并用EtOAc(100mL×3)萃取。将合并的有机相用饱和NaCl水溶液(100mL)洗涤,经Na2SO4干燥,过滤并减压浓缩,以给出呈黄色油状物的粗标题化合物(3.1g,93%)。MS(ES+)C15H24IN3O3要求:421,实测:422[M+H]+。
1-碘-3-(四氢-2H-吡喃-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪HCl盐。
将来自前一步骤的产物(3.1g,7.4mmol)用2M HCl的MeOH溶液(50mL,100mmol)处理。将混合物在室温下搅拌3h,然后减压浓缩。将残余物溶于EtOH(50mL)中,并将混合物用多聚甲醛(6.66g,222mmol)处理。将混合物在回流下搅拌2h,然后使其冷却至室温。将固体通过过滤收集,并用EtOH(10mL)洗涤,以给出呈白色固体的标题化合物(1.8g,66%)。MS(ES+)C11H16IN3O要求:333,实测:334[M+H]+。
1-(1-碘-3-(四氢-2H-吡喃-4-基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙-1-酮。
在0℃下,向来自前一步骤的产物(25.0g,67.6mmol)在CH2Cl2(200ml)中的悬浮液中添加Et3N(28.3ml,203mmol)和AcCl(5.77ml,81.0mmol),并将所得混合物在0℃下搅拌0.5h。添加饱和NaCl水溶液(100mL),并将白色固体通过过滤除去。将滤液层分离,将水相用CH2Cl2(3x200mL)萃取,并将合并的有机层经MgSO4干燥,过滤并在减压下浓缩。将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至8%MeOH)纯化,以给出呈白色固体的标题化合物(25.4mg,100%)。MS(ES+)C13H18IN3O2要求:375,实测:376[M+H]+。
中间体“C”
N-甲基-5-(8-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异喹啉-3-基)吡啶酰胺
5-(8-氯异喹啉-3-基)-N-甲基吡啶酰胺
将8-氯异喹啉-3-基三氟甲磺酸酯(11.9g,38.2mmol)、N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶酰胺(10.0g,38.2mmol)、Pd(dppf)Cl2(2.80g,3.82mmol)和K2CO3(13.8g,100mmol)在THF(250mL)和H2O(50ml)中的混合物在80℃下搅拌3h。将混合物倒入水(400mL)中,并用EtOAc(400mL×3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在EtOAc中的70%至90%石油醚)纯化,以给出呈黄色固体的标题化合物(330mg,73%)。MS(ES+)C16H12ClN3O要求:297,实测:298[M+H]+。
N-甲基-5-(8-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异喹啉-3-基)吡啶酰胺。
将来自前一步骤的产物(3.5g,11.8mmol)、Pd2(dba)3(1.08g,1.18mmol)、Cy3P(1.32g,4.72mmol)、AcOK(3.43g,35.0mmol)和B2Pin2(4.58g,18.0mmol)在二噁烷(200mL)中的悬浮液在120℃下搅拌过夜。将混合物倒入水(400mL)中,并用EtOAc(400mL×3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在石油醚中的70%至100%EtOAc)纯化,以给出呈黄色固体的标题化合物(4.1g,89%)。MS(ES+)C22H24BN3O3要求:389,实测390[M+H]+。
中间体“D”
8-氯-7-氟异喹啉-3-基三氟甲磺酸酯
N-(2-氯-3-氟苄基)-2,2-二乙氧基乙酰胺。
向(2-氯-3-氟苯基)甲胺(12g,75mmol)和2,2-二乙氧基乙酸乙酯(19.93g,113.2mmol)在MeOH(120mL)中的混合物中添加Et3N(22.87g,226.4mmol),并将混合物在80℃下搅拌过夜,然后减压浓缩。将残留的油倒入水(150mL)中,并将混合物用Et2O(150ml×3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在石油醚中的40%至60%EtOAc)纯化,以给出呈黄色固体的标题化合物(17.3g,79%)。MS(ES+)C13H17ClFNO3要求:289,实测:290[M+H]+。
8-氯-7-氟异喹啉-3-醇
将来自前一步骤的产物(17.3g,59.9mmol)溶于浓H2SO4水溶液(200ml)中,并将混合物在室温下搅拌过夜。将混合物倒入冰水(400mL)中,将pH调至7,并将混合物用Et2O(400ml×3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩,以给出呈黄色固体的粗标题化合物(15.8g)。
8-氯-7-氟异喹啉-3-基三氟甲磺酸酯
将来自前一步骤的产物(15.8g,80.2mmol)、1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(34.36g,96.24mmol)和Et3N(24.3g,241mmol)在CH2Cl2(500ml)中的混合物在室温下搅拌3h,然后倒入水(500mL)中,并用CH2Cl2(500mL×3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在石油醚中的3%至5%EtOAc)纯化,以给出呈黄色固体的标题化合物(14.7g,75%)。MS(ES+)C10H4ClF4NO3S要求:329,实测:330[M+H]+。
实例1
1-(1-(3-(2-甲基噻唑-5-基)异喹啉-8-基)-3-(四氢-2H-吡喃-4-基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙-1-酮
5-(8-溴异喹啉-3-基)-2-甲基噻唑
将8-溴异喹啉-3-基三氟甲磺酸酯(0.90g,2.5mmol)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)噻唑(0.57g,2.5mmol)、NaHCO3(0.63g,7.5mmol)和Pd(PPh3)4(280mg,0.25mmol)在THF/H2O(20mL/4mL)中的混合物脱气并用N2吹扫,然后在50℃下搅拌过夜。将混合物减压浓缩,并将残余物通过SiO2凝胶色谱法(在石油醚中的0%至50%EtOAc)纯化,以给出呈黄色固体的标题化合物(450mg,60%)。MS(ES+):C13H9BrN2S要求:304,实测:305[M+H]+。
2-甲基-5-(8-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异喹啉-3-基)噻唑
向前一步骤的产物(450mg,1.48mmol)、B2Pin2(450mg,1.78mmol)和KOAc(435mg,4.44mmol)在二噁烷(20mL)中的混合物中添加PdCl2(dppf)(120mg,0.15mmol)。将所得混合物用N2吹扫5min,然后密封并在100℃下搅拌过夜。将混合物减压浓缩,并将残余物通过SiO2凝胶色谱法(在石油醚中的0%至100%EtOAc)纯化,以给出呈黄色固体的标题化合物(400mg,76%)。MS(ES+):C19H21BN2O2S要求:352,实测:353[M+H]+。
1-(1-(3-(2-甲基噻唑-5-基)异喹啉-8-基)-3-(四氢-2H-吡喃-4-基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙酮
向中间体“B”(30g,80mmol)在DMF(400ml)中的悬浮液中添加来自前一步骤的产物(28.2g,80.0mmol)、PdCl2(dppf)-CH2Cl2(3.26g,4.00mmol)和2.0M K2CO3水溶液(80ml,160mmol)。通过用N2鼓泡将混合物脱气5min,然后将所得混合物在N2下在100℃下搅拌2h。使反应冷却至室温,然后用饱和NaCl水溶液(200mL)处理,并将固体通过过滤除去。将混合物用EtOAc(3x300mL)萃取,并将合并的有机层经MgSO4干燥,过滤并减压浓缩。将所得残余物用EtOAc研磨,并将沉淀物分离,以给出所希望的产物。将滤液减压浓缩,并将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至15%MeOH)纯化,以给出所希望的产物,将该产物与上述沉淀的产物合并,以给出呈灰白色固体的标题化合物(13.5g,36%)。
MS(ES+)C26H27N5O2S要求:473,实测:474[M+H]+。
1H NMR(400MHz,DMSO-d6)(旋转异构体的约2:1混合物)δ9.97(s,1H),8.38-8.37(m,2H),7.96–7.74(m,2H),7.56-7.47(m,1H),4.87(s,0.7H),4.79(d,1.3H),4.30–4.04(m,2H),4.00-3.92(m,4H),3.59–3.38(m,2H),3.12(五重峰,J=7.4Hz,1H),2.71(s,3H),2.11(s,2H),2.04(s,1H),1.94–1.71(m,4H)。
实例2
5-(8-(7-乙酰基-3-环丙基-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)异喹啉-3-基)-N-甲基吡啶酰胺
向中间体“A”(83mg,0.25mmol)在4:1二噁烷/水(3mL)中的经脱气的溶液中添加中间体“C”(100mg,0.25mmol)、K2CO3(69mg,0.50mmol)和Pd(dppf)Cl2(20mg,0.025mmol),并将所得混合物在100℃下搅拌2h。将混合物减压浓缩,并将残余物通过反相制备型HPLC(流动相:A=0.1%NH4HCO3/H2O,B=MeCN;梯度:B=14min内35%至75%;柱:C18)纯化,以给出呈白色固体的标题化合物(28mg,24%)。
MS(ES+):C27H26N6O2要求:466,实测:467[M+H]+。
1H NMR(500MHz,CDCl3)(旋转异构体的约2:1混合物)δ9.83-9.82(m,1H),9.41-9.22(m,1H),8.68-8.43(m,1H),8.35-8.32(m,1H),8.17-8.11(m,2H),7.93-7.57(m,2H),7.57-7.43(m,1H),4.87(s,0.7H),4.75(s,1.3H),4.37-3.83(m,4H),3.08(d,J=5.0Hz,3H),2.24(s,1H),2.12(s,2H),1.95-1.81(m,1H),1.18-1.04(m,4H)。
实例3
5-(8-(7-乙酰基-3-(四氢-2H-吡喃-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)异喹啉-3-基)-N-甲基吡啶酰胺
将中间体“C”(7.00g,18.0mmol)、中间体“B”(6.75g,18.0mmol)、Pd(dppf)Cl2(1.32g,1.80mmol)和K2CO3(7.5g,54mmol)在THF(200mL)和水(40ml)中的悬浮液通过用N2吹扫脱气,并将混合物在N2下在80℃下搅拌3h。将混合物倒入水(400mL)中,并用EtOAc(400mL×3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在EtOAc中的0%至10%MeOH)纯化,以给出呈黄色固体的标题化合物(4.6g,50%)。
MS(ES+)C29H30N6O3要求:510,实测:511[M+H]+。
1H NMR(500MHz,CD3OD)(旋转异构体的约2:1混合物)δ9.70(s,0.3H),9.69(s,0.7H),9.40(br s,1H),8.68-8.67(m,1H),8.49(s,0.3H),8.48(s,0.7H),8.23(appar d,J=8.2Hz,1H),8.09-8.06(m,1H),7.91-7.87(m,1H),7.71-7.66(m,1H),4.86(s,0.7H),4.82(s,1.3H),4.33(t,J=5.5Hz,1.3H),4.23(t,J=5.4Hz,0.7H),4.15–4.01(m,4H),3.65(t,J=11.8Hz,2H),3.26-3.21(m,1H),3.03(s,3H),2.24(s,2H),2.12(s,1H),2.12–2.02(m,2H),1.98-1.83(m,2H)。
实例4
5-(8-(7-乙酰基-3-(2-氧杂二环[2.2.2]辛-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)异喹啉-3-基)-N-甲基吡啶酰胺
2-氧杂二环[2.2.2]辛烷-4-甲酸
在0℃下,向2-氧杂二环[2.2.2]辛-4-基甲醇(3.00g,21.1mmol)在丙酮(50mL)中的混合物中添加琼斯(Jones)试剂(18.6mL,49.7mmol)。将混合物在室温下搅拌1h,然后用水(50mL)稀释,并用EtOAc(50mL×3)萃取。将合并的有机层用饱和NaCl水溶液(25mL)洗涤,经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至10%MeOH)纯化,以给出呈白色固体的标题化合物(2.73g,83%)。MS(ES-):C8H12O3要求:156,实测:155[M-H]-。
N-(吡嗪-2-基甲基)-2-氧杂二环[2.2.2]辛烷-4-甲酰胺
向来自前一步骤的产物(2.73g,17.5mmol)、吡嗪-2-基甲胺(2.10g,19.2mmol)和DIEA(8.67mL,2.44mmol)在DMF(45mL)中的混合物中添加HATU(7.31g,19.2mmol)。将混合物在室温下搅拌1h,然后减压浓缩。将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至5%MeOH)纯化,以给出呈黄色固体的标题化合物(3.30g,76%)。MS(ES+):C13H17N3O2要求:247,实测:248[M+H]+。
3-(2-氧杂二环[2.2.2]辛-4-基)咪唑并[1,5-a]吡嗪
向来自前一步骤的产物(2.00g,8.09mmol)和N,N-二甲基苯胺(206.33μL,1.62mmol)在二噁烷(160mL)中的溶液中添加三氯氧磷(3.77mL,40.4mmol)和Et3N(3.37mL,24.3mmol)。将所得混合物在90℃下搅拌4h,然后在减压下部分浓缩。将残余物用饱和NaHCO3水溶液(50mL)加冰处理,并将各层分离。将水相用EtOAc(3×100mL)萃取,并将合并的有机层用饱和NaCl水溶液洗涤,经MgSO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至10%MeOH)纯化,以给出呈黄色固体的标题化合物(819.00mg,44%)。MS(ES+):C13H15N3O要求:229,实测:230[M+H]+。
3-(2-氧杂二环[2.2.2]辛-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪
向来自前一步骤的产物(1.51g,6.59mmol)在EtOH(90mL)中的混合物中添加10%Pd/C(1.00g,940μmol)。将混合物在室温下在H2(气球)下搅拌5h,然后过滤并减压浓缩,以获得呈黄色固体的标题化合物(1.55g,定量)。MS(ES+):C13H19N3O要求:233,实测:234[M+H]+。
1-(3-(2-氧杂二环[2.2.2]辛-4-基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙酮
在0℃下,向来自前一步骤的产物(1.55g,6.64mmol)在CH2Cl2(75mL)中的溶液中添加Et3N(2.77mL,19.9mmol)和乙酸酐(935.92μL,9.90mmol)。将所得混合物搅拌1h,然后用饱和NaHCO3水溶液处理,并用CH2Cl2(75mL×3)萃取。将合并的有机层用饱和NaCl水溶液(45mL)洗涤,经Na2SO4干燥,过滤并减压浓缩,以给出呈黄色油状物的标题化合物(1.40g,77%)。MS(ES+):C15H21N3O2要求:275,实测:276[M+H]+。
1-(3-(2-氧杂二环[2.2.2]辛-4-基)-1-溴-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙酮。
向来自前一步骤的产物(1.50g,5.08mmol)在THF(60mL)中的混合物中添加NBS(904.95mg,5.08mmol)。将混合物在室温下搅拌15min,然后倒入冰水中并用CH2Cl2(75mL×3)萃取。将合并的有机层经MgSO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至10%MEOH)纯化,以给出呈白色固体的标题化合物(1.16g,64%)。MS(ES+):C15H20BrN3O2要求:353,实测:354[M+H]+。
5-(8-(7-乙酰基-3-(2-氧杂二环[2.2.2]辛-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)异喹啉-3-基)-N-甲基吡啶酰胺
将中间体“C”(1.65g,4.25mmol)、来自前一步骤的产物(1.16g,3.27mmol)和Pd(dppf)Cl2(272.40mg,326.89μmol)在THF(75mL)中的混合物通过用N2吹扫脱气,然后通过注射器注射用2.0M K2CO3水溶液(4.9mL,9.8mmol)处理。将混合物用N2吹扫3次,然后在N2下在90℃下搅拌过夜。将混合物浓缩,并将残余物通过SiO2凝胶色谱法(在CH2Cl2中的0%至75%(于EtOAc中的10%MeOH))纯化,以给出呈淡黄色固体的标题化合物(1.29g,73%)。
MS(ES+):C31H32N6O3要求:536,实测:537[M+H]+。
1H NMR(400MHz,CDCl3)(旋转异构体的约1:1混合物)δ9.85(appar d,J=10.7Hz,1H),9.28(appar d,J=5.4Hz,1H),8.57(appar d,J=8.1Hz,1H),8.32(appar d,J=8.1Hz,1H),8.15(appar d,J=9.2Hz,1H),8.14-8.10(m,1H),7.89-7.84(m,1H),7.77-7.73(m,1H),7.51-7.47(m,1H),4.84(s,1H),4.75(s,1H),4.43-4.21(m,4H),4.09-3.83(m,3H),3.08(d,J=5.1Hz,3H),2.33-2.20(m,6H),2.20(s,1.5H),2.09(s,1.5H)1.89-1.72(m,2H)。
实例5
5-(8-(7-乙酰基-3-(四氢-2H-吡喃-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)-7-氟异喹啉-3-基)-N-甲基吡啶酰胺
5-(8-氯-7-氟异喹啉-3-基)-N-甲基吡啶酰胺
向中间体“D”(1.00g,3.04mmol)在4:1THF/水(50mL)中的经脱气的溶液中添加N-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶酰胺(0.797g,3.04mmol)、K2CO3(839mg,6.08mmol)和Pd(dppf)Cl2(244mg,0.333mmol)。将所得混合物在100℃下搅拌6h,然后减压浓缩。将残余物在水(20mL)中浆化,并将固体通过过滤分离,以给出呈灰色固体的标题化合物(0.7g,73%)。MS(ES+)C16H11ClFN3O要求:315,实测:316[M+H]+。
5-(7-氟-8-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异喹啉-3-基)-N-甲基吡啶酰胺
向来自前一步骤的产物(60mg,0.19mmol)在二噁烷(3ml)中的经脱气的溶液中添加B2Pin2(720mg,0.285mmol)、KOAc(37mg,0.38mmol)、三环己基膦(5.3mg,0.019mmol)和Pd2(dba)3(17mg,0.019mmol)。将所得混合物在110℃下在氩气下在密闭管中搅拌16h,然后减压浓缩,以给出粗标题化合物,其直接用于下一步。MS(ES+)C22H23BFN3O3要求:407,实测:408[M+H]+。
叔丁基5-(8-(7-乙酰基-3-(四氢-2H-吡喃-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-基)-7-氟异喹啉-3-基)-N-甲基吡啶酰胺
向中间体“B”(假定为0.19mmol)在4:1二噁烷/水(10mL)中的经脱气的溶液中添加来自前一步骤的产物(76mg,0.19mmol)、K2CO3(50mg,0.36mmol)、Pd(dppf)Cl2(14mg,0.018mmol)。将所得混合物在100℃下搅拌2h,然后减压浓缩。将残余物通过反相制备型HPLC(流动相:A=0.1%NH4HCO3/H2O,B=MeCN;梯度:B=12min内25%至65%;柱:C18)纯化,以给出呈白色固体的标题化合物(7.5mg,7%)。
MS(ES+)C29H29FN6O3要求:528,实测:529[M+H]+。
1H NMR(500MHz,CD3OD)(旋转异构体的约2:1混合物)δ9.82(s,0.7H),9.75(s,0.3H),9.30-9.28(m,1H),8.66(appar d,J=8.1Hz,1H),8.50(appar d,J=8.2Hz,1H),8.23-8.15(m,2H),7.79-7.73(m,1H),4.76(s,0.7H),4.71(s,1.3H),4.34(t,J=6.0Hz,1.3H),4.25(t,J=5.5Hz,0.7H),4.10-4.06(m,4H),3.65(t,J=12.0Hz,2H),3.27-3.23(m,1H),3.02(s,3H),2.25(s,2H),2.14(s,1H),2.09-1.96(m,4H)。
实例6
1-(1-(7-氟-3-(2-甲基噻唑-5-基)异喹啉-8-基)-3-(四氢-2H-吡喃-4-基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙-1-酮
5-(8-氯-7-氟异喹啉-3-基)-2-甲基噻唑。
将中间体“D”(500mg,1.52mmol)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)噻唑(412mg,1.83mmol)、Pd(dppf)Cl2(110mg,0.15mmol)和K2CO3(630mg,4.56mmol)在二噁烷(15mL)和H2O(3mL)中的混合物在80℃下搅拌2h。将混合物倒入水(40mL)中,并用EtOAc(40mL×3)萃取。将合并的有机层经Na2SO4干燥,过滤并减压浓缩。将残余物通过SiO2凝胶色谱法(在石油醚中的70%至100%EtOAc)纯化,以给出呈灰色固体的标题化合物(460mg,100%)。MS(ES+)C13H8ClFN2S要求:278,实测:279[M+H]+。
5-(7-氟-8-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异喹啉-3-基)-2-甲基噻唑。
将来自前一步骤的产物(70mg,0.25mmol)和Pd2(dba)3(28mg,0.03mmol)、Cy3P(23mg,0.08mmol)、KOAc(106mg,1.08mmol)和B2Pin2(97mg,0.38mmol)在二噁烷(3mL)中的混合物在120℃下搅拌过夜。使混合物冷却至室温,过滤,并将滤液浓缩,以给出粗标题化合物(63mg,68%),其无需进一步纯化即可使用。MS(ES+)C19H20BFN2O2S要求:370,实测:371[M+H]+。
1-(1-(7-氟-3-(2-甲基噻唑-5-基)异喹啉-8-基)-3-(四氢-2H-吡喃-4-基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基)乙酮
向中间体“B”(70mg,0.18mmol)在4:1二噁烷/水(10mL)中的经脱气的溶液中添加5-(7-氟-8-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异喹啉-3-基)-2-甲基噻唑(68.8mg,0.186mmol)、K2CO3(50mg,0.37mmol)和Pd(dppf)Cl2(14mg,0.018mmol)。将所得混合物在100℃下搅拌2h,然后减压浓缩。将残余物通过反相制备型HPLC(流动相:A=0.1%NH4HCO3/H2O,B=MeCN;梯度:B=11min内30%至85%;柱:C18)纯化,以给出呈白色固体的标题化合物(13.5mg,15%)。
MS(ES+)C26H26FN5O2S要求:491,实测:492[M+H]+。
1H NMR(500MHz,CDCl3)(旋转异构体的约2:1混合物)δ9.62(s,0.7H),9.56(s,0.3H),8.18(s,1H),7.92-7.91(m,1H),7.84-7.81(m,1H),7.52(appar t,J=9.4Hz,1H),4.74(s,0.7H),4.65(s,1.3H),4.33–3.96(m,6H),3.56(t,J=11.7Hz,2H),3.02–2.83(m,1H),2.77(s,3H),2.27–2.01(m,5H),1.90-1.88(m,2H)。
在以下测定法中证实了实例1-6中的化合物作为CBP和BRD4抑制剂的活性。预计尚未制备和/或测试的上列其他化合物也将在这些测定法中具有活性。
生物活性测定
在不存在或存在抑制剂的情况下,测量了CBP或BRD4溴结构域与衍生自H4组蛋白底物的乙酰化肽(四乙酰化H4(1-21)Ac-K5/8/12/16)的特异性结合。从BPS生物科技公司(BPS Bioscience)获得GST标记的CBP(1081-1197)和BRD4(49-170)的溴结构域,并通过AlphaScreen技术(珀金埃尔默公司(Perkin Elmer))评估与生物素化的H4(1-21)Ac-K5/8/12/16(AnaSpec.64989)的结合。
CBP AlphaScreen测定:将5nM GST-CBP(1081-1197)和20nM生物素-H4(1-21)Ac-K5/8/12/16(AnaSpec.64989)与不同浓度的CBP抑制剂在15μL缓冲液中孵育,该缓冲液包含50mM HEPES 7.5、100nM NaCl、1mM TCEP和0.003%Tween-20。在室温下孵育30min后,然后将15μL检测缓冲液(BPS Bio.33006)添加到先前的混合物中,该检测缓冲液包含7μg/mL的谷胱甘肽AlphaLisa受体珠(珀金埃尔默公司AL109)和14μg/mL的链霉亲和素供体珠(珀金埃尔默公司676002)。将反应物在室温下再孵育2小时,并使用Envision Multilabel酶标仪对AlphaScreen信号进行定量。作为阴性对照,将GST-CBP(1081-1197)与未乙酰化的生物素-H4(1-21)肽(AnaSpec.62555)并在最终DMSO浓度为0.25%的情况下孵育。
BRD4 AlphaScreen测定:按照针对CBP测定法所述的相同程序评估2.5nM BRD4(49-170)与10nM生物素-H4(1-21)Ac-K5/8/12/16(AnaSpec.64989)的结合。标准剂量反应曲线由Genedata Screener软件使用以下可变斜率模型拟合:
信号=信号阴性对照+(信号DMSO对照-信号阴性对照)/(1+(IC50/剂量)^希尔斜率)。
等式中仅信号和剂量被视为已知值。
结果在下表1中给出,其表明本发明的化合物抑制CBP并且对BRD4具有选择性。结构类似物化合物7和8先前披露于美国专利公开号2019/0298729(美国申请号16/370,404),该美国专利以其全文并入本文。
表1.生物活性
DOHH2增殖测定:在第1天,将1000个DOHH2细胞接种到40μL RPMI 1640培养基中的384孔TC板(珀金埃尔默公司#6007680)上,随后添加CBP抑制剂,但第13列除外,其中添加3.3μM星形孢菌素作为阴性对照。在所有孔中DMSO为0.1%。在第7天,将细胞通过40μLCellTiter Glo(普洛麦格公司(Promega)#G9243)裂解并计数其活力。通过EnvisionMultilabel酶标仪对发光信号进行定量,并且标准剂量反应曲线由Genedata Screener软件使用以下可变斜率模型拟合:
信号=信号阴性对照+(信号DMSO对照-信号阴性对照)/(1+(IC50/剂量)^希尔斜率)。
等式中仅信号和剂量被视为已知值。
测定结果如下所示。
表2.生物活性
本文描述的化合物在体内药代动力学方面显示出意想不到的改善,特别是作为用于筛选药代动力学行为的体内模型在小鼠中的清除率和半衰期,这不是通过体外微粒体稳定性数据预测的,也明显不是基于结构的。相关的比较数据在表3和表4中示出。表3显示,与先前披露的结构类似物相比,化合物1和3的体外微粒体稳定性与之相似或更低。然而,如表4所示,与先前披露的结构类似物相比,化合物1和3的小鼠体内清除率显著降低,半衰期增加。
表3.肝微粒体制剂的代谢稳定性
方法:在NADPH的存在下、于37℃下,将测试化合物与来自CD-1小鼠、斯普拉格-道利(Sprague Dawley)大鼠和人的肝微粒体(0.5mg/mL)一起孵育45分钟。通过LC-MS/MS,使用峰面积比率确定了随时间推移的剩余母体%。使用以下方程计算半衰期(t1/2):t1/2=ln2/k,其中k是随时间推移的母体衰变的速率常数(log[剩余母体%]相对于时间的曲线的斜率)。
表4.单次给药后的体内药代动力学–雌性CD-1小鼠
0.2或0.3mg/kg IV(静脉内)给药。
进一步表征了化合物1在大鼠、猴和狗中的体内药代动力学。表5显示了化合物1在表3中未显示的那些物种中的微粒体稳定性。表6显示了静脉内(IV)和口服(PO)单次给药后大鼠、猴和狗中的药代动力学参数。
表5.化合物1在猴和狗肝微粒体制剂中的代谢稳定性
表6.单次给药化合物1后在大鼠、猴和狗中的体内药代动力学
PK参数 | 斯普拉格-道利大鼠 | 食蟹猴 | 比格犬 |
清除率(L/h/kg) | 0.673 | 0.418 | 0.258 |
Vss(L/kg) | 2.31 | 2.28 | 3.38 |
t1/2(h) | 3.82 | 4.74 | 9.74 |
C最大(μM) | 23.0 | 1.97 | 2.56 |
AUC最终(h*μM) | 124 | 11.3 | 26.2 |
%F | 129 | 70.5 | 119 |
剂量为1mg/kg IV(静脉内)和3mg/kg PO(口服),大鼠PO剂量(30mg/kg)除外。由IV剂量确定清除率、Vdss和t1/2,由PO剂量确定Cmax、AUClast和F%。
微粒体稳定性.微粒体稳定性测定在Beckmann Biomek FXp实验室自动化系统上进行。肝微粒体孵育混合物由在磷酸钾缓冲液(100mM,pH 7.4)中的肝微粒体(0.5mg微粒体蛋白/mL)、化合物(1μM)、MgCl2(3mM)和EDTA(1mM)组成。将咪达唑仑(Midazolam)和酮舍林(Ketanserin)用作测定对照底物。添加NADPH再生溶液(1.3mM NADPH)启动反应,并在37℃下在振荡下维持反应。在范围从0至45min的五个时间点内,取出等分试样(50μL)并用含有内标(丙咪嗪)的乙腈(100μL)淬灭。在涡旋和离心后,将样品通过LC-MS/MS进行分析。体外半衰期和清除率的计算遵循文献指南。
体内药代动力学.
在20%DMSO+60%PEG400+20%水中配制IV(静脉内)剂量。在0.5%甲基纤维素水溶液中配制PO(口服)剂量。
小鼠:将体重20-30g的雌性小鼠(CD1品系,购自上海JH实验动物有限公司(Shanghai JH Laboratory Animal Co.LTD))用于研究。所有动物都可以随意获得食物和水。测试物品分别经由尾静脉(IV剂量)或口服管饲(PO剂量)给药。在给药前和给药后0.083、0.25、0.5、1、2、4、8和24h从所有动物收集血液样品,放入含有抗凝剂K2EDTA的管中(每个时间点3只动物,并且每只动物收集3个时间点)。在4℃下通过离心从血液中分离血浆,并储存在-70℃下直至分析。使用液相色谱串联质谱(LC-MS/MS)法对血浆中的测试物品的浓度进行定量。
大鼠:将体重200-300g的雄性大鼠(SD品系,购自上海JH实验动物有限公司)用于研究。将动物禁食过夜,并在给药后4h饲喂。所有动物都可以随意获得水。测试物品经由足背静脉(IV剂量)或口服管饲(PO剂量)给药。在给药前和给药后0.083、0.25、0.5、1、2、4、8和24h经由尾静脉从所有动物收集血液样品,放入含有抗凝剂K2EDTA的管中。在4℃下通过离心从血液中分离血浆,并储存在-70℃下直至分析。使用液相色谱串联质谱(LC-MS/MS)法对血浆中的测试物品的浓度进行定量。
狗:将体重7-10kg的雄性比格犬(购自北京玛斯生物技术有限公司(BeijingMarshall Biotechnology Co.,Ltd))用于研究。将动物禁食过夜,并在给药后4h饲喂。将测试物品经由头静脉(IV剂量)或口服管饲(PO剂量)施用至狗。在给药前和给药后0.083、0.25、0.5、1、2、4、8和24h经由隐静脉或头静脉从所有动物收集血液样品,放入含有抗凝剂K2EDTA的管中。在4℃下通过离心从血液中分离血浆,并储存在-70℃下直至分析。使用液相色谱串联质谱(LC-MS/MS)法对血浆中的测试物品的浓度进行定量。
猴:将体重3-5kg的雄性食蟹猴(购自海南金港生物技术股份有限公司(HainanJingang Biotech.Co.,Ltd))用于研究。将动物禁食过夜,并在给药后4h饲喂。将测试物品经由头静脉(IV剂量)或经鼻管饲(PO剂量)施用至猴。在给药前和给药后0.083、0.25、0.5、1、2、4、8和24h经由隐静脉或头静脉从所有动物收集血液样品,放入含有抗凝剂K2EDTA的管中。在4℃下通过离心从血液中分离血浆,并储存在-70℃下直至分析。使用液相色谱串联质谱(LC-MS/MS)法对血浆中的测试物品的浓度进行定量。
DOHH2异种移植研究将DOHH2细胞(1x106个细胞/小鼠,用基质胶按1:1稀释)植入4-6周龄的CB17/scid雌性小鼠(杰克森实验室(Jackson Labs))中,皮下注射在这些小鼠的右胁腹,使其生长至200-300mm3的平均体积(如通过卡尺测量来监测)。此时,将动物随机分成每组8只动物。所有动物随意接受LabDiet 5053食物。向动物口服给药实例1(50mg/kg,BID,以给药5天/停药2天的时间表),该实例1在于无菌水中的0.5%甲基纤维素媒介物中配制。通过卡尺每周测量两次肿瘤体积,并使用以下公式计算其体积:V=l2*L/2(l=长度;L=宽度)。在研究期间监测体重。GraphPad Prism用于生成图表,数据表示为平均值±平均值标准误差。
本申请中引用的所有参考文献、专利或申请,无论是美国的还是国外的,都以其全文通过引用并入本文(就像写在本文中一样)。如果出现任何不一致之处,以本文实际披露的材料为准。
通过以上的说明,本领域的技术人员可以很容易地确定本披露的实质特征并且在不偏离本披露的精神和范围的情况下可以对本披露作出不同变化和修改,以使它适应不同用途和情况。
Claims (32)
2.如权利要求1所述的化合物或其盐,其中R1选自环丙基和四氢-2H-吡喃-4-基。
3.如权利要求1和2中任一项所述的化合物或其盐,其中R3选自6-(甲基氨甲酰基)吡啶-3-基和2-甲基噻唑-5-基。
6.如权利要求4和5中任一项所述的化合物或其盐,其中R1是四氢-2H-吡喃-4-基。
7.如权利要求4至6中任一项所述的化合物或其盐,其中R7是烷基。
8.如权利要求7所述的化合物或其盐,其中R7是甲基。
9.如权利要求4至6中任一项所述的化合物或其盐,其中R7是-C(O)NHCH3。
11.一种药物组合物,其包含如权利要求1至10中任一项所述的化合物或其盐以及药学上可接受的载体。
12.一种抑制CBP的方法,该方法包括使CBP与如权利要求1至10中任一项所述的化合物或其盐接触。
13.一种抑制P300的方法,该方法包括使P300与如权利要求1至10中任一项所述的化合物或其盐接触。
14.一种治疗由CBP或P300中的任一种介导的疾病的方法,该方法包括向有需要的患者施用治疗有效量的如权利要求1至10中任一项所述的化合物或其盐。
15.如权利要求14所述的方法,其中所述疾病选自增生性疾病、炎性障碍、自身免疫性疾病和纤维化疾病。
16.如权利要求15所述的方法,其中所述疾病是增生性疾病。
17.如权利要求16所述的方法,其中所述疾病是癌症。
18.如权利要求17所述的方法,其中所述癌症选自听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B细胞淋巴瘤、异常增生改变、胚胎性癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食道癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤因氏肿瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、胶质瘤、成胶质细胞瘤、胶质肉瘤、重链疾病、头颈癌、成血管细胞瘤、肝癌、肝细胞癌、激素不敏感型前列腺癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、淋巴管内皮肉瘤、淋巴管肉瘤、淋巴母细胞性白血病、淋巴瘤、T细胞或B细胞来源的淋巴恶性肿瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、神经母细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突胶质细胞瘤、口腔癌、成骨性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺癌、甲状腺癌、华氏巨球蛋白血症、睾丸肿瘤、子宫癌和维尔姆斯瘤。
19.如权利要求18所述的方法,其中所述癌症选自肺癌、乳腺癌、胰腺癌、结肠直肠癌和黑色素瘤。
20.如权利要求17至19中任一项所述的方法,该方法进一步包括施用细胞毒性剂。
21.如权利要求20所述的方法,其中所述细胞毒性剂选自抗微管剂、铂配位络合物、烷化剂、抗生素剂、拓扑异构酶II抑制剂、抗代谢药、拓扑异构酶I抑制剂、激素和激素类似物、信号转导通路抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、LDH-A抑制剂、脂肪酸生物合成抑制剂、细胞周期信号传导抑制剂、HDAC抑制剂、蛋白酶体抑制剂、和癌症代谢抑制剂。
22.如权利要求17至21中任一项所述的方法,该方法进一步包括施用非化学癌症治疗方法。
23.如权利要求22所述的方法,其中所述非化学癌症治疗方法选自手术、放射疗法、热消融、聚焦超声疗法和冷冻疗法。
24.如权利要求15所述的方法,其中所述疾病是自身免疫性疾病。
25.如权利要求24所述的方法,其中所述自身免疫性疾病选自爱迪生氏病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、白塞氏病、大疱性皮肤病、慢性阻塞性肺病、克罗恩氏病、皮炎、湿疹、巨细胞动脉炎、纤维化、肾小球肾炎、肝血管闭塞、肝炎、垂体炎、免疫缺陷综合征、炎症性肠病、川崎病、狼疮性肾炎、多发性硬化症、心肌炎、肌炎、肾炎、器官移植排斥反应、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、肺炎、原发性胆汁性肝硬化、银屑病、银屑病性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、系统性红斑狼疮、多发性大动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、血管炎和韦格纳氏肉芽肿。
26.如权利要求15所述的方法,其中所述疾病是纤维化疾病。
27.如权利要求26所述的方法,其中所述纤维化疾病选自肺纤维化、硅肺病、囊性纤维化、肾纤维化、肝纤维化、肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、心内膜纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性大块纤维化、肾源性系统性纤维化、克罗恩氏病、瘢痕疙瘩、心肌梗塞、系统性硬化症或关节纤维化。
28.如权利要求27所述的方法,其中所述纤维化疾病是肺纤维化疾病。
29.如权利要求28所述的方法,其中所述肺纤维化疾病选自特发性肺纤维化、纤维化间质性肺病、间质性肺炎、非特异性间质性肺炎的纤维化变体、囊性纤维化、肺纤维化、慢性阻塞性肺病(COPD)或肺动脉高压。在某些实施例中,该纤维化肺病是特发性肺纤维化。
30.一种治疗CBP介导的疾病的方法,该方法包括施用:
(a)治疗有效量的如权利要求1至10中任一项所述的化合物或其盐;以及
(b)第二治疗剂。
31.一种治疗P300介导的疾病的方法,该方法包括施用:
(a)治疗有效量的如权利要求1至10中任一项所述的化合物或其盐;以及
(b)第二治疗剂。
32.一种用于在患者中实现效果的方法,该方法包括向患者施用治疗有效量的如权利要求1至10中任一项所述的化合物或其盐,其中该效果是减轻炎症。
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US202063086728P | 2020-10-02 | 2020-10-02 | |
US63/086,728 | 2020-10-02 | ||
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