CN113727756A - P300/cbp hat抑制剂和其使用方法 - Google Patents
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- CN113727756A CN113727756A CN202080031338.7A CN202080031338A CN113727756A CN 113727756 A CN113727756 A CN 113727756A CN 202080031338 A CN202080031338 A CN 202080031338A CN 113727756 A CN113727756 A CN 113727756A
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- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明提供式(I)化合物,
Description
相关申请案的交叉参考
本申请案要求于2019年7月29日提出申请的美国临时申请案第62/879,852号和于2019年2月27日提出申请的美国临时申请案第62/811,143号的优先权,所述申请案中的每一个的全部内容均以引用方式并入本文中。
背景技术
染色质是DNA与蛋白质的复杂组合,其构成染色体。其发现于真核细胞的细胞核内部,且分为异染色质(缩合)和真染色质(扩展)形式。染色质的主要组分是DNA和蛋白质。组蛋白是染色质的首要蛋白组分,其用作DNA缠绕的线轴。染色质的功能是将DNA包装成较小体积以适合细胞,强化DNA以便进行有丝分裂和减数分裂,以及用作控制表达和DNA复制的机制。染色质结构受组蛋白(尤其组蛋白H3和H4)的一系列翻译后修饰控制,且所述修饰最通常位于延伸出核心核小体结构的“组蛋白尾部”内。组蛋白尾部往往无蛋白质-蛋白质相互作用,且也是组蛋白最易于翻译后修饰的部分(Goll和Bestor,2002,《基因与发展(GenesDev.)》16:1739-1742;Grant,2001,《基因组生物学(Genome Biol.)》2:)。所述修饰包括乙酰基化、甲基化、磷酸化、泛素化、SUMO蛋白质修饰化。所述表观遗传标记是由特定酶书写和擦除,所述酶将标签放置于组蛋白尾部内的特定残基上,由此形成表观遗传密码,其随后由细胞解译以允许染色质结构的基因特异性调控且由此进行转录。
组蛋白的共价修饰是控制基因表达的基本机制,且是真核细胞中发挥作用的主要表观遗传机制之一(Kouzarides,《细胞(Cell)》,128,693-705(2007))。由于不同转录状态定义基本细胞过程(例如细胞类型分类、谱系定型、细胞活化和细胞死亡),故其异常调控是一系列疾病的核心(Medzhitov等人,《自然免疫学综述(Nat.Rev.Immunol.)》,9,692-703(2009);Portela等人,《自然生物技术(Nat.Biotech.)》,28,1057-1068(2010))。不同类别的酶(即组蛋白乙酰基转移酶(HATS)和组蛋白去乙酰酶(HDAC))使特异性组蛋白赖氨酸残基乙酰化或去乙酰化(Struhl K.,《基因与发展》,1998,12,5,599-606)。
组蛋白乙酰基转移酶(HAT)催化底物组蛋白内的靶赖氨酸侧链的ε-氨基上的乙酰化(乙酰基的转移),且组蛋白去乙酰酶(HDAC)催化从赖氨酸残基去除乙酰基。随后,乙酰化核心组蛋白显示优先与转录活性染色质缔合。参见《核酸研究(Nucleic Acids Res.)》5:1863-1876(1978);《美国国家科学院院刊(Proc.Natl.Acad.Sci.)》75:2239-2243(1978);和《欧洲分子生物学杂志(EMBO J.)》7:1395-1402(1988)。HAT基于一级序列同源性、共有结构特征和功能作用分类为四个主要家族:Gcn5/PCAF(通用对照未抑制蛋白5和p300以及CBP相关因子);MYST(以建立成元MOZ、Ybf2/Sas3、Sas2和Tip60命名);p300/CBP(300kDa的蛋白和CREB结合蛋白);和Rttl09(Tyl转座基因产生109的调控剂)。
同种同源物p300和CBP(CREB结合蛋白)最初分别被鉴别为腺病毒早期区域1A(E1A)蛋白的结合搭配物(Yee和Branton,1985,《病毒学(Virology)》147:142-153;Harlow等人,1986,《分子细胞生物学(Mol.Cell Biol.)》6:1579-1589)和cAMP调控的增强剂(CRE)结合蛋白的结合搭配物(Chrivia等人,1993,《自然(Nature)》365:855-859)。p300和CBPHAT结构域具有>90%的序列一致性,且在后生动物中是保守的,具有许多重叠功能。除了HAT结构域以外,p300/CBP还含有其它蛋白质相互作用结构域,包括三个富含半胱氨酸-组氨酸的结构域(CH1、CH2和CH3)、KIX结构域、溴结构域和类固醇受体共活化因子相互作用结构域(SID,也是SRC-1相互作用结构域)(Arany等人,《细胞(Cell.)》1994年6月17日;77(6):799-800)。发现p300/CBP具有固有HAT活性(Ogryzko等人,1996,《细胞》87:953-959;Bannister和Kouzarides,1996,《自然》384:641-643)。除了乙酰化所有四种核心组蛋白(H2A、H2B、H3和H4)上的多个赖氨酸以外,p300/CBP已显示对>70种底物具有乙酰基转移酶活性(Wang等人,2008,《结构生物学当前观点(Curr.Opin.Struct.Biol.)》18:741-747),所述底物包括例如p53(Gu等人,1997,《细胞》90:595-606)、MyoD(Polesskaya等人,2002,《生物化学杂志(J.Biol.Chem.)》275:34359-64)、STAT3(Yuan等人,2005,《科学(Science)》307:269-73)和ΝFκβ(Chen等人,2002,《欧洲分子生物学杂志》21:6539-48)。这两种乙酰基转移酶负责大多数组蛋白H3赖氨酸18乙酰化(H3K18ac)和H3K27ac,即与活性启动子和增强子相关的修饰(Horwitz等人2008;Jin等人,2011)。
p300除了用作乙酰基转移酶外,还用作转录因子的支架或连接转录因子和基础转录机制以活化转录的桥(Chan和Thangue,2001,《细胞科学杂志(J.Cell Sci.)》114:2363-2373;Chen和Li,2011,《实验胚胎学(Epigenetics)》6:957-961)。P300/CBP蛋白参与许多细胞过程,包括细胞生长、增殖和分化(综述见Chan和Thange,2001,《细胞科学杂志》114:2363-2373)。已在许多人类疾病、特别是癌症中观察到p300/CBP突变,频率高达30%。所述突变在HAT结构域内出现的频率较高,表明在癌症中改变此活性的选择性压力。所述突变主要是单等位基因突变,第二等位基因的异型接合性损失,与经典肿瘤阻抑基因的Knudson假说一致。参见《自然》376,348-351,1995;《致癌基因(Oncogene)》12,1565-1569,1996;和《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》94,8732-8737,1997。CBP中的异型接合突变首先阐述于RTS中,所述RTS是一种特征在于智力迟钝、骨骼异常和高赘瘤形成发病率的体染色体显性疾病(《自然》376,348-351,1995)。这表明CBP基因剂量的全部补充是正常发育所需的。P300/CBP基因还参与各种染色体易位,尤其血液恶性病,且可能通过获得功能而促使异常生长(Kitabayashi等人2001;Panagopoulos等人,2001)。
已在以下疾病中观察到与不良存活和侵袭性表型有关的高p300表达:前列腺癌(Debes等人2003;《癌症研究(Cancer Res.)》63:7638-7640;Heemers等人,2008,《实验医学生物学进展(Adv.Exp.Med.Biol.)》617:535-40;Isharwal等人,2008,《前列腺(Prostate)》68:1097-104)、肝癌(Yokomizo等人,2011,《癌症学报(Cancer Lett.)》310:1407;Li等人,2011,《转化医学杂志(J.Transl.Med.)》9:5)、乳癌(Fermento等人,2010,《实验和分子病理学(Exp.Mol.Pathol.)》88:256-64)、食道癌(Li等人,2011,《胸外科年鉴(Ann ThoracSurg.)》91:1531-1538)和皮肤鳞状细胞癌(Chen等人,2014,《英国皮肤病学杂志(Br JDermatol.)》172:111-119)。p300/CBP的抑制在以下疾病中具有治疗潜能:癌症(Iyer等人,2004,《美国国家科学院院刊》101:7386-7391;Stimson等人,2005,《分子癌症治疗学(Mol.Cancer Ther.)》4:1521-1532;Zheng等人,2004,《酶学方法(Methods Enzymol.)》376:188-199)、心脏病(Davidson等人,2005,《化学生物学(Chembiochem.)》6:162-170)、糖尿病(Zhou等人,2004,《自然医学(Nat.Med.)》10:633-637)和HIV(Varier和Kundu,2006,《当前药物设计(Curr.Pharm.Des.)》12:1975-1993)。P300/CBP还参与调控发炎介质(Deng等人,2004,《血液(Blood)》WO 2016/044770 PCT/US2015/051028103:2135-42;Tumer-Brannen等人,2011,《免疫学杂志(J.Immunol.)》186:7127-7135)。P300/CBP还与其它疾病相关联,所述疾病是例如纤维化(Ghosh和Varga,2007,《细胞生理学杂志(J.Cell.Physiol.)》213:663-671)、代谢综合征(Bricambert等人,2010,《临床研究杂志(J.Clin.Invest.)》120:4316-4331)和进行性神经变性疾病(例如杭丁顿氏病(HuntingtonDisease)(Cong等人,2005,《分子与细胞神经科学(Mol.Cell.Neurosci.)》30:12-23)、肯尼迪氏症(Kennedy's disease)(Lieberman等人,2002,《人类分子遗传学(Hum.Mol.Genet.)》11:1967-76)和阿尔茨海默氏病(Alzheimer's disease)(Francis等人,2007,《神经科学通讯(Neurosci.Lett.)》413:137-140))。
p300/CBP活性在疾病致病性中的关联表明p300/CBP作为治疗靶标的潜在效用。然而,鉴别强效的特异性组蛋白乙酰基转移酶抑制剂具有挑战性(Cole,2008,《自然化学生物学(Nat.Chem.Biol.)》4:590-97)。衍生自天然化合物的P300 HAT抑制剂具有中等功效但缺乏特异性(Dekker和Haisma,2009,《当今Dmg研究(Dmg Disc.Today)》14:942-8)。转变为具有Tat肽附接的细胞可渗透形式的Lys-CoA更具选择性,但由于其复杂性而在药理学研究中具有有限的用途。最近,在虚拟配体筛选方法中使用Lys-CoA/p300 HAT结构鉴别选择性p300抑制剂C646(Bowers等人,2010,《化学和生物学(Chemistry&Biology)》17:471-482)。尽管在此领域中已经取得了进展,但业内仍需要改良的HAT抑制剂。
发明内容
本文提供具有式I的化合物:
和其医药上可接受的盐和组合物,其中R1、R2、R3、R4、R5、Ra、Rb、q和p是如本文所述。所公开的化合物和组合物调节组蛋白乙酰基转移酶(例如,参见表2),且可以用于各种治疗应用,例如用于治疗癌症。
具体实施方式
1.化合物的一般说明
本文提供式I化合物:
或其医药上可接受的盐,其中
R1、R3和R4各自独立地是氢或C1-4烷基;
R2是苯基或5至6元杂芳基,其各自任选地被1至3个选自Rc的基团取代;
R5是被4至6元杂环基或5至6元杂芳基取代的C1-6烷基,其中所述4至6元杂环基或所述5至6元杂芳基中的每一个任选地被1至3个选自Rd的基团取代;或R5是4至6元杂环基或5至6元杂芳基,其中所述4至6元杂环基或所述5至6元杂芳基中的每一个任选地被1至3个选自Rd的基团取代;
Ra、Rb、Rc和Rd各自独立地是卤基、CN、侧氧基、NO2、C1-6烷基、C2-6烯基、C1-6烷氧基、卤基(C1-6烷氧基)、卤基(C1-6烷基)、-C1-6烷基ORe、-C(O)Rf、-C(O)OR、-C1-6烷基C(O)ORe、-C(O)N(Re)2、-C(O)NReC1-6烷基ORe、-OC1-6烷基N(Re)2、-C1-6烷基C(O)N(Re)2、-C1-6烷基N(Re)2、-N(Re)2、-C(O)NReC1-6烷基N(Re)2、-NReC1-6烷基N(Re)2、-NReC1-6烷基ORe、-SORe、-S(O)2Re、-SON(Re)2、-SO2N(Re)2、SF5、-O(C3-C6)环烷基、-O-C1-4烷基芳基、-C1-6烷基(C3-C6)环烷基、-C1-6烷基芳基、-C1-6烷基杂芳基、-C1-6烷基杂环基、(C3-C6)环烷基、杂环基、杂芳基或芳基,其中所述(C3-C6)环烷基、杂环基、芳基和杂芳基中的每一个单独和结合-O(C3-C6)环烷基、-C1-6烷基(C3-C6)环烷基、-C1-6烷基芳基、-C1-6烷基杂芳基和-C1-6烷基杂环基任选地被1至3个选自以下的基团取代:卤基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、-N(Re)2、-C(O)Rf和-C1-6烷基ORe;
每一Re独立地是氢、卤基(C1-4烷基)或C1-4烷基;
每一Rf独立地是氢、卤基(C1-4烷基)、C1-4烷基或(C3-C4)环烷基;
q是0、1或2;且
p是0、1、2或3。
2.定义
在结合使用以阐述可具有多个附接点的化学基团时,连字符(-)命名所述基团与其所定义的变量的附接点。举例来说,-N(Rd)2和-NRdC1-6烷基ORd意指此基团的附接点出现在氮原子上。
术语“卤基”和“卤素”是指选自氟(氟,-F)、氯(氯,-Cl)、溴(溴,-Br)和碘(碘,-I)的原子。
术语“烷基”在单独使用或作为较大部分(例如“卤代烷基”)的一部分使用时意指饱和直链或分支链单价烃基团。除非另外规定,否则烷基通常具有1-6个碳原子,即(C1-C6)烷基。
“烷氧基”意指通过氧连接原子附接的烷基基团,由-O-烷基表示。举例来说,“(C1-C4)烷氧基”包括甲氧基、乙氧基、丙氧基和丁氧基。
术语“卤代烷基”包括单卤代烷基、多卤代烷基和全卤代烷基,其中卤素独立地选自氟、氯、溴和碘。
“卤代烷氧基”是通过氧原子附接至另一部分的卤代烷基,例如但不限于-OCHCF2或-OCF3。
术语“侧氧基”是指=O。
术语“芳基”是指芳香族碳环单环或含有6至10个碳原子的两个稠合环系统。实例包括苯基、二氢茚基、四氢萘和萘基。
完全饱和的术语“环烷基”是指4至12元单环、二环(例如桥接或螺二环)、多环(例如三环)或稠合烃环系统。单环环烷基包括(但不限于)环丙基、环丁基、环戊基、环己基、环庚基和环辛基。桥接二环环烷基包括(但不限于)二环[3.2.1]辛烷、二环[2.2.1]庚烷、二环[3.1.0]己烷、二环[1.1.1]戊烷等。螺二环环烷基包括(例如)螺[3.6]癸烷、螺[4.5]癸烷等。稠合环烷基环包括(例如)十氢萘、八氢并环戊二烯等。应理解,当指明时,环烷基上的任选的取代基可以存在于任何可取代的位置上,且包括(例如)环烷基所附接的位置。在一个方面中,环烷基是完全饱和的C3-C6单环烃环系统。
单独使用或作为较大部分的一部分使用的术语“杂芳基”是指含有1-4个选自N、O和S杂原子的5至12元(例如5至7元或5至6元)芳香族基团。杂芳基可以是单环或二环。单环杂芳基包括(例如)噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、噻二唑基、吡啶基、嗒嗪基、嘧啶基、吡嗪基等。二环杂芳基包括其中单环杂芳基环稠合至一个或多个芳基或杂芳基环的基团。非限制性实例包括吲哚基、咪唑并吡啶基、苯并噁唑基、苯并噁二唑基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、喹唑啉基、喹喏啉基、吡咯并吡啶基、吡咯并嘧啶基、吡唑并吡啶基、噻吩并吡啶基、噻吩并嘧啶基、吲嗪基、嘌呤基、萘啶基和蝶啶基。应理解,当指明时,杂芳基上的任选的取代基可以存在于任何可取代的位置上,且包括(例如)杂芳基所附接的位置。
术语“杂环基”意指含有1至4个独立地选自N、O和S的杂原子的4至12元(例如4至7元或4至6元)饱和或部分不饱和杂环。其可以是单环、二环(例如,桥接、稠合或螺二环)或三环。杂环基环可以在任一杂原子或碳原子处与其侧基附接,从而得到稳定结构。所述饱和或部分不饱和杂环基团的实例包括(但不限于)四氢呋喃基、四氢噻吩基、四氢吡喃基、吡咯烷基、吡啶酮基、吡咯酮基、六氢吡啶基、噁唑烷基、六氢吡嗪基、二噁烷基、二氧戊环基、吗啉基、二氢呋喃基、二氢吡喃基、二氢吡啶基、四氢吡啶基、二氢嘧啶基、氧杂环丁基、氮杂环丁基和四氢嘧啶基。杂环基可以是单环或二环。术语“杂环基”还包括(例如)稠合至另一不饱和杂环基团或芳基或杂芳基环的不饱和杂环基团,例如四氢萘啶、吲哚啉酮、二氢吡咯并三唑、咪唑并嘧啶、喹啉酮、二氧杂螺癸烷。还应理解,当指明时,杂环基上的任选的取代基可以存在于任何可取代的位置上,且包括(例如)杂环基所附接的位置(例如,在任选地被取代的杂环基或杂环基任选地被取代的情形下)。
术语“螺”是指共用一个环原子(例如碳)的两个环。
术语“稠合”是指彼此共用两个毗邻环原子的两个环。
术语“桥接”是指彼此共用三个环原子的两个环。
所公开的化合物以各种立体异构形式存在。立体异构物是仅在其空间排列上不同的化合物。镜像异构物是立体异构物对,其镜像是不能重叠的,最通常是由于其含有用作手性中心的不对称取代的碳原子。“镜像异构物”意指彼此是镜像且不能重叠的一对分子中的一个。非镜像异构物是含有两个或更多个不对称取代的碳原子的立体异构物。“R”和“S”代表一个或多个手性碳原子周围的取代基的构形。
“外消旋物”或“外消旋混合物”意指等摩尔量的两种镜像异构物的化合物,其中所述混合物不展现光学活性,即其不使偏光的平面旋转。
本文的化合物可以通过镜像异构特异性合成制备为各个镜像异构物或从镜像异构富集的混合物拆分。常规拆分技术包括使用光学活性酸形成镜像异构物对的每一异构物的游离碱的盐(随后是游离碱的分段结晶和再生)、使用光学活性胺形成镜像异构物对的每一镜像异构物的酸形式的盐(随后是游离酸的分段结晶和再生)、使用光学纯的酸、胺或醇形成镜像异构物对的每一镜像异构物的酯或酰胺(随后是色谱分离和去除手性助剂)、或使用各种众所周知的色谱方法拆分起始材料或最终产物的镜像异构物混合物。另外,可以通过使用常规手性色谱技术分离外消旋混合物将化合物制备成各个镜像异构物。
在所公开的化合物的立体化学由结构命名或绘示时,所命名或绘示的立体异构物相对于所有其它立体异构物的纯度为至少60重量%、70重量%、80重量%、90重量%、99重量%或99.9重量%。相对于所有其它立体异构物的重量百分比纯度是一种立体异构物的重量与其它立体异构物的重量的比率。当单一镜像异构物由结构命名或绘示时,所绘示或命名的镜像异构物是至少60重量%、70重量%、80重量%、90重量%、99重量%或99.9重量%光学纯。光学纯度重量百分比是镜像异构物的重量与镜像异构物的重量加上其光学异构物的重量的比率。
在所公开化合物的立体化学由结构命名或绘示,且命名或绘示的结构涵盖一种以上立体异构物(例如,呈非镜像异构对)时,应理解,包括所涵盖立体异构物中的一种或所涵盖立体异构物的任何混合物。应进一步理解,所命名或绘示的立体异构物的立体异构纯度相对于所有其它立体异构物为至少60重量%、70重量%、80重量%、90重量%、99重量%或99.9重量%纯。在此情形下,立体异构纯度是通过将由名称或结构所涵盖的立体异构物的混合物的总重量除以所有立体异构物的混合物的总重量来确定。除非另外规定,否则如果仅公开的化合物中的一些立体化学中心由结构绘示或命名,那么所命名或绘示的构形相对于其余构形富集,例如,摩尔浓度过量至少60%、70%、80%、90%、99%或99.9%。举例来说,结构:
意指绘示立体化学的手性碳周围的构形立体化学富集为S(例如摩尔浓度过量至少60%、70%、80%、90%、99%或99.9%)且未鉴别立体化学的另一手性中心的立体化学可以是R或S或其混合物。
在所公开的化合物由结构命名或绘示而不指示立体化学,且所述化合物具有一个手性中心时,应理解,名称或结构涵盖不含相应光学异构物的化合物的一种镜像异构物、所述化合物的外消旋混合物或相对于其相应光学异构物富集一种镜像异构物的混合物。
在所公开的化合物由结构命名或绘示而不指示立体化学且(例如)所述化合物具有一个以上手性中心(例如,至少两个手性中心)时,应理解,名称或结构涵盖不含其它立体异构物的一种立体异构物、立体异构物的混合物或其中一种或多种立体异构物相对于其它立体异构物富集的立体异构物的混合物。举例来说,名称或结构可涵盖不含其它非镜像异构物的一种立体异构物、立体异构物的混合物或其中一种或多种非镜像异构物相对于其它非镜像异构物富集的立体异构物的混合物。
术语“受试者”和“患者”可互换使用,且意指需要治疗的哺乳动物,例如伴侣动物(例如狗、猫等)、农场动物(例如牛、猪、马、绵羊、山羊等)和实验室动物(例如大鼠、小鼠、天竺鼠等)。通常,受试者是需要治疗的人类。
术语“抑制”(“inhibit”、“inhibition”或“inhibiting”)包括生物活性或过程的基线活性降低。
如本文所用术语“治疗”(“treatment”、“treat”和“treating”)是指逆转、减轻、延迟如本文所述的疾病或病症或其一种或多种症状的发作或抑制其进展。在一些方面中,治疗可以在已发生一种或多种症状之后给予,即治疗性治疗。在其它方面中,治疗可以在不存在症状的情况下给予。举例来说,治疗可以在症状发作前(例如,鉴于症状的历史和/或鉴于暴露于具体生物体或其它易感性因素)给予易感受试者,即预防性治疗。也可以在症状已消退后继续治疗以(例如)延迟其复发。
术语“医药上可接受的载剂”是指不破坏与其一起配制的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本文所述组合物中的医药上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人类血清白蛋白)、缓冲物质(例如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段共聚物、聚乙二醇和羊毛脂。
术语“有效量”或“治疗有效量”是指本文所述化合物将引发受试者的生物或医学反应的量,例如介于0.01-100mg/kg体重/天之间的剂量。
3.化合物
在第一实施例中,本文提供式I化合物:
或其医药上可接受的盐,其中变量是如上文所述。
在第二实施例中,式I化合物具有式II:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第三实施例中,式I化合物具有式III:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第四实施例中,式I化合物具有式IV:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第五实施例中,式I、II、III或IV化合物中的q是0或1,其中其余变量是如针对式I所述。
在第六实施例中,式I、II、III或IV化合物中的Ra(如果存在)是C1-3烷基、C1-3烷氧基、卤基(C1-3烷基)、卤基C1-3烷氧基或卤基,其中其余变量是如针对式I或第五实施例所述。
在第七实施例中,式I化合物具有式V:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第八实施例中,式I化合物具有式VI或VII:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第九实施例中,式I化合物具有式VIII、IX、X或XI:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第十实施例中,式I化合物具有式XII、XIII、XIV或XV:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第十一实施例中,式I化合物具有式XVI或XVII:
或其医药上可接受的盐,其中其余变量是如针对式I所述。
在第十二实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的R2是苯基或吡唑基,其各自任选地被1至3个选自Rc的基团取代,其中其余变量是如针对式I所述。
在第十三实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的Rc是卤基、C1-6烷基、卤基(C1-6烷基)、C1-6烷氧基或卤基(C1-6烷氧基),其中其余变量是如针对式I或第十二实施例所述。
在第十四实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的R2是苯基或吡唑基,其各自任选地被卤基或C1-4烷基取代,其中其余变量是如针对式I或第十二或第十三实施例所述。或者,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的R2是苯基,其中其余变量是如针对式I或第十二或第十三实施例所述。
在第十五实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的p是1,其中其余变量是如针对式I或第十二、第十三或第十四实施例所述。
在第十六实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的Rb是卤基、氰基或-SO2NH2,其中其余变量是如针对式I或第十二、第十三、第十四或第十五实施例所述。或者,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的Rb是氰基,其中其余变量是如针对式I或第十二、第十三、第十四或第十五实施例所述。
在第十七实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的R5是被吡唑基或噁唑烷基取代的C1-4烷基,所述吡唑基或噁唑烷基各自任选地被1至3个选自Rd的基团取代;或R5是六氢吡啶基、氮杂环丁基、六氢嘧啶基、四氢呋喃基、四氢吡喃基、氧杂环丁基、吡唑基、吡咯烷基或嘧啶基,其各自任选地被1至3个选自Rd的基团取代,其中其余变量是如针对式I或第十二、第十三、第十四、第十五或第十六实施例所述。
在第十八实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、或XVII化合物中的Rd是选自卤基、侧氧基、C1-4烷基、C1-4烷氧基、卤基(C1-4烷基)、-C1-4烷基ORe、-C(O)Rf、-C(O)N(Re)2、-C1-6烷基C(O)N(Re)2和-S(O)2Re,其中其余变量是如针对式I或第十二、第十三、第十四、第十五、第十六或第十七实施例所述。或者,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的Rd是选自C1-6烷基、-C(O)Rf和侧氧基,其中其余变量是如针对式I或第十二、第十三、第十四、第十五、第十六或第十七实施例所述。
在第十九实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的Re是氢或C1-3烷基,其中其余变量是如针对式I或第十二、第十三、第十四、第十五、第十六、第十七或第十八实施例所述。
在第二十实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的Rf是环丙基或C1-4烷基,其中其余变量是如针对式I或第十二、第十三、第十四、第十五、第十六、第十七、第十八或第十九实施例所述。
在第二十一实施例中,式I、II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI或XVII化合物中的R5是
其中其余变量是如针对式I或第十二、第十三、第十四、第十五、第十六、第十七、第十八、第十九或第二十实施例所述。
在第二十一实施例中,式I化合物是选自下式:
或上述中任一个的医药上可接受的盐。
化合物的具体实例提供于例示部分且包括作为本文的第二十一实施例的一部分。还包括所述化合物的医药上可接受的盐以及中性形式。
本文还提供包含本文所述化合物和医药上可接受的载剂的医药组合物。
4.用途、配制物和给药
本文所述的化合物和组合物通常可以用于调节p300和/或CBP HAT的活性。在一些方面中,本文所述的化合物和组合物抑制p300和/或CBP HAT的活性。
在一些方面中,本文所述的化合物和组合物可以用于治疗与p300和/或CBP HAT功能相关的病症。因此,本文提供治疗与p300和/或CBP HAT功能相关的病症的方法,其包含向有需要的受试者给予治疗有效量的本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物。还提供本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物的用途,其用于制造用于治疗与p300和/或CBP HAT功能相关的病症的药剂。还提供本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物,其用于治疗与p300和/或CBPHAT相关的病症。
在一些方面中,本文所述的化合物和组合物可以用于治疗与在由p300和/或CBP酶起作用的染色质的碱性残基上的H3K27、H3K18和其它乙酰化位点处的染色质乙酰化相关的病症。因此,本文提供治疗与在由p300和/或CBP酶起作用的染色质碱性残基上的H3K27、H3K18和其它乙酰化位点处的染色质乙酰化相关的病症的方法,其包含向有需要的受试者给予治疗有效量的本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物。还提供本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物的用途,其用于制造用于治疗与在由p300和/或CBP酶作用的染色质碱性残基上的H3K27、H3K18和其它乙酰化位点处的染色质乙酰化相关的病症的药剂。还提供本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物,其用于治疗与在由p300和/或CBP酶作用的染色质碱性残基上的H3K27、H3K18和其它乙酰化位点处的染色质乙酰化相关的病症。
在一些方面中,本文所述的化合物和组合物可以用于治疗与染色质超乙酰化和/或已知由p300和/或CBP乙酰基的蛋白质超乙酰化相关的病症。因此,本文提供治疗与染色质超乙酰化和/或已知由p300和/或CBP乙酰基的蛋白质超乙酰化相关的病症的方法,其包含向有需要的受试者给予治疗有效量的本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物。还提供本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物的用途,其用于制造用于治疗与染色质超乙酰化和/或已知由p300和/或CBP乙酰基的蛋白质超乙酰化相关的病症的药剂。还提供本文所述化合物或其医药上可接受的盐、或包含所公开的化合物或其医药上可接受的盐的组合物,其用于治疗与染色质超乙酰化和/或已知由p300和/或CBP乙酰基的蛋白质超乙酰化相关的病症。
在一些方面中,本文所述的化合物和组合物可以用于治疗癌症、心脏病、代谢疾病、纤维变性疾病、发炎性疾病或病毒感染。
在一些方面中,由本文所述的化合物和组合物治疗的癌症是选自乳房、前列腺和结肠的腺癌;肺的支气管癌;骨髓癌;黑色素瘤;肝细胞瘤;神经胚细胞瘤;乳头瘤;APUD瘤;迷芽瘤;鳃原瘤;恶性类癌综合征;类癌心脏病;癌(例如沃克癌(Walker)、基底细胞癌、鳞状细胞癌、布朗-皮西二氏癌(Brown-Pearce)、导管癌、艾利希氏瘤(Ehrlich tumor)、克雷布斯2癌(Krebs 2)、默克尔细胞癌(merkel cell)、粘蛋白癌、非小细胞肺癌、燕麦细胞癌、乳头状癌、硬癌、细支气管癌、支气管原癌、鳞状细胞癌和移行细胞癌);组织细胞障碍;白血病;恶性组织球增生症;霍奇金氏病(Hodgkin's disease);小免疫增生;非霍奇金氏淋巴瘤;浆细胞瘤;网状内皮组织增生;黑色素瘤;成软骨细胞瘤;软骨瘤;软骨肉瘤;纤维瘤;纤维肉瘤;巨细胞肿瘤;组织细胞瘤;脂肪瘤;脂肪肉瘤;间皮瘤;粘液瘤;粘液肉瘤;骨瘤;骨肉瘤;脊索瘤;颅咽管瘤;无性细胞瘤;错构瘤;间叶瘤;中肾瘤;肌肉瘤;成釉细胞瘤;牙骨质瘤;牙瘤;畸胎瘤;胸腺瘤;滋养层肿瘤;腺瘤;胆管瘤;胆脂瘤;圆柱瘤;囊腺癌(cystadenocarcinoma);囊腺瘤(cystadenoma);颗粒细胞肿瘤;两性胚细胞瘤;肝细胞瘤;汗腺腺瘤;胰岛细胞肿瘤;莱迪希氏细胞肿瘤(Leydig cell tumor);乳头瘤;赛特利细胞肿瘤(sertoli cell tumor);泡膜细胞肿瘤;平滑肌瘤;平滑肌肉瘤;成肌细胞瘤;肌瘤;肌肉瘤;横纹肌瘤;横纹肌肉瘤;室管膜瘤;神经节瘤;神经胶质瘤;髓母细胞瘤;脑脊髓膜瘤;神经鞘瘤;神经胚细胞瘤;神经上皮瘤;神经纤维瘤;神经瘤;副神经节瘤;非嗜铬副神经节瘤;血管角化瘤;血管淋巴样增生伴嗜酸性粒细胞增多症;血管瘤硬化;血管瘤病;血管球瘤;血管内皮瘤;血管瘤;血管周皮细胞瘤;血管肉瘤;淋巴管瘤;淋巴管肌瘤;淋巴管肉瘤;松果体瘤;癌肉瘤;软骨肉瘤;叶状囊性肉瘤;纤维肉瘤;平滑肌肉瘤;白血病性肉瘤;脂肪肉瘤;肌肉瘤;粘液肉瘤;卵巢癌;横纹肌肉瘤;肉瘤;赘生物;神经纤维瘤病;和子宫颈发育不良。
在其它方面中,由本文所述化合物和组合物治疗的癌症是选自听神经瘤、急性白血病、急性淋巴球性白血病、急性骨髓细胞性白血病、急性T细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳癌、支气管癌、子宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴球性白血病、慢性骨髓细胞性白血病、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、增殖不良病变(dysproliferative change)、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、雌激素受体阳性乳癌、原发性血小板过多症、尤恩氏肿瘤(Ewing's tumor)、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睪丸癌、胶质瘤、胶质母细胞瘤、神经胶质肉瘤、重链病、头颈癌、血管母细胞瘤、肝细胞瘤、肝细胞癌、激素不敏感前列腺癌、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细胞源的淋巴恶性病、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中线瘤(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨原性肉瘤、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(Waldenstrom's macroglobulinemia)、睪丸肿瘤、子宫癌和威尔姆氏瘤(Wilms'tumor)。
在一些方面中,由本文所述的化合物和组合物治疗的癌症是选自结肠癌、胃癌、甲状腺癌、肺癌、白血病、胰腺癌、黑色素瘤、多发性黑色素瘤、脑癌、CNS癌、肾癌、前列腺癌、卵巢癌、白血病和乳癌。
在一些方面中,由本文所述的化合物和组合物是选自肺癌、乳癌、胰腺癌、结肠直肠癌和黑色素瘤。
在一些方面中,由本文所述的化合物和组合物治疗的癌症是选自前列腺癌、增强子驱动癌、多发性骨髓瘤和淋巴瘤(例如外套细胞淋巴瘤)。参见(例如)Santer等人2011,《分子癌症治疗学》10:1644-1655;Lasko等人,2017,《自然》10月5日;550(7674):128-132;Tie F等人2009《发展(Development)》136:3131-3141;Bergsagel PL,Kuehl WM 2001,《致癌基因》,20(40):5611-22;Chesi和Bergsagel 2013,《国际血液学杂志(Int J Hematol.)》97(3):313-323;和Jares P等人2007,《自然癌症综述(Nat Rev Cancer.)》7(10):750-762。
在一个方面中,由本文所述化合物和组合物治疗的心脏病是选自心肥大和心脏衰竭。
在一个方面中,由本文所述化合物和组合物治疗的代谢疾病是选自肥胖症、脂肪肝、异常血脂症、高血压、冠状动脉心脏病、肝发炎和2型糖尿病。
在一个方面中,由本文所述化合物和组合物治疗的纤维变性疾病是选自辐射诱导的肺炎、辐射纤维化、急性呼吸窘迫综合征、慢性阻塞性肺病、特发性肺纤维化、间质性肺病、心肌梗塞、缺血性中风、缺血性肾病、移植排斥、利什曼体病(Leishmaniasis)、I型糖尿病、类风湿性关节炎、慢性肝炎、硬化、发炎性肠病、克隆氏病(Crohn's disease)、硬皮症、瘢瘤、术后纤维化、化学疗法诱导的纤维化(例如化学疗法诱导的肺纤维化或卵巢皮质纤维化)、肾性全身性纤维化、腹膜后纤维化、骨髓纤维化、纵膈纤维化、囊性纤维化、石棉肺病、气喘和肺高血压。
在一个方面中,由本文所述化合物和组合物治疗的发炎性疾病是选自气喘、发炎性肠病(克隆氏病或溃疡性结肠炎)、慢性阻塞性肺病、类风湿性关节炎和牛皮癣。在另一个方面中,由本文所述化合物和组合物治疗的发炎性疾病是选自阿狄森氏病(Addison'sdisease)、急性痛风、僵直性脊椎炎、气喘、动脉粥样硬化、贝切特氏病(Behcet'sdisease)、大疱性皮肤病、慢性阻塞性肺病、克隆氏病、皮炎、湿疹、巨细胞动脉炎、纤维化、肾小球肾炎、肝血管堵塞、肝炎、垂体炎、免疫缺陷综合征、发炎性肠病、川崎病(Kawasakidisease)、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、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、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、全身性红斑狼疮、高安氏动脉炎(Takayasu'sArteritis)、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白斑症、血管炎和韦格纳氏肉芽肿病(Wegener's granulomatosis)。
在一个方面中,由本文所述的化合物和组合物治疗的病毒感染是选自人类免疫缺陷病毒、C型肝炎病毒和人类乳头瘤病毒。
在一个方面中,本文所述的化合物和组合物可以用于治疗神经病症。
神经病症的实例包括:(i)慢性神经变性疾病,例如额颞叶变性(额颞叶失智症,FTD)、FTD-GRN、家族性和散发性肌肉萎缩性脊髓侧索硬化症(分别FALS和ALS)、家族性和散发性帕金森氏病(Parkinson's disease)、帕金森氏病失智症、杭丁顿氏病(Huntington'sdisease)、家族性和散发性阿尔茨海默氏病(Alzheimer's disease)、多发性硬化、肌肉营养不良症、橄榄体脑桥小脑萎缩、多系统萎缩、威尔森氏症(Wilson's disease)、进行性核上性麻痹、弥漫性路易氏体病(diffuse Lewy body disease)、皮质齿状核变性、进行性家族性肌阵挛性癫痫、纹状体黑质变性、扭转性肌张力障碍、家族性颤抖、唐氏综合征(Down'sSyndrome)、乔治吉尔斯妥瑞综合征(Gilles de la Tourette syndrome)、哈勒沃登-施帕茨病(Hallervorden-Spatz disease)、外周神经病变、糖尿病型外周神经病变、拳击手型失智症、AIDS失智症、年龄相关的失智症、年龄相关的记忆损害和类淀粉变性相关的神经变性疾病(例如由普里昂蛋白蛋白质(PrP)引起的疾病,所述普里昂蛋白蛋白质与可传播海绵状脑病相关(库贾氏病(Creutzfeldt-Jakob disease)、格斯特曼-施特劳斯综合征(Gerstmann-Straussler-Scheinker syndrome)、绵羊疯痒病和库鲁病(kuru))、和由过度胱抑素C累积引起的疾病(遗传性胱抑素C血管病变);和(ii)急性神经变性病症,例如创伤性脑损伤(例如手术相关的脑损伤)、大脑水肿、周围神经损害、脊髓损伤、雷氏病(Leigh'sdisease)、格林-巴利综合征(Guillain-Barre syndrome)、溶酶体贮积症(例如脂褐质沈积症)、阿尔珀斯病(Alper's disease);由长期酒精或药物滥用引起的病理,包括(例如)蓝斑和小脑中神经元的变性、药物诱导的运动障碍;由衰老引起的病理,包括导致认知和运动损害的小脑神经元和皮质神经元变性;和由长期安非他命(amphetamine)滥用引起的病理,包括导致运动损害的基底神经节神经元变性;由局灶性创伤(例如中风、局灶性缺血、血管功能不全、缺氧-缺血性脑病、高血糖症、低血糖症或直接创伤引起的病理变化;作为治疗性药物和治疗的负面副作用出现的病理(例如因应抗痉挛剂剂量的NMDA类谷氨酸受体的拮抗剂的扣带和内嗅皮质神经元变性)和韦尼克-柯萨可夫相关的失智症(Wernicke-Korsakoff'srelated dementia)。
其它神经病症包括神经损伤或与脊髓损伤相关的创伤。边缘和皮质系统的神经病症包括(例如)大脑类淀粉变性、匹克氏萎缩(Pick's atrophy)和蕾特氏综合征(Rettsyndrome)。在另一个方面中,神经病症包括情绪障碍,例如情感障碍和焦虑症;社交障碍,例如性格缺陷和人格异常;学习、记忆和智力障碍,例如智力迟钝和失智症。因此,在一个方面中,所公开的化合物和组合物可以用于治疗精神分裂症、谵妄、注意力缺失过动症(ADHD)、情感型精神分裂症、阿尔茨海默氏病、血管型失智症、鲁宾斯坦-泰必氏综合征(Rubinstein-Taybi syndrome)、抑郁症、狂躁症、注意力缺失症、药物成瘾、失智症和包括BPSD表达在内的失智症。
其它神经病况包括(例如)tau蛋白病变、脊髓和延髓肌肉萎缩、3型脊髓小脑性失调症、疼痛(包括例如急性和慢性疼痛、躯体疼痛、内脏疼痛、神经病性疼痛、外周神经病变、伤害感受性疼痛、中枢疼痛综合征、肌肉或关节疼痛)和神经发炎。
在一个方面中,本文所述的化合物和组合物可以用于治疗选自额颞叶失智症、阿尔茨海默氏病、tau蛋白病变、血管型失智症、帕金森氏病和路易体失智症的神经病症。
在某些方面中,本文所述组合物被配制用于给予需要所述组合物的患者。本文所述组合物可经口、非经肠、通过吸入喷雾、经局部、经直肠、经鼻、经颊、经阴道或通过植入型药盒给予。本文所用术语“非经肠”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。在一些实施例中,经口、经腹膜内或经静脉内给予组合物。本文所述组合物的无菌可注射形式可以是水性或油性悬浮液。所述悬浮液可根据业内已知技术使用适宜分散或湿润剂和悬浮剂进行配制。
在一些方面中,经口给予组合物。
用于任一具体患者的具体剂量和治疗方案将取决于多种因素,包括所采用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、排泄速率、药物组合和治疗医生的判断和所治疗具体疾病的严重程度。组合物中本文所述化合物的量还将取决于所述组合物中的具体化合物。
本文所述化合物可以医药上可接受的盐形式存在。对于医学中的用途,本文所述化合物的盐是指无毒“医药上可接受的盐”。医药上可接受的盐形式包括医药上可接受的酸性/阴离子性或碱性/阳离子性盐。本文所述化合物的适宜医药上可接受的酸加成盐包括(例如)无机酸(例如盐酸、氢溴酸、磷酸、硝酸和硫酸)的盐和有机酸(例如乙酸、苯磺酸、苯甲酸、甲磺酸和对甲苯磺酸)的盐。具有酸性基团(例如羧酸)的本教示的化合物可以与医药上可接受的碱形成医药上可接受的盐。适宜医药上可接受的碱性盐包括(例如)铵盐、碱金属盐(例如钠盐和钾盐)和碱土金属盐(例如镁盐和钙盐)。具有季铵基团的化合物还含有抗衡阴离子,例如氯离子、溴离子、碘离子、乙酸根、高氯酸根等。所述盐的其它实例包括盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、硝酸盐、苯甲酸盐和与氨基酸(例如谷氨酸)的盐。
本文中还包括使用治疗有效量的式I化合物或其医药上可接受的盐和有效量的一种或多种额外医药活性剂的组合疗法。可与式I化合物或其医药上可接受的盐组合的额外活性剂包括(例如)靶向雌激素受体(ER)的活性剂。所述活性剂包括(但不限于)选择性雌激素受体降解剂(SERD)、ER拮抗剂、选择性雌激素受体调节剂(SERM)和芳香酶抑制剂(AI)。SERD和ER拮抗剂的实例包括(但不限于)氟维司群(fulvestrant)、RAD-1901(艾拉司群(elacestrant))、GDC-0927((2S)-2-(4-{2-[3-(氟甲基)-1-氮杂环丁基]乙氧基}苯基)-3-(3-羟基苯基)-4-甲基-2H-苯并哌喃-6-醇)、GDC-0810(波兰司群(brilanestrant))、AZD-9496((2E)-3-[3,5-二氟-4-[(1R,3R)-2-(2-氟-2-甲基丙基)-2,3,4,9-四氢-3-甲基-1H-吡啶并[3,4-b]吲哚-1-基]苯基]-2-丙烯酸)、OP-1250(US 9,018,244中发现的(S)-3-(4-羟基苯基)-4-甲基-2-(4-(2-((R)-3-甲基吡咯烷-1-基)乙氧基)苯基)-2H-苯并哌喃-7-醇的前药,所述案件的内容以引用方式并入本文中)、也于US 9,018,244中发现的(S)-3-(4-羟基苯基)-4-甲基-2-(4-(2-((R)-3-甲基吡咯烷-1-基)乙氧基)苯基)-2H-苯并哌喃-7-醇,所述案件的内容以引用方式并入本文中)、LSZ102((E)-3-(4-((2-(2-(1,1-二氟乙基)-4-氟苯基)-6-羟基苯并[b]噻吩-3-基)氧基)苯基)丙烯酸)和H3B-6545((E)-N,N-二甲基-4-((2-((5-((Z)-4,4,4-三氟-1-(3-氟-1H-吲唑-5-基)-2-苯基丁-1-烯-1-基)吡啶-2-基)氧基)乙基)氨基)丁-2-烯酰胺)。SERM的实例包括(但不限于)他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、巴多昔芬(bazedoxifene)、奥培米芬(ospemifene)和萘福昔定(nafoxidene)。AI的实例包括(但不限于)阿那曲唑(anastrozole)、来曲唑(letrozole)、依西美坦(exemestane)、伏氯唑(vorozole)、福美坦(formestane)和法曲唑(fadrozole)。在一个方面中,提供式I化合物或其医药上可接受的盐和选自以下的额外治疗剂:氟维司群、RAD-1901、GDC-0927、GDC-0810、AZD-9496、OP-1250、LSZ102、H3B-6545、他莫昔芬、托瑞米芬、雷洛昔芬、巴多昔芬、奥培米芬、萘福昔定、阿那曲唑、来曲唑、依西美坦、伏氯唑、福美坦和法曲唑。在一个方面中,额外治疗剂是氟维司群。本发明的范围内还包括上文讨论的用于治疗本文所列举的病况的组合疗法中的一种或多种的用途。举例来说,在一个方面中,上文提及的组合治疗可以用于治疗癌症,例如乳癌。
例示
在以下非限制性方法、方案和实例阐释所公开的化合物的代表性实例。
以下缩写具有指示的含义:Ac=乙酰基;ACN=乙腈;AcO,乙酸酯;BOC=叔丁基氧基羰基;CBZ=苄氧羰基;CDI=羰基二咪唑;DBU=1,8-二氮杂二环十一-7-烯;DCC=1,3-二环己基碳二亚胺;DCE=1,2-二氯乙烷;DI=去离子化;DIAD=偶氮二甲酸二异丙基酯;DIBAL=二异丁基氢化铝;DIPA=二异丙胺;DIPEA或DIEA=N,N-二异丙基乙胺,也称为休尼格碱(Hunig's base);DMA=二甲基乙酰胺;DMAP=4-(二甲基氨基)吡啶;DMF=二甲基甲酰胺;DMP=戴斯-马丁过碘烷(Dess-Martin periodinane);DPPA=二苯基磷酰基叠氮化物;DPPP=1,3-双(二苯基膦基)丙烷;Dtbbpy=4,4'-二-/e/7-丁基-2,2'-二吡啶基;EDC或EDCI=1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐;EDTA=乙二胺四乙酸,四钠盐;EtOAc=乙酸乙酯;FAB=快速原子轰击;FMOC=9-茀基甲氧基羰基;HFIP=六氟异丙醇;HMPA=六甲基磷酰胺;HATU=(9-(7-氮杂苯并三唑-l-基)-N,N,N,N-四甲基脲鎓六氟磷酸盐;HOAt=1-羟基-7-氮杂苯并三唑或3H-[1,2,3]三唑并[4,5-b]吡啶-3-醇;HOBt=1-羟基苯并三唑;HRMS=高分辨率质谱;KHMDS=六甲基二硅氮烷钾;LC-MS=液相色谱-质谱;LDA=二异丙基氨基锂;LiHMDS=六甲基二硅氮烷锂;MCPBA=间-氯过氧苯甲酸;MMPP=单过氧邻苯二甲酸镁六水合物;Ms=甲烷磺酰基=甲磺酰基;MsO=甲烷磺酸酯=甲磺酸酯;MTBE=甲基叔丁基醚;NBS=N-溴琥珀酰亚胺;NMM=4-甲基吗啉;NMP=N-甲基吡咯烷酮;NMR=核磁共振;PCC=吡啶鎓氯铬酸盐;PDC=吡啶鎓二铬酸盐;Ph=苯基;PPTS=吡啶鎓对甲苯磺酸盐;pTSA=对甲苯磺酸;r.t./RT=室温;rac.=外消旋;T3P=2,4,6-三丙基-1,3,5,2,4,6-三氧杂次膦酸盐2,4,6-三氧化物;TEA=三乙胺;TFA=三氟乙酸;TfO=三氟甲烷磺酸酯=三氟甲磺酸酯;THF=四氢呋喃;TLC=薄层色谱;TMSCl=三甲基硅基氯。
通常通过TLC或LC-MS监测反应的进程。使用以下方法中的一种记录LC-MS。
方法-C3:
PDS方法-J:
方法H:
方法F:
方法G:
除非另有说明,否则NMR是在室温下在Varian Inova 400或500MHz光谱仪上以溶剂峰作为参照记录,或在Bruker300或400MHz光谱仪上使用TMS峰作为内部参照记录。
除非另外陈述,否则未鉴别以下实例中的每一溶析立体异构物的绝对构形。
本文所述的化合物可以使用以下方法和方案来制备。除非另有说明,否则所用的所有原料皆有市售。
方法1
方法1是用于由1,3-二氨基丙-2-醇合成5-羟基-1,3-二甲基四氢嘧啶-2(1H)-酮的四步方案,其可以用于合成在本文所述化合物的途中的中间体。
方法2
方法2是由卤代硝基吡啶与醇的反应制备烷氧基-硝基吡啶的方案,其可以用于合成在本文所述化合物的途中的中间体。
方法3
方法3是用于制备1-(3-((6-硝基吡啶-3-基)氧基)杂环-1-基)乙-1-酮衍生物的两步方案,其可以用于合成在本文所述化合物的途中的中间体。
方法4
方法4是通过钯催化的氢化反应由2-硝基吡啶制备被取代的2-氨基吡啶的方案,其可以用于合成在本文所述化合物的途中的中间体。
方法5
方法5是用于由氯嘧啶制备嘧啶基氧基吡啶-2-胺的三步方案,其可以用于合成在本文所述化合物的途中的中间体。
方法6
方法6是采用被取代的苯甲醛或酮制备被取代的2-芳基乙胺和2-杂芳基乙胺的六步方案,其可以用于合成在本文所述化合物的途中的中间体。
方法7
方法7是用于由芳基乙胺和被取代的硼酸酯(或硼酸)吡唑开始制备被取代的2-(芳基乙基氨基)-2-(1-取代的1H-吡唑-4-基)乙酸乙酯的两步方案,其可以用于合成在本文所述化合物的途中的中间体。
方案1
方案1图解说明用于将α-溴酯转化为N-芳基-2-(烷基氨基)乙酰胺的两步合成顺序。所述方法可以用于合成式I化合物的亚组,其中R1是被取代的苯基且B、Ra、R2、R3、R4和R5是如本文所述。
方法1
5-羟基-1,3-二甲基四氢嘧啶-2(1H)-酮
方法1,步骤1.2-((三异丙基硅基)氧基)丙烷-1,3-二胺:
于0℃下在氮气氛下向1,3-二氨基丙-2-醇(2.0g,22.19mmol)于无水DCM(26ml)中的搅拌溶液中添加三乙胺(6.74g,66.57mmol),之后逐滴添加TIPS-氯化物(4.71g,24.41mmol)。将反应混合物升温至室温并搅拌20小时。反应完成后,将反应混合物用饱和碳酸氢钠水溶液(10ml)淬灭且用DCM(2×10ml)萃取。将合并的有机层经硫酸钠干燥且在减压下浓缩,以得到标题化合物(5.0g),其不经进一步纯化即原样用于下一步骤。LCMS:m/z=247.46[M+1]。
方法1,步骤2.5-((三异丙基硅基)氧基)四氢嘧啶-2(1H)-酮:
向2-((三异丙基硅基)氧基)丙烷-1,3-二胺(5.0g,20.28mmol)于甲醇(81ml)中的搅拌溶液中添加二硫代碳酸S,S'-二甲基酯(3.72g,30.43mmol)。然后将反应物加热至60℃并保持20小时。反应完成后,在减压下浓缩反应混合物。通过硅胶色谱纯化残余物,以得到标题化合物(1.25g,21%;2个步骤)。LCMS:m/z=273.48[M+1]。
方法1,步骤3.1,3-二甲基-5-((三异丙基硅基)氧基)四氢嘧啶-2(1H)-酮:
于0℃下向5-((三异丙基硅基)氧基)四氢嘧啶-2(1H)-酮(1.25g,4.59mmol)于DMF(25ml)中的搅拌溶液中添加NaH(0.551g,60%于油中;13.77mmol)。将所得反应混合物于0℃下搅拌1小时。然后向反应混合物中添加碘甲烷(1.96g,13.77mmol)。将反应升温至室温并搅拌20小时。反应完成后,将反应混合物倾倒至冰冷水(25ml)中且用乙酸乙酯(2×25ml)萃取。将有机层用水(2×25ml)洗涤,经硫酸钠干燥,并在减压下浓缩。通过硅胶色谱纯化残余物,以得到标题化合物(1.0g,73%)。LCMS:m/z=301.23[M+1]。
方法1,步骤4.5-羟基-1,3-二甲基四氢嘧啶-2(1H)-酮:
于0℃下向1,3-二甲基-5-((三异丙基硅基)氧基)四氢嘧啶-2(1H)-酮(1.0g,3.33mmol)于无水乙醇(10ml)中的搅拌溶液中添加4M 1,4-二噁烷中的HCl(8.32ml,33.28mmol)。然后将反应混合物于室温下搅拌5小时。反应完成后,在减压下浓缩反应混合物。用水(5ml)稀释固体且用乙酸乙酯(3×10ml)萃取水层。将合并的有机层用盐水(10ml)洗涤,经无水Na2SO4干燥且在减压下浓缩,以得到标题化合物(1.5g,未经进一步纯化即原样用于下一步骤)。LCMS:m/z=145.17[M+1]。
方法2
5-((1-甲基六氢吡啶-4-基)氧基)-2-硝基吡啶
方法2.5-((1-甲基六氢吡啶-4-基)氧基)-2-硝基吡啶:
于0℃下向1-甲基六氢吡啶-4-醇(1.44g,12.49mmol)和5-氟-2-硝基吡啶(0.7g,6.25mmol)于无水DMF(7ml)中的搅拌溶液中逐份添加NaH(0.3g,95%,12.49mmol)。将反应混合物于室温下搅拌1小时。然后将反应混合物倾倒至冰冷水(10ml)中且将混合物用乙酸乙酯(2×30ml)萃取。将合并的有机层用盐水(10ml)洗涤,经无水Na2SO4干燥且在减压下浓缩,以得到标题化合物(0.54g,66%)。LCMS:m/z=238.3[M+1]。
3-((6-硝基吡啶-3-基)氧基)氮杂环丁烷-1-甲酸叔丁基酯
方法2.3-((6-硝基吡啶-3-基)氧基)氮杂环丁烷-1-甲酸叔丁基酯:
于0℃下向3-羟基氮杂环丁烷-1-甲酸叔丁基酯(3.00g,17.32mmol)于无水THF(20ml)中的搅拌溶液中添加NaH(1.38g,60%于油中,34.64mmol)。将反应混合物于相同温度下搅拌30分钟且于0℃下向反应混合物中添加5-氟-2-硝基吡啶(2.04g,14.35mmol)。反应完成后,将反应混合物倾倒至冰冷水(75ml)中且用乙酸乙酯(2×100ml)萃取。将合并的有机层用盐水(70ml)洗涤,经无水硫酸钠干燥且在减压下浓缩,以得到粗产物。通过硅胶色谱纯化残余物,以获得标题化合物(2.00g,47.1%)。1H NMR(400MHz,DMSO-d6)δ:1.40(s,9H),3.89(d,J=7.2Hz,2H),4.37(d,J=7.6Hz,2H),5.25(s,1H),7.60-7.63(m,1H),8.31(dd,J=8.8Hz,J=3.2Hz,2H)。
方法3
1-(3-((6-硝基吡啶-3-基)氧基)氮杂环丁-1-基)乙-1-酮
方法3,步骤1.5-(氮杂环丁-3-基氧基)-2-硝基吡啶HCl:
于0℃下向3-((6-硝基吡啶-3-基)氧基)氮杂环丁烷-1-甲酸叔丁基酯(3.50g,11.85mmol)于DCM(35ml)中的搅拌溶液中添加逐滴4M 1,4-二噁烷中的HCl(3.5ml,14.0mmol)。将反应混合物于室温下搅拌3小时。反应完成后,在减压下浓缩反应混合物。将所得残余物与正戊烷(15ml)一起研磨且过滤,以得到固体状标题化合物(2.50g,91.0%)。LCMS:m/z=196.04[M+1]。
方法3,步骤2.1-(3-((6-硝基吡啶-3-基)氧基)氮杂环丁-1-基)乙-1-酮:
于0℃下向5-(氮杂环丁-3-基氧基)-2-硝基吡啶盐酸盐(2.5g,10.79mmol)于DCM(25ml)中的搅拌溶液中添加TEA(4.3g,43.17mmol)。将反应混合物于0℃下搅拌10分钟。然后于0℃下添加逐滴乙酰氯(1.2g,15.19mmol)。将反应混合物于0℃下再搅拌1小时。反应完成后,将反应混合物倾倒至饱和碳酸氢钠溶液(15ml)中且用DCM(2×30ml)萃取。将合并的有机层用盐水(20ml)洗涤,经无水硫酸钠干燥且在减压下浓缩。通过硅胶色谱纯化所得残余物,以得到标题化合物(2.0g,78.1%)。LCMS:m/z=238.51[M+1]。
(S)-1-(3-((6-硝基吡啶-3-基)氧基)六氢吡啶-1-基)乙-1-酮
方法3,步骤1.(S)-2-硝基-5-(六氢吡啶-3-基氧基)吡啶:
于0℃下向(S)-3-((6-硝基吡啶-3-基)氧基)六氢吡啶-1-甲酸叔丁基酯(0.50g,1.54mmol)于DCM(10ml)中的搅拌溶液中添加逐滴TFA(2.5ml,5V)。将反应混合物于室温下搅拌3小时。反应完成后,将反应混合物倾倒至饱和碳酸氢钠溶液(15ml)中且用DCM(2×30ml)萃取。将合并的有机层用盐水(20ml)洗涤,经无水硫酸钠干燥,并在减压下浓缩。将所得残余物与戊烷(5体积)一起研磨,以得到固体状标题化合物(0.4g,70%)。1H NMR(400MHz,DMSO-d6):δ8.31-8.33(m,2H),7.75-7.78(m,1H),4.53-4.59(m,1H),3.10-3.13(m,1H),2.75-2.80(m,1H),2.57-2.62(m,2H),2.05-2.09(m,1H),1.68-1.71(m,1H),1.51-1.68(m,1H),1.46-1.50(m,1H);LCMS:m/z=224.3[M+1]。
方法3,步骤2.(S)-1-(3-((6-硝基吡啶-3-基)氧基)六氢吡啶-1-基)乙-1-酮:
于0℃下向(S)-2-硝基-5-(六氢吡啶-3-基氧基)吡啶(0.40g,1.79mmol)于DCM(8ml,20volumes)中的搅拌溶液中添加三乙胺(0.38ml,2.69mmol)。将反应混合物于0℃下搅拌10分钟且添加逐滴DCM(1ml)中的乙酰氯(0.168ml,2.15mmol)。将反应混合物于0℃下搅拌1小时。将反应混合物倾倒至饱和碳酸氢钠溶液(15ml)中且用DCM(2×30ml)萃取。将合并的有机层用盐水(20ml)洗涤,经无水硫酸钠干燥,并在减压下浓缩。通过硅胶色谱纯化所得残余物,以得到标题化合物(0.3g,47%)。LCMS:m/z=266.4[M+1]。
方法4
5-((1-甲基六氢吡啶-4-基)氧基)吡啶-2-胺
方法4.5-((1-甲基六氢吡啶-4-基)氧基)吡啶-2-胺:
向5-((1-甲基六氢吡啶-4-基)氧基)-2-硝基吡啶(0.54g,2.29mmol)于1:1甲醇:乙酸乙酯的混合物(12ml)中的搅拌溶液中添加10%Pd/C(0.054g,50%水分)。然后将反应物于室温下在H2气体气氛下搅拌3小时。反应完成后,将反应混合物用乙酸乙酯稀释且通过硅藻土垫过滤。在减压下浓缩溶析物,以得到固体状标题化合物(0.22g,44%)。1H NMR(400MHz,DMSO-d6):1.50-1.70(m,2H),1.80-1.90(m,2H),2.09-2.21(m,5H),2.40-2.68(m,2H),4.03-4.15(m,1H),5.51(s,2H,-NH2),6.40(d,J=8.8Hz,1H),7.10(dd,J=8.8Hz,2.8Hz,1H),7.64(d,J=2.8Hz,1H)。
方法4.1-(3-((6-氨基吡啶-3-基)氧基)氮杂环丁-1-基)乙-1-酮:
向1-(3-((6-硝基吡啶-3-基)氧基)氮杂环丁-1-基)乙-1-酮(2.0g,8.43mmol)于1:1乙醇:乙酸乙酯的混合物(60ml)中的搅拌溶液中添加Pt2O(0.2g,10%w/w.)。将反应物于室温下在15Kg H2气体压力下搅拌16小时。反应完成后,将反应混合物用乙酸乙酯(25ml)稀释且通过硅藻土垫过滤。将硅藻土垫用乙酸乙酯(2×25ml)洗涤且在减压下浓缩合并的滤液,以得到固体状标题化合物(1.40g,80.1%)。LCMS:m/z=208.05[M+1]。
方法5
5-((5-甲基嘧啶-2-基)氧基)吡啶-2-胺
方法5,步骤1.2-((6-氯吡啶-3-基)氧基)-5-甲基嘧啶:向6-氯吡啶-3-醇(1g,7.77mmol)于NMP(5ml)中的搅拌溶液中添加叔丁醇钾(1.3g,11.62mmol)且将反应混合物于室温下搅拌1小时。添加2-氯-5-甲基嘧啶(0.99g,7.77mmol)且将反应混合物于80℃下加热2小时。反应完成后,将反应混合物用水(15ml)淬灭且用乙酸乙酯(2×20ml)萃取。将合并的有机层用盐水(10ml)洗涤,经无水硫酸钠干燥,并在减压下浓缩,以得到粗产物。通过硅胶色谱纯化粗产物,以得到标题化合物(1g,58%)。LCMS:m/z=222.35[M+1]。
方法5,步骤2.N-(4-甲氧基苄基)-5-((5-甲基嘧啶-2-基)氧基)吡啶-2-胺:
向2-((6-氯吡啶-3-基)氧基)-5-甲基嘧啶(0.5g,2.26mmol)于1,4-二噁烷(10ml)中的搅拌溶液中添加4-甲氧基苄基胺(0.37g,2.71mmol)、BINAP(0.07g,0.11mmol)、Pd2(dba)3(0.04g,0.05mmol)和叔丁醇钠(0.65g,6.78mmol)。将反应混合物用氩气吹扫15分钟且加热至100℃并保持4小时。反应完成后,将反应混合物用水(50ml)淬灭且用乙酸乙酯(2×50ml)萃取。将合并的有机层用盐水(10ml)洗涤,经无水硫酸钠干燥且在减压下浓缩,以得到粗产物。通过硅胶色谱纯化粗产物,以得到标题化合物(0.15g,21%)。LCMS:m/z=323.43[M+1]。
方法5,步骤3.5-((5-甲基嘧啶-2-基)氧基)吡啶-2-胺:
于0℃下向N-(4-甲氧基苄基)-5-((5-甲基嘧啶-2-基)氧基)吡啶-2-胺(0.13g,0.40mmol)中添加逐滴TFA(1.3ml,10V)。将反应混合物于室温下搅拌3小时。反应完成后,在减压下浓缩反应混合物。将所得残余物与戊烷(5体积)一起研磨,以得到粗制化合物,其不经进一步纯化即用于下一步骤(0.2g,TFA盐)。LCMS:m/z=203.51[M+1]。
方法6
(S)-4-(1-氨基丙-2-基)苯甲腈盐酸盐
方法6,步骤1.(E,Z)-3-(4-氰基苯基)丁-2-烯酸乙基酯:
于0℃下在氮气氛下向叔丁醇钾(10.09g,89.7mmol)于无水THF(90ml)中的搅拌溶液中添加膦酰乙酸三乙基酯(20.08g,89.7mmol)。然后将反应混合物于相同温度下搅拌15分钟。然后将反应物升温至室温并搅拌1小时。然后添加在THF(50ml)中的溶液的4-乙酰基苯甲腈(10.0g,69.0mmol)且将反应物加热至70℃并保持3小时。在反应完成(通过TLC监测)后,用1N HCl将反应混合物的pH调整至3-4。在减压下去除THF且用乙酸乙酯(2×50ml)萃取水层。将合并的有机层用盐水(50ml)洗涤,经无水Na2SO4干燥,并在减压下浓缩。通过硅胶色谱纯化残余物,以得到标题化合物(8.5g,58%)。1H NMR(400MHz,DMSO-d6):1.15(t,J=6.8Hz,1.5H),1.36(t,J=6.8Hz,3H),2.21(s,1.5H),2.60(s,3H),4.05(q,J=7.1Hz,1H),4.27(q,J=7.2Hz,2H),6.01(S,0.5H),6.19(S,1H),7.30-7.71(m,6H)。
方法6,步骤2.3-(4-氰基苯基)丁酸乙基酯:
向(E,Z)3-(4-氰基苯基)丁-2-烯酸乙基酯(8.0g,37.2mmol)于甲醇:乙酸乙酯(1:4,140ml)中的搅拌溶液中添加Pd/C(0.8g,10%w/w,50%水分)。将反应物于室温下在氢气体气氛下搅拌3小时。将反应混合物用乙酸乙酯稀释且通过硅藻土垫过滤。在减压下浓缩合并的有机层,以得到标题化合物(4.5g,56%)。1H NMR(400MHz,CDCl3):1.23(t,J=7.2Hz,3H),1.33(d,J=6.8Hz,3H),2.62(dd,J=7.6Hz,1.2Hz,2H),3.70(q,J=7.2Hz,1H),4.07-4.15(m,2H),7.37(d,J=8.0Hz,2H),7.37(d,J=8.4Hz,2H)。
方法6,步骤3.3-(4-氰基苯基)丁酸:
于5℃至10℃下向3-(4-氰基苯基)丁酸乙基酯(4.5g,20.71mmol)于MeOH:THF:H2O的混合物(4:2:1,100ml)中的搅拌溶液中添加LiOH(3.48g,82.95mmol)。将所得反应混合物于室温下搅拌1.5小时。在反应完成(通过TLC监测)后,蒸发反应溶剂。将残余物溶解于水(10ml)中,并用乙酸乙酯(2×15ml)萃取。用浓HCl将水层的pH调整至3-4。过滤出形成的沉淀,以得到白色固体状标题化合物(3.8g,97%)。1H NMR(400MHz,DMSO-d6):1.23(d,J=6.8,3H),2.58(d,J=7.6Hz,2H),3.24(q,J=7.2,1H),7.49(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),12.15(s,1H)。
方法6,步骤4.(2-(4-氰基苯基)丙基)氨基甲酸叔丁基酯:
于室温下向3-(4-氰基苯基)丁酸(5.0g,26.45mmol)于叔丁醇(65ml)中的搅拌溶液中添加三乙胺(11.0ml,79.36mmol)。然后将反应混合物冷却至5-10℃且逐滴添加DPPA(12.30g,44.97mmol)。形成酰叠氮后,将反应物于90℃下搅拌过夜。将反应混合物用水(40ml)稀释且用乙酸乙酯(2×40ml)萃取。将合并的有机层用盐水(25ml)洗涤,经无水Na2SO4干燥,并在减压下浓缩。通过硅胶色谱纯化所得残余物,以得到固体状标题化合物(4.5g,66%)。1H NMR(400MHz,DMSO-d6):1.17(d,J=6.8Hz,2H),1.33(s,9H),2.90-3.00(m,1H),3.04-3.15(m,2H),6.91(t,J=5.2Hz,1H,-NH),7.42(d,J=8.4Hz,2H),7.77(d,J=7.2Hz,2H)。
方法6,步骤5.4-(1-氨基丙-2-基)苯甲腈盐酸盐:
于0℃下向(2-(4-氰基苯基)丙基)氨基甲酸叔丁基酯(4.5g,17.29mmol)于甲醇(9ml)中的搅拌溶液中逐滴添加4M HCl于二噁烷中的溶液(10.8ml,2.4vol.)。将所得混合物于室温下搅拌2小时。在减压下浓缩反应混合物,以得到固体状标题化合物(2.81g,83%)。1H NMR(400MHz,DMSO-d6):1.28(d,J=6.8Hz,2H),3.03(d,J=5.6Hz,2H),3.15-3.26(m,1H),7.55(d,J=8.0Hz,2H),7.83(d,J=8.0Hz,2H),8.21(s,3H)。LCMS:m/z=161.6[M+1]。
方法6,步骤6.4-(1-氨基丙-2-基)苯甲腈:
将4-(1-氨基丙-2-基)苯甲腈盐酸盐用饱和碳酸氢钠水溶液处理且用乙酸乙酯(3×30ml)萃取,以获得液体状粗制化合物,通过硅胶色谱(DCM:MeOH=90:10)对其进行纯化,以得到稠油状外消旋标题化合物(2.29g,83%)。1H NMR(400MHz,CDCl3):1.28(d,J=6.8Hz,3H),2.85(d,J=5.6Hz,3H),7.34(d,J=7.2Hz,2H),7.63(d,J=7.2Hz,2H)。LCMS:m/z=161.5[M+1]。可以通过制备型手性SFC使用CHIRALPAK AD-H柱(250mm,50mm,5微米;移动相75%CO2中的25%乙腈:甲醇:二甲胺(80:20:0.1))将外消旋胺拆分成镜像纯标题化合物。通过获得具有p300的截短形式的相关结构相关抑制剂的x射线共晶体结构,早期溶析的异构物已明确分配为(S)-4-(1-氨基丙-2-基)苯甲腈。
方法7
2-((2-(4-氰基苯基)丙基)氨基)-2-(1-甲基-1H-吡唑-4-基)乙酸乙酯
方法7,步骤1.2-((2-(4-氰基苯基)丙基)氨基)-2-(1-甲基-1H-吡唑-4-基)乙酸:
于室温下向4-(1-氨基丙-2-基)苯甲腈盐酸盐(5g,30.86mmol)于DCM(75ml)中的搅拌溶液中添加TEA(3.12g,30.86mmol)、2-侧氧基乙酸(2.28g,30.86mmol)和(1-甲基-1H-吡唑-4-基)硼酸(3.80g,30.86mmol)。将反应混合物于相同温度下搅拌15分钟。其后添加HFIP(13.48g,80.24mmol)且将反应混合物于室温下搅拌16小时。浓缩反应物且将残余物与DCM:戊烷(3:7;150ml)一起搅拌30分钟。在布氏漏斗(Büchner funnel)上过滤沉淀的固体且用正戊烷洗涤,以得到标题化合物(5.5g,59%)。LCMS:m/z=299[M+1]。
方法7,步骤2.2-((2-(4-氰基苯基)丙基)氨基)-2-(1-甲基-1H-吡唑-4-基)乙酸
乙酯:
将2-((2-(4-氰基苯基)丙基)氨基)-2-(1-甲基-1H-吡唑-4-基)乙酸(5g,16.77mmol)于DMF(100ml)中的混合物于80℃下加热直到反应混合物变为澄清溶液为止。于相同温度下添加K2CO3(5.79g,41.94mmol)和碘乙烷(2.61g,16.77mmol)且将混合物搅拌30分钟。然后将反应混合物于室温下搅拌16小时。将反应物用冰冷水(200ml)淬灭且用乙酸乙酯(2×75ml)萃取。将合并的有机层用盐水(100ml)洗涤,经无水硫酸钠干燥,并在减压下浓缩。通过硅胶色谱纯化残余物,以得到粘稠液体状标题化合物(2.5g,45%)。LCMS:m/z=327.7[M+1]。
方案1
使用方案1制备的实例的合成所需的起始材料有市售或是使用方法1至7制备。
实例1
(R)-和(S)-2-((4-氰基苯乙基)氨基)-N-(5-((1-甲基六氢吡啶-4-基)氧基)吡
啶-2-基)-2-苯基乙酰胺
方案1,步骤1.2-((4-氰基苯乙基)氨基)-2-苯基乙酸乙酯:将2-溴-2-苯基乙酸乙酯(2.0g,8.22mmol)、4-(2-氨基乙基)苯甲腈盐酸盐(2.25g,12.33mmol)和TEA(2.50g,24.66mmol)于DMF(20ml)中的混合物于60℃下加热3小时。将反应混合物倾倒至冰冷水(50ml)中且用乙酸乙酯(2×50ml)萃取。将合并的有机层用盐水(25ml)洗涤,经无水Na2SO4干燥,并在减压下浓缩。通过硅胶色谱纯化所得残余物,以得到粘稠液体状标题化合物(2.2g,86%)。1H NMR(400MHz,DMSO-d6):δ1.10(t,J=7.2Hz,3H),2.62-2.82(m,4H),4.02-4.09(m,2H),4.39(d,J=8.4Hz,1H),7.28-7.35(m,5H),7.40(d,J=8.4Hz,2H),7.72(d,J=8.4Hz,2H)。LCMS:m/z=309.28[M+1]。
方案1,步骤2,程序2.(R)-和(S)-2-((4-氰基苯乙基)氨基)-N-(5-((1-甲基六氢 吡啶-4-基)氧基)吡啶-2-基)-2-苯基乙酰胺:于0℃下向5-((1-甲基六氢吡啶-4-基)氧基)吡啶-2-胺(0.10g,0.48mmol)、2-((4-氰基苯乙基)氨基)-2-苯基乙酸乙酯(0.14g,0.48mmol)于无水甲苯(2ml)中的搅拌溶液中添加三甲基铝(0.5ml,2M,于甲苯中,0.96mmol)。将反应混合物于100℃下搅拌2小时。反应完成后,将反应混合物倾倒至冰冷水(25ml)中且用乙酸乙酯(2×50ml)萃取。将合并的有机层用盐水(25ml)洗涤,经无水硫酸钠干燥,并在减压下浓缩。通过硅胶色谱纯化所得残余物,以得到呈外消旋混合物形式的标题化合物(0.10g,45%)。
通过手性HPLC(CHIRALCEL OJ-H;液体CO2中的25%MeOH+0.1%DEA)拆分外消旋标题化合物,以供给镜像纯化合物。获得固体状较快溶析的标题化合物的镜像异构物(异构物1)。1H NMR(400MHz,DMSO-d6):δ1.60-1.65(m,2H),1.89(bs,2H),2.12-2.17(m,5H),2.51(bs,2H),2.74-2.77(m,2H),2.85-2.86(m,2H),4.36(d,J=4.0Hz,1H),4.49(d,J=8.0Hz,1H),7.26-7.36(m,3H),7.42-7.45(m,5H),7.74(d,J=8.4Hz,2H),7.96(d,J=8.8Hz,1H),8.02(d,J=2.8Hz,1H),10.32(s,1H)。LCMS:m/z=470.51[M+1]。
获得固体状较慢溶析的标题化合物的镜像异构物(异构物2)。1H NMR(400MHz,DMSO-d6):δ1.58-1.66(m,2H),1.89(bs,2H),2.12-2.17(m,5H),2.51(bs,2H),2.75(bs,2H),2.85-2.88(m,2H),4.34-4.38(m,1H),4.49(d,J=4.8Hz,1H),7.25-7.35(m,3H),7.42-7.45(m,5H),7.74(d,J=8.0Hz,2H),7.96(d,J=8.8Hz,1H),8.02(d,J=2.8Hz,1H),10.31(s,1H)。LCMS:m/z=470.51[M+1]。
实例2
方案1,步骤1.(R,S)-和(S,S)-2-((2-(4-氰基苯基)丙基)氨基)-2-苯基乙酸乙
酯:
将2-溴-2-苯基乙酸乙酯(9.11g,37.5mmol)、(S)-4-(1-氨基丙-2-基)苯甲腈(5.0g,31.2mmol)和TEA(13.1ml,93.7mmol)于DMF(50ml)中的混合物于60℃下加热3小时。将反应混合物倾倒至冰冷水(150ml)中并用乙酸乙酯(2×150ml)萃取。将合并的有机层用盐水(150ml)洗涤,经无水Na2SO4干燥,并在减压下浓缩。通过硅胶色谱纯化所得残余物,以得到粘稠液体状标题化合物的混合物(7.0g,70%)。1H NMR(400MHz,DMSO-d6):1.08(t,J=6.8Hz,3H),1.16(d,J=6.8Hz,3H),2.35-2.44(m,1H),2.49-2.66(m,1H),2.96(q,J=6.8Hz,1H),3.96-4.06(m,2H),4.32(s,1H),7.26-7.42(m,7H),7.74(t,J=7.6Hz,2H)。LCMS:m/z=323.6[M+1]。
方案1,步骤2,程序1.(R)-和(S)-N-(5-((1-乙酰基氮杂环丁-3-基)氧基)吡啶-2-
基)-2-(((S)-2-(4-氰基苯基)丙基)氨基)-2-苯基乙酰胺:
于0℃下向1-(3-((6-氨基吡啶-3-基)氧基)氮杂环丁-1-基)乙-1-酮(2.0g,9.65mmol)、2-((2-(4-氰基苯基)丙基)氨基)-2-苯基乙酸乙酯(3.7g,11.58mmol)于DMF(20ml)中的搅拌溶液中添加1M THF中的LiHMDS(24.2ml,24.12mmol)。将反应混合物于50℃下搅拌1小时。在反应完成(通过TLC监测)后,将反应混合物倾倒至冰冷水(15ml)中且用乙酸乙酯(2×25ml)萃取。将合并的有机层用盐水(15ml)洗涤,经无水硫酸钠干燥并在减压下浓缩。通过硅胶色谱纯化所得残余物,以得到呈混合物形式的标题化合物(3.0g,61%)。
通过手性HPLC(CHIRALCEL OJ-H;液体CO2中的15%MeOH+0.1%DEA)拆分标题化合物,以供给镜像纯化合物。获得固体状较快溶析的标题化合物的镜像异构物(异构物1):1HNMR(400MHz,DMSO-d6):1.23(d,J=6.8Hz,3H),1.79(s,3H),2.64(d,J=6.8Hz,3H),3.00-3.04(m,1H),3.74-3.77(m,1H),4.07-4.10(m,1H),4.25-4.29(m,1H),4.44(s,1H),4.51-4.55(m,1H),5.05(s,1H),7.24-7.45(m,8H),7.75(d,J=8.0Hz,2H),7.96-8.00(m,2H),10.41(s,1H)。LCMS:m/z=484.5[M+1]。获得固体状较慢溶析的标题化合物的镜像异构物(异构物2):1H NMR(400MHz,DMSO-d6):1.23(d,J=8.0Hz,3H),1.79(s,3H),2.68(s,3H),3.02(d,J=6.0Hz,1H),3.75-3.77(m,1H),4.08-4.10(m,1H),4.25-4.29(m,1H),4.42(s,1H),4.51-4.55(m,1H),5.04(s,1H),7.24-7.46(m,8H),7.75(d,J=8Hz,2H),7.94-7.98(m,2H),10.22(s,1H)。LCMS:m/z=484.47[M+1]。
以下化合物是使用与针对实例1和2所述的程序类似的程序使用适当起始材料来制备。
以下化合物是使用与针对实例1和2所述的程序类似的程序使用适当起始材料来制备。每一化合物的分离的异构物以其溶析的次序列举。举例来说,在其中存在两种异构物的情况下,异构物1是较快溶析的异构物且异构物2是较慢溶析的异构物。在存在四种异构物的情况下,异构物1是最快溶析的异构物,之后是异构物2,然后是异构物3,且然后是异构物4。另外,在列举一个以上手性柱时,所述柱是以所列举的依序次序使用。举例来说,如果列举两个柱用于纯化具有2个立体中心的化合物,则第一柱用于将混合物拆分成纯立体异构物1、纯立体异构物2、和立体异构物3和4的混合物,且第二柱用于拆分立体异构物3和4的混合物。在一些情况下,单一手性柱可拆分所有四种立体异构物。
化合物的每一异构物的立体化学表示(即,R或S)在表中未绘制,而是进行命名以明确表示意图支持二者。手性碳原子由星号(*)命名。
表1.
实例26
(R,S)-和(S,S)-N-(5-(氮杂环丁-3-基氧基)吡啶-2-基)-2-(((S)-2-(4-氰基苯
基)丙基)氨基)-2-苯基乙酰胺
步骤1.(R,S)-和(S,S)-N-(5-(氮杂环丁-3-基氧基)吡啶-2-基)-2-(((S)-2-(4- 氰基苯基)丙基)氨基)-2-苯基乙酰胺:于0℃下向3-((6-(2-((2-(4-氰基苯基)丙基)氨基)-2-苯基乙酰胺基)吡啶-3-基)氧基)氮杂环丁烷-1-甲酸叔丁基酯(0.50g,0.92mmol)于DCM(15ml)中的搅拌溶液中添加逐滴TFA(2.5ml)。将反应混合物于室温下搅拌3小时。反应完成后,将反应混合物倾倒至饱和碳酸氢钠水溶液(15ml)中且用DCM(2×30ml)萃取。将合并的有机层用盐水(20ml)洗涤,经无水硫酸钠干燥并在减压下浓缩。将所得残余物与戊烷(50ml)一起研磨且通过反相色谱纯化所得固体,以得到外消旋标题化合物(0.275g,68%)。
通过手性HPLC(CHIRALCEL AD-H;液体CO2中的30%(50:50MeOH:ACN)+0.1%DEA)拆分外消旋标题化合物,以供给镜像纯化合物。获得固体状较快溶析的标题化合物的镜像异构物(异构物1):1H NMR(400MHz,DMSO-d6):δ1.19(d,J=6.4Hz,3H),2.65(d,J=8.8Hz,2H),3.00-3.02(m,1H),3.51(s,2H),3.79(bs,2H),4.39(s,1H),4.99(d,J=5.6Hz,1H),7.25-7.45(m,8H),7.73(d,J=7.6Hz,2H),7.88-7.93(m,2H),10.15(s,1H)。LCMS:m/z=442.46[M+1]。获得固体状较慢溶析的标题化合物的镜像异构物(异构物2):1H NMR(400MHz,DMSO-d6):δ1.21(d,J=6.8Hz,3H),2.62(d,J=6.8Hz,2H),3.00-3.01(m,1H),3.66(s,2H),3.98(bs,2H),4.42(s,1H),5.01(s,1H),7.24-7.44(m,8H),7.74(d,J=8.0Hz,2H),7.91-7.96(m,2H),10.37(s,1H)。LCMS:m/z=442.35[M+1]。
实例27
(R,S)-和(S,S)-2-(((S)-2-(4-氰基苯基)丙基)氨基)-N-(5-((1-(2-羟基乙酰
基)氮杂环丁-3-基)氧基)吡啶-2-基)-2-苯基乙酰胺
步骤1.(R,S)-和(S,S)-2-(((S)-2-(4-氰基苯基)丙基)氨基)-N-(5-((1-(2-羟基
乙酰基)氮杂环丁-3-基)氧基)吡啶-2-基)-2-苯基乙酰胺:
于室温下在氮气氛下向乙醇酸(0.058g,0.76mmol)于无水DMF(1.5ml)中的搅拌溶液中添加HATU(0.35g,0.92mmol)。将上述反应混合物在室温下搅拌1小时。1小时后,向反应混合物中添加DMF(1.5ml)中的N-(5-(氮杂环丁-3-基氧基)吡啶-2-基)-2-((2-(4-氰基苯基)丙基)氨基)-2-苯基乙酰胺的TFA盐(0.3g,0.54mmol),之后添加DIPEA(0.21g,1.62mmol)。将反应混合物在室温下搅拌16小时。在反应完成(通过TLC监测)后,将反应混合物用冰水淬灭且用EtOAc(2×10ml)萃取。将合并的有机层用盐水(20ml)洗涤,经无水硫酸钠干燥,并在减压下浓缩以获得粗产物。通过DCM:MeOH中的Combi-急速色谱、之后反相HPLC纯化粗产物,以得到外消旋标题化合物(0.105g,39%)。
通过手性HPLC(CHIRALCEL OJ-H;液体CO2中的20%(50:50IPA:ACN)+0.1%DEA)拆分外消旋标题化合物,以供给镜像纯化合物。获得固体状较快溶析的标题化合物的镜像异构物(异构物1):异构物-1:1H NMR(400MHz,DMSO-d6):δ1.22(d,J=6.8Hz,3H),2.69(s,3H),3.03(d,J=6.4Hz,1H),3.83(d,J=8.8Hz,1H),3.94(d,J=6.0Hz,2H),4.15(d,J=7.2Hz,1H),4.34(t,J=6.4Hz,1H),4.43(s,1H),4.62(t,J=6.4Hz,1H),5.03(t,J=6.0Hz,1H),5.09(s,1H),7.25-7.47(m,6H),7.76(d,J=8.0Hz,2H),7.97(d,J=10.8Hz,2H),10.22(s,1H)。LCMS:m/z=500.5[M+1]。异构物-2:1H NMR(400MHz,DMSO-d6):δ1.23(d,J=6.4Hz,3H),2.65(s,3H),3.02(d,J=6.8Hz,1H),3.82(d,J=10.4Hz,1H),3.93(d,J=5.6Hz,2H),4.10-4.15(m,1H),4.33-4.43(m,2H),4.61(m,1H),5.00(t,J=6.4Hz,1H),5.08(s,1H),7.26-7.45(m,6H),7.75(d,J=7.6Hz,2H),7.98(d,J=13.2Hz,2H),10.39(s,1H)。LCMS:m/z=500.8[M+1]。
生物化学和细胞分析
可使用邻近闪烁分析(SPA)方法容易地确定作为p300/CBP HAT抑制剂的本文所述化合物的活性(Udenfriend,S.;Gerber,L.;Nelson,N.《邻近闪烁分析:用于监测配体/受体和抗原/抗体相互作用的敏感和持续性同位素方法(Scintillation Proximity Assay:ASensitive and Continuous Isotopic Method for Monitoring Ligand/Receptor andAntigen/Antibody Interactions.)》《分析生物化学(Anal.Biochem.)》1987,161,494-500)。具体来说,以下实例的化合物在参考分析中通过展现由p300酶的截短形式(p300HAT)抑制组蛋白肽乙酰化的能力而具有活性。展现约100μM或更低的IC50的任何化合物可被认为是如本文定义的p300/CBP-HAT抑制剂。
在典型实验中,根据以下实验方法确定本文所述化合物的p300 HAT抑制活性。
使p300 HAT结构域(残基1287-1666)表达且用来自大肠杆菌细胞的N-末端His标签进行纯化。通过Ni2+亲和性、之后阴离子交换色谱纯化表达的蛋白质。汇集适当部分,且缓冲更换成20mM Hepes pH 7.5、150mM NaCl和1mM TCEP。
将溶解于DMSO中的感兴趣化合物以10点重复剂量反应在Greiner黑色384孔板中使用Echo 550(Labcyte)压印。将内部纯化的p300-HAT结构域(aa 1287-1666)在反应缓冲液(50mM Tris pH 8.0、100mM NaCl、1mM DTT、0.069mM Brij-35、0.1mM EDTA、0.1mg/mLBSA)中稀释至6nM,与4.14μM AcCoA(Sigma-Aldrich)和0.46μM 3H-AcCoA(PerkinElmer)组合,并向每一孔中添加12.5μL,并在RT下培育30分钟。用12.5μL 2μM生物素化H3(1-21)肽(New England Peptide)起始反应,且在RT下运行1小时,然后用20μL停止溶液(200mM TrispH 8.0、200mM EDTA、2M NaCl、160μM漆树酸)淬灭。使用Bravo液体处置器(Velocity 11)将35μL的反应体积转移至384孔链霉抗生物素蛋白FlashPlate(PerkinElmer),并在RT下培育1.5小时。抽吸板,用95μL洗涤缓冲液(15mM Tris pH 8.5、0.069μM Brij-35)洗涤,抽吸,密封,且在Topcount(PerkinElmer)上读取闪烁计数。在Genedata中分析数据以确定抑制剂IC50值。
遵循与p300 HAT SPA分析相同的方案运行全长p300 SPA分析,但使用6nM纯化的全长p300(购自Active Motif)代替纯化的p300-HAT结构域。
也在H3K18Ac MSD细胞分析中评估选择的化合物,所述分析量测化合物抑制染色质在H3K18乙酰化的能力,这是由p300和CBP催化的过程。在典型实验中,根据以下实验方法确定本文所述化合物在细胞内的p300 HAT抑制活性。在处理前晚,将每孔20k个HCT-116细胞接种于75μL RPMI+10%FBS培养基中。将以4x最终浓度接种于DMSO中的化合物重悬于30μL RPMI+10%FBS中,然后将25μL与含有细胞的相应孔组合。将处理的细胞在37℃下培育2小时,然后在500μL最终体积中溶解并在-80℃下冷冻。在4℃下将MSD板(Meso ScaleDiscovery)用PBS的60μL 1:500α-总组蛋白抗体(Millipore MAB3422)包被过夜。然后将板于RT下振荡下用TBST中的5%BSA封阻1小时,洗涤,且向每一孔中添加30μL溶解物,于RT下振荡2小时。洗涤板,且添加25μL 1:216的PBS中的α-H3K18ac抗体(CST9675),然后于RT下振荡培育1小时。再次洗涤板,然后添加25μL 1:1000的PBS中的Sulfo-Tag山羊α-兔抗体(MesoScale Discovery R32Ab-1),于RT下振荡1小时。再次洗涤板,然后将150μL 1x读取缓冲液(MSD#R92TD-3)添加至所有孔中,且使用常规读取设置在MSD SECTOR成像器2400上读取。
以下实例的化合物在上文所提及的分析中具有抑制p300酶的HAT结构域的活性,且IC50小于约100μM。在上文所提及的分析中,本文所述的许多化合物在抑制p300酶的HAT结构域中具有活性,且IC50小于约10μm、优选小于或约为0.1μm。在以下实例中提供额外数据。所述结果指示化合物在用作p300酶的组蛋白乙酰基转移酶结构域的抑制剂中的固有活性。一般来说,所属领域的技术人员将了解,如果物质的IC50小于或约为1μm、优选小于或约为0.1μm,则认为所述物质能有效抑制p300 HAT活性。本发明还包括具有作为其它组蛋白乙酰基转移酶(例如CBP-HAT)的抑制剂的活性的化合物。p300 HAT IC50是测试化合物抑制p300酶的作用的能力的量度。
表2显示由P300 HAT SPA分析估计的本文所述化合物的P300抑制活性。所有活性皆是至少2次重复滴定的平均值。
表2
尽管已对本发明的许多实施例进行了阐述,但显而易见,可改变基本实例以提供利用发明化合物和方法的其它实施例。因此,应了解,本发明的范围将由随附权利要求书而非以实例方式所代表的具体实施例界定。
本申请案中引用的所有参考文献(包括文献来源、授权专利、公开的专利申请案和共同待决的专利申请案)的内容以引用方式全部明确地并入本文中。除非另有定义,否则本文所用的所有技术和科学术语符合所属领域的技术人员通常已知的含义。
Claims (44)
1.一种具有式I的化合物,
或其医药上可接受的盐,其中
R1、R3和R4各自独立地是氢或C1-4烷基;
R2是苯基或5至6元杂芳基,其各自任选地被1至3个选自Rc的基团取代;
R5是被4至6元杂环基或5至6元杂芳基取代的C1-6烷基,其中所述4至6元杂环基或所述5至6元杂芳基中的每一个任选地被1至3个选自Rd的基团取代;或R5是4至6元杂环基或5至6元杂芳基,其中所述4至6元杂环基或所述5至6元杂芳基中的每一个任选地被1至3个选自Rd的基团取代;
Ra、Rb、Rc和Rd各自独立地是卤基、CN、侧氧基、NO2、C1-6烷基、C2-6烯基、C1-6烷氧基、卤基(C1-6烷氧基)、卤基(C1-6烷基)、-C1-6烷基ORe、-C(O)Rf、-C(O)OR、-C1-6烷基C(O)ORe、-C(O)N(Re)2、-C(O)NReC1-6烷基ORe、-OC1-6烷基N(Re)2、-C1-6烷基C(O)N(Re)2、-C1-6烷基N(Re)2、-N(Re)2、-C(O)NReC1-6烷基N(Re)2、-NReC1-6烷基N(Re)2、-NReC1-6烷基ORe、-SORe、-S(O)2Re、-SON(Re)2、-SO2N(Re)2、-O(C3-C6)环烷基、-O-C1-4烷基芳基、-C1-6烷基(C3-C6)环烷基、-C1-6烷基芳基、-C1-6烷基杂芳基、-C1-6烷基杂环基、(C3-C6)环烷基、杂环基、杂芳基或芳基,其中所述(C3-C6)环烷基、杂环基、芳基和杂芳基中的每一个单独和结合-O(C3-C6)环烷基、-C1-6烷基(C3-C6)环烷基、-C1-6烷基芳基、-C1-6烷基杂芳基和-C1-6烷基杂环基任选地被1至3个选自以下的基团取代:卤基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、-N(Re)2、-C(O)Rf和-C1-6烷基ORe;
每一Re独立地是氢、卤基(C1-4烷基)或C1-4烷基;
每一Rf独立地是氢、卤基(C1-4烷基)、C1-4烷基或(C3-C4)环烷基;
q是0、1或2;且
p是0、1、2或3。
5.根据权利要求1至4中任一项所述的化合物,其中q是0或1。
6.根据权利要求1至5中任一项所述的化合物,其中Ra如果存在,那么是C1-3烷基、C1-3烷氧基、卤基(C1-3烷基)、卤基C1-3烷氧基或卤基。
12.根据权利要求1至11中任一项所述的化合物,其中R2是苯基或吡唑基,其各自任选地被1至3个选自Rc的基团取代。
13.根据权利要求1至12中任一项所述的化合物,其中Rc是卤基、C1-6烷基、卤基(C1-6烷基)、C1-6烷氧基或卤基(C1-6烷氧基)。
14.根据权利要求1至13中任一项所述的化合物,其中R2是苯基或吡唑基,其各自任选地被卤基或C1-4烷基取代。
15.根据权利要求1至14中任一项所述的化合物,其中R2是苯基。
16.根据权利要求1至15中任一项所述的化合物,其中p是1。
17.根据权利要求1至16中任一项所述的化合物,其中Rb是卤基、氰基或-SO2NH2。
18.根据权利要求1至17中任一项所述的化合物,其中Rb是氰基。
19.根据权利要求1至18中任一项所述的化合物,其中R5是被吡唑基或噁唑烷基取代的C1-4烷基,所述吡唑基或所述噁唑烷基各自任选地被1至3个选自Rd的基团取代;或R5是六氢吡啶基、氮杂环丁基、六氢嘧啶基、四氢呋喃基、四氢吡喃基、氧杂环丁基、吡唑基、吡咯烷基或嘧啶基,其各自任选地被1至3个选自Rd的基团取代。
20.根据权利要求1至19中任一项所述的化合物,其中Rd是选自卤基、侧氧基、C1-4烷基、C1-4烷氧基、卤基(C1-4烷基)、-C1-4烷基ORe、-C(O)Rf、-C(O)N(Re)2、-C1-6烷基C(O)N(Re)2和-S(O)2Re。
21.根据权利要求1至20中任一项所述的化合物,其中Rd是选自C1-6烷基、-C(O)Rf和侧氧基。
22.根据权利要求1至20中任一项所述的化合物,其中Re是氢或C1-3烷基。
23.根据权利要求1至22中任一项所述的化合物,其中Rf是环丙基或C1-4烷基。
25.一种医药组合物,其包含根据权利要求1至24中任一项所述的化合物或其医药上可接受的盐和医药上可接受的载剂。
26.根据权利要求25所述的医药组合物,其用于治疗CBP和/或EP300介导的病症。
27.一种治疗有需要的受试者中CBP和/或EP300介导的病症的方法,其包含向所述受试者给予治疗有效量的根据权利要求1至24中任一项所述的化合物或其医药上可接受的盐、或根据权利要求25所述的组合物。
28.一种根据权利要求1至24中任一项所述的化合物或其医药上可接受的盐或根据权利要求25所述的组合物的用途,其用于制造用于治疗受试者中CBP和/或EP300介导的病症的药剂。
29.根据权利要求1至24中任一项所述的化合物或其医药上可接受的盐、或根据权利要求25所述的组合物,其用于治疗CBP和/或EP300介导的病症。
30.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是选自癌症、心脏病、代谢疾病、纤维变性疾病、发炎性疾病和病毒感染。
31.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是癌症。
32.根据权利要求26至31中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是选自以下的癌症:听神经瘤、急性白血病、急性淋巴球性白血病、急性骨髓性白血病、急性t细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳癌、支气管癌、柏基特氏淋巴瘤(Burkitt's lymphoma)、子宫颈癌、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴球性白血病、慢性骨髓细胞性白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、发育不良、化生、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、雌激素受体阳性乳癌、原发性血小板过多症、尤恩氏肿瘤(Ewing's tumor)、纤维肉瘤、胃癌(gastric carcinoma)、生殖细胞睪丸癌、妊娠期滋养层疾病、胶质母细胞瘤、头颈癌、重链病、血管母细胞瘤、肝细胞瘤、肝细胞癌、激素不敏感前列腺癌、平滑肌肉瘤、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;膀胱、乳房、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性病和过度增生病症;T细胞或B细胞源的淋巴恶性病、白血病、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、少突神经胶质瘤、口腔癌、骨原性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、外周T细胞淋巴瘤、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、胃癌(stomach cancer)、鳞状细胞癌、滑膜瘤、汗腺癌、睪丸癌、甲状腺癌、华氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、睪丸肿瘤、子宫癌和威尔姆氏瘤(Wilms'tumor)。
33.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是心脏病。
34.根据权利要求33使用的医药组合物、方法、用途和使用的化合物,其中所述心脏病是心肥大或心脏衰竭。
35.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是代谢疾病。
36.根据权利要求35使用的医药组合物、方法、用途和使用的化合物,其中所述代谢疾病是选自肥胖症、脂肪肝、异常血脂症、高血压、冠状动脉心脏病、肝发炎和2型糖尿病。
37.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是纤维变性疾病。
38.根据权利要求37使用的医药组合物、方法、用途和使用的化合物,其中所述纤维变性疾病是选自辐射诱导的肺炎、辐射纤维化、急性呼吸窘迫综合征、慢性阻塞性肺病、特发性肺纤维化、间质性肺病、心肌梗塞、缺血性中风、缺血性肾病、移植排斥、利什曼体病(Leishmaniasis)、I型糖尿病、类风湿性关节炎、慢性肝炎、硬化、发炎性肠病、克隆氏病(Crohn's disease)、硬皮症、瘢瘤、术后纤维化、化学疗法诱导的纤维化(例如化学疗法诱导的肺纤维化或卵巢皮质纤维化)、肾性全身性纤维化、腹膜后纤维化、骨髓纤维化、纵膈纤维化、囊性纤维化、石棉肺病、气喘和肺高血压。
39.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是发炎性疾病。
40.根据权利要求39使用的医药组合物、方法、用途和使用的化合物,其中所述发炎疾病是选自阿狄森氏病(Addison's disease)、急性痛风、僵直性脊椎炎、气喘、动脉粥样硬化、贝切特氏病(Behcet's disease)、大疱性皮肤病、慢性阻塞性肺病、克隆氏病、皮炎、湿疹、巨细胞动脉炎、纤维化、肾小球肾炎、肝血管堵塞、肝炎、垂体炎、免疫缺陷综合征、发炎性肠病、川崎病(Kawasaki disease)、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、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、牛皮癣、牛皮癣性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、败血症、全身性红斑狼疮、高安氏动脉炎(Takayasu's Arteritis)、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白斑症、血管炎和韦格纳氏肉芽肿病(Wegener's granulomatosis)。
41.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是病毒感染。
42.根据权利要求41使用的医药组合物、方法、用途和使用的化合物,其中所述病毒感染是选自人类免疫缺陷病毒、C型肝炎病毒和人类乳头瘤病毒。
43.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是神经病症。
44.根据权利要求26至29中任一项使用的医药组合物、方法、用途和使用的化合物,其中所述CBP和/或EP300介导的病症是选自额颞叶失智症、阿尔茨海默氏病(Alzheimer'sdisease)、tau蛋白病变、血管型失智症、帕金森氏病(Parkinson's disease)和路易体(Lewy bodies)失智症的神经病症。
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