CN117616015A - 作为pd-l1相互作用的免疫调节剂的杂环化合物 - Google Patents
作为pd-l1相互作用的免疫调节剂的杂环化合物 Download PDFInfo
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- CN117616015A CN117616015A CN202180099727.8A CN202180099727A CN117616015A CN 117616015 A CN117616015 A CN 117616015A CN 202180099727 A CN202180099727 A CN 202180099727A CN 117616015 A CN117616015 A CN 117616015A
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Abstract
在总体上和具体地两个方面公开了具有各种化合物式的PD‑L1抑制剂。在总体上和具体地两个方面公开了制备这种PD‑L1抑制剂化合物的方法。公开了单独使用这种PD‑L1抑制剂化合物或与这种PD‑L1抑制剂化合物的附加的药剂和组合物组合使用这种PD‑L1抑制剂化合物以用于治疗癌症和其他病状的方法。
Description
技术领域
本申请总体上涉及化合物,并且更具体地涉及调节PD-L1蛋白的生物活性的化合物。
背景技术
程序性死亡配体1(“PD-L1”)是在抑制免疫系统的适应臂中起主要作用的蛋白质。通常,适应性免疫系统通过外源性或内源性危险信号对与免疫系统激活相关联的抗原作出反应。进而,抗原特异性CD8+T细胞和/或CD4+辅助细胞的克隆扩增得以繁殖。T细胞上的PD-L1与抑制性检查点分子PD-1的结合会传输抑制信号,该抑制信号减少淋巴结中抗原特异性T细胞的增殖,同时减少了调节性T细胞(抗炎抑制性T细胞)的凋亡。
因此,能够调节PD-L1活性的分子可广泛应用于对各种疾病病状的治疗。
发明内容
本申请的一方面涉及具有如式(I)所示的通用结构的化合物:
或其药学上可接受的盐、立体异构体、立体异构体的混合物、溶剂化物或互变异构体,其中,
A和B各自独立地选自卤素、氰基、-N3、烷基和经取代的烷基、胺、烷基胺、烷氧基;
Z1为-CR1=或-N=;
Z2为-CR2=;
Z3为-CR3=或-N=;
Z4为-CR4=或-N=,
Z5为-CR5=;
Z6为-CR6=或-N=;
R1和R4各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R2和R5各自独立,各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R3和R6各自独立,各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
Y1和Y2独立地为-C(R7)(R8)-、-CR9=、-NR10-、-O-或-S-;
X1和X2各自独立地为-C(R11)(R12)-、-N=、-NR13-、-S-或-O-;
R7、R8、R9、R11和R12各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R10和R13各自独立地为-H、烷基、环烷基、经取代的烷基、烯基、烯基、炔基、芳基、烷基胺、烷氧基;
L1和L2各自为在环3和W1之间以及环6和W2之间含有m个原子的烷基、经取代的烷基或杂原子链,其中m=0、1、2、3、4、5或6;当m为0时,W1或W2分别与环3或环6中的对应氮直接连接;
W1和W2各自独立地为氢、五元杂环或经取代的五元杂环、六元杂环或经取代的六元杂环、羧基烷基或经取代的羧基烷基、氰烷基或经取代的氰烷基、氨基烷基或经取代的氨基烷基、羟烷基或经取代的羟烷基、氨基酸、氨基酸酯、氨基酸酰胺、非天然氨基酸、非天然氨基酸酯或非天然氨基酸酰胺。
本申请的另一方面涉及一种用于治疗受试者的与PD-L1和PD-1之间的相互作用相关的疾病或病状的方法,该方法包括以下步骤:向该受试者施用有效量的式(I)化合物、或其药学上可接受的盐、立体异构体、立体异构体的混合物、溶剂化物或互变异构体。
本申请的另一方面涉及一种用于制备式(I)化合物的方法。
具体实施方式
将详细参考本申请的某些方面和示例性实施方案,在所附的结构和附图中例示了示例。将结合示例性实施方案描述本申请的各方面,包括方法、材料和示例,这种描述是非限制性的,并且本申请的范围旨在涵盖所有等效物、替代物和修改,无论是一般公知的还是并入此处的。除非另外定义,否则本文所使用的所有技术及科学术语均具有与本申请所属领域的普通技术人员通常所理解的含义相同的含义。本领域技术人员将认识到与此处描述的技术和材料类似或等效的技术和材料,这些技术和材料可在实践本申请的各方面和实施方案时使用。本申请描述的各方面和实施方案不限于所描述的方法和材料。
如在本说明书和所附权利要求中使用的,除非内容另外明确指明,否则单数形式的“一个/种(a/an)”以及“所述(the)”包括复数指示物。
范围在本文中可表示为从“约”一个特定值和/或到“约”另一个特定值。当表达这样的范围时,另一个实施方案包括从一个特定值和/或到另一个特定值。类似地,在通过使用先行词“约”将值表达为近似值时,应当理解,特定值形成另一个实施方案。还应理解,每个范围的端点相对于另一端点,以及独立于另一端点都是显著的。还应理解,本文公开了多个值,并且每个值在本文中还被公开为除了该特定值本身之外,还包括“约”该值。例如,如果公开了值“10”,则还公开了“约10”。还应当理解,如本领域技术人员适当理解的,当公开的值“小于或等于”该值时,还公开了“大于或等于该值”以及这些值之间的可能范围。例如,如果公开了值“10”,则还公开了“小于或等于10”以及“大于或等于10”。
在本说明书的各个地方,这些化合物的某些特征以组或范围公开。其具体意图是,这种公开内容包括这种组和范围的成员的每一个单独的子组合。
本文所描述的化合物可为不对称的(例如,具有一个或多个立体中心)。除非另外指示,否则意指诸如对映异构体和非对映异构体的所有立体异构体。本申请的含有不对称取代的碳原子的化合物可以光学活性形式或外消旋形式被分离。关于如何由无光学活性起始材料制备光学活性形式的方法在本领域诸如通过外消旋混合物拆分或通过立体选择性合成是已知的。烯烃的许多几何异构体、C=N双键等也可存在于本文所描述的化合物中,并且在本申请中设想了所有这种稳定的异构体。描述了本申请的化合物的顺式和反式几何异构体,并且可将其分离为异构体的混合物或单独的异构体形式。
可通过本领域中已知的众多方法中的任何方法执行化合物的外消旋混合物拆分。一种方法包括使用手性拆分酸的分步重结晶,该手性拆分酸是一种光学活性的成盐有机酸。用于分步重结晶方法的合适的拆分剂是例如光学活性酸,诸如D型和L型的酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种光学活性樟脑磺酸(诸如β-樟脑磺酸)。适于分步结晶方法的其他拆分剂包括立体异构纯形式的α-甲基苄胺(例如,S和R形式,或非对映异构纯形式)、2-苯基甘氨醇、去甲麻黄碱、麻黄碱、TV-甲基麻黄碱、环己基乙胺、1,2-二氨基环己烷等。
还可通过在填充有光学活性拆分剂(例如,二硝基苯甲酰基苯基甘氨酸)的柱上洗脱来执行外消旋混合物拆分。本领域技术人员可确定适合的洗脱溶剂组合物。
在具有多于一个手性中心的化合物中,除非另有说明,否则化合物中的每个手性中心可独立地为(R)或(S)。
本申请的化合物还包括互变异构形式。互变异构形式由单键与相邻双键的交换以及伴随的质子迁移而产生。互变异构形式包括质子异变互变异构体,这些质子异变互变异构体是具有相同经验式和总电荷的同分异构质子化态。示例质子异变互变异构体包括酮-烯醇对、酰胺-亚氨酸对、内酰胺-内酰亚胺对、烯胺-亚胺对以及质子可占据杂环系统的两个或更多个位置的环状形式,例如,1H-和3/f-咪唑、1H-、2H-和4H-1,2,4-三唑、\H-和211-异吲哚以及1H-和2//-吡唑。互变异构形式可处于平衡状态,或者通过适当的取代,在空间上锁定为一种形式。
本申请的化合物还可包括存在于中间体或最终化合物中的所有原子的同位素。同位素包括具有相同原子序数但不同质量数的那些原子。例如,氢的同位素包括氚和氘。本申请化合物的一个或多个组成原子可被处于天然或非天然丰度的原子同位素替换或取代。在一些实施方案中,该化合物包括至少一个氘原子。例如,本公开化合物中的一个或多个氢原子可被氘替换或取代。在一些实施方案中,该化合物包括两个或更多个氘原子。
I.定义
如本文所使用的,术语“化合物”意旨包括所描绘结构的所有立体异构体、几何异构体、互变异构体和同位素。该术语还意旨本申请的化合物,无论这些化合物的制备方式如何,例如,合成、通过生物过程(例如,代谢或酶转化)、或它们的组合。
所有化合物及其药学上可接受的盐可与诸如水和溶剂(例如,水合物和溶剂化物)的其他物质在一起被发现,也可被分离出来。当处于固态时,本文所述的化合物及其盐可以各种形式存在并且可例如采取溶剂化物的形式,包括水合物。化合物可为任何固态形式,诸如多晶型物或溶剂化物,因此除非另有明确说明,否则说明书中对化合物及其盐的引用应被理解为涵盖化合物的任何固态形式。
在一些实施方案中,本申请的化合物或其盐基本上分离的。“基本上分离的”意指化合物至少部分地或基本上被从其形成或被检测的环境中分离出来。部分分离可包括例如富含本申请的化合物的组合物。
基本上分离可包括按重量计含有至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约95%、至少约97%或至少约99%的本申请的化合物或其盐的组合物。
短语“药学上可接受的”在本文中用于指在正确医学判断的范围内适合于与人和动物的组织接触使用而不会产生过多毒性、刺激、过敏性反应或其他问题或并发症的、与合理的益处/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所使用的,表达“环境温度”和“室温”是如本领域中所理解的,并且通常是指约为执行反应的房间的温度的温度(例如,反应温度),例如从约20℃到约30℃的温度。
本申请还包括本文所述的化合物的药学上可接受的盐。术语“药学上可接受的盐”是指所公开化合物的衍生物,其中通过将现存的酸或碱部分转化为其盐形式而对母体化合物进行修饰。药学上可接受的盐的示例包括但不限于诸如胺的碱性残基的无机酸盐或有机酸盐;诸如羧酸的酸性残基的碱盐或有机盐等。本申请的药学上可接受的盐包括例如从无毒的无机酸或有机酸形成的母体化合物的无毒盐。本申请的药学上可接受的盐可通过传统化学方法从含有碱性或酸性部分的母体化合物合成。通常,这种盐可通过将这些化合物的游离酸或碱形式与化学计量的适当碱或酸在水中或有机溶剂中或在两者的混合物中反应来制备;通常,非水性介质如乙醚、乙酸乙酯、醇类(例如,甲醇、乙醇、异丙醇或丁醇)或乙腈(MeCN)是优选的。合适的盐的列表可见于以下文献中:雷明顿药物科学(Remington′sPharmaceutical Sciences),第17版,(伊斯顿马克出版公司(Mack Publishing Company,Easton),1985),第1418页;Berge等人,药物科学杂志(J.Pharm.Sci,1977,66(1),1-19和Stahl等人,药用盐手册:性质、选择和使用(Handbook ofPharmaceutical Salts:Properties,Selection,andUse),(威利出版社(Wiley),2002)。在一些实施方案中,本文所述的化合物包括N-氧化物形式。
可互换使用的术语“个体”或“患者”是指任何动物,包括哺乳动物,优选地为小鼠、大鼠、其他啮齿类动物、兔、狗、猫、猪、牛、绵羊、马或灵长类动物,并且最优选地为人。
短语“治疗有效量”是指研究员、兽医、医师或其他临床医生寻找的在组织、系统、动物、个体或人中引发生物学或医学反应的活性化合物或药剂的量。
如本文所使用的,术语“治疗(treating)”或“治疗(treatment)”是指以下项中的一种或多种:(1)抑制疾病;例如,抑制正在经历或表现出疾病、病状或病症的病理学或症状学的个体的疾病、病状或病症(即,阻止病理学和/或症状学上的进一步发展);以及(2)缓解疾病;例如,缓解正在经历或表现出疾病、病状或病症的病理学或症状学的个体的疾病、病状或病症(即,逆转病理学和/或症状学),诸如降低疾病的严重程度。
术语“溶剂化物”是指由溶剂与EPI、代谢物或其盐相互作用形成的化合物。合适的溶剂化物是药学上可接受的溶剂化物,包括水合物。
如本发明中使用的,术语“取代”或“可选地被取代”意指术语“取代”或“可选地被取代”所指代的基团的一个或多个氢原子被取代基替换,这些取代基独立地选自低级烷基、低级芳基、低级芳烷基、低级环状烷基、低级杂环烷基、羟基、低级烷氧基、低级芳氧基、全卤代烷氧基、芳烷氧基、低级杂芳基、低级杂芳氧基(heteroaryloxy)、低级杂芳烷基、低级杂芳烷氧基、叠氮基、氨基、卤代、低级烷硫基、氧代、低级酰基烷基、低级羧基酯、羧基、甲酰氨基、硝基、低级酰氧基、低级氨烷基、低级烷基氨基芳基、低级烷基芳基、低级烷基氨基烷基、低级烷氧基芳基、低级芳基氨基、低级芳烷基氨基、磺酰基、低级甲酰氨基烷基芳基、低级甲酰氨基芳基、低级羟烷基、低级卤代烷基、低级烷基氨基烷基羧基-、低级氨基甲酰氨基烷基、氰基、低级烷氧基烷基、低级全卤代烷基、以及低级芳基烷氧基烷基,前提是不超过考虑取代的原子的正常化合价,并且该取代产生稳定的化合物,也就是说,该化合物充分稳健,以便从反应混合物中分离出来。
术语“烷基”是指仅具有单个碳-碳键的直链、支链或环烃基。代表性示例包括甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、叔丁基、环丁基、戊基、环戊基、己基和环己基,所有这些基团都可能可选地被取代。
术语“芳基”是指具有5-14个环原子以及具有共轭π电子系统的至少一个环的芳基,并且该术语包括碳环芳基、杂环芳基和联芳基,所有这些芳基都可能可选地被取代
碳环芳基是具有6-14个环原子的基团,其中芳族环上的环原子为碳原子。碳环芳基包括单环碳环芳基和多环或稠合化合物,诸如可选地被取代的萘基。
杂环芳基或杂芳基是具有5-14个环原子的基团,其中1至4个杂原子是芳环中的环原子,而其余的环原子是碳原子。合适的杂原子包括氧、硫、氮和硒。合适的杂芳基包括呋喃基、噻吩基、吡啶基、吡咯基、N-低级烷基吡咯基、吡啶基-N-氧化物、嘧啶基、吡嗪基、咪唑基等,所有这些基团都可选地被取代。
术语“联芳基”表示具有5-14个原子的芳基,这些芳基含有多于一个芳环,包括稠环系统和被其他芳基取代的芳基两者。这种基团可能可选地被取代。合适的联芳基包括萘基和联苯。
术语“被取代的芳基”和“被取代的杂芳基”是指被1-3个取代基取代的芳基和杂芳基。这些取代基选自由以下组成的组:低级烷基、低级烷氧基、低级全卤代烷基、卤代、羟基和氨基。
术语“芳烷基”是指被芳基取代的亚烷基。合适的芳烷基包括苄基、吡啶甲基等,并且可能可选地被取代。
术语“杂芳基烷基”是指被杂芳基取代的亚烷基。
术语“烷基芳基”是指被烷基取代的芳基。“低级烷基芳基”是指其中烷基是低级烷基的这种基团。
本文中与有机基团或化合物相关的术语“低级”分别是指6个或更少的碳原子。这种基团可为直链、支链或环状的。
本文中与有机基团或化合物相关的术语“高级”分别是指7个或更多个碳原子。这种基团可为直链、支链或环状的。
术语“环烷基(cyclic alkyl或cycloalkyl)”是指具有3至10个碳原子(并且在一个方面是3至6个碳原子)的环状烷基合适的环状基团包括降冰片基和环丙基。这种基团可被取代。
术语“杂环”、“杂环烷基(heterocyclic alkyl)”或“杂环烷基(heterocycloalkyl)”是指具有3至10个原子(并且在一个方面是3至6个碳原子,含有至少一个杂原子,并且在另一个方面是1至3个杂原子)的环状基团。合适的杂原子包括氧、硫和氮。杂环基可通过氮或通过环中的碳原子连接。杂环烷基包括不饱和环、稠环和螺环基团。合适的杂环基包括吡咯烷基、吗啉代、吗啉乙基和吡啶基。
术语“芳基氨基”(a)和“芳烷基氨基”(b)分别是指基团-NRR',其中分别地,(a)R为芳基并且R′为氢、烷基、芳烷基、杂环烷基或芳基,和(b)R′为芳烷基并且R′为氢、芳烷基、芳基、烷基或杂环烷基。
术语“酰基”是指-C(O)-R,其中R为烷基、杂环烷基或芳基。
术语“羧基酯”是指-C(O)-OR,其中R为烷基、芳基、芳烷基、环烷基或杂环烷基,所有这些基团都可选地被取代。
术语“羧基”是指-C(O)-OH。
术语“氧代”是指烷基或杂环烷基中的=O。
术语“氨基”是指-NRR′,其中R和R′独立地选自氢、烷基、芳基、芳烷基和杂环烷基,除H之外的所有基团都可选地被取代;并且R和R′可形成环状环系统。
术语“甲酰氨基”是指-C(O)NR2,其中每个R独立地为氢或烷基。
术语“磺酰氨基”或“-磺酰氨基”是指-S(=O)2R2,其中每个R独立地为氢或烷基。
术语“卤素”或“卤代”是指-F、-Cl、-Br和-I。
术语“烷基氨基烷基羧基”是指基团烷基-NR-烷-C(O)-O-,其中“烷”是亚烷基,并且R为H或低级烷基。
术语“磺酰基(sulphonyl或sulfonyl)”是指-SO2R,其中R为H、烷基、芳基、芳烷基或杂环烷基。
术语“磺酸盐(sulphonate或sulfonate)”是指-SO2-OR,其中R为-H、烷基、芳基、芳烷基或杂环烷基。
术语“烯基”是指具有2至12个原子并且含有至少一个碳-碳双键的不饱和基团并且包括直链、支链和环状基团。烯基可能可选地被取代。合适的烯基包括烯丙基。“1-烯基”是指双键位于第一个碳原子和第二个碳原子之间的烯基。如果1-烯基连接到另一个基团上(例如,1-烯基是连接到环状膦酸酯上的W取代基),则1-烯基连接在第一个碳上。
术语“炔基”是指具有2至12个原子并且含有至少一个碳-碳三键的不饱和基团并且包括直链、支链和环状基团。炔基可能可选地被取代。合适的炔基包括乙炔基。“1-炔基”是指三键位于第一个碳原子和第二个碳原子之间的炔基。如果1-炔基连接到另一个基团上(例如,1-炔基是连接到环状膦酸酯上的W取代基),则1-炔基连接在第一个碳上。
术语“亚烷基”是指二价直链、支链或环状饱和脂肪族基团。在一个方面,亚烷基含有至多并且包括10个原子。在另一个方面,亚烷基含有至多并且包括6个原子。在另一个方面,亚烷基含有至多并且包括4个原子。亚烷基可为直链、支链或环状的。
术语“酰氧基”是指酯基-O-C(O)R,其中R为H、烷基、烯基、炔基、芳基、芳烷基或杂环烷基。
术语“氨基烷基”是指基团NR2-烷-,其中“烷”是亚烷基,并且R选自-H、烷基、芳基、芳烷基和杂环烷基。
术语“烷基氨基烷基”是指基团烷基-NR-烷-,其中每个“烷”是独立选择的亚烷基,并且R为H或低级烷基。“低级烷基氨基烷基”是指其中烷基和亚烷基分别为低级烷基和亚烷基的基团。
术语“芳基氨基烷基”是指基团芳基-NR-烷-,其中“烷”是亚烷基,并且R为-H、烷基、芳基、芳烷基或杂环烷基。在“低级芳基氨基烷基”中,亚烷基是低级亚烷基。
术语“烷基氨基芳基-”是指基团烷基-NR-芳基-,其中“芳基”是二价基团,并且R为-H、烷基、芳烷基或杂环烷基。在“低级烷基氨基芳基”中,烷基是低级烷基。
术语“烷氧基芳基”是指被烷氧基取代的芳基。在“低级烷氧基芳基”中,烷基是低级烷基。
术语“芳氧烷基”是指被芳氧基取代的烷基。
术语“芳烷基氧烷基”是指基团芳基-烷-O-烷-,其中“烷”为亚烷基。“低级芳烷基氧烷基”是指这样的基团,其中亚烷基是低级亚烷基。
术语“烷氧基-(alkoxy-或alkyloxy-)”是指基团烷基-O-。
术语“烷氧基烷基(alkoxyalkyl或alkyloxyalkyl)”是指基团烷基-O-烷-,其中“烷”为亚烷基。在“低级烷氧基烷基”中,每个烷基和亚烷基分别为低级烷基和亚烷基。
术语“烷硫基-”是指基团烷基-S-。
术语“烷基硫代烷基”是指基团烷基-5-烷-,其中“烷”为亚烷基。在“低级烷基硫代烷基”中,每个烷基和亚烷基分别为低级烷基和亚烷基。
术语“烷氧基羰氧基-”是指烷基-O-C(O)-O-。
术语“芳氧基羰氧基-”是指芳基-O-C(O)-O-。
术语“烷基硫代羰基氧基”是指烷基-S-C(O)-O-。
术语“酰氨基”是指与酰基或磺酰基相邻的NR2基团,如在NR2-C(O)-、RC(O)-NR1-、NR2-S(=O)2-和RS(=O)2-NR1-中,其中R和R1包括-H、烷基、芳基、芳烷基和杂环烷基
术语“甲酰氨基”是指NR2-C(O)-和RC(O)-NR1-,其中R和R1包括-H、烷基、芳基、芳烷基和杂环烷基。该术语不包括尿素-NR-C(O)-NR-。
术语“磺酰胺基(sulphonamido或sulfonamido)”是指NR2-S(=O)2-和RS(=O)2-NR1-,其中R和R1包括-H、烷基、芳基、芳烷基和杂环烷基。该术语不包括磺酰脲-NR-S(=O)2-NR-。
术语“甲酰氨基烷基芳基”或“甲酰氨基芳基”分别是指芳基-烷-NR1-C(O)和芳-NR1-C(O)-烷-,其中“芳”为芳基,“烷”为亚烷基,R1和R包括H、烷基、芳基、芳烷基和杂环烷基。
术语“磺酰氨基烷基芳基”或“磺酰氨基芳基”分别是指芳基-烷-NR1-S(=O)2-和ar-NR1-S(=O)2-,其中“芳”为芳基,“烷”为亚烷基,R1和R包括H、烷基、芳基、芳烷基和杂环烷基。
术语“羟烷基”是指被一个-OH取代的烷基。
术语“卤代烷基”是指被卤代取代的烷基。
术语“氰基”是指-CN。
术语“硝基”是指-NO2。
术语“酰基烷基”是指烷基-C(O)-烷-,其中“烷”为亚烷基。
术语“氨基甲酰氨基烷基”是指基团NR2-C(O)-N(R)-烷-,其中R为烷基或H,而“烷”为亚烷基。“低级氨基甲酰氨基烷基”是指这样的基团,其中“烷”是低级亚烷基
术语“杂芳基烷基”是指被杂芳基取代的亚烷基。
II.干扰PD-L1活性的化合物
本申请的一个方面涉及干扰PD-L1活性的化合物。在一些实施方案中,该化合物具有如式(I)所示的通用结构:
或其药学上可接受的盐、立体异构体、立体异构体的混合物、溶剂化物或互变异构体,其中,
A和B各自独立地选自卤素、氰基、-N3、烷基和经取代的烷基、胺、烷基胺、烷氧基;
Z1为-CR1=或-N=;
Z2为-CR2=;
Z3为-CR3=或-N=;
Z4为-CR4=或-N=,
Z5为-CR5=;
Z6为-CR6=或-N=;
R1和R4各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R2和R5各自独立,各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R3和R6各自独立,各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
Y1和Y2独立地为-C(R7)(R8)-、-CR9=、-NR10-、-O-或-S-;\
X1和X2各自独立地为-C(R11)(R12)-、-N=、-NR13-、-S-或-O-;
R7、R8、R9、R11和R12各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R10和R13各自独立地为-H、烷基、环烷基、经取代的烷基、烯基、烯基、炔基、芳基、烷基胺、烷氧基;
L1和L2各自为在环3和W1之间以及环6和W2之间含有m个原子的烷基、经取代的烷基或杂原子链,其中m=0、1、2、3、4、5或6;当m为0时,W1或W2分别与环3或环6中的对应氮直接连接;
W1和W2各自独立地为氢、五元杂环或经取代的五元杂环、六元杂环或经取代的六元杂环、羧基烷基或经取代的羧基烷基、氰烷基或经取代的氰烷基、氨基烷基或经取代的氨基烷基、羟烷基或经取代的羟烷基、氨基酸、氨基酸酯、氨基酸酰胺、非天然氨基酸、非天然氨基酸酯或非天然氨基酸酰胺。
式(I)化合物可为关于轴线DD对称(即,式(I)的左侧部分是式(I)的右侧部分的镜像)或不对称(即,式(I)的左侧部分不同于式(I)的右侧部分)。
优选的核心结构
在一些实施方案中,式(I)化合物包括选自由式(II)-(XXIII)组成的组的核心结构:
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在一些实施方案中,式(I)化合物包括以下核心结构:
在一些实施方案中,L1和L2各自独立地选自-CH2-、
(CH2)2–和–(CH2)3-。
在一些实施方案中,L1和L2各自独立地选自
–CH(CH3)-、-CH2–和–CH2-CH(CH3)–。
I型侧链
在一些实施方案中,W1和/或W2各自独立地为I型侧链。如本文所使用的,术语“I型侧链”是指含有以下的结构:(1)具有至少一个氮原子作为环原子的五元杂环或具有至少一个氮原子作为环原子的被取代的五元杂环,或(2)具有至少一个氮原子作为环原子的六元杂环或具有至少一个氮原子作为环原子的被取代的五元杂环,其中连接子L1或L2直接连接到五元或六元杂环中的环原子。
在一些实施方案中,W1和/或W2各自独立地为杂环。在一些实施方案中,W1和/或W2各自独立地为具有至少一个氮原子作为环原子的五元杂环。在一些实施方案中,W1和/或W2各自独立地为具有至少一个氮原子作为环原子的六元杂环。
在一些实施方案中,W1和/或W2各自独立地选自下文列出的I型侧链的组:
以及/>
2型侧链
在一些实施方案中,W1和/或W2各自独立地为II型侧链。如本文所使用的,术语“II型侧链”是指具有通式:
的W1结构和具有通式:/>的W2结构
其中R14和R16各自独立地为-H、烷基、经取代的烷基、羟烷基或经取代的羟烷基、羟基羧酸或其盐或酯、经取代的羟基羧酸或其盐或酯、羧酸或其盐或酯或烷基醚、经取代的羧酸或其盐或酯或烷基醚、甲酰氨基或内酯;并且
其中R15和R17各自独立地为-H、烷基或经取代的烷基。
在一些实施方案中,R14或R16或两者均具有通式-L3-C(O)-Q2R18,其中L3为烷基、经取代的烷基、烷基氨基或烷基-氨基-烷基,Q2为–O-或-CH2-,并且R18为–H、烷基或经取代的烷基。
在一些实施方案中,R14或R16或两者独立地选自由以下组成的组:
/>以及/>
在一些实施方案中,W1或W2各自独立地为氨基酸。
在一些实施方案中,侧链W1或W2为L-丝氨酸
在一些实施方案中,侧链W1或W2为L-丝氨酸酯。
在一些实施方案中,侧链W1和W2两者均为L-丝氨酸
在一些实施方案中,侧链W1和W2两者均为L-丝氨酸酯。
其他侧链
在一些实施方案中,W1或W2各自独立地为–C(O)-ONa、–CN、–CH2OH或–CH2NH2。
示例性化合物
在一些实施方案中,式(I)化合物包括以下核心结构:
在一些实施方案中,式(I)化合物包括以下核心结构:
在一些实施方案中,式(I)化合物由两个相同的核心结构连接在一起组成。
在一些实施方案中,式(I)化合物由两个相同的核心结构连接在一起组成。/>
在一些实施方案中,式(I)化合物由核心结构和核心结构/>连接在一起组成。
在一些实施方案中,侧链W1和/或W2独立地选自由以下组成的组:
在一些实施方案中,式(I)化合物仅包括一个侧链,其中:
W1为
W2为H,并且L2不存在(即,m=0)。换句话说,环6的氮原子上没有侧链。在另外的实施方案中,L1为C1-C3烷基。
在一些实施方案中,式(I)化合物包括关于轴线DD不对称的侧链。
在一些实施方案中,W1为并且W2选自I型和II型侧链。在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,W1为并且W2选自I型和II型侧链。在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,W1为并且W2选自I型和II型侧链。在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,W1为并且W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。/>
在一些实施方案中,W1为并且W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,W1为并且W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,侧链W1为并且侧链W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,侧链W1为并且侧链W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,侧链W1为并且侧链W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,侧链W1为并且侧链W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,侧链W1为并且侧链W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,侧链W1为并且侧链W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
在一些实施方案中,侧链W1为并且侧链W2为/>在另外的实施方案中,L1和L2各自独立地为C1-C3烷基。
不限于在表1中列出了本文公开的化合物(或其药学上可接受的盐、立体异构体、立体异构体的混合物、溶剂化物或互变异构体)的某些实施方案:
表1
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
本申请还包括本公开的同位素取代的化合物。“同位素取代的”化合物是本申请的化合物,其中一个或多个原子被具有相同原子序数但不同的原子质量或质量数,例如与通常在自然界中发现的(即,天然存在的)原子质量或质量数不同的原子质量或质量数的原子替换或取代。应当理解,“放射性标记的”化合物是已经并入有至少一种放射性同位素(例如,核素)的化合物。
III.式(I)化合物的用途
本申请的另一方面涉及式(I)化合物的用途。式(I)化合物干扰PD-L1与PD-1之间的相互作用,并且因此可用于治疗与PD-1活性相关联的疾病和病症以及与PD-L1相关联的疾病和病症。
在一些实施方案中,式(I)化合物促进PD-L1二聚体的形成,并且因此抑制PD-L1与PD-1之间的相互作用。在某些实施方案中,本公开的化合物或其药学上可接受的盐或立体异构体可用于治疗性施用以增强、刺激和/或增加癌症、慢性感染或败血症中的免疫力,包括增强对疫苗接种的反应。在一些实施方案中,本公开提供了一种用于抑制PD-1/PD-L1蛋白/蛋白质相互作用的方法。该方法包括向个体或患者施用有效量的式(I)化合物或其药学上可接受的盐或立体异构体。式(I)化合物可单独使用、与其他药剂或疗法组合使用或作为佐剂或新佐剂以用于治疗疾病或病症,包括癌症或感染疾病。对于本文所述的用途,可使用本公开的任何化合物,包括其任何实施方案。
本申请的化合物抑制PD-1/PD-L1蛋白/蛋白质相互作用,导致PD-1通路阻断。PD-1阻断可增强对包括人类的哺乳动物的癌细胞和感染疾病的免疫反应。在一些实施方案中,本公开使用本文任何式的化合物或其盐或立体异构体向个体或患者提供体内治疗,从而抑制癌性肿瘤的生长。如本文所述的任何式的化合物或如任何权利要求中阐述和本文所述的化合物或其盐或立体异构体可用于抑制癌性肿瘤的生长。可替代地,如本文所述的任何式的化合物或如任何权利要求中阐述和本文所述的化合物或其盐或立体异构体可与如下文所描述的其他药剂或标准癌症治疗结合使用。在一个实施方案中,本公开提供了一种用于体外抑制肿瘤细胞生长的方法。该方法包括:使肿瘤细胞与如本文所述的任何式的化合物或如任何权利要求中阐述和本文所述的化合物或其盐或立体异构体在体外接触。在另一实施方案中,本公开提供了一种用于抑制个体或患者的肿瘤细胞生长的方法。该方法包括:向有需要的个体或患者施用治疗有效量的如本文所述的任何式的化合物或如任何权利要求中阐述和本文所述的化合物或其盐或立体异构体。
在一些实施方案中,本文提供了用于治疗癌症的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式,如任何权利要求中阐述和本文所述的化合物或其盐。癌症的示例包括可使用本公开的化合物抑制其生长的那些癌症以及通常对免疫疗法有反应的癌症。
可使用本公开的化合物治疗的癌症的示例包括但不限于骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌(carcinoma ofthe endometrium)、子宫内膜癌(endometrialcancer)、宫颈癌、阴道癌、外阴癌、霍奇金氏病(Hodgkin′s Disease)、非霍奇金氏淋巴瘤(non-Hodgkin′s lymphoma)、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包括急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病)、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾癌或输尿管癌、肾盂癌、中枢神经系统肿瘤(CNS)、原发性CNS淋巴瘤、肿瘤血管、脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、卡波西氏肉瘤(Kaposi′s sarcoma)、表皮癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的癌症)以及所述癌症的组合。本公开的化合物还可用于治疗转移性癌症,尤其是表达PD-L1的转移性癌症。
在一些实施方案中,可用本公开的化合物治疗的癌症包括黑色素瘤(例如,转移性恶性黑色素瘤、皮肤黑色素瘤)、肾癌(例如,透明细胞癌)、前列腺癌(例如,激素难治性前列腺腺癌)、乳腺癌(例如,浸润性乳腺癌)、结肠癌、肺癌(例如,非小细胞肺癌和小细胞肺癌)、鳞状细胞头颈癌(例如,头颈部鳞状细胞癌)、尿路上皮癌(例如,膀胱癌、非肌层浸润性膀胱癌(NMIBC))和高微卫星不稳定性癌(MSIhlgh)。
另外,本公开包括可使用本公开的化合物抑制其生长的难治性或复发性恶性肿瘤。
在一些实施方案中,可使用本公开的化合物治疗的癌症包括但不限于实体瘤(例如,前列腺癌、结肠癌、食管癌、子宫内膜癌、卵巢癌、子宫癌、肾癌、肝癌、胰腺癌、胃癌、乳腺癌、肺癌、头颈癌、甲状腺癌、胶质母细胞瘤、肉瘤、膀胱癌等)、血液学癌症(例如,淋巴瘤、白血病,诸如急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL)、慢性髓系白血病(CML)、DLBCL、套细胞淋巴瘤、非霍奇金淋巴瘤(Non-Hodgkin lymphoma)(包括复发性或难治性NHL和复发性滤泡)、霍奇金淋巴瘤或多发性骨髓瘤)以及所述癌症的组合。
在一些实施方案中,可使用本公开的化合物治疗的癌症包括但不限于胆管细胞癌、胆道癌、三阴性乳腺癌、横纹肌肉瘤、小细胞肺癌、平滑肌肉瘤、肝细胞癌、尤文氏肉瘤(Ewing′s sarcoma)、脑癌、脑肿瘤、星形细胞瘤、成神经细胞瘤、神经纤维瘤、基底细胞癌、软骨肉瘤、上皮样肉瘤、眼癌、输卵管癌、胃肠道癌、胃肠道间质瘤、毛细胞白血病、肠癌、胰岛细胞癌、口腔癌(oral cancer)、口腔癌(mouth cancer)、喉癌(throat cancer)、喉癌(laryngeal cancer)、唇癌、间皮瘤、颈癌、鼻腔癌、眼癌、眼黑色素瘤、盆腔癌、直肠癌、肾细胞癌、唾液腺癌、鼻窦癌、脊柱癌、舌癌、小管癌、尿道癌和输尿管癌。
在一些实施方案中,可使用本公开的化合物治疗的疾病和适应症包括但不限于血液学癌症、肉瘤、肺癌、胃肠道癌、泌尿生殖道癌、肝癌、骨癌、神经系统癌、妇科癌和皮肤癌。
示例性血液学癌症包括淋巴瘤和白血病,诸如急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、急性早幼粒细胞白血病(APL)、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤、非霍奇金淋巴瘤(包括复发性或难治性NHL和复发性滤泡性NHL)、霍奇金淋巴瘤、骨髓增生性疾病(例如,原发性骨髓纤维化(PMF)、真性红细胞增多症(PV)和原发性血小板增多症(ET))、骨髓发育不良综合征(MDS)、T细胞急性淋巴细胞性淋巴瘤(T-ALL)和多发性骨髓瘤(MM)。
示例性肉瘤包括软骨肉瘤、尤文氏肉瘤、骨肉瘤、横纹肌肉瘤、血管肉瘤、纤维肉瘤、脂肪肉瘤、粘液瘤、横纹肌瘤、横纹肌肉瘤、纤维瘤、脂肪瘤、错构瘤和畸胎瘤。
示例性肺癌包括非小细胞肺癌(NSCLC)(例如,鳞状细胞NSCLC)、小细胞肺癌、支气管癌(鳞状细胞癌、未分化小细胞癌、未分化大细胞癌、腺癌)、肺泡(细支气管)癌、支气管腺瘤、软骨瘤性错构瘤和间皮瘤。
示例性胃肠道癌包括食道癌(癌、鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌、淋巴瘤、平滑肌肉瘤、腺癌)、胰腺癌(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌、舒血管肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌癌)和结直肠癌(例如,结直肠腺癌)。
示例性泌尿生殖道癌包括肾癌(腺癌、维尔姆氏肿瘤(Wilm′s tumor)[肾母细胞瘤])、膀胱和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)和睾丸癌(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤)。在一些实施方案中,该癌症是泌尿系统癌(例如,乳头状肾癌、睾丸生殖细胞癌、嫌色细胞肾细胞癌、透明细胞肾癌或前列腺癌)。
示例性肝癌包括肝癌(肝细胞癌)、胆管细胞癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤和血管瘤。
示例性骨癌包括例如骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤文氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨疣)、良性软骨瘤、软骨母细胞瘤、软骨粘液样纤维瘤、骨样骨瘤和巨细胞瘤。
示例性神经系统癌包括头骨癌(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑脊膜癌(脑膜瘤、脑膜肉瘤、神经胶质过多)、脑癌(星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、胶质母细胞瘤、多形性胶质母细胞瘤、少突胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)和脊髓癌(神经纤维瘤、脑膜瘤、胶质瘤、肉瘤)以及神经母细胞瘤和埃尔米特-杜多斯病(Lhermitte-Duclos disease)。
示例性妇科癌包括子宫癌(子宫内膜癌)、宫颈癌(宫颈癌、前肿瘤子宫颈非典型增生)、卵巢癌(卵巢癌(浆液性囊腺癌、浆液性腺癌、粘液性囊腺癌、未分类的癌症)、粒膜细胞肿瘤、塞-莱二氏细胞瘤(Sertoli-Leydig cell tumor)、无性细胞瘤、恶性畸胎瘤)、阴门癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎性横纹肌肉瘤)和输卵管(癌)。
示例性皮肤癌包括黑色素瘤、基底细胞癌、鳞状细胞癌(例如,皮肤鳞状细胞癌)、卡波西氏肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤和痣发育不良痣。在一些实施方案中,可使用本公开的化合物治疗的疾病和适应症包括但不限于镰状细胞病(例如,镰状细胞贫血)、三阴性乳腺癌(TNBC)、骨髓增生异常综合征、睾丸癌、胆管癌、食管癌和尿路上皮癌。
可利用本公开的化合物阻断的PD-1通路还可用于治疗感染,诸如病毒、细菌、真菌和寄生虫感染。在一些实施方案中,本文提供了用于治疗感染的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式,如任何权利要求中阐述和本文所述的化合物、其盐。可通过本公开的方法治疗的引起感染的病毒的示例包括但不限于人免疫缺陷病毒、人乳头瘤病毒、流感、甲型、乙型、丙型或丁型肝炎病毒、腺病毒、痘病毒、单纯疱疹病毒、人巨细胞病毒、冠状病毒、严重急性呼吸综合征病毒、埃博拉病毒(ebola virus)和麻疹病毒。在一些实施方案中,可通过本公开的方法治疗的引起感染的病毒包括但不限于肝炎(甲型、乙型或丙型)、疱疹病毒(例如,VZV、HSV-1、HAV-6、HSV-II和CMV、人疱疹病毒第四型)、腺病毒、流感病毒、黄病毒、艾柯病毒、鼻病毒、柯萨奇病毒、冠状病毒、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒、肺结核和虫媒病毒性脑炎病毒。
本公开提供了一种用于治疗细菌感染的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式的化合物,如任何权利要求中阐述和本文所述的化合物或其盐。可通过本公开的方法治疗的引起感染的病原细菌的非限制性示例包括衣原体、立克次氏菌(rickettsial bacteria)、分枝杆菌、葡萄球菌、链球菌、肺炎球菌、脑膜炎球菌和淋球菌、克雷伯氏菌、变形杆菌、沙雷氏菌、假单胞菌、军团菌、白喉、沙门氏菌、杆菌、霍乱、破伤风、肉毒中毒、炭疽、鼠疫、钩端螺旋体病和莱姆病细菌(Lyme′s disease bacteria)。
本公开提供了一种用于治疗真菌感染的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式的化合物,如任何权利要求中阐述和本文所述的化合物或其盐。可通过本公开的方法治疗的引起感染的病原真菌的非限制性示例包括假丝酵母(白色念珠菌、克柔假丝酵母、光滑念珠菌、热带念珠菌等)、新型隐球菌、曲霉菌(烟曲霉菌、黑曲霉等)、毛霉菌属(毛霉菌、梨头霉、如根霉)、申克氏孢子丝菌、皮炎芽生菌、巴西副球孢子菌、粗球孢子菌和荚膜组织胞浆菌。
本公开提供了一种用于治疗寄生虫感染的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式的化合物,如任何权利要求中阐述和本文所述的化合物或其盐。可通过本公开的方法治疗的引起感染的病原性寄生虫的非限制性示例包括痢疾内变形虫(Entamoeba histolytica)、结肠小袋纤毛虫(Balantidium coli)、福氏耐格里变形虫(Naegleriafowleri)、棘阿米巴(Acanthamoeba sp.)、蓝氏贾第虫(Giardia lambia)、隐孢子虫(Cryptosporidium sp.)、卡氏肺孢子虫(Pneumocystis carinii)、间日疟原虫(Plasmodium vivax)、田鼠巴贝虫(Babesia microti)、布氏锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、杜氏利什曼虫(Leishmania donovani)、弓形虫(Toxoplasma gondi)和巴西日圆线虫(Nippostrongylus brasiliensis)。
在一些实施方案中,本文提供了用于治疗炎症的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式的化合物,如任何权利要求中阐述和本文所述的化合物或其盐。
在一些实施方案中,本文提供了用于治疗自身免疫性疾病的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式的化合物,如任何权利要求中阐述和本文所述的化合物或其盐。
据信,式(I)化合物或其任何实施方案可具有令人满意的药理学特性和有前途的生物制药学特性,诸如毒理学特性、代谢和药代动力学特性、溶解度和渗透性。应当理解,确定合适的生物制药学特性在本领域技术人员的知识范围内,例如,确定细胞中的细胞毒性或抑制某些靶标或通道以确定潜在毒性。
在一些实施方案中,本申请的化合物可用于预防本文所提及的疾病中的任何疾病或降低患上所述疾病的风险;例如,预防可能被预先诊断出疾病、病状或病症但尚未经历或显示出疾病的病理学或症状学的个体的疾病、病状或病症或降低患上所述疾病、病状或病症的风险。
在一些实施方案中,本公开提供了一种增强、刺激和/或增加患者免疫反应的方法。该方法包括:向有需要的患者施用治疗有效量的如本文所述的任何式,如任何权利要求中阐述和本文所述的化合物或组合物或其盐。
组合疗法
本公开的化合物可与一个或多个其他疗法组合以用于治疗疾病,诸如癌症或感染。可用组合疗法治疗的疾病和适应症的示例包括如本文所述的那些疾病和适应症。
癌症的示例包括实体瘤和非实体瘤,诸如液体肿瘤、血癌。感染的示例包括病毒感染、细菌感染、真菌感染或寄生虫感染。例如,本公开的化合物可与以下激酶的一种或多种抑制剂组合以用于治疗癌症:Aktl、Akt2、Akt3、BCL2、CDK、TGF-PR、PKA、PKG、PKC、CaM-激酶、磷酸化酶激酶、MEKK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、INS-R、IDH2、IGF-1R、IR-R、PDGFotR、PDGi′PR、PI3K(α、β、γ、δ以及多发性或选择性)、CSF1R、KIT、FLK-1I、KDR/FLK-1、FLK-4、flt-1、FGFR1、FGFR2、FGFR3、FGFR4、c-Met、PARP、Ron、Sea、I RKA、TRKB、TRKC、TAM激酶(Axl、Mer、Tyro3)、FLT3、VEGFR/FH2、Flt4、EphAl、EphA2、EphA3、EphB2、EphB4、Tie2、Src、Fyn、Lck、Fgr、Btk、Fak、SYK、FRK、JAK、ABL、ALK和B-Raf。在一些实施方案中,本公开的化合物可与以下抑制剂中的一种或多种抑制剂组合以用于治疗癌症或感染。可与本公开的化合物组合以用于治疗癌症和感染的抑制剂的非限制性示例包括FGFR抑制剂(FGFR1、FGFR2、FGFR3或FGFR4,例如,佩米替尼(pemigatinib)(INCY54828)、INCB62079)、JAK抑制剂(JAK1和/或JAK2,例如,鲁索替尼(ruxolitinib)、巴瑞替尼(baricitinib)或依他替尼(itacitinib)(INCB39110))、IDO抑制剂(例如,依帕卡哚司他(epacadostat)、NLG919或BMS-986205,MK7162)、LSD1抑制剂(例如,INCB59872和INCB60003)、TDO抑制剂、PI3K-δ抑制剂(例如,帕萨利司片(Parsaclisib)(INCB50465)和INCB50797)、PI3K-γ抑制剂,诸如PI3K-γ选择性抑制剂、Pirn抑制剂(例如,INCB53914)、EGFR抑制剂(也称为ErB-1或HER-1;例如,厄洛替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、奥希替尼(osimertinib)、西妥昔单抗(cetuximab)、耐昔妥珠单抗(necitumumab)或帕尼单抗(panitumumab))、VEGFR抑制剂或通路阻断剂(例如,贝伐单抗(bevacizumab)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、阿西替尼(axitinib)、瑞戈非尼(regorafenib)、帕纳替尼(ponatinib)、卡博替尼(cabozantinib)、艾维替尼(axitinib)、凡德他尼(vandetanib)、雷莫芦单抗(ramucirumab)、乐伐替尼(lenvatinib)、阿柏西普(ziv-aflibercept))、PARP抑制剂(例如,奥拉帕尼(olaparib)、卢卡帕尼(rucaparib)、、维利帕瑞布(veliparib)、他拉唑帕尼(talazoparib)或尼拉帕尼(niraparib))、CSF1R抑制剂、TAM受体酪氨酸激酶(Tyro-3、Axl和Mer)、腺苷受体拮抗剂(例如,A2a/A2b受体拮抗剂)、HPK1抑制剂、趋化因子受体抑制剂(例如,CCR2或CCR5抑制剂)、SHP1/2磷酸酶抑制剂、组蛋白脱乙酰酶抑制剂(HDAC),诸如HDAC8抑制剂、血管生成抑制剂、白介素受体抑制剂、溴和额外末端家族成员抑制剂(例如,溴结构域抑制剂或BET抑制剂,诸如INCB54329和INCB57643)、精氨酸酶抑制剂(INCB001158)、PARP抑制剂(诸如卢卡帕尼或奥拉帕尼)、司曲替尼(sitravatinib)、B-Raf抑制剂-MEK抑制剂组合(诸如康奈非尼(encorafenib)加比美替尼(binimetinib)、达拉菲尼(dabrafenib)加曲美替尼(trametinib)、或考比替尼(cobimetinib)加威罗菲尼(vemurafenib))和腺苷受体拮抗剂或它们的组合。
在一些实施方案中,本公开的化合物可与TLR7激动剂(例如,咪喹莫特(imiquimod))组合。
本公开的化合物还可用于与例如通过化疗、照射疗法、肿瘤靶向疗法、辅助疗法、免疫疗法或外科手术治疗癌症的其他方法组合。免疫疗法的示例包括细胞因子治疗(例如,干扰素、GM-CSF、g-CSF和IL-2)、CRS-207免疫疗法、癌症疫苗、单克隆抗体、双特异性或多特异性抗体、抗体药物缀合物、过继性T细胞转移、Toll受体激动剂、STING激动剂、RIG-I激动剂、溶瘤病毒疗法和免疫调节小分子,包括沙利度胺(thalidomide)或JAK1/2抑制剂、PI3K6抑制剂等。这些化合物可与诸如化学治疗剂的一种或多种抗癌药物组合施用。化学疗法的示例包括以下各项中的任何一项:阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿仑单抗(alemtuzumab)、阿屈替诺(alitretinoin)、别嘌醇(allopurinol)、六甲蜜胺(altretamine)、阿那曲唑(anastrozole)、三氧化二砷、天冬酰胺酶、阿扎胞苷(azacitidine)、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、巴瑞替尼、博莱霉素(bleomycin)、硼替佐米(bortezomib)、静脉用白消安(busulfan intravenous)、口服白消安(busulfan oral)、卡普睾酮(calusterone)、卡培他滨(capecitabine)、卡铂(carboplatin)、卡莫司汀(carmustine)、西妥昔单抗(cetuximab)、苯丁酸氮芥(chlorambucil)、顺铂(cisplatin)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、放线菌素(dactinomycin)、达肝素钠(dalteparin sodium)、达沙替尼(dasatinib)、道诺霉素(daunorubicin)、地西他滨(decitabine)、地尼白介素(denileukin)、地尼白介素(denileukin diftitox)、右雷佐生(dexrazoxane)、多西他赛(docetaxel)、阿霉素(doxorubicin)、丙酸屈他雄酮(dromostanolone propionate)、依库丽单抗(eculizumab)、表柔比星(epirubicin)、厄洛替尼(erlotinib)、雌莫司汀(estramustine)、磷酸依托泊苷(etoposide phosphate)、依托泊苷(etoposide)、依西美坦(exemestane)、柠檬酸芬太尼(fentanyl citrate)、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟尿嘧啶(fluorouracil)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、吉西他滨(gemcitabine)、吉妥珠单抗(gemtuzumab ozogamicin)、乙酸戈舍瑞林(goserelin acetate)、乙酸组氨瑞林(histrelin acetate)、替伊莫单抗(ibritumomab tiuxetan)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、甲磺酸伊马替尼(imatinib mesylate)、干扰素α2a(interferon alfa 2a)、伊立替康(irinotecan)、二甲苯磺酸拉帕替尼(lapatinib ditosylate)、来那度胺(lenalidomide)、来曲唑(letrozole)、甲酰四氢叶酸(leucovorin)、乙酸亮丙瑞林(leuprolide acetate)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、盐酸氮芥(meclorethamine)、乙酸甲地孕酮(megestrol acetate)、美法仑(melphalan)、巯嘌呤(mercaptopurine)、甲氨蝶呤(methotrexate)、甲氧沙林(methoxsalen)、丝裂霉素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、苯丙酸诺龙(nandrolone phenpropionate)、奈拉滨(nelarabine)、nofetumomab、奥沙利铂(oxaliplatin)、紫杉醇(paelitaxel)、帕米膦酸酯(pamidronate)、帕尼单抗(panitumumab)、培门冬酶(pegaspargase)、培非格司亭(pegfilgrastim)、培美曲塞二钠(pemetrexed disodium)、喷司他丁(pentostatin)、哌泊溴烷(pipobroman)、普卡霉素(plicamycin)、丙卡巴肼(procarbazine)、奎纳克林(quinacrine)、拉布立酶(rasburicase)、利妥昔单抗(rituximab)、鲁索替尼(ruxolitinib)、索拉非尼(sorafenib)、链脲佐菌素(streptozocin)、舒尼替尼(sunitinib)、马来酸舒尼替尼(sunitinib maleate)、它莫西芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、睾内酯(testolactone)、沙利度胺(thalidomide)、硫鸟嘌呤(thioguanine)、噻替派(thiotepa)、拓扑替康(topotecan)、托瑞米芬(toremifene)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、维甲酸(tretinoin)、乌拉莫司汀(uracil mustard)、戊柔比星(valrubicin)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、伏立诺他(vorinostat)和唑来膦酸酯(zoledronate)。
其他抗癌剂包括抗体治疗剂,诸如曲妥珠单抗(赫赛汀(Herceptin))、共刺激分子的抗体,诸如CTLA-4(例如,易普利姆玛(ipilimumab))、4-1BB(例如,乌瑞芦单抗(urelumab)、乌托鲁单抗(utomilumab))、针对PD-1和PD-L1的抗体或细胞因子抗体(IL-10、TGF-b等)。针对PD-1和/或PD-L1的可与本公开的化合物组合以用于治疗癌症或诸如病毒、细菌、真菌和寄生虫感染的感染的抗体的示例包括但不限于纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、阿特珠单抗(atezolizumab)、德瓦鲁单抗(durvalumab)、阿维鲁单抗(avelumab)和SHR-1210。
本公开的化合物可与一种或多种免疫检查点抑制剂组合以用于治疗疾病,诸如癌症或感染。
示例性免疫检查点抑制剂包括针对免疫检查点分子的抑制剂,诸如CBL-B、CD27、CD28、CD40、CD122、CD96、CD73、CD47、OX40、GITR、CSF1R、JAK、PI3Kδ、PI3Kγ、TAM、精氨酸酶、CD137(也称4-1BB)、ICOS、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、TIGIT、CD112R、VISTA、PD-1、PD-L1和PD-L2。在一些实施方案中,免疫检查点分子是选自以下的刺激性检查点分子:CD27、CD28、CD40、ICOS、OX40、GITR和CD137。在一些实施方案中,免疫检查点分子是选自以下的抑制性检查点分子:A2AR、B7-H3、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、PD-1、TIM3和VISTA。在一些实施方案中,本文提供的化合物可与选自以下的一种或多种药剂组合使用:KIR抑制剂、TIGIT抑制剂、LAIR1抑制剂、CD 160抑制剂、2B4抑制剂和TGFRβ抑制剂。
在一些实施方案中,免疫检查点分子的抑制剂是抗PD1抗体、抗PD-L1抗体或抗CTLA-4抗体。
在一些实施方案中,免疫检查点分子的抑制剂是PD-1的抑制剂,例如,抗PD-1单克隆抗体。在一些实施方案中,抗PD-1单克隆抗体是纳武单抗、派姆单抗(也称为MK-3475)、皮地利珠单抗(pidilizumab)、SHR-1210、PDR001或AMP-224。在一些实施方案中,抗PD-1单克隆抗体是纳武单抗或派姆单抗。在一些实施方案中,抗PD1抗体是派姆单抗。
在一些实施方案中,免疫检查点分子的抑制剂是CTLA-4的抑制剂,例如,抗CTLA-4抗体。在一些实施方案中,抗CTLA-4抗体是伊匹木单抗或曲美木单抗(tremelimumab)。
在一些实施方案中,免疫检查点分子的抑制剂是LAG3的抑制剂,例如,抗LAG3抗体。在一些实施方案中,抗LAG3抗体是BMS-986016、LAG525或INCAGN2385。
在一些实施方案中,免疫检查点分子的抑制剂是TIM3的抑制剂,例如,抗TIM3抗体。在一些实施方案中,抗TIM3抗体是INCAGN2390、MBG453或TSR-022。
在一些实施方案中,免疫检查点分子的抑制剂是GITR的抑制剂,例如,抗GITR抗体。在一些实施方案中,抗GITR抗体是TRX518、MK-4166、INCAGN1876、MK-1248、AMG228、BMS-986156、GWN323或MEDI1873。
在一些实施方案中,免疫检查点分子的抑制剂是OX40的抑制剂,例如,抗OX40抗体或OX40L融合蛋白。在一些实施方案中,抗OX40抗体是MEDI0562、MOXR-0916、PF-04518600、GSK3174998或BMS-986178。在一些实施方案中,OX40L融合蛋白是MEDI6383。
本公开的化合物还可与一种或多种抗炎剂、类固醇、免疫抑制剂或治疗性抗体组合使用。
如本文所述的任何式的化合物、如任何权利要求中阐述和本文所述的化合物或其盐可与另一种免疫原性剂组合,诸如癌细胞、经纯化的肿瘤抗原(包括重组蛋白、肽和碳水化合物分子)、细胞和用编码免疫刺激细胞因子的基因转染的细胞。可使用的肿瘤疫苗的非限制性示例包括黑色素瘤抗原的肽,诸如gplOO、MAGE抗原、Trp-2、MARTI和/或酪氨酸酶的肽,或被转染以表达细胞因子GM-CSF的肿瘤细胞。
如本文所述的任何式的化合物、如任何权利要求中阐述和本文所述的化合物或其盐可与疫苗接种方案组合使用,以用于治疗癌症。在一些实施方案中,肿瘤细胞被转导以表达GM-CSF。在一些实施方案中,肿瘤疫苗包括来自涉及人癌症的病毒的蛋白质,诸如人乳头状瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西氏疱疹肉瘤病毒(KHSV)。在一些实施方案中,本公开的化合物可与诸如从肿瘤组织本身分离的热休克蛋白的肿瘤特异性抗原组合使用。在一些实施方案中,如本文所述的任何式的化合物、如任何权利要求中阐述和本文所述的化合物或其盐可与树突细胞免疫组合以激活强效的抗肿瘤反应。
本公开的化合物可与双特异性大环肽组合使用,这些双特异性大环肽将表达Feα或Feγ受体的效应细胞靶向到肿瘤细胞。本公开的化合物还可与激活宿主免疫反应的大环肽组合。
本公开的化合物可与骨髓移植组合使用,以用于治疗造血来源引起的各种肿瘤。
如本文所述的任何式的化合物、如任何权利要求中阐述和本文所述的化合物或其盐可与疫苗组合使用,以刺激对病原体、毒素和自身抗原的免疫反应。
当向患者施用多于一种药剂时,这些药剂可同时、单独、顺序或组合施用(例如,对于多于两种药剂)。
调配物、剂型和施用途径
当被用作药物时,本公开的化合物可以药物组合物的形式施用。因此,本公开提供一种组合物,该组合物包括如本文所述的任何式的化合物、如任何权利要求中阐述和本文所述的化合物或其药学上可接受的盐、或其任何实施方案、以及至少一种药学上可接受的载体或赋形剂。这些组合物可以药学领域众所周知的方式制备,并且可通过多种途径施用,这取决于需要局部治疗还是全身治疗以及要治疗的区域。施用可为局部(包括经皮、表皮、眼部和施用到粘膜,包括鼻内、经阴道和直肠传递)、肺(例如通过吸入或吹入粉剂或气雾剂,包括过喷雾器;气管内或鼻内)、经口或肠胃外的。肠胃外施用包括静脉内、动脉内、皮下、腹膜内肌内或注射或输注;或颅内,例如,鞘内或脑室内施用。
肠胃外施用可呈单次团注剂量的形式,也可例如通过连续的灌注泵进行。用于局部施用的药物组合物以及制剂可包括透皮贴剂、软膏、洗剂、乳膏、凝胶剂、滴剂、栓剂、喷雾剂、液体以及粉末。常规的药物载体、水性基质、粉末或油性基质、增稠剂等可为必要的或令人期望的。
本申请还包括含有作为活性成分的本公开的化合物或其药学上可接受的盐与一种或多种药学上可接受的载体或赋形剂的组合的药物组合物。在一些实施方案中,该组合物适用于局部施用。在制备本申请的组合物中,通常将活性成分与赋形剂混合,用赋形剂稀释或封装在这种载剂之内,这种载剂呈例如胶囊、药袋(sachet)、纸或其他容器的形式。当该赋形剂作为稀释剂时,该赋形剂可为固体、半固体或液体材料,该材料可充当活性成分的媒剂、载剂或介质。因此组合物可呈片剂、丸剂、粉剂、锭剂、药袋、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆剂、气溶胶(作为固体或在液体介质中)、含有例如高达10重量%的活性化合物的软膏、软明胶胶囊和硬明胶胶囊剂、栓剂、无菌可注射溶液以及无菌包装粉剂的形式。
在制备调配物中,在与其他成分组合之前,可将活性化合物研磨以便提供适当的粒径。如果活性化合物是基本上不可溶的,可将该活性化合物研磨到小于200目的粒径。如果活性化合物是基本上水可溶的,可通过研磨调整粒径,以便在制剂中提供基本上均匀的分布,例如约40目。
可使用已知的研磨程序(诸如湿磨)研磨本申请的化合物,以便获得适于片剂形成以及适于其他调配物类型的粒度。本申请化合物的细分(纳米颗粒)制剂可通过本领域已知的方法制备,参见例如WO 2002/000196。
合适的赋形剂的一些示例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯树胶、磷酸钙、海藻酸盐、黄芪胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆以及甲基纤维素。另外,制剂还可包括:润滑剂,诸如滑石、硬脂酸镁和矿物油;润湿剂;乳化剂和悬浮剂;防腐剂,诸如羟基苯甲酸甲酯和羟基苯甲酸丙酯;甜味剂;和调味剂。可对本申请的组合物进行调配,以便通过采用本领域中已知的程序施用于患者之后,提供活性成分的快速、持续或延迟释放。
在一些实施方案中,药物组合物包括硅化微晶纤维素(SMCC)和至少一种本文所述的化合物或其药学上可接受的盐。在一些实施方案中,硅化微晶纤维素包括约98%的微晶纤维素和约2%的二氧化硅w/w。
在一些实施方案中,该组合物是包括至少一种本文所述的化合物或其药学上可接受的盐和至少一种药学上可接受的载体或赋形剂的持续释放组合物。在一些实施方案中,该组合物包括至少一种本文所述的化合物或其药学上可接受的盐以及至少一种选自微晶纤维素、乳糖一水合物、羟丙基甲基纤维素和聚环氧乙烷的组分。在一些实施方案中,该组合物包括至少一种本文所述的化合物或其药学上可接受的盐以及微晶纤维素、乳糖一水合物和羟丙基甲基纤维素。在一些实施方案中,该组合物包括至少一种本文所述的化合物或其药学上可接受的盐以及微晶纤维素、乳糖一水合物和聚环氧乙烷。在一些实施方案中,该组合物进一步包括硬脂酸镁或二氧化硅。在一些实施方案中,微晶纤维素是AvicelPH102TM。在一些实施方案中,乳糖一水合物是Fast-flo 316TM。在一些实施方案中,羟丙基甲基纤维素是羟丙基甲基纤维素2208K4M(例如,Methocel K4 M PremierTM)和/或羟丙基甲基纤维素2208K100LV(例如,Methocel K00LVTM)。在一些实施方案中,聚环氧乙烷是聚环氧乙烷WSR 1105(例如,Poly ox WSR 1105TM)。
在一些实施方案中,使用湿法制粒工艺来产生该组合物。在一些实施方案中,使用干法制粒工艺来产生该组合物。
可将该组合物调配成单位剂型,每个剂量含有约5到约1,000mg(1g)的活性成分,更通常为约100mg到约500mg的活性成分。在一些实施方案中,每个剂量含有约10mg的活性成分。在一些实施方案中,每个剂量含有约50mg的活性成分。在一些实施方案中,每个剂量含有约25mg的活性成分。术语“单位剂型”是指适于作为用于人类受试者和其他哺乳动物的单位剂量的物理离散单位,每个单位含有经计算用于产生希望的治疗效果的预定量的活性材料以及适合的药物赋形剂。
用于调配药物组合物的组分具有高纯度并且基本上不含潜在有害污染物(例如,至少是国家食品级,通常至少是分析级,并且更通常至少是药物级)。特别是对于人类消费,该组合物优选地根据美国食品和药物管理局适用法规中定义的优质生产规范标准制造或调配。例如,合适的调配物可为无菌的和/或基本上等渗的和/或完全符合美国食品和药物管理局的所有优质生产规范规定。
活性化合物可在宽的剂量范围内有效,并且通常以治疗有效量施用。然而应当理解,实际施用的化合物的量通常将由医师根据相关情况(包括要治疗的病状、所选择的施用途径、所施用的实际化合物、个体患者的年龄、体重和反应、患者症状的严重性等)来确定。
本申请的化合物的治疗剂量可根据例如进行治疗的具体用途、化合物的施用方式、患者的健康和病状以及开处方医师的判断而变化。本申请的化合物在药物组合物中的比例或浓度可取决于许多因素(包括剂量、化学特征(例如,疏水性)和施用途径)而变化。例如,本申请的化合物可被提供于用于肠胃外施用的水性生理缓冲溶液中,该溶液含有约0.1至约10%w/v的化合物。一些典型的剂量范围是从约1pg/kg体重/天至约1g/kg体重/天。在一些实施方案中,剂量范围是从约0.01mg/kg体重/天到约100mg/kg体重/天。剂量可能取决于诸如疾病或病症的类型和进展程度、具体患者的整体健康状况、所选择的化合物的相对生物功效、赋形剂的配方及其施用途径的变量。可从来源于体外或动物模型测试系统的剂量-反应曲线外推出有效剂量。
对于制备固体组合物(诸如片剂)而言,将主要的活性成分与药物赋形剂混合,以形成含有本申请的化合物的均匀混合物的固体预调配组合物。当称这些预调配组合物均匀时,活性成分通常被均匀分散到该组合物各处,从而可容易地将该组合物再分成同样有效的单位剂型,诸如片剂、丸剂和胶囊剂。然后将此固体预调配物再分成上述类型的单位剂型,该剂型含有例如从约0.1mg至约1000mg的本申请的活性成分。
本申请的片剂或丸剂可被包衣或者以其他方式被混合,以得到提供延长作用优势的剂型。例如,片剂或丸剂可包括内剂量组分和外剂量组分,后者在前者之上采用包膜的形式。两种组分可通过肠溶层分开,该肠溶层用于抵抗胃中的崩解并且允许内组分完整地传递进入十二指肠或被延迟释放。多种材料可用于这种肠溶层或包衣,这种材料包括多种聚合酸以及聚合酸与诸如虫胶、十六醇和乙酸纤维素的这种材料的混合物。
可并入口服施用或注射施用的本申请的化合物和组合物的液体形式包括水溶液、适当调味糖浆、水性或油性悬浮液、以及含食用油(诸如棉籽油、麻油、椰子油或花生油)的调味乳剂以及酏剂和类似的药用媒剂。
用于吸入或吹入的组合物包括药学上可接受的水性或有机溶剂中的溶液和悬浮液或其混合物以及粉剂。液体或固体组合物可含有如上所述的适合的药学上可接受的赋形剂。在一些实施方案中,这些组合物通过口或鼻的呼吸途径施用,用于得到局部或全身性作用。可通过使用惰性气体来雾化组合物。可直接从雾化设备中吸入雾化溶液,或者雾化设备可以附接到面罩塞条或间歇正压呼吸机。可从以适当方式递送调配物的设备通过口服或经鼻施用溶液、悬浮液或粉剂组合物。
局部调配物可含有一种或多种常规载体。在一些实施方案中,软膏剂可含有水和一种或多种疏水载体,这些疏水载体选自例如液体石蜡、聚氧乙烯烷基醚、丙二醇、白凡士林等。乳膏剂的载体组合物可基于水与甘油和一种或多种其他组分(例如单硬脂酸甘油酯、PEG-单硬脂酸甘油酯和十六基硬脂醇)组合。可使用异丙醇和水、适当地与其他组分(诸如像甘油、羟乙基纤维素等)组合来调配凝胶剂。在一些实施方案中,局部调配物含有至少约0.1wt%、至少约0.25wt%、至少约0.5wt%、至少约1wt%、至少约2wt%或至少约5wt%的本申请的化合物。局部调配物可被适当地封装在例如100g的管中,该管任选地带有用于治疗所选择的适应症(例如,银屑病或其他皮肤病状)的说明书。
施用给患者的化合物或组合物的量将取决于施用的药物、施用的目的(诸如预防或治疗)、患者的状态、施用方式等而变化。在治疗性应用中,可按足以治愈或至少部分地抑制疾病的症状及其并发症的量将组合物施用给已经患有该疾病的患者。有效剂量将取决于正在治疗的疾病病状并且通过主治临床医师的判断取决于以下因素,诸如疾病的严重性,患者的年龄、体重和一般病状等。
施用给患者的组合物可处于上述药物组合物的形式。这些组合物可通过常规灭菌技术灭菌,也可为经无菌过滤的。水溶液可被包装以按原样使用,或者被冻干,在施用前将所述冻干制剂与无菌水性载体组合。化合物制剂的pH通常介于3与11之间,更优选地为5到9,并且最优选地为7到8。应当理解,使用某些前述的赋形剂、载体或稳定剂应导致形成药用盐。
本申请的化合物的治疗剂量可根据例如进行治疗的具体用途、化合物的施用方式、患者的健康和病状以及开处方医师的判断而变化。本申请的化合物在药物组合物中的比例或浓度可取决于许多因素(包括剂量、化学特征(例如,疏水性)和施用途径)而变化。例如,本申请的化合物可被提供于用于肠胃外施用的水性生理缓冲溶液中,该溶液含有约0.1至约10%w/v的化合物。一些典型的剂量范围是从约1pg/kg体重/天至约1g/kg体重/天。在一些实施方案中,剂量范围是从约0.01mg/kg体重/天到约100mg/kg体重/天。剂量可能取决于诸如疾病或病症的类型和进展程度、具体患者的整体健康状况、所选择的化合物的相对生物功效、赋形剂的配方及其施用途径的变量。可从来源于体外或动物模型测试系统的剂量-反应曲线外推出有效剂量。
通过以下示例进一步例示本申请,但是这些示例不应被解释为限制性的。贯穿本申请引用的所有参考文献、专利和公开的专利申请的内容以及附图和表通过引用并入本文。
实施例
实施例1
4-甲基苯磺酸(S)-(5-氧代吡咯烷-2-基)甲酯(中间体SM1)的制备
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将(S)-5-(羟甲基)吡咯烷-2-酮(0.100g,0.869mmol,1当量)、TsCl(0.182g,0.954mmol,1.10当量)、TEA(0.132g,1.306mmol,1.5当量)、DMAP(0.006g,0.049mmol,0.05当量)于DCM(2ml)中的溶液在室温下搅拌16h,缓慢添加1N HCl(5ml),用DCM萃取,对有机物进行浓缩以产生SM1(0.170g,73%)。
实施例2
2,2′-(2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷)(中间体SM2)的制备
步骤1和2
向500ml圆底烧瓶中添加3-溴-2-氯苯酚(12.4g,0.060mol,1.0当量)、B2Pin2(16.4g,0.065mol,1.08当量)、KOAc(20.5g,0.210mol,3.5当量)、Pd(dppf)Cl2·DCM(4.1g,5.1mmol,0.085当量),之后添加溶剂二噁烷(300ml),向最终混合物中装入N2,并且在95℃下搅拌3h。然后,将反应混合物冷却到室温并对其进行过滤,将滤饼用二噁烷(100ml)洗涤,滤液将在下一步骤中直接使用。
向先前滤液中添加3-溴-2-氯苯酚(12.0g,0.059mol,0.99当量)、K2CO3(24.8g,0.180mol,3.0当量)和Pd(dppf)Cl2·DCM(2.1g,2.40mmol,0.042当量),之后添加H2O(80ml),向最终混合物中装入N2,并且在85℃下搅拌3.5h。然后,将反应混合物冷却至室温并对其进行过滤,将滤饼用EA(300ml)洗涤。将盐水(300ml)添加到滤液中并进行分离,用EA(100mlx2)萃取水相,在室温下将合并的有机相用活性炭脱色过夜。通过硅藻土垫过滤混合物,将滤饼用EA洗涤,并将合并的有机相在真空下浓缩。通过从DCM/PE=1.5/1中重结晶纯化残余物,以得到呈浅黄色固体的期望产物(10.1g,产率:46%)。
步骤3
在0℃下向SM2-02(10.1g,0.039mol,1.0当量)于DCM(200ml)中的经搅拌的混合物中添加DIPEA(19.4g,0.151mol,3.8当量),在SM2-02溶解后,之后在该温度下添加Tf2O(26.8g,0.095mol,2.4当量),然后允许达到室温并继续搅拌2h。添加水(100ml)以引起反应,然后进行分离,用DCM(100ml)萃取水相。将合并的有机相用盐水(200ml)洗涤,经无水硫酸钠干燥、过滤,将滤液真空中浓缩。通过用EtOH/H2O=1/1重结晶来纯化残余物,以得到呈浅黄色固体的期望产物(18.3g,产率:89%)。
步骤4
在室温下向SM2-03(14.2g,0.027mol,1.0当量)于二噁烷(80ml)中的经搅拌的溶液中添加B2Pin2(27.8g,0.109mol,4.0当量)、KOAc(16g,0.164mol,6.0当量)和Pd(dppf)Cl2DCM(3.3g,4.1mmol,0.15当量),然后装入N2并在85℃下搅拌2h。然后冷却至室温,向混合物中添加EA(150ml)和水(150ml),分离,用EA(100ml)萃取水相。将合并的有机相用盐水(200ml)洗涤,经无水硫酸钠干燥、过滤,将滤液真空中浓缩。用EA(50ml)溶解残余物,然后缓慢地向溶液中添加PE(300ml)以形成黑色悬浮液。在搅拌30min后,过滤,将滤饼用140ml(PE/EA=6/1)洗涤,将滤液在真空下浓缩。用EtOH(150ml)重结晶残余物,以得到呈灰白色固体的期望产物(9.5g,产率:75%)。
实施例3
2,2′-((2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))二乙醛(中间体SM3)的制备
步骤1
在60℃下搅拌7-溴-2H-苯并[b][1,4]噁嗪-3(4H)-酮(5.00g,21.93mmol,1当量)、溴代乙醛缩二甲醇(5.55g,32.89mmol,1.5当量)、Cs2CO3(14.29g,43.86mmol,2.0当量)于DMF(60ml)中的溶液持续16h,添加180mL H2O,通过EA萃取,收集有机层并通过硅胶纯化以产生7-溴-4-(2,2-二甲氧基乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(5.40g,78%)。
步骤2
在80℃下、在N2下搅拌化合物SM2(2.50g,5.26mmol,1当量)、7-溴-4-(2,2-二甲氧基乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮(3.49g,11.04mmol,2.1当量)、K2CO3(2.90g,21.04mmol,4.0当量)、Pd(dppf)Cl2 DCM(0.21g,0.263mmol,0.05当量)于二噁烷(40ml)和H2O(8ml)中的溶液持续2h,添加30mL H2O,通过EA萃取,收集有机层并通过硅胶纯化以产生7,7′-(2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(4-(2,2-二甲氧基乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮)(3.10g,85%)
步骤3
在80℃下搅拌1N HCl(水溶液)/二噁烷(15ml/30ml)的7,7′-(2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(4-(2,2-二甲氧基乙基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮)(3.10g,4.47mmol,1当量)溶液持续1h,添加30mL H2O,通过EA萃取,用NaHCO3洗涤有机层并浓缩至标题化合物SM3(2.91g,粗产物)。
3,3′-((2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))二聚丙烯醛(中间体SM4)的制备
可在与获得SM3相同的程序后使用3-溴-1,1-二甲氧基丙烷作为反应物来制备化合物SM4。
实施例4
7,7′-(2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(2H-苯并[b][1,4]噁嗪-3(4H)-酮)(中间体SM5)的制备
参考以下反应式,将SM2(0.05g,0.11mmol,1当量)、7-溴-2H-苯并[b][1,4]噁嗪-3(4H)-酮(0.062g,0.27mmol,2.5当量)、Pd(dppf)Cl2(0.008g,0.01mmol,0.1当量)和碳酸钾(0.058g,0.42mmol,4当量)溶解于二噁烷/H2O(3ml,v/v=5:1)中。反应在N2气氛下在85℃下进行2h。冷却后,添加10ml水和10ml EA以进行萃取,并且浓缩有机相并通过制备型TLC(DCM/MeOH=10/1洗脱)纯化以产生化合物SM5,即7,7′-(2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(2H-苯并[b][1,4]噁嗪-3(4H)-酮)(13mg,产率:15.6%)。
实施例5(还原胺化的制备)
5A.1-(2-(7-(2,2′-二氯-3′-(4-(2-((S)-3-羟基吡咯烷-1-基)乙基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)-[1,1′-联苯]-3-基)-3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)乙基)吡咯烷-3-羧酸的制备
在室温下向化合物SM3(0.015g,0.024mmol,1当量)、吡咯烷-3-羧酸(0.0035g,0.03mmol,1.3当量)、(S)-吡咯烷-3-醇盐酸盐(0.004g,0.032mmol,1.3当量)和一滴AcOH于CH2Cl2/MeOH(1mL/0.5mL)中的经搅拌的溶液中添加三乙酰氧基硼氢化钠(0.051g,0.24mmol,10当量)。在4h后,直接浓缩,并且添加0.5mL H2O和3mL MeOH,通过反相HPLC(0.1%三氟乙酸于水/乙腈中)纯化混合物,从而提供GLC01-481(6mg,31%)。
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.6Hz,2H),7.46(d,J=7.8Hz,2H),7.41(d,J=7.5Hz,2H),7.36(d,J=8.4Hz,2H),7.19(d,2H),7.14(d,J=2.0Hz,2H),5.53(s,2H),4.75(s,4H),4.49–4.43(m,2H),4.34–4.26(m,4H),3.75–3.67(m,4H),3.24–3.17(m,4H),2.34–2.16(m,4H),1.57–1.35(m,4H)。
LCMS(ESI):针对C41H40Cl2N4O7计算;[M+H]+:771.23,实测值:771.50
5B.可使用不同的胺底物与SM3或SM4制备以下化合物:
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.5Hz,2H),7.45(d,J=7.5Hz,2H),7.41(d,J=7.5Hz,2H),7.36(d,J=8.4Hz,2H),7.18(d,J=8.3Hz,2H),7.14(s,2H),4.75(s,4H),4.29(s,4H),3.66(s,2H)3.35-3.29(m,8H),2.29-2.20(m,8H)。
LCMS(ESI):针对C36H36Cl2N4O6计算;[M+H]+:691.2,实测值:691.2
1H NMR(500MHz,DMSO-d6)δ7.62(s,2H),7.52-7.44(m,5H),7.38(dd,J=17.4Hz,7.9Hz,4H),7.16(d,J=8.4Hz,2H),7.10(s,2H),4.70(s,4H),3.99(td,J=14.8Hz,7.5Hz,4H),3.55(dd,J=12.1Hz,6.0Hz,2H),2.76(s,4H),2.55(d,J=5.7Hz,4H),2.15-1.96(m,8H),1.71-1.61(m,2H)。
LCMS(ESI):针对C42H42Cl2N4O6计算;[M+H]+:797.3,实测值:797.3
1H NMR(500MHz,DMSO-d6)δ7.51(t,J=7.5Hz,2H),7.46(dd,J=7.6,1.8Hz,2H),7.40(d,J=7.3Hz,2H),7.35(d,J=8.4Hz,2H),7.19–7.15(m,2H),7.13(d,J=2.0Hz,2H),4.73(s,4H),4.36(s,2H),4.31–4.14(m,6H),3.72–3.64(m,4H),3.12–2.97(m,4H),2.20–2.08(m,4H)。
LCMS(ESI):针对C42H40Cl2N4O10计算;[M+H]+:831.22,实测值:831.45
1H NMR(500MHz,DMSO-d6)δ7.48(dt,J=13.7,7.5Hz,6H),7.40(d,J=7.4Hz,2H),7.33(d,J=8.3Hz,2H),7.17(d,J=8.5Hz,2H),7.11(s,2H),4.69(s,4H),4.08(s,2H),4.02(s,2H),3.50(s,2H),2.63(s,2H),2.58(d,J=6.6Hz,4H),2.27(s,6H),2.14–1.92(m,8H),1.65–1.57(m,2H)。
LCMS(ESI):针对C44H46Cl2N6O6计算;[M+H]+:825.3,实测值:825.3
1H NMR(500MHz,DMSO-d6)δ8.18(t,J=5.8Hz,2H),7.52(t,J=7.6Hz,2H),7.45(d,J=7.6Hz,2H),7.41(d,J=7.3Hz,2H),7.36(d,J=8.4Hz,2H),7.17(dd,J=8.3,1.9Hz,2H),7.13(s,2H),4.74(s,4H),4.24(t,J=6.7Hz,4H),3.32(q,J=6.2Hz,5H),3.23(d,J=8.0Hz,4H),3.07(t,J=5.9Hz,4H),1.84(s,6H)。
LCMS(ESI):针对C40H42Cl2N4O6计算;[M+H]+:773.26,实测值:773.55
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.5Hz,2H),7.46(dd,J=7.7,1.9Hz,2H),7.41(dd,J=7.4,1.8Hz,2H),7.37(d,J=8.5Hz,2H),7.19(dd,J=8.4,2.0Hz,2H),7.13(d,J=2.0Hz,2H),4.73(s,4H),4.38–4.18(m,4H),4.04(s,2H),3.97–3.77(m,4H),3.22(t,J=7.1Hz,4H),2.53–2.51(m,2H)。
LCMS(ESI):针对C38H36Cl2N4O10计算;[M+H]+:779.19,实测值:779.25
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.5Hz,2H),7.46(d,J=7.6Hz,2H),7.41(d,J=7.5Hz,2H),7.35(d,J=8.4Hz,2H),7.18(d,J=8.5Hz,2H),7.13(s,2H),4.74(s,4H),4.24(t,J=5.8Hz,4H),3.24–3.15(m,8H),2.63(t,J=6.8Hz,4H)。
LCMS(ESI):针对C38H36Cl2N4O8计算;[M+H]+:747.2,实测值:747.2
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.5Hz,2H),7.45(d,J=7.6Hz,2H),7.41(d,J=7.5Hz,2H),7.37(d,J=8.4Hz,2H),7.18(d,J=8.3Hz,2H),7.14(s,2H),4.75(s,4H),4.30(s,4H),3.50-3.30(m,14H),2.20(d,J=63.2Hz,4H)
LCMS(ESI):针对C42H40Cl2N4O8计算;[M+H]+:799.2,实测值:799.2
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.5Hz,2H),7.46(d,J=7.4Hz,2H),7.42–7.38(m,2H),7.36(d,J=8.4Hz,2H),7.18(d,J=8.2Hz,2H),7.13(d,J=1.9Hz,2H),4.74(s,4H),4.34–4.18(m,4H),4.15(s,2H),3.20(d,J=6.9Hz,4H),3.13(d,J=12.2Hz,2H),2.97(t,J=11.0Hz,2H),2.45(d,J=5.4Hz,4H),2.39–2.36(m,4H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.22,实测值:807.25
1H NMR(500MHz,DMSO-d6)δ9.74(s,2H),7.52(t,J=7.6Hz,2H),7.48–7.44(m,2H),7.43–7.38(m,4H),7.19(dd,J=8.4,2.0Hz,2H),7.14(d,J=2.0Hz,2H),5.42(s,2H),4.75(s,4H),4.34(t,J=7.3Hz,4H),3.76(t,J=5.2Hz,4H),3.50-3.40(m,4H),3.33–3.16(m,4H),2.93(s,6H)。
LCMS(ESI):针对C38H40Cl2N4O6计算;[M+H]+:719.23,实测值:719.52
1H NMR(500MHz,DMSO-d6)δ7.51(t,J=7.6Hz,2H),7.46(dd,J=7.6,1.9Hz,2H),7.40(dd,J=7.3,1.9Hz,2H),7.37(d,J=8.5Hz,2H),7.19(dd,J=8.3,2.0Hz,2H),7.13(d,J=2.1Hz,2H),4.72(s,4H),4.25(s,4H),3.75(d,J=11.7Hz,2H),3.60(d,J=11.6Hz,2H),3.11(d,J=8.6Hz,4H),2.65–2.55(m,4H),1.35(s,6H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.22,实测值:807.41
1HNMR(500MHz,DMSO-d6)δ7.52–7.44(m,4H),7.39(d,J=7.3Hz,2H),7.29(d,J=8.3Hz,2H),7.17(d,J=8.3Hz,2H),7.11(s,2H),4.70(s,6H),4.18(s,2H),4.03(t,J=7.0Hz,4H),2.80(dd,J=9.4,6.2Hz,2H),2.67–2.60(m,6H),2.38(dd,J=9.9,3.4Hz,2H),2.03–1.91(m,4H),1.53(dd,J=8.5,4.2Hz,2H)。
LCMS(ESI):针对C40H40Cl2N4O6计算;[M+H]+:743.2,实测值:743.2
1HNMR(500MHz,DMSO-d6)δ7.52–7.44(m,4H),7.39(d,J=7.3Hz,2H),7.29(d,J=8.3Hz,2H),7.17(d,J=8.3Hz,2H),7.11(s,2H),4.70(s,5H),4.24-4.18(m,3H),4.03(t,J=7.0Hz,2H)3.24–3.15(m,4H),2.80(dd,J=9.4,6.2Hz,1H),2.67-2.60(m,5H)。2.38(dd,J=9.9,3.4Hz,1H),2.03–1.91(m,2H),1.53(dd,J=8.5,4.2Hz,1H)。
LCMS(ESI):针对C42H40Cl2N4O10计算;[M+H]+:831.2,实测值:831.2
1H NMR(500MHz,DMSO-d6)δ7.51(t,J=7.5Hz,2H),7.46(dd,J=7.8,1.9Hz,2H),7.40(dd,J=7.5,1.9Hz,2H),7.33(d,J=8.5Hz,2H),7.17(dd,J=8.2,2.0Hz,2H),7.12(d,J=1.9Hz,2H),5.30(s,2H),4.72(s,4H),4.33–4.29(m,2H),4.20–4.12(m,4H),4.07–3.87(m,4H),3.59–3.56(m,2H),3.07–3.02(m,2H),2.88–2.82(m,2H),2.10–2.03(m,4H)。
LCMS(ESI):针对C42H40Cl2N4O10计算;[M+H]+:831.21,实测值:831.50
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.5Hz,2H),7.46(dd,J=7.7,1.9Hz,2H),7.41(dd,J=7.4,1.8Hz,2H),7.37(d,J=8.5Hz,2H),7.19(dd,J=8.4,2.0Hz,2H),7.13(d,J=2.0Hz,2H),4.73(s,4H),4.38–4.18(m,4H),4.04(s,2H),3.97–3.77(m,4H),3.22(t,J=7.1Hz,4H),2.53–2.51(m,2H)。
LCMS(ESI):针对C36H36Cl2N4O6计算;[M+H]+:779.19,实测值:779.25
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.6Hz,2H),7.46(d,J=7.6Hz,2H),7.41(d,J=7.7Hz,4H),7.19(d,J=8.4Hz,2H),7.13(d,J=2.1Hz,2H),4.73(s,4H),4.39(s,2H),4.35-4.25(m,6H),3.55–3.51(m,4H),3.25–3.20(m,4H),2.65–2.60(m,2H),2.07(d,J=13.5Hz,2H)。
LCMS(ESI):针对C42H40Cl2N4O10计算;[M+H]+:831.21,实测值:831.45
1H NMR(500MHz,DMSO-d6)δ12.16(s,2H),8.56(s,4H),7.52(t,J=7.6Hz,2H),7.45(d,J=7.5Hz,2H),7.41(d,J=7.4Hz,2H),7.34(d,J=8.4Hz,2H),7.18(dd,J=8.2,2.0Hz,2H),7.14(d,J=1.9Hz,2H),4.75(s,4H),4.24(t,J=6.5Hz,4H),3.23–3.16(m,4H),3.03–2.97(m,4H),2.27(t,J=7.0Hz,4H),1.62–1.52(m,8H)。
LCMS(ESI):针对C42H44Cl2N4O8计算;[M+H]+:803.25,实测值:803.51
1HNMR(500MHz,DMSO-d6)δ7.52–7.44(m,4H),7.39(d,J=7.3Hz,2H),7.29(d,J=8.3Hz,2H),7.17(d,J=8.3Hz,2H),7.11(s,2H),4.70(s,4H),4.24-4.18(m,3H),4.03(t,J=7.0Hz,2H)3.24–3.15(m,4H),2.80(dd,J=9.4,6.2Hz,1H),2.67-2.60(m,5H)。2.38(dd,J=9.9,3.4Hz,1H),2.03–1.91(m,2H),1.53(dd,J=8.5,4.2Hz,1H)。
LCMS(ESI):针对C39H38Cl2N4O7计算;[M+H]+:745.2,实测值:745.2
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.5Hz,2H),7.45(d,J=7.5Hz,2H),7.41(d,J=7.5Hz,2H),7.36(d,J=8.4Hz,2H),7.18(d,J=8.3Hz,2H),7.14(s,2H),4.75(s,4H),4.29(s,4H),3.65(s,1H),3.40-3.20(m,11H),3.10(s,1H),2.23(s,4H)
LCMS(ESI):针对C39H38Cl2N4O7计算;[M+H]+:745.2,实测值:745.2
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1H NMR(500MHz,DMSO-d6)δ7.50(t,J=7.5Hz,2H),7.47–7.44(m,2H),7.41(t,J=7.9Hz,4H),7.18(dd,J=8.4,2.0Hz,2H),7.12–7.09(m,2H),4.67(s,4H),4.08(t,J=6.4Hz,4H),3.32(t,J=6.0Hz,2H),3.01–2.93(m,4H),2.92–2.81(m,4H),2.74–2.66(m,2H),1.91–1.81(m,4H),1.67–1.48(m,6H)。
LCMS(ESI):针对C44H44Cl2N4O8计算;[M+H]+:827.25,实测值:827.50
1H NMR(500MHz,DMSO-d6)δ7.53-7.48(m,1H),7.46(dd,J=7.6,1.9Hz,1H),7.40(dd,J=7.4,1.9Hz,1H),7.35(d,J=8.4Hz,1H),7.16(dd,J=8.3,2.0Hz,1H),7.10(d,J=2.1Hz,1H),4.70(s,2H),4.29(dd,J=9.2,5.4Hz,1H),4.02(dd,J=9.3,2.9Hz,1H),3.98(t,J=7.2Hz,2H),3.57(s,1H),2.82-2.66(m,4H),2.24(dd,J=17.2,3.3Hz,1H)。
LCMS(ESI):针对C40H36Cl2N4O8计算;[M+H]+:771.20,实测值:771.48.
1H NMR(500MHz,DMSO-d6)δ7.51-7.43(m,2H),7.38(dd,J=7.8,1.9Hz,1H),7.31(d,J=8.3Hz,1H),7.15(d,J=8.3Hz,1H),7.11(d,J=2.1Hz,1H),4.82(s,1H),4.70(s,2H),4.01-3.94(m,2H),3.59-3.44(s,3H),2.83-2.64(m,4H),2.25-2.20(m,1H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.22,实测值:807.45.
1H NMR(500MHz,DMSO-d6)δ7.52-7.46(m,1H),7.45(d,J=7.6Hz,1H),7.40(dd,J=7.4,2.1Hz,1H),7.35(d,J=8.2Hz,1H),7.16(dd,J=8.2,2.0Hz,1H),7.10(d,J=2.1Hz,1H),4.69(s,2H),3.98(t,J=7.2Hz,2H),3.41-3.33(m,1H),2.78-2.66(m,2H),1.29(d,J=6.6Hz,3H)。
LCMS(ESI):针对C38H36Cl2N4O8计算;[M+H]+:747.20,实测值:747.41.
1H NMR(500MHz,DMSO-d6)δ7.50(t,J=7.5Hz,2H),7.48-7.43(m,2H),7.39(dd,J=7.4,1.7Hz,2H),7.35(d,J=8.5Hz,2H),7.17-7.13(m,2H),7.11-7.07(m,2H),4.81(t,J=5.6Hz,2H),4.69(s,4H),4.07(q,J=7.1Hz,4H),4.02-3.91(m,4H),3.59-3.49(m 4H),3.32-3.28(m,2H),2.88-2.78(m,2H),2.72–2.65(m,2H),1.16(t,J=7.1,1.0Hz,6H)。
LCMS(ESI):针对C42H44Cl2N4O10计算;[M+H]+:835.24,实测值:835.51.
1H NMR(500MHz,DMSO-d6)δ9.36(s,3H),7.52(t,J=7.5Hz,2H),7.46(d,J=6.9Hz,2H),7.41(d,J=7.5Hz,2H),7.36(d,J=8.4Hz,2H),7.19(d,J=8.4Hz,2H),7.13(d,J=1.9Hz,2H),5.75(s,2H),4.73(s,4H),4.40–4.21(m,6H),3.95–3.87(m,4H),3.78(s,6H),3.30–3.22(m,4H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.49.
1H NMR(400MHz,DMSO-d6)δ7.51-7.45(m,4H),7.40-7.37(m,4H),7.15(d,J=8.0Hz,2H),7.10(s,2H),4.70(s,4H),4.16(m,2H),4.08(m,2H),3.85(m,2H),3.08(d,J=4Hz,2H),3.04(m,2H),2.87(m,2H),1.13(d,J=8.0Hz,6H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.21.
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1H NMR(400MHz,DMSO-d6)δ7.53-7.43(m,4H),7.41-7.36(m,4H),7.20(d,J=8.0Hz,2H),7.12(s,2H),4.71(s,4H),4.15(m,2H),4.09(m,2H),3.87(m,2H),3.10(d,J=4Hz,2H),3.05(m,2H),2.90(m,2H),1.14(d,J=8.0Hz,6H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.21.
1H NMR(400MHz,DMSO-d6)δ7.52-7.35(m,10H),7.16(d,J=8.0Hz,2H),7.11(s,2H),7.02-6.82(m,2H),4.74(s,4H),4.10(m,4H),3.51(m,4H),2.99(t,J=6Hz,4H),2.87(m,2H),1.78(m,2H),1.67(m,2H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.21.
1HNMR(500MHz,DMSO-d6)δ7.53(t,J=7.5Hz,2H),7.48(d,J=6.9Hz,2H),7.43(d,J=7.5Hz,2H),7.38(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),7.15(d,J=1.9Hz,2H),4.73(s,4H),4.69(s,2H),3.92(dd,J=6.0,2.7Hz,4H),3.72–3.65(m,4H),3.31–3.29(m,2H),3.08–2.87(m,4H)。
LCMS(ESI):针对C38H36Cl2N4O10计算;[M+H]+:779.18,实测值:779.40.
1H NMR(400MHz,DMSO-d6)δ7.52-7.35(m,10H),7.16(d,J=8.0Hz,2H),7.11(s,2H),7.02-6.82(m,2H),4.74(s,4H),4.11(m,4H),3.49(m,4H),3.02(t,J=6Hz,4H),2.90(m,2H),1.81(m,2H),1.69(m,2H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.21.
1H NMR(500MHz,DMSO-d6)δ8.20(s,1H),7.50(t,J=7.5Hz,2H),7.45(dd,J=7.8,1.8Hz,2H),7.39(dd,J=7.5,1.8Hz,2H),7.35(d,J=8.4Hz,2H),7.15(dd,J=8.3,2.0Hz,2H),7.09(d,J=2.0Hz,2H),4.92–4.87(m,2H),4.69(s,4H),4.03–3.95(m,4H),3.55–3.51(m,6H),3.29–3.27(m,2H),2.85–2.80(m,2H),2.71–2.64(m,2H),1.16(t,J=6.6Hz,12H)。
LCMS(ESI):针对C44H48Cl2N4O10计算;[M+H]+:863.27,实测值:863.77
1HNMR(500MHz,DMSO-d6)δ7.7(s,2H),7.52-7.21(m,10H),4.73(s,4H),4.40-4.20(m,4H),3.94-3.90(m,2H),3.50-3.20(m,4H),2.82(d,J=4.8Hz,4H),2.87(m,2H)。
LCMS(ESI):针对C40H38Cl2N6O10计算;[M+H]+:833.20,实测值:833.20.
1H NMR(500MHz,DMSO-d6)δ7.5(t,J=7.5Hz,2H),7.45(dd,J=7.7,1.8Hz,4H),7.42-7.36(m,4H),7.15(dd,J=8.3,2.0Hz,2H),4.70(s,4H),4.14(hept,J=7.2,6.7Hz,4H),3.61(dd,J=9.6,4.1Hz,2H),3.54(dd,J=9.5,6.2Hz,2H),3.33(t,J=5.1Hz,2H),3.33(p,J=6.0Hz,4H),1.10(s,18H)。
LCMS(ESI):针对C46H52Cl2N4O10计算;[M+H]+:891.31,实测值:891.31.
1H NMR(500MHz,DMSO-d6)δ13.07(s,2H),7.52-7.38(m,10H),7.10(s,2H),4.87(s,4H),4.4-4.3(m,2H),4.22-4.15(m,4H),4.01-3.95(m,4H),3.87-3.79(m,4H),3.11-3.04(m,4H)。
LCMS(ESI):针对C42H36Cl2N4O10计算;[M+H]+:827.18,实测值:827.18.
1H NMR(500MHz,DMSO-d6)δ7.51(t,J=7.5Hz,2H),7.46(dd,J=7.7,1.9Hz,2H),7.42-7.35(m,4H),7.17(dd,J=8.3,1.9Hz,2H),7.11(d,J=2.0Hz,2H),4.71(s,4H),4.18(q,J=11.6,9.3Hz,4H),3.66(m,4H),3.26(s,6H),3.07(m,4H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.21.
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.6Hz,2H),7.46(dd,J=7.8,1.8Hz,2H),7.40(dd,J=7.4,1.9Hz,2H),7.35(d,J=8.4Hz,2H),7.18(dd,J=8.1,2.0Hz,2H),7.13(d,J=2.0Hz,2H),4.73(s,4H),4.01(t,J=7.0Hz,4H),3.81(s,4H),3.04–3.00(m,4H),1.97(t,J=8.1Hz,4H)。
LCMS(ESI):针对C38H36Cl2N4O8计算;[M+H]+:747.19,实测值:747.46
1H NMR(500MHz,DMSO-d6)δ7.51(t,J=7.6Hz,2H),7.45(dd,J=7.7,1.8Hz,2H),7.40(dd,J=7.4,1.8Hz,2H),7.35(d,J=8.4Hz,2H),7.18(dd,J=8.3,2.0Hz,2H),7.13(d,J=1.9Hz,2H),4.74(s,4H),4.01(t,J=7.1Hz,4H),3.12(t,J=7.0Hz,4H),3.03(t,J=7.8Hz,4H),2.61(d,J=7.0Hz,4H),1.98–1.90(m,4H)。
LCMS(ESI):针对C40H40Cl2N4O8计算;[M+H]+:775.22,实测值:775.50
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.6Hz,2H),7.46(dd,J=7.8,1.8Hz,2H),7.40(dd,J=7.4,1.9Hz,2H),7.35(d,J=8.4Hz,2H),7.18(dd,J=8.1,2.0Hz,2H),7.13(d,J=2.0Hz,2H),4.73(s,4H),4.13(t,J=7.5Hz,4H),4.01(t,J=7.0Hz,4H),3.31–3.29(m,2H),3.04–3.00(m,4H),1.97(t,J=8.1Hz,4H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.50
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.6Hz,2H),7.46(dd,J=7.8,1.8Hz,2H),7.40(dd,J=7.4,1.9Hz,2H),7.35(d,J=8.4Hz,2H),7.18(dd,J=8.1,2.0Hz,2H),7.13(d,J=2.0Hz,2H),5.47(s,2H),4.73(s,4H),4.39–4.34(m,2H),4.28–4.19(m,4H),4.01(t,J=7.0Hz,4H),3.71–3.67(m,2H),3.24–3.20(m,2H),2.68–2.56(m,2H),2.46–2.34(m,2H),2.20–2.11(m,4H)
LCMS(ESI):针对C44H44Cl2N4O10计算;[M+H]+:859.24,实测值:859.50
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.6Hz,2H),7.46(dd,J=7.8,1.8Hz,2H),7.40(dd,J=7.4,1.9Hz,2H),7.35(d,J=8.4Hz,2H),7.18(dd,J=8.1,2.0Hz,2H),7.13(d,J=2.0Hz,2H),4.73(s,4H),4.13(t,J=7.5Hz,4H),4.07(q,J=7.1Hz,4H),4.01(t,J=7.0Hz,4H),3.31–3.29(m,2H),3.04–3.00(m,4H),1.97(t,J=8.1Hz,4H),1.19-1.14(t,J=7.1Hz,6H)。
LCMS(ESI):针对C44H48Cl2N4O10计算;[M+H]+:863.27,实测值:863.50.
实施例6
(2S,2′S)-2,2′-(((2R,2′R)-((2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))双(丙烷-1,2-二基))双(丙酰基))双(3-羟基丙酸)的制备
中间体2的合成
在室温下搅拌化合物SM4(0.515g,2.258mmol,1当量)、1-溴丙烷-2-酮(0.340g,2.48mmol,1.10当量)、Cs2CO3(0.960g,2.93mmol,1.30当量)于DMF(5ml)中的溶液持续1h,缓慢添加15mL H2O,收集固体并进行干燥以产生标题化合物2(0.400g,62%)。
中间体4的合成
在室温下向化合物SM2(0.300g,1.056mmol,1当量)、化合物3(0.315g,2.024mmol,1.90当量)、DIEA(0.274g,2.124mmol,2.01当量)、4A和2滴AcOH于DCM(6ml)中添加NaBH(OAc)3(1.00g,4.73mmol,4当量)。在3-4h后,添加10mL H2O,通过DCM萃取,收集有机层并通过硅胶纯化以产生标题化合物4(0.07g,17%)。
中间体6的合成
在N2下,在80℃下搅拌化合物SM2(0.043g,0.09mmol,1当量)、化合物4(0.07g,0.18mmol,2.0当量)、K2CO3(0.05g,0.36mmol,4.0当量)、Pd(dppf)Cl2 DCM(0.008g,0.009mmol,0.1当量)于二噁烷(3ml)和H2O(0.5ml)中的溶液持续2h,添加5mL H2O,通过EA萃取,收集有机层并通过Pre-TLC纯化以产生标题化合物6(0.05g,66%)。
GLC01-563的合成
在室温下向化合物6(0.025g,0.030mmol,1当量)于MeOH(2mL)中的经搅拌的溶液中添加NaOH(0.020g,0.50mmol,16.6当量)于H2O(0.5mL)中的溶液。在1h后,通过反相HPLC(0.1%三氟乙酸于水/乙腈中)纯化混合物,从而提供GLC01-563(12mg,50%)。
1H NMR(500MHz,DMSO-d6)δ7.49(d,J=7.4Hz,2H),7.46(d,J=7.4Hz,2H),7.40(t,J=8.0Hz,4H),7.14(d,J=8.5Hz,2H),7.11(d,2H),4.71(s,4H),4.12–4.07(m,2H),4.00–3.96(m,2H),3.63–3.57(m,6H),3.24–3.22(m,2H),1.08(d,J=6.4Hz,6H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.43
使用程序制备GLC01-550
1H NMR(500MHz,DMSO-d6)δ7.49(d,J=7.4Hz,2H),7.46(d,J=7.4Hz,2H),7.40(t,J=8.0Hz,4H),7.14(d,J=8.5Hz,2H),7.11(d,2H),4.71(s,4H),4.12–4.07(m,2H),4.00–3.96(m,2H),3.63–3.57(m,6H),3.24–3.22(m,2H),1.08(d,J=6.4Hz,6H)。
LCMS(ESI):针对C40H40Cl2N4O10计算;[M+H]+:807.21,实测值:807.43
实施例7
7A.2,2′-((((2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(6-氟-3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))双(乙烷-2,1-二基))双(氮杂二基))(2S,2′S)-双(3-羟基丙酸)二乙酯和(2S,2′S)-2,2′-((((2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(6-氟-3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))双(乙烷-2,1-二基))双(氮杂二基))双(3-羟基丙酸)的制备
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中间体2的合成
在50℃下搅拌化合物1(0.100g,0.598mmol,1.00当量)、NBS(0.115g,0.646mmol,1.08当量)、一滴AcOH于CH3CN(1.5ml)中的溶液持续16h,缓慢添加H2O(5ml),用EA萃取,对有机物进行浓缩以产生标题化合物2(0.100g,68%)。
中间体3的合成
在60℃下搅拌化合物2(1.50g,6.09mmol,1.00当量)、2-溴-1,1-二甲氧基乙烷(2.00g,11.83mmol,1.94当量)、Cs2CO3(5.00g,15.33mmol,2.51当量)于DMF(15ml)中的溶液持续16h,缓慢添加45mL H2O,收集固体在真空中干燥以产生化合物3(0.65g,32%)。
中间体5的合成
在N2下,在80℃下搅拌化合物SM2(0.280g,0.589mmol,1.00当量)、化合物3(0.400g,1.197mmol,2.03当量)、K2CO3(0.350g,2.536mmol,4.3当量)、Pd(dppf)Cl2 DCM(0.030g,0.036mmol,0.06当量)于二噁烷(3ml)和H2O(0.5ml)中的溶液持续2h,添加5mLH2O,通过EA萃取,对有机层进行浓缩并通过过硅胶(PE:EA=3:1-1:1)纯化以产生标题化合物5(0.330g,77%)。
中间体6的合成
在80℃下搅拌化合物5(0.340g,0.466mmol,1当量)于二噁烷/1N HCl(4ml/2ml)中的溶液持续0.5h,添加10mL H2O,通过EA萃取,对有机层进行浓缩以产生化合物6(0.330g,粗产物)。
GLC01-589的合成
在室温下向化合物6(0.330g,0.520mmol,1.0当量)、化合物7(0.440g,2.59mmol,5.0当量)、DIEA(0.351g,2.72mmol,5.2当量)、4A和AcOH(0.155g,2.59mmol,5.0当量)于DCM(7ml)中添加NaBH(OAc)3(0.500g,2.37mmol,4.5当量)。在3-4h后,添加10mL H2O,通过DCM萃取,收集有机层并通过硅胶(DCM:MeOH=50:1-20:1)纯化以产生GLC01-589(0.200g,44%)。
1H NMR(500MHz,DMSO-d6)δ7.53(t,J=7.6Hz,2H),7.49-7.43(m,4H),7.37(d,J=11.2Hz,2H),7.04(d,J=6.8Hz,2H),4.81(t,J=5.6Hz,2H),4.68(s,4H),4.07(q,J=7.1Hz,4H),4.00-3.90(m,4H),3.60–3.49(m,4H),3.37-3.33(m,2H),2.87-2.77(m,2H),2.68–2.62(m,2H),1.19-1.14(t,J=7.1Hz,6H)。
LCMS(ESI):针对C42H42Cl2F2N4O10计算;[M+H]+:871.22,实测值:871.50
GLC01-554的合成
在室温下向MeOH(0.2ml)的GLC01-589(0.015g,0.017mmol,1当量)溶液中添加NaOH(0.020g,0.5mmol,29当量)于H2O(0.1ml)中的溶液。在1h后,通过反相HPLC(0.1%三氟乙酸于水/乙腈中)纯化混合物,从而提供GLC01-554(7.7mg,55%)。
1HNMR(500MHz,DMSO-d6)δ7.53(t,J=7.6Hz,2H),7.48–7.39(m,6H),7.06(d,J=6.9Hz,2H),4.70(s,4H),4.13(t,J=7.5Hz,4H),3.72–3.65(m,4H),3.31–3.29(m,2H),3.07–3.03(m,2H),3.02–2.97(m,2H)。
LCMS(ESI):针对C38H34Cl2F2N4O10计算;[M+H]+:815.16,实测值:815.33
7B.可使用不同的起始材料制备以下化合物
1HNMR(400MHz,DMSO-d6)δ7.54(m,2H),7.49(d,J=4Hz,2H),7.43(d,J=4.0Hz,2H),7.20(d,J=8Hz,2H),7.06(s,2H),4.72(s,4H),4.26(m,4H),4.14(s,2H),3.90(m,4H),3.34(m,4H)。
LCMS(ESI):针对C38H34F2Cl2N4O10计算;[M+H]+:815.16,实测值:815.16.
1HNMR(400MHz,DMSO-d6)δ7.54(m,2H),7.49(d,J=4Hz,2H),7.43(d,J=4.0Hz,2H),7.30(d,J=8Hz,2H),7.06(s,2H),4.72(s,4H),4.26(m,4H),4.14(s,2H),3.90(m,4H),3.34(m,4H)。
LCMS(ESI):针对C38H34F2Cl2N4O10计算;[M+H]+:815.16,实测值:815.16.
1H NMR(500MHz,DMSO-d6)δ7.31(dd,J=8.1,5.3Hz,4H),7.21(d,J=7.7Hz,2H),7.14(d,J=7.5Hz,2H),7.06(dd,J=8.3,1.7Hz,2H),7.01(d,J=2.0Hz,2H),4.82(s,2H),4.68(s,4H),4.07(q,J=7.1Hz,4H),4.03-3.90(m,4H),3.56(hept,J=5.1Hz,4H),2.85(dd,J=12.36.8Hz,2H),2.69(dq,J=13.3,7.1,6.3Hz,2H),1.94(s,6H),1.16(t,J=7.0Hz,6H),
LCMS(ESI):针对C44H50N4O10计算;[M+H]+:795.35,实测值:795.35.
1H NMR(500MHz,DMSO-d6)δ9.16(s,3H),7.42-7.28(m,4H),7.22(d,J=7.7Hz,2H),7.15(d,J=7.5Hz,2H),7.10(dd,J=8.2,1.9Hz,2H),7.05(d,J=2.0Hz,2H),5.71(s,1H),4.72(s,4H),4.29(hept,J=7.5,7.0Hz,4H),4.18(d,J=3.4Hz,2H),3.91(d,J=3.4Hz,4H),3.25(t,J=7.7Hz,4H),1.95(s,6H),
LCMS(ESI):针对C40H42N4O10计算;[M+H]+:739.29,实测值:739.50.
1H NMR(500MHz,DMSO-d6)δ7.33(dd,J=8.3,5.4Hz,4H),7.22(d,J=7.6Hz,2H),7.15(d,J=7.5Hz,2H),7.08(dd,J=8.2,1.8Hz,2H),7.05(d,J=2.0Hz,2H),5.47(s,2H),4.72(s,4H),4.39–4.34(m,2H),4.28–4.19(m,4H),3.71–3.67(m,2H),3.24–3.20(m,2H),3.08–3.02(m,2H),2.68–2.56(m,2H),2.46–2.34(m,2H),2.20–2.11(m,4H),1.95(s,6H)。
LCMS(ESI):针对C44H46N4O10计算;[M+H]+:791.32,实测值:791.58
实施例8
8A.2,2′-((((2,2′-二氟-[1,1′-联苯]-3,3′-二基)双(3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))双(乙烷-2,1-二基))双(氮杂二基))(2S,2′S)-双(3-羟基丙酸)二乙酯和(2S,2′S)-2,2′-((((2,2′-二氟-[1,1′-联苯]-3,3′-二基)双(3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))双(乙烷-2,1-二基))双(氮杂二基))双(3-羟基丙酸)的制备
中间体GLC01-612-04的合成
在氮气的气氛下、在室温下向GLC01-612-03(100mg,0.206mmol,1.0当量)和SM(164mg,0.453mmol,2.2当量)于4ml 1,4-二噁烷和0.8ml水中的经搅拌溶液中添加K2CO3(114mg,0.826mmol,4.0当量)和Pd(dppf)Cl2 DCM(33mg,0.04mmol,0.2当量)。然后,将所得混合物在85℃下加热2h。添加水(15ml)以稀释反应混合物,用EA(3x15ml)进行萃取。将合并的有机相用15ml饱和盐水洗涤,经无水硫酸钠干燥、过滤,将滤液在真空下浓缩。通过制备型TLC(PE/EA=2/1)纯化残余物,以得到呈浅黄色固体的期望产物(70mg,产率:52%)。
GLC01-612的合成
在室温下向GLC01-612-04(50mg)于ACN(3ml)和水(3ml)中的经搅拌的混合物中添加TFA(0.3ml)。在80℃下搅拌1h后,利用K2CO3水溶液调节所得溶液的pH=8-9,用EA萃取,用盐水洗涤,在减压下浓缩有机相,在下一步骤中直接使用残余物(43mg,产率:100%)。在上文程序后进行还原胺化步骤。
1H NMR(500MHz,DMSO)δ7.53–7.31(m,8H),7.12(dd,J=31.2,8.5Hz,4H),4.81(t,J=5.5Hz,2H),4.68(s,4H),4.10–4.03(m,4H),3.98(ddd,J=21.0,14.1,7.1Hz,4H),3.54(ddt,J=16.0,10.5,5.2Hz,4H),2.83(dt,J=14.1,7.1Hz,2H),2.69–2.63(m,2H),1.22–1.12(m,6H)。
LCMS(ESI):针对C42H44F2N4O10计算;[M+H]+:803.3,实测值:803.3
GLC01-613的合成
在上文程序后进行水解反应。
1H NMR(500MHz,DMSO)δ7.52(t,J=7.5Hz,2H),7.46(dd,J=7.6,1.8Hz,2H),7.43–7.34(m,4H),7.19(dd,J=8.4,1.9Hz,2H),7.13(d,J=1.9Hz,2H),4.73(s,4H),4.31-4.20(m,4H),4.10-4.01(m,2H),3.90-3.81(m,4H),3.25-3.19(m,4H)。
LCMS(ESI):针对C38H36F2N4O10计算;[M+H]+:747.3,实测值:747.3
实施例9(同侧不同核心的制备)
9A.6,6′-(2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(1-(((S)-5-氧代吡咯烷-2-基)甲基)-3,4-二氢喹啉-2(1H)-酮)的制备
使用与SM5相同的程序制备底物A
在40℃下搅拌化合物A(100mg,1当量)、Cs2CO3(253mg,4.0当量)、SM1(157mg,3.0当量)于DMF中的混合物持续2h。将反应混合物用水稀释并用EA萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在减压下浓缩。通过柱(DCM/MeOH=20/1)纯化残余物以产生标题化合物281(98mg,产率:71%)。1HNMR(500MHz,Chloroform-d)δ7.46-7.37(m,3H),7.36(d,J=2.1Hz,1H),7.33(dd,J=7.4,2.0Hz,1H),7.08(d,J=8.5Hz,1H),5.89(s,1H),4.20-3.98(m,3H),2.99(t,J=7.5Hz,2H),2.83-2.66(m,2H),2.40-2.30(m,2H),2.10-1.85(m,2H)。
LCMS(ESI):针对C40H36Cl2N4O4计算;[M+H]+:707.22,实测值:707.43.
9B.可使用不同的溴化物底物制备以下化合物:
1HNMR(500MHz,DMSO-d6)δ7.93(s,2H),7.80(d,J=8.8Hz,2H),7.75(dd,J=8.7,2.1Hz,2H),7.71(s,2H),7.60–7.54(m,4H),7.51–7.47(m,2H),3.91–3.82(m,2H),3.61–3.53(m,4H),3.41–3.33(m,4H),2.85–2.76(m,4H),2.39–2.26(m,4H),2.25–2.06(m,6H),1.92–1.84(m,2H)
LCMS(ESI):针对C40H40Cl2N4O2计算;[M+H]+:679.25,实测值:679.45
1H NMR(500MHz,DMSO-d6)δ7.78(s,2H),7.50(t,J=7.5Hz,2H),7.45(dd,J=7.7,1.7Hz,2H),7.40(d,J=7.4Hz,2H),7.34(d,J=8.4Hz,2H),7.14(d,J=8.3Hz,2H),7.10(d,J=2.0Hz,2H),4.71(s,4H),4.06–3.89(m,6H),2.34–2.24(m,2H),2.20–2.07(m,4H),1.84–1.72(m,2H)。
LCMS(ESI):针对C38H32Cl2N4O6计算;[M+H]+:711.17,实测值:711.47
1H NMR(500MHz,DMSO-d6)δ7.78(s,2H),7.50(t,J=7.5Hz,2H),7.45(dd,J=7.8,1.8Hz,2H),7.40(d,J=7.5Hz,2H),7.34(d,J=8.4Hz,2H),7.14(dd,J=8.6,1.8Hz,2H),7.10(d,J=2.1Hz,2H),4.71(s,4H),4.07–3.88(m,6H),2.35–2.24(m,2H),2.21–2.04(m,4H),1.84–1.73(m,2H)。
LCMS(ESI):针对C38H32Cl2N4O6计算;[M+H]+:711.17,实测值:711.50
1H NMR(500MHz,DMSO-d6)δ7.78(s,2H),7.50(t,J=7.5Hz,2H),7.45(dd,J=7.8,1.8Hz,2H),7.40(d,J=7.5Hz,2H),7.34(s,2H),7.10(s,2H),4.71(s,4H),4.07–3.88(m,6H),2.35–2.24(m,2H),2.21–2.04(m,4H),1.84–1.73(m,2H)。
LCMS(ESI):针对C38H34Cl2N6O6计算;[M+H]+:741.19,实测值:741.50
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1H NMR(500MHz,DMSO-d6)δ8.29(s,1H),7.93(t,J=1.7Hz,1H),7.80(d,J=8.9Hz,1H),7.75(dd,J=8.7,2.1Hz,1H),7.70(s,1H),7.57(d,J=3.9Hz,2H),7.49(dd,J=5.6,3.8Hz,1H),4.44-4.37(m,1H),4.27-4.20(m,1H),4.11-4.03(m,1H),2.42-2.30(m,1H),2.24-2.16(m,1H),2.03-1.95(m,1H),1.891-1.84(m,1H)。
LCMS(ESI):针对C38H30Cl2N6O4计算;[M+H]+:705.18,实测值:705.52.
1HNMR(500MHz,DMSO-d6)δ8.29(s,2H),7.93(s,2H),7.80(d,J=8.8Hz,2H),7.75(dd,J=8.7,2.1Hz,2H),7.71(s,2H),7.60–7.54(m,4H),7.51–7.47(m,2H),4.41(dd,J=14.0,8.6Hz,2H),4.23(dd,J=13.8,5.3Hz,2H),4.09–4.02(m,2H),2.60–2.54(m,2H),2.41–2.32(m,3H),2.25–2.06(m,5H),1.92–1.84(m,2H)。
LCMS(ESI):针对C38H34Cl2N6O4计算;[M+H]+:709.20,实测值:709.44
1H NMR(500MHz,DMSO-d6)δ8.13(s,2H),7.86(s,2H),7.58–7.53(m,6H),7.46(dd,J=5.9,3.6Hz,2H),4.21–4.15(m,2H),4.05(dd,J=13.2,6.6Hz,2H),4.01–3.96(m,2H),2.20(q,J=10.8Hz,4H),2.08(dd,J=11.3,3.9Hz,4H),1.53(s,6H),1.48(s,6H)。
LCMS(ESI):针对C42H40Cl2N4O6计算;[M+H]+:767.24,实测值:767.50
1H NMR(500MHz,DMSO-d6)δ7.79-7.71(m,2H),7.55-7.49(m,2H),7.48-7.41(m,4H),7.38(td,J=7.2,1.7Hz,2H),7.06(d,J=2.6Hz,1H),7.01(d,J=1.9Hz,1H),4.73(s,4H),4.04-3.88(m,6H),2.33-1.94(m,6H),1.78(d,J=13.0Hz,2H)。
LCMS(ESI):针对C38H30Cl4N4O6计算;[M+H]+:779.10,实测值:779.41.
1H NMR(400MHz,DMSO-d6)δ7.94(s,2H),7.62(d,J=8Hz,2H),7.56-7.49(m,6H),7.45(s,2H),4.22(m,2H),4.06(dd,J=4Hz,2H),3.95(m,2H),2.32(m,2H),2.20(m,2H),2.10(m,2H)1.80(m,2H)。
LCMS(ESI):针对C36H26F4Cl2N6O6计算;[M+H]+:785.12,实测值:785.12.
1H NMR(500MHz,DMSO-d6)δ8.13(s,2H),7.86(s,2H),7.58–7.53(m,6H),7.46(dd,J=5.9,3.6Hz,2H),4.21–4.15(m,2H),4.05(dd,J=13.2,6.6Hz,2H),4.01–3.96(m,2H),2.20(q,J=10.8Hz,4H),2.08(dd,J=11.3,3.9Hz,4H),1.53(s,6H),1.48(s,6H)。
LCMS(ESI):针对C40H38Cl2N6O6计算;[M+H]+:769.23,实测值:769.50.
1HNMR(500MHz,DMSO-d6)δ7.76(s,2H),7.53(t,J=7.4Hz,3H),7.48–7.42(m,4H),7.31(t,J=10.8Hz,2H),7.05(d,J=6.9Hz,2H),4.70(s,4H),4.05–3.87(m,6H),2.33–2.23(m,2H),2.20–2.04(m,4H),1.77(dd,J=13.6,7.7Hz,2H)。
LCMS(ESI):针对C38H30Cl2F2N4O6计算;[M+H]+:747.15,实测值:747.10
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1H NMR(500MHz,DMSO-d6)δ7.79(d,J=2.9Hz,2H),7.54(t,J=7.5Hz,2H),7.46(d,J=7.1Hz,4H),7.19(d,J=8.6Hz,2H),7.04(t,J=7.8Hz,2H),4.81(d,J=14.7Hz,4H),4.08–4.01(m,2H),3.93(d,J=12.0Hz,4H),2.34–2.23(m,2H),2.21–2.04(m,4H),1.77(dd,J=13.2,8.2Hz,2H)。
LCMS(ESI):针对C38H30Cl2F2N4O6计算;[M+H]+:747.15,实测值:747.11
1H NMR(500MHz,DMSO-d6)δ7.88(s,2H),7.51(dt,J=14.3,7.2Hz,4H),7.42(d,J=7.0Hz,2H),7.15(d,J=14.0Hz,2H),7.04(s,2H),4.74–4.67(m,4H),4.10(dd,J=14.3,7.5Hz,2H),3.98–3.85(m,4H),2.19(t,J=9.6Hz,2H),2.15–2.06(m,4H),1.70(dd,J=16.5,7.0Hz,2H)。
LCMS(ESI):针对C38H30Cl2F2N4O6计算;[M+H]+:747.15,实测值:747.15
1H NMR(400MHz,DMSO-d6)δ8.61(s,2H),7.92(s,2H),7.81(s,2H),7.62-7.75(m,6H),4.78(s,4H),4.22(m,2H),4.06(dd,J=4Hz,2H),3.95(m,2H),2.32(m,2H),2.20(m,2H),2.10(m,2H)1.80(m,2H)。
LCMS(ESI):针对C36H30Cl2N6O6计算;[M+H]+:713.16,实测值:713.16.
1H NMR(500MHz,DMSO-d6)δ7.93(s,2H),7.80(d,J=8.8Hz,2H),7.75(dd,J=8.7,2.1Hz,2H),7.71(s,2H),7.60–7.54(m,4H),7.51–7.47(m,2H),4.41(dd,J=14.0,8.6Hz,2H),4.23(dd,J=13.8,5.3Hz,2H),4.09–4.02(m,2H),3.50(s,6H),2.60–2.54(m,2H),2.41–2.32(m,3H),2.25–2.06(m,5H),1.92–1.84(m,2H)。
LCMS(ESI):针对C40H38Cl2N6O4计算;[M+H]+:737.23,实测值:737.52
1H NMR(500MHz,DMSO-d6)δ7.81(s,2H),7.52(t,J=7.5Hz,2H),7.46(dd,J=7.6,1.7Hz,2H),7.42(dd,J=7.4,1.9Hz,2H),7.31(d,J=8.5Hz,2H),7.25–7.20(m,2H),7.19(d,J=2.1Hz,2H),5.53(s,4H),3.99–3.88(m,2H),3.78(d,J=5.6Hz,4H),2.32–2.24(m,2H),2.23–2.09(m,4H),1.90–1.80(m,2H)。
LCMS(ESI):针对C36H32Cl2N4O8S2计算;[M+H]+:783.10,实测值:783.42
1H NMR(500MHz,DMSO-d6)δ7.50(t,J=7.5Hz,1H),7.48-7.43(m,1H),7.41-7.32(m,3H),7.12(d,J=2.1Hz,1H),7.07(dt,J=8.3,1.6Hz,1H),5.38(s,1H),3.91-3.74(m,2H),3.68-3.50(m,3H),2.48-2.32(m,2H),2.15-1.93(m,4H)。
LCMS(ESI):针对C40H38Cl2N6O4计算;[M+H]+:737.24,实测值:737.57.
1H NMR(500MHz,DMSO-d6)δ7.78-7.73(m,2H),7.58(dd,J=7.7,1.9Hz,1H),7.54(t,J=7.6Hz,1H),7.43(dd,J=7.4,1.9Hz,1H),7.38(d,J=8.1Hz,1H),4.91(d,J=1.4Hz,2H),4.06-4.01(m,1H),3.96-3.90(m,2H),2.37-2.24(m,2H),2.16-2.05(m,2H)。
LCMS(ESI):针对C36H30Cl2N6O6计算;[M+H]+:713.17,实测值:713.48.
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1H NMR(400MHz,DMSO-d6)δ8.71(s,2H),7.92(s,2H),7.62-7.75(m,6H),4.78(s,4H),4.22(m,2H),4.06(dd,J=4Hz,2H),3.95(m,2H),2.32(m,2H),2.20(m,2H),2.10(m,2H)1.80(m,2H)。
LCMS(ESI):针对C34H28Cl2N8O6计算;[M+H]+:715.15,实测值:715.15.
实施例10(同核心不同侧的制备)
10A.2,2′-((2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-7,4-二基))二乙腈的制备
在40℃下搅拌化合物SM5(100mg,1当量)、Cs2CO3(251mg,4.0当量)、溴乙腈(69mg,3.0当量)于DMF中的混合物持续2h。将反应混合物用水稀释并用EA萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并在减压下浓缩。通过柱(DCM/MeOH=20/1)纯化残余物以产生标题化合物397(92mg,产率:67.6%)。
1H NMR(500MHz,DMSO-d6)δ7.54-7.46(m,2H),7.44-7.38(m,2H),7.25(dd,J=8.3,2.0Hz,1H),7.18(d,J=2.0Hz,1H),5.15(s,2H),4.84(s,2H)。
LCMS(ESI):针对C32H20Cl2N4O4计算;[M+H]+:595.09,实测值:595.40.
10B.在下文程序中,可由不同的溴化物侧链制备化合物
1H NMR(500MHz,DMSO-d6)δ7.55(br s,1H),7.52-7.45(m,2H),7.41-7.36(m,2H),7.16(dd,J=8.4,2.0Hz,1H),7.12(d,J=2.0Hz,1H),4.73(s,2H),4.11-3.98(m,2H),3.34-3.28(m,1H),3.06-2.99(m,1H),2.83-2.74(m,1H),2.30-2.22(m,1H),2.02-1.95(m,1H)。
LCMS(ESI):针对C38H32Cl2N4O6计算;[M+H]+:711.18,实测值:711.47.
1H NMR(500MHz,DMSO-d6)δ8.53(d,J=1.2Hz,1H),7.95(d,J=1.5Hz,1H),7.52-7.47(m,1H),7.44(dd,J=7.7,1.8Hz,1H),7.39(dd,J=7.4,1.7Hz,1H),7.12-7.08(m,3H),4.67(s,2H),4.49(t,J=6.0Hz,2H),4.33(t,J=6.1Hz,2H)。
LCMS(ESI):针对C36H28Cl2N8O4计算;[M+H]+:707.17,实测值:707.43.
1H NMR(500MHz,DMSO-d6)δ7.74(d,J=1.9Hz,1H),7.52-7.47(m,1H),7.46-7.41(m,2H),7.39(dd,J=7.4,1.8Hz,1H),7.09(d,J=1.9Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),6.94(d,J=8.5Hz,1H),6.18(t,J=2.0Hz,1H),4.68(d,J=1.4Hz,2H),4.40(t,J=6.2Hz,2H),4.28(t,J=6.2Hz,2H)。
LCMS(ESI):针对C38H30Cl2N6O4计算;[M+H]+:705.18,实测值:705.42.
1H NMR(500MHz,DMSO-d6)δ7.50(t,J=7.5Hz,2H),7.45(dd,J=7.7,1.9Hz,2H),7.42–7.36(m,4H),7.15(dd,J=8.2,2.0Hz,2H),7.09(d,J=2.0Hz,2H),4.93(t,J=5.7Hz,2H),4.69(s,4H),4.00(t,J=6.1Hz,4H),3.65–3.59(m,4H)。
LCMS(ESI):针对C32H26Cl2N2O6计算;[M+H]+:605.12,实测值:605.50
1H NMR(500MHz,DMSO-d6)δ7.52-7.45(m,2H),7.41-7.37(m,2H),7.18(dd,J=8.4,2.0Hz,1H),7.10(d,J=2.0Hz,1H),4.68(s,2H),4.06(t,J=6.5Hz,2H),3.43(dd,J=9.0,6.8Hz,2H),3.31(t,J=6.5Hz,2H),3.17(dd,J=8.9,6.8Hz,2H)。
LCMS(ESI):针对C38H34Cl2N6O6计算;[M+H]+:741.20,实测值:741.50.
1H NMR(500MHz,DMSO-d6)δ7.48(t,J=7.6Hz,1H),7.43(dd,J=7.6,1.9Hz,1H),7.35(dd,J=7.4,1.8Hz,1H),7.07(dd,J=8.3,2.0Hz,1H),7.03(d,J=2.0Hz,1H),6.94(d,J=8.4Hz,1H),4.65(s,2H),4.16(s,2H)。
LCMS(ESI):针对C32H22Cl2N2O8计算;[M+H]+:633.08,实测值:633.37.
1H NMR(500MHz,DMSO-d6)δ8.87(d,J=2.0Hz,2H),8.74(d,J=2.1Hz,2H),8.28(d,J=2.3Hz,2H),7.52(t,J=7.6Hz,2H),7.46(dd,J=7.7,1.9Hz,2H),7.44–7.39(m,4H),7.16(dd,J=8.3,2.0Hz,2H),7.12(d,J=2.0Hz,2H),4.67(s,4H),4.23(t,J=7.3Hz,4H),3.01(t,J=7.3Hz,4H)。
LCMS(ESI):针对C44H30Cl2N6O4计算;[M+H]+:777.17,实测值:777.45
1H NMR(500MHz,DMSO-d6)δ7.52(t,J=7.6Hz,2H),7.46(d,J=7.8Hz,2H),7.41(d,J=7.5Hz,2H),7.36(d,J=8.4Hz,2H),7.19(d,2H),7.14(d,J=2.0Hz,2H),4.75(s,4H),3.75–3.67(m,4H),3.24–3.17(m,4H),3.08–3.02(m,4H),2.34–2.16(m,4H),1.97–2.01(m,4H)。
LCMS(ESI):针对C40H36Cl2N4O6计算;[M+H]+:739.20,实测值:739.50
1H NMR(500MHz,DMSO-d6)δ7.54-7.48(m,2H),7.46(dd,J=7.6,1.9Hz,1H),7.40(dd,J=7.4,1.9Hz,1H),7.19(dd,J=8.4,2.1Hz,1H),7.13(d,J=2.0Hz,1H),4.59(s,2H),4.52(d,J=13.1Hz,1H),4.39(t,J=12.3Hz,1H),3.92(d,J=13.5Hz,1H),3.25-3.13(m,1H),2.70-2.53(m,2H),2.42-2.27(m,1H),2.04(s,3H),1.86-1.71(m,2H)。
LCMS(ESI):针对C42H40Cl2N4O6计算;[M+H]+:767.24,实测值:767.56.
1H NMR(500MHz,DMSO-d6)δ7.53-7.31(m,4H),7.25(dd,J=8.3,2.0Hz,1H),7.05(d,J=2.0Hz,1H),5.36(s,2H),4.77(s,2H)。
LCMS(ESI):针对C32H22Cl2N10O4计算;[M+H]+:681.13,实测值:681.41.
1H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.51(t,J=7.5Hz,1H),7.46(dd,J=7.7,1.9Hz,1H),7.42-7.38(m,1H),7.36(d,J=8.5Hz,1H),7.15(dd,J=8.3,2.1Hz,1H),7.11(d,J=2.0Hz,1H),4.72(d,J=3.3Hz,2H),4.41(t,J=7.9Hz,1H),4.20-4.08(m,3H),4.02-3.94(m,1H)。
LCMS(ESI):针对C36H28Cl2N4O8计算;[M+H]+:715.14,实测值:715.42.
1H NMR(500MHz,DMSO-d6)δ7.78(s,2H),7.50(t,J=7.5Hz,2H),7.45(dd,J=7.8,1.8Hz,2H),7.40(d,J=7.5Hz,2H),7.34(d,J=8.4Hz,2H),7.14(dd,J=8.6,1.8Hz,2H),7.10(d,J=2.1Hz,2H),7.09(d,J=5.4,2.8Hz,2H),6.96(d,J=2.7Hz,2H),4.74(s,4H),
LCMS(ESI):针对C36H26Cl2N6O4计算;[M+H]+:677.14,实测值:677.43
1H NMR(500MHz,DMSO-d6)δ8.95(d,J=2.0Hz,1H),8.91(d,J=2.3Hz,1H),8.29(q,J=2.4Hz,1H),7.47(dq,J=7.7,4.2Hz,1H),7.42(dt,J=7.5,2.4Hz,1H),7.37(dt,J=7.6,2.3Hz,1H),7.13(d,J=4.1Hz,1H),7.05(d,J=4.2Hz,2H),5.27(d,J=4.2Hz,2H),4.91(d,J=4.2Hz,2H)。
LCMS(ESI):针对C42H26Cl2N6O4计算;[M+H]+:749.15,实测值:749.44.
实施例11(同核心不同侧)
11A.7,7′-(2,2′-二氯-[1,1′-联苯]-3,3′-二基)双(4-(((S)-吡咯烷-2-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮)的制备
1.
向411-01(500mg,2.49mmol,1.0当量)于DCM(5ml)中的经搅拌的溶液中添加TosCl(567mg,2.98mmol,1.2当量)和TEA(502mg,4.97mmol,2.0当量),然后在室温下添加DMAP(30mg,0.249mmol,0.1当量),并搅拌4h。向反应中添加水和DCM并进行分离,将有机相经无水硫酸钠干燥,过滤,将滤液在真空下浓缩。在下一步骤中直接使用残余物(950mg,产率:107%)。
2.
在环境温度下向SM4(117mg,0.51mmol,1.0当量)于DMF(2ml)中的经搅拌的溶液中添加411-02(219mg,0.62mmol,1.2当量)和CS2CO3(337mg,1.03mmol,2.0当量)。然后将所得混合物在70℃下搅拌过夜。将反应用水淬灭,用EA萃取。将合并的有机层经Na2SO4干燥,过滤,将滤液在真空下浓缩。通过制备型TLC(PE/EA=4/1)纯化残余物,以得到呈浅黄色油的期望产物(105mg,产率:50%)。
3.
在N2气氛下,向411-03(105mg,0.26mmol,2.2当量)和SM2(55mg,0.12mmol,1.0当量)于二噁烷(2.5ml)和H2O(0.5ml)中的溶液中添加Pd(dppf)Cl2·DCM(19mg,0.024mmol,0.2当量)、K2CO3(64mg,0.48mmol,4.0当量)。然后将最终混合物在80℃下搅拌2h。冷却至室温,添加水,并且用EA萃取两次,将合并的有机相用盐水洗涤,并且经无水硫酸钠干燥,过滤,将滤液在真空下浓缩。通过制备型TLC(DCM/MeOH=15/1)纯化残余物,以得到呈白色固体的期望产物(50mg,产率:49%)。
4.
向411-03(50mg,0.056mmol,1.0当量)于MeOH(1ml)中的经搅拌的溶液中添加HCl于二噁烷(1ml,4M)中,然后在室温下搅拌溶液持续2h。在反应完成后,将溶剂通过减压去除,并且在冻干下干燥,以得到期望产物(36mg,产率:95%)。
1H NMR(500MHz,DMSO-d6)δ9.61(s,2H),8.72(s,2H),7.52(t,J=7.5Hz,2H),7.48–7.43(m,4H),7.41(d,J=7.4Hz,2H),7.19–7.12(m,4H),4.78(t,J=8.6Hz,4H),4.35(dd,J=15.0,7.8Hz,2H),4.24(dd,J=14.9,5.0Hz,2H),3.71(s,2H),3.28(s,2H),3.11(s,2H),2.17(d,J=6.7Hz,2H),2.02–1.88(m,4H),1.71(dt,J=18.8,9.3Hz,2H)。
LCMS(ESI):针对C38H36Cl2N4O4(游离形式)计算;[M+H]+:683.2,实测值:683.2
11B.也可制备以下化合物:
1HNMR(500MHz,DMSO-d6)δ9.26(s,4H),7.51(t,J=7.5Hz,2H),7.48–7.42(m,4H),7.40(d,J=7.3Hz,2H),7.17(d,J=8.6Hz,2H),7.13(s,2H),4.73(d,J=12.0Hz,4H),4.08(ddd,J=41.2,14.4,7.4Hz,4H),3.32–3.23(m,4H),3.15–3.05(m,2H),2.98–2.89(m,2H),2.66(dd,J=15.2,7.7Hz,2H),2.07–1.99(m,2H),1.69(dq,J=16.8,8.4Hz,2H)。
LCMS(ESI):针对C38H36Cl2N4O4(游离形式)计算;[M+H]+:683.2,实测值:683.2
1H NMR(500MHz,DMSO-d6)δ10.35(s,2H),9.63(s,2H),7.54–7.45(m,6H),7.41(d,J=7.3Hz,2H),7.16(d,J=8.6Hz,2H),7.14(s,2H),4.81–4.72(m,4H),4.45(dd,J=15.2,7.8Hz,2H),4.28(dd,J=15.2,4.7Hz,2H),4.07(s,2H),3.84(dd,J=24.5,11.5Hz,2H),3.73–3.54(m,4H),2.92(d,J=14.7Hz,2H)。
LCMS(ESI):针对C38H32Cl2F4N4O4(游离形式)计算;[M+H]+:755.2,实测值:755.2
1HNMR(500MHz,DMSO-d6)δ9.25(s,4H),7.51(t,J=7.5Hz,2H),7.48–7.42(m,4H),7.40(d,J=7.3Hz,2H),7.17(d,J=8.5Hz,2H),7.13(s,2H),4.74(s,4H),4.08(ddd,J=41.0,14.5,7.4Hz,4H),3.31–3.22(m,4H),3.11(dd,J=11.9,5.8Hz,2H),2.94(td,J=13.5,6.5Hz,2H),2.66(dd,J=15.2,7.6Hz,2H),2.04(dt,J=12.6,6.4Hz,2H),1.69(dq,J=16.7,8.3Hz,2H)。
LCMS(ESI):针对C38H36Cl2N4O4(游离形式)计算;[M+H]+:683.2,实测值:683.2
1H NMR(500MHz,DMSO-d6)δ9.72(s,2H),8.51(d,J=9.4Hz,2H),7.52(t,J=7.5Hz,2H),7.47–7.40(m,6H),7.16(d,J=8.5Hz,2H),7.14(s,2H),4.77(s,4H),4.42(dd,J=15.4,8.2Hz,2H),4.19(dd,J=15.0,4.3Hz,2H),3.75(s,2H),3.51(s,2H),2.21(d,J=8.5Hz,2H),2.14–2.06(m,2H),1.83(dd,J=13.9,8.4Hz,2H),1.67–1.59(m,2H),1.33(d,J=6.4Hz,6H)。
LCMS(ESI):针对C40H40Cl2N4O4(游离形式)计算;[M+H]+:711.2,实测值:711.2
1H NMR(500MHz,DMSO-d6)δ9.14(s,2H),8.87(s,2H),7.52(t,J=7.5Hz,2H),7.47(d,J=7.4Hz,2H),7.43–7.38(m,4H),7.19(d,J=8.3Hz,2H),7.15(s,2H),4.77(dd,J=31.2,15.1Hz,4H),4.39–4.30(m,2H),4.03(s,2H),3.91(d,J=14.2Hz,2H),3.48(s,2H),1.95(d,J=10.9Hz,2H),1.73(dd,J=18.0,10.2Hz,2H),1.62(dd,J=18.2,9.8Hz,6H),1.33(d,J=8.7Hz,2H),1.23(s,2H)。
LCMS(ESI):针对C42H40Cl2N4O4(游离形式)计算;[M+H]+:735.2,实测值:735.2
1H NMR(500MHz,DMSO-d6)δ9.82(s,2H),9.03(s,2H),7.53–7.46(m,6H),7.41(d,J=7.5Hz,2H),7.17(d,J=9.3Hz,2H),7.14(s,2H),4.78(d,J=15.5Hz,4H),4.41–4.30(m,4H),3.94(s,2H),3.22(s,2H),3.11–3.05(m,2H),2.02–1.92(m,4H),0.74–0.61(m,8H)。
LCMS(ESI):针对C42H40Cl2N4O4(游离形式)计算;[M+H]+:735.2,实测值:735.2
1H NMR(500MHz,DMSO-d6)δ8.21(s,6H),7.74(d,J=8.4Hz,2H),7.54–7.45(m,4H),7.40(d,J=7.3Hz,2H),7.16(d,J=7.9Hz,2H),7.11(s,2H),4.72(dd,J=39.8,15.0Hz,4H),4.45(s,2H),4.27–4.19(m,2H),3.95(d,J=4.6Hz,2H),3.80(d,J=9.3Hz,2H),3.68–3.56(m,4H),2.11(d,J=5.7Hz,4H),1.97–1.89(m,2H),1.83(s,4H),1.00(d,J=6.8Hz,6H),0.91(d,J=6.7Hz,6H)。
LCMS(ESI):针对C48H54Cl2N6O6(游离形式)计算;[M+H]+:881.4,实测值:881.4
1H NMR(500MHz,DMSO-d6)7.73(d,J=8.4Hz,2H),7.53–7.44(m,4H),7.39(d,J=7.3Hz,2H),7.15(d,J=7.9Hz,2H),7.09(s,2H),4.72(m,4H),4.44(s,2H),4.27–4.19(m,2H),3.95(d,J=4.6Hz,2H),3.80(d,J=9.3Hz,2H),3.70(s,6H),3.68–3.56(m,4H),2.11(d,J=5.7Hz,4H),1.97–1.89(m,2H),1.83(s,4H),1.00(d,J=6.8Hz,6H),0.91(d,J=6.7Hz,6H)。
LCMS(ESI):针对C52H58Cl2N6O10计算;[M+H]+:997.4,实测值:997.4
1H NMR(500MHz,DMSO-d6)δ9.74(s,2H),8.84(s,2H),7.53–7.44(m,6H),7.41(d,J=7.2Hz,2H),7.18(d,J=8.5Hz,2H),7.14(s,2H),5.32(s,2H),4.76(t,J=10.6Hz,4H),4.35(ddd,J=20.6,17.7,8.9Hz,8H),3.91(d,J=5.5Hz,2H),3.00–2.93(m,2H),2.09(dd,J=12.9,5.0Hz,2H),1.87(td,J=12.8,4.7Hz,2H)。
LCMS(ESI):针对C38H36Cl2N4O6(游离形式)计算;[M+H]+:715.2,实测值:715.2
1H NMR(500MHz,DMSO-d6)δ7.78(d,J=8.4Hz,2H),7.53–7.44(m,4H),7.40(d,J=7.3Hz,2H),7.17(d,J=8.2Hz,2H),7.10(s,2H),4.78–4.64(m,4H),4.24(dd,J=24.9,11.7Hz,4H),3.74(d,J=10.6Hz,2H),3.52(t,J=9.0Hz,2H),3.38(dd,J=17.3,9.7Hz,2H),2.09–2.01(m,2H),1.94(s,6H),1.92–1.87(m,2H),1.80–1.70(m,4H)。
LCMS(ESI):针对C42H40Cl2N4O6计算;[M+H]+:767.2,实测值:767.2
1H NMR(500MHz,DMSO-d6)δ9.65(br s,1H),8.76(br s,1H),7.54-7.49(m,J=7.6Hz,1H),7.46(dd,J=9.0,3.1Hz,2H),7.41(d,J=7.3Hz,1H),7.16(dd,J=8.2,2.1Hz,1H),7.13(d,J=2.0Hz,1H),4.77(s,2H),4.38-4.25(m,2H),3.70(s,1H),3.31-3.04(m,2H),2.20-1.95(m,2H),1.94-1.66(m,2H)。
LCMS(ESI):针对C38H36Cl2N4O4计算;[M+H]+:683.22,实测值:683.49.
1H NMR(500MHz,DMSO-d6)δ9.07(br s,1H),8.81(br s,1H),7.52(m,1H),7.48-7.44(m,2H),7.41(dd,J=7.5,1.8Hz,1H),7.18-7.10(m,2H),4.77(s,2H),4.35-4.01(m,2H),3.30-3.31(m,2H),2.84(s,1H),2.02-1.91(m,2H),1.73-1.61(m,2H),1.56-1.42(m,2H)。
LCMS(ESI):针对C40H40Cl2N4O4计算;[M+H]+:711.25,实测值:711.43
1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),9.40(s,1H),7.51(d,J=7.9Hz,2H),7.47(d,J=1.8Hz,1H),7.41(d,J=7.5Hz,1H),7.15(d,J=8.4Hz,1H),7.12(d,J=1.9Hz,1H),4.77(d,J=2.2Hz,2H),4.36-4.25(m,1H),4.16-4.04(m,2H),3.91-3.74(m,2H),3.69-3.53(m,2H),3.32-3.26(m,2H)。
LCMS(ESI):针对C38H36Cl2N4O6计算;[M+H]+:715.21,实测值:715.39.
1HNMR(400MHz,DMSO-d6)δ7.94(s,6H),7.52(t,J=6Hz,2H),7.45(d,J=4.0Hz,2H),7.40(d,J=4Hz,2H),7.35(d,J=4Hz,2H),7.17(d,J=4.0Hz,2H),7.13(s,2H),4.73(s,4H),4.19(t,J=6Hz,4H),3.09(t,J=6Hz,4H)。
LCMS(ESI):针对C32H28Cl2N4O4计算;[M+H]+:603.15,实测值:603.15.
实施例12(非对称的、不对称的)
(S)-7-(2,2′-二氯-3′-(3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)-[1,1′-联苯]-3-基)-4-((5-氧代吡咯烷-2-基)甲基)-2H-苯并[b][1,4]噁嗪-3(4H)-酮的制备
将SM5(20.0mg,1当量)、SM1(10.4mg,1当量)和碳酸铯(25mg,2当量)溶解于DMF(1ml)中。将反应在40℃下进行2h。冷却后,添加5ml水和5ml EA以进行萃取,并且将有机相用水洗涤并浓缩至干燥。通过柱(DCM/MeOH=20/1)纯化残余物以产生标题化合物429(11mg,产率:46.3%)。1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),7.76(s,1H),7.52-7.46(m,2H),7.46-7.41(m,2H),7.41-7.36(m,2H),7.34(d,J=8.4Hz,1H),7.14(dd,J=8.3,2.1Hz,1H),7.10(d,J=2.0Hz,1H),7.07-7.02(m,2H),6.98(d,J=7.9Hz,1H),4.71(s,2H),4.63(s,2H),4.04-3.92(m,3H),2.34-2.23(m,1H),2.21-2.05(m,2H),1.83-1.74(m,1H)。LCMS(ESI):针对C33H25Cl2N3O5计算;[M+H]+:614.13,实测值:614.41
在下文程序中,通过相同的程序获得名称为385的化合物。
1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),7.52-7.45(m,3H),7.43(dd,J=7.7,1.8Hz,1H),7.40-7.36(m,3H),7.17(dd,J=8.3,2.0Hz,1H),7.10(d,J=2.0Hz,1H),7.07-7.02(m,2H),6.98(d,J=7.9Hz,1H),4.68(s,2H),4.62(s,2H),4.05(t,J=6.5Hz,2H),3.46-3.41(m,2H),3.31(t,J=6.5Hz,2H),3.19-3.14(m,2H)。LCMS(ESI):针对C33H26Cl2N4O5计算;[M+H]+:629.14,实测值:629.44
实施例13
13A.(2-(7-(2,2′-二氯-3′-(3-氧代-4-(((S)-吡咯烷-2-基)甲基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)-[1,1′-联苯]-3-基)-3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)乙基)-L-丝氨酸的制备
(a)参考以下反应式,将化合物1A-1(0.35g,1.54mmol,1当量)、化合物1A-2(1.10g,3.07mmol,2.0当量)和碳酸铯(0.75g,2.30mmol,1.5当量)溶解于DMF(10ml)中。将反应在60℃下进行5h。冷却后,添加10ml水和10ml EA(乙酸乙酯)以进行萃取,并且将有机相用水洗涤并且在硅胶上纯化,用PE/EA(v/v,8:1)洗脱以产生化合物1A,即(S)-2-((7-溴-3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)吡咯烷-1-甲酸叔丁酯(0.35g,产率:55.5%)
(b)参考以下反应式,将化合物1B(25mg)溶解于二噁烷(0.5ml)中,然后逐滴添加1N HCl溶液(0.5ml),将温度提升到85℃,并且将反应进行0.5h。通过添加Na2CO3饱和溶液将反应溶液的pH调整到7至8,并且添加10ml EA以进行萃取。将有机相浓缩以产生1B(25mg,产率:107.0%)。
(c)参考以下反应式,将化合物1C(25mg,0.09mmol,1当量)、1D(29mg,0.19mmol,2当量)、TEA(19mg,0.19mmol)和一滴AcOH溶解于DCM(3ml)中,并且允许所得混合物在室温下搅拌持续1h。然后,添加NaBH(OAc)3(37mg,0.45mmol,5当量),并且将反应进行1h。然后,添加10ml H2O和10ml DCM以进行萃取。将有机相浓缩以产生1C(25mg,产率:72%)。
(d)参考以下反应式,将化合物1F(0.05g,0.11mmol,1当量)、1A(0.043g,0.11mmol,1当量)、1E(0.04g,0.11mmol,1当量)、Pd(dppf)Cl2(0.008g,0.01mmol,0.1当量)和碳酸钾(0.058g,0.42mmol,4当量)溶解于二噁烷/H2O(3ml,v/v=5:1)中。反应在N2气氛下在85℃下进行2h。冷却后,添加10ml水和10ml EA以进行萃取,并且将有机相浓缩并通过制备型TLC(PE/EA=1/1洗脱)纯化以产生化合物1G,即(S)-2-((7-(2,2′-二氯-3′-(4-(2-(((S)-3-羟基-1-甲氧基-1-氧丙烷-2-基)氨基)乙基)-3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)-[1,1′-联苯]-3-基)-3-氧代-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲基)吡咯烷-1-甲酸叔丁酯,0.017g,产率:20%。
LCMS(ESI):针对C44H46Cl2N4O9计算;[M+H]+:845.26,实测值:845.26.
(e)参考以下反应式,将1N HCl(1mL)添加到化合物1G(17mg,0.02mmol)于二噁烷(1mL)中的溶液中,然后在室温下搅拌持续3h。然后,将Na2CO3(水溶液)添加到反应混合物中以中和未反应的HCl。将反应混合物用EA和水萃取。将有机相浓缩,并且通过制备型HPLC纯化以产生1F(10mg,产率:67%)。
(f)参考以下反应式,将NaOH(0.5ml,0.26M于水中)添加到1F(10mg,0.013mmol)于MeOH/THF(3mL,2:1)中的溶液中,然后在室温下搅拌持续1h。然后,将HCl(1M)添加到反应混合物中以中和未反应的NaOH。通过制备型HPLC纯化反应混合物以产生标题化合物1(7.4mg,产率:75.5%)。
1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.43(s,1H),7.53-7.36(m,8H),7.19-7.12(m,4H),5.58(s,1H),4.78(s,2H),4.71(s,2H),4.36(m,1H),4.32-4.13(m,3H),4.04(m,1H),3.87(s,2H),3.72(m,1H),3.21(m,2H),3.12(m,2H),2.20(m,1H),1.94(m,2H),1.70(m,1H)。
LCMS(ESI):针对C40H36Cl2N4O8计算;[M+H]+:731.21,实测值:731.21.
13B.使用相同程序制备以下化合物
1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.64(s,2H),8.44(s,1H),8.15(t,J=6.0Hz,1H),7.52(t,J=8.0Hz,2H),7.45(d,J=4.0Hz,2H),7.41(d,J=8.0Hz,2H),7.36(m,2H),7.17(d,J=8.0Hz,2H),7.14(s,2H),4.75(s,2H),4.71(s,2H),4.36(m,1H),4.24(t,J=4.0Hz,2H),419(dd,J=12.0Hz,4.0Hz,1H),3.72(m,1H),3.31(m,3H),3.23(m,2H),3.12(m,1H),3.06(m,2H),2.20(m,1H),1.97(m,2H),1.85(s,3H),1.70(m,1H)
LCMS(ESI):针对C39H39Cl2N5O5计算;[M+H]+:728.23,实测值:728.23.
1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.44(s,1H),7.53-7.49(m,2H),7.47-7.43(m,2H),7.42-7.33(m,4H),7.21-7.12(m,3H),7.10(s,1H),5.54,(s,1H),4.75(s,2H),4.71(s,2H),4.46-4.40(m,2H),4.34-4.28(m,2H),4.06-3.89(m,3H),3.78-3.66(m,2H),3.44-3.40(m,2H),3.27-3.03(m,2H),2.32-2.20(m,2H),2.18-2.08(m,2H),2.02-1.91(m,2H),1.75-1.86(m,2H)。
LCMS(ESI):针对C39H38Cl2N4O5计算;[M+H]+:713.22,实测值:713.22.
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),7.51-7.37(m,7H),7.17-6.97(m,5H),4.71(s,2H),4.62(s,2H),4.15(t,J=4.0Hz,2H),3.70-3.62(m,3H),3.05-2.99(m,2H)。
LCMS(ESI):针对C33H27Cl2N3O7计算;[M+H]+:648.12,实测值:648.12.
1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.53-7.48(m,2H),7.47-7.44(m,2H),7.41-7.38(m,2H),7.36-7.33(m,2H),7.18(d,J=4.0Hz,1H),7.15-7.12(m,2H),7.10(s,1H),4.75(s,2H),4.71(s,2H),4.22(t,J=4.0Hz,2H),4.05-4.00(m,1H),3.96-3.93(m,2H),3.69-3.58(m,1H),3.29(t,J=4.0Hz,2H),3.27-3.25(m,3H),2.16-2.06(m,2H),2.30-2.28(m,2H),2.12-2.02(m,2H)。
LCMS(ESI):针对C40H36Cl2N4O8计算;[M+H]+:771.19,实测值:771.19.
1H NMR(400MHz,DMSO-d6)δ8.61(s,2H),8.14(t,J=4.0Hz,1H),7.78(s,1H),7.53-7.48(m,2H),7.47-7.44(m,2H),7.41-7.38(m,2H),7.36-7.33(m,2H),7.18(d,J=4.0Hz,1H),7.15-7.12(m,2H),7.10(s,1H),4.75(s,2H),4.71(s,2H),4.24(t,J=4.0Hz,2H),4.04-4.00(m,1H),3.97-3.92(m,2H),3.32-3.30(t,J=4.0Hz,2H),3.25-3.21(m,2H),3.08-3.04(m,2H),2.31-2.26(m,2H),2.17-2.07(m,2H),1.85(s,3H)。
LCMS(ESI):针对C39H37Cl2N5O6计算;[M+H]+:742.21,实测值:742.21.
1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.53-7.49(m,2H),7.47-7.43(m,2H),7.42-7.33(m,4H),7.21-7.12(m,3H),7.10(s,1H),5.54,(s,1H),4.75(s,2H),4.71(s,2H),4.46-4.40(m,2H),4.34-4.28(m,2H),3.89-4.06(m,3H),3.78-3.66(m,2H),3.27-3.03(m,2H),2.32-2.20(m,2H),2.18-2.08(m,2H),2.02-1.91(m,2H),1.75-1.86(m,2H)。
LCMS(ESI):针对C39H36Cl2N4O6计算;[M+H]+:727.20,实测值:727.20.
1H NMR(500MHz,DMSO-d6)δ7.76(br s,1H),7.55(br s,1H),7.53-7.47(m,2H),7.48-7.44(m,2H),7.42-7.36(m,3H),7.34(d,J=8.4Hz,1H),7.18-7.13(m,2H),7.11(dd,J=6.9,2.0Hz,2H),4.73(s,2H),4.71(s,2H),4.09-3.90(m,5H),3.34-3.29(m,1H),3.06-3.01(m,1H),2.82-2.75(m,1H),2.30-2.23(m,2H),2.18-2.05(m,2H),2.02-1.96(m,1H),1.83-1.74(m,1H)。LCMS(ESI):针对C38H32Cl2N4O6计算;[M+H]+:711.18,实测值:711.51.
1H NMR(500MHz,DMSO-d6)δ7.76(br s,1H),7.53-7.44(m,4H),7.42-7.32(m,4H),7.18-7.10(m,4H),4.74(s,2H),4.71(s,2H),4.38-4.25(m,2H),4.04-3.70(m,4H),3.31-3.04(m,2H),2.40-1.66(m,8H)。
LCMS(ESI):针对C38H34Cl2N4O5计算;[M+H]+:697.20,实测值:697.47.
实施例14
PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定
在最终体积为20μL的标准黑色384孔聚苯乙烯板中进行测定。首先将抑制剂在DMSO中连续稀释,然后添加到板孔中,之后添加其他反应组分。测定中DMSO的最终浓度为1%。在25℃下,在具有0.05%Tween-20和0.1%BSA的PBS缓冲液(pH 7.4)中进行测定。C末端处带有组氨酸标记的重组人PD-L1蛋白(19-238)购自北京百普赛斯生物科技股份有限公司(AcroBiosystems)(PD1-H5229)。C末端处带有Fe标记的重组人PD-1蛋白(25-167)也购自北京百普赛斯生物科技股份有限公司(PD1-H5257)。PD-L1蛋白和PD-1蛋白在测定缓冲液中稀释,并向板孔中添加10μL。将板离心,并且将蛋白质与抑制剂预温育40分钟。在温育后添加10μL HTRF检测缓冲液,该检测缓冲液补充有对Fe具有特异性的铕穴状化合物标记的抗人IgG(PerkinElmer-AD0212)和与别藻蓝蛋白(APC,PerkinElmer-AD0059H)缀合的抗His抗体。离心后,将板在25℃下温育60min,之后在PHERAstar FS读板仪(比率为665nm/620nm)上读取。测定中的最终浓度为3nM PD1、10nM PD-L1、1nM铕抗人IgG和20nM抗His别藻蓝蛋白。通过拟合对照活性百分比与抑制剂浓度的对数的曲线来进行IC50测定。
表1
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实施例15
PD-L1内化
1.实验方案
第1天。接种细胞:通过烧瓶中的胰蛋白酶消化PD-L1/CHO-K1细胞,然后对细胞数进行计数并稀释到1×105个细胞/ml。将细胞接种到6孔板(康宁公司(Corning),3516号),2mL/孔。将板在37℃下、在5%CO2温育箱中温育24小时。
第2天。制备化合物并处理细胞:通过使用DMSO将GLC01-258从15mM稀释至0.5mM,通过DMSO将15mM化合物从15mM稀释至15nM,然后通过使用测定缓冲液将化合物稀释500倍。在测定缓冲液中制备0.2%DMSO,用于媒剂对照和低对照。取出板,吸出培养基并丢弃。向对应孔中添加2mL经稀释的化合物、媒剂对照和低对照。然后将板在37℃下、在5%CO2温育箱中温育17个小时。
第3天。为FACS制备样品:在17个小时的温育后,丢弃培养基并通过PBS洗涤。通过胰蛋白酶消化每个孔中的细胞。离心并丢弃上清液,然后通过DPBS(不含Ca2+、Mg2+)洗涤细胞两次。通过DPBS将抗体(PE缀合的小鼠抗人CD274)稀释10倍,然后将染色溶液添加到经化合物处理的样品和媒剂对照样品中。低对照仅添加DPBS而不添加抗体。在室温下将板温育20分钟并且避光。20分钟后,通过DPBS洗涤样品两次。然后离心并丢弃上清液。通过300uLDPBS重新悬浮细胞,并且将样品转移到5mL聚苯乙烯圆底管(Falcon,352054号)中,然后通过BD FACSCanto进行测试。通过BD FACSCanto测试样品。
2.数据分析
将媒剂对照的PD-L1信号设置为100%,低对照的PD-L1信号设置为0%。然后计算经化合物处理的样品的PD-L1信号
0%PD-L1信号:不用抗CD274染色的低对照
100%PD-L1信号:用抗CD274染色的媒剂对照
PD-L1内化的激活%=1-化合物的PD-L1信号。
表2
实施例16
PD-L1二聚化
在生化蛋白质-蛋白质相互作用测定中测试化合物,以确定这些化合物是否能特异性二聚化PD-L1的胞外结构域。
(1)在DMSO中按1:3的比例依次稀释cpd,每列10+0个重复品(参考稀释板图)
(2)使用Echo将每行0.2μL cpd溶液转移至384测定板,每列含有2个重复品(参考测定板图)。
(3)将包括PDL1-Eu和PDL1-A2的20μL已制备的混合物溶液添加到测定板,以1000rpm离心1min。
(4)在25℃下温育120min。
(5)读取Envision 2104读板仪上的荧光信号。
(6)读取Envision上的比率(665nm/615nm)信号。
(7)使用等式(V.数据分析)分析原始数据
表3
实施例17
PDL1 Jurkat-NFAT报告基因测定
a.Hep3B-OS8-hPDL1的制备
1.将Hep3B-OS8-hPDL1细胞培养在补充有10%胎牛血清、1%青霉素和链霉素的1640培养基中,还向该培养基中添加了100μg/mL G418和潮霉素B。
2.用含有10%FBS的RPMI 1640培养基重新悬浮细胞,并将细胞密度调节至1.25E5个细胞/mL。
3.将细胞接种到96孔平底板(1.25E4个细胞/100μL/孔)上。
b.化合物溶液制备
4.从预先铺板的Hep3B-OS8-PDL1细胞中除去培养基。用200μL测定培养基洗涤一次。
5.根据布局,在含10%FBS的RPMI 1640培养基中制备化合物稀释液。
6.向每个孔中添加体积为50μL的9种浓度(3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM和0.0003μM)的化合物。可瑞达(Keytruda)将作为阳性对照的一部分,浓度为5μg/mL。
7.在37℃、5%CO2下温育20-30min。
c.Jurkat-NFAT-PD1的制备
8.将Jurkat-NFAT-PD1细胞培养在补充有10%胎牛血清、1%青霉素和链霉素的1640培养基中,还向该培养基中添加了1000μg/mL潮霉素B和0.3μg/mL嘌呤霉素。
9.在测定的第二天,用含有10%FBS的RPMI 1640培养基重新悬浮细胞,并将细胞密度调节至2.5E5个细胞/mL。
10.将细胞接种到96孔平底板(1.25E4个细胞/50μL/孔)上。
11.将测定板温育在37℃、5%CO2的加湿温育箱中持续6个小时。
12.在室温下平衡培养的细胞持续5-10min。
13.向每个孔中添加等体积(100μL/孔)的ONE-GloTM荧光素酶测定系统,等待至少3min以进行完全的细胞裂解并在光度计中测量。
表4
化合物ID | Jurkat-NFATEC50(nm) |
465 | 0.3 |
529 | 111.1 |
实施例18
a.Hep3B-OS8-hPDL1和T细胞共培养测定
肿瘤制备
1.将Hep3B-OS8-hPDL1细胞培养在补充有10%胎牛血清、1%青霉素和链霉素的1640培养基中,还向该培养基中添加了100μg/mL G418和潮霉素B。
2.收获Hep3B-OS8-hPDL1细胞,并在37℃下用10μg/mL丝裂霉素C处理1.5h,然后用PBS彻底洗涤细胞四次。
3.用含有10%FBS的RPMI 1640培养基重新悬浮细胞,并将细胞密度调节至5E5个细胞/mL。
4.将细胞接种到96孔平底板(2.5E4个细胞/50μL/孔)上。
b.CD3+T细胞分离(30mL血液)
5.通过相同体积的无菌PBS稀释来自单个供体的人血液样品,例如将25mL无菌PBS添加到25mL新鲜全血中,并通过轻轻摇动充分混合。
6.将15mL Lymphoprep培养基转移至新的50mL离心管中。
7.将稀释的血液样品尽可能轻柔地添加到Ficoll培养基的表面上,以确保两种液体之间有清晰的分界线,并且Ficoll和稀释的血液(30mL)之间的体积比为1:2。
8.轻轻地移动试管以在离心期间利用加速(5)和最小减速(0)设置在20℃下以1000×g离心25min。
9.离心后可观察到总共四个界面,从上到下为血浆层、单核细胞层、Ficoll培养基层和RBC层,并尽可能轻柔地移动试管以保持四个界面分离。小心地吸取第二层单核细胞并转移到另一个新的无菌离心管中,并且如果不可避免的话,则吸取特定体积的血浆代替Ficoll培养基。
10.在装有PBMC的试管中添加三倍于PBMC体积的无菌PBS。
11.用5-10mL PBS洗涤细胞两次,之后利用血细胞计数器进行细胞计数。在20℃下以350×g离心10min。在离心期间利用加速(5)和减速(5)设置。
12.用推荐的培养基重新悬浮细胞,并将PBMC的密度调节至5E7个细胞/mL的最终浓度。
13.用EasySepTM人T细胞分离试剂盒(干细胞技术公司(STEMCELL Technologies)17951号)分离CD3+T细胞,并且将细胞接种到96孔平底板(5E4个细胞/100μL/孔)上。
c.化合物溶液的制备
14.根据布局,在含10%FBS的RPMI 1640培养基中制备化合物稀释液。15.向每个孔中添加体积为50μL的化合物{3种化合物(GLC01-258、GLC01-269、GLC01-465)为7种浓度(0.03μM、0.1μM、0.3μM、1μM、3μM、10μM和30μM),并且6种化合物(GLC01-411、GLC01-292、GLC01-445、GLC01-475、GLC01-470和GLC01-468)为相同浓度(1μM)}。
16.可瑞达将作为阳性对照的一部分,浓度将为5μg/mL。
17.在37℃、5%CO2下温育72个小时。
18.通过离心收集上清液,并通过ELISA测量IFN-γ。
表5
化合物ID | 肿瘤和T细胞EC50(nm) |
465 | 1.2 |
529 | 324.9 |
533 | 6.032 |
554 | 5.1 |
实施例19
小鼠PK研究
(1)将化合物称重并溶解于1mg/mL 5%solutol于盐水中的媒剂中,充分摇匀,并进行超声处理以形成无色透明的溶液。在过夜禁食后,以10mg/kg的剂量给一组3只小鼠口服该溶液。
(2)从颌下静脉采血,并且用肝素钠进行抗凝。收集后将血液置于冰上,并在1小时内通过离心分离血浆(离心条件:8000rpm,6分钟,2℃-8℃)。血液采样时间点为0.083个小时、0.25个小时、0.5个小时、1个小时、2个小时、4个小时、8个小时和24个小时。
(3)将样品储存在-20℃的冰箱中。向血浆样品(40μL)中添加160μL含有内标物的冰冷乙腈,涡旋3分钟,并以11,000rpm离心5分钟。将100μL上清液添加到100μL水中,并且将5μL上清液注入LC/MS/MS仪器中以检测化合物(如果化合物是酯,则检测酸)。
数据在表6中:
表6
虽然上文已经描述了各个实施方案,但应当理解,这种公开内容仅通过示例而不是限制的方式来进行呈现。因此,本发明组合物和方法的广度和范围不应受限于任何上述示例性实施方案,而是应仅根据下面的权利要求及其等效物来限定。
以上描述是为了教授本领域普通技术人员如何实践本申请,并且不旨在详述所有那些在阅读描述后对于技术人员将变得显而易见的修改和变化。然而,所有这样的明显的修改和变化都旨在包括在由所附权利要求限定的本申请的范围内。除非上下文另有明确说明,否则这些权利要求旨在以任何有效地满足预期目标的顺序涵盖部件和步骤。
Claims (27)
1.一种式(I)化合物:
或其药学上可接受的盐、立体异构体、立体异构体的混合物、溶剂化物或互变异构体,其中,
A和B各自独立地选自卤素、氰基、-N3、烷基和经取代的烷基、胺、烷基胺、烷氧基;
Z1为-CR1=或-N=;
Z2为-CR2=;
Z3为-CR3=或-N=;
Z4为-CR4=或-N=,
Z5为-CR5=;
Z6为-CR6=或-N=;
R1和R4各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R2和R5各自独立,各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R3和R6各自独立,各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
Y1和Y2独立地为-C(R7)(R8)-、-CR9=、-NR10-、-O-或-S-;
X1和X2各自独立地为-C(R11)(R12)-、-N=、-NR13-、-S-或-O-;
R7、R8、R9、R11和R12各自独立地为-H、卤素、氰基、烷基、环烷基、经取代的烷基、烯基、炔基、芳基、胺、烷基胺、烷氧基;
R10和R13各自独立地为-H、烷基、环烷基、经取代的烷基、烯基、烯基、炔基、芳基、烷基胺、烷氧基;
L1和L2各自为在环3和W1之间以及环6和W2之间含有m个原子的烷基、经取代的烷基或杂原子链,其中m=0、1、2、3、4、5或6;当m为0时,W1或W2分别与环3或环6中的对应氮直接连接;
W1和W2各自独立地为氢、五元杂环或经取代的五元杂环、六元杂环或经取代的六元杂环、羧基烷基或经取代的羧基烷基、氰烷基或经取代的氰烷基、氨基烷基或经取代的氨基烷基、羟烷基或经取代的羟烷基、氨基酸、氨基酸酯、氨基酸酰胺、非天然氨基酸、非天然氨基酸酯或非天然氨基酸酰胺。
2.根据权利要求1所述的化合物,其中
A和B各自独立地选自卤素、烷基和经取代的烷基、氰基和-N3,
Z1为-CR1=或-N=;
Z2为-CR2=;
Z3为-CR3=或-N=;
Z4为-CR4=或-N=,
Z5为-CR5=;
Z6为-CR6=或-N=;
R1和R4各自独立地为-H或-F、-Cl或-CH3;
R2和R5各自独立地为-H、-Cl、-F、-CH3或-NH2;
R3和R6各自独立地为-H、-Cl、-F、-CH3或-NH2;
X1和X2各自独立地为-C(R11)(R12)-、-N=、-NH-、-N(R13)-或-O-;
Y1和Y2独立地为-CH2-、-CH=、-NH-、-O-、-C(R7)(R8)-;
R7、R8、R11和R12各自独立地为-H、-F、-Cl或-CH3;
L1和L2各自为含有m个碳原子的烷基或经取代的烷基,其中m=0、1、2、3、4、5或6;当m为0时,W1或W2分别与环3或环6中的对应氮直接连接;
W1和W2各自独立地为氢、五元杂环或经取代的五元杂环、六元杂环或经取代的六元杂环、羧基烷基或经取代的羧基烷基、氰烷基或经取代的氰烷基、氨基烷基或经取代的氨基烷基、羟烷基或经取代的羟烷基、氨基酸、氨基酸酯、氨基酸酰胺、非天然氨基酸、非天然氨基酸酯或非天然氨基酸酰胺。
3.根据权利要求1所述的化合物,其中所述化合物包括选自由式(II)至(XXIII)组成的组的核心结构:
4.根据权利要求1所述的化合物,所述化合物包括以下的核心结构:
或者
5.根据权利要求3所述的化合物,L1和L2各自独立地为C1-C3烷基。
6.根据权利要求1至4中任一项所述的化合物,其中W1和W2各自独立地为I型侧链,其中I型侧链由以下组成:
-C(O)ONa、-CN、-CH2OH和-CH2NH2。
7.根据权利要求1至4中任一项所述的化合物,其中W1和W2各自独立地为II型侧链,其中W1的II型侧链具有以下通式:
其中R14和R15独立地为-H、烷基或经取代的烷基,
其中W2的II型侧链具有以下通式:
其中R16和R17独立地为-H、烷基或经取代的烷基。
8.根据权利要求6中任一项所述的化合物,其中R14为以下中的一种:
R15独立地为-H、烷基或经取代的烷基,
其中R16为以下中的一种:
并且R17独立地为-H、烷基或经取代的烷基。
9.根据权利要求6所述的化合物,其中R14和R16各自独立地选自以下的组:
10.根据权利要求6所述的化合物,其中W1或W2为L-丝氨酸。
11.根据权利要求9所述的化合物,其中W1和W2两者均为L-丝氨酸。
12.根据权利要求6所述的化合物,其中W1或W2为L-丝氨酸酯。
13.根据权利要求11所述的化合物,其中W1和W2两者均为L-丝氨酸酯。
14.根据权利要求6所述的化合物,其中W1和/或W2为L-丝氨酸酯。
15.根据权利要求1至4中任一项所述的化合物,其中W1和W2独立地选自由以下组成的组:
16.根据权利要求1至4中任一项所述的化合物,其中
W1为并且
W2为H,并且L2不存在(即,m=0)。
17.根据权利要求1至4中任一项所述的化合物,其中
W1为并且W2为I型或II型侧链。
18.根据权利要求1至4中任一项所述的化合物,其中
W1为并且W2为I型或II型侧链。
19.根据权利要求1至4中任一项所述的化合物,其中
W1为并且W2为I型或II型侧链。
20.根据权利要求1至4中任一项所述的化合物,其中
W1为并且W2为I型或II型侧链。
21.根据权利要求1至4中任一项所述的化合物,其中
W1为并且W2为/>
22.根据权利要求16至20中任一项所述的化合物,其中L1和L2各自独立地为C1-C3烷基。
23.根据权利要求1所述的化合物,其中所述化合物选自由以下组成的组:表1中的化合物编号281、303、448、338、354、361、363、372、376、381、382、388、395、396、401、402、457、466、481、445、449、454、460、461、465、468、469、470、471、475、476、478、482、483、484、490、491、493、513、527、528、536、537、541、545、551、552、553、560、566、570、571、573、588、479、480、563、550、554、589、561、557、586、585、514、373、374、375、378、384、386、427、394、397、408、411、503、530、531、535、539、540、412、413、415、459、422、430、472、567、529、558、559、538、429、385、533、516、515、542、488、489、492、450、517、其药学上可接受的盐、其立体异构体、其立体异构体的混合物及其互变异构体。
24.根据权利要求1所述的化合物,其中所述化合物选自由以下组成的组:表1中的化合物编号338、361、411、465、475、483、529、533、537、541、554、585、613、614、619、620、628、633、648、649、其药学上可接受的盐、其立体异构体、其立体异构体的混合物及其互变异构体。
25.一种化合物或其药学上可接受的盐、立体异构体、立体异构体的混合物或互变异构体,所述化合物为
26.一种用于治疗受试者的与PD-L1和PD-1之间的相互作用相关的疾病或病状的方法,所述方法包括以下步骤:
向所述受试者施用有效量的根据权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、立体异构体的混合物、溶剂化物或互变异构体。
27.根据权利要求26所述的方法,其中所述疾病是癌症。
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