CN115315427B - Hpk1抑制剂及其制备方法和用途 - Google Patents
Hpk1抑制剂及其制备方法和用途 Download PDFInfo
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- CN115315427B CN115315427B CN202180023281.0A CN202180023281A CN115315427B CN 115315427 B CN115315427 B CN 115315427B CN 202180023281 A CN202180023281 A CN 202180023281A CN 115315427 B CN115315427 B CN 115315427B
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及一种通式(1)所示的化合物及其制备方法，及如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为HPK1抑制剂的用途。本发明化合物可用于制备治疗或者预防由HPK1介导的相关疾病。
Description
本申请要求申请日为2020年4月20日的中国专利申请CN2020103138714的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及一类新型HPK1抑制剂化合物，及其制备方法和该类化合物用于制备治疗或者预防由HPK1介导的相关疾病。
背景技术
造血祖细胞激酶1(hematopoietic progenitor kinase1，HPK1)为造血祖细胞中克隆出来的丝氨酸/苏氨酸蛋白激酶，属于哺乳动物Ste-20相关蛋白激酶MAP4K家族成员之一，其它成员包括MAP4K2/GCK、MAP4K3/GLK、MAP4K4/HGK、MAP4K5/KHS和MAP4K6/MINK[Mol.Cell Biol.，1999，19(2)：1359-1368.]。HPK1主要在造血祖细胞、T细胞、B细胞、NK细胞、免疫树突细胞、巨噬细胞和肥大细胞等造血免疫相关的细胞中表达[J.Biol.Chem.，2004，279(47)：49551-49561.]。
HPK1在T，B细胞受体以及树突细胞活化时激活，反馈抑制T，B细胞受体活化，树突细胞抗原递呈等多种免疫响应。HPK1与许多接头蛋白，如SLP-76家族、CARD11、HIS、HIP-55、GRB2家族、LAT、CRK家族等相互作用，发挥功能。在T、B细胞受体活化时，HPK1磷酸化SLP-76家族蛋白，调节SLP-76蛋白复合物的活性，从而对T细胞受体，B细胞受体信号转导通路进行负向调节。与HPK1的免疫抑制作用相符，HPK1缺失的T细胞和树突细胞活力增强，对肿瘤的杀伤力更强。因此，抑制HPK1增强肿瘤的免疫反应，而HPK1作为T细胞介导的免疫反应的调节机制，成为新的免疫抗肿瘤的研发热点。HPK1抑制剂在治疗恶性实体瘤或者血液癌(如急性髓性白血病、膀胱上皮癌、乳腺癌、结肠癌、肺癌、胰腺癌、黑色素瘤)，以及HPK1相关的免疫性疾病中具有潜在的应用价值。
目前针对HPK1靶点尚未有药物上市，为了更好的满足巨大的临床需求，开发调节HPK1活性的新化合物将为治疗相关疾病提供新的方向。
发明内容
本发明旨在提供一种如通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
式(1)中：
“*”表示手性中心；
n为0、1、2或3的整数；
X为H、卤素、C1-3烷基、C1-3卤代烷基或C3-6环烷基；
Y为-O-、-NH-或-N(C1-3烷基)-；
当各个R连接到不同的碳原子时，各个R独立为H或C1-3烷基；当两个R同时连接到同一碳原子上时，这两个R可以独立为H或C1-3烷基或者与其相连的碳原子形成碳基(C＝O)；
R1为H、C1-6烷基、C3-6环烷基、杂环烷基、羟基取代C1-6烷基、卤素取代C1-6烷基、C1-6烷氧基取代C1-6烷基或氰基取代C1-6烷基；
A为下列基团：其中“**”表示和基团B连接的位置，X1为N、CH、CF、C-Cl、C-Me或C-CN，X2为N、CH、CF、C-Cl、C-Me或C-CN，X3为N或CH，Y1为N或CH，Y2为N、CH、C-Me或C-CN；
B为C6-10芳基或5-10元杂芳基，其中该5-10元杂芳基由至少含有1个碳原子及1-4个选自N、O或S的杂原子组成；其中该N或S原子可被氧化；其中该5-10元杂芳基的环形碳原子可被选地经氧取代形成羰基(C＝O)；且该C6-10芳基和5-10元杂芳基可选地经1-5个独立选自R2的取代基取代；
R2独立为卤素、CN、NO2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、氰基取代C1-6烷基、羟基取代C1-6烷基、C1-3烷氧基取代C1-6烷基、C1-3卤代烷氧基取代C1-6烷基、C3-6环烷基、4-7元杂环烷基、5-7元杂芳基、OR3、SR3、C(O)R3、S(O)R3、S(O)2R3、C(O)OR3、OC(O)R3、NR4R5、P(O)R4R5、C(O)NR4R5、OC(O)NR4R5、-C1-6烷基-NR4R5、-O-C1-6烷基-NR4R5、-C1-6烷基-OR3、-O-C1-6烷基-R3、-羟基取代C1-6烷基-R3、-NR6C(O)R3、-NR6S(O)2R3、-NR6CO-C1-3烷基-R3或-NR6CO-C1-3烷基-NR4R5；
或B环上两个相邻的R2取代基与它们所连接的原子合在一起形成稠合4-7元杂环烷基或C3-7环烷基，该稠合4-7元杂环烷基至少含有1个碳原子及1-4个选自N、O或S的杂原子组成；其中该N或S原子可被氧化；其中该4-7元稠合杂环烷基的环形碳原子可被选地经氧取代形成羰基(C＝O)；且该稠合4-7元杂环烷基或C3-7环烷基可选地经1-5个独立选自R7的取代基取代；
各R3独立为H、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C3-6环烷基、4-7元杂环烷基、C6-10芳基、5-7元杂芳基、氰基取代C1-6烷基、羟基取代C1-6烷基、C1-3烷氧基取代C1-6烷基或C1-3卤代烷氧基取代C1-6烷基；
各R4和R5独立为H、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C3-6环烷基、氰基取代C1-6烷基、羟基取代C1-6烷基、C1-3烷氧基取代C1-6烷基或C1-3卤代烷氧基取代C1-6烷基、C6-10芳基取代C1-6烷基、5-10元杂芳基取代C1-6烷基或R4和R5共N原子形成4-12元杂环烷基，该4-12元杂环烷基可选地经1-5个独立选自R7的取代基取代；
各R6为H或C1-3烷基；
各R7为OH、CN、NH2、NHMe、NMe2、C1-6烷基、C1-6卤代烷基或C1-6烷氧基。
在另一优选例中，其中所述通式(1)中，X为H、F、Cl、Me、Et、CF3、异丙基或环丙基。
在另一优选例中，其中所述通式(1)中，Y为-O-、-NH-、-N(Me)-或-N(Et)-。
在另一优选例中，其中所述通式(1)中，R为H或Me。
在另一优选例中，其中所述通式(1)中，R1为H、Me、Et、
在另一优选例中，其中所述通式(1)中，A为下列基团： 其中“**”表示和基团B连接的位置。
在另一优选例中，其中所述通式(1)中，B为R2独立为H、CH3、F、Cl、OCH3、CF3、CN、CONH2、/>NHSO2CH3、NHCOCH3、PO(CH3)2、SO2CH3、SO2NH2、SO2NHCH3、CH2NHCH3，CH2NHCH2CH3、/>CH(CH3)NHCH3、CH2CN、CH2OCH3、NHCOCH2N(CH3)2、OCH2CH2CH2NH2、OCH2CH2CH2N(CH3)2、/> m为0、1、2或3的整数。
在另一优选例中，其中所述通式(1)中，B为
在另一优选例中，其中所述通式(1)中，B为
在各种不同实施方式中，本发明代表性化合物具有以下结构之一：
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本发明的另一个目的是提供了一种药物组合物，其含有药理上可接受的赋形剂或载体，以及作为活性成分的本发明通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物。
本发明的再一个目的提供了本发明的上述化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或本发明的上述药物组合物在制备治疗或者预防由HPK1介导的相关疾病中的用途。
本发明的一个目的是提供一种治疗由HPK1介导的疾病的方法，其包括给与受试者本发明通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或本发明的上述药物组合物。所述HPK1介导的疾病可为癌症，所述癌症可以为血液癌或实体瘤。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式(1)所示的化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的通式(1)所示的化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANICCHEMISTRY 4thEd.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4thEd.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANICSYNTHESIS 3rdEd.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示的化合物的制备方法，其采用下列一般反应流程1制备：
一般反应流程1
通式(1)所示的化合物的实施方式可根据一般反应流程1制备，其中Y、X1、X2、X3、Y1、Y2、R1和基团B如上文中所定义，PG1和PG2表示保护基，V表示氯、溴、碘、OTf等基团。如一般反应流程1所示，化合物A1和化合物3，4-二氟硝基苯在碱性条件下反应生成化合物A2，化合物A2在强碱性条件下关环得到化合物A3，化合物A3脱除保护基PG1得到化合物A4，化合物A4进一步反应得到化合物A5，化合物A5进行硝基还原得到化合物A6，化合物A6进行重氮化和双联频哪醇硼酸酯反应得到化合物A7，化合物A7和化合物A8a(或A8b)进行偶联反应得到化合物A9a(或A9b)，化合物A9a(或A9b)进一步脱除保护基PG2得到目标化合物A10a(或A10b)。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，式(1)化合物存在手性中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个这种手性中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)、碘-125(125I)和C-14(14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH3、CH3CH2、CF3、CHF2、CF3CH2、CF3(CH3)CH、iPr、nPr、iBu、nBu或tBu。
除非另有规定，“环烷基”指3至6元全碳单环脂肪烃基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。例如，环丙基、环丁基、环戊基、环己烷、环己二烯等。
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH3、OCF3、CHF2O、CF3CH2O、i-PrO、n-PrO、i-BuO、n-BuO或t-BuO。
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的，例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基和吡咯并嘧啶基。
除非另有规定，“杂环烷基”指含有一个或多个杂原子(O、S或N)的饱和或部分不饱和环体系基团，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化，作为环原子。除非另有说明，“杂环烷基”的环体系可以是单环、双环、螺环、桥环或多环的环体系。“杂环烷基”可以通过一个以上环碳或杂原子连接于分子的其余部分。“杂环烷基”的例子包括但不限于吡咯烷、哌啶、N-甲基哌啶、四氢咪唑、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、嘧啶-2，4(1H，3H)-二酮、1，4-二氧六环、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S，S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环、2-氮杂螺[3.3]庚烷等。
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示的化合物，以及通式(1)所示的化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g_润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中，1H-NMR用Vian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：MeCN代表乙腈；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；Dioxane代表1，4-二氧六环；DMF代表二甲基甲酰胺；EA代表乙酸乙酯；h代表小时；I2代表碘；KOH代表氢氧化钾；K3PO4代表磷酸钾；min代表分钟；MS代表质谱；NaBH3CN代表氰基硼氢化钠；NaH代表氢化钠；NaHCO3代表碳酸氢钠；Na2SO4代表硫酸钠；NMR代表核磁共振；Pd(dppf)Cl2代表1，1′-双(二苯基膦基)二茂铁]二氯化钯；PE代表石油醚；Sphos-Pd-G3代表甲烷磺酸(2-二环己基膦基-2′，6′-二甲氧基-1，1′-联苯基)(2′-氨基-1，1′-联苯-2-基)钯(II)；TFA(CF3COOH)代表三氟乙酸；TLC代表薄层色谱。
具体实施方式
实施例1 5-(2-氟苯基)-3-(3-甲基-1，2，3，4，4a，5-六氢苯并[b]吡嗪并[1，2-d][1，4]噁嗪-8-基)-1H-吲唑-6-甲腈(化合物1)的合成
步骤1：化合物1-1的合成
将3-羟甲基哌嗪-1-甲酸叔丁酯(1.0g，4.63mmol)，1，2-二氟-4-硝基苯(809mg，5.1mmol)溶于DMF(20mL)中，加入DIPEA(1.8g，13.89mmol)，升温至120℃，反应过夜，LC-MS监测，反应完毕，到入水(100mL)中，EA(50mL*3)萃取，合并有机相，有机相用水(50mL)洗，无水Na2SO4干燥，浓缩，柱层析(PE/EA＝10/1 to 5/1)，得到黄色固体化合物1-1(1.0g，收率61％)，ESI-MS m/z：356.1[M+H]+。
步骤2：化合物1-2的合成
将化合物1-1(3.6g，10mmol)溶于DMF(30mL)中，冰浴冷却下，加入NaH(440mg，11mmol)，后升温至80℃反应过夜，LC-MS监测反应完毕，冷却，倒入冰水(100mL)中，EA(50mL*2)萃取，合并有机相，有机相用水洗(150mL*2)，饱和食盐水(50mL)洗，浓缩，柱层析(PE/EA＝20/1 to 10/1)，得到黄色固体化合物1-2(2.1g，收率62％)，ESI-MS m/z：336.1[M+H]+。
步骤3：化合物1-3的合成
将化合物1-2(2.0g，6.0mmol)溶于EA(40mL)中，加入HCl/二氧六环(4.0M，10mL)，室温搅拌3h，LC-MS监测反应完毕，直接浓缩，得到黄色固体化合物1-3(2.0g，收率100％)，ESI-MS m/z：236.1[M+H]+。所得初产物不经纯化，直接投入下一步反应。
步骤4：化合物1-4的合成
将上步所得粗产物1-3溶于MeCN(20mL)中，加入甲醛水溶液(35％～40％，0.5mL)，HOAc(360mg，6.0mmol)，室温搅拌1h，加入NaBH3CN(0.76g，12mmol)，室温反应过夜，LC-MS监测反应完毕，浓缩，残留物用EA(50mL)溶解，NaHCO3水溶液(50mL)洗，浓缩，柱层析(DCM/MeOH＝100/1 to 20/1)得到黄色固体化合物1-4(1.0g，收率66％)，ESI-MS m/z：250.1[M+H]+。
步骤5：化合物1-5的合成
将化合物1-4(1.0g，4.0mmol)溶于MeOH(50mL)中，加入Pd/C(10％，200mg)，通入氢气，室温反应过夜，LC-MS监测反应完毕，过滤，浓缩，得到浅黄色固体化合物1-5(800mg，收率91％)，ESI-MS m/z：220.1[M+H]+。所得初产物不经纯化，直接投入下一步反应。
步骤6：化合物1-6的合成
将化合物1-5(440mg，2mmol)溶于MeOH(4mL)中，冰浴，加入盐酸水溶液(3.0M，2mL)，加入NaNO2(138mg，2mmol)水溶液(1mL)，冰浴下搅拌30min，加入联硼酸频哪醇酯(1.52g，6mmol)，搅拌1h，LC-MS监测反应完毕，加入NaHCO3水溶液淬灭反应，DCM(50mL*2)萃取，有机相无水Na2SO4干燥，浓缩，经柱层析(DCM/MeOH＝50/1 to 20/1)得到浅黄色胶状物1-6(500mg，收率75％)，ESI-MS m/z：331.1[M+H]+。
步骤7：化合物1-8的合成
将5-氯-6-氰基-1H-吲唑-1-甲酸叔丁酯(2.78g，10mmol)，2-氟苯硼酸(1.40g，10mmol)溶于1，4-dioxane/H2O(v/v＝5/1，30mL)中，加入K3PO4(4.24g，20mmol)，Pd XPhosG3(423mg，0.05mmol)，氩气保护下升温90℃反应5h，LC-MS监测反应完毕，冷却，加入EA(50mL)稀释，水洗(50mL*2)，有机相浓缩，经柱层析(PE/EA＝20/1 to 5/1)得到浅黄色固体化合物1-8(0.83g，收率35％)，ESI-MS m/z：238.1[M+H]+。
步骤8：化合物1-9的合成
将化合物1-8(474mg，2mmol)于DMF(10mL)中，加入KOH(280mg，5mmol)和I2(760mg，3mmol)，室温搅拌两小时，LC-MS监测反应完毕，冷却至室温，加1N盐酸调节pH为7左右，加入EA/H2O(50mL/50mL)，分液，水相用EA(50mL*2)萃取，合并有机相，减压浓缩，柱层析(PE/EA＝10/1 to 2/1)，得到浅黄色固体化合物1-9(425mg，收率56％)，ESI-MS m/z：378.2[M+H]+。
步骤9：化合物1-10的合成
将化合物1-9(377mg，1.0mmol)溶于DCM(20mL)中，加入TEA(202mg，2.0mmol)，最后加入(Boc)2O(262mg，1.2mmol)，室温下搅拌3小时，LC-MS监测反应完毕，加入EA/H2O(50mL/50mL)，分液，有机相浓缩，经柱层析(PE/EA＝20/1 to 10/1)得到浅黄色固体化合物1-10(402mg，收率87％)，ESI-MS m/z：464.3[M+H]+。
步骤10：化合物1-11的合成
将化合物1-10(232mg，0.5mmol)和化合物1-6(198mg，0.6mmol)溶于1，4-dioxane/H2O(V/V＝5/1，10mL)中，加入K3PO4(212mg，1.0mmol)，Pd(dppf)2Cl(73mg，0.1mmol)，氩气保护下升温90℃反应5h，LC-MS监测反应完毕，冷却，加入EA(50mL)稀释，水洗(20mL*1)，有机相浓缩，经柱层析(DCM/MeOH＝50/1 to 20/1)得到浅黄色固体化合物1-11(168mg，收率62％)，ESI-MS m/z：540.2[M+H]+。
步骤11：化合物1的合成
将化合物1-11(162mg，0.3mmol)溶于HCl/dioxane(4.0N，2mL)中，室温反应3h，LC-MS监测反应完毕，直接浓缩，残留物加入DCM(50mL)溶解，NaHCO3水溶液调至碱性，分层，有机相无水Na2SO4干燥，浓缩，经柱层析(DCM/MeOH＝50/1 to 20/1)得到浅黄色固体化合物1(96mg，收率73％)。
1H NMR(400MHz，DMSO-d6)δ：8.36(s，1H)，8.21(s，1H)，7.78-7.70(m，2H)，7.52(d，J＝8.8Hz，1H)，7.42-7.32(m，2H)，7.23(dd，J＝10.0，5.3Hz，1H)，6.98(d，J＝8.7Hz，1H)，4.29-4.16(m，1H)，3.91(t，J＝9.7Hz，1H)，3.66-3.72(m，1H)，3.09(s，1H)，2.85(d，J＝10.3Hz，1H)，2.79(d，J＝10.9Hz，1H)，2.71-2.62(m，1H)，2.19(s，3H)，2.13-2.00(m，1H)，1.72(t，J＝10.7Hz，1H)，ESI-MS m/z：440.2[M+H]+.
以(S)-3-羟甲基哌嗪-1-甲酸叔丁酯或(R)-3-羟甲基哌嗪-1-甲酸叔丁酯为起始原料，类似化合物1的合成，可以得到化合物1的两个光学异构体1-a和1-b：
实施例2-129化合物2-129的合成
采用不同原料，根据实施例1中类似的合成方法得到目标化合物2-129。
表1
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实施例130化合物对HPK1酶活性测试
以PKC为底物，运用lantha Screen方法测定化合物对HPK1酶活的抑制作用。具体如下：将HPK1蛋白与梯度稀释的化合物在28度孵育10分钟后加入fluorescein-标记的PKC底物和ATP反应90分钟。终止反应后加入针对磷酸化PKC的Terbium标记的抗体，孵育60分钟。通过检测520nm和450nm的发光，监测Teribium和fluorescein的能量转移，定量PKC为HPK1磷酸化的水平。与对照组相比，计算化合物抑制百分比和IC50。
表2.本发明化合物对HPK1的酶抑制活性
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+表示IC50大于或等于100nM
++表示IC50大于10nM但小于100nM
+++表示IC50小于或等于10nM。
从表2数据可知，本发明化合物对HPK1的酶抑制活性IC50值小于或等于10nM，化合物具有很强的HPK1酶抑制活性。
实施例131化合物对hERG通道抑制活性测试
采用hERG钾通道稳定表达的HEK293细胞系，手动膜片钳进行检测。首先将hERG钾通道稳定表达的HEK293细胞系在膜片钳检测试验之前，分离后铺到盖玻片上，培养18个小时后进行试验检测。再将毛细玻璃管拉制成记录电极，在倒置显微镜下将记录电极接触到细胞上，形成全细胞记录模式。进行必要的补偿并记录膜电容及串联电阻之后，按设置的电流刺激方案进行电流记录。hERG电流稳定后开始给药，每个细胞在不含化合物的外液中检测到的电流作为自己的对照组，独立重复检测多个细胞。将每一个药物浓度作用后的电流和空白对照电流标准化，然后计算每一个药物浓度对应的抑制率，最后再算出每种化合物的半抑制浓度IC50值。
表3.本发明化合物对hERG通道抑制活性(IC50)
| 化合物 | hERG通道抑制活性(IC50，μM) |
| 6 | 17.8 |
| 16 | 23.6 |
| 18 | 11.8 |
| 35 | 31.8 |
| 43 | 17.4 |
| 67 | 51.2 |
| 73 | 41.2 |
| 112 | 35.6 |
从表2数据可知，本发明化合物对hERG通道的抑制较弱，抑制活性IC50值大于10μM，预示化合物在心脏安全性方面具有较好的安全性。
Claims (12)
1.一种结构如通式(1)所示的化合物、其旋光异构体或药学上可接受的盐：
式(1)中：
“*”表示手性中心；
n为0；
X为H；
Y为-O-、-NH-或-N(C1-3烷基)-；
R不存在；
R1为H、C1-6烷基、C3-6环烷基、 卤素取代C1-6烷基或氰基取代C1-6烷基；
A为下列基团：其中“**”表示和基团B连接的位置，X1为N、CH或C-CN，X2为N或CH，X3为N或CH，Y1为N或CH，Y2为N或CH；
B为C6-10芳基或5-10元杂芳基，其中该5-10元杂芳基由至少含有1个碳原子及1-4个选自N、O或S的杂原子组成；且该C6-10芳基和5-10元杂芳基可选地经1-5个独立选自R2的取代基取代；
R2独立为卤素、CN、C1-6烷基、C1-6卤代烷基、氰基取代C1-6烷基、C1-3烷氧基取代C1-6烷基、C1-3卤代烷氧基取代C1-6烷基、C3-6环烷基、4-7元杂环烷基、5-7元杂芳基、OR3、S(O)2R3、P(O)R4R5、C(O)NR4R5、OC(O)NR4R5、-C1-6烷基-NR4R5、-O-C1-6烷基-NR4R5、-C1-6烷基-OR3、-O-C1-6烷基-R3、-NR6C(O)R3、-NR6S(O)2R3、-NR6CO-C1-3烷基-R3或-NR6CO-C1-3烷基-NR4R5；
各R3独立为H、C1-6烷基、C1-6卤代烷基、C3-6环烷基、氰基取代C1-6烷基；
各R4和R5独立为H、C1-6烷基；
各R6为H或C1-3烷基。
2.一种结构如通式(1)所示的化合物、其旋光异构体或药学上可接受的盐：
式(1)中：
“*”表示手性中心；
n为0；
X为H；
Y为-O-、-NH-或-N(C1-3烷基)-；
R不存在；
R1为H、C1-6烷基、C3-6环烷基、 卤素取代C1-6烷基或氰基取代C1-6烷基；
A为下列基团：其中“**”表示和基团B连接的位置，X1为N、CH或C-CN，X2为N或CH，X3为N或CH，Y1为N或CH，Y2为N或CH；
B为
各R3独立为H、C1-6烷基、C1-6卤代烷基、C3-6环烷基、氰基取代C1-6烷基；
各R4和R5独立为H、C1-6烷基；
各R6为H或C1-3烷基。
3.如权利要求1或2所述的化合物、其旋光异构体或药学上可接受的盐，其中所述通式(1)中，Y为-O-、-NH-、-N(Me)-或-N(Et)-。
4.如权利要求1或2中任一项所述的化合物、其旋光异构体或药学上可接受的盐，其中所述通式(1)中，R1为H、Me、Et、
5.如权利要求1或2中任一项所述的化合物、其旋光异构体或药学上可接受的盐，其中所述通式(1)中，A为下列基团： 其中“**”表示和基团B连接的位置。
6.如权利要求1所述的化合物、其旋光异构体或药学上可接受的盐，其中所述通式(1)中，B为R2独立为CH3、F、Cl、OCH3、CF3、CN、CONH2、NHSO2CH3、NHCOCH3、PO(CH3)2、SO2CH3、CH2NHCH3、CH2NHCH2CH3、CH(CH3)NHCH3、CH2CN、CH2OCH3、NHCOCH2N(CH3)2、OCON(CH3)2、OCH2CH2CH2NH2、OCH2CH2CH2N(CH3)2；m为0、1、2或3的整数。
7.如权利要求1所述的化合物、其旋光异构体或药学上可接受的盐，其中所述通式(1)中，B为
8.如权利要求1所述的化合物、其旋光异构体或药学上可接受的盐，其中所述通式(1)中，B为
9.一种化合物、其旋光异构体或药学上可接受的盐，其中所述化合物具有以下结构之一：
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10.一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及作为活性成分的如权利要求1-9中任一项所述的化合物、其旋光异构体或药学上可接受的盐。
11.一种如权利要求1-9中任一项所述的化合物、其旋光异构体或药学上可接受的盐如权利要求10所述的药物组合物在制备治疗、调节和/或预防HPK1介导的相关疾病的药物中的应用。
12.如权利要求11所述的应用，其中所述的疾病是癌症，所述癌症是血液癌或实体瘤。
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| US11453681B2 (en) | 2019-05-23 | 2022-09-27 | Gilead Sciences, Inc. | Substituted eneoxindoles and uses thereof |
| WO2023083299A1 (zh) * | 2021-11-12 | 2023-05-19 | 微境生物医药科技(上海)有限公司 | 作为hpk1抑制剂的稠环化合物 |
| WO2023083282A1 (zh) * | 2021-11-12 | 2023-05-19 | 微境生物医药科技(上海)有限公司 | 作为hpk1抑制剂的稠环化合物 |
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| WO2016197987A1 (zh) * | 2015-06-12 | 2016-12-15 | 杭州英创医药科技有限公司 | 作为Syk抑制剂和/或Syk-HDAC双重抑制剂的杂环化合物 |
| WO2018108083A1 (zh) * | 2016-12-12 | 2018-06-21 | 杭州英创医药科技有限公司 | 作为Syk抑制剂和/或Syk-HDAC双重抑制剂的杂环化合物 |
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| CN115279760A (zh) * | 2020-03-03 | 2022-11-01 | 轶诺(浙江)药业有限公司 | 新型hpk1抑制剂及其制备方法和应用 |
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| WO2016197987A1 (zh) * | 2015-06-12 | 2016-12-15 | 杭州英创医药科技有限公司 | 作为Syk抑制剂和/或Syk-HDAC双重抑制剂的杂环化合物 |
| WO2018108083A1 (zh) * | 2016-12-12 | 2018-06-21 | 杭州英创医药科技有限公司 | 作为Syk抑制剂和/或Syk-HDAC双重抑制剂的杂环化合物 |
| WO2019238067A1 (en) * | 2018-06-13 | 2019-12-19 | Beigene, Ltd. | Pyrrolo [2, 3-b] pyridines or pyrrolo [2, 3-b] pyrazines as hpk1 inhibitor and the use thereof |
| WO2021013083A1 (en) * | 2019-07-17 | 2021-01-28 | Beigene, Ltd. | Tricyclic compounds as hpk1 inhibitor and the use thereof |
| CN115279760A (zh) * | 2020-03-03 | 2022-11-01 | 轶诺(浙江)药业有限公司 | 新型hpk1抑制剂及其制备方法和应用 |
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