WO2023221900A1 - 选择性her2和her2异变抑制剂 - Google Patents
选择性her2和her2异变抑制剂 Download PDFInfo
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- WO2023221900A1 WO2023221900A1 PCT/CN2023/094022 CN2023094022W WO2023221900A1 WO 2023221900 A1 WO2023221900 A1 WO 2023221900A1 CN 2023094022 W CN2023094022 W CN 2023094022W WO 2023221900 A1 WO2023221900 A1 WO 2023221900A1
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- 229960004964 temozolomide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D471/02—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 in which the condensed system contains two hetero rings
- 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
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种如式I所示的选择性HER2抑制剂化合物或其药学上可接受的盐
Description
本发明属于医药领域,具体涉及一种选择性HER2和HER2异变抑制剂。
目前HER2(也称ErbB2)和HER2异变己经成为许多癌症的治疗靶点。己经上市及在研的HER2小分子激酶抑制剂通常对别的通道(如EGFR)也有抑制作用。因此,会引起皮疹、腹泻等副作用。同时有脑透功能的HER2抑制剂对脑转移的患者有特殊的应用。唯一的上市选择性HER2小分子激酶抑制剂,Tucatinib,由于其活性的原因,正在进行许多联用的临床研究。此外,新的针对HER2的ADC,如T-DM1和T-DXd,虽然有很好的药效,但都不可避免地产生耐药,而且脑透功能很差。
综上所述,本领域迫切需要开发性能更加优良的、高选择性的、有透脑功能的、对EGFR没有抑制作用的HER2和HER2异变的小分子激酶抑制剂来满足临床需求。以及可以作为HER3,4和HER3,4异变的小分子激酶抑制剂来满足临床需求
发明内容
本发明的目的就是提供新颖的选择性HER2抑制剂。本发明的另一个目的是提供使用该抑制剂的方法或提供该抑制剂的用途。
在本发明的第一方面,提供了一种化合物或其药学上可接受的盐,所述的化合物如式I所示,
其中,
Q1为-CONR'-,Q2为含一个环氮(N)原子的4-6元单环杂环基;或者,-Q1-Q2-代表由两个相同或不同的含一个环氮原子的4-6元单环杂环基形成的稠环或螺环;并且所述4-6元单环杂环基任选地被一个或多个(如1、2或3个)R'基团所取代;其中,R'各自独立地为H或C1-2烷基;
R1选自下组:H、取代或未取代的C1-4烷基、取代或未取代的C2-4烯基、取代或未取代的C2-4炔基、C1-4烷氧基,和卤素;
R2选自下组:H、取代或未取代的C1-4烷基,和卤素;
R3选自下组:
R4为
R5为H或取代或未取代的C1-4烷基;
R6选自下组:H、取代或未取代的C1-4烷基、-C1-2亚烷基-N(R")2;其中,R"为H或C1-4烷基;
除非特别说明,所述的取代是指基团上一个或多个(如1、2或3个)H原子被选自下组的取代基取代:氘(D)、卤素、C1-4烷基、C1-4卤代烷基。
在另一优选例中,R'为H。
在另一优选例中,所述含一个环N原子的4-6元单环杂环基的环上除所述一个环N原子外,均为碳(C)原子。
在另一优选例中,所述含一个环氮原子的4-6元单环杂环基是饱和的或不饱和的(如含1个双键);优选地,是饱和的。
在另一优选例中,由两个相同或不同的含一个环氮原子的4-6元单环杂烷基形成的稠环或螺环是饱和的或不饱和地(如含1或2个双键);优选地,是饱和的。
在另一优选例中,-Q1-Q2-通过N原子与分子的其余部分连接;
在另一优选例中,-Q2-Q1-为
其中,
表示单键或双键(较佳地,为单键);
*代表位于Q1上的连接位点;
W1为-(CR'2)n1-,W2为-(CR'2)n2-;其中n1=0、1或2,n2=0、1或2,且n1+n2≥1;
W3为-(CR'2)n3-,W4为-(CR'2)n4-;其中n3=0、1或2,n4=0、1或2,且n3+n4≥1;
R'各自独立地为H或C1-2烷基(较佳地,R'均为H)。
在另一优选例中,-Q2-Q1-为
在另一优选例中,n1+n2=1、2或3,且n3+n4=1、2或3。
在另一优选例中,n1+n2=1或2,且n3+n4=1或2。
在另一优选例中,n1+n2=1、2或3,且n3+n4=2。
在另一优选例中,n1+n2=1或2,且n3+n4=2。
在另一优选例中,n1+n2=2,且n3+n4=1或2。
在另一优选例中,n1=0,n2=2,n3=1且n4=0。在另一优选例中,n1=0,n2=1,n3=2且n4=0。在另一优选例中,n1=0,n2=1,n3=1且n4=1。在另一优选例中,n1=1,n2=1,n3=1且n4=0。在另一优选例中,n1=1,n2=1,n3=2且n4=0。在另一优选例中,n1=1,n2=1,n3=1且n4=1。在另一优选例中,n1=2,n2=0,n3=1且n4=1。在另一优选例中,n1=2,n2=0,n3=0且n4=2。在另一优选例中,n1=2,n2=1,n3=1且n4=0。
在另一优选例中,-Q2-Q1-选自下组:
在另一优选例中,-Q2-Q1-为
其中,
*代表位于Q1上的连接位点;
W5为-(CR'2)n5-,W6为-(CR'2)n6-;其中n5=0、1、2或3,n6=0、1、2或3且2≤n5+n6≤4;
W7为-(CR'2)n7-,W8为-(CR'2)n8-;其中n7=0、1、2或3,n8=0、1、2或3且2≤n7+n8≤4;
R'各自独立地为H或C1-2烷基(较佳地,R'均为H)。
在另一优选例中,n5=n6=1或2。
在另一优选例中,n5=n6=2,且n7=n8=2。
在另一优选例中,n5=n6=1,且n7和n8之一为0,另一个为1。
在另一优选例中,-Q2-Q1-为
其中,
*代表位于Q1上的连接位点;
W9为-(CR'2)n9-;其中n9=1、2或3;
R'各自独立地为H或C1-2烷基(较佳地,R'均为H)。
在另一优选例中,当下标n1、n2、n3、n4、n5、n6、n7、n8、或n9为0时,相应地-(CR'2)n1-、-(CR'2)n2-、-(CR'2)n3-、-(CR'2)n4-、-(CR'2)n5-、-(CR'2)n6-、-(CR'2)n7-、-(CR'2)n8-、或-(CR'2)n9-表示无(单键)。
在另一优选例中,-Q2-Q1-选自下组:
在另一优选例中,所述的化合物如式Ia所示
其中,
表示单键或双键;
W1为-(CR'2)n1-,W2为-(CR'2)n2-;其中,下标n1=0、1或2,下标n2=0、1或2,且n1+n2≥1;
W3为-(CR'2)n3-,W4为-(CR'2)n4-;其中,下标n3=0、1或2,下标n4=0、1或2,且n3+n4≥1;
R1、R2、R3、R4和R'如前中定义。
在另一优选例中,W1、W2、W3、W4、下标n1、下标n2、下标n3、和下标n4如前定义。
在另一优选例中,所述的化合物如式Ib所示
其中,
W5为-(CR'2)n5-,W6为-(CR'2)n6-;其中,下标n5=0、1、2或3,下标n6=0、1、2或3,且2≤n5+n6≤4;
W7为-(CR'2)n7-,W8为-(CR'2)n8-;其中,下标n7=0、1、2或3,下标n8=0、1、2或3,且2≤n7+n8≤4;
R1、R2、R3、R4和R'如前定义。
在另一优选例中,W5、W6、W7、W8、下标n5、下标n6、下标n7、和下标n8如前定义。
在另一优选例中,所述的化合物如式Ic所示
其中,
W9为-(CR'2)n9-;其中,下标n9=1、2或3;
R1、R2、R3、R4和R'如前定义。
在另一优选例中,W9、下标n9如前定义。
在另一优选例中,R1选自下组:H、取代或未取代的C1-4烷基。在另一优选例中,R1为取代或未取代的C1-4烷基。在另一优选例中,R1为C1-4烷基。在另一优选例中,R1选自下组:甲基、乙基。在另一优选例中,R1为甲基。
在另一优选例中,R2选自下组:H、甲基、和乙基。在另一优选例中,R2为H。
在另一优选例中,R3为
在另一优选例中,R5为C1-4烷基。在另一优选例中,R5为甲基。
在另一优选例中,R6选自下组:H、-C1-2亚烷基-N(R")2;其中,R"为C1-4烷基(较佳地,甲基)。
在另一优选例中,R1、R2、R3、R4、R5、R6、R1、Q1、Q2、R'、R"、W1、W2、W3、W4、W5、W6、W7、W8、W9、下标n1、下标n2、下标n3、下标n4、下标n5、下标n6、下标n7、下标n8、和下标n9各自独立地为实施例化合物活表A、表B和表C化合物中对应基团。
在另一优选例中,所述的化合物选自表A、表B和表C:
表A
表B
表C
在本发明的第二方面中,提供了一种药物组合物,其中,包括:(i)如第一方面所述的化合物或其药学上可接受的盐,和(ii)药学上可接受的载体或赋形剂。
在本发明的第三方面中,提供了一种如第一方面所述的化合物在制备用于治疗或预防疾病或病症的药物中用途,其中所述疾病或病症是由HER2介导的疾病或病症,或者可通过抑制HER2改善的疾病或病症。
在另一优选例中,所述化合物通过选择性抑制HER2来治疗或预防所述疾病或病症。
在另一优选例中,所述疾病或病症包括:癌症。
在另一优选例中,所述疾病或病症包括:脑癌、乳腺癌、胆囊癌、膀胱癌。宫颈癌、结直肠癌、胃癌、胃食管交界处癌、子宫内膜癌、皮肤癌、食道肿瘤、头颈部肿瘤、星形肠道癌、胆管癌、肾癌、肝癌、卵巢癌、胰腺癌、肺癌或前列腺癌中的一种或多种。
在本发明的第四方面中,提供了一种抑制HER2的方法,所述方法包括:使对象与如第一方面所述的化合物接触,从而抑制HER2。
在另一优选例中,所述对象为细胞。
在另一优选例中,所述HER2包括野生型HER2、突变型HER2(如HER2YVMA),或其组合。
在另一优选例中,所述抑制是对HER2的选择性抑制。
在另一优选例中,所述选择性抑制是指基本不抑制EGFR。
在另一优选例中,所述基本不抑制是指,对EGFR的抑制活性的IC50值是对HER2的抑制活性的IC50值的至少20倍,较佳地至少50倍。
在另一优选例中,所述的方法是体外非治疗性的。
在本发明的第五方面中,提供了一种治疗或预防疾病或病症的方法,其中所述疾病
或病症是由HER2介导的疾病或病症,或者可通过抑制HER2改善的疾病或病症方法,所述的方法包括步骤:
向有需要的对象施用治疗有效量的如第一方面的化合物或如第二方面所述的药物组合物,从而治疗或预防所述疾病或病症。
在另一优选例中,所述疾病或病症包括:癌症。
在另一优选例中,所述疾病或病症包括:脑癌、乳腺癌、胆囊癌、膀胱癌、宫颈癌、结直肠癌、胃癌、胃食管交界处癌、子宫内膜癌、皮肤癌、食道肿瘤、头颈部肿瘤、星形肠道癌、胆管癌、肾癌、肝癌、卵巢癌、胰腺癌、肺癌或前列腺癌中的一种或多种。
在另一优选例中,所述对象为哺乳动物,较佳地,为人。
在另一优选例中,所述化合物通过选择性抑制HER2来治疗或预防所述疾病或病症。
在另一优选例中,所述方法还包括向需要的对象施用治疗有效量的另外的药剂。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
发明人经过广泛而深入地研究。发现具有本申请式I所示的化合物具有优异的对HER2抑制活性以及选择性。基于此,本发明人完成了本发明。
术语
在本文中,除非另有说明,基团定义中以虚线表示的单键代表该基团与其他部分连接的位置。
在本文中,除非另有定义,当基团以从左到右的书写方式被定义时,该书写方式并不代表对该基团与分子其他部分连接连接位置限定,也就是说,当基团被以左到右的书写方式定义时,也包括从右到左方式书写的基团。例如,Q1为-CONR'-时,与Q2连接的既可以是CO端点的连接位置也可以是NR'端的连接位置。
如本文所述,术语“卤素”是指F、Cl、Br或I。相应地,“卤代”是指基团中的氢原子被F、Cl、Br或I取代。
除非特别说明,术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烃基(即,C1-6表示1-6个碳)。烷基(如C1-6烷基)的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基等。
除非特别说明,术语“环烷基”是指具有指定环原子数(例如,C3-6环烷基具有3-6个环原子)并且完全饱和的烃环,环烷基(如C3-6环烷基)的例子包括环丙基、环丁基、环戊基环己基等。“环烷基”也指双环和多环烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。
除非特别说明,术语“烯基”指具有一个或多个(优选1个)双键的不饱和烷基。类似地,术语“炔基”指具有一个或多个(优选1个)三键的不饱和烷基。一般地,烯基具有1-4个碳原子即C1-4烯基,炔基具有1-4个碳原子即C1-4炔基。这类不饱和烷基的例子包括:乙烯基、2-丙烯基、乙炔基、1-和3-丙炔基、3-丁炔基。
除非特别说明,术语"烷氧基"以其常规含义使用,指经氧原子连接于分子的其余部
分的具有指定碳原子数的那些烷基,例如,C1-4烷氧基可以是甲氧基(-OCH3)、乙氧基等。
如本文所用,术语“亚烷基”,其本身或作为另一取代基的一部分,是指衍生自烷烃的二价基团,例如-CH2-。
除非特别说明,术语“杂环基”,是指含有1至3个选自N、O和S的杂原子的环烷基,其中氮和硫原子任选被氧化,且氮原子任选被季铵化。在本文中,杂环基优选是指含4到6个环原子(即4-6元)的饱和或含一个双键的单环杂环。优选地,在本文中,杂环基仅含1个氮杂原子,其余环原子为碳原子。
对于本文提供的化合物,从取代基(通常为R基团)到环的中心的键将被理解为是指连接至环的任何可用顶点的键。
如本文所用,术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此,术语“主要由...组成”和“由...组成”包含在术语“含有”中。
如本文所用,术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。
应当理解,除非特别说明,对各基团名称术语的说明涵盖了指定了碳原子数/环原子数的情况,例如,要碳原子数满足,烷基的例子/实例也可以是C1-6烷基的例子/实例。
除非特别说明,本发明中,所有出现的化合物均意在包括所有可能的光学异构体,如单一手性的化合物,或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,术语“杂原子”意在包括氧(O)、氮(N)、硫(S)。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键;消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如,分离的对映体)均应包括在本发明范围内。当本文提供的化合物具有确定的立体化学(表示为R或S,或具有虚线或楔形键指明)时,被本领域技术人员将理解那些化合物为基本上不含其他异构体(例如至少80%,90%,95%,98%,99%和至多100%不含其他异构体)。
本发明化合物还可在构成此类化合物的一个或多个同位素原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100%该原子的量。例如,化合物可以掺入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。除了本申请所述的那些用途,此类同位素变体可提供额外的用途。例如,本发明化合物的同位素变体可以有额外的用途,包括但不限于作为诊断的和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可具有改变的药代动力学和药效学特征,从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性,本发明化合物的所有同位素变体均应包括在本发明范围内。
活性成分
如本文所用,术语“本发明化合物”或“本发明化合物”指本文中式I、式Ia、Ib或Ic所示的化合物。该术语还包括及式I、式Ia、Ib或Ic化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
其中,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、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、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外,本发明化合物还包括式I、式Ia、Ib或Ic所示的化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式I、式Ia、Ib或Ic的一类化合物,或式I、式Ia、Ib或Ic的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
本文中具体地描述本发明式I、式Ia、Ib或Ic结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。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地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
药物组合物和施用方法
由于本发明化合物具有优异的对HER2的选择抑制活性和抗肿瘤活性,因此,本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及改善与HER2相关或者由HER2介导的疾病或者治疗、预防以及改善肿瘤。根据现有技术,本发明化合物可用于治疗以下疾病:脑癌、乳腺癌、胆囊癌、膀胱癌。宫颈癌、结直肠癌、胃癌、胃食管交界处癌、子宫内膜癌、皮肤癌、食道肿瘤、头颈部肿瘤、星形肠道癌、胆管癌、肾癌、肝癌、卵巢癌、胰腺癌、肺癌或前列腺癌中的一种或多种。
在本文中,术语“选择性”是指对指定靶标(如HER2)的活性或效力(如抑制活性)高于对其他靶标(如EGFR)的活性或效力(如抑制活性)。
本发明的药物组合物包含安全有效量或治疗有效量范围内的本发明化合物或其药理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。通常,药物组合物含有0.01-500mg
本发明化合物/剂,更佳地,含有0.01-100mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”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和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。药学上可以接受的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。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
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。例如,本发明的化合物可作为抗肿瘤药物的增敏剂与至少一种另外的抗肿瘤药物联合给药。另外的抗肿瘤药物可以是靶向药物或化疗和放射治疗的药物(如卡铂、紫杉醇、替莫唑胺等),和质子治疗。
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0.01~500mg,优选0.01~100mg。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。
本发明的主要优点包括:
1.本发明的化合物在具有优异的选择性的同时具有优异的抑制活性
2.本发明的化合物具有优异的选择性。因此,本发明的化合物具有更低的毒性和更优异的安全性。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
A.制备实施例
实施例1:化合物1的合成
步骤A
将化合物1a(2g,14.80mmol),化合物1b(2.53g,16.28mmol)和碳酸铯(12.06g,37.00mmol)依次加入到二甲基亚砜(50mL)中,80℃搅拌6小时。LCMS监控反
应,反应完成后加水(200mL)稀释,乙酸乙酯萃取(200mL x 3),有机相用饱和氯化钠水溶液洗涤(100mL x 2),无水硫酸钠干燥,经中压快速制备色谱仪分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得类白色固体化合物1c(3.5g,87.50%)。1H NMR(400MHz,CDCl3):δppm 8.62(d,J=7.2Hz,1H),8.38(s,1H),8.27(d,J=2.4Hz,1H),8.17(dd,J=8.8,2.4Hz,1H),7.16(d,J=8.8Hz,1H),7.10(d,J=2.4Hz,1H),7.00(dd,J=7.6,2.4Hz,1H),2.36(s,3H).LCMS:271.2[M+H]+.
步骤B
将化合物1c(3.5g,14.80mmol)和还原铁粉(3.62g,64.76mmol)依次加入到乙醇(125mL)中,加入氯化铵水溶液(3.46g,64.76mmol溶解于25mL水中),70℃搅拌4小时。LCMS监控反应,反应完全后减压除去溶剂,加水(100mL)稀释,乙酸乙酯萃取(200mL x 3),无水硫酸钠干燥,经中压快速制备色谱仪分离(洗脱液:石油醚/乙酸乙酯,3/1,v/v),得淡黄色固体化合物1d(2g,64.27%)。1H NMR(400MHz,CDCl3):δppm 8.44(d,J=7.6Hz,1H),8.19(s,1H),6.81–6.86(m,2H),6.77(d,J=2.4Hz,1H),6.60(d,J=2.4Hz,1H),6.56(dd,J=8.4,2.8Hz,1H),2.07(s,3H).LCMS:241.2[M+H]+.
步骤C
将化合物1d(2g,8.32mmol),化合物1e(1.94g,9.99mmol),N,N-二异丙基乙胺(1.78g,13.73mmol)和PyBOP(5.72g,9.99mmol)依次加入到N,N-二甲基甲酰胺(100mL)中,室温搅拌4小时。LCMS监控反应,反应完全后减压除去溶剂,加水(100mL)溶解,乙酸乙酯萃取(100mL x 2),无水硫酸钠干燥,经中压快速制备色谱仪分离(洗脱液:二氯甲烷/乙酸乙酯,1/10,v/v),得淡棕色固体化合物1f(2.5g,72.12%)。LCMS:417.0[M+H]+.
步骤D
将化合物1f(2.5g,6.00mmol)加入到二氯甲烷(50mL)中,冰水浴降温至0℃,加入间氯过氧苯甲酸(1.81g,8.40mmol,80%),室温搅拌4小时。LCMS监控反应,反应完全后冰水浴降温至0℃,加入饱和碳酸氢钠水溶液(100mL)淬灭反应,二氯甲烷萃取(100mL x 2),无水硫酸钠干燥,经中压快速制备色谱仪分离(洗脱液:二氯甲烷/甲醇,10/1,v/v),得棕色固体产品化合物1g(1g,38.52%)。LCMS:432.9[M+H]+.
步骤E
将化合物1g(150mg,0.35mmol),化合物1h(100mg,0.50mmol)和N,N-二异丙基乙胺(135mg,1.04mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩得粗品,经中压快速制备色谱仪分离(洗脱液:二氯甲烷/乙酸乙酯,1/1 to 1/10,v/v),得到黄色粘稠化合物1i(60mg,30.5%)。LCMS:567[M+H]+.
步骤F
将化合物1i(60mg,0.076mmol)溶于二氯甲烷(2mL)中,0℃下加入三氟乙酸(0.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠化合物1j(40mg),粗品。无需纯化,直接用于下一步反应。LCMS:467.0[M+H]+.
步骤G
将化合物1j(40mg,粗品)和N,N-二异丙基乙胺(45mg,0.35mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(0.5M in DCM,0.1mL),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(30-50%)],得到黄色固体化合物1(4.5mg,8.1%)。1H NMR(400MHz,CD3OD):δppm 9.09(s,1H),8.77(d,J=7.6Hz,1H),8.55(d,J=2Hz,1H),8.34(s,1H),7.94–7.86(m,2H),7.24(d,J=8.8Hz,1H),7.11(dd,J=7.6,2.4Hz,1H),6.83–6.79(m,1H),6.58–6.25(m,2H),5.87–5.69(m,1H),5.43–5.08(m,2H),4.75–4.30(m,2H),4.06–3.66(m,2H),2.63–2.40(m,1H),2.27(s,3H),2.25–2.10(m,1H).LCMS:521.2[M+H]+.
实施例2:化合物2的合成
步骤A
将化合物1h(250mg,0.6mmol)和N,N-二异丙基乙胺(324mg,2.51mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(170mg,1.88mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得到黄色粘稠化合物2a(300mg,94.4%)。无需纯化,直接
用于下一步反应。LCMS:253.1[M+H]+.
步骤B
将化合物2a(300mg,1.18mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(2mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠化合物2b(170mg),粗品。无需纯化,直接用于下一步反应。LCMS:153.2[M+H]+.
步骤C
将化合物2b(32mg,0.21mmol),化合物1g(60mg,0.14mmol)和N,N-二异丙基乙胺(54mg,0.42mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得到黄色固体化合物2(8.5mg,11.75%)。1H NMR(400MHz,CD3OD):δppm 8.99(d,J=3.0Hz,1H),8.72(d,J=7.5Hz,1H),8.44(d,J=2.4Hz,1H),8.27(s,1H),7.91–7.87(m,2H),7.17(d,J=8.6Hz,1H),7.05(dd,J=7.5,2.4Hz,1H),6.77–6.56(m,2H),6.34–6.30(m,1H),5.85–5.73(m,1H),5.36–5.24(m,1H),4.93–4.86(m,1H),4.53–4.46(m,1H),4.33–4.17(m,1H),4.00–3.62(m,2H),2.62–2.52(m,1H),2.23(s,3H),2.19–2.00(m,1H).LCMS:521.0[M+H]+.
实施例3:化合物3的合成
步骤A
将化合物1g(200mg,0.46mmol),化合物3a(183mg,0.92mmol)和N,N-二异丙基乙胺(179mg,1.39mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩得粗品,经中压快速制备色谱仪分离(洗脱液:二氯甲烷/乙酸乙酯,1/1 to 1/10,v/v),得到黄色粘稠化合物3b(150mg,56.5%)。LCMS:567.2[M+H]+.
步骤B
将化合物3b(150mg,0.26mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(1.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠化合物3c(90mg),粗品。无需纯化,直接用于下一步反应。LCMS:467.2[M+H]+.
步骤C
将化合物3c(90mg,crude)和N,N-二异丙基乙胺(75mg,0.58mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(0.5M in DCM,0.38mL),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得到黄色固体化合物3(24mg,两步16.9%)。1H NMR(400MHz,DMSO-d6):δppm 9.64-9.59(m,1H),9.13(s,1H),
8.84(d,J=7.6Hz,1H),8.47(d,J=4.4Hz,1H),8.38(s,1H),8.01–7.96(m,2H),7.26–7.23(m,1H).7.03(dd,J=7.2,2.4Hz,1H),6.80(d,J=2.4Hz,1H),6.54–6.24(m,1H),6.18–6.08(m,1H),5.75–5.64(m,1H),5.23–4.95(m,1H),4.61–4.50(m,1H),4.40(t,J=8.4Hz,1H),4.13–3.89(m,1H),3.58–3.49(m,4H),2.21(s,3H).LCMS:521.2[M+H]+.
实施例4:化合物4的合成
步骤A
将化合物3a(100mg,0.5mmol)和N,N-二异丙基乙胺(259mg,2.0mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(136mg,1.5mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得到黄色粘稠化合物4a(120mg,94.4%)。无需纯化,直接用于下一步反应。LCMS:275.2[M+Na]+.
步骤B
将化合物4a(120mg,0.47mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(1.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠化合物4b(70mg),粗品。无需纯化,直接用于下一步反应。LCMS:153.1[M+H]+.
步骤C
将化合物4b(70mg,0.46mmol),化合物1g(80mg,0.18mmol)和N,N-二异丙基乙胺(94mg,0.92mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物4(29mg,28.64%)。1H NMR(400MHz,CD3OD):δppm 9.08(d,J=4.4Hz,1H),8.85(d,J=7.2Hz,1H),8.63(s,1H),8.47(s,1H),7.92–7.73(m,2H),7.30(d,J=8.8Hz,1H),7.18(d,J=7.2Hz,1H),6.88(s,1H),6.79–6.62(m,1H),6.32–6.26(m,1H),5.83–5.71(m,1H),5.25(s,H),4.67–4.63(m,2H),4.34–4.32(m,1H),4.00–3.90(m,1H),3.65–3.61(m,1H),3.43–3.32(m,2H),2.31(s,3H).LCMS:521.0[M+H]+.
实施例5:化合物5的合成
步骤A
将化合物1g(150mg,0.35mmol),化合物5a(118mg,0.52mmol)和N,N-二异丙基乙胺(135mg,1.04mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩得粗品,经中压快速制备色谱仪分离(洗脱液:二氯甲烷/乙酸乙酯,1/1 to 1/10,v/v),得黄色粘稠化合物5b(48mg,23.2%)。LCMS:595.1[M+H]+.
步骤B
将化合物5b(45mg,0.076mmol)溶于二氯甲烷(2mL)中,0℃下加入三氟乙酸(0.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠化合物5c(40mg),粗品。无需纯化,直接用于下一步反应。LCMS:495.1[M+H]+.
步骤C
将化合物5c(35mg,crude)和N,N-二异丙基乙胺(45mg,0.35mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(0.5M in DCM,0.17mL),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物5(8.7mg,20.9%)。1H NMR(400MHz,CD3OD):δppm 8.94(s,1H),8.71(d,J=7.5Hz,1H),8.36(s,1H),8.26(s,1H),8.03–7.79(m,2H),7.16(d,J=8.4Hz,1H),7.04(dd,J=7.5,2.4Hz,1H),6.76(d,J=2.3Hz,1H),6.40–6.37(m,1H),6.24(dd,J=17.0,1.9Hz,1H),5.73(dd,J=10.3,1.8Hz,1H),4.10(s,2H),4.04–4.02(m,4H),3.86(s,2H),2.22(s,3H),1.95–1.81(m,4H).LCMS:549.1[M+H]+.
实施例6:化合物6的合成
步骤A
将化合物1g(150mg,0.347mmol),化合物6a(95mg,0.420mmol)和N,N-二异丙基乙胺(135mg,1.04mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩得粗品,经中压快速制备色谱仪分离(洗脱液:二氯甲烷/乙酸乙酯,1/1 to 1/10,v/v),得到黄色粘稠化合物6b(80mg,38.78%)。LCMS:595.3[M+H]+.
步骤B
将化合物6b(80mg,0.134mmol)溶于二氯甲烷(5mL)中,0℃下加入三氟乙酸(1mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠化合物6c(50mg),粗品。无需纯化,直接用于下一步反应。LCMS:495.1[M+H]+.
步骤C
将化合物6c(50mg,crude)和N,N-二异丙基乙胺(35mg,0.346mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(0.5M in DCM,0.11mL),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(20-50%)],得到黄色固体化合物6(8mg,14.42%)。1H NMR(400MHz,CD3OD):δppm 8.84(s,1H),8.63(d,J=7.6Hz,1H),8.31(s,1H),8.18(s,1H),7.82(s,1H),7.80(d,J=2.4Hz,1H),7.07(d,J=8.4Hz,
1H),6.96(dd,J=7.6,2.4Hz,1H),6.71–6.67(m,2H),6.10(dd,J=16.8,2Hz,1H),5.65(dd,J=10.4,1.6Hz,1H),3.97(s,4H),3.64–3.54(m,4H),2.14(s,3H),1.86–1.78(m,4H).LCMS:549.3[M+H]+.
实施例7:化合物7的合成
步骤A
将化合物7a(100mg,0.5mmol)和二异丙基乙基胺(195mg,1.5mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(91mg,1.01mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得黄色粘稠化合物7b(100mg,78.7%)。无需纯化,直接用于下一步反应。LCMS:253.1[M+H]+.
步骤B
将化合物7b(100mg,1.16mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(1.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠物化合物7c(100mg),粗品。无需纯化,直接用于下一步反应。LCMS:153.2[M+H]+.
步骤C
将化合物7c(110mg,crude),化合物1g(80mg,0.19mmol)和N,N-二异丙基乙胺(120mg,0.9mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN为洗脱剂(20-50%)],得到黄色固体化合物7(11mg,11.1%)。1H NMR(400MHz,CD3OD):δppm 9.04(s,1H),8.79(d,J=7.6Hz,1H),8.60(d,J=4.4Hz,1H),8.41(s,1H),7.89–7.83(m,2H),7.25(d,J=8.4Hz,1H),7.13(dd,J=7.6,2.4Hz,1H),6.83(d,J=2.4Hz,1H),6.55–6.21(m,1H),5.76–5.72(m,1H),5.01–4.98(m,2H),4.43(d,J=10.4Hz,2H),4.24–4.20(m,2H),2.68–2.64(m,2H),2.26–2.23(m,4H).LCMS:521.2[M+H]+.
实施例8:化合物8的合成
步骤A
将化合物8a(130mg,0.65mmol)和N,N-二异丙基乙胺(337mg,2.6mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(177mg,1.95mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得黄色粘稠化合物8b(110mg,66.5%)。无需纯化,直接
用于下一步反应。LCMS:253.1[M+H]+.
步骤B
将化8b(110mg,0.41mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(1.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠物化合物8c(60mg),粗品。无需纯化,直接用于下一步反应。LCMS:153.2[M+H]+.
步骤C
将化合物8c(60mg,0.39mmol),化合物1g(80mg,0.18mmol)和N,N-二异丙基乙胺(72mg,0.56mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物8(16mg,16.1%)。1H NMR(400MHz,CD3OD):δppm 8.79(d,J=5.6Hz,1H),8.73(d,J=7.6Hz,1H),8.53(s,1H),8.37(s,1H),7.86–7.74(m,2H),7.18–7.13(m,1H),7.08–7.06(m,1H),6.75(s,1H),6.41–6.28(m,1H),6.22–6.13(m,1H),5.69–5.65(m,1H),5.05–4.94(m,2H),4.46–4.42(m,1H),4.16–4.13(m,3H),2.70–2.66(m,H),2.18(S,3H).LCMS:521.0[M+H]+.
实施例9:化合物9的合成
步骤A
将化合物9a(300mg,1.41mmol)和三乙胺(285mg,2.81mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(191mg,2.11mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得黄色粘稠化合物9b(300mg,82.9%)。无需纯化,直接用于下一步反应。LCMS:289.1[M+Na]+.
步骤B
将化合物9b(300mg,1.13mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(2mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得黄色粘稠化合物9c(260mg),粗品。无需纯化,直接用于下一步反应。LCMS:167.1[M+H]+.
步骤C
将化合物9c(50mg,crude),化合物1g(60mg,0.14mmol)和N,N-二异丙基乙胺(90mg,0.69mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(20-50%)],得黄色固体化合物9(30mg,40.4%)。1H NMR(400MHz,CD3OD):δppm 9.06(s,1H),8.79(d,J=7.5Hz,1H),8.58(s,1H),8.38(s,1H),7.90–7.83(m,2H),7.25(d,J=8.6Hz,1H),7.12(dd,J=7.5,2.4Hz,1H),6.82(d,J=2.3Hz,1H),6.40–6.23(m,2H),5.74(dd,J=10.2,1.9Hz,1H),4.34(s,2H),4.15–3.95(m,4H),3.91–3.79(m,2H),2.36(t,J=6.7Hz,2H),2.26(s,3H).LCMS:535.1[M+H]+.
实施例10:化合物10的合成
步骤A
将化合物10a(50mg,0.24mmol)和N,N-二异丙基乙胺(90mg,0.70mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(0.5M于DCM中,0.35mL),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得黄色粘稠化合物10b(55mg),粗品。无需纯化,直接用于下一步反应。LCMS:267.1[M+H]+.
步骤B
将化合物10b(55mg,粗品)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(2mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得黄色粘稠化合物10c(70mg),粗品。无需纯化,直接用于下一步反应。LCMS:167.2[M+H]+.
步骤C
将化合物10c(50mg,粗品),化合物1g(60mg,0.14mmol)和N,N-二异丙基
乙胺(54mg,0.42mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN为洗脱剂(20-70%)],得黄色固体化合物10(4.8mg,6.4%)。1H NMR(400MHz,CD3OD):δppm 9.02(s,1H),8.74(d,J=7.6Hz,1H),8.43(s,1H),8.29(s,1H),7.89–7.97(m,2H),7.19(d,J=8.8Hz,1H),7.07(d,J=7.2Hz,1H),6.79(s,1H),6.68–6.62(m,1H),6.26–6.21(m,1H),5.77–5.68(m,1H),3.99–3.81(m,4H),3.72–3.61(m,2H),3.22–3.13(m,1H),2.31–2.25(m,1H),2.25(s,3H),2.04–1.98(m,1H),1.33–1.28(m,2H).LCMS:535.2[M+H]+.
实施例11:化合物11的合成
步骤A
将化合物11a(100mg,0.47mmol)和N,N-二异丙基乙胺(243mg,1.89mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(128mg,1.41mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得到黄色粘稠物化合物11b(110mg,87.7%)。无需纯化,直接用于下一步反应。LCMS:289.1[M+Na]+.
步骤B
将化合物11b(110mg,0.41mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(1.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得黄色粘稠化合物11c(70mg),粗品。无需纯化,直接用于下一步反应。LCMS:167.1[M+H]+.
步骤C
将化合物11c(70mg,0.42mmol),化合物1g(80mg,0.18mmol)和N,N-二异丙基乙胺(95mg,0.74mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物11(20mg,19.8%)。1H NMR(400MHz,CD3OD):δppm 8.96(d,J=4.0Hz,1H),8.69(d,J=7.2Hz,1H),8.48(s,1H),8.28(s,1H),7.82–7.79(m,2H),7.16(d,J=8.4Hz,1H),7.04–7.02(m,1H),6.74(s,1H),6.58–6.51(m,1H),6.29–6.20(m,1H),5.76–5.66(m,1H),4.74–4.60(m,1H),4.41–3.92(m,3H),3.76–3.69(m,3H),3.21–3.13(m,1H),2.20–2.13(m,4H),1.96–1.91(m,1H).LCMS:535.0[M+H]+.
实施例12:化合物12的合成
步骤A
将化合物12a(100mg,0.47mmol)和二异丙基乙基胺(182mg,1.41mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(85mg,0.94mmol),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,得黄色粘稠化合物12b(110mg,87.8%)。无需纯化,直接用于下一步反应。LCMS:267.1[M+H]+.
步骤B
将化合物12b(110mg,0.41mmol)溶于二氯甲烷(6mL)中,0℃下加入三氟乙酸(1.5mL),氮气保护,室温搅拌2小时。LCMS监控,反应完成后减压浓缩,得到黄色粘稠化合物12c(100mg),粗品。无需纯化,直接用于下一步反应。LCMS:167.1[M+H]+.
步骤C
将化合物12c(100mg,crude),化合物1g(80mg,0.19mmol)和N,N-二异丙基乙胺(120mg,0.9mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(20-50%)],得黄色固体化合物12(10.2mg,10.1%)。1H NMR(400MHz,CD3OD):δppm 9.00(s,1H),8.71(d,J=7.6Hz,1H),8.40(s,1H),8.26(s,1H),7.92–7.88(m,2H),7.16(d,J=8.8Hz,1H),7.04(dd,J=7.6,2.0Hz,1H),6.78–6.76(m,1H),6.74–6.61(m,1H),6.37–6.26(m,1H),5.83–5.73(m,1H),5.01–4.92(m,1H),4.85–4.77(m,1H),4.23(s,1H),3.98–3.88(m,1H),3.56–3.49(m,2H),2.42–2.37(m,2H),2.33–2.18(m,5H).LCMS:535.0[M+H]+.
实施例13:化合物13的合成
步骤A
将化合物13a(235mg,0.864mmol)和三乙胺(210mg,2.08mmol)溶于N,N-二甲基甲酰胺(10mL)中,室温搅拌10分钟。加入化合物1g(150mg,0.347mmol),氮气保护,70℃搅拌6小时。LCMS监控反应,反应完成后加水(30mL)稀释,乙酸乙酯萃取(30mL x 3),有机相用饱和氯化钠水溶液(100mL)洗涤,无水硫酸钠干燥,减压浓缩,中压快速制备色谱仪分离(洗脱液:二氯甲烷/甲醇,10/1,v/v),得淡黄色固体化合物13b(50mg,30.1%)。LCMS:479.2[M+H]+.
步骤B
将化合物13b(50mg,0.105mmol)和N,N-二异丙基乙胺(32mg,0.319mmol)溶于二氯甲烷(10mL)中,0℃下滴加丙烯酰氯(0.5M in DCM,0.23mL),氮气保护,室温搅拌1小时。LCMS监控,反应完成后加入甲醇(1mL)淬灭反应,减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化铵洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物13(4mg,7.19%)。1H NMR(400MHz,DMSO-d6):δppm 9.50(s,1H),9.14(s,1H),8.94(d,J=7.6Hz,1H),8.47(s,1H),8.39(s,1H),8.04(d,J=8.8Hz,1H),7.99(d,J=2.4Hz,1H),7.24(d,J=8.8Hz,1H),7.03(dd,J=7.6,2.4Hz,1H),6.81(d,J=2Hz,1H),6.56–6.68(m,1H),6.23(dd,J=16.8,2Hz,1H),5.75(dd,J=10.4,2.4Hz,1H),4.58–4.40(m,6H),4.28(d,J=13.6Hz,2H),2.21(s,3H).LCMS:533.0[M+H]+.
实施例14:化合物14的合成
将化合物14a(100mg,0.31mmol,TFA盐),化合物1g(80mg,0.18mmol)和N,N-二异丙基乙胺(120mg,0.93mmol)依次加入到1,4-二氧六环(6mL)中,70℃搅拌4小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(10-40%)],得黄色固体化合物14(7.1mg,6.6%)。1H NMR(400MHz,CD3OD):δppm 9.02(s,1H),8.74(d,J=7.2Hz,1H),8.43(s,1H),8.28(s,1H),7.96–7.91(m,2H),7.19(d,J=8.8Hz,1H),7.07(dd,J=7.2,2.4Hz,1H),6.86–6.74(m,2H),6.44–6.17(m,1H),5.35–5.24(m,0.5H),5.09–5.06(m,0.5H),4.77–4.65(m,1H),4.58–4.47(m,2H),4.26–3.96(m,1H),3.57–3.41(m,4H),2.41(s,2H),2.35(s,6H),2.25(s,3H).LCMS:578.1[M+H]+.
实施例15:化合物15的合成
将化合物15a(100mg,0.31mmol,TFA salt),化合物1g(80mg,0.18mmol)和N,N-二异丙基乙胺(120mg,0.93mmol)依次加入到1,4-二氧六环(6mL)中,70℃搅拌4小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(10-40%)],得黄色固体化合物15(9.1mg,8.5%)。1H NMR(400MHz,CD3OD):δppm 9.02(s,1H),8.74(d,J=7.2Hz,1H),8.43(s,1H),8.28(s,1H),7.96–7.91(m,2H),7.19(d,J=8.8Hz,1H),7.07(dd,J=7.2,2.4Hz,1H),6.86–6.74(m,2H),6.44–6.17(m,1H),5.35–5.24(m,0.5H),5.09–5.06(m,0.5H),4.77–4.65(m,1H),4.58–4.47(m,2H),4.26–3.96(m,1H),3.57–3.41(m,4H),2.41(s,2H),2.35(s,6H),2.25(s,3H).LCMS:578.1[M+H]+.
实施例16:化合物16的合成
步骤A
将化合物16a(10.0g,67.5mmol),化合物1b(11.5g,74.2mmol)和碳酸铯(44.0g,135.0mmol)依次加入到二甲基亚砜(200mL)中,80℃搅拌6小时。LCMS监控反应,反应完成后加水(300mL)稀释,乙酸乙酯萃取(200mL x 3),有机相用水洗涤(100mL x 3),饱和氯化钠水溶液洗涤(100mL x 2),无水硫酸钠干燥,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得类黄色油状化合物16b(18.0g,84.7%)。1H NMR(400MHz,DMSO-d6):δppm 8.28(s,1H),8.22(d,J=2.8Hz,1H),8.01(dd,J=9.1,2.9Hz,1H),7.68(d,J=8.7Hz,1H),7.44(d,J=2.2Hz,1H),7.11(dd,J=8.7,2.2Hz,1H),6.69(d,J=9.1Hz,1H),3.89(s,3H),2.49–2.38(m,3H).LCMS:284.0[M+H]+.
步骤B
将化合物16b(18.0g,63.5mmol)和钯碳催化剂(4.0g)依次加入到甲醇(200mL)中,在氢气条件下室温搅拌14小时。LCMS监控反应,反应完全后过滤,收集滤液,减压浓缩,残留物加水(100mL)稀释,二氯甲烷萃取(200mL x 3),无水硫酸钠干燥,柱层析分离(洗脱液:二氯甲烷/甲醇,10/1,v/v),得淡黄色固体化合物16c(7.2g,40.4%)。1H NMR(400MHz,CDCl3):δppm 7.83(s,1H),7.29–7.26(m,1H),7.17(d,J=2.2Hz,1H),7.01(dd,J=8.7,2.3Hz,1H),6.77(d,J=8.5Hz,1H),6.60(d,J=2.7Hz,1H),6.51(dd,J=8.4,2.8Hz,1H),3.81(s,3H),2.14(s,3H).LCMS:254.1[M+H]+.
步骤C
将化合物16c(7.2g,28.5mmol),化合物1e(6.6g,34.2mmol),N,N-二异丙基乙胺(14.7g,114.0mmol)和PyBOP(21.4g,41.0mmol)依次加入到N,N-二甲基甲酰胺(110mL)中,室温搅拌14小时。LCMS监控反应,反应完全后将反应液逐滴加入到500mL水中,搅拌十分钟,待分散完全后过滤,收集固体,减压浓缩除去固体中水分,加入乙醚以及少量乙腈打浆,然后再次过滤得淡棕色固体化合物16d(10.46g,85.6%)。LCMS:430.1[M+H]+.
步骤D
将化合物16d(10.46g,24.4mmol)加入到二氯甲烷(100mL)中,冰水浴降温至0℃,加入间氯过氧苯甲酸(6.3g,36.6mmol,80%),室温搅拌4小时。LCMS监控反应,反应完全后冰水浴降温至0℃,加入饱和碳酸氢钠水溶液(200mL)淬灭反应,
二氯甲烷萃取(200mL x 2),无水硫酸钠干燥,柱层析分离(洗脱液:二氯甲烷/甲醇,10/1,v/v),得棕色固体化合物16e(4.23g,38.93%)。1H NMR(400MHz,CDCl3)δppm9.62(s,1H),9.42(s,1H),8.87(s,1H),8.12(s,1H),7.82(d,J=2.4Hz,1H),7.70(dd,J=8.8,2.8Hz,1H),7.39–7.33(m,2H),7.11(dd,J=8.8,2.2Hz,1H),6.91(d,J=8.7Hz,1H),3.90(s,3H),3.07(s,3H),2.35(s,3H).LCMS:446.0[M+H]+.
步骤E
将化合物14a(100mg,粗品,TFA盐),化合物16e(80mg,0.18mmol)和N,N-二异丙基乙胺(116mg,0.90mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(15-40%)],得到黄色固体化合物16(7.8mg,7.4%)。1H NMR(400MHz,CD3OD):δppm8.97(s,1H),8.37(s,1H),8.10(s,1H),7.80–7.79(m,1H),7.74–7.69(m,1H),7.53(d,J=8.4Hz,1H),7.11–7.06(m,2H),6.88(d,,J=8.8Hz,1H),6.85–6.73(m,1H),6.41–6.16(m,1H),5.26–5.04(m,1H),4.77–4.63(m,1H),4.55–4.45(m,2H),4.23–3.95(m,1H),3.90(s,3H),3.53–3.37(m,4H),2.43(s,2H),2.37(s,6H),2.29(s,3H).LCMS:591.0[M+H]+.
实施例17:化合物17的合成
将化合物15a(100mg,粗品,TFA盐),化合物16e(80mg,0.18mmol)和N,N-二异丙基乙胺(116mg,0.90mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂
(15-40%)],得黄色固体化合物17(10mg,9.6%)。1H NMR(400MHz,CD3OD):δppm8.97(s,1H),8.37(s,1H),8.10(s,1H),7.80–7.79(m,1H),7.74–7.69(m,1H),7.53(d,J=8.4Hz,1H),7.11–7.06(m,2H),6.88(d,,J=8.8Hz,1H),6.85–6.73(m,1H),6.41–6.16(m,1H),5.26–5.04(m,1H),4.77–4.63(m,1H),4.55–4.45(m,2H),4.23–3.95(m,1H),3.90(s,3H),3.53–3.37(m,4H),2.43(s,2H),2.37(s,6H),2.29(s,3H).LCMS:591.0[M+H]+.
实施例18:化合物18的合成
步骤A
将化合物1f(100mg,0.24mmol)加入到二氯甲烷(5mL)中,0℃下滴加入磺酰氯(81mg,0.6mmol),氮气保护下搅拌1小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化钠洗涤(20mL),无水硫酸钠干燥,减压浓缩,中压快速制备色谱仪分离(洗脱液:二氯甲烷/乙酸乙酯,1/4,v/v),得黄色固体化合物18a(60mg,55.56%)。LCMS:405.1[M+H]+.
步骤B
将化合物18b(67mg,0.37mmol),化合物18a(50mg,0.12mmol),XPhos Pd G2(9.7mg,0.012mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(21mg,0.037mmol)和碳酸铯(80mg,0.25mmol)依次加入到二氧六环(10mL)中,氮气保护下90℃搅拌16小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20
mL×2),饱和氯化钠洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物18(5.0mg,6.96%)。1H NMR(400MHz,,DMSO-d6):δppm 9.26(s,1H),8.82–8.79(m,1H),8.67(s,1H),8.46(s,1H),7.96–7.91(m,2H),7.23–7.21(m,1H),7.16–7.12(m,1H),6.89–6.79(m,2H),6.24–6.19(m,1H),5.78–5.76(m,1H),5.37(d,J=4.0Hz,1H),4.10–4.07(m,1H),3.67–3.62(m,1H),2.24(s,3H),1.93–1.76(m,4H),1.64–1.59(m,2H).LCMS:551.0[M+H]+.
实施例19:化合物19的合成
步骤A
将化合物19a(67mg,0.37mmol),化合物18a(50mg,0.12mmol),XPhos Pd G2(9.7mg,0.012mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(21mg,0.037mmol)和碳酸铯(80mg,0.25mmol)依次加入到二氧六环(10mL)中,氮气保护下90℃搅拌16小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化钠洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物19(3.5mg,4.88%)。1H NMR(400MHz,DMSO-d6):δppm 9.29(s,1H),8.85–8.80(m,1H),8.69(s,1H),8.49–8.25(m,1H),7.24(d,J=8.4Hz,1H),7.17(d,J=7.6Hz,1H),6.92–6.85(m,2H),6.27–6.22(m,1H),5.81–5.78(m,1H),5.40(d,J=4.0Hz,1H),4.13–4.09(m,1H),3.70–3.64(m,1H),2.27(s,3H),1.86–1.78(m,4H),1.67–1.61(m,2H).LCMS:551.0[M+H]+.
实施例20:化合物20的合成
将化合物20a(150mg,crude),化合物1g(80mg,0.18mmol)和N,N-二异丙基乙胺(71.7mg,0.55mmol)依次加入到1,4-二氧六环(6mL)中,70℃搅拌4小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(30-50%)],得黄色固体化合物20(4.8mg,5.0%)。1H NMR(400MHz,CD3OD):δppm 8.98(s,1H),8.69(d,J=7.6Hz,1H),8.47(s,1H),8.27(s,1H),7.83–7.77(m,2H),7.15(d,J=8.4Hz,1H),7.02(dd,J=7.2,1.5Hz,1H),6.73(s,1H),6.226.16(m,2H),5.72–5.60(m,1H),5.19–4.98(m,1H),4.73–4.65(m,1H),4.42–4.38(m,2H),4.18–3.86(m,1H),3.50–3.31(m,4H),2.17(s,3H).LCMS:521.0[M+H]+.
实施例21:化合物21的合成
将化合物21a(35mg,0.23mmol),化合物1g(50mg,0.11mmol)和N,N-二异丙基乙胺(45mg,0.35mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌48小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物21(7mg,12.23%)。1H NMR(400MHz,CD3OD):δppm 9.02(s,1H),8.73(d,J=7.2Hz,1H),8.44(s,1H),8.28(s,1H),7.94–7.91(m,2H),7.13(d,J=8.8Hz,1H),7.08–7.05(m,1H),6.79–6.78(m,1H),6.51–6.25(m,2H),5.82–5.72(m,1H),5.41–5.06(m,2H),4.59–4.38(m,2H),3.99–3.69(m,2H),2.59–2.41(m,1H),2.34–2.13(m,4H).LCMS:521.0[M+H]+.
实施例22:化合物22的合成
将化合物22a(35mg,0.23mmol),化合物1g(50mg,0.11mmol)和N,N-二异丙基乙胺(60mg,0.46mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌48小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物22(7mg,12.23%)。1H NMR(400MHz,CD3OD):δppm 9.03(s,1H),8.74(d,J=7.2Hz,1H),8.45(s,1H),8.28(s,1H),7.95–7.91(m,2H),7.19(d,J=8.4Hz,1H),7.08–7.06(m,1H),6.79–6.78(m,1H),6.51–6.28(m,2H),5.81–5.72(m,1H),5.41–5.11(m,2H),4.59–4.39(m,2H),3.99–3.69(m,2H),2.59–2.54(m,1H),2.41–2.17(m,4H).LCMS:521.0[M+H]+.
实施例23:化合物23的合成
将化合物23a(35mg,粗品),化合物1g(50mg,0.11mmol)和N,N-二异丙基乙胺(71mg,0.55mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(10-40%)],得黄色固体化合物23(4.0mg,7.0%)。1H NMR(400MHz,MeOD)δppm 9.04(s,1H),8.74(d,J=7.6Hz,1H),8.43(s,1H),8.28(s,1H),7.98–7.88(m,2H),7.19(d,J=8.6Hz,1H),7.07(dd,J=7.6,2.4Hz,1H),6.80–6.62(m,2H),6.39–6.28(m,1H),5.88–5.78(m,1H),4.26(s,1H),4.01–3.90(m,1H),3.70–3.50(m,2H),2.58–2.05(m,8H),1.28(s,1H).LCMS:535.0[M+H]+.
实施例24:化合物24的合成
将化合物24a(35mg,粗品),化合物1g(50mg,0.11mmol)和N,N-二异丙基乙胺(71mg,0.55mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。
LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(10-40%)],得黄色固体化合物24(4.0mg,7.0%)。1H NMR(400MHz,MeOD)δppm 9.05(s,1H),8.74(d,J=7.6Hz,1H),8.45(s,1H),8.29(s,1H),7.97–7.87(m,2H),7.20(d,J=8.6Hz,1H),7.07(dd,J=7.6,2.4Hz,1H),6.79(t,J=4.2Hz,1H),6.76–6.62(m,1H),6.39–6.28(m,1H),5.85–5.76(m,1H),4.77(m,1H),4.27(s,1H),4.00–3.90(m,1H),3.65–3.45(m,2H),2.54–2.07(m,8H).LCMS:535.0[M+H]+.
实施例25:化合物25的合成
将化合物23a(35mg,粗品),化合物16e(50mg,0.11mmol)和N,N-二异丙基乙胺(71mg,0.55mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(10-40%)],得黄色固体化合物25(4.0mg,7.0%)。1H NMR(400MHz,MeOD)δppm 8.99(s,1H),8.37(s,1H),8.18(s,1H),7.80(s,1H),7.72(d,J=8.6Hz,1H),7.56(d,J=8.6Hz,1H),7.14–7.05(m,2H),6.90(d,J=8.8Hz,1H),6.78–6.63(m,1H),6.38–6.27(m,1H),5.84–5.73(m,1H),4.77(m,1H),4.28–4.21(m,1H),4.01–3.92(m,4H),3.68–3.50(m,2H),2.57–2.04(m,8H).LCMS:548.1[M+H]+.
实施例26:化合物26的合成
将化合物24a(35mg,粗品),化合物16e(50mg,0.11mmol)和N,N-二异丙基乙胺(71mg,0.55mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(10-40%)],得黄色固体化合物26(4.4mg,7.2%)。1H NMR(400MHz,MeOD)δppm 9.04(d,J=2.2Hz,1H),8.88(d,J=5.4Hz,1H),8.41(s,1H),7.86(s,1H),7.80(dd,J=12.6,6.0Hz,2H),7.28(d,J=8.8Hz,1H),7.16(d,J=2.2Hz,1H),7.02(d,J=8.8Hz,1H),6.70–6.55(m,1H),6.35–6.28(m,1H),5.80–5.65(m,1H),4.77(m,1H),4.31–4.23(m,1H),4.05(s,3H),3.97–3.89(m,1H),3.68–3.55(m,2H),2.55–2.25(m,8H).LCMS:548.0[M+H]+.
实施例27:化合物27的合成
将化合物16e(80mg,0.18mmol),化合物7c(50mg,粗品)和N,N-二异丙基乙胺(120mg,0.93mmol)依次加入到1,4-二氧六环(10mL)中,70℃搅拌4小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Xbridge-C18柱,5μ二氧化硅,21mm直径,长度150mm),水(0.05%TFA)和MeCN作为洗脱剂(20-60%)],得黄色固体化合物27(4.3mg,4.49%)。1H NMR(400MHz,CD3OD):δppm 8.94–8.36(m,1H),8.46–8.38(m,1H),8.34–8.28(m,1H),7.73(d,J=2.4Hz,1H),7.66(dd,J=8.4,2.4Hz,1H),7.57(dd,J=8.8,3.2Hz,1H),7.11–7.07(m,1H),7.04(d,J=2.0Hz,1H),6.86(d,J=8.8Hz,1H),6.35–6.07(m,2H),5.70–5.62(m,1H),4.89(d,J=10Hz,1H),4.29(d,J=10.4Hz,2H),4.14(t,J=7.4Hz,2H),3.89(s,3H),2.63–2.51(m,2H),2.18(s,3H),1.23–1.19(m,2H).LCMS:534.2[M+H]+.
实施例28:化合物28的合成
将化合物1g(80mg,0.18mmol),化合物28a(100mg,粗品)和N,N-二异丙基乙胺(120mg,0.93mmol)依次加入到1,4-二氧六环(10mL)中,70℃搅拌4小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Xbridge-C18柱,5μ二氧化硅,21mm直径,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-50%)],得黄色固体化合物28(4.3mg,4.49%)。1H NMR(400MHz,CD3OD):δppm 9.00(s,1H),8.72(d,J=7.6Hz,1H),8.41(s,1H),8.26(s,1H),7.95–7.87(m,2H),7.17(d,J=8.8Hz,1H),7.07–7.02(m,1H),6.7-6.15(m,1H),6.31–6.21(m,2H),5.08–5.66(m,1H),5.34–5.02(m,1H),4.73(d,J=13.2Hz,1H),4.58–4.42(m,2H),4.00–3.66(m,1H),3.54–3.40(m,3H),2.23(m,4H).LCMS:521.0[M+H]+.
实施例29:化合物29的合成
将化合物29a(98mg,0.65mmol),化合物1g(100mg,0.23mmol)和N,N-二异丙基乙胺(150mg,1.15mmol)依次加入到1,4-二氧六环(10mL)中,70℃搅
拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物29(55mg,45.9%)。1H NMR(400MHz,CD3OD):δppm8.96(s,1H),8.75(s,1H),8.42–8.32(m,2H),7.89–7.87(m,2H),7.15(d,J=8.4Hz,1H),7.03(d,J=7.6Hz,1H),6.77–6.57(m,2H),6.35–6.29(m,1H),5.79(d,J=10.4Hz,1H),5.34–5.22(m,1H),4.50–4.44(m,1H),4.27–4.19(m,1H),3.90–3.36(m,2H),2.60–2.51(m,1H),2.21(s,3H),2.15–1.99(m,2H).LCMS:521.0[M+H]+.
实施例30:化合物30的合成
将化合物30a(98mg,0.65mmol),化合物1g(100mg,0.23mmol)和N,N-二异丙基乙胺(150mg,1.15mmol)依次加入到1,4-二氧六环(10mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物30(45mg,37.6%)。1H NMR(400MHz,CD3OD):δppm8.96(s,1H),8.74(s,1H),8.42–8.31(m,2H),7.89–7.87(m,2H),7.15(d,J=8.4Hz,1H),7.03(d,J=7.6Hz,1H),6.77–6.56(m,2H),6.35–6.29(m,1H),5.79(d,J=10.4Hz,1H),5.34–5.22(m,1H),4.50–4.44(m,1H),4.26–4.19(m,1H),3.93–3.36(m,2H),2.61–2.51(m,1H),2.21(s,3H),2.16–1.99(m,2H).LCMS:521.0[M+H]+.
实施例31:化合物31的合成
将化合物22a(40mg,0.27mmol),化合物16e(50mg,0.11mmol)和N,N-二异丙基乙胺(72mg,0.56mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌48小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物31(12mg,20.46%)。1H NMR(400MHz,CD3OD):δppm 8.95(s,1H),8.35(s,1H),8.07(s,1H),7.77(s,1H),7.68(d,J=8.4Hz,1H),7.50(d,J=8.8Hz,1H),7.09–7.04(m,2H),6.85(d,J=8.4Hz,1H),6.50–6.21(m,2H),5.78–5.68(m,1H),5.35–5.04(m,2H),4.55–4.35(m,2H),3.95–3.65(m,5H),2.55–2.49(m,1H),2.27(s,3H),2.15–2.11(m,1H).LCMS:534.0[M+H]+.
实施例32:化合物32的合成
将化合物21a(35mg,0.22mmol),化合物16e(50mg,0.11mmol)和N,N-二异丙基乙胺(72mg,0.56mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌48小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物32(9mg,15.35%)。1H NMR(400MHz,CD3OD):δppm 8.98(s,1H),8.38(s,1H),8.15(s,1H),7.79(s,1H),7.72–7.69(m,1H),7.56(s,1H),6.8-7.2(m,3H),6.49–6.24(m,2H),5.81–5.71(m,1H),5.38–5.08(m,2H),4.58–4.36(m,2H),3.97–3.68(m,5H),2.57–2.52(m,1H),2.29(s,3H),2.19–2.17(m,1H).LCMS:534.1[M+H]+.
实施例33:化合物33的合成
将化合物20a(150mg,粗品),化合物16e(80mg,0.18mmol)和N,N-二异丙基乙胺(70mg,0.54mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(10-40%)],得黄色固体化合物33(6.2mg,6.5%)。1H NMR(400MHz,CD3OD):δppm 8.98(s,1H),8.37(s,1H),8.1(s,1H),7.80–7.79(m,1H),7.74–7.69(m,1H),7.54(d,J=8.8Hz,1H),7.12(s,1H),7.09–7.06(m,1H),6.88(d,J=8.8Hz,1H),6.31–6.21(m,2H),5.81–5.68(m,1H),5.26–5.06(m,1H),4.73–4.64(m,1H),4.54–4.45(m,2H),4.26–3.96(m,1H),3.90(s,3H),3.53–3.36(m,3H),2.29(s,3H).LCMS:534.2[M+H]+.
实施例34:化合物34的合成
将化合物28a(100mg,粗品),化合物16e(80mg,0.18mmol)和N,N-二异丙
基乙胺(75mg,0.58mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(15-40%)],得黄色固体化合物34(3.6mg,3.76%)。1H NMR(400MHz,CD3OD):δppm 9.02(s,1H),8.64(d,J=7.6Hz,1H),8.40(s,1H),8.0–7.6(m,4H),7.22(d,J=9.2Hz,1H),7.15(s,1H),6.98(d,J=8.8Hz,1H),6.34–6.25(m,2H),5.82–5.69(m,1H),5.36–5.23(m,1H),4.77–4.66(m,1H),4.60–4.42(m,2H),4.28–4.20(m,1H),4.04–3.95(m,3H),3.56–3.39(m,3H),2.29(s,3H).LCMS:534.2[M+H]+.
实施例35:化合物35的合成
将化合物29a(102mg,0.67mmol),化合物16e(100mg,0.22mmol)和N,N-二异丙基乙胺(145mg,1.12mmol)依次加入到1,4-二氧六环(10mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物35(60mg,51.1%)。1H NMR(400MHz,MeOD)δppm8.99(d,J=3.0Hz,1H),8.57(s,1H),8.40(d,J=3.1Hz,1H),7.82(s,1H),7.75(d,J=8.9Hz,1H),7.68(d,J=8.9Hz,1H),7.19(d,J=8.9Hz,1H),7.14(s,1H),6.95(d,J=8.7Hz,1H),6.78–6.59(m,1H),6.37–6.32(m,1H),5.81(d,J=10.6Hz,1H),5.36–5.24(m,1H),4.54–4.44(m,1H),4.32–4.19(m,1H),3.99(s,3H),3.95–3.90(m,1H),3.76–3.63(m,1H),2.58(s,1H),2.28(s,3H),2.24–1.96(m,2H).LCMS:534.0[M+H]+.
实施例36:化合物36的合成
将化合物30a(102mg,0.67mmol),化合物16e(100mg,0.22mmol)和N,N-二异丙基乙胺(145mg,1.12mmol)依次加入到1,4-二氧六环(10mL)中,70℃搅拌6小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物36(53mg,45.1%)。1H NMR(400MHz,MeOD)δppm8.99(d,J=3.0Hz,1H),8.57(s,1H),8.40(d,J=3.1Hz,1H),7.82(s,1H),7.75(d,J=8.9Hz,1H),7.68(d,J=8.9Hz,1H),7.19(d,J=8.9Hz,1H),7.14(s,1H),6.95(d,J=8.7Hz,1H),6.78–6.59(m,1H),6.37–6.32(m,1H),5.81(d,J=10.6Hz,1H),5.36–5.24(m,1H),4.54–4.44(m,1H),4.32–4.19(m,1H),3.99(s,3H),3.95–3.90(m,1H),3.76–3.63(m,1H),2.58(s,1H),2.28(s,3H),2.24–1.96(m,2H).LCMS:534.0[M+H]+.
实施例37:化合物37的合成
将化合物37a(10mg,0.59mmol),化合物18a(40mg,0.1mmol),XPhos Pd G2
(8mg,0.01mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(17mg,0.03mmol)和碳酸铯(64mg,0.2mmol)依次加入到二氧六环(10mL)中,氮气保护下90℃搅拌16小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化钠洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物37(10mg,8.1%)。1H NMR(400MHz,CD3OD):δppm 9.29(s,1H),8.84–8.82(m,2H),8.70–8.58(m,1H),8.47(s,1H),7.98–7.93(m,2H),7.25–7.23(m,1H),7.18–7.16(m,1H),6.88–6.81(m,1H),6.75–6.69(m,1H),6.33–6.29(m,1H),5.82–5.79(m,1H),4.91–4.81(m,1H),3.88–3.78(m,2H),2.39–2.37(m,1H),2.28(s,3H),2.20–2.03(m,3H).LCMS:537.0[M+H]+.
实施例38:化合物38的合成
将化合物38a(50mg,0.3mmol),化合物18a(40mg,0.1mmol),XPhos Pd G2(8mg,0.01mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(17mg,0.03mmol)和碳酸铯(64mg,0.2mmol)依次加入到二氧六环(10mL)中,氮气保护下90℃搅拌16小时。LCMS监控,反应完成后减压浓缩,残留物加乙酸乙酯稀释(30mL),用水洗涤(20mL×2),饱和氯化钠洗涤(20mL),无水硫酸钠干燥,减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物38(5mg,8.1%)。1H NMR(400MHz,CD3OD):δppm 9.26(s,1H),8.78(d,J=7.6Hz,1H),8.66(s,1H),8.37(s,1H),7.99–7.93(m,2H),7.21(d,J=8.4Hz,1H),7.12–7.10(m,1H),6.84(d,J=2.0Hz,1H),6.75–6.69(m,1H),6.28(m,1H),5.82–5.79(m,1H),4.88–4.81(m,1H),3.88–3.77(m,2H),2.39–2.34(m,1H),2.26(s,3H),2.19–2.09(m,3H).LCMS:537.0[M+H]+.
实施例39:化合物39的合成
将化合物39a(40mg,0.23mmol),化合物1g(50mg,0.11mmol)和N,N-二异丙基乙胺(60mg,0.46mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌16小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物39(10mg,17.02%)。1H NMR(400MHz,CD3OD):δppm 8.98(s,1H),8.74(d,J=8.0Hz,1H),8.40(s,1H),8.28(s,1H),8.14(s,1H),7.95–7.91(m,1H),7.19(d,J=8.0Hz,1H),7.07–7.06(m,1H),6.80–6.79(m,1H),6.15–6.07(m,2H),5.69–5.21(m,3H),4.32–4.28(m,2H),3.94–3.64(m,3H),3.13–3.10(m,1H),2.17–2.14(m,4H),2.03(s,1H).LCMS:535.0[M+H]+.
实施例40:化合物40的合成
将化合物39a(40mg,0.23mmol),化合物16e(50mg,0.11mmol)和N,N-二异丙基乙胺(60mg,0.46mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌
16小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得到黄色固体化合物40(11mg,18.25%)。1H NMR(400MHz,CD3OD):δppm 8.96(s,1H),8.46–8.43(m,1H),8.35(s,1H),8.08–8.07(m,1H),7.83–7.63(m,2H),7.18–7.14(m,2H),6.96–6.94(m,1H),6.21–6.07(m,2H),5.68–5.19(m,3H),4.31–4.02(m,3H),3.97(s,3H),3.80–3.63(m,2H),3.13–3.09(m,1H),2.33–2.23(m,4H),2.03(s,1H).LCMS:548.0[M+H]+.
实施例41:化合物41的合成
将化合物41a(20mg,0.12mmol),化合物1g(30mg,0.07mmol)和N,N-二异丙基乙胺(27mg,0.21mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌16小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得到黄色固体化合物41(4mg,10.7%)。1H NMR(400MHz,CD3OD):δppm 9.13–8.99(m,1H),8.84–8.82(m,1H),8.62(s,1H),8.45(s,1H),8.11–8.07(m,1H),7.91–7.86(m,1H),7.29(d,J=8.4Hz,1H),7.18(s,1H),6.87(s,1H),6.18–6.04(m,2H),5.64–5.55(m,1H),5.40–5.20(m,1H),4.81–4.78(m,1H),4.35–4.23(m,3H),4.16–3.84(m,1H),3.75–3.67(m,1H),3.15–3.04(m,1H),2.34–2.23(m,4H),2.09–2.03(m,1H).LCMS:535.0[M+H]+.
实施例42:化合物42的合成
将化合物41a(20mg,0.12mmol),化合物16e(30mg,0.07mmol)和N,N-二异丙基乙胺(27mg,0.21mmol)依次加入到1,4-二氧六环(5mL)中,70℃搅拌16小时。LCMS监控,反应完成后减压浓缩,高效液相制备色谱分离[(Gemini-C18柱,5μ二氧化硅,直径21mm,长度150mm),水(0.1%TFA)和MeCN作为洗脱剂(25-55%)],得黄色固体化合物42(5mg,13.05%)。1H NMR(400MHz,CD3OD):δppm 9.31(s,1H),9.08–8.97(m,1H),8.57–8.55(m,1H),8.06–7.98(m,1H),7.92–7.91(m,1H),7.86–7.79(m,1H),7.39(d,J=8.8Hz,1H),7.26(s,1H),7.10(d,J=8.8Hz,1H),6.17–6.04(m,2H),5.64–5.54(m,1H),5.39–5.18(m,2H),4.90–4.78(m,1H),4.35–4.31(m,2H),4.14(s,3H),3.90–3.84(m,1H),3.69–3.66(m,1H),3.14–3.09(m,1H),2.33–2.26(m,4H),2.09–2.03(m,1H).LCMS:548.0[M+H]+.
B.测试实施例
1实验目的
本实验采用Promega公司提供的CellTiter-Glo(CTG)试剂盒,它是一种均质法细胞活力检测方法,通过对ATP的定量来测定培养细胞的细胞活力。本实验的目的是利用CTG方法评估待测化合物对BAF3-HER2细胞株的细胞增殖的影响。
2实验材料及仪器设备
2.1实验试剂耗材
2.2实验仪器设备
3实验方法
3.1细胞培养
1)细胞株:Ba/F3-HER2WT、Ba/F3-HER2A775_G776ins YVMA clone#5、Ba/F3-EGFR WT
2)完全培养基:RPMI 1640+10%胎牛血清+1X青霉素链霉素、RPMI 1640+10%胎牛血清+1X青霉素链霉素+2μg/mL嘌呤霉素、RPMI 1640+10%胎牛血清+1X青霉素链霉素+100ng/mL EGF
3)细胞接种培养基:RPMI 1640+10%胎牛血清+1X青霉素链霉素、RPMI 1640+10%胎牛血清+1X青霉素链霉素、RPMI 1640+10%胎牛血清+1X青霉素链霉素+100ng/mL EGF
3.2.HER2、EGFR野生型及突变型细胞株增殖实验
1)Ba/F3-HER2WT、Ba/F3-HER2_A775_G776ins YVMA clone#5&Ba/F3-EGFR
WT细胞株于37℃,5%CO2条件下培养于完全培养基。
2)将参考化合物储液和待测化合物储液稀释到1mM,然后再进行3倍连续稀释,10个剂量,两个复孔,待用。
3)然后利用Echo将连续稀释化合物各转移30nL至384孔细胞板中,200g,室温离心3-5秒。
4)收集细胞,并将细胞重悬于接种培养基中,接种于384孔细胞培养板的相应实验孔中,HER2WT、HER2A775_G776ins YVMA每孔接种30μL共600个细胞,EGFR WT每孔接种30μL共800个细胞。
5)随后将细胞培养板于37℃孵育72小时。
6)配制CTG检测试剂工作液,待用。
7)孵育完成后,将细胞培养板平衡至室温,然后加入30μL CTG试剂至细胞板的所有实验孔中。
8)将细胞培养板置于振荡器上振荡3分钟,然后室温避光放置30分钟。
9)利用Envision读取化学发光信号值,收集数据。
3.3.数据分析
1)Z’factor=1-3*(SDMax+SDMin)/(MeanMax-MeanMin)
2)Z’factor=1-3*(SDMax+SDMin)/(MeanMax-MeanMin)
3)CVMax=(SDMax/MeanMax)*100%
4)CVMin=(SDMin/MeanMin)*100%
5)实验窗口=信号值/背景值
6)阴性对照:0.1%DMSO
7)阳性对照:1,000nM来那替尼
8)利用GraphPad非线性拟合公式计算化合物IC50:
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:化合物浓度log值;Y:抑制率百分比
9)Inhibition(%)=(1-(Cpd-MeanMin)/(MeanMax-MeanMin))×100%
100%抑制率:1,000nM来那替尼;0%抑制率:0.1%DMSO
4化合物IC50值
表中,NA是指未测试。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (13)
- 一种化合物或其药学上可接受的盐,其特征在于,所述的化合物如式I所示,
其中,Q1为-CONR'-,Q2为含一个环氮原子的4-6元单环杂环基;或者,-Q1-Q2-代表由两个相同或不同的含一个环氮原子的4-6元单环杂环基形成的稠环或螺环;并且所述4-6元单环杂环基任选地被一个或多个R'基团所取代;其中,R'各自独立地为H或C1-2烷基;R1选自下组:H、取代或未取代的C1-4烷基、取代或未取代的C2-4烯基、取代或未取代的C2-4炔基、C1-4烷氧基,和卤素;R2选自下组:H、取代或未取代的C1-4烷基,和卤素;R3选自下组:
R4为
R5为H或取代或未取代的C1-4烷基;R6选自下组:H、取代或未取代的C1-4烷基、-C1-2亚烷基-N(R")2;其中,R"为H或C1-4烷基;除非特别说明,所述的取代是指基团上一个或多个(如1、2或3个)H原子被选自下组的取代基取代:氘(D)、卤素、C1-4烷基、C1-4卤代烷基。 - 如权利要求1所述的化合物,其特征在于,所述的化合物如式Ia所示
其中,表示单键或双键;W1为-(CR'2)n1-,W2为-(CR'2)n2-;其中,下标n1=0、1或2,下标n2=0、1或2,且n1+n2≥1;W3为-(CR'2)n3-,W4为-(CR'2)n4-;其中,下标n3=0、1或2,下标n4=0、1或2,且n3+n4≥1;R1、R2、R3、R4和R'如权利要求1中定义。 - 如权利要求1所述的化合物,其特征在于,-Q2-Q1-为
- 如权利要求1所述的化合物,其特征在于,所述的化合物如式Ib所示
其中,W5为-(CR'2)n5-,W6为-(CR'2)n6-;其中,下标n5=0、1、2或3,下标n6=0、1、2或3,且2≤n5+n6≤4;W7为-(CR'2)n7-,W8为-(CR'2)n8-;其中,下标n7=0、1、2或3,下标n8=0、1、2或3,且2≤n7+n8≤4;R1、R2、R3、R4和R'如权利要求1中定义。 - 如权利要求1所述的化合物,其特征在于,n5=n6=1或2。
- 如权利要求1所述的化合物,其特征在于,所述的化合物如式Ic所示
其中,W9为-(CR'2)n9-;其中,下标n9=1、2或3;R1、R2、R3、R4和R'如权利要求1中定义。 - 如权利要求1所述的化合物,其特征在于,R1为取代或未取代的C1-4烷基;和/或,R2选自下组:H、甲基、和乙基。
- 如权利要求1所述的化合物,其特征在于,所述的化合物选自表A、表B和表C:表A
表B
表C
- 一种药物组合物,其特征在于,包括:(i)如权利要求1所述的化合物或其药学上可接受的盐,和(ii)药学上可接受的载体或赋形剂。
- 一种如权利要求1所述的化合物在制备用于治疗或预防疾病或病症的药物中用途,其中所述疾病或病症是由HER2介导的疾病或病症,或者可通过抑制HER2改善的疾病或病症。
- 如权利要求10所述的用途,其特征在于,所述疾病或病症包括:癌症。
- 如权利要求10所述的用途,其特征在于,所述疾病或病症包括:脑癌、乳腺癌、胆囊癌、膀胱癌、宫颈癌、结直肠癌、胃癌、胃食管交界处癌、子宫内膜癌、皮肤癌、食道肿瘤、头颈部肿瘤、星形肠道癌、胆管癌、肾癌、肝癌、卵巢癌、胰腺癌、肺癌或前列腺癌中的一种或多种。
- 一种抑制HER2的方法,所述方法包括:使对象与如权利要求1所述的化合物接触,从而抑制HER2,其中,所述的方法是体外非治疗性的。
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CN101356171A (zh) * | 2005-11-15 | 2009-01-28 | 阿雷生物药品公司 | 作为erbbi型受体酪氨酸激酶抑制剂用于治疗增殖性疾病的n4-苯基-喹唑啉-4-胺衍生物和相关化合物 |
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