CN110734436A - 嘧啶或吡嗪并环化合物及其应用 - Google Patents
嘧啶或吡嗪并环化合物及其应用 Download PDFInfo
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- CN110734436A CN110734436A CN201810776810.4A CN201810776810A CN110734436A CN 110734436 A CN110734436 A CN 110734436A CN 201810776810 A CN201810776810 A CN 201810776810A CN 110734436 A CN110734436 A CN 110734436A
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- cancer
- substituted
- independently
- pyrimidine
- pharmaceutically acceptable
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
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- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
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- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
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- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
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- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了嘧啶或吡嗪并五元杂环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物。本发明也提供了该类化合物的制备方法、含有该类化合物的组合物以及该类化合物用于制备治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关疾病或障碍的药物用途。
Description
技术领域
本发明公开了嘧啶或吡嗪并环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或其同位素标记化合物。本发明也提供了该类化合物及其中间体的制备方法、含有该类化合物的组合物及其作为治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关疾病的药物用途。
背景技术
PcG(Polycomb Group)蛋白是一类重要的染色质修饰酶。它通过对染色质的修饰达到调控基因的转录,从而对干细胞的生长、分化及长期的细胞记忆有重要作用。在哺乳动物细胞中,PcG蛋白主要分为两类转录抑制复合物,分别是PRC1(Polycomb RepressiveComplex 1)和PRC2(Polycomb Repressive Complex 2)。其中,PRC2是通过对染色质中组蛋白3的27位赖氨酸(H3K27)的甲基化修饰来抑制相关基因的表达。PRC2蛋白复合物主要由EZH2(Enhancer of Zeste Homolog 2)(或其非常类似的同源蛋白EZH1),EED(Embryonicectoderm Development)以及SUZ12(Suppressor of Zeste 12)等核心蛋白组成。其中,EZH2具有酶催化活性,通过SET(Su(var),E(Z),and Trithorax)蛋白结构域能够把底物SAM(S-adenosyl-L-methionine)的甲基转移到H3K27上,从而达到H3K27的一到三甲基化修饰。EZH2的酶催化活性也依赖于PRC2其他组成部分,比如属于WD40重复结构蛋白家族的EED蛋白。EED与三甲基化的H3K27Me3的结合作用一方面对EZH2的酶催化功能有很大的变构促进作用,另一方面也能把PCR2复合物定位在需要修饰的染色质上。PRC2的功能异常,比如EZH2的过表达或功能获得性突变,与临床上许多肿瘤疾病相关,包括肺癌,乳腺癌,直肠癌,前列腺癌,膀胱癌,胰腺癌,肉瘤以及淋巴癌等等。PRC2也与多种细胞免疫功能相关,比如EZH2参与调节淋巴细胞活化,也能与糖酵解共同促进T细胞对肿瘤细胞的应答。因此,研发PRC2小分子抑制剂有重要且广阔的药物开发价值。
围绕PRC2抑制剂的研发主要是开发EZH2抑制剂以及EED抑制剂两个策略。目前进入临床的EZH2抑制剂有EPZ-6438(Epizyme,临床二期),GSK2816126(GSK,临床一期),以及CPI-1205(Constellation,临床一期)等等。尽管EZH2抑制剂研发有多个进入临床研究阶段,但这些抑制剂都含有一个共同的2-吡啶酮的药效团。并且,在用已有EZH2抑制剂于临床治疗中,已经开始出现二次突变。EED抑制剂对EZH2酶功能有变构抑制的作用,可以达到与EZH2相同或类似的生物功能。而且一方面EED抑制剂很好的克服了EZH2的耐药性问题,另一方面EED抑制剂可以与EZH2抑制剂联用达到更好的协同作用效果。
发明内容
本发明提供的嘧啶或吡嗪并环化合物是一类全新的EED抑制剂,表现出对肿瘤细胞很好的抑制活性,具有广阔的药物开发前景。而且该类化合物的制备方法简单,反应条件温和,收率和纯度高,后处理简单,绿色环保,有利于工业化生产。
第一方面本发明提供式(I)所示的嘧啶或吡嗪并环化合物、药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,
其中
X1独立地为C或N;
X2独立地为C或N;
X3独立地为C或N;
X4独立地为C,N或S;
Z独立地为C或O;
其中
m独立地为0或1;
n独立地为0或1;
p独立地为0或1;
R1独立地为氢或卤素;
R2独立地为氢、卤素、氰基、C1-8烷基、C1-8卤代烷基、R2a取代或未取代的C3-8环烷基、R2b取代或未取代的C3-8杂环基、R2c取代或未取代的烯基、R2b取代或未取代的C5-8环烯基、R2b取代或未取代的C5-8杂环烯基、R2d取代或未取代的氨基、R2d取代或未取代的氧基、R2d取代或未取代的酰胺、0-3个R2e取代的C6-10芳基或0-3个R2e取代的含有C1-20碳原子及1-4个N、NR2e1、O或S(O)0-2等杂原子的杂芳环;
R2a和R2b独立的为氨基、保护基团保护的氨基、单氟或多氟;
R2c独立的为C1-4烷基、酯基;
R2d独立的为C1-20烷基、苄基、取代或未取代的C6-10芳基、取代或未取代的含有C1-20碳原子及1-4个N、NR2e1、O或S(O)0-2等杂原子的杂芳环;
R2e独立的为卤素、-C(=O)NR2e1R2e2、-S(=O)2R2e3、N R2e1R2e2、含有C1-20碳原子及1-4个NR2e1、O或S(O)0-2等杂原子的杂环;其中,R2e1独立的为氢或C1-4烷基;R2e2独立的为氢或C1-4烷基;R2e3为C1-4烷基。
在另一优选例中,Z不存在时,是单键或双键;m,n为0;p为1;
在另一优选例中,X1为C时,X2为N,X3为C,X4为N;
在另一优选例中,X1为N,X2为N时,X3为C,X4为C;
在另一优选例中,X1为N,X2为C时,X3为N,X4为C;
在另一优选例中,X1为N,X2为C时,X3为C,X4为S;
在另一优选例中,R1选自H、F。
在另一优选例中,R2是卤素、氰基、C1-8烷基、C1-8卤代烷基或具有以下结构:
其中,j为0、1、2或3;k为0、1、2、3或4;l为0、1或2;V为C、N或O,且在同一环中最多同时有两个N或O;环A含有1-3个杂原子的取代或未取代的C5-10杂芳基;环B选自含有1-4个杂原子的取代或未取代的C5-10杂芳基,其中所述杂原子选自N、O或S;Q为N、O或S。
在另一优选例中,所述环A为含有1-3个杂原子的六元杂芳基。
在另一优选例中,所述环B是含有1-4个杂原子的五元杂环基。
在另一优选例中,所述的化合物选自下列任一化合物:
在另一优选例中,所述的化合物选自下列任一化合物:
本发明还提供式(I)所示的嘧啶或吡嗪并环化合物、药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物。通式(I)所示化合物中能够被同位素标记的原子包括但不局限于氢、碳、氮、氧、磷、氟、氯和碘等。它们可分别被同位素2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I等代替。
本发明还提供式(I)所示的嘧啶酮化合物及其中间体的制备方法,包括以下方面:
本发明提供式(I)所示的嘧啶酮化合物的制备方法,包含如下步骤:
其中,W代表卤素,优选Br、I;X1、X2、X3、X4、R1、R2、Z、m、n和p的定义如上所述。
在另一优选例中,化合物I-A的制备方法,包含如下步骤:
卤代中间体A与硼酸,硼酸酯或硼酸盐在偶联的条件下,生成化合物I-A。
其中,W、R1、R2、X1、X2、X3、X4、Z、j、k、m、n、p、R2b、R2c、R2e的定义如上所述。
在另一优选例中,化合物I-B的制备方法,包含以下步骤:
卤代中间体A与氰化锌偶联的条件下,生成氰基化合物I-B。
反应方程式如下:
其中,W、R1、R2、X1、X2、X3、X4、Z、m、n和p的定义如上所述。
在另一优选例中,化合物I-C的制备方法,包含以下步骤:
卤代中间体A与取代胺或硫醇在偶联的条件下,生成化合物I-C。
反应方程式如下:
其中,W、R1、R2、X1、X2、X3、X4、Z、m、n和p的定义如上所述,Q为N或S。
本发明还提供一种化合物A的制备方法,包含以下步骤:
氯代嘧啶或氯代吡嗪中间体B在碱性条件下被中间体胺C取代得到卤代嘧啶或吡嗪并环中间体A。
反应方程式如下:
其中,W、R1、X1、X2、X3、X4、Z、m、n和p的定义如上所述。
本发明还提供一种化合物B1的制备方法,包含以下步骤:
二溴吡嗪B1-a与水合肼反应得到取代的肼B1-b,B1-b在原甲酸三甲酯中关环得到中间体B1。
反应方程式如下:
本发明还提供化合物B2的制备方法,包含以下步骤:
氯溴嘧啶B2-a与N,N-二甲基甲酰胺二甲基缩醛缩合得到B2--b,B2-b与羟胺反应得到B2-c,B2-c在多聚磷酸中关环得到中间体B2。
反应方程式如下:
本发明还提供化合物B3的制备方法,包含以下步骤:
二氨基吡啶B3-a溴代得到中间体B3-b,B3-b在二氯亚砜中回流得到中间体B3。
反应方程式如下:
本发明还提供化合物C1或C2,
其中,R1的定义如上所述。
本发明还提供C1或C2的制备方法,包含以下步骤:
间溴苯酚C1-a经取代酚羟基得到缩醛C1-b后分子内缩合得到中间体C1-c,需要指出的是当R1是氢时,缩合过程生成的副产物C1-d可通过下一步转化为氰基后用柱层析的方法分离去除;溴代苯并呋喃C1-c经氰基化后得到中间体C1-e;化合物C1-e经还原氰基后得到胺C2。
胺C2氢化还原后得到胺C1。另外化合物C1-e也可通过氢化还原呋喃和氰基的同时Boc保护生成的氨基而得到C1-f;最后,化合物C1-f经脱Boc保护后得到胺C1。
其中,R1的定义如上所述。
本发明还提供化合物C3,
其中,R1的定义如上所述。
本发明还提供化合物C3的制备方法,包含如下步骤:
间溴苯酚C1-a经取代酚羟基被炔丙基取代后得到化合物C3-a;化合物C3-a在高温的条件下发生重排得到中间体C3-b,类似的,当R1是氢时,会生成重排副产物C3-c;得到化合物C3-b后,经过与合成C1的类似方法可以得到胺C3。
反应方程式如下:
其中,R1的定义如上所述。
本发明还提供C4,
其中n为1或2;R1同上所述。
本发明还提供化合物C4的制备方法,包含如下步骤:
C4-a脱甲基后得到邻二苯酚C4-b;邻二苯酚C4-b环烷基化得到C4-c后引入醛基取代得到中间体C4-d;醛C4-d与羟胺缩合后得到甲醛肟C4-e;还原甲醛肟的同时Boc保护后得到C4-f;最后,脱保护后得到胺C4。
反应方程式如下:
其中n为1或2;R1同上所述。
本发明所涉及到的惰性溶剂选自:二氯甲烷、氯仿、1,2-二氯乙烷、二氧六环、DMF、乙腈、DMSO、NMP、THF或其组合。
本发明所涉及到的碱包括有机碱和无机碱。
本发明所涉及到的有机碱选自:TEA、DIPEA或其组合。
本发明所涉及到的无机碱选自:氢化钠、碳酸钾、碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠、LiHMDS、LDA、丁基锂或其组合。
本发明所述的通式(I)所示化合物的同位素标记化合物可通过与未标记化合物类似的合成方法来制备,所不同的是把未标记的起始原料和/或试剂换成同位素标记的起始原料和/或试剂。
本发明还提供了一种药物组合物,其包含通式(I)所示的化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或通式(I)所示的化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物、以及药学上可接受的辅料。作为优选,所述药学上可接受的辅料选自稀释剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂。
发明还提供了所述的通式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物用于制备预防和/或治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关的癌症药物方面的用途。作为优选,所述癌症包括但不局限于包括扩散大B细胞淋巴癌、滤泡性淋巴瘤;或作为优选,所述癌症包括但不局限于淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、前列腺癌、乳腺癌、脑瘤、宫颈癌、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等等,所述脑瘤包括但不限于神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤。
本发明还提供了一种药物制剂,包含所述的通式(I)所示的嘧啶酮化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或通式(I)所示的化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物,可以合适的方式服用,比如作为片剂、胶囊(如持续释放或定时释放的胶囊)、药丸、粉末、颗粒(如小颗粒)、酏剂、酊剂、悬浮液(如纳米混悬液、微悬浮液)和喷雾干燥的分散体等形式的悬浮物、糖浆、乳液、溶液等形式,可用于口服、舌下含服、包括皮下注射、静脉注射、肌肉注射、胸骨内注射、注入等形式的注射、鼻部服用(比如鼻膜吸入)、局部表面(如乳霜和药膏)、直肠给药(如栓剂)等等方式。本发明公开的化合物可以单独服用也可以与适当的药物载体一起服用。
本发明还提供了前述药物制剂可配方成适当的药物剂量以方便并控制药物的服用量。本发明公开的化合物的剂量方案根据具体的因素有所不同,比如药效学及服用的方式、服用对象、性别、年龄、健康状况以及服药对象的体重、病情特征、其它同时服药状况、服药的频率、肝肾功能以及想达到的效果等等。本发明公开的化合物可以每天单剂量的服用,也可以总剂量分多次服用(比如每天两至四次)。
本发明还提供了通式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物与其他药物联合使用的产品,所述其他药物选自:抗癌药、肿瘤免疫药物、抗过敏药、止吐药、镇痛药、细胞保护药物等等,一起联用具有更好的效果。
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。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
基团定义
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-6烷基是指具有总共1至6个碳原子(表明该范围内的整数,如0、1、2、3、4、5、6)的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(=O)-基团。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子,且通过单键与分子的其余部分连接,例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言,术语“烷基”指含有1至6个碳原子的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烃基中的碳原子可以任选地被氧化。环烃基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中,“任选地”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。本发明权利要求书和说明书部分所述的“任选地”的取代基选自烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、氰基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烃基、任选取代的杂环烃基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”包括但不限于脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌、多发性骨髓瘤、间皮瘤、恶性横纹肌样瘤、子宫内膜癌、头颈癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganiSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下述实施例中所用的起始物可由化学品销售商如Aldrich、TCI、Alfa Aesar、毕得、安耐吉等处购得,或者可通过已知的方法来合成。
下述实施例中,冰浴是指-5摄氏度至0摄氏度,室温是指10摄氏度至30摄氏度,回流温度一般是指溶剂常压下溶剂回流温度。反应过夜是指时间为8-15小时。下述实施例中,未限定具体操作温度的,均在室温下进行。
下述实施例中,中间体和最终产物的分离提纯是通过正相或反相色谱柱分离或者其它合适的方法。正相快速色谱柱是用乙酸乙酯和正己烷或甲醇和二氯甲烷等作为流动相。反相制备性高压液相色谱(HPLC)是用C18柱并用UV 214nm和254nm来检测,其流动相为A(水和体积比0.1%的甲酸)、B(乙腈)或者流动相A(水和质量比0.1%的碳酸氢铵)、B(乙腈)。
各实施例中:
LCMS仪器:Pump Agilent 1260 UV检测器:Agilent 1260 DAD MassSpectrometer API 3000
层析柱:Waters sunfire C18,4.6×50mm,5um
流动相:A-H2O(0.1%HCOOH);B-乙腈
NMR仪器:Bruker Ascend 400M(1H NMR:400MHz;13C NMR:100MHz)。
实施例1:5-溴-8-氯-[1,2,4]三唑并[4,3-a]吡嗪(B1)
步骤一:5-溴-2-氯-3-肼基吡嗪(B1-b)的合成:
在50mL单口瓶中加入B1-a(2g,7.34mmol)和乙醇(20mL),冰浴中缓慢滴加水合肼(1.72g,53.65mmol),悬浊液于40℃搅拌3小时。反应结束后,降至室温,析出淡黄色固体,过滤收集固体,滤饼用乙醇(5mL)洗,干燥得到淡黄色固体产物B1-b(1g,收率60%)。
1H NMR(400MHz,CDCl3)δ7.76(s,1H),6.55(d,J=0.5Hz,1H),3.97(s,2H)ppm。
步骤二:5-溴-8-氯-[1,2,4]三唑并[4,3-a]吡嗪(B1)的合成:
在50mL单口瓶中加入B1-b(1g,4.48mmol),原甲酸三甲酯(20mL),升温至120℃反应10h。反应结束后,降温至室温,旋蒸除去原甲酸三甲酯,浓缩物用硅胶柱(PE:EA=20:1)纯化得到黄色固体产物5-溴-8-氯-[1,2,4]三唑并[4,3-a]吡嗪B1(700mg,收率67%)。
1H NMR(400MHz,CDCl3)δ9.09(s,1H),7.85(s,1H)ppm;LCMS:m/z 232.9[M+H]+
实施例2:5-氯-8-溴-[1,2,4]三唑[1,5-c]嘧啶(B2)
步骤一:N’-(5-溴-2-氯嘧啶-4-基)-N,N-二甲基甲脒(B2-b)的合成
在500mL单口瓶中依次加入B2-a(40g,192mmol),N,N-二甲基甲酰胺二甲基缩醛(30,250mmol)和甲苯(200mL),升温至120℃反应3小时。反应结束后,减压除去甲苯,过滤收集固体,滤饼用200mL二氯甲烷洗涤,干燥得到白色固体产物N’-(5-溴-2-氯嘧啶-4-基)-N,N-二甲基甲脒B2-b(42g,收率82%)。
LCMS:m/z 269.2[M+H]+
步骤二:N'-(5-溴-2-氯嘧啶-4-基)-N-羟基甲脒(B2-c)的合成
在干燥的500mL单口瓶中依次加入B2-b(42g,160mmol),甲醇(250mL),盐酸羟胺(14g,46mmol)。室温下搅拌反应3小时。反应完毕后,减压除去甲醇,过滤收集,滤饼用100mL二氯甲烷洗涤,干燥得到白色固体产物N'-(5-溴-2-氯嘧啶-4-基)-N-羟基甲脒(B2-c)(40g,收率84%)。
1H NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.67(s,1H),8.50(dd,J=9.2,6.1Hz,1H),7.88(d,J=8.2Hz,1H)ppm;LCMS:m/z 250.9[M+H]+
步骤三:8-溴-[1,2,4]三唑[1,5-c]嘧啶-5-羟基(B2-d)的合成
在干燥的250mL单口瓶中依次加入20mL多聚磷酸,B2-c(7.5g,29.6mmol)。反应温度升到120℃并搅拌反应过夜。反应完毕后,向反应体系中加入150m冰水,用2N氢氧化钠水溶液调节PH至8左右,反应液用正丁醇萃取(150mL)三次,合并有机相,将有机相减压浓缩,得到8-溴-[1,2,4]三唑[1,5-c]嘧啶-5-羟基(B2-d)(3.5g,产率:50%)。
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.45(s,1H),7.96(s,1H)ppm;LCMS:m/z215.0[M+H]+
步骤四:8-溴-5-氯-[1,2,4]三唑[1,5-c]嘧啶(B2)的合成
在干燥的50mL单口瓶中依次加入10mL三氯氧磷和B2-d(3.5g,16.28mmol)。反应温度升到110℃并搅拌12小时。反应完毕后,减压除去三氯氧磷。所得固体用柱层析(乙酸乙酯:石油醚=1:10)纯化得到黄色固体8-溴-5-氯-[1,2,4]三唑[1,5-c]嘧啶(B2)(0.8g,产率:21%)。
1H NMR(400MHz,CDCl3)δ8.53(s,1H),8.32(s,1H)ppm;LCMS:m/z 232.9[M+H]+
使用如上方法,用类似的起始原料得到中间体5-溴-8-氯-[1,2,4]三唑并[1,5-a]吡嗪B3
LCMS:m/z 232.9[M+H]+
实施例3:7-溴-4-氯-[1,2,5]噻二唑并[3,4-c]吡啶(B3)
步骤一:2,5-二溴吡啶-3,4-二胺(B3-b)的合成
在干燥的250mL三口瓶中依次加入B3-a(4.0g,36.7mmol)和48%氢溴酸(80mL)。在常温搅拌下滴加液溴(7.0g,44mmol)。反应液在110℃搅拌5小时。反应结束后冷却至室温,过滤得到棕色固体,用少量的冷水洗涤。将固体溶于乙酸乙酯(200mL),用饱和碳酸氢钠(100mL)和饱和食盐水(100mL)洗涤。乙酸乙酯层用无水硫酸钠干燥,过滤后浓缩后得到棕色固体B3-b(6.6g,产率67.5%)。
步骤二:7-溴-4-氯-[1,2,5]噻二唑并[3,4-c]吡啶(B3)的合成
在干燥的50mL单口瓶中依次加入10mL二氯亚砜和B3-b(750mg,2.8mmol)。反应液在100℃搅拌5小时后冷却至室温。反应液旋干除去过量的二氯亚砜,残余物溶于乙酸乙酯(200mL),用饱和食盐水(200mL)洗,用无水硫酸钠干燥,过滤浓缩后得到粗品B3(4.64g,100%),直接用于下一步。
1H NMR(400MHz,CDCl3)δ8.48(s,1H)
实施例4:中间体(2,3-二氢苯并呋喃-4-基)甲胺(C1-1)和苯并呋喃-4-基甲胺(C2-1)的合成
步骤一:中间体溴-3-(2,2-二乙氧基乙氧基)苯(C1-1b)
在500mL的单口烧瓶中依次加入间溴苯酚C1-1a(13g,75.14mmol)和N,N二甲基甲酰胺(150mL)。在0℃条件下,加入氢化钠(1.98g,82.66mmol)并搅拌半个小时。然后,向反应液中加入2-溴-1,1-二乙氧基乙烷(16.29g,82.66mmol),升温到120℃并搅拌过夜。冷却至室温后,将反应液用100mL水淬灭,用乙酸乙酯萃取(500mL X 2)。合并的有机相用盐水洗涤两次,经无水硫酸钠干燥,过滤,在减压下浓缩,得到21g产物C1-1b。
1H NMR(400MHz,CDCl3)δ7.16-7.06(m,3H),6.88-6.83(m,1H),4.81(t,J=5.2Hz,1H),3.98(d,J=5.2Hz,2H),3.80-3.71(m,2H),3.67-3.59(m,2H),1.26-1.23(m,6H)ppm;LCMS:m/z 289.0[M+H]+
步骤二:中间体4-溴苯并呋喃(C1-1c)
在500mL的单口烧瓶中依次加入溴-3-(2,2-二乙氧基乙氧基)苯C1-1b(21g,72.6mmol),150mL甲苯和多聚磷酸(10.68g,108.93mmol)。反应液于95℃加热并搅拌4个小时。冷却至室温后,反应液用1L冰水淬灭,用乙酸乙酯萃取(500mL X 3)。合并的有机相用盐水洗涤两次,经无水硫酸钠干燥,过滤,在减压下浓缩,得到C1-1c和C1-1d的混合物粗品共5g。
步骤三:中间体苯并呋喃-4-甲腈(C1-1e)
在100mL的三口烧瓶中依次加入C1-1c和C1-1d的混合物(5g,25.1mmol),氰化锌(4.2g,37.7mmol),四三苯基膦钯(2.9g,2.5mmol)和无水N,N-二甲基甲酰胺(50mL)。反应混合物在氮气下100℃加热搅拌18个小时。冷却至室温后,加入200mL水,用乙酸乙酯萃取(200mL X 3)。合并的有机相用盐水洗涤两次,经无水硫酸钠干燥,过滤,在减压下浓缩。残余物在硅胶上纯化(石油醚:乙酸乙酯=100:1),得到苯并呋喃-4-甲腈C1-1e(1.1g,30%产率),为淡黄色固体。C1-1d的转化产物在这一步分离除去。
1H NMR(400MHz,DMSO-d6)δ8.31(d,J=2.2Hz,1H),8.03(d,J=8.4Hz,1H),7.84-7.71(m,1H),7.58-7.46(m,1H),7.20(dd,J=2.2,1.0Hz,1H)ppm。
步骤四:中间体苯并呋喃-4-基甲胺(C2-1)
在单口烧瓶中加入苯并呋喃-4-甲腈C1-1e(300mg,2.09mmol),甲醇(50mL),氯化镍(543mg,4.19mmol),慢慢加入硼氢化钠(159mg,4.19mmol),室温反应2个小时。混合物经硅藻土过滤,用甲醇洗涤,滤液减压浓缩得到粗品。粗品在硅胶上纯化(二氯甲烷:甲醇=10:1),得到苯并呋喃-4-基甲胺C2-1(50mg,16.2%产率),为黄色固体。
1H NMR(400MHz,DMSO-d6)δ9.20-7.80(m,3H),7.60(d,J=8.2Hz,1H),7.44(d,J=7.3Hz,1H),7.35(t,J=7.8Hz,1H),7.28(dt,J=9.6,4.8Hz,1H),4.23(s,2H)ppm;LCMS:m/z148.1[M+H]+。
步骤五:中间体((2,3-二氢苯并呋喃-4-基)甲基)氨基甲酸叔丁酯(C1-1f)
在100mL单口瓶中依次加入苯并呋喃-4-甲腈C1-1e(1.1g,7.68mmol),BOC酸酐(2.5g,11.52mmol),甲醇(50mL)和10%钯碳(2g,含50%水)。反应混合物用氢气鼓气5分钟,用氢气球换气三次,在氢气球下60℃搅拌18小时。混合物经硅藻土过滤,用甲醇(50mL X 2)洗涤,滤液减压浓缩,得到化合物C1-1f(1.5g,79%产率)。
LCMS:m/z 195.1[M+H-tBu]+。
步骤六:中间体(2,3-二氢苯并呋喃-4-基)甲胺(C1-1)
在50mL单口瓶中依次加入((2,3-二氢苯并呋喃-4-基)甲基)氨基甲酸叔丁酯C1-1f(1.3g,5.21mmol)和15mL HCl/二恶烷(4M),室温搅拌4小时。反应完毕,混合物在减压下浓缩。残余物用混合溶剂(甲醇:乙腈=1:10,50mL)稀释,然后加入碳酸钾(2g,14.6mmol)。混合物于60℃加热并搅拌3小时,冷却至室温,过滤,滤液减压浓缩,得到化合物C1-1(700mg,90%产率),为白色固体。
1H NMR(400MHz,CD3OD)δ7.15(t,J=7.8Hz,1H),6.89(d,J=7.7Hz,1H),6.72(d,J=8.0Hz,1H),4.59(t,J=8.7Hz,2H),3.93(s,2H),3.27(t,J=8.7Hz,2H)ppm;LCMS:m/z150.1[M+H]+.
使用如上方法,用类似的起始原料得到以下中间体C2-2和C1-2。
实施例5:中间体(6-氟苯并二氢吡喃-5-基)甲胺(C3-1)
步骤一:中间体2-溴-1-氟-4-(丙-2-炔-1-基氧基)苯(C3-1b)
在干燥的2L单口烧瓶瓶中室温下加入3-溴-4-氟苯酚C3-1a(87g,455.5mmol),干燥的N,N-二甲基甲酰胺(800mL)。用氮气置换体系空气三次,在冰水浴下历时30分钟分批次加入60%的氢化钠(20g,501mmol)。反应液室温下搅拌15分钟后用冰水浴冷却,然后加入氯丙炔(50.9g,683.3mmol)。反应液室温下搅拌18小时。反应完毕后,加入水(1L),用乙酸乙酯(1L)萃取三次。有机相用饱和氯化钠水溶液(500mL)洗涤一次,有机相用硫酸钠干燥,过滤,减压蒸馏得到粗产品。通过硅胶柱(石油醚:乙酸乙酯=20:1)纯化得到产品黄色油状液体2-溴-1-氟-4-(丙-2-炔-1-基氧基)苯C3-1b(80g,76.7%产率)。
1H NMR(400MHz,CDCl3)δ7.17(dd,J=5.5,3.0Hz,1H),7.05(dd,J=9.0,8.1Hz,1H),6.89(ddd,J=9.1,3.7,3.2Hz,1H),4.66(d,J=2.4Hz,2H),2.54(t,J=2.4Hz,1H)ppm。
步骤二:中间体5-溴-6-氟-2H-色烯(C3-1c)
在干燥的20mL微波管中加入2-溴-1-氟-4-(丙-2-炔-1-基氧基)苯C3-1b(2g,8.7mmol)和N,N-二乙基苯胺(15mL)。反应液在微波合成仪中加热至250℃反应2.5小时。反应完毕后,用乙酸乙酯(100mL)稀释,用2N盐酸洗涤除去N,N-二乙基苯胺。有机相用饱和氯化钠水溶液(50mL)洗涤一次,有机相用硫酸钠干燥,过滤,减压蒸馏得到粗产品。粗产品通过硅胶柱(石油醚:乙酸乙酯=20:1)纯化得到C3-1c和C3-1d的棕色油状混合物(1.88g,94%产率)。
步骤三:中间体6-氟-2H-色烯-5-腈(C3-1e)
在干燥的500mL三口瓶中依次加入C3-1c和C3-1d的棕色油状混合物(20.2g,88.2mmol),氰化锌(13.5g,115mmol),无水N,N二甲基甲酰胺(250mL)和四三苯基膦钯(10.2g,8.8mmol)。反应液在氮气保护条件下110℃下搅拌18小时。反应完毕后,冷却到室温,加入1L水,用乙酸乙酯(500mL)萃取三次。有机相用饱和氯化钠水溶液(500mL)洗涤一次,有机相用硫酸钠干燥,过滤,减压蒸馏得到粗产品。通过硅胶柱(石油醚:乙酸乙酯=50:1~10:1)纯化得到产品白色固体6-氟-2H-色烯-5-腈C3-1e(8.12g,52.6%产率)。C3-1d的转化产物被分离除去。
1H NMR(400MHz,CDCl3)δ7.02-6.85(m,2H),6.70(dt,J=10.0,1.8Hz,1H),6.07(dt,J=10.0,3.6Hz,1H),4.88(dd,J=3.6,2.0Hz,2H)ppm;LC-MS:m/z 176.1[M+H]+。
步骤四:中间体((6-氟苯并二氢吡喃-5-基)甲基)氨基甲酸叔丁酯(C3-1f)
在500mL单口瓶中依次加入6-氟-2H-色烯-5-腈C3-1e(4.6g,26.3mmol),BOC酸酐(7.45g,34.1mmol),甲醇(200mL)和10%钯碳(1.6g,50%)。反应液先用氢气鼓泡5分钟,然后装上氢气球换气三次,在氢气中加热到60℃搅拌过夜。反应完毕后,冷却到室温,反应液过滤,减压蒸馏得到较纯的产品C3-1f(7.4g,100%),直接用于下一步。
1H NMR(400MHz,CDCl3)δ6.81(t,J=9.1Hz,1H),6.70(dd,J=9.0,4.9Hz,1H),4.75(s,1H),4.32(d,J=5.2Hz,2H),4.18-4.05(m,2H),3.49(d,J=1.8Hz,2H),2.86(t,J=6.4Hz,2H),2.10-1.91(m,2H),1.45(d,J=8.0Hz,9H)ppm;LC-MS:m/z226.1[M-tBu+H]+。
步骤五:中间体(6-氟苯并二氢吡喃-5-基)甲胺(C3-1)
在50mL单口瓶中依次加入C3-1f(1.0g,3.55mmol)和10mL HCl/二恶烷溶液(4M),室温搅拌4小时。反应完毕,混合物在减压下浓缩,得到化合物C3-1(612mg,95%产率),为白色固体。
1H NMR(400MHz,CD3OD)δ6.98(t,J=9.2Hz,1H),6.86(dd,J=9.1,5.1Hz,1H),4.28-4.07(m,4H),2.89(t,J=6.4Hz,2H),2.14-2.01(m,2H)ppm;LC-MS:m/z182.1[M+H]+。
实施例6:中间体(5-氟苯并[d][1,3]二氧杂环戊烯-4-基)甲胺(C4-1)
步骤一:中间体4-氟苯-1,2-二醇(C4-1b)
将4-氟-1,2-二甲氧基苯C4-1a(10g,64.0mmol)溶于无水二氯甲烷(120mL)中。在-78℃下,将三溴化硼(1摩尔的二氯甲烷溶液)缓慢加入到反应液中。反应混合物升到室温并继续搅拌16小时。将反应混合物倒入碎冰(200g)中,并用乙酸乙酯(3x 50mL)萃取。有机相用饱和氯化钠水溶液(100mL)洗涤一次,有机相用硫酸钠干燥,过滤,减压蒸馏得到4-氟苯-1,2-二醇C4-1b(8.0g,100%),为无色液体。
1H NMR(400MHz,CDCl3):δ6.80-6.77(m,1H),6.65-6.63(m,1H),6.50-6.46(m,1H),6.25(s,1H),5.81(s,1H)ppm.
步骤二:中间体5-氟苯并[d][1,3]二氧杂环戊烯(C4-1c)
将4-氟苯-1,2-二醇C4-1b(8.0g,62.5mmol)溶于DMF(25.0mL),在室温下缓慢加入碳酸铯(30.4g,93.75mmol)并在相同温度下搅拌10分钟。在相同温度下,在3分钟内向该反应混合物中分批加入氯溴甲烷(5.5mL,93.75mmol)。所得反应混合物在120℃搅拌1小时。将反应混合物冷却至室温并倒入碎冰(200mL)中并搅拌15分钟,然后用乙醚(3×50mL)萃取。合并的有机相用盐水(200mL)洗涤,无水硫酸钠干燥并减压浓缩。粗产物通过硅胶柱(石油醚:乙酸乙酯=20:1)纯化得到5-氟苯并[d][1,3]间二氧杂环戊烯C4-1c(4.0克,粗品)为无色液体。
GC-MS:m/z 139.1[M+H]+.
步骤三:中间体5-氟苯并[d][1,3]二氧杂环戊烯-4-甲醛(C4-1d)
将5-氟苯并[d][1,3]间二氧杂环戊烯C4-1c(4.0g,28.57mmol)溶于无水THF(50mL)。反应液冷却至-78℃,在氮气保护下历时15分钟加入二异丙基氨基锂(2M的THF溶液,28.57mL,57.14mmol),在相同温度下继续搅拌1小时。向反应液中加入DMF(4.17mL,57.14mmol),并将反应混合物缓慢升至室温并搅拌16h。反应完毕后,将反应混合物倒入碎冰(200mL)中,搅拌15分钟,用乙酸乙酯(2×50mL)萃取。合并的有机相用盐水(200mL)洗涤,无水硫酸钠干燥并减压浓缩。粗产物通过硅胶柱(石油醚:乙酸乙酯=20:1)纯化得到5-氟苯并[d][1,3]间二氧杂环戊烯-4-酮C4-1d(1.5g,两步产率76%),为黄色固体。
1H NMR(400MHz,CDCl3):δ10.26(s,1H),6.92(dd,J=8.5,4.0Hz,1H),6.60(dd,J=10.5,9.0Hz,1H),6.16(s,2H)ppm.
步骤四:中间体5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛肟(C4-1e)
将5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛C4-1d(1.5g,8.92mmol)溶于乙醇(10mL),加入溶解在乙醇(10mL)中的氢氧化钠(535mg,13.38mmol),水(8.0mL)和羟胺盐酸盐(727mg,10.70mmol)。反应液在室温下搅拌30分钟。反应完成后,将反应物倒入冷水中。过滤收集固体沉淀物,用水(100mL)洗涤并干燥,得到5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛肟C4-1e(1.2g,75%产率),为淡黄色固体。
1H NMR(400MHz,CDCl3):δ9.20(s,1H),8.30(s,1H),6.76-6.73(m,1H),6.60-6.56(m,1H),6.61(s,2H)ppm.
步骤五:中间体((5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲基)氨基甲酸叔丁酯(C4-1f)
在0℃下,向5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛肟C4-1e(1.2g,6.55mmol)的MeOH(10mL)溶液中加入六水氯化镍(1.86g,7.86mmol)。搅拌5分钟后,历时3分钟分批加入硼氢化钠(2.48g,65.5mmol),然后加入(Boc)2O(1.71g,7.86mmol)。反应液在室温下继续搅拌30分钟后用乙酸乙酯(50mL)稀释并通过硅藻土过滤。将滤液减压浓缩后得到的粗产物通过硅胶柱(石油醚:乙酸乙酯=20:1)纯化得到((5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲基)氨基甲酸叔丁酯C4-1f(1.2g,68%产率),为灰白色固体。
1H NMR(400MHz,CDCl3):δ6.65-6.63(m,1H),6.52-6.49(m,1H),6.01(s,2H),4.93(bs,1H),4.35(s,2H),1.44(s,9H)ppm.
步骤六:中间体(5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲胺(C4-1)
将((5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲基)氨基甲酸叔丁酯C4-1f(1.2g,10.11mmol)溶于二氯甲烷(15mL)中,加入4M HCl的二氧六环溶液(15mL,60.6mmol)。常温搅拌30分钟后,减压蒸馏除去挥发物。粗产物用乙酸乙酯(10mL)打浆并过滤,得到(5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲胺的盐酸盐C4-1(800mg,定量),为白色固体。
1H NMR(400MHz,CDCl3):δ8.46(s,D2O exchangeable,3H),6.98-6.95(m,2H),6.75(t,J=2.0Hz,2H),6.13(s,2H),3.96(s,2H)ppm;LC-MS:m/z 170.1[M+H]+.
使用如上方法,用类似的起始原料得到以下化合物
实施例7:中间体(6-氟-2,3-二氢苯并[b][1,4]二氧杂环己烯-5-基)甲胺(C4-2)。
1H NMR(400MHz,DMSO-d6):δ6.89(dd,J=9.0,5.5Hz,1H),6.73(t,J=9.0Hz,1H),4.33-4.31(m,2H),4.24-4.22(m,2H),3.86(d,J=1.0Hz,2H)ppm;LC-MS:m/z184.1[M+H]+.
实施例8:5-溴-N-((2,3-二氢苯并呋喃-4-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺(A-1)
在25mL圆底烧瓶中依次加入B1(98mg,0.42mmol),C1-1(100mg,0.38mmol),乙醇(8mL)和三乙胺(115mg,1.14mmol)。反应在90℃搅拌2小时后冷却至室温,减压蒸馏除去挥发物。粗品用硅胶柱(二氯甲烷:甲醇=30:1)纯化得到5-溴-N-((2,3-二氢苯并呋喃-4-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺A-1(70mg,53%产率)。
使用如上方法,用类似的起始原料得到以下中间体A-2,A-3,A-4,A-5,A-6,A-7,A-8,A-9和A-10。
实施例9:N-((2,3-二氢苯并呋喃-4-基)甲基)-5-(4-(甲磺酰)苯基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
在20mL的封管中室温下依次加入中间体A-1(30mg,0.086mmol),1,4-二氧六环(2mL),纯净水(0.5mL),(4-(甲基磺酰基)苯基)硼酸(21mg,0.10mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(6mg,0.008mmol)和碳酸钾(24mg,0.17mmol)。氮气氛围下封管加热至80摄氏度,反应6个小时。反应完毕,向反应液中加入20mL水并用乙酸乙酯(30mL×3)萃取。有机相依次用水(20mL×1),饱和食盐水(20mL×1)洗涤。收集有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后溶于甲醇(3mL),用高效液相色谱柱纯化得到2–(((2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲基磺酰基)苯基)嘧啶-4(3H)-酮(12mg,产率:32.9%),为白色固体。
1H NMR(400MHz,MeOD)δ9.13(s,1H),8.15(d,J=8.3Hz,2H),7.89(d,J=8.2Hz,2H),7.49(s,1H),7.12(t,J=7.7Hz,1H),6.94(d,J=7.6Hz,1H),6.72(d,J=8.0Hz,1H),4.81(s,2H),4.62(t,J=8.7Hz,2H),3.31(d,J=8.8Hz,2H),3.20(s,3H)ppm;LCMS:m/z 421[M+H]+
采用以上方法,可以合成以下化合物:
实施例10:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(4-(甲磺酰)苯基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,MeOD)δ9.13(s,1H),8.15(d,J=8.3Hz,2H),7.89(d,J=8.2Hz,2H),7.49(s,1H),7.12(t,J=7.7Hz,1H),6.94(d,J=7.6Hz,1H),6.72(d,J=8.0Hz,1H),4.81(s,2H),4.62(t,J=8.7Hz,2H),3.31(d,J=8.8Hz,2H),3.20(s,3H)ppm;LCMS:m/z 421[M+H]+
实施例11:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(4-(甲磺酰)苯基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,CDCl3)δ8.71(dd,J=4.8,1.5Hz,1H),8.32(s,1H),7.68(dd,J=7.7,1.5Hz,1H),7.37-7.29(m,2H),6.87(t,J=9.3Hz,1H),6.74-6.60(m,2H),4.84(d,J=5.5Hz,2H),4.63(t,J=8.7Hz,2H),3.40(t,J=8.7Hz,2H),2.44(s,3H)ppm;LCMS:m/z377.1[M+H]+
实施例12:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(4-甲基吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,CDCl3)δ8.66(d,J=4.6Hz,1H),8.59(s,1H),8.30(s,1H),7.39-7.29(m,2H),6.86(t,J=9.3Hz,1H),6.68(d,J=8.6Hz,2H),4.85(d,J=4.3Hz,2H),4.63(t,J=8.5Hz,2H),3.41(t,J=8.4Hz,2H),2.23(s,3H)ppm;LCMS:m/z 377.1[M+H]+
实施例13:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(2-氟吡啶-4-基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),9.07(s,1H),8.36(d,J=5.1Hz,1H),7.74-7.63(m,2H),7.55(s,1H),6.89(t,J=9.4Hz,1H),6.64(dd,J=8.5,3.6Hz,1H),4.73(d,J=4.2Hz,2H),4.51(t,J=8.7Hz,2H),3.30(d,J=8.7Hz,2H)ppm;LCMS:m/z 380.8[M+H]+
实施例14:N-((6-氟色烷-5-基)甲基)-5-(4-甲基吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,CDCl3)δ8.67(d,J=5.0Hz,1H),8.60(s,1H),8.30(s,1H),7.42-7.31(m,2H),6.90(t,J=9.0Hz,1H),6.79(dd,J=9.0,4.9Hz,1H),6.36(s,1H),4.85(d,J=4.2Hz,2H),4.22-4.11(m,2H),2.95(t,J=6.5Hz,2H),2.24(s,3H),2.04(dd,J=11.2,5.7Hz,2H)ppm;LCMS:m/z 391.1[M+H]+
实施例15:N-((6-氟色烷-5-基)甲基)-5-(2-甲基吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,CDCl3)δ8.72(dd,J=4.9,1.6Hz,1H),8.32(s,1H),7.69(dd,J=7.7,1.6Hz,1H),7.40-7.29(m,2H),6.90(t,J=9.1Hz,1H),6.79(dd,J=9.0,4.9Hz,1H),6.36(s,1H),4.84(d,J=4.4Hz,2H),4.20-4.08(m,2H),2.95(t,J=6.6Hz,2H),2.46(s,3H),2.04(dd,J=11.1,5.8Hz,2H)ppm;LCMS:m/z 391.1[M+H]+
实施例16:4-(8-(((6-氟色烷-5-基)甲基)氨基)-[1,2,4]三唑并[4,3-a]吡嗪-5-基)苯酰胺
1H NMR(400MHz,DMSO-d6)δ9.34(s,1H),8.53(s,1H),8.12(s,1H),8.04(d,J=7.8Hz,2H),7.79(d,J=7.8Hz,2H),7.49(s,2H),6.93(t,J=9.0Hz,1H),6.78-6.66(m,1H),4.72(s,2H),4.06(s,2H),2.91(s,2H),1.92(s,2H)ppm;LCMS:m/z 418.8[M+H]+
实施例17:叔-丁基(4-(8-(((6-氟色烷-5-基)甲基)氨基)-[1,2,4]三唑并[4,3-a]吡嗪-5-基)环己-3-烯-1-基)氨基甲酸酯
1H NMR(400MHz,MeOD)δ9.15(s,1H),7.64-7.33(m,1H),7.16(s,1H),6.76(t,J=9.2Hz,1H),6.62(dd,J=9.0,4.8Hz,1H),6.06(s,1H),4.63(d,J=8.6Hz,2H),4.06-3.94(m,2H),3.68(d,J=4.5Hz,1H),2.81(t,J=6.5Hz,2H),2.46(dd,J=28.2,16.9Hz,3H),2.08(dd,J=15.8,8.0Hz,1H),1.99-1.80(m,3H),1.74-1.61(m,1H),1.37(s,9H)ppm;LCMS:m/z 494.8[M+H]+
实施例18:5-(4-氨基环己-1-烯-1-基)-N-((6-氟色烷-5-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,MeOD)δ9.29(d,J=3.4Hz,1H),7.31(s,1H),6.90(t,J=9.2Hz,1H),6.76(dd,J=9.0,4.9Hz,1H),6.22(s,1H),4.79(s,2H),4.18-4.07(m,2H),3.60(s,1H),2.94(t,J=6.5Hz,2H),2.83-2.56(m,3H),2.43(d,J=7.0Hz,1H),2.26(d,J=9.9Hz,1H),2.08-1.92(m,3H)ppm;LCMS:m/z 395.2[M+H]+
实施例19:N-((5-氟苯并呋喃-4-基)甲基)-5-(2-甲基吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.98(t,J=5.6Hz,1H),8.91(s,1H),8.61(d,J=4.2Hz,1H),8.02(d,J=1.6Hz,1H),7.83(d,J=7.3Hz,1H),7.53(dd,J=8.7,3.7Hz,1H),7.38(dd,J=7.4,5.0Hz,1H),7.29(d,J=12.9Hz,2H),7.16(t,J=9.6Hz,1H),4.98(d,J=4.7Hz,2H),2.32(s,3H)ppm;LCMS:m/z 375.1[M+H]+
实施例20:N-((5-氟苯并呋喃-4-基)甲基)-5-(4-(甲磺酰)苯基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.15(s,1H),8.08-7.89(m,4H),7.53(dd,J=10.8,5.3Hz,2H),7.28(s,1H),7.16(t,J=9.7Hz,1H),4.99(d,J=5.5Hz,2H),3.29(s,3H)ppm;LCMS:m/z 438.1[M+H]+
实施例21:N-((6-氟-2,3-二氢苯并[b][1,4]二噁英-5-基)甲基)-5-(4-(甲磺酰)苯基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.36(t,J=4.9Hz,1H),8.07(d,J=8.3Hz,2H),7.99(d,J=8.3Hz,2H),7.56(s,1H),6.84(dd,J=9.0,5.5Hz,1H),6.68(t,J=9.1Hz,1H),4.74(d,J=4.6Hz,2H),4.32(d,J=4.0Hz,2H),4.24(d,J=3.8Hz,2H),3.30(s,3H)ppm;LCMS:m/z 456.1[M+H]+
实施例22:N-((6-氟-2,3-二氢苯并[b][1,4]二噁英-5-基)甲基)-5-(2-甲基吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.63(d,J=3.8Hz,1H),8.15(t,J=5.0Hz,1H),7.86(d,J=6.7Hz,1H),7.40(dd,J=7.6,4.9Hz,1H),7.33(s,1H),6.85(dd,J=9.0,5.5Hz,1H),6.69(t,J=9.2Hz,1H),4.70(dd,J=23.0,4.5Hz,2H),4.32(d,J=10.6,6.2Hz,2H),4.24(d,J=4.3Hz,2H),2.34(s,3H)ppm;LCMS:m/z 393.1[M+H]+
实施例23:N-((5-氟苯并[d][1,3]二噁唑-4-基)甲基)-5-(2-甲基吡啶-3-基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.63(d,J=4.5Hz,1H),8.54(t,J=5.2Hz,1H),7.86(d,J=7.5Hz,1H),7.40(dd,J=7.6,4.9Hz,1H),7.30(s,1H),6.84(dd,J=8.5,4.2Hz,1H),6.72-6.58(m,1H),6.03(d,J=13.0Hz,2H),4.70(dd,J=21.2,5.7Hz,2H),2.33(s,3H)ppm;LCMS:m/z 379.1[M+H]+
实施例24:N-((5-氟苯并[d][1,3]二噁唑-4-基)甲基)-5-(4-(甲磺酰)苯基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.72(d,J=5.3Hz,1H),8.06(d,J=8.3Hz,2H),7.99(d,J=8.4Hz,2H),7.53(s,1H),6.83(dd,J=8.5,4.2Hz,1H),6.65(dd,J=10.7,8.6Hz,1H),6.04(s,2H),4.74(d,J=4.9Hz,2H),3.30(s,3H)ppm;LCMS:m/z 442.1[M+H]+
实施例25:5-环丙基-N-((6-氟色烷-5-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.09(s,1H),7.12(s,1H),6.90(t,J=9.1Hz,1H),6.70(d,J=4.6Hz,1H),4.63(s,2H),4.05(s,2H),2.87(s,2H),2.04(s,1H),1.89(s,2H),0.97(d,J=7.0Hz,2H),0.74(s,2H)ppm;LCMS:m/z 340.1[M+H]+
实施例26:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(4-(甲磺酰)苯基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.62(s,1H),8.25(s,2H),8.05(s,2H),7.99(s,1H),6.89(s,1H),6.64(s,1H),4.75(s,2H),4.51(s,2H),3.32(s,2H),3.28(s,3H)ppm;LCMS:m/z 440.1[M+H]+
实施例27:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(2-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,CDCl3)δ8.66(dd,J=4.9,1.6Hz,1H),8.25(s,1H),7.71(dd,J=7.7,1.7Hz,1H),7.57(s,1H),7.29(dd,J=7.7,5.0Hz,1H),6.86(t,J=9.4Hz,1H),6.68(dd,J=8.7,3.9Hz,1H),6.28(t,J=5.4Hz,1H),4.83(d,J=5.7Hz,2H),4.63(t,J=8.7Hz,2H),3.41(t,J=8.7Hz,2H),2.44(s,3H)ppm;LCMS:m/z 377.1[M+H]+
实施例28:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(4-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,CDCl3)δ8.61(dd,J=4.9,1.6Hz,1H),8.57(s,1H),8.24(s,1H),7.59(s,1H),7.30(dd,J=7.7,5.0Hz,1H),6.87(t,J=9.4Hz,1H),6.68(dd,J=8.7,3.9Hz,1H),6.33(s,1H),4.83(d,J=5.7Hz,2H),4.63(t,J=8.7Hz,2H),3.41(t,J=8.7Hz,2H),2.22(s,3H)ppm;LCMS:m/z 377.1[M+H]+
实施例29:N-((6-氟色烷-5-基)甲基)-5-(2-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,MeOD)δ8.46(d,J=3.9Hz,1H),8.22(s,1H),7.77(d,J=7.3Hz,1H),7.52(s,1H),7.35-7.24(m,1H),6.77(t,J=9.0Hz,1H),6.63(dd,J=8.6,4.7Hz,1H),4.70(d,2H),4.00(t,J=4.6Hz,2H),3.21(s,3H),2.86(t,J=6.1Hz,2H),2.27(s,3H),1.88(t,J=4.9Hz,2H)ppm;LCMS:m/z 391.1[M+H]+
实施例30:N-((6-氟色烷-5-基)甲基)-5-(4-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.90(d,J=5.4Hz,1H),8.64(s,1H),8.55(s,1H),8.05(d,J=5.6Hz,1H),7.82(s,1H),6.94(t,J=9.2Hz,1H),6.76-6.72(m,1H),4.73(d,J=4.1Hz,2H),4.12-4.02(m,2H),2.93(t,J=6.3Hz,2H),2.43(s,3H),1.99-1.87(m,2H)ppm;LCMS:m/z 391.1[M+H]+
实施例31:N-((6-氟色烷-5-基)甲基)-5-(嘧啶-5-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ9.38(s,2H),9.23(s,1H),8.62(s,1H),8.53(t,J=4.9Hz,1H),8.07(s,1H),6.92(t,J=9.2Hz,1H),6.72(dd,J=8.9,4.8Hz,1H),4.72(d,J=4.7Hz,2H),4.12-4.00(m,2H),2.90(t,J=6.4Hz,2H),1.98-1.85(m,2H)ppm;LCMS:m/z377.8[M+H]+
实施例32:N-((6-氟色烷-5-基)甲基)-5-(丙-1-烯-2-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.20(t,J=5.2Hz,1H),7.71(s,1H),6.91(t,J=9.2Hz,1H),6.70(dd,J=9.0,4.8Hz,1H),6.32(s,1H),5.40(s,1H),4.68(d,J=4.9Hz,2H),4.10-3.99(m,2H),2.87(t,J=6.5Hz,2H),2.22(s,3H),1.97-1.81(m,2H)ppm;LCMS:m/z 339.9[M+H]+
实施例33:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(4-氟苯基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.47(t,J=5.8Hz,1H),8.02-7.92(m,2H),7.80(s,1H),7.36(t,J=8.9Hz,2H),6.93-6.84(m,1H),6.63(dd,J=8.6,3.8Hz,1H),4.71(d,J=5.7Hz,2H),4.51(t,J=8.7Hz,2H),3.29(d,J=8.7Hz,2H)ppm;LCMS:m/z 379.8[M+H]+
实施例34:N-((6-氟色烷-5-基)甲基)-5-甲基-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.78(t,J=5.1Hz,1H),7.47(s,1H),6.90(t,J=9.2Hz,1H),6.70(dd,J=9.0,4.8Hz,1H),4.63(d,J=4.8Hz,2H),4.09-3.99(m,2H),2.86(t,J=6.5Hz,2H),2.50-2.48(m,3H),1.95-1.81(m,2H)ppm;LCMS:m/z 313.9[M+H]+
实施例35:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(1-甲基-1,2,3,6-四氢吡啶-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.36(t,J=5.8Hz,1H),7.60(s,1H),6.99(t,J=3.3Hz,1H),6.92-6.80(m,1H),6.62(dd,J=8.6,3.8Hz,1H),4.67(d,J=5.7Hz,2H),4.49(t,J=8.8Hz,2H),3.26(t,J=8.7Hz,2H),3.13(d,J=2.6Hz,2H),2.62(s,4H),2.31(s,3H)ppm;LCMS:m/z 380.9[M+H]+
实施例36:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(1,2,3,6-四氢吡啶-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.43(t,J=5.7Hz,1H),8.24(s,1H),7.63(s,1H),7.01(s,1H),6.92-6.83(m,1H),6.63(dd,J=8.6,3.8Hz,1H),4.68(d,J=5.7Hz,2H),4.49(t,J=8.7Hz,2H),3.63(s,2H),3.28(d,J=8.8Hz,2H),3.12(t,J=5.5Hz,2H),2.62(s,2H)ppm;LCMS:m/z 366.9[M+H]+
实施例37:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-8-(4-(甲磺酰)苯基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.26(s,1H),8.18(d,J=8.4Hz,2H),8.05(d,J=8.4Hz,2H),6.87(t,J=8.8Hz,1H),6.70-6.67(m,2H),4.89(d,J=6.0Hz,2H),4.63(t,J=8.8Hz,2H),3.42(t,J=8.4Hz,2H)ppm;LCMS:m/z 440.1[M+H]+
实施例38:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.58(d,J=4.5Hz,1H),8.27(s,1H),7.89(s,1H),7.68(d,J=7.5Hz,1H),7.24(d,J=7.2Hz,1H),6.88(t,J=9.2Hz,1H),6.69(dd,J=8.5,3.8Hz,1H),6.58(s,1H),4.87(d,J=5.9Hz,2H),4.64(t,J=8.7Hz,2H),3.43(t,J=8.7Hz,2H),2.53(s,3H)ppm;LCMS:m/z 377.1[M+H]+
实施例39:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-8-(4-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.53(s,2H),8.26(s,1H),7.89(s,1H),7.27(s,1H),6.87(t,J=9.4Hz,1H),6.69(dd,J=8.6,3.9Hz,1H),6.58(s,1H),4.88(d,J=6.0Hz,2H),4.64(t,J=8.7Hz,2H),3.44(t,J=8.7Hz,2H),2.29(s,3H)ppm;LCMS:m/z 377.1[M+H]+
实施例40:N-((6-氟色烷-5-基)甲基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.58(dd,J=4.8,1.6Hz,1H),8.26(s,1H),7.91(s,1H),7.69(dd,J=7.6,1.5Hz,1H),7.25-7.20(m,1H),6.91(t,J=9.1Hz,1H),6.80(dd,J=9.0,5.0Hz,1H),4.89(dd,J=5.5,1.3Hz,2H),4.21-4.10(m,2H),2.99(t,J=6.5Hz,2H),2.54(s,3H),2.05(p,J=6.4Hz,2H)ppm;LCMS:m/z 391.1[M+H]+
实施例41:N-((6-氟色烷-5-基)甲基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.53(t,J=2.4Hz,2H),8.25(s,1H),7.92(s,1H),7.27(s,1H),7.26-7.25(m,1H),6.91(s,1H),6.81(d,J=5.0Hz,1H),6.39(t,J=5.3Hz,1H),4.90(dd,J=5.5,1.4Hz,2H),4.22-4.09(m,2H),3.00(t,J=6.5Hz,2H),2.31(s,3H),2.12-1.98(m,2H)ppm;LCMS:m/z 391.1[M+H]+
实施例42:8-(2,4-二氟苯基)-N-((6-氟色烷-5-基)甲基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.14(d,J=1.5Hz,1H),7.82(td,J=8.5,6.5Hz,1H),7.00(tdd,J=11.1,8.7,2.5Hz,2H),6.90(t,J=9.1Hz,1H),6.78(dd,J=9.0,5.0Hz,1H),6.38(t,J=5.2Hz,1H),4.89(dd,J=5.5,1.4Hz,2H),4.17-4.12(m,2H),2.97(t,J=6.6Hz,2H),2.03(dd,J=10.2,4.9Hz,2H)ppm;LCMS:m/z 411.8[M+H]+
实施例43:N-((6-氟色烷-5-基)甲基)-8-(2-氟苯基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.55(s,1H),8.10(s,1H),7.81(t,J=7.7Hz,1H),7.46(dd,J=13.0,6.0Hz,1H),7.33(dd,J=16.5,8.7Hz,2H),6.93(t,J=9.3Hz,1H),6.73(dd,J=9.0,4.8Hz,1H),4.76(d,J=4.7Hz,2H),4.10-4.03(m,2H),2.92(t,J=6.4Hz,2H),1.97-1.82(m,2H)ppm;LCMS:m/z 393.8[M+H]+
实施例44:N-((6-氟色烷-5-基)甲基)-8-(4-(三氟甲基)苯基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.24(s,1H),8.08(d,J=8.2Hz,2H),7.74(d,J=8.3Hz,2H),6.90(t,J=9.1Hz,1H),6.79(dd,J=9.0,5.0Hz,1H),6.45(t,J=5.3Hz,1H),4.90(dd,J=5.5,1.2Hz,2H),4.17-4.12(m,2H),2.97(t,J=6.6Hz,2H),2.08-2.02(m,2H)ppm;LCMS:m/z 443.8[M+H]+
实施例45:8-(环己-1-烯-1-基)-N-((6-氟色烷-5-基)甲基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.24(s,1H),7.90(s,1H),6.94(t,J=3.9Hz,1H),6.92-6.83(m,1H),6.76(dd,J=9.0,4.9Hz,1H),6.19(t,J=5.2Hz,1H),4.82(dd,J=5.5,1.2Hz,2H),4.18-4.06(m,2H),2.93(t,J=6.6Hz,2H),2.57-2.45(m,2H),2.31(dd,J=6.1,2.4Hz,2H),2.01(dq,J=12.9,6.4Hz,2H),1.89-1.80(m,2H),1.76-1.65(m,2H)ppm;LCMS:m/z379.9[M+H]+
实施例46:N-((6-氟色烷-5-基)甲基)-8-(3-氟苯基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.20(s,1H),7.78-7.68(m,2H),7.46(dt,J=14.1,7.1Hz,1H),7.07(td,J=8.4,2.5Hz,1H),6.95-6.86(m,1H),6.78(dd,J=9.0,5.0Hz,1H),6.38(t,J=5.1Hz,1H),4.89(dd,J=5.5,1.4Hz,2H),4.19-4.12(m,2H),2.97(t,J=6.6Hz,2H),2.09-1.99(m,2H)ppm;LCMS:m/z 393.8[M+H]+实施例47:8-(2,3-二氯苯基)-N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.26(s,1H),8.00(s,1H),7.54(dd,J=8.0,1.3Hz,1H),7.42(dd,J=7.6,1.3Hz,1H),7.31(t,J=7.8Hz,1H),6.87(t,J=9.4Hz,1H),6.69(dd,J=8.6,3.9Hz,1H),6.60(t,J=5.7Hz,1H),4.88(d,J=5.9Hz,2H),4.63(t,J=8.7Hz,2H),3.43(t,J=8.7Hz,2H)ppm;LCMS:m/z 429.7[M+H]+
实施例48:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-8-(4-甲氧苯基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.30(s,1H),8.10(s,1H),7.86(d,J=8.8Hz,2H),7.02(t,J=8.6Hz,2H),6.91-6.82(m,1H),6.67(dd,J=8.6,3.9Hz,1H),6.47(d,J=6.1Hz,1H),4.86(d,J=6.0Hz,2H),4.62(t,J=8.7Hz,2H),3.86(s,3H),3.41(t,J=8.7Hz,2H)ppm;LCMS:m/z 391.8[M+H]+
实施例49:8-(3,5-二甲基异噻唑-4-基)-N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.81(s,1H),6.90-6.84(m,1H),6.69(dd,J=8.7,3.9Hz,1H),6.58(s,1H),4.85(d,J=5.9Hz,2H),4.64(t,J=8.7Hz,2H),3.43(t,J=8.7Hz,2H),2.41(s,3H),2.27(s,3H)ppm;LCMS:m/z 380.8[M+H]+
实施例50:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-8-乙烯基-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.89(s,1H),6.85(t,J=9.4Hz,1H),6.75(dd,J=17.6,11.3Hz,1H),6.66(dd,J=8.6,3.9Hz,1H),6.56-6.43(m,2H),5.49(d,J=11.3Hz,1H),4.83(d,J=6.0Hz,2H),4.61(t,J=8.7Hz,2H),3.37(t,J=8.7Hz,2H)ppm;LCMS:m/z 311.9[M+H]+
实施例51:8-(4,4-二氟环己-1-烯-1-基)-N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-[1,2,4]三唑并[1,5-c]嘧啶-5-胺
1H NMR(400MHz,CDCl3)δ8.26(s,1H),7.90(s,1H),6.84(dd,J=11.8,6.7Hz,2H),6.66(dd,J=8.7,3.9Hz,1H),6.48(t,J=5.7Hz,1H),4.82(d,J=6.0Hz,2H),4.61(t,J=8.7Hz,2H),3.38(t,J=8.7Hz,2H),2.82(dd,J=19.1,10.5Hz,4H),2.23(ddd,J=20.4,13.5,6.6Hz,2H)ppm;LCMS:m/z 401.8[M+H]+
实施例52:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-7-(4-(甲基磺酰基)苯基)-[1,2,5]噻二唑并[3,4-c]吡啶-4-胺
1H NMR(400MHz,CDCl3)δ8.24(s,1H),8.05(d,J=8.5Hz,2H),7.97(d,J=8.5Hz,2H),6.85–6.71(m,1H),6.59(dd,J=8.7,3.9Hz,1H),6.46(s,1H),4.84(d,J=5.8Hz,2H),4.55(t,J=8.7Hz,2H),3.35(t,J=8.7Hz,2H),3.03(s,3H)ppm;LCMS:m/z 457.1[M+H]+
实施例53:N8–((6-氟-2,3-二氢苯并[b][1,4]二氧杂环己烯-5-基)甲基)-N 5-(吡啶-2-基)-[1,2,4]三唑并[4,3-a]吡嗪-5,8-二胺
在25mL单口瓶中依次加入5-溴-N-((6-氟-2,3-二氢苯并[b][1,4]二氧杂环己烯-5-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺(80mg,0.21mmol),吡啶-2-胺(30mg,0.32mmol),Pd2(dba)3(38mg,0.042mmol),Brett-Phos(17mg,0.032mmol),碳酸铯(137mg,0.42mmol),加入1,4-二氧六环(4mL),反应液在氮气氛围中于100℃搅拌过夜,反应结束后,反应液加入乙酸乙酯(8mL)稀释,加入水(2mL*2)洗2次,有机相干燥浓缩,粗品用液相色谱制备得到灰白色固体产物N8–((6-氟-2,3-二氢苯并[b][1,4]二氧杂环己烯-5-基)甲基)-N5-(吡啶-2-基)-[1,2,4]三唑并[4,3-a]吡嗪-5,8-二胺(6mg,7%产率)。
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.17(d,J=4.8Hz,1H),7.52(t,J=7.3Hz,1H),7.42(s,1H),6.86–6.74(m,2H),6.62(t,J=8.9Hz,1H),6.56(s,1H),6.44(d,J=8.5Hz,2H),4.87(d,J=5.5Hz,2H),4.42–4.31(m,2H),4.29–4.16(m,2H)ppm;LCMS:m/z394.1[M+H]+
实施例54:N-((6-氟苯并二氢吡喃-5-基)甲基)-5-(苯硫基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
在微波管中依次加入5-溴-N-((6-氟苯并二氢吡喃-5-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺(50mg,132umol),苯硫醇钠(34.94mg,264umol),三二亚苄基丙酮二钯(36.32mg,39.66unol),4,5-双二苯基膦-9 9-二甲基氧杂蒽(22.95mg,39.66umol),N-乙基-N-异丙基丙-2-胺(34.17,264umol)和1,4-二氧六环(4mL)。反应温度升到100℃并搅拌反应2个小时。反应完毕后,过滤得到反应液,把反应液旋干,用液相色谱仪分离得到白色固体N-((6-氟苯并二氢吡喃-5-基)甲基)-5-(苯硫基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺(16mg,产率:30%)。
1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.88(s,1H),7.78(s,1H),7.32(d,J=4.1Hz,4H),7.26(dd,J=9.0,4.2Hz,1H),6.92(t,J=9.2Hz,1H),6.72(dd,J=9.0,4.8Hz,1H),4.70(d,J=3.6Hz,2H),4.12–3.98(m,2H),2.89(t,J=6.4Hz,2H),1.97–1.83(m,2H)ppm;LCMS:408.1[M+H]+
采用以上方法,可以合成以下化合物:
实施例55:5-((2,3-二氯吡啶-4-基)硫代)-N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.24(s,1H),8.04(d,J=5.3Hz,1H),7.80(s,1H),6.89(dd,J=17.1,7.2Hz,2H),6.66(dd,J=8.6,3.8Hz,1H),4.73(d,J=5.0Hz,2H),4.53(t,J=8.7Hz,2H),3.31–3.29(m,2H)ppm;LCMS:m/z 463.0[M+H]+
实施例56:N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(1,2,3,6-四氢吡啶-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺
在干燥的25mL单口瓶中依次加入(8-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-[1,2,4]三唑并[1,5-a]吡嗪-5-基基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(50mg,107umol)和4mol/L盐酸-1,4-二氧六环溶液(2mL)。在室温条件下反应并搅拌半个小时。反应完毕后,旋干有机溶剂,用液相色谱仪分离得到白色固体N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-5-(1,2,3,6-四氢吡啶-4-基)-[1,2,4]三唑并[1,5-a]吡嗪-8-胺(10mg,产率:26%)。
1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.43(t,J=5.7Hz,1H),8.24(s,1H),7.63(s,1H),7.01(s,1H),6.92–6.83(m,1H),6.63(dd,J=8.6,3.8Hz,1H),4.68(d,J=5.7Hz,2H),4.49(t,J=8.7Hz,2H),3.63(s,2H),3.28(d,J=8.8Hz,2H),3.12(t,J=5.5Hz,2H),2.62(s,2H)ppm;LCMS:m/z 366.9[M+H]+
采用以上方法,可以合成以下化合物:
实施例57:5-(4-氨基环己-1-烯-1-基)-N-((6-氟色烷-5-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺
1H NMR(400MHz,MeOD)δ9.29(d,J=3.4Hz,1H),7.31(s,1H),6.90(t,J=9.2Hz,1H),6.76(dd,J=9.0,4.9Hz,1H),6.22(s,1H),4.79(s,2H),4.18–4.07(m,2H),3.60(s,1H),2.94(t,J=6.5Hz,2H),2.83–2.56(m,3H),2.43(d,J=7.0Hz,1H),2.26(d,J=9.9Hz,1H),2.08–1.92(m,3H)ppm;LCMS:m/z 395.2[M+H]+
实施例58:8–(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-[1,2,4]三唑并[4,3-a]吡嗪-5-甲腈
在25mL单口瓶中分别加入5-溴-N-((5-氟-2,3-二氢苯并呋喃-4-基)甲基)-[1,2,4]三唑并[4,3-a]吡嗪-8-胺A-2(200mg,0.64mmol),氰化锌(114mg,0.97mmol),四三苯基膦钯(112mg,0.097mmol),DMF(6mL),反应于110反应16h,反应结束后降温至室温,加入乙酸乙酯(20mL)稀释溶解,并用饱和食盐水(5mL*3)洗3次,有机相用无水硫酸钠干燥,减压浓缩,粗品用柱层析纯化得到淡黄色固体产物8–((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-[1,2,4]三唑并[4,3-a]吡嗪-5-甲腈(160mg,收率80%)。
1H NMR(400MHz,DMSO-d6)δ7.34(s,1H),6.36(s,1H),5.30(t,J=10.5Hz,1H),5.13(dd,J=8.5,3.8Hz,1H),3.31(d,J=5.8Hz,2H),3.06(t,J=8.7Hz,2H),1.78(t,J=8.8Hz,2H)ppm;LCMS:m/z 311.1[M+H]+
药理学及应用
EED作为PRC2蛋白复合物的主要组成部分之一,虽然并不具有酶催化的活性,但是它对PRC2的整体功能具有重要的作用。EED对PRC2的作用具体表现为两个方面:1)EED直接与三甲基化的H3K27Me3结合,这样能够把PCR2复合物定位在需要修饰的染色质上;2)EED对EZH2的酶催化功能有很大的变构促进作用。因此,开发作为变构蛋白EED的靶点化合物为提供抑制EZH2酶活性提供了新策略。而且这样的抑制剂具有比EZH2酶催化位点抑制剂具有更好或互补的优势,比如当病人对于EZH2酶抑制剂产生耐药性时,EED抑制剂同样可以起到抑制EZH2酶活性的作用。本发明公开了嘧啶酮化合物可以作为EED靶点抑制剂,并对与EED和/或PRC2作用机理相关的疾病有治疗作用。
本发明公开化合物的生物学功能在生化以及细胞水平的测试中得到了证明。比如在生化测试中,本发明公开的化合物能够与和EED蛋白结合的H3K27Me3多肽有很强的竞争结合作用(IC50可达<10nM)。在细胞水平上,本发明公开化合物不仅可以抑制组蛋白H3K27的甲基化水平而且也可以通过这一作用抑制癌细胞的增殖。
通过AlphaScreen(a-筛选)方法评价化合物在阻断EED与H3K27me3结合的效果
首先配置不同浓度梯度的化合物溶液。化合物粉末用DMSO溶解成母液。取1.5μl化合物母液至198.5μl反应缓冲液(25mM HEPES(pH 8.0),50mM NaCl,0.015%Tween 20,0.5%BSA)中混匀,再用含有0.75%DMSO的上述缓冲液进行3-倍梯度稀释,同一化合物设置9个不同的测试浓度。取5μL不同浓度梯度的化合物至ProxiPlate-384Plus,White检测板(PerkinElmer,6008280)中,每个浓度梯度设置2个平行重复。
其次进行结合阻断反应。用上述缓冲液稀释带有His6标签的全长EED蛋白(441个氨基酸)至60nM,以及生物素标记的多肽片段H3K27me3(第19-33位氨基酸)(Biotinylated-H3K27me3)至75nM。分别转移5μl浓度为75nM多肽片段以及5μl的60nM蛋白至含有化合物的检测孔内,薄膜封住检测板,室温孵育30分钟。
最后AlphaScreen方法检测。临用前,镍螯合受体珠与链霉抗生物素供体珠以1:1的比例(Perkin Elmer,产品号6760619M)混入上述反应缓冲液中,再向各检测孔中加入5μl上述预混的检测液,供体珠和受体珠终浓度均为5μg/mL。锡箔遮封住检测板,室温避光放置1小时。使用Spectra max i3上的AlphaScreen检测器读取信号。根据阳性对照(最大信号对照)和阴性对照(最小信号对照)获得的读数对AlphaScreen信号进行标准化,以给出不同浓度化合物的抑制率,之后用GraphPad Prism 5进行非线性回归分析,通过Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))剂量响应方程做出抑制曲线,得到各化合物的IC50值。
为了排除由于化合物干扰AlphaScreen检测系统而产生的假阳性,以同样的方法稀释化合物,用生物素标记的多肽Biotinylated-(His)6代替检测体系中的EED和多肽H3K27me3,孵育同等时间后,在Spectra max i3上读取信号值。以同样的方法处理数据。
结果
下表显示了本发明部分化合物的IC50值。
字母A代表IC50小于100nM;
字母B代表IC50为100nM至1000nM;
字母C代表IC50为1000nM以上
ELISA(H3K27三甲基化)分析
将代表性的本公开内容的化合物用DMSO中进行3-倍梯度稀释,每化合物检测10个浓度梯度,最高测定浓度为10μM。化合物200-倍稀释到在96-孔板中培养的G401细胞中(DMSO终浓度为0.5%)。给药细胞培养72小时后,ELISA方法检测组蛋白H3K27三甲基化水平。
组蛋白提取:96-孔板中化合物处理的细胞用1x PBS(10x PBS缓冲液(80g NaCl(Sigma,产品号S3014),2gKCl(Sigma,产品号60128),14.4g Na2HP04(Sigma,产品号S5136),2.4gKH2P04(Sigma,产品号P9791)至1L水中,pH至7.4)洗涤三次,每孔加入100μL0.4N HCl,置于4℃,温和振摇2小时裂解细胞。细胞裂解液再用80μL中和缓冲液(0.5M磷酸氢二钠,pH 12.5,2.5mM DTT;1%cocktail(Sigma,产品号P8340)中和(充分混匀细胞裂解液与中和缓冲液)。
ELISA检测方法:将细胞裂解液平行转移至2个384-孔检测板(PerkinElmer,OptiPlate-384HB,产品号6007290)中,一块板用于检测H3K27三甲基化水平,另一块板用于测定H3的水平,PBS调至终体积为50μL/孔,4℃包被过夜。次日,弃去孔内溶液,用TBST缓冲液(l xTBS(10x TBS:24.2g Tris(Sigma,产品号T6066),80g NaCl(Sigma,产品号S3014)至1L水中,HCl调pH至7.6),0.1%Tween-20)洗涤5次,于吸水纸上扣干水分。将70μL封闭缓冲液(TBST,5%BSA)加入已包被之反应孔中,于室温孵育1小时。弃去封闭缓冲液,加入一级抗体(30μL/孔)。所需一级抗体均用封闭缓冲液稀释,稀释倍数如下:抗H3K27me3抗体(CellSignaling Technology,产品号9733),1:2000稀释;抗H3抗体(Cell SignalingTechnology,产品号4499),1:10000稀释。加入一抗后,置室温孵育1小时。TBST洗涤5次后,扣干水分,各反应孔加入二级抗体(30μL/孔),室温孵育1小时。二级抗体(抗兔抗体(Jackson ImmunoResearch,产品号111-035-003))用封闭缓冲液稀释2000倍后使用。1小时后,TBST洗涤,扣干水分。于各孔中加入30μL的ECL底物(Pierce,产品号34080),2000rpm离心30秒。利用Molecular Devices,SpectraMax检测各样品信号。数据处理:H3K27甲基化读数先用H3信号进行标准化,0.5%DMSO处理的样品作为对照,计算出化合物的抑制百分率。采用GraphPad prisim5程序将数据拟合为剂量响应曲线,得到测试化合物的IC50值。结果
下表显示了本发明部分化合物的IC50值。
字母A代表IC50小于100nM;
字母B代表IC50为100nM至1000nM;
字母C代表IC50为1000nM以上
细胞增殖分析
采用标准细胞培养条件,人类B细胞非霍奇金淋巴瘤细胞KARPAS-422S培养在培养瓶中。培养基为含15%胎牛血清(FBS,Invitrogen,产品号10099-141),1%青霉素/链霉素溶液(P/S)RPMI-1640(Invitrogen,产品号11875),培养瓶置于温度37℃,相对湿度95%,5%CO2的无菌培养箱中培养。为了检测PRC2抑制剂对细胞增殖的影响,取指数生长期的细胞,以1x104细胞/孔的密度接种到96孔板(Corning,产品号3904)中,每孔加入100μL培养基。随后,将本文公开内容的、不同浓度的化合物加入到已接种细胞的孔中(每个化合物设置9个浓度梯度,最高检测浓度为10μM,3-倍梯度稀释),每个处理浓度设置2个平行重复,DMSO终浓度为0.5%。之后每隔3~4天用Vi-CELL(Beckman Coulter)测定存活细胞数。每次计过数的细胞以同等密度(1X 104个细胞/孔)接种到新的96-孔板中,补充新鲜培养基至100μL,同时加入不同浓度的化合物。培养至第13天,每孔加入100μL的CellTiter-Glo(CTG)(Promega,产品号G7573),室温避光放置10~20分钟,利用Molecular Devices,SpectraMaxi3X读取发光信号。采用GraphPad prisim5将数据拟合为剂量响应曲线,从而得到测试化合物的IC50值。
结果
下表显示了本发明部分化合物的IC50值。
字母A代表IC50小于100nM;
字母B代表IC50为100nM至1000nM;
字母C代表IC50为1000nM以上
本发明公开的化合物可用于治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关的癌症,包括但不局限于包括扩散大B细胞淋巴癌、滤泡性淋巴瘤等等淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、前列腺癌、乳腺癌、脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、宫颈癌、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等等。
Claims (16)
1.一种通式(I)所示的嘧啶或吡嗪并五元杂环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,
其中,X1独立地为C或N;
X2独立地为C或N;
X3独立地为C或N;
X4独立地为C,N,S;
Z独立地为C或O;
其中
m独立地为0或1;
n独立地为0或1;
p独立地为0或1;
R1独立地为氢或卤素;
R2独立地为氢、卤素、氰基、C1-8烷基、C1-8卤代烷基、R2a取代或未取代的C3-8环烷基、R2b取代或未取代的C3-8杂环基、R2c取代或未取代的烯基、R2b取代或未取代的C5-8环烯基、R2b取代或未取代的C5-8杂环烯基、R2d取代或未取代的氨基、R2d取代或未取代的氧基、R2d取代或未取代的酰胺、0-3个R2e取代的C6-10芳基或0-3个R2e取代的含有C1-20碳原子及1-4个N、NR2e1、O或S(O)0-2等杂原子的杂芳环;
R2a和R2b独立的为氨基、保护基团保护的氨基、单氟或多氟;
R2c独立的为C1-4烷基、酯基;
R2d独立的为C1-20烷基、苄基、取代或未取代的C6-10芳基、取代或未取代的含有C1-20碳原子及1-4个N、NR2e1、O或S(O)0-2杂原子的杂芳环;
R2e独立的为卤素、-C(=O)NR2e1R2e2、-S(=O)2R2e3、N R2e1R2e2、含有C1-20碳原子及1-4个NR2e1、O或S(O)0-2杂原子的杂环;其中,R2e1独立的为氢或C1-4烷基;R2e2独立的为氢或C1-4烷基;R2e3为C1-4烷基。
4.如权利要求1所述的嘧啶或吡嗪并五元杂环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物,其中
R1是H或F。
8.一种如权利要求1-7任一项所述的通式(I)所示的嘧啶或吡嗪并五元杂环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物的同位素标记化合物,所述同位素选自2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl和125I。
12.一种如权利要求1-7任一项所述的嘧啶或吡嗪并五元杂环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或权利要求8所述的同位素标记化合物用于制备预防和/或治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关的癌症药物的用途。
13.一种如权利要求12所述的用途,所述癌症选自扩散大B细胞淋巴癌、滤泡性淋巴瘤。
14.一种如权利要求12所述的用途,所述癌症选自淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、前列腺癌、乳腺癌、脑瘤、宫颈癌、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤。
15.一种药物组合物,包含根据权利要求1-7任一项所述的嘧啶或吡嗪并五元杂环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或权利要求8所述的同位素标记化合物,以及药学上可接受的辅料。
16.一种如权利要求1-7任一项所述的嘧啶或吡嗪并五元杂环化合物、其药学上可接受的盐、水合物、前药、立体异构体或其溶剂化物或权利要求8所述的同位素标记化合物与其他药物联合使用的产品,所述其他药物选自:抗癌药、肿瘤免疫药物、抗过敏药、止吐药、镇痛药、细胞保护药物。
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