CN116023380A - 一类吡唑并嘧啶衍生物及制备方法和应用 - Google Patents
一类吡唑并嘧啶衍生物及制备方法和应用 Download PDFInfo
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- CN116023380A CN116023380A CN202111252253.4A CN202111252253A CN116023380A CN 116023380 A CN116023380 A CN 116023380A CN 202111252253 A CN202111252253 A CN 202111252253A CN 116023380 A CN116023380 A CN 116023380A
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- CN
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- Prior art keywords
- methyl
- pyrazolo
- pyrazol
- pyrimidine
- diamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 121
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 101000582914 Homo sapiens Serine/threonine-protein kinase PLK4 Proteins 0.000 claims abstract description 26
- 102100030267 Serine/threonine-protein kinase PLK4 Human genes 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 12
- 230000000694 effects Effects 0.000 claims abstract description 12
- -1 aromatic sulfonamide Chemical class 0.000 claims description 281
- 125000005842 heteroatom Chemical group 0.000 claims description 86
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 37
- 125000001931 aliphatic group Chemical group 0.000 claims description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims description 32
- 125000002723 alicyclic group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 15
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 11
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 10
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
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- 206010028980 Neoplasm Diseases 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 150000003457 sulfones Chemical class 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 230000014509 gene expression Effects 0.000 claims description 7
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- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
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- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 150000008430 aromatic amides Chemical class 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000005002 aryl methyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000006287 difluorobenzyl group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- YDVJBLJCSLVMSY-UHFFFAOYSA-N carbamoyl cyanide Chemical compound NC(=O)C#N YDVJBLJCSLVMSY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229940043274 prophylactic drug Drugs 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 229960003053 thiamphenicol Drugs 0.000 claims description 2
- PZURVUQVDFSJJO-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical compound NC1=CC(N)=N[C]=N1 PZURVUQVDFSJJO-UHFFFAOYSA-N 0.000 claims 4
- 125000004175 fluorobenzyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 56
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
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- 238000003786 synthesis reaction Methods 0.000 abstract description 15
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- 229940079593 drug Drugs 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 3
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract description 2
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 abstract 1
- 239000003909 protein kinase inhibitor Substances 0.000 abstract 1
- MISVBCMQSJUHMH-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical compound NC1=CC(N)=NC=N1 MISVBCMQSJUHMH-UHFFFAOYSA-N 0.000 description 168
- 239000007858 starting material Substances 0.000 description 75
- 238000005481 NMR spectroscopy Methods 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- FYTLHYRDGXRYEY-UHFFFAOYSA-N 5-Methyl-3-pyrazolamine Chemical compound CC=1C=C(N)NN=1 FYTLHYRDGXRYEY-UHFFFAOYSA-N 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
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- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical group COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 14
- 108091000080 Phosphotransferase Proteins 0.000 description 14
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- 239000007810 chemical reaction solvent Substances 0.000 description 13
- CYCWBZMKKCTOGR-UHFFFAOYSA-N oxan-4-ylhydrazine;hydrochloride Chemical compound Cl.NNC1CCOCC1 CYCWBZMKKCTOGR-UHFFFAOYSA-N 0.000 description 13
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
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Abstract
本发明属药物合成领域,涉及一类新型吡唑并嘧啶衍生物与其类似物,及其制备方法和作为治疗剂特别是作为PLK4抑制剂的用途。如通式(I)的化合物及其几何异构体或其药学上可接受的盐和它们的制备方法。优选的化合物具有作为蛋白激酶抑制剂,特别是PLK4激酶抑制剂的活性。
Description
技术领域
本发明属药物合成领域,涉及一类新型吡唑并嘧啶衍生物及其制备方法和作为治疗剂特别是作为PLK4抑制剂的用途。
背景技术
恶性肿瘤是目前全世界的主要死亡原因之一。针对恶性肿瘤的化学药物正在经历由早期的非选择性药物到如今拥有特定靶点的小分子药物转变。随着精准医疗概念的提出,靶向肿瘤细胞中异常表达的蛋白激酶,应是未来抗肿瘤领域的主要研究方向。近年来,以控制中心体扩增为途径达到抑制肿瘤细胞增殖目的的治疗手段已成为肿瘤化疗的新兴方案。
Polo样激酶4(PLK4)作为细胞内中心体复制的关键蛋白,在中心体复制和有丝分裂过程中发挥重要功能。已有不少研究表明PLK4过表达会导致中心体扩增而诱发癌症。目前,设计PLK4小分子ATP竞争性抑制剂已成为治疗中心体错误复制诱发的肿瘤的重要手段,且PLK4抑制剂能实现对含有TRIM37基因扩增的肿瘤的精准治疗,这一研究已在乳腺癌、胶质母细胞瘤中得以证实。
Polo样激酶4为Polo样蛋白激酶家族的成员之一,是一种进化上高度保守的丝氨酸/苏氨酸蛋白激酶,其共有5种亚型,即PLK1-5。PLK4主要在分裂活跃组织和细胞中表达,一系列的生物学研究表明,PLK4与细胞周期中中心体复制密切相关,而肿瘤细胞又具有无限增殖的特点。因此,PLK4在肿瘤细胞的增殖,迁移,侵袭,凋亡等多种生物学功能中,发挥着不可替代的作用。大量研究发现,PLK4在人类大部分肿瘤中均存在异常表达,如肝癌、胃癌、肺癌、乳腺癌、黑色素瘤和恶性血液病等。目前,尚未有PLK4抑制剂上市,迄今已报道的PLK4抑制剂仅有两类母核结构。其中一类结构的代表性抑制剂LCR-263对PLK4具有纳摩尔激酶活性且具有高选择性,但其至今未进入临床前研究;另一类结构的代表性抑制剂CFI-400945已进入临床二期研究,但其对TRKA、Aurora A/B缺乏选择性。因此,找到高效、高选择性且具有良好体内性质的新型PLK4抑制剂具有重大科学价值和研究意义。
发明内容
本发明的目的在于提供一种新型吡唑并嘧啶衍生物及其制备方法和作为治疗剂特别是作为PLK4抑制剂的用途。
为实现上述目的,本发明采用技术方案为:
一种吡唑并嘧啶衍生物,衍生物为通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;通式(I)所示化合物如下:
其中,R1选自氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟烷基、未取代或被1-4个可相同或不同的Ra取代的芳基、未取代或被1-2个下述基团取代的C3-C7环烷基、含1-2个杂原子的C3-C7脂肪环;下述基团为C1-C4烷基或氨基;所述环、含杂原子脂肪环中还可含1-2个羰基,所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合;
R2选自氢、卤素、氰基、甲酰胺、C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、含杂原子的C3-C6脂肪环;
A选自:
R3选自氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C4烷氧基,未取代或被1-4个可相同或不同的Ra取代的芳基;
C环选自未取代或被1-4个可相同或不同的Ra取代的芳基;
Ra选自卤素、C1-C4烷基或C1-C4卤代烷基;
B选自含最多2个杂原子的C5-C7脂肪环或NHRc;
Rc选自未取代或被1-4个可相同或不同的Rb取代的:芳基、芳基甲基、芳基乙基、含1-2个杂原子的C5-C7脂肪环或C5-C7脂肪杂环并苯基甲基;
Rb选卤素,氰基,甲砜乙基氨基,C1-C4烷氧基,C1-C4烷氨基,C3-C7环烷基,含最多2个杂原子的C4-C7脂肪环,NRdRe;
Rd选自C1-C4烷氧基C1-C4烷基、C1-C6羟烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、C1-C4烷基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;芳基为苯基,吡啶基,嘧啶基;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜。
当Rc选自C5-C7脂肪杂环并苯基甲基,且杂原子为N时,氮原子其还可进一步被C1-C4烷基取代。
优选,所述衍生物通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,R1选自氢,甲基,异丙基,三氟乙基,羟叔丁基,环己基,未取代或被1-4个可相同或不同的Ra取代的芳基,含1-2个杂原子的C3-C7脂肪环;所述含杂原子脂肪环中还可含1-2个羰基,所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合;
R2选自氢,卤素或甲酰胺;
A环部分选自
R3选自氢,卤素,甲基,乙基,环丙基,叔丁基,未取代或被1-4个可相同或不同的Ra取代的芳基;
C环选自未取代或被1-4个可相同或不同的Ra取代的芳基;
Ra选自卤素,C1-C4烷基,C1-C4卤代烷基;
B选自哌嗪基或NHRc;
Rc选自未取代或被1-4个可相同或不同的Rb取代的:苯基,吡啶基,嘧啶基,含1-2个杂原子的C5-C7脂肪环,C5-C7脂肪杂环并苯基甲基;
Rb选自卤素,氰基,甲砜乙基氨基,甲氧基,吗啉基,硫代吗啉基,C1-C4烷基、C1-C4烷氨基,NRdRe;
Rd选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、C1-C4烷基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜;
当Rc选自C5-C7脂肪杂环并苯基甲基,且杂原子为N时,氮原子其还可进一步被C1-C4烷基取代。
进一步优选,所述衍生物通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,R1选自氢,甲基,异丙基,三氟乙基,羟叔丁基,环己基,对氟苯基,4-四氢吡喃,2-四氢吡喃,4-六氢吡啶;
R2选自氢,卤素或甲酰胺;
A环部分选自
R3选自氢,卤素,甲基,乙基,环丙基,叔丁基,未取代或被1-4个可相同或不同的Ra取代的苯基;
C环选自未取代或被1-4个可相同或不同的Ra取代的苯基;
Ra选自卤素,C1-C4烷基,C1-C4卤代烷基;
B选自哌嗪基,
未取代或被1-4个可相同或不同的Rb取代的:4-六氢吡啶氨基,3-四氢吡咯氨基,苯氨基,苯甲氨基,1-(2,4-二氟苯基)乙氨基,2-苯基乙氨基;
Rb选自卤素,氰基,甲砜乙基氨基,甲氧基,吗啉基,硫代吗啉基,C1-C4烷基,C1-C4烷氨基,NRdRe
Rd选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、甲基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
在进一步优选,所述衍生物通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,R1选自氢,甲基,异丙基,三氟乙基,羟叔丁基,环己基,对氟苯基,4-四氢吡喃,2-四氢吡喃,4-六氢吡啶;
R2选自氢,溴;
A环部分选自
R3选自氢,卤素,甲基,乙基,环丙基,叔丁基,苯基,对氟苯基;
C环选自苯基,3-氯苯基;
B选自哌嗪基,
Rb选自氯,溴,双氟,三氟,氰基,甲砜乙基氨基,甲氧基,吗啉基,硫代吗啉基,C1-C4烷基,C1-C4烷氨基,NRdRe;
Rd选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、甲基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
更进一步优选,所述衍生物为:
N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1H-吡唑[3,4-d]嘧啶-4-胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-(吡咯烷-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-苯基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-苯乙基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3-溴苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-溴苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-(2,4,6-三氟苄基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
4-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苄腈;
N6-(4-甲氧基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-,二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
1-{6-[(4-氯苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇;
1-{6-[(2,4-二氟苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇;
1-环己基-N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
1-环己基-N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-[(3,5-二氟吡啶-2-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-1-甲基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-1-甲基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-1-异丙基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-1-异丙基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-1-(4-氟苯基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-(2,2,2,-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-苯基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-环丙基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-叔丁基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-[5-(4-氟苯基)-1H-吡唑-3-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-[5-甲基噻唑-2-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-苯基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-环丙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-叔丁基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-[5-(4-氟苯基)-1H-吡唑-3-基]-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-乙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-氯-1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯-3-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
4-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢-2H-噻喃-1,1-二氧化物;
3-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢噻吩-1,1-二氧化物;
N6-(4-氟-3-吗啉代苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氟-3-硫代吗啉代苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氯-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氟-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氟-3-[(四氢吡喃-3-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
2-{[2-氟-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇;
2-{[2-氯-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇;
N6-[(3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-((4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氟-3-[(2-甲氧基乙基)甲氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-N6-((2,3,4,5-四氢苯并[b][1,4]氧杂氮杂-7-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
3-溴-N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺。
上面给出的通式I化合物的定义中,汇集所用术语一般定义如下:
卤素:指氟、氯、溴或碘。烷基:直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基或叔丁基。环烷基:取代或未取代的环状烷基,例如环丙基、环戊基或环己基。取代基如甲基、卤素等。卤代烷基:直链或支链烷基,在这些烷基上的氢原子可部分或全部被卤原子所取代,例如,氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基等。羟烷基:直链或支链烷基,在这些烷基上的氢原子可部分被羟基所取代,例如,羟甲基、羟乙基、羟丙基、烷基,在这些烷基上的氢原子可部分被羟基所取代,例如,羟甲基、羟乙基、羟丁基、1,2-二羟基丙基、羟丙基-2-基等。烷氧基:直链或支链烷基,羟基的氢原子可被这些直链或支链烷基所取代,例如,甲基氧基,乙基氧基,丙基氧基,异丙基氧基等。烷氨基:直链或支链烷基,氨基的氢原子可被这些直链或支链烷基所取代,例如,甲基氨基,乙基氨基,丙基氨基,异丙基氨基等。含1-2个杂原子的脂肪环,如N、O、S的环状烷基,如四氢呋喃基,哌啶基,哌嗪基。脂肪杂环并苯基甲基:指含有一个或多个选自N、O、S杂原子的脂肪环并苯基甲基,如
上述通式I所示衍生物的制备方法,所述通式I所示衍生物得到制备反应如下:
1)当R1为哌啶基,4-六氢吡啶氨基,3-四氢吡咯氨基,苯氨基,有Rb取代的苯甲氨基时,通式I所示衍生物结构如通式7所示,具体为:
以巴比妥酸为起始原料,发生Vilsmeier-Haack反应和三氯氧磷氯代得到中间体2,中间体2在低温碱性条件下,与水合肼扣环得到中间体3,再在酸性条件下,THP保护得到中间体4,中间体4在碱性条件下,经过取代反应得到中间体5,再在高温碱性条件下,发生取代反应得到中间体6,最后酸性条件下脱除THP保护基得到目标化合物7。根据上述通式方法亦可制备具有类似结构的目标化合物。
进一步的说,进一步的说,以巴比妥酸为起始原料,在低温下发生Vilsmeier-Haack反应,紧接着在高温下发生三氯氧磷氯代得到中间体2,低温反应温度为-78~0℃,优选-40℃,高温反应温度为100~140℃,优选120℃;中间体2在低温碱性条件下,与水合肼扣环得到中间体3,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选乙醇,反应温度为-78~0℃,优选-78℃,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选三乙胺;中间体3在酸性条件下,THP保护得到中间体4,反应溶剂可为二甲基亚砜,四氢呋喃,二氯甲烷,1,4-二氧六环,N,N-二甲基甲酰胺或者其中两者混合溶剂,优选四氢呋喃与二氯甲烷混合溶剂,反应温度为0~78℃,优选25℃,反应中的酸可为氯化氢的乙酸乙酯饱和溶液,氯化氢的乙醇溶液,氯化氢的1,4-二氧六环溶液,氯化氢的水溶液,对甲苯磺酸,苯磺酸等,优选对甲苯磺酸;中间体4在碱性条件下,经过取代反应得到中间体5,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选N,N-二甲基甲酰胺,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选N,N-二异丙基乙胺,反应温度为40~80℃,优选65℃;中间体5在高温碱性条件下,发生取代反应得到中间体6,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选异丙醇,反应温度为100~160℃,优选135℃,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选三乙胺;中间体6在酸性条件下脱除THP保护基得到目标化合物7,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,乙酸乙酯,优选乙酸乙酯,反应温度为0~70℃,优选25℃,反应中的酸可为氯化氢的乙酸乙酯饱和溶液,氯化氢的乙醇溶液,氯化氢的1,4-二氧六环溶液,氯化氢的甲醇溶液,氯化氢的水溶液,对甲苯磺酸,苯磺酸等,优选氯化氢的乙酸乙酯饱和溶液。
2)X、Y为卤素取代,R3为氢或甲基取代时,通式(I)所示衍生物结构如通式13所示,具体为:
以多卤素取代苯腈为起始原料,发生Buchwald-hartwig偶联反应得到中间体9,中间体9进一步在硼烷四氢呋喃下还原得到中间体10;中间体2与不同取代基的肼扣环得到中间体11,接着再通过两步取代反应即可得到目标化合物13。根据上述通式方法亦可制备具有类似结构的目标化合物。
进一步的说,以多卤素取代苯腈为起始原料,发生Buchwald-hartwig偶联反应得到中间体9,反应温度为80~150℃,优选100~120℃,反应溶剂可为二甲基亚砜,甲苯,N,N-二甲基甲酰胺,N-甲基吡咯烷酮,1,4-二氧六环,四氢呋喃等,优选甲苯,催化剂可为乙酸钯,Pd(dba)2,四三苯基磷钯,PdCl2(dppf)2等,优选乙酸钯,配体可为三苯基磷,Xphos,Xtanphos,BINAP等,优选BINAP,碱可为乙酸钾,碳酸钾,碳酸钠,碳酸氢钠,氢化钠,叔丁醇钾,叔丁醇钠,碳酸铯,甲醇钠,乙醇钠等,优选叔丁醇钠;中间体9进一步在硼烷四氢呋喃下还原得到中间体10,反应温度为0~100℃,优选70℃;中间体2在低温碱性条件下,与不同取代基的肼扣环得到中间体11,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选乙醇,反应温度为-78~0℃,优选-78℃,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选三乙胺;中间体11在碱性条件下,经过取代反应得到中间体12,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选N,N-二甲基甲酰胺,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选N,N-二异丙基乙胺,反应温度为40~80℃,优选65℃;中间体12在高温碱性条件下,发生取代反应得到中间体13,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选异丙醇,反应温度为100~160℃,优选135℃,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选三乙胺;
3)且Z为卤素时,通式(I)所示衍生物结构如通式17所示,具体为:
中间体3经过卤代得到中间体14,中间体14与四氢吡喃-4-醇发生光延反应得到中间体15,中间体15再发生两步取代反应即可得到目标化合物17。根据上述通式方法亦可制备具有类似结构的目标化合物。
进一步的说,中间体3经过卤代得到中间体14,反应溶剂可为乙腈,二氯甲烷,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选乙腈,反应温度为40~100℃,优选75℃;中间体14与四氢吡喃-4-醇发生光延反应得到中间体15,反应溶剂可为二甲基亚砜,甲苯,N,N-二甲基甲酰胺,N-甲基吡咯烷酮,1,4-二氧六环,四氢呋喃等,优选四氢呋喃,反应温度为0~50℃,优选25℃;中间体15在碱性条件下,经过取代反应得到中间体16,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选N,N-二甲基甲酰胺,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选N,N-二异丙基乙胺,反应温度为40~80℃,优选65℃;中间体16在高温碱性条件下,发生取代反应得到中间体17,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选异丙醇,反应温度为100~160℃,优选135℃,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选三乙胺;
吡唑并嘧啶衍生物的应用,所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或抗肿瘤药物中的应用。
一种药用组合物,包含通式I所示的化合物及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
所述组合物在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
所述组合物在制备预防或抗肿瘤药物中的应用。
本发明所具有的优点:
本发明着眼于中心体异常引发的肿瘤,设计具有通式I所示结构的化合物,并发现具有此类结构的化合物表现出较好的PLK4抑制活性,用以治疗PLK4表达异常相关的其它疾病。
本发明通式I所示结构的化合物,不限定于其具体同分异构体,且对PLK4均表现出较好抑制活性,用以治疗PLK4表达异常相关的其它疾病。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定;所用试剂均为分析纯或化学纯。
具体实施例结构如下:
实施例1的制备路线如下所示:
具体合成步骤如下:2,4,6-三氯嘧啶-5-甲醛(2)的合成
向50mL干燥的反应瓶加入三氯氧磷9.2mL,置于-40℃低温下,后滴加干燥的N,N-二甲基甲酰胺1.2mL,再分批加入巴比妥酸(2.00g,15.60mmol),加毕,移至120℃回流反应15h。TLC监测(PE:EA=4:1)原料反应完全,待反应冷却至室温,将反应液缓慢倒入冰水中,有黄色固体析出,抽滤得棕黄色固体,乙酸乙酯萃取滤液三次,浓缩,合并经柱层析纯化(PE:EA=40:1)得白色固体,产率82%。
4,6-二氯-1H-吡唑并[3,4-d]嘧啶(3)的合成
将80%水合肼0.027mL溶于10.0mL乙醇中,置于-78℃低温下,再缓慢滴入中间体2(0.65g,3.10mmol)的乙醇溶液10.0mL,再加入三乙胺0.650mL,继续-78℃反应30min,随后移至室温反应1h。TLC监测(PE:EA=4:1)原料反应完全,旋除溶剂,柱层析纯化(PE:EA=4:1),得白色固体,收率71%。
4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶(4)的合成
将中间体3(0.5g,2.65mmol),对甲苯磺酸(0.23g,1.32mmo1)溶于THF(10mL)和DCM(30mL)的混合液中,再加入3,4-二氢吡喃(0.67g,7.96mmol),室温搅拌10h,TLC检测(PE:EA=4:1),原料反应完全,旋干溶剂,经柱层析(PE:EA=40:1)得白色固体,产率78%。
6-氯-N-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(5)的合成
将中间体4(0.65g,2.39mmol)溶于5mL DMF中,再依次5-甲基-1H-吡唑-3-胺(0.24g,2.39mmol)、N,N-二异丙基乙胺(0.555mL,3.11mmol)、碘化钾(0.48g,2.87mmol),后65℃反应1h。TLC检测(DCM:MeOH=15:1),原料反应完全,待反应冷却至室温,加入水50mL,析出白色沉淀,抽滤,得到白色固体,产率92%。
N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(6)的合成
将中间体5(0.10g,0.30mmol)溶于1.5mL异丙醇中,再加入哌嗪(0.065g,0.75mmol)、三乙胺0.11mL,后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH=10:1)原料反应完毕,待反应冷却至室温,旋干溶剂,经柱层析(DCM:MeOH=40:1)得白色固体,产率53%。
N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(实施例1)的制备
将中间体6(0.05g,0.13mmol),溶于1mL氯化氢的乙酸乙酯饱和溶液,室温搅拌4h。TLC监测(DCM:MeOH=8:1)反应完全,减压过滤,用乙酸乙酯洗涤滤饼三次,将滤饼溶于20mL水,乙酸乙酯萃取(10mL×3),弃去有机层。水层在冰浴条件下用10%的氢氧化钠溶液调pH>10,乙酸乙酯萃取(10mL×3),饱和食盐水洗涤(10mL×3),无水硫酸钠干燥。减压过滤除去硫酸钠,旋除乙酸乙酯,得白色固体,收率69%。1H NMR(600MHz,DMSO-d6)δ11.35(s,1H),9.60(s,2H),8.47(s,1H),6.40(s,1H),4.07(s,4H),3.25(s,4H),2.30(s,3H).HRMS(ESI,m/z)calcd for C13H17N9[M+H]+,300.1685;found 300.1660.
实施例2
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为吡咯烷-3-胺,即得实施例2.1H NMR(600MHz,DMSO-d6)δ12.54–11.82(m,1H),9.82(s,1H),9.68–8.45(m,3H),6.53(s,1H),4.62(s,2H),3.51(dt,J=11.9,6.0Hz,1H),3.40(s,1H),3.32–3.23(m,2H),2.38–2.28(m,4H),2.07(s,1H).HRMS(ESI,m/z)calcd for C13H17N9[M+H]+,300.1685;found300.1682.
实施例3
N4-(5-甲基-1H-吡唑-3-基)-N6-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例3)的制备:
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为哌啶-4-胺,即得实施例3.1H NMR(600MHz,DMSO-d6)δ12.75(s,1H),12.11–11.79(m,1H),9.09(s,2H),9.02–8.84(m,1H),6.82–6.41(m,1H),4.02(s,1H),3.76–3.73(m,1H),3.36(s,2H),3.01(d,J=62.4Hz,2H),2.30(s,3H),2.13(d,J=38.1Hz,2H),1.84(s,2H).HRMS(ESI,m/z)calcd forC14H19N9[M+H]+,314.1842;found 314.1844.
实施例4
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为苯胺,即得实施例4.1H NMR(600MHz,DMSO-d6)δ11.70(s,1H),10.33(s,1H),8.48(s,1H),7.77(s,2H),7.45(s,3H),7.18(d,J=28.3Hz,1H),6.36(s,1H),2.32(s,3H).HRMS(ESI,m/z)calcd for C15H14N8[M+H]+,307.1420;found 307.1422.
实施例5
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为苯乙胺,即得实施例5.1H NMR(600MHz,DMSO-d6)δ13.02–12.55(m,1H),12.10–11.48(m,1H),8.72(s,1H),8.24(s,1H),7.38(dt,J=22.5,7.7Hz,5H),6.66(s,1H),3.84–3.82(m,2H),3.01(t,J=7.2Hz,2H),2.34(d,J=34.1Hz,3H).HRMS(ESI,m/z)calcd for C17H18N8[M+H]+,335.1733;found335.1739.
实施例6
N6-(3-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例6)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为3-氯苄胺,即得实施例6.1H NMR(600MHz,DMSO-d6)δ13.74–12.21(m,1H),11.83(s,1H),9.76–8.81(s,1H),8.67(s,1H),7.55–7.31(m,5H),6.65–6.14(m,1H),4.72(s,2H),2.26(d,J=62.5Hz,3H).HRMS(ESI,m/z)calcd for C16H15ClN8[M+H]+,355.1186;found 355.1190.
实施例7
N6-(3-溴苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例7)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为3-溴苄胺,即得实施例7.1H NMR(600MHz,DMSO-d6)δ13.84–12.37(m,1H),11.83(s,1H),9.86–8.81(m,1H),8.68(s,1H),7.67–7.29(m,5H),6.61–6.17(m,1H),4.71(s,2H),2.32–2.18(m,3H).HRMS(ESI,m/z)calcd for C16H15BrN8[M+H]+,399.0681;found 399.0685.
实施例8
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例8)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为4-氯苄胺,即得实施例8.1H NMR(600MHz,DMSO-d6)δ13.49–12.35(m,1H),11.83(s,1H),9.82–8.77(m,1H),8.68(s,1H),7.43(d,J=5.7Hz,5H),6.62–6.13(m,1H),4.70(s,2H),2.28(d,J=62.3Hz,3H).HRMS(ESI,m/z)calcd for C16H15ClN8[M+H]+,355.1186;found355.1194.
实施例9
N6-(4-溴苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例9)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为4-溴苄胺,即得实施例9.1H NMR(600MHz,DMSO-d6)δ12.54–12.37(m,1H),11.81(s,1H),9.80–8.72(m,1H),8.67(s,1H),7.56(d,J=7.3Hz,2H),7.34(s,2H),6.11(s,1H),4.68(s,2H),2.32–2.16(m,3H).HRMS(ESI,m/z)calcd for C16H15BrN8[M+H]+,399.0681;found399.0704.
实施例10
N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例10)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺,即得实施例10.1H NMR(600MHz,DMSO-d6)δ13.45–12.16(m,1H),11.74(s,1H),9.36–8.61(m,1H),8.59–8.42(m,1H),7.38(d,J=49.5Hz,1H),7.23(t,J=8.9Hz,1H),6.99(s,1H),6.54–6.07(m,1H),4.63(s,2H),2.23–2.08(m,3H).HRMS(ESI,m/z)calcd forC16H15F2N8[M+H]+,357.1388;found 357.1402.
实施例11
N6-(3,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例11)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为3,4-二氟苄胺,即得实施例11.1H NMR(600MHz,DMSO-d6)δ13.60–12.32(m,1H),11.82(s,1H),9.77–8.75(m,1H),8.68(s,1H),7.53–7.38(m,2H),7.23(s,1H),6.61(s,1H),6.14(s,1H),4.69(s,2H),2.24(d,J=55.0Hz,3H).HRMS(ESI,m/z)calcd for C16H15F2N8[M+H]+,357.1388;found 357.1406.
实施例2
N4-(5-甲基-1H-吡唑-3-基)-N6-(2,4,6-三氟苄基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例12)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为2,4,6-三氟苄胺,即得实施例12.1H NMR(600MHz,DMSO-d6)δ13.65–12.29(m,1H),11.89(s,1H),8.68(s,2H),7.28(t,J=8.4Hz,2H),6.57(s,1H),4.78(s,2H),2.29(s,3H).HRMS(ESI,m/z)calcd for C16H13F3N8[M+H]+,375.1294;found 375.1313.
实施例13
4-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苄腈(实施例13)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为4-氰基苄胺,即得实施例13.1H NMR(600MHz,DMSO-d6)δ12.59(s,1H),11.98(s,1H),10.10(s,1H),8.04(s,1H),7.78(d,J=8.2Hz,2H),7.52(d,J=8.0Hz,2H),7.40(d,J=7.6Hz,1H),6.06–5.66(m,1H),4.60(d,J=5.3Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd forC17H15N9[M+H]+,346.1529;found 346.1530.
实施例14
N6-(4-甲氧基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例14)的制备
参考制备实施例1的方法,将e步骤中哌嗪原料等比例替换为4-甲氧基苄胺,即得实施例14.1H NMR(600MHz,DMSO-d6)δ13.33–12.54(m,1H),11.84(s,1H),9.80–8.79(m,1H),8.68(s,1H),7.33(d,J=35.0Hz,3H),6.93(d,J=5.6Hz,2H),6.63–6.32(m,1H),4.64(s,2H),3.74(s,3H),2.26(d,J=41.1Hz,3H).HRMS(ESI,m/z)calcd forC17H18N8O[M+H]+,351.1682;found 351.1684.
实施例15采用如下路线进行制备:
4,6-二氯-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶(11)的合成
将(四氢-2H-吡喃-4-基)肼盐酸盐(1.00g,6.58mmol)溶于15.0mL乙醇中,置于-78℃低温下,再缓慢滴入中间体2(1.38g,6.58mmol)的乙醇溶液15.0mL,再加入三乙胺4.58mL,继续-78℃反应30min,随后移至室温反应1h。TLC监测(PE:EA=4:1)原料反应完全,旋除溶剂,柱层析纯化(PE:EA=10:1),得白色固体,收率85%。
6-氯-N-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(12)的合成
将中间体11(0.50g,1.84mmol)溶于5mL DMF中,再依次5-甲基-1H-吡唑-3-胺(0.18g,1.84mmol)、N,N-二异丙基乙胺(0.425mL,2.40mmol)、碘化钾(0.37g,2.21mmol),后65℃反应1h。TLC检测(DCM:MeOH=15:1),原料反应完全,待反应冷却至室温,加入水50mL,析出白色沉淀,抽滤,得到白色固体,产率88%。
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例15)的制备
将中间体12(0.08g,0.24mmol)溶于1.5mL异丙醇中,再加入对氯苄胺(0.041g,0.29mmol)、三乙胺0.10mL,后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH=10:1)原料反应完毕,待反应冷却至室温,旋干溶剂,经柱层析(DCM:MeOH=40:1)得白色固体,产率46%。1H NMR(600MHz,DMSO-d6)δ12.67–11.89(m,1H),10.67–9.93(m,1H),8.07(s,1H),7.53–7.31(m,5H),4.61(s,1H),4.51(s,2H),3.97(d,J=8.9Hz,2H),3.48(t,J=11.5Hz,2H),2.15(d,J=26.0Hz,3H),2.12–2.06(m,2H),1.76(s,2H).HRMS(ESI,m/z)calcd forC21H23ClN8O[M+H]+,439.1762;found 439.1774.
实施例16
N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例16)的制备
参考制备实施例15的方法,将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺,即得实施例16.1H NMR(600MHz,DMSO-d6)δ12.66–11.86(m,1H),10.72–9.91(m,1H),8.08(s,1H),7.47(s,2H),7.21(s,1H),7.01(t,J=7.4Hz,1H),4.63(s,1H),4.52(s,2H),3.98(d,J=7.8Hz,2H),3.49(t,J=11.6Hz,2H),2.18(s,3H),2.09(d,J=9.3Hz,2H),1.76(s,2H).HRMS(ESI,m/z)calcd for C21H22F2N8O[M+H]+,441.1963;found 441.1970.
实施例17
1-{6-[(4-氯苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇(实施例17)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为1-肼-2-甲基丙烷-2-醇,即得实施例17.1H NMR(600MHz,DMSO-d6)δ12.63–11.98(m,1H),10.65–10.09(m,1H),8.09(s,1H),7.50(s,1H),7.35(s,4H),4.80(s,1H),4.50(s,2H),4.04(s,2H),2.22(d,J=25.1Hz,3H),1.03(s,6H).HRMS(ESI,m/z)calcd for C20H23ClN8O[M+H]+,427.1762;found 427.1777.
实施例18
1-{6-[(2,4-二氟苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇(实施例18)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为1-肼-2-甲基丙烷-2-醇,将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺,即得实施例18.1H NMR(600MHz,DMSO-d6)δ12.66–11.94(m,1H),10.66–10.00(m,1H),8.09(s,1H),7.47(s,2H),7.20(s,1H),7.00(d,J=7.0Hz,1H),4.75(s,1H),4.52(s,2H),4.04(s,2H),2.20(s,3H),1.02(s,6H).HRMS(ESI,m/z)calcd for C20H22F2N8O[M+H]+,429.1963;found 429.1972.
实施例19
1-环己基-N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例19)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为环己基肼,即得实施例19.1H NMR(600MHz,DMSO-d6)δ12.68–11.83(m,1H),10.67–9.87(m,1H),8.21–7.74(m,1H),7.40(d,J=61.6Hz,5H),4.50(s,2H),4.36(s,1H),2.17(s,3H),1.82(d,J=9.8Hz,6H),1.67(d,J=12.4Hz,1H),1.49–1.25(m,3H).HRMS(ESI,m/z)calcd for C22H25ClN8[M+H]+,437.1969;found 437.1977.
实施例20
1-环己基-N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例20)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为环己基肼,将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺,即得实施例20.1H NMR(600MHz,DMSO-d6)δ11.98(s,1H),10.68–9.95(m,1H),8.05(s,1H),7.45(s,2H),7.20(s,1H),7.01(d,J=7.3Hz,1H),4.51(s,2H),4.37(s,1H),2.18(s,3H),1.83(d,J=10.6Hz,6H),1.68(d,J=12.2Hz,1H),1.50–1.33(m,3H).HRMS(ESI,m/z)calcd for C22H24F2N8[M+H]+,439.2170;found 439.2177.
实施例21
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例21)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为4-肼基哌啶-1-羧酸叔丁酯,即得实施例21.1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),9.33(s,1H),9.09(s,1H),8.51(s,1H),7.51(d,J=20.8Hz,3H),7.41(d,J=8.3Hz,2H),6.25(s,1H),4.82(s,1H),4.63(s,2H),4.02(d,J=5.7Hz,1H),3.39(d,J=3.4Hz,2H),3.13(s,2H),2.40–2.23(m,5H),2.09–1.96(m,2H).HRMS(ESI,m/z)calcd for C21H24ClN9[M+H]+,438.1921;found 438.1931.
实施例22
N6-(2,4-,二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例22)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为4-肼基哌啶-1-羧酸叔丁酯,将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺,即得实施例22.1H NMR(600MHz,DMSO-d6)δ11.87(s,1H),9.04(s,1H),8.79(s,1H),8.25(s,1H),7.61(s,1H),7.26(t,J=8.8Hz,1H),7.06(s,1H),6.30(s,1H),4.80(t,J=10.9Hz,1H),4.61(s,2H),3.42(d,J=11.8Hz,2H),3.16(d,J=6.4Hz,2H),2.33–2.21(m,5H),2.04(d,J=12.7Hz,2H).HRMS(ESI,m/z)calcd for C21H24ClN9[M+H]+,438.1921;found 438.1931.
实施例23
N6-[(3,5-二氟吡啶-2-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例23)的制备
参考制备实施例15的方法,将e步骤中哌嗪原料等比例替换为(3,5-二氟吡啶-2-基)甲胺,即得实施例23.1H NMR(600MHz,DMSO-d6)δ12.03(s,1H),10.14(s,1H),8.43–7.88(m,2H),6.89–6.10(m,1H),4.69–4.53(m,2H),3.97(dd,J=11.1,3.5Hz,2H),3.63(q,J=6.9Hz,2H),3.51–3.45(m,2H),2.22(d,J=14.4Hz,3H),2.18–2.05(m,2H),1.81(dd,J=12.6,2.3Hz,1H),1.71(s,1H).HRMS(ESI,m/z)calcd for C20H21F2N9O[M+H]+,442.1915;found 442.1943.
实施例24
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例24)的制备
参考制备实施例8的方法,不对THP保护基进行脱除,即得实施例24.1H NMR(600MHz,DMSO-d6)δ12.75–11.87(m,1H),10.84–9.86(m,1H),8.11(s,1H),7.56(s,1H),7.36(d,J=5.7Hz,5H),5.62(d,J=9.9Hz,1H),4.52(s,2H),3.94(d,J=11.0Hz,1H),3.59(s,1H),2.38(dd,J=22.2,9.6Hz,1H),2.18(s,3H),1.99(d,J=11.4Hz,1H),1.76(d,J=11.4Hz,1H),1.69(dd,J=14.0,5.8Hz,1H),1.53(s,2H).HRMS(ESI,m/z)calcd for C21H23ClN8O[M+H]+,439.1762;found 439.1779.
实施例25
N6-(4-氯苄基)-1-甲基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例25)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为甲基肼,即得实施例25.1H NMR(600MHz,DMSO-d6)δ12.53–11.77(m,1H),10.60–9.91(m,1H),7.97(s,1H),7.35(d,J=69.9Hz,5H),4.46(d,J=4.5Hz,2H),3.64(s,3H),2.11(s,3H).HRMS(ESI,m/z)calcd for C17H17ClN8[M+H]+,369.1343;found 369.1350.
实施例26
N6-(2,4-二氟苄基)-1-甲基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例26)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为甲基肼,将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺,即得实施例26.1H NMR(600MHz,DMSO-d6)δ12.59–11.89(m,1H),10.59–9.95(m,1H),7.99(s,1H),7.39(s,2H),7.14(s,1H),6.95(s,1H),4.48(s,2H),3.65(s,3H),2.11(s,3H).HRMS(ESI,m/z)calcd for C17H16F2N8[M+H]+,371.1544;found 371.1557.
实施例27
N6-(4-氯苄基)-1-异丙基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例27)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为异丙基肼,即得实施例27.1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.19(s,1H),8.12(s,1H),7.57(s,1H),7.47(t,J=6.4Hz,4H),4.91–4.87(m,1H),4.62(d,J=5.7Hz,2H),2.29(s,3H),1.48(d,J=6.7Hz,6H).HRMS(ESI,m/z)calcd forC19H21ClN8[M+H]+,397.1656;found 397.1659.
实施例28
N6-(2,4-二氟苄基)-1-异丙基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例28)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为异丙基肼,将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺,即得实施例28.1H NMR(600MHz,DMSO-d6)δ11.98(s,1H),10.13(s,1H),8.03(s,1H),7.46(d,J=57.4Hz,2H),7.21(s,1H),7.01(s,1H),4.79(s,1H),4.52(s,2H),2.18(s,3H),1.37(d,J=5.9Hz,6H).HRMS(ESI,m/z)calcd for C19H20F2N8[M+H]+,399.1857;found399.1864.
实施例29
N6-(4-氯苄基)-1-(4-氟苯基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例29)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为对氟苯肼,即得实施例29.1H NMR(600MHz,DMSO-d6)δ12.59–11.89(m,1H),10.88–9.99(m,1H),8.36–8.00(m,3H),7.74(d,J=73.0Hz,1H),7.39–7.23(m,6H),4.44(s,2H),2.15(t,J=31.3Hz,3H).HRMS(ESI,m/z)calcd for C22H18ClFN8[M+H]+,449.1405;found 449.1422.
实施例30
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-(2,2,2,-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例30)的制备
参考制备实施例15的方法,将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为三氟乙基肼,即得实施例30.1H NMR(600MHz,DMSO-d6)δ12.76–12.07(m,1H),10.96–10.08(m,1H),8.32(s,1H),7.78(s,1H),7.49(d,J=31.8Hz,4H),5.11–5.04(m,2H),4.63(s,2H),2.33(s,3H).HRMS(ESI,m/z)calcd for C18H16ClF3N8[M+H]+,437.1217;found 437.1235.
实施例31
N6-(2,4-二氟苄基)-N4-(5-苯基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例31)的制备
参考制备实施例22的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-苯基-1H-吡唑-3-胺,即得实施例31.1H NMR(600MHz,DMSO-d6)δ12.46–11.39(m,1H),9.44(d,J=41.7Hz,1H),9.18(s,1H),8.86–8.44(m,1H),7.85(t,J=24.6Hz,2H),7.71–6.87(m,6H),5.03(t,J=11.1Hz,1H),4.83(d,J=124.1Hz,2H),3.45(d,J=12.4Hz,2H),3.23(dd,J=23.2,11.5Hz,2H),2.41–2.33(m,2H),2.14(d,J=12.0Hz,2H).HRMS(ESI,m/z)calcd for C26H25F2N9[M+H]+,502.2279;found 502.2303.
实施例32
N6-(2,4-二氟苄基)-N4-(5-环丙基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例32)的制备
参考制备实施例22的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-环丙基-1H-吡唑-3-胺,即得实施例32.1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),9.37(d,J=9.0Hz,1H),9.11(s,1H),8.55(s,1H),7.67(dt,J=23.6,11.8Hz,1H),7.26(t,J=9.4Hz,1H),7.06(t,J=8.0Hz,1H),6.06(s,1H),4.82(s,1H),4.63(s,2H),4.04–3.99(m,1H),3.40(d,J=11.5Hz,2H),3.15(d,J=8.1Hz,2H),2.29(dd,J=22.0,10.7Hz,2H),2.04(s,3H),1.07–0.93(m,2H),0.88–0.67(m,2H).HRMS(ESI,m/z)calcd forC23H25F2N9[M+H]+,466.2279;found 466.2252.
实施例33
N6-(2,4-二氟苄基)-N4-(5-叔丁基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例33)的制备
参考制备实施例22的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-叔丁基-1H-吡唑-3-胺,即得实施例33.1H NMR(600MHz,DMSO-d6)δ13.25–11.32(m,1H),9.33(s,1H),9.07(s,1H),8.44(d,J=61.8Hz,1H),7.69–7.40(m,1H),7.19(td,J=10.5,2.5Hz,1H),7.00(t,J=7.7Hz,1H),6.18(s,1H),4.78(s,1H),4.59(s,2H),4.01–3.90(m,1H),3.35(d,J=11.0Hz,2H),3.06(s,2H),2.23(d,J=11.6Hz,2H),2.00(s,2H),1.24(s,9H).HRMS(ESI,m/z)calcd for C24H29F2N9[M+H]+,482.2592;found482.2615.
实施例34
N6-(2,4-二氟苄基)-N4-[5-(4-氟苯基)-1H-吡唑-3-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例34)的制备
参考制备实施例22的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-(4-氟苯基)-1H-吡唑-3-胺,即得实施例34.1H NMR(600MHz,DMSO-d6)δ11.88–11.18(m,1H),9.24(d,J=34.6Hz,1H),8.99(s,1H),8.46–8.223(m,1H),7.77(d,J=42.3Hz,2H),7.55(s,1H),7.37–7.08(m,3H),7.05–6.91(m,1H),6.77(s,1H),4.92–4.81(m,1H),4.77(s,1H),4.57(s,2H),3.33(s,2H),3.08(t,J=11.7Hz,2H),2.22(dd,J=22.4,10.8Hz,2H),2.00(d,J=11.7Hz,2H).HRMS(ESI,m/z)calcd for C26H24F3N9[M+H]+,520.2185;found 520.2202.
实施例35
N6-(2,4-二氟苄基)-N4-[5-甲基噻唑-2-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例35)的制备
参考制备实施例22的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-甲基噻唑-2-胺,即得实施例35.1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),9.18(s,1H),8.27(s,1H),7.24(s,2H),7.02(t,J=7.6Hz,1H),4.92–4.52(m,3H),3.40(d,J=10.9Hz,2H),3.11(s,2H),2.47–2.18(m,6H),2.08(s,2H).HRMS(ESI,m/z)calcd forC21H22F2N8S[M+H]+,457.1734;found 457.1751.
实施例36
N6-(2,4-二氟苄基)-N4-(5-苯基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例36)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-苯基-1H-吡唑-3-胺,即得实施例36.1H NMR(600MHz,DMSO-d6)δ13.27–12.73(m,1H),11.44–10.17(m,1H),8.04(d,J=51.0Hz,1H),7.89–7.32(m,7H),7.23(s,1H),7.03(s,1H),4.65(s,2H),4.56(s,1H),3.99(d,J=9.2Hz,2H),3.52(dt,J=22.7,9.3Hz,2H),2.11(d,J=9.3Hz,2H),1.78(s,2H).HRMS(ESI,m/z)calcd for C26H24F2N8O[M+H]+,503.2119;found 503.2139.
实施例37
N6-(2,4-二氟苄基)-N4-(5-环丙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例37)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-环丙基-1H-吡唑-3-胺,即得实施例37.1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.14(s,1H),7.98(s,1H),7.42(s,2H),7.13(t,J=9.1Hz,1H),6.94(t,J=8.4Hz,1H),4.56(t,J=11.2Hz,1H),4.46(s,2H),3.91(d,J=8.2Hz,2H),3.42(t,J=11.4Hz,2H),2.02(dt,J=11.9,8.2Hz,2H),1.93(dd,J=15.5,7.8Hz,1H),1.69(d,J=11.5Hz,2H),0.82(d,J=8.0Hz,2H),0.62(s,2H).HRMS(ESI,m/z)calcd for C23H24F2N8O[M+H]+,467.2119;found 467.2134.
实施例38
N6-(2,4-二氟苄基)-N4-(5-叔丁基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例38)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-叔丁基-1H-吡唑-3-胺,即得实施例38.1H NMR(600MHz,DMSO-d6)δ11.96(s,1H),10.75–9.90(m,1H),8.00(d,J=93.1Hz,1H),7.35(s,2H),7.11(t,J=8.6Hz,1H),6.94(d,J=6.5Hz,1H),4.56(s,3H),3.91(d,J=8.9Hz,2H),3.41(t,J=11.5Hz,2H),2.03(d,J=9.7Hz,2H),1.70(s,2H),1.20(d,J=45.5Hz,9H).HRMS(ESI,m/z)calcd forC24H28F2N8O[M+H]+,483.2432;found 483.2449.
实施例39
N6-(2,4-二氟苄基)-N4-[5-(4-氟苯基)-1H-吡唑-3-基]-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例39)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-(4-氟苯基)-1H-吡唑-3-胺,即得实施例39.1H NMR(600MHz,DMSO-d6)δ13.24–12.64(m,1H),11.47–10.16(m,1H),8.50–7.78(m,3H),7.76–7.12(m,6H),7.03(s,1H),4.61(d,J=52.7Hz,3H),3.99(d,J=8.7Hz,2H),3.50(s,2H),2.12(d,J=9.4Hz,2H),1.78(s,2H).HRMS(ESI,m/z)calcd for C26H23F3N8O[M+H]+,521.2025;found521.2044.
实施例40
N6-(2,4-二氟苄基)-N4-(5-乙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例40)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-乙基-1H-吡唑-3-胺,即得实施例40.1H NMR(600MHz,DMSO-d6)δ12.69–11.93(m,1H),10.74–9.85(m,1H),8.10(s,1H),7.61–7.31(m,2H),7.19(s,1H),7.00(s,1H),4.67–4.49(m,3H),3.98(d,J=8.9Hz,2H),3.48(t,J=11.5Hz,2H),2.54(s,2H),2.09(d,J=9.7Hz,2H),1.76(s,2H),1.27–1.08(m,3H).HRMS(ESI,m/z)calcd forC22H24F2N8O[M+H]+,455.2119;found 455.2132.
实施例41
N6-(2,4-二氟苄基)-N4-(1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例41)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为1H-吲唑-3-胺,即得实施例41.1H NMR(600MHz,DMSO-d6)δ12.79(s,1H),10.02(s,1H),7.66–7.41(m,3H),7.35(s,1H),7.27(s,1H),7.21–6.65(m,4H),4.62(s,1H),4.39(s,2H),3.98(d,J=8.5Hz,2H),3.48(t,J=11.6Hz,2H),2.08(d,J=9.4Hz,2H),1.75(s,2H).HRMS(ESI,m/z)calcd for C24H22F2N8O[M+H]+,477.1963;found 477.1984.
实施例42
N6-(2,4-二氟苄基)-N4-(5-氯-1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例42)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-氯-1H-吲唑-3-胺,即得实施例42.1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),10.06(s,1H),7.60(s,2H),7.47(d,J=8.9Hz,1H),7.29(dd,J=6.8,2.1Hz,2H),7.21(s,1H),7.05–6.81(m,2H),4.57(d,J=9.3Hz,1H),4.30(s,2H),3.93–3.89(m,2H),3.41(s,2H),2.02(d,J=8.8Hz,2H),1.68(d,J=11.3Hz,2H).HRMS(ESI,m/z)calcd forC24H21ClF2N8O[M+H]+,511.1573;found 511.1605.
实施例43
(S)-N6-[1-(2,4-二氟苯基)乙基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例43)的制备
参考制备实施例16的方法,将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为(S)-1-(2,4-二氟苯基)乙基-1-胺,即得实施例43.1H NMR(600MHz,DMSO-d6)δ12.83–11.89(m,1H),10.85–9.80(m,1H),8.37–7.84(m,1H),7.49(s,2H),7.15(s,1H),7.00(t,J=7.6Hz,1H),6.20(s,1H),5.51–5.18(m,1H),4.73–4.42(m,1H),3.99(s,2H),3.47(t,J=11.5Hz,2H),2.23(s,3H),2.16–1.91(m,2H),1.79(s,2H),1.47(s,3H).HRMS(ESI,m/z)calcd for C22H24F2N8O[M+H]+,455.2119;found 455.2147.
实施例44采用如下路线进行制备:
2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄腈(9)的合成
将原料8(0.25g,1.16mmol),2-(甲基磺酰基)乙基-1-胺盐酸盐(0.18g,1.16mmol)和叔丁醇钠(0.22g,2.31mmol)溶于8mL无水甲苯,加入催化量的醋酸钯(0.03g,0.116mmol)和BINAP(0.07g,0.116mmol),惰性气体置换,100℃反应10h。TLC监测,原料反应完全,旋除溶剂,经柱层析得白色固体,产率76%。
5-(氨甲基)-2,4-二氟-N-[2-(甲基磺酰基)乙基]苯胺(10)的合成
将中间体9(0.18g,0.69mmol)溶于1mL四氢呋喃中,再加入1mmol/L硼烷四氢呋喃溶液2mL,70℃反应4h。TLC监测,原料反应完全,待反应冷却至室温,置于冰浴中,缓慢加入2mmol/L盐酸溶液2mL,加毕,继续70℃加热1h,后将反应冷却至室温。加20mL乙酸乙酯,用水萃取三次,收集水层,用氨水调PH 8~9,再用乙酸乙酯萃取三次,收集有机层,用饱和食盐水洗,无水硫酸钠干燥,浓缩,得无色透明液体,产率78%。
N6-(2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例44)的制备
将中间体12(0.17g,0.50mmol)溶于1.5mL异丙醇中,再加入中间体10(0.16g,0.61mmol)、三乙胺0.14mL,后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH=10:1)原料反应完毕,待反应冷却至室温,旋干溶剂,经柱层析(DCM:MeOH=40:1)得白色固体,产率53%。1H NMR(600MHz,DMSO-d6)δ12.81–11.91(m,1H),10.26(s,1H),8.07(s,1H),7.40(s,1H),7.10(t,J=10.0Hz,1H),6.86(s,1H),5.42(s,1H),4.65(s,1H),4.51(s,2H),3.98(d,J=8.7Hz,2H),3.58–3.37(m,6H),2.96(s,3H),2.19(s,3H),2.10(d,J=9.0Hz,2H),1.78(d,J=11.2Hz,2H).HRMS(ESI,m/z)calcd for C24H29F2N9O3S[M+H]+,562.2160;found562.2198.
实施例45
N6-(3,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例45)的制备
参考制备实施例44的方法,将g步骤中5-溴-2,4-二氟苯腈原料等比例替换为3-溴-4,5-二氟苯腈,即得实施例45.1H NMR(600MHz,DMSO-d6)δ12.66–11.88(m,1H),10.72–9.90(m,1H),8.07(s,1H),7.41(s,1H),6.64(s,2H),5.92(s,1H),4.64(s,1H),4.44(s,2H),3.97(d,J=8.0Hz,2H),3.49(t,J=11.7Hz,4H),3.37(s,2H),3.01(s,3H),2.19(s,3H),2.11(dt,J=12.0,8.1Hz,2H),1.77(d,J=11.5Hz,2H).HRMS(ESI,m/z)calcd for C24H29F2N9O3S[M+H]+,562.2160;found 562.2194.
实施例46
N6-(4-氯-3-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例46)的制备
参考制备实施例44的方法,将g步骤中5-溴-2,4-二氟苯腈原料等比例替换为3-溴-4-氯苯腈,即得实施例46.1H NMR(600MHz,DMSO-d6)δ12.02(s,1H),10.23(s,1H),8.10(d,J=37.3Hz,1H),7.43(s,1H),7.20(d,J=7.8Hz,1H),6.80(s,1H),6.68(s,1H),5.52(s,1H),4.63(s,1H),4.49(s,2H),3.97(d,J=8.7Hz,2H),3.55(s,2H),3.48(t,J=11.6Hz,2H),3.35(s,2H),3.02(s,3H),2.19(s,3H),2.12(dd,J=11.6,8.7Hz,2H),1.77(d,J=11.2Hz,2H).HRMS(ESI,m/z)calcd for C24H30ClN9O3S[M+H]+,560.1959;found 560.1990.
实施例47
4-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢-2H-噻喃-1,1-二氧化物(实施例47)的制备
参考制备实施例46的方法,将g步骤中2-(甲磺酰基)乙胺原料等比例替换为4-氨基四氢-2H-硫代吡喃-1,1-二氧化物,即得实施例47.1H NMR(600MHz,DMSO-d6)δ12.00(s,1H),10.20(s,1H),8.09(s,2H),7.48–7.20(m,2H),6.81(s,1H),6.66(s,1H),5.09(s,1H),4.61(s,1H),4.47(s,2H),4.24(s,1H),3.96(s,2H),3.51(s,2H),3.47(s,2H),2.10(d,J=8.3Hz,3H),2.04–1.97(m,4H),1.76(t,J=31.6Hz,4H).HRMS(ESI,m/z)calcd for C26H32ClN9O3S[M+H]+,586.2116;found 586.2143.
实施例48
3-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢噻吩-1,1-二氧化物(实施例48)的制备
参考制备实施例46的方法,将g步骤中2-(甲磺酰基)乙胺原料等比例替换为3-氨基四氢噻吩-1,1-二氧化物,即得实施例48.1H NMR(600MHz,DMSO-d6)δ12.64–11.96(m,1H),10.18(s,1H),8.07(s,1H),7.39(s,1H),7.19(d,J=8.0Hz,1H),6.87(s,1H),6.69(s,1H),5.49(d,J=6.6Hz,1H),4.62(t,J=11.2Hz,1H),4.47(s,2H),4.30(s,1H),3.97(d,J=8.9Hz,2H),3.57(s,1H),3.48(t,J=11.6Hz,2H),3.08(s,2H),2.45(s,1H),2.19(s,3H),2.14–2.07(m,2H),1.76(d,J=11.4Hz,2H).HRMS(ESI,m/z)calcd for C25H30ClN9O3S[M+H]+,572.1959;found 572.1992.
实施例49
N6-(4-氟-3-吗啉代苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例49)的制备
参考制备实施例44的方法,将g步骤中5-溴-2,4-二氟苯腈原料等比例替换为3-溴-4-氟苯腈,且2-(甲磺酰基)乙胺原料等比例替换为吗啉,即得实施例49.1H NMR(600MHz,DMSO-d6)δ12.78–11.85(m,1H),10.17(s,1H),8.07(d,J=24.7Hz,1H),7.41(s,1H),7.10–6.90(m,3H),4.63(s,1H),4.47(d,J=4.1Hz,2H),3.97(dd,J=10.9,3.4Hz,2H),3.71(s,4H),3.48(t,J=11.5Hz,2H),2.94(s,4H),2.19(s,3H),2.12(d,J=9.5Hz,2H),1.77(d,J=11.0Hz,2H).HRMS(ESI,m/z)calcd for C25H30FN9O2[M+H]+,508.2585;found 508.2607.
实施例50
N6-(4-氟-3-硫代吗啉代苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例50)的制备
参考制备实施例49的方法,将g步骤中吗啉原料等比例替换为硫代吗啉,即得实施例50.1H NMR(600MHz,DMSO-d6)δ12.62–11.84(m,1H),10.56–9.84(m,1H),8.00(s,1H),7.34(s,1H),7.05(d,J=7.6Hz,1H),7.01–6.60(m,3H),4.57(s,1H),4.40(s,2H),3.91(d,J=10.7Hz,2H),3.44–3.39(m,2H),3.11(d,J=8.4Hz,4H),2.66–2.54(m,4H),2.13(s,3H),2.05(d,J=9.9Hz,2H),1.70(d,J=11.3Hz,2H).HRMS(ESI,m/z)calcdfor C25H30FN9OS[M+H]+,524.2356;found 524.2377.
实施例51
N6-{4-氯-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例51)的制备
参考制备实施例46的方法,将g步骤中2-(甲磺酰基)乙胺原料等比例替换为四氢-2H-吡喃-4-胺,即得实施例51.1H NMR(600MHz,DMSO-d6)δ11.92(s,1H),10.13(s,1H),8.00(s,1H),7.31(s,1H),7.09(d,J=7.8Hz,1H),6.74(s,1H),6.69–6.08(m,2H),4.67(s,1H),4.54(s,1H),4.39(s,2H),3.89(d,J=6.7Hz,2H),3.70(s,2H),3.42–3.38(m,2H),2.15–2.00(m,5H),1.69(s,4H),1.36(s,2H),1.17(s,2H).HRMS(ESI,m/z)calcd for C26H32ClN9O2[M+H]+,538.2446;found 538.2470.
实施例52
N6-{4-氟-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例52)的制备
参考制备实施例51的方法,将g步骤中3-溴-4-氯苯腈原料等比例替换为3-溴-4-氟苯腈,即得实施例52.1H NMR(600MHz,DMSO-d6)δ12.65–11.94(m,1H),10.21(s,1H),8.09(s,1H),7.34(s,1H),6.98–6.34(m,4H),5.06(s,1H),4.62(s,1H),4.44(s,2H),3.97(d,J=8.2Hz,2H),3.78(s,2H),3.48(t,J=11.6Hz,2H),3.39–3.17(m,4H),2.21(d,J=31.7Hz,3H),2.11(dt,J=11.9,8.2Hz,2H),1.76(d,J=10.8Hz,2H),1.44–1.37(m,2H).HRMS(ESI,m/z)calcd for C26H32FN9O2
[M+H]+,522.2741;found 522.2765.
实施例53
N6-{4-氟-3-[(四氢吡喃-3-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例53)的制备
参考制备实施例52的方法,将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为四氢吡喃-3-胺,即得实施例53.1H NMR(600MHz,DMSO-d6)δ12.07(s,1H),10.28(s,1H),8.12(d,J=13.4Hz,1H),7.43(s,1H),7.00–6.94(m,1H),6.80(d,J=7.9Hz,1H),6.73–6.31(m 2H),5.43(s,1H),4.67(s,1H),4.48(s,2H),4.01(d,J=8.4Hz,2H),3.82(d,J=7.1Hz,2H),3.70(d,J=5.2Hz,1H),3.59–3.49(m,4H),2.23(s,3H),2.15(d,J=9.0Hz,4H),1.81(d,J=11.7Hz,2H).HRMS(ESI,m/z)calcd for C25H30FN9O2[M+H]+,508.2585;found 508.2611.
实施例54
2-{[2-氟-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇(实施例54)的制备
参考制备实施例53的方法,将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为氧杂环丁烷-3-胺,即得实施例54.1H NMR(600MHz,DMSO-d6)δ12.77–11.82(m,1H),10.80–9.60(m,1H),8.03(s,1H),7.34(s,1H),6.92(dd,J=11.4,8.5Hz,1H),6.85–6.22(m,3H),4.77(s,1H),4.73(s,1H),4.64(s,1H),4.43(s,2H),3.97(dd,J=10.9,3.7Hz,2H),3.47(dd,J=31.9,20.3Hz,4H),2.19(s,3H),2.12(dt,J=11.6,8.4Hz,2H),1.78(d,J=12.4Hz,2H),1.07(s,3H).HRMS(ESI,m/z)calcd for C24H30FN9O2[M+H]+,496.2585;found 496.2610.
实施例55
2-{[2-氯-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇(实施例55)的制备
参考制备实施例51的方法,将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为氧杂环丁烷-3-胺,即得实施例55.1H NMR(600MHz,DMSO-d6)δ12.78–11.77(m,1H),10.16(s,1H),8.07(s,1H),7.39(s,1H),7.16(d,J=8.0Hz,1H),6.81(s,1H),6.74–6.16(m,2H),4.85(s,1H),4.71(s,1H),4.64(d,J=10.9Hz,1H),4.45(s,2H),3.97(d,J=8.1Hz,2H),3.49(d,J=11.7Hz,2H),3.42(s,2H),2.19(s,3H),2.14–2.08(m,2H),1.77(d,J=11.3Hz,2H),1.07(s,3H).HRMS(ESI,m/z)calcd for C24H30ClN9O2[M+H]+,512.2289;found 512.2312.
实施例56
N6-[(3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例56)的制备
参考制备实施例52的方法,将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为乙醇胺,即得实施例56.1H NMR(600MHz,DMSO-d6)δ12.73–11.76(m,1H),10.13(s,1H),8.18–7.76(m,1H),7.26(s,1H),6.64–6.23(m,4H),5.66(s,1H),4.63(s,1H),4.36(s,2H),4.07–4.04(m,2H),3.97(dd,J=11.0,3.3Hz,2H),3.50(t,J=11.5Hz,2H),3.22(s,2H),2.19(s,3H),2.12(dt,J=11.9,8.1Hz,2H),1.78(d,J=11.0Hz,2H).HRMS(ESI,m/z)calcd for C23H27N9O2[M+H]+,462.2366;found 462.2386.
实施例57
N4-(5-甲基-1H-吡唑-3-基)-N6-((4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例57)的制备
参考制备实施例52的方法,将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为2-(甲氨基)乙基-1-醇,即得实施例57.1H NMR(600MHz,DMSO-d6)δ12.80–11.78(m,1H),10.87–9.78(m,1H),8.49–7.72(m,1H),7.27(s,1H),6.76(s,1H),6.57(d,J=5.9Hz,2H),4.75–4.60(m,1H),4.40–4.36(m,2H),4.17(s,2H),3.98(dd,J=11.0,3.0Hz,2H),3.52–3.45(m,2H),3.38(dd,J=6.6,4.0Hz,2H),2.93–2.52(m,3H),2.24–2.07(m,5H),1.78(d,J=11.3Hz,2H).HRMS(ESI,m/z)calcd for C24H29N9O2[M+H]+,476.2522;found476.2541.
实施例58
N6-{4-氟-3-[(2-甲氧基乙基)甲氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例58)的制备
参考制备实施例52的方法,将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为2-甲氧基-N-甲基乙基-1-胺,即得实施例58.1H NMR(600MHz,DMSO-d6)δ12.01(s,1H),10.23(s,1H),8.06(s,1H),7.42(s,1H),7.11–6.51(m,4H),4.64(s,1H),4.47(s,2H),3.97(d,J=8.6Hz,2H),3.49(d,J=11.2Hz,2H),3.43(s,3H),3.24(s,2H),3.16(s,3H),2.82(d,J=49.5Hz,2H),2.22–2.08(m,5H),1.77(d,J=11.1Hz,2H).HRMS(ESI,m/z)calcd for C25H32FN9O2[M+H]+,510.2741;found 510.2764.
实施例59
N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-N6-((2,3,4,5-四氢苯并[b][1,4]氧杂氮杂-7-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例59)的制备
参考制备实施例52的方法,将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为2-甲氧基-N-甲基乙基-1-胺,即得实施例59.1H NMR(600MHz,DMSO-d6)δ12.72–11.75(m,1H),10.70–9.71(m,1H),8.00(s,1H),7.21(s,1H),6.81–6.00(m,4H),5.74–5.09(m,1H),4.56(s,1H),4.32(s,2H),3.92–3.81(m,4H),3.42(d,J=10.5Hz,2H),2.97(s,2H),2.16–2.02(m,5H),1.77–1.68(m,4H).HRMS(ESI,m/z)calcd for C24H29N9O2[M+H]+,476.2522;found 476.2535.
实施例60采用如下路线进行制备:
3-溴-4,6-二氯-1H-吡唑并[3,4-d]嘧啶(14)的合成
将中间体3(0.30g,1.59mmol)溶于8mL乙腈中,再加入NBS(0.31g,1.75mmol),加热至70℃反应10h。TLC监测(PE:EA=4:1)原料反应完毕,待反应冷却至室温,旋干溶剂,经柱层析(PE:EA=20:1)得白色固体,产率94%。
3-溴-4,6-二氯-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶(15)的合成
将中间体14(0.10g,0.38mmol)、四氢-2H-吡喃-4-醇(0.04g,0.40mmol)、三苯基膦(0.11g,0.42mmol)溶于17mL四氢呋喃中,再缓慢加入DIAD 0.096mL,室温反应6h。TLC监测(PE:EA=4:1)原料反应完毕,待反应冷却至室温,旋干溶剂,经柱层析(PE:EA=20:1)得白色固体,产率48%。
3-溴-6-氯-N-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(16)的合成
将中间体15(0.02g,0.06mmol)溶于3mL DMF中,再依次5-甲基-1H-吡唑-3-胺(0.006g,0.06mmol)、N,N-二异丙基乙胺(0.014mL,0.08mmol)、碘化钾(0.012g,0.07mmol),后65℃反应1h。TLC检测(DCM:MeOH=15:1),原料反应完全,待反应冷却至室温,加入水30mL,析出白色沉淀,抽滤,得到白色固体,产率88%。
3-溴-N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例60)的制备
将中间体16(0.08g,0.19mmol)溶于1.5mL异丙醇中,再加入2,4-二氟苄胺(0.028mL,0.24mmol)、三乙胺0.053mL,后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH=10:1)原料反应完毕,待反应冷却至室温,旋干溶剂,经柱层析(DCM:MeOH=40:1)得白色固体,产率46%。1H NMR(600MHz,DMSO-d6)δ12.15(s,1H),8.05–7.84(m,2H),7.55–7.31(m,1H),7.19(s,1H),7.01(t,J=7.5Hz,1H),6.84–6.02(m,1H),4.64(s,1H),4.53(d,J=41.9Hz,2H),3.97(d,J=8.5Hz,2H),3.48(t,J=11.6Hz,2H),2.19(d,J=54.5Hz,3H),2.05(s,2H),1.80(d,J=35.1Hz,2H).HRMS(ESI,m/z)calcd for C21H21BrF2N8O[M+H]+,519.1068;found 519.1095.
实施例61:本发明部分产物的体外酶抑制活性研究
实验材料:
Eu Kinase Binding Assay试剂盒(包含Kinase Tracer 236、Eu-Anti-GST Antibody、激酶缓冲溶液(1X Kinase Buffer A)),384浅孔板,重组人PLK4蛋白(aa 1-836,含一个GST tag)。
重组人PLK4蛋白激酶浓度50ng/μL(Thermo Scientific:PV6395),蒸馏水,DMSO。
实验方法:
首先将上述实施例制备化合物样品用DMSO配成20mM的溶液,之后根据测试需要,再用激酶缓冲溶液(1X Kinase Buffer A))稀释成200μM、40μM、10μM、1.6μM、0.32μM、0.064μM、0.0128μM、0.00256μM、0.000512、0.0001024μM;后向384孔板加入化合物样品(4μL),再加入将8μL含重组人PLK4激酶(浓度为50ng/μL)和Eu-Anti-GST Antibody的激酶缓冲溶液、4μL含Tracer 236的激酶缓冲溶液,后在室温下孵育60分钟,读板。
结果评定方法:通过添加Eu标记抗体检测激酶“示踪剂”结合。示踪剂和抗体与激酶的结合导致高度的FRET,反之使用激酶抑制因子代替示踪剂会造成FRET丢失。铕供体由一个带30nm光栅的340nm激发滤镜激发,使用中心在665纳米处、带通为10纳米的滤光片,以检测转移至Alexa Fluor 647示踪剂的能量。然后这一信号被替代为铕的峰值激发,这是使用一个615nm,10nm光栅的滤镜完成的。使用665纳米信号除以615纳米信号来计算“发射比”。所以每一个孔板反应的HTRF信号(665/615)比值被计算。结果被表征为Delta F(DF%):
计算抑制率(%activity):在不加化合物样品的情况下,激酶活性的DF%被定义为100%。当加入化合物样品后,激酶活性率:
计算IC50:在加入化合物的情况下,激酶活性的DF%被绘制成Y-轴,化合物的浓度对数值被绘制成X-轴。IC50值是通过数据拟合成S-型计量反应曲线获得(表1)。
表1部分实施例化合物得IC50值
实施例 | <![CDATA[IC<sub>50</sub>(nM)]]> | 实施例 | <![CDATA[IC<sub>50</sub>(nM)]]> |
实施例2 | 453.9 | 实施例3 | 483.9 |
实施例4 | 206.0 | 实施例5 | 87.1 |
实施例6 | 5.5 | 实施例7 | 23.3 |
实施例8 | 0.3 | 实施例9 | 1.1 |
实施例10 | 0.1 | 实施例11 | 22.1 |
实施例12 | 78.4 | 实施例13 | 10.5 |
实施例14 | 6.5 | 实施例15 | 4.0 |
实施例16 | 0.2 | 实施例17 | 3.8 |
实施例18 | 2.7 | 实施例19 | 47.9 |
实施例20 | 7.9 | 实施例21 | 7.0 |
实施例22 | 0.7 | 实施例23 | 26.1 |
实施例24 | 2.1 | 实施例25 | 20.2 |
实施例26 | 27.6 | 实施例27 | 3.7 |
实施例28 | 1.1 | 实施例29 | 241.3 |
实施例30 | 117.9 | 实施例32 | 3.6 |
实施例35 | 20.7 | 实施例37 | 1.8 |
实施例39 | 282.1 | 实施例40 | 0.7 |
实施例43 | 13.9 | 实施例44 | 24.5 |
实施例45 | 35.4 | 实施例46 | 21.7 |
实施例47 | 41.1 | 实施例48 | 25.2 |
实施例49 | 21.8 | 实施例50 | 55.4 |
实施例51 | 24.2 | 实施例52 | 44.7 |
实施例53 | 42.1 | 实施例54 | 24.3 |
实施例55 | 8.8 | 实施例56 | 11.5 |
实施例57 | 27.1 | 实施例58 | 90.7 |
实施例59 | 38.2 | 实施例60 | 8.6 |
由上述可见本发明部分化合物具有明显的体外酶抑制活性,尤其化合物8、9、10、16、17、18、22、24、27、28、32、37和40所示化合物其体外酶抑制活性尤其突出,IC50(nM)均在4.0以下,优于实验阳性对照centrinone。
Claims (10)
1.一种吡唑并嘧啶衍生物,其特征在于:衍生物为通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;通式(I)所示化合物如下:
其中,R1选自氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟烷基、未取代或被1-4个可相同或不同的Ra取代的芳基、未取代或被1-2个下述基团取代的C3-C7环烷基、含1-2个杂原子的C3-C7脂肪环;下述基团为C1-C4烷基或氨基;所述环、含杂原子脂肪环中还可含1-2个羰基,所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合;
R2选自氢、卤素、氰基、甲酰胺、C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、含杂原子的C3-C6脂肪环;
A选自:
R3选自氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C4烷氧基,未取代或被1-4个可相同或不同的Ra取代的芳基;
C环选自未取代或被1-4个可相同或不同的Ra取代的芳基;
Ra选自卤素、C1-C4烷基或C1-C4卤代烷基;
B选自含最多2个杂原子的C5-C7脂肪环或NHRc;
Rc选自未取代或被1-4个可相同或不同的Rb取代的:芳基、芳基甲基、芳基乙基、含1-2个杂原子的C5-C7脂肪环或C5-C7脂肪杂环并苯基甲基;
Rb选卤素,氰基,甲砜乙基氨基,C1-C4烷氧基,C1-C4烷氨基,C3-C7环烷基,含最多2个杂原子的C4-C7脂肪环,NRdRe;
Rd选自C1-C4烷氧基C1-C4烷基、C1-C6羟烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、C1-C4烷基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;芳基为苯基,吡啶基,嘧啶基;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜。
当Rc选自C5-C7脂肪杂环并苯基甲基,且杂原子为N时,氮原子还可进一步被C1-C4烷基取代。
2.按权利要求1所述的吡唑并嘧啶衍生物,其特征在于:所述衍生物通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,R1选自氢,甲基,异丙基,三氟乙基,羟叔丁基,环己基,未取代或被1-4个可相同或不同的Ra取代的芳基,含1-2个杂原子的C3-C7脂肪环;所述含杂原子脂肪环中还可含1-2个羰基,所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合;
R2选自氢,卤素或甲酰胺;
A环部分选自
R3选自氢,卤素,甲基,乙基,环丙基,叔丁基,未取代或被1-4个可相同或不同的Ra取代的芳基;
C环选自未取代或被1-4个可相同或不同的Ra取代的芳基;
Ra选自卤素,C1-C4烷基,C1-C4卤代烷基;
B选自哌嗪基或NHRc;
Rc选自未取代或被1-4个可相同或不同的Rb取代的:苯基,吡啶基,嘧啶基,含1-2个杂原子的C5-C7脂肪环,C5-C7脂肪杂环并苯基甲基;
Rb选自卤素,氰基,甲砜乙基氨基,甲氧基,吗啉基,硫代吗啉基,C1-C4烷基、C1-C4烷氨基,NRdRe;
Rd选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、C1-C4烷基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜;
当Rc选自C5-C7脂肪杂环并苯基甲基,且杂原子为N时氮原子其还可进一步被C1-C4烷基取代。
3.按权利要求2所述的吡唑并嘧啶类衍生物,其特征在于:所述衍生物通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,R1选自氢,甲基,异丙基,三氟乙基,羟叔丁基,环己基,对氟苯基,4-四氢吡喃,2-四氢吡喃,4-六氢吡啶;
R2选自氢,卤素或甲酰胺;
A环部分选自
R3选自氢,卤素,甲基,乙基,环丙基,叔丁基,未取代或被1-4个可相同或不同的Ra取代的苯基;
C环选自未取代或被1-4个可相同或不同的Ra取代的苯基;
Ra选自卤素,C1-C4烷基,C1-C4卤代烷基;
B选自哌嗪基,
未取代或被1-4个可相同或不同的Rb取代的:4-六氢吡啶氨基,3-四氢吡咯氨基,苯氨基,苯甲氨基,1-(2,4-二氟苯基)乙氨基,2-苯基乙氨基;
Rb选自卤素,氰基,甲砜乙基氨基,甲氧基,吗啉基,硫代吗啉基,C1-C4烷基,C1-C4烷氨基,NRdRe
Rd选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、甲基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
4.按权利要求3所述的吡唑并嘧啶类衍生物,其特征在于:所述衍生物通式(I)所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,R1选自氢,甲基,异丙基,三氟乙基,羟叔丁基,环己基,对氟苯基,4-四氢吡喃,2-四氢吡喃,4-六氢吡啶;
R2选自氢,溴;
A环部分选自
R3选自氢,卤素,甲基,乙基,环丙基,叔丁基,苯基,对氟苯基;
C环选自苯基,3-氯苯基;
B选自哌嗪基,
Rb选自氯,溴,双氟,三氟,氰基,甲砜乙基氨基,甲氧基,吗啉基,硫代吗啉基,C1-C4烷基,C1-C4烷氨基,NRdRe;
Rd选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环;
Re选自氢、甲基;
上述含1-2个杂原子的脂肪环时,杂原子为氮,氧或硫;
当Rd选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
5.按权利要求4所述的吡唑并嘧啶类衍生物,其特征在于:所述衍生物为:
N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1H-吡唑[3,4-d]嘧啶-4-胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-(吡咯烷-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-苯基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-苯乙基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3-溴苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-溴苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-(2,4,6-三氟苄基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
4-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苄腈;
N6-(4-甲氧基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-,二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
1-{6-[(4-氯苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇;
1-{6-[(2,4-二氟苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇;
1-环己基-N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
1-环己基-N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-[(3,5-二氟吡啶-2-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-1-甲基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-1-甲基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-1-异丙基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-1-异丙基-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-1-(4-氟苯基)-N4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯苄基)-N4-(5-甲基-1H-吡唑-3-基)-1H-(2,2,2,-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-苯基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-环丙基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-叔丁基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-[5-(4-氟苯基)-1H-吡唑-3-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-[5-甲基噻唑-2-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-苯基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-环丙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-叔丁基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-[5-(4-氟苯基)-1H-吡唑-3-基]-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-乙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟苄基)-N4-(5-氯-1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(3,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氯-3-{[2-(甲磺酰基)乙基]氨基}苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
4-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢-2H-噻喃-1,1-二氧化物;
3-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢噻吩-1,1-二氧化物;
N6-(4-氟-3-吗啉代苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-(4-氟-3-硫代吗啉代苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氯-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氟-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氟-3-[(四氢吡喃-3-基)氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
2-{[2-氟-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇;
2-{[2-氯-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇;
N6-[(3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-N6-((4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N6-{4-氟-3-[(2-甲氧基乙基)甲氨基]苄基}-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-N6-((2,3,4,5-四氢苯并[b][1,4]氧杂氮杂-7-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺;
3-溴-N6-(2,4-二氟苄基)-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺。
6.按权利要求1-5任意一项所述吡唑并嘧啶衍生物的应用,其特征在于:所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
7.按权利要求1-5任意一项所述吡唑并嘧啶衍生物的应用,其特征在于:所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或抗肿瘤药物中的应用。
8.一种药用组合物,其特征在于:包含权利要求1至6中任何一项的通式I所示的化合物及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
9.按权利要求7所述药用组合物的应用,其特征在于:所述组合物在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
10.按权利要求7所述药用组合物的应用,其特征在于:所述组合物在制备预防或抗肿瘤药物中的应用。
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