CN109897036B - ***并吡啶类化合物及其制备方法和用途 - Google Patents
***并吡啶类化合物及其制备方法和用途 Download PDFInfo
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- CN109897036B CN109897036B CN201910200914.5A CN201910200914A CN109897036B CN 109897036 B CN109897036 B CN 109897036B CN 201910200914 A CN201910200914 A CN 201910200914A CN 109897036 B CN109897036 B CN 109897036B
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- alkyl
- pharmaceutically acceptable
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- methyl
- stereoisomers
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- -1 Triazolopyridine compound Chemical class 0.000 title abstract description 75
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 23
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 5
- 230000019491 signal transduction Effects 0.000 claims abstract description 4
- 230000009385 viral infection Effects 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- 150000008523 triazolopyridines Chemical class 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical group CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 14
- 238000006467 substitution reaction Methods 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 208000018359 Systemic autoimmune disease Diseases 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 206010061311 nervous system neoplasm Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000001204 Hashimoto Disease Diseases 0.000 claims description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 2
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010029240 Neuritis Diseases 0.000 claims description 2
- 206010036105 Polyneuropathy Diseases 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 208000004732 Systemic Vasculitis Diseases 0.000 claims description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000019629 polyneuritis Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 201000000849 skin cancer Diseases 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 claims description 2
- 201000005787 hematologic cancer Diseases 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 201000011682 nervous system cancer Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
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- 102100040678 Programmed cell death protein 1 Human genes 0.000 abstract description 6
- 101710089372 Programmed cell death protein 1 Proteins 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 102000004169 proteins and genes Human genes 0.000 abstract description 2
- 108090000623 proteins and genes Proteins 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 30
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 16
- 239000011259 mixed solution Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- DPGSPRJLAZGUBQ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane Substances CC1(C)OB(C=C)OC1(C)C DPGSPRJLAZGUBQ-UHFFFAOYSA-N 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- BABPEUPHRVFJIJ-UHFFFAOYSA-N 6-[(2-hydroxyethylamino)methyl]-N-(2-methyl-3-phenylphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide Chemical compound OCCNCC=1C=C(C=2N(C=1)C=NN=2)C(=O)NC=1C(=C(C=CC=1)C1=CC=CC=C1)C BABPEUPHRVFJIJ-UHFFFAOYSA-N 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- NEZGSPBXJRTLBH-UHFFFAOYSA-N OC(=O)c1cc(Br)cn2cnnc12 Chemical compound OC(=O)c1cc(Br)cn2cnnc12 NEZGSPBXJRTLBH-UHFFFAOYSA-N 0.000 description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000013024 dilution buffer Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
- IILVSKMKMOJHMA-UHFFFAOYSA-N 3-bromo-2-methylaniline Chemical compound CC1=C(N)C=CC=C1Br IILVSKMKMOJHMA-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 5
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052740 iodine Chemical group 0.000 description 4
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- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
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- NKTREENIJKJCEC-UHFFFAOYSA-N 6-formyl-N-(2-methyl-3-phenylphenyl)-[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide Chemical compound C(=O)C=1C=C(C=2N(C=1)C=NN=2)C(=O)NC=1C(=C(C=CC=1)C1=CC=CC=C1)C NKTREENIJKJCEC-UHFFFAOYSA-N 0.000 description 3
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
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Abstract
本发明属于医药技术领域,涉及***并吡啶类化合物及其制备方法和用途。具体涉及具有通式Ⅰ结构的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中R1、R2、R3、R4如权利要求和说明书所述。本发明所述的化合物及其立体异构体以及药学上可接受的盐和含有该化合物的组合物均对PD‑1/PD‑L1蛋白/蛋白相互作用具有显著抑制作用,能够治疗癌症、病毒感染等多种疾病,因此,可用于制备预防和/或治疗与PD‑1/PD‑L1信号通路有关的疾病的药物。
Description
技术领域:
本发明属于医药技术领域,涉及***并吡啶类化合物及其立体异构体以及药学上可接受的盐,它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该类化合物及其立体异构体以及药学上可接受的盐在制备治疗与PD-1/PD-L1信号通路有关的疾病如癌症、感染性疾病、自身免疫性疾病的药物方面的用途。
背景技术:
免疫治疗是近年来肿瘤治疗的热点领域,于2013年被《Science》评为十大科学突破之首。程序性死亡受体1(programmed death 1,PD-1)是T细胞表面受体,当其与程序性死亡配体1(PD-L1)结合时产生负性免疫调节信号,从而抑制T细胞活化、增殖以及白细胞介素2(IL-2)、干扰素γ(IFN-γ)等细胞因子的释放(Eur.J.Immunol.,2002,32(3),634-643.)。大量研究表明,机体内的肿瘤微环境会诱导浸润的T细胞中PD-1表达上调,同时肿瘤细胞高表达PD-L1,导致PD-1/PD-L1介导的信号通路持续激活,肿瘤特异性CD8+T细胞功能被抑制以至于不能识别或杀伤肿瘤细胞,即肿瘤细胞实现免疫逃逸。因此靶向阻断PD-1/PD-L1蛋白/蛋白相互作用,可以恢复T细胞功能,使其重新识别并杀伤肿瘤细胞。
基于PD-1/PD-L1的免疫疗法备受瞩目,目前已被批准上市的PD-1/PD-L1单抗包括默沙东的Pembrolizumab、百时美施贵宝的Nivolumab、默克的Avelumab、阿斯利康的Durvalumab、罗氏的Atezolizumab等。上述单抗已在多种肿瘤类型的治疗中显示出明显疗效,被批准的适应症包括黑色素瘤、非小细胞肺癌、胃癌、尿路上皮癌等。随着临床研究的开展,单抗药物有望在更多的适应症中实现突破。
虽然单抗药物在临床治疗中显示出优势,但也存在明显的缺陷如制备和纯化困难、生产成本高昂;易被蛋白酶分解,半衰期短;不能口服,只能注射给药;单抗的免疫原性导致严重的毒副作用。相比于生物大分子药物,小分子化合物经化学修饰后药物代谢动力学性质可控,另外在生产工艺、给药方式等方面也具有更大的探索与优化空间。因此,开发靶向PD-1/PD-L1蛋白/蛋白相互作用的小分子抑制剂是实现免疫治疗的可行性选择。
目前小分子PD-1/PD-L1抑制剂研发处于早期阶段,因此,迫切需要开发具有新颖化学结构的小分子PD-1/PD-L1抑制剂。
发明内容:
本发明人在参考文献基础上,设计并合成了一系列***并吡啶类化合物。活性研究结果表明,该类化合物可以显著抑制PD-1/PD-L1蛋白/蛋白相互作用。
本发明涉及通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,
其中,
R5独立地选自卤素、(C1-C4)烷基、(C1-C4)烷氧基、氰基、羟基、羧基、氨基;
R2选自卤素、氰基、(C1-C4)烷基;
R3、R4独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基;所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基可任选被1-3个R6取代;
或者R3、R4和与它们相连的氮原子一起形成一个3-7元的含氮杂环;所述含氮杂环可任选被1-3个R7取代;
R6独立地选自氢、卤素、羟基、羧基、氨基、(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基、(C1-C4)酰基;
R7独立地选自氢、羟基、羧基、氨基、氨甲酰基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧甲酰基、羟基(C1-C4)烷基。
本发明优选涉及通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,
其中,
R2选自卤素、氰基、(C1-C4)烷基;
R3、R4独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基;所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基可任选被1-3个R6取代;
或者R3、R4和与它们相连的氮原子一起形成一个3-7元的含氮杂环;所述含氮杂环可任选被1-3个R7取代;
R6独立地选自氢、卤素、羟基、羧基、氨基、(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基、(C1-C4)酰基;
R7独立地选自氢、羟基、羧基、氨基、氨甲酰基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧甲酰基、羟基(C1-C4)烷基。
本发明更加优选涉及通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中,
R2选自卤素、氰基、甲基;
R3、R4独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基;所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基可任选被1-3个R6取代;
或者R3、R4和与它们相连的氮原子一起形成一个5-6元的含氮杂环;所述含氮杂环可任选被1-3个R7取代;
R6独立地选自氢、卤素、羟基、羧基、氨基、(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基、(C1-C4)酰基;
R7独立地选自氢、羟基、羧基、氨基、氨甲酰基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧甲酰基、羟基(C1-C4)烷基。
本发明特别优选涉及通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中,
R2选自氯、氰基、甲基;
本发明通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐优选自以下化合物,但这些化合物并不意味着对本发明的任何限制:
此外,本发明还包括本发明化合物的前药。本发明化合物的前药是通式Ⅰ的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
以上所述的通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,所述的药学上可接受的盐包括与无机酸、有机酸、碱金属离子形成的盐;所述的无机酸选自:盐酸、氢溴酸、氢氟酸、硫酸、磷酸;所述的有机酸选自:琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸或对甲苯磺酸;所属的碱金属离子选自锂离子、钠离子或钾离子。
本发明中“卤素”是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“含氮杂环”是指含有氮原子的单环或多环的环状体系,环状体系是非芳香性或芳香性的。
本发明可以含有上式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐作为活性成分,与药学上可接受的载体或赋形剂混合制备成组合物。所述载体或赋形剂包括本领域公知的稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂等。稀释剂包括但不限于淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、磷酸氢钙等;润湿剂包括水、乙醇、异丙醇等;粘合剂包括但不限于淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、***胶浆、明胶浆、羧甲基纤维素钠、羟丙基甲基纤维素、乙基纤维素、聚乙二醇等;崩解剂包括但不限于干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、十二烷基磺酸钠等;润滑剂和助流剂包括但不限于滑石粉、二氧化硅、聚乙二醇等。
本发明的药用组合物可配制成若干种剂型,所述剂型包括但不限于注射剂、片剂、胶囊剂等。
本发明的***并吡啶类化合物及其立体异构体以及药学上可接受的盐可以与其他活性成分组合使用,从而达到更优的治疗效果。
本发明还提供了通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。所述的癌症选自肺癌、皮肤癌、血液肿瘤、胶质瘤、消化***肿瘤、乳腺癌、淋巴瘤、神经***肿瘤、黑色素瘤;所述的感染性疾病选自细菌感染、病毒感染;所述的自身免疫性疾病选自器官特异性自身免疫病、***性自身免疫病。其中,所述器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、溃疡性结肠炎、急性特发性多神经炎,所述的***性自身免疫病包括类风湿性关节炎、***性红斑狼疮、***性血管炎、自身免疫性溶血性贫血。
本发明的积极进步效果在于:本发明的***并吡啶类化合物具有新颖的化学结构,并在体外研究中对PD-1/PD-L1蛋白/蛋白相互作用具有很高的抑制活性,可用于癌症等多种疾病的治疗和预防。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。
下面的合成路线概括并描述了本发明的式Ⅰ衍生物的制备,所有的原料都是通过这些流程中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过这些流程中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些流程中应用的全部可变因数如权利要求中的定义。
(a)以取代的苯胺衍生物1和苯、取代苯或杂芳环硼酸或硼酸酯为原料,通过Suzuki偶联反应得到中间体2;
(b)以5-溴-2-氯烟酸甲酯3为原料,与水合肼反应得到中间体4;
(c)以中间体4为原料,与原甲酸三甲酯反应得到***并吡啶中间体5;
(d)以中间体5为原料,在碱性条件下水解反应得到羧酸中间体6;
(e)以中间体6和中间体2为原料,在缩合剂条件下经过酰胺化反应得到中间体7;或由中间体6制备酰氯再与中间体2反应得到中间体7;
(f)以中间体7为原料,与乙烯基硼酸频哪醇酯通过Suzuki偶联反应得到中间体8;
(g)以中间体8为原料,在高碘酸钠等氧化条件下制备得到醛类化合物中间体9;
(h)以中间体9为原料,与胺类化合物HNR3R4缩合及氰基硼氢化钠或三乙酰氧基硼氢化钠作用下还原得到通式Ⅰ的目标化合物。
所述的R1、R2、R3、R4的定义如权利要求所述。在中间体1中,当R2为(C1-C4)烷基时,X为氯、溴或碘;当R2为氰基时,X为溴或碘;当R2为氯时,X为溴或碘;当R2为溴时,X为碘。
本发明的具有通式Ⅰ的***并吡啶类化合物均可按照上述反应路线制备得到。
具体实施方式:
在以下的实施例中,描绘了制备部分所述化合物的方法。应了解,以下方法及所属领域的普通技术人员已知的其他方法均可适用于本发明所述的所有化合物的制备。实施例旨在阐述而不是限制本发明的范围。
实施例1:6-(((2-羟乙基)氨基)甲基)-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-1)
步骤1:2-甲基-[1,1'-联苯]-3-胺
室温下,将3-溴-2-甲基苯胺(15g,0.081mol)、苯硼酸(12.2g,0.1mol)、醋酸钯(1.82g,8.1mmol)、碳酸钾(24.9g,0.18mol)加入至乙醇/水的混合溶液中(体积比1:1,100mL),于N2保护下搅拌反应5小时。反映完毕后,抽滤,蒸干滤液,柱层析分离得浅黄色固体12.6g,收率85.2%。
步骤2:5-溴-2-肼基烟酸甲酯
室温下,将5-溴-2-氯烟酸甲酯(13.55g,0.054mol)溶于1,4-二氧六环(150mL)中,加入水合肼(6g,0.096mol),60℃下反应3小时。反应完毕后,向溶液中加入50mL水,搅拌0.5小时,抽滤,干燥,得黄色固体10.2g,收率为77.4%。
步骤3:6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸甲酯
将5-溴-2-肼基烟酸甲酯(5g,0.02mol)溶于原甲酸三甲酯(25mL)中,于100℃反应12小时。将反应液冷却至室温,搅拌0.5小时,抽滤,水洗滤饼,干燥,得白色固体4.6g,收率为88.5%。
步骤4:6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸
室温下,将6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸甲酯(1g,0.004mol)溶于甲醇(5mL)中,加入1mol/L的NaOH水溶液(10mL),升温至回流反应0.5小时。将反应液冷却至室温,蒸除甲醇,向体系中加入少量水,用稀盐酸调节pH至5-6,搅拌20分钟,抽滤得白色固体0.67g,收率为70.9%。
步骤5:6-溴-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸(2.18g,9mmol)、2-甲基-[1,1'-联苯]-3-胺(1.65g,9.5mmol)、HATU(5.13g,13.5mmol)、N,N-二异丙基乙胺(2.32g,18mmol)溶于N,N-二甲基甲酰胺(15mL)中,搅拌反应15小时。反应完毕后,将反应液倒入大量水中,搅拌20分钟,抽滤,水洗滤饼,干燥,柱层析分离得黄色固体2.97g,收率为81.3%。
步骤6:N-(2-甲基-[1,1'-联苯]-3-基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(2.3g,5.7mmol)、乙烯基硼酸频哪醇酯(0.96g,6.2mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(0.42g,0.57mmol)、碳酸铯(3.4g,10.3mmol)溶于1,4-二氧六环/水(体积比3:1,10mL)的混合溶液中,N2保护下90℃反应2小时。反应液冷却至室温,用乙酸乙酯萃取,蒸干有机层,柱层析分离得白色固体1.21g,收率为60%。
步骤7:6-甲酰基-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将N-(2-甲基-[1,1'-联苯]-3-基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.65g,1.8mmol)溶于1,4-二氧六环/水(体积比5:1,10mL)的混合溶液中,快速加入2%的OsO4水溶液(3.5mL),搅拌5分钟后加入高碘酸钠(1.54g,7.2mmol),室温搅拌反应9小时。抽滤,得浅黄色固体0.41g,收率为64.2%。
步骤8:6-(((2-羟乙基)氨基)甲基)-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(实施例1)
室温下,将6-甲酰基-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.08g,0.22mmol)溶于DMF中,加入乙醇胺(0.067g,1.1mmol)、冰醋酸(0.02g,0.33mmol),搅拌反应2小时。向体系中加入氰基硼氢化钠(0.07g,1.1mmol),25℃搅拌反应12小时。反应液中加水,用二氯甲烷萃取,蒸干溶剂,柱层析分离得白色固体0.032g,收率为35.6%。
ESI-MS m/z:402.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.20(s,1H),8.77(s,1H),8.56(d,J=1.3Hz,1H),8.20(d,J=7.9Hz,1H),7.48(t,J=7.3Hz,2H),7.43–7.29(m,4H),7.10(d,J=7.1Hz,1H),4.63(s,1H),3.99(s,2H),3.52(d,J=4.8Hz,2H),3.17(d,J=4.6Hz,1H),2.67(t,J=5.7Hz,2H),2.35(s,3H).
根据实施例1的合成方法,以6-甲酰基-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺为原料,通过与不同的胺类化合物反应,再经氰基硼氢化钠或三乙酰氧基硼氢化钠还原制备得到实施例2-9的化合物。
实施例2:6-(((2-羟乙基)(甲基)氨基)甲基)-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-2)
ESI-MS m/z:416.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.19(s,1H),8.75(s,1H),8.48(d,J=1.3Hz,1H),8.19(d,J=7.9Hz,1H),7.48(t,J=7.5Hz,2H),7.42–7.33(m,4H),7.09(d,J=7.3Hz,1H),4.51(t,J=5.4Hz,1H),3.72(s,2H),3.56(q,J=6.0Hz,2H),2.54(t,J=6.1Hz,2H),2.35(s,3H),2.24(s,3H).
实施例3:6-(((2,3-二羟基丙基)(甲基)氨基)甲基)-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-3)
ESI-MS m/z:446.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.20(s,1H),8.75(s,1H),8.48(s,1H),8.20(d,J=8.0Hz,1H),7.48(t,J=7.5Hz,2H),7.40(t,J=7.4Hz,1H),7.38–7.36(m,2H),7.34(d,J=7.9Hz,1H),7.09(d,J=7.5Hz,1H),4.54(br,2H),3.74(s,2H),3.69(dd,J=9.9,5.0Hz,1H),3.38(d,J=5.3Hz,1H),3.32(d,J=5.8Hz,1H),2.54(dd,J=12.8,4.6Hz,1H),2.40(dd,J=12.7,7.1Hz,1H),2.35(s,3H),2.25(s,3H).
实施例4:反-6-(((4-羟基环己基)氨基)甲基)-N-(2-甲基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-4)
ESI-MS m/z:456.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.14(s,1H),8.74(s,1H),8.53(s,1H),8.20(d,J=7.8Hz,1H),7.48(t,J=6.8Hz,2H),7.43–7.32(m,4H),7.10(d,J=7.1Hz,1H),4.47(s,1H),3.91(s,2H),3.43(s,1H),2.41(s,1H),2.35(s,3H),1.90(d,J=8.5Hz,2H),1.80(d,J=9.3Hz,2H),1.24(s,1H),1.18–1.03(m,4H).
实施例5:N-(2-甲基-[1,1'-联苯]-3-基)-6-(((2-氨磺酰基乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-5)
ESI-MS m/z:465.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.18(s,1H),8.75(s,1H),8.54(t,J=14.7Hz,1H),8.21(t,J=15.1Hz,1H),7.60–7.23(m,6H),7.09(d,J=7.4Hz,1H),6.82(s,2H),3.93(s,2H),3.19(t,J=7.1Hz,2H),2.92(t,J=7.1Hz,2H),2.35(s,3H),1.23(s,1H).
实施例6:N-(2-甲基-[1,1'-联苯]-3-基)-6-(((2-(甲磺酰胺基)乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-6)
ESI-MS m/z:479.2[M+H]+;
实施例7:((8-((2-甲基-[1,1'-联苯]-3-基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-丙氨酸(I-7)
ESI-MS m/z:430.2[M+H]+;
实施例8:((8-((2-甲基-[1,1'-联苯]-3-基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-L-丙氨酸(I-8)
ESI-MS m/z:430.2[M+H]+;
实施例9:(S)-3-羟基-4-(((8-((2-甲基-[1,1'-联苯]-3-基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)氨基)丁酸(I-9)
ESI-MS m/z:460.2[M+H]+;
实施例10:N-(2-氰基-[1,1'-联苯]-3-基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-10)
步骤1:3-氨基-[1,1'-联苯]-2-甲腈
室温下,将2-氨基-6-溴苯甲腈(15.88g,0.081mol)、苯硼酸(12.2g,0.1mol)、醋酸钯(1.82g,8.1mmol)、碳酸钾(24.9g,0.18mol)加入至乙醇/水的混合溶液中(体积比1:1,100mL),于N2保护下搅拌反应8小时。反映完毕后,抽滤,蒸干滤液,柱层析分离得白色固体12g,收率76.4%。
步骤2:6-溴-N-(2-氰基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸(5g,0.021mol)、3-氨基-[1,1'-联苯]-2-甲腈(3.88g,0.02mol)、HATU(11.8g,0.031mol)、N,N-二异丙基乙胺(5.42g,0.042mol)溶于N,N-二甲基甲酰胺(50mL)中,搅拌反应12小时。反应完毕后,将反应液倒入大量水中,搅拌30分钟,抽滤,水洗滤饼,干燥,柱层析分离得黄色固体6.94g,收率为79.2%。
步骤3:N-(2-氰基-[1,1'-联苯]-3-基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-N-(2-氰基-[1,1'-联苯]-3-基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(2.38g,5.7mmol)、乙烯基硼酸频哪醇酯(0.96g,6.2mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(0.42g,0.57mmol)、碳酸铯(3.4g,10.4mmol)溶于1,4-二氧六环/水(体积比3:1,20mL)的混合溶液中,N2保护下90℃反应3小时。反应液冷却至室温,用二氯甲烷萃取,蒸干有机层,柱层析分离得白色固体0.96g,收率为46.1%。
步骤4:N-(2-氰基-[1,1'-联苯]-3-基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将N-(2-氰基-[1,1'-联苯]-3-基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.66g,1.8mmol)溶于1,4-二氧六环/水(体积比5:1,15mL)的混合溶液中,快速加入2%的OsO4水溶液(3.5mL),搅拌10分钟后加入高碘酸钠(1.54g,7.2mmol),室温搅拌反应10小时。抽滤,得黄色固体0.51g,收率为77.2%。
步骤5:N-(2-氰基-[1,1'-联苯]-3-基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(实施例10)
室温下,将N-(2-氰基-[1,1'-联苯]-3-基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.08g,0.22mmol)溶于DMF中,加入乙醇胺(0.067g,1.1mmol)、冰醋酸(0.02g,0.33mmol),搅拌反应2小时。向体系中加入氰基硼氢化钠(0.07g,1.1mmol),25℃搅拌反应12小时。反应液中加水,用二氯甲烷萃取,蒸干溶剂,柱层析分离得白色固体0.025g,收率为27.3%。
ESI-MS m/z:413.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),9.17(s,1H),8.75(s,1H),8.41(d,J=1.2Hz,1H),8.19(d,J=7.7Hz,1H),7.49(m,2H),7.47–7.16(m,4H),7.10(d,J=7.6Hz,1H),4.67(s,1H),3.82(s,2H),3.55(d,J=4.8Hz,2H),3.21(d,J=4.7Hz,1H),2.67(m,2H).
根据实施例10的合成方法,以N-(2-氰基-[1,1'-联苯]-3-基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺为原料,通过与不同的胺类化合物反应,再经氰基硼氢化钠或三乙酰氧基硼氢化钠还原制备得到实施例11-14的化合物。
实施例11:((8-((2-氰基-[1,1'-联苯]-3-基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-丙氨酸(I-13)
ESI-MS m/z:441.2[M+H]+;
实施例12:((8-((2-氰基-[1,1'-联苯]-3-基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-丝氨酸(I-14)
ESI-MS m/z:457.2[M+H]+;
实施例13:((8-((2-氰基-[1,1'-联苯]-3-基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-苏氨酸(I-15)
ESI-MS m/z:471.2[M+H]+;
实施例14:(S)-N-(氰基-[1,1'-联苯]-3-基)-6-((2-(羟甲基)吡咯烷-1-基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-16)
ESI-MS m/z:453.2[M+H]+;
实施例15:N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-17)
步骤1:3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯胺
室温下,将3-溴-2-甲基苯胺(1.89g,10.21mmol)、2-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-4,4,5,5-四甲基-1,3,2--二杂氧环戊硼烷(4.02g,15.32mmol)、[1,1-双(二苯基磷)二茂铁]二氯化钯(0.74g,1.02mmol)、碳酸钾(4.23g,30.63mmol)加入至二氧六环/水的混合溶液中(体积比2:1,30mL),于N2保护下100度搅拌反应10小时。反映完毕后,抽滤,蒸干滤液,柱层析分离得白色固体1.53g,收率62.1%。
步骤2:6-溴-N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸(5g,0.021mol)、3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯胺(5.06g,0.021mol)、HATU(11.8g,0.031mol)、N,N-二异丙基乙胺(5.4g,0.042mol)溶于N,N-二甲基甲酰胺(50mL)中,搅拌反应12小时。反应完毕后,将反应液倒入大量水中,搅拌30分钟,抽滤,水洗滤饼,干燥,柱层析分离得淡黄色固体8.7g,收率为89.3%。
步骤3:N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(3g,6.5mmol)、乙烯基硼酸频哪醇酯(1.1g,7.2mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(0.48g,0.65mmol)、碳酸铯(3.81g,11.7mmol)溶于1,4-二氧六环/水(体积比3:1,30mL)的混合溶液中,N2保护下90℃反应3小时。反应液冷却至室温,用二氯甲烷萃取,蒸干有机层,柱层析分离得黄色固体1.61g,收率为60.2%。
步骤4:N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.62g,1.5mmol)溶于1,4-二氧六环/水(体积比5:1,15mL)的混合溶液中,快速加入2%的OsO4水溶液(3mL),搅拌10分钟后加入高碘酸钠(1.28g,6mmol),室温搅拌反应8小时。抽滤,干燥,得类白色固体0.52g,收率为83.7%。
步骤5:N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(实施例15)
室温下,将N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.09g,0.22mmol)溶于二氯甲烷中(8mL),加入乙醇胺(0.067g,1.1mmol)、冰醋酸(0.02g,0.33mmol),搅拌反应2小时。向体系中加入三乙酰氧基硼氢化钠(0.07g,1.1mmol),25℃搅拌反应12小时。反应液中加水,用二氯甲烷萃取,蒸干溶剂,柱层析分离得白色固体0.04g,收率为17.5%。
ESI-MS m/z:460.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.37(s,1H),9.16(s,1H),8.74(s,1H),8.52(s,1H),8.15(d,J=7.9Hz,1H),7.30(t,J=7.5Hz,1H),7.05(d,J=7.4Hz,1H),6.93(d,J=8.1Hz,1H),6.85–6.78(m,2H),4.52(s,1H),4.29(s,4H),3.92(s,2H),3.49(d,J=4.9Hz,2H),2.61(t,J=4.9Hz,2H),2.35(s,3H),1.23(s,1H).
根据实施例15的合成方法,以N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺为原料,通过与不同的胺类化合物反应,再经与三乙酰氧基硼氢化钠还原制备得到实施例16-21的化合物。
实施例16:N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-(((2-羟乙基)(甲基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-18)
ESI-MS m/z:474.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.37(s,1H),9.20(s,1H),8.75(s,1H),8.47(s,1H),8.14(d,J=7.8Hz,1H),7.30(t,J=7.7Hz,1H),7.05(d,J=7.4Hz,1H),6.93(d,J=8.1Hz,1H),6.85–6.79(m,2H),4.50(s,1H),4.29(s,4H),3.72(s,2H),3.56(d,J=5.5Hz,2H),2.35(s,3H),2.23(s,3H),1.23(s,2H).
实施例17:6-(((2-乙酰胺基乙基)氨基)甲基)-N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-19)
ESI-MS m/z:501.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.38(s,1H),9.16(s,1H),8.75(s,1H),8.53(s,1H),8.15(d,J=8.0Hz,1H),7.82(s,1H),7.31(t,J=7.8Hz,1H),7.06(d,J=7.5Hz,1H),6.94(d,J=8.2Hz,1H),6.85(d,J=1.8Hz,1H),6.81(dd,J=8.2,1.8Hz,1H),4.30(s,4H),3.91(s,2H),3.16(dd,J=12.1,6.1Hz,2H),2.58(t,J=6.4Hz,2H),2.36(s,3H),1.80(s,3H).
实施例18:N-(3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)-6-(((2-(甲磺酰胺基)乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-20)
ESI-MS m/z:537.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.38(s,1H),9.18(s,1H),8.76(s,1H),8.53(s,1H),8.15(d,J=8.0Hz,1H),7.31(t,J=7.8Hz,1H),7.06(d,J=7.5Hz,1H),6.98(s,1H),6.94(d,J=8.2Hz,1H),6.85(d,J=1.8Hz,1H),6.81(dd,J=8.2,1.9Hz,1H),4.30(s,4H),3.92(s,2H),3.08(d,J=5.3Hz,2H),2.92(s,3H),2.67(t,J=6.3Hz,2H),2.36(s,3H).
实施例19:((8-((3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-丙氨酸(I-21)
ESI-MS m/z:488.2[M+H]+;
实施例20:((8-((3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-L-丙氨酸(I-22)
ESI-MS m/z:488.2[M+H]+;
实施例21:(S)-4-(((8-((3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-2-甲基苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)氨基)-3-羟基丁酸(I-23)
ESI-MS m/z:518.2[M+H]+;
实施例22:N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-24)
步骤1:2-氨基-6-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯甲腈
室温下,将2-氨基-6-溴苯甲腈(2g,10.2mmol)、2-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-4,4,5,5-四甲基-1,3,2--二杂氧环戊硼烷(2.94g,11.22mmol)、四(三苯基膦)钯(1.18g,1.02mmol)、碳酸铯(6.65g,20.4mmol)加入至甲苯/乙醇/水的混合溶液中(体积比3:3:1,23mL)。在N2保护下,反应液于95℃搅拌反应12小时。反映完毕后,抽滤,蒸干滤液,柱层析分离得白色固体1.53g,收率为62.1%。
步骤2:6-溴-N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸(1g,4.15mmol)溶于氯化亚砜中(15mL),升温至80℃搅拌反应4小时。反应完毕后,蒸干反应液得黄色固体。将制得的黄色固体溶于二氯甲烷中(15mL),冰浴条件下缓慢滴加到2-氨基-6-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯甲腈(1.05g,4.15mmol)和三乙胺(1.05g,10.38mmol)的二氯甲烷(10mL)溶液中,并于室温搅拌反应1小时。反应结束后,向反应液中加入大量二氯甲烷,平台搅拌1小时,加水洗涤有机层,蒸干有机层,得浅黄色固体。将粗品溶于乙醇中,80℃下搅拌半小时,抽滤,干燥得黄色固体0.89g,收率45.3%。
步骤3:N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(3.09g,6.5mmol)、乙烯基硼酸频哪醇酯(1.1g,7.2mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(0.48g,0.65mmol)、碳酸铯(3.81g,11.7mmol)溶于1,4-二氧六环/水(体积比3:1,30mL)的混合溶液中,N2保护下90℃反应3小时。反应液冷却至室温,用二氯甲烷萃取,蒸干有机层,柱层析分离得黄色固体1.75g,收率为63.7%。
步骤4:N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.63g,1.5mmol)溶于1,4-二氧六环/水(体积比5:1,15mL)的混合溶液中,快速加入2%的OsO4水溶液(3mL),搅拌10分钟后加入高碘酸钠(1.28g,6mmol),室温搅拌反应12小时。抽滤,干燥,得类白色固体0.58g,收率为90.2%。
步骤5:N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(实施例22)
室温下,将N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.094g,0.22mmol)溶于DMF中,加入乙醇胺(0.067g,1.1mmol)、冰醋酸(0.02g,0.33mmol),搅拌反应2小时。向体系中加入氰基硼氢化钠(0.07g,1.1mmol),25℃搅拌反应12小时。反应液中加水,用二氯甲烷萃取,蒸干溶剂,柱层析分离得白色固体0.029g,收率为27.6%。
ESI-MS m/z:471.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.99(s,1H),9.21(s,1H),8.74(s,1H),8.55(s,1H),8.31(d,J=8.2Hz,1H),7.80(t,J=8.0Hz,1H),7.39(d,J=7.6Hz,1H),7.14(s,1H),7.10(d,J=7.5Hz,1H),7.03(d,J=8.3Hz,1H),4.52(s,1H),4.33(s,4H),3.93(s,2H),3.50(d,J=5.2Hz,2H),2.62(t,J=5.5Hz,2H).
根据实施例22的合成方法,以N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-甲酰基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺为原料,通过与不同的胺类化合物反应,再经与三乙酰氧基硼氢化钠还原制备得到实施例23-28的化合物。
实施例23:N-(2氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-(((2-羟乙基)(甲基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-25)
ESI-MS m/z:485.2[M+H]+;
实施例24:6-(((2-乙酰胺基乙基)氨基)甲基)-N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-26)
ESI-MS m/z:512.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ11.99(s,1H),9.20(s,1H),8.75(s,1H),8.54(s,1H),8.32(s,1H),7.82(s,2H),7.40(s,1H),7.23–7.02(m,3H),4.33(s,4H),3.91(s,2H),3.16(s,2H),2.58(s,2H),1.80(s,3H).
实施例25:N-(2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-6-(((2-(甲磺酰胺基)乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-27)
ESI-MS m/z:548.2[M+H]+;
实施例26:((8-((2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-丙氨酸(I-28)
ESI-MS m/z:499.2[M+H]+;
实施例27:((8-((2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-L-丙氨酸(I-29)
ESI-MS m/z:499.2[M+H]+;
实施例28:(S)-4-(((8-((2-氰基-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)氨基)-3-羟基丁酸(I-30)
ESI-MS m/z:529.2[M+H]+;
按照实施例15的制备方法,在第一步中采用3-溴-2-氯苯胺代替3-溴-2-甲基苯胺,与2-(2,3-二氢苯并[b][1,4]二氧芑-6-基)-4,4,5,5-四甲基-1,3,2-二杂氧环戊硼烷经过Suzuki偶联反应制得2-氯-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯胺,随后先后经过与6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸酰胺化、乙烯基硼酸频哪醇酯偶联、高碘酸钠氧化、胺类化合物还原胺化制得实施例29-31的化合物。
实施例29:6-(((2-乙酰胺基乙基)氨基)甲基)-N-(2-氯-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-33)
ESI-MS m/z:521.2[M+H]+;
实施例30:((8-((2-氯-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-丙氨酸(I-34)
ESI-MS m/z:508.1[M+H]+;
实施例31:(S)-1-((8-((2-氯-3-(2,3-二氢苯并[b][1,4]二氧芑-6-基)苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)哌啶-2-甲酸(I-37)
ESI-MS m/z:548.2[M+H]+;
实施例32:6-(((2-羟乙基)氨基)甲基)-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-38)
步骤1:2-甲基-3-(1-甲基-1H-吲唑-4-基)苯胺
室温下,将3-溴-2-甲基苯胺(12g,0.065mol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二杂氧环戊硼烷-2-基)-1H-吲唑(33.5g,0.13mol)、醋酸钯(1.46g,6.5mmol)、碳酸钾(26.9g,0.195mol)加入至乙醇/水的混合溶液中(体积比1:1,200mL),于N2保护下搅拌反应6小时。反映完毕后,抽滤,蒸干滤液,柱层析分离得白色固体9.85g,收率63.9%。
步骤2:6-溴-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸(10g,0.042mol)、2-甲基-3-(1-甲基-1H-吲唑-4-基)苯胺(9.49g,0.04mol)、HATU(22.8g,0.06mol)、N,N-二异丙基乙胺(10.3g,0.08mol)溶于N,N-二甲基甲酰胺(20mL)中,搅拌反应13小时。反应完毕后,将反应液倒入大量水中,搅拌30分钟,抽滤,水洗滤饼,干燥,柱层析分离得浅黄色固体13.7g,收率为71.9%。
步骤3:N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将6-溴-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(2g,4.3mmol)、乙烯基硼酸频哪醇酯(0.73g,4.7mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(0.31g,0.43mmol)、碳酸铯(2.5g,7.7mmol)溶于1,4-二氧六环/水(体积比3:1,15mL)的混合溶液中,N2保护下90℃反应5小时。反应液冷却至室温,用二氯甲烷萃取,蒸干有机层,柱层析分离得白色固体1.19g,收率为67.7%。
步骤4:6-甲酰基-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺
室温下,将N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-6-乙烯基-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.73g,1.8mmol)溶于1,4-二氧六环/水(体积比5:1,8mL)的混合溶液中,快速加入2%的OsO4水溶液(3.5mL),搅拌5分钟后加入高碘酸钠(1.54g,7.2mml),室温搅拌反应5小时。抽滤,得淡黄色固体0.53g,收率为72.3%。
步骤5:6-(((2-羟乙基)氨基)甲基)-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(实施例32)
室温下,将6-甲酰基-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(0.09g,0.22mmol)溶于DMF中,加入乙醇胺(0.067g,1.1mmol)、冰醋酸(0.02g,0.33mmol),搅拌反应2小时。向体系中加入氰基硼氢化钠(0.07g,1.1mmol),25℃搅拌反应15小时。反应液中加水,用二氯甲烷萃取,蒸干溶剂,柱层析分离得白色固体0.02g,收率为20.1%。
根据实施例32的合成方法,以6-甲酰基-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺为原料,通过与不同的胺类化合物反应,再经氰基硼氢化钠还原制备得到实施例33和34的化合物。
实施例33:6-(((2-乙酰胺基乙基)氨基)甲基)-N-(2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-40)
ESI-MS m/z:497.2[M+H]+;
实施例34:((8-((2-甲基-3-(1-甲基-1H-吲唑-4-基)苯基)氨甲酰基)-[1,2,4]***并[4,3-a]吡啶-6-基)甲基)-D-丙氨酸(I-41)
ESI-MS m/z:484.2[M+H]+;
按照实施例1的制备方法,在第一步中采用取代的苯硼酸代替苯硼酸,与3-溴-2-甲基苯胺经过Suzuki偶联反应制得联苯胺类衍生物,随后先后经过与6-溴-[1,2,4]***并[4,3-a]吡啶-8-甲酸酰胺化、乙烯基硼酸频哪醇酯偶联、高碘酸钠氧化、乙醇胺还原胺化制得实施例35-39的化合物。
实施例35:N-(2,4'-二甲基-[1,1'-联苯]-3-基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-42)
ESI-MS m/z:416.2[M+H]+;
实施例36:N-(2'-氟-3'-甲氧基-2-甲基-[1,1'-联苯]-3-基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-43)
ESI-MS m/z:450.2[M+H]+;
实施例37:N-(3'-溴-2-甲基-[1,1'-联苯]-3-基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-44)
ESI-MS m/z:480.1[M+H]+;
实施例38:N-(4'-氯-2-甲基-[1,1'-联苯]-3-基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-45)
ESI-MS m/z:436.2[M+H]+;
实施例39:N-(3',4'-二甲氧基-2-甲基-[1,1'-联苯]-3-基)-6-(((2-羟乙基)氨基)甲基)-[1,2,4]***并[4,3-a]吡啶-8-甲酰胺(I-46)
ESI-MS m/z:462.2[M+H]+;
本发明化合物生物学活性研究
采用均相时间分辨荧光(Homogenouse Time-Resolved Fluorescence,HTRF)试验来检测本发明化合物抑制PD-1/PD-L1相互作用的能力。检测试剂盒购买于CisBio公司(CAT#63ADK000CPAPEG),其中包含Anti-Tag1-Cyptate、Anti-Tag2-XL665/d2、Tag1-PD-L1、Tag2-PD-1、Dilution Buffer、Detection Buffer等实验所需试剂。
实验步骤:PD-1重组蛋白和PD-L1重组蛋白分别用Dilution Buffer稀释至500nM和50nM。用Dilution Buffer稀释4mM用DMSO溶解的小分子化合物20倍至200uM。用含5%DMSO的Dilution Buffer四倍梯度稀释。同时用Dilution Buffer稀释600uM用DMSO溶解的PD-1/PD-L1抑制剂20倍至30uM,用含5%DMSO的Dilution Buffer四倍梯度稀释。依次向384孔中加入2uL稀释好的待测化合物、4uL稀释好的PD-1和4uL稀释好的PDL-1。充分混匀,室温放置15min。用Detection buffer稀释anti-Tag1-Eu3+(1:25)和anti-Tag2-XL665(1:100)。然后等体积混合稀释好的检测试剂,每反应孔加入10μL抗体混合液。封膜室温孵育2h。用ENVISION(Perkinelmer)仪器检测荧光信号(320nm刺激,665nm,615nm发射)。每个化合物检测8-12个浓度。
化合物抑制PD-1/PD-L1相互作用的活性结果见表1。
表1本发明化合物抑制PD-1/PD-L1相互作用的活性范围或IC50。
范围如下:A=1nM-100nM;B=100.01nM-1μM;C=1.01μM-20μM。
HTRF测试结果表明,实施例化合物在分子水平可显著抑制PD-1/PD-L1相互作用。有望在治疗与PD-1/PD-L1相互作用有关的疾病中展示出积极的作用。
Claims (17)
1.通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,
其中,
R5独立地选自卤素、(C1-C4)烷基、(C1-C4)烷氧基;
R2选自卤素、氰基、(C1-C4)烷基;
R3、R4独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基;所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基可任选被1-3个R6取代;
或者R3、R4和与它们相连的氮原子一起形成一个3-7元的含氮杂环;所述含氮杂环可任选被1-3个R7取代;
R6独立地选自氢、卤素、羟基、(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基;
R7独立地选自氢、羟基、羧基、(C1-C4)烷基、(C1-C4)烷氧基、羟基(C1-C4)烷基。
3.如权利要求1或2所述的通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中,
R2选自卤素、氰基、(C1-C4)烷基。
4.如权利要求1或2所述的通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中,
R2选自氯、氰基、甲基。
5.如权利要求1或2所述的通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中,
R3、R4独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基;所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基可任选被1-3个R6取代;
或者R3、R4和与它们相连的氮原子一起形成一个5-6元的含氮杂环;所述含氮杂环可任选被1-3个R7取代。
6.如权利要求3所述的通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中,
R3、R4独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基;所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基可任选被1-3个R6取代;
或者R3、R4和与它们相连的氮原子一起形成一个5-6元的含氮杂环;所述含氮杂环可任选被1-3个R7取代。
7.如权利要求4所述的通式Ⅰ的***并吡啶类化合物及其立体异构体以及药学上可接受的盐,其中,
R3、R4独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基;所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰胺基(C1-C4)烷基、羧基(C1-C4)烷基可任选被1-3个R6取代;
或者R3、R4和与它们相连的氮原子一起形成一个5-6元的含氮杂环;所述含氮杂环可任选被1-3个R7取代。
13.一种药物组合物,所述药物组合物包含作为有效成分的权利要求1-12中任何一项所述的化合物及其立体异构体以及药学上可接受的盐和药学上可接受的载体或赋形剂。
14.权利要求1-12任何一项所述化合物及其立体异构体以及药学上可接受的盐,或权利要求13所述的药物组合物在制备预防和/或治疗与PD-1/PD-L1信号通路有关的疾病的药物中的应用。
15.根据权利要求14所述的应用,其特征在于,所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病或自身免疫性疾病。
16.根据权利要求15所述的应用,其特征在于,所述的癌症选自肺癌、皮肤癌、血液肿瘤、消化***肿瘤、乳腺癌、淋巴瘤、神经***肿瘤、黑色素瘤;所述的感染性疾病选自细菌感染、病毒感染;所述的自身免疫性疾病选自器官特异性自身免疫病、***性自身免疫病,所述器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、溃疡性结肠炎、急性特发性多神经炎,所述的***性自身免疫病包括类风湿性关节炎、***性红斑狼疮、***性血管炎、自身免疫性溶血性贫血。
17.根据权利要求16所述的应用,其特征在于,所述的神经***肿瘤为胶质瘤。
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