CN117486885A - 吡唑并嘧啶类化合物的用途 - Google Patents
吡唑并嘧啶类化合物的用途 Download PDFInfo
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- CN117486885A CN117486885A CN202210883004.3A CN202210883004A CN117486885A CN 117486885 A CN117486885 A CN 117486885A CN 202210883004 A CN202210883004 A CN 202210883004A CN 117486885 A CN117486885 A CN 117486885A
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- Prior art keywords
- alkyl
- saturated
- halogen
- group
- cyclic hydrocarbon
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- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
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- 208000035475 disorder Diseases 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 208000026278 immune system disease Diseases 0.000 claims abstract description 7
- -1 pyrazolopyrimidine compound Chemical class 0.000 claims description 88
- 229920006395 saturated elastomer Polymers 0.000 claims description 61
- 229910052736 halogen Inorganic materials 0.000 claims description 58
- 150000002367 halogens Chemical class 0.000 claims description 58
- 125000001424 substituent group Chemical group 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 35
- 125000000217 alkyl group Chemical class 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 34
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 13
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 8
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- 125000003003 spiro group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
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- 229940002612 prodrug Drugs 0.000 claims description 6
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- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 206010004593 Bile duct cancer Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
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- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
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- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
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- 201000005202 lung cancer Diseases 0.000 claims description 2
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- 125000004434 sulfur atom Chemical group 0.000 claims description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 22
- 150000002431 hydrogen Chemical class 0.000 claims 17
- 102100022464 5'-nucleotidase Human genes 0.000 abstract description 36
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- 150000003384 small molecules Chemical class 0.000 abstract description 4
- 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 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 239000000047 product Substances 0.000 description 30
- 125000004432 carbon atom Chemical group C* 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 24
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 24
- 239000007858 starting material Substances 0.000 description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 238000004949 mass spectrometry Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 12
- 229960005305 adenosine Drugs 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 10
- ZCJRWQDZPIIYLM-UHFFFAOYSA-N 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC=C1N ZCJRWQDZPIIYLM-UHFFFAOYSA-N 0.000 description 9
- KUCBMSUTIBMISH-UHFFFAOYSA-N 5-phenyl-1h-pyrazolo[1,5-a]pyrimidin-7-one Chemical compound N1=C2C=CNN2C(=O)C=C1C1=CC=CC=C1 KUCBMSUTIBMISH-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- UWQMTCYMAVNCQY-UHFFFAOYSA-N 7-chloro-5-phenylpyrazolo[1,5-a]pyrimidine Chemical compound N=1C2=CC=NN2C(Cl)=CC=1C1=CC=CC=C1 UWQMTCYMAVNCQY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 4
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通式(I)所示的吡唑并嘧啶化合物的用途。所述化合物能够有效抑制CD73的活性,可作为CD73小分子抑制剂,在CD73相关疾病、失调和病症,特别是癌症和免疫失调的治疗和/或预防中具有良好的应用前景。
Description
技术领域
本发明涉及CD73抑制剂,具体涉及一类吡唑并嘧啶化合物在制备CD73抑制剂中的用途,尤其是在制备治疗和/或预防CD73相关疾病、失调和病症,特别是癌症和免疫失调的药物中的用途。
背景技术
肿瘤免疫逃逸是肿瘤细胞通过自身或者非自身的手段,逃避免疫系统对其的监视和清除。肿瘤免疫逃逸的实现与肿瘤细胞自身细胞表位的转变和肿瘤免疫微环境的变化相关。其中,肿瘤自身的改变指的是出于基因突变等原因,发生的抗原封闭、低氧代谢或者上皮—间质转化,变得更难被机体的免疫系统识别。而肿瘤对微环境的影响则源于肿瘤细胞同周围正常组织或者免疫因子等互相作用后,形成免疫抑制的环境。此时调节性T细胞(Treg)会显著抑制效应T细胞等对肿瘤细胞的杀伤作用。由于当前的肿瘤免疫治疗药物存在一定局限性,免疫逃逸机制正逐渐受到越来越多研究者的重视。综合以上信息,需要研发新机制的肿瘤免疫药物,开发同时遏制多条免疫抑制途径的联合治疗手段来改善临床反应,更好的满足患者需求。
CD73是一种胞外核苷酸酶,肿瘤中高表达的CD73可以水解一磷酸腺苷(AMP)产生腺苷(ADO),显著改变肿瘤的微环境;CD73同时也在细胞表面充当黏附信号分子(MINOR M,ALCEDO K P,BATTAGLIA R A,et al.Cell type-and tissue-specific functions ofecto-5'-nucleotidase(CD73)[J].Am J Physiol Cell Physiol,2019,317(6):C1079-C1092.)。胞外腺苷的生成是肿瘤微环境中最重要的免疫抑制调节途径之一,其主要经过CD39(属于NTPdases)和CD73的级联水解反应生成。作为胞外腺苷的主要生产酶,CD73成为多种组织中细胞稳态、应激、损伤和炎症疾病机制中的重要调节因子。ATP从受到压力或者面临死亡的细胞中释放出来,代表着一种提示“危险”的炎症信号,并且在该类分子被迅速转化为抗炎信号分子腺苷时候停止释放,从而避免引发严重的炎症反应伤害机体。在缺氧的肿瘤微环境中,积聚了高水平的细胞外ATP,此时,CD39(外核苷三磷酸二磷酸水解酶1,NTPDase1,或EC3.6.1.5)和CD73能够将其连续水解为ADP、AMP和腺苷(ADO),微环境改变,腺苷浓度上调。而人体组织中广泛分布着腺苷受体A2AR(属于P1受体),受体结合了腺苷之后,会增强Treg细胞扩增,提升其免疫抑制能力,抑制T细胞增殖作用和NK细胞的激活和功能,促进巨噬细胞M2分化(LAPPAS C M,RIEGER J M,LINDEN J.A2A Adenosine ReceptorInduction Inhibits IFN-γProduction in Murine CD4+T Cells[J].The Journal ofImmunology,2005,174(2):1073-1080.)。通过A2BR的信号传递可以促使髓源性抑制细胞(MDSC)扩增,MDSC上的CD73也可以抑制T细胞以及NK细胞。在肿瘤发展过程中,微环境里的缺氧和炎症环境会持续保持,肿瘤细胞也持续地通过提高相关基因表达(如NT5E,编码CD73的基因)来增强免疫抑制,肿瘤组织细胞表面的CD73显著上调是促成肿瘤免疫逃逸的重要原因之一(NEO S Y,YANG Y,RECORD J,et al.CD73 immune checkpoint definesregulatory NK cells within the tumor microenvironment[J].J Clin Invest,2020,130(3):1185-1198.)。所以抑制CD39和CD73将有效阻断由腺苷介导的免疫抑制。
CD73由NT5E基因编码,广泛表达于人体淋巴细胞,内皮细胞等正常人体组织中。癌症基因组图谱(TCGA)显示,相比正常细胞中而言,NT5E在大多数实体癌细胞中高度上调,尤其在Treg等细胞表面有很高的表达(YANG H,YAO F,DAVIS P F,et al.CD73,TumorPlasticity and Immune Evasion in Solid Cancers[J].Cancers(Basel),2021,13(2).)。在甲状腺癌、肉瘤和急性髓细胞白血病中NT5E表达最为丰富,在乳腺癌和膀胱肿瘤中的表达也很高。有证据显示,CD73的高表达与乳腺癌细胞密度正相关,其活性增强可能引发腺苷的积累从而增强嘌信号通路激活(周婷婷,周平,殷莲华.CD73对人乳腺癌细胞侵袭力和运动力的影响[J].中国病理生理杂志,2006,22(2)∶360-364.)。这些证据提示CD73在这些实体瘤癌症中,应当作为一个潜在靶点来优先考虑。
此外,越来越多的证据表明CD73与肿瘤细胞的转移有关。Stagg等人研究发现,CD73在鼠类的乳腺癌模型中是肿瘤转移的驱动因素(STAGG J,DIVISEKERA U,MCLAUGHLINN,et al.Anti-CD73 antibody therapy inhibits breast tumor growth andmetastasis[J].Proc Natl Acad Sci U S A,2010,107(4):1547-1552.)。该过程仍然主要是通过腺苷作为信号分子,对淋巴细胞发挥免疫抑制作用,同时也增强肿瘤细胞的迁移能力。实验环境的条件下已经证实,靶向CD73也可以有效预防胃癌的转移(XU Z,GU C,YAO X,et al.CD73 promotes tumor metastasis by modulating RICS/RhoA signaling andEMT in gastric cancer[J].Cell Death Dis,2020,11(3):202)。
Tu及其同事通过实验证实,相比较单独使用抗PD-L1或者抗CD73治疗,采用抗PD-L1和抗CD73的联合用药治疗,能够促进T细胞对EGFR突变的非小细胞肺癌(NSCLC)的免疫反应,并且显著缩小肿瘤(TU E,MCGLINCHEY K,LAZDUN Y,et al.Abstract 911:Anti-PD-L1and anti-CD73 combination therapy promotes T cell response to EGFR mutantNSCLC[J].Cancer Research,2020,80(16_Supplement):911-911.)。与同型对照相比,联合治疗增加了肿瘤中MART1(Melanoma antigen recognized by T-cells 1)特异性的CD8+T细胞数量,也使得脾脏中CD8+T细胞的CD62L+/CD45RO+/CCR7+表型出现率有所提高。他们的研究结果可以为CD73联合用药治疗提供理论基础。
因此,作为一种近年来极有潜力的癌症治疗靶点,CD73抑制剂具有与其他肿瘤免疫药物或化疗药物联用,从而形成协同治疗策略的潜力。尽管已有多个单抗CD73药物在临床阶段,但是CD73小分子抑制剂因其独有的理化性质特性、代谢分布特性和非免疫原性的特性,仍然具有重要的研究价值。
发明内容
本发明提供通式(I)所示的吡唑并嘧啶化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物、其药学上可以接受的盐、多晶型物、溶剂化物或经同位素标记的化合物在制备CD73抑制剂中的用途,尤其是在制备治疗和/或预防CD73相关疾病、失调和病症,特别是癌症和免疫失调的药物中的用途:
其中:
A选自氢、卤素、C1-C6烷基、-C(=O)NR5R6、-C(=S)NR5R6、-SO2NR5R6、-S(=O)NR5R6、-CH2NR5R6、或-C(=O)OR5,其中R5和R6独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、3-10元杂环基、C6-C12芳基或5-10元杂芳基;所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、3-10元杂环基、C6-C12芳基或5-10元杂芳基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代;
B选自氢、卤素、C1-C6烷基、C2-C6烯基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-10元杂环基;所述C1-C6烷基、C2-C6烯基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-10元杂环基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代;
R1、R2独立地选自氢、卤素、C1-C6烷基、C3-C10饱和或不饱和环烃基;
R3和R4各自独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-10元杂环基,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-10元杂环基任选地被一个或多个选自W1组的取代基取代;或者
R3和R4与其连接的N原子共同形成含有1-4个选自N、O和S中的杂原子的单环、螺环或桥环,所述单环、螺环或桥环任选地被一个或多个选自W1组的取代基取代;所述W1组取代基包括D、卤素、氧代(=O)、C1-C6烷基、羟基、C1-C6羟烷基、-NR7R8、氰基、硝基、羧基;
R7、R8各自独立地选自氢、C1-C6烷基、C3-C10饱和或不饱和环烃基;所述C1-C6烷基、C3-C10饱和或不饱和环烃基任选地被一个或多个选自W2组的取代基取代,所述W2组取代基包括D、卤素、羟基、-NH2、C1-C3烷基。
在一些实施方式中,A选自氢、卤素、C1-C4烷基、-C(=O)NR5R6。
在一些实施方式中,A选自氢、在一些实施方式中,R5和R6独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7饱和或不饱和环烃基、3-7元杂环基、C6-C12芳基或5-10元杂芳基;所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7饱和或不饱和环烃基、3-7元杂环基、C6-C12芳基或5-10元杂芳基任选被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代,特别是任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基的取代基取代。
在一些实施方式中,R5和R6独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基。
在一些实施方式中,B选自氢、卤素、C1-C6烷基、C2-C6烯基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-7元杂环基;所述C1-C6烷基、C2-C6烯基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-7元杂环基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代,特别是任选地被一个或多个选自D、卤素、羟基、-NH2、Boc、C1-C4烷基的取代基取代。
在一些实施方式中,B选自: 其中,i选自0,1,2,3,4;R12各自独立地选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基,特别是选自D、卤素、羟基、-NH2、Boc、C1-C4烷基。
在一些实施方式中,B选自
在一些实施方式中,R1、R2独立地选自氢、卤素、C1-C4烷基、C3-C7饱和或不饱和环烃基,特别是独立地选自氢、卤素。
在一些实施方式中,R3和R4各自独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-7元杂环基,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-7元杂环基任选地被一个或多个选自W1组的取代基取代;或者
R3和R4与其连接的N原子共同形成含有1-4个选自N、O和S中的杂原子的单环、螺环或桥环,所述单环、螺环或桥环任选地被一个或多个选自W1组的取代基取代;
所述W1取代基包括D、卤素、氧代(=O)、C1-C4烷基、羟基、C1-C4羟烷基、-NR7R8、氰基、硝基、羧基;
R7、R8各自独立地选自氢、C1-C4烷基、C3-C7饱和或不饱和环烃基,所述C1-C4烷基、C3-C7饱和或不饱和环烃基任选地被一个或多个选自W2组的取代基取代,所述W2组取代基包括D、卤素、羟基、-NH2、C1-C3烷基。
在一些实施方式中,R3和R4与其连接的N原子共同形成选自以下的环结构:
特别地,R3和R4与其连接的N原子共同形成选自以下的环结构:
其中,n选自1,2,3,4;m选自0,1,2,3,4,5,6;
X选自N、O和S原子;
R9各自独立地选自D、卤素、羟基、氰基、氧代(=O)、C1-C4羟烷基、-NR10R11;
R10、R11独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基;所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基任选地被选自D、卤素、羟基、-NH2、氰基的取代基取代。在一些实施方式中,R3和R4与其连接的N原子共同形成选自以下的环结构:
在一些实施方式中,式(I)所示的化合物选自以下结构:
其中,A、R1、R2如上所定义,
R9选自羟基、氧代(=O)、C1-C4羟烷基、-NR10R11;
R10、R11独立地选自氢、C1-C4烷基;所述C1-C4烷基任选地被选自D、卤素、羟基、-NH2的取代基取代;
R9’选自H、羟基、C1-C4羟烷基;
R12选自卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷基;
B1选自C3-C7饱和或不饱和环烃基、3-7元杂环基、C2-C6烯基;所述C3-C7饱和或不饱和环烃基、3-7元杂环基、C2-C6烯基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷基羰氧基、C1-C4烷基的取代基取代,特别是任选地被一个或多个选自D、卤素、羟基、-NH2、Boc、C1-C4烷基的取代基取代;特别地,B1选自:
在一些实施方式中,式(I)所示的化合物选自如下结构:
本发明的化合物可以单独地、与其它的本发明的化合物组合地或与一种或多种、优选一种或两种其它治疗剂组合地同时或依次使用。
除了本发明的通式(I)所示的吡唑并嘧啶化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物、其药学上可以接受的盐、多晶型物、溶剂化物或经同位素标记的化合物以外,所述CD73抑制剂或者所述药物中还可以包含药学上可接受的载体以及任选地,一种或多种其他治疗剂。
本发明还提供一种药物组合物在制备CD73抑制剂的用途,尤其是在制备治疗和/或预防CD73相关疾病、失调和病症,特别是癌症和免疫失调的药物中的用途,所述药物组合物包含治疗有效剂量的选自通式(I)所示的化合物、其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物、其药学上可以接受的盐、多晶型物、溶剂化物或经同位素标记的化合物中的一种或多种,和至少一种药学上可接受的载体。
在一些实施方式中,所述组合物还可以包含一种或多种其他治疗剂。
本发明的还提供一种抑制CD73酶活性的方法或者治疗和/或预防CD73相关疾病、失调和病症,特别是癌症和免疫失调的方法,所述方法包括向有此需要的个体施用治疗有效量的选自通式(I)所示的化合物、其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物、其药学上可以接受的盐、多晶型物、溶剂化物或经同位素标记的化合物中的一种或多种或上述药物组合物。在一些实施方式中,该方法还包括给所述个体施用有效剂量的一种多种其他治疗剂。
在实施方式中,所述其它治疗剂,包括但不限于免疫检查点PD-1/PD-L1单克隆抗体、免疫检查点小分子抑制剂、作用于DNA化学结构的抗肿瘤药、影响核酸合成的抗肿瘤药物、影响核酸转录的抗肿瘤药物、作用于微管蛋白合成的抗肿瘤药物、芳香化酶抑制剂、细胞信号通路抑制剂。
特别地,所述其它治疗剂包括顺铂、甲氨蝶呤(MTX)、5-氟尿嘧啶(5FU)、阿霉素、表阿霉素、阿克拉霉素、光辉霉素、紫杉醇、长春瑞滨、氨鲁米特、兰特隆、来曲唑、瑞宁德、伊马替尼(Imatinib)、吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)。
在一些实施方式中,所述CD73相关疾病、失调和病症包括癌症和免疫失调。
优选地,所述癌症包括膀胱癌、乳腺癌、胆管癌、结直肠癌、结肠癌、胃癌、肺癌、肝癌、胰腺癌、前列腺癌、肾癌、胶质母细胞瘤、肉瘤、白血病、淋巴瘤或黑色素瘤。
有益效果
本发明的吡唑并嘧啶类化合物能够有效抑制CD73的活性,可作为CD73小分子抑制剂。
具体实施方式
通过参考以下实施例将帮助理解本发明,实施例用于说明本发明,而不应被解释为以任何方式限制本发明的范围。
在本发明的上下文中(尤其在权利要求的上下文中)使用的单数术语应被理解为包括复数含义,除非文中另外特别指出或根据上下文明显矛盾。
如本文所用,“卤素”或“卤代”指氟、氯、溴和碘。优选的作为取代基的卤素是氟和氯。
如本文所用,“烷基”指完全饱和的直链或支链的一价烃基团。烷基优选包含1-20个碳原子,更优选1-16个碳原子、1-10个碳原子、1-8个碳原子、1-6个碳原子、1-4个碳原子或1-3个碳原子。烷基前的数字表示碳原子的个数。例如,“C1-C6烷基”表示具有1-6个碳原子的烷基,“C1-C4烷基”表示具有1-4个碳原子的烷基,“C1-C3烷基”表示具有1-3个碳原子的烷基,依此类推。烷基的代表性示例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。无论术语“烷基”单独出现,还是作为其它基团如卤代烷基、烷氧基等的一部分出现,均适用该定义。
如本文所用,“烯基”指包含至少一个双键的直链或支链的一价烃基团。烯基优选包含2-20个碳原子,更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。烯基前的数字表示碳原子的个数。“C2-C6烯基”是指2-6个碳原子的烯基,烯基的代表性示例包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、戊烯基、异戊烯基、己烯基等。
如本文所用,“炔基”指包含至少一个叁键的直链或支链的一价烃基团。炔基优选包含2-20个碳原子,更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。炔基前的数字表示碳原子的个数。“C2-C6炔基”是指2-6个碳原子的炔基,代表性示例包括但不限于乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、戊炔基、异戊炔基、己炔基等。
如本文所用,“环烃基”指饱和或部分饱和的非芳香族碳环,包括单-、双-或三环,优选具有3-12个环碳原子,更优选3-10个环碳原子,例如3-8个、3-7个、3-6个、4-10个、或4-8个环碳原子。“C3-C10饱和或不饱和环烃基”意欲包括C3、C4、C5、C6、C7、C8、C9、C10环烃基;"C3-C7环烃基"意欲包括C3、C4、C5、C6、C7环烃基;以此类推。示例性的单环环烃基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基等。示例性的二环环烃基包括冰片基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基等。示例性的三环环烃基包括金刚烷基等。
如本文所用,“芳基”是由一个环或多个环稠合构成的具有6-20个、优选6-14个、更优选6-12个、最优选6-10个。具有6-10个环碳原子的芳基,即C6-C10芳基,其包括:单环芳基(例如苯基);或稠合二环系统,其中一个环是芳族环、而另一个环是芳族(例如在萘、联苯基中)或非芳族环(例如在二氢茚、四氢萘中)。芳基的非限制性示例包括苯基、联苯基、萘基、四氢萘基、茚基、二氢茚基或蒽基等。
如本文所用,“杂芳基”指含有1-4个、优选1-3个选自N、O或S的环杂原子的5-15元、优选5-13元,包括单环或二环或稠合多环,其余环原子为碳原子。杂芳基的实例包括但不限于:吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、三唑基、噻唑基、异噻唑基、噁唑基、吡啶基、吡喃基、吡嗪基、哒嗪基、嘧啶基、噁嗪基、噁二嗪基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、苯并噁嗪基、2H-色烯、苯并吡喃基、苯并噻吩基、吲哚基、吲唑基、苯并吡唑、苯并咪唑基、咪唑并吡啶基、苯并噁唑基、苯并噻唑基、7-氮杂吲哚基、6-氮杂吲哚基、5-氮杂吲哚基、4-氮杂吲哚基、1H-苯并[d][1,2,3]三唑基、[1,2,4]三唑并[1,5-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶、吡唑并[1,5-a]吡啶、二苯并呋喃、二苯并[b,d]呋喃、9H-咔唑、二苯并[b,d]噻吩等。
如本文所用,“杂环基”指如本申请中所定义的环烃基中的一个或多个环碳被选自N、O或S的杂原子替换所得的基团,所述杂原子例如是-O-、-N=、-NR-、-S-、-S(=O)-和-S(=O)2-,其中R是氢、C1-4烷基或氮保护基(例如,苄氧羰基、对甲氧基苄基羰基、叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等。优选地,杂环基是具有3-20个环原子、例如3-12个环原子、例如3-8个环原子、例如3-7个环原子的单环、二环或三环的饱和和部分不饱和非芳族环。更优选地,杂环基优选含有1、2或3个选自N、O或S的杂原子的4-至12-元杂环基,优选4-至8-元杂环基、更优选是3-至7-元、4-至6元或5-至6-元杂环基,其中所述杂原子是取代或未取代的,例如被C1-C4烷基取代。例如,杂环基的实例包括但不限于:环氧乙烷基、氮丙啶基、氮杂环丁烷基、氧杂环丁烷基、氮杂环戊烷基(吡咯烷基)、四氢呋喃基、四氢噻吩基、四氢噻吩基1,1-二氧化物、四氢吡啶基、吡唑烷基、咪唑烷基、噁唑烷基、噻唑烷基、异噻唑烷基、吡咯烷基-2-酮、咪唑酮基、哌啶基(六氢吡啶)、N-甲基哌啶基、四氢吡喃基、噁嗪烷基、1,3-噁嗪烷基、六氢嘧啶基、哌嗪基、哌啶酮基(piperidinylone)、1,4-二氧杂-8-氮杂-螺[4.5]癸烷-8-基、吗啉代基、硫吗啉代基、硫代吗啉代-S-单氧化物(sulfanomorpholino)、硫代吗啉代-S,S-二氧化物(sulfonomorpholino)、八氢吡咯并[3,2-b]吡咯基等。
如本文所用,“Boc”为叔丁氧羰基。
如本文所用,术语“氧代”是指氧原子通过双键与其它原子连接,可表示为“=O”。术语“-C(=O)”为羰基,“-S(=O)”为亚砜基、“-S(=O)2”为砜基。
如本文所用,“羟烷基”为羟基取代的烷基。
本文所用的“任选”、“任选的”或“任选地”意指随后描述的事件可以发生或可以不发生,并且该描述包括所述事件发生的情形以及所述事件不发生的情形。例如,“任选被取代的烷基”包括本文定义的“未取代的烷基”和“被取代的烷基”。“任选被卤素取代”包括“被卤素取代”的情形和“未被卤素取代”的情形,例如被0-3个卤素取代。本领域技术人员应当理解的是,对于含有一个或多个取代基的任意基团而言,所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。
本文所用的术语“取代”、“取代的”或“被……取代”意指给定原子或基团上的一个或多个氢被一个或多个选自给定的取代基组的取代基替换,条件是不超过该给定原子的正常化合价。当取代基是氧代(即=O)时,则单个原子上的两个氢原被氧替换。在芳香族部分上不存在氧代取代基。当环系(例如碳环或杂环)被羰基基团或双键取代时,意欲羰基基团或双键是环的一部分(即,在环内)。只有当取代基和/或变量的组合导致化学上正确的且稳定的化合物时,这类组合才是允许的。化学上正确的且稳定的化合物意味着化合物足够稳定,以至于能从反应混合物中被分离出来并能确定化合物的化学结构,并且随后能被配制成至少具有实际效用的制剂。例如,在没有明确列出取代基的情况下,本文所用的术语“取代”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代。当一个原子或基团被多个取代基取代时,所述取代基可以相同或不同。
除非另有指出,否则术语“本发明化合物”或“本发明的化合物”指包括本发明的一种或多种本文定义的式(I)或其亚式、如式(I-1)、(I-2)等的化合物,或其可药用盐,以及所有异构体如立体异构体(包括非对映异构体、对映异构体和外消旋物)、几何异构体、构象异构体(包括旋转异构体和阻转异构体)、互变异构体、异构体的内部加成产物、前药以及同位素标记的化合物(包括氘取代)和固有形成的部分(例如多晶型物、溶剂合物和/或水合物)。当存在能够形成盐的部分时,则也包括盐、特别是可药用盐。互变异构体或异构体的内部加成产物的存在可由本领域技术人员使用诸如NMR的工具来鉴别。本发明的式(I)化合物能够容易地形成如本文所描绘的互变异构体和异构体的内部加成产物。
本领域技术人员将认可,本发明的化合物可以含有手性中心,照此可以存在不同的异构形式。如本文所用的“异构体”指具有相同分子式、但是原子的排列和构型有区别的不同化合物。
如本文所用,“对映异构体”是相互为不可重叠的镜像的一对立体异构体。一对对映异构体的1:1混合物是"外消旋”混合物。合适时,该术语用于指外消旋混合物。当指示本发明的化合物的立体化学时,采用常规的RS系统指定了具有两个手性中心的已知的相对和绝对构型的单一立体异构体(例如(1S,2S));具有已知的相对构型、但是绝对构型未知的单一立体异构体标示了星号(例如(1R*,2R*));具有两个字母的外消旋物(例如(1RS,2RS)为(1R,2R)和(1S,2S)的外消旋混合物;(1RS,2SR)为(1R,2S)和(1S,2R))的外消旋混合物。"非对映异构体”是具有至少两个不对称原子、但是相互不为镜像的立体异构体。根据Cahn-lngold-Prelog R-S系统指明绝对立体化学。当化合物是纯的对映异构体时,各手性碳处的立体化学可以通过R或S说明。绝对构型未知的被拆分的化合物可以根据它们在钠D线波长处旋转平面偏振光的方向(右旋或左旋)指定为(+)或(-)。或者,被拆分的化合物可以通过相应的对映异构体/非对映异构体经由手性HPLC的各自的保留时间来定义。
本文所述的一些化合物含有一个或多个不对称中心或轴,因此可以产生对映异构体、非对映异构体和可以以绝对立体化学定义为(R)-或(S)-的其它立体异构体。
当化合物含有双键或一些其它的使得分子具有一定量结构刚性的特征时,可以发生几何异构体。如果化合物含有双键,则取代基可以是E或Z构象。如果化合物含有二取代的环烷基,则环烷基取代基可以具有顺式或反式构型。
构象异构体是通过有关一个或多个价键的旋转而不同的异构体。旋转异构体是通过仅单个价键的旋转而不同的构象异构体。
"阻转异构体"指基于分子中的旋转受限所产生的轴向或平面手性的结构异构体。
除非另有说明,否则本发明的化合物意欲包括所有这类可能的异构体,包括外消旋混合物、具有旋光活性的形式和中间体混合物。具有旋光活性的(R)-和(S)-异构体可以采用手性合成子或手性试剂进行制备,或者采用常规技术进行拆分。
本发明的化合物可以分离为具有旋光活性的形式或外消旋形式。用旋光活性的形式可以通过外消旋形式的拆分或通过由具有旋光活性的原料合成来制备。用于制备本发明的化合物的所有方法和其中制备的中间体被认为是本发明的一部分。当制备对映体或非对映异构体产物时,它们可以通过常规方法如通过色谱法或分步结晶来进行分离。
根据方法条件,本发明的终产物以游离(中性)或盐形式获得。这些终产物的游离形式和盐形式在本发明的范围内。如果期望的话,则化合物的一种形式可以转化为其它形式。游离碱或酸可以转化为盐;盐可以转化为游离化合物或其它盐;本发明的同分异构化合物的混合物可以分离为单独异构体。
如本文所用,“药学上可以接受的盐”指保持本发明化合物的生物学效应和性能的盐,并且该盐在生物学上或其它方面不是不被期望的。所述盐的非限制性示例包括本发明化合物的无毒的、无机或有机碱或酸的加成盐。在许多情况下,由于氨基和/或羧基或与之相似的基团的存在,本发明化合物能够形成酸盐和/或碱盐。可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。可以用无机和有机碱形成药学上可接受的碱加成盐。可以由其衍生得到盐的无机碱包括例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等;特别优选的是铵、钾、钠、钙和镁盐。可以由其衍生得到盐的有机碱包括例如伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代的胺)、环状的胺、碱性离子交换树脂等,尤其例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。通过常规化学方法,可以从母体化合物(碱性或酸性部分)合成本发明药学上可以接受的盐。一般来讲,可以如下制备所述的盐:使所述化合物的游离酸形式与化学计算量的适当的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或使所述化合物的游离碱形式与化学计算量的适当的酸反应。这类反应通常在水或有机溶剂或两者的混合溶剂中进行。一般来讲,在可行时,非水介质例如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。其它合适的盐可以见于Remington氏药物科学(Remington's PharmaceuticalSciences),第20版,Mack出版公司(Mack Publishing Company),Easton,Pa.,(1985),将其引入文中作为参考。
本文所给的任意式还意欲代表化合物的未标记的形式以及同位素标记的形式。除了一个或多个原子被具有所选原子质量或质量数的原子所代替外,同位素标记的化合物具有本文所给的式所描述的结构。可以掺入到本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别有2H(即D)、3H(即T)、11C、13C、14C、15N、18F31P、32P、35S、36Cl、125I。本发明包括如本文定义的不同的同位素标记的化合物,例如其中存在放射性同位素如3H、13C和14C的那些。这类同位素标记的化合物可用于代谢研究(用14C)、反应动力学研究(例如用2H或3H)、检测或显像技术、例如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT)、包括药物或底物组织分布测定,或者可用于患者的放射性治疗。特别地,18F或标记的化合物可以特别希望用于PET或SPECT研究。通常可以通过进行下文所述的流程中或实施例和制备例中所述的那些方法、用容易获得的同位素标记的试剂代替未同位素标记的试剂来制备同位素标记的本发明的化合物。
而且,被较重同位素、特别是氘(即2H或D)所取代还可以获得由更大的代谢稳定性引起的某些治疗益处,例如延长体内半衰期或降低剂量要求或改善治疗指数。可以理解,上下文中的氘可被看作是本发明的化合物的取代基。这类较重同位素、特别是氘的浓度可以由同位素富集因子来定义。
如本文所用,本发明化合物的“治疗有效剂量”指可以引起个体生物学或医学反应或改善症状、减慢或延缓疾病恶化或预防疾病等的本发明化合物的量。“治疗有效量”可以由参与医师或兽医执业者来确定,并且将随着化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医执业者的判断等因素而变化。
如本文所用,“个体”指动物。优选地,动物是哺乳动物。个体还指例如灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在一优选实施方案中,个体是人。
如本文所用,“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
如本文所用,“抑制”指特定的病患、症状或病症或疾病的减轻或抑制,或者生物学活性或过程基线活性的显著降低。
以下实施例说明上述本发明,然而其不以任何方式限制本发明的范围。本发明的组合的有益效果也可以通过本领域技术人员已知的其他测试模型确定。
化合物的合成:
本发明中,室温指环境温度,为10℃-35℃。过夜是指8-15小时。回流的温度是指常压下溶剂回流温度。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。MS的测定用Finnigan LCQ/Deca(ESI)质谱仪。高效液相色谱法(HPLC)分析使用Gilson Nebula Series高效液相色谱仪。
薄层层析硅胶板使用烟台黄海HSGF 254或青岛GF 254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。硅胶柱色谱法一般使用烟台黄海硅胶200-300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自上海皓鸿生物医药科技有限公司、毕得医药等公司。实施例中无特殊说明,反应均能够在氩气氛或氮气氛下进行。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂,纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括二氯甲烷/甲醇体系和石油醚/乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
第一步
苯甲酰乙酸乙酯(1g,5.2mmol)和5-氨基-吡唑-3-甲酸乙酯(673mg,4.34mmol)在醋酸溶剂中,80℃的条件下,反应8h。反应液减压除去醋酸之后用柱色谱分离(DCM:MeOH=20:1),得到7-羟基-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸乙酯,产物为白色固体,收率61.07%。
1H NMR(400MHz,DMSO-d6)δ7.96–7.79(m,2H),7.73–7.49(m,3H),6.56(s,1H),6.18(s,1H),4.34(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).
第二步
将7-羟基-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸乙酯(750mg,2.65mmol)溶于冰浴的三氯氧磷(15ml)中,搅拌五分钟之后撤去冰浴,80℃反应3h,直到TLC显示原料消耗完全,减压除去三氯氧磷,之后将反应液倾入到冰水中,再加入饱和碳酸氢钠水溶液,调节pH到7左右,乙酸乙酯(EA)萃取,无水硫酸钠干燥,柱色谱分离(PE:EA=5:1,v:v),得到7-氯-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸乙酯,产物为白色固体,收率52.58%。
1H NMR(400MHz,DMSO-d6)δ8.33–8.24(m,3H),7.59(p,J=3.9Hz,3H),7.35(s,1H),4.42(q,J=7.1Hz,2H),1.37(t,J=7.2Hz,3H).
第三步
将7-氯-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸乙酯(420mg,1.39mmol)溶解在二氧六环(10ml)中,加入3-羟基吡咯烷(146mg,1.67mmol)和二异丙基乙基胺(DIPEA)(0.5ml),室温反应8h,TLC显示原料消耗完全,柱色谱分离(DCM:MeOH=30:1,v:v),得到化合物1:7-(3-羟基吡咯烷-1-基)-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸乙酯,产物为白色固体,收率67.28%。
1H NMR(400MHz,Chloroform-d)δ7.99–7.93(m,2H),7.54–7.40(m,3H),6.94(s,1H),6.18(s,1H),4.67(s,1H),4.43(q,J=7.1Hz,2H),4.28(d,J=2.8Hz,2H),4.09(q,J=9.4,8.9Hz,1H),3.99(dq,J=10.8,6.3,5.0Hz,1H),2.16(tt,J=9.2,5.1Hz,2H),1.43(t,J=7.1Hz,3H).MS(ESI):m/z=353.18[M+H]+
第四步
将原料7-(3-羟基吡咯烷-1-基)-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸乙酯(330mg,1.39mmol)溶于甲醇/水溶液(10ml,v:v=1:1),之后滴加氢氧化锂(10%)溶液,在室温条件下搅拌3h,减压除去溶剂,之后用EA萃取,水相使用2M盐酸调节pH到2左右,再使用EA萃取三次,合并有机相,使用无水硫酸钠干燥有机相,柱色谱分离(DCM:MeOH=15:1,v:v)得到7-(3-羟基吡咯烷-1-基)-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸,产物为白色固体,收率72.43%
1H NMR(400MHz,Methanol-d4)δ8.09–7.92(m,2H),7.49(dd,J=8.8,3.9Hz,3H),6.77(s,1H),6.29(s,1H),4.62–4.55(m,1H),4.31(d,J=2.9Hz,2H),4.14(dd,J=9.0,5.0Hz,2H),2.21–2.12(m,2H).MS(ESI):m/z=325.20[M+H]+
第五步
将7-(3-羟基吡咯烷-1-基)-5-苯基吡唑并[1,5-a]嘧啶-2-羧酸(80mg,0.25mmol),DIPEA(64mg,0.49mmol)和环丙胺(16mg,0.28mmol)溶于DMF,加入HATU(283mg,0.74mmol),室温反应12h,反应液用EA萃取、饱和氯化钠体系洗涤后,有机相用2M的盐酸、水和5%的碳酸氢钠依次洗涤,有机相用无水硫酸钠干燥之后,柱色谱分离(DCM:MeOH=20:1)得到化合物1:N-环丙基-7-(3-羟基吡咯烷-1-基)-5-苯基吡唑并[1,5-a]嘧啶-2-甲酰胺,产物为白色固体,收率44.62%。
1H NMR(400MHz,DMSO-d6)δ8.29(d,J=4.1Hz,1H),8.15(dd,J=7.3,2.5Hz,2H),7.50(dd,J=5.0,2.2Hz,3H),6.69(s,1H),6.50(s,1H),5.12(d,J=3.4Hz,1H),4.46(s,1H),4.19–4.09(m,2H),2.95(s,2H),2.84(dt,J=7.2,3.8Hz,2H),2.08–1.97(m,4H).
MS(ESI):m/z=364.26[M+H]+
实施例2
采用实施例1的合成路线,将第五步原料环丙胺替换为环己胺制得化合物2:N-环己基-7-(3-羟基吡咯烷-1-基)-5-苯基吡唑并[1,5-a]嘧啶-2-甲酰胺,产物为白色固体,收率45.55%。
1H NMR(400MHz,DMSO-d6)δ8.21–8.12(m,2H),7.94(d,J=8.4Hz,1H),7.50(dd,J=5.1,2.1Hz,3H),6.70(s,1H),6.51(s,1H),5.14(d,J=3.4Hz,1H),4.47(s,1H),4.24–4.00(m,3H),3.80(d,J=6.9Hz,1H),2.04(d,J=26.0Hz,2H),1.82(d,J=11.5Hz,2H),1.74(d,J=12.6Hz,2H),1.62(d,J=12.9Hz,1H),1.47–1.20(m,8H).
MS(ESI):m/z=406.20[M+H]+
实施例3
第一步
苯甲酰乙酸乙酯(500mg,2.6mmol)和3-氨基吡唑(180.12mg,2.17mmol)在醋酸溶剂中,80℃的条件下,反应8h,得到5-苯基吡唑并[1,5-a]嘧啶-7-醇,减压除去醋酸之后用水和二氯甲烷分别洗涤得到粗产物5-苯基吡唑并[1,5-a]嘧啶-7-醇,不需要进一步纯化,产物为白色固体,收率65.52%。
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.90(d,J=1.9Hz,1H),7.89–7.78(m,2H),7.59(dd,J=5.2,1.9Hz,3H),6.22(d,J=2.0Hz,1H),6.06(s,1H).
第二步
将5-苯基吡唑并[1,5-a]嘧啶-7-醇(330mg,1.56mmol)分批小心地加入到冰浴的三氯氧磷(15ml)中,搅拌一段时间撤去冰浴,加热80℃反应3h,直到TLC显示原料消耗完全,减压除去三氯氧磷,之后将反应液倾入到冰水中,再加入饱和碳酸氢钠水溶液,调节pH到7左右,EA萃取,有机相无水硫酸钠干燥,柱色谱分离(PE:EA=5:1,v:v),得到7-氯-5-苯基吡唑并[1,5-a]嘧啶,产物为白色固体,收率55.74%。
1H NMR(400MHz,DMSO-d6)δ8.35(d,J=2.3Hz,1H),8.27–8.21(m,2H),8.05(s,1H),7.60–7.49(m,3H),6.91(d,J=2.2Hz,1H).
第三步
将7-氯-5-苯基吡唑并[1,5-a]嘧啶(200mg,0.87mmol)溶解在二氧六环中,加入3-羟基吡咯烷(151.74mg,1.74mmol)和DIPEA(337.65mg,2.61mmol),室温反应8h得到化合物3:1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,收率65.54%。
1H NMR(400MHz,Methanol-d4)δ8.01–7.93(m,3H),7.53–7.45(m,3H),6.38(d,J=2.3Hz,1H),6.25(s,1H),4.56(tt,J=4.1,2.5Hz,1H),4.22(d,J=4.0Hz,2H),4.11(dd,J=9.7,5.9Hz,2H),2.22–2.10(m,2H).
实施例4
采用实施例1的合成路线,将第三步原料吡咯烷醇替换为(S)-3-吡咯烷醇制得化合物4:(S)-1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,收率66.54%。
1H NMR(400MHz,Chloroform-d)δ8.01–7.94(m,2H),7.92(d,J=2.3Hz,1H),7.51–7.40(m,3H),6.48(d,J=2.3Hz,1H),6.06(s,1H),4.63(p,J=3.2Hz,1H),4.20(d,J=3.1Hz,2H),4.05(dt,J=10.3,8.6Hz,1H),3.97(dt,J=10.6,5.5Hz,1H),2.13(ddt,J=8.9,5.8,2.5Hz,2H).
实施例5
采用实施例1的合成路线,将第三步原料吡咯烷醇替换为(R)-3-吡咯烷醇制得化合物5:(R)-1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,收率53.25%。
1H NMR(400MHz,Chloroform-d)δ8.02–7.96(m,2H),7.94(d,J=2.2Hz,1H),7.51–7.41(m,3H),6.50(d,J=2.3Hz,1H),6.13(s,1H),4.67(p,J=3.1Hz,1H),4.24(d,J=2.9Hz,2H),4.11(td,J=9.9,8.0Hz,1H),4.02(dt,J=10.7,5.0Hz,1H),2.18–2.13(m,2H).
实施例6
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采用实施例1的合成路线,将第三步原料吡咯烷醇替换为(3S,5S)-5-(羟甲基)吡咯烷-3-醇制得化合物6:(3S,5S)-5-(羟甲基)-1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,收率39.22%。
1H NMR(400MHz,Chloroform-d)δ7.69–7.51(m,3H),7.30(d,J=6.9Hz,3H),6.21(d,J=2.2Hz,1H),5.74(s,1H),4.81(tt,J=7.4,3.5Hz,1H),4.72–4.47(m,2H),4.39(q,J=4.3,3.6Hz,1H),3.61(td,J=8.9,4.4Hz,2H),2.11(dt,J=12.6,5.4Hz,1H).
实施例7
采用实施例1的合成路线,将第三步原料吡咯烷醇替换为(3R,4R)-吡咯烷-3,4-二醇制得化合物7:(3R,4R)-1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3,4-二醇,产物为白色固体,收率37.50%。
1H NMR(400MHz,DMSO-d6)δ8.18–8.11(m,2H),8.03(d,J=2.3Hz,1H),7.54–7.44(m,3H),6.43–6.38(m,2H),5.31(d,J=3.0Hz,2H),4.09(t,J=3.3Hz,2H),4.03(q,J=7.1Hz,2H).
实施例8
将化合物3(50mg,0.18mmol)溶解在冰浴的THF中,滴加戴斯-马丁氧化剂(DMP)(381mg,0.90mmol)的THF溶液,搅拌五分钟后撤去冰浴,升至室温后反应4h,直到TLC显示原料消耗完全,加入饱和碳酸氢钠溶液洗涤,再使用饱和硫代硫酸钠溶液洗涤,EA萃取,有机相使用无水硫酸钠干燥,柱色谱分离(DCM:MeOH=50:1)得到化合物8:1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-酮,产物为白色固体,收率41.11%。
实施例9
采用实施例1的合成路线,将第三步原料吡咯烷醇替换为(S)-吡咯烷-3-基氨基甲酸叔丁酯。第三步之后采用盐酸二氧六环脱除boc保护基得到化合物9:(S)-1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-胺,产物为白色固体,两步收率54.33%。
1H NMR(400MHz,DMSO-d6)δ8.47(s,3H),8.20(d,J=2.2Hz,1H),8.12(dd,J=6.7,3.0Hz,2H),7.59(h,J=5.0,4.4Hz,3H),6.56(d,J=3.0Hz,2H),4.51(s,2H),4.16(d,J=36.8Hz,2H),2.37(dt,J=11.0,4.2Hz,1H),2.28–2.17(m,1H),1.99(dt,J=13.3,6.9Hz,1H).
实施例10
采用实施例9的合成路线,将第三步原料(S)-吡咯烷-3-基氨基甲酸叔丁酯替换为(R)-吡咯烷-3-基氨基甲酸叔丁酯制得化合物10:(R)-1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-胺,产物为白色固体,两步收率49.33%。
1H NMR(400MHz,DMSO-d6)δ8.51(s,3H),8.23–8.13(m,2H),8.06(d,J=2.3Hz,1H),7.56–7.46(m,3H),6.45(d,J=1.8Hz,2H),4.41(d,J=4.5Hz,2H),4.08(q,J=8.6,8.0Hz,1H),3.97(s,2H),2.34(dt,J=14.3,6.9Hz,1H),2.21(dq,J=12.0,6.9,5.6Hz,1H).
实施例11
采用实施例3的合成路线,将第三步原料吡咯烷醇替换为(S)-2-氨基丙-1-醇得到化合物11:(S)-2-((5-苯基吡唑并[1,5-a]嘧啶-7-基)氨基)丙-1-醇。产物为白色固体,收率34.24%。
1H NMR(400MHz,Chloroform-d)δ8.00(dd,J=5.6,2.6Hz,3H),7.47(q,J=6.9Hz,3H),6.55(q,J=2.3Hz,1H),6.42(d,J=5.3Hz,1H),4.09–3.94(m,1H),3.89(dt,J=10.6,4.7Hz,1H),3.77(dt,J=11.1,5.5Hz,1H),1.43(t,J=6.1Hz,3H).
实施例12
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采用实施例3的合成路线,将第三步原料吡咯烷醇替换为氮杂环丁烷-3-醇得到化合物12:1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)氮杂环丁烷-3-醇。产物为白色固体,收率36.65%。
1H NMR(500MHz,DMSO-d6)δ8.16–8.11(m,2H),8.03(d,J=2.3Hz,1H),7.53–7.45(m,3H),6.41(d,J=2.3Hz,1H),6.32(s,1H),5.87(d,J=6.3Hz,1H),4.75(s,2H),4.67–4.62(m,1H),4.26(s,2H).MS(ESI):m/z=267.20[M+H]+
实施例13
采用实施例3的合成路线,将第三步原料吡咯烷醇替换为氮杂环丁烷-3-基甲醇得到化合物13:(1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)氮杂环丁烷-3-基)甲醇。产物为白色固体,收率49.16%。
1H NMR(400MHz,Chloroform-d)δ8.02–7.96(m,2H),7.94(d,J=2.3Hz,1H),7.52–7.42(m,3H),6.47(d,J=2.3Hz,1H),5.96(s,1H),4.63(t,J=8.7Hz,2H),4.43–4.30(m,2H),3.03(ddq,J=14.3,8.3,6.0Hz,1H).MS(ESI):m/z=281.26[M+H]+
实施例14
采用实施例3的合成路线,将第三步原料吡咯烷醇替换为哌啶-4-醇得到化合物14:1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)哌啶-4-醇。产物为白色固体,收率29.16%。
1H NMR(400MHz,Chloroform-d)δ8.08(d,J=2.3Hz,1H),8.05–7.99(m,2H),7.53–7.43(m,3H),6.63(d,J=2.3Hz,1H),6.56(s,1H),4.16(dt,J=12.4,3.4Hz,2H),4.06(td,J=8.5,8.0,4.5Hz,1H),3.49(ddd,J=12.3,8.8,3.3Hz,2H),2.20–2.10(m,2H),1.86(dtd,J=12.5,8.5,3.7Hz,2H).
实施例15
采用实施例3的合成路线,将第三步原料吡咯烷醇替换为哌啶-3-醇得到化合物15:1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)哌啶-3-醇。产物为白色固体,收率39.16%。
1H NMR(400MHz,DMSO-d6)δ8.23–8.09(m,3H),7.59–7.46(m,3H),6.82(s,1H),6.57(d,J=2.3Hz,1H),5.01(d,J=4.3Hz,1H),4.35(dd,J=12.3,3.8Hz,1H),4.13(d,J=12.8Hz,1H),3.75(tt,J=8.7,4.3Hz,1H),3.19(dd,J=12.2,8.5Hz,1H),2.02–1.85(m,2H),1.73–1.58(m,1H),1.49(q,J=10.5,8.8Hz,1H).
实施例16
采用实施例3的合成路线,将第三步原料吡咯烷醇替换为吗啉得到化合物16:4-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吗啉。产物为白色固体,收率32.77%。
1H NMR(400MHz,Chloroform-d)δ8.05(d,J=2.3Hz,1H),8.00(dd,J=7.5,2.0Hz,2H),7.50–7.42(m,3H),6.63(d,J=2.3Hz,1H),6.50(s,1H),4.04–3.93(m,4H),3.74(dd,J=5.8,3.4Hz,4H).
实施例17
第一步
将丙二酸二乙酯(3.86g,24.07mmol)和3-氨基吡唑(2.00g,24.07mmol)溶于乙醇(20ml)中,加入新制的乙醇钠(16.38g,240.69mmol),回流反应6h后,调节pH到3,用水和DCM洗涤之后取固体干燥,无需进一步纯化直接进行下一步反应,产物为白色,收率60.48%。
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),10.53(s,1H),7.60(d,J=2.3Hz,1H),6.48(d,J=2.3Hz,1H).MS(ESI):m/z=152.02[M+H]+
第二步
将吡唑并[1,5-a]嘧啶-5,7-二醇的(2.2g,14.56mmol)溶于冰浴的三氯氧磷(25ml)中,搅拌五分钟之后撤去冰浴,80℃反应3h,直到TLC显示原料消耗完全,减压除去三氯氧磷,之后将反应液倾入到冰水中,再加入饱和碳酸氢钠水溶液,调节pH到7左右,EA萃取,柱色谱分离(PE:EA=5:1,v:v),得到5,7-二氯吡唑并[1,5-a]嘧啶,产物为白色固体,收率40.19%。
1H NMR(400MHz,DMSO-d6)δ8.39(d,J=2.3Hz,1H),7.67(s,1H),6.89(d,J=2.3Hz,1H).
第三步
将5,7-二氯吡唑并[1,5-a]嘧啶(1.10g,5.85mmol)溶解在二氧六环(15ml)中,加入3-羟基吡咯烷(612mg,7.02mmol)和DIPEA,室温反应3h,TLC显示原料消耗完全,EA萃取,无水硫酸钠干燥,柱色谱分离(DCM:MeOH=30:1,v:v),得到1-(5-氯吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,收率57.29%。
1H NMR(400MHz,DMSO-d6)δ8.04(d,J=2.2Hz,1H),6.33(d,J=2.2Hz,1H),5.95(s,1H),5.12(d,J=3.5Hz,1H),4.44–4.34(m,1H),4.00(s,3H),1.98(dddd,J=19.1,14.5,7.7,3.6Hz,2H).
第四步
将1-(5-氯吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇(40mg,0.17mmol),和2 2-氨基苯硼酸频哪醇酯(47mg,0.21mmol),以及K2CO3(71mg,0.51mmol)溶于溶剂(5ml,二氧六环:水=3:1)中,脱气5分钟后,加入1,1'-双二苯基膦二茂铁二氯化钯催化剂(10mg,0.01mmol),N2保护,80℃反应8h,原料消耗完全后,EA/H2O体系萃取,柱色谱分离(DCM:MeOH=30:1)得到化合物17:1-(5-(2-氨基苯基)吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,产率19.39%。
1H NMR(400MHz,Chloroform-d)δ7.92(d,J=2.3Hz,1H),7.52(dd,J=7.7,1.6Hz,1H),7.21–7.14(m,1H),6.75(t,J=8.6Hz,2H),6.37(d,J=2.3Hz,1H),6.06(s,1H),4.65(dq,J=5.8,2.8Hz,1H),4.26–4.16(m,2H),4.09(td,J=9.9,7.4Hz,1H),4.00(ddd,J=10.7,7.5,3.8Hz,1H),2.15(dt,J=10.3,3.9Hz,2H).
实施例18
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为3-氟苯硼酸得到化合物18:1-(5-(3-氟苯基)吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率41.60%。
1H NMR(400MHz,Chloroform-d)δ7.97(d,J=2.3Hz,1H),7.79(dt,J=7.8,1.3Hz,1H),7.73(dt,J=10.2,2.2Hz,1H),7.45(td,J=8.0,5.8Hz,1H),7.20–7.10(m,1H),6.52(d,J=2.3Hz,1H),6.11(s,1H),4.70(p,J=3.2Hz,1H),4.28(d,J=3.3Hz,2H),4.20–4.10(m,1H),4.05(dt,J=10.7,5.5Hz,1H),2.19(ddt,J=8.7,5.7,2.4Hz,2H).MS(ESI):m/z=299.24[M+H]+
实施例19
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为3-氨基苯硼酸频哪醇酯得到化合物19:1-(5-(3-氨基苯基)吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率40.41%。
1H NMR(400MHz,DMSO-d6)δ7.91(d,J=2.3Hz,1H),7.78(d,J=8.6Hz,2H),6.64(d,J=8.6Hz,2H),6.26(d,J=2.3Hz,1H),6.17(s,1H),5.49–5.33(m,3H),4.41(s,2H),2.01(dq,J=9.1,4.4Hz,1H),1.94(s,2H).
实施例20
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为4-氨基苯硼酸频哪醇酯得到化合物20:1-(5-(4-氨基苯基)吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率27.16%。
1H NMR(500MHz,Chloroform-d)δ7.91(d,J=2.3Hz,1H),7.88–7.83(m,2H),6.78–6.72(m,2H),6.42(d,J=2.3Hz,1H),6.10(s,1H),4.66(s,1H),4.29–4.16(m,2H),4.14–4.09(m,1H),4.03–3.96(m,1H),2.19–2.11(m,2H).
实施例21
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)硼酸得到化合物21:4-(7-(3-羟基吡咯烷-1-基)吡唑并[1,5-a]嘧啶-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯。产物为白色固体,收率43.34%。
1H NMR(400MHz,Chloroform-d)δ7.89(t,J=2.0Hz,1H),6.53(s,1H),6.38(t,J=1.9Hz,1H),5.75(s,1H),4.63(d,J=4.2Hz,1H),4.26–4.09(m,4H),4.03(q,J=9.1Hz,1H),3.92(dt,J=10.4,5.5Hz,1H),3.62(t,J=5.7Hz,2H),2.63(s,2H),2.13(p,J=4.1Hz,2H).MS(ESI):m/z=386.14[M+H]+
实施例22
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为二苯并[b,d]呋喃-4-基硼酸得到化合物22:1-(5-(二苯并[b,d]呋喃-4-基)吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率54.13%。
1H NMR(600MHz,Chloroform-d)δ8.27(dd,J=7.8,1.3Hz,1H),8.00(dd,J=7.6,1.3Hz,1H),7.99–7.95(m,2H),7.62(d,J=8.2Hz,1H),7.48(ddd,J=10.2,8.7,7.4Hz,2H),7.38(t,J=7.5Hz,1H),6.90(s,1H),6.55(d,J=2.2Hz,1H),4.72(d,J=4.0Hz,1H),4.38–4.28(m,2H),4.22(q,J=9.0Hz,1H),4.16(dt,J=11.1,5.8Hz,1H),1.55–1.47(m,2H).
MS(ESI):m/z=325.25[M+H]+
实施例23
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为(2-甲基丙-1-烯-1-基)硼酸得到化合物23:1-(5-(2-甲基丙-1-烯-1-基)吡唑[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率53.90%。
1H NMR(400MHz,Chloroform-d)δ7.84(d,J=2.3Hz,1H),6.31(d,J=2.3Hz,1H),6.18–6.10(m,1H),5.50(s,1H),4.58(dd,J=5.1,2.5Hz,1H),4.19–4.05(m,2H),3.98(td,J=10.0,7.4Hz,1H),3.84(ddd,J=10.6,7.5,3.6Hz,1H),2.14–2.07(m,2H),2.06(s,3H),1.92(s,3H).
实施例24
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为环丙基硼酸得到化合物24:1-(5-环丙基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率60.61%。
1H NMR(400MHz,Chloroform-d)δ7.84(d,J=2.3Hz,1H),6.25(d,J=2.3Hz,1H),5.54(s,1H),4.62(p,J=3.2Hz,1H),4.14(d,J=2.9Hz,2H),4.07–3.95(m,1H),3.89(dt,J=10.6,5.6Hz,1H),2.12(ddd,J=8.8,6.0,3.5Hz,2H),1.93–1.89(m,1H),1.05(td,J=6.1,5.4,2.7Hz,2H),0.97(dq,J=8.1,2.6,1.8Hz,3H).
实施例25
第一步
将3-环丁基-3-氧代丙酸乙酯(250mg,1.47mmol)和3-氨基吡唑(102mg,1.22mmol)溶解在醋酸溶剂中,80℃的条件下,反应8h,得到5-环丁基吡唑并[1,5-a]嘧啶-7-醇,减压除去醋酸之后用水和二氯甲烷分别洗涤得到粗产物,不需要进一步纯化,产物为白色固体,收率51.81%。
MS(ESI):m/z=190.27[M+H]+
第二步
将5-环丁基吡唑并[1,5-a]嘧啶-7-醇(120mg,0.63mmol)分批小心地加入到零度的三氯氧磷(10ml)中,之后搅拌一段时间撤去冰浴,加热80℃反应3h,直到TLC显示原料消耗完全,减压除去三氯氧磷,之后将反应液倾入到冰水中,再加入饱和碳酸氢钠水溶液,调节pH到7左右,EA萃取,有机相用无水硫酸钠干燥后,柱色谱分离(PE:EA=5:1,v:v),得到7-氯-5-环丁基吡唑并[1,5-a]嘧啶,产物为白色固体,收率49.36%。
1H NMR(400MHz,Chloroform-d)δ8.16(d,J=2.3Hz,1H),6.84(s,1H),6.71(d,J=2.3Hz,1H),3.77–3.61(m,1H),2.46–2.36(m,4H),2.19–2.04(m,1H),2.02–1.88(m,1H).
第三步
将7-氯-5-环丁基吡唑并[1,5-a]嘧啶(65mg,0.3mmol)溶解在二氧六环(3ml)中,加入3-羟基吡咯烷(33mg,0.38mmol)和DIPEA(121mg,0.94mmol),室温反应8h得到化合物25:1-(5-环丁基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,收率55.65%。
1H NMR(500MHz,Chloroform-d)δ7.82(d,J=2.2Hz,1H),6.30(d,J=2.3Hz,1H),5.47(s,1H),4.59(dp,J=4.3,2.0Hz,1H),4.23–4.07(m,2H),3.98(td,J=10.0,7.2Hz,1H),3.85(ddd,J=10.6,7.9,3.2Hz,1H),3.58–3.48(m,1H),2.29(tdd,J=9.8,5.4,4.2Hz,4H),2.14–2.05(m,2H),2.04–1.96(m,1H),1.91–1.79(m,1H).
实施例26
采用实施例17的合成路线,将第四步原料2-氨基苯硼酸频哪醇酯替换为环戊-1-烯-1-基硼酸得到化合物26:1-(5-(环戊-1-烯-1-基)吡唑[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率54.44%。
1H NMR(400MHz,Chloroform-d)δ7.85(d,J=2.3Hz,1H),6.59(p,J=2.3Hz,1H),6.38(d,J=2.2Hz,1H),5.73(s,1H),4.61(dq,J=4.1,2.1Hz,1H),4.24–4.09(m,2H),4.00(td,J=10.0,7.5Hz,1H),3.87(ddd,J=10.6,7.4,3.7Hz,1H),2.77(tq,J=7.1,2.3Hz,2H),2.57(ddt,J=10.2,7.6,2.6Hz,2H),2.15–2.10(m,2H),2.04(q,J=7.6Hz,3H).MS(ESI):m/z=271.43[M+H]+
实施例27
将化合物26(50mg,0.18mmol)溶解在甲醇(15ml)中,加入钯碳(8mg,15%),在常压条件下室温进行氢化反应,反应时长3小时,反应结束后抽滤除去钯碳(用过的钯碳易燃需要单独处理),减压抽干溶剂,柱色谱分离(DCM:MeOH=30:1,v:v)得到产物透明油状,得到化合物27:1-(5-环戊基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,收率66%。
1H NMR(500MHz,Chloroform-d)δ7.79(d,J=2.2Hz,1H),6.27(d,J=2.2Hz,1H),5.55(s,1H),4.56(dq,J=4.3,2.2Hz,1H),4.15–4.05(m,2H),3.98(td,J=9.9,7.4Hz,1H),3.85(ddd,J=10.6,7.5,3.7Hz,1H),3.06–2.94(m,1H),2.11–1.97(m,4H),1.84–1.69(m,4H),1.69–1.58(m,2H).
实施例28
采用实施例25的合成路线,将第一步3-环丁基-3-氧代丙酸乙酯替换为3-环己基-3-氧代丙酸乙酯得到化合物28:1-(5-cyclohexylpyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-ol 1-(5-环己基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇。产物为白色固体,收率59.86%。
1H NMR(400MHz,Chloroform-d)δ7.86(dd,J=2.4,1.0Hz,1H),6.33(dd,J=2.3,1.0Hz,1H),5.62(d,J=1.2Hz,1H),4.63(p,J=3.2Hz,1H),4.17(t,J=2.6Hz,2H),4.09–3.97(m,1H),3.92(dt,J=10.7,5.2Hz,1H),2.57(tt,J=12.0,3.4Hz,1H),2.12(dt,J=8.4,3.6Hz,2H),1.94(d,J=12.7Hz,2H),1.84(dt,J=12.8,3.2Hz,2H),1.79–1.66(m,2H),1.52(qd,J=12.3,3.0Hz,2H),1.39(ddt,J=15.6,12.4,6.2Hz,2H).
实施例29
第一步
将苯甲酰乙酸乙酯(500mg,2.6mmol)和3-氨基吡唑(180.12mg,2.17mmol)溶解在醋酸溶剂中,80℃的条件下,反应8h,得到5-苯基吡唑并[1,5-a]嘧啶-7-醇,减压除去醋酸之后用水和二氯甲烷分别洗涤得到粗产物5-苯基吡唑并[1,5-a]嘧啶-7-醇,不需要进一步纯化,产物为白色固体,收率65.52%。
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.90(d,J=1.9Hz,1H),7.89–7.78(m,2H),7.59(dd,J=5.2,1.9Hz,3H),6.22(d,J=2.0Hz,1H),6.06(s,1H).
第二步
将5-苯基吡唑并[1,5-a]嘧啶-7-醇(330mg,1.56mmol)分批小心地加入到冰浴的三氯氧磷(15ml)中,之后搅拌一段时间撤去冰浴,加热80℃反应3h,直到TLC显示原料消耗完全,减压除去三氯氧磷,之后将反应液倾入到冰水中,再加入饱和碳酸氢钠水溶液,调节pH到7左右,EA萃取,无水硫酸钠干燥,柱色谱分离(PE:EA=5:1,v:v),得到7-氯-5-苯基吡唑并[1,5-a]嘧啶,产物为白色固体,收率55.74%。
1H NMR(400MHz,DMSO-d6)δ8.35(d,J=2.3Hz,1H),8.27–8.21(m,2H),8.05(s,1H),7.60–7.49(m,3H),6.91(d,J=2.2Hz,1H).
第三步
将中间体7-氯-5-苯基吡唑并[1,5-a]嘧啶(150mg,0.65mmol)溶解在氯仿中,分批加入NCS(105mg,0.78mmol),加热60℃反应6h,EA萃取有机相,干燥后柱色谱分离(DCM:MeOH=50:1)得到产物3,7-二氯-5-苯基吡唑并[1,5-a]嘧啶,产物为白色固体,收率46.38%。
第四步
将3,7-二氯-5-苯基吡唑并[1,5-a]嘧啶(274mg,0.87mmol)溶解在二氧六环中,加入3-羟基吡咯烷(151.74mg,1.74mmol)和DIPEA(337.65mg,2.61mmol),室温反应8h得到化合物29:1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色固体,收率44.31%。
1H NMR(500MHz,Chloroform-d)δ8.07–7.99(m,2H),7.88(s,1H),7.51–7.43(m,3H),6.12(s,1H),4.65(p,J=3.2Hz,1H),4.19(d,J=3.5Hz,2H),4.10–3.97(m,2H),2.14(ddd,J=8.7,6.4,3.5Hz,2H).
实施例30
第一步
将苯甲酰乙酸乙酯(500mg,2.6mmol)和3-氨基吡唑(180.12mg,2.17mmol)溶解在醋酸溶剂中,80℃的条件下,反应8h,5-苯基吡唑并[1,5-a]嘧啶-7-醇被得到,减压除去醋酸之后用水和二氯甲烷分别洗涤得到粗产物5-苯基吡唑并[1,5-a]嘧啶-7-醇,不需要进一步纯化,产物为白色固体,收率65.52%。
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.90(d,J=1.9Hz,1H),7.89–7.78(m,2H),7.59(dd,J=5.2,1.9Hz,3H),6.22(d,J=2.0Hz,1H),6.06(s,1H).
第二步
将5-苯基吡唑并[1,5-a]嘧啶-7-醇(330mg,1.56mmol)分批小心地加入到冰浴的三氯氧磷(15ml)中,之后搅拌一段时间撤去冰浴,加热80℃反应3h,直到TLC显示原料消耗完全,减压除去三氯氧磷,之后将反应液倾入到冰水中,再加入饱和碳酸氢钠水溶液,调节pH到7左右,EA萃取,无水硫酸钠干燥,柱色谱分离(PE:EA=5:1,v:v),得到7-氯-5-苯基吡唑并[1,5-a]嘧啶,产物为白色固体,收率55.74%。
1H NMR(400MHz,DMSO-d6)δ8.35(d,J=2.3Hz,1H),8.27–8.21(m,2H),8.05(s,1H),7.60–7.49(m,3H),6.91(d,J=2.2Hz,1H).
第三步
将7-氯-5-苯基吡唑并[1,5-a]嘧啶(200mg,0.87mmol)溶解在二氧六环中,加入3-羟基吡咯烷(151.74mg,1.74mmol)和DIPEA(337.65mg,2.61mmol),室温反应8h得到1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色,收率65.54%。
1H NMR(400MHz,Methanol-d4)δ8.01–7.93(m,3H),7.53–7.45(m,3H),6.38(d,J=2.3Hz,1H),6.25(s,1H),4.56(tt,J=4.1,2.5Hz,1H),4.22(d,J=4.0Hz,2H),4.11(dd,J=9.7,5.9Hz,2H),2.22–2.10(m,2H).
第四步
将化合物1-(5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇(80mg,0.29mmol)溶解在氯仿(5ml)中,分批加入NCS(46mg,0.34mmol),加热60℃反应6h,EA萃取有机相,干燥后柱色谱分离(DCM:MeOH=50:1)得到化合物30:1-(6-氯-5-苯基吡唑并[1,5-a]嘧啶-7-基)吡咯烷-3-醇,产物为白色,收率55.66%。
1H NMR(400MHz,Chloroform-d)δ8.03(d,J=2.3Hz,1H),7.73–7.67(m,2H),7.47(qd,J=4.3,1.5Hz,3H),6.64(d,J=2.4Hz,1H),4.60(dt,J=4.9,3.1Hz,1H),4.33–4.28(m,1H),4.15(dt,J=10.2,8.2Hz,1H),3.99–3.92(m,1H),3.88(dd,J=12.0,3.6Hz,1H),2.20(ddt,J=7.2,5.9,2.9Hz,2H).
MS(ESI):m/z=315.20[M+H]+
实验例:生物活性测试
CD73酶活测定
1.测试方式:使用Promega公司的CTG-KIT试剂盒进行CD73的活性测定;
2检测操作:将4μL酶和1μL不同浓度的待测化合物分别加入384反应板中预孵育0.5小时,加入4μL底物(ATP和AMP)室温孵育40分钟,用CTG-KIT试剂盒检测酶活性。同时用DMSO替代待测化合物设置溶剂对照组和空白对照组,反应终体积为15μL,具体反应体系为2%DMSO,50ng/mlCD73,100μM ATP,300μM AMP,数据处理以浓度的对数值对活性百分数作图,
3数据处理:采用非线性回归计算出拟合曲线,利用软件GraphPad Prism 5公式log(inhibitor)vs.response-Variable slope计算得到IC50值。结果见表1。
表1化合物对CD73酶活抑制结果
化合物 | IC50 | 化合物 | IC50 |
1 | + | 16 | + |
2 | + | 17 | + |
3 | ++ | 18 | ++ |
4 | ++ | 19 | + |
5 | ++ | 20 | ++ |
6 | + | 21 | ++ |
7 | ++ | 22 | + |
8 | + | 23 | ++ |
9 | + | 24 | +++ |
10 | + | 25 | ++ |
11 | + | 26 | ++ |
12 | ++ | 27 | +++ |
13 | ++ | 28 | ++ |
14 | + | 29 | + |
15 | + | 30 | + |
注:“+”表示化合物对CD73的抑制的IC50值>10μM;“++”表示IC50值在1-10μM之间;“+++”表示IC50值<1μM。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.通式(I)所示的吡唑并嘧啶化合物,或其前体药物、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物、其药学上可以接受的盐、多晶型物、溶剂化物或经同位素标记的化合物在制备CD73抑制剂中的用途,尤其是在制备治疗和/或预防CD73相关疾病、失调和病症的药物中的用途:
其中:
A选自氢、卤素、C1-C6烷基、-C(=O)NR5R6、-C(=S)NR5R6、-SO2NR5R6、-S(=O)NR5R6、-CH2NR5R6、或-C(=O)OR5,其中R5和R6独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、3-10元杂环基、C6-C12芳基或5-10元杂芳基;所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、3-10元杂环基、C6-C12芳基或5-10元杂芳基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代;
B选自氢、卤素、C1-C6烷基、C2-C6烯基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-10元杂环基;所述C1-C6烷基、C2-C6烯基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-10元杂环基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代;
R1、R2独立地选自氢、卤素、C1-C6烷基、C3-C10饱和或不饱和环烃基;
R3和R4各自独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-10元杂环基,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-10元杂环基任选地被一个或多个选自W1组的取代基取代;或者
R3和R4与其连接的N原子共同形成含有1-4个选自N、O和S中的杂原子的单环、螺环或桥环,所述单环、螺环或桥环任选地被一个或多个选自W1组的取代基取代;
所述W1组取代基包括D、卤素、氧代(=O)、C1-C6烷基、羟基、C1-C6羟烷基、-NR7R8、氰基、硝基、羧基;
R7、R8各自独立地选自氢、C1-C6烷基、C3-C10饱和或不饱和环烃基;所述C1-C6烷基、C3-C10饱和或不饱和环烃基任选地被一个或多个选自W2组的取代基取代,所述W2组取代基包括D、卤素、羟基、-NH2、C1-C3烷基。
2.根据权利要求1所述的用途,其特征在于,
A选自氢、卤素、C1-C4烷基、-C(=O)NR5R6;和/或
R5和R6独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7饱和或不饱和环烃基、3-7元杂环基、C6-C12芳基或5-10元杂芳基;所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7饱和或不饱和环烃基、3-7元杂环基、C6-C12芳基或5-10元杂芳基任选被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代;和/或
B选自氢、卤素、C1-C6烷基、C2-C6烯基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-7元杂环基;所述C1-C6烷基、C2-C6烯基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-7元杂环基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基的取代基取代;和/或
R1、R2独立地选自氢、卤素、C1-C4烷基、C3-C7饱和或不饱和环烃基;和/或
R3和R4各自独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-7元杂环基,所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-10元杂芳基、3-7元杂环基任选地被一个或多个选自W1组的取代基取代;或者
R3和R4与其连接的N原子共同形成含有1-4个选自N、O和S中的杂原子的单环、螺环或桥环,所述单环、螺环或桥环任选地被一个或多个选自W1组的取代基取代;
所述W1取代基包括D、卤素、氧代(=O)、C1-C4烷基、羟基、C1-C4羟烷基、-NR7R8、氰基、硝基、羧基;
R7、R8各自独立地选自氢、C1-C4烷基、C3-C7饱和或不饱和环烃基,所述C1-C4烷基、C3-C7饱和或不饱和环烃基任选地被一个或多个选自W2组的取代基取代,所述W2组取代基包括D、卤素、羟基、-NH2、C1-C3烷基。
3.根据权利要求2所述的用途,其特征在于,
R5和R6中,所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C7饱和或不饱和环烃基、3-7元杂环基、C6-C12芳基或5-10元杂芳基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基的取代基取代;和/或
B中,所述C1-C6烷基、C2-C6烯基、C3-C7饱和或不饱和环烃基、C6-C12芳基、5-15元杂芳基、3-7元杂环基任选地被一个或多个选自D、卤素、羟基、-NH2、Boc、C1-C4烷基的取代基取代。
4.根据权利要求1-3任一项所述的用途,其特征在于,
R5和R6独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基;和/或
B选自:其中,i选自0,1,2,3,4;R12各自独立地选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷氧基羰基、C1-C4烷基;和/或
R3和R4与其连接的N原子共同形成选自以下的环结构:
其中,n选自1,2,3,4;m选自0,1,2,3,4,5,6;
X选自N、O和S原子;
R9各自独立地选自D、卤素、羟基、氰基、氧代(=O)、C1-C4羟烷基、-NR10R11;
R10、R11独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基;所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基任选地被选自D、卤素、羟基、-NH2、氰基的取代基取代。
5.根据权利要求4所述的用途,其特征在于,
R12各自独立地选自D、卤素、羟基、-NH2、Boc、C1-C4烷基;和/或
R3和R4与其连接的N原子共同形成选自以下的环结构:
其中,m选自0,1,2,3,4,5,6;
R9各自独立地选自D、卤素、羟基、氰基、氧代(=O)、C1-C4羟烷基、-NR10R11;
R10、R11独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基;所述C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6饱和或不饱和环烃基任选地被选自D、卤素、羟基、-NH2、氰基的取代基取代。
6.根据权利要求1-5任一项所述的用途,其特征在于,式(I)所示的吡唑并嘧啶化合物中,
A选自氢、和/或
B选自 和/或
R1、R2独立地选自氢、卤素;和/或
R3和R4与其连接的N原子共同形成选自以下的环结构:
7.根据权利要求1-6任一项所述的用途,其特征在于,式(I)所示的化合物选自以下结构:
其中,A、R1、R2如相应权利要求中所定义,
R9选自羟基、氧代(=O)、C1-C4羟烷基、-NR10R11;
R10、R11独立地选自氢、C1-C4烷基;所述C1-C4烷基任选地被选自D、卤素、羟基、-NH2的取代基取代;
R9’选自H、羟基、C1-C4羟烷基;
R12选自卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷基;
B1选自C3-C7饱和或不饱和环烃基、3-7元杂环基、C2-C6烯基;所述C3-C7饱和或不饱和环烃基、3-7元杂环基、C2-C6烯基任选地被一个或多个选自D、卤素、羟基、-NH2、C1-C4烷基氨基、C1-C4烷基羰氧基、C1-C4烷基的取代基取代,特别是任选地被一个或多个选自D、卤素、羟基、-NH2、Boc、C1-C4烷基的取代基取代;特别地,B1选自:
8.根据权利要求1所述的用途,其特征在于,式(I)所示的化合物选自如下结构:
9.根据权利要求1所述的用途,其特征在于,所述CD73抑制剂或者所述药物中包含药学上可接受的载体以及任选地,一种或多种其他治疗剂。
10.根据权利要求1所述的用途,其特征在于,所述CD73相关疾病、失调和病症包括癌症和免疫失调;
特别地,所述癌症包括膀胱癌、乳腺癌、胆管癌、结直肠癌、结肠癌、胃癌、肺癌、肝癌、胰腺癌、前列腺癌、肾癌、胶质母细胞瘤、肉瘤、白血病、淋巴瘤或黑色素瘤。
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