CN112079836B - 三唑并嘧啶类化合物及其盐、组合物和应用 - Google Patents
三唑并嘧啶类化合物及其盐、组合物和应用 Download PDFInfo
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- CN112079836B CN112079836B CN201910511371.9A CN201910511371A CN112079836B CN 112079836 B CN112079836 B CN 112079836B CN 201910511371 A CN201910511371 A CN 201910511371A CN 112079836 B CN112079836 B CN 112079836B
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- compound
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- triazolopyrimidine compound
- triazolopyrimidine
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- -1 Triazolopyrimidine compound Chemical class 0.000 title claims abstract description 57
- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 239000000203 mixture Substances 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 122
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 102000004190 Enzymes Human genes 0.000 claims description 16
- 108090000790 Enzymes Proteins 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 5
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- 239000003814 drug Substances 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- 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 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
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- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 125000000623 heterocyclic group Chemical group 0.000 description 21
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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- 239000011734 sodium Substances 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000007865 diluting Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
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- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000009987 spinning Methods 0.000 description 6
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical class BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 102000044159 Ubiquitin Human genes 0.000 description 5
- 108090000848 Ubiquitin Proteins 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 125000003003 spiro group Chemical group 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 4
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- 239000002253 acid Substances 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
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- 238000010791 quenching Methods 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明涉及三唑并嘧啶类化合物及其盐、组合物和应用,该三唑并嘧啶类化合物具有式(I)所示结构:
Description
技术领域
本发明涉及药物化学技术领域,特别涉及三唑并嘧啶类化合物及其盐、组合物和应用。
背景技术
真核细胞中,泛素-蛋白酶体系统(UPS)介导细胞内蛋白质降解,维持体内蛋白质动态平衡,参与调控多种重要生理过程(细胞周期、信号传导、基因转录、细胞凋亡、DNA复制、肿瘤发生等)。泛素分子通过三步级联酶催化(泛素激活酶(E1)、泛素结合酶(E2)、及泛素连接酶(E3))共价连接到底物蛋白上,使底物蛋白被蛋白酶体识别并降解。如UPS失调将会导致多种疾病的发生,有研究表明,UPS异常多见于肿瘤中,因此,针对UPS进行抗肿瘤药物开发具有重要意义。针对UPS中26S蛋白酶体的抑制剂硼替佐米已作为多发性骨髓癌药物上市,进一步证明可通过调节UPS来治疗肿瘤。但硼替佐米抑制蛋白酶体不具有选择性,在临床中表现出严重的不良反应。
泛素连接酶E3种类繁多并且具有严格的底物特异性,cullin-RING连接酶(Cullin-RING Ligase,CRL)是细胞内最大多亚基泛素连接酶,负责细胞中约20%的蛋白质降解,且CRL的众多底物蛋白都与肿瘤的生长息息相关,比如cdt-1、p27、pIκBα等,因此可通过抑制UPS中CRL的活性来调控UPS达到抑制肿瘤细胞生长的作用。
CRL作为多亚基泛素连接酶,其功能发挥除了需要组成各亚基有效组合外,还依赖类泛素分子NEDD8(Neural precursor cell-expressed develop-mentally down-regulated 8)对其骨架蛋白--cullin蛋白进行类泛素化修饰(cullin neddylation)。NAE(NEDD8activating emzyme)是neddylation信号通路中的唯一的活化酶,因此通过抑制NAE活性可以控制CRL活性,使特定底物蛋白增多从而抑制肿瘤细胞生长,达到治疗肿瘤的目的。NAE抑制剂是靶向CRL活化中的类泛素化修饰过程,与硼替佐米相比选择性更高,具有更好的安全性。
发明内容
基于此,有必要提供一种对于NAE具有较好活性及高度选择性的三唑并嘧啶类化合物及其盐、组合物和应用。
一种三唑并嘧啶类化合物,具有式(I)所示结构:
其中,
环A为五元或六元环,且所述环A中至少含有两个N;
X和Y各自独立地选自:C或N;
R1、R2、R3、R4、R5和R6各自独立地选自:H、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳香基团、取代或未取代的杂芳香基团、硅烷基、酮基、羰基、酯基、烷氧基羰基、芳氧基羰基、氨基、氰基、氨基甲酰基、卤甲酰基、异氰基、异氰酸酯基、硫氰酸酯基、异硫氰酸酯基、羟基、硝基或卤素;
R1、R2、R3和R4中任选两个或两个以上可以相连形成螺环、桥环或稠环,且所述螺环、桥环或稠环任选含有0个或0个以上杂原子;
R7和R8各自独立地选自:H、取代或未取代的直链烷基、取代或未取代的支链烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳香基团、或取代或未取代的杂芳香基团;
R7和R8可任选与相连的氮原子一起构成3-8元杂环基或5-10元杂芳基;
m为1-20的整数;
n为1、2、3或4。
在其中一实施例中,环A中含有三个N。
在其中一实施例中,m为1、2、3、4、5、6、7或8。
在其中一实施例中,n为1或2。
在其中一实施例中,R7和R8中至少有一个为H。
在其中一实施例中,所述三唑并嘧啶类化合物具有式(II)所示结构:
其中,X和Y中至少有一个为N。
在其中一实施例中,X和Y均为N。
在其中一实施例中,所述三唑并嘧啶类化合物具有式(II-1)所示的结构
R1、R2、R3、R4、R5、R6、R7或R8如上所定义;
n、m、X和Y如上所定义。
在其中一实施例中,所述三唑并嘧啶类化合物具有式(III)所示结构:
在其中一实施例中,所述三唑并嘧啶类化合物具有式(III-1)所示结构:
在其中一实施例中,所述R1、R2、R3、R4和R6各自独立地选自:氢原子、羟基、氨基、卤素、C1-C8烷基、3-8元环烷基、酰胺、酯基,其中所述C1-C8烷氧基、3-8元环烷基任选被一个或多个羟基、羟甲基或卤素取代;
R5选自氢原子、羟基、氨基、卤素。
在其中一实施例中,所述三唑并嘧啶类化合物具有式(IV)所示结构
在其中一实施例中,所述三唑并嘧啶类化合物具有式(IV-1)所示结构
在其中一实施例中,所述三唑并嘧啶类化合物具有式(IV-2)所示结构
在其中一实施例中,所述R7选自C1-C20直链烷烃、C1-C20支链烷烃、3到10元饱和环烷基、3到10元不饱和环烷基、或具有以下结构式(V-1)~(V-4)所示的取代基:
其中,X和Y各自独立地为C或N;
环B选自:3-8元环烷烃、苯环、噻吩环、呋喃环、吡唑环、咪唑环、吡喃环、吡咯环、噻唑环或噁唑环;
p为1或2;
q为0、1、2、3、4、5、6、7或8;
R11选自:取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳香基团、取代或未取代的杂芳香基团、硅烷基、酮基、羰基、酯基、氨基、烷氧基羰基、芳氧基羰基、氰基、氨基甲酰基、卤甲酰基、异氰基、异氰酸酯基、硫氰酸酯基、异硫氰酸酯基、羟基、硝基或卤素;
R12选自氢原子、C1-C6烷基、烷氧基羰基、烷胺基羰基、氨基羰基。
在其中一实施例中,结构式(V-1)中X和Y均为N。
在其中一实施例中,结构式(V-1)中X和Y均为C。
在其中一实施例中,R11选自:C1-C6直链烷基、C1-C6支链烷基、C1-C6烷氧基、3-8元环烷基、3-8元杂环基、芳香基团、杂芳香基团、甲硅烷基、酮基、羰基、酯基、烷氧基羰基、芳氧基羰基、氰基、氨基甲酰基、卤甲酰基、羟基、硝基或卤素;其中所述C1-C6直链烷基、C1-C6支链烷基、C1-C6烷氧基、3-8元环烷基、3-8元杂环基、芳香基团、杂芳香基团任选被一个或多个烷基、烷氧基、羟基、氰基、氨基、硝基或卤素取代。
在其中一实施例中,所述R7选自以下基团:
R14选自氢原子、C1-C6烷基或-Boc;
R15选自氢原子或C1-C6烷基;
q为0、1、2、3或4。
在其中一实施例中,所述三唑并嘧啶类化合物任选自具有以下结构的化合物:
一种制备上述三唑并嘧啶类化合物的制备方法,包括以下步骤:
提供式(I-1)所示结构的化合物;
将式(I-1)所示结构化合物与NHR7R8反应,制得式(I-2)所示结构化合物;
将式(I-2)所示结构化合物与氨基磺酰氯反应,制得式(I)所示三唑并嘧啶类化合物;
其中,M表示卤素。
在其中一实施例中,提供式(I-1)所示结构的化合物的步骤包括以下步骤:
将式(I-3)所示化合物和式(I-4)所示化合物反应,制得式(I-1)所示结构的化合物。
在其中一实施例中,所述式(IV)的化合物由以下路线合成:
一种三唑并嘧啶类盐,由上述三唑并嘧啶类化合物和药学上可接受的盐制备而成。
在其中一实施例中,药学上可接受的盐为无机酸盐或有机盐,所述无机盐选自:盐酸盐、氢溴酸盐、硝酸盐、硫酸盐或磷酸盐;有机酸盐选自:甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、烷基磺酸盐或芳基磺酸盐。
在其中一实施例中,烷基磺酸盐选自甲基磺酸盐或乙基磺酸盐;所述芳基磺酸盐选自苯磺酸盐或对甲苯磺酸盐。
一种三唑并嘧啶类溶剂合物,包括上述三唑并嘧啶类化合物和溶剂。
在其中一实施例中,所述溶剂选自:水、乙醇、异丙醇、乙醚和丙酮中的一种或多种。
一种组合物,包括上述三唑并嘧啶类化合物。
一种三唑并嘧啶类前药,包括上述三唑并嘧啶类化合物。
上述三唑并嘧啶类化合物、上述三唑并嘧啶类盐、上述三唑并嘧啶类溶剂合物和上述组合物在制备细胞增殖类疾病或抑制E1活化酶相关的疾病的药物中的应用。
在其中一实施例中,所述细胞增殖类疾病为癌症或肿瘤,如骨髓增生异常综合征、急性骨髓性白血病、慢性髓细胞性白血病、非小细胞肺癌、多发性骨髓瘤等。
上述三唑并嘧啶类化合物对于NAE具有较好活性及高度选择性,能够用于制备细胞增殖类疾病或抑制E1活化酶相关的疾病的药物。
具体实施方式
为了便于理解本发明,下面将对本发明进行更全面的描述,并给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
定义和通用术语
除非有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。
本发明中术语“任选地被一个或多个取代基取代”是指被一个或多个取代基取代,或者未取代。具体地,“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“C1-C8烷基任选被一个或多个羟基取代”意味着羟基可以但不必须存在,该说明包括C1-C8烷基被羟基取代的情形和C1-C8烷基不被羟基取代的情形。
“烷基”是指饱和脂肪族烃基,包括直链和支链基团。C1-C6烷基是指含有1至6个碳原子的烷基。非限定性实施例包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基。C1-C4烷基烷基是指含有1至4个碳原子的烷基。在一实施例中,C1-C4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃基取代基。3-8元环烷基是指包括3至8个碳原子。在一实施例中,3-8元单环环烷基为环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选被一个或一个以上的取代基取代。
“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元、5元/6元或6元/6元双环烷基。
“桥环烷基”任意两个环共用两个不直接连接的碳原子的全碳多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。
上述“环烷基”、“螺环烷基”、“稠环烷基”或“桥环烷基”的环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,在一实施例中,环烷基为茚满基、四氢萘基等。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,优选氮或氧杂原子;但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。4-10元杂环基是指环包含4至10个环原子,其中1~3个是杂原子;优选杂环基环包含5至6个环原子,其中1~2个是杂原子。在一实施例中,单环杂环基为二氢呋喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基或高哌嗪基等。
本发明中,螺环、桥环或稠环任选含有0个或0个以上杂原子,即螺环、桥环或稠环可以含有杂原子也可以不含有杂原子,当含有杂原子时,构成“稠杂环基”、“桥杂环基”等,基是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳原子。“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳原子。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基。杂环基可以是任选被一个或一个以上的取代基取代。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,更优选苯基和萘基,最优选苯基。芳基环可以稠合于杂芳基、杂环基或环烷基环上,芳基可以是取代的或未取代的。
5-10元“杂芳基”指包含1至4个杂原子,5至10个环原子的杂芳族体系,其中杂原子包括氧、硫和氮。杂芳基优选为是5元或6元,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。杂芳基环可以稠合于芳基、杂环基或环烷基环上,其与母体结构连接在一起的环为杂芳基环。杂芳基可以任选取代或未取代。
本发明中取代基“氨基”包括伯仲叔氨基,具体地,氨基包括-NR16R17,其中,R16和R17为氢原子或任意可选基团,例如:H、取代或未取代的直链烷基、取代或未取代的支链烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳香基团、或取代或未取代的杂芳香基团等。
烷氧基包括-O-(烷基)和-O-(环烷基)。其中烷基、环烷基的定义如上所述。在一实施例中,C1-C4烷氧基为甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基或环丁氧基。烷氧基可以是任选取代的或未取代。
“羰基”是指“-CO-”;“羧基”指-COOH;“酯基”指“-COOR17”,氨基甲酰基指“-CONR17R18”其中R17和R18为任意可选基团,例如:H、取代或未取代的直链烷基、取代或未取代的支链烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳香基团、或取代或未取代的杂芳香基团等。
“硅烷基”指-Si(烷基)3,且与硅相连的三个烷基彼此相同或不相同;“羟基”指-OH基团;“卤素”指氟、氯、溴或碘;“氰基”指-CN;“硝基”指-NO2。
本发明的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式存在,即包括溶剂化和非溶剂化形式。
本发明中,通式中“*”描述的立体化学构型表示相对的立体化学;
本发明中,某可取代位点可被一个或多个取代基取代,且当该可取代位点存在多个取代基时,多个取代基可以彼此相同或不同。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分。例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
组合物中所含有的赋形剂,可以为一种或多种缓冲剂、稳定剂、抗粘剂、表面活性剂、润湿剂、润滑剂、乳化剂、粘合剂、悬浮剂、崩解剂、填充剂、吸附剂、涂料(肠的或缓释的)防腐剂、抗氧化剂,不透明的剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其它已知的添加剂。
“可药用的盐”即“医药上可接受的盐”,是指医药上可接受的化合物的有机或无机盐。
当化合物是酸性或包括足够酸性生物电子等排体时,适当的“可药用的盐”指从医药上可接受的包括无机碱和有机碱的无毒碱中制备的盐。该盐衍生自含有铝、铵、钙、铜、铁、铁、锂、镁、锰盐、锰、钾、钠、辛等的无机碱。特定的实施方式包括铵、钙、镁、钾和钠盐。盐衍生自医药上可接受的有机无毒碱,该有机无毒碱包括一级、二级和三级胺的盐、包括自然存在的取代胺的取代胺、环胺和碱性离子交换树脂,如精氨酸、甜菜碱、咖啡因、胆碱、N,N.sup.1-二苄基乙二胺、乙二胺、2-二乙氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基六氢吡啶、还原葡糖胺、氨基葡萄糖、组氨酸、海巴明、异丙胺、赖氨酸、葡甲胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙基胺、三甲胺、三丙胺、氨丁三醇等等。
当化合物是碱性的或包括足够碱性生物电子等排体时,盐可以从医药上可接受的无毒酸中制备,包括无机和有机酸。这样的酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡萄糖酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、苦杏仁酸,甲基磺酸、粘液酸、硝酸、双羟萘酸、泛酸、磷酸、硫酸、琥珀酸、酒石酸、对甲苯磺酸等等。特定的实施方式包括柠檬酸、氢溴酸、盐酸、磷酸、硫酸、马来酸、酒石酸。其它示例性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐,硫酸盐,磷酸盐、酸性磷酸盐、异烟酸、乳酸、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、富马酸盐、马来酸盐、龙胆酸盐、葡萄糖酸盐,葡萄糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲基磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(例如,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。
另外,包含化合物的药物制剂可以为片剂、胶囊剂、口服液体剂、丸剂、颗粒剂、散剂、软膏剂、贴剂、栓剂、口含片、滴眼剂、眼膏剂、眼膏剂、滴耳剂、喷剂、气雾剂、吸入剂、注射剂等。
术语“治疗有效量”是指有效化合物或药物试剂的用量,改善、治愈或治疗疾病或病症的一种或多种症状的必要的最小量。
另外,本发明所述的化合物和药物组合物可单独给药,也可以与其他药剂联合施用。对于与一种以上的活性剂的联合治疗,当该活性剂在分开的剂量制剂中时,该活性剂可以分开施用或联合施用。另外,一种药剂的施用可在另一种药剂施用之前、同时或之后进行。当与其他药剂联合施用时,第二药剂的“有效量”将视所用药物的类型而定。
本发明的化合物或药物组合物也可以包含在试剂盒中。
需要说明的是,本发明未注明具体来源的试剂,为市场购买的常规试剂。
下面结合具体实施例对本发明作进一步阐述。这些实施例仅是出于解释说明的目的,而不限制本发明的范围和实质。
1H-NMR和13C-NMR用Varian MercuryAMX300,400或500型仪测定;液溴[Br2]、硼氢化锂、10%钯碳(50%wet)、三乙胺、亚硝酸钠、吡啶购于J&K Chemica百灵威化学试剂公司、中国医药试剂有限公司和韶远科技有限公司。所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得;除说明外,所有反应均是在氮气保护下进行并TLC跟踪,后处理时均经饱和氯化钠水溶液洗涤和无水硫酸钠干燥过程;产品的纯化除说明外均使用硅胶(200-300目)柱色谱法;其中硅胶(200-300目)由青岛海洋化工厂生产,GF-254薄层硅胶板由烟台江友硅胶开发有限公司生产。
中间体H的制备
将化合物A溶于DME和H2O中,加入吡啶(2.5eq),-10℃下向溶液中加入Br2(1.25eq),-10℃下搅拌3小时。抽滤,水洗3次,将滤饼用水浸泡2小时在进行抽滤,滤饼干燥得化合物B。
将化合物B溶于THF中,0℃下加入2M硼氢化锂的四氢呋喃溶液(1eq),继续反应,1小时后原料完全反应,加入饱和氯化铵淬灭反应,加入乙酸乙酯,加水萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析分离的化合物C。
将化合物C溶于异丙醇中,加入4M HCl的甲醇溶液(6eq),室温搅拌4小时,旋干得化合物D,可直接投下一步。
将化合物D溶于甲醇中,加入10%钯碳(0.2eq),在氢气的氛围下,室温搅拌6小时后,加入碳酸钠调PH到碱性后,旋干,硅胶柱层析分离的化合物E。
将化合物E溶于正丁醇中,加入化合物F(1.5eq),三乙胺(2eq),120℃微波反应1小时,旋干,硅胶柱层析分离的化合物G。
将化合物G溶于乙酸和水的混合溶剂中,冰浴下,加入亚硝酸钠的水溶液(1.2eq),反应1小时后,加入乙酸乙酯进行萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析分离的化合物H。
化合物S1的制备
氮气保护下,将化合物H溶于乙腈中,向溶液中加入化合物1-1(1.3eq)、DIPEA(3eq),室温搅拌8小时,原料完全反应,旋干溶剂,硅胶柱层析分离,DCM:MeOH=30:1,得化合物1-2。
将化合物1-2溶于乙腈中,0℃下向溶液中加入吡啶(3eq)、氨基磺酰氯(1.2eq),搅拌2小时后,原料完全反应,旋干溶剂,硅胶柱层析分离,DCM:MeOH=20:1,得化合物S1。1HNMR(500MHz,Methanol-d4)δ8.40(s,1H),7.28(d,J=7.5Hz,2H),7.24(q,J=7.8,6.2Hz,1H),7.16(q,J=7.5,6.2Hz,1H),5.99(t,J=7.6Hz,1H),5.60(qd,J=8.2,4.8Hz,1H),4.58(td,J=4.6,1.8Hz,1H),4.41(dd,J=9.8,7.5Hz,1H),4.24(dd,J=9.8,7.2Hz,1H),3.11(ddd,J=15.9,8.7,3.6Hz,1H),3.00–2.87(m,2H),2.71–2.55(m,2H),2.45(ddd,J=14.0,8.0,2.0Hz,1H),2.38–2.27(m,2H),2.10(dq,J=12.9,8.4Hz,1H).MS(ESI):[M+H]+m/z446.1
化合物S2的制备
以2-1为原料,参考实施例S1的合成,得到化合物S2。1H NMR(400MHz,Methanol-d4)δ8.36(s,1H),7.42(t,J=7.5Hz,1H),7.29(q,J=7.1Hz,1H),7.14–7.05(m,2H),5.59(dt,J=13.2,6.6Hz,1H),4.90(s,2H),4.56(t,J=4.6Hz,1H),4.39(dd,J=9.6,7.6Hz,1H),4.22(dd,J=9.8,7.2Hz,1H),2.90(s,1H),2.60(ddd,J=12.9,7.6,4.7Hz,1H),2.43(dd,J=14.0,8.2Hz,1H),2.35–2.25(m,2H).MS(ESI):[M+Na]+m/z 460.2
化合物S3的制备
以3-1为原料,参考实施例S1的合成,得到化合物S3。1H NMR(400MHz,Methanol-d4)δ8.40(s,1H),7.27(d,J=5.1Hz,1H),7.09(d,J=3.4Hz,1H),6.94(dd,J=5.1,3.6Hz,1H),5.60(td,J=8.0,5.3Hz,1H),5.01(s,2H),4.57(d,J=4.6Hz,1H),4.39(dd,J=9.7,7.5Hz,1H),4.22(dd,J=9.7,7.3Hz,1H),2.90(h,J=8.6Hz,1H),2.59(ddd,J=12.8,7.6,4.7Hz,1H),2.43(ddd,J=14.1,8.2,1.8Hz,1H),2.35–2.25(m,2H).MS(ESI):[M+Na]+m/z 448.1
化合物S4的制备
以4-1为原料,参考实施例S1的合成,得到化合物S4。1H NMR(400MHz,Methanol-d4)δ8.38(s,1H),7.43(s,1H),6.34(dt,J=5.9,3.0Hz,2H),5.60(td,J=8.1,5.3Hz,1H),4.83(s,2H),4.57(d,J=4.4Hz,1H),4.39(dd,J=9.7,7.5Hz,1H),4.22(dd,J=9.7,7.3Hz,1H),2.96–2.83(m,1H),2.59(ddd,J=12.7,7.5,4.8Hz,1H),2.43(ddd,J=14.1,8.2,1.8Hz,1H),2.38–2.24(m,2H).MS(ESI):[M+Na]+m/z 432.1
化合物S5的制备
以5-1为原料,参考实施例S1的合成,得到化合物S5。1H NMR(400MHz,Methanol-d4)δ8.35(s,1H),7.19(dd,J=4.8,1.6Hz,1H),6.90(s,2H),5.58(qd,J=7.9,5.0Hz,1H),4.56(t,J=4.4Hz,1H),4.39(dd,J=9.7,7.5Hz,1H),4.22(dd,J=9.8,7.3Hz,1H),3.89(t,J=7.2Hz,2H),3.24(q,J=7.9,7.3Hz,2H),2.90(h,J=8.6Hz,1H),2.59(ddd,J=12.8,7.5,4.6Hz,1H),2.48–2.38(m,1H),2.37–2.23(m,2H).MS(ESI):[M+Na]+m/z 432.1
化合物S6的制备
以6-1为原料,参考实施例S1的合成,得到化合物S6。1H NMR(400MHz,Methanol-d4)δ7.33–7.21(m,4H),7.16(dq,J=11.3,7.1,5.7Hz,1H),5.57(qd,J=8.0,4.8Hz,1H),4.56(t,J=4.7Hz,1H),4.45–4.35(m,1H),4.31–4.17(m,2H),3.85(t,J=7.4Hz,2H),3.01(q,J=7.5Hz,2H),2.89(tt,J=11.6,6.2Hz,1H),2.59(ddd,J=12.6,7.6,4.7Hz,1H),2.43(ddd,J=14.1,8.1,1.8Hz,1H),2.37–2.24(m,2H).MS(ESI):[M+Na]+m/z 456.3
化合物S7的制备
以7-1为原料,参考实施例S1的合成,得到化合物S7。
1H NMR(400MHz,Methanol-d4)δ8.32(s,1H),7.21(h,J=7.3Hz,4H),7.12(t,J=7.1Hz,1H),5.63–5.52(m,1H),4.57(d,J=4.4Hz,1H),4.39(dd,J=9.8,7.6Hz,1H),4.22(dd,J=9.7,7.4Hz,1H),3.65(t,J=7.1Hz,2H),2.90(h,J=8.2Hz,1H),2.74(q,J=7.9Hz,2H),2.59(ddd,J=12.8,7.6,4.9Hz,1H),2.46–2.37(m,1H),2.30(dd,J=11.6,7.8Hz,2H),2.03(p,J=7.5Hz,2H).MS(ESI):[M+Na]+m/z 470.2
化合物S8的制备
以8-1为原料,参考实施例S1的合成,得到化合物S8。1H NMR(400MHz,Methanol-d4)δ8.32(s,1H),5.58(qd,J=8.0,5.0Hz,1H),4.57(s,1H),4.39(dd,J=9.7,7.5Hz,1H),4.22(dd,J=9.7,7.3Hz,1H),3.61(t,J=7.2Hz,2H),2.90(ddt,J=9.7,6.6,3.3Hz,1H),2.59(ddd,J=14.2,7.5,4.7Hz,1H),2.43(ddd,J=14.0,8.1,1.8Hz,1H),2.36–2.26(m,2H),1.72(dp,J=15.0,7.2Hz,2H),1.42(q,J=7.7,6.7Hz,2H),1.35(dt,J=7.5,3.9Hz,4H),0.91(m,3H).MS(ESI):[M+Na]+m/z 436.3
化合物S9的制备
以9-1为原料,参考实施例S1的合成,得到化合物S9。1H NMR(400MHz,Methanol-d4)δ8.43(s,1H),7.33–7.17(m,4H),5.90(d,J=5.0Hz,1H),5.63(qd,J=7.9,5.1Hz,1H),4.75(td,J=5.1,2.0Hz,1H),4.58(td,J=4.6,1.8Hz,1H),4.40(dd,J=9.8,7.4Hz,1H),4.23(dd,J=9.8,7.3Hz,1H),3.25(dd,J=16.5,5.2Hz,1H),3.03(dd,J=16.5,2.0Hz,1H),2.92(ttd,J=9.7,7.3,4.3Hz,1H),2.62(ddd,J=14.1,7.4,4.6Hz,1H),2.46(ddd,J=14.0,8.1,2.0Hz,1H),2.37–2.28(m,2H).MS(ESI):[M+H]+m/z 462.5
化合物S10的制备
将化合物10-1溶于二氯甲烷中,向溶液中加入三乙胺(2eq)、BOC酸酐(1.05eq),室温搅拌3小时,原料完全反应,旋干溶剂,硅胶柱层析分离(DCM:MeOH=30:1),得化合物10-2。
将化合物10-2加入到装有二氯甲烷的耐压管中,氮气保护下,向溶液中加入氧化银(5eq)、碘甲烷(6eq),80℃下加热反应30分钟后,原料完全反应,硅藻土抽滤,滤液旋干,硅胶柱层析分离,PE:EA=20:1,得化合物10-3。
将化合物10-3溶于二氯甲烷中,向反应液中加入4M HCl的二氧六环溶液,30分钟后,旋干溶剂,得化合物10-4。
以10-4为原料,参考实施例S1的合成,得到化合物S10。1H NMR(400MHz,Methanol-d4)δ8.45(s,1H),7.35–7.14(m,4H),6.00(d,J=5.4Hz,1H),5.62(s,1H),4.57(s,1H),4.44–4.33(m,2H),4.23(dd,J=9.8,7.3Hz,1H),3.38(d,J=7.9Hz,3H),3.17(qd,J=16.4,4.3Hz,2H),2.91(s,1H),2.61(dt,J=12.7,5.7Hz,1H),2.46(ddd,J=12.7,7.8,4.5Hz,1H),2.33(t,J=7.2Hz,2H).MS(ESI):[M+H]+m/z 476.4
化合物S11的制备
将化合物10-2溶于二氯甲烷中,向溶液中加入三乙胺(1.5eq),0℃下向反应液中加入甲基磺酰氯(1.1eq),室温反应1小时后,原料完全反应,旋干溶剂,用乙酸乙酯溶解,依次用水洗3次、饱和食盐水洗,无水硫酸钠干燥,旋干得化合物11-1。
将化合物11-1溶于DMF中,向溶液中加入叠氮化钠(1.5eq),90℃油浴反应5小时,原料完全反应,浓缩DMF,用乙酸乙酯稀释,依次用水洗3次、饱和食盐水洗,无水硫酸钠干燥,旋干得化合物11-2。
将化合物11-2溶于乙酸乙酯中,向溶液中加入10%Pd/C(0.2eq),氢气氛围下,室温反应6小时,原料完全反应,硅藻土抽滤,滤液旋干,硅胶柱层析分离,DCM:MeOH=40:1,得化合物11-3。
将化合物11-3溶于二氯甲烷中,向溶液中加入DIPEA(1.5eq),0℃下向反应液中加入甲基磺酰氯(1.2eq),0℃下反应1小时,原料完全反应,加饱和氯化铵淬灭反应,加入二氯甲烷和水进行萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析分离DCM:MeOH=80:1,得化合物11-4。
将化合物11-4溶于二氯甲烷中,向反应液中加入4M HCl的二氧六环溶液,30分钟后,旋干溶剂,得化合物11-5。
以11-5为原料,参考实施例S1的合成,得到化合物S11。1H NMR(400MHz,Methanol-d4)δ8.38(d,J=1.5Hz,1H),7.24(dt,J=19.5,2.4Hz,4H),6.17(d,J=8.9Hz,1H),5.59(s,1H),4.72(q,J=9.0Hz,1H),4.57(t,J=4.5Hz,1H),4.40(dd,J=9.8,7.5Hz,1H),4.23(dd,J=9.8,7.3Hz,1H),3.91–3.74(m,2H),3.37(d,J=1.4Hz,3H),3.21(s,1H),3.03–2.84(m,2H),2.59(q,J=5.8,5.2Hz,1H),2.43(dd,J=14.2,8.1Hz,1H),2.37–2.25(m,2H).MS(ESI):[M+H]+m/z533.6
化合物S12的制备
以12-1为原料,参考实施例S10和S11的合成,得到化合物S12。1H NMR(400MHz,Methanol-d4)δ8.42(s,1H),7.33(ddd,J=31.4,19.3,7.4Hz,4H),6.11(d,J=6.6Hz,1H),5.66–5.55(m,1H),5.05(q,J=6.5Hz,1H),4.56(d,J=4.9Hz,1H),4.39(dd,J=9.7,7.4Hz,1H),4.22(dd,J=9.8,7.2Hz,1H),3.75(d,J=15.1Hz,1H),3.64(d,J=15.1Hz,1H),3.36(d,J=7.6Hz,5H),3.21–3.12(m,1H),2.88(s,1H),2.64–2.52(m,1H),2.49–2.38(m,1H),2.38–2.23(m,2H).MS(ESI):[M+H]+m/z 533.6
化合物S13的制备
氩气保护下,将化合物13-1溶于THF中,0℃下,向溶液中滴加HMDSLi(2eq),0℃反应1小时后,将N,N-双(2-氯乙基)氨基甲酸叔丁酯(1eq)用THF稀释后,滴加到反应瓶中,继续反应2小时,原料完全反应,用饱和氯化铵淬灭反应,浓缩反应液,用乙酸乙酯溶解,加水萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析分离,PE:EA=40:1,得化合物13-2。
将化合物13-2溶于THF中,向溶液中加入9-BBN(3eq),70℃下反应3小时,原料完全反应,将反应液冷却到0℃,向反应液中加入3M NaOH溶液(1.2eq)、30%过氧化氢溶液(1.2eq),室温反应1小时后,浓缩反应液,用乙酸乙酯稀释,加水萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,旋干得化合物13-3。
将化合物13-3溶于二氯甲烷中,向溶液中加入PDC(2.1eq),室温搅拌反应10小时,原料完全反应,硅藻土抽滤,滤液旋干,硅胶柱层析分离,PE:EA=8:1,得化合物13-4。
氮气保护下,使用分水装置,将化合物13-4溶于无水甲苯中,向溶液中加入S-苯乙胺(1.2eq)、无水氯化锌(0.03eq),冷凝回流反应8小时,原料完全反应,旋干溶剂,用乙酸乙酯溶解,依次用0.1M NaOH溶液洗2次、饱和氯化铵洗1次、饱和食盐水洗1次,无水硫酸钠干燥,旋干得化合物13-5。
氮气保护下,将化合物13-5溶于无水甲醇中,-40℃下向溶液中分批加入硼氢化钠(1eq),缓慢升温到0℃,继续反应2小时,原料完全反应,用饱和氯化铵淬灭反应,浓缩反应液,用乙酸乙酯溶解,加水萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,旋干的粗产物,将粗产物溶于乙醚中,向溶液中加入2M HCl的乙醚溶液至有大量固体析出,抽滤的化合物13-6。
将化合物13-6溶液甲醇中,向反应中加入10%Pd/C(0.2eq)、甲酸铵(20eq),60℃下反应24小时,原料完全反应,硅藻土抽滤,滤液旋干,用乙酸乙酯溶解,有机层依次用饱和碳酸氢钠洗、饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析分离,DCM:MeOH=10:1,得化合物13-7。
以13-7为原料,参考实施例S1的合成,得到化合物S13。1H NMR(400MHz,Methanol-d4)δ8.42–8.35(m,1H),7.27(ddd,J=16.2,9.9,6.8Hz,4H),6.06(t,J=7.9Hz,1H),5.60(d,J=8.1Hz,1H),4.57(s,1H),4.40(dd,J=9.8,7.4Hz,1H),4.23(dd,J=9.8,7.3Hz,1H),4.11(d,J=13.6Hz,2H),3.15–2.85(m,4H),2.59(q,J=7.1,5.9Hz,1H),2.44(dd,J=14.1,8.1Hz,1H),2.38–2.25(m,2H),2.09(tt,J=12.4,6.1Hz,1H),1.97(dd,J=13.0,8.2Hz,1H),1.73–1.56(m,3H),1.49(s,9H).MS(ESI):[M+H]+m/z 615.4
化合物S14的制备
将化合物S13溶于甲醇中,向反应液中加入2M HCl的甲醇溶液,室温搅拌反应5小时,原料完全反应,旋干溶剂,用乙酸乙酯和饱和碳酸氢钠萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,旋干,硅胶柱层析分离DCM:MeOH=20:1,得化合物S14。1H NMR(400MHz,Methanol-d4)δ8.40(s,1H),7.35–7.29(m,2H),7.29–7.17(m,2H),6.04(t,J=7.9Hz,1H),5.61(dt,J=8.1,4.0Hz,1H),4.57(dt,J=4.6,2.4Hz,1H),4.40(dd,J=9.8,7.5Hz,1H),4.23(dd,J=9.8,7.3Hz,1H),3.07(d,J=12.9Hz,2H),2.92(qd,J=9.8,7.8,3.1Hz,3H),2.80(td,J=12.7,2.7Hz,1H),2.61(ddd,J=14.0,7.5,4.5Hz,1H),2.45(ddd,J=14.1,8.2,1.9Hz,1H),2.32(ddd,J=9.7,6.8,3.6Hz,2H),2.17(td,J=13.0,4.2Hz,1H),1.99–1.87(m,1H),1.82–1.56(m,3H).MS(ESI):[M+H]+m/z 515.6
化合物S15的制备
将化合物S14溶于DMF中,向溶液中加入DIPEA(2eq)、碘甲烷(1.05eq),室温搅拌反应20分钟,原料完全反应,浓缩DMF,用乙酸乙酯稀释,依次用水洗、饱和食盐水洗,无水硫酸钠干燥,旋干得化合物S15。1H NMR(400MHz,Methanol-d4)δ8.40(s,1H),7.32(d,J=4.0Hz,2H),7.29–7.19(m,2H),6.03(t,J=7.9Hz,1H),5.66–5.56(m,1H),4.57(td,J=4.5,1.9Hz,1H),4.40(dd,J=9.8,7.4Hz,1H),4.23(dd,J=9.8,7.3Hz,1H),2.88(ddd,J=26.1,12.6,8.6Hz,4H),2.61(ddd,J=13.9,7.5,4.6Hz,1H),2.45(ddd,J=14.0,8.1,1.8Hz,1H),2.39–2.20(m,8H),1.88(ddd,J=26.8,13.3,8.8Hz,2H),1.76–1.59(m,2H).MS(ESI):[M+H]+m/z529.6
化合物S16的制备
以16-1为原料,参考实施例S1的合成,得到化合物S16。1H NMR(400MHz,Methanol-d4)δ8.42(s,1H),7.25–7.01(m,3H),5.66–5.56(m,1H),4.58(t,J=4.5Hz,1H),4.41(dd,J=9.8,7.5Hz,1H),4.24(dd,J=9.7,7.3Hz,1H),3.21(dt,J=8.0,3.9Hz,1H),2.92(s,1H),2.62(ddd,J=12.7,7.5,4.8Hz,1H),2.45(dd,J=14.1,8.2Hz,1H),2.36–2.19(m,3H),1.51–1.36(m,2H).MS(ESI):[M+Na]+m/z 504.2
化合物S17的制备
以17-1为原料,参考实施例S1的合成,得到化合物S17。1H NMR(400MHz,Methanol-d4)δ9.00–8.93(m,1H),7.63(d,J=7.2Hz,1H),7.39(d,J=9.3Hz,1H),7.26(t,J=7.9Hz,1H),6.72(s,1H),5.82(s,1H),4.62(s,1H),4.42(dd,J=9.8,7.4Hz,1H),4.29–4.20(m,1H),2.98(s,1H),2.75–2.64(m,1H),2.58–2.48(m,1H),2.41(dd,J=10.7,7.6Hz,2H).MS(ESI):[M+H]+m/z 446.4
化合物S18的制备
氮气保护下,将化合物H溶于DMF中,向溶液中加入化合物18-1(1.5eq)、Pd2(dba)3(0.1eq)、Cs2CO3(2.5eq)、Xantohos(0.3eq),100℃搅拌反应4小时,原料完全反应,抽滤,滤液旋干,硅胶柱层析分离,DCM:MeOH=20:1,得化合物18-2。
以18-2为原料,参考实施例S1的合成,得到化合物S18。1H NMR(400MHz,Methanol-d4)δ8.33(s,1H),7.64–7.59(m,1H),7.31(d,J=3.4Hz,1H),7.22(d,J=7.9Hz,1H),7.13(dtd,J=18.1,7.1,1.3Hz,2H),6.61(d,J=3.4Hz,1H),5.66(s,1H),4.57(s,1H),4.40(dd,J=9.8,7.5Hz,1H),4.23(dd,J=9.7,7.2Hz,1H),2.92(s,1H),2.61(s,1H),2.53–2.41(m,1H),2.33(s,2H).MS(ESI):[M+Na]+m/z 467.3
化合物S19的制备
以19-1为原料,参考实施例S18的合成,得到化合物S19。1H NMR(400MHz,Methanol-d4)δ8.36(s,1H),8.21–8.11(m,1H),7.79–7.62(m,2H),7.48(t,J=8.0Hz,1H),7.03(t,J=6.9Hz,1H),5.66(s,1H),4.58(s,1H),4.40(dd,J=9.8,7.4Hz,1H),4.23(dd,J=9.8,7.3Hz,1H),2.92(s,1H),2.61(s,1H),2.46(s,1H),2.34(t,J=8.7Hz,2H).MS(ESI):[M+H]+m/z 446.4
化合物S20的制备
将化合物20-1溶于甲醇中,0℃下向溶液中加入二氯亚砜(2.2eq),0℃下搅拌反应2小时,原料完全反应,旋干溶剂得化合物20-2。
以20-2为原料,参考实施例S1的合成,得到化合物S20。1H NMR(400MHz,Methanol-d4)δ8.37(s,1H),6.09–5.95(m,2H),5.64–5.55(m,1H),5.46(ddd,J=8.2,5.8,2.0Hz,1H),4.57(td,J=4.6,1.9Hz,1H),4.40(dd,J=9.7,7.4Hz,1H),4.22(dd,J=9.8,7.3Hz,1H),3.73(s,3H),3.68(tt,J=6.2,2.7Hz,1H),2.89(s,1H),2.75(dt,J=13.7,8.5Hz,1H),2.60(ddd,J=14.0,7.5,4.6Hz,1H),2.43(ddd,J=14.0,8.1,1.8Hz,1H),2.31(ddd,J=9.5,6.9,3.3Hz,2H),2.13–2.04(m,1H).MS(ESI):[M+H]+m/z 454.4
化合物S21的制备
以21-1为原料,参考实施例S1的合成,得到化合物S21。1H NMR(400MHz,Methanol-d4)δ8.33(s,1H),5.58(qd,J=8.0,4.9Hz,1H),4.64–4.53(m,2H),4.40(dd,J=9.8,7.4Hz,1H),4.22(dd,J=9.8,7.3Hz,1H),2.95–2.83(m,1H),2.59(ddd,J=13.9,7.4,4.7Hz,1H),2.43(ddd,J=14.0,8.2,1.9Hz,1H),2.30(ddd,J=9.7,6.8,3.8Hz,2H),2.11(s,2H),1.83(h,J=4.3,3.8Hz,2H),1.68(tq,J=11.9,7.9,6.2Hz,4H).MS(ESI):[M+H]+m/z 398.4
生物学评价
以下结合测试例进一步描述解释本发明,但这些实施例并非意味着限制本发明的范围。
实验实施例:实施例中部分化合物分子水平上抑制NAE酶的活性测试
1.化合物分子水平上NAE酶活性初步评价实验
使用HTRF技术(均相时间分辨荧光,Homogeneous Time-Resolved Fluorescence)检测化合物对NAE酶活的体外抑制作用。其实验操作步骤如下:
(1)配制酶反应缓冲液:50mM HEPES(pH7.5)、0.05%BSA、5mM MgCl2、20μM ATP、250μM L-谷胱甘肽;
(2)将NAE酶(人重组APPBP1/UBA3)配成4nM,将底物配成含600nM His6-NEDD8和320nM GST-UBE2M/Ubc12的混合物;
(3)将待测化合物稀释成40μM,然后10倍梯度稀释;
(4)在384孔板中配制10μL的反应体系,加入5μL NAE酶、2.5μL混合底物、2.5μL待测化合物,最终的反应体系为:2nM NAE酶、150nM His6-NEDD8、80nMGST-UBE2M/Ubc12和10μM起始的待测化合物。每组设置2复孔,另设无酶阴性对照、酶组对照;
(5)在27℃摇床孵育2h,加入10μL反应终止液:0.1M HEPES(pH7.5)、0.05%Tween20、20mM EDTA、410mM KF、Anti-6HIS-Eu Cryptate(CisBio,1:200)、Anti-GST-XL665(CisBio,1:200);
(6)室温过夜,用荧光酶标仪(PE Envision)读板,激发光源为Lance,吸收波长为620nm/665nm。
(7)采用以下公式计算化合物的抑制率:
a.读值处理:(665/620)*10000均值-阴性对照组均值
c.用GraphPad软件计算IC50
2.化合物分子水平上NAE酶活性初步评价实验
表二:实施例中部分化合物对NAE酶活性的抑制作用
*A指IC50<100nM,B指100nM≤IC50<1μM,C指IC50≥1μM
实验实施例:实施例中部分化合物对HCT-116细胞增殖活性的抑制作用
化合物对人结肠癌细胞HCT-116的增殖抑制作用以磺酰罗单明B(sulforodamineB,SRB)法检测。具体步骤如下:处于对数生长期的HCT-116细胞按合适密度接种至96孔培养板中,每孔90μL,培养过夜后,加入不同浓度的化合物作用72h,并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后,化合物对细胞增殖的影响采用SRB法检测:弃去培养液,加入4℃预冷的10%的三氯醋酸(TCA)100μl/孔,4℃固定1小时后用蒸馏水洗涤5次,空气中自然干燥;加入由1%冰醋酸配制的SRB(4mg/ml)溶液100μl/孔,室温中染色15分钟;去上清液,用1%醋酸洗涤5次,空气干燥;加入150μl/孔的Tris(10mM)溶液,室温放置15分钟;最后用全波长式微孔板酶标仪SpectraMax 190读数,测定波长为560nm。
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(%):
抑制率(%)=(OD对照孔-OD给药孔)/OD对照孔×100%
表三:实施例中部分化合物对HCT-116细胞的增殖抑制作用
*A指IC50<10μM,B指10μM≤IC50<100μM,C指IC50≥100μM
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.一种三唑并嘧啶类化合物,其特征在于,具有式(III)所示结构:
其中,
R1独立地选自:羟基;
R2、R3、R4、R5和R6各自独立地选自:H;
R7独立地选自正戊基、正己基、环戊基、环戊烯基、环己基、环己烯基、或具有以下结构式(V-1)~(V-4)所示的取代基:
其中,X和Y各自独立地为C或N;
环B选自:3-8元环烷烃、苯环、噻吩环、呋喃环、吡唑环、咪唑环、吡喃环、吡咯环、噻唑环或噁唑环;
p为1;
q为0、1、2、3、4、5、6、7或8;
R12选自氢原子、或C1-C6烷基。
3.根据权利要求1所述的三唑并嘧啶类化合物,其特征在于,
式(V-2)中的环B选自:环戊基、环戊烯基、苯环、噻吩环或呋喃环;
式(V-4)中的环B选自环丙基;
R1独立地选自:羟基。
8.一种三唑并嘧啶类化合物的盐,其特征在于,由权利要求1-7任一项所述的三唑并嘧啶类化合物和药学上可接受的盐制备而成。
9.一种组合物,其特征在于,包括权利要求1-7任一项所述的三唑并嘧啶类化合物。
10.权利要求1-7任一项所述的三唑并嘧啶类化合物、权利要求8所述的三唑并嘧啶类化合物的盐或权利要求9所述的组合物在制备细胞增殖类疾病或抑制E1活化酶相关的疾病的药物中的应用;所述细胞增殖类疾病为癌症或肿瘤。
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