CN115611868A - 一种呋喃酰胺类衍生物及其制备方法与应用 - Google Patents
一种呋喃酰胺类衍生物及其制备方法与应用 Download PDFInfo
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- CN115611868A CN115611868A CN202210498821.7A CN202210498821A CN115611868A CN 115611868 A CN115611868 A CN 115611868A CN 202210498821 A CN202210498821 A CN 202210498821A CN 115611868 A CN115611868 A CN 115611868A
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- Prior art keywords
- furan
- amino
- methylpiperidin
- methanone
- thio
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- TVFIYRKPCACCNL-UHFFFAOYSA-N furan-2-carboxamide Chemical class NC(=O)C1=CC=CO1 TVFIYRKPCACCNL-UHFFFAOYSA-N 0.000 title description 2
- -1 furan amide Chemical class 0.000 claims abstract description 146
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims abstract description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 81
- 210000004027 cell Anatomy 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 210000004881 tumor cell Anatomy 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000004185 ester group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
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- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- IHCCAYCGZOLTEU-UHFFFAOYSA-M 3-furoate Chemical compound [O-]C(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-M 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 claims description 3
- 201000011177 bladder transitional cell papilloma Diseases 0.000 claims description 3
- 201000001528 bladder urothelial carcinoma Diseases 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
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- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical group 0.000 claims description 2
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- 125000004122 cyclic group Chemical group 0.000 claims description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
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- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 2
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- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 claims 1
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- 125000000068 chlorophenyl group Chemical group 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 44
- 229940079593 drug Drugs 0.000 abstract description 8
- YGUFCDOEKKVKJK-UHFFFAOYSA-N 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine Chemical compound NC1(CCN(CC1)C1=CN=C(C(=N1)N)C1=C(C(=CC=C1)Cl)Cl)C YGUFCDOEKKVKJK-UHFFFAOYSA-N 0.000 abstract description 7
- 239000013641 positive control Substances 0.000 abstract description 7
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- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 3
- 230000036961 partial effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 76
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 42
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 14
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000001028 anti-proliverative effect Effects 0.000 description 9
- 238000000039 preparative column chromatography Methods 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
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- 239000012467 final product Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
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- 230000003281 allosteric effect Effects 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
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Abstract
Description
技术领域
本发明属于生物医药技术领域,涉及一种呋喃酰胺类衍生物及其制备方法与应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
SHP2(含Src同源2结构域蛋白酪氨酸磷酸酶)是由原癌基因PTPN11编码的一种非受体蛋白酪氨酸磷酸酶,PTPN11功能获得性突变可导致努南综合征以及多种血液***肿瘤,同时很多实体瘤也存在SHP2的过度激活或异常高表达。研究表明,SHP2介导的RAS-MAPK信号激活及其对JAK-STAT信号的负调控作用使得SHP2成为致癌或抑癌信号通路的重要参与者。此外,SHP2可被PD-1招募,参与T细胞受体信号通路,也是肿瘤免疫的潜在靶点。因此,抑制SHP2可起到“靶向+免疫”的双重抗肿瘤作用。当前,针对SHP2抑制剂的研发主要聚焦在变构抑制剂领域,现有文献和专利披露了很多高活性变构抑制剂,大部分均为SHP099吡嗪类衍生物,如下所示,这类高活性活化合物中,含氮脂肪杂环均与中间芳杂环直接相连。截止目前,靶向SHP2的抑制剂尚无上市药物,第一代SHP2变构抑制剂正处于临床I或II期试验阶段,其研发走向尚不明确。此外,SHP2在肿瘤发生发展过程中的作用机制存在争议。因此,开发高活性、高选择性、结构新颖、作用机制明确且药代动力学性质良好的SHP2变构抑制剂显得迫在眉睫。
发明内容
为解决现有技术不足,本发明主要目的是提供一种呋喃酰胺类衍生物及其制备方法与应用,本发明提供的新型具有呋喃酰胺类母核结构的衍生物对SHP2蛋白具有变构抑制作用,且部分化合物比阳性对照SHP099表现出更好的抗肿瘤活性。
为实现上述目的,本发明的技术方案为:
一方面,一种呋喃酰胺类衍生物,其化学结构如式I所示:
其中,X1选自不存在、O、S、-CH2S-、SO、SO2、CO、CR5R6或NR7,R5、R6分别独立地选自氢、羟基、氨基、卤素、氰基、酯基、羧基、硝基、C1-7烷氧基、C1-7烷基、C3-7杂环基或C3-7碳环基;R7选自氢、C1-7烷基或C3-7碳环基。
R1选自芳环,通式可表示为Ar(R9)m;Ar选自五元环(呋喃环、噻唑环、噻吩环、咪唑环、恶唑环、异噻唑环、异恶唑环)、六元环(苯环、吡啶环、吡嗪环、嘧啶环、哒嗪环)、并环(萘环、喹啉环、异喹啉环、吲哚环),其中每个环系可以独立地被单取代、多取代或不被取代;R9选自氢、卤素、二氟甲基、三氟甲基、三氟甲氧基、氰基、羟基、酯基、羧基、硝基、氨基、C1-6烷氧基、C1-6烷基取代的烷胺基、C1-6烷基、C3-7杂环基、C3-7碳环基;m为0~8的自然数。
R2可以在呋喃环的任意位置,选自氢、卤素、二氟甲基、三氟甲基、三氟甲氧基、氰基、羟基、酯基、羧基、硝基、氨基、C1-6烷氧基、C1-6烷基取代的烷胺基、C1-6烷基、C3-7杂环基、C3-7碳环基;n为0-2的自然数。
R3、R4分别独立选自氢、C1-6烷胺基、C1-6烷基、C3-7杂环基或C3-7碳环基,或者R3和R4环合后形成不取代、单取代或多取代的C3-7氮杂环,所述取代基选自卤素、氨基、BocNH-、羟基、羰基、氧代、酯基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷胺基。
优选地,其化学结构如式II所示:
其中,R1、R2、X1和n同式I中所述基团。X2、X3和X4可以分别独立的为C、NR11、O;n1为0-4的任意自然数;R10选自卤素、氨基、BocNH、羟基、羰基、氧代、酯基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷胺基;n2为0-6的任意自然数。R11选自氢、Boc、C1-6烷基、C1-6烷羰基。
分析本发明实施例的构效关系可以发现,呋喃环上引入取代基对活性不利;因此,n=1且R2=H时活性最高。当X1为S原子时活性最高,换成O原子、亚甲基及羰基时活性降低;当R1为取代苯环、吡啶环或者萘环时实施例化合物均对SHP2蛋白酶活具有一定的抑制作用。当R1为取代苯环时,环上氯原子取代要优于其他基团取代,且邻位取代要优于间位和对位取代。同时,多取代化合物活性要明显优于单取代,但是当2位和6位同时被取代时SHP2酶活抑制活性丧失。
优选地,包括以下化合物:
(SDUY037)(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苯基)呋喃-2-基)甲酮;
(SDUY038)(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯苯基)硫代)呋喃-2-基)甲酮;
(SDUY039)(4-氨基-4-甲基哌啶-1-基)(4-溴-5-((2,3-二氯苯基)硫代)呋喃-2-基)甲酮;
(SDUY040)(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯苯基)硫代)噻吩-2-基)甲酮;
(SDUY049)(4-氨基-4-甲基哌啶-1-基)(4-氨基-5-((2,3-二氯苯基)硫代)呋喃-2-基)甲酮;
(SDUY050)(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯苯基)硫代)-4-甲基呋喃-2-基)甲酮;
(SDUY052)5-(4-氨基-4-甲基哌啶-1-羰基)-2-((2,3-二氯苯基)硫代)呋喃-3-羧酸甲酯;
(SDUY054)(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苯氧基)呋喃-2-基)甲酮;
(SDUY055)(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苯甲酰基)呋喃-2-基)甲酮;
(SDUY056)(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苄基)呋喃-2-基)甲酮;
(SDUY057)(4-氨基-4-甲基哌啶-1-基)(5-((2-氯苯基)硫代)呋喃-2-基)甲酮;
(SDUY058)(4-氨基-4-甲基哌啶-1-基)(5-((2-甲氧基苯基)硫代)呋喃-2-基)甲酮;
(SDUY059)(4-氨基-4-甲基哌啶-1-基)(5-((2-氟苯基)硫代)呋喃-2-基)甲酮;
(SDUY060)(4-氨基-4-甲基哌啶-1-基)(5-(对甲苯硫基)呋喃-2-基)甲酮;
(SDUY061)(4-氨基-4-甲基哌啶-1-基)(5-((4-氯苯基)硫代)呋喃-2-基)甲酮;
(SDUY062)(4-氨基-4-甲基哌啶-1-基)(5-((2-氨基苯基)硫代)呋喃-2-基)甲酮;
(SDUY063)(4-氨基-4-甲基哌啶-1-基)(5-((4-氟苯基)硫代)呋喃-2-基)甲酮;
(SDUY064)(4-氨基-4-甲基哌啶-1-基)(5-((4-(三氟甲基)苯基)硫代)呋喃-2-基)甲酮;
(SDUY065)(4-氨基-4-甲基哌啶-1-基)(5-((2-(三氟甲基)苯基)硫代)呋喃-2-基)甲酮;
(SDUY066)4-氨基-4-甲基哌啶-1-基)(5-((3-(三氟甲基)苯基)硫代)呋喃-2-基)甲酮;
(SDUY067)(4-氨基-4-甲基哌啶-1-基)(5-((3-氟苯基)硫代)呋喃-2-基)甲酮;
(SDUY068)(4-氨基-4-甲基哌啶-1-基)(5-((3-氨基苯基)硫代)呋喃-2-基)甲酮;
(SDUY069)(4-氨基-4-甲基哌啶-1-基)(5-((4-氨基苯基)硫代)呋喃-2-基)甲酮;
(SDUY070)(4-氨基-4-甲基哌啶-1-基)(5-(邻甲苯硫基)呋喃-2-基)甲酮;
(SDUY071)(4-氨基-4-甲基哌啶-1-基)(5-(萘-2-基硫基)呋喃-2-基)甲酮;
(SDUY072)2-((5-(4-氨基-4-甲基哌啶-1-羰基)呋喃-2-基)硫代)苯甲酸甲酯;
(SDUY073)2-((5-(4-氨基-4-甲基哌啶-1-羰基)呋喃-2-基)硫代)苯甲酸;
(SDUY074)(4-氨基-4-甲基哌啶-1-基)(5-((3-甲氧基苯基)硫代)呋喃-2-基)甲酮;
(SDUY075)(4-氨基-4-甲基哌啶-1-基)(5-((4-甲氧基苯基)硫代)呋喃-2-基)甲酮;
(SDUY076)(4-氨基-4-甲基哌啶-1-基)(5-((3-氯苯基)硫代)呋喃-2-基)甲酮;
(SDUY077)(4-氨基-4-甲基哌啶-1-基)(5-(间甲苯硫基)呋喃-2-基)甲酮;
(SDUY079)(4-氨基-4-甲基哌啶-1-基)(5-((2-(三氟甲基)吡啶-3-基)硫基)呋喃;-2-基)甲酮;
(SDUY080)(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯吡啶-4-基)硫基)呋喃-2-基)甲酮;
(SDUY081)(5-((2-氨基-3-氯吡啶-4-基)硫代)呋喃-2-基)(4-氨基-4-甲基哌啶-1-基)甲酮;
(SDUY082)4-氨基-4-甲基哌啶-1-基5-(2,5-二氯苯基硫代)呋喃-2-甲酮;
(SDUY083)4-氨基-4-甲基哌啶-1-基5-(2,4-二氯苯基硫代)呋喃-2-甲酮;
(SDUY084)4-氨基-4-甲基哌啶-1-基5-(3,4-二氯苯基硫代)呋喃-2-甲酮;
(SDUY085)4-氨基-4-甲基哌啶-1-基5-(全氯苯基)硫代呋喃-2-甲酮;
(SDUY088)4-氨基-4-甲基哌啶-1-基5-(2,6-二氯苯基硫代)呋喃-2-甲酮;
(SDUY089)5-(3-氨基-2-氯苯基)硫代呋喃4-氨基-4-甲基哌啶-1-甲酮。
除SDUY085和SDUY088,上述化合物均对SHP2蛋白活性具有变构抑制作用。
另一方面,一种上述呋喃酰胺类衍生物的制备方法,包括如下反应路线;
第三方面,一种药物组合物,包括至少两种活性药物,其中一种活性药物为上述呋喃酰胺类衍生物或其药学上可接受的盐。
本发明所述的药学上可接受的盐,包括枸橼酸盐、磺酸盐、盐酸盐、硫酸盐等。
第四方面,一种药物制剂,包括上述呋喃酰胺类衍生物或其药学上可接受的盐和药学上可接受的辅料和/或载体。
所述辅料可以为赋形剂(如:糖浆等)、填充剂(如:磷酸钙等)、润滑剂(如:硬脂酸镁等)等。
所述载体可以为血清蛋白、缓冲液、聚乙二醇等。
第五方面,一种上述呋喃酰胺类衍生物或其药学上可接受的盐在制备SHP2抑制剂中的应用。
第六方面,一种上述呋喃酰胺类衍生物或其药学上可接受的盐在制备抗肿瘤细胞增殖药物中的应用。
优选地,所述肿瘤细胞为人膀胱移行细胞***瘤细胞、人膀胱癌细胞、人膀胱移行细胞癌细胞或人乳腺癌细胞等。
本发明的有益效果为:
本发明的实验数据表明,除SDUY085和SDUY088外,本发明提供的呋喃酰胺类衍生物对SHP2蛋白均有明显的变构抑制作用。其中,在10μM浓度下,SDUY038、SDUY057、SDUY058、SDUY059、SDUY061、SDUY065、SDUY070、SDUY071、SDUY076、SDUY077、SDUY080、SDUY081、SDUY083、SDUY089对SHP2酶活的抑制率均高于60%;SDUY038、SDUY081、SDUY089对SHP2酶活的抑制率均高于90%;SDUY089对SHP2酶活的抑制率高于95%。其中,部分实施例化合物,如:SDUY038对RT4、5637、T24三种膀胱癌肿瘤细胞及乳腺癌肿瘤细胞4T1的抗增殖活性显著强于阳性对照SHP099。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明试验例1的SHP2变构抑制剂酶活测定的原理图;
图2为本发明试验例1提供的部分呋喃酰胺类化合物对SHP2蛋白酶活的抑制曲线;
图3为本发明试验例2测定的SDUY038对人多种肿瘤细胞的抗增殖活性图,A为对RT4肿瘤细胞抗增殖活性的量效曲线,B为对5637肿瘤细胞抗增殖活性的量效曲线,C为对T24肿瘤细胞抗增殖活性的量效曲线,D为对4T1肿瘤细胞抗增殖活性的量效曲线,E为对多种肿瘤细胞抗增殖活性的IC50柱状图。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。
试验例1:SHP2变构抑制剂酶活测定
选取胰岛素受体底物1(2p-IRSl)作为SHP2激活剂,以6,8-二氟-4-甲基-7-羟基香豆素磷酸酯(DiFMUP)作为底物,活化的SHP2可使其去磷酸化生成带荧光的物质DiFMU,在358nm激发光和455nm发射光条件下检测其荧光强度。小分子化合物抑制SHP2蛋白酶的活性,从而抑制DiFMUP的去磷酸化,荧光产物DiFMU生成减少。因此,本发明以反应体系中荧光强度的变化来评估化合物对SHP2酶活的抑制作用,实验原理如图1所示。步骤如下:
(1)小分子抑制剂溶液配置:化合物溶于DMSO配置成50mM母液,于-20℃保存待用,单浓度活性筛选选用10μM,每次实验现配现用。
(2)用DMSO分别配置DiFMUP母液(2mM)和2p-IRS1母液(1mM),分别于-20℃和-80℃保存备用,每次实验现配现用。
(3)SHP2蛋白母液浓度为3.4mg/mL,于-80℃保存备用,每次实验现配现用。
(4)实验buffer准备:60mM HEPES,75mM NaCl,75mM KCl,1mM EDTA,5mM DTT,0.05%P20,pH=7.2。
(5)实验方法:以加入SHP2蛋白、2p-IRS1和DiFMUP的体系为阳性对照(定义为100%),只加荧光底物的体系为阴性对照(定义为0%)。鉴于部分化合物本身在358/455nm下产生荧光,为避免化合物自身荧光对实验结果的影响,此处以只加抑制剂及荧光底物的体系作为空白对照。单浓度活性筛选至少独立重复2次,曲线测试至少独立重复3次,每次实验设置至少3组重复。具体实验方法如下所示:
检测体系 | 阴性对照 | 阳性对照 | 空白对照 | |
SHP2-WT | 30μL | - | 30μL | - |
2p-IRS1 | 10μL | 10μL | - | |
Inhibitors | 10μL | - | - | 10μL |
DiFMUP | 50μL | 50μL | 50μL | 50μL |
Assay buffer | 0 | 50μL | 10μL | 40μL |
(6)实验过程:①取适量3.4mg/mL SHP2蛋白母液和1mM 2p-IRS1母液,加入实验buffer分别稀释至7.8ng/mL和1.2μM,得样品I;②向96孔酶标板每孔中加入40μL样品I(阴性对照和空白对照均加40μL实验buffer),然后加入10μL特定浓度的待测化合物(阳性对照和阴性对照加10μL实验buffer),25℃下震荡孵育40min;③取适量2mM DiFMUP母液,加入实验buffer稀释至20μM,得样品II;④向各孔中加入50μL样品II,25℃下震荡孵育30min;⑤测定在激发光355nm、发射光460nm条件下反应体系的荧光强度,按照如下公式计算抑制率,使用GraphPad Prism 6.0拟合量效曲线计算IC50。实施例1~40制备的化合物在10μM浓度下对SHP2酶活的抑制率如表1所示:
表1.化合物在10μM浓度下对SHP2酶活的抑制率
如表1所示,在10μM浓度下,除SDUY085与SDUY088外,所制备化合物对SHP2蛋白酶活均表现出明显的抑制作用。其中,化合物SDUY038、SDUY057、SDUY058、SDUY059、SDUY061、SDUY065、SDUY070、SDUY071、SDUY074、SDUY075、SDUY076、SDUY077、SDUY080、SDUY081、SDUY083、SDUY089对SHP2酶活的抑制率均高于50%;化合物SDUY038、SDUY057、SDUY058、SDUY059、SDUY061、SDUY065、SDUY070、SDUY071、SDUY076、SDUY077、SDUY080、SDUY081、SDUY083、SDUY089对SHP2酶活的抑制率均高于60%;化合物SDUY038、SDUY057、SDUY058、SDUY070、SDUY071、SDUY080、SDUY081、SDUY083、SDUY089对SHP2酶活的抑制率均高于70%;化合物SDUY038、SDUY057、SDUY080、SDUY081、SDUY083、SDUY089对SHP2酶活的抑制率均高于80%;化合物SDUY038、SDUY081、SDUY089对SHP2酶活的抑制率均高于90%;化合物SDUY089对SHP2酶活的抑制率达到96%。
选取10μM浓度下抑制率大于50%的化合物测定其对SHP2酶活抑制的IC50,如表2所示。其中,化合物SDUY038、SDUY057、SDUY058、SDUY080、SDUY081、SDUY083和SDUY089对SHP2酶活抑制的IC50均小于5μM;其中,化合物SDUY089对SHP2酶活抑制的IC50小于1μM。化合物SDUY077、SDUY080和SDUY081对SHP2酶活抑制的量效曲线如图2所示,所测化合物均对SHP2表现出浓度依赖性的酶活抑制作用。
表2.部分化合物对SHP2酶活抑制作用的IC50
试验例2:变构抑制剂体外抗肿瘤活性
实验方法:取处于对数生长期的细胞,接种于96孔培养板,密度为5000个/孔。种板时最外圈加入PBS,用于保持湿润。设空白对照(没有细胞、不加药物)、加药对照(有细胞、不加药物)及不同浓度的给药组,每组设置六个复孔。接种细胞后的96孔板在37℃和5%CO2培养箱培养24h,待细胞贴壁,加入不同浓度的药物(每孔100μL)。药物作用24h后,弃去培养基,避光加入CCK-8染液,培养箱中孵育1h,使用酶标仪测定其在450nm处的吸光度,按照如下公式计算细胞生长抑制率,使用GraphPad Prism 6.0拟合量效曲线计算IC50。
实验结果:化合物SDUY038对RT4(人膀胱移行细胞***瘤细胞)、5637(人膀胱癌细胞)、T24(人膀胱移行细胞癌细胞)、4T1(人乳腺癌细胞)增殖的抑制曲线如图3A-图3D所示。据发明人研究了解,阳性对照药SHP099对SHP2蛋白酶活抑制活性较高,比较SDUY038与SHP099对上述细胞抗增殖活性的IC50(图3E)得出:SDUY038对RT4、5637、T24、4T1的抗增殖活性显著优于SHP099,即SDUY038的体外抗肿瘤活性高于SHP099。
为获得上述实施例中的化合物,对其合成过程进行如下说明。
实施例SDUY037、SDUY038、SDUY040、SDUY057-SDUY089的通用制备路线如路线1所示。下面以实施例SDUY037和SDUY038为例介绍其制备方法:首先5-溴呋喃-2-羧酸(1a)与叔丁基(4-甲基哌啶-4-基)氨基甲酸酯通过缩合反应得1b,1b与2,3-二氯苯硼酸发生钯催化的Suzuki反应,然后脱Boc得终产物SDUY037;1b与2,3-二氯苯硫酚发生铜催化的乌尔曼反应得1d,进而脱保护基得到目标化合物SDUY038。
路线1:
中间体1b的制备方法:
将原料5-溴呋喃-2-羧酸(1a,400mg,2.09mmol)、叔丁基(4-甲基哌啶-4-基)氨基甲酸酯(449mg,2.10mmol)和N,N-二异丙基乙胺(541mg,4.19mmol)溶于5mLN,N-二甲基甲酰胺中,于室温下加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(119mg,3.13mmol)后反应1h。反应结束后向反应体系中加入50mL水和50mL乙酸乙酯,分液萃取,有机相用饱和食盐水洗涤四次(50mL×4),有机相干燥、浓缩后残留物经硅胶柱层析(乙酸乙酯:石油醚=1:2)得产品1b(630mg,反应产率77.7%)。
中间体1c的制备方法:
将化合物叔丁基(1-(5-溴呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(1b,200mg,0.516mmol),2,3-二氯苯硼酸(99mg,0.519mmol),Pd(dppf)Cl2(38mg,0.0519mmol)和碳酸钾(214mg,1.55mmol)溶于5mL1,4-二氧六环和1mL水中,氮气保护后于90℃下反应3h。反应结束后,浓缩反应液,残留物直接经硅胶柱层析(乙酸乙酯:石油醚=1:2)得产品1c(190mg,反应产率81.2%)。
终产物SDUY037的制备方法:
将化合物叔丁基(1-(5-(2,3-二氯苯基)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(1c,190mg,0.42mmol)溶于6mL二氯甲烷中,加入2mL三氟乙酸后于室温下反应2h。反应结束后,浓缩反应液,残留物用氢氧化钠的饱和甲醇溶液中和至pH=8-9,浓缩,残留物经C18反相中压制备柱层析(5%-80%甲醇/水)得终产品SDUY037(102mg,反应产率68.9%)。
SDUY037:1H NMR(400MHz,DMSO-d6)δ7.80(dd,J=7.9,1.6Hz,1H),7.70(dd,J=8.0,1.5Hz,1H),7.51(t,J=8.0Hz,1H),7.27(d,J=3.7Hz,1H),7.12(d,J=3.7Hz,1H),3.95-3.76(m,2H),3.73-3.41(m,2H),1.66-1.31(m,6H),1.10(s,3H).
中间体1d的制备方法:
将化合物叔丁基(1-(5-溴呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(1b,200mg,0.516mmol),2,3-二氯苯硫酚(92mg,0.514mmol),碘化亚铜(10mg,0.0525mmol),1,10-非罗琳(19mg,0.105mmol)和磷酸钾(329mg,1.55mmol)溶于10mL 1,4-二氧六环中,氮气保护后于90℃下反应10h。反应液浓缩,残留物直接经硅胶柱层析(乙酸乙酯:石油醚=1:2)得产品1d(156mg,反应产率62.4%)。
终产物SDUY038的制备方法:
脱Boc的制备方法同SDUY037,反应产率63.7%。
SDUY038:1H NMR(400MHz,DMSO-d6)δ7.55(dd,J=8.1,1.4Hz,1H),7.34(t,J=8.0Hz,1H),7.23(d,J=3.5Hz,1H),7.11(d,J=3.4Hz,1H),6.79(dd,J=8.1,1.4Hz,1H),3.85-3.44(m,4H),1.69-1.31(m,6H),1.07(s,3H).
SDUY039的合成路线如路线2所示。原料2a在溴素条件下进行双溴代反应得产物2b,然后发生乌尔曼偶联反应制得中间体2c,接着再通过水解、缩合、脱保护基制得终产物SDUY039。
路线2:
SDUY039的制备方法:
步骤1:将化合物呋喃-2-甲酸甲酯(2a,6.37g,50.5mmol)溶于50mL氯仿中,冷却至-10℃,缓慢加入三氯化铝(14.8g,111mmol)后,氮气保护,然后于-10℃下缓慢滴加溴素(16.1g,100mmol)的氯仿溶液10mL,缓慢恢复至室温后搅拌16h。TLC监测反应结束后,向反应体系中慢慢加入饱和硫代硫酸钠水溶液淬灭反应直至反应液透明无色,再加入200mL水和200mL二氯甲烷,分液萃取,水相用二氯甲烷萃取一次(200mL×1),收集有机相,干燥浓缩后,残留物经硅胶柱层析(乙酸乙酯:石油醚=1:10)得产品2b(10.3g,反应产率73.9%)。
步骤2:将化合物4,5-二溴呋喃-2-甲酸甲酯(2b,560mg,1.97mmol)、2,3-二氯苯硫酚(424mg,2.37mmol)、碘化亚铜(38mg,0.20mmol),1,10-菲啰啉(18mg,0.10mmol)和磷酸钾(318mg,1.5mmol)加入到5mL 1,4-二氧六环中,氮气保护后于90℃油浴中反应。TLC监测反应进程,反应结束后反应液抽滤,滤饼用二氯甲烷洗涤,滤液浓缩后残留物依次经硅胶柱层析(乙酸乙酯:石油醚=1:3)和反相C18中压制备柱层析(5%-80%甲醇/水)得产品2c(105mg,反应产率41.8%)。
步骤3:将化合物4-溴-5-((2,3-二氯苯基)硫代)呋喃-2-甲酸甲酯(2c,290mg,0.76mmol)溶于5mL甲醇和5mL四氢呋喃中,室温下加入氢氧化锂(55mg,2.29mmol)水溶液2mL后于室温下反应。TLC监测反应结束后,反应液浓缩至2mL,1N稀盐酸中和至pH=6-7,再加入20mL水,二氯甲烷萃取两次(20mL×2),收集有机相,干燥浓缩后得产物2d粗品,直接用于下一步反应。
步骤4:将化合物4-溴-5-((2,3-二氯苯基)硫代)呋喃-2-羧酸(2d,粗品)、叔丁基(4-甲基哌啶-4-基)氨基甲酸酯(57mg,0.266mmol)和N,N-二异丙基乙胺(69mg,0.534mmol)溶于5mL N,N-二甲基甲酰胺中,于室温下加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(153mg,0.402mmol)后室温搅拌18h。反应结束后,将反应液缓慢倒入20mL水中,搅拌5min后抽滤,滤饼水洗、干燥得产品2e粗品,直接用于下一步反应。
步骤5:将化合物叔丁基(1-(4-溴-5-(2,3-二氯苯基)硫代)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(2e,粗品)溶于6mL二氯甲烷中,加入2mL三氟乙酸后于室温下反应1h。反应液浓缩,加入1mL甲醇后,用饱和氢氧化钠的甲醇溶液中和反应液至pH=8-9,体系浓缩,残留物经反相C18中压制备柱层析(5%-75%甲醇/水)得产品SDUY039(102mg,步骤3、4、5三步反应总产率29.0%)。
SDUY039:1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)δ7.59(dd,J=8.0,1.4Hz,1H),7.47-7.28(m,2H),6.81(dd,J=8.0,1.4Hz,1H),3.72(d,J=63.3Hz,4H),1.57(brs,2H),1.48-1.34(m,4H),1.09(s,3H).
SDUY040的合成路线如路线3所示,其制备过程及方法与SDUY038相同。
路线3:
SDUY040:1H NMR(400MHz,DMSO-d6)δ7.64-7.41(m,3H),7.34(t,J=8.0Hz,1H),6.88(dd,J=8.1,1.4Hz,1H),3.80-3.54(m,4H),1.58-1.39(m,4H),1.14(s,3H).
SDUY049与SDUY052的合成路线如路线4所示,其过程为:路线2所得中间体2e通过与二苯甲酮亚胺发生Buchwald偶联反应引入氨基,然后在酸性条件下脱掉两个保护基得终产物SDUY049;中间体2e经钯催化下的插羰反应引入酯基,脱Boc后制得终产物SDUY052。
路线4:
SDUY049的制备方法:
将化合物叔丁基(1-(4-溴-5-(2,3-二氯苯基)硫代)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(2e,56mg,0.10mmol)、二苯甲酮亚胺(4a,36mg,0.20mmol)、三(二亚苄基丙酮)二钯(9mg,0.01mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(12mg,0.02mmol)和碳酸铯(65mg,0.20mmol)加入到5mL 1,4-二氧六环中,氮气保护后回流反应。TLC监测反应结束后,反应液抽滤,滤饼用乙酸乙酯洗涤,滤液浓缩后残留物经硅胶柱层析(乙酸乙酯:石油醚=1:3)得中间体4b(26mg,反应产率39.4%)。
将化合物叔丁基(1-(5-(2,3-二氯苯基)硫代)-4-(二苯基亚甲基氨基)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(4b,26mg,0.039mmol)溶于1mL甲醇中,再加入1mL 4N稀盐酸·二氧六环溶液,室温下反应18h。反应液浓缩,加入1mL甲醇后,用饱和氢氧化钠的甲醇溶液中和反应液至pH=8-9,体系浓缩,残留物经反相C18中压制备柱层析(5%-75%甲醇/水)得产品SDUY049(9mg,反应产率57.3%)。
SDUY049:1H NMR(400MHz,DMSO-d6)δ7.46(d,J=8.0Hz,1H),7.30(t,J=8.0Hz,1H),6.64(s,1H),6.60(d,J=8.0Hz,1H),5.12(s,2H),3.79-3.64(m,2H),3.62-3.41(m,2H),1.64(brs,2H),1.45-1.32(m,4H),1.06(s,3H).
SDUY052的制备方法:
将化合物叔丁基(1-(4-溴-5-(2,3-二氯苯基)硫代)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(2e,180mg,0.32mmol)、醋酸钯(7mg,0.03mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(37mg,0.06mmol)和三乙胺(97mg,0.96mmol)加入到3mL甲醇和6mLN,N-二甲基甲酰胺中,一氧化碳气体换气两次,于80℃油浴中反应8h。待反应结束,反应液浓缩,残留物经硅胶柱层析(乙酸乙酯:石油醚=1:2)得产品4c粗品40mg,直接用于下一步反应。
将上步所得化合物5-(4-((叔丁氧羰基)氨基)-4-甲基哌啶-1-羰基)-2-((2,3-二氯苯基)硫代)呋喃-3-羧酸甲酯(4c,40mg粗品)溶于2mL二氯甲烷中,加入0.5mL三氟乙酸后于室温下反应16h。反应液浓缩,加入1mL甲醇后,用饱和氢氧化钠的甲醇溶液中和反应液至pH=8-9,体系浓缩,残留物依次经反相C18中压制备柱层析(5%-80%甲醇/水)和硅胶柱层析(二氯甲烷:氨甲醇=15:1)得产品SDUY052(27mg,两步反应产率19.1%)。
SDUY052:1H NMR(400MHz,DMSO-d6)δ7.76(dd,J=8.1,1.5Hz,1H),7.58(dd,J=8.0,1.4Hz,1H),7.44(t,J=8.0Hz,1H),7.23(s,1H),3.82(s,3H),3.79-3.35(m,4H),1.62(brs,s),1.36-1.12(m,4H),1.02(s,3H).
SDUY050的合成路线如路线5所示,制备过程为:先通过Stille偶联反应引入甲基,水解后缩合,最后脱Boc得终产物。
路线5:
SDUY050的制备方法:
步骤1:将化合物4-溴-5-(2,3-二氯苯基)硫代)呋喃-2-甲酸甲酯(2c,300mg,0.785mmol)、四甲基锡(707mg,3.93mmol)和双(三邻甲苯基膦)二氯化钯(123mg,0.156mmol),加入到5mLN,N-二甲基甲酰胺中,氮气保护后90℃反应10h。反应液中加入50mL乙酸乙酯,饱和食盐水洗涤三次有机相(30mL×3),有机相干燥、浓缩,残留物经硅胶柱层析(乙酸乙酯:石油醚:二氯甲烷=1:10:1)得产品5a(20mg,反应产率8.0%)。
步骤2:将化合物5-(2,3-二氯苯基)硫代-4-甲基呋喃-2-羧酸甲酯(5a,20mg,0.063mmol)溶于0.5mL甲醇和0.5mL四氢呋喃中,室温下加入氢氧化锂(5mg,0.21mmol)水溶液0.1mL后于室温下反应16h。反应结束后反应液浓缩后加入15mL水,1N稀盐酸中和至pH=6-7,乙酸乙酯萃取两次(15mL×2),收集有机相,干燥浓缩后得产物5b粗品,直接用于下一步反应。
步骤3:将化合物5-(2,3-二氯苯基)4-甲基呋喃-2-羧酸(5b,粗品)、叔丁基(4-甲基哌啶-4-基)氨基甲酸酯(20mg,0.093mmol)和N,N-二异丙基乙胺(36mg,0.279mmol)溶于4mL二氯甲烷中,于室温下加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(8mg,0.126mmol)后室温搅拌4h。反应结束后反应液浓缩,残留物直接经硅胶柱层析(乙酸乙酯:石油醚=1:2)得产品5c(28mg,两步反应产率88.9%)。
步骤4:将化合物叔丁基(1-(5-(2,3-二氯苯基)硫代)-4-甲基呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(5c,28mg,0.056mmol)溶于2mL二氯甲烷中,加入0.5mL三氟乙酸后于室温下反应3h。反应液浓缩,加入1mL甲醇,用饱和氢氧化钠的甲醇溶液中和反应液至pH=8-9,体系浓缩,残留物经反相C18中压制备柱层析(5%-80%甲醇/水)得产品SDUY050(20mg,反应产率89.3%)。
SDUY050:1H NMR(600MHz,Chloroform-d)δ7.25(d,J=1.4Hz,1H),7.03(t,J=8.0Hz,1H),7.00(s,1H),6.54(dd,J=8.1,1.4Hz,1H),3.90-3.79(m,2H),3.78-3.61(m,2H),2.13(s,3H),1.95(brs,2H),1.66-1.58(m,2H),1.56-1.48(m,2H),1.21(s,3H).
SDUY054的合成路线如路线6所示,制备过程为:起始原料6a和2,3-二氯苯酚在碱性条件下发生取代反应制得关键中间体6b,剩余制备方法(水解、缩合、脱Boc)同SDUY050。
路线6:
SDUY054的制备方法。
将化合物5-溴呋喃-2-甲酸甲酯(6a,755mg,3.68mmol)、2,3-二氯苯酚(600mg,3.68mmol)溶于15mLN,N-二甲基甲酰胺中,于100℃下反应10h。待反应结束,向反应液中加入50mL乙酸乙酯,饱和氯化钠水溶液洗涤有机相三次(30mL×3),有机相干燥、浓缩,残留物经硅胶柱层析(乙酸乙酯:石油醚=1:2)得产品6b(220mg,反应产率20.9%)。
剩余步骤制备方法同SDUY050。
SDUY054:1H NMR(400MHz,DMSO-d6)δ7.62-7.52(m,1H),7.44(t,J=8.2Hz,1H),7.29(dd,J=8.4,1.4Hz,1H),6.98(d,J=3.6Hz,1H),5.91(d,J=3.6Hz,1H),3.81-3.63(m,2H),3.60-3.39(m,2H),1.54(brs,2H),1.45-1.32(m,4H),1.06(s,3H).
SDUY055和SDUY056的合成路线如路线7所示,其制备过程为:首先起始原料呋喃-2-甲酸甲酯(2a)与2,3-二氯苯甲酰氯发生傅-克酰基化反应得中间体7a,SDUY055的制备同SDUY050,依次经过水解、缩合、脱Boc。SDUY056的合成是由中间体7c先还原为羟基化合物7d,然后在三乙基硅烷和三氟乙酸条件下同时脱掉羟基和Boc制得。
路线7:
步骤1:将化合物呋喃-2-甲酸甲酯(241mg,1.91mmol)、2,3-二氯苯甲酰氯(400mg,1.91mmol)溶于10mL 1,2-二氯乙烷中,加入三氯化铝(51mg,0.383mmol)于80℃下反应50h。反应液恢复至室温后,缓慢加入饱和碳酸氢钠水溶液淬灭反应,然后再加入50mL二氯甲烷,有机相用饱和氯化钠水溶液洗涤有机相三次(30mL×3),有机相干燥、浓缩,残留物经硅胶柱层析(乙酸乙酯:石油醚=1:10)得产品7a(120mg,反应产率21.0%)。
终产物SDUY055剩余步骤(步骤2-4)的制备方法同化合物SDUY050。
SDUY055:1H NMR(600MHz,Chloroform-d)δ7.62(dd,J=6.5,3.0Hz,1H),7.38-7.30(m,2H),7.17(d,J=3.7Hz,1H),7.11(d,J=3.7Hz,1H),3.91-3.57(m,4H),1.71-1.58(m,4H),1.21(s,3H).
SDUY056的制备方法:
将化合物叔丁基(1-(5-(2,3-二氯苯甲酰基)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(7c,130mg,0.27mmol)溶于3mL甲醇中,于0℃下缓慢加入硼氢化钠(30.6mg,0.81mmol),于25℃下反应0.5h。反应结束后于反应液中缓慢加入5滴冰水淬灭反应,然后加入20mL二氯甲烷和20mL水,分液萃取,有机相用饱和氯化钠水溶液洗涤两次(30mL×2),有机相干燥、浓缩,残留物直接用于下一步反应。
将此粗品溶于3mL二氯甲烷中,依次加入三氟乙酸(0.5mL)和三乙基硅烷(0.5mL),于30℃下反应16h。补加1mL三氟乙酸后继续于室温下反应3h。反应液浓缩,加入1mL甲醇后,用饱和氢氧化钠的甲醇溶液中和反应液至pH=8-9,体系浓缩,残留物经反相C18中压制备柱层析(5%-80%甲醇/水)得产品SDUY056(33mg,两步反应产率33.3%)。
SDUY057-SDUY072及SDUY074-SDUY089的通用合成路线如路线1所示,不同之处在于将2,3二氯苯硫酚换为其他硫酚结构。
SDUY057的制备方法:
步骤1:将化合物5 5-溴呋喃-2-羧酸(2.0g,10.0mmol)、叔丁基(4-甲基哌啶-4-基)氨基甲酸酯(2.3g,10.0mmol)和N,N-二异丙基乙胺(2.7g,20.0mmol)溶于10mLN,N-二甲基甲酰胺中,于室温下加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.9g,15.0mmol)后室温搅拌1h。反应结束后于反应液中加入100mL乙酸乙酯和100mL水,分液萃取,有机相用饱和食盐水洗涤三次(100mL×3)后干燥、浓缩,残留物经硅胶柱层析(乙酸乙酯:石油醚=1:4)得产品叔丁基(1-(5-溴呋喃-2-羰基)-4-甲基哌啶-4-基)氨基甲酸酯(3.19g,反应产率78.6%)。
步骤2:将化合物叔丁基(1-(5-溴呋喃-2-羰基)-4-甲基哌啶-4-基)氨基甲酸酯(150mg,0.39mmol)、2-氯苯硫酚(56mg,0.39mmol)、碘化亚铜(7.4mg,0.039mmol),1,10-菲啰啉(14mg,0.078mmol)和磷酸钾(164mg,0.77mmol)加入到5mL 1,4-二氧六环中,氮气保护后于100℃油浴中反应。TLC监测反应结束后,反应液直接浓缩,残留物经硅胶柱层析(乙酸乙酯:石油醚=1:4)得产品叔丁基(1-(5-(2-氯苯基)硫代)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(120mg,反应产率68.6%)。
步骤3:将上步所得叔丁基(1-(5-(2-氯苯基)硫代)呋喃-2-羰基)-4-甲基哌啶-4-基氨基甲酸酯(92mg,0.20mmol)溶于6mL二氯甲烷中,加入2mL三氟乙酸后于室温下反应3h。反应液浓缩,加入1mL甲醇,用饱和氢氧化钠的甲醇溶液中和反应液至pH=8-9,体系浓缩,残留物经反相C18中压制备柱层析(5%-80%甲醇/水)得产品SDUY057(82mg,反应产率89.0%)。
SDUY057:1H NMR(600MHz,Chloroform-d)δ7.38-7.35(m,1H),7.16-7.11(m,2H),7.08(d,J=3.4Hz,1H),6.90-6.86(m,1H),6.85(d,J=3.4Hz,1H),3.90-3.64(m,4H),1.53-1.39(m,4H),1.18(s,3H).
SDUY058的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-甲氧基苯硫酚。
SDUY059的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-氟苯硫酚。1HNMR(600MHz,Chloroform-d)δ7.26-7.22(m,1H),7.18-7.14(m,1H),7.10-7.04(m,2H),7.01(d,J=3.4Hz,1H),6.75(d,J=3.4Hz,1H),3.85-3.58(m,4H),1.52-1.40(m,6H),1.18(s,3H).
SDUY060的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为4-甲基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.23-7.17(m,2H),7.10(d,J=8.0Hz,2H),6.99(d,J=3.4Hz,1H),6.65(d,J=3.4Hz,1H),3.85-3.57(m,4H),2.32(s,3H),1.51-1.38(m,4H),1.18(s,3H).
SDUY061的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为4-氯苯硫酚。1HNMR(600MHz,Chloroform-d)δ7.27–7.26(m,1H),7.25(t,J=2.1Hz,1H),7.21-7.16(m,2H),7.00(d,J=3.4Hz,1H),6.73(d,J=3.4Hz,1H),3.86-3.57(m,5H),1.54-1.36(m,6H),1.19(s,3H).
SDUY062的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-氨基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.43(dd,J=7.7,1.6Hz,1H),7.19-7.13(m,1H),6.92(d,J=3.4Hz,1H),6.75-6.66(m,2H),6.46(d,J=3.4Hz,1H),4.37(s,2H),3.79-3.57(m,4H),1.47-1.35(m,4H),1.18(s,3H).
SDUY063的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为4-氟基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.35-7.27(m,2H),7.04-6.95(m,3H),6.67(d,J=3.4Hz,1H),3.82-3.62(m,4H),1.63-1.47(m,4H),1.22(s,3H).
SDUY064的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为4-三氟甲基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.51(d,J=8.3Hz,2H),7.25(d,J=8.2Hz,2H),7.05(d,J=3.4Hz,1H),6.83(d,J=3.4Hz,1H),3.91-3.57(m,4H),1.55-1.33(m,6H),1.18(s,3H).
SDUY065的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-三氟甲基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.67(dd,J=7.9,1.5Hz,1H),7.40(t,J=7.3Hz,1H),7.31(t,J=7.6Hz,1H),7.18(d,J=8.0Hz,1H),7.04(d,J=3.4Hz,1H),6.83(d,J=3.4Hz,1H),3.88-3.56(m,4H),1.50-1.37(m,4H),1.18(s,3H).
SDUY066的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3-三氟甲基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.47(d,J=5.7Hz,2H),7.44-7.36(m,2H),7.03(d,J=3.4Hz,1H),6.81(d,J=3.3Hz,1H),3.89-3.58(m,4H),1.51-1.35(m,4H),1.18(s,3H).
SDUY067的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3-氟苯硫酚。1HNMR(600MHz,Chloroform-d)δ7.26-7.21(m,2H),7.03(d,J=3.4Hz,1H),7.01-6.98(m,1H),6.95-6.86(m,2H),6.79(d,J=3.4Hz,1H),3.89-3.58(m,4H),1.52-1.36(m,6H),1.18(s,3H).
SDUY068的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3-氨基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.08-6.99(m,2H),6.71(d,J=3.4Hz,1H),6.64-6.60(m,1H),6.55-6.49(m,2H),3.89-3.76(m,2H),3.68-3.60(m,2H),1.54-1.39(m,6H),1.18(s,3H).
SDUY069的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为4-氨基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.26-7.24(m,2H),6.94(d,J=3.4Hz,1H),6.63-6.58(m,2H),6.48(d,J=3.4Hz,1H),3.86-3.72(m,4H),3.61(brs,2H),1.52-1.38(m,6H),1.18(s,3H).
SDUY070的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-甲基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.21-7.13(m,2H),7.12-7.07(m,2H),7.02(d,J=3.4Hz,1H),6.65(d,J=3.4Hz,1H),3.88-3.73(m,2H),3.67-3.54(m,2H),2.43(s,3H),1.52-1.31(m,6H),1.17(s,3H).
SDUY071的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为萘-2-硫醇。1HNMR(600MHz,Chloroform-d)δ7.83-7.77(m,1H),7.78-7.69(m,3H),7.52-7.44(m,2H),7.33(dd,J=8.6,1.9Hz,1H),7.05(d,J=3.4Hz,1H),6.77(d,J=3.4Hz,1H),3.86-3.72(m,2H),3.67-3.55(m,2H),1.30-1.21(m,6H),1.14(s,3H).
SDUY072的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-巯基苯甲酸甲酯。1H NMR(600MHz,Chloroform-d)δ8.02(dd,J=7.8,1.7Hz,1H),7.36-7.30(m,1H),7.23-7.17(m,1H),7.11(d,J=3.4Hz,1H),6.89(d,J=3.3Hz,1H),6.75(d,J=8.2Hz,1H),3.96(s,3H),3.91-3.79(m,2H),3.77-3.60(m,2H),1.54-1.36(m,4H),1.17(s,3H).
SDUY074的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3-甲氧基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.19(t,J=8.0Hz,1H),7.02(d,J=3.4Hz,1H),6.84-6.70(m,4H),3.88-3.58(m,7H),1.52-1.38(m,6H),1.18(s,3H).
SDUY075的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为4-甲氧基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.39-7.31(m,2H),6.96(d,J=3.4Hz,1H),6.87-6.80(m,2H),6.56(d,J=3.4Hz,1H),3.90-3.70(m,5H),3.67-3.56(m,2H),1.62-1.38(m,6H),1.18(s,3H).
SDUY076的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3-氯苯硫酚。1HNMR(600MHz,Chloroform-d)δ7.24-7.17(m,3H),7.14-7.09(m,1H),7.02(d,J=3.4Hz,1H),6.77(d,J=3.4Hz,1H),3.95-3.77(m,2H),3.69-3.55(m,2H),1.52-1.38(m,4H),1.18(s,3H).
SDUY077的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3-甲基苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.17(t,J=7.7Hz,1H),7.10-6.99(m,4H),6.71(d,J=3.4Hz,1H),3.88-3.75(m,2H),3.69-3.56(m,2H),2.30(s,3H),1.53-1.32(m,6H),1.18(s,3H).
SDUY078的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为(4-氯苯基)甲硫醇。1H NMR(600MHz,Chloroform-d)δ7.26-7.22(m,2H),7.13-7.08(m,2H),6.89(d,J=3.4Hz,1H),6.42(d,J=3.4Hz,1H),3.95(s,2H),3.89-3.68(m,2H),3.64-3.57(m,2H),1.64-1.40(m,6H),1.20(s,3H).
SDUY079的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-三氟甲基吡啶-3-硫醇。1H NMR(600MHz,Chloroform-d)δ8.51(d,J=4.5Hz,1H),7.43(d,J=8.2Hz,1H),7.35(dd,J=8.2,4.6Hz,1H),7.05(d,J=3.4Hz,1H),6.91(d,J=3.4Hz,1H),3.92-3.60(m,4H),1.59-1.38(m,6H),1.19(s,3H).
SDUY080的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2,3-二氯吡啶-4-硫醇。1H NMR(600MHz,Chloroform-d)δ8.04(d,J=5.3Hz,1H),7.11(d,J=3.4Hz,1H),6.97(d,J=3.5Hz,1H),6.50(d,J=5.3Hz,1H),3.93-3.60(m,4H),1.55-1.41(m,7H),1.20(s,3H).
SDUY081的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2-氨基-3-氯吡啶-4-硫醇。1H NMR(600MHz,Chloroform-d)δ7.74(d,J=5.5Hz,1H),7.10(d,J=3.4Hz,1H),6.92(d,J=3.4Hz,1H),5.97(d,J=5.4Hz,1H),4.90(s,2H),3.93-3.59(m,4H),1.55-1.37(m,6H),1.19(s,3H).
SDUY082的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2,5-二氯苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.28(d,J=8.5Hz,1H),7.13-7.06(m,2H),6.89(d,J=3.3Hz,1H),6.80(d,J=2.4Hz,1H),3.90-3.61(m,4H),1.53-1.30(m,6H),1.19(s,3H).
SDUY083的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2,4-二氯苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.39(d,J=2.2Hz,1H),7.12(dd,J=8.6,2.2Hz,1H),7.06(d,J=3.3Hz,1H),6.87-6.79(m,2H),3.89-3.56(m,4H),1.53-1.28(m,6H),1.19(s,3H).
SDUY084的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3,4-二氯苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.35(d,J=8.4Hz,1H),7.31(d,J=2.2Hz,1H),7.06(dd,J=8.4,2.2Hz,1H),7.02(s,1H),6.78(d,J=3.4Hz,1H),3.85-3.56(m,4H),1.49-1.24(m,6H),1.19(s,3H).
SDUY085的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为五氯苯硫酚。1HNMR(600MHz,Chloroform-d)δ6.97(d,J=3.5Hz,1H),6.74(d,J=3.5Hz,1H),3.89-3.52(m,4H),1.54-1.38(m,6H),1.19(s,3H).
SDUY088的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为2,6-二氯苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.40(d,J=8.0Hz,2H),7.23(t,J=8.0Hz,1H),6.99(d,J=3.3Hz,1H),6.67(d,J=3.4Hz,1H),3.86-3.54(m,4H),1.62-1.50(m,2H),1.46-1.38(m,2H),1.18(s,3H).
SDUY089的制备方法同SDUY057,不同之处在于将2-氯苯硫酚换为3-氨基-2-氯苯硫酚。1H NMR(600MHz,Chloroform-d)δ7.06(d,J=3.3Hz,1H),6.91(t,J=7.9Hz,1H),6.81(d,J=3.4Hz,1H),6.61(dd,J=8.0,1.4Hz,1H),6.26(dd,J=7.9,1.4Hz,1H),4.13(s,2H),3.91-3.77(m,2H),3.70-3.55(m,2H),1.55-1.34(m,6H),1.18(s,3H).
SDUY073的合成路线如路线8所示,由SDUY072在碱性条件下水解制得。
路线8:
SDUY073制备方法:将化合物SDUY072(80mg,0.214mmol)溶于四氢呋喃和甲醇的混合溶液(2mL/2mL)中,加入氢氧化锂(15mg,0.625mmol)的水溶液(0.5mL),室温下反应2h。反应结束后,用1N稀盐酸调节pH=7,反应液直接浓缩,残留物经C18反相中压制备柱层析(5%-70%甲醇/水)得产品SDUY073(53mg,反应产率68.8%)。
SDUY073:1H NMR(600MHz,DMSO-d6)δ8.46(brs,3H),7.84(dd,J=7.6,1.7Hz,1H),7.19-7.13(m,1H),7.10-6.99(m,2H),6.91(d,J=3.4Hz,1H),6.45(d,J=7.9Hz,1H),4.07-3.94(m,2H),3.59-3.38(m,2H),1.96-1.75(m,2H),1.74-1.63(m,2H),1.36(s,3H).
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种呋喃酰胺类衍生物,其特征是,化学结构如式I所示,
其中,X1选自不存在、O、S、-CH2S-、SO、SO2、CO、CR5R6或NR7,R5、R6分别独立地选自氢、羟基、氨基、卤素、氰基、酯基、羧基、硝基、C1-7烷氧基、C1-7烷基、C3-7杂环基或C3-7碳环基;R7选自氢、C1-7烷基或C3-7碳环基;
R1选自芳环,通式可表示为Ar(R9)m;Ar选自五元环、六元环、并环,其中每个环系可以独立地被单取代、多取代或不被取代;R9选自氢、卤素、二氟甲基、三氟甲基、三氟甲氧基、氰基、羟基、酯基、羧基、硝基、氨基、C1-6烷氧基、C1-6烷基取代的烷胺基、C1-6烷基、C3-7杂环基、C3-7碳环基;m为0~8的自然数;
R2位于呋喃环的任意位置,选自氢、卤素、二氟甲基、三氟甲基、三氟甲氧基、氰基、羟基、酯基、羧基、硝基、氨基、C1-6烷氧基、C1-6烷基取代的烷胺基、C1-6烷基、C3-7杂环基、C3-7碳环基;n为0-2的自然数;
R3、R4分别独立选自氢、C1-6烷胺基、C1-6烷基、C3-7杂环基或C3-7碳环基,或者R3和R4环合后形成不取代、单取代或多取代的C3-7氮杂环,所述取代基选自卤素、氨基、BocNH-、羟基、羰基、氧代、酯基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷胺基。
3.如权利要求1所述的呋喃酰胺类衍生物,其特征是,R2为H;
或,X1为S;
或,R1为取代苯环、吡啶环或者萘环;优选地,R1为氯苯基,优选为2-氯苯基;优选地,R1为多取代苯环,且苯环中的2位、6位不同时存在取代基团。
4.如权利要求1所述的呋喃酰胺类衍生物,其特征是,包括以下化合物:
(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苯基)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(4-溴-5-((2,3-二氯苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯苯基)硫代)噻吩-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(4-氨基-5-((2,3-二氯苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯苯基)硫代)-4-甲基呋喃-2-基)甲酮;
5-(4-氨基-4-甲基哌啶-1-羰基)-2-((2,3-二氯苯基)硫代)呋喃-3-羧酸甲酯;
(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苯氧基)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苯甲酰基)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-(2,3-二氯苄基)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2-氯苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2-甲氧基苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2-氟苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-(对甲苯硫基)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((4-氯苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2-氨基苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((4-氟苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((4-(三氟甲基)苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2-(三氟甲基)苯基)硫代)呋喃-2-基)甲酮;
4-氨基-4-甲基哌啶-1-基)(5-((3-(三氟甲基)苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((3-氟苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((3-氨基苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((4-氨基苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-(邻甲苯硫基)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-(萘-2-基硫基)呋喃-2-基)甲酮;
2-((5-(4-氨基-4-甲基哌啶-1-羰基)呋喃-2-基)硫代)苯甲酸甲酯;
2-((5-(4-氨基-4-甲基哌啶-1-羰基)呋喃-2-基)硫代)苯甲酸;
(4-氨基-4-甲基哌啶-1-基)(5-((3-甲氧基苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((4-甲氧基苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((3-氯苯基)硫代)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-(间甲苯硫基)呋喃-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2-(三氟甲基)吡啶-3-基)硫基)呋喃;-2-基)甲酮;
(4-氨基-4-甲基哌啶-1-基)(5-((2,3-二氯吡啶-4-基)硫基)呋喃-2-基)甲酮;
(5-((2-氨基-3-氯吡啶-4-基)硫代)呋喃-2-基)(4-氨基-4-甲基哌啶-1-基)甲酮;
4-氨基-4-甲基哌啶-1-基5-(2,5-二氯苯基硫代)呋喃-2-甲酮;
4-氨基-4-甲基哌啶-1-基5-(2,4-二氯苯基硫代)呋喃-2-甲酮;
4-氨基-4-甲基哌啶-1-基5-(3,4-二氯苯基硫代)呋喃-2-甲酮;
5-(3-氨基-2-氯苯基)硫代呋喃4-氨基-4-甲基哌啶-1-甲酮。
6.一种药物组合物,其特征是,包括至少两种活性药物,其中一种活性药物为权利要求1-4中任一所述的呋喃酰胺类衍生物或其药学上可接受的盐。
7.一种药物制剂,其特征是,包括权利要求1-4中任一所述的呋喃酰胺类衍生物或其药学上可接受的盐和药学上可接受的辅料和/或载体。
8.一种权利要求1-4中任一所述的呋喃酰胺类衍生物或其药学上可接受的盐在制备SHP2抑制剂中的应用。
9.一种权利要求1-4中任一所述的呋喃酰胺类衍生物或其药学上可接受的盐在制备抗抗肿瘤细胞增殖药物中的应用。
10.如权利要求9所述的应用,其特征是,所述肿瘤细胞为人膀胱移行细胞***瘤细胞、人膀胱癌细胞、人膀胱移行细胞癌细胞或人乳腺癌细胞。
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CN113316574A (zh) * | 2019-01-31 | 2021-08-27 | 贝达药业股份有限公司 | Shp2抑制剂及其应用 |
WO2021218755A1 (zh) * | 2020-04-30 | 2021-11-04 | 贝达药业股份有限公司 | Shp2抑制剂及其组合物和应用 |
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WO2021218755A1 (zh) * | 2020-04-30 | 2021-11-04 | 贝达药业股份有限公司 | Shp2抑制剂及其组合物和应用 |
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