CN108715585A - 苯基联三氮唑类mll1-wdr5蛋白-蛋白相互作用抑制剂 - Google Patents
苯基联三氮唑类mll1-wdr5蛋白-蛋白相互作用抑制剂 Download PDFInfo
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- CN108715585A CN108715585A CN201810365880.0A CN201810365880A CN108715585A CN 108715585 A CN108715585 A CN 108715585A CN 201810365880 A CN201810365880 A CN 201810365880A CN 108715585 A CN108715585 A CN 108715585A
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- Prior art keywords
- phenyl
- compound
- methyl
- amino
- alkyl
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 50
- 230000004850 protein–protein interaction Effects 0.000 title abstract description 17
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 150000003852 triazoles Chemical class 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- -1 methoxyl group Chemical group 0.000 claims description 51
- 101001045846 Homo sapiens Histone-lysine N-methyltransferase 2A Proteins 0.000 claims description 31
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Chemical group 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 206010000830 Acute leukaemia Diseases 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 230000008707 rearrangement Effects 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
- 150000003951 lactams Chemical class 0.000 claims description 2
- 229950002366 nafoxidine Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims 4
- 150000001555 benzenes Chemical class 0.000 claims 1
- 239000001273 butane Substances 0.000 claims 1
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 claims 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 56
- 239000007787 solid Substances 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 description 28
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 21
- 208000032839 leukemia Diseases 0.000 description 18
- TVTPCFMCNRLMAP-UHFFFAOYSA-N n-fluoro-3-methylbenzamide Chemical compound CC1=CC=CC(C(=O)NF)=C1 TVTPCFMCNRLMAP-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 12
- 230000002255 enzymatic effect Effects 0.000 description 12
- 108700041619 Myeloid Ecotropic Viral Integration Site 1 Proteins 0.000 description 11
- MAGVJLLHDZWQFM-UHFFFAOYSA-N n-chloro-n-methylmethanamine Chemical compound CN(C)Cl MAGVJLLHDZWQFM-UHFFFAOYSA-N 0.000 description 11
- 102000047831 Myeloid Ecotropic Viral Integration Site 1 Human genes 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 101100477411 Dictyostelium discoideum set1 gene Proteins 0.000 description 7
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 230000011987 methylation Effects 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- KZVYALGJGCJPLQ-UHFFFAOYSA-N n-fluoro-3-nitroaniline Chemical class [O-][N+](=O)C1=CC=CC(NF)=C1 KZVYALGJGCJPLQ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 5
- 101000771599 Homo sapiens WD repeat-containing protein 5 Proteins 0.000 description 5
- 102100029445 WD repeat-containing protein 5 Human genes 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 3
- SXJNRYPVXFTJOU-UHFFFAOYSA-N 2-fluoro-5-nitrobenzoyl chloride Chemical class [O-][N+](=O)C1=CC=C(F)C(C(Cl)=O)=C1 SXJNRYPVXFTJOU-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)C(C(NC1(C)C=CC(C(CC2)CC(NC(c(*c3N4CC4)c(*)*(C)c3F)=O)=C2N2CCN(C)CC2)=CC1)=O)N Chemical compound CC(C)C(C(NC1(C)C=CC(C(CC2)CC(NC(c(*c3N4CC4)c(*)*(C)c3F)=O)=C2N2CCN(C)CC2)=CC1)=O)N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
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- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- HCKNAJXCHMACDN-UHFFFAOYSA-N 1-methylpiperidine-4-carboxylic acid Chemical compound CN1CCC(C(O)=O)CC1 HCKNAJXCHMACDN-UHFFFAOYSA-N 0.000 description 2
- GTODOEDLCNTSLG-UHFFFAOYSA-N 2h-triazole-4-carboxylic acid Chemical class OC(=O)C1=CNN=N1 GTODOEDLCNTSLG-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
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- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical group NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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Abstract
本发明涉及药物化学领域,具体涉及一类苯基联三氮唑类MLL1‑WDR5蛋白‑蛋白相互作用抑制剂(I)及其制备方法,药效学试验证明,本发明的化合物具有较强的MLL1‑WDR5蛋白‑蛋白相互作用抑制活性。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类苯基联三氮唑类MLL1-WDR5蛋白-蛋白相互作用抑制剂,其制备及医药用途。
背景技术
组蛋白甲基化在许多生物学过程中起到了关键作用,是表观遗传调控领域的主要研究内容。组蛋白H3K4的甲基转移酶MLL1基因易位重排会导致混合系白血病(mixedlineage leukemia,MLL1,急性骨髓性白血病和急性淋巴性白血病)。约10%的白血病人存在MLL1 基因的重排。MLL1基因重排后,与其他伴侣蛋白基因发生融合,形成融合基因,表达具有致癌作用的MLL融合蛋白。融合蛋白可以与RNA聚合酶II(RNA polymerase II,Pol II)相关延伸因子相互作用,构成超级延伸复合物(super elongation complex,SEC)。该复合物通过Pol II 使得MLL1所调控的Hox基因的表达异常,进而引起一系列的严重后果,诱发MLL白血病的发生。
MLL1的染色体易位只发生在单等位基因上,还存在着一个野生型的MLL1。如果敲除野生型MLL1等位基因,单独的MLL融合蛋白是不能导致白血病的,野生型MLL1的酶催化活性对MLL1融合蛋白诱发白血病生成是必需的。因此特异性地抑制野生型MLL1的酶催化活性能达到治疗白血病的作用。
MLL1单独催化H3K4甲基化活性很差,并且仅能催化单甲基化;形成MLL1核心催化复合物后酶催化活性大大提升,尤其是对H3K4me2的催化活性。MLL-C端WIN motif部分能够结合WDR5、RbBP5、Ash2L和DPY30,形成复合物。MLL1通过其C-端WIN motif部分与WDR5直接相互作用,介导MLL1SET催化域与其他蛋白复合物相互作用。敲除WDR5 后,H3K4me2/3水平下降,Hox基因的表达下调。
因此,利用小分子抑制剂干扰MLL1-WDR5的蛋白-蛋白相互作用是抑制MLL1的酶催化活性、下调Hox和Meis-1基因表达、进而阻断白血病进展的一种有效手段。
发明内容
本发明公开了一种可以调节MLL1-WDR5蛋白-蛋白相互作用的小分子化合物,其通过干扰MLL1-WDR5蛋白-蛋白相互作用,抑制MLL1的酶催化活性,下调H3K4的甲基化水平、Hox和Meis-1基因表达水平,从而诱导白血病细胞的凋亡,用于治疗白血病。本发明化合物结构如下:
其中其中X代表氢、甲基、甲氧基或卤素;
Y代表-CH2-、-O-、-S-、-CO-、-CH2O-、-NR5-、-CONR6-或-NR7CO-,其中,R5、R6、 R7各自独立代表氢、C1-C4烷基、C1-C4卤代烷基、苯基或取代苯基,取代基是卤素、C1-C4烷基、C1-C4烷氧基、氨基、羟基、巯基、羧基、氰基、三氟甲基或咪唑基;
m代表0~6;
R1代表氢、氨基、羟基、巯基、羧基、氰基、-CONH2、C1-C4烷基、C1-C4烷氧基、苯基、取代苯基、取代的或未取代的含氮或含氧3~7元杂环、-NR8COR9、-CONR10R11或-NR10R11,其中R8代表氢、C1-C4烷基、C1-C4卤代烷基、苯基或取代苯基,R9代表氨基、羟基、C1-C4烷基、C1-C4烷氧基、苯基或取代苯基、取代的或未取代的含氮或含氧3~7元杂环,R10、R11独立代表氢、C1-C4烷基、苯基或取代苯基、取代的或未取代的含氮或含氧3~7元杂环或R10、 R11连接形成含氮或含氧的3~7元杂环,所述取代基是卤素、C1-C4烷基、C1-C4烷氧基、氨基、羟基、巯基、羧基、氰基、三氟甲基或咪唑基;
R2代表双取代或三取代的卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、硝基或氰基;
R3代表氨基、甲氨基、氨甲基、羟基、羟甲基、巯基或-CONH2;
R4代表N-甲基哌嗪、1,2-二甲基哌嗪或N-甲基高哌嗪。
X优选代表氢、氟、氯或甲基。
Y优选代表-NR5-、-CONR6-或-NR7CO-;R5、R6、R7各自独立代表氢、甲基、乙基、丙基、环丙基或异丙基。
Y还优选代表-NR5-、-CONR6-或-NR7CO-;R5、R6和R7各自独立代表取代的苯基,取代基是甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、氰基、卤素、三氟甲基或咪唑基。
上面所述的取代或未取代的含氮或含氧的3~7元杂环优选氮杂环丙烷、杂氮环丁烷、四氢吡咯、哌啶、环己亚胺、内酰胺、四氢呋喃、四氢吡喃、吗啉、1,4-噁氮杂烷、六氢哒嗪、咪唑啉、吡唑啶、哌嗪,取代基是卤素、甲基、乙基、苯基、羟基、氨基、羟甲基或氨甲基。
R1优选代表-NR8COR9、-CONR10R11或-NR10R11,R8、R9、R10、R11代表C1-C4烷基。
R2优选代表三取代,取代基是氟、氯、溴、甲基、甲氧基、硝基、三氟甲基或氰基。
本发明同时包括化合物(I)的药学上可接受的盐,及其溶剂化物,都与化合物(I)有同样的药理功效。
本发明公开了一种药物组合物,其包含化合物(I)或其可药用盐,或溶剂合物,以及一种或多种可药用载体、稀释剂和赋形剂。
本发明还提供式(I)化合物或其可药用盐或溶剂合物在制备用于通过抑制MLL1-WDR5蛋白-蛋白相互作用来治疗该酶介导的疾病的药物中的用途,所述疾病如MLL基因融合型白血病,其可通过抑制MLL1的酶活性来治疗。
本发明的化合物临床所用剂量为0.01mg~1000mg/天,也可以根据病情的轻重或剂型的不同偏离此范围。
在某些实施方案中,根据式(I)的化合物可含有足以形成盐的碱性官能团。代表性的盐包括药用无机酸盐,有盐酸盐、氢溴酸盐和硫酸盐;药用有机酸盐,有乙酸盐、三氟乙酸盐、乳酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、甲磺酸盐、对苯甲酸盐和对苯甲磺酸盐。
同时本发明还公开了式(I)相关化合物的制备方法,包括以下步骤:
其中R1、R2、R3、R4、X、Y、n定义同前;
其中中间体Ia可通过下式进行合成得到,
下面是本发明化合物的部分药效学试验及结果:
MLL1与WDR5的蛋白-蛋白相互作用决定MLL1的酶活性;MLL1的酶活性影响H3K4 甲基化水平。在MLL融合型白血病中,H3K4的甲基化水平异常升高,下游的Hox和Meis-1 基因表达异常上调。当MLL1-WDR5的蛋白-蛋白相互作用受到抑制时,MLL1的酶催化活性下降,H3K4的甲基化水平下降,Hox和Meis-1基因表达下调,抑制白血病细胞的增殖。
联苯类化合物DDO-2084是已经报道的能够抑制MLL1-WDR5蛋白-蛋白相互作用、降低 MLL1酶催化活性、下调Hox和Meis-1基因表达小分子抑制剂(Eur.J.Med.Chem.2016,124, 480-489.),本发明中DDO-2084作为阳性对照化合物。
表1.本发明化合物MLL1-WDR5蛋白-蛋白相互作用抑制活性及其相关生物学活性
a化合物的结构见具体实施例;bDDO-2084的结构:
由表1可见,本发明的化合物具有较强的MLL1-WDR5蛋白-蛋白相互作用抑制活性。
同时,本发明的部分化合物也进行了细胞水平的RT-PCR实验,表1中为本发明部分化合物是否对下游Hox和Meis-1基因表达水平具有抑制作用的实验结果。实验结果表明本发明中对MLL1-WDR5蛋白-蛋白相互作用具有抑制作用的化合物均能抑制下游Hox和Meis-1基因表达。部分化合物的细胞水平的对下游Hox和Meis-1基因表达水平抑制结果见图1,通过图1可知,本发明实施例7化合物在2.5μM的浓度时,与5μM浓度的阳性对照DDO-2084 抑制Hoxa9和Meis-1基因表达的活性上达到相同水平,并且在相同的5μM浓度时,实施例7 的效果优于DDO-2084。
另外,本发明的部分化合物也进行了细胞水平的Western-blot实验,表1中为本发明部分化合物是否具有抑制H3K4的甲基化水平作用的实验结果。实验结果表明本发明中对MLL1-WDR5蛋白-蛋白相互作用具有抑制作用的化合物均能下调H3K4的甲基化水平。部分化合物在细胞水平的对MLL1的催化抑制作用结果见图2。通过图2可知,实施例7能够剂量依赖性的抑制MLL1的酶催化活性而降低H3K4me1/2/3的表达含量,并且可以看出在相同的10μM浓度时,实施例7的效果优于DDO-2084。
此外,在已发表文章(Eur.J.Med.Chem.2016,124,480-489.以下简称文章1)中报道了一系列的联苯类的MLL1-WDR5蛋白-蛋白相互作用抑制剂,其结构为:本发明的化合物与其不同点在于改变了两个苯环相连的结构,5位以三氮唑基团相连,通过这样的改造,本发明化合物大幅度提升了水溶性,降低了化合物的毒性,并且保持了原有的MLL1-WDR5抑制活性。我们选取了文章1中部分联苯类化合物以及部分未报道的联苯类的化合物,并采用与本发明中相同的测试方法、同一批次进行溶解性、毒性进行测定,结果对比如下:
表2.本发明中部分化合物与文章1中部分化合物的靶标活性及溶解度对比情况
由表2化合物的数据对比可以看出,在其他基团相同的情况下,本发明中以三氮唑替换苯环,能够保持靶标活性,并且可以显著提升化合物的水溶性。
同时本发明的部分化合物也进行了小鼠的亚急毒实验评价本发明化合物的安全性。选取雌性balb/c老鼠,每组各6只,分别将本发明中的部分三氮唑系列化合物(实施例4、6、7、 16、22)和文章1中部分化合物DDO-2113和DDO-2117以80mg/kg的给药剂量腹腔注射给药,连续给药10天后观察老鼠的生存状况及平均体重变化情况。如图3所示,本发明中部分化合物(实施例4、6、7、16、22)给药10天后未出现死亡,并且体重略有上升,而文章(Eur.J.Med.Chem.2016,124,480-489.)中化合物DDO-2113和DDO-2117给药后,DDO-2113以80mg/kg给药5天小鼠全部死亡,而DOO-2117给药后小鼠体重明显下降。对比给药后小鼠生存情况及平均体重变化,本发明中苯基联三氮唑化合物给药10天后未出现死亡,并且体重略有上升,而联苯系列化合物DDO-2113和DDO-2117给药后出现死亡与体重下降,显示出本发明的苯基三氮唑类化合物的良好的用药安全性。
其中,DDO-2113与DDO-2117为文章1中报道的化合物,其结构为:
本发明的部分化合物也进行了白血病细胞的抗增殖活性实验。表3为本发明的部分化合物评价抑制急性白血病细胞增殖活性的结果,其中MV4-11为人急性单核白血病细胞,Molm-13 为人极性髓性白血病细胞,K562为人慢性髓系白血病细胞。表3表明本发明的化合物具良好有抑制各种白血病细胞增殖的作用。
表3.本发明部分化合物对白血病细胞的抗增殖活性
a化合物的结构见具体实施例;bND为未进行测试;
本发明的苯基三氮唑类化合物具有较强的MLL1-WDR5蛋白-蛋白相互作用抑制活性,可以在细胞水平降低MLL1酶催化活性、下调Hox和Meis-1基因表达,诱导白血病细胞的凋亡,并且本发明中的苯基联三氮唑类化合物展现出良好的水溶性及用药安全性,可用于治疗白血病。
附图说明
图1是RT-PCR实验检测实施例7在细胞内对下调Hoxa9和Meis-1基因表达
图2是Western-blot实验检测实施例7在细胞内对MLL1酶催化活性的影响
图3是本发明部分化合物与文章1中部分化合物的毒性对比
具体实施方式
实施例1
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4- 甲酸甲酯(1)
4-(4-甲基哌嗪-1-基)-3-硝基苯胺(IIb)的制备:
将化合物4-氟-3-硝基苯胺(II)(6g,38.4mmol)溶于50mL乙腈中,加入N-甲基哌嗪(5.8 g,6.3mL,57.6mmol)和N,N-二异丙基乙胺(9.5mL,57.6mmol)后加热回流12h。旋干后粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1)得红棕色固体(8.9g,97.8%).1H NMR(300MHz, DMSO-d6)δ7.06(d,J=8.6Hz,1H),6.76(s,1H),6.69(d,J=8.5Hz,1H),5.34(s,2H),2.70(t,J =4.4Hz,4H),2.27(br s,4H),2.09(s,3H).m/z(EI-MS):259.1[M+Na]+。
1-(4-叠氮基-2-硝基苯基)-4-甲基哌嗪(Ia)的制备:
将化合物4-(4-甲基哌嗪-1-基)-3-硝基苯胺(IIb)(4.0g,17.0mmol)溶于100mL的2M/HCl 中,降温至0℃,滴加亚硝酸钠(1.76g,25.5mmol)的水溶液10mL,0℃搅拌30min后,滴加叠氮化钠(2.2g,34.0mmol)的水溶液10mL,0℃搅拌30min后室温搅拌2h。然后用2M/NaOH 条件pH=9~10析出产物,抽滤、烘干得红棕色固体(4.0g,91.3%).1H NMR(300MHz,DMSO-d6) δ7.48(d,J=2.2Hz,1H),7.34-7.20(m,2H),2.85(t,J=4.7Hz,4H),2.31(t,J=4.8Hz,4H),2.11 (s,3H).m/z(EI-MS):261.1[M-H]-.
1-(4-(4-甲基哌嗪-1-基)-3-硝基苯基)-1H-1,2,3-三唑-4-羧酸甲酯(Ib)的制备:
将化合物1-(4-叠氮基-2-硝基苯基)-4-甲基哌嗪(Ia)(1.0g,3.8mmol)溶于50mL甲醇,加入丙炔酸甲酯(0.96g,11.4mmol),碘化亚铜(0.07g,0.38mmol)、N,N-二异丙基乙胺(0.12mL, 0.76mmol),加热回流48h后,过滤、浓缩、乙酸乙酯打浆得红棕色固体(0.8g,61.5%).1H NMR (300MHz,DMSO-d6)δ9.45(s,1H),8.36(d,J=2.7Hz,1H),8.11-8.01(m,1H),7.42(d,J=9.1 Hz,1H),3.80(s,3H),2.99(t,J=5.4Hz,4H),2.35(t,J=5.2Hz,4H),2.13(s,3H).m/z(EI-MS): 369.2[M+Na]+.
1-(3-氨基-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸甲酯(Ic)的制备:
将化合物1-(4-(4-甲基哌嗪-1-基)-3-硝基苯基)-1H-1,2,3-三唑-4-羧酸甲酯(Ib)(3.8g, 12.0mmol)溶于50mL甲醇中,加入催化量的Pd/C,通入氢气,室温搅拌7h后,抽滤浓缩得粉色固体(3.0g,78.9%).1H NMR(300MHz,DMSO-d6)δ9.28(s,1H),7.28(d,J=1.9Hz,1H), 7.07(d,J=1.9Hz,2H),5.15(s,2H),3.90(s,3H),2.87(t,J=4.5Hz,4H),2.53(br s,4H),2.26(s, 3H).m/z(ESI-MS):317.1763[M+H]+.
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4- 甲酸甲酯(1)的制备
将化合物1-(3-氨基-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4-羧酸甲酯(Ic)(1.7g, 5.3mmol)溶于100mL无水二氯甲烷中,加入吡啶后(0.43mL,5.3mmol),冰水浴下滴加2-氯 -3-甲基-4-氟-5-硝基苯甲酰氯(1.6g,6.4mmol)的二氯甲烷溶液20mL,室温搅拌2h后,抽滤、烘干得浅黄色固体;将浅黄色固体(2.6g,4.9mmol)溶于乙酸乙酯中,加入氯化亚锡(5.5g,24.4 mmol),加热回流3h后冷却至室温,加入100mL乙酸乙酯稀释,然后用饱和碳酸氢钠溶液中和至无更多白色胶状物出现,抽滤,滤饼用乙酸乙酯洗至无紫外吸收、滤液用乙酸乙酯萃取至无紫外吸收,合并有机相,无水硫酸钠干燥,浓缩得粗品,乙酸乙酯打浆抽滤的灰白色固体1(2.3g,93.9%).1H NMR(300MHz,DMSO-d6)δ9.52-9.45(m,2H),8.69(s,1H),7.73(dd,J= 8.7,2.7Hz,1H),7.46(d,J=8.6Hz,1H),6.92(d,J=9.2Hz,1H),5.53(s,2H),3.92(s,3H), 3.00-2.90(m,4H),2.51(br s,4H),2.28(d,J=2.6Hz,3H),2.24(s,3H).(EI-MS):502.9[M+H]+.
实施例2
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3-三唑-4- 羧酸(2)的制备:
将化合物1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基) -1H-1,2,3-三唑-4-甲酸甲酯(1)(2.3g,4.6mmol)溶于THF中,加入氢氧化锂溶液(1M,15mL),室温搅拌8h后,旋干去除THF,而后用2M盐酸酸化得白色固体(1.7g,80.4%).1HNMR(300 MHz,DMSO-d6)δ9.52-9.45(m,2H),8.69(s,1H),7.73(dd,J=8.7,2.7Hz,1H),7.46(d,J=8.6 Hz,1H),6.92(d,J=9.2Hz,1H),5.53(s,2H),3.92(s,3H),3.00-2.90(m,4H),2.50(br s,4H), 2.28(d,J=2.6Hz,3H),2.24(s,3H).(EI-MS):488.9[M+H]+.
实施例3
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-N,N-二甲基-1H-1,2,3 三唑-4-甲酰胺(3)的制备:
将化合物1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基) -1H-1,2,3-三唑-4-羧酸(2)(0.18g,0.36mmol)溶于10mL的DMF,加入BOP(0.32g,0.72mmol)、三乙胺(0.10mL,0.72mmol)和二甲氨基盐酸盐(58.7mg,0.72mmol)后,室温搅拌4h。然后反应液加入50mL乙酸乙酯稀释后,饱和氯化钠溶液洗去DMF,取有机相无水硫酸钠干燥,旋干有机溶剂得粗品,硅胶柱层析分离纯化(二氯甲烷:甲醇=50:1)得灰白色固体。产率78.4%. 1H NMR(300MHz,DMSO-d6)δ9.59(s,1H),9.18(s,1H),8.63(d,J=2.5Hz,1H),7.71(dd,J= 8.6,2.6Hz,1H),7.42(d,J=8.6Hz,1H),6.83(d,J=9.2Hz,1H),5.50(s,2H),3.11(br s,10H), 3.02(s,3H),2.70-2.69(m,4H),2.24(d,J=2.5Hz,3H).(EI-MS):515.9[M+H]+.
实施例4
5-氨基-2-氯-4-氟-3-甲基-N-(2-(4-甲基哌嗪-1-基)-5-(4-(吗啉-4-羰基)-1H-1,2,3-三唑-1- 基)苯基)苯甲酰胺(4)的制备:
按照实施例3的方法,用吗啉替换二甲氨基盐酸盐,得灰白色固体。产率67.5%.1HNMR (300MHz,DMSO-d6)δ9.61(s,1H),9.24(s,1H),8.64(d,J=2.5Hz,1H),7.73(dd,J=8.6,2.6 Hz,1H),7.44(d,J=8.7Hz,1H),6.86(d,J=9.2Hz,1H),5.52(s,2H),4.06(s,2H),3.68(s,6H), 3.12(br s,8H),2.69(s,3H),2.26(d,J=2.6Hz,3H).(EI-MS):558.9[M+H]+.
实施例5
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(四氢-2H- 吡喃-4-基)-1H-1,2,3-三唑-4-甲酰胺(5)的制备:
按照实施例3的方法,用4-氨基四氢吡喃替换二甲氨基盐酸盐,得灰白色固体。产率82.9%. 1H NMR(300MHz,DMSO-d6)δ9.52(s,1H),9.26-9.24(m,1H),8.65(s,2H),7.71(d,J=8.7Hz, 1H),7.42(d,J=9.4Hz,1H),6.89(s,1H),5.53(s,2H),4.06(s,1H),3.9-3.86(m,2H),2.99(s,6H), 2.71(s,4H),2.38(s,3H),2.25(s,3H),1.71(s,4H).(EI-MS):572.0[M+H]+.
实施例6
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(1-甲基哌啶 -4-基)-1H-1,2,3-三唑-4-甲酰胺(6)的制备:
按照实施例3的方法,用4-氨基-1-甲基哌啶替换二甲氨基盐酸盐,得灰白色固体。产率 49.9%.1H NMR(300MHz,DMSO-d6)δ9.48(s,1H),9.22(s,1H),8.65(d,J=2.6Hz,1H),8.52 (d,J=8.2Hz,1H),7.70(dd,J=8.5,2.7Hz,1H),7.42(d,J=8.6Hz,1H),6.89(d,J=9.2Hz,1H), 5.54(s,2H),3.78(s,1H),2.92(t,J=4.6Hz,4H),2.82-2.78(m,2H),2.26(d,J=2.7Hz,3H),2.22 (s,3H),2.19(s,3H),2.07-1.86(m,4H),1.75-1.66(m,4H).(EI-MS):585.0[M+H]+.
实施例7
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(3-吗啉代丙基)-1H-1,2,3-三唑-4-甲酰胺(7)的制备:
按照实施例3的方法,用N-(3-氨丙基)吗啉替换二甲氨基盐酸盐,得灰白色固体。产率 94.2%.1H NMR(300MHz,DMSO-d6)δ9.51(s,1H),9.22(s,1H),8.85(t,J=5.8Hz,1H),8.66(s, 1H),7.71(dd,J=8.6,2.7Hz,1H),7.43(d,J=8.8Hz,1H),6.89(d,J=9.2Hz,1H),5.53(s,2H), 3.62(t,J=4.6Hz,4H),2.98-2.97(m,4H),2.63(s,4H),2.54(s,2H),2.46-2.36(m,6H),2.33(s, 3H),2.26(d,J=2.6Hz,3H),1.74-1.70(m,2H).(EI-MS):615.1[M+H]+.
实施例8
5-氨基-2-氯-4-氟-3-甲基-N-(2-(4-甲基哌嗪-1-基)-5-(4-(4-甲基哌嗪-1-羰基)-1H-1,-1H-1,2,3- 三唑-1-基)苯基)苯甲酰胺(8)的制备:
按照实施例3的方法,用N-甲基哌嗪替换二甲氨基盐酸盐,得灰白色固体。产率94.2%. 1H NMR(300MHz,DMSO-d6)δ9.51(s,1H),9.22(s,1H),8.85(t,J=5.8Hz,1H),8.66(s,1H), 7.71(dd,J=8.6,2.7Hz,1H),7.43(d,J=8.8Hz,1H),6.89(d,J=9.2Hz,1H),5.53(s,2H),3.62 (t,J=4.6Hz,4H),2.98-2.97(m,4H),2.63(s,4H),2.54(s,2H),2.46-2.36(m,6H),2.33(s,3H), 2.26(d,J=2.6Hz,3H),1.74-1.70(m,2H).(EI-MS):571.0[M+H]+.
实施例9
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(2-吗啉代乙基)-1H-1,2,3-三唑-4-甲酰胺(9)的制备:
按照实施例3的方法,用N-(2-氨基乙基)吗啉替换二甲氨基盐酸盐,得灰白色固体。产率72.5%.1H NMR(300MHz,DMSO-d6)δ9.51(s,1H),9.24(s,1H),8.66(d,J=2.4Hz,1H), 8.56(t,J=5.8Hz,1H),7.71(dd,J=8.7,2.6Hz,1H),7.43(d,J=8.7Hz,1H),6.89(d,J=9.2Hz, 1H),5.54(s,2H),3.58(t,J=4.6Hz,4H),3.44(s,2H),2.96(t,J=4.8Hz,4H),2.59(s,4H),2.54 (s,2H),2.44(s,4H),2.30(s,3H),2.26(d,J=2.6Hz,3H).(EI-MS):601.0[M+H]+.
实施例10
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-N-(3-氨基丙基) -1H-1,2,3-三唑-4-甲酰胺(10)的制备:
按照实施例3的方法,用1,3-丙二胺替换二甲氨基盐酸盐,得灰白色固体。产率64.5%.1H NMR(300MHz,DMSO-d6)δ8.85(s,1H),8.70(s,1H),8.45(d,J=2.1Hz,1H),7.36(dd,J=7.5, 2.0Hz,1H),7.25(s,1H),6.84(d,J=7.5Hz,1H),6.78(d,J=5.7Hz,1H),4.13(s,2H),3.25-3.19 (m,6H),2.98(t,J=4.9Hz,4H),2.67-2.58(m,5H),2.39(s,3H),2.19-2.13(m,2H),1.14(s,2H). (EI-MS):545.0[M+H]+.
实施例11
5-氨基-2-氯-4-氟-3-甲基-N-(2-(4-甲基哌嗪-1-基)-5-(1H-1,2,3-三唑-1-基)苯基)苯甲酰胺(11)
按照实施例1的方法,三甲基乙炔基硅替换丙炔酸甲酯,三步反应得灰白色固体。三步产率23.8%.1H NMR(300MHz,DMSO-d6)δ8.76-8.68(m,2H),8.49(d,J=2.1Hz,1H),8.18(d, J=7.5Hz,1H),7.27(dd,J=7.5,2.0Hz,1H),6.82(d,J=7.5Hz,1H),6.75(d,J=5.7Hz,1H), 4.15(s,2H),3.20(t,J=5.1Hz,4H),2.98(t,J=5.0Hz,4H),2.60(s,3H),2.39(s,3H).(EI-MS): 444.9[M+H]+.
实施例12
叔丁基(1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3- 三唑-4-基)氨基甲酸酯(12)
按照实施例1的方法,叔丁基乙炔基氨基甲酸酯替换丙炔酸甲酯,三步反应得灰白色固体。三步产率20.1%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.59(d,J=2.0Hz,1H),8.08 (s,1H),7.25(dd,J=7.5,2.0Hz,1H),7.18(s,1H),6.80(dd,J=19.7,6.6Hz,2H),4.17(s,2H), 3.20(t,J=5.1Hz,4H),2.98(t,J=5.1Hz,4H),2.60(s,3H),2.39(s,3H),1.50(s,9H).(EI-MS): 560.0[M+H]+.
实施例13
5-氨基-N-(5-(4-氨基-1H-1,2,3-三唑-1-基)-2-(4-甲基哌嗪-1-基)苯基)-2-氯-4-氟-3-甲基苯甲酰胺(13)
将化合物叔丁基(1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基) 苯基)-1H-1,2,3-三唑-4-基)氨基甲酸酯(12)(1.0g,2.2mmol)溶于20mL二氯甲烷中,加入10mL三氟乙酸,室温搅拌1h后,饱和碳酸氢钠溶液调pH=8~9,二氯甲烷萃取,无水硫酸钠干燥有机相,旋干后得灰色固体。产率87.3%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H), 8.49(d,J=2.0Hz,1H),8.08(s,1H),7.25(dd,J=7.5,2.0Hz,1H),6.80(d,J=7.5Hz,1H),6.70 (d,J=5.7Hz,1H),5.80(s,2H),4.15(s,2H),3.20(t,J=5.3Hz,4H),2.98(t,J=5.2Hz,4H),2.60 (s,3H),2.39(s,3H).(EI-MS):459.9[M+H]+.
实施例14
N-(1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3- 三唑吡啶-4-基)-1-甲基哌啶-4-甲酰胺(14)
将化合物5-氨基-N-(5-(4-氨基-1H-1,2,3-三唑-1-基)-2-(4-甲基哌嗪-1-基)苯基)-2- 氯-4-氟-3-甲基苯甲酰胺(13)(0.2g,0.34mmol)溶于5mL的DMF,加入BOP(0.30g,0.68 mmol)、三乙胺(0.09mL,0.68mmol)和1-甲基哌啶-4-甲酸(97.3mg,0.68mmol)后,室温搅拌 4h。然后反应液加入50mL乙酸乙酯稀释后,饱和氯化钠溶液洗去DMF,取有机相无水硫酸钠干燥,旋干有机溶剂得粗品,硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1)得灰白色固体。产率73.9%.1H NMR(300MHz,DMSO-d6)δ8.72-8.64(m,2H),8.08(s,1H),7.71(s,1H),7.25 (dd,J=7.5,2.0Hz,1H),6.87(d,J=7.5Hz,1H),6.69(d,J=5.7Hz,1H),4.16(s,2H),3.20(t,J= 5.3Hz,4H),3.05-2.95(m,6H),2.60(s,3H),2.50-2.45(m,1H),2.39-2.37(m,6H),2.14-2.09(m, 2H),2.05-1.98(m,2H),1.81-1.70(m,2H).(EI-MS):485.1[M+H]+.
实施例15
N-(1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基哌嗪-1-基)苯基)-1H-1,2,3- 三唑吡啶-4-基)哌啶-4-甲酰胺(15)
按照实施例14的方法,用4-哌啶甲酸替换1-甲基哌啶-4-甲酸,得灰白色固体。产率 88.7%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.55(d,J=2.0Hz,1H),8.08(s,1H),7.71(s, 1H),7.26(dd,J=7.5,2.0Hz,1H),6.80(dd,J=23.8,6.6Hz,2H),4.15(s,2H),3.27-3.17(m,6H), 2.98(t,J=5.0Hz,4H),2.82-2.65(m,3H),2.60(s,3H),2.39(s,3H),2.03-1.96(m,2H),1.74-1.69 (m,2H),1.22(s,1H).(EI-MS):571.1[M+H]+.
实施例16
5-氨基-N-(5-(4-(4-氨基丁酰氨基)-1H-1,2,3-三唑-1-基)-2-(4-甲基哌嗪-1-基)苯基)-2- 氯-4-氟-3-甲基苯甲酰胺(16)
按照实施例14的方法,用γ-氨基丁酸替换1-甲基哌啶-4-甲酸,得灰白色固体。产率 88.7%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.08(s,1H),7.71(s,1H),7.25(dd,J=7.5, 2.0Hz,1H),6.80(dd,J=21.4,6.6Hz,2H),4.17(s,2H),3.20(t,J=5.1Hz,4H),3.08-3.04(m, 2H),2.98(t,J=5.1Hz,4H),2.60(s,3H),2.50(t,J=8.2Hz,2H),2.39(s,3H),2.10-2.04(m,2H), 1.19(s,2H).(EI-MS):545.0[M+H]+.
实施例17
5-氨基-2-氯-4-氟-N-(5-(4-(3-羟基丙酰氨基)-1H-1,2,3-三唑-1-基)-2-(4-甲基哌嗪-1-基) 苯基)-3-甲基苯甲酰胺
按照实施例14的方法,用3-羟丙酸替换1-甲基哌啶-4-甲酸,得灰白色固体。产率84.9%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.57(d,J=2.0Hz,1H),8.08(s,1H),7.71(s,1H), 7.25(dd,J=7.5,2.0Hz,1H),6.80(dd,J=21.8,6.6Hz,2H),4.36(t,J=5.0Hz,1H),4.17(s,2H), 3.83-3.79(m,2H),3.20(t,J=5.1Hz,4H),2.98(t,J=5.0Hz,4H),2.60(s,3H),2.39-2.35(m,5H). (EI-MS):532.1[M+H]+.
实施例18
5-氨基-2-氯-N-(5-(4-(4-(二甲基氨基甲基)苄基)-1H-1,2,3-三唑-1-基)-2-(4-甲基哌嗪 -1-基基)苯基)-4-氟-3-甲基苯甲酰(18)
按照实施例1的方法,N,N-二甲基-4-(丙-2-炔-1-基)苯甲酰胺替换丙炔酸甲酯,三步反应得灰白色固体。三步产率34.4%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.49-8.44(m, 2H),7.74-7.68(m,2H),7.56-7.50(m,2H),7.26(dd,J=7.4,1.9Hz,1H),6.75(d,J=5.9Hz,1H), 4.16(s,2H),3.88(d,J=1.2Hz,2H),3.20(t,J=5.1Hz,4H),3.0-2.95(m,10H),2.60(s,3H),2.38 (s,3H).(EI-MS):606.1[M+H]+.
实施例19
5-氨基-2-氯-N-(5-(4-(2-(二甲基氨基)乙基)-1H-1,2,3-三唑-1-基)-2-(4-甲基哌嗪-1- 基基)苯基)-4-氟-3-甲基苯甲酰(19)
按照实施例1的方法,N,N-二甲基-丁-3-炔-1-胺替换丙炔酸甲酯,三步反应得灰白色固体。三步产率31.6%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.48(d,J=2.0Hz,1H),8.28 (s,1H),7.26(dd,J=7.5,2.0Hz,1H),6.82(d,J=7.5Hz,1H),6.74(d,J=5.7Hz,1H),4.15(s, 2H),3.20(t,J=5.1Hz,4H),2.98(t,J=5.0Hz,4H),2.71-2.61(m,4H),2.60(s,3H),2.40-2.39(m, 9H).(EI-MS):516.0[M+H]+.
实施例20
5-氨基-2-氯-N-(3-(4-乙氧基-1H-1,2,3-三唑-1-基)-2-氟-6-(4-甲基哌嗪-1-基)苯基)-4- 氟-3-甲基苯甲酰(20)
按照实施例1的方法,以2,4-二氟-3-硝基苯胺替换4-氟-3-硝基苯胺,乙基乙炔基醚替换丙炔酸甲酯,五步反应得灰白色固体。五步产率12.8%.1H NMR(300MHz,DMSO-d6)δ8.70(s, 1H),7.98(s,1H),7.30(dd,J=7.5,5.7Hz,1H),6.74(d,J=5.7Hz,1H),6.59(d,J=7.5Hz,1H), 4.76-4.72(m,2H),4.15(s,2H),3.20(t,J=5.1Hz,4H),2.98(t,J=5.0Hz,4H),2.60(s,3H),2.39 (s,3H),1.56(t,J=8.0Hz,3H).(EI-MS):507.1[M+H]+.
实施例21
N-(3-(4-((2-氨基-2-氧代乙基)氨基)-1H-1,2,3-三唑-1-基)-2-氟-6-(4-甲基哌嗪-1-基基)苯基)-2-氯-4-氟-5-羟基-3-甲基苯甲酰(21)
按照实施例1的方法,以2,4-二氟-3-硝基苯胺替换4-氟-3-硝基苯胺,2-(乙炔基氨基) 乙酰胺替换丙炔酸甲酯,2-氯-3-甲基-4-氟-5-羟基苯甲酰氯替换2-氯-3-甲基-4-氟-5-硝基苯甲酰氯,五步反应得白色固体。五步产率9.7%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.07 (d,J=10.4Hz,2H),7.34-7.24(m,2H),6.59(d,J=7.5Hz,1H),5.98(s,2H),5.93(s,1H),4.03(s, 2H),3.20(t,J=5.1Hz,4H),2.98(t,J=5.0Hz,4H),2.60(s,3H),2.38(s,3H).(EI-MS):536.2[M +H]+.
实施例22
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-2-甲基-4-(4-甲基哌嗪-1-基)苯基)-N-(2- 吗啉代乙基)-1H--1,2,3-三唑-4-甲酰胺(22)
按照实施例3的方法,以2-氟-4-甲基-3-硝基苯胺替换4-氟-3-硝基苯胺,N-(2-氨基乙基) 吗啉替换二甲氨基盐酸盐,得灰白色固体。六步产率8.8%.1H NMR(300MHz,DMSO-d6)δ 8.70(s,1H),8.52(s,1H),7.25(s,1H),7.13(d,J=7.5Hz,1H),6.78(d,J=5.7Hz,1H),6.72(d,J =7.5Hz,1H),4.15(s,2H),3.74(t,J=4.7Hz,4H),3.55-3.53(m,2H),3.20(t,J=5.1Hz,4H), 2.98(t,J=5.1Hz,4H),2.61-2.59(m,5H),2.51(t,J=4.7Hz,4H),2.40-2.39(m,6H).(EI-MS): 615.1[M+H]+.
实施例23
N-(3-(4-(3-氨基丙酰氨基)-1H-1,2,3-三唑-1-基)-2-甲基-6-(4-甲基哌嗪-1-基)苯基)-2- 氯-4-氟-5-羟基-3-甲基苯甲酰胺(23)
按照实施例14的方法,以2-氟-4-甲基-3-硝基苯胺替换4-氟-3-硝基苯胺,2-氯-3-甲基-4- 氟-5-羟基苯甲酰氯替换2-氯-3-甲基-4-氟-5-硝基苯甲酰氯,β-丙氨酸替换1-甲基哌啶-4-甲酸,六步反应得白色固体。六步产率7.2%.1H NMR(300MHz,DMSO-d6)δ8.70(s,1H),8.08(s,1H), 7.71(s,1H),7.19(d,J=7.5Hz,1H),7.06(d,J=5.7Hz,1H),6.72(d,J=7.5Hz,1H),5.93(s, 1H),3.20(t,J=5.1Hz,4H),3.01-2.93(m,4H),2.93-2.91(m,1H),2.60(s,3H),2.45(s,3H), 2.44-2.42(m,2H),2.38(s,3H),1.24(s,2H).(EI-MS):615.1[M+H]+.
实施例24
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(4-甲基-1,4-二氮杂环庚-1-基)苯基)-N- (2-吗啉代乙基)-1H-1,2,3-三唑-4-甲酰胺(24)
按照实施例3的方法,以N-甲基高哌嗪替代N-甲基哌嗪,N-(2-氨基乙基)吗啉替换二甲氨基盐酸盐,得灰白色固体。六步产率7.3%.1H NMR(300MHz,DMSO-d6)δ8.79(s,1H),8.70 (s,1H),7.31(dd,J=7.5,2.0Hz,1H),7.25(s,1H),6.83(d,J=7.5Hz,1H),6.70(d,J=5.7Hz, 1H),4.16(s,2H),3.74(t,J=4.7Hz,4H),3.60(t,J=4.8Hz,2H),3.55-3.53(m,2H),3.46-3.44(m, 2H),2.91-2.89(m,2H),2.61-2.58(m,4H),2.52-2.50(m,4H),2.39(s,3H),2.31(s,3H),1.64-1.60 (m,2H).(EI-MS):615.1[M+H]+.
实施例25
1-(3-(5-氨基-2-氯-4-氟-3-甲基苯甲酰氨基)-4-(3,4-二甲基哌嗪-1-基)苯基)-N-(2-吗啉代乙基)-1H-1,2,3-三唑-4-甲酰胺(25)
按照实施例3的方法,以1,2-二甲基哌嗪替代N-甲基哌嗪,N-(2-氨基乙基)吗啉替换二甲氨基盐酸盐,得灰白色固体。六步产率7.3%.1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.70 (s,1H),8.54(d,J=2.0Hz,1H),7.31(dd,J=7.5,2.0Hz,1H),7.25(s,1H),6.81(d,J=7.5Hz, 1H),6.70(d,J=5.7Hz,1H),4.18-4.04(m,7H),3.66-3.53(m,2H),3.35-3.31(m,1H),3.20-3.07 (m,4H),2.93-2.87(m,1H),2.73-2.58(m,2H),2.51-2.37(m,7H),2.34-2.20(m,3H),1.16(d,J= 6.8Hz,3H).(EI-MS):615.1[M+H]+。
Claims (10)
1.通式(I)的化合物或其药学上可接受的盐:
其中X代表氢、甲基、甲氧基或卤素;
Y代表-CH2-、-O-、-S-、-CO-、-CH2O-、-NR5-、-CONR6-或-NR7CO-,其中,R5、R6、R7各自独立代表氢、C1-C4烷基、C1-C4卤代烷基、苯基或取代苯基,取代基是卤素、C1-C4烷基、C1-C4烷氧基、氨基、羟基、巯基、羧基、氰基、三氟甲基或咪唑基;
m代表0~6;
R1代表氢、氨基、羟基、巯基、羧基、氰基、-CONH2、C1-C4烷基、C1-C4烷氧基、苯基、取代苯基、取代的或未取代的含氮或含氧3~7元杂环、-NR8COR9、-CONR10R11或-NR10R11,其中R8代表氢、C1-C4烷基、C1-C4卤代烷基、苯基或取代苯基,R9代表氨基、羟基、C1-C4烷基、C1-C4烷氧基、苯基或取代苯基、取代的或未取代的含氮或含氧3~7元杂环,R10、R11独立代表氢、C1-C4烷基、苯基或取代苯基、取代的或未取代的含氮或含氧3~7元杂环或R10、R11连接形成含氮或含氧的3~7元杂环,所述取代基是卤素、C1-C4烷基、C1-C4烷氧基、氨基、羟基、巯基、羧基、氰基、三氟甲基或咪唑基;
R2代表双取代或三取代的卤素、C1-C4烷基、C1-C4烷氧基、三氟甲基、硝基或氰基;
R3代表氨基、甲氨基、氨甲基、羟基、羟甲基、巯基或-CONH2;
R4代表N-甲基哌嗪、1,2-二甲基哌嗪或N-甲基高哌嗪。
2.权利要求1的化合物或其药学上可接受的盐,其中X代表氢、氟、氯或甲基。
3.权利要求1的化合物或其药学上可接受的盐,其中Y代表-NR5-、-CONR6-或-NR7CO-;R5、R6、R7各自独立代表氢、甲基、乙基、丙基、环丙基或异丙基。
4.权利要求1的化合物或其药学上可接受的盐,其中Y代表-NR5-、-CONR6-或-NR7CO-;R5、R6和R7各自独立代表取代的苯基,取代基是甲基、乙基、异丙基、叔丁基、环丙基、甲氧基、氰基、卤素、三氟甲基或咪唑基。
5.权利要求1的化合物或其药学上可接受的盐,其中所述的取代或未取代的含氮或含氧的3~7元杂环是氮杂环丙烷、杂氮环丁烷、四氢吡咯、哌啶、环己亚胺、内酰胺、四氢呋喃、四氢吡喃、吗啉、1,4-噁氮杂烷、六氢哒嗪、咪唑啉、吡唑啶、哌嗪,取代基是甲基、乙基、苯基、羟基、氨基、羟甲基或氨甲基,取代基是卤素、C1-C4烷基、C1-C4烷氧基、氨基、羟基、巯基、羧基、氰基或三氟甲基。
6.权利要求1的化合物或其药学上可接受的盐,其中R1代表-NR8COR9、-CONR10R11或-NR10R11,R8、R9、R10、R11代表C1-C4烷基。
7.权利要求1的化合物或其药学上可接受的盐,其中R2代表三取代,取代基是氟、氯、溴、甲基、甲氧基、硝基、三氟甲基或氰基。
8.一种药物组合物,其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
9.权利要求1的化合物或其药学上可接受的盐用于制备治疗急性白血病的药物的用途。
10.权利要求9的用途,其中急性白血病是具有MLL1基因重排型急性白血病。
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CN201810365880.0A CN108715585A (zh) | 2018-04-23 | 2018-04-23 | 苯基联三氮唑类mll1-wdr5蛋白-蛋白相互作用抑制剂 |
MX2020011205A MX2020011205A (es) | 2018-04-23 | 2018-12-25 | Inhibidor de la interaccion proteina-proteina fenil triazol mll1-wdr5. |
CA3097925A CA3097925A1 (en) | 2018-04-23 | 2018-12-25 | Phenyl triazole mll1-wdr5 protein-protein interaction inhibitor |
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JP2020558628A JP7274765B2 (ja) | 2018-04-23 | 2018-12-25 | フェニルトリアゾールmll1-wdr5タンパク質間相互作用阻害剤 |
KR1020207033699A KR20210019414A (ko) | 2018-04-23 | 2018-12-25 | 페닐 트리아졸 mll1-wdr5 단백질-단백질 상호 작용 억제제 |
AU2018420231A AU2018420231A1 (en) | 2018-04-23 | 2018-12-25 | Phenyl triazole MLL1-WDR5 protein-protein interaction inhibitor |
SG11202010492SA SG11202010492SA (en) | 2018-04-23 | 2018-12-25 | Phenyl triazole mll1-wdr5 protein-protein interaction inhibitor |
IL278255A IL278255B2 (en) | 2018-04-23 | 2018-12-25 | Inhibitor of mll1-wdr5 protein-protein interaction Phenyltriazole |
CN201880092659.0A CN112368268A (zh) | 2018-04-23 | 2018-12-25 | 苯基联三氮唑类mll1-wdr5蛋白-蛋白相互作用抑制剂 |
PCT/CN2018/123500 WO2019205687A1 (zh) | 2018-04-23 | 2018-12-25 | 苯基联三氮唑类mll1-wdr5蛋白-蛋白相互作用抑制剂 |
EA202092317A EA202092317A1 (ru) | 2018-04-23 | 2018-12-25 | Ингибитор белок-белковых взаимодействий фенилтриазольных соединений mll1-wdr5 |
BR112020021569-4A BR112020021569A2 (pt) | 2018-04-23 | 2018-12-25 | Inibidor da interação proteína-proteína mll1-wdr5 de fenil triazol |
PH12020551756A PH12020551756A1 (en) | 2018-04-23 | 2020-10-22 | Phenyl triazole mll1-wdr5 protein-protein interaction inhibitor |
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US17/078,052 US11479545B2 (en) | 2018-04-23 | 2020-10-22 | Compositions and methods for inhibiting phenyl triazole MLL1-WDR5 protein-protein interaction |
CONC2020/0014430A CO2020014430A2 (es) | 2018-04-23 | 2020-11-20 | Inhibidor de la interacción proteína-proteína fenil triazol mll1-wdr5 |
US17/944,757 US20230098016A1 (en) | 2018-04-23 | 2022-09-14 | Compositions and methods for inhibiting phenyl triazole mll1-wdr5 protein-protein interaction |
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CN109734674A (zh) * | 2019-02-26 | 2019-05-10 | 中国药科大学 | 苯胺类wdr5蛋白-蛋白相互作用抑制剂及其制法和用途 |
WO2019205687A1 (zh) * | 2018-04-23 | 2019-10-31 | 中国药科大学 | 苯基联三氮唑类mll1-wdr5蛋白-蛋白相互作用抑制剂 |
WO2024002379A1 (zh) * | 2022-07-01 | 2024-01-04 | 甘李药业股份有限公司 | 一种用作wdr5抑制剂的化合物或其可药用盐及其应用 |
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JP7458324B2 (ja) | 2018-04-23 | 2024-03-29 | セルジーン コーポレイション | 置換された4-アミノイソインドリン-1,3-ジオン化合物、及びリンパ腫の治療のためのそれらの使用 |
US20230286925A1 (en) * | 2022-03-14 | 2023-09-14 | Huyabio International, Llc | Phenyl triazole mll1-wdr5 protein-protein interaction inhibitor |
US20230286948A1 (en) * | 2022-03-14 | 2023-09-14 | Huyabio International, Llc | Haloalkylpyridyl triazole mll1-wdr5 protein-protein interaction inhibitor |
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WO2020172932A1 (zh) * | 2019-02-26 | 2020-09-03 | 中国药科大学 | 苯胺类wdr5蛋白-蛋白相互作用抑制剂及其制法和用途 |
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WO2024002379A1 (zh) * | 2022-07-01 | 2024-01-04 | 甘李药业股份有限公司 | 一种用作wdr5抑制剂的化合物或其可药用盐及其应用 |
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ZA202006581B (en) | 2023-05-31 |
SG11202010492SA (en) | 2020-11-27 |
KR20210019414A (ko) | 2021-02-22 |
CA3097925A1 (en) | 2019-10-31 |
WO2019205687A1 (zh) | 2019-10-31 |
CN112368268A (zh) | 2021-02-12 |
CO2020014430A2 (es) | 2021-05-20 |
US20210139466A1 (en) | 2021-05-13 |
IL278255B1 (en) | 2023-05-01 |
IL278255A (zh) | 2020-12-31 |
PH12020551756A1 (en) | 2021-08-16 |
BR112020021569A2 (pt) | 2021-04-13 |
MX2020011205A (es) | 2021-02-09 |
IL278255B2 (en) | 2023-09-01 |
EA202092317A1 (ru) | 2021-07-23 |
AU2018420231A1 (en) | 2020-12-10 |
EP3786157A1 (en) | 2021-03-03 |
US11479545B2 (en) | 2022-10-25 |
JP7274765B2 (ja) | 2023-05-17 |
CL2020002736A1 (es) | 2021-05-28 |
JP2021525226A (ja) | 2021-09-24 |
US20230098016A1 (en) | 2023-03-30 |
EP3786157A4 (en) | 2022-01-05 |
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