CN112368268A - 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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- CN112368268A CN112368268A CN201880092659.0A CN201880092659A CN112368268A CN 112368268 A CN112368268 A CN 112368268A CN 201880092659 A CN201880092659 A CN 201880092659A CN 112368268 A CN112368268 A CN 112368268A
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- Prior art keywords
- phenyl
- amino
- compound
- pharmaceutically acceptable
- methyl
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- 230000004850 protein–protein interaction Effects 0.000 title abstract description 18
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- JOTARNAQDJLHAF-UHFFFAOYSA-N 3-phenyl-5-(1,2,4-triazol-3-ylidene)-1,2,4-triazole Chemical compound C1(=CC=CC=C1)C1=NC(N=N1)=C1N=NC=N1 JOTARNAQDJLHAF-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 26
- 101001045846 Homo sapiens Histone-lysine N-methyltransferase 2A Proteins 0.000 claims description 32
- -1 amino, hydroxy, mercapto, carboxyl Chemical group 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 150000002431 hydrogen Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052736 halogen Chemical group 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 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
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 150000002829 nitrogen Chemical class 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 206010000830 Acute leukaemia Diseases 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 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
- 150000003254 radicals Chemical class 0.000 claims description 4
- ARHYWWAJZDAYDJ-UHFFFAOYSA-N 1,2-dimethylpiperazine Chemical compound CC1CNCCN1C ARHYWWAJZDAYDJ-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000008707 rearrangement Effects 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 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
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 125000004069 aziridinyl group Chemical group 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 17
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 150000003852 triazoles Chemical class 0.000 abstract description 5
- 238000012360 testing method Methods 0.000 abstract description 3
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 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
- 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 208000032839 leukemia Diseases 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000003197 catalytic effect Effects 0.000 description 14
- 230000014509 gene expression Effects 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 108700041619 Myeloid Ecotropic Viral Integration Site 1 Proteins 0.000 description 11
- 230000002401 inhibitory effect Effects 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 230000011987 methylation Effects 0.000 description 8
- 238000007069 methylation reaction Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 7
- 230000036961 partial effect Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- LLIOADBCFIXIEU-UHFFFAOYSA-N 4-fluoro-3-nitroaniline Chemical compound NC1=CC=C(F)C([N+]([O-])=O)=C1 LLIOADBCFIXIEU-UHFFFAOYSA-N 0.000 description 6
- 101100477411 Dictyostelium discoideum set1 gene Proteins 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- SKNBJKQSMQVYLP-UHFFFAOYSA-N methyl 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]triazole-4-carboxylate Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)OC)C=1)Cl)C)F SKNBJKQSMQVYLP-UHFFFAOYSA-N 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- XKPCPQQOUHNXNP-UHFFFAOYSA-N 1-(4-azido-2-nitrophenyl)-4-methylpiperazine Chemical compound CN1CCN(CC1)C1=C(C=C(C=C1)N=[N+]=[N-])[N+](=O)[O-] XKPCPQQOUHNXNP-UHFFFAOYSA-N 0.000 description 5
- ULYZOXPTGWTZKW-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]triazole-4-carboxylic acid Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)O)C=1)Cl)C)F ULYZOXPTGWTZKW-UHFFFAOYSA-N 0.000 description 5
- HCKNAJXCHMACDN-UHFFFAOYSA-N 1-methylpiperidine-4-carboxylic acid Chemical compound CN1CCC(C(O)=O)CC1 HCKNAJXCHMACDN-UHFFFAOYSA-N 0.000 description 5
- GLDSTIMBMURWLC-UHFFFAOYSA-N 5-amino-N-[5-(4-aminotriazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl]-2-chloro-4-fluoro-3-methylbenzamide Chemical compound NC=1C(=C(C(=C(C(=O)NC2=C(C=CC(=C2)N2N=NC(=C2)N)N2CCN(CC2)C)C=1)Cl)C)F GLDSTIMBMURWLC-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- MRKLOFJXWXDNEO-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-3-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C=C1[N+]([O-])=O MRKLOFJXWXDNEO-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
- MPTAUAHHFUFKAG-UHFFFAOYSA-N NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)NCCCN2CCOCC2)C=1)Cl)C)F Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)NCCCN2CCOCC2)C=1)Cl)C)F MPTAUAHHFUFKAG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- MJYBYXZQUPJBHB-UHFFFAOYSA-N methyl 1-[3-amino-4-(4-methylpiperazin-1-yl)phenyl]triazole-4-carboxylate Chemical compound CN1CCN(CC1)C2=C(C=C(C=C2)N3C=C(N=N3)C(=O)OC)N MJYBYXZQUPJBHB-UHFFFAOYSA-N 0.000 description 4
- OUQJWURFEOSRKU-UHFFFAOYSA-N methyl 1-[4-(4-methylpiperazin-1-yl)-3-nitrophenyl]triazole-4-carboxylate Chemical compound CN1CCN(CC1)C1=C(C=C(C=C1)N1N=NC(=C1)C(=O)OC)[N+](=O)[O-] OUQJWURFEOSRKU-UHFFFAOYSA-N 0.000 description 4
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical group NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- TTYBUFHPIOFIOP-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-2-methyl-4-(4-methylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)triazole-4-carboxamide Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C(=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)NCCN2CCOCC2)C)C=1)Cl)C)F TTYBUFHPIOFIOP-UHFFFAOYSA-N 0.000 description 3
- MFUAIPRTUSTRPW-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(3,4-dimethylpiperazin-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)triazole-4-carboxamide Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC2N2CC(N(CC2)C)C)N2N=NC(=C2)C(=O)NCCN2CCOCC2)C1)Cl)C)F MFUAIPRTUSTRPW-UHFFFAOYSA-N 0.000 description 3
- FSZIWZALILWHEA-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(4-methyl-1,4-diazepan-1-yl)phenyl]-N-(2-morpholin-4-ylethyl)triazole-4-carboxamide Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CCC2)C)N2N=NC(=C2)C(=O)NCCN2CCOCC2)C=1)Cl)C)F FSZIWZALILWHEA-UHFFFAOYSA-N 0.000 description 3
- YVYDEUSEBPMHIF-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N,N-dimethyltriazole-4-carboxamide Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)N(C)C)C=1)Cl)C)F YVYDEUSEBPMHIF-UHFFFAOYSA-N 0.000 description 3
- AQQCBBDWEBSYPT-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(1-methylpiperidin-4-yl)triazole-4-carboxamide Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)NC2CCN(CC2)C)C=1)Cl)C)F AQQCBBDWEBSYPT-UHFFFAOYSA-N 0.000 description 3
- QZIOXRRIRQBSBM-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(3-aminopropyl)triazole-4-carboxamide Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)NCCCN)C=1)Cl)C)F QZIOXRRIRQBSBM-UHFFFAOYSA-N 0.000 description 3
- WKDPERRTFWPQQI-UHFFFAOYSA-N 1-[3-[(5-amino-2-chloro-4-fluoro-3-methylbenzoyl)amino]-4-(4-methylpiperazin-1-yl)phenyl]-N-(oxan-4-yl)triazole-4-carboxamide Chemical compound NC=1C(=C(C(=C(C(=O)NC=2C=C(C=CC=2N2CCN(CC2)C)N2N=NC(=C2)C(=O)NC2CCOCC2)C=1)Cl)C)F WKDPERRTFWPQQI-UHFFFAOYSA-N 0.000 description 3
- QFWNTXSERPSMQB-UHFFFAOYSA-N 2-chloro-4-fluoro-3-methyl-5-nitrobenzoyl chloride Chemical compound CC1=C(F)C([N+]([O-])=O)=CC(C(Cl)=O)=C1Cl QFWNTXSERPSMQB-UHFFFAOYSA-N 0.000 description 3
- BWSQOLJUEAPEEZ-UHFFFAOYSA-N 5-amino-N-[5-[4-(4-aminobutanoylamino)triazol-1-yl]-2-(4-methylpiperazin-1-yl)phenyl]-2-chloro-4-fluoro-3-methylbenzamide Chemical compound NC=1C(=C(C(=C(C(=O)NC2=C(C=CC(=C2)N2N=NC(=C2)NC(CCCN)=O)N2CCN(CC2)C)C=1)Cl)C)F BWSQOLJUEAPEEZ-UHFFFAOYSA-N 0.000 description 3
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
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- 102100029445 WD repeat-containing protein 5 Human genes 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
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- 231100000419 toxicity Toxicity 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RZRSNIUMZHFTDJ-UHFFFAOYSA-N 2,4-difluoro-3-nitroaniline Chemical compound Nc1ccc(F)c(c1F)[N+]([O-])=O RZRSNIUMZHFTDJ-UHFFFAOYSA-N 0.000 description 2
- SUUNMVDVAGJIPD-UHFFFAOYSA-N 2-chloro-4-fluoro-5-hydroxy-3-methylbenzoyl chloride Chemical compound ClC1=C(C(=O)Cl)C=C(C(=C1C)F)O SUUNMVDVAGJIPD-UHFFFAOYSA-N 0.000 description 2
- MIBJGGVRRGWJCI-UHFFFAOYSA-N 2-fluoro-4-methyl-3-nitroaniline Chemical compound Cc1ccc(N)c(F)c1[N+]([O-])=O MIBJGGVRRGWJCI-UHFFFAOYSA-N 0.000 description 2
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract
本发明公开了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
PCT国内申请，说明书已公开。
Claims (10)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2018103658800 | 2018-04-23 | ||
| 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 |
| 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 |
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|---|---|
| CN112368268A true CN112368268A (zh) | 2021-02-12 |
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| CN201880092659.0A Pending 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 |
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| US (2) | US11479545B2 (zh) |
| EP (1) | EP3786157A4 (zh) |
| JP (1) | JP7274765B2 (zh) |
| KR (1) | KR20210019414A (zh) |
| CN (2) | CN108715585A (zh) |
| AU (1) | AU2018420231A1 (zh) |
| BR (1) | BR112020021569A2 (zh) |
| CA (1) | CA3097925A1 (zh) |
| CL (1) | CL2020002736A1 (zh) |
| CO (1) | CO2020014430A2 (zh) |
| EA (1) | EA202092317A1 (zh) |
| IL (1) | IL278255B2 (zh) |
| MX (1) | MX2020011205A (zh) |
| PH (1) | PH12020551756A1 (zh) |
| SG (1) | SG11202010492SA (zh) |
| WO (1) | WO2019205687A1 (zh) |
| ZA (1) | ZA202006581B (zh) |
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| CN108715585A (zh) * | 2018-04-23 | 2018-10-30 | 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 |
| CN113214220B (zh) | 2018-04-23 | 2024-04-02 | 细胞基因公司 | 取代的4-氨基异吲哚啉-1,3-二酮化合物以及它们用于治疗淋巴瘤的用途 |
| CN109734674B (zh) * | 2019-02-26 | 2022-08-26 | 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 |
| WO2023177593A1 (en) * | 2022-03-14 | 2023-09-21 | 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 |
| 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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| CN105175284A (zh) * | 2015-07-21 | 2015-12-23 | 中国药科大学 | 酰胺类化合物、制备方法及其医药用途 |
| WO2017147700A1 (en) * | 2016-03-01 | 2017-09-08 | Ontario Institute For Cancer Research (Oicr) | Inhibitors of wdr5 protein-protein binding |
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| JP4824576B2 (ja) | 2003-12-03 | 2011-11-30 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | サイトカイン生成のインヒビターとしての１，２，３−トリアゾールアミド誘導体 |
| WO2011149827A1 (en) | 2010-05-24 | 2011-12-01 | Glaxosmithkline Llc | Compounds and methods |
| CN104844573A (zh) | 2015-04-17 | 2015-08-19 | 中国药科大学 | 嘧啶类btk抑制剂、其制备方法及医药用途 |
| CA3012133A1 (en) | 2016-02-09 | 2017-08-17 | Inventisbio Inc. | Inhibitor of indoleamine-2,3-dioxygenase (ido) |
| EP3423437A4 (en) | 2016-03-01 | 2019-07-24 | Propellon Therapeutics Inc. | INHIBITORS OF THE LINK BETWEEN THE WDR5 PROTEIN AND ITS LIAISON PARTNERS |
| CN107382840B (zh) | 2016-05-16 | 2020-09-01 | 四川大学 | 吡啶类化合物及其作为idh功能变异突变体抑制剂类药物的用途 |
| CN108715585A (zh) * | 2018-04-23 | 2018-10-30 | 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 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175284A (zh) * | 2015-07-21 | 2015-12-23 | 中国药科大学 | 酰胺类化合物、制备方法及其医药用途 |
| WO2017147700A1 (en) * | 2016-03-01 | 2017-09-08 | Ontario Institute For Cancer Research (Oicr) | Inhibitors of wdr5 protein-protein binding |
Non-Patent Citations (4)
| Title |
|---|
| DONG-DONG LI等: "《High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity》", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, no. 124, pages 480 * |
| DONG-DONG LI等: "《Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5》", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, no. 118, pages 1 - 8, XP029562555, DOI: 10.1016/j.ejmech.2016.04.032 * |
| MATTHÄUS GETLIK等: "《Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)》", J. MED. CHEM, no. 59, pages 2478 * |
| YURI BOLSHAN等: "《Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5‑MLL Interaction》", ACS MED. CHEM. LETT., no. 4, pages 353 * |
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| CN108715585A (zh) | 2018-10-30 |
| IL278255B2 (en) | 2023-09-01 |
| AU2018420231A1 (en) | 2020-12-10 |
| US11479545B2 (en) | 2022-10-25 |
| EP3786157A4 (en) | 2022-01-05 |
| US20230098016A1 (en) | 2023-03-30 |
| CL2020002736A1 (es) | 2021-05-28 |
| EA202092317A1 (ru) | 2021-07-23 |
| MX2020011205A (es) | 2021-02-09 |
| KR20210019414A (ko) | 2021-02-22 |
| BR112020021569A2 (pt) | 2021-04-13 |
| CO2020014430A2 (es) | 2021-05-20 |
| WO2019205687A1 (zh) | 2019-10-31 |
| IL278255A (zh) | 2020-12-31 |
| SG11202010492SA (en) | 2020-11-27 |
| JP7274765B2 (ja) | 2023-05-17 |
| CA3097925A1 (en) | 2019-10-31 |
| ZA202006581B (en) | 2023-05-31 |
| US20210139466A1 (en) | 2021-05-13 |
| IL278255B1 (en) | 2023-05-01 |
| PH12020551756A1 (en) | 2021-08-16 |
| JP2021525226A (ja) | 2021-09-24 |
| EP3786157A1 (en) | 2021-03-03 |
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