JP2021525226A - 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 - Google Patents
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 Download PDFInfo
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- JP2021525226A JP2021525226A JP2020558628A JP2020558628A JP2021525226A JP 2021525226 A JP2021525226 A JP 2021525226A JP 2020558628 A JP2020558628 A JP 2020558628A JP 2020558628 A JP2020558628 A JP 2020558628A JP 2021525226 A JP2021525226 A JP 2021525226A
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- substituted
- phenyl
- amino
- pharmaceutically acceptable
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- 230000004850 protein–protein interaction Effects 0.000 title abstract description 14
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- LUEYUHCBBXWTQT-UHFFFAOYSA-N 4-phenyl-2h-triazole Chemical compound C1=NNN=C1C1=CC=CC=C1 LUEYUHCBBXWTQT-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 101001045846 Homo sapiens Histone-lysine N-methyltransferase 2A Proteins 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052736 halogen Chemical group 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 150000002431 hydrogen 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
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 9
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 8
- 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 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
- 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
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 206010000830 Acute leukaemia Diseases 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([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
- ARHYWWAJZDAYDJ-UHFFFAOYSA-N 1,2-dimethylpiperazine Chemical compound CC1CNCCN1C ARHYWWAJZDAYDJ-UHFFFAOYSA-N 0.000 claims description 3
- FXHRAKUEZPSMLJ-UHFFFAOYSA-N 1-methyl-1,4-diazepane Chemical compound CN1CCCNCC1 FXHRAKUEZPSMLJ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000008707 rearrangement Effects 0.000 claims description 3
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003341 7 membered heterocyclic 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
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 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
- 239000003814 drug Substances 0.000 claims description 2
- 229940079593 drug Drugs 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
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 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
- 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
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 22
- 238000012360 testing method Methods 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
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- 238000010586 diagram Methods 0.000 abstract 1
- -1 Ash2L Proteins 0.000 description 43
- 239000007787 solid Substances 0.000 description 31
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 28
- 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 208000032839 leukemia Diseases 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 14
- 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
- 230000003197 catalytic effect Effects 0.000 description 9
- 230000002255 enzymatic effect Effects 0.000 description 9
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- 101100477411 Dictyostelium discoideum set1 gene Proteins 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 230000011987 methylation Effects 0.000 description 8
- 238000007069 methylation reaction Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 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
- 239000012043 crude product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 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
- 230000001413 cellular effect Effects 0.000 description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 5
- 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 4
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- 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 4
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- 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
- 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 3
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Abstract
Description
Xは水素、メチル基、メトキシ基、又はハロゲンであり;
MLL1が媒介する疾患を処置するための薬剤の調製における化合物(I)、その薬学的に許容可能な塩、又は溶媒和物の使用を提供し、前記疾患は、例えば、MLL融合遺伝子型白血病であり、MLL1の酵素活性を抑制することによって処置できる。
Claims (10)
- 式(I)の化合物又はその薬学的に許容可能な塩:
Xは水素、メチル基、メトキシ基、又はハロゲンであり;
Yは−CH2−、−O−、−S−、−CO−、−CH2O−、−NR5−、−CONR6−、又は−NR7CO−であり、ここで、R5、R6、及びR7はそれぞれ独立して、水素、C1−C4アルキル基、C1−C4ハロアルキル基、フェニル基、又は置換フェニル基であり、置換基はハロゲン、C1−C4アルキル基、C1−C4アルコキシ基、アミノ基、ヒドロキシル基、メルカプト基、カルボキシル基、シアノ基、トリフルオロメチル基、又はイミダゾリル基であり;
mは0〜6であり;
R1は水素、アミノ基、ヒドロキシル基、メルカプト基、カルボキシル基、シアノ基、−CONH2、C1−C4アルキル基、C1−C4アルコキシ基、フェニル基、置換フェニル基、置換または非置換の窒素含有、又は酸素含有3〜7員の複素環、−NR8COR9、−CONR10R11、又は−NR10R11であり;ここで、R8は水素、C1−C4アルキル基、C1−C4ハロアルキル基、フェニル基、又は置換フェニル基であり;R9はアミノ基、ヒドロキシル基、C1−C4アルキル基、C1−C4アルコキシ基、フェニル基、又は置換フェニル基、置換または非置換の窒素含有、又は酸素含有3〜7員の複素環であり;R10、R11はそれぞれ独立して、水素、C1−C4アルキル基、フェニル基、又は置換フェニル基、置換または非置換の窒素含有、又は酸素含有3〜7員の複素環であり、又はR10とR11は結合して窒素含有、又は酸素含有3〜7員の複素環を形成し、前記置換基はハロゲン、C1−C4アルキル基、C1−C4アルコキシ基、アミノ基、ヒドロキシル基、メルカプト基、カルボキシル基、シアノ基、トリフルオロメチル基、又はイミダゾリル基であり;
R2は二置換または三置換のためのハロゲン、C1−C4アルキル基、C1−C4アルコキシ基、トリフルオロメチル基、ニトロ基、又はシアノ基であり;
R3はアミノ基、メチルアミノ基、アミノメチル基、ヒドロキシル基、ヒドロキシメチル基、メルカプト基、又は−CONH2であり;
R4はN−メチルピペラジン、1,2−ジメチルピペラジン、又はN−メチルホモピペラジンである
ことを特徴とする化合物又はその薬学的に許容可能な塩。 - Xは水素、フッ素、塩素、又はメチル基であることを特徴とする、請求項1に記載の化合物又はその薬学的に許容可能な塩。
- Yは−NR5−、−CONR6−、又は−NR7CO−であり;R5、R6、及びR7はそれぞれ独立して、水素、メチル基、エチル基、プロピル基、シクロプロピル基、又はイソプロピル基であることを特徴とする、請求項1に記載の化合物又はその薬学的に許容可能な塩。
- Yは−NR5−、−CONR6−、又は−NR7CO−であり;R5、R6、及びR7はそれぞれ独立して、置換フェニル基であり、置換基はメチル基、エチル基、イソプロピル基、t−ブチル基、シクロプロピル基、メトキシ基、シアノ基、ハロゲン、トリフルオロメチル基、又はイミダゾリル基であることを特徴とする、請求項1に記載の化合物又はその薬学的に許容可能な塩。
- 上記の置換または非置換の窒素含有、又は酸素含有3〜7員の複素環はアジリジン、アゼチジン、テトラヒドロピロール、ピペリジン、ヘキサメチレンイミン、ラクタム、テトラヒドロフラン、テトラヒドロピラン、モルホリン、1,4−オキサゼパン、ヘキサヒドロピリダジン、イミダゾリン、ピラゾリジン、ピペラジンであり;置換基はメチル基、エチル基、フェニル基、ヒドロキシル基、アミノ基、ヒドロキシメチル基、又はアミノメチル基であり、置換基はハロゲン、C1−C4アルキル基、C1−C4アルコキシ基、アミノ基、ヒドロキシル基、メルカプト基、カルボキシル基、シアノ基、又はトリフルオロメチル基であることを特徴とする、請求項1に記載の化合物又はその薬学的に許容可能な塩。
- R1は−NR8COR9、−CONR10R11、又は−NR10R11であり;R8、R9、R10、及びR11はC1−C4アルキル基であることを特徴とする、請求項1に記載の化合物又はその薬学的に許容可能な塩。
- R2は三置換のための置換体であり、置換基はフッ素、塩素、臭素、メチル基、メトキシ基、ニトロ基、トリフルオロメチル基、又はシアノ基であることを特徴とする、請求項1に記載の化合物又はその薬学的に許容可能な塩。
- 請求項1に記載の化合物又はその薬学的に許容可能な塩と、薬学的に許容可能な担体を含む医薬組成物。
- 急性白血病の処置のための薬剤の調製における、請求項1に記載の化合物又はその薬学的に許容可能な塩の使用。
- 急性白血病はMLL1遺伝子再構成を伴う急性白血病であることを特徴とする、請求項9に記載の使用。
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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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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 |
RU2018128334A (ru) | 2016-02-09 | 2020-03-10 | Инвентисбио Инк. | Ингибиторы индоламин-2,3-диоксигеназы (ido) |
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 |
WO2019127385A1 (en) | 2017-12-29 | 2019-07-04 | Shenzhen United Imaging Healthcare Co., Ltd. | Systems and methods for patient positioning |
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 (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007513167A (ja) * | 2003-12-03 | 2007-05-24 | 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 |
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 |
WO2017147701A1 (en) * | 2016-03-01 | 2017-09-08 | Ontario Institute For Cancer Research (Oicr) | Inhibitors of wdr5 protein-protein binding |
Non-Patent Citations (5)
Title |
---|
BOLSHAN, YURI ET AL: "Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interact", ACS MEDICINAL CHEMISTRY LETTERS, vol. Vol.4(3), JPN6022054082, 2013, pages 353 - 357, ISSN: 0004949532 * |
GETLIK, MATTHAUS ET AL: "Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Con", JOURNAL OF MEDICINAL CHEMISTRY, vol. Vol.59(6), JPN6022054081, 2016, pages 2478 - 2496, ISSN: 0004949531 * |
LI, DONG-DONG ET AL: "High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit M", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 124, JPN6022054080, 2016, pages 480 - 489, XP055649028, ISSN: 0004949530, DOI: 10.1016/j.ejmech.2016.08.036 * |
LI, DONG-DONG ET AL: "Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 118, JPN6022054083, 2016, pages 1 - 8, XP029562555, ISSN: 0004949533, DOI: 10.1016/j.ejmech.2016.04.032 * |
LI, YONG-TAO ET AL: "Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. Vol.26(5), JPN6022054084, 2016, pages 1419 - 1427, ISSN: 0004949534 * |
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CN112368268A (zh) | 2021-02-12 |
IL278255B1 (en) | 2023-05-01 |
EA202092317A1 (ru) | 2021-07-23 |
CN108715585A (zh) | 2018-10-30 |
US20230098016A1 (en) | 2023-03-30 |
EP3786157B1 (en) | 2024-08-07 |
AU2018420231A1 (en) | 2020-12-10 |
AU2018420231B2 (en) | 2024-08-22 |
JP7274765B2 (ja) | 2023-05-17 |
US11479545B2 (en) | 2022-10-25 |
MX2020011205A (es) | 2021-02-09 |
SG11202010492SA (en) | 2020-11-27 |
US20210139466A1 (en) | 2021-05-13 |
CA3097925A1 (en) | 2019-10-31 |
EP3786157A4 (en) | 2022-01-05 |
BR112020021569A2 (pt) | 2021-04-13 |
WO2019205687A1 (zh) | 2019-10-31 |
PH12020551756A1 (en) | 2021-08-16 |
ZA202006581B (en) | 2023-05-31 |
EP3786157A1 (en) | 2021-03-03 |
IL278255B2 (en) | 2023-09-01 |
CL2020002736A1 (es) | 2021-05-28 |
US12054478B2 (en) | 2024-08-06 |
CO2020014430A2 (es) | 2021-05-20 |
IL278255A (ja) | 2020-12-31 |
KR20210019414A (ko) | 2021-02-22 |
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