KR102673967B1 - Mdm2-p53 상호작용의 아이소인돌린온 저해제 및 이를 제조하는 방법 - Google Patents

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Publication number

KR102673967B1

KR102673967B1 KR1020197030377A KR20197030377A KR102673967B1 KR 102673967 B1 KR102673967 B1 KR 102673967B1 KR 1020197030377 A KR1020197030377 A KR 1020197030377A KR 20197030377 A KR20197030377 A KR 20197030377A KR 102673967 B1 KR102673967 B1 KR 102673967B1

Authority

KR

South Korea

Prior art keywords

alkyl

formula

compound

ring members

chlorophenyl

Prior art date

2017-03-28

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 238000000034 method Methods 0.000 title claims abstract description 134
• PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title abstract description 14
• 230000003993 interaction Effects 0.000 title description 5
• 239000003112 inhibitor Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 493
• 150000003839 salts Chemical class 0.000 claims abstract description 155
• 238000004519 manufacturing process Methods 0.000 claims abstract description 60
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 55
• 125000000217 alkyl group Chemical group 0.000 claims description 1199
• 125000000623 heterocyclic group Chemical group 0.000 claims description 382
• 229910052736 halogen Inorganic materials 0.000 claims description 179
• 150000002367 halogens Chemical class 0.000 claims description 179
• 229910052739 hydrogen Inorganic materials 0.000 claims description 176
• 125000003545 alkoxy group Chemical group 0.000 claims description 174
• 239000001257 hydrogen Substances 0.000 claims description 169
• -1 oxan-4-yl Chemical group 0.000 claims description 128
• 150000002825 nitriles Chemical class 0.000 claims description 121
• 239000012453 solvate Substances 0.000 claims description 116
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 111
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 103
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 101
• 150000002431 hydrogen Chemical class 0.000 claims description 94
• 125000003118 aryl group Chemical group 0.000 claims description 82
• 125000005842 heteroatom Chemical group 0.000 claims description 78
• 239000012022 methylating agents‎ Substances 0.000 claims description 78
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 74
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 65
• 229910052760 oxygen Inorganic materials 0.000 claims description 65
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 64
• RMCVDTXCEAJNTG-UHFFFAOYSA-N 1-methoxy-2,3-dihydro-1h-isoindole Chemical compound C1=CC=C2C(OC)NCC2=C1 RMCVDTXCEAJNTG-UHFFFAOYSA-N 0.000 claims description 63
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 62
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 62
• 238000006243 chemical reaction Methods 0.000 claims description 58
• 229910052717 sulfur Inorganic materials 0.000 claims description 57
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 43
• 230000008569 process Effects 0.000 claims description 43
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 41
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 38
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
• 239000002253 acid Substances 0.000 claims description 36
• 229910052799 carbon Inorganic materials 0.000 claims description 36
• 239000000203 mixture Substances 0.000 claims description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 33
• 125000000304 alkynyl group Chemical group 0.000 claims description 33
• 125000001188 haloalkyl group Chemical group 0.000 claims description 32
• 101100482220 Sulfurisphaera tokodaii (strain DSM 16993 / JCM 10545 / NBRC 100140 / 7) triC gene Proteins 0.000 claims description 30
• 239000003960 organic solvent Substances 0.000 claims description 28
• 238000007257 deesterification reaction Methods 0.000 claims description 26
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 23
• 150000001204 N-oxides Chemical class 0.000 claims description 22
• 150000001721 carbon Chemical group 0.000 claims description 22
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 22
• 239000002904 solvent Substances 0.000 claims description 22
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
• 125000004432 carbon atom Chemical group C* 0.000 claims description 21
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 20
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
• 125000005843 halogen group Chemical group 0.000 claims description 19
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 19
• OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 19
• 125000004076 pyridyl group Chemical group 0.000 claims description 19
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
• 125000003342 alkenyl group Chemical group 0.000 claims description 18
• 150000002148 esters Chemical class 0.000 claims description 18
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
• 150000001412 amines Chemical class 0.000 claims description 17
• 238000005859 coupling reaction Methods 0.000 claims description 17
• GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 claims description 16
• 230000008878 coupling Effects 0.000 claims description 16
• 238000010168 coupling process Methods 0.000 claims description 16
• WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 16
• 239000000010 aprotic solvent Substances 0.000 claims description 15
• DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical group [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 15
• ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 claims description 14
• LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 14
• 125000006239 protecting group Chemical group 0.000 claims description 14
• UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 13
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 12
• 150000001299 aldehydes Chemical class 0.000 claims description 12
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 12
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 12
• MBXNQZHITVCSLJ-UHFFFAOYSA-N methyl fluorosulfonate Chemical compound COS(F)(=O)=O MBXNQZHITVCSLJ-UHFFFAOYSA-N 0.000 claims description 11
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 11
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
• BXVSAYBZSGIURM-UHFFFAOYSA-N 2-phenoxy-4h-1,3,2$l^{5}-benzodioxaphosphinine 2-oxide Chemical group O1CC2=CC=CC=C2OP1(=O)OC1=CC=CC=C1 BXVSAYBZSGIURM-UHFFFAOYSA-N 0.000 claims description 10
• 150000002466 imines Chemical class 0.000 claims description 10
• JDCHPEZNOKLHPK-KJEAJVGRSA-N (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxoisoindol-2-yl]-2-methylpropanoic acid Chemical compound ClC1=CC=C(C=C1)[C@H]([C@@H](C(=O)O)C)N1[C@@](C2=C(C=C(C=C2C1=O)[C@](CC)(C1CCOCC1)O)F)(OC)C1=CC=C(C=C1)Cl JDCHPEZNOKLHPK-KJEAJVGRSA-N 0.000 claims description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 9
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 8
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
• HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 6
• CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 5
• 230000003647 oxidation Effects 0.000 claims description 5
• 238000007254 oxidation reaction Methods 0.000 claims description 5
• 229920001296 polysiloxane Polymers 0.000 claims description 5
• UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 claims description 4
• 238000003379 elimination reaction Methods 0.000 claims description 4
• KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 4
• GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 4
• 239000007800 oxidant agent Substances 0.000 claims description 4
• 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
• 239000000243 solution Substances 0.000 claims description 4
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical group OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
• 229930182821 L-proline Natural products 0.000 claims description 3
• XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
• 238000005575 aldol reaction Methods 0.000 claims description 3
• 238000003776 cleavage reaction Methods 0.000 claims description 3
• WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 claims description 3
• 230000007017 scission Effects 0.000 claims description 3
• NXLACVVNHYIYJN-KBPBESRZSA-N (1s)-1-phenyl-n-[(1s)-1-phenylethyl]ethanamine Chemical group C1([C@H](C)N[C@@H](C)C=2C=CC=CC=2)=CC=CC=C1 NXLACVVNHYIYJN-KBPBESRZSA-N 0.000 claims description 2
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
• GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
• 229910052740 iodine Inorganic materials 0.000 claims description 2
• 239000011630 iodine Substances 0.000 claims description 2
• WCNLCIJMFAJCPX-UHFFFAOYSA-N pethidine hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 WCNLCIJMFAJCPX-UHFFFAOYSA-N 0.000 claims 2
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims 1
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 139
• 239000002585 base Substances 0.000 description 71
• 125000000896 monocarboxylic acid group Chemical group 0.000 description 66
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 61
• 229910052731 fluorine Inorganic materials 0.000 description 53
• 239000000460 chlorine Substances 0.000 description 52
• 125000001424 substituent group Chemical group 0.000 description 41
• 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 38
• 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 38
• 125000003386 piperidinyl group Chemical group 0.000 description 38
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 36
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 35
• 239000000126 substance Substances 0.000 description 35
• 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 31
• 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 31
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 31
• 239000011737 fluorine Substances 0.000 description 31
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 29
• 125000004093 cyano group Chemical group *C#N 0.000 description 28
• 229910052801 chlorine Inorganic materials 0.000 description 25
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 24
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 24
• 239000000047 product Substances 0.000 description 23
• 125000003226 pyrazolyl group Chemical group 0.000 description 23
• 125000002883 imidazolyl group Chemical group 0.000 description 21
• 206010028980 Neoplasm Diseases 0.000 description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
• 229910052757 nitrogen Inorganic materials 0.000 description 19
• 125000004122 cyclic group Chemical group 0.000 description 17
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 17
• 230000011987 methylation Effects 0.000 description 16
• 238000007069 methylation reaction Methods 0.000 description 16
• 108090000623 proteins and genes Proteins 0.000 description 16
• 238000011282 treatment Methods 0.000 description 16
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• 125000001072 heteroaryl group Chemical group 0.000 description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 description 14
• 125000005103 alkyl silyl group Chemical group 0.000 description 13
• 125000006615 aromatic heterocyclic group Chemical group 0.000 description 13
• 238000002425 crystallisation Methods 0.000 description 13
• 230000008025 crystallization Effects 0.000 description 13
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 13
• 125000004193 piperazinyl group Chemical group 0.000 description 13
• 125000002619 bicyclic group Chemical group 0.000 description 12
• 201000010099 disease Diseases 0.000 description 12
• 230000027455 binding Effects 0.000 description 11
• 125000001153 fluoro group Chemical group F* 0.000 description 11
• 230000003287 optical effect Effects 0.000 description 11
• 235000018102 proteins Nutrition 0.000 description 11
• 102000004169 proteins and genes Human genes 0.000 description 11
• 229920006395 saturated elastomer Polymers 0.000 description 11
• 238000004587 chromatography analysis Methods 0.000 description 10
• 239000011734 sodium Substances 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
• 238000006345 epimerization reaction Methods 0.000 description 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
• 239000000463 material Substances 0.000 description 9
• 229910052751 metal Inorganic materials 0.000 description 9
• 239000002184 metal Substances 0.000 description 9
• 125000002757 morpholinyl group Chemical group 0.000 description 9
• 239000001301 oxygen Substances 0.000 description 9
• 230000004044 response Effects 0.000 description 9
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
• 125000004429 atom Chemical group 0.000 description 8
• 125000002393 azetidinyl group Chemical group 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 8
• 229920000728 polyester Polymers 0.000 description 8
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 8
• 102000005962 receptors Human genes 0.000 description 8
• 108020003175 receptors Proteins 0.000 description 8
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 7
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 7
• 150000007513 acids Chemical class 0.000 description 7
• 230000004913 activation Effects 0.000 description 7
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• 208000035475 disorder Diseases 0.000 description 7
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• 238000006460 hydrolysis reaction Methods 0.000 description 7
• 230000001965 increasing effect Effects 0.000 description 7
• 125000002950 monocyclic group Chemical group 0.000 description 7
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 7
• 230000001225 therapeutic effect Effects 0.000 description 7
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
• KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 6
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 239000003814 drug Substances 0.000 description 6
• 230000006870 function Effects 0.000 description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
• SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 6
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• 238000006722 reduction reaction Methods 0.000 description 6
• 238000004808 supercritical fluid chromatography Methods 0.000 description 6
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 6
• JDCHPEZNOKLHPK-WAURZEPHSA-N (2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxoisoindol-2-yl]-2-methylpropanoic acid Chemical compound ClC1=CC=C(C=C1)[C@H]([C@@H](C(=O)O)C)N1C(C2=C(C=C(C=C2C1=O)[C@](CC)(C1CCOCC1)O)F)(OC)C1=CC=C(C=C1)Cl JDCHPEZNOKLHPK-WAURZEPHSA-N 0.000 description 5
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
• 125000003277 amino group Chemical group 0.000 description 5
• 239000005557 antagonist Substances 0.000 description 5
• 201000011510 cancer Diseases 0.000 description 5
• 210000004027 cell Anatomy 0.000 description 5
• JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 5
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