WO2024017372A1 - 一种吲哚酮衍生物及其应用 - Google Patents
一种吲哚酮衍生物及其应用 Download PDFInfo
- Publication number
- WO2024017372A1 WO2024017372A1 PCT/CN2023/108658 CN2023108658W WO2024017372A1 WO 2024017372 A1 WO2024017372 A1 WO 2024017372A1 CN 2023108658 W CN2023108658 W CN 2023108658W WO 2024017372 A1 WO2024017372 A1 WO 2024017372A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- reaction
- dioxopiperidin
- independently selected
- piperazin
- Prior art date
Links
- 150000005624 indolones Chemical class 0.000 title abstract 3
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 253
- -1 cyano, hydroxyl Chemical group 0.000 claims description 243
- 229910052757 nitrogen Inorganic materials 0.000 claims description 148
- 150000003839 salts Chemical class 0.000 claims description 43
- 229940002612 prodrug Drugs 0.000 claims description 41
- 239000000651 prodrug Substances 0.000 claims description 41
- 239000013078 crystal Substances 0.000 claims description 40
- 239000012453 solvate Substances 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 239000002207 metabolite Substances 0.000 claims description 36
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000002619 bicyclic group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 abstract description 11
- 108090000623 proteins and genes Proteins 0.000 abstract description 11
- 230000015556 catabolic process Effects 0.000 abstract description 8
- 238000006731 degradation reaction Methods 0.000 abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 279
- 238000006243 chemical reaction Methods 0.000 description 262
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 250
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 220
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 189
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 182
- 239000007787 solid Substances 0.000 description 157
- 239000000243 solution Substances 0.000 description 115
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 108
- 238000003756 stirring Methods 0.000 description 96
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000012074 organic phase Substances 0.000 description 68
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- 238000005481 NMR spectroscopy Methods 0.000 description 43
- 239000012043 crude product Substances 0.000 description 39
- 239000012065 filter cake Substances 0.000 description 39
- 239000002253 acid Substances 0.000 description 37
- 239000003480 eluent Substances 0.000 description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- 238000001308 synthesis method Methods 0.000 description 35
- 238000004809 thin layer chromatography Methods 0.000 description 32
- 238000004440 column chromatography Methods 0.000 description 31
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 description 24
- 108010002838 hematopoietic progenitor kinase 1 Proteins 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 21
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 15
- CRAUTELYXAAAPW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione Chemical compound O=C1C=2C(F)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O CRAUTELYXAAAPW-UHFFFAOYSA-N 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 230000004481 post-translational protein modification Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- JVTSHOJDBRTPHD-UHFFFAOYSA-N 2,2,2-trifluoroacetaldehyde Chemical compound FC(F)(F)C=O JVTSHOJDBRTPHD-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- WBGPNPZUWVTYAA-UHFFFAOYSA-N methane;dihydrochloride Chemical compound C.Cl.Cl WBGPNPZUWVTYAA-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 6
- ROFGDCOBISHGRK-UHFFFAOYSA-N 4-fluoroisoindole-1,3-dione Chemical compound FC1=CC=CC2=C1C(=O)NC2=O ROFGDCOBISHGRK-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- GFCKACFUYUKAPW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-5-piperazin-1-ylisoindole-1,3-dione Chemical compound O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CCNCC1)=O)=O GFCKACFUYUKAPW-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000000593 degrading effect Effects 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- IOKGWQZQCNXXLD-UHFFFAOYSA-N tert-butyl n-(3-bromopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCBr IOKGWQZQCNXXLD-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 101001059984 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 4 Proteins 0.000 description 4
- 102100028193 Mitogen-activated protein kinase kinase kinase kinase 3 Human genes 0.000 description 4
- 101710144521 Mitogen-activated protein kinase kinase kinase kinase 3 Proteins 0.000 description 4
- 102100028194 Mitogen-activated protein kinase kinase kinase kinase 4 Human genes 0.000 description 4
- 229940125907 SJ995973 Drugs 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000005496 eutectics Effects 0.000 description 4
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 4
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 3
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 3
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 3
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 3
- MWMSBQXTHIEBNT-UHFFFAOYSA-N 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound O=C1C2=CC(Br)=CC=C2C(=O)N1C1CCC(=O)NC1=O MWMSBQXTHIEBNT-UHFFFAOYSA-N 0.000 description 3
- RRELDGDKULRRDM-UHFFFAOYSA-N 6-[2-chloro-4-nitro-5-(oxan-4-yloxy)anilino]-3,4-dihydro-1H-quinolin-2-one Chemical compound [O-][N+](=O)c1cc(Cl)c(Nc2ccc3NC(=O)CCc3c2)cc1OC1CCOCC1 RRELDGDKULRRDM-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- 229940126639 Compound 33 Drugs 0.000 description 3
- 229940127007 Compound 39 Drugs 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 3
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- 229940125833 compound 23 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- DZTBXBZXHKXCOV-UHFFFAOYSA-N dimethyl 4-iodo-1h-pyrazole-3,5-dicarboxylate Chemical compound COC(=O)C1=NNC(C(=O)OC)=C1I DZTBXBZXHKXCOV-UHFFFAOYSA-N 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- MQUPWTBHHPUUMC-UHFFFAOYSA-N isoindole Chemical compound C1=CC=C[C]2C=NC=C21 MQUPWTBHHPUUMC-UHFFFAOYSA-N 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- LAJAFFLJAJMYLK-CVOKMOJFSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[[(7s)-4-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5h-benzo[7]annulen-3-yl]amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N1([C@H]2CCC3=CC=C(C(=C3CC2)OC)NC=2N=C(C(=CN=2)Cl)N[C@H]2[C@H]([C@@]3([H])C[C@@]2(C=C3)[H])C(N)=O)CCOCC1 LAJAFFLJAJMYLK-CVOKMOJFSA-N 0.000 description 2
- SLTBMTIRYMGWLX-XMMPIXPASA-N (2r)-2-[(4-chloroanilino)carbamoylamino]-3-(1h-indol-3-yl)-n-(2-phenylethyl)propanamide Chemical compound C1=CC(Cl)=CC=C1NNC(=O)N[C@@H](C(=O)NCCC=1C=CC=CC=1)CC1=CNC2=CC=CC=C12 SLTBMTIRYMGWLX-XMMPIXPASA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 description 2
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- RXNPEQZHMGFNAY-GEALJGNFSA-N (5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one Chemical compound C[C@@H]1CC(=O)NC2=C1C(=NC=N2)N3CCN([C@H]4[C@@H]3C4)C(=O)[C@H](CNC(C)C)C5=CC=C(C=C5)Cl RXNPEQZHMGFNAY-GEALJGNFSA-N 0.000 description 2
- RNOAOAWBMHREKO-QFIPXVFZSA-N (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)[C@@H]1CCNC=2N1N=C(C=2C(=O)N)C1=CC=C(C=C1)OC1=CC=CC=C1 RNOAOAWBMHREKO-QFIPXVFZSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- FJZNNKJZHQFMCK-LRDDRELGSA-N 1-[(3S,4R)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-phenylurea Chemical compound C1(=CC(=CC(=C1[C@H]1[C@@H](C(=O)NC1)NC(=O)NC1=CC=CC=C1)F)OC)F FJZNNKJZHQFMCK-LRDDRELGSA-N 0.000 description 2
- YCGQPIRMLGEWMW-UHFFFAOYSA-N 1-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-3-[4-[(dimethylamino)methyl]-2,6-di(propan-2-yl)phenyl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN(C)C)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 YCGQPIRMLGEWMW-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 2
- YRTFLDFDKPFNCJ-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-2-oxo-4-[3-(3-pyrrolidin-1-ylpropoxy)phenyl]-1,8-naphthyridin-3-yl]urea;dihydrochloride Chemical compound Cl.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCCCN1CCCC1 YRTFLDFDKPFNCJ-UHFFFAOYSA-N 0.000 description 2
- ZFNNBIMQDHBELV-UHFFFAOYSA-N 1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-cyclohexylpropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea;dihydrochloride Chemical compound Cl.Cl.CC(C)C=1C=C(N)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C(C=1)=CC=CC=1OCCCC1CCCCC1 ZFNNBIMQDHBELV-UHFFFAOYSA-N 0.000 description 2
- YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 description 2
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 2
- BNMZWHCDQMRJGG-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-5-[4-(piperidin-4-ylmethyl)piperidin-1-yl]isoindole-1,3-dione Chemical compound O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CCC(CC1)CC1CCNCC1)=O)=O BNMZWHCDQMRJGG-UHFFFAOYSA-N 0.000 description 2
- XZORQADPEUSNQJ-UHFFFAOYSA-N 2-(3-piperidin-4-yloxy-1-benzothiophen-2-yl)-5-[(1,3,5-trimethylpyrazol-4-yl)methyl]-1,3,4-oxadiazole Chemical compound CC1=NN(C)C(C)=C1CC1=NN=C(C2=C(C3=CC=CC=C3S2)OC2CCNCC2)O1 XZORQADPEUSNQJ-UHFFFAOYSA-N 0.000 description 2
- MSSQOQPKGAMUSY-LEAFIULHSA-N 2-[1-[2-[(4r,6s)-8-chloro-6-(2,3-dimethoxyphenyl)-4,6-dihydropyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl]piperidin-4-yl]acetic acid Chemical compound COC1=CC=CC([C@@H]2C3=CC(Cl)=CC=C3N3C=CC=C3[C@@H](CC(=O)N3CCC(CC(O)=O)CC3)O2)=C1OC MSSQOQPKGAMUSY-LEAFIULHSA-N 0.000 description 2
- WGABOZPQOOZAOI-UHFFFAOYSA-N 2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid Chemical compound COC1=C(C)C(OC)=CC(C(=O)N(CCCC=2C=CC=CC=2)CC=2C=CC(CC(O)=O)=CC=2)=C1 WGABOZPQOOZAOI-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- QKKNFEZKVKMSGW-UHFFFAOYSA-N 3-(4-ethoxycarbonyl-5-methyl-1h-pyrrol-3-yl)propanoic acid Chemical compound CCOC(=O)C1=C(C)NC=C1CCC(O)=O QKKNFEZKVKMSGW-UHFFFAOYSA-N 0.000 description 2
- WOULORBKOHBDKE-UHFFFAOYSA-N 3-(4-piperazin-1-ylphenyl)piperidine-2,6-dione Chemical compound N1(CCNCC1)C1=CC=C(C=C1)C1C(NC(CC1)=O)=O WOULORBKOHBDKE-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- HNFMVVHMKGFCMB-UHFFFAOYSA-N 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine Chemical compound NC1=NC=CC=C1C1=NC2=CC=C(C=3C=CC=CC=3)N=C2N1C1=CC=C(C2(N)CCC2)C=C1 HNFMVVHMKGFCMB-UHFFFAOYSA-N 0.000 description 2
- ISRVBGKOIUPBAL-UHFFFAOYSA-N 3-[4-[4-(3-aminopropyl)piperazin-1-yl]phenyl]piperidine-2,6-dione Chemical compound NCCCN(CC1)CCN1C1=CC=C(C(CCC(N2)=O)C2=O)C=C1 ISRVBGKOIUPBAL-UHFFFAOYSA-N 0.000 description 2
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 2
- RXCVUHMIWHRLDF-HXUWFJFHSA-N 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1H-pyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1-one Chemical compound ClC1=C2CCN(C(C2=C(C(=C1)[C@@H](C1COC1)OC)Cl)=O)CC=1C(NC(=CC=1OC)C)=O RXCVUHMIWHRLDF-HXUWFJFHSA-N 0.000 description 2
- QKFVFEDOYRRLME-UHFFFAOYSA-N 5-(2,7-diazaspiro[3.5]nonan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound O=C1N(C2CCC(=O)NC2=O)C(=O)C2=C1C=CC(=C2)N1CC2(C1)CCNCC2 QKFVFEDOYRRLME-UHFFFAOYSA-N 0.000 description 2
- MVXAKOGJWVQPKC-UHFFFAOYSA-N 5-(3-ethynyl-5-fluorophenyl)-2-pyridin-2-yl-4,6,7,8-tetrahydro-[1,3]oxazolo[4,5-c]azepine Chemical compound FC1=CC(C#C)=CC(N2CC=3N=C(OC=3CCC2)C=2N=CC=CC=2)=C1 MVXAKOGJWVQPKC-UHFFFAOYSA-N 0.000 description 2
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 2
- XKNPNKJFMLILER-UHFFFAOYSA-N 5-[4-(azetidin-3-yl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound N1CC(C1)C1CCN(CC1)C=1C=C2C(N(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O)=O XKNPNKJFMLILER-UHFFFAOYSA-N 0.000 description 2
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 2
- LPWKFUVWWQYLOD-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-methylphenyl)pyrido[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CN=CC=2SC(C2=O)=C1N=CN2C1=CC=C(C)C=C1 LPWKFUVWWQYLOD-UHFFFAOYSA-N 0.000 description 2
- 238000003727 ADP Glo Kinase Assay Methods 0.000 description 2
- YUXOGVJBGYTVJO-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1=NC(=CC=C1C1=CC=C(C=C1)N1CCN(CC1)C(=O)OC(C)(C)C)OCC1=CC=CC=C1 Chemical compound C(C1=CC=CC=C1)OC1=NC(=CC=C1C1=CC=C(C=C1)N1CCN(CC1)C(=O)OC(C)(C)C)OCC1=CC=CC=C1 YUXOGVJBGYTVJO-UHFFFAOYSA-N 0.000 description 2
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- UQDWELYJNPCIGK-UHFFFAOYSA-N Cl.O=C1NC(CCC1N1C(C2=CC(=C(C=C2C1=O)F)N1CCNCC1)=O)=O Chemical compound Cl.O=C1NC(CCC1N1C(C2=CC(=C(C=C2C1=O)F)N1CCNCC1)=O)=O UQDWELYJNPCIGK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- LGJOFYKTTKCVKK-UHFFFAOYSA-N O=C(C(C1=C2)=CC=C2N(CC2)CCN2C2CNC2)N(C(CCC(N2)=O)C2=O)C1=O Chemical compound O=C(C(C1=C2)=CC=C2N(CC2)CCN2C2CNC2)N(C(CCC(N2)=O)C2=O)C1=O LGJOFYKTTKCVKK-UHFFFAOYSA-N 0.000 description 2
- KDDHGEAGVGFSMU-UHFFFAOYSA-N O=C1CCC(Oc2ccc(cc2)N2CCNCC2)C(=O)N1 Chemical compound O=C1CCC(Oc2ccc(cc2)N2CCNCC2)C(=O)N1 KDDHGEAGVGFSMU-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- NPUXORBZRBIOMQ-RUZDIDTESA-N [(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]-2-pyrrolidinyl]methanol Chemical compound C=1C(OCC=2C=CC(CN3[C@H](CCC3)CO)=CC=2)=CC(C)=CC=1CS(=O)(=O)C1=CC=CC=C1 NPUXORBZRBIOMQ-RUZDIDTESA-N 0.000 description 2
- NELWQUQCCZMRPB-UBPLGANQSA-N [(2r,3r,4r,5r)-4-acetyloxy-5-(4-amino-5-ethenyl-2-oxopyrimidin-1-yl)-2-methyloxolan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(C=C)=C1 NELWQUQCCZMRPB-UBPLGANQSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125876 compound 15a Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940126212 compound 17a Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 229940125936 compound 42 Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000003979 granulating agent Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 2
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 2
- BODLESUVCQEUII-UHFFFAOYSA-N n-[4-[2-(hydroxyamino)-2-oxoethyl]piperidin-4-yl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide Chemical compound C=12C=CC=CC2=NC(C)=CC=1COC(C=C1)=CC=C1C(=O)NC1(CC(=O)NO)CCNCC1 BODLESUVCQEUII-UHFFFAOYSA-N 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 239000005416 organic matter Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 2
- DVWOYOSIEJRHKW-UIRZNSHLSA-M sodium (2S)-2-[[(2S)-2-[[(4,4-difluorocyclohexyl)-phenylmethoxy]carbonylamino]-4-methylpentanoyl]amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonate Chemical compound FC1(CCC(CC1)C(OC(=O)N[C@H](C(=O)N[C@H](C(S(=O)(=O)[O-])O)C[C@H]1C(NCC1)=O)CC(C)C)C1=CC=CC=C1)F.[Na+] DVWOYOSIEJRHKW-UIRZNSHLSA-M 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- ZNCUKMXOJHHWHJ-UHFFFAOYSA-N tert-butyl 3-prop-2-ynylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(CC#C)C1 ZNCUKMXOJHHWHJ-UHFFFAOYSA-N 0.000 description 2
- YEHWSWXESXPBOS-UHFFFAOYSA-N tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(O)C=C1 YEHWSWXESXPBOS-UHFFFAOYSA-N 0.000 description 2
- PMKVKOLFYHLKAP-UHFFFAOYSA-N tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazine-1-carboxylate Chemical compound O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CCN(CC1)C(=O)OC(C)(C)C)=O)=O PMKVKOLFYHLKAP-UHFFFAOYSA-N 0.000 description 2
- DTIVTHOMUDEPOH-UHFFFAOYSA-N tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)oxyphenyl]piperazine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCN(CC1)C1=CC=C(C=C1)OC1C(NC(CC1)=O)=O DTIVTHOMUDEPOH-UHFFFAOYSA-N 0.000 description 2
- MZJMHHWOOZFMPV-UHFFFAOYSA-N tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazine-1-carboxylate Chemical compound O=C1NC(CCC1C1=CC=C(C=C1)N1CCN(CC1)C(=O)OC(C)(C)C)=O MZJMHHWOOZFMPV-UHFFFAOYSA-N 0.000 description 2
- RTQAXEOHXCJYON-UHFFFAOYSA-N tert-butyl 4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl]piperidine-1-carboxylate Chemical compound O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CCC(CC1)CC1CCN(CC1)C(=O)OC(C)(C)C)=O)=O RTQAXEOHXCJYON-UHFFFAOYSA-N 0.000 description 2
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 2
- NCSLSIAFPCTEGD-UHFFFAOYSA-N tert-butyl 4-[[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CN2CCN(CC2)C2=CC=C3C(=O)N(C4CCC(=O)NC4=O)C(=O)C3=C2)CC1 NCSLSIAFPCTEGD-UHFFFAOYSA-N 0.000 description 2
- ZYGNIEGLKZNPOL-UHFFFAOYSA-N tert-butyl 9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCOC2(CCN(CC2)C2=CC=C3C(=O)N(C4CCC(=O)NC4=O)C(=O)C3=C2)C1 ZYGNIEGLKZNPOL-UHFFFAOYSA-N 0.000 description 2
- HUSVVORAPHRNLC-UHFFFAOYSA-N tert-butyl N-[2-[4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperazin-1-yl]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCN1CCN(CC1)C1=CC2=C(C=C1)C(=O)N(C2)C1CCC(=O)NC1=O HUSVVORAPHRNLC-UHFFFAOYSA-N 0.000 description 2
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 2
- HTBNREYQOZPEQT-UHFFFAOYSA-N tert-butyl n-(2-methyl-3-oxopropyl)carbamate Chemical compound O=CC(C)CNC(=O)OC(C)(C)C HTBNREYQOZPEQT-UHFFFAOYSA-N 0.000 description 2
- ACNRTYKOPZDRCO-UHFFFAOYSA-N tert-butyl n-(2-oxoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC=O ACNRTYKOPZDRCO-UHFFFAOYSA-N 0.000 description 2
- VPOIPCJBJNWHSJ-UHFFFAOYSA-N tert-butyl n-(2-piperazin-1-ylethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN1CCNCC1 VPOIPCJBJNWHSJ-UHFFFAOYSA-N 0.000 description 2
- RYXOGEGCRBIYKR-UHFFFAOYSA-N tert-butyl n-(3-piperazin-1-ylpropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCN1CCNCC1 RYXOGEGCRBIYKR-UHFFFAOYSA-N 0.000 description 2
- FBQUIIPSWDMUBM-UHFFFAOYSA-N tert-butyl n-[(1-formylcyclopropyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1(C=O)CC1 FBQUIIPSWDMUBM-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- LENAVORGWBTPJR-UHFFFAOYSA-N (5-pyridin-3-ylfuran-2-yl)methanamine Chemical compound O1C(CN)=CC=C1C1=CC=CN=C1 LENAVORGWBTPJR-UHFFFAOYSA-N 0.000 description 1
- JHLIGYPHPBLDDL-UHFFFAOYSA-N (5-pyridin-3-ylthiophen-2-yl)methanamine Chemical compound S1C(CN)=CC=C1C1=CC=CN=C1 JHLIGYPHPBLDDL-UHFFFAOYSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- ILWJAOPQHOZXAN-UHFFFAOYSA-N 1,3-dithianyl Chemical group [CH]1SCCCS1 ILWJAOPQHOZXAN-UHFFFAOYSA-N 0.000 description 1
- AKFXQYMORAUSBD-UHFFFAOYSA-N 1-chloro-3-methylpyrido[1,2-a]benzimidazole-4-carbonitrile Chemical compound C12=CC=CC=C2N=C2N1C(Cl)=CC(C)=C2C#N AKFXQYMORAUSBD-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 description 1
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 description 1
- QFINOKRWTWRQRO-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-5-[4-(piperidin-4-ylmethyl)piperazin-1-yl]isoindole-1,3-dione Chemical compound O=C1N(C2CCC(=O)NC2=O)C(=O)C2=C1C=CC(=C2)N1CCN(CC2CCNCC2)CC1 QFINOKRWTWRQRO-UHFFFAOYSA-N 0.000 description 1
- WMDHQEHPOVOEOG-UHFFFAOYSA-N 2-(2-bromoethyl)-1,3-dioxane Chemical compound BrCCC1OCCCO1 WMDHQEHPOVOEOG-UHFFFAOYSA-N 0.000 description 1
- VGOALPIDEXVYQI-UHFFFAOYSA-N 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-n-[3-imidazol-1-yl-5-(trifluoromethyl)phenyl]-4-methylbenzamide Chemical compound C1=C(C#CC=2N3N=CC=CC3=NC=2)C(C)=CC=C1C(=O)NC(C=C(C=1)C(F)(F)F)=CC=1N1C=CN=C1 VGOALPIDEXVYQI-UHFFFAOYSA-N 0.000 description 1
- CMRQAKJTXKOGSF-UHFFFAOYSA-N 3-(6-bromo-3-oxo-1h-isoindol-2-yl)piperidine-2,6-dione Chemical compound C1C2=CC(Br)=CC=C2C(=O)N1C1CCC(=O)NC1=O CMRQAKJTXKOGSF-UHFFFAOYSA-N 0.000 description 1
- UNSHMXUHOHBLIQ-UHFFFAOYSA-N 3-[4-chloro-3-(2-methylphenoxy)naphthalen-1-yl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione Chemical compound ClC1=C(C=C(C2=CC=CC=C12)N1C(NC(=CC1=O)C(F)(F)F)=O)OC1=C(C=CC=C1)C UNSHMXUHOHBLIQ-UHFFFAOYSA-N 0.000 description 1
- FUJMEAZJJURSIV-UHFFFAOYSA-N 3-[6-[4-(2-aminoethyl)piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound NCCN1CCN(CC1)C1=CC2=C(C=C1)C(=O)N(C2)C1CCC(=O)NC1=O FUJMEAZJJURSIV-UHFFFAOYSA-N 0.000 description 1
- RYSICGXZRVMXDP-UHFFFAOYSA-N 3-bromopiperidine-2,6-dione Chemical compound BrC1CCC(=O)NC1=O RYSICGXZRVMXDP-UHFFFAOYSA-N 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 1
- WNNMPSCAZVBLNL-UHFFFAOYSA-N 4-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound NCCN1CCN(CC1)c1cccc2C(=O)N(C3CCC(=O)NC3=O)C(=O)c12 WNNMPSCAZVBLNL-UHFFFAOYSA-N 0.000 description 1
- KJTRXVXWSSPHRV-UHFFFAOYSA-N 4-benzoyl-5-methyl-2-phenyl-1h-pyrazol-3-one Chemical compound O=C1C(C(=O)C=2C=CC=CC=2)=C(C)NN1C1=CC=CC=C1 KJTRXVXWSSPHRV-UHFFFAOYSA-N 0.000 description 1
- GPEOAEVZTOQXLG-UHFFFAOYSA-N 4-piperazin-1-ium-1-ylphenolate Chemical compound C1=CC(O)=CC=C1N1CCNCC1 GPEOAEVZTOQXLG-UHFFFAOYSA-N 0.000 description 1
- ITISJEFTRDVKMX-UHFFFAOYSA-N 5-(3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound O=C1N(C(=O)C2=C1C=CC(=C2)N1CCC2(CC1)CCNCC2)C1CCC(=O)NC1=O ITISJEFTRDVKMX-UHFFFAOYSA-N 0.000 description 1
- PNZFFGBFBSRCDT-UHFFFAOYSA-N 5-[4-(2-aminoethyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione Chemical compound NCCN1CCN(CC1)C=1C=C2C(N(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O)=O PNZFFGBFBSRCDT-UHFFFAOYSA-N 0.000 description 1
- DDIIYGHHUMKDGI-UHFFFAOYSA-N 5-fluoro-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2NC(=O)CC2=C1 DDIIYGHHUMKDGI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- PPOMIYGLVGCOCF-UHFFFAOYSA-N C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C=C(C=C3)N4CC5CNCC5C4 Chemical compound C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C=C(C=C3)N4CC5CNCC5C4 PPOMIYGLVGCOCF-UHFFFAOYSA-N 0.000 description 1
- DFRCTMCXNOBCLU-UHFFFAOYSA-N C1CC(N2C(=O)C3=CC=4CNCC=4C=C3C2=O)C(=O)NC1=O Chemical compound C1CC(N2C(=O)C3=CC=4CNCC=4C=C3C2=O)C(=O)NC1=O DFRCTMCXNOBCLU-UHFFFAOYSA-N 0.000 description 1
- VZGZYBBERPLEOE-UHFFFAOYSA-N CC(C)(C)OC(N(C1)CC1N(CC1)CCN1C(C=C1C(N2C(CCC(N3)=O)C3=O)=O)=CC=C1C2=O)=O Chemical compound CC(C)(C)OC(N(C1)CC1N(CC1)CCN1C(C=C1C(N2C(CCC(N3)=O)C3=O)=O)=CC=C1C2=O)=O VZGZYBBERPLEOE-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 101150024075 Mapk1 gene Proteins 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- YYZYBSVEBHMCOQ-UHFFFAOYSA-N N/S(\[N+]([O-])=O)=N\C#N Chemical group N/S(\[N+]([O-])=O)=N\C#N YYZYBSVEBHMCOQ-UHFFFAOYSA-N 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- OLQFTCYXNZTLNC-UHFFFAOYSA-N O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CC(C1)N1CCNCC1)=O)=O Chemical compound O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CC(C1)N1CCNCC1)=O)=O OLQFTCYXNZTLNC-UHFFFAOYSA-N 0.000 description 1
- QQYASGJFPDNABU-UHFFFAOYSA-N O=C1NC(CCC1N1C(C=2C=C3C(=CC=2C1=O)CN(C3)C(=O)OC(C)(C)C)=O)=O Chemical compound O=C1NC(CCC1N1C(C=2C=C3C(=CC=2C1=O)CN(C3)C(=O)OC(C)(C)C)=O)=O QQYASGJFPDNABU-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 101100174184 Serratia marcescens fosA gene Proteins 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 108010018242 Transcription Factor AP-1 Proteins 0.000 description 1
- 241000009298 Trigla lyra Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960000781 aminolevulinic acid hydrochloride Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 229940126209 compound 43b Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- STRNXFOUBFLVIN-UHFFFAOYSA-N diethyl but-2-ynedioate Chemical compound CCOC(=O)C#CC(=O)OCC STRNXFOUBFLVIN-UHFFFAOYSA-N 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SIPQVJNEQSWAOK-UHFFFAOYSA-N dimethyl 1h-pyrazole-3,5-dicarboxylate Chemical compound COC(=O)C=1C=C(C(=O)OC)NN=1 SIPQVJNEQSWAOK-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- NGIJGIMEKGYNFJ-UHFFFAOYSA-N ethyl 2-methyl-6-oxo-4,5-dihydro-1h-cyclopenta[b]pyrrole-3-carboxylate Chemical compound O=C1CCC2=C1NC(C)=C2C(=O)OCC NGIJGIMEKGYNFJ-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 101150078861 fos gene Proteins 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- SKEAGJWUKCNICJ-LSDHHAIUSA-N n-[(4-fluoro-3-methoxyphenyl)methyl]-6-[2-[[(2s,5r)-5-(hydroxymethyl)-1,4-dioxan-2-yl]methyl]tetrazol-5-yl]-2-methylpyrimidine-4-carboxamide Chemical compound C1=C(F)C(OC)=CC(CNC(=O)C=2N=C(C)N=C(C=2)C2=NN(C[C@@H]3OC[C@@H](CO)OC3)N=N2)=C1 SKEAGJWUKCNICJ-LSDHHAIUSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ASOADIZOVZTJSR-UHFFFAOYSA-N opicapone Chemical compound CC1=C(Cl)C(C)=[N+]([O-])C(Cl)=C1C1=NOC(C=2C=C(C(O)=C(O)C=2)[N+]([O-])=O)=N1 ASOADIZOVZTJSR-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000002262 penten-4-yl group Chemical group C=CCC(C)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 238000011865 proteolysis targeting chimera technique Methods 0.000 description 1
- 239000012629 purifying agent Substances 0.000 description 1
- NPWMTBZSRRLQNJ-UHFFFAOYSA-N pyroglutamine Chemical compound NC1CCC(=O)NC1=O NPWMTBZSRRLQNJ-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 108010026668 snake venom protein C activator Proteins 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- NRADOPGBTAJXKB-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11CNC1 NRADOPGBTAJXKB-UHFFFAOYSA-N 0.000 description 1
- MGHFVXFMQGQAKJ-UHFFFAOYSA-N tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11CNCC1 MGHFVXFMQGQAKJ-UHFFFAOYSA-N 0.000 description 1
- SGIAPGALSCDKJC-UHFFFAOYSA-N tert-butyl 2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC2(CN(C2)C2=CC3=C(C=C2)C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1 SGIAPGALSCDKJC-UHFFFAOYSA-N 0.000 description 1
- GAFBHGCAUQFDBO-UHFFFAOYSA-N tert-butyl 2-ethyldecanoate Chemical compound CCCCCCCCC(CC)C(=O)OC(C)(C)C GAFBHGCAUQFDBO-UHFFFAOYSA-N 0.000 description 1
- YLKHACHFJMCIRE-UHFFFAOYSA-N tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11CCNCC1 YLKHACHFJMCIRE-UHFFFAOYSA-N 0.000 description 1
- OKPLHPXLAMMVKG-UHFFFAOYSA-N tert-butyl 3-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]azetidine-1-carboxylate Chemical compound O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CCC(CC1)C1CN(C1)C(=O)OC(C)(C)C)=O)=O OKPLHPXLAMMVKG-UHFFFAOYSA-N 0.000 description 1
- KEQBTRKQDYXHTO-UHFFFAOYSA-N tert-butyl 3-piperazin-1-ylazetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1N1CCNCC1 KEQBTRKQDYXHTO-UHFFFAOYSA-N 0.000 description 1
- NVJNOFWSEGNPKX-UHFFFAOYSA-N tert-butyl 3-piperidin-4-ylazetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1C1CCNCC1 NVJNOFWSEGNPKX-UHFFFAOYSA-N 0.000 description 1
- FWKMGWWNAQGBFB-UHFFFAOYSA-N tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CNC1 FWKMGWWNAQGBFB-UHFFFAOYSA-N 0.000 description 1
- UYZVZLYOXDJHPR-UHFFFAOYSA-N tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CN1CCNCC1 UYZVZLYOXDJHPR-UHFFFAOYSA-N 0.000 description 1
- YRSSUIZMGOJGOZ-JTQLQIEISA-N tert-butyl 4-[(2s)-2-aminopropyl]piperazine-1-carboxylate Chemical compound C[C@H](N)CN1CCN(C(=O)OC(C)(C)C)CC1 YRSSUIZMGOJGOZ-JTQLQIEISA-N 0.000 description 1
- OAXARSVKYJPDPA-UHFFFAOYSA-N tert-butyl 4-prop-2-ynylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CC#C)CC1 OAXARSVKYJPDPA-UHFFFAOYSA-N 0.000 description 1
- CRKWWYGNDADDNI-UHFFFAOYSA-N tert-butyl 9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate Chemical compound C1(=O)N(C(=O)C2=C1C=CC(=C2)N1CCC2(CC1)CCN(CC2)C(=O)OC(C)(C)C)C1CCC(=O)NC1=O CRKWWYGNDADDNI-UHFFFAOYSA-N 0.000 description 1
- YVNSIKOIOJPXER-UHFFFAOYSA-N tert-butyl N-[2-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperazin-1-yl]ethyl]carbamate Chemical compound O=C1NC(CCC1N1C(C2=CC=C(C=C2C1=O)N1CCN(CC1)CCNC(OC(C)(C)C)=O)=O)=O YVNSIKOIOJPXER-UHFFFAOYSA-N 0.000 description 1
- BPKHWXYPEWXEAL-UHFFFAOYSA-N tert-butyl n,n-bis(prop-2-ynyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CC#C)CC#C BPKHWXYPEWXEAL-UHFFFAOYSA-N 0.000 description 1
- OEQRZPWMXXJEKU-UHFFFAOYSA-N tert-butyl n-(1-oxopropan-2-yl)carbamate Chemical compound O=CC(C)NC(=O)OC(C)(C)C OEQRZPWMXXJEKU-UHFFFAOYSA-N 0.000 description 1
- RQRMFFGCUUGYPC-UHFFFAOYSA-N tert-butyl n-(2-piperidin-4-ylethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCC1CCNCC1 RQRMFFGCUUGYPC-UHFFFAOYSA-N 0.000 description 1
- MLDSDVASYUUDLT-UHFFFAOYSA-N tert-butyl n-(3-oxopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCC=O MLDSDVASYUUDLT-UHFFFAOYSA-N 0.000 description 1
- BLROSIRAEKEFNI-UHFFFAOYSA-N tert-butyl n-(4-bromobutan-2-yl)carbamate Chemical compound BrCCC(C)NC(=O)OC(C)(C)C BLROSIRAEKEFNI-UHFFFAOYSA-N 0.000 description 1
- OSDBYOUUVQAPFC-UHFFFAOYSA-N tert-butyl n-[1-(2-oxoethyl)cyclopropyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1(CC=O)CC1 OSDBYOUUVQAPFC-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Definitions
- the present invention relates to an indolinone derivative and its application.
- Protein degradation targeting chimera is a small molecule compound that recruits E3 ubiquitin ligase to target proteins to promote their degradation.
- Bifunctional PROTAC can recognize and simultaneously bind the target protein and E3 ubiquitin ligase, inducing the spatial proximity of the target protein and E3 ubiquitin ligase, which is conducive to the ubiquitination of the target protein and subsequent degradation by the proteasome, thereby selectively Reduce the level of target protein in the body.
- HPK1 hematopoietic progenitor kinase 1
- MAP4K1 hematopoietic progenitor kinase 1
- HPK1 belongs to the MAP4K family and is a serine/threonine kinase that is mainly expressed in hematopoietic cells.
- HPK1 negatively regulates the immune response of T cells and B cells through the AP-1, NF- ⁇ B, Erk2 and Fos pathways, which manifests as inhibiting T cell proliferation and downregulating B cell receptor signal transduction.
- inhibiting HPK1 can enhance the activity of T cells and B cells, thereby improving anti-tumor immunity. Therefore, inhibiting HPK1 is expected to become an innovative therapy for the treatment of cancer, or it can be used in combination with existing cancer immunotherapy to improve the effectiveness of cancer treatment.
- PROTAC compounds Compared with traditional HPK1 small molecule inhibitors, PROTAC compounds have dual functions. They can not only inhibit the activity of HPK1, but also catalytically promote multiple rounds of HPK1 degradation and reduce HPK1 levels. Thus, PROTAC compounds can effectively inhibit the resistance mutations and/or up-regulation of HPK1 and have better tolerance. Therefore, PROTACs provide a new mechanism to treat HPK1-mediated diseases.
- the purpose of the present invention is to provide an indolinone derivative that can enhance the degradation of target proteins and its application in the preparation of anti-tumor drugs.
- One or more embodiments of the present invention provide a compound capable of enhancing the degradation of a target protein, a compound represented by formula (I), or all its stereoisomers, solvates, prodrugs, metabolites, deuterium Substitutes, pharmaceutically acceptable salts or co-crystals:
- the L is a
- the R 2 is absent; or the R 2 is selected from
- the A ring and B ring are each independently selected from a 3-12-membered carbocyclylene group and a 3-12-membered heterocyclylene group;
- the PTM is a first
- the ULM is a
- the R 1b is selected from C 1-6 alkylene, C 1-6 haloalkylene or imino;
- the X 1 , X 2 , X 3 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from C, N, O, S, -C(O)NH-;
- the R 5 is selected from hydrogen, F, Br, cyano, and trifluoromethyl
- R 4 , R 6 , R 7 and R 8 are independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, hydroxyl, C 3-6 cycloalkyl, 3-6 One-membered heterocycloalkyl, 5-8-membered aryl or 5-8-membered heteroaryl;
- the a, b, c, h, k are independently selected from 0, 1, 2, 3, 4, 5 or 6.
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from the group consisting of: Compounds represented by formula (II):
- the R 1b is selected from C 1-6 alkylene or C 1-6 haloalkylene
- the R 2 is absent; or the R 2 is selected from
- the A ring and B ring are each independently selected from the group consisting of 3-8 membered monocyclic carbocyclylene, 6-12 membered bicyclic carbocyclylene, 3-8 membered monocyclic heterocyclylene, and 6-12 membered bicyclic carbocyclylene.
- Heterocyclyl; the 6-12-membered bicyclic carbocyclylene and 6-12-membered bicyclic heterocyclylene are selected from the group consisting of fused bicyclic, bridged bicyclic or spiro bicyclic;
- the e is selected from 0, 1, 2, 3, 4, 5 or 6;
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from the group consisting of: Compounds represented by formula (II), wherein:
- the R 1b is selected from C 1-6 linear alkylene or C 1-6 branched alkylene;
- the R 2 is absent; or the R 2 is selected from
- the A ring and B ring are each independently selected from 3-8 membered monocyclic cycloalkylene, 6-12 membered bicyclic cycloalkylene, 3-8 membered monocyclic heterocycloalkylene, 6-12 membered bicyclic Heterocycloalkylene; the 6-12-membered bicyclic cycloalkylene and 6-12-membered bicyclic heterocycloalkylene are selected from the group consisting of fused bicyclic, bridged bicyclic or spiro bicyclic;
- the e is selected from 0, 1, 2, 3, 4, 5 or 6.
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from the group consisting of: A compound represented by formula (I) or general formula (II), wherein:
- the PTM is a first
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from A compound represented by general formula (I) or general formula (II), wherein:
- the PTM is a first
- the R 5 is selected from hydrogen, F, Br, cyano, and trifluoromethyl
- the R 6 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
- Each of the a's is independently selected from 0, 1, 2, 3, 4, 5 or 6.
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from A compound represented by general formula (I) or general formula (II), wherein:
- the ULM is a
- the X 2 , X 6 , X 7 , and X 8 are each independently selected from C, N, and O;
- R 4 , R 7 , and R 8 are each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano group, and hydroxyl;
- the b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6.
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from A compound represented by general formula (I) or general formula (II), wherein:
- the ULM is a
- the X 2 , X 6 , X 7 , and X 8 are each independently selected from C, N, and O;
- the X 3 is selected from -C 1-3 alkylene-, -NH-, -O-, -S- or -C(O)NH-;
- R 4 , R 7 , and R 8 are each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano group, and hydroxyl;
- the b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6.
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from Compounds represented by general formula (I), wherein:
- the PTM is
- the L is a
- the ULM is a
- the X 1 , X 2 and X 3 are each independently selected from C, N or O;
- the R 1b is independently selected from C 1-6 alkylene or C 1-6 haloalkylene
- the R 2 is selected from
- the A ring and B ring are each independently selected from a 3-10-membered carbocyclic group and a 3-10-membered heterocyclic group;
- the R 3 is selected from carbonyl, methylene or imino
- the R 5 is selected from hydrogen, F, Br, cyano, and trifluoromethyl
- R 4 , R 6 and R 7 are each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano or hydroxyl;
- the a, b, c, d and e are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- the h is selected from 0 or 1.
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from A compound represented by general formula (I) or general formula (II), wherein:
- the PTM is a first
- the R 5 is selected from hydrogen, F, Br, cyano, and trifluoromethyl
- the R 6 is selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl;
- Each of the a's is independently selected from 0, 1, 2, 3 or 4;
- the ULM is a
- the R 3 is selected from carbonyl or methylene
- the R 4 and R 7 are each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano group, and hydroxyl;
- the b and c are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- the L is a
- the R 2 is absent; or the R 2 is selected from
- the A ring and B ring are each independently selected from
- the X 4 , X 5 , and X 11 are each independently selected from C, N or O;
- the e, f, g, i, j are each independently selected from 0, 1, 2, 3 or 4.
- the R 2 is selected from
- provided compounds, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof are selected from:
- One or more embodiments of the present application provide a compound represented by formula (I'), or all its stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or Eutectic:
- W is selected from
- R 1 is selected from carbonyl, methylene or amino
- R 2 is selected from Among them, n is an integer from 1 to 4;
- R 3 is selected from methylene or carbonyl
- R 10 is selected from H or halogen.
- One or more embodiments of the present application include compounds represented by formula (I"), or all stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals thereof :
- the PTM is
- the L is a
- the ULM is a
- the X 1 , X 2 and X 3 are each independently selected from C, N or O;
- the R 1b is independently selected from C 1-6 alkyl or C 1-6 haloalkyl
- R 2 is selected from
- the A ring and B ring are each independently selected from a 3-10-membered carbocyclic group and a 3-10-membered heterocyclic group;
- the R 3 is selected from carbonyl, methylene or imino
- the R 5 is selected from hydrogen, F, Br, cyano, and trifluoromethyl
- R 4 , R 6 , and R 7 are each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano group or hydroxyl;
- the a, b, c, d and e are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- the h is selected from 0 or 1.
- the compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof is selected from the group consisting of Compounds represented by formula (II), wherein:
- the PTM is a first
- the ULM is a
- the R 3 is selected from carbonyl or methylene
- the compound, or all stereoisomers, solvates, prodrugs, metabolites, deuterates, pharmaceutically acceptable salts or co-crystals thereof is selected from the group consisting of Compounds represented by general formula (II”):
- the R 1b are each independently selected from C 1-6 alkyl
- the R 2 is selected from
- the A ring and B ring are each independently selected from
- the X 4 and X 5 are each independently selected from C or N;
- the f and g are each independently selected from 1, 2, 3 or 4.
- the A ring and B ring are each independently selected from
- At least one of X 4 and X 5 is selected from N.
- the R 2 is selected from
- composition provided by one or more embodiments of the present application, the pharmaceutical composition includes:
- composition provided by one or more embodiments of the present application, the pharmaceutical composition includes:
- One or more embodiments of the present application provide the compounds of the present application or their stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals, or the above pharmaceutical compositions in the preparation of anti-tumor drugs. uses in.
- One or more embodiments of the present application provide the compounds described in the present application or their stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or co-crystals or the pharmaceutical compositions of the present application. Use in the preparation of drugs for degrading HPK1 protein.
- the hydrogen isotopes involved in the groups and compounds of the present invention include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen).
- Alkyl refers to a linear or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably An alkyl group of 1 to 4 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And its various branched chain isomers; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
- Alkoxy refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom.
- Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
- alkyl is the same as the definition of "alkyl" mentioned above.
- Cycloalkyl refers to a saturated cyclic hydrocarbon group, the ring of which can be a 3 to 10-membered monocyclic ring, a 4 to 12-membered bicyclic ring, or a 10 to 20-membered polycyclic ring system, and the ring carbon atoms are preferably 3 to 10 carbon atoms, further 3 to 8 carbon atoms are preferred.
- Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptadienyl, etc. When substituted, it may optionally be further substituted with zero or more substituents.
- Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 3 heteroatoms selected from N, O or S, preferably 3 to 8 yuan Heterocyclyl.
- the selectively substituted N and S in the ring of "heterocycloalkyl” can be oxidized to various oxidation states; the “heterocycloalkyl” can be connected to a heteroatom or a carbon atom; the “heterocycloalkyl” can be a bridge Ring or spiro ring.
- heterocycloalkyl examples include oxetyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-di Oxopentyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
- Alkenyl refers to a straight group containing 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds and composed of 2 to 20 carbon atoms. Chain or branched unsaturated aliphatic hydrocarbon group, preferably an alkenyl group with 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 carbon atoms. An alkenyl group of 8 carbon atoms is further preferred, and an alkenyl group of 2 to 6 carbon atoms is further preferred.
- Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decene-4-yl, and undecayl En-3-yl.
- the alkenyl group may be optionally further substituted by one or more substituents.
- Alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group containing 1 to 3 carbon-carbon triple bonds and composed of 2 to 20 carbon atoms, preferably an alkynyl group of 2 to 12 carbon atoms, more preferably An alkynyl group having 2 to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms.
- Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl Base, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
- the alkynyl group can optionally be further selected from 0 to 4 F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, mercapto , amide group, carbocyclic group or heterocyclic group substituent.
- Heterocycle refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl” above; when When it is a non-aromatic heterocyclic ring, it can be a 3- to 10-membered (for example, 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4 to 12-membered (for example, 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring system or 10 to 15-membered (such as 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably 3 to 8-membered heterocyclic groups.
- heterocyclyl or “heterocycle”
- N and S in the ring of “heterocyclyl” or “heterocycle” can be oxidized into various oxidation states;
- heterocyclyl or “Heterocyclic ring” can be connected to a heteroatom or a carbon atom;
- heterocyclyl or “heterocyclic ring” can be a branched ring, a bridged ring or a spiro ring.
- the “heterocyclyl” or “heterocycle” may be optionally further substituted by one or more substituents.
- “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, their pharmaceutically acceptable salts or prodrugs and other chemical components, where "other chemical components” refers to pharmaceutically acceptable Acceptable carriers, excipients and/or one or more other therapeutic agents.
- Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
- Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound.
- Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
- “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
- Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of the compound.
- Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders agents and disintegrants.
- Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body.
- the prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound.
- the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
- Co-crystal refers to a crystal formed by combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds.
- API active pharmaceutical ingredient
- CCF co-crystal form
- the pure states of API and CCF are both Solids, and there are fixed stoichiometric ratios between the components.
- a eutectic is a multicomponent crystal that includes both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed between a neutral solid and a salt or solvate.
- Stepoisomers refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers. isomers, enantiomers and conformers.
- heterocyclyl optionally substituted by alkyl means that the alkyl group may but need not be present, and this description includes the case where the heterocyclyl is substituted by an alkyl group, and the case where the heterocyclyl is not substituted by an alkyl group.
- the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates.
- compounds described herein exist as solvates with pharmaceutically acceptable solvents such as water, ethanol, and the like.
- the compounds described herein exist in unsolvated forms.
- Solvates contain stoichiometric or non-stoichiometric solvents, and they may be formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
- One or more embodiments of the present application provide compounds and compositions of the present application for use in the treatment and/or prevention of disease.
- One or more embodiments of the present application provide compounds and compositions of the present application for use in the treatment and/or prevention of cancer and/or tumors.
- One or more embodiments of the present application provide compounds and compositions of the present application for use in degrading HPK1 protein.
- One or more embodiments of the present application provide methods of treating and/or preventing disease comprising administering the compounds and compositions of the present application to a subject in need thereof.
- One or more embodiments of the present application provide methods of treating and/or preventing cancer and/or tumors comprising administering the compounds and compositions of the present application to a subject in need thereof.
- One or more embodiments of the present application provide a method of degrading HPK1 protein, the method comprising applying the compounds and compositions of the present application to the HPK1 protein.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10-6 (ppm). NMR is measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments.
- the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and internal standards. is tetramethylsilane (TMS);
- HPLC HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
- Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
- the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
- the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
- the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. company.
- N,N-diisopropylethylamine (0.70g, 5.40mmol) was added dropwise to compound 2-(2,6-dioxo-piperidin-3-yl)-4 -N,N-Difluoro-isoindole-1,3-dione compound 1a (0.50g, 1.81mmol) and 1-(N-Boc-aminoethyl)piperazine (0.50g, 2.17mmol)
- methylformamide (20 mL) solution the temperature was raised to 90°C and the reaction was stirred for 6.0 h; TLC detected the reaction until the end of the reaction; water (40 mL) was added dropwise and stirred for 10 min, filtered with suction, and the filter cake was dried to obtain the title compound 1b (yellow solid, 0.48g, yield: 55.0%).
- N,N-diisopropylethylamine (0.70g, 5.43mmol) was added dropwise to compound 2-(2,6-dioxo-piperidin-3-yl)-5 -N,N-dimethyl of fluoro-isoindole-1,3-dione compound 2a (0.50g, 1.81mmol) and 1-(N-Boc-aminoethyl)piperazine (0.41g, 1.81mmol) methyl formamide (20 mL) solution, the temperature was raised to 90°C and the reaction was stirred for 7.0 h; TLC detected until the reaction was completed; water (40 mL) was added dropwise and stirred for 10 min, extracted with ethyl acetate (100 mL*2), and the organic phases were combined and washed with saturated salt Wash with water (50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is pur
- trifluoroacetic acid (1.80g, 15.90mmol) was added dropwise to a solution of compound 3b (0.80g, 1.59mmol) in dichloromethane (10mL), and the reaction was stirred for 7 hours after the drops were completed; LC-MS The reaction was detected until the reaction was completed; concentrated under reduced pressure to obtain the title compound 3c (yellow solid, 0.82g, yield: 99.0%).
- N,N-diisopropylethylamine (0.70g, 5.40mmol) was added dropwise to compound 2-(2,6-dioxo-piperidin-3-yl)-4 -Fluoro-isoindole-1,3-dione compound 1a (0.50g, 1.81mmol) and (3-(piperazin-1-yl)propyl)carbamic acid tert-butyl ester (0.53g, 2.18mmol) of N, N-dimethylformamide (20 mL) solution, the temperature was raised to 90°C and the reaction was stirred for 7.0 h; TLC detected until the reaction was completed; water (40 mL) was added dropwise and stirred for 10 min, filtered with suction, and the filter cake was dried to obtain the title Compound 5b (yellow solid, 0.13 g, yield: 15.0%).
- N,N-diisopropylethylamine (0.70g, 5.43mmol) was added dropwise to 2-(2,6-dioxo-piperidin-3-yl)-5- N of fluoro-isoindole-1,3-dione compound 2a (0.50g, 1.81mmol) and (3-(piperazin-1-yl)propyl)carbamic acid tert-butyl ester (0.53g, 2.21mmol) , in N-dimethylformamide (20mL) solution, increase the temperature to 90°C and stir for 7.0h; TLC detects until the reaction is completed; add water (40mL) dropwise and stir for 10min, extract with dichloromethane (60mL*2), and combine The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography
- N-tert-butoxycarbonyl-2-aminopropionaldehyde (0.26g, 1.50mmol) was slowly added to compound 3-(1-oxy-5-(piperazin-1-yl) Isoindol-2-yl)piperidine-2,6-dione hydrochloride compound 4a (0.5g, 1.37mmol) was dissolved in dichloroethane (10mL) and anhydrous methanol (1mL), and the reaction was stirred at room temperature.
- N,N-diisopropylethylamine (0.70g, 5.40mmol) was added dropwise to compound 2-(2,6-dioxo-piperidin-3-yl) -4-Fluoro-isoindole-1,3-dione 1a (0.50g, 1.81mmol) and 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylic acid tert-butyl
- ester (0.56g, 2.17mmol) in N,N-dimethylformamide (20mL)
- TLC detected that the reaction was completed
- water (40mL) was added dropwise and stirred for 10min.
- N,N-diisopropylethylamine (0.70g, 5.40mmol) was added dropwise to compound 2-(2,6-dioxo-piperidin-3-yl) -4-Fluoro-isoindole-1,3-dione 1a (0.50g, 1.81mmol) and 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylic acid tert-butyl
- ester (0.56g, 2.17mmol) in N,N-dimethylformamide (20mL)
- TLC detected that the reaction was completed
- water (40mL) was added dropwise and stirred for 10min.
- N,N-diisopropylethylamine (0.50g, 3.90mmol) was added dropwise to compound 2-(2,6-dioxo-piperidin-3-yl) -N,N- of 4-fluoro-isoindole-1,3-dione 1a (0.36g, 1.31mmol) and 4-(2-BOC-aminoethyl)piperidine (0.30g, 1.31mmol)
- N,N-diisopropylethylamine (0.50g, 3.90mmol) was added dropwise to compound 2-(2,6-dioxo-piperidin-3-yl) -4-Fluoro-isoindole-1,3-dione 1a (0.36g, 1.31mmol) and 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl
- ester (0.34g, 1.31mmol) in N,N-dimethylformamide (10mL)
- TLC detected until the reaction was completed
- N,N-diisopropylethylamine (207.0mg, 1.60mmol) and 2-(7-azobenzotriazole)-N,N,N', N′-Tetramethylurea hexafluorophosphate (133.0 mg, 0.35 mmol) was added to (Z)-6-(5-fluoro-2-oxoindole-3-ylidene)-2-methyl-1 , in a solution of 4,5,6-tetrahydrocyclopentanoic acid [b]pyrrole-3-carboxylic acid (100.0mg, 0.32mmol) in N,N-dimethylformamide (2mL), stir and react for 0.5h.
- compound 31c (3g, 7.71mmol) was dissolved in dichloromethane (30mL), and then trifluoroacetic acid (7.5mL) was added dropwise. The reaction was carried out for 0.5 hours, and then concentrated under reduced pressure to obtain crude compound 31d (yellow liquid, 2.2 g, yield: 99%).
- compound 36a (1g, 5mmol), 2,2,6,6-tetramethylpiperidine oxide (23mg, 0.15mmol), potassium bromide (59mg, 0.5mmol) were dissolved in dichloro To methane (10 mL) and water (30 mL), slowly add the prepared mixed solution of sodium bicarbonate (2.6 g, 31 mmol) and sodium hypochlorite (50 mL) at -10°C to 0°C, and complete the reaction dropwise for 30 minutes.
- Dess-Martin reagent (1.46g, 3.44mmol) was slowly added to a solution of compound 37a (500mg, 2.65mmol) in dichloromethane (5mL), and the reaction was carried out at room temperature for 2 hours. After the reaction, saturated sodium sulfite aqueous solution (10 mL) was added, extracted with dichloromethane (10 mL*3), the organic phases were combined, dried, and concentrated under reduced pressure to obtain compound 37b (white solid, 180 mg, yield: 36%).
Abstract
本发明涉及吲哚酮衍生物及其应用,该吲哚酮衍生物能够增强靶蛋白降解,可用于制备抗肿瘤药物。
Description
本发明涉及一种吲哚酮衍生物及其应用。
蛋白降解靶向嵌合体(proteolysis targeting chimera,PROTAC)是一种招募E3泛素连接酶至靶蛋白以促进其降解的小分子化合物。双功能PROTAC能够识别并同时结合靶蛋白和E3泛素连接酶,诱导靶蛋白与E3泛素连接酶在空间位置上的接近,有利于靶蛋白泛素化并随后被蛋白酶体降解,从而选择性地降低靶蛋白在体内的水平。
HPK1(hematopoietic progenitor kinase 1,造血祖细胞激酶1),又名MAP4K1,属于MAP4K家族,是一种丝氨酸/苏氨酸激酶,主要在造血细胞中表达。HPK1通过AP-1、NF-κB、Erk2和Fos途径对T细胞和B细胞的免疫应答进行负向调控,表现为抑制T细胞增殖,下调B细胞受体信号转导等。研究发现抑制HPK1可增强T细胞和B细胞的活性,从而提高抗肿瘤免疫。因此抑制HPK1有望成为治疗癌症的创新疗法,或可与已有癌症免疫疗法联用,提高癌症治疗效果。
与传统HPK1小分子抑制剂相比,PROTAC化合物具有双重功能,不仅可以抑制HPK1的活性,而且可以催化量地促进对HPK1的多轮降解,降低HPK1水平。从而使PROTAC化合物能够有效抑制HPK1的抗性突变和/或上调,有更好的耐受性。因此,PROTAC提供了治疗HPK1介导的疾病的新机制。
发明内容
本发明的目的是提供一种能够增强靶蛋白降解的吲哚酮衍生物及其在制备抗肿瘤药物上的应用。
本发明的一个或多个实施方式提供一种能够增强靶蛋白降解的化合物,一种式(I)所示的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶:
PTM-L-ULM (I);
其中,
所述L为
所述R2不存在;或所述R2选自
所述A环、B环各自独立地选自3-12元亚碳环基、3-12元亚杂环基;
所述PTM为
所述ULM为
所述R1、R3、R9、R11彼此独立地选自-C(=O)-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C1-6卤代亚烷基-、-NH-、-NHR1b-、-C(=O)NH-、-NHC(=O)-、-C(=O)NHR1b-、-NHC(=O)R1b-、-OC(=O)R1b-、-C(=O)OR1b-、-C(=O)R1b-、-SO2R1b-、-OR1b-、-O-或-S-;
所述R1b选自C1-6亚烷基、C1-6卤代亚烷基或亚氨基;
所述X1、X2、X3、X6、X7、X8、X9、X10彼此独立地选自C、N、O、S、-C(O)NH-;
所述R5选自氢、F、Br、氰基、三氟甲基;
所述R4、R6、R7、R8彼此独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基、C3-
6环烷基、3-6元杂环烷基、5-8元芳基或5-8元杂芳基;
所述a、b、c、h、k彼此独立地选自0、1、2、3、4、5或6。
在一个或多个实施方式中,提供的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(II)所示的化合物:
PTM-R1-R2-ULM (II);
其中,
所述R1选自羰基、C1-6亚烷基、亚氨基、-NHR1b-、-C(=O)NH-、-NHC(=O)-、-C(=O)NHR1b-
或-NHC(=O)R1b-;
所述R1b选自C1-6亚烷基或C1-6卤代亚烷基;
所述R2不存在;或所述R2选自
所述A环、B环各自独立地选自3-8元单环亚碳环基、6-12元双环亚碳环基、3-8元单环亚杂环基、6-12元双环亚杂环基;所述6-12元双环亚碳环基、6-12元双环亚杂环基选自稠合双环、桥接双环或螺接双环;
所述e选自0、1、2、3、4、5或6;
所述PTM、ULM的定义与上文相同。
在一个或多个实施方式中,提供的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(II)所示的化合物,其中:
所述R1选自羰基、C1-6亚烷基、亚氨基、-NHR1b-、-C(=O)NH-、或-C(=O)NHR1b-;
所述R1b选自C1-6直链亚烷基或C1-6支链亚烷基;
所述R2不存在;或所述R2选自
所述A环、B环各自独立地选自3-8元单环亚环烷基、6-12元双环亚环烷基、3-8元单环亚杂环烷基、6-12元双环亚杂环烷基;所述6-12元双环亚环烷基、6-12元双环亚杂环烷基选自稠合双环、桥接双环或螺接双环;
所述e选自0、1、2、3、4、5或6。
在一个或多个实施方式中,提供的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:
所述PTM为
X1、R5、a、R6、h的定义与上文相同。
在一个或多个实施方式中,提供的化合物,,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:
所述PTM为
所述R5选自氢、F、Br、氰基、三氟甲基;
所述R6选自卤素、C1-6烷基、C1-6卤代烷基;
所述a各自独立地选自0、1、2、3、4、5或6。
在一个或多个实施方式中,提供的化合物,,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:
所述ULM为
所述R3选自-C(=O)-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C1-6卤代亚烷基-、-NH-、-O-或-S-;
所述X2、X6、X7、X8各自独立地选自C、N、O;
所述X3选自-C(=O)-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C1-6卤代亚烷基-、-NH-、-O-、-S-或-C(O)NH-;
所述R4、R7、R8各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基;
所述b、c各自独立地选自0、1、2、3、4、5或6。
在一个或多个实施方式中,提供的化合物,,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:
所述ULM为
所述R3选自-C(=O)-、-C1-3亚烷基-、-C1-3卤代亚烷基-、-NH-、-O-或-S-;
所述X2、X6、X7、X8各自独立地选自C、N、O;
所述X3选自-C1-3亚烷基-、-NH-、-O-、-S-或-C(O)NH-;
所述R4、R7、R8各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基;
所述b、c各自独立地选自0、1、2、3、4、5或6。
在一个或多个实施方式中,提供的化合物,,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示的化合物,其中:
其中,所述PTM为
所述L为
所述ULM为
所述X1、X2、X3各自独立地选自C、N或O;
所述R1独立地选自羰基、亚甲基、亚氨基、-NHR1b-、-C(=O)NHR1b-或-NHC(=O)R1b-;
所述R1b独立地选自C1-6亚烷基或C1-6卤代亚烷基;
所述R2选自
所述A环、B环各自独立地选自3-10元碳环基、3-10元杂环基;
所述R3选自羰基、亚甲基或亚氨基;
所述R5选自氢、F、Br、氰基、三氟甲基;
所述R4、R6、R7各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基或羟基;
所述a、b、c、d、e各自独立地选自0、1、2、3、4、5或6;
所述h选自0或1。
在一个或多个实施方式中,提供的化合物,,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:
所述PTM为
所述R5选自氢、F、Br、氰基、三氟甲基;
所述R6选自卤素、C1-3烷基、C1-3卤代烷基;
所述a各自独立地选自0、1、2、3或4;
所述ULM为
所述R3选自羰基或亚甲基;
所述R4、R7各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基;
所述b、c各自独立地选自0、1、2、3、4、5或6;
所述L为
所述R1选自-C(=O)NH-或-C(=O)NH-C1-6亚烷基-;
所述R2不存在;或所述R2选自
所述A环、B环各自独立地选自
所述X4、X5、X11各自独立地选自C、N或O;
所述e、f、g、i、j各自独立地选自0、1、2、3或4。
在一个或多个实施方式中,提供的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,其中:
所述R2选自
在一个或多个实施方式中,提供的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自:
本申请一个或多个实施方式提供了一种式(I’)所示的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶:
其中,
W选自
R1选自羰基、亚甲基或氨基;
R2选自
其中,n为1-4的整数;
R3选自亚甲基或羰基;
R10选自H或卤素。
本申请的一个或多个实施方式了式(I”)所示的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶:
PTM-L-ULM (I”);
其中,所述PTM为
所述L为
所述ULM为
所述X1、X2、X3各自独立地选自C、N或O;
所述R1独立地选自羰基、亚甲基、亚氨基、-NHR1b-、-C(=O)NHR1b-或-NHC(=O)R1b-;
所述R1b独立地选自C1-6烷基或C1-6卤代烷基;
R2选自
所述A环、B环各自独立地选自3-10元碳环基、3-10元杂环基;
所述R3选自羰基、亚甲基或亚氨基;
所述R5选自氢、F、Br、氰基、三氟甲基;
所述R4、R6、R7各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基或羟基;
所述a、b、c、d、e各自独立地选自0、1、2、3、4、5或6;
所述h选自0或1。
在一个或多个实施方式中,所述化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(II)所示的化合物,其中:
所述PTM为
所述ULM为
所述R3选自羰基或亚甲基;
所述X2、R4、R5、R6、R7、a、b、c的定义与上文相同。
在一个或多个实施方式中,所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(II”)所示的化合物:
PTM-R1-R2-ULM (II”);
其中,
所述R1各自独立地选自羰基、亚甲基、亚氨基、-NHR1b-或-C(=O)NHR1b-;
所述R1b各自独立地选自C1-6烷基;
所述R2选自
在一个或多个实施方式中,所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,其中:
所述A环、B环各自独立地选自
所述X4、X5各自独立地选自C或N;
所述f、g各自独立地选自1、2、3或4。
在一个或多个实施方式中,所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,其中:
所述A环、B环各自独立地选自
所述X4、X5至少有一个选自N。
在一个或多个实施方式中,所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,其中:
所述R2选自
本申请一个或多个实施方式提供的一种药物组合物,所述药物组合物包括:
(1)上述化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶;
(2)药学上可接受的载体和/或赋形剂。
本申请一个或多个实施方式提供的一种药物组合物,所述药物组合物包括:
(1)上述化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶;
(2)一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
本申请一个或多个实施方式提供本申请化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶或者上述药物组合物在制备抗肿瘤药物中的用途。
本申请一个或多个实施方式提供本申请所述的化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶或者本申请的药物组合物在制备用于降解HPK1蛋白的药物中的用途。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢)。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“环烷基”是指饱和的环烃基,其环可以为3至10元的单环、4至12元双环或者10至20元多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当被取代时,可以任选进一步被0个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至8元
杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基,更优选2至8个碳原子的烯基,进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指含有1至3个碳-碳叁键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个碳原子的炔基,更优选2至8个碳原子的炔基,进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被0至4个选自F、Cl、Br、I、烷基、烷氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代。
“杂环”或“杂环基”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为并环、桥环或者螺环。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“杂环基”、“杂环”、“环烷基”或者“杂环烷基”被取代时,可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、=NRq6、-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRq4Rq5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-OC(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-OC(=O)C3-8环烷基、-C(=O)OC3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C6-
10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8杂环烷基或者-NHC(=O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5或者=O的取代基所取代;Rq1选自C1-6烷基、C1-6烷氧基或者C6-10芳基;Rq2、Rq3选自H或者C1-6烷基;Rq4、Rq5选自H、C1-6烷基、-NH(C=NRq1)NRq2Rq3、-S(=O)2NRq2Rq3、-C(=O)Rq1或者-C(=O)NRq2Rq3,其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rq4与Rq5及N原子形成一个3至8元杂环,所述的环可以含有1个或者多个选自N、O或者S的杂原子。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构
体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“任选地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
应当理解,本文描述的方法和组合包括晶体形式(还称为多晶型,其包括化合物相同元素组合物的不同晶体堆积排列)、非晶相、盐、溶剂化物和水合物。在一些实施方案中,本文描述的化合物以具有诸如水、乙醇等的药物可接受的溶剂的溶剂化物形式存在。在其他实施方案中,本文描述的化合物以非溶剂化物形式存在。溶剂化物包含化学计量或非化学计量的溶剂,并且其可在结晶过程中与诸如水、乙醇等的药物可接受的溶剂形成。当溶剂为水时形成水合物,或者当溶剂为醇时形成醇化物。此外,本文提供的化合物能以非溶剂化物以及溶剂化物形式存在。通常,为了本文提供的化合物和方法的目的,溶剂化物形式被认为等价于非溶剂化物形式。
本申请的一个或多个实施方案提供了本申请的化合物和组合物,其用于治疗和/或预防疾病。
本申请的一个或多个实施方案提供了本申请的化合物和组合物,其用于治疗和/或预防癌症和/或肿瘤。
本申请的一个或多个实施方案提供了本申请的化合物和组合物,其用于降解HPK1蛋白。
本申请的一个或多个实施方案提供了治疗和/或预防疾病的方法,该方法包括将本申请的化合物和组合物施用于有此需要的对象。
本申请的一个或多个实施方案提供了治疗和/或预防癌症和/或肿瘤的方法,该方法包括将本申请的化合物和组合物施用于有此需要的对象。
本申请一个或多个实施方式提供降解HPK1蛋白的方法,该方法包括将本申请的化合物和组合物施用于HPK1蛋白。
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Brruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5
μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体;
本发明的己知起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例
中间体1
第一步:
3-(4-(乙氧羰基)-5-甲基-1H-吡咯-3-基)丙酸A2
3-(4-(ethoxycarbonyl)-5-methyl-1H-pyrrol-3-yl)propanoic acid A2
在25℃下,将乙酸钠(196.0g,2.4mol)加到化合物A15-氨基乙酰丙酸盐酸盐(200.0g,1.2mol)和乙酰乙酸乙酯(155.0g,1.2mol)的水(1.2L)溶液中,氮气保护下升至100℃搅拌反应6h;TLC检测至反应结束;降至25℃,过滤,30%的乙醇(300mL)洗涤,滤饼烘干得到标题化合物A2(白色固体,238.0g,产率:89.0%)
1H NMR(400MHz,DMSO)δ11.95(s,1H),10.95(s,1H),6.40(d,1H),4.13(q,2H),2.86-2.71(m,2H),2.44-2.38(m,2H),2.35(s,3H),1.25(t,3H)
LC-MS m/z(ESI)=226.3[M+1]
第二步:
2-甲基-6-氧代-1,4,5,6-四氢环戊烷[b]吡咯-3-羧酸乙酯A3
ethyl 2-methyl-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate A3
在25℃,氮气保护下,将甲磺酸(491.0g,5.1mol)缓慢滴加到五氧化二磷(49.0g,0.4mol)中,滴毕升至100℃反应1h,降至40℃,分批加入化合物A2(65.0g,0.3mol),40℃反应1h,后降至25℃反应10h;TLC检测至反应结束;降至0℃,滴加饱和碳酸氢钠溶液(10L)淬灭,调节PH=8,过滤,水洗(1.0L),滤饼烘干得到标题化合物A3(黄色固体,60g,产率:99.0%)
1H NMR(400MHz,CDCl3)δ11.48(s,1H),4.29(q,2H),3.03(dd,2H),2.92-2.87(m,2H),2.69(s,3H),1.36(t,3H).
LC-MS m/z(ESI)=208.4[M+1]
第三步:
(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸乙酯化合物A4
ethyl(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate A4
在T=25℃,氮气保护下,将哌啶(20.00g,0.24mol)滴加到化合物A3(9.80g,0.05mol)和5-氟-2-氧化吲哚(7.9g,52.0mmol)的N,N-二甲基甲酰胺(100mL)溶液中,滴毕升温至T=110℃搅拌反应21h;LC-MS检测至反应结束;降至室温静置10h,过滤,滤饼用无水乙醇(150mL)打浆30min,抽滤,滤饼烘干得到标题化合物A4(黄色固体,10.0g,产率:62.0%)
1H NMR(400MHz,DMSO)δ11.76(s,1H),10.62(s,1H),7.21(d,1H),6.93(t,1H),6.83(dd,1H),4.20(q,2H),3.53(s,2H),3.04(d,2H),2.62(s,3H),1.29(t,3H).
LC-MS m/z(ESI)=341.2[M+1]
第四步:
(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1
(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylic acid中间体1
在T=25℃,氮气保护下,将一水合氢氧化锂(6.20g,0.12mol)加到化合物A4(10.0g,24.0mmol)的二氧六环(180mL)和水(90mL)溶液中,滴加甲醇(2mL)和二甲基亚砜(2mL),升至T=110℃搅拌反应8.0h;LC-MS检测至反应结束;降至20℃,滴加盐酸水溶液(1N)调节PH=2,过滤,乙醇(100mL)打浆30min,过滤,滤饼
烘干得到标题中间体1(黄色固体,8.5g,产率:94.0%)
1H NMR(400MHz,DMSO)δ11.51(s,1H),10.61(s,1H),7.18(dd,1H),6.92-6.76(m,2H),3.54-3.48(m,2H),3.02(d,2H),2.61(s,3H).
LC-MS m/z(ESI)=313.4[M+1]
实施例1
第一步:
(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)哌嗪-1-基)乙基)氨基甲酸叔丁酯1b
tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)carbamate 1b
在25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.40mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮化合物1a(0.50g,1.81mmol)和1-(N-Boc-氨乙基)哌嗪(0.50g,2.17mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至90℃搅拌反应6.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,抽滤,滤饼烘干得到标题化合物1b(黄色固体,0.48g,产率:55.0%)。
LC-MS m/z(ESI)=486.3[M+1]
第二步:
2,2,2-三氟乙醛与4-(4-(2-氨基乙基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-
二酮的化合物1c
2,2,2-trifluoroacetaldehyde compound with 4-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound 1c
在25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物1b(0.48g,0.98mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物1c(黄色固体,0.49g,产率:99.0%)。
LC-MS m/z(ESI)=386.4[M+1]
第三步:
(Z)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌嗪-1-基)乙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物1
(Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 1
在25℃,氮气保护下,将N,N-二异丙基乙胺(124.0mg,0.96mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到中间体1(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物1c(176.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物1(黄色固体,84.0mg,产率:38.7%)。
1H NMR(400MHz,DMSO)δ11.66(s,1H),11.10(s,1H),10.58(s,1H),7.73-7.69(m,1H),7.36(d,J=7.7Hz,2H),7.24-7.20(m,1H),7.06(s,1H),6.90(dd,J=12.6,5.4Hz,1H),6.82(dd,J=8.4,4.8Hz,1H),5.10(dd,J=12.9,5.3Hz,1H),3.58(d,J=4.5Hz,2H),3.39(d,J=5.5Hz,4H),3.14(s,2H),2.93-2.81(m,1H),2.65(s,5H),2.60(s,3H),2.54(dd,J=11.0,6.8Hz,5H),2.02(dd,J=13.7,8.6Hz,1H).
LC-MS m/z(ESI)=680.5[M+1]。
实施例2
第一步:
(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)乙基)氨基甲酸叔丁酯2b
tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 2b
在25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.43mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-5-氟-异吲哚-1,3-二酮化合物2a(0.50g,1.81mmol)和1-(N-Boc-氨乙基)哌嗪(0.41g,1.81mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至90℃搅拌反应7.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,乙酸乙酯(100mL*2)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,减压浓缩得到粗品,经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物2b(黄色固体,0.22g,产率:25.0%)。
1H NMR(400MHz,DMSO)δ11.08(s,1H),7.96(d,J=9.3Hz,1H),7.67(d,J=8.5Hz,1H),7.25(dd,J=8.6,2.2Hz,1H),6.69(d,J=5.9Hz,1H),5.07(dd,J=12.9,5.4Hz,1H),3.42(s,3H),3.06(dd,J=14.9,6.5Hz,2H),2.89(s,3H),2.73(d,J=0.5Hz,3H),2.39-2.29(m,4H),2.00(dd,J=11.1,3.7Hz,1H),1.37(s,9H).
LC-MS m/z(ESI)=486.3[M+1]
第二步:
2,2,2-三氟乙醛与5-(4-(2-氨基乙基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮的化合物2c
2,2,2-trifluoroacetaldehyde compound with 5-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound2c
在25℃,氮气保护下,将三氟乙酸(0.51g,4.50mmol)滴加到化合物2b(0.22g,0.45mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物2c(黄色固体,0.22g,产率:99.0%)。
LC-MS m/z(ESI)=386.4[M+1]
第三步:
(Z)-N-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)乙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物2
(Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound2
在25℃,氮气保护下,将N,N-二异丙基乙胺(103.0mg,0.80mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(60.0mg,0.16mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(50.0mg,0.16mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物2c(90.0mg,0.17mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物2(黄色固体,29.0mg,产率:26.0%)。
1H NMR(400MHz,DMSO)δ11.66(s,1H),11.09(s,1H),10.58(s,1H),7.68(d,J=8.5Hz,1H),7.37(d,J=1.9Hz,1H),7.28(dd,J=8.6,2.1Hz,1H),7.21(d,J=7.6Hz,1H),7.07(t,J=5.1Hz,1H),6.94-6.87(m,1H),6.83(dt,J=8.4,3.6Hz,1H),5.08(dd,J=12.9,5.4Hz,1H),3.58(d,J=5.2Hz,3H),3.47(s,3H),3.44-3.35(m,3H),3.14(s,2H),2.94-2.82(m,1H),2.62-2.52(m,10H),2.01(dd,J=11.3,6.4Hz,1H).
LC-MS m/z(ESI)=680.5[M+1]
实施例3
第一步:
叔丁基(2-(4-(2,6-二氧哌啶-3-基)-6-氟-1,3-二氧异吲哚-5-基)哌嗪-1-基)乙基)氨基甲酸酯3b
tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 3b
在25℃,氮气保护下,将N-叔丁氧羰基-2-氨基乙醛(0.44g,2.76mmol)缓慢加到2-(2,6-二氧哌啶-3-基)-5-氟-6-(哌嗪-1-基)异吲哚-1,3-二酮盐酸盐化合物3a(1.0g,2.52mmol)的二氯乙烷(20mL)和无水甲醇(2mL)溶液中,室温搅拌反应0.5h,加入三乙酰氧基硼氢化钠(0.58g,2.76mmol)和冰醋酸(0.01mL),继续搅拌反应2.5h;TLC检测至反应结束;减压浓缩得到粗品,经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物3b(黄色固体,0.82g,产率:65.0%)。
1H NMR(400MHz,DMSO)δ11.11(s,1H),7.73(d,J=11.5Hz,1H),7.45(d,J=7.3Hz,1H),6.70(s,1H),5.10(dd,J=12.8,5.3Hz,1H),3.23(s,5H),3.07(s,2H),2.88(ddd,J=16.5,13.7,5.1Hz,1H),2.62-2.52(m,6H),2.39(s,2H),1.38(s,9H).
LC-MS m/z(ESI)=504.5[M+1]
第二步:
2,2,2-三氟乙醛与5-(4-(2-氨基乙基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异二氢吲哚-1,3-二酮的化合物3c
2,2,2-trifluoroacetaldehyde compound with 5-(4-(2-aminoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione compound3c
在25℃,氮气保护下,将三氟乙酸(1.80g,15.90mmol)滴加到化合物3b(0.80g,1.59mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应7h;LC-MS检测至反应结束;减压浓缩得到标题化合物3c(黄色固体,0.82g,产率:99.0%)。
LC-MS m/z(ESI)=404.5[M+1]
第三步:
(Z)-N-(2-(4-(2-(2,6-二氧哌啶-3-基)-6-氟-1,3-二氧异吲哚-5-基)哌嗪-1-基)乙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物3
(Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide Compound3
在25℃,氮气保护下,将N,N-二异丙基乙胺(206.0mg,1.6mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物3c(182.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(6mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物3(黄色固体,32.0mg,产率:14.0%)。
1H NMR(400MHz,DMSO)δ11.67(s,1H),11.12(s,1H),10.59(s,1H),7.75(d,J=11.3Hz,1H),7.49(d,J=6.4Hz,1H),7.23(dd,J=9.8,2.2Hz,1H),7.08(s,1H),6.95-6.88(m,1H),6.83(dd,J=8.5,4.8Hz,1H),5.11(dd,J=13.0,5.1Hz,1H),3.60(s,2H),3.31-3.24(m,6H),3.15(s,2H),2.93-2.82(m,1H),2.70-2.54(m,11H),2.06-1.98(m,1H).
LC-MS m/z(ESI)=698.4[M+1]。
实施例4
第一步:
(2-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌嗪-1-基)乙基)氨基甲酸叔丁酯4b
tert-butyl(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)carbamate 4b
在25℃,氮气保护下,将N-叔丁氧羰基-2-氨基乙醛(0.24g,1.50mmol)缓慢加到3-(1-氧基-5-(哌嗪-1-基)异吲哚-2-基)哌啶-2,6-二酮盐酸盐化合物4a(0.5g,1.37mmol)的二氯乙烷(10mL)和无水甲醇(1mL)溶液中,室温搅拌反应0.5h,加入三乙酰氧基硼氢化钠(0.32g,1.50mmol)和冰醋酸(0.01mL),继续搅拌反应2.5h;TLC检测至反应结束;减压浓缩得到粗品,经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物4b(灰色固体,0.52g,产率:81.0%)。
1H NMR(400MHz,DMSO)10.95(s,1H),7.52(d,J=8.7Hz,1H),7.06(d,J=8.2Hz,2H),6.70(s,1H),5.05(dd,J=13.3,5.1Hz,1H),4.26(dd,J=50.5,17.0Hz,2H),3.27(s,6H),3.08(s,2H),3.00-2.84(m,2H),2.60(s,2H),2.42-2.31(m,3H),2.00-1.92(m,1H),1.38(s,9H).
LC-MS m/z(ESI)=472.3[M+1]
第二步:
2,2,2-三氟乙醛化合物与3-(5-(4-(2-氨基乙基)哌嗪-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮化合物4c
2,2,2-trifluoroacetaldehyde compound with 3-(5-(4-(2-aminoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione compound 4c
在25℃,氮气保护下,将三氟乙酸(1.27g,11.0mmol)滴加到化合物4b(0.52g,
1.10mmol)的二氯甲烷(15mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物4c(黄色固体,0.54g,产率:99.0%)。
LC-MS m/z(ESI)=372.4[M+1]
第三步:
(Z)-N-(2-(4-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)哌嗪-1-基)乙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物4
(Z)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 4
在25℃,氮气保护下,将N,N-二异丙基乙胺(206.0mg,1.6mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物4c(170.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(6mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物4(黄色固体,55.0mg,产率:26.0%)。
1H NMR(400MHz,DMSO)δ11.66(s,1H),10.96(s,1H),10.59(s,1H),7.53(d,J=9.2Hz,1H),7.22(dd,J=9.7,2.4Hz,1H),7.08(d,J=9.5Hz,3H),6.94-6.87(m,1H),6.82(dd,J=8.4,4.8Hz,1H),5.05(dd,J=13.3,5.0Hz,1H),4.27(dd,J=50.0,17.0Hz,2H),3.57(s,2H),3.39(d,J=5.8Hz,2H),3.33-3.25(m,4H),3.13(s,2H),2.97-2.84(m,1H),2.68-2.52(m,10H),2.44-2.29(m,1H),2.04-1.87(m,1H).
LC-MS m/z(ESI)=666.5[M+1]
实施例5
第一步:
(3-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)哌嗪-1-基)丙基)氨基甲酸叔丁酯5b
tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)carbamate 5b
在25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.40mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮化合物1a(0.50g,1.81mmol)和(3-(哌嗪-1-基)丙基)氨基甲酸叔丁酯(0.53g,2.18mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至90℃搅拌反应7.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,抽滤,滤饼烘干得到标题化合物5b(黄色固体,0.13g,产率:15.0%)。
1H NMR(400MHz,DMSO)δ11.09(s,1H),7.70(dd,J=8.3,7.2Hz,1H),7.34(t,J=7.6Hz,2H),6.82(t,J=5.3Hz,1H),5.09(dd,J=12.9,5.4Hz,1H),3.29(s,4H),3.00-2.82(m,3H),2.55(dd,J=26.9,11.9Hz,6H),2.33(t,J=7.0Hz,2H),2.06-1.97(m,1H),1.56(dd,J=13.6,6.7Hz,2H),1.37(s,9H).
LC-MS m/z(ESI)=500.3[M+1]
第二步:
2,2,2-三氟乙醛与4-(4-(3-氨基丙基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮的化合物5c
2,2,2-trifluoroacetaldehyde compound with 4-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound5c
在25℃,氮气保护下,将三氟乙酸(0.15g,1.32mmol)滴加到化合物1b(0.13g,0.27mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应7h;LC-MS检测至反应结束;
减压浓缩得到标题化合物5c(黄色固体,0.13g,产率:99.0%)。
LC-MS m/z(ESI)=400.3[M+1]
第三步:
(Z)-N-(3-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物5
(Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 5
在25℃,氮气保护下,将N,N-二异丙基乙胺(103.0mg,0.8mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(60.0mg,0.16mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(50.0mg,0.16mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物5c(90.0mg,0.17mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(3mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物5(黄色固体,37.0mg,产率:33.0%)。
1H NMR(400MHz,DMSO)δ11.65(s,1H),11.09(s,1H),10.58(s,1H),7.75-7.63(m,1H),7.35(dd,J=7.7,4.4Hz,2H),7.22(dd,J=9.9,2.4Hz,2H),6.95-6.87(m,1H),6.83(dd,J=8.4,4.8Hz,1H),5.09(dd,J=12.8,5.4Hz,1H),3.58(d,J=4.3Hz,2H),3.27(s,6H),3.15(s,2H),2.93-2.81(m,1H),2.56(d,J=15.9Hz,9H),2.42(s,2H),2.01(dd,J=13.3,6.1Hz,1H),1.72(s,2H).
LC-MS m/z(ESI)=694.5[M+1]
实施例6
第一步:
(3-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)丙基)氨基甲酸叔丁酯6b
tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 6b
在25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.43mmol)滴加到2-(2,6-二氧代-哌啶-3-基)-5-氟-异吲哚-1,3-二酮化合物2a(0.50g,1.81mmol)和(3-(哌嗪-1-基)丙基)氨基甲酸叔丁酯(0.53g,2.21mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至90℃搅拌反应7.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,二氯甲烷(60mL*2)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,减压浓缩得到粗品,经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物6b(黄色固体,0.20g,产率:22.0%)。
1H NMR(400MHz,DMSO)δ11.08(s,1H),7.67(d,J=8.5Hz,1H),7.34(d,J=1.9Hz,1H),7.25(dd,J=8.6,2.1Hz,1H),6.82(s,1H),5.07(dd,J=12.9,5.4Hz,1H),3.43(s,4H),2.99-2.85(m,5H),2.58(d,J=17.3Hz,1H),2.30(dd,J=13.6,6.1Hz,5H),2.05-1.97(m,1H),1.57-1.52(m,2H),1.37(s,9H).
LC-MS m/z(ESI)=500.3[M+1]
第二步:
2,2,2-三氟乙醛与5-(4-(3-氨基丙基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基)异二氢吲哚-1,3-二酮的化合物6c
2,2,2-trifluoroacetaldehyde compound with 5-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compound6c
在25℃,氮气保护下,将三氟乙酸(1.0g,8.0mmol)滴加到化合物6b(0.20g,0.40mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应6h;LC-MS检测至反应结束;减压浓缩得到标题化合物6c(黄色固体,0.2g,产率:99.0%)。
LC-MS m/z(ESI)=400.4[M+1]
第三步:
(Z)-N-(3-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物6
(Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamid
e compound 6
在25℃,氮气保护下,将N,N-二异丙基乙胺(103.0mg,0.80mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(60.0mg,0.16mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(50.0mg,0.16mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物6c(90.0mg,0.17mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(3mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物6(黄色固体,17.0mg,产率:16.0%)。
1H NMR(400MHz,DMSO)δ11.65(s,1H),11.08(s,1H),10.58(s,1H),7.67(d,J=8.8Hz,1H),7.35(s,1H),7.24(dd,J=17.1,9.1Hz,3H),6.90(dd,J=13.7,6.6Hz,1H),6.83(dd,J=8.4,4.8Hz,1H),5.07(dd,J=12.8,5.2Hz,1H),3.57(s,2H),3.44(s,4H),3.28(d,J=6.1Hz,2H),3.15(s,2H),2.87(d,J=13.8Hz,1H),2.57(d,J=7.9Hz,6H),2.36(d,J=29.7Hz,3H),1.99(dd,J=14.4,7.0Hz,3H),1.71(s,2H).
LC-MS m/z(ESI)=694.5[M+1]
实施例7
第一步:
叔丁基(3-(4-(2-(2,6-二氧哌啶-3-基)-6-氟-1,3-二氧异吲哚-5-基)哌嗪-1-基)丙基)氨基甲酸酯7b
tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 7b
在25℃,氮气保护下,将(3-氧代丙基)氨基甲酸叔丁酯(0.48g,2.77mmol)缓慢加
到2-(2,6-二氧哌啶-3-基)-5-氟-6-(哌嗪-1-基)异吲哚-1,3-二酮盐酸盐化合物3a(1.0g,2.52mmol)的二氯乙烷(20mL)和无水甲醇(2mL)溶液中,室温搅拌反应0.5h,加入三乙酰氧基硼氢化钠(0.58g,2.76mmol)和冰醋酸(0.01mL),继续搅拌反应2.5h;TLC检测至反应结束;减压浓缩得到粗品,经硅胶柱层析(洗脱剂:乙酸乙酯)纯化,得到标题化合物7b(黄色固体,0.55g,产率:42.0%)。
1H NMR(400MHz,DMSO)δ11.11(s,1H),7.72(d,J=11.5Hz,1H),7.45(d,J=7.4Hz,1H),6.82(s,1H),5.10(dd,J=12.8,5.1Hz,1H),3.24(s,4H),2.99-2.82(m,3H),2.66-2.51(m,6H),2.33(d,J=1.7Hz,2H),2.07-2.00(m,1H),1.61-1.52(m,2H),1.37(s,9H).
LC-MS m/z(ESI)=518.3[M+1]
第二步:
2,2,2-三氟乙醛与5-(4-(3-氨基丙基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异二氢吲哚-1,3-二酮化合物7c
2,2,2-trifluoroacetaldehyde compound with 5-(4-(3-aminopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione 7c
在25℃,氮气保护下,将三氟乙酸(1.2g,10.6mmol)滴加到化合物7b(0.55g,1.06mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应7h;LC-MS检测至反应结束;减压浓缩得到标题化合物7c(黄色固体,0.56g,产率:99.0%)。
LC-MS m/z(ESI)=418.4[M+1]
第三步:
(Z)-N-(3-(4-(2-(2,6-二氧哌啶-3-基)-6-氟-1,3-二氧异吲哚-5-基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物7
(Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound7
在25℃,氮气保护下,将N,N-二异丙基乙胺(206.0mg,1.6mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物7c(186.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(6mL)搅拌10min,抽滤,
滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物7(黄色固体,40.0mg,产率:17.0%)。
1H NMR(400MHz,DMSO)δ11.65(s,1H),11.11(s,1H),10.58(s,1H),7.73(d,J=11.5Hz,1H),7.46(d,J=7.2Hz,1H),7.23(dd,J=9.8,2.6Hz,2H),6.94-6.88(m,1H),6.83(dd,J=8.4,4.8Hz,1H),5.10(dd,J=12.7,5.2Hz,1H),3.57(s,2H),3.26(s,6H),3.15(s,2H),2.94-2.82(m,1H),2.62-2.53(m,9H),2.41(s,2H),2.04-1.97(m,1H),1.71(s,2H).
LC-MS m/z(ESI)=712.3[M+1]
实施例8
第一步:
(3-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌嗪-1-基)丙基)氨基甲酸叔丁酯8b
tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)carbamate 8b
在25℃,氮气保护下,将N-叔丁氧羰基-2-氨基丙醛(0.26g,1.50mmol)缓慢加到化合物3-(1-氧基-5-(哌嗪-1-基)异吲哚-2-基)哌啶-2,6-二酮盐酸盐化合物4a(0.5g,1.37mmol)的二氯乙烷(10mL)和无水甲醇(1mL)溶液中,室温搅拌反应0.5h,加入三乙酰氧基硼氢化钠(0.32g,1.50mmol)和冰醋酸(0.01mL),继续搅拌反应2.5h;TLC检测至反应结束;减压浓缩得到粗品,经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物8b(灰色固体,0.33g,产率:50.0%)。
LC-MS m/z(ESI)=486.3[M+1]
第二步:
2,2,2-三氟乙醛与3-(5-(4-(3-氨基丙基)哌嗪-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮的化合物8c
2,2,2-trifluoroacetaldehyde compound with 3-(5-(4-(3-aminopropyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8c
在25℃,氮气保护下,将三氟乙酸(0.8g,6.8mmol)滴加到化合物8b(0.33g,0.68mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物8c(黄色固体,0.34g,产率:99.0%)。
LC-MS m/z(ESI)=386.4[M+1]
第三步:
(Z)-N-(3-(4-(2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-5-基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物8
(Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide compound 8
在25℃,氮气保护下,将N,N-二异丙基乙胺(206.0mg,1.6mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物8c(175.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(6mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=10/1)纯化,得到标题化合物8(黄色固体,27.0mg,产率:13.0%)。
1H NMR(400MHz,DMSO)δ11.65(s,1H),10.95(s,1H),10.59(s,1H),7.52(d,J=9.1Hz,1H),7.22(dd,J=13.6,3.8Hz,2H),7.07(d,J=7.2Hz,2H),6.96-6.87(m,1H),6.83(dd,J=8.4,4.8Hz,1H),5.05(dd,J=13.2,5.0Hz,1H),4.26(dd,J=48.8,16.9Hz,2H),3.57(d,J=4.4Hz,2H),3.30(d,J=13.0Hz,8H),3.15(s,2H),2.96-2.84(m,1H),2.58(s,8H),2.39(d,J=8.6Hz,1H),2.02-1.90(m,1H),1.72(s,2H).
LC-MS m/z(ESI)=680.3[M+1]。
实施例9
第一步:
5-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸叔丁酯9b
tert-butyl 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 9b
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.40mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.50g,1.81mmol)和2-Boc-八氢吡咯基[3,4-C]吡咯(0.46g,2.17mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至T=90℃搅拌反应6.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=50/1)纯化得标题化合物9b(黄色固体,0.49g,产率:58%)。
LC-MS m/z(ESI)=469.3[M+1]
第二步:
三氟乙酸与2-(2,6-二氧哌啶-3-基)-5-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)异吲哚-1,3-二酮的化合物9c
Trifluoroacetic acid compound with 2-(2,6-dioxopiperidin-3-yl)-5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione 9c
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物9b(0.50g,1.07mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物9c(橙红色固体,0.50g,产率:99.0%)。
LC-MS m/z(ESI)=369.2[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(5-(6-(5-氟-2-氧吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)六氢吡咯[3,4-c]吡咯-2(1H)-基)异吲哚-1,3-二酮化合物9
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(5-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione化合物9
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.6mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物9c(154.0mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化,得到标题化合物化合物9(黄色固体,80.0mg,产率:38%)。
1H NMR(400MHz,DMSO-dc)δ11.67(s,1H),11.07(s,1H),10.57(s,1H),7.66(d,1H),7.18(dd,1H),6.96-6.87(m,2H),6.87-6.78(m,2H),5.05(dd,1H),3.77(dd,2H),3.65(d,2H),3.60-3.49(m,3H),3.10(s,2H),2.99-2.82(m,3H),2.64-2.54(m,2H),2.06-1.92(m,1H),1.45-1.14(m,6H).
LC-MS m/z(ESI)=663.2[M+1]
实施例10
第一步:
1′-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)-[3,3′-联氮杂环丁烷]-1-羧酸叔丁酯10b
tert-butyl 1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[3,3′-biazetidine]-1-carbo
xylate 10b
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.40mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.50g,1.81mmol)和[3,3′-二氮杂环丁烷]-1-羧酸叔丁酯盐酸盐(0.54g,2.17mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至T=90℃搅拌反应6.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=50/1)纯化得标题化合物10b(黄色固体,0.51g,产率:59%)。
LC-MS m/z(ESI)=469.1[M+1]
第二步:
5-([3,3′-双氮杂环丁烷]-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮三氟乙酸盐10c
5-([3,3′-biazetidin]-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物10b(0.51g,1.09mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物10c(黄色固体,0.51g,产率:99.0%)。
LC-MS m/z(ESI)=369.1[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(1′-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)-[3,3′-双氮杂环丁烷]-1-基)异吲哚-1,3-二酮化合物10
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(1′-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-[3,3′-biazetidin]-1-yl)isoindoline-1,3-dione化合物10
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(133.0mg,0.33mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物10c(154.0mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经硅胶柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化,得到标题化合物10(黄色固体,75.0mg,产率:35%)。
1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),11.07(s,1H),10.59(s,1H),7.65(d,1H),7.19(dd,1H),6.91(ddd,1H),6.86-6.77(m,2H),6.66(dd,1H),5.05(dd,1
H),4.16(t,3H),3.75(dd,3H),3.54(d,2H),3.09(d,1H),2.98(s,3H),2.51(s,3H),2.05-1.95(m,1H),1.23(m,5H).
LC-MS m/z(ESI)=663.2[M+1]
实施例11
第一步:
9-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-1-氧-4,9-二氮杂螺[5.5]十一烷-4-羧酸叔丁酯11b
tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate 11b
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.40mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.50g,1.81mmol)和1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-甲酸叔丁酯(0.56g,2.17mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至T=90℃搅拌反应6.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=100/1)纯化得标题化合物11b(黄色固体,0.63g,产率:68%)。
LC-MS m/z(ESI)=513.2[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(1-氧杂-4,9-二氮杂[5.5]十一烷-9-基)异吲哚-1,3-二酮三氟乙酸盐11c
2-(2,6-dioxopiperidin-3-yl)-5-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione
trifluoroacetate 11c
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物11b(0.63g,1.23mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物11c(黄色固体,0.64g,产率:99.0%)。
LC-MS m/z(ESI)=413.2[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(4-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)-1-氧杂-4,9-二氮杂[5.5]十一烷-9-基)异吲哚-1,3-二酮化合物11
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione化合物11
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(124.0mg,0.96mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物11c(169.0mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,通过乙醇(10mL)打浆得到标题化合物11(黄色固体,190.0mg,产率:84%)。
1H NMR(400MHz,DMSO-c6)δ11.64(s,1H),11.06(s,1H),10.56(s,1H),7.63(d,1H),7.31(s,1H),7.20(t,2H),6.86(dt,2H),5.10-4.98(m,1H),3.80-3.51(m,11H),2.88(d,4H),2.43(m,4H),2.07-1.40(m,6H).
LC-MS m/z(ESI)=707.2[M+1]
实施例12
第一步:
9-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-1-氧-4,9-二氮杂螺[5.5]十一烷-4-羧酸叔丁酯12b
tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate 12b
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.70g,5.40mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.50g,1.81mmol)和1-氧杂-4,9-二氮杂螺[5.5]十一烷-4-甲酸叔丁酯(0.56g,2.17mmol)的N,N-二甲基甲酰胺(20mL)溶液中,滴毕升温至T=90℃搅拌反应6.0h;TLC检测至反应结束;滴加水(40mL)搅拌10min,用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=100/1)纯化得标题化合物12b(黄色固体,0.63g,产率:68%)。
LC-MS m/z(ESI)=513.2[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(1-氧杂-4,9-二氮杂[5.5]十一烷-9-基)异吲哚-1,3-二酮三氟乙酸盐12c
2-(2,6-dioxopiperidin-3-yl)-5-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione trifluoroacetate 12c
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物12b(0.63g,1.23mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物12c(黄色固体,0.64g,产率:99.0%)。
LC-MS m/z(ESI)=413.2[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(4-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)-1-氧杂-4,9-二氮杂[5.5]十一烷-9-基)异吲哚-1,3-二酮化合物12
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)isoindoline-1,3-dione化合物12
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(124.0mg,0.96mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟
-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物12c(169.0mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,通过乙醇(10mL)打浆得到标题化合物12(黄色固体,190.0mg,产率:84%)。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.06(s,1H),10.56(s,1H),7.63(d,1H),7.31(s,1H),7.20(t,2H),6.86(dt,2H),5.10-4.98(m,1H),3.80-3.51(m,11H),2.88(d,4H),2.43(m,4H),2.07-1.40(m,6H).
LC-MS m/z(ESI)=707.2[M+1]
实施例13
第一步:
4-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)丙-2-炔-1-基)哌嗪-1-羧酸叔丁酯13b
tert-butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)piperazine-1-carboxylate 13b
在T=25℃,氮气保护下,将5-溴-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮13a(0.50g,1.48mmol)、4-(丙-2-炔-1-基)哌嗪-1-羧酸叔丁酯(0.33g,1.48mmol)、碘化亚铜(56mg,0.30mmol)、双三苯基磷二氯化钯(104mg,0.15mmol)和三乙胺(0.45g,4.45mmol)加入到圆底烧瓶中,随后加入N,N-二甲基甲酰胺(5mL)并置换氮气。在氮气保护下将反应升温至T=80℃搅拌反应8.0h;LC-MS检测反应结束;滴加氯化铵水溶液(10mL)淬灭反应。用乙酸乙酯(20mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物13b(黄色固体,0.47g,产率:66%)。
LC-MS m/z(ESI)=481.2[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(3-(哌嗪-1-基)丙-1-炔-1-)异吲哚-1,3-二酮三氟乙酸盐13c
2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione trifluoroacetate 13c
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物13b(0.47g,0.98mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物13c(黄色固体,0.48g,产率:99.0%)。
LC-MS m/z(ESI)=381.2[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(3-(4-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)哌嗪-1-基)丙-1-炔-1-基]异吲哚-1,3-二酮化合物13
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)prop-1-yn-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(133.0mg,0.35mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物13c(158.0mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经乙醇(10mL)两次后得到标题化合物13(黄色固体,110.0mg,产率:51%)。
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),11.14(s,1H),10.57(s,1H),7.92(s,3H),7.20(d,J=9.8Hz,1H),6.92-6.77(m,2H),5.17(dd,1H),3.61(d,8H),2.91(d,3H),2.58(s,5H),2.41(d,4H),2.14-2.00(m,1H).
LC-MS m/z(ESI)=675.3[M+1]
实施例14
第一步:
4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)乙炔基)哌嗪-1-甲酸叔丁酯14b
tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ethynyl)piperazine-1-carboxylate 14b
在T=25℃,氮气保护下,将5-溴-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮13a(0.50g,1.48mmol)、4-乙炔基哌嗪-1-羧酸叔丁酯(0.31g,1.48mmol)、碘化亚铜(56mg,0.30mmol)、双三苯基磷二氯化钯(104mg,0.15mmol)和三乙胺(0.45g,4.45mmol)加入到圆底烧瓶中,随后加入N,N-二甲基甲酰胺(5mL)并置换氮气。在氮气保护下将反应升温至T=80℃搅拌反应8.0h;LC-MS检测反应结束;滴加氯化铵水溶液(10mL)淬灭反应。用乙酸乙酯(20mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=50/1)纯化得标题化合物14b(黄色固体,0.33g,产率:48%)。
LC-MS m/z(ESI)=466.3[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(哌嗪-1-基亚乙基)异吲哚-1,3-二酮三氟乙酸盐14c
2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-ylethynyl)isoindoline-1,3-dione trifluoroacetate
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物14b(0.33g,0.71mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物14c(黄色固体,0.34g,产率:99.0%)。
LC-MS m/z(ESI)=366.2[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-((1-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,
6-四氢环戊[b]吡咯-3-羰基)哌啶-4-基)乙炔基)异吲哚-1,3-二酮化合物14
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-((1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)ethynyl)isoindoline-1,3-dione化合物14
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(154.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物14c(154.0mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆两次后得到标题化合物14(黄色固体,110.0mg,产率:52%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),11.14(s,1H),10.57(s,1H),7.91(d,3H),7.20(d,1H),6.96-6.79(m,2H),5.16(dd,1H),3.85(s,2H),3.56(s,2H),3.40(d,2H),3.11-2.80(m,5H),2.60(d,1H),2.43(s,3H),2.00(d,3H),1.65(d,2H).
LC-MS m/z(ESI)=660.2[M+1]
实施例15
第一步:
(Z)-3-(3-氨基-2-甲基-4,5-二氢环戊[b]吡咯-6(1H)-亚基)-5-氟吲哚-2-酮15b
(Z)-3-(3-amino-2-methyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-ylidene)-5-fluoroindolin-2-one 15b
在T=25℃,氮气保护下将(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(500.0mg,1.60mmol)溶于四氢呋喃(20mL)中,依次加入三乙胺(325mg,3.20mmol)和叠氮磷酸二苯酯(530mg,1.90mmol)。搅拌反应16.0h;TLC检测至反应结束;加水(40mL)淬灭反应,抽滤,滤饼烘干得到叠氮中间体。叠氮中间体溶于盐酸、1,4-二氧六环溶液中(4M,10mL),加入少量水(2mL),随后加热至T=100℃下反应。LC-MS检测反应完全,减压浓缩得到标题化合物15b(黄色固体,0.29g,产率:59%)。
LC-MS m/z(ESI)=284.1[M+1]
第二步:
5-(4-(2-(1,3-二氧杂环戊-2-基)乙基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮15c
5-(4-(2-(1,3-dioxolan-2-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 15c
在T=25℃,氮气保护下,将2-(2,6-二氧哌啶-3-基)-5-(哌嗪-1-基)异吲哚-1,3-二酮15a(100mg,0.26mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中,依次加入碳酸钾(55mg,0.39mmol)和2-(2-溴乙基)-1,3-二恶烷(57mg,0.32mmol)。将反应加热至T=60℃反应。LC-MS检测反应完全,用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物15c(黄色固体,51mg,产率:50%)。
LC-MS m/z(ESI)=443.3[M+1]
第三步:
3-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)哌嗪-1-基)丙醛15d
3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanal 15d
在T=25℃,将化合物15c(51mg,0.12mmol)的溶于丙酮和盐酸的混合溶液(9∶1,5mL)中,搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物15d(黄色固体,45mg,产率:99.0%)。
LC-MS m/z(ESI)=399.2[M+1]
第四步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(4-(3-((6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-基]氨基)丙基)哌嗪-1-基)异吲哚-1,3-二酮化合物15
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-((6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-3-yl)amino)propyl)piperazin-1-yl)isoindoline-1,3-dion在T=25℃,氮气保护下,将化合物15b(32mg,0.11mmol)和化合物15d溶于二氯甲烷(45mg,0.11mmol)中,搅拌反应10分钟。随后加入三乙酰氧基硼氢化钠(120mg,0.56mmol)和冰醋酸(0.1mL)。搅拌反应8h。LC-MS检测反应完全,用饱和碳酸氢钠溶液淬灭反应。用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过制备HPLC纯化得标题化合物15。
LC-MS m/z(ESI)=666.3[M+1]
实施例16
第一步:
(2-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)乙基)氨基甲酸叔丁酯16b
tert-butyl(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)carbamate 16b
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和4-(2-BOC-氨乙基)哌啶(0.30g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物16b(黄色固体,0.28g,产率:44%)。
LC-MS m/z(ESI)=485.2[M+1]
第二步:
5-(4-(2-氨基乙基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮盐酸盐16c
5-(4-(2-aminoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione chloricacid 16c
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物16b(0.28g,0.58mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物16c(黄色固体,0.25g,产率:99.0%)。
LC-MS m/z(ESI)=385.2[M+1]
第三步:
(Z)-N-(2-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌啶-4-基)乙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物16
(Z)-N-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物16c(148.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物16(黄色固体,160.0mg,产率:74%)。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.07(s,1H),10.57(s,1H),7.65(s,1H),7.31(d,J=2.3Hz,1H),7.22(td,J=9.9,9.3,3.0Hz,3H),6.90(td,J=9.6,9.1,2.5Hz,1H),6.82(dd,J=8.5,4.8Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.35(t,J=5.1Hz,1H),4.06(d,J=12.9Hz,2H),3.61-3.52(m,2H),3.44(qd,J=7.0,5.0Hz,1H),3.28(q,J=6.7Hz,2H),3.17-3.09(m,2H),3.00-2.86(m,3H),2.57(s,5H),2.06-1.94(m,1H),1.81(d,J=12.7Hz,2H),1.62(d,J=11.1Hz,1H),1.29-1.14(m,2H).
LC-MS m/z(ESI)=679.2[M+1]
实施例17
第一步:
4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌嗪-1-羧酸叔丁酯17a
tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和N-Boc-哌嗪(0.24g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物17a(黄色固体,0.3g,产率:52%)。
LC-MS m/z(ESI)=443.20[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(哌嗪-1-基)异吲哚-1,3-二酮15a
2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione 15a
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物17a(0.3g,0.67mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物15a(黄色固体,0.23g,产率:99.0%)。
LC-MS m/z(ESI)=343.20[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(4-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)哌嗪-1-基)异吲哚-1,3-二酮化合物17
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)isoindoline-1,3-dione化合物17
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物15a(120.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物17(黄色固体,70.0mg,产率:34%)。
1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),11.09(s,1H),10.59(s,1H),7.71(d,1H),7.38(d,1H),7.28(dd,1H),7.21(dd,1H),6.97-6.88(m,1H),6.84(dd,1H),5.08(dd,1H),3.69-6.66(m,4H),3.58-3.56(m,2H),3.54-3.51(m,4H),2.96-2.94(s,2H),2.92-2.82(m,1H),2.61-2.59(m,1H),2.59-2.52(m,1H),2.45(s,3H),2.05-1.97(m,1H).
LC-MS m/z(ESI)=637.20[M+1]
实施例18
第一步:
3-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌嗪-1-基)氮杂环丁烷-1-羧酸叔丁酯18a
tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carboxylate
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和3-(哌嗪-1-基)氮杂环丁烷-1-羧酸叔丁酯(0.31g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液
中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物18a(黄色固体,0.4g,产率:62%)。
LC-MS m/z(ESI)=498.20[M+1]
第二步:
5-(4-(氮杂环丁烷-3-基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基]异吲哚-1,3-二酮18b
5-(4-(azetidin-3-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 18b
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物18a(0.4g,0.8mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物18b(黄色固体,0.31g,产率:98.0%)。
LC-MS m/z(ESI)=398.20[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(4-(1-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)氮杂环丁烷-3-基]哌嗪-1-基)异吲哚-1,3-二酮化合物18
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)piperazin-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物18b(127.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物18(黄色固体,40.0mg,产率:18%)。
1H NMR(400MHz,DMSO-d6)δ11.76(s,1H),11.09(s,1H),10.59(s,1H),7.67(d,1H),7.35(d,1H),7.26(dd,1H),7.20(dd,1H),6.91(td,1H),6.84(p,1H),5.07(dd,1H),4.13(d,2H),3.96(d,2H),3.62-3.52(m,2H),3.48-3.45(M,4H),3.24-3.17(m,1H),3.02(d,2H),2.95-2.80(m,1H),2.65-2.53(m,2H),2.52-2.51(m,4H),2.47(s,3H),2.06-1.94(m,1H).
LC-MS m/z(ESI)=692.30[M+1]
实施例19
第一步:
4-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)氮杂环丁烷-3-基哌嗪-1-羧酸叔丁酯19a
tert-butyl 4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carboxylate 19a
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和4-(氮杂环丁烷-3-基)哌嗪-1-羧酸叔丁酯(0.31g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物19a(黄色固体,0.36g,产率:55%)。
LC-MS m/z(ESI)=498.20[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(3-(哌嗪-1-基)氮杂环丁烷-1-)异吲哚-1,3-二酮19b
2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione 19b
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物19a(0.36g,0.72mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物19b(黄色固体,0.28g,产率:99.0%)。
LC-MS m/z(ESI)=398.20[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(3-(4-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)哌嗪-1-基)氮杂环丁-1-基]异吲哚-1,3-二酮化合物19
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物19b(127.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物19(黄色固体,45.0mg,产率:20%)。
1H NMR(400MHz,Chloroform-d)δ10.39(s,1H),8.68-8.56(m,1H),7.76-7.63(m,2H),7.51-7.45(m,1H),7.43-7.37(m,1H),7.25-7.18(m,2H),6.68-6.58(m,2H),5.04-4.87(m,1H),4.81(q,1H),3.87-3.57(m,9H),3.43(dt,1H),3.18(ddd,1H),2.84(q,1H),2.08(s,3H),1.68-1.62(m,4H),1.46-1.43(m,1H).
LC-MS m/z(ESI)=692.30[M+1]
实施例20
第一步:
2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯20a
tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate 20a
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯(0.30g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物20a(黄色固体,0.45g,产率:71%)。
LC-MS m/z(ESI)=483.20[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(2,7-二氮杂螺[3.5]壬-2-基)异吲哚-1,3-二酮20b
2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione 20b
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物20a(0.45g,0.93mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物20b(黄色固体,0.35g,产率:97.0%)。
LC-MS m/z(ESI)=383.20[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(7-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)-2,7-二氮杂螺[3.5-]壬-2-基)异吲哚-1,3-二酮化合物20
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(7-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物20b(127.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物20(黄色固体,70.0mg,产率:32%)。
1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),11.07(s,1H),10.57(s,1H),7.65(d,1H),7.21(dd,1H),6.91(ddd,1H),6.83(dd,1H),6.78(d,1H),6.66(dd,1H),5.05(dd,1H),3.84-
3.82(m,4H),3.64-3.41(m,6H),2.98-2.81(m,3H),2.63-2.53(m,2H),2.42(s,3H),2.06-1.95(m,1H),1.80-1.77(m,4H).
LC-MS m/z(ESI)=676.20[M+1]
实施例21
第一步:
9-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯21a
tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 21a
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.33g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物21a(黄色固体,0.42g,产率:64%)。
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.65(d,1H),7.31(d,1H),7.22(dd,1H),5.06(dd,1H),3.53-3.41(m,4H),3.32-3.30(M,4H),2.94-2.82(m,2H),2.58-2.53(m,1H),2.06-1.94(m,1H),1.55-1.52(M,4H),1.42-1.40(m,4H),1.39(s,9H).
LC-MS m/z(ESI)=510.20[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(3,9-二氮杂螺[5.5]十一烷-3-基]异吲哚-1,3-二酮21b
2-(2,6-dioxopiperidin-3-yl)-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione 21b
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物21a(0.42g,0.82mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物21b(黄色固体,0.33g,产率:99.0%)。
LC-MS m/z(ESI)=410.20[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(9-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)-3,9-二氮杂螺[5.5]十一烷-3-基]异吲哚-1,3-二酮化合物21
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(9-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-3,9-diazaspiro[5.5]undecan-3-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物21b(143.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物21(黄色固体,100.0mg,产率:44%)。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.08(s,1H),10.56(s,1H),7.64(d,1H),7.30(d,1H),7.25-7.15(m,2H),6.90(ddd,1H),6.83(dd,1H),5.07(dd,1H),3.65-3.42(m,10H),2.97-2.82(m,3H),2.65-2.53(m,2H),2.42(s,3H),2.10-1.94(m,1H),1.70-1.54(m,4H),1.55-1.40(m,4H).
LC-MS m/z(ESI)=705.30[M+1]
实施例22
第一步:
4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-1-氧杂-4,9-二氮杂[5.5]十一烷-9-羧酸叔丁酯22a
tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate 22a
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和1-氧杂-4,9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯(0.34g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物22a(黄色固体,0.43g,产率:62%)。
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.65(d,1H),7.31(d,1H),7.22(dd,1H),5.06(dd,1H),3.53-3.40(m,4H),3.31-3.29(m,3H),2.90-2.83(m,2H),2.62-2.50(m,4H),2.06-1.96(m,1H),1.54-1.51(m,4H),1.43-1.40(m,4H),1.39(s,9H).
LC-MS m/z(ESI)=529.30[M+1]
第二步:
2-(2,6-二氧哌啶-3-基)-5-(1-氧杂-4,9-二氮杂[5.5]十一烷-4-基)异吲哚-1,3-二酮22b
2-(2,6-dioxopiperidin-3-yl)-5-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物22a(0.43g,0.81mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物22b(黄色固体,0.34g,产率:97.0%)。
LC-MS m/z(ESI)=429.30[M+1]
第三步
(Z)-2-(2,6-二氧哌啶-3-基)-5-(9-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)-1-氧杂-4,9-二氮杂[5.5]十一烷-4-基)异吲哚-1,3-二酮化合物22
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(9-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)isoindoline-1,3-dione化合物22
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物22b(138.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物22(黄色固体,66.0mg,产率:30%)。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.08(s,1H),10.56(s,1H),7.67(d,1H),7.41(d,1H),7.28(dd,1H),7.20(dd,1H),6.97-6.87(m,1H),6.83(dd,1H),5.07(dd,1H),3.82-3.80(m,2H),3.63-3.51(m,2H),3.47-3.44(m,4H),3.26-3.22(m,2H),2.97-2.83(m,3H),2.64-2.51(m,4H),2.43(s,3H),2.08-1.95(m,1H),1.85-1.82(m,2H),1.67-1.54(m,2H).
LC-MS m/z(ESI)=707.30[M+1]
实施例23
第一步:
2-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-5-基)-2,8-二氮杂螺[4.5]癸烷-8-羧酸叔丁酯23a
tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate 23a
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和2,8-二氮杂螺[4.5]癸烷-8-羧酸叔丁酯(0.31g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物23a(黄色固体,0.35g,产率:54%)。
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.64(d,1H),6.94(d,1H),6.81(dd,1H),5.05(dd,1H),3.52-3.39(m,4H),3.33(s,2H),3.31-3.23(m,2H),2.94-2.82(m,1H),2.61-2.53(m,2H),2.06-1.96(m,1H),1.91(t,2H),1.56-1.45(m,4H),1.40(s,9H).
LC-MS m/z(ESI)=497.20[M+1]
第二步
2-(2,6-二氧哌啶-3-基)-5-(2,8-二氮杂螺[4.5]癸-2-基)异吲哚-1,3-二酮23b
2-(2,6-dioxopiperidin-3-yl)-5-(2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione 23b
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物23a(0.35g,0.70mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物23b(黄色固体,0.27g,产率:97.0%)。
LC-MS m/z(ESI)=397.20[M+1]
第三步
(Z)-2-(2,6-二氧哌啶-3-基)-5-(8-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)-2,8-二氮杂螺[4.5]癸-2-基)异吲哚-1,3-二酮化合物23
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(8-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)isoindoline-1,3-dione化合物23
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2
-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物23b(139.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物23(黄色固体,55.0mg,产率:25%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),11.07(s,1H),10.56(s,1H),7.64(d,1H),7.19(dd,1H),6.95(d,1H),6.94-6.87(m,1H),6.82(dt,2H),5.06(dd,1H),3.69-3.63(m,2H),3.60-3.43(m,6H),3.39(s,2H),2.98-2.82(m,3H),2.65-2.53(m,2H),2.43(s,3H),2.07-1.92(m,3H),1.66-1.47(m,4H).
LC-MS m/z(ESI)=691.20[M+1]
实施例24
第一步:
3-(1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异哌啶-5-基)哌啶-4-基)氮杂环丁烷-1-羧酸叔丁酯24a
tert-butyl 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidine-1-carboxylate 24a
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和3-(哌啶-4-基)氮杂环丁烷-1-羧酸叔丁酯(0.31g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后
的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物24a(黄色固体,0.4g,产率:62%)。
LC-MS m/z(ESI)=497.20[M+1]
第二步:
5-(4-(氮杂环丁烷-3-基)哌啶-1-基)-2-(2,6-二氧哌啶-3-基]异吲哚-1,3-二酮24b
5-(4-(azetidin-3-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 24b
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物24a(0.40g,0.80mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物24b(黄色固体,0.31g,产率:97.2%)。
LC-MS m/z(ESI)=397.20[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(4-(1-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)氮杂环丁烷-3-基]哌啶-1-基)异吲哚-1,3-二酮化合物24
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)piperidin-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物24b(139.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物24(黄色固体,63.0mg,产率:29%)。
1H NMR(400MHz,DMSO-d6)δ11.75(s,1H),11.07(s,1H),10.59(s,1H),7.65(d,1H),7.32(d,1H),7.22(ddd,2H),6.96-6.88(m,1H),6.84(dd,1H),5.06(dd,1H),4.14-4.03(m,4H),3.84-3.80(m,2H),3.57-3.55(m,2H),3.07-2.81(m,5H),2.63-2.53(m,2H),2.49(s,3H),2.42-2.36(m,2H),2.07-1.95(m,1H),1.77-1.73(m,3H),1.27-1.22(m,1H).
LC-MS m/z(ESI)=691.20[M+1]
实施例25
第一步:
3-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)丙-2-炔-1-基)氮杂环丁烷-1-羧酸叔丁酯25a
tert-butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)azetidine-1-carboxylate 25a
在T=25℃,氮气保护下,将5-溴-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮13a(0.50g,1.48mmol)、3-(丙-2-炔-1-基)氮杂环丁烷-1-羧酸叔丁酯(0.29g,1.48mmol)、碘化亚铜(56mg,0.30mmol)、双三苯基磷二氯化钯(104mg,0.15mmol)和三乙胺(0.45g,4.45mmol)加入到圆底烧瓶中,随后加入N,N-二甲基甲酰胺(5mL)并置换氮气。在氮气保护下将反应升温至T=80℃搅拌反应8.0h;LC-MS检测反应结束;滴加氯化铵水溶液(10mL)淬灭反应。用乙酸乙酯(20mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物25a(黄色固体,0.41g,产率:61%)。
LC-MS m/z(ESI)=452.20[M+1]
第二步:
5-(3-(氮杂环丁烷-3-基)丙-1-炔-1-基)-2-(2,6-二氧哌啶-3-基]异吲哚-1,3-二酮25b
5-(3-(azetidin-3-yl)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 25b
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物25a(0.41g,0.91mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物25b(黄色固体,0.31g,产率:97.2%)。
LC-MS m/z(ESI)=352.2[M+1]
第三步:
(Z)-2-(2,6-二氧哌啶-3-基)-5-(3-(1-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)氮杂环丁烷-3-基]丙-1-炔-1-基)异吲哚-1,3-二酮化合物25
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(3-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)prop-1-yn-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(133.0mg,0.35mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物25b(112.7mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经乙醇(10mL)两次后得到标题化合物25(黄色固体,76.0mg,产率:37%)。
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),11.15(s,1H),10.60(s,1H),7.94-7.84(m,3H),7.20(dd,1H),6.90(dd,1H),6.83(dd,1H),5.16(dd,1H),4.29-4.16(m,2H),3.94-3.90(m,2H),3.54(d,2H),2.98(d,2H),2.94-2.92(m,1H),2.90-2.87(m,1H),2.82(d,2H),2.58-2.52(m,2H),2.46(s,3H),2.12-2.00(m,1H).
LC-MS m/z(ESI)=646.20[M+1]
实施例26
第一步:
3-(3-(2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚-5-基)丙-2-炔-1-基)氮杂环丁烷-1-羧酸叔丁酯26b
tert-butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)azetidine-1-carboxylate 26b
在T=25℃,氮气保护下,将3-(5-溴-1-氧代异吲哚-2-基)哌啶-2,6-二酮26a(0.478g,1.48mmol)、3-(丙-2-炔-1-基)氮杂环丁烷-1-羧酸叔丁酯(0.29g,1.48mmol)、碘化亚铜(56mg,0.30mmol)、双三苯基磷二氯化钯(104mg,0.15mmol)和三乙胺(0.45g,4.45mmol)加入到圆底烧瓶中,随后加入N,N-二甲基甲酰胺(5mL)并置换氮气。在氮气
保护下将反应升温至T=80℃搅拌反应8.0h;LC-MS检测反应结束;滴加氯化铵水溶液(10mL)淬灭反应。用乙酸乙酯(20mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物26b(黄色固体,0.38g,产率:58%)。
LC-MS m/z(ESI)=438.20[M+1]
第二步:
3-(5-(3-(氮杂环丁烷-3-基)丙-1-炔-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮26c
3-(5-(3-(azetidin-3-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 26c
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物26b(0.38g,0.87mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物26c(黄色固体,0.31g,产率:97.2%)。
LC-MS m/z(ESI)=338.2[M+1]
第三步:
(Z)-3-(5-(3-(1-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-羰基)氮杂环丁烷-3-基)丙-1-炔-1-基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮化合物26
(Z)-3-(5-(3-(1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)azetidin-3-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(133.0mg,0.35mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸中间体1(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物26c(108.2mg,0.32mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经乙醇(10mL)两次后得到标题化合物26(黄色固体,66.0mg,产率:33%)。
1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),11.01(s,1H),10.60(s,1H),7.70(d,1H),7.62(s,1H),7.51(d,1H),7.24-7.17(m,1H),6.92(t,1H),6.83(dd,1H),5.11(dd,1H),4.37(dd,2H),4.28-4.13(m,2H),3.93-3.88(m,2H),3.56-3.54(m,2H),3.04-2.85(m,4H),2.79(d,2H),2.57-2.54(m,2H),2.45(s,3H),2.02-1.98(m,1H).
LC-MS m/z(ESI)=632.20[M+1]
实施例27
第一步:
(R,Z)-4-(2-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺基)丙基)哌嗪-1-羧酸叔丁酯27a
tert-butyl(R,Z)-4-(2-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamido)propyl)piperazine-1-carboxylate
在T=25℃、氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(133.0mg,0.35mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入(R)-4-(2-氨基-丙基)-哌嗪-1-羧酸叔丁基酯(94mg,0.38mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经乙醇(10mL)两次后得到标题27a(黄色固体,160mg,产率:93%)。
LC-MS m/z(ESI)=538.30[M+1]
第二步:
(R,Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-N-(1-(哌嗪-1-基)丙-2-基)-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺27b
(R,Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-N-(1-(piperazin-1-yl)propan-2-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃、氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物27a(0.16g,0.30mmol)的二氯甲烷(4mL)溶液中,滴毕搅拌反应0.5h;LC-MS检测至反应结束;减压浓缩得到标题化合物27b(黄色固体,0.13g,产率:99%)。
LC-MS m/z(ESI)=438.30[M+1]
第三步:
N-((2R)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)丙-2-基)-6-((Z)-5-氟-2-氧代吲哚啉-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物27
N-((2R)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propan-2-yl)-6-((Z)-5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃、氮气保护下,将N,N-二异丙基乙胺(0.15g,1.16mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.082g,0.29mmol)和化合物27b(0.13g,0.29mmol)的N,N-二甲基甲酰胺(4mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;加入4mL水搅拌10分钟,过滤,干燥。粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物27(黄色固体,20mg,产率:10%)。
LC-MS m/z(ESI)=694.30[M+1]
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.10(s,1H),10.59(s,1H),7.68(d,1H),7.35(d,1H),7.24(ddd,2H),6.97(d,1H),6.95-6.86(m,1H),6.83(dd,1H),5.10-5.04(m,1H),4.16-4.07(m,1H),3.58(s,2H),3.45(s,4H),3.19-3.11(m,2H),2.93-2.82(m,1H),2.61-2.53(m,10H),2.36(dd,1H),2.06-1.97(m,1H),1.19(d,3H).
实施例28
第一步:
(S,Z)-4-(2-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺基)丙基)哌嗪-1-羧酸叔丁酯28a
tert-butyl(S,Z)-4-(2-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamido)propyl)piperazine-1-carboxylate
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(133.0mg,0.35mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入(S)-4-(2-氨基-丙基)-哌嗪-1-羧酸叔丁基酯(94mg,0.38mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经乙醇(10mL)两次后得到标题28a(黄色固体,155mg,产率:91%)。
LC-MS m/z(ESI)=538.30[M+1]
第二步:
(S,Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-N-(1-(哌嗪-1-基)丙-2-基)-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺28b
(S,Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-N-(1-(piperazin-1-yl)propan-2-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃,氮气保护下,将三氟乙酸(0.28g,2.40mmol)滴加到化合物28a(0.155
g,0.29mmol)的二氯甲烷(4mL)溶液中,滴毕搅拌反应0.5h;LC-MS检测至反应结束;减压浓缩得到标题化合物28b(黄色固体,0.12g,产率:95%)。
LC-MS m/z(ESI)=438.30[M+1]
第三步:
N-((2S)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)丙-2-基)-6-((Z)-5-氟-2-氧代吲哚啉-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-甲酰胺化合物28
N-((2S)-1-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propan-2-yl)-6-((Z)-5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.14g,1.1mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.075g,0.27mmol)和化合物28b(0.12g,0.27mmol)的N,N-二甲基甲酰胺(4mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;加入4mL水搅拌10分钟,过滤,干燥。粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物28(黄色固体,30mg,产率:16%)。
LC-MS m/z(ESI)=694.30[M+1]
1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),11.09(s,1H),10.58(s,1H),7.67(d,1H),7.33(d,1H),7.23(ddd,2H),6.95(d,1H),6.94-6.85(m,1H),6.81(dd,1H),5.09-5.02(m,1H),4.15-4.06(m,1H),3.56(s,2H),3.44(s,4H),3.18-3.10(m,2H),2.91-2.80(m,1H),2.60-2.52(m,10H),2.35(dd,1H),2.04-1.95(m,1H),1.17(d,3H).
实施例29
第一步:
4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-羧酸叔丁酯29a
tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和4-(哌嗪-1-基甲基)哌啶-1-甲酸叔丁酯(0.37g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物29a(黄色固体,0.5g,产率:71%)。
LC-MS m/z(ESI)=540.30[M+1]
第二步:
2-(2,6-二氧奥匹啶-3-基)-5-(4-(哌啶-4-基甲基)哌嗪-1-基)异吲哚-1,3-二酮29b
2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物29a(0.5g,0.93mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物29b(黄色固体,0.4g,产率:98.3%)。
LC-MS m/z(ESI)=440.30[M+1]
第三步:
(Z)-2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-羰基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚-1,3-二酮化合物29
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物29b(155.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物29(黄色固体,70.0mg,产率:30%)。
LC-MS m/z(ESI)=734.30[M+1]
1H NMR(4()()MHz,DMSO-d6)δ11.64(s,1H),11.09(s,1H),10.58(s,1H),7.68(d,1H),7.34(d,1H),7.29-7.17(m,2H),6.91(td,1H),6.83(dd,1H),5.07(dd,1H),4.26-4.00(m,2H),3.57(s,2H),3.44(s,4H),2.93-2.83(m,5H),2.62-2.50(m,6H),2.41(s,3H),2.22(d,2H),2.06-1.97(m,1H),1.85-1.76(m,3H),1.08-0.99(m,2H).
实施例30
第一步:
4-((1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-1-羧酸叔丁酯30a
tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine-1-carboxylate
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(0.50g,3.90mmol)滴加到化合物2-(2,6-二氧代-哌啶-3-基)-4-氟基-异吲哚-1,3-二酮1a(0.36g,1.31mmol)和4-(哌啶-4-亚甲基)-哌啶-1-甲酸叔丁酯(0.368g,1.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中,滴毕升温至T=80℃搅拌反应6.0h;TLC检测至反应结束;用二氯甲烷(10mL×3)萃取有机相。有机相合并后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。浓缩后的粗品通过柱层析(洗脱剂:二氯甲烷/甲醇(v/v)=30/1)纯化得标题化合物30a(黄色固体,0.5g,产率:70%)。
LC-MS m/z(ESI)=539.30[M+1]
第二步:
2-(2,6-二氧代哌啶-3-基)-5-(4-(哌啶-4-基甲基)哌啶-1-基)异吲哚-1,3-二酮30b
2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将盐酸/1,4-二氧六环溶液(4M,1.0mL)滴加到化合物30a(0.5g,0.927mmol)的二氯甲烷(10mL)溶液中,滴毕搅拌反应4h;LC-MS检测至反应结束;减压浓缩得到标题化合物30b(黄色固体,0.38g,产率:95%)。
LC-MS m/z(ESI)=439.30[M+1]
第三步:
(Z)-2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊烷[b]吡咯-3-羰基)哌啶-4-基)甲基)哌啶-1-基)异吲哚-1,3-二酮化合物30
(Z)-2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carbonyl)piperidin-4-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione
在T=25℃,氮气保护下,将N,N-二异丙基乙胺(207.0mg,1.60mmol)和2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(122.0mg,0.32mmol)加到(Z)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊酸[b]吡咯-3-羧酸(100.0mg,0.32mmol)的N,N-二甲基甲酰胺(2mL)溶液中,滴毕搅拌反应0.5h;加入化合物30b(1154.0mg,0.35mmol),搅拌反应2h;LC-MS检测至反应结束;滴加水(2mL)搅拌10min,抽滤,滤饼经甲醇(10mL)打浆得到标题化合物30(黄色固体,65.0mg,产率:27%)。
LC-MS m/z(ESI)=733.30[M+1]
1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),11.08(s,1H),10.58(s,1H),7.64(d,1H),7.30(d,1H),7.21(td,2H),6.91(td,1H),6.83(dd,1H),5.06(dd,1H),4.04(d,2H),3.56(s,2H),3.39(s,4H),2.93-2.84(m,4H),2.64-2.51(m,2H),2.40(s,3H),2.07-1.95(m,1H),1.79-1.58(m,6H),1.24-1.08(m,5H),1.07-0.95(m,2H).
实施例31
第一步:
4-(4-羟基苯基)哌嗪-1-羧酸叔丁酯31b
tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate
在T=25℃,氮气保护下,将二碳酸二叔丁酯(7.34g,33.6mmol)和三乙胺(11.3g,112mmol)加到4-(1-哌嗪基)苯酚(5g,28mmol)的二氯甲烷(2mL)溶液中,滴毕搅拌反应2h;LC-MS检测至反应结束;浓缩柱层析得到化合物31b(白色固体,7g,产率:90%)。
LC-MS m/z(ESI)=279.20[M+1]
第二步:
4-(4-((2,6-二氧代哌啶-3-基)氧基)苯基)哌嗪-1-羧酸叔丁酯31c
tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazine-1-carboxylate
在T=25℃,氮气保护下,将31b(7g,25mmol)溶解在四氢呋喃(70mL)中,再加入60%钠氢(1g,25mmol)回流条件下,再加3-溴哌啶-2,6-二酮(7.55g,25mmol)的四氢呋喃溶液,滴毕回流搅拌反应2h;LC-MS检测至反应结束;加入乙酸乙酯(100mL),过滤,浓缩有机相,柱层析得到化合物31c(白色固体,6g,产率:62%)。
LC-MS m/z(ESI)=390.20[M+1]
第三步:
3-(4-(哌嗪-1-基)苯氧基)哌啶-2,6-二酮31d
3-(4-(piperazin-1-yl)phenoxy)piperidine-2,6-dione
在T=25℃,氮气保护下,将化合物31c(3g,7.71mmol)溶解于二氯甲烷(30mL)中,再滴加三氟乙酸(7.5mL)。反应0.5小时,减压浓缩得到化合物31d粗品(黄色液体,2.2g,产率:99%)。
LC-MS m/z(ESI)=290.20[M+1]
第四步:
(3-(4-(4-((2,6-二氧哌啶-3-基)氧基)苯基)哌嗪-1-基)丙基)氨基甲酸叔丁酯31e
tert-butyl(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)propyl)carbamate
在T=25℃,氮气保护下,将31d(2.2g,7.6mmol),N-Boc-3-氨基丙基溴(2.18g,9.1mmol),碳酸钾(3.15g,22.8mmol)溶解在N,N-二甲基甲酰胺(20mL)中,反应过夜。反应完向反应液中加入饱和氯化铵水溶液(50mL),再用乙酸乙酯(80mL*3)萃取,合并有机相用饱和食盐水(50mL*2)洗涤,有机相再用无水硫酸钠(50g)干燥,减压浓缩,硅胶柱层析得到化合物31e(白色固体,3.0g,产率:88%)。
LC-MS m/z(ESI)=447.20[M+1]
第五步:
3-(4-(4-(3-氨基丙基)哌嗪-1-基)苯氧基)哌啶-2,6-二酮31f
3-(4-(4-(3-aminopropyl)piperazin-1-yl)phenoxy)piperidine-2,6-dione
参照化合物31d合成方法,得到化合物31f粗品(黄色液体,2.2g,产率:97%)。
LC-MS m/z(ESI)=347.20[M+1]
第六步:
(Z)-N-(3-(4-(4-((2,6-二氧代哌啶-3-基)氧基)苯基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚啉-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物31
(Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
参照化合物30合成方法,得到化合物31(黄色固体,40mg,产率:22%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.90(s,1H),10.60(s,1H),7.27-7.20(m,2H),6.92-6.87(m,4H),6.83(dd,1H),5.04-4.98(m,1H),3.58(t,2H),3.31(dd,2H),3.27(d,2H),3.14(dt,2H),3.04-3.00(m,2H),2.75-2.60(m,3H),2.58(s,3H),2.52-2.45(m,3H),2.33-2.31(m,1H),2.18-2.05(m,4H),1.74-1.7(m,2H)..
LC-MS m/z(ESI)=641.30[M+1]
实施例32
第一步:
2-(叔丁基)5,6-二乙基异吲哚啉-2,5,6-三羧酸盐32c
2-(tcrt-butyl)5,6-diethyl isoindoline-2,5,6-tricarboxylate
在室温氮气保护下,将N-Boc-二炔丙胺(17g,88mmol)32a,丁炔二酸二乙酯(60g,352mmol)32b,三(三苯基膦)氯化铑(1.63g,1.76mmol)溶解在乙醇(200mL)中回流8小时。反应完减压浓缩,硅胶柱层析得到化合物32c(黄色油状液体,6g,产率:19%)。
LC-MS m/z(ESI)=364.20[M+1]
第二步:
2-(叔丁氧基羰基)异吲哚啉-5,6-二羧酸32d
2-(tert-butoxycarbonyl)isoindoline-5,6-dicarboxylic acid
在室温氮气保护下,将化合物32c(6g,16.5mmol),溶解在甲醇(60mL)和水(60mL)中,再把氢氧化钠(1.98g,49.6mmol)加入反应瓶中,50℃下反应2小时。反应完先减压浓缩除去甲醇,恢复到室温后,用1N稀盐酸缓慢调节PH=3-4,析出大量固体再搅拌30分钟。过滤,干燥,得到化合物32d(黄色固体,3.8g,产率:75%)。
LC-MS m/z(ESI)=308.10[M+1]
第三步:
1,3-二氧代-5,7-二氢-1H-呋喃[3,4-f]异吲哚-6(3H)-羧酸叔丁酯32e
tert-butyl 1,3-dioxo-5,7-dihydro-1H-furo[3,4-f]isoindole-6(3H)-carboxylate
在室温氮气保护下,将醋酸酐(30mL)加入到化合物32d(3.8g,12.34mmol)的反应瓶中,于100℃下反应4小时。反应完加入乙酸乙酯(300mL),再分别用水(50mL),饱和食盐水(50mL)洗涤有机相,将有机相用无水硫酸钠干燥,减压浓缩得到化合物32e粗品(黄色液体,3.5g)。
LC-MS m/z(ESI)=289.10[M+1]
第四步:
6-(2,6-二氧哌啶-3-基)-5,7-二氧代-3,5,6,7-四氢吡咯并[3,4-f]异吲哚-2(1H)-羧酸叔丁酯32f
tert-butyl 6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-carboxylate
在室温氮气保护下,将3-氨基-2,6-哌啶二酮(1.6g,12.46mmol)和三乙胺(3.77g,37.4mmol)加入到化合物32e(3.6g,12.46mmol)的丙酮(40mL)中,100℃下反应3小时。反应完加入饱和氯化铵水溶液(50mL),用乙酸乙酯(50mL*3)萃取,合并有机相再用无水硫酸钠干燥,减压浓缩硅胶柱层析得到化合物32f(黄色固体,1.8g,产率:36%)。
LC-MS m/z(ESI)=400.10[M+1]
第五步:
2-(2,6-二氧哌啶-3-基)-6,7-二氢吡咯并[3,4-f]异吲哚-1,3(2H,5H)-二酮32g
2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione
在室温氮气保护下,缓慢将4N盐酸·二氧六环溶液(9mL)加入到化合物32f(0.9g,2.25mmol)的反应瓶中,室温反应0.5小时。反应完过滤,干燥,得到化合物32g(黄色固体,0.65g,产率:96%)。
LC-MS m/z(ESI)=300.10[M+1]
第六步:
(3-(6-(2,6-二氧代哌啶-3-基)-5,7-二氧代-3,5,6,7-四氢吡咯并[3,4-f]异吲哚-2(1H)-基)丙基)氨基甲酸叔丁酯32h
tert-butyl(3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)propyl)carbamate
在T=25℃,氮气保护下,将32g(0.65g,2.17mmol),N-Boc-3-氨基丙基溴(0.618g,2.6mmol),碳酸钾(0.9g,6.5mmol)溶解在N,N-二甲基甲酰胺(7mL)中,反应过夜。反应完向反应液中加入饱和氯化铵水溶液(10mL),再用乙酸乙酯(10mL*3)萃取,合并有机相用饱和食盐水(5mL*2)洗涤,有机相再用无水硫酸钠(5g)干燥,减压浓缩,硅胶柱层析得到化合物32h(白色固体,0.78g,产率:79%)。
LC-MS m/z(ESI)=457.20[M+1]
第七步:
6-(3-氨基丙基)-2-(2,6-二氧哌啶-3-基)-6,7-二氢吡咯并[3,4-f]异吲哚-1,3(2H,5H)-二酮32i
6-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione
参照化合物32g合成方法,得到化合物32i(黄色固体,600mg,产率:98%)。
LC-MS m/z(ESI)=357.20[M+1]
第八步:
(Z)-N-(3-(6-(2,6-二氧代哌啶-3-基)-5,7-二氧代-3,5,6,7-四氢吡咯并[3,4-f]异吲哚-2(1H)-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊基[b]吡咯-3-甲酰胺化合物32
(Z)-N-(3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
参照化合物30合成方法,得到化合物32(黄色固体,45mg,产率:25%)。
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.13(s,1H),10.58(s,1H),7.33(t,1H),7.30-7.21(m,1H),7.18(dd,1H),7.02-6.86(m,2H),6.82(dd,1H),5.12(dd,1H),3.57-3.55(m,1H),3.53-3.45(m,2H),3.33-3.21(m,4H),3.20-3.17(m,1H),3.09-3.07(m,2H),2.94-2.84(m,1H),2.82-2.74(m,2H),2.60-2.55(m,5H),2.05-1.97(m,1H),1.82-1.71(m,2H).
LC-MS m/z(ESI)=651.20[M+1]
实施例33
第一步:
(3-(4-(2-氟-4-硝基苯基)哌嗪-1-基)丙基)氨基甲酸叔丁酯33b
tert-butyl(3-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)propyl)carbamate
将化合物33a(3.0g,13.3mmol),N-Boc-3-氨基丙基溴(4.7g,19.8mmol),碘化钾(2.2g,13.2mmol),碳酸钾(5.5g,39.8mmol)溶于乙腈(30mL)中,反应瓶置换氮气后置于60℃反应,反应3小时后减压浓缩反应液,得到化合物33b(黄色固体,4.0g)。
LCMS m/s=383.55[M+1].
第二步:
(3-(4-(4-氨基-2-氟苯基)哌嗪-1-基)丙基)氨基甲酸叔丁酯33c
tert-butyl(3-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)propyl)carbamate
将化合物33b(4.0g,10.4mmol),锌粉(3.4g,51.9mmol),氯化铵(5.5g,102.8mmol)溶于甲醇∶水=3∶1(40mL)中,反应瓶置换氮气后置于60℃反应,反应2小时后冷却到室温,抽滤,得到化合物33c(黄色固体,3.25g)。
LCMS m/s=353.55[M+1].
第三步:
(3-(4-(4-((2,6-二氧哌啶-3-基)氨基)-2-氟苯基)哌嗪-1-基)丙基)氨基甲酸叔丁酯33d
tert-butyl(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propyl)carbamate
将化合物33c(1.0g,2.8mmol),3-溴哌啶-2,6-二酮(0.8g,4.1mmol),碳酸氢钠(1.4g,16.6mmmol),溶于N,N-二甲基甲酰胺(15mL)中,反应瓶置换氮气后置于85℃反应,反应8小时后冷却到室温,加水(40mL)稀释,加入乙酸乙酯(3×30mL)萃取,萃取完成
后有机相用饱和食盐水洗涤(3×30mL),合并有机相并减压浓缩,粗品经柱层析纯化(二氯甲烷∶甲醇=25∶1),得到化合物33d(黄色固体,200mg)。
LCMS m/s=464.26[M+1].
第四步:
3-((4-(4-(3-氨基丙基)哌嗪-1-基)-3-氟苯基)氨基)哌啶-2,6-二酮33e
3-((4-(4-(3-aminopropyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione
按照化合物3c合成方法,得到化合物33e(黄色固体,156mg)。
LCMS m/s=364.56[M+1].
第五步:
(Z)-N-(3-(4-(4-(((2,6-二氧代哌啶-3-基)氨基)-2-氟苯基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊二烯[b]吡咯-3-甲酰胺化合物33
(Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
按照化合物3合成方法,得到化合物33(黄色固体,80mg,产率46%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.90(s,1H),10.60(s,1H),7.27-7.20(m,2H),6.92-6.87(m,3H),6.83(dd,1H),5.01-4.98(m,1H),3.57(t,2H),3.31(dd,2H),3.27(d,2H),3.15(dt,2H),3.03-3.00(m,2H),2.75-2.60(m,3H),2.55(s,3H),2.52-2.45(m,3H),2.34-2.31(m,1H),2.18-2.05(m,4H),1.74-1.72(m,2H).
LCMS m/s=658.26[M+1]
实施例34
第一步:
4-(4-(2,6-双(苄氧基)吡啶-3-基)苯基)哌嗪-1-羧酸叔丁酯34c
tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate
在室温氮气保护下,将化合物34a(2g,4.8mmol),化合物34b(1.6g,4.8mmo l),四三苯基膦钯(555mg,0.48mmol),碳酸钠(1.02g,9.6mmol)溶解在N,N-二甲基甲酰胺∶水=1∶6(20mL)中,100℃下加热4小时。反应完加入水(20mL),用乙酸乙酯(20mL*3),合并有机相用饱和食盐水(10mL*2)洗涤,干燥,减压浓缩柱层析硅胶得到化合物34c(白色固体,2.2g,产率:85%)。
LC-MS m/z(ESI)=552.30[M+1]
第二步:
4-(4-(2,6-二氧哌啶-3-基)苯基)哌嗪-1-羧酸叔丁酯34d
tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate
在室温氢气保护下,将钯/碳(440mg)加入到化合物34c(2.2g,4mmol)的乙醇(20mL)中,室温反应过夜。反应完过滤浓缩,得到化合物34d(黄色固体,880mg,产率:60%)。
LC-MS m/z(ESI)=374.20[M+1]
第三步:
3-(4-(哌嗪-1-基)苯基)哌啶-2,6-二酮34e
3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione
参照化合物32g合成方法,得到化合物34e(黄色固体,600mg,产率:93%)。
LC-MS m/z(ESI)=274.20[M+1]
第四步:
(3-(4-(4-(2,6-二氧哌啶-3-基)苯基)哌嗪-1-基)丙基)氨基甲酸叔丁酯34f
tert-butyl(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl)carbamate
参照化合物32h合成方法,得到化合物34f(白色固体,800mg,产率:85%)。
LC-MS m/z(ESI)=431.20[M+1]
第五步:
3-(4-(4-(3-氨基丙基)哌嗪-1-基)苯基)哌啶-2,6-二酮34g
3-(4-(4-(3-aminopropyl)piperazin-1-yl)phenyl)piperidine-2,6-dione
参照化合物32g合成方法,得到化合物34g(黄色固体,600mg,产率:97%)。
LC-MS m/z(ESI)=331.20[M+1]
第六步:
(Z)-N-(3-(4-(4-(2,6-二氧代哌啶-3-基)苯基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊二烯[b]吡咯-3-甲酰胺化合物34
(Z)-N-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
参照化合物30合成方法,得到化合物34(黄色固体,20mg,产率:15%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.78(s,1H),10.59(s,1H),7.26-7.20(m,2H),7.04(d,2H),6.92-6.88(m,3H),6.83(dd,1H),3.71(dd,1H),3.57(d,2H),3.32-3.22(m,4H),3.15-3.10(m,6H),2.67-2.60(m,2H),2.58(s,3H),2.44-2.36(m,4H),2.11(dd,1H),1.98(dd,1H),1.71(d,2H).
LC-MS m/z(ESI)=625.30[M+1]
实施例35
第一步:
2-(2,6-二氧哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮35b
2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione
参照化合物32g合成方法,得到化合物35b(黄色固体,3.8g,产率:98%)。
LC-MS m/z(ESI)=343.10[M+1]
第二步:
叔丁基(4-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)丁-2-基)氨基甲酸酯35c
tert-butyl(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butan-2-yl)carbamate
化合物35b(300mg,0.87mmol),(3-溴-1-甲基丙基)氨基甲酸叔丁酯(264mg,1.05mmol)。参照化合物32h合成方法,得到化合物35c(黄色固体,160mg,产率:36%)。
LC-MS m/z(ESI)=514.20[M+1]
第三步:
5-(4-(3-氨基丁基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮35d
5-(4-(3-aminobutyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
参照化合物32g合成方法,得到化合物35d(黄色固体,3.8g,产率:98%)。
LC-MS m/z(ESI)=343.10[M+1]
第四步:
(Z)-N-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)丁-2-基)-6-(5-氟-2-氧代吲哚啉-3-亚基)-2-甲基-1,4,5,6-四氢环戊二烯[b]吡咯-3-甲酰胺化合物35
(Z)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butan-2-yl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
中间体1(100mg,0.32mmol)。参照化合物30合成方法,得到化合物35(黄色固体,60mg,产率:26%)。
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),11.05(s,1H),10.55(s,1H),7.63(d,J=8.7Hz,1H),7.30(d,J=2.5Hz,1H),7.19(ddd,J=19.2,9.2,2.5Hz,2H),7.00(d,J=8.5Hz,1H),6.91-6.83(m,1H),6.79(dd,J=8.4,4.8Hz,1H),5.03(dd,J=12.9,5.4Hz,1H),3.98(p,J=7.4Hz,1H),3.52(s,2H),3.40(d,J=5.4Hz,4H),3.23-2.99(m,2H),2.94-2.75(m,1H),2.54(s,10H),2.37(t,J=6.9Hz,1H),2.03-1.92(m,1H),1.67(ddt,J=28.2,13.3,6.9Hz,2H),1.24-1.07(m,3H).
LC-MS m/z(ESI)=708.30[M+1]
实施例36
第一步:
(1-(2-氧乙基)环丙基)氨基甲酸叔丁酯36b
tert-butyl(1-(2-oxoethyl)cyclopropyl)carbamate
在室温氮气保护下,将化合物36a(1g,5mmol),2,2,6,6-四甲基哌啶氧化物(23mg,0.15mmol),溴化钾(59mg,0.5mmol)溶解在二氯甲烷(10mL)和水(30mL)中,在-10℃~0℃下缓慢加入配置好的碳酸氢钠(2.6g,31mmol)和次氯酸钠(50mL)的混合溶液,滴加完反应30分钟。反应完加入饱和亚硫酸钠水溶液(20mL),用二氯甲烷(50mL*3)萃取,合并有机相干燥,减压浓缩得到化合物36b粗品(白色固体,800mg,产率:81%)。
LC-MS m/z(ESI)=200.10[M+1]
第二步:
(1-(2-(4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)哌嗪-1-基)乙基)环丙基)氨基甲酸叔丁酯36c
tert-butyl(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)cyclopropyl)carbamate
在室温氮气保护下,将化合物36b(100mg,0.5mmol),化合物35b(160mg,0.46mmol),醋酸钠(136mg,1mmol)溶于二氯甲烷∶甲醇=1∶10(1mL)搅拌30分钟,再加入三乙酰氧基硼氢化钠(212mg,1mmol),室温过夜。反应完加入饱和氯化铵水溶液(10mL),用乙酸乙酯(10mL*3)萃取,合并有机相减压浓缩,硅胶柱层析得到化合物36c(黄色固体,100mg,产率:41%)。
LC-MS m/z(ESI)=526.20[M+1]
第三步:
5-(4-(2-(1-氨基环丙基)乙基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮化合物36d
5-(4-(2-(1-aminocyclopropyl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
参照化合物32g合成方法,得到化合物36d(黄色固体,80mg,产率:98%)。
LC-MS m/z(ESI)=426.20[M+1]
第四步:
(Z)-N-(1-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)乙基)环丙基)-6-(5-氟-2-氧代吲哚啉-3-亚基)-2-甲基-1,4,5,6-四氢环戊二烯[b]吡咯-3-甲酰胺化合物36
(Z)-N-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)cyclopropyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
中间体1(50mg,0.16mmol)。参照化合物30合成方法,得到化合物36(黄色固体,20mg,产率:17%)。
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),11.03(s,1H),10.48(s,1H),7.54(d,J=8.5Hz,1H),7.35(d,J=2.4Hz,1H),7.15(dd,J=8.7,2.3Hz,1H),7.07-6.98(m,2H),6.80(td,J=9.4,9.0,2.6Hz,1H),6.72(dd,J=8.5,4.8Hz,1H),5.68(s,1H),4.99(dd,J=12.8,5.4Hz,1H),3.45-3.32(m,6H),3.07-2.98(m,2H),2.85-2.74(m,1H),2.53-2.40(m,10H),2.26(s,2H),1.99-1.88(m,1H),0.68-0.55(m,2H),0.32-0.18(m,2H).
LC-MS m/z(ESI)=720.30[M+1]
实施例37
第一步:
(2-甲基-3-氧代丙基)氨基甲酸叔丁酯37b
tert-butyl(2-methyl-3-oxopropyl)carbamate
在室温氮气保护下,将戴斯-马丁试剂(1.46g,3.44mmol)缓慢加入到化合物37a(500mg,2.65mmol)的二氯甲烷(5mL)溶液中,室温下反应2小时。反应完加入饱和亚硫酸钠水溶液(10mL),用二氯甲烷(10mL*3)萃取,合并有机相,干燥,减压浓缩后得到化合物37b(白色固体,180mg,产率:36%)。
LC-MS m/z(ESI)=188.10[M+1]
第二步:
(3-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)-2-甲基丙基)氨基甲酸叔丁酯37c
tert-butyl(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-methylpropyl)carbamate
参照化合物36c合成方法,得到化合物37c(黄色固体,180mg,产率:38%)。
LC-MS m/z(ESI)=514.20[M+1]
第三步:
5-(4-(3-氨基-2-甲基丙基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮37d
5-(4-(3-amino-2-methylpropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
参照化合物32g合成方法,得到化合物37d(黄色固体,140mg,产率:96%)。
LC-MS m/z(ESI)=141.20[M+1]
第四步:
(Z)-N-(3-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)-2-甲基丙基)-6-(5-氟-2-氧代吲哚啉-3-亚烷基)-2-甲基-1,4,5,6-四氢环戊二烯[b]吡咯-3-甲酰胺化合物37
(Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-methylpropyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
中间体1(100mg,0.16mmol)。参照化合物30合成方法,得到化合物37(黄色固体,30mg,产率:14%)。
1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),11.04(s,1H),10.52(s,1H),7.59(d,J=8.4Hz,1H),7.32-7.07(m,4H),6.90-6.72(m,2H),5.01(dd,J=12.9,5.4Hz,1H),3.55-3.34(m,7H),3.06(dd,J=20.6,5.6Hz,3H),2.89-2.76(m,1H),2.58-2.45(m,9H),2.26(dd,J=12.0,6.8Hz,1H),2.15-2.05(m,1H),1.94(dd,J=8.0,5.2Hz,2H),1.18(d,J=8.0Hz,1H),0.86(d,J=6.5Hz,3H).
LC-MS m/z(ESI)=708.30[M+1]
实施例38
第一步:
(1-甲酰基环丙基)甲基氨基甲酸叔丁酯38b
tert-butyl((1-formylcyclopropyl)methyl)carbamate
化合物38a(500mg,2.48mmol)。参照化合物36b合成方法,得到化合物38b(白色固体,250mg,产率:50%)。
LC-MS m/z(ESI)=200.10[M+1]
第二步:
(1-((4-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-5-基)哌嗪-1-基)甲基)环丙基)甲基)氨基甲酸叔丁酯38c
tert-butyl((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclopropyl)methyl)carbamate
化合物38b(250mg,1.56mmol)。参照化合物36c合成方法,得到化合物38c(黄色固体,480mg,产率:78%)。
LC-MS m/z(ESI)=526.20[M+1]
第三步:
5-(4-((1-(氨基甲基)环丙基)甲基)哌嗪-1-基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮38d
5-(4-((1-(aminomethyl)cyclopropyl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
化合物38c(250mg,0.47mmol)。参照化合物32g合成方法,得到化合物38d(黄色固体,200mg,产率:99%)。
LC-MS m/z(ESI)=426.20[M+1]
第四步:
(Z)-N-((1-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)环丙基)甲基)-6-(5-氟-2-氧代吲哚啉-3-亚基)-2-甲基-1,4,5,6-四氢环戊基[b]吡咯-3-甲酰胺化合物38
(Z)-N-((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclopropyl)methyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
中间体1(100mg,0.16mmol)。参照化合物30合成方法,得到化合物38(黄色固体,42mg,产率:18%)。
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),11.03(s,1H),10.48(s,1H),7.54(d,J=8.5Hz,1H),7.24(d,J=2.4Hz,1H),7.13(dd,J=8.7,2.3Hz,1H),7.07-6.98(m,2H),6.80(td,J=
9.4,9.0,2.6Hz,1H),6.72(dd,J=8.5,4.8Hz,1H),5.68(s,1H),4.99(dd,J=12.8,5.4Hz,1H),3.45-3.32(m,6H),3.07-2.98(m,2H),2.85-2.74(m,1H),2.53-2.40(m,10H),2.26(s,2H),1.99-1.88(m,1H),0.54-0.44(m,2H),0.26-0.15(m,2H).
LC-MS m/z(ESI)=720.30[M+1]
实施例39
第一步:
4-(5-((2,6-二氧代哌啶-3-基)氧基)吡啶-2-基)哌嗪-1-羧酸叔丁酯39b
tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxylate
将化合物39a(2.8g,10mmol)加入到N,N-二甲基甲酰胺(30ml)中,冰浴下加入NaH(645mg,27mmol)搅拌30分钟后加入3-溴哌啶-2,6-二酮(1.73g,9mmol)反应瓶置换氮气后置于冰浴下反应2小时后加入饱和氯化铵(50mL)淬灭,加入乙酸乙酯(3×35mL)萃取,有机相用无水硫酸钠干燥,干燥后的有机相经过减压浓缩得到粗品,粗品经柱层析纯化(二氯甲烷∶甲醇=8∶1),得到39b黄色固体,2.64g。
LCMS m/s=391.34[M+1].
第二步:
3-((6-(哌嗪-1-基)吡啶-3-基)氧基)哌啶-2,6-二酮39c
4-((6-(piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione
将化合物39b(2.35g,6mol)溶于二氯甲烷∶三氟乙酸=4∶1(25mL)中,反应瓶置换氮气后置于25℃反应,反应1.5小时后加入N,N-二异丙基乙胺(20mL)调节PH到8,减压浓缩得到粗品,得到化合物39c黄色固体,2.0g。
LCMS m/s=291.34[M+1].
第三步:
叔丁基(3-(4-(5-((2,6-二氧代哌啶-3-基)氧基)吡啶-2-基)哌嗪-1-基)丙基)氨基甲酸酯39d
tert-butyl(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazin-1-yl)propyl)carbamate
将化合物39c(1.7g,6mol),N-Boc-3-氨基丙基溴(1.2g,5mol),碘化钾(830mg,5mmol),碳酸钾(0.7g,5mmol)溶于N,N-二甲基甲酰胺(15mL)中,反应瓶置换氮气后置于25℃反应,反应3小时后加入水(40mL)稀释,加入乙酸乙酯(3×30mL)萃取,萃取完成后有机相用饱和食盐水洗涤(3×30mL),合并有机相并减压浓缩,粗品经柱层析纯化(二氯甲烷∶甲醇=15∶1),得到化合物39d黄色固体,130mg。
LCMS m/s=448.34[M+1].
第四步:
3-((6-(4-(3-氨基丙基)哌嗪-1-基)吡啶-3-基)氧基)哌啶-2,6-二酮39e
3-((6-(4-(3-aminopropyl)piperazin-1-yl)pyridin-3-yl)oxy)piperidine-2,6-dione
将化合物39d(130mg,0.29mmol),溶于二氯甲烷∶三氟乙酸=4∶1(5mL)中,反应瓶置换氮气后置于25℃反应,反应1.5小时后加入N,N-二异丙基乙胺(5mL)调节PH到约为8,减压浓缩得到粗品,得到化合物39e黄色固体100mg。
LCMS m/s=348.24[M+1].
第五步:
(Z)-N-(3-(4-(5-(((2,6-二氧代哌啶-3-基)氧基)吡啶-2-基)哌嗪-1-基)丙基)-2-甲基-6-(2-氧代吲哚-3-亚基)-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物39
(Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyridin-2-yl)piperazin-1-yl)propyl)-2-methyl-6-(2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
将化合物39e(111mg,0.36mmol),2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(164mg,0.5mmol),N,N-二异丙基乙胺(185mg,1.0mmol)加入到N,N-二甲基甲酰胺(5mL)中,反应瓶置换氮气后置于25℃反应30分钟,30分钟后将中间体1(100mg,0.29mmol)加入到反应液中,反应瓶置换氮气后置于25℃反应,反应3小时后加入水(20mL),过滤得到滤饼,滤饼用乙醇(5mL)洗涤得到化合物39(黄色固体,20mg,产率50%)。
1H NMR(400MHz,DMSO-d6)δ12.00(m,1H),11.08(m,1H),10.00(m,1H),7.88-7.02(m,4H),3.21-2.12(m,17H),2.33(d,J=12.0Hz,3H),2.31(d,J=8.0Hz,1H),2.17(m,4H),2.09
(m,3H),2.06(dd,J=12.0Hz,1H).
LCMS m/s=641.23[M+1].
实施例40
第一步:
4-碘-1H-吡唑-3,5-二甲酸二甲酯40b
dimethyl 4-iodo-1H-pyrazole-3,5-dicarboxylate
将化合物40a 1H-吡唑-3,5-二甲酸二甲酯(10g,54mmol)置于乙腈(200mL)中,加入硝酸铈铵(29g,54mmol),加入碘单质(13.74g,54mmol),加热回流反应48小时,加入硫代硫酸钠饱和溶液200mL淬灭反应,乙酸乙酯(150mL*3)萃取,有机相合并浓缩后得到化合物40b粗产物12g。LC-MS m/z(ESI)=311.2[M+1]
第二步:
4-(3-乙氧基-3-氧代丙基)-1H-吡唑-3,5-二甲酸二甲酯40c
dimethyl 4-(3-ethoxy-3-oxopropyl)-1H-pyrazole-3,5-dicarboxylate
将化合物40b 4-碘-1H-吡唑-3,5-二甲酸二甲酯(12g,38.7mmol)置于N,N-二甲基甲酰胺(120mL)中,加入醋酸钯(870mg,3.87mmol)、二异丙基乙基胺(10g,77.4mmol)、3-丁烯酸乙酯(4.4g,38.7mmol),置换氮气后,120摄氏度下反应12小时,加入饱和氯化铵(200mL)淬灭反应,乙酸乙酯(150mL*3)萃取有机相,合并有机相减压浓缩住分离(石油醚∶乙酸乙酯=2∶1),得到黄色固体化合物40c(8g,收率73%)。
第三步:
5-乙基3-甲基6-氧代-1,4,5,6-四氢环戊[c]吡唑-3,5-二甲酸40d
5-ethyl 3-methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3,5-dicarboxylate
将化合物40c 4-(3-乙氧基-3-氧代丙基)-1H-吡唑-3,5-二甲酸二甲酯(8g,28mmol)置于四氢呋喃(80mL)中,零下-78摄氏度下加入叔丁醇钾(3.2g,28mmol),反应液自然升至室温后继续搅拌1小时,加入饱和氯化铵(50mL)淬灭反应,乙酸乙酯(50mL*3),合并浓缩有机相得到黄色固体化合物40d(5g)。
第四步:
6-氧代-1,4,5,6-四氢环戊[c]吡唑-3-甲酸甲酯40e
methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate
将5-乙基3-甲基6-氧代-1,4,5,6-四氢环戊[c]吡唑-3,5-二甲酸化合物40d(5g,20mmol)置于1M/L的盐酸\1,4-二氧六环溶液(30mL)中,加入水(3mL),反应液90摄氏度下搅拌三小时,加入饱和碳酸氢钠溶液(230mL)淬灭反应,乙酸乙酯(100*3)萃取有机相,合并有机相干燥浓缩得到化合物40e 4g。
第五步:
(Z)-3-(3-乙酰基-4,5-二氢环戊二烯[c]吡唑-6(1H)-亚基)-5-氟二氢吲哚-2-酮化合物40f
(Z)-3-(3-acetyl-4,5-dihydrocyclopenta[c]pyrazol-6(1H)-ylidene)-5-fluoroindolin-2-one
加入化合物40e(4g,22mmol)参照化合物A4合成方法,得到化合物40f(3g)。
第六步
(Z)-6-(5-氟-2-氧代吲哚啉-3-亚基)-1,4,5,6-四氢环戊[c]吡唑-3-甲酸40g
(Z)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid
加入化合物40f(3g,10mmol)参照中间体1合成方法,得到化合物40g(2.5g)。
第七步:
(Z)-N-(3-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚啉-3-亚基)-1,4,5,6-四氢环戊二烯[c]吡唑-3-甲酰胺化合物40
(Z)-N-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide
化合物40g(80mg,0.27mmol)。参照化合物30合成方法,得到化合物40(黄色固体,23mg,产率:13%)。
1H NMR(400MHz,DMSO)δ11.08(s,1H),7.96(d,J=9.3Hz,1H),7.67(d,J=8.5Hz,1H),7.25(dd,J=8.6,2.2Hz,1H),6.69(d,J=5.9Hz,1H),5.07(dd,J=
12.9,5.4Hz,1H),3.42(s,3H),3.06(dd,J=14.9,6.5Hz,2H),2.89(s,3H),2.73(d,J=0.5Hz,3H),2.39-2.29(m,4H),2.00(dd,J=11.1,3.7Hz,1H),1.37(s,6H).
LC-MS m/z(ESI)=681.30[M+1]
实施例41
(Z)-N-(3-(4-((2,6-二氧代哌啶-3-基)氧基)苯基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-1,4,5,6-四氢环戊二烯[c]吡唑-3-甲酰胺化合物41
(Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-vl)oxy)phenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide
化合物40g(80mg,0.27mmol)。参照化合物30合成方法,得到化合物41(黄色固体,20mg,产率:13%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.90(s,1H),10.60(s,1H),7.27-7.20(m,2H),6.92-6.87(m,4H),6.83(dd,1H),5.04-4.98(m,1H),3.58(t,2H),3.31(dd,2H),3.27(d,2H),3.14(dt,2H),3.04-3.00(m,2H),2.75-2.60(m,3H),2.52-2.45(m,3H),2.33-2.31(m,1H),2.18-2.05(m,4H),1.74-1.7(m,2H).
LC-MS m/z(ESI)=628.30[M+1]
实施例42
第一步:
4-(5-((2,6-二氧代哌啶-3-基)氧基)嘧啶-2-基)哌嗪-1-羧酸叔丁酯42b
tert-butyl 4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazine-1-carboxylate
将化合物42a(3g,11mmol)加入到N,N-二甲基甲酰胺(30ml)中,冰浴下加入NaH(0.36g,15mmol)搅拌30分钟,30分钟后加入3-溴哌啶-2,6-二酮(1.71g,9mmol)反应瓶置换氮气后置于冰浴下反应,反应2小时后加入饱和氯化铵(50mL)淬灭,加入乙酸乙酯(3×35mL)萃取,有机相用无水硫酸钠干燥,干燥后的有机相经过减压浓缩得到粗品,粗品经柱层析纯化(二氯甲烷∶甲醇=8∶1),得到42b(黄色固体,2.7g,产率65%)。
LCMS m/s=392.34[M+1].
第二步:
5-3-((2-(哌嗪-1-基)嘧啶-5-基)氧基)哌啶-2,6-二酮42c
3-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)piperidine-2,6-dione
将化合物42b(2.7g,7mol)溶于二氯甲烷∶三氟乙酸=4∶1(25mL)中,反应瓶置换氮气后置于25℃反应,反应1.5小时后加入N,N-二异丙基乙胺(20mL)调节PH到约为8,减压浓缩得到粗品,得到化合物42c黄色固体,1.6g。
LCMS m/s=292.52[M+1].
第三步:
叔丁基(3-(4-(5-((2,6-二氧嘧啶-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙基)氨基甲酸酯42d
tert-butyl(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propyl)carbamate
将化合物42c(1.6g,6mmol),N-Boc-3-氨基丙基溴(1.2g,5mmol),碘化钾(830mg,5mmol),碳酸钾(0.83g,6mmol)溶于N,N-二甲基甲酰胺(15mL)中,反应瓶置换氮气后置于25℃反应,反应3小时后加入水(40mL)稀释,加入乙酸乙酯(3×30mL)萃取,萃取完成后有机相用饱和食盐水洗涤(3×30mL),合并有机相并减压浓缩,粗品经柱层析纯化(二氯甲烷∶甲醇=15∶1),得到化合物42d黄色固体,270mg。
LCMS m/s=449.42[M+1].
第四步:
4-((2-(4-(3-氨基丙基)哌嗪-1-基)嘧啶-5-基)氧基)哌啶-2,6-二酮42e
3-((2-(4-(3-aminopropyl)piperazin-1-yl)pyrimidin-5-yl)oxy)piperidine-2,6-dione
将化合物42d(270mg 0.6mmol),溶于二氯甲烷∶三氟乙酸=4∶1(5mL)中,反应瓶
置换氮气后置于25℃反应,反应1.5小时后加入N,N-二异丙基乙胺(5mL)调节PH到约为8,减压浓缩得到粗品,得到化合物42e(黄色固体,200mg
LCMS m/s=349.38[M+1].
第五步:
(Z)-N-(3-(4-(5-((2,6-二氧代哌啶-3-基)氧基)嘧啶-2-基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊[b]吡咯-3-甲酰胺化合物42
(Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)oxy)pyrimidin-2-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
将化合物42e(187mg,0.6mmol),2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(226mg,0.6mmol),N,N-二异丙基乙胺(78mg,0.6mmol)加入到N,N-二甲基甲酰胺(5mL)中,反应瓶置换氮气后置于25℃反应30分钟,30分钟后将中间体1(200mg,0.6mmol)加入到反应液中,反应瓶置换氮气后置于25℃反应,反应3小时后加入水(20mL),过滤得到滤饼,滤饼用乙醇(5mL)洗涤得到化合物42(黄色固体,192mg,产率50%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.90(s,1H),10.60(s,1H),7.27-7.20(m,2H),6.92-6.87(m,2H),6.83(dd,1H),5.01-4.98(m,1H),3.58(t,2H),3.31(dd,2H),3.25(d,2H),3.14(dt,2H),3.04-3.00(m,2H),2.75-2.60(m,3H),2.55(s,3H),2.52-2.45(m,3H),2.34-2.31(m,1H),2.15-2.03(m,4H),1.74-1.71(m,2H).
LCMS m/s=643.23[M+1].
实施例43
第一步:
(3-(4-(4-(((2,6-二氧代哌啶-3-基)氧基)-2-氟苯基)哌嗪-1-基)丙基)氨基甲
酸叔丁酯43b
(4-tert-butyl(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperazin-1-yl)propyl)carbamate
化合物43a(700mg)。按照化合物42d合成方法,得到化合物43b(棕色固体,609mg,产率47%)。
LCMS m/s=465.42[M+1].
第二步:
4-(4-(4-(3-氨基丙基)哌嗪-1-基)-3-氟苯氧基)哌啶-2,6-二酮43c
5-3-(4-(4-(3-aminopropyl)piperazin-1-yl)-3-fluorophenoxy)piperidine-2,6-dione
按照化合物42e合成方法,得到化合物43c白色固体,400mg。
LCMS m/s=365.42[M+1].
第三步:
(Z)-N-(3-(4-(4-(((2,6-二氧代哌啶-3-基)氧基)-2-氟苯基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊基[b]吡咯-3-甲酰胺化合物43
(Z)-N-(3-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
按照化合物39合成方法,得到化合物43(黄色固体,100mg,产率23%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.90(s,1H),10.60(s,1H),7.27-7.20(m,2H),6.92-6.87(m,3H),6.83(dd,1H),5.01-4.98(m,1H),3.58(t,2H),3.31(dd,2H),3.27(d,2H),3.14(dt,2H),3.04-3.00(m,2H),2.75-2.60(m,3H),2.55(s,3H),2.52-2.45(m,3H),2.34-2.31(m,1H),2.18-2.05(m,4H),1.74-1.72(m,2H).
LCMS m/s=659.47[M+1].
实施例45
第一步:
(3-(4-(5-硝基吡啶-2-基)哌嗪-1-基)丙基)氨基甲酸叔丁酯45b
tert-butyl(3-(4-(5-nitropyridin-2-yl)piperazin-1-yl)propyl)carbamate
化合物45a(300mg)。按照化合物44b合成方法,得到化合物45b(黄色固体,350mg,产率73%)。
LCMS m/s=366.40[M+1].
第二步:
(3-(4-(5-氨基吡啶-2-基)哌嗪-1-基)丙基)氨基甲酸叔丁酯45c
tert-butyl(3-(4-(5-aminopyridin-2-yl)piperazin-1-yl)propyl)carbamate
按照化合物33c合成方法,得到化合物45c(黄色固体,260mg)。
LCMS m/s=336.20[M+1].
第三步:
(3-(4-(5-((2,6-二氧哌啶-3-基)氨基)吡啶-2-基)哌嗪-1-基)丙基)氨基甲酸叔丁酯45d
tert-butyl(3-(4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)propyl)carbamate
按照化合物33d合成方法,得到化合物45d(棕色固体,407mg)。
LCMS m/s=447.32[M+1].
第四步:
3-((6-(4-(3-氨基丙基)哌嗪-1-基)吡啶-3-基)氨基)哌啶-2,6-二酮45e
3-((6-(4-(3-aminopropyl)piperazin-1-yl)pyridin-3-yl)amino)piperidine-2,6-dione
按照化合物33e合成方法,得到化合物45e,黄色固体,315mg。
LCMS m/s=347.39[M+1].
第五步:
(Z)-N-(3-(4-(5-((2,6-二氧代哌啶-3-基)氨基)吡啶-2-基)哌嗪-1-基)丙基)-6-(5-氟-2-氧代吲哚-3-亚基)-2-甲基-1,4,5,6-四氢环戊二烯[b]吡咯-3-甲酰胺化合物45
(Z)-N-(3-(4-(5-((2,6-dioxopiperidin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)propyl)-6-(5-fluoro-2-oxoindolin-3-ylidene)-2-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxamide
按照化合物33合成方法,得到化合物45(黄色固体,76mg,产率13%)。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),10.90(s,1H),10.60(s,1H),7.27-7.20(m,2H),6.92-6.87(m,4H),6.83(dd,1H),5.01-4.98(m,1H),3.58(t,2H),3.31(dd,2H),3.27(d,2H),3.14(dt,2H),3.04-3.00(m,2H),2.75-2.60(m,3H),2.55(s,3H),2.52-2.45(m,3H),2.34-2.31(m,1H),2.18-2.05(m,4H),1.74-1.72(m,2H).
LCMS m/s=641.56[M+1].
生物测试例
1. Jurkat细胞培养
人急性T淋巴细胞白血病细胞Jurkat(北纳生物,BNCC338495)培养于含10%FBS和1%双抗的RPMI-1640培养基中,培养条件为37℃,5%CO2。
2.HPK1、GLK、HGK蛋白降解测试
第一天收集处于指数生长期的Jurkat细胞接种于6孔板,接种密度为4×105个/孔,置于37℃,5%CO2培养箱。第二天孔中加入终浓度为50和500nM的测试化合物,并置于培养箱中继续培养48小时。培养结束后,收集细胞,每管加入40μL细胞裂解液,冰上裂解30分钟,4℃13000rpm离心15分钟,收集上清低温保存。采用BCA试剂盒进行蛋白定量并制备蛋白样品,将蛋白样品置于95℃金属浴中变性10分钟。按照western blot实验步骤进行蛋白检测,其中HPK1 antibody(CST,4472s)、GLK antibody(CST,92427S)、HGK antibody(CST,3485S)、和β-Actin antibody(CST,4970S)稀释比例均为1∶1000。结果如表1所示。
表1 本发明化合物对HPK1、GLK、HGK蛋白降解结果
结论:本发明化合物对HPK1蛋白具有显著的降解活性,而对GLK、HGK蛋白降解活性相对较低。
3.HPK1激酶检测
采用ADP-Glo Kinase Assay(Promega,V9102)检测化合物HPK1激酶活性。首先使用DMSO配制测试化合物至终浓度为10000、2500、625、156.3、39.1、9.8、2.4、0.6、0.15、0.04nM。同时设置阳性对照组(10000nM Sunitinib)和阴性对照组(0.5%DMSO)。根据板布局用Echo加入20nL的化合物至384孔板中,每个浓度2个复孔。每孔加入2μL 2×HPK1kinase&Metal solution(Thermo Fisher,2230140)溶液,在25℃孵育10分钟。10分钟后,每孔加入2μL 2×Substrate&ATP solution溶液,在25℃孵育60分钟。60分钟后,每孔加入4μLADP-Glo Reagent(ADP-Glo Kinase Assay,Promega,V9102),在25℃孵育40分钟。40分钟后,每孔加入8μL Kinase Detection Reagent,在25℃孵育30分钟。用Plate reader(BMG,PHERAstar FSX)读取化学发光的数值。根据抑制率计算公式:100-(化合物读值-阳性对照组读值)/(阴性对照组读值-阳性对照组读值)*100%,将抑制率的数值代入GraphPad8.0,计算拟合IC50,结果如表2所示。
表2本发明化合物对HPK1激酶活性测试结果
结论:本发明化合物对HPK1蛋白有显著的降解作用。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (14)
- 一种式(I)所示的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶:
PTM-L-ULM (I);其中,所述L为所述R2不存在;或所述R2选自所述A环、B环各自独立地选自3-12元亚碳环基、3-12元亚杂环基;所述PTM为:
所述ULM为:
所述R1、R3、R9、R11彼此独立地选自-C(=O)-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C1-6卤代亚烷基-、-NH-、-NHR1b-、-C(=O)NH-、-NHC(=O)-、-C(=O)NHR1b-、-NHC(=O)R1b-、 -OC(=O)R1b-、-C(=O)OR1b-、-C(=O)R1b-、-SO2R1b-、-OR1b-、-O-或-S-;所述R1b选自C1-6亚烷基、C1-6卤代亚烷基或亚氨基;所述X1、X2、X3、X6、X7、X8、X9、X10彼此独立地选自C、N、O、S、-C(O)NH-;所述R5选自氢、F、Br、氰基、三氟甲基;所述R4、R6、R7、R8彼此独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基、C3- 6环烷基、3-6元杂环烷基、5-8元芳基或5-8元杂芳基;所述a、b、c、h、k彼此独立地选自0、1、2、3、4、5或6。 - 根据权利要求1所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(II)所示的化合物:
PTM-R1-R2-ULM (II);其中,所述R1选自羰基、C1-6亚烷基、亚氨基、-NHR1b-、-C(=O)NH-、-NHC(=O)-、-C(=O)NHR1b-或-NHC(=O)R1b-;所述R1b选自C1-6亚烷基或C1-6卤代亚烷基;所述R2不存在;或所述R2选自所述A环、B环各自独立地选自3-8元单环亚碳环基、6-12元双环亚碳环基、3-8元单环亚杂环基、6-12元双环亚杂环基;所述6-12元双环亚碳环基、6-12元双环亚杂环基选自稠合双环、桥接双环或螺接双环;所述e选自0、1、2、3、4、5或6;所述PTM、ULM的定义与权利要求1相同。 - 根据权利要求2所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(II)所示的化合物,其中:所述R1选自羰基、C1-6亚烷基、亚氨基、-NHR1b-、-C(=O)NH-、或-C(=O)NHR1b-;所述R1b选自C1-6直链亚烷基或C1-6支链亚烷基;所述R2不存在;或所述R2选自所述A环、B环各自独立地选自3-8元单环亚环烷基、6-12元双环亚环烷基、3-8元单环亚杂环烷基、6-12元双环亚杂环烷基;所述6-12元双环亚环烷基、6-12元双环亚杂环烷基选自稠合双环、桥接双环或螺接双环;所述e选自0、1、2、3、4、5或6。
- 根据权利要求1~3任一项所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:所述PTM为X1、R5、a、R6、h的定义与权利要求1相同。
- 根据权利要求4所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:所述PTM为所述R5选自氢、F、Br、氰基、三氟甲基;所述R6选自卤素、C1-6烷基、C1-6卤代烷基;所述a各自独立地选自0、1、2、3、4、5或6。
- 根据权利要求1~3任一项所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:所述ULM为所述R3选自-C(=O)-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C1-6卤代亚烷基-、-NH-、-O-或-S-;所述X2、X6、X7、X8各自独立地选自C、N、O;所述X3选自-C(=O)-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C1-6卤代亚烷基-、-NH-、-O-、-S-或-C(O)NH-;所述R4、R7、R8各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基;所述b、c各自独立地选自0、1、2、3、4、5或6。
- 根据权利要求6所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:所述ULM为所述R3选自-C(=O)-、-C1-3亚烷基-、-C1-3卤代亚烷基-、-NH-、-O-或-S-;所述X2、X6、X7、X8各自独立地选自C、N、O;所述X3选自-C1-3亚烷基-、-NH-、-O-、-S-或-C(O)NH-;所述R4、R7、R8各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基;所述b、c各自独立地选自0、1、2、3、4、5或6。
- 根据权利要求1所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示的化合物,其中:其中,所述PTM为所述L为所述ULM为所述X1、X2、X3各自独立地选自C、N或O;所述R1独立地选自羰基、亚甲基、亚氨基、-NHR1b-、-C(=O)NHR1b-或-NHC(=O)R1b-;所述R1b独立地选自C1-6亚烷基或C1-6卤代亚烷基;所述R2选自所述A环、B环各自独立地选自3-10元碳环基、3-10元杂环基;所述R3选自羰基、亚甲基或亚氨基;所述R5选自氢、F、Br、氰基、三氟甲基;所述R4、R6、R7各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基或羟基;所述a、b、c、d、e各自独立地选自0、1、2、3、4、5或6;所述h选自0或1。
- 根据权利要求1~3任一项所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自通式(I)所示或通式(II)所示的化合物,其中:所述PTM为所述R5选自氢、F、Br、氰基、三氟甲基;所述R6选自卤素、C1-3烷基、C1-3卤代烷基;所述a选自0、1、2、3或4;所述ULM为所述R3选自羰基或亚甲基;所述R4、R7各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、氰基、羟基;所述b、c各自独立地选自0、1、2、3、4、5或6;所述L为所述R1选自-C(=O)NH-或-C(=O)NH-C1-6亚烷基-;所述R2不存在;或所述R2选自所述A环、B环各自独立地选自所述X4、X5、X11各自独立地选自C、N或O;所述e、f、g、i、j各自独立地选自0、1、2、3或4。
- 根据权利要求1~9任一项所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,其中:所述R2选自
- 一种式(I’)所示的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶:
其中,W选自R1选自羰基、亚甲基或氨基;R2选自 其中,n为1-4的整数;R3选自亚甲基或羰基;R10选自H或卤素。 - 根据权利要求1~11任一项所述的化合物,或者其所有的立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,所述化合物选自:
- 一种药物组合物,所述药物组合物包括:(1)权利要求1-12任一项所述的化合物或其立体异构体、溶剂化物、前药、代谢产物、 氘代物、药学上可接受的盐或共晶;(2)任选的一种或者多种其他活性成分;以及(3)药学上可接受的载体和/或赋形剂。
- 权利要求1-12任一项所述的化合物或其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶或者权利要求13所述的药物组合物在制备抗肿瘤药物中的用途。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210861626.6 | 2022-07-22 | ||
CN202210861626 | 2022-07-22 | ||
CN202211462274 | 2022-11-22 | ||
CN202211462274.3 | 2022-11-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024017372A1 true WO2024017372A1 (zh) | 2024-01-25 |
Family
ID=89617206
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2023/108658 WO2024017372A1 (zh) | 2022-07-22 | 2023-07-21 | 一种吲哚酮衍生物及其应用 |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024017372A1 (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040063773A1 (en) * | 2000-02-15 | 2004-04-01 | Sugen, Inc. & Pharmacia & Upjohn Co. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
WO2020070332A1 (en) * | 2018-10-05 | 2020-04-09 | Ichnos Sciences S.A. | Oxindole compounds for use as map4k1 inhibitors |
CN112979618A (zh) * | 2021-03-02 | 2021-06-18 | 东南大学 | 一种靛玉红衍生物及其制备方法和应用 |
WO2022006412A2 (en) * | 2020-07-02 | 2022-01-06 | The Regents Of The University Of Colorado, A Body Corporate | Conjugates of ampk inhibitors and protac degraders and related uses |
CN114423463A (zh) * | 2019-05-06 | 2022-04-29 | 西奈山伊坎医学院 | 作为hpk1的降解剂的异双功能化合物 |
-
2023
- 2023-07-21 WO PCT/CN2023/108658 patent/WO2024017372A1/zh unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040063773A1 (en) * | 2000-02-15 | 2004-04-01 | Sugen, Inc. & Pharmacia & Upjohn Co. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
WO2020070332A1 (en) * | 2018-10-05 | 2020-04-09 | Ichnos Sciences S.A. | Oxindole compounds for use as map4k1 inhibitors |
CN113227049A (zh) * | 2018-10-05 | 2021-08-06 | 艾科诺斯科技股份有限公司 | 用作map4k1抑制剂的吲哚啉酮化合物 |
CN114423463A (zh) * | 2019-05-06 | 2022-04-29 | 西奈山伊坎医学院 | 作为hpk1的降解剂的异双功能化合物 |
WO2022006412A2 (en) * | 2020-07-02 | 2022-01-06 | The Regents Of The University Of Colorado, A Body Corporate | Conjugates of ampk inhibitors and protac degraders and related uses |
CN112979618A (zh) * | 2021-03-02 | 2021-06-18 | 东南大学 | 一种靛玉红衍生物及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
DING, LEI ET AL.: "Design, synthesis, and biological evaluation of novel 3-pyrrolo[b]cyclohexylene-2-dihydroindolinone derivatives as potent receptor tyrosine kinase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, 15 August 2013 (2013-08-15), XP028731077, DOI: 10.1016/j.bmcl.2013.08.037 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7005582B2 (ja) | ブルトン型チロシンキナーゼ(btk)インヒビターとしての多フルオロ置換化合物 | |
WO2020073949A1 (zh) | 含氮杂芳类衍生物调节剂、其制备方法和应用 | |
CN107530329B (zh) | 用作CDK抑制剂的吡唑并[1,5-a][1,3,5]三嗪和吡唑并[1,5-a]嘧啶衍生物 | |
CN106957314B (zh) | 用作raf激酶抑制剂的嘧啶衍生物 | |
US9249145B2 (en) | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors | |
US9193733B2 (en) | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors | |
JP6084291B2 (ja) | Fgfr阻害剤の間歇投与用抗腫瘍剤 | |
JP6035423B2 (ja) | 新規な縮合ピリミジン化合物又はその塩 | |
JP2023521698A (ja) | Krasの標的化分解のための化合物及び方法 | |
BR112014017749B1 (pt) | Composto alquinilbenzeno 3,5-dissubstituído e sal do mesmo | |
AU2015266453C1 (en) | Alk kinase inhibitor, and preparation method and use thereof | |
JP2013523756A (ja) | プロテインキナーゼ阻害剤としての置換ピロロトリアジン化合物 | |
WO2018010514A1 (zh) | 作为fgfr抑制剂的杂环化合物 | |
CN113631557B (zh) | Jak激酶抑制剂及其制备方法和在医药领域的应用 | |
BR112019023918A2 (pt) | Inibidores de quinase e usos dos mesmos | |
US11542275B2 (en) | Substituted imidazolidin-2-one derivatives as PRMT5 inhibitors | |
KR20210052500A (ko) | 바닌 억제제로서의 헤테로방향족 화합물 | |
KR20230173234A (ko) | 인다졸계 화합물 및 관련된 사용 방법 | |
WO2023186069A1 (zh) | 一类白介素-1受体相关激酶4的双功能嵌合体杂环化合物及其制备方法、药用组合物和用途 | |
TW202237597A (zh) | 新型egfr降解劑 | |
WO2022166793A1 (zh) | Cdk抑制剂 | |
WO2020156319A1 (zh) | N-甲酰胺衍生物、其制备方法及其在医药上的用途 | |
TW202334167A (zh) | 作為erbb2抑制劑之稠合四環喹唑啉衍生物 | |
WO2024017372A1 (zh) | 一种吲哚酮衍生物及其应用 | |
WO2022253309A1 (zh) | 取代的杂环化合物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23842434 Country of ref document: EP Kind code of ref document: A1 |