TW202130631A - ３—（５—甲氧基—１—側氧基異吲哚啉—２—基）哌啶—２，６—二酮衍生物及其用途 - Google Patents
３—（５—甲氧基—１—側氧基異吲哚啉—２—基）哌啶—２，６—二酮衍生物及其用途 Download PDFInfo
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- TW202130631A TW202130631A TW109144481A TW109144481A TW202130631A TW 202130631 A TW202130631 A TW 202130631A TW 109144481 A TW109144481 A TW 109144481A TW 109144481 A TW109144481 A TW 109144481A TW 202130631 A TW202130631 A TW 202130631A
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- Taiwan
- Prior art keywords
- alkyl
- group
- independently selected
- piperidin
- membered
- Prior art date
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- UCRSTLCVZRQISL-UHFFFAOYSA-N 3-(6-methoxy-3-oxo-1h-isoindol-2-yl)piperidine-2,6-dione Chemical class C1C2=CC(OC)=CC=C2C(=O)N1C1CCC(=O)NC1=O UCRSTLCVZRQISL-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 400
- 108010044495 Fetal Hemoglobin Proteins 0.000 claims abstract description 39
- 238000011282 treatment Methods 0.000 claims abstract description 30
- 208000007056 sickle cell anemia Diseases 0.000 claims abstract description 19
- 208000034737 hemoglobinopathy Diseases 0.000 claims abstract description 13
- 208000018020 Sickle cell-beta-thalassemia disease syndrome Diseases 0.000 claims abstract description 10
- 206010043391 Thalassaemia beta Diseases 0.000 claims abstract description 10
- 230000001939 inductive effect Effects 0.000 claims abstract description 9
- 208000018337 inherited hemoglobinopathy Diseases 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 102100020716 Protein Wiz Human genes 0.000 claims abstract 14
- 125000005842 heteroatom Chemical group 0.000 claims description 432
- 229910052760 oxygen Inorganic materials 0.000 claims description 380
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 368
- 229910052717 sulfur Inorganic materials 0.000 claims description 365
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims description 336
- 125000001072 heteroaryl group Chemical group 0.000 claims description 335
- 150000003839 salts Chemical class 0.000 claims description 294
- 239000012453 solvate Substances 0.000 claims description 261
- 239000000651 prodrug Substances 0.000 claims description 256
- 229940002612 prodrug Drugs 0.000 claims description 256
- -1 -C(=O)-OH Chemical group 0.000 claims description 224
- 125000003118 aryl group Chemical group 0.000 claims description 213
- 125000000217 alkyl group Chemical group 0.000 claims description 194
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 170
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 163
- 229910052739 hydrogen Inorganic materials 0.000 claims description 148
- 239000001257 hydrogen Substances 0.000 claims description 148
- 125000000623 heterocyclic group Chemical group 0.000 claims description 144
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 136
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 134
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 128
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 119
- 150000004677 hydrates Chemical class 0.000 claims description 115
- 125000001424 substituent group Chemical group 0.000 claims description 109
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 108
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 106
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 104
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 92
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 79
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 79
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 77
- 150000002367 halogens Chemical class 0.000 claims description 74
- 229910052799 carbon Inorganic materials 0.000 claims description 73
- 229910052736 halogen Inorganic materials 0.000 claims description 73
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 67
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 61
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 61
- 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 claims description 56
- 208000035475 disorder Diseases 0.000 claims description 48
- 238000006467 substitution reaction Methods 0.000 claims description 47
- 241000009298 Trigla lyra Species 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 43
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 27
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 24
- 238000004519 manufacturing process Methods 0.000 claims description 23
- ZLBWZEARBDLCFH-UHFFFAOYSA-N 3h-pyridine-2,6-dione Chemical compound O=C1CC=CC(=O)N1 ZLBWZEARBDLCFH-UHFFFAOYSA-N 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 16
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 15
- 230000001965 increasing effect Effects 0.000 claims description 15
- 125000002947 alkylene group Chemical group 0.000 claims description 14
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 claims description 14
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 12
- 125000003943 azolyl group Chemical group 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 230000015556 catabolic process Effects 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 238000006731 degradation reaction Methods 0.000 claims description 8
- 125000002720 diazolyl group Chemical group 0.000 claims description 8
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- 208000005980 beta thalassemia Diseases 0.000 claims description 7
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 230000007420 reactivation Effects 0.000 claims description 5
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 4
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- KIYOXVPZRXLLDR-UHFFFAOYSA-N imidazo[1,2-a]pyridine-7-carbonitrile Chemical compound C1=C(C#N)C=CN2C=CN=C21 KIYOXVPZRXLLDR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000005945 imidazopyridyl group Chemical group 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- MQUPWTBHHPUUMC-UHFFFAOYSA-N isoindole Chemical compound C1=CC=C[C]2C=NC=C21 MQUPWTBHHPUUMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000006085 pyrrolopyridyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 claims description 3
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012964 benzotriazole Substances 0.000 claims description 3
- 230000033228 biological regulation Effects 0.000 claims description 3
- 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 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 claims description 3
- 230000004952 protein activity Effects 0.000 claims description 3
- 125000005494 pyridonyl group Chemical group 0.000 claims description 3
- RONWGALEIBILOG-VMJVVOMYSA-N quinine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 RONWGALEIBILOG-VMJVVOMYSA-N 0.000 claims description 3
- JJRMOUOVYXNVIK-RHSMWYFYSA-N (3R)-3-[6-[[(2R)-1-ethyl-4,4-difluoropiperidin-2-yl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@H](CC(CC1)(F)F)COC=1C=C2CN(C(C2=CC=1)=O)[C@H]1C(NC(CC1)=O)=O JJRMOUOVYXNVIK-RHSMWYFYSA-N 0.000 claims description 2
- JJRMOUOVYXNVIK-WMLDXEAASA-N (3R)-3-[6-[[(2S)-1-ethyl-4,4-difluoropiperidin-2-yl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@@H](CC(CC1)(F)F)COC=1C=C2CN(C(C2=CC=1)=O)[C@H]1C(NC(CC1)=O)=O JJRMOUOVYXNVIK-WMLDXEAASA-N 0.000 claims description 2
- JJRMOUOVYXNVIK-PBHICJAKSA-N (3S)-3-[6-[[(2R)-1-ethyl-4,4-difluoropiperidin-2-yl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@H](CC(CC1)(F)F)COC=1C=C2CN(C(C2=CC=1)=O)[C@@H]1C(NC(CC1)=O)=O JJRMOUOVYXNVIK-PBHICJAKSA-N 0.000 claims description 2
- JJRMOUOVYXNVIK-YOEHRIQHSA-N (3S)-3-[6-[[(2S)-1-ethyl-4,4-difluoropiperidin-2-yl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@@H](CC(CC1)(F)F)COC=1C=C2CN(C(C2=CC=1)=O)[C@@H]1C(NC(CC1)=O)=O JJRMOUOVYXNVIK-YOEHRIQHSA-N 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- NIFKWUSOZDUTDG-LJQANCHMSA-N 1-[6-[[(2R)-1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]piperidin-2-yl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound CC=1SC(=C(N=1)C)CN1[C@H](CCCC1)COC=1C=C2CN(C(C2=CC=1)=O)N1C(CCCC1=O)=O NIFKWUSOZDUTDG-LJQANCHMSA-N 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- XCDKIQOOYHGSCT-RXVAYIKUSA-N 3-[3-oxo-6-[[(2R)-1-[[2-(2-oxo-2-piperidin-1-ylethoxy)phenyl]methyl]piperidin-2-yl]methoxy]-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound O=C1N(CC2=CC(=CC=C12)OC[C@@H]1N(CCCC1)CC1=C(C=CC=C1)OCC(N1CCCCC1)=O)C1C(NC(CC1)=O)=O XCDKIQOOYHGSCT-RXVAYIKUSA-N 0.000 claims description 2
- HFKRYPXYGCFGQU-DXDQHDRFSA-N 3-[3-oxo-6-[[(2R)-1-[[3-(pyrazol-1-ylmethyl)phenyl]methyl]piperidin-2-yl]methoxy]-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound N1(N=CC=C1)CC=1C=C(CN2[C@H](CCCC2)COC=2C=C3CN(C(C3=CC=2)=O)C2C(NC(CC2)=O)=O)C=CC=1 HFKRYPXYGCFGQU-DXDQHDRFSA-N 0.000 claims description 2
- XCDKIQOOYHGSCT-ALLRNTDFSA-N 3-[3-oxo-6-[[(2S)-1-[[2-(2-oxo-2-piperidin-1-ylethoxy)phenyl]methyl]piperidin-2-yl]methoxy]-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound O=C1N(CC2=CC(=CC=C12)OC[C@H]1N(CCCC1)CC1=C(C=CC=C1)OCC(N1CCCCC1)=O)C1C(NC(CC1)=O)=O XCDKIQOOYHGSCT-ALLRNTDFSA-N 0.000 claims description 2
- HFKRYPXYGCFGQU-BXXZMZEQSA-N 3-[3-oxo-6-[[(2S)-1-[[3-(pyrazol-1-ylmethyl)phenyl]methyl]piperidin-2-yl]methoxy]-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound N1(N=CC=C1)CC=1C=C(CN2[C@@H](CCCC2)COC=2C=C3CN(C(C3=CC=2)=O)C2C(NC(CC2)=O)=O)C=CC=1 HFKRYPXYGCFGQU-BXXZMZEQSA-N 0.000 claims description 2
- GMSRIMVHZSTKRG-ZZHFZYNASA-N 3-[3-oxo-6-[[(2S)-1-[[4-(2-oxopyrrolidin-1-yl)phenyl]methyl]piperidin-2-yl]methoxy]-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound O=C1N(CC2=CC(=CC=C12)OC[C@H]1N(CCCC1)CC1=CC=C(C=C1)N1C(CCC1)=O)C1C(NC(CC1)=O)=O GMSRIMVHZSTKRG-ZZHFZYNASA-N 0.000 claims description 2
- YPOMBOMUPFSHOZ-UHFFFAOYSA-N 3-[6-[(1-ethyl-4-fluoropiperidin-2-yl)methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1C(CC(CC1)F)COC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O YPOMBOMUPFSHOZ-UHFFFAOYSA-N 0.000 claims description 2
- FVZCFUKXGUUDBQ-QSFPRURJSA-N 3-[6-[(1R)-1-[(2R)-1-ethylpiperidin-2-yl]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@H](CCCC1)[C@@H](C)OC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O FVZCFUKXGUUDBQ-QSFPRURJSA-N 0.000 claims description 2
- FVZCFUKXGUUDBQ-FQPPOJKCSA-N 3-[6-[(1R)-1-[(2S)-1-ethylpiperidin-2-yl]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@@H](CCCC1)[C@@H](C)OC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O FVZCFUKXGUUDBQ-FQPPOJKCSA-N 0.000 claims description 2
- TYMLMVVEPPLHIL-GTDUKUAFSA-N 3-[6-[(1R)-1-[(2S)-1-ethylpyrrolidin-2-yl]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@@H](CCC1)[C@@H](C)OC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O TYMLMVVEPPLHIL-GTDUKUAFSA-N 0.000 claims description 2
- FVZCFUKXGUUDBQ-BQGOGBDGSA-N 3-[6-[(1S)-1-[(2R)-1-ethylpiperidin-2-yl]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@H](CCCC1)[C@H](C)OC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O FVZCFUKXGUUDBQ-BQGOGBDGSA-N 0.000 claims description 2
- FVZCFUKXGUUDBQ-ZWSMLAFMSA-N 3-[6-[(1S)-1-[(2S)-1-ethylpiperidin-2-yl]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@@H](CCCC1)[C@H](C)OC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O FVZCFUKXGUUDBQ-ZWSMLAFMSA-N 0.000 claims description 2
- TYMLMVVEPPLHIL-VELWFJCASA-N 3-[6-[(1S)-1-[(2S)-1-ethylpyrrolidin-2-yl]ethoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound C(C)N1[C@@H](CCC1)[C@H](C)OC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O TYMLMVVEPPLHIL-VELWFJCASA-N 0.000 claims description 2
- JBUJIHGPJGAYLR-UHFFFAOYSA-N 3-[6-[(4,4-difluoropiperidin-2-yl)methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound FC1(CC(NCC1)COC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O)F JBUJIHGPJGAYLR-UHFFFAOYSA-N 0.000 claims description 2
- MOKNFZWBPHPCRQ-VTBWFHPJSA-N 3-[6-[[(2R)-1-(1H-imidazol-2-ylmethyl)piperidin-2-yl]methoxy]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound N1C(=NC=C1)CN1[C@H](CCCC1)COC=1C=C2CN(C(C2=CC=1)=O)C1C(NC(CC1)=O)=O MOKNFZWBPHPCRQ-VTBWFHPJSA-N 0.000 claims description 2
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
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| CN115959976A (zh) * | 2022-12-30 | 2023-04-14 | 安徽诺全药业有限公司 | 一种甲氧基取代双环戊烷衍生物的制备方法 |
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| CN120717945A (zh) * | 2025-08-15 | 2025-09-30 | 泰迩生物医药泰州有限公司 | 一种(2r,4s)-n-boc-4-羟基哌啶-2-甲酸甲酯的合成方法 |
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| BR112022011796A2 (pt) | 2022-08-30 |
| EP4076650A1 (en) | 2022-10-26 |
| KR20220114065A (ko) | 2022-08-17 |
| JP2023506642A (ja) | 2023-02-17 |
| CN114828959A (zh) | 2022-07-29 |
| WO2021124172A1 (en) | 2021-06-24 |
| UY38986A (es) | 2021-07-30 |
| CN114828959B (zh) | 2024-04-02 |
| EP4076650B1 (en) | 2024-02-28 |
| AR120773A1 (es) | 2022-03-16 |
| CR20220278A (es) | 2022-07-01 |
| US11566022B2 (en) | 2023-01-31 |
| JOP20220152A1 (ar) | 2023-01-30 |
| MX2022007351A (es) | 2022-07-19 |
| US20220402904A1 (en) | 2022-12-22 |
| CO2022008243A2 (es) | 2022-07-08 |
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