TW202340210A - １，３，４，７－四氫－２Ｈ－吡咯并［３＇，２＇：５，６］吡啶并［２，３－ｂ］［１，４］氮呯Ｂｃｌ－２抑制劑 - Google Patents
１，３，４，７－四氫－２Ｈ－吡咯并［３＇，２＇：５，６］吡啶并［２，３－ｂ］［１，４］氮呯Ｂｃｌ－２抑制劑 Download PDFInfo
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- TW202340210A TW202340210A TW112102814A TW112102814A TW202340210A TW 202340210 A TW202340210 A TW 202340210A TW 112102814 A TW112102814 A TW 112102814A TW 112102814 A TW112102814 A TW 112102814A TW 202340210 A TW202340210 A TW 202340210A
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- TW
- Taiwan
- Prior art keywords
- pyridine
- dimethyl
- pyrrolo
- pyrido
- dihydro
- Prior art date
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- -1 1,3,4,7-tetrahydro-2h-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine Chemical compound 0.000 title claims description 61
- 239000012664 BCL-2-inhibitor Substances 0.000 title description 2
- 229940123711 Bcl2 inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 344
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims abstract description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 432
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 238
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 215
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 134
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 106
- 229910052757 nitrogen Inorganic materials 0.000 claims description 79
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 43
- 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 25
- 150000001412 amines Chemical class 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 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
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 673
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 447
- 239000000243 solution Substances 0.000 description 309
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 259
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 236
- 238000005481 NMR spectroscopy Methods 0.000 description 230
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 218
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 214
- 238000006243 chemical reaction Methods 0.000 description 195
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 188
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 186
- 239000000203 mixture Substances 0.000 description 185
- 239000011541 reaction mixture Substances 0.000 description 180
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 130
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 124
- 239000000706 filtrate Substances 0.000 description 120
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 114
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 102
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 102
- 239000012044 organic layer Substances 0.000 description 101
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 98
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 86
- 239000012267 brine Substances 0.000 description 78
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 78
- 239000000377 silicon dioxide Substances 0.000 description 77
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 70
- 238000003756 stirring Methods 0.000 description 65
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 61
- 235000019341 magnesium sulphate Nutrition 0.000 description 61
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- 238000003818 flash chromatography Methods 0.000 description 53
- 230000002829 reductive effect Effects 0.000 description 49
- 239000003208 petroleum Substances 0.000 description 47
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- 229920006395 saturated elastomer Polymers 0.000 description 37
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000012074 organic phase Substances 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 30
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 30
- 229910052737 gold Inorganic materials 0.000 description 30
- 239000010931 gold Substances 0.000 description 30
- 239000012312 sodium hydride Substances 0.000 description 30
- 229910000104 sodium hydride Inorganic materials 0.000 description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 29
- 229910052938 sodium sulfate Inorganic materials 0.000 description 29
- 235000011152 sodium sulphate Nutrition 0.000 description 29
- 239000001257 hydrogen Substances 0.000 description 27
- 229910052739 hydrogen Inorganic materials 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 239000010410 layer Substances 0.000 description 25
- FAYVDRRKPVJSPE-UHFFFAOYSA-N 4-fluoro-3-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(F)C([N+]([O-])=O)=C1 FAYVDRRKPVJSPE-UHFFFAOYSA-N 0.000 description 24
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 23
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 238000004007 reversed phase HPLC Methods 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 17
- 239000002480 mineral oil Substances 0.000 description 17
- 235000010446 mineral oil Nutrition 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 150000001335 aliphatic alkanes Chemical class 0.000 description 16
- 235000019270 ammonium chloride Nutrition 0.000 description 16
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 16
- 238000010828 elution Methods 0.000 description 15
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- 229910052763 palladium Inorganic materials 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 12
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 10
- 150000004702 methyl esters Chemical class 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- BTOVVHWKPVSLBI-UHFFFAOYSA-N 2-methylprop-1-enylbenzene Chemical compound CC(C)=CC1=CC=CC=C1 BTOVVHWKPVSLBI-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- SPZGXONNVLTQDE-UHFFFAOYSA-N 4-chloro-3-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 SPZGXONNVLTQDE-UHFFFAOYSA-N 0.000 description 7
- MSUQCJKXHIGCMN-UHFFFAOYSA-N 5,6-dichloropyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CN=C(Cl)C(Cl)=C1 MSUQCJKXHIGCMN-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000012455 biphasic mixture Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241001251200 Agelas Species 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 6
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 description 6
- 241000009298 Trigla lyra Species 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 235000010265 sodium sulphite Nutrition 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- LVQFHDAKZHGEAJ-UHFFFAOYSA-M 4-methylbenzenesulfonate Chemical compound [CH2]C1=CC=C(S([O-])(=O)=O)C=C1 LVQFHDAKZHGEAJ-UHFFFAOYSA-M 0.000 description 5
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 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 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 5
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 5
- 235000010290 biphenyl Nutrition 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 229910052759 nickel Inorganic materials 0.000 description 5
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- KKVQDRHEXRGIMI-UHFFFAOYSA-N 3-chloro-4-fluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(F)C(Cl)=C1 KKVQDRHEXRGIMI-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
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- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
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- NKDUBHHPRRTYJO-UHFFFAOYSA-N ethyl 1-(2-methoxyethyl)piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCN(CCOC)CC1 NKDUBHHPRRTYJO-UHFFFAOYSA-N 0.000 description 1
- GQJWTOYPOHWVKC-UHFFFAOYSA-N ethyl 1-oxaspiro[2.5]octane-6-carboxylate Chemical compound C1CC(C(=O)OCC)CCC11OC1 GQJWTOYPOHWVKC-UHFFFAOYSA-N 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical class OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
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- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
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- JYOCKIVAXFOJOK-UHFFFAOYSA-N n-propan-2-ylbutan-2-amine Chemical compound CCC(C)NC(C)C JYOCKIVAXFOJOK-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 210000000496 pancreas Anatomy 0.000 description 1
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- UVBBCQLPTZEDHT-UHFFFAOYSA-N pent-4-en-1-amine Chemical compound NCCCC=C UVBBCQLPTZEDHT-UHFFFAOYSA-N 0.000 description 1
- AXSDLRYYKIKAPZ-UHFFFAOYSA-N pent-4-en-2-ol Chemical compound [CH2]C(O)CC=C AXSDLRYYKIKAPZ-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- VDVJGIYXDVPQLP-UHFFFAOYSA-N piperonylic acid Chemical compound OC(=O)C1=CC=C2OCOC2=C1 VDVJGIYXDVPQLP-UHFFFAOYSA-N 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
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- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical group [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
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- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
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- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
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- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- FCYNTMBZASDPHJ-UHFFFAOYSA-N tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(F)(CN)CC1 FCYNTMBZASDPHJ-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical group CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202263267018P | 2022-01-21 | 2022-01-21 | |
| US63/267,018 | 2022-01-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202340210A true TW202340210A (zh) | 2023-10-16 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW112102814A TW202340210A (zh) | 2022-01-21 | 2023-01-19 | １，３，４，７－四氫－２Ｈ－吡咯并［３＇，２＇：５，６］吡啶并［２，３－ｂ］［１，４］氮呯Ｂｃｌ－２抑制劑 |
Country Status (13)
| Country | Link |
|---|---|
| US (3) | US11964990B2 (https=) |
| EP (1) | EP4466273A1 (https=) |
| JP (2) | JP7714811B2 (https=) |
| KR (1) | KR20240136972A (https=) |
| CN (1) | CN119053610A (https=) |
| AR (1) | AR128310A1 (https=) |
| AU (1) | AU2023210279A1 (https=) |
| CA (1) | CA3242074A1 (https=) |
| CO (1) | CO2024009334A2 (https=) |
| IL (1) | IL312709A (https=) |
| MX (1) | MX2024008840A (https=) |
| TW (1) | TW202340210A (https=) |
| WO (1) | WO2023141536A1 (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11964990B2 (en) * | 2022-01-21 | 2024-04-23 | Abbvie Inc. | 1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine bcl-2 inhibitors |
| CN117820134A (zh) * | 2024-01-10 | 2024-04-05 | 山东盛安贝新材料有限公司南京分公司 | 一种顺式-3-甲氧基环丁胺盐酸盐的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2018322059C1 (en) | 2017-08-23 | 2024-09-12 | Guangzhou Lupeng Pharmaceutical Company Ltd. | BCL-2 inhibitors |
| US12220419B2 (en) | 2018-08-22 | 2025-02-11 | Newave Pharmaceutical Inc. | BCL-2 inhibitors |
| WO2020140005A2 (en) | 2018-12-29 | 2020-07-02 | Newave Pharmaceutical Inc. | Bcl-2 inhibitors |
| WO2021066873A1 (en) | 2019-10-03 | 2021-04-08 | Newave Pharmaceutical Inc. | Condensed heterocycles as bcl-2 inhibitors |
| WO2021083135A1 (en) | 2019-10-28 | 2021-05-06 | Beigene, Ltd. | Bcl-2 INHIBITORS |
| WO2021133817A1 (en) | 2019-12-27 | 2021-07-01 | Guangzhou Lupeng Pharmaceutical Company Ltd. | 1h-pyrrolo[2,3-b]pyridine derivatives as bcl-2 inhibitors for the treatment of neoplastic and autoimmune diseases |
| KR20220158725A (ko) | 2020-02-24 | 2022-12-01 | 광조우 루펭 파마슈티칼 컴퍼니 엘티디. | Bcl2 억제제를 함유하는 핫 멜트 압출 고체 분산체 |
| US11964990B2 (en) * | 2022-01-21 | 2024-04-23 | Abbvie Inc. | 1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepine bcl-2 inhibitors |
-
2023
- 2023-01-19 US US18/156,987 patent/US11964990B2/en active Active
- 2023-01-19 TW TW112102814A patent/TW202340210A/zh unknown
- 2023-01-20 AU AU2023210279A patent/AU2023210279A1/en active Pending
- 2023-01-20 WO PCT/US2023/060944 patent/WO2023141536A1/en not_active Ceased
- 2023-01-20 CA CA3242074A patent/CA3242074A1/en active Pending
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- 2023-01-20 MX MX2024008840A patent/MX2024008840A/es unknown
- 2023-01-20 KR KR1020247023725A patent/KR20240136972A/ko active Pending
- 2023-01-20 JP JP2024540933A patent/JP7714811B2/ja active Active
- 2023-01-20 CN CN202380016422.5A patent/CN119053610A/zh active Pending
- 2023-01-20 IL IL312709A patent/IL312709A/en unknown
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2024
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- 2024-07-15 CO CONC2024/0009334A patent/CO2024009334A2/es unknown
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2025
- 2025-07-02 US US19/258,642 patent/US20260028356A1/en active Pending
- 2025-07-15 JP JP2025118767A patent/JP2025160251A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| KR20240136972A (ko) | 2024-09-19 |
| WO2023141536A1 (en) | 2023-07-27 |
| US11964990B2 (en) | 2024-04-23 |
| JP7714811B2 (ja) | 2025-07-29 |
| IL312709A (en) | 2024-07-01 |
| CN119053610A (zh) | 2024-11-29 |
| CO2024009334A2 (es) | 2024-07-18 |
| JP2025160251A (ja) | 2025-10-22 |
| AR128310A1 (es) | 2024-04-17 |
| AU2023210279A1 (en) | 2024-05-23 |
| US20250066388A1 (en) | 2025-02-27 |
| US20260028356A1 (en) | 2026-01-29 |
| EP4466273A1 (en) | 2024-11-27 |
| JP2025504382A (ja) | 2025-02-12 |
| MX2024008840A (es) | 2024-07-25 |
| US20230234971A1 (en) | 2023-07-27 |
| CA3242074A1 (en) | 2023-07-27 |
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