WO2022214053A1 - 泛素特异性蛋白酶1(usp1)抑制剂 - Google Patents
泛素特异性蛋白酶1(usp1)抑制剂 Download PDFInfo
- Publication number
- WO2022214053A1 WO2022214053A1 PCT/CN2022/085703 CN2022085703W WO2022214053A1 WO 2022214053 A1 WO2022214053 A1 WO 2022214053A1 CN 2022085703 W CN2022085703 W CN 2022085703W WO 2022214053 A1 WO2022214053 A1 WO 2022214053A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- cycloalkyl
- optionally substituted
- mmol
- Prior art date
Links
- 101000607909 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 1 Proteins 0.000 title claims abstract description 34
- 102100039865 Ubiquitin carboxyl-terminal hydrolase 1 Human genes 0.000 title claims abstract description 30
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 459
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 16
- -1 said C 1 -C 6 alkyl Chemical group 0.000 claims description 306
- 125000000623 heterocyclic group Chemical group 0.000 claims description 135
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 106
- 238000002360 preparation method Methods 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 74
- 229910052736 halogen Inorganic materials 0.000 claims description 71
- 150000002367 halogens Chemical class 0.000 claims description 66
- 125000004429 atom Chemical group 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 37
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 15
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims 2
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 414
- 239000000243 solution Substances 0.000 description 221
- 238000006243 chemical reaction Methods 0.000 description 215
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 163
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
- 230000002829 reductive effect Effects 0.000 description 116
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 113
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 100
- 239000012074 organic phase Substances 0.000 description 96
- 238000005481 NMR spectroscopy Methods 0.000 description 94
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 92
- 239000000203 mixture Substances 0.000 description 92
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
- 239000002904 solvent Substances 0.000 description 73
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
- 238000010898 silica gel chromatography Methods 0.000 description 72
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 66
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 59
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 59
- 238000012360 testing method Methods 0.000 description 58
- 239000007787 solid Substances 0.000 description 53
- 239000003208 petroleum Substances 0.000 description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 40
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 36
- 239000000523 sample Substances 0.000 description 36
- 239000012043 crude product Substances 0.000 description 35
- 125000004432 carbon atom Chemical group C* 0.000 description 33
- 229910000027 potassium carbonate Inorganic materials 0.000 description 33
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 31
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 28
- 238000004237 preparative chromatography Methods 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000003643 water by type Substances 0.000 description 27
- 238000004949 mass spectrometry Methods 0.000 description 25
- 229910052757 nitrogen Inorganic materials 0.000 description 25
- 239000012071 phase Substances 0.000 description 25
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 21
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- 241000700159 Rattus Species 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 15
- 238000011534 incubation Methods 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- 238000010791 quenching Methods 0.000 description 15
- 239000012312 sodium hydride Substances 0.000 description 15
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 14
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 13
- 239000005457 ice water Substances 0.000 description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 230000004913 activation Effects 0.000 description 12
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 12
- 238000010828 elution Methods 0.000 description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 239000012299 nitrogen atmosphere Substances 0.000 description 12
- 229910000160 potassium phosphate Inorganic materials 0.000 description 12
- 235000011009 potassium phosphates Nutrition 0.000 description 12
- YLKHVKXTIXZXRI-UHFFFAOYSA-N 2-pyrimidin-5-ylpyrimidine Chemical compound N1=CC=CN=C1C1=CN=CN=C1 YLKHVKXTIXZXRI-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000006413 ring segment Chemical group 0.000 description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- 238000010790 dilution Methods 0.000 description 10
- 239000012895 dilution Substances 0.000 description 10
- 210000003494 hepatocyte Anatomy 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 239000013641 positive control Substances 0.000 description 10
- 108010093668 Deubiquitinating Enzymes Proteins 0.000 description 9
- 102000001477 Deubiquitinating Enzymes Human genes 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- VERBHEOBZBFQOY-UHFFFAOYSA-N [3-fluoro-4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanamine Chemical group FC=1C=C(C=CC=1C=1N(C=C(N=1)C(F)(F)F)C)CN VERBHEOBZBFQOY-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012391 XPhos Pd G2 Substances 0.000 description 8
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 8
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 8
- 229940127271 compound 49 Drugs 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 8
- 239000007983 Tris buffer Substances 0.000 description 7
- KKTQSZYFMLGTDA-UHFFFAOYSA-N [4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanamine Chemical compound CC1=CC(C(F)(F)F)=NN1C1=CC=C(CN)C=C1 KKTQSZYFMLGTDA-UHFFFAOYSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 230000035699 permeability Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 239000012085 test solution Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 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 6
- VNMOXVXRYNMFCI-UHFFFAOYSA-N 4-amino-2-chloropyrimidin-5-ol Chemical compound NC1=NC(Cl)=NC=C1O VNMOXVXRYNMFCI-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XZULUAVFLKVCOJ-UHFFFAOYSA-N COC(N=CN=C1C2CC2)=C1C(N=C1)=NC2=C1OCCN2CC(C=C1)=CC=C1C1=NC2(CC2)CO1 Chemical compound COC(N=CN=C1C2CC2)=C1C(N=C1)=NC2=C1OCCN2CC(C=C1)=CC=C1C1=NC2(CC2)CO1 XZULUAVFLKVCOJ-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 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 6
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 6
- 229960001225 rifampicin Drugs 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 6
- BYXHEUWWJYYRNH-UHFFFAOYSA-N (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid Chemical compound COC1=NC=NC(C2CC2)=C1B(O)O BYXHEUWWJYYRNH-UHFFFAOYSA-N 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- LOEUJBDJSWWJPA-UHFFFAOYSA-N 2-bromo-1-methyl-4-(trifluoromethyl)imidazole Chemical compound CN1C(Br)=NC(C(F)(F)F)=C1 LOEUJBDJSWWJPA-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- VZZCIBQSVZYHCR-UHFFFAOYSA-N CC(C(N1)=O)OC(C=N2)=C1N=C2Cl Chemical compound CC(C(N1)=O)OC(C=N2)=C1N=C2Cl VZZCIBQSVZYHCR-UHFFFAOYSA-N 0.000 description 5
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 5
- 102100039414 WD repeat-containing protein 48 Human genes 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- HVTICUPFWKNHNG-BJUDXGSMSA-N iodoethane Chemical group [11CH3]CI HVTICUPFWKNHNG-BJUDXGSMSA-N 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 101150042041 wdr48 gene Proteins 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 4
- HTNLODQQNAUXRB-UHFFFAOYSA-N 2-chloro-6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine Chemical compound CC1CNc2nc(Cl)ncc2O1 HTNLODQQNAUXRB-UHFFFAOYSA-N 0.000 description 4
- GYQORXHFUXETMQ-UHFFFAOYSA-N 2-chloro-7,8-dihydro-6h-pyrimido[5,4-b][1,4]oxazine Chemical compound O1CCNC2=NC(Cl)=NC=C21 GYQORXHFUXETMQ-UHFFFAOYSA-N 0.000 description 4
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 4
- HEPPAPZASXFWTB-UHFFFAOYSA-N 3,3-dibromo-1,1,1-trifluoropropan-2-one Chemical compound FC(F)(F)C(=O)C(Br)Br HEPPAPZASXFWTB-UHFFFAOYSA-N 0.000 description 4
- YUTVJOZNBUSBPJ-UHFFFAOYSA-N 3-fluoro-4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile Chemical compound CN1C(C(C=CC(C#N)=C2)=C2F)=NC(C(F)(F)F)=C1 YUTVJOZNBUSBPJ-UHFFFAOYSA-N 0.000 description 4
- LOHNPLWOCVLNPO-UHFFFAOYSA-N 3-fluoro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]benzonitrile Chemical compound N#CC(C=C1)=CC(F)=C1C1=NC(C(F)(F)F)=CN1 LOHNPLWOCVLNPO-UHFFFAOYSA-N 0.000 description 4
- DPGSPRJLAZGUBQ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane Substances CC1(C)OB(C=C)OC1(C)C DPGSPRJLAZGUBQ-UHFFFAOYSA-N 0.000 description 4
- XKYKGKIPBXUMIK-UHFFFAOYSA-N 4-[5-(trifluoromethyl)-1h-imidazol-2-yl]benzonitrile Chemical compound N1C(C(F)(F)F)=CN=C1C1=CC=C(C#N)C=C1 XKYKGKIPBXUMIK-UHFFFAOYSA-N 0.000 description 4
- ONWJMORXKKROJS-UHFFFAOYSA-N 4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]benzonitrile Chemical compound CC1=CC(=NN1C1=CC=C(C#N)C=C1)C(F)(F)F ONWJMORXKKROJS-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- QFUNYIOOOSMDJE-UHFFFAOYSA-N CC(C)(C1=C(N2CC(C=C3)=CC(F)=C3C3=NC(C(F)(F)F)=CN3C)N=C(C(C(C3CC3)=NC=N3)=C3OC)N=C1)OC2=O Chemical compound CC(C)(C1=C(N2CC(C=C3)=CC(F)=C3C3=NC(C(F)(F)F)=CN3C)N=C(C(C(C3CC3)=NC=N3)=C3OC)N=C1)OC2=O QFUNYIOOOSMDJE-UHFFFAOYSA-N 0.000 description 4
- JHLIGPSTIHQORT-UHFFFAOYSA-N CN1C(C2=CC=C(C3(CC3)NC3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3NC(CCl)=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(C3(CC3)NC3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3NC(CCl)=O)C=C2)=NC(C(F)(F)F)=C1 JHLIGPSTIHQORT-UHFFFAOYSA-N 0.000 description 4
- DPPIOVOQIXBBES-UHFFFAOYSA-N CN1C(C2=CC=C(CN(C34CC3)C(N=C(C(C(C3CC3)=NC=N3)=C3OC)N=C3)=C3NC4=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN(C34CC3)C(N=C(C(C(C3CC3)=NC=N3)=C3OC)N=C3)=C3NC4=O)C=C2)=NC(C(F)(F)F)=C1 DPPIOVOQIXBBES-UHFFFAOYSA-N 0.000 description 4
- MEGOCYCPZARBEO-UHFFFAOYSA-N CN1C(C2=CC=C(CN(C3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3CN3C)C3=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN(C3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3CN3C)C3=O)C=C2)=NC(C(F)(F)F)=C1 MEGOCYCPZARBEO-UHFFFAOYSA-N 0.000 description 4
- RWERENIXODKFGM-UHFFFAOYSA-N CN1C(C2=CC=C(CN3C(N=C(N=C4)Cl)=C4SCC3=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN3C(N=C(N=C4)Cl)=C4SCC3=O)C=C2)=NC(C(F)(F)F)=C1 RWERENIXODKFGM-UHFFFAOYSA-N 0.000 description 4
- ITFBWPSBJPPVEK-UHFFFAOYSA-N CN1C(C2=CC=C(CNC3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3N)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CNC3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3N)C=C2)=NC(C(F)(F)F)=C1 ITFBWPSBJPPVEK-UHFFFAOYSA-N 0.000 description 4
- GPPMOSLTSIWINJ-UHFFFAOYSA-N CN1C(C2=CN=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4OCC3)N=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CN=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4OCC3)N=C2)=NC(C(F)(F)F)=C1 GPPMOSLTSIWINJ-UHFFFAOYSA-N 0.000 description 4
- ZCZHEKHDBAAWLB-UHFFFAOYSA-N COC(=O)CSC1=CNC(=O)NC1=O Chemical compound COC(=O)CSC1=CNC(=O)NC1=O ZCZHEKHDBAAWLB-UHFFFAOYSA-N 0.000 description 4
- AFWXKLNITRRMES-UHFFFAOYSA-N COC(CSC(C(Cl)=N1)=CN=C1Cl)=O Chemical compound COC(CSC(C(Cl)=N1)=CN=C1Cl)=O AFWXKLNITRRMES-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 239000012981 Hank's balanced salt solution Substances 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- FNKQDMJAXLKYRT-UHFFFAOYSA-N N#CC(C=C1)=CC(Br)=C1C1=NC(C(F)(F)F)=CN1 Chemical compound N#CC(C=C1)=CC(Br)=C1C1=NC(C(F)(F)F)=CN1 FNKQDMJAXLKYRT-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- JFJVQQRPDVSNBS-UHFFFAOYSA-N O=C(C1=CC=C(CBr)C=C1)NC1(CBr)CC1 Chemical compound O=C(C1=CC=C(CBr)C=C1)NC1(CBr)CC1 JFJVQQRPDVSNBS-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000012054 celltiter-glo Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- LKGNVBFBYDSIDD-UHFFFAOYSA-N ethyl 1-[(2-chloro-5-nitropyrimidin-4-yl)amino]cyclopropane-1-carboxylate Chemical compound ClC1=NC=C(C(=N1)NC1(CC1)C(=O)OCC)[N+](=O)[O-] LKGNVBFBYDSIDD-UHFFFAOYSA-N 0.000 description 4
- 238000004020 luminiscence type Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- FYJMUWOTWLKYGI-UHFFFAOYSA-N methyl 2,3-difluoro-4-formylbenzoate Chemical compound FC1=C(C(=O)OC)C=CC(=C1F)C=O FYJMUWOTWLKYGI-UHFFFAOYSA-N 0.000 description 4
- YCFUSIDKEYANIW-UHFFFAOYSA-N methyl 2,3-difluoro-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(F)=C1F YCFUSIDKEYANIW-UHFFFAOYSA-N 0.000 description 4
- DKTXXBLWUUYFNL-UHFFFAOYSA-N methyl 4-(bromomethyl)-2,3-difluorobenzoate Chemical compound COC(=O)C1=CC=C(CBr)C(F)=C1F DKTXXBLWUUYFNL-UHFFFAOYSA-N 0.000 description 4
- VATZWIDNCRHSNY-UHFFFAOYSA-N methyl 4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]benzoate Chemical compound CN1C(=NC(=C1)C(F)(F)F)C1=CC=C(C(=O)OC)C=C1 VATZWIDNCRHSNY-UHFFFAOYSA-N 0.000 description 4
- UJWBCESALZUPJV-UHFFFAOYSA-N methyl 4-[5-(trifluoromethyl)-1H-imidazol-2-yl]benzoate Chemical compound FC(C=1N=C(NC=1)C1=CC=C(C(=O)OC)C=C1)(F)F UJWBCESALZUPJV-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 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 3
- 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 3
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 3
- 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 3
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 3
- WAJDAMXWYAIGNT-UHFFFAOYSA-N (5-bromopyrimidin-2-yl)methoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCC1=NC=C(Br)C=N1 WAJDAMXWYAIGNT-UHFFFAOYSA-N 0.000 description 3
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- 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 3
- LYFNAJACLPGPIK-UHFFFAOYSA-N 1-methyl-4-(trifluoromethyl)imidazole Chemical compound CN1C=NC(C(F)(F)F)=C1 LYFNAJACLPGPIK-UHFFFAOYSA-N 0.000 description 3
- INUSQTPGSHFGHM-UHFFFAOYSA-N 2,4-dichloro-5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=C(Cl)N=C1Cl INUSQTPGSHFGHM-UHFFFAOYSA-N 0.000 description 3
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 3
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 3
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- YHIBCIDSHJXHRI-UHFFFAOYSA-N 4-[[tert-butyl(dimethyl)silyl]oxymethyl]benzoic acid Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC=C(C(O)=O)C=C1 YHIBCIDSHJXHRI-UHFFFAOYSA-N 0.000 description 3
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 3
- IDXDWFFUFAQSND-UHFFFAOYSA-N CN1C(C2=CC=C(CN(C3=C(C4(CC4)O4)C=NC(C(C(C5CC5)=NC=N5)=C5OC)=N3)C4=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN(C3=C(C4(CC4)O4)C=NC(C(C(C5CC5)=NC=N5)=C5OC)=N3)C4=O)C=C2)=NC(C(F)(F)F)=C1 IDXDWFFUFAQSND-UHFFFAOYSA-N 0.000 description 3
- SZUQNGFDCUUNPC-UHFFFAOYSA-N CN1C(C2=CC=C(CN(C3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3CN3)C3=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN(C3=NC(C(C(C4CC4)=NC=N4)=C4OC)=NC=C3CN3)C3=O)C=C2)=NC(C(F)(F)F)=C1 SZUQNGFDCUUNPC-UHFFFAOYSA-N 0.000 description 3
- QMTFJHMAWNLPCD-UHFFFAOYSA-N CN1C(C2=CC=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4N=CC3=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4N=CC3=O)C=C2)=NC(C(F)(F)F)=C1 QMTFJHMAWNLPCD-UHFFFAOYSA-N 0.000 description 3
- OITQPGHAZZECKE-UHFFFAOYSA-N CN1C(C2=CC=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4SCC3=O)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4SCC3=O)C=C2)=NC(C(F)(F)F)=C1 OITQPGHAZZECKE-UHFFFAOYSA-N 0.000 description 3
- JSTMKRKHIINMLX-UHFFFAOYSA-N CN1C(C2=CN=C(CO)N=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CN=C(CO)N=C2)=NC(C(F)(F)F)=C1 JSTMKRKHIINMLX-UHFFFAOYSA-N 0.000 description 3
- OMBFXGXMUGEYNK-UHFFFAOYSA-N COC(N=CN=C1C2CC2)=C1C(N=C1)=NC2=C1OCCN2CC(C=C1)=CC=C1C1=NNN=N1 Chemical compound COC(N=CN=C1C2CC2)=C1C(N=C1)=NC2=C1OCCN2CC(C=C1)=CC=C1C1=NNN=N1 OMBFXGXMUGEYNK-UHFFFAOYSA-N 0.000 description 3
- 206010053138 Congenital aplastic anaemia Diseases 0.000 description 3
- 201000004939 Fanconi anemia Diseases 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 3
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 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 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 3
- 239000013553 cell monolayer Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940125846 compound 25 Drugs 0.000 description 3
- 229940125851 compound 27 Drugs 0.000 description 3
- 229940126540 compound 41 Drugs 0.000 description 3
- 229940125844 compound 46 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229960005371 tolbutamide Drugs 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- 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 2
- 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 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
- 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
- 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 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 2
- 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 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
- FNHHVPPSBFQMEL-KQHDFZBMSA-N (3S)-5-N-[(1S,5R)-3-hydroxy-6-bicyclo[3.1.0]hexanyl]-7-N,3-dimethyl-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide Chemical compound CNC(=O)c1cc(cc2c1OC[C@@]2(C)c1ccccc1)C(=O)NC1[C@H]2CC(O)C[C@@H]12 FNHHVPPSBFQMEL-KQHDFZBMSA-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
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 description 2
- SRKGZXIJDGWVAI-GVAVTCRGSA-M (e,3r)-7-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)C1=NC(C(C)(C)C)=CC(C=2C=CC(F)=CC=2)=C1\C=C\C(O)C[C@@H](O)CC([O-])=O SRKGZXIJDGWVAI-GVAVTCRGSA-M 0.000 description 2
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QXOGPTXQGKQSJT-UHFFFAOYSA-N 1-amino-4-[4-(3,4-dimethylphenyl)sulfanylanilino]-9,10-dioxoanthracene-2-sulfonic acid Chemical compound Cc1ccc(Sc2ccc(Nc3cc(c(N)c4C(=O)c5ccccc5C(=O)c34)S(O)(=O)=O)cc2)cc1C QXOGPTXQGKQSJT-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- DWFPZDNYWVYUMK-UHFFFAOYSA-N 1h-pyrimido[4,5-d]pyrimidine-2,4-dione Chemical compound C1=NC=C2C(=O)NC(=O)NC2=N1 DWFPZDNYWVYUMK-UHFFFAOYSA-N 0.000 description 2
- 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 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
- VCUXVXLUOHDHKK-UHFFFAOYSA-N 2-(2-aminopyrimidin-4-yl)-4-(2-chloro-4-methoxyphenyl)-1,3-thiazole-5-carboxamide Chemical compound ClC1=CC(OC)=CC=C1C1=C(C(N)=O)SC(C=2N=C(N)N=CC=2)=N1 VCUXVXLUOHDHKK-UHFFFAOYSA-N 0.000 description 2
- KJBONRGCLLBWCJ-UHFFFAOYSA-N 2-(tert-butylamino)-1-(7-ethyl-1-benzofuran-2-yl)ethanol;hydron;chloride Chemical compound Cl.CCC1=CC=CC2=C1OC(C(O)CNC(C)(C)C)=C2 KJBONRGCLLBWCJ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 2
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- DFRAKBCRUYUFNT-UHFFFAOYSA-N 3,8-dicyclohexyl-2,4,7,9-tetrahydro-[1,3]oxazino[5,6-h][1,3]benzoxazine Chemical compound C1CCCCC1N1CC(C=CC2=C3OCN(C2)C2CCCCC2)=C3OC1 DFRAKBCRUYUFNT-UHFFFAOYSA-N 0.000 description 2
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 2
- UXDLLFIRCVPPQP-UHFFFAOYSA-N 4-hydrazinylbenzonitrile;hydrochloride Chemical compound [Cl-].[NH3+]NC1=CC=C(C#N)C=C1 UXDLLFIRCVPPQP-UHFFFAOYSA-N 0.000 description 2
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 2
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 2
- XASOHFCUIQARJT-UHFFFAOYSA-N 8-methoxy-6-[7-(2-morpholin-4-ylethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-1-one Chemical compound C(N1C(=O)C2=C(OC)C=C(C=3N4C(=NC=3)C=C(C=C4)OCCN3CCOCC3)C=C2CC1)C(F)(F)F XASOHFCUIQARJT-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 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
- SBPSRDHXOSRDHX-UHFFFAOYSA-N CN1C(C(C=CC(CN(C(N=C(C(C(C2CC2)=NC=N2)=C2OC)N=C2)=C2N2C)N(C)C2=O)=C2)=C2F)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C(C=CC(CN(C(N=C(C(C(C2CC2)=NC=N2)=C2OC)N=C2)=C2N2C)N(C)C2=O)=C2)=C2F)=NC(C(F)(F)F)=C1 SBPSRDHXOSRDHX-UHFFFAOYSA-N 0.000 description 2
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- 108050006400 Cyclin Proteins 0.000 description 2
- 108010074922 Cytochrome P-450 CYP1A2 Proteins 0.000 description 2
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 2
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 2
- 102100026533 Cytochrome P450 1A2 Human genes 0.000 description 2
- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 2
- 102100039205 Cytochrome P450 3A4 Human genes 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 201000000097 Fanconi anemia complementation group I Diseases 0.000 description 2
- 102100034554 Fanconi anemia group I protein Human genes 0.000 description 2
- 101710096018 Fanconi anemia group I protein Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 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
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 102000009339 Proliferating Cell Nuclear Antigen Human genes 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 108010066496 Ubiquitin-Specific Proteases Proteins 0.000 description 2
- 102000018390 Ubiquitin-Specific Proteases Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-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
- 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
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000011166 aliquoting Methods 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 229960004538 alprazolam Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000003149 assay kit Methods 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940125936 compound 42 Drugs 0.000 description 2
- 229940126545 compound 53 Drugs 0.000 description 2
- 229940127113 compound 57 Drugs 0.000 description 2
- 229940125900 compound 59 Drugs 0.000 description 2
- 229940126179 compound 72 Drugs 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 2
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 2
- DGODWNOPHMXOTR-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium;dihydrate Chemical compound O.O.[K+].[K+].[O-][Os]([O-])(=O)=O DGODWNOPHMXOTR-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- GWNFQAKCJYEJEW-UHFFFAOYSA-N ethyl 3-[8-[[4-methyl-5-[(3-methyl-4-oxophthalazin-1-yl)methyl]-1,2,4-triazol-3-yl]sulfanyl]octanoylamino]benzoate Chemical compound CCOC(=O)C1=CC(NC(=O)CCCCCCCSC2=NN=C(CC3=NN(C)C(=O)C4=CC=CC=C34)N2C)=CC=C1 GWNFQAKCJYEJEW-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 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 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- DLBFLQKQABVKGT-UHFFFAOYSA-L lucifer yellow dye Chemical compound [Li+].[Li+].[O-]S(=O)(=O)C1=CC(C(N(C(=O)NN)C2=O)=O)=C3C2=CC(S([O-])(=O)=O)=CC3=C1N DLBFLQKQABVKGT-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 2
- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 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
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960003893 phenacetin Drugs 0.000 description 2
- 125000004437 phosphorous atom Chemical group 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 230000034512 ubiquitination Effects 0.000 description 2
- 238000010798 ubiquitination Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- JEQDSBVHLKBEIZ-REOHCLBHSA-N (2s)-2-chloropropanoyl chloride Chemical compound C[C@H](Cl)C(Cl)=O JEQDSBVHLKBEIZ-REOHCLBHSA-N 0.000 description 1
- ZRHVXSBXNUJBGF-UHFFFAOYSA-N (5-bromopyrimidin-2-yl)methanol Chemical compound OCC1=NC=C(Br)C=N1 ZRHVXSBXNUJBGF-UHFFFAOYSA-N 0.000 description 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- GMHKMTDVRCWUDX-LBPRGKRZSA-N (S)-Mephenytoin Chemical compound C=1C=CC=CC=1[C@]1(CC)NC(=O)N(C)C1=O GMHKMTDVRCWUDX-LBPRGKRZSA-N 0.000 description 1
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- RKOUFQLNMRAACI-UHFFFAOYSA-N 1,1,1-trifluoro-2-iodoethane Chemical compound FC(F)(F)CI RKOUFQLNMRAACI-UHFFFAOYSA-N 0.000 description 1
- SHXHPUAKLCCLDV-UHFFFAOYSA-N 1,1,1-trifluoropentane-2,4-dione Chemical compound CC(=O)CC(=O)C(F)(F)F SHXHPUAKLCCLDV-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- ILWJAOPQHOZXAN-UHFFFAOYSA-N 1,3-dithianyl Chemical group [CH]1SCCCS1 ILWJAOPQHOZXAN-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- 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 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ANVIYYKETYLSRV-UHFFFAOYSA-N 2,3-difluoro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(F)=C1F ANVIYYKETYLSRV-UHFFFAOYSA-N 0.000 description 1
- OBHCCORLMBZISY-UHFFFAOYSA-N 2,3-dimethylbutane-2,3-diol;ethenylboronic acid Chemical compound OB(O)C=C.CC(C)(O)C(C)(C)O OBHCCORLMBZISY-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- NQYUCHZJGKSXNL-UHFFFAOYSA-N 2-chloro-4-N-[[4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrimidine-4,5-diamine Chemical compound ClC1=NC=C(C(=N1)NCC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C)N NQYUCHZJGKSXNL-UHFFFAOYSA-N 0.000 description 1
- ORUMXWAUZBTDLW-UHFFFAOYSA-N 2-chloro-5-methoxypyrimidin-4-amine Chemical compound COC1=CN=C(Cl)N=C1N ORUMXWAUZBTDLW-UHFFFAOYSA-N 0.000 description 1
- ULQNAQJGIFHLSB-UHFFFAOYSA-N 2-chloro-N-[[4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-5-nitropyrimidin-4-amine Chemical compound ClC1=NC=C(C(=N1)NCC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C)[N+](=O)[O-] ULQNAQJGIFHLSB-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- FMKOJHQHASLBPH-OUBTZVSYSA-N 2-iodopropane Chemical group CC([13CH3])I FMKOJHQHASLBPH-OUBTZVSYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- XBQNZPDIRJPFAI-UHFFFAOYSA-N 3,3-dimethylpyrrolidine Chemical compound CC1(C)CCNC1 XBQNZPDIRJPFAI-UHFFFAOYSA-N 0.000 description 1
- ADHKMYHLJHBOKB-UHFFFAOYSA-N 3-bromo-4-formylbenzonitrile Chemical compound BrC1=CC(C#N)=CC=C1C=O ADHKMYHLJHBOKB-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- QXHUSGWCFSXQMF-UHFFFAOYSA-N 3-fluoro-4-formylbenzonitrile Chemical compound FC1=CC(C#N)=CC=C1C=O QXHUSGWCFSXQMF-UHFFFAOYSA-N 0.000 description 1
- FEWJMEMEEABOOS-UHFFFAOYSA-N 3-fluoro-4-hydrazinylbenzonitrile Chemical group NNC1=CC=C(C#N)C=C1F FEWJMEMEEABOOS-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 description 1
- UIADWSXPNFQQCZ-UHFFFAOYSA-N 4-[4-(3,4-dichlorophenyl)-5-phenyl-1,3-oxazol-2-yl]butanoic acid Chemical group ClC=1C=C(C=CC=1Cl)C=1N=C(OC=1C1=CC=CC=C1)CCCC(=O)O UIADWSXPNFQQCZ-UHFFFAOYSA-N 0.000 description 1
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 1
- WROMFHICINADER-UHFFFAOYSA-N 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine Chemical compound C1NCCN2C=NC=C21 WROMFHICINADER-UHFFFAOYSA-N 0.000 description 1
- DFLGRTIPTPCKPJ-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-imidazole Chemical compound FC(F)(F)C1=CN=CN1 DFLGRTIPTPCKPJ-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VHIBOFWCGOAFJE-UHFFFAOYSA-N C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.Cl.Cl.[Fe+2] Chemical compound C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.C1=CC=C[C-]1P(C1=CC=CC=C1)C1=CC=CC=C1.Cl.Cl.[Fe+2] VHIBOFWCGOAFJE-UHFFFAOYSA-N 0.000 description 1
- WYTOQOHZMQIASO-UHFFFAOYSA-N CC(C)C1=NC=CC=C1C(N=C1)=NC2=C1OCCN2CC(C=C1)=CC=C1C1=NC(C(F)(F)F)=CN1C Chemical compound CC(C)C1=NC=CC=C1C(N=C1)=NC2=C1OCCN2CC(C=C1)=CC=C1C1=NC(C(F)(F)F)=CN1C WYTOQOHZMQIASO-UHFFFAOYSA-N 0.000 description 1
- ADVYUWSUUYVLIB-UHFFFAOYSA-N CCN1C(C(C=CC(CN(C2=C(C(C)(C)O3)C=NC(C(C(C4CC4)=NC=N4)=C4OC)=N2)C3=O)=C2)=C2F)=NC(C(F)(F)F)=C1 Chemical compound CCN1C(C(C=CC(CN(C2=C(C(C)(C)O3)C=NC(C(C(C4CC4)=NC=N4)=C4OC)=N2)C3=O)=C2)=C2F)=NC(C(F)(F)F)=C1 ADVYUWSUUYVLIB-UHFFFAOYSA-N 0.000 description 1
- OZGMPNPXKUCNOJ-UHFFFAOYSA-N CCOC(C(C(NCC(C=C1)=CC=C1C1=NC(C(F)(F)F)=CN1C)=N1)=CN=C1Cl)=O Chemical compound CCOC(C(C(NCC(C=C1)=CC=C1C1=NC(C(F)(F)F)=CN1C)=N1)=CN=C1Cl)=O OZGMPNPXKUCNOJ-UHFFFAOYSA-N 0.000 description 1
- VDXBTVPLGGROPT-UHFFFAOYSA-N CN1C(C(C=CC(CN(C2=C(C3(CC3)O3)C=NC(C(C(C4CC4)=NC=N4)=C4OC)=N2)C3=O)=C2)=C2F)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C(C=CC(CN(C2=C(C3(CC3)O3)C=NC(C(C(C4CC4)=NC=N4)=C4OC)=N2)C3=O)=C2)=C2F)=NC(C(F)(F)F)=C1 VDXBTVPLGGROPT-UHFFFAOYSA-N 0.000 description 1
- AWMAIQKYRJAUMH-UHFFFAOYSA-N CN1C(C2=CC=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4N(CC(F)(F)F)CC3)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CN3C(N=C(C(C(C4CC4)=NC=N4)=C4OC)N=C4)=C4N(CC(F)(F)F)CC3)C=C2)=NC(C(F)(F)F)=C1 AWMAIQKYRJAUMH-UHFFFAOYSA-N 0.000 description 1
- RDZSMSXOUBXIQL-UHFFFAOYSA-N CN1C(C2=CC=C(CNC3=NC(Cl)=NC=C3C#N)C=C2)=NC(C(F)(F)F)=C1 Chemical compound CN1C(C2=CC=C(CNC3=NC(Cl)=NC=C3C#N)C=C2)=NC(C(F)(F)F)=C1 RDZSMSXOUBXIQL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 102100024462 Cyclin-dependent kinase 4 inhibitor B Human genes 0.000 description 1
- 230000000970 DNA cross-linking effect Effects 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241001233988 Erysimum cheiri Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 101000980919 Homo sapiens Cyclin-dependent kinase 4 inhibitor B Proteins 0.000 description 1
- 101100298362 Homo sapiens PPIG gene Proteins 0.000 description 1
- 101000653548 Homo sapiens Trichoplein keratin filament-binding protein Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 238000003725 ONE-Glo Luciferase Assay System Methods 0.000 description 1
- NTKVWOTYTNWGRK-UHFFFAOYSA-N P.Br.Br.Br Chemical compound P.Br.Br.Br NTKVWOTYTNWGRK-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 102100030645 Trichoplein keratin filament-binding protein Human genes 0.000 description 1
- 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 1
- ULEMJGCUGKDKTD-UHFFFAOYSA-N [1-(hydroxymethyl)cyclopropyl]azanium;chloride Chemical compound Cl.OCC1(N)CC1 ULEMJGCUGKDKTD-UHFFFAOYSA-N 0.000 description 1
- UJQAHAANAPEYLR-UHFFFAOYSA-N [2-chloro-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]-dicyclohexylphosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(Cl)=C1P(C1CCCCC1)C1CCCCC1 UJQAHAANAPEYLR-UHFFFAOYSA-N 0.000 description 1
- WDVKDMUOFAUURW-UHFFFAOYSA-N [4-[1-methyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanamine Chemical compound CN1C(=NC(=C1)C(F)(F)F)C1=CC=C(C=C1)CN WDVKDMUOFAUURW-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 1
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 238000012200 cell viability kit Methods 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical group O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 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
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([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
- 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
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000009504 deubiquitination Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 125000005959 diazepanyl group Chemical group 0.000 description 1
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 OCXGTPDKNBIOTF-UHFFFAOYSA-N 0.000 description 1
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- DBLXOVFQHHSKRC-UHFFFAOYSA-N ethanesulfonic acid;2-piperazin-1-ylethanol Chemical compound CCS(O)(=O)=O.OCCN1CCNCC1 DBLXOVFQHHSKRC-UHFFFAOYSA-N 0.000 description 1
- SRJBDGLSCPDXBL-UHFFFAOYSA-N ethyl 2,4-dichloropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)N=C1Cl SRJBDGLSCPDXBL-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 102000056262 human PPIG Human genes 0.000 description 1
- 102000054399 human USP1 Human genes 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- VLODBNNWEWTQJX-UHFFFAOYSA-N iodocyclopropane Chemical group IC1CC1 VLODBNNWEWTQJX-UHFFFAOYSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical group I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 108010076401 isopeptidase Proteins 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- PQUSVJVVRXWKDG-UHFFFAOYSA-N methyl 2-bromo-2-methylpropanoate Chemical compound COC(=O)C(C)(C)Br PQUSVJVVRXWKDG-UHFFFAOYSA-N 0.000 description 1
- ACEONLNNWKIPTM-UHFFFAOYSA-N methyl 2-bromopropanoate Chemical compound COC(=O)C(C)Br ACEONLNNWKIPTM-UHFFFAOYSA-N 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 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
- 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
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- TWSTVYFPWIGASI-UHFFFAOYSA-N oxetan-3-ol Chemical compound OC1COC1.OC1COC1 TWSTVYFPWIGASI-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 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
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 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
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- WCONKKYQBKPMNZ-UHFFFAOYSA-N prop-1-en-2-ylboronic acid Chemical compound CC(=C)B(O)O WCONKKYQBKPMNZ-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- GGZRVXCSRWTOME-UHFFFAOYSA-N pyridine;toluene Chemical compound C1=CC=NC=C1.CC1=CC=CC=C1 GGZRVXCSRWTOME-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 230000006824 pyrimidine synthesis Effects 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 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
- 239000011986 second-generation catalyst Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- PACZWTPIBAWVLF-UHFFFAOYSA-N tert-butyl n-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]carbamate Chemical compound C=1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1C1(NC(=O)OC(C)(C)C)CC1 PACZWTPIBAWVLF-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
- YCCHNFGPIFYNTF-UHFFFAOYSA-N tertiary cymene hydroperoxide Natural products CC1=CC=C(C(C)(C)OO)C=C1 YCCHNFGPIFYNTF-UHFFFAOYSA-N 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 229960001722 verapamil 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
- 239000001993 wax Substances 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring 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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring 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
-
- 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
- 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
-
- 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- 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
- C07D498/02—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 two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- C07D498/02—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 two hetero rings
- C07D498/10—Spiro-condensed systems
-
- 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
- C07D498/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- 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
Definitions
- Patent application No. 202110403760.7 submitted to the State Intellectual Property Office of China on April 9, 2021;
- Patent application No. 202110829701.6 submitted to the State Intellectual Property Office of China on July 22, 2021;
- Patent application No. 202111166322.X submitted to the State Intellectual Property Office of China on September 30, 2021;
- Patent application No. 202210242231.8 submitted to the State Intellectual Property Office of China on March 11, 2022.
- the present application belongs to the field of medical technology, and relates to compounds as ubiquitin-specific protease 1 (USP1) inhibitors or optical isomers, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and as USP1 inhibitors in the prevention or Use in the treatment of diseases associated with USP1.
- USP1 ubiquitin-specific protease 1
- Ubiquitination is a reversible process that involves a series of deubiquitinating enzymes (DUBs) that regulate a variety of cellular processes by deubiquitinating substrates.
- DUBs are encoded by about 100 human genes and are divided into 6 families, the largest of which are ubiquitin-specific proteases (USPs) with more than 50 members.
- USPs ubiquitin-specific proteases
- DUBs and their substrate proteins are frequently dysregulated in cancer, supporting that targeting of specific DUB enzymes may be involved in tumor growth, survival, differentiation, and maintenance of the tumor microenvironment by enhancing the ubiquitination and degradation of oncogenic substrates and regulating the The hypothesis of the activity of other key proteins (Hussain, S., et.al., "DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors.” Cell Cycle 8, 1688-1697 (2009)) .
- USP1 is a cysteine isopeptidase of the USP subfamily in DUBs.
- the full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593 and Asp751.
- USP1 plays a role in DNA damage repair. USP1 is relatively inactive by itself, and complete enzymatic activity can only be obtained by binding to the cofactor UAF1 to form the complex required for deubiquitinase activity.
- the USP1/UAF1 complex deubiquitinates the monoubiquitinated PCNA (proliferating cell nuclear antigen) and the monoubiquitinated FANCD2 (Fanconianemia group complementary group D2), which are involved in translational synthesis (TLS) and It plays an important role in the Fanconi anemia (FA) pathway. Both of these pathways are required for the repair of DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC).
- MMC mitomycin C
- the USP1/UAF1 complex also deubiquitinates FANCI (Fanconianemia complementation group I).
- the importance of these findings was further confirmed by experiments that mice lacking USP1 were highly sensitive to DNA damage. Interestingly, USP1 expression was significantly increased in many cancers. Blocking USP1 to inhibit DNA repair induces apoptosis in multiple myeloma cells and also enhances the sensitivity of lung cancer cells to cisplatin.
- the application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
- X 1 is selected from CR 3 or N;
- X 2 is selected from N;
- X 5 is independently selected from C(R 4 )(R 5 ), NR 6 or O;
- R 3 , R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , -C(O)-C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group, the OH, NH 2.
- Ring A is selected from aryl or 5-10 membered heteroaryl optionally substituted by R b ;
- Ring B is selected from aryl, 5-10-membered heteroaryl, 4-10-membered heterocyclic, C3 - C10 cycloalkyl or C3 - C10 cycloalkenyl, the aryl, 5-10-membered Heteroaryl, 4-10 membered heterocyclyl, C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl optionally substituted with R c ;
- R b and R c are each independently selected from halogen, CN, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl,
- the OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by Ra ;
- R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4- 7-membered heterocyclyl, the NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by R a ;
- R 7 and R 8 together with the P to which they are attached form a 4-7 membered heterocyclyl group optionally substituted by Ra ;
- R 13 and R 14 together with the atoms to which they are attached form a 4-7 membered heterocyclyl group optionally substituted by Ra ;
- Ring C is selected from aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl optionally substituted by R;
- R d is selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, said OH, NH 2 , C 1 -C 6 Alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by R a ; or R c and R d together with the atoms to which they are attached form a 5-8 membered heterocyclyl or 5- 6-membered heteroaryl, the 5-8-membered heterocyclyl or 5-6-membered heteroaryl is optionally substituted by R a ;
- R 1 and R 2 are each independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by Ra ,
- R 1 and R 2 and the atoms to which they are attached together form a C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl, said C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl being any is replaced by Ra ;
- R f is selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl.
- R 4 and R 6 at different positions in the ring together with the atoms to which they are attached form a C 3 -C 10 heterocyclyl group means when the group C(R 4 )(R 5 ) or CR 4 and NR When 6 is located at different positions in the ring, R 4 and R 6 may together form a C 3 -C 10 heterocyclyl with the atoms to which R 4 and R 6 are attached.
- R 4 and R 6 together with the atoms to which they are attached form a C 3 -C 10 heterocyclyl.
- X 1 is selected from N and X 2 is selected from N.
- X 1 is selected from CR 3 and X 2 is selected from N.
- X1 is selected from CH and X2 is selected from N.
- X 1 is selected from CR 3 or N, wherein R 3 is H.
- X 3 and X 4 are each independently selected from C(R 4 )(R 5 ), CR 4 , NR 6 , or O.
- X 3 is selected from S.
- X 5 is selected from C(R 4 )(R 5 ).
- R 3 , R 4 , R 5 , R 6 are independently selected from H, halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -C(O)-C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 2 - C 6 alkenyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by Ra .
- R 3 , R 4 , R 5 , R 6 are independently selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C(O)-C 1 -C 6 alkyl, -C(O)OC 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, said C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 3 -C 10 ring Alkyl is optionally substituted with Ra .
- each Ra is independently selected from halogen or OH; each halogen is independently selected from F or Cl.
- R 6 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -C(O)-C 1 -C 6 alkyl, -C(O)OC 1 - C 6 alkyl or C 3 -C 10 cycloalkyl, said C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 3 -C 10 cycloalkyl optionally substituted by Ra , or R 6 is selected from H, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, said C 1 -C 6 alkyl is optionally substituted by Ra , or R is selected from H, C 1 -C 4 alkane or C 3 -C 6 cycloalkyl, said C 1 -C 4 alkyl is optionally substituted by R a , or R 6 is selected from H, C 1 -C 4 alkyl or C 3 -C 4 cycloalkyl , the
- R 4 and R 6 together with the atoms to which they are attached form a C 3 -C 6 heterocyclyl, so The C3 - C6 heterocyclyl group is optionally substituted by R a ; or, when X 4 is NR 6 and X 5 is C(R 4 )(R 5 ), R 4 and R 6 and the atom to which they are attached Together they form a C4 - C5 heterocyclyl optionally substituted with Ra .
- Ring A is selected from phenyl or 5-6 membered heteroaryl optionally substituted with Rb .
- Ring A is selected from phenyl, pyridyl, pyrimidinyl, or pyrazolyl optionally substituted with Rb .
- Ring A is selected from phenyl, pyridyl, or pyrimidinyl, optionally substituted with Rb .
- Ring A is selected from
- Ring A is selected from
- each R b is independently selected from halogen, OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or Said OH, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted by R a , wherein R a is selected from C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, so Said C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl is optionally substituted by R e , and R e is selected from halogen; or, each R b is independently selected from halogen, OH, C 1 -C 4 alkane or C 3 -C 6 cycloalkyl, said OH, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl is optionally substituted by R a , wherein R a is selected from C 1 -C 4 alkyl or
- Ring B is selected from aryl, 5-6 membered heteroaryl, 4-10 membered heterocyclyl, C3 - C10 cycloalkyl or C3 - C10 cycloalkenyl, the aryl group, 5-6 membered heteroaryl, 4-10 membered heterocyclyl, C3 - C10 cycloalkyl, C3 - C10 cycloalkenyl optionally substituted by Rc .
- Ring B is selected from phenyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3 - C8 cycloalkyl, or C4 - C6 cycloalkenyl, the benzene radical, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3 - C8 cycloalkyl or C4 - C6 cycloalkenyl optionally substituted with Rc .
- Ring B is selected from phenyl, 4-6 membered heterocyclyl, C3 - C8 cycloalkyl, or C4 - C6 cycloalkenyl, said phenyl, 4-6 membered heterocyclyl group, C3- C8cycloalkyl or C4 - C6cycloalkenyl optionally substituted with Rc .
- Ring B is selected from said Optionally substituted with Rc .
- Ring B is selected from said Optionally substituted with Rc .
- each R c is independently selected from halogen or C 1 -C 6 alkyl optionally substituted with R ; alternatively, each R c is independently selected from halogen or C 1 -C 4 alkyl optionally substituted with R a ; or, each R c is independently selected from F, Cl or C 1 -C 4 alkyl, the The C 1 -C 4 alkyl is optionally substituted with R a ; or, each R c is independently selected from F , Cl or C 1 -C 2 alkyl optionally substituted by R a replace.
- Ra is selected from halogen such as F or Cl.
- R b and R c are each independently selected from halogen, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocyclyl,
- the OH, NH2 , SH, C1 - C6 alkyl, C3 - C10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted with Ra .
- R b and R c are each independently selected from halogen, OH, NH 2 , SH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocyclyl,
- the OH, NH2 , SH, C1 - C6 alkyl, C3 - C10 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted with Ra .
- R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or a 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-7 membered heterocyclic group is optionally substituted by R a ;
- R 7 and R 8 together with the P to which they are attached form a 4-7 membered heterocyclyl group optionally substituted by Ra ;
- R 13 and R 14 together with the atoms to which they are attached form a 4-7 membered heterocyclyl optionally substituted with Ra .
- R b and R c are each independently selected from
- Ring C is selected from aryl or 5-10 membered heteroaryl optionally substituted with Rd .
- Ring C is selected from 5-6 membered heteroaryl optionally substituted with Rd .
- Ring C is selected from 4-10 membered heterocyclyl optionally substituted with Rd .
- R d is selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, said OH, NH 2 , C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl optionally substituted with Ra .
- R d is selected from C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, optionally by R a substituted; alternatively, R d is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, said C 1 -C 4 alkyl is optionally substituted by R a ; alternatively, R d is selected from C 1 - C 4 alkyl or C 3 -C 6 cycloalkyl, said C 1 -C 4 alkyl optionally substituted with R a selected from halogen such as F or Cl ; or R d selected from optionally R a substituted C 1 -C 4 alkyl, R a is selected from halogen such as F or Cl.
- R c and R d together with the atoms to which they are attached form a 6-7 membered heterocyclyl or 5-6 membered heteroaryl, which 6-7 membered heterocyclyl or 5-6 membered heterocyclyl Aryl is optionally substituted with Ra .
- Ring C is selected from
- Ring C is selected from
- Ring C is selected from
- R 1 and R 2 are each independently selected from H, halogen, CN, OH, NH 2 or C 1 -C 6 alkyl, said OH, NH 2 or C 1 -C 6 alkyl being any is replaced by Ra ,
- R 1 and R 2 are each independently selected from H, methyl, ethyl, or R 1 and R 2 and the atoms to which they are attached together form a ring as follows: said Optionally substituted with Ra .
- R 1 and R 2 are each independently selected from H, or R 1 and R 2 and the atoms to which they are attached together form a ring as follows: said Optionally substituted with Ra .
- both R 1 and R 2 are H.
- each R is independently selected from halogen, OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, said OH, C 1 -C 6 alkyl or C 3 - C 6 cycloalkyl is optionally substituted with R e , alternatively, each R a is independently selected from F, Cl, OH, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, OH or C 1 - C6 alkyl is optionally substituted with Re .
- R e is halogen, such as F or Cl.
- R f is selected from halogen, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl.
- a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present application is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof,
- Ring A, Ring B, Ring C, X 1 , X 2 , X 5 , R 1 , R 2 , R 4 , R 5 , R 6 are as defined in formula (I).
- the compound of formula (I), or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof,
- the present application relates to a preparation method of a compound of formula (I) or a pharmaceutically acceptable salt thereof, specifically as follows:
- X 3 is selected from O, S or NR 6 ;
- Ring A, Ring B, Ring C, X 1 , X 5 , R 1 , R 2 , R 4 , R 5 , R 6 are as defined in formula (I);
- LG 1 , LG 2 and LG 3 represent leaving groups commonly used in the art.
- the present application relates to a preparation method of a compound of formula (I) or a pharmaceutically acceptable salt thereof, specifically as follows:
- X 3 is selected from O, S or NR 6 ;
- Ring A, Ring B, Ring C, X 1 , X 5 , R 1 , R 2 , R 4 , R 5 , R 6 are as defined in formula (I);
- LG, LG 1 and LG 2 represent leaving groups commonly used in the art.
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
- the application provides a method of treating a disease mediated by USP1 in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or its pharmaceutical composition.
- the present application provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating USP1-mediated diseases.
- the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of USP1 mediated diseases.
- the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating USP1-mediated diseases.
- the USP1-mediated disease is a tumor.
- the tumor is, for example, a solid tumor, an adenocarcinoma, or a hematological cancer, such as breast cancer.
- bonds delineated by solid and dashed lines is a single or double bond.
- the components Covers both of the following:
- the compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present application may exist in specific geometric isomer or stereoisomeric forms.
- Particular geometric or stereoisomeric forms may be cis and trans isomers, E-, Z-geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers
- Enantiomerically enriched mixtures all of the above isomers and mixtures thereof are within the scope of the definition of the compounds of the present application.
- asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituent groups are also included in the Within the definition of the compounds of the present application.
- Compounds of the present application containing asymmetric atoms can be isolated in optically pure form or in racemic form, optically pure forms can be resolved from racemic mixtures, or synthesized by using chiral starting materials or chiral reagents .
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may be deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted ( eg, CH2CH2F , CH2CH2Cl , etc. ) , polysubstituted (eg CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc.
- any variable eg, Ra , Rb
- its definition in each case is independent. For example, if a group is substituted with 2 R bs , each R b has independent options.
- L 1 When a linking group referred to herein does not indicate its direction of attachment, its direction of attachment is arbitrary.
- L 1 when the structural unit When L 1 is selected from “C 1 -C 3 alkylene-O", at this time L 1 can connect ring Q and R 1 in the same direction as the reading sequence from left to right to form “ring QC 1 -C 3 alkylene-OR 1 ", can also connect ring Q and R 1 in the opposite direction of the reading order from left to right to form “ring QOC 1 -C 3 alkylene-R 1 ".
- R 5 can be substituted at any position on the benzene ring, and R 5 can also be substituted at any position on the piperidine ring.
- halo or halogen refers to fluorine, chlorine, bromine or iodine.
- Cm - Cn herein means having an integer number of carbon atoms in the range mn.
- C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
- LG is the abbreviation of leaving group, specific examples include but are not limited to halogen, mesylate, p-toluenesulfonate, alkoxy, haloalkoxy, O-N-succinimidyl, penta Fluorophenoxy, 4-nitrophenoxy, etc.
- alkyl refers to a hydrocarbon group of the general formula CnH2n+1 .
- the alkyl group can be straight or branched.
- C1 - C10 alkyl is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2 -dimethylbutyl, etc.; term "C 1-6 alkyl " refers to an alkyl group containing 1 to 6 carbon atoms
- alkyl portion (ie, alkyl) of alkoxy, alkylamino and dialkylamino has the same definitions above.
- alkyl group is described as being optionally substituted with R groups, this means that the alkyl group is optionally substituted with one or more R groups.
- alkoxy, alkylamino and dialkylamino are described as being optionally substituted with R groups, this means that the alkoxy, alkylamino and dialkylamino are substituted with one or more R groups Optionally substituted.
- the "C 1 -C 10 alkyl” described herein may comprise “C 1 -C 6 alkyl", “C 1 -C 4 alkyl", “C 1 -C 3 alkyl” or “C 1 -C 2 alkyl”Alkyl", the “C 1 -C 6 alkyl” may further comprise “C 1 -C 4 alkyl", “C 1 -C 3 alkyl” or "C 1 -C 2 alkyl”.
- alkenyl refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
- C 2 -C 10 alkenyl is to be understood as preferably denoting a linear or branched monovalent hydrocarbon group comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
- C 2 -C 10 alkenyl is preferably "C 2 -C 6 alkenyl", more preferably "C 2 -C 4 alkenyl", still more preferably C 2 or C 3 alkenyl.
- alkenyl group contains more than one double bond
- the double bonds may be separated from each other or conjugated.
- alkenyl groups are eg vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-butanyl -2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2 -Alkenyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl.
- R group When an alkenyl group is described as being optionally substituted with an R group, this means that the alkenyl group is optionally substituted with one or more R groups.
- alkynyl refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond.
- C 2 -C 10 alkynyl is understood to mean a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- Examples of "C 2 -C 10 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ CCH 3, -CH 2 C ⁇ CH), but-1-ynyl, butanyl -2-alkynyl or but-3-ynyl.
- C 2 -C 10 alkynyl may include “C 2 -C 3 alkynyl", examples of “C 2 -C 3 alkynyl” include ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (-CH 2 C ⁇ CH).
- alkynyl group is described as being optionally substituted with an R group, this means that the alkynyl group is optionally substituted with one or more R groups.
- cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, paracyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 3- to 10-membered ring.
- C 3 -C 10 cycloalkyl should be understood to mean a saturated monovalent monocyclic, paracyclic, spirocyclic or bridged form of a carbocyclic group having 3, 4, 5, 6, 7 , 8, 9 or 10 carbon atoms.
- Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2. 1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decane, etc.
- Spirocycloalkyl refers to a cycloalkyl group that exists as a spiro ring.
- C 3 -C 10 cycloalkyl may include “C 3 -C 6 cycloalkyl", “C 3 -C 6 cycloalkyl” should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which Having 3, 4, 5 or 6 carbon atoms, specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- R groups When a cycloalkyl group is described as being optionally substituted with R groups, this means that the cycloalkyl group is optionally substituted with one or more R groups.
- cycloalkenyl refers to a partially saturated, non-aromatic carbocyclic ring that may exist as a monocyclic, paracyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 5, 6, 7 or 8 membered ring.
- Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like. When a cycloalkenyl group is described as being optionally substituted with R groups, this means that the cycloalkenyl group is optionally substituted with one or more R groups.
- 4-10 membered heterocyclyl means a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms and containing 1, 2, 3, 4 or 5 independent ring atoms Selected from the heteroatom or heteroatom group described above, preferably, "4-10-membered heterocyclic group” includes "4-7 membered heterocyclic group", wherein, non-limiting examples of 4-membered heterocyclic group include but Not limited to azetidinyl, oxetanyl; examples of 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl , pyrrolinyl, 4,5-dihydrooxazole, or 2,5-dihydro-1H-pyrrolyl; examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidiny
- the heterocyclic group may also be a bicyclic group, wherein, examples of 5,5-membered bicyclic heterocyclic groups include but are not limited to hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, 5,6-membered bicyclic heterocyclic group Examples of ring groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, 5,6,7,8-tetrahydro-[1,2,4]triazolo [4,3-a]pyrazinyl ring or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine.
- the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7 membered heterocyclic group, examples including but not limited to dihydroisoquinolinyl and the like.
- 4-7 membered heterocyclyl may include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocycloalkyl”, “4-6 membered heterocyclyl”Heterocycloalkyl",”5-6 membered heterocycloalkyl” and the like.
- heterocyclic groups are still non-aromatic in their entirety.
- a heterocyclyl group is described as being optionally substituted with an R group, this means that the heterocyclyl group is optionally substituted with one or more R groups.
- 4-10 membered heterocycloalkyl means a heterocycloalkyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms and containing 1, 2, 3, 4 or 5 ring atoms
- a heteroatom or heteroatom group is independently selected from the above-mentioned heteroatoms, preferably, "4-10-membered heterocycloalkyl” includes “4-7-membered heterocycloalkyl", wherein the 4-membered heterocycloalkyl group is not Limiting examples include, but are not limited to, azetidinyl, oxetanyl, thibutanyl, and examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, Examples of oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, te
- aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi electron system.
- an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
- C 6 -C 20 aryl is to be understood as preferably denoting a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms.
- rings with 6 carbon atoms such as phenyl; or rings with 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or with 10
- a ring of 13 carbon atoms such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or is a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
- C 6 -C 10 aryl is to be understood as preferably denoting a monovalent aromatic or partially aromatic all-carbon monocyclic or bicyclic group having 6 to 10 carbon atoms.
- rings with 6 carbon atoms such as phenyl; or rings with 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or with 10
- a ring of two carbon atoms such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl.
- heteroaryl refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, and an aromatic ring group in which the remaining ring atoms are C.
- heteroaryl refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, and an aromatic ring group in which the remaining ring atoms are C.
- 5-10 membered heteroaryl is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms and it contains 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. And, additionally in each case may be benzo-fused.
- heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc; Naph
- 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2 or 3, preferably 1 or 2 heteroatoms independently selected from N, O and S .
- a heteroaryl group is described as being optionally substituted with R groups, this means that the heteroaryl group is optionally substituted with one or more R groups.
- terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying as described herein
- the amount of a compound of the present application for the onset of one or more symptoms of a particular disease, condition or disorder will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the content of this application.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts refers to pharmaceutically acceptable acid or base addition salts, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
- composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
- the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
- pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
- the present application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature.
- isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
- isotopically-labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred for their ease of preparation and detectability.
- Positron emitting isotopes such as15O , 13N , 11C and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
- Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
- Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
- the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
- the pharmaceutical composition is in oral form.
- the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
- Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core.
- Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
- compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
- the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the units of NMR shifts are 10 ⁇ 6 (ppm).
- the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
- TMS tetramethylsilane
- IC50 refers to the half inhibitory concentration, the concentration at which half of the maximal inhibitory effect is achieved.
- DCM dichloromethane
- BBr 3 boron tribromide
- DMF N,N-dimethylformamide
- DMSO dimethyl sulfoxide
- LAH lithium aluminum tetrahydride or lithium aluminum hydride
- TsCl p-toluenesulfonic acid Acid chloride
- Pd(dppf)Cl 2 Pd(dppf)Cl 2 .
- CH 2 Cl 2 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane complex; 1,4-dioxane: dioxygen Hexacyclic; DIEA: N,N-diisopropylethylamine; THF: tetrahydrofuran; Imidazole: imidazole; TBSCl: tert-butyldimethylchlorosilane; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; Iodomethane: iodomethane; DIBAL-H: diisopropylaluminum hydride; MeCN : acetonitrile; NBS: N-bromosuccinimide; AIBN: azobisisobutyronitrile
- the synthetic route is as follows:
- compound 1B (0.76g, 5.2mmol) was added to N,N-dimethylformamide (10mL), followed by potassium carbonate (1.4g, 10mmol, 2.0eq), 1,2-dibromoethyl alkane (1.9 g, 10 mmol, 2.0 eq). After the resulting mixture was stirred at 60°C for 16 hours, the reaction solution was added to ice water (30 mL).
- the resulting solid (0.54 g, 2.1 mmol) was added to dimethyl sulfoxide (5 mL) followed by potassium carbonate (0.59 g, 4.2 mmol, 2.0 eq) at room temperature. After the resulting mixture was stirred and reacted at 100°C for 16 hours, the reaction solution was added to ice water (30 mL), and extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
- Step 7 2-Chloro-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydro-6H-pyrimidine Ipo[5,4-b][1,4]oxazine (1J)
- Step 8 2-(2-Isopropylpyridin-3-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)- 7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazine (Compound 1)
- the synthetic route is as follows:
- 2,4-Dichloro-5-nitropyrimidine (0.71 g, 3.7 mmol) and N,N-diisopropylethylamine (1.0 g, 7.8 mmol, 2.0 eq) were dissolved in tetrahydrofuran at room temperature (20 mL), after cooling to 0°C, compound 4B (0.93 g, 3.7 mmol, 1.0 eq) was added to the reaction solution. The resulting mixture was stirred at 0°C for 0.5 hours and then slowly returned to room temperature for 2 hours. The reaction solution was added to ice water (50 mL) and extracted with ethyl acetate (50 mL*3).
- Step 2 2-Chloro-N4-( 4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4,5-diamine (4D )
- compound 4D (0.5 g, 1.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), the resulting solution was cooled to 0 °C, and chloroacetyl chloride (0.15 g, 1.3 mmol) was slowly added. mmol, 1 eq), then potassium carbonate (0.36 g, 2.61 mmol, 2 eq) was added. The resulting mixture was reacted at 0°C for 2 hours, quenched by adding water (30 mL), and extracted with ethyl acetate (20 mL*3).
- Step 5 2-(2-Isopropylpyridin-3-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) -7,8-Dihydropteridine-6(5H)-one (4)
- Example 7 8-(4-(6-oxa-4-azaspiro[2.4]hept-4-en-5-yl)benzyl)-2-(4-cyclopropyl-6-methyl Preparation of oxypyrimidin-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (Compound 7)
- the synthetic route is as follows:
- Step 5 8-(4-(6-oxa-4-azaspiro[2.4]hept-4-en-5-yl)benzyl)-2-(4-cyclopropyl-6-methoxy pyrimidin-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (7)
- Example 8 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5,5-dimethyl-4,5-dihydrooxazole-2- Preparation of yl)benzyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (Compound 8)
- the synthetic route is as follows:
- the synthetic route is as follows:
- Step 1 Synthesis of methyl 6-(3,3-dimethylpyrrolidin-1-yl)nicotinate (14B)
- Compound 14 was prepared by substituting compound 14C for compound 1H and compound 2K for compound 1K.
- the synthetic route is as follows:
- intermediate 15B (200 mg, 1.0 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and borane tetrahydrofuran complex (2 mL, 1 mol/L, 2.0 eq) was added to it, and the React to room temperature for 16 hours. Then, methanol (5 mL) was added to the reaction system to quench the reaction, the solvent was distilled off under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate three times (20 mL*3).
- the synthetic route is as follows:
- the synthetic route is as follows:
- Step 1 4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4 Synthesis of ]oxazin-8-yl)methyl)benzonitrile (19B)
- Step 2 8-(4-(2H-Tetrazol-5-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydro- 6H-pyrimido[5,4-b][1,4]oxazine (19)
- the synthetic route is as follows:
- Step 1 8-(4-(2-Methyl-tetrazol-5-yl)benzyl)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8- Synthesis of Dihydro-6H-pyrimido[5,4-b][1,4]oxazine(20)
- the synthetic route is as follows:
- the synthetic route is as follows:
- Step 1 2-Chloro-5-cyclopropyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8- Dihydropteridine-6(5H)-one (24B)
- Step 2 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-cyclopropyl-8-(4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)-7,8-dihydropterin-6(5H)-one (24)
- reaction solution was cooled to room temperature, it was filtered with celite, the filter cake was rinsed with ethyl acetate, the obtained filtrates were combined, and the solvent was distilled off under reduced pressure to obtain the crude compound, which was subjected to preparative chromatography (Waters Xbridge C18, 10-90% acetonitrile) aqueous solution) to give the title compound 24 as a solid (5 mg, 17% yield).
- the synthetic route is as follows:
- Step 1 2-Chloro-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(2,2,2-tris Synthesis of Fluoroethyl)-7,8-dihydropteridine-6(5H)-one (25B)
- the synthetic route is as follows:
- Step 2 2-Chloro-7-methyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-di Hydropteridine-6(5H)-one (26C)
- Step 3 2-Chloro-5,7-dimethyl-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7, 8-Dihydropteridine-6(5H)-one (26D)
- Step 4 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5,7-dimethyl-8-(4-(1-methyl-4-(trifluoromethyl) )-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridine-6(5H)-one (26)
- reaction solution was cooled to room temperature, it was filtered with celite, the filter cake was rinsed with ethyl acetate, the obtained filtrates were combined, and the solvent was distilled off under reduced pressure to obtain the crude compound, which was subjected to preparative chromatography (Waters Xbridge C18, 10-90% acetonitrile) aqueous solution) to give the title compound 26 as a solid (16 mg, 32% yield).
- the synthetic route is as follows:
- Step 1 2-Chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5-carbonitrile (27B )
- Step 2 4'-Cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-[2,5'-bipyrimidine]-5-carbonitrile (27C)
- Step 3 5-(Aminomethyl)-4'-cyclopropyl-6'-methoxy-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2 -yl)benzyl)-[2,5'-bipyrimidin]-4-amine (27D)
- Step 4 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2- yl)benzyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (27)
- the synthetic route is as follows:
- Step 3 Synthesis of (4-(1-(difluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (28D)
- compound 28F (0.30 g, 0.72 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), the resulting solution was cooled to 0 °C, and chloroacetyl chloride (97 mg, 0.86 mmol, chloroacetyl chloride) was slowly added.
- Step 7 2-Chloro-8-(4-(1-(difluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydro Pteridine-6(5H)-one (28H)
- compound 28G (0.30 g, 0.61 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), potassium carbonate (0.17 mg, 1.2 mmol, 2.0 eq) was added, and the resulting mixture was heated to 50 After stirring at °C for 2 hours, water (30 mL) was added to quench, and extracted with ethyl acetate (20 mL*3). The resulting organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered.
- Step 8 2-Chloro-8-(4-(1-(difluoromethyl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-methyl-7 ,8-Dihydropteridine-6(5H)-one (28I)
- Step 9 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((4-(1-(difluoromethyl)-4-(trifluoromethyl)-1H -Imidazol-2-yl)phenyl)methyl)-5-methyl-7,8-dihydropteridine-6(5H)-one (28)
- the synthetic route is as follows:
- Step 1 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H -imidazol-2-yl)benzyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (29)
- Example 28 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole- Preparation of 2-yl)piperidin-4-yl)methyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (Compound 30)
- the synthetic route is as follows:
- reaction solution was poured into saturated aqueous ammonium chloride solution (20 mL), and extracted with ethyl acetate (20 mL*3).
- the resulting organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was combined.
- Step 3 Synthesis of methyl 1-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-4-carboxylate (30E)
- Step 6 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((1-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2 Synthesis of -yl)piperidin-4-yl)methyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (30)
- the synthetic route is as follows:
- Step 3 2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl) Pyrimidine (31D)
- Step 6 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((5-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2 -yl)pyrimidin-2-yl)methyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (31)
- Compound 32 was prepared by a method similar to Example 1, substituting compound 32E for methyl 4-formylbenzoate in step 3, and substituting compound 2K for compound 1K.
- the synthetic route is as follows:
- the synthetic route is as follows:
- Step 2 4'-Cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Synthesis of ethyl amino)-[2,5'-bipyrimidine]-5-carboxylate (35C)
- Step 3 4'-Cyclopropyl-6'-methoxy-N-methyl-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl) )benzyl)amino)-[2,5'-bipyrimidine]-5-carboxamide (35D)
- Step 4 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H Synthesis of -imidazol-2-yl)benzyl)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione (35)
- the synthetic route is as follows:
- Step 1 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-3-methyl-1-(4-(1-methyl-4-(trifluoromethyl)-1H Synthesis of -imidazol-2-yl)benzyl)-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one (36)
- the synthetic route is as follows:
- Step 1 Synthesis of methyl 2-((2,4-dihydroxypyrimidin-5-yl)thio)acetate (38C)
- Step 3 2-((2-Chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5- yl)thio)methyl acetate (38E)
- Step 4 2-((2-Chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine-5- base)thio)acetic acid (38F)
- Step 5 2-Chloro-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6H-pyrimido[5,4-b ][1,4]thiazin-7(8H)-one (38G)
- Step 6 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2- yl)benzyl)-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one (38)
- Example 36 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(1-(4-(1-methyl-4-(trifluoromethyl) Preparation of yl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-7,8-dihydropteridine-6(5H)-one (compound 39)
- the synthetic route is as follows:
- Step 2 Synthesis of tert-butyl (1-(4-(1-methyl-4-trifluoromethyl-1H-imidazol-2-yl)phenyl)cyclopropyl)carbamate (39C)
- Step 3 Synthesis of 1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropan-1-amine hydrochloride (39D)
- Step 4 2-Chloro-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)cyclopropyl)-5-nitro Pyrimidine-4-amine (39E)
- Step 5 4'-Cyclopropyl-6'-methoxy-N-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl )cyclopropyl)-5-nitro-[2,5'-bipyrimidine]-4-amine (39F)
- compound 39E (0.10 g, 0.23 mmol, 1.0 eq) and compound 2K (59 mg, 0.30 mmol, 1.5 eq) were dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL), then Tris(dibenzylideneacetone)dipalladium (18mg, 0.02mmol, 0.1eq), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6- Phosphoryladamantane (15mg, 0.05mmol, 0.2eq) and potassium carbonate (95mg, 0.69mmol, 3.0e.).
- Step 6 4'-Cyclopropyl-6'-methoxy-N4-(1-(4-(1-methyl- 4- (trifluoromethyl)-1H-imidazol-2-yl)benzene yl)cyclopropyl)-[2,5'-bipyrimidine]-4,5-diamine (39G)
- Step 7 2-Chloro-N-(4'-cyclopropyl-6'-methoxy-4-((1-(4-(1-methyl-4-(trifluoromethyl)-1H- Imidazol-2-yl)phenyl)cyclopropyl)amino)-[2,5'-bipyrimidin]-5-yl)acetamide (39H)
- Step 8 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole) -2-yl)phenyl)cyclopropyl)-7,8-dihydropteridine-6(5H)-one (39I)
- Step 9 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(1-(4-(1-methyl-4-(trifluoromethyl) )-1H-imidazol-2-yl)phenyl)cyclopropyl)-7,8-dihydropteridine-6(5H)-one (39)
- the synthetic route is as follows:
- Step 1 4'-Cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-[2,5'-bipyrimidine]-5-carboxylic acid (42A)
- Step 2 4'-Cyclopropyl-N-(4,4-diethoxybutyl)-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl) yl)-1H-imidazol-2-yl)benzyl)amino)-[2,5'-bipyrimidine]-5-carboxamide (42C)
- compound 42A 52mg, 0.10mmol, 1.0eq
- compound 42B 20mg, 0.13mmol, 1.3eq
- 2-(7-azabenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate 50mg, 0.13mmol, 1.3eq
- dichloromethane 5mL
- N,N-diisopropylethylamine (0.33g, 0.26mmol, 2.6eq
- the resulting mixture was reacted under nitrogen atmosphere at 25°C for 0.5 hour.
- reaction solution was concentrated and purified by reverse phase C18 silica gel column chromatography (elution phase: 5-65% acetonitrile in water) to give the product 42C (42 mg, 63% yield).
- Step 3 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-10-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2- (42)
- the synthetic route is as follows:
- compound 43C (1.0 g, 4.0 mmol) was added to tetrahydrofuran (20 mL), and lithium aluminum hydride (0.30 g, 8.0 mmol, 2 eq) was slowly added in portions with stirring.
- the reaction solution was slowly returned to room temperature and stirred for 1 hour, then 0.3 ml of water, 0.3 ml of 15% aqueous sodium hydroxide solution, and 0.9 ml of water were slowly added in sequence to quench the reaction, and the stirring was continued at room temperature for 1 hour.
- the reaction solution was filtered and distilled under reduced pressure to give 43D as a pale yellow oil (0.85 g, 3.3 mmol, 84% yield).
- the synthetic route is as follows:
- 1,1-Dibromo-3,3,3-trifluoroacetone (2.6 g, 9.5 mmol, 1.3 mL) and sodium acetate (0.78 g, 9.5 mmol) were dissolved in water (3.0 mL) and the mixture was dissolved at 100 After stirring at °C for 1 hour, the temperature was lowered to room temperature.
- 2-Bromo-4-cyanobenzaldehyde (1.0 g, 4.8 mmol) was dissolved in methanol (32 mL) and ammonia water (7.0 mL) and slowly added to the above reaction solution, then stirred at room temperature for 40 minutes and then increased to The reaction was carried out under reflux at 100°C for 2 hours.
- reaction solution was poured into a mixed system of ethyl acetate and water, extracted three times with ethyl acetate (30 mL*3), the organic phases were combined, spin-dried, and purified by column chromatography to obtain the product 45D (0.30 g, 0.99 mmol). , the yield is 44%).
- Hoveyda-Grubbs second generation catalyst (CAS NO.: 301224-40-8, 43 mg, 69 ⁇ mol) was added to a solution of Intermediate 45D (0.21 g, 0.69 mmol) in dichloromethane (5.0 mL). The mixture was stirred at room temperature for 5 hours, then a mixed solution of dichloromethane and water was added to the mixture, extracted with dichloromethane three times (10 mL*3), the organic phases were combined and concentrated, and the product intermediate 45E (0.15 g, 0.55 g) was obtained by column chromatography. mmol, yield 79%). MS m/z(ESI): 276.1[M+H] + .
- Step 5 (2-(Trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine -9-yl)methylamine (45F)
- Nickel dichloride (23 mg, 95 ⁇ mol) was added to a solution of intermediate 45E (0.13 g, 0.47 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) at 0°C, and the reaction solution was then divided into Sodium borohydride (72 mg, 1.9 mmol) was added in batches and reacted at room temperature for 3 hours. 1.0 mL of water was added to the reaction solution and stirred for half an hour to quench excess sodium borohydride.
- Step 6 2-Chloro-5-nitro-N-((2-((trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]nitrogen miscellaneous -9-yl)methyl)pyrimidin-4-amine (45G)
- Step 7 2-Chloro- N4 -((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine -9-yl)methyl)pyrimidine-4,5-diamine (45H)
- Step 8 2-Chloro-N-(2-Chloro-4-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a] Aza -9-yl)methyl)amino)pyrimidin-5-yl)acetamide (45I)
- Step 9 2-Chloro-8-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine -9-yl)methyl)-7,8-dihydropteridine-6(5H)-one (45J)
- Step 10 2-Chloro-5-methyl-8-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine -9-yl)methyl)-7,8-dihydropteridine-6(5H)-one (45K)
- Step 11 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-((2-(trifluoromethyl)-6,7-dihydro-5H -Benzo[c]imidazo[1,2-a]azepine -9-yl)methyl)-7,8-dihydropteridine-6(5H)-one (45)
- the synthetic route is as follows:
- Step 1 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c ]imidazo[1,2-a]aza -9-yl)methyl)-7,8-dihydropteridine-6(5H)-one (48A)
- Step 2 5-Cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-((2-(trifluoromethyl)-6,7-dihydro- 5H-Benzo[c]imidazo[1,2-a]azepine -9-yl)methyl)-7,8-dihydropteridine-6(5H)-one (48)
- the synthetic route is as follows:
- Step 1 2-(2-Chloro-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine- 5-yl)propan-2-ol (49B)
- Step 2 7-Chloro-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-4,4-dimethyl -1,4-Dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (49C)
- Step 3 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(3-fluoro-4-(1-methyl-4-( Trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (49)
- Example 47 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(1-methyl-4-(trifluoromethyl) yl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 50)
- Example 48 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)) -1H-imidazol-2-yl)benzyl)spiro[cyclopropane-1,4'-pyrimido[4,5-d][1,3]oxazine]-2'(1'H)-one Preparation of (Compound 51)
- the synthetic route is as follows:
- Step 4 5-Bromo-2-chloro-N-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrimidine-4 -Amine (51G)
- Step 5 2-Chloro-N-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(1-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)cyclopropyl)pyrimidin-4-amine (51I)
- Step 6 1-(2-Chloro-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidine -5-yl)cyclopropan-1-ol (51J)
- Step 7 1-(4'-Cyclopropyl-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)cyclopropan-1-ol (51K)
- Step 8 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)spiro[cyclopropane-1,4'-pyrimido[4,5-d][1,3]oxazine]-2'(1'H)-one ( 51)
- Example 50 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(5-methyl-3-(trifluoromethyl)-1H-pyridine oxazol-1-yl)benzyl)spiro[cyclopropane-1,4'-pyrimido[4,5-d][1,3]oxazine]-2'(1'H)-one (Compound 53 ) preparation
- Example 51 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(5-methyl-3-(trifluoromethyl)-1H-pyridine oxazol-1-yl)benzyl)spiro[oxetane-3,4'-pyrimido[4,5-d][1,3]oxazine]-2'(1'H)-one ( Preparation of compound 54)
- Step 3 1-(2-Chloro-4-((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)amino)pyrimidine-5- yl)oxetan-3-ol (54E)
- Step 4 7'-Chloro-1'-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)spiro[oxetan-3 ,4'-Pyrimido[4,5-d][1,3]oxazine]-2'(1'H)-one (54F)
- Step 5 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole) -1-yl)benzyl)spiro[oxetan-3,4'-pyrimido[4,5-d][1,3]oxazine]-2'(1'H)-one (54 )
- Example 52 7'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(5-methyl-3-(trifluoromethyl)-1H-pyridine oxazol-1-yl)benzyl)spiro[cyclobutane-1,4'-pyrimido[4,5-d][1,3]oxazine]-2'(1'H)-one (Compound 55 ) preparation
- Example 54 7-(4-Cyclopropyl-6-(difluoromethoxy)pyrimidin-5-yl)-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl) yl)-1H-imidazol-2-yl)benzyl)-4,4-dimethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine- Preparation of 2-keto (Compound 57)
- Step 1 2-Chloro-N-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5-(propan-1 -En-2-yl)pyrimidin-4-amine (58B)
- Step 2 4'-Cyclopropyl-N-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6'- Methoxy-5-(prop-1-en-2-yl)-[2,5'-bipyrimidin]-4-amine (58C)
- Step 3 2-(4'-Cyclopropyl-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)propane-1,2-diol (58D)
- N-methylmorpholine oxide (112 mg, 0.96 mmol) and potassium osmate dihydrate (9 mg, 0.03 mmol) were added to compound 58C (0.17 g, 0.32 mmol) in acetone (5 mL) and water ( 2mL) solution.
- the resulting mixture was stirred at room temperature for 16 hours.
- Step 4 2-(4'-Cyclopropyl-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-ol ( 58E)
- Step 5 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H- Imidazol-2-yl)benzyl)-4-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1,4-dihydro-2H-pyrimidine Ipo[4,5-d][1,3]oxazin-2-one (58F)
- Step 6 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H- Imidazol-2-yl)benzyl)-4-(hydroxymethyl)-4-methyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine- 2-keto (58)
- Example 56 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-ethynyl-1-(3-fluoro-4-(1-methyl-4-(trifluoro) Methyl)-1H-imidazol-2-yl)benzyl)-4-methyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine-2- Preparation of ketone (compound 59)
- Step 1 1-(4'-Cyclopropyl-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)ethan-1-one (59A)
- Step 2 2-(4'-Cyclopropyl-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) Amino)-6'-methoxy-[2,5'-bipyrimidin]-5-yl)but-3-yn-2-ol (59B)
- Step 3 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-ethynyl-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl) yl)-1H-imidazol-2-yl)benzyl)-4-methyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (59)
- Step 1 4'-Cyclopropyl-6'-methoxy-N4-(4-(1-methyl- 4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl) -[2,5'-bipyrimidine]-4,5-diamine (60A)
- Step 2 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2- yl)benzyl)pteridine-7(8H)-one (60)
- Compound 66B was prepared in a similar manner to compound 51E, substituting compound 66A for compound 51A in Step 1 .
- Compound 66 was prepared by a method similar to Example 26, substituting compound 66B for compound 28D in step 4.
- Example 62 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5-methyl-8-(3-fluoro-4-(1-isopropyl-4-(tris) Preparation of Fluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydropteridine-6(5H)-one (Compound 67)
- Compound 67A was prepared in a similar manner to compound 51E, substituting iodoisopropane for methyl iodide in step 2.
- Compound 67 was prepared by a method similar to Example 26, substituting compound 67A for compound 28D in step 4.
- Compound 68A was prepared in a similar manner to compound 51E, substituting iodoethane for iodomethane in step 2.
- Compound 68 was prepared by a method similar to Example 26, substituting compound 68A for compound 28D in step 4.
- Compound 70 was prepared using a procedure analogous to Example 26, substituting compound 51E for compound 28D in step 4 and compound 70A for chloroacetyl chloride in step 6.
- Example 65 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H) Preparation of -imidazol-2-yl)benzyl)-5-cyclopropyl-7,8-dihydropteridine-6(5H)-one (compound 71)
- Compound 71A was prepared using a procedure analogous to Example 26, steps 4 to 7, substituting compound 51E for compound 28D in step 4.
- Compound 71 was prepared by a method similar to that in Example 45, substituting compound 71A for compound 45J.
- Example 66 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazole- Preparation of 1-yl)benzyl)-5-cyclopropyl-7,8-dihydropterin-6(5H)-one (Compound 72)
- Compound 72A was prepared using a procedure analogous to Example 26, steps 4 to 7, substituting compound 43D for compound 28D in step 4. Compound 72 was prepared by a procedure similar to that in Example 45, substituting compound 72A for compound 45J.
- Compound 73B was prepared using a procedure analogous to Example 26, steps 4 to 7, substituting compound 68A for compound 28D in step 4. Compound 73 was prepared by a procedure similar to that in Example 45, substituting compound 73B for compound 45J.
- Example 68 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(4-(5-methyl-3-(trifluoromethyl) yl)-1H-pyrazol-1-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 74) preparation
- Compound 74A was prepared using an analogous synthetic procedure to compound 35B, substituting compound 43D for compound 4B. Compound 74 was prepared using a similar synthetic procedure for compound 49, substituting compound 74A for compound 49A.
- Compound 75 was prepared using an analogous synthetic procedure for compound 49, substituting compound 74A for compound 49A and compound 57A for compound 2K.
- Example 70 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4,4-dimethyl-1-(3-fluoro-4-(1-ethyl-4- (Trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one ( Preparation of compound 76)
- Compound 76A was prepared using an analogous synthetic procedure to compound 35B, substituting compound 68A for compound 4B. Compound 76 was prepared using a similar synthetic procedure for compound 49, substituting compound 76A for compound 49A.
- Example 71 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(1-cyclopropyl-4-(trifluoromethyl)- Preparation of 1H-imidazol-2-yl)benzyl)-5-cyclopropyl-7,8-dihydropteridine-6(5H)-one (compound 77)
- Compound 77A was prepared using a procedure analogous to Example 48, steps 1 to 3, substituting iodocyclopropane for iodomethane in step 2.
- Compound 77B was prepared using a procedure analogous to Example 26, steps 4 to 7, substituting compound 77A for compound 28D in step 4.
- Compound 77 was prepared by a procedure similar to that in Example 45, substituting compound 77B for compound 45J.
- Example 72 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2 Preparation of -yl)benzyl)-5-isopropyl-7,8-dihydropteridine-6(5H)-one (Compound 78)
- Example 74 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2 Preparation of -yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 80)
- the synthetic route is as follows:
- Step 1 2-Chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)methanol (80A )
- Example 75 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-4-methyl-1-(4-(1-methyl-4-(trifluoromethyl)- Preparation of 1H-imidazol-2-yl)benzyl)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one (Compound 81)
- the synthetic route is as follows:
- Compound 81A was prepared by a synthetic method similar to compound 51G in Example 48, substituting compound 4B for compound 51E.
- Compound 81B was prepared by substituting compound 81A for compound 51G and using a synthetic method similar to compound 58C in Example 55.
- Compound 81C was prepared by a similar synthetic method to compound 59A in Example 56, substituting compound 81B for compound 58C. Substituting compound 81C for compound 35B, and using a synthetic route and method similar to Example 74, compound 81 was prepared.
- the synthetic route is as follows:
- Lawson's reagent 2,4-bis(p-methoxyphenyl)-1,3-dithio-diphosphotidine-2,4 sulfide (14.0 mg, 34.7 ⁇ mol) was added to compound 45 (10.0 mg , 17.3 ⁇ mol) in toluene (1 mL) solution. The resulting mixture was stirred at 100°C for 2 hours and then concentrated under reduced pressure. The resulting crude product was purified by preparative chromatography (Waters Xbridge C18, 20-80% acetonitrile in water) to give compound 82 (3.0 mg, 29% yield).
- the synthetic route is as follows:
- Lawson's reagent (20.9 mg, 51.8 ⁇ mol) was added to a solution of compound 65 (14.7 mg, 25.9 ⁇ mol) in toluene (1 mL). The resulting mixture was stirred at 100°C for 2 hours and then concentrated under reduced pressure. The resulting crude product was purified by preparative chromatography (Waters Xbridge C18, 20-80% acetonitrile in water) to give compound 83 (5.0 mg, 33% yield).
- Example 78 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H) -imidazol-2-yl)benzyl)-2,4-dimethyl-1,4-dihydropyrimido[5,4-e][1,2,4]triazine-3(2H)- Preparation of ketone (compound 84)
- the synthetic route is as follows:
- Step 1 2-(2-Chloro-5-nitropyrimidin-4-yl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (84B)
- Step 2 2-(2-Chloro-5-nitropyrimidin-4-yl)-2-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2) -yl)benzyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (84C)
- Step 3 2-(5-Amino-2-chloropyrimidin-4-yl)-2-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazole-2- yl)benzyl)-1-methylhydrazine-1-carboxylic acid tert-butyl ester (84D)
- Step 4 2-Chloro-4-(1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl hydrazino)pyrimidin-5-amine (84E)
- Step 5 7-Chloro-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2-methyl-1 ,4-Dihydropyrimido[5,4-e][1,2,4]triazin-3(2H)-one (84F)
- Step 6 7-Chloro-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-2,4-dimethyl yl-1,4-dihydropyrimido[5,4-e][1,2,4]triazin-3(2H)-one (84G)
- Step 7 7-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-1-(3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H- Imidazol-2-yl)benzyl)-2,4-dimethyl-1,4-dihydropyrimido[5,4-e][1,2,4]triazin-3(2H)-one (84)
- the synthetic route is as follows:
- Step 2 Ethyl 1-((4'-Cyclopropyl-6'-methoxy-5-nitro-[2,5'-bipyrimidin]-4-yl)amino)cyclopropane-1-carboxylate (85C)
- Step 3 1-((4'-Cyclopropyl-6'-methoxy-5-nitro-[2,5'-bipyrimidin]-4-yl)(4-(1-methyl-4 -(Trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)cyclopropane-1-carboxylate (85D)
- Step 4 2'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8'-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazole- 2-yl)benzyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (85E)
- Step 5 2'-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-5'-methyl-8'-(4-(1-methyl-4-(trifluoromethyl) )-1H-imidazol-2-yl)benzyl)-5',8'-dihydro-6'H-spiro[cyclopropane-1,7'-pteridine]-6'-one (85)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (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)
Abstract
Description
仪器名称 | 设备厂家 | 型号 |
振荡器 | Boxun | BSD-YX3400 |
读板仪 | PerkinElmer | Envision |
离心机 | Eppendorf | Eppendorf Mixmate |
化合物稀释及加样仪 | PerkinElmer | Echo |
试剂 | 品牌 | 货号 |
CHAPS | Sangon | A600110-0001 |
1M Tris-HCl Solution,pH 8.0 | Sangon | B548127 |
氯化钙二水合物 | Sangon | A501331 |
β-mercaptoethanol | sigmaaldrich | M3148-100ml |
96孔板 | Thermofisher | 249952 |
黑色384孔板 | Perkinelmer | 6007270 |
仪器名称 | 设备厂家 | 型号 |
振荡器 | Boxun | BSD-YX3400 |
读板仪 | PerkinElmer | Envision |
离心机 | Eppendorf | Eppendorf Mixmate |
化合物稀释及加样仪 | PerkinElmer | Echo |
细胞培养箱 | THERMO | THERMOHeracellVIOS 250i |
试剂 | 品牌 | 货号 |
PBS | Hyclone | SH30256.01 |
DMEM | Gibco | 11995-065 |
FBS | Gibco | 10099-141C |
白色384-well plate | Corning | 3765 |
加样槽 | Corning | 4877 |
10ml移液管灭菌 | Corning | 4492 |
ML323 | Selleck | S7529 |
化合物编号 | P app(A-B)(10 -6,cm/s) | P app(B-A)(10 -6,cm/s) | Efflux Ratio |
化合物11 | 4.9 | 17.6 | 3.6 |
化合物50 | 7.5 | 17.3 | 2.3 |
化合物编号 | 溶解度(μg/mL) | 计算得出溶解度(μM) |
化合物11 | 99.7 | 181.0 |
化合物编号 | 计算得出溶解度(μM) |
化合物11 | 214 |
化合物16 | 284 |
化合物24 | 228 |
化合物26 | 115 |
化合物28 | 73 |
化合物30 | 225 |
化合物40 | 122 |
化合物41 | 88 |
化合物45 | 88 |
化合物46 | 50 |
化合物66 | 115 |
化合物70 | 98 |
化合物80 | 72 |
Claims (20)
- 一种式(I)化合物或其药学上可接受的盐,其中,X 1选自CR 3或N;X 2选自N;X 3和X 4各自独立地选自C(R 4)(R 5)、CR 4、NR 6、N、O、S、S=O或S(=O) 2;X 5独立地选自C(R 4)(R 5)、NR 6或O;R 3、R 4、R 5和R 6各自独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、-C(O)-C 1-C 6烷基、-C(O)O-C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述OH、NH 2、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 10环烷基或4-7元杂环基任选被R a取代,或者R 4和R 5合并为=O或=S;或者R 4和R 5与和其连接的C共同形成C 3-C 10环烷基,所述C 3-C 10环烷基任选被R a取代;或者R 4和R 5与和其连接的原子共同形成C 3-C 10杂环基,所述C 3-C 10杂环基任选被R a取代;或者位于环中不同位置处的R 4和R 6与和其连接的原子共同形成C 3-C 10杂环基,所述C 3-C 10杂环基任选被R a取代;环A选自芳基或5-10元杂芳基,所述芳基或5-10元杂芳基任选被R b取代;环B选自芳基、5-10元杂芳基、4-10元杂环基、C 3-C 10环烷基或C 3-C 10环烯基,所述芳基、5-10元杂芳基、4-10元杂环基、C 3-C 10环烷基或C 3-C 10环烯基任选被R c取代;R b和R c各自独立地选自卤素、CN、OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基、 所述OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R a取代;R 7、R 8、R 9、R 10、R 11、R 12、R 13和R 14各自独立地选自NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R a取代;或者R 7和R 8与和其连接的P共同形成4-7元杂环基,所述4-7元杂环基任选被R a取代;或者R 13和R 14与和其连接的原子共同形成4-7元杂环基,所述4-7元杂环基任选被R a取代;环C选自芳基、5-10元杂芳基或4-10元杂环基,所述芳基、5-10元杂芳基或4-10元杂环基任选被R d取代;R d选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R a取代;或R c、R d与其连接的原子共同形成5-8元杂环基或5-6元杂芳基,所述5-8元杂环基或5-6元杂芳基任选被R a取代;R 1和R 2各自独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R a取代,或者R 1和R 2以及它们所连接的原子共同形成C 3-C 10环烷基或4-7元杂环基,所述C 3-C 10环烷基或4-7元杂环基任选被R a取代;每一个R a独立地选自卤素、CN、=O、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R e取代;R e选自卤素、CN、=O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基,所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R f取代;R f选自卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基。
- 根据权利要求1所述的式(I)化合物或其药学上可接受的盐,所述的X 1选自N,X 2选自N;或者,X 1选自CR 3,X 2选自N;或者X 1选自CH,X 2选自N;或者,X 1选自CR 3或N,其中R 3为H,X 2选自N。
- 根据权利要求1或2所述的式(I)化合物或其药学上可接受的盐,所述的R 3、R 4、R 5和R 6各自独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述OH、NH 2、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R a取代;或R 4和R 5合并为=O;或R 4和R 5与和其连接的C共同形成C 3-C 10环烷基,所述C 3-C 10环烷基任选被R a取代;或R 4和R 5与和其连接的原子共同形成C 3-C 10杂环基,所述C 3-C 10杂环基任选被R a取代;或位于环中不同位置处的R 4和R 6与和其连接的原子共同形成C 3-C 10杂环基,所述C 3-C 10杂环基任选被R a取代;或者,所述的R 3、R 4、R 5和R 6各自独立地选自H、卤素、CN、C 1-C 6烷基、C 2-C 6烯基、-C(O)-C 1-C 6烷基、-C(O)O-C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述C 1-C 6烷基、C 2-C 6烯基、C 3-C 10环烷基或4-7元杂环基任选被R a取代;或者,所述的R 3、R 4、R 5和R 6各自独立地选自H、卤素、C 1-C 6烷基、C 2-C 6烯基、-C(O)-C 1-C 6烷基、-C(O)O-C 1-C 6烷基或C 3-C 10环烷基,所述C 1-C 6烷基、C 2-C 6烯基或C 3-C 10环烷基任选被R a取代;或者,所述的R 3为H;所述的R 4和R 5各自独立地选自H、卤素、C 1-C 6烷基或C 2-C 6炔基,所述C 1-C 6烷基或C 2-C 6炔基任选被R a取代,或R 4和R 5合并为=O或=S,或R 4和R 5与和其连接的C共同形成C 3-C 10环烷基,所述C 3-C 10环烷基任选被R a取代,或R 4和R 5与和其连接的原子共同形成C 3-C 10杂环基,所述C 3-C 10杂环基任选被R a取代,或位于环中不同位置处的R 4和R 6与和其连接的原子共同形成C 3-C 10杂环基,所述C 3-C 10杂环基任选被R a取代;或者,所述的R 4和R 5各自独立地选自H、卤素、C 1-C 6烷基或C 2-C 6炔基,所述C 1-C 6烷基任选被R a取代,或R 4和R 5合并为=O或=S,或R 4和R 5与和其连接的C共同形成C 3-C 10环烷基,或R 4和R 5与和其连接的原子共同形成C 3-C 10杂环基,或位于环中不同位置处的R 4和R 6与和其连接的原子共同形成C 3-C 10杂环基;或者所述的R 4和R 5各自独立地选自H、卤素、C 1-C 4烷基或C 2-C 3炔基,所述C 1-C 4烷基任选被R a取代,或R 4和R 5合并为=O或=S,或R 4和R 5与和其连接的C共同形成C 3-C 7环烷基,或R 4和R 5与和其连接的原子共同形成C 3-C 6杂环基,或位于环中不同位置处的R 4和R 6与和其连接的原子共同形成C 3-C 6杂环基;以及R 6选自H、C 1-C 6烷基、C 2-C 6烯基、-C(O)-C 1-C 6烷基、-C(O)O-C 1-C 6烷基或C 3-C 10环烷基,所述C 1-C 6烷基、C 2-C 6烯基或C 3-C 10环烷基任选被R a取代;或者R 6选自H、C 1-C 6烷基或C 3-C 10环烷基,所述C 1-C 6烷基任选被R a取代;或者R 6选自H、C 1-C 4烷基或C 3-C 6环烷基,所述C 1-C 4烷基任选被R a取代;或者R 6选自H、C 1-C 4烷基或C 3-C 4环烷基,所述C 1-C 4烷基任选被R a取代;或者当X 4为NR 6且X 5为C(R 4)(R 5)时,R 4和R 6与和其连接的原子共同形成C 3-C 6杂环基,所述C 3-C 6杂环基任选被R a取代。
- 根据权利要求1-3中任一项所述的式(I)化合物或其药学上可接受的盐,所述的X 3选自C(R 4)(R 5)、CR 4、NR 6、N、O或S;或者,所述的X 3和X 4各自独立地选自C(R 4)(R 5)、CR 4、NR 6或O;或者,X 3选自C(R 4)(R 5)、NR 6或O;或者X 3选自S。
- 根据权利要求1-4中任一项所述的式(I)化合物或其药学上可接受的盐,所述的X 4选自C(R 4)(R 5)、CR 4、NR 6或O;或者,X 4选自C(R 4)(R 5)、NR 6或O。
- 根据权利要求1-5中任一项所述的式(I)化合物或其药学上可接受的盐,所述的X 5选自C(R 4)(R 5)或NR 6;或者,X 5选自C(R 4)(R 5)。
- 根据权利要求1-7中任一项所述的式(I)化合物或其药学上可接受的盐,所述的环B选自芳基、5-6元杂芳基、4-10元杂环基、C 3-C 10环烷基或C 3-C 10环烯基,所述芳基、5-6元杂芳基、4-10元杂环基、C 3-C 10环烷基、C 3-C 10环烯基任选被R c取代;或者,所述的环B选自苯基、5-6元杂芳基、4-6元杂环基、C 3-C 8环烷基或C 4-C 6环烯基,所述苯基、5-6元杂芳基、4-6元杂环基、C 3-C 8环烷基或C 4-C 6环烯基任选被R c取代;或者,所述的环B选自苯基、4-6元杂环基、C 3-C 8环烷基或C 4-C 6环烯基,所述苯基、4-6元杂环基、C 3-C 8环烷基或C 4-C 6环烯基任选被R c取代;或者,
- 根据权利要求1-8中任一项所述的式(I)化合物或其药学上可接受的盐,所述的R b和R c各自独立地选自卤素、OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基、4-7元杂环基、 所述OH、NH 2、SH、C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R a取代,其中,所述的R 7、R 8、R 9、R 10、R 11、R 12、R 13和R 14各自独立地选自C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基,所述C 1-C 6烷基、C 3-C 10环烷基或4-7元杂环基任选被R a取代;或R 7和R 8与和其连接的P共同形成4-7元杂环基,所述4-7元杂环基任选被R a取代;或R 13和R 14与和其连接的原子共同形成4-7元杂环基,所述4-7元杂环基任选被R a取代;或者,R b选自卤素、OH、C 1-C 4烷基或C 3-C 6环烷基,所述OH、C 1-C 4烷基或C 3-C 6环烷基任选被R a取代;或者,R b选自F、Cl、OH、C 1-C 3烷基或C 3环烷基,所述OH被R a取代;或者R c选自卤素或C 1-C 6烷基,所述C 1-C 6烷基任选被R a取代;或者,R c选自卤素或C 1-C 4烷基,所述C 1-C 4烷基任选被R a取代;或者,R c选自F、Cl或C 1-C 4烷基,所述C 1-C 4烷基任选被R a取代;或者,R c选自F、Cl或C 1-C 2烷基,所述C 1-C 2烷基任选被R a取代。
- 根据权利要求1-10中任一项所述的式(I)化合物或其药学上可接受的盐,所述的R d选自卤素、CN、OH、NH 2、C 1-C 6烷基或C 3-C 10环烷基,所述OH、NH 2、C 1-C 6烷基或C 3-C 10环烷基任选被R a取代,或所述的R c和R d与和其连接的原子共同形成6-7元杂环基或5-6元杂芳基,所述6-7元杂环基或5-6元杂芳基任选被R a取代;或者R d选自C 1-C 6烷基或C 3-C 10环烷基,所述C 1-C 6烷基或C 3-C 10环烷基任选被R a取代;或者,R d选自C 1-C 4烷基或C 3-C 6环烷基,所述C 1-C 4烷基任选被R a取代;或者,R d为任选被R a取代的C 1-C 4烷基。
- 根据权利要求1-11中任一项所述的式(I)化合物或其药学上可接受的盐,所述的R 1和R 2各自独立地选自H、卤素、CN、OH、NH 2或C 1-C 6烷基,所述OH、NH 2或C 1-C 6烷基任选被R a取代,或R 1和R 2以及它们所连接的原子共同形成C 3-C 6环烷基或4-7元杂环基,所述的C 3-C 6环烷基或4-7元杂环基任选被R a取代;或者,所述的R 1和R 2均为H
- 根据权利要求1-12中任一项所述的式(I)化合物或其药学上可接受的盐,所述的每一个R a独立地选自卤素、=O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基,所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R e取代;或者每一个R a独立地选自卤素、OH、C 1-C 6烷基或C 3-C 6环烷基,所述OH、C 1-C 6烷基或C 3-C 6环烷基任选被R e取代,或者,每一个R a独立地选自F、Cl、OH、C 1-C 6烷基或C 3-C 6环烷基,所述OH或C 1-C 6烷基任选被R e取代。
- 根据权利要求1-13中任一项所述的式(I)化合物或其药学上可接受的盐,所述的R e选自卤素、=O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基,所述OH、NH 2、 C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R f取代;或者R e为卤素,例如F或Cl。
- 根据权利要求1-14中任一项所述的式(I)化合物或其药学上可接受的盐,所述的R f选自卤素、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基。
- 药物组合物,其包含权利要求1-17中任一项所述的式(I)化合物或其药学上可接受的盐和药学上可接受的辅料。
- 治疗哺乳动物由USP1介导的疾病的方法,包括对需要所述治疗的所述哺乳动物,优选人类,给予治疗有效量的权利要求1-17中任一项所述的式(I)化合物或其药学上可接受的盐或权利要求18所述的药物组合物,优选地,所述USP1介导的疾病为肿瘤。
- 权利要求1-17中任一项所述的式(Ⅰ)化合物或其药学上可接受的盐或权利要求18所述的药物组合物在制备用于预防或者治疗USP1介导的疾病的药物中的用途,优选地,所述USP1介导的疾病为肿瘤。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020237033597A KR20230170658A (ko) | 2021-04-09 | 2022-04-08 | 유비퀴틴 특이적 프로테아제 1(usp1) 억제제 |
US18/554,426 US20240226107A1 (en) | 2021-04-09 | 2022-04-08 | Ubiquitin-specific protease 1 (usp1) inhibitor |
EP22784119.4A EP4321515A1 (en) | 2021-04-09 | 2022-04-08 | Ubiquitin-specific protease 1 (usp1) inhibitor |
BR112023020442A BR112023020442A2 (pt) | 2021-04-09 | 2022-04-08 | Inibidor da protease 1 específica de ubiquitina (usp1) |
JP2023560334A JP2024513554A (ja) | 2021-04-09 | 2022-04-08 | ユビキチン特異的プロテアーゼ1(usp1)阻害剤 |
AU2022253524A AU2022253524A1 (en) | 2021-04-09 | 2022-04-08 | Ubiquitin-specific protease 1 (usp1) inhibitor |
CA3213709A CA3213709A1 (en) | 2021-04-09 | 2022-04-08 | Ubiquitin-specific protease 1 (usp1) inhibitor |
CN202280024236.1A CN117136189A (zh) | 2021-04-09 | 2022-04-08 | 泛素特异性蛋白酶1(usp1)抑制剂 |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110403760.7 | 2021-04-09 | ||
CN202110403760 | 2021-04-09 | ||
CN202110829701.6 | 2021-07-22 | ||
CN202110829701 | 2021-07-22 | ||
CN202111166322 | 2021-09-30 | ||
CN202111166322.X | 2021-09-30 | ||
CN202111591747 | 2021-12-23 | ||
CN202111591747.5 | 2021-12-23 | ||
CN202210242231 | 2022-03-11 | ||
CN202210242231.8 | 2022-03-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022214053A1 true WO2022214053A1 (zh) | 2022-10-13 |
Family
ID=83545106
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/085703 WO2022214053A1 (zh) | 2021-04-09 | 2022-04-08 | 泛素特异性蛋白酶1(usp1)抑制剂 |
Country Status (10)
Country | Link |
---|---|
US (1) | US20240226107A1 (zh) |
EP (1) | EP4321515A1 (zh) |
JP (1) | JP2024513554A (zh) |
KR (1) | KR20230170658A (zh) |
CN (1) | CN117136189A (zh) |
AU (1) | AU2022253524A1 (zh) |
BR (1) | BR112023020442A2 (zh) |
CA (1) | CA3213709A1 (zh) |
TW (1) | TW202304933A (zh) |
WO (1) | WO2022214053A1 (zh) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023083297A1 (en) * | 2021-11-12 | 2023-05-19 | Insilico Medicine Ip Limited | Small molecule inhibitors of ubiquitin specific protease 1 (usp1) and uses thereof |
CN116496252A (zh) * | 2022-04-29 | 2023-07-28 | 江苏亚虹医药科技股份有限公司 | 嘧啶类化合物、其制备方法及其医药用途 |
WO2023148643A1 (en) * | 2022-02-03 | 2023-08-10 | Aurigene Oncology Limited | Fused bicyclic heterocyclyl compounds as usp1 inhibitors |
US11739077B2 (en) | 2021-11-12 | 2023-08-29 | Insilico Medicine Ip Limited | Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof |
CN116768906A (zh) * | 2023-05-29 | 2023-09-19 | 遵义医科大学珠海校区 | 一种三并环化合物及其制备方法和应用 |
WO2023216910A1 (zh) * | 2022-05-07 | 2023-11-16 | 苏州浦合医药科技有限公司 | 取代的双环杂芳基化合物作为usp1抑制剂 |
WO2024006879A1 (en) * | 2022-06-29 | 2024-01-04 | Zentaur Therapeutics Usa Inc. | Usp1 inhibitors and uses thereof |
WO2024022266A1 (en) * | 2022-07-25 | 2024-02-01 | Guangdong Newopp Biopharmaceuticals Co., Ltd. | Heteroaryl compounds as inhibitors of usp1 |
WO2024041634A1 (zh) * | 2022-08-26 | 2024-02-29 | 先声再明医药有限公司 | 三环类化合物及其应用 |
WO2024078436A1 (zh) * | 2022-10-09 | 2024-04-18 | 海南先声再明医药股份有限公司 | 杂环并嘧啶类化合物、药物组合物及其应用 |
WO2024094170A1 (zh) * | 2022-11-04 | 2024-05-10 | 深圳晶泰科技有限公司 | 泛素特异性蛋白酶1的抑制剂及其应用 |
WO2024153175A1 (en) * | 2023-01-19 | 2024-07-25 | Laekna Therapeutics Shanghai Co., Ltd. | Heteroaromatic compounds and their use as usp1 inhibitors |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2082668A1 (en) * | 1991-12-04 | 1993-06-05 | Martin Paul Edwards | Heterocyclic derivatives |
US5330989A (en) * | 1991-10-24 | 1994-07-19 | American Home Products Corporation | Heterocycles substituted with biphenyl-3-cyclobutene-1,2-dione derivatives |
WO1996037481A1 (fr) * | 1995-05-26 | 1996-11-28 | Chugoku Kayaku Kabushiki Kaisha | Nouveau reactif de synthese de tetrazole et son emploi dans un procede de production de tetrazoles |
US5620978A (en) * | 1994-01-03 | 1997-04-15 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon | 8-aza, 6-aza and 6,8-diaza-1,4-dihydroquinoxaline-2,3-diones and the use thereof as antagonists for the glycine/NMDA receptor |
WO2014086737A1 (de) * | 2012-12-06 | 2014-06-12 | Bayer Cropscience Ag | Kondensierte 2-pyridon-3-carboxamide und ihre verwendung als herbizide |
CN106714800A (zh) * | 2014-07-11 | 2017-05-24 | 吉利德科学公司 | 用于治疗hiv的toll样受体调节剂 |
CN109311868A (zh) * | 2015-12-22 | 2019-02-05 | 尚医治疗有限责任公司 | 用于治疗癌症和炎性疾病的化合物 |
CN111032662A (zh) * | 2017-06-21 | 2020-04-17 | 尚医治疗有限责任公司 | 与ras超家族相互作用的用于治疗癌症、炎性疾病、ras蛋白病和纤维化疾病的化合物 |
-
2022
- 2022-04-08 BR BR112023020442A patent/BR112023020442A2/pt unknown
- 2022-04-08 TW TW111113413A patent/TW202304933A/zh unknown
- 2022-04-08 CA CA3213709A patent/CA3213709A1/en active Pending
- 2022-04-08 US US18/554,426 patent/US20240226107A1/en active Pending
- 2022-04-08 CN CN202280024236.1A patent/CN117136189A/zh active Pending
- 2022-04-08 EP EP22784119.4A patent/EP4321515A1/en active Pending
- 2022-04-08 AU AU2022253524A patent/AU2022253524A1/en active Pending
- 2022-04-08 WO PCT/CN2022/085703 patent/WO2022214053A1/zh active Application Filing
- 2022-04-08 JP JP2023560334A patent/JP2024513554A/ja active Pending
- 2022-04-08 KR KR1020237033597A patent/KR20230170658A/ko unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5330989A (en) * | 1991-10-24 | 1994-07-19 | American Home Products Corporation | Heterocycles substituted with biphenyl-3-cyclobutene-1,2-dione derivatives |
CA2082668A1 (en) * | 1991-12-04 | 1993-06-05 | Martin Paul Edwards | Heterocyclic derivatives |
US5620978A (en) * | 1994-01-03 | 1997-04-15 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon | 8-aza, 6-aza and 6,8-diaza-1,4-dihydroquinoxaline-2,3-diones and the use thereof as antagonists for the glycine/NMDA receptor |
WO1996037481A1 (fr) * | 1995-05-26 | 1996-11-28 | Chugoku Kayaku Kabushiki Kaisha | Nouveau reactif de synthese de tetrazole et son emploi dans un procede de production de tetrazoles |
WO2014086737A1 (de) * | 2012-12-06 | 2014-06-12 | Bayer Cropscience Ag | Kondensierte 2-pyridon-3-carboxamide und ihre verwendung als herbizide |
CN106714800A (zh) * | 2014-07-11 | 2017-05-24 | 吉利德科学公司 | 用于治疗hiv的toll样受体调节剂 |
CN109311868A (zh) * | 2015-12-22 | 2019-02-05 | 尚医治疗有限责任公司 | 用于治疗癌症和炎性疾病的化合物 |
CN111032662A (zh) * | 2017-06-21 | 2020-04-17 | 尚医治疗有限责任公司 | 与ras超家族相互作用的用于治疗癌症、炎性疾病、ras蛋白病和纤维化疾病的化合物 |
Non-Patent Citations (1)
Title |
---|
HUSSAIN, S.: "DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors", CELL CYCLE, vol. 8, 2009, pages 1688 - 1697 |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11739077B2 (en) | 2021-11-12 | 2023-08-29 | Insilico Medicine Ip Limited | Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof |
WO2023083297A1 (en) * | 2021-11-12 | 2023-05-19 | Insilico Medicine Ip Limited | Small molecule inhibitors of ubiquitin specific protease 1 (usp1) and uses thereof |
WO2023148643A1 (en) * | 2022-02-03 | 2023-08-10 | Aurigene Oncology Limited | Fused bicyclic heterocyclyl compounds as usp1 inhibitors |
WO2023208130A1 (zh) * | 2022-04-29 | 2023-11-02 | 江苏亚虹医药科技股份有限公司 | 嘧啶类化合物、其制备方法及其医药用途 |
CN116496252A (zh) * | 2022-04-29 | 2023-07-28 | 江苏亚虹医药科技股份有限公司 | 嘧啶类化合物、其制备方法及其医药用途 |
WO2023216910A1 (zh) * | 2022-05-07 | 2023-11-16 | 苏州浦合医药科技有限公司 | 取代的双环杂芳基化合物作为usp1抑制剂 |
WO2024006879A1 (en) * | 2022-06-29 | 2024-01-04 | Zentaur Therapeutics Usa Inc. | Usp1 inhibitors and uses thereof |
WO2024022266A1 (en) * | 2022-07-25 | 2024-02-01 | Guangdong Newopp Biopharmaceuticals Co., Ltd. | Heteroaryl compounds as inhibitors of usp1 |
WO2024041634A1 (zh) * | 2022-08-26 | 2024-02-29 | 先声再明医药有限公司 | 三环类化合物及其应用 |
WO2024078436A1 (zh) * | 2022-10-09 | 2024-04-18 | 海南先声再明医药股份有限公司 | 杂环并嘧啶类化合物、药物组合物及其应用 |
WO2024094170A1 (zh) * | 2022-11-04 | 2024-05-10 | 深圳晶泰科技有限公司 | 泛素特异性蛋白酶1的抑制剂及其应用 |
WO2024153175A1 (en) * | 2023-01-19 | 2024-07-25 | Laekna Therapeutics Shanghai Co., Ltd. | Heteroaromatic compounds and their use as usp1 inhibitors |
CN116768906A (zh) * | 2023-05-29 | 2023-09-19 | 遵义医科大学珠海校区 | 一种三并环化合物及其制备方法和应用 |
CN116768906B (zh) * | 2023-05-29 | 2024-04-09 | 遵义医科大学珠海校区 | 一种三并环化合物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
BR112023020442A2 (pt) | 2023-11-21 |
KR20230170658A (ko) | 2023-12-19 |
JP2024513554A (ja) | 2024-03-26 |
US20240226107A1 (en) | 2024-07-11 |
CA3213709A1 (en) | 2022-10-13 |
CN117136189A (zh) | 2023-11-28 |
AU2022253524A1 (en) | 2023-10-12 |
EP4321515A1 (en) | 2024-02-14 |
TW202304933A (zh) | 2023-02-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022214053A1 (zh) | 泛素特异性蛋白酶1(usp1)抑制剂 | |
CN112368283B (zh) | 含二并环类衍生物抑制剂、其制备方法和应用 | |
WO2020239123A1 (zh) | 芳香杂环类衍生物调节剂、其制备方法和应用 | |
CN103038233B (zh) | 吡啶酮和氮杂吡啶酮化合物及使用方法 | |
KR101955914B1 (ko) | 헤테로아릴 화합물 및 이의 용도 | |
TWI643857B (zh) | 作為jak1抑制劑之哌啶-4-基三亞甲亞胺衍生物 | |
WO2021088945A1 (zh) | 作为shp2抑制剂的化合物及其应用 | |
CN113135910A (zh) | 嘧啶-4(3h)-酮类杂环化合物、其制备方法及其在医药学上的应用 | |
WO2023217230A1 (zh) | 驱动蛋白kif18a抑制剂及其应用 | |
WO2022007869A1 (zh) | 吡啶或嘧啶类衍生物及其制备方法和用途 | |
CN110494433A (zh) | 布鲁顿酪氨酸激酶抑制剂 | |
WO2022012409A1 (zh) | 一种rock抑制剂及其制备方法和用途 | |
WO2018010514A1 (zh) | 作为fgfr抑制剂的杂环化合物 | |
CN112292378A (zh) | 含吲哚类衍生物抑制剂、其制备方法和应用 | |
CN109745321A (zh) | 包含fgfr4抑制剂的药物组合物 | |
WO2018228275A1 (zh) | 作为mnk抑制剂的杂环化合物 | |
CN112979655A (zh) | 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途 | |
CN109745325A (zh) | Fgfr4抑制剂、其制备方法和用途 | |
KR102708872B1 (ko) | 피라졸로피라진 유래 화합물, 의약 조성물 및 그의 용도 | |
WO2021197467A1 (zh) | 多靶点的抗肿瘤化合物及其制备方法和应用 | |
WO2023067546A1 (en) | Novel bicyclic heteroaryl derivatives as sos1:kras proteinprotein interaction inhibitors | |
CN115073426A (zh) | 嘧啶杂环化合物及其制备方法和应用 | |
WO2019223777A1 (zh) | 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用 | |
WO2023036252A1 (zh) | 吡咯并嘧啶类或吡咯并吡啶类衍生物及其医药用途 | |
WO2022100738A1 (zh) | 含二并环类衍生物抑制剂自由碱的晶型及其制备方法和应用 |
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: 22784119 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3213709 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023560334 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022253524 Country of ref document: AU Ref document number: AU2022253524 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 18554426 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112023020442 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2022253524 Country of ref document: AU Date of ref document: 20220408 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022784119 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2022784119 Country of ref document: EP Effective date: 20231109 |
|
ENP | Entry into the national phase |
Ref document number: 112023020442 Country of ref document: BR Kind code of ref document: A2 Effective date: 20231003 |