WO2023280283A1 - 用作shp2抑制剂的化合物及其应用 - Google Patents
用作shp2抑制剂的化合物及其应用 Download PDFInfo
- Publication number
- WO2023280283A1 WO2023280283A1 PCT/CN2022/104449 CN2022104449W WO2023280283A1 WO 2023280283 A1 WO2023280283 A1 WO 2023280283A1 CN 2022104449 W CN2022104449 W CN 2022104449W WO 2023280283 A1 WO2023280283 A1 WO 2023280283A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- group
- reaction
- alkyl
- synthesis
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 408
- 239000003112 inhibitor Substances 0.000 title claims abstract description 14
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims abstract description 32
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims abstract description 32
- 230000000694 effects Effects 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 62
- 125000005842 heteroatom Chemical group 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 46
- 229910052717 sulfur Inorganic materials 0.000 claims description 43
- -1 hydroxy, methyl Chemical group 0.000 claims description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000004178 (C1-C4) alkyl group Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 15
- 229910052805 deuterium Inorganic materials 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 125000004001 thioalkyl group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000004970 halomethyl group Chemical group 0.000 claims description 6
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 6
- 206010029260 Neuroblastoma Diseases 0.000 claims description 5
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 208000037538 Myelomonocytic Juvenile Leukemia Diseases 0.000 claims description 3
- 206010029748 Noonan syndrome Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 208000005017 glioblastoma Diseases 0.000 claims description 3
- 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 claims description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000005101 LEOPARD Syndrome Diseases 0.000 claims description 2
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 claims description 2
- 206010062901 Multiple lentigines syndrome Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 208000010708 Noonan syndrome with multiple lentigines Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 abstract description 2
- 102000007607 Non-Receptor Type 11 Protein Tyrosine Phosphatase Human genes 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 199
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 239000000243 solution Substances 0.000 description 141
- 230000015572 biosynthetic process Effects 0.000 description 106
- 238000003786 synthesis reaction Methods 0.000 description 106
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 87
- 230000002829 reductive effect Effects 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 74
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 55
- 239000012074 organic phase Substances 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 238000005481 NMR spectroscopy Methods 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 22
- 239000001301 oxygen Substances 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 239000005457 ice water Substances 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 16
- 238000001816 cooling Methods 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 13
- 235000008504 concentrate Nutrition 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 238000010791 quenching Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 235000011056 potassium acetate Nutrition 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 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 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 239000005909 Kieselgur Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- NSGDYZCDUPSTQT-UHFFFAOYSA-N N-[5-bromo-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxopyridin-3-yl]cycloheptanecarboxamide Chemical compound Cc1c(Br)cn(Cc2ccc(F)cc2)c(=O)c1NC(=O)C1CCCCCC1 NSGDYZCDUPSTQT-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- XLQDQRMFMXYSQS-UHFFFAOYSA-N dichloromethane;hydrochloride Chemical compound Cl.ClCCl XLQDQRMFMXYSQS-UHFFFAOYSA-N 0.000 description 3
- PREAJPIKNPDDON-APAIHEESSA-N dideuterio-[dichloro(deuterio)methyl]-lambda3-chlorane Chemical compound C(Cl([2H])[2H])(Cl)(Cl)[2H] PREAJPIKNPDDON-APAIHEESSA-N 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- ZLJKQOWJEZSNBE-UHFFFAOYSA-N 2-methylpropane-2-sulfinyl chloride Chemical compound CC(C)(C)S(Cl)=O ZLJKQOWJEZSNBE-UHFFFAOYSA-N 0.000 description 2
- DZANYXOTJVLAEE-UHFFFAOYSA-N 6,8-difluoro-4-methylumbelliferyl phosphate Chemical compound FC1=C(OP(O)(O)=O)C(F)=CC2=C1OC(=O)C=C2C DZANYXOTJVLAEE-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 102000014400 SH2 domains Human genes 0.000 description 2
- 108050003452 SH2 domains Proteins 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-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
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- HKLYDUXIXBVZOQ-UHFFFAOYSA-N 2-aminoethane-1,1,1-triol Chemical class NCC(O)(O)O HKLYDUXIXBVZOQ-UHFFFAOYSA-N 0.000 description 1
- MLFIYYDKLNZLAO-UHFFFAOYSA-N 2-aminoethane-1,1-diol Chemical class NCC(O)O MLFIYYDKLNZLAO-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 210000003771 C cell Anatomy 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 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
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 229910003827 NRaRb Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101150048674 PTPN11 gene Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 229940126002 RMC-4630 Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HISJAYUQVHMWTA-BLLLJJGKSA-N [6-(2-amino-3-chloropyridin-4-yl)sulfanyl-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl]methanol Chemical compound NC1=NC=CC(=C1Cl)SC1=C(N=C(C(=N1)CO)N1CCC2([C@@H]([C@@H](OC2)C)N)CC1)C HISJAYUQVHMWTA-BLLLJJGKSA-N 0.000 description 1
- PYVZXJWQADAHLT-UHFFFAOYSA-N [bromo(difluoro)methyl] diethyl phosphate Chemical compound P(=O)(OC(F)(F)Br)(OCC)OCC PYVZXJWQADAHLT-UHFFFAOYSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000004656 dimethylamines Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- JZJQCLZQSHLSFB-WCCKRBBISA-N ethyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.CCOC(=O)[C@@H](N)CO JZJQCLZQSHLSFB-WCCKRBBISA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 125000004474 heteroalkylene group Chemical group 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- BYRPTKZOXNFFDB-UHFFFAOYSA-N lithium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Li+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C BYRPTKZOXNFFDB-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- AQIAIZBHFAKICS-UHFFFAOYSA-N methylaminomethyl Chemical compound [CH2]NC AQIAIZBHFAKICS-UHFFFAOYSA-N 0.000 description 1
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- XYGIWVMGXHARGN-UHFFFAOYSA-N propan-2-ylperoxyboronic acid Chemical compound CC(C)OOB(O)O XYGIWVMGXHARGN-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 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
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical class CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/4985—Pyrazines or piperazines 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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- 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
- 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
- C07D491/02—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 two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (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)
Abstract
本发明涉及用作SHP2抑制剂的化合物及其应用。具体地,本发明化合物具有式I'所示结构,其中各基团和取代基的定义如说明书中所述。所述化合物对SHP2磷酸酶的活性有较高的抑制,可以用来预防或治疗与SHP2相关的疾病。
Description
本发明涉及医药技术领域,具体涉及用作SHP2抑制剂的化合物,及其在调节SHP2活性或治疗相关疾病方面的应用。
SHP2(PTPN11基因编码)是PTP家族成员,包含一个保守的酪氨酸磷酸酶结构域、两个N端SH2结构域、一个C端尾部。两个SH2结构域决定了SHP2的亚细胞定位及功能调节。SHP2表达广泛,且参与到多条细胞信号过程中,比如Ras-Erk、PI3K-Akt、JakStat、Met、FGFR、EGFR,以及胰岛素受体和NF-kB通路,对于促有丝分裂、代谢控制、转录调节、细胞迁移等多种细胞功能非常重要。
SHP2与多种疾病的发生相关,如努南综合征,以及多种形式的白血病(例如,青少年髓单核细胞白血病、急性骨髓性白血病)和多种实体瘤(例如,肺癌、结肠癌、成神经细胞瘤、成胶质细胞瘤、黑素瘤和肝癌)。
围绕SHP2抑制剂的开发,有针对SHP2的PTP催化区域的抑制剂开发和非催化区域的变构抑制剂开发两大策略;由于PTP催化区域抑制剂有选择性和成药性差的问题,目前更多的研究趋于变构抑制剂的开发。近年来,研究者发现通过变构位点抑制SHP2的活性可以提高活性和选择性,药物研究也取得了一些进展。不过,仍然需要开发更优异的SHP2抑制剂,以便获得活性优、药代性质更好的药物,从而用于治疗SHP2介导的相关疾病。
发明内容
本发明的目的在于提供一种式I’所示化合物和其在调节SHP2活性或治疗相关疾病方面的应用。
本发明的第一方面,提供了一种式I’化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药,
其中:R
1选自下组:双环的C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、C6-C10芳基杂环烷基;R
1上的任意氢原子任选地被一个或多个以下取代基取代:氘、羟基、卤素、氰基、=O、酯基、酰胺基、酮羰基、氨基、羟基取代的C1-C4烷基、-C(O)OR
a、-NHC(O)R
a、-NHC(O)OR
a、-C(O)(C1-C4亚烷基)OH、C1~C6烷基、C1~C6卤代烷基、C1~C6硫代烷基、C1~C6烷氧基、C1~C6杂烷基、C1~C6烷胺基、C3~C6环烷基、C3~C8环烷胺基、C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基;R
a为C1-C4烷基;所述C6-C10芳基杂环烷基为-(C6-C10芳基)并(含1-3个选自N、O、S的杂原子的饱和或不饱和的3-8元杂环烷基);R
1为双环结构且为并环结构;
R
2选自下组:H、氘、氨基、氰基、卤素、羟基、甲基、CH
2OH、CH(CH
3)OH、C(CH
3)
2OH、卤代甲基、氘代甲基、CONH
2、CF
2OH、NHSO
2Me、CH
2NHSO
2Me;
R
3选自下组:氢、氘、羟基、氨基、氰基、卤素、甲基、氘代甲基、卤代甲基;
A环选自下组:单环或双环的含1-3个选自N、O、S的杂原子的3-11元杂环烷基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、-(含1-3个选自N、O、S的杂原子的3-8元亚杂环烷基)-(含1-3个选自N、O、S的杂原子的3-8元杂环烷基)、含1-3个选自N、O、S的杂原子的4-8元杂桥环烷基;
A环上的任意氢原子未被取代或被以下取代基单取代、双取代或三取代:
(CH
2)
nNHR’
1、(CH
2)
nCONH
2、(CH
2)
nCF
2H、(CH
2)
nCF
3、(CH
2)
nOH、=O、C1-C6烷基、卤素、氨基、羟基、-N-(C1-C6烷基)、-(C1-C6亚烷基)-NH
2,其中烷基上的氢未被取代或被OR’
1单取代或双取代;
R’
1选自下组:H、C1-C4烷基、羟基取代的C1-C4烷基;
n选自下组:0、1、2、3。
在另一优选例中,R
1选自下组:单环或双环的C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、C6-C10芳基杂环烷基;R
1上的任意氢原子任选地被一个或多个以下取代基取代:氘、羟基、卤素、氰基、=O、酯基、酰胺基、酮羰基、氨基、羟基取代的C1-C4烷基、-C(O)OR
a、-NHC(O)R
a、-NHC(O)OR
a、C1~C6烷基、C1~C6卤代烷基、C1~C6硫代烷基、C1~C6烷氧基、C1~C6杂烷基、C1~C6烷胺基、C3~C6环烷基、C3~C8环烷胺基、C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基;R
a为C1-C4烷基;
R
2选自下组:H、氘、氨基、氰基、卤素、羟基、甲基、CH
2OH、CH(CH
3)OH、C(CH
3)
2OH、卤代甲基、氘代甲基;
R
3选自下组:氢、氘、羟基、氨基、氰基、卤素、甲基、氘代甲基、卤代甲基;
A环选自下组:单环或双环的含1-3个选自N、O、S的杂原子的3-11元杂环烷基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、-(含1-3个选自N、O、S的杂原子的3-8元亚杂环烷基)-(含1-3个选自N、O、S的杂原子的3-8元杂环烷基)、含1-3个选自N、O、S的杂原子的4-8元杂桥环烷基;
A环上的任意氢原子未被取代或被以下取代基单取代、双取代或三取代:
(CH
2)
nNHR’
1、(CH
2)
nCONH
2、(CH
2)
nCF
2H、(CH
2)
nCF
3、(CH
2)
nOH、=O、C1-C6烷基、卤素、氨基、羟基、-N-(C1-C6烷基)、-(C1-C6亚烷基)-NH
2,其中烷基上的氢未被取代或被OR’
1单取代或双取代;
R’
1选自下组:H、C1-C4烷基、羟基取代的C1-C4烷基;
n选自下组:0、1、2、3。
在另一优选例中,R
1为B环并C环,其中,
B环、C环各自独立地选自下组:C5-C6芳基、含1-3个选自N、O、S的杂原子的5-6元杂芳基、C5-C6环烷基、含1-3个选自N、O、S的杂原子的饱和的5-6元杂环烷基;
R
1上的任意氢原子任选地被一个或多个以下取代基取代:氘、羟基、卤素、氰基、=O、氨基、羟基取代的C1-C4烷基、C1~C6烷基、C1~C6卤代烷基、C1~C6硫代烷基、C1~C6烷氧基、C3~C6环烷基、C1~C6烷胺基、C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、-C(O)C(CH
3)
2OH。
在另一优选例中,R
1选自下组:单环或双环的C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基;
R
1上的任意氢原子任选地被一个或多个以下取代基取代:氘、羟基、卤素、氰基、=O、氨基、羟基取代的C1-C4烷基、C1~C6烷基、C1~C6卤代烷基、C1~C6硫代烷基、C1~C6烷氧基、C3~C6环烷基、C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基。
Z
1、Z
2、Z
3、Z
4、Z
5、Z
6、Z
7、Z
8、Z
9各自独立地选自下组:N、O、S、C、 C(R
4)
m、NR
4;
R
4各自独立地选自下组:氢、氘、羟基、卤素、氰基、=O、氨基、羟基取代的C1-C4烷基、C1~C6烷基、C1~C6卤代烷基、C1~C6硫代烷基、C1~C6烷氧基、C3~C6环烷基、C1~C6烷氨基、C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、-COC(CH
3)
2OH;
m各自独立地选自下组:1、2。
在另一优选例中,A环选自下组:单环或双环的含1-3个选自N、O、S的杂原子的3-11元杂环烷基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、-(含1-3个选自N、O、S的杂原子的3-8元亚杂环烷基)-(含1-3个选自N、O、S的杂原子的3-8元杂环烷基)、含1-3个选自N、O、S的杂原子的4-8元杂桥环烷基;
A环上的任意氢原子未被取代或被以下取代基单取代、双取代或三取代:
(CH
2)
nNHR’
1、(CH
2)
nCONH
2、(CH
2)
nCF
2H、(CH
2)
nCF
3、(CH
2)
nOH、=O、C1-C6烷基、卤素、氨基、羟基、-N-(C1-C6烷基)、-(C1-C6亚烷基)-NH
2,其中烷基上的氢未被取代或被OR’
1单取代或双取代;
R’
1选自下组:H、C1-C4烷基、羟基取代的C1-C4烷基;
n选自下组:0、1、2、3。
在另一优选例中,双环的含1-3个选自N、O、S的杂原子的3-11元杂环烷基为螺环结构。
在另一优选例中,所述化合物选自下组:
在另一优选例中,所述化合物选自下组:
在另一优选例中,所述药学上可接受的盐为无机酸盐或有机酸盐。
在另一优选例中,所述无机酸盐选自下组:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐。
在另一优选例中,所述有机酸盐选自下组:甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。
本发明的第二方面,提供了一种药物组合物,包含药学上可接受的载体和一种或 多种安全有效量的本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药。
本发明的第三方面,提供了一种本发明第二方面所述的药物组合物的用途,用于制备用作SHP2抑制剂的药物。
本发明的第四方面,提供了一种本发明第二方面所述的药物组合物的用途,用于制备用于调节SHP2活性或治疗SHP2相关疾病的药物。
在另一优选例中,所述SHP2相关疾病选自下组:努南综合征、豹综合征、青少年骨髓单核细胞性白血病、急性髓样白血病、神经母细胞瘤、黑色素瘤、乳腺癌、食道癌、肺癌、胃癌、头癌、间变性大细胞淋巴瘤、成神经细胞瘤、成胶质细胞瘤、头颈的鳞状细胞癌、结肠癌、肝癌。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明人经过长期而深入的研究,通过结构设计获得了一类对SHP2磷酸酶的活性有较高的抑制作用的化合物。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“卤素”指F、Cl、Br或I。
在本发明中,“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。“C1-C4烷基”具有类似含义。
在本发明中,术语“C2-C6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中,术语“C2-C6炔基”是指具有2-6个碳原子的含有一个三键的直 链或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中,术语“C3-C8环烷基”是指在环上具有3-8个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。“C3~C6环烷基”、“C5-C6环烷基”具有类似含义。
在本发明中,术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基,如苯基、萘基等。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1~4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括:呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“卤代”是指被卤素取代。
在本发明中,术语“氘代”是指被氘取代。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中,术语“多个”是指1-7个。
在本发明中,术语1-6个指1、2、3、4、5或6个。其他类似术语具有类似含义。
术语“酯基”具有-C(O)-O-R’或R’-C(O)-O-结构,其中,R’独立地代表氢、C1-C6烷基、C3-C6环烷基、C6-C10芳基、杂芳基、杂环基,如上文所定义。
术语“酮羰基”具有R-C(=O)-,其中R为如上所述的烷基、环烷基等。
术语“酰胺基”是指带有结构-CONRR'的基团,其中,R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环,如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
术语“C6-C10芳基杂环烷基”是指含杂原子的环烷基和芳基形成的含6到10个碳原子的并环结构或者含杂原子的环烷基通过该环上的原子连接到芳基。
术语“氨基”是指-NH2。
术语“C1~C6杂烷基”是指被取代的烷基,其具有一个或多个选自除碳以外的原子的骨架链原子,例如,氧、氮、硫、磷、Si或其组合。可以给出数值范围,例如,C1-C6杂烷基是指链中的碳数目,其包括1至6个碳原子。例如-CH
2OCH
2CH
3基团被称为“C3”杂烷基。其与分子其余部分的连接可以通过杂烷基链中的杂原子或碳。“杂烷基”的例子包括但不限于:CH
2OCH
3、CH
2CH
2OCH
3、CH
2NHCH
3、CH
2CH
2NHCH
3、Me
3Si、Me
3SiCH
2CH
2O-、Me
3SiCH
2CH
2OCH
2-(SEM)。“杂亚烷基”是指任选被取代的二价烷基,其具有一个或多个选自除碳以外的原子的骨架链原子,例如,氧、氮、硫、磷、Si或其组合。
术语“C1~C6烷胺基”是指具有烷基-NR-结构的基团,其中,R为H、或如上所述的烷基、环烷基、芳基、杂芳基等。
术语“C3~C8环烷胺基”是指式-NRaRb基团,其中,Ra为H、如本文所定义的烷基或如本文所定义的环烷基,Rb为如本文所定义的环烷基,或者Ra和Rb与其连接的N原子一起形成3-10元含N单环或双环杂环基,如四氢吡咯基。如本发明所用,C3~C8环烷胺基是指含有3-8个碳原子的胺基。
术语“杂桥环烷基”是指具有桥碳原子的杂环烷基。
化合物
本发明提供了式I’化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前 药,
其中,各基团定义如上文所示。
在另一优选例中,所述的化合物中,R
1、R
2、R
3、A环任一个独立地为本发明所述具体化合物中所对应的基团。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂化物”指本发明化合物与溶剂分子配位形成特定比例的配合物。
术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式I’的一类化合物,或式I’的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
药物组合物和施用方法
本发明还提供了一种药物组合物,包含药学上可接受的载体和一种或多种安全有 效量的本发明所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包 埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明具有以下主要优点:
(1)本发明化合物具有优异的SHP2活性抑制作用;
(2)本发明化合物具有良好的生物利用度以及更低毒性。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
中间体A的合成:
合成路线如下:
冰水浴冷却下,将化合物1(2g,5.3mmol)溶于三氟乙酸和二氯甲烷(7mL/21mL)组成的混合溶剂中,然后反应液移至室温搅拌40min。反应结束后,减压浓缩后得2.5g化合物A的三氟乙酸盐.Ms[M+H]+275.3
化合物A的核磁数据:1H NMR(400MHz,Chloroform-d)δ4.27-4.22(m,1H),4.04(d,J=10.8Hz,1H),3.92(d,J=9.6Hz,1H),3.66-3.57(m,2H),3.54-3.42(m,2H),3.16-3.05(m,2H),2.25-2.08(m,2H),1.87-1.73(m,2H),1.31(s,9H),1.24(d,J=6.4Hz,3H).
中间体B的合成
合成路线如下:
1、化合物2的合成
将化合物1(54.7g,0.48mol)溶于440mL N,N-二甲基甲酰胺中,然后依次加入4-甲氧基苄氯(83.6g,0.53mol)和碳酸钾(100.2g,0.73mol),升温至80℃反应3小时。反应结束后,将反应液冷至室温并逐滴滴入2L水中,然后乙酸乙酯萃取,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后纯化得到110g化合物2。
化合物2的核磁数据:1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.92(s,1H),7.19-7.17(d,J=8.39Hz,2H),6.87-6.85(d,J=8.39Hz,2H),5.17(s,2H),3.75(s,3H).
2、化合物3的合成
将化合物2(50.6g,0.22mol)溶于500mL无水四氢呋喃中,氮气保护下,将反应液冷至-60℃,滴加260mL浓度为1M的双(三甲基硅基)氨基锂四氢呋喃溶液,滴加完毕后将反应液-60℃搅拌1小时,然后-60℃再滴加溶于300mL无水四氢呋喃的六氯乙烷(61.6g,0.26mol)溶液并搅拌1小时。反应结束后,在-60℃下滴加1L饱和氯化铵溶液以淬灭反应,然后将反应液升至室温,乙酸乙酯萃取,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后纯化得43.5g化合物3.
化合物3的核磁数据:1H NMR(90MHz,Chloroform-d3)δ8.08(s,1H),7.23-7.13(m,2H),6.85-6.75(m,2H),5.22(s,2H),3.72(s,3H).
3、化合物4的合成
将化合物3(43.5g,0.16mmol)和L-丝氨酸乙酯盐酸盐(83.2g,0.49mmol)溶于600mL乙醇和600mL水组成的混合溶剂中,然后加入碳酸氢钠(110g,1.31mol),将反应液升温至90℃搅拌72小时。反应结束后,将反应液冷却至室温,减压浓缩除去乙醇,加入二氯甲烷稀释,分液,水相滴加浓盐酸至pH<4,然后 用乙酸乙酯萃取,合并乙酸乙酯有机相,用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得到49g化合物4.Ms[M+Na]+359.1
化合物4的核磁数据:1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),7.17-7.14(d,J=8.91Hz,2H),6.88-6.86(d,J=8.39Hz,2H),6.82(s,1H),6.06-6.05(d,J=3.68Hz,1H),5.04-5.03(d,J=2.55Hz,2H),4.89-4.87(t,1H),3.80-3.76(q,1H),3.72(s,3H),3.60-3.57(t,2H).
4、化合物5的合成
将化合物4(8.5g,25.3mmol)溶于340mL的乙酸中,加入还原铁粉(14.1g,253mmol),氮气保护下加热至50℃反应6小时。反应结束后,将反应液冷却至室温,用乙酸乙酯稀释,通过硅藻土过滤后,滤液减压浓缩蒸去溶剂,残渣用饱和碳酸氢钠调至pH>7,然后用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后得4.4g粗品化合物5。Ms[M+H]+289.1
化合物5的核磁数据:1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),7.16-7.14(d,J=9.03Hz,2H),6.88-6.86(d,J=8.53Hz,2H),6.82(s,1H),6.08-6.07(d,J=3.51Hz,1H),5.04-5.03(d,J=2.23Hz,2H),4.92-4.89(t,1H),3.80-3.77(q,1H),3.72(s,3H),3.60-3.57(t,2H).
5、化合物6的合成
将粗品化合物5(3.47g,12mmol)溶于25mL N,N-二甲基甲酰胺中,加入咪唑(2.47g,36mmol),冰水浴冷却下,氮气保护时缓慢滴加叔丁基二苯基氯硅烷(9.9g,36mmol),滴加完毕后,将反应液逐渐升至室温反应1小时。反应结束后,加入饱和氯化钠溶液稀释反应体系,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得5.4g化合物6.Ms[M+H]+527.4
化合物6的核磁数据:1H NMR(400MHz,Chloroform-d3)δ7.96(s,1H),7.60-7.56(m,4H),7.47-7.40(m,2H),7.39-7.35(m,4H),7.13-7.11(m,2H),7.06(s,1H),6.80(d,J=8.6Hz,2H),4.09-4.04(m,1H),3.96-3.91(m,3H),3.72(s,3H),2.92(d,J=28.3Hz,2H),0.99(s,9H).
6、化合物7的合成
将化合物6(5.4g,10.24mmol)溶于70mL二氧六环中,加入二氧化锰(4.47g,51.35mmol),加热至35℃反应1小时。反应结束后,将反应液冷至室温,并 通过硅藻土过滤,滤液减压浓缩后得4.95g化合物7.Ms[M+H]+525.2
化合物7的核磁数据:1H NMR(400MHz,Chloroform-d3)δ7.78-7.71(m,4H),7.48(s,1H),7.42-7.36(m,2H),7.36-7.28(m,6H),6.84-6.77(m,2H),5.48(s,2H),5.04(s,2H),3.76(s,3H),1.16(s,9H).
7、化合物8的合成
将化合物7(5g,9.54mmol)溶于45mL N,N-二甲基甲酰胺中,然后冰水浴冷却下,依次加入三乙胺(5.4mL,38mmol)和N-苯基双(三氟甲磺酰)亚胺(6.8g,19mmol),然后将反应液移至室温,搅拌1小时。反应结束后,反应液用饱和食盐水稀释,然后乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到8g化合物8.
8、化合物9的合成
将化合物8(3.9g,5.87mmol)溶于70mL乙腈中,然后加入N,N-二异丙基乙胺(10mL,53mmol)和化合物A的三氟乙酸盐(1.46g,5.3mmol),氮气保护下,反应液于75℃搅拌20小时。反应结束后,将反应液冷至室温,减压浓缩,残渣溶于乙酸乙酯中,饱和食盐水洗涤,分出有机相用无水硫酸钠干燥,减压浓缩后经纯化得到3.2g化合物9.Ms[M+H]+781.4
化合物9的核磁数据:1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.75-7.73(m,J=8.0Hz,4H),7.44-7.37(m,6H),7.21(dd,J=8.8,2.2Hz,2H),6.85-6.78(m,2H),5.51(s,2H),5.11(d,J=10.8Hz,1H),4.97(s,2H),4.16-4.10(m,1H),3.78(d,J=8.6Hz,1H),3.69(s,3H),3.48(d,J=8.6Hz,1H),3.43-3.39(m,1H),3.26-3.22(m,2H),2.83(m,2H),1.94-1.79(m,2H),1.60(m,2H),1.18(s,9H),1.10(d,J=6.4Hz,3H),1.01(s,9H).
9、化合物10的合成
将化合物9(1.4g,1.79mmol)溶于30mL无水四氢呋喃中,冰水浴冷却下加入1mol/L的四丁基氟化铵的四氢呋喃溶液(2.7mL,2.7mmol),然后移至室温搅拌2小时。反应结束后,乙酸乙酯稀释反应,饱和食盐水洗涤,分出有机相用无水硫酸钠干燥,减压浓缩后经纯化得830mg化合物10.Ms[M+H]+543.4
化合物10的核磁数据:1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.28-7.20(m,2H),6.91-6.83(m,2H),5.58(s,2H),5.42(s,1H),5.14(d, J=10.8Hz,1H),4.71(s,2H),4.16-4.10(m,1H),3.82(d,J=8.6Hz,1H),3.70(s,3H),3.52(d,J=8.6Hz,1H),3.46-3.42(m,3H),2.85-2.84(m,2H),1.97-1.90(m,2H),1.66(t,J=16.5Hz,2H),1.18(s,9H),1.11(d,J=6.4Hz,3H).
10、化合物11的合成
将化合物10(1.5g,2.77mmol)溶于40mL二氯甲烷中,加入三乙胺(0.78mL,5.54mmol),然后冰水浴冷却下滴加叔丁基亚磺酰氯(584mg,4.16mmol,溶于2mL二氯甲烷中),滴加完毕后移至室温搅拌1小时。反应结束后,加水淬灭反应,然后反应液用二氯甲烷萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得1.26g化合物11.Ms[M+H]+647.4
化合物11的核磁数据:1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.27-7.17(m,2H),6.90-6.80(m,2H),5.56(s,2H),5.37-5.27(m,2H),5.15(d,J=10.5Hz,1H),4.16-4.10(m,1H),3.82(d,J=8.6Hz,1H),3.70(s,3H),3.57-3.48(m,1H),3.48-3.42(m,1H),3.29-3.21(m,2H),2.95-2.81(m,2H),1.99-1.92(m,2H),1.71-1.62(m,2H),1.18(s,9H),1.14(s,9H),1.11(d,J=6.3Hz,3H).
11、化合物B的合成
冰水浴下将化合物11(1.26g,1.86mmol)溶于12mL三氟乙酸中,氮气置换三次,冰水浴冷却下加入三氟甲磺酸(1.2mL),移至室温搅拌2.5小时。反应结束后,于冰水浴冷却下加饱和碳酸氢钠水溶液调pH 8,反应液用乙酸乙酯萃取三次,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得700mg化合物B.Ms[M+H]+527.4
化合物B的核磁数据:1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),5.29-5.23(m,2H),5.15(d,J=10.7Hz,1H),4.19-4.13(m,1H),3.85-3.80(m,1H),3.55-3.51(m,1H),3.49-3.45(m,1H),3.32-3.23(m,2H),2.95-2.85(m,2H),1.98-1.93(m,2H),1.72-1.64(m,2H),1.18(s,9H),1.14(s,9H),1.11(d,J=6.4Hz,3H).
实施例1
本发明合成的化合物:
化合物C2的合成路线如下:
1、C2-2的合成
将化合物B(90mg,0.17mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C2-1(60mg,0.34mmol),醋酸铜(31mg,0.17mmol)和吡啶(27mg,0.34mmol),氧气保护下,于25℃搅拌3小时。反应结束后,用乙酸乙酯稀释,饱和氯化钠洗涤,分出有机相用无水硫酸钠干燥,减压浓缩后经纯化得60mg化合物C2-2.Ms[M+H]+657.5
2、C2的合成
将化合物C2-2(60mg,0.09mmol)溶于2mL甲醇中,再加入5mL盐酸甲醇,氮气保护下,于25℃搅拌30min,升温至55℃搅拌5h。反应结束后,冷至室温,减压浓缩后经纯化得5mg化合物C2的三氟乙酸盐.Ms[M+H]+449.4
化合物C2的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),8.34(d,J=7.9Hz,1H),8.33(s,1H),7.57-7.48(m,2H),4.84(s,2H),4.27-4.22(m,1H),4.09(s,3H),3.84(d,J=8.6Hz,1H),3.71(d,J=8.7Hz,1H),3.44-3.39(m,2H),3.13-2.95(m,3H),1.97-1.89(m,2H),1.79-1.75(m,2H),1.20(d,J=6.5Hz,3H).
实施例2
本发明合成的化合物:
化合物C3的合成路线如下:
1、化合物C3-2的合成
将化合物B(100mg,0.19mmol)溶于5mL乙腈中,依次加入化合物C3-1(146mg,0.57mmol),醋酸铜(35mg,0.19mmol)和硼酸(23mg,0.38mmol),氧气保护下80℃搅拌过夜。反应结束后,反应液用乙酸乙酯稀释,饱和氯化钠溶液洗涤,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得35mg化合物C3-2.Ms[M+H]+655.3
2、化合物C3的合成
将化合物C3-2(35mg,0.054mmol)溶于1.5mL甲醇中,再加入3.5mL的4M氯化氢甲醇溶液,氮气保护下25℃搅拌30min,升温至55℃搅拌3小时。反应结束后,讲反应液冷至室温,减压浓缩后经纯化得3mg化合物C3的三氟乙酸盐.Ms[M+H]+447.2
化合物C3的核磁数据:1H NMR(400MHz,Methanol-d4)δ9.28(d,J=2.4Hz,1H),9.01(dd,J=9.3,2.4Hz,1H),8.95(d,J=1.9Hz,1H),8.91(d,J=1.9Hz,1H),8.39(s,1H),8.28(d,J=9.3Hz,1H),4.96(s,2H),4.35-4.31(m,1H),4.00(d,J=9.1Hz,1H),3.90(d,J=9.1Hz,1H),3.67-3.56(m,2H),3.52-3.49(m,1H),3.14-3.02(m,2H),2.10-2.04(m,2H),1.98(d,J=13.3Hz,1H),1.81(d,J=12.8Hz,1H),1.35(d,J=6.5Hz,3H).
实施例3
本发明合成的化合物:
化合物C4的合成路线如下:
1、化合物C4-2的合成
将化合物B(80mg,0.15mmol)溶于6mL N,N-二甲基甲酰胺中,依次加入化合物C4-1(54mg,0.30mmol),醋酸铜(27mg,0.15mmol)和吡啶(24mg,0.30mmol),氧气保护下25℃搅拌5小时。反应结束后,反应液用乙酸乙酯稀释,饱和氯化钠溶液洗涤,分出有机相用无水硫酸钠干燥,减压浓缩后经纯化得70mg化合物C4-2.Ms[M+H]+657.5
2、化合物C4的合成
将化合物C4-2(70mg,0.11mmol)溶于4mL甲醇中,再加入6mL的4M氯化氢甲醇溶液,氮气保护下25℃搅拌30min,然后升温至55℃搅拌4小时。反应结束后,将反应液冷至室温,减压浓缩后经纯化得8mg C4的三氟乙酸盐.Ms[M+H]+449.2
化合物C4的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.55(s,1H),8.33(s,1H),8.22(dd,J=8.8,1.8Hz,1H),8.08(d,J=1.0Hz,1H),7.93(dd,J=8.8,0.7Hz,1H),4.95(s,2H),4.37-4.32(m,1H),4.17(s,3H),4.00(d,J=12Hz,1H),3.90(d,J=12Hz,1H),3.65-3.51(m,3H),3.13-3.01(m,2H),2.11-1.97(m,3H),1.83-1.79(m,1H),1.36(d,J=6.5Hz,3H).
实施例4
本发明合成的化合物:
化合物C5的合成路线如下:
1、化合物C5-2的合成
将化合物B(100mg,0.19mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C5-1(67mg,0.38mmol),醋酸铜(35mg,0.19mmol)和吡啶(30mg,0.38mmol),氧气保护下25℃搅拌2小时。反应结束后,反应液用乙酸乙酯稀释,饱和氯化钠溶液洗涤,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得76mg化合物C5-2.Ms[M+H]
+656.4
2、化合物C5的合成
将化合物C5-2(70mg,0.11mmol)溶于4mL甲醇中,再加入6mL的4M氯化氢甲醇溶液,氮气保护下25℃搅拌30min,升温至55℃搅拌5h。反应结束后,将反应液冷至室温,旋干浓缩后经纯化得3mg C5的三氟乙酸盐.Ms[M+H]
+448.3
化合物C5的核磁数据:
1H NMR(400MHz,Methanol-d
4)δ8.33(s,1H),7.68(dd,J=7.7,0.8Hz,1H),7.54-7.51(m,1H),7.38(t,J=7.8Hz,1H),7.27(d,J=3.2Hz,1H),6.63(dd,J=3.2,0.9Hz,1H),4.86(s,2H),4.35-4.33(m,J=6.5,4.1Hz,1H),4.00(d,J=9.1Hz,1H),3.91-3.89(m,4H),3.63-3.48(m,3H),3.13-2.98(m,2H),2.10-2.04(m,2H),1.99-1.95(m,1H),1.82-1.79(m,1H),1.36(d,J=6.5Hz,3H).
实施例5
本发明合成的化合物:
化合物C6的合成路线如下:
1、化合物C6-2的合成
将化合物B(100mg,0.19mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C6-1(120mg,0.57mmol),醋酸铜(17mg,0.095mmol)和吡啶(45mg,0.57mmol),氧气保护下25℃搅拌1小时。反应结束后,用乙酸乙酯稀释反应,饱和氯化钠洗涤,无水硫酸钠干燥,减压浓缩后经纯化得80mg化合物C6-2.Ms[M+H]+691.3
2、化合物C6的合成
将化合物C6-2(80mg,0.12mmol)溶于3mL甲醇中,再加入5mL的4M氯化氢甲醇溶液,将反应液氮气保护下25℃搅拌30min,然后升温至55℃搅拌4h。反应结束后,冷至室温,减压浓缩后经纯化得20mgC6的三氟乙酸盐。Ms[M+H]+483.2
化合物C6的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),8.34(s,1H),7.74(dd,J=9.0,0.9Hz,1H),7.44(d,J=8.9Hz,1H),4.82(s,2H),4.38-4.32(m,4H),4.00(d,J=9.1Hz,1H),3.89(d,J=9.2Hz,1H),3.62-3.49(m,3H),3.11-2.98(m,2H),2.05(d,J=9.5Hz,2H),1.98-1.95(m,1H),1.82-1.79(m,1H),1.35(d,J=6.5Hz,3H).
实施例6
本发明合成的化合物:
化合物C7的合成路线如下:
1、化合物C7-2的合成
将化合物B(70mg,0.13mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C7-1(49mg,0.26mmol),醋酸铜(28mg,0.13mmol)和吡啶(21mg,0.26mmol),氧气氛围下,于25℃搅拌3小时。反应结束后,用乙酸乙酯稀释反应液,饱和氯化钠溶液洗涤,分出有机相,无水硫酸钠干燥,减压浓缩后经纯化得30mg化合物C7-2.Ms[M+H]+657.4
2、化合物C7的合成
将化合物C7-2(30mg,0.046mmol)溶于2mL甲醇中,然后加入4mL的4M氯化氢甲醇溶液,反应液氮气保护下25℃搅拌30min,再升温至55℃搅拌6h。反应结束后,将反应液冷至室温,减压浓缩后经纯化得3mg C7的三氟乙酸盐.Ms[M+H]+449.2
化合物C7的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.39(s,1H),8.15(s,1H),7.98(dd,J=8.2,1.0Hz,1H),7.51(dd,J=7.3,1.0Hz,1H),7.32(dd,J=8.1,7.3Hz,1H),4.78(s,2H),4.35-4.29(m,1H),3.98(d,J=9.1Hz,1H),3.87(d,J=9.1Hz,1H),3.62-3.47(m,3H),3.42(s,3H),3.10-2.97(m,2H),2.09-2.00(m,2H),1.96-1.93(m,1H),1.80-1.77(m,1H),1.33(d,J=6.5Hz,3H).
实施例7
本发明合成的化合物:
化合物C8的合成路线如下:
1、化合物C8-1的合成
将化合物9(700mg,0.90mmol)溶于8mL乙腈和8mL醋酸的混合溶剂中,冰盐浴冷却下,分批加入N-溴代丁二酰亚胺(480mg,2.69mmol),并保温搅拌30min,然后将反应移至室温,搅拌2h。反应结束后,加水淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到500mg化合物C8-1.Ms[M+H]+755.4
2、化合物C8-2的合成
将化合物C8-1(500mg,0.66mmol)溶于1,4-二氧六环和水(10mL/1mL)混合溶剂中,然后依次加入甲基硼酸(120mg,1.99mmol),1,1'-双(二-苯基膦基)二茂铁氯化钯,二氯甲烷复合物(54mg,0.66mmol)和碳酸钠(210mg,1.98mmol),氮气保护下,反应液于100℃搅拌10小时。反应结束后,将反应液冷至室温,加水淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到270mg化合物C8-2.Ms[M+H]+691.5
3、化合物C8-3的合成
将化合物C8-2(270mg,0.39mmol)溶于5mL四氢呋喃中,冰水浴下加入1M四丁基氟化铵的四氢呋喃溶液(0.47mL,0.47mmol),然后移至室温搅拌2小时。反应结束后,直接减压浓缩经纯化得180mg化合物C8-3.
化合物C8-3的核磁数据:1H NMR(400MHz,DMSO-d6)δ7.25-7.18(m,2H),6.89-6.83(m,2H),5.49(s,2H),5.36(t,J=5.9Hz,1H),4.70(d,J=5.8Hz,2H),4.11-4.04(m,1H),3.70(s,4H),3.51(d,J=8.3Hz,1H),3.46-3.40(m,1H),3.28-3.20(m,2H),3.02-2.89(m, 2H),2.44(s,3H),1.91-1.76(m,2H),1.68-1.53(m,2H),1.10(d,J=6.5Hz,3H).
4、化合物C8-4的合成
将化合物C8-3(200mg,0.44mmol)溶于6mL二氯甲烷中,加入三乙胺(0.2mL,1.32mmol),然后冰水浴冷却下,滴加叔丁基亚磺酰氯的二氯甲烷溶液(160mg,1.1mmol,溶于3mL二氯甲烷中),滴加完毕后,将反应液移至室温搅拌1小时。反应结束后,加水淬灭反应,二氯甲烷萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得180mg化合物C8-4.Ms[M+H]+661.4
5、化合物C8-5的合成
冰水浴下将化合物C8-4(180mg,0.27mmol)溶于2mL三氟乙酸中,冰水浴冷却下,缓慢滴加三氟甲磺酸(0.2mL),滴加完毕后,将反应液移至室温搅拌6.5小时。反应结束后,冰水浴冷却下,滴加饱和碳酸氢钠水溶液,调至pH 8,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得90mg化合物C8-5.Ms[M+H]+541.3
6、化合物C8-7的合成
将化合物C8-5(90mg,0.16mmol)溶于5Ml N,N-二甲基甲酰胺中,依次加入化合物C8-6(60mg,0.34mmol),醋酸铜(31mg,0.17mmol)和吡啶(27mg,0.34mmol),氧气保护下,于25℃搅拌2小时。反应结束后,用乙酸乙酯稀释反应液,加饱和氯化钠萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得70mg化合物C8-7.Ms[M+H]+671.4
7、化合物C8的合成
将化合物C8-7(70mg,0.10mmol)溶于3mL甲醇中,再加入6mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min,然后将反应液升温至55℃搅拌7h。反应结束后,冷至室温,减压浓缩后经纯化得3mg C8的三氟乙酸盐.Ms[M+H]+463.2
化合物C8的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.46(s,1H),8.20(dd,J=8.8,1.8Hz,1H),8.03(d,J=1.0Hz,1H),7.88(d,J=8.9Hz,1H),4.92(s,2H),4.36-4.29(m, 1H),4.14(s,3H),3.99(d,J=9.1Hz,1H),3.89(d,J=9.2Hz,1H),3.60-3.46(m,3H),3.10-2.98(m,2H),2.65(s,3H),2.10-2.01(m,2H),1.98-1.95(m,1H),1.81-1.78(m,1H),1.34(d,J=6.5Hz,3H).
实施例8
本发明合成的化合物:
化合物C9的合成路线如下:
1、化合物C9-2的合成
将化合物B(90mg,0.17mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C9-1(70mg,0.34mmol),醋酸铜(31mg,0.17mmol)和吡啶(27mg,0.34mmol),氧气氛围下,于25oC搅拌3小时。反应结束后,用乙酸乙酯稀释,饱和氯化钠洗涤,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得130mg化合物C9-2.Ms[M+H]+686.4
2、化合物C9的合成
将化合物C9-2(60mg,0.19mmol)溶于3mL甲醇中,再加入4mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min,然后升温至55℃搅拌5h。反应结束后,将反应液冷至室温,减压浓缩后经纯化得7mg C9的三氟乙酸盐.Ms[M+H]+436.3.
化合物C9的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.30(s,1H),7.92(dd,J=8.1,0.9Hz,1H),7.50(t,J=8.0Hz,1H),7.30-7.27(m,1H),4.33-4.29(m,1H),4.00-3.96(d,J=12Hz,1H),3.88-3.84(d,J=12Hz,1H),3.79(t,J=7.9Hz,2H),3.62-3.45(m,5H),3.09-2.97(m,2H),2.09-2.03(m,2H),1.96-1.93(m,1H),1.80-1.76(m,1H),1.34(d,J=6.4Hz,3H).
实施例9
本发明合成的化合物:
化合物C10的合成路线如下:
1、化合物C10-2的合成
将化合物B(90mg,0.17mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C10-1(63mg,0.34mmol),醋酸铜(34mg,0.17mmol)和吡啶(27mg,0.34mmol),氧气氛围下,于25℃搅拌2小时。反应结束后,用乙酸乙酯稀释,饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后经纯化得52mg化合物C10-2.Ms[M+H]+656.4
2、化合物C10的合成
将化合物C10-2(52mg,0.08mmol)溶于2mL甲醇中,再加入2mL的氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min,然后将反应液升温至55℃,搅拌8h。反应结束后,冷却至室温,减压浓缩后经纯化得2.08mg C10的三氟乙酸盐。Ms[M+H]+448.3
化合物C10的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.26(d,J=2.0Hz,1H),8.22(s,1H),7.87(dd,J=8.8,2.1Hz,1H),7.54(d,J=8.8Hz,1H),7.28(s,1H),6.55(d,J=3.1Hz,1H),4.88(s,2H),4.36-4.28(m,1H),3.98(d,J=9.2Hz,1H),3.91-3.83(m,4H),3.61-3.52(m,2H),3.49-3.48(m,1H),3.10-2.95(m,2H),2.07-2.00(m,2H),1.95(d,J=12.9Hz,1H),1.78(d,J=12.8Hz,1H),1.33(d,J=6.5Hz,3H).
实施例10
本发明合成的化合物:
化合物C11的合成路线如下:
1、化合物C11-2的合成
将化合物B(100mg,0.19mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C11-1(67mg,0.38mmol),醋酸铜(35mg,0.19mmol)和吡啶(30mg,0.38mmol),氧气氛围下,于25℃搅拌2小时。反应结束后,用乙酸乙酯稀释,饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后经纯化得35mg化合物C11-2.Ms[M+H]+657.4
1、化合物C11的合成
将化合物C11-2(35mg,0.05mmol)溶于2mL甲醇中,再加入2mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min后,再将反应液升温至55℃搅拌6h。反应结束后,冷至室温,减压浓缩后经纯化得8.32mg C11的三氟乙酸盐。Ms[M+H]+449.2
化合物C11的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.65(d,J=1.9Hz,1H),8.31(dd,J=9.1,1.9Hz,1H),8.27(s,1H),8.13(s,1H),7.75(d,J=9.1Hz,1H),4.92(s,2H),4.37-4.31(m,1H),4.15(s,3H),4.00(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.64-3.47(m,3H),3.11-2.99(m,2H),2.92(s,3H),2.11-2.05(m,2H),1.97(d,J=12.9Hz,1H),1.81(d,J=12.8Hz,1H),1.36(d,J=6.5Hz,3H).
实施例11
本发明合成的化合物:
化合物C12的合成路线如下:
1、化合物C12-2的合成
将化合物B(70mg,0.13mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C12-1(46mg,0.26mmol),醋酸铜(24mg,0.13mmol)和吡啶(21mg,0.26mmol),氧气氛围下,于25℃搅拌2小时。反应结束后,用乙酸乙酯稀释,饱和氯化钠溶液洗涤,分出有机相,无水硫酸钠干燥,减压浓缩后经纯化得104mg化合物C12-2.Ms[M+H]+656.4
2、化合物C12的合成
将化合物C12-2(104mg,0.16mmol)溶于5mL甲醇中,再加入5mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min,升温至55℃搅拌6h。反应结束后,冷却至室温,减压浓缩后经纯化得1mg化合物C12的三氟乙酸盐.Ms[M+H]+448.2
实施例12
本发明合成的化合物:
化合物C13的合成路线如下:
1、化合物C13-2的合成
将化合物C13-1(2.4g,12.12mmol)溶于90mL无水四氢呋喃中,氮气保护冰水浴冷却下,分批加入含量为60%的氢化钠(970mg,24.24mmol),保持温度搅拌30min,再缓慢滴加碘甲烷(1.5mL,24.24mmol),滴加完毕后将反应液移至室温并搅拌16h。反应结束后,冰水浴冷却下,缓慢滴加水淬灭反应。反应液用乙酸乙酯萃取,饱和食盐水洗涤,分液,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得到1.43g化合物C13-2。Ms[M+H]+212
2、化合物C13-3的合成
将化合物C13-2(1.0g,4.7mmol)溶于25mL 1,4-二氧六环中,然后依次加入联硼酸频那醇酯(1.44g,5.66mmol),1,1'-双(二-苯基膦基)二茂铁氯化钯二氯甲烷复合物(192mg,0.24mmol)和乙酸钾(1.4g,14.1mmol),氮气保护下,将反应液加热至95℃并搅拌20小时。反应结束后,将反应液冷至室温,加入饱和食盐水反应液,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得到600mg化合物C13-3。Ms[M+H]+260.2
3、化合物C13-4的合成
将化合物C13-3(300mg,1.15mmol)溶于12mL四氢呋喃中,然后向反应液中加入12mL的1M稀盐酸水溶液,室温搅拌3h。反应结束后,将反应液直接减压蒸干,用PE/EA重结晶,抽滤,用石油醚冲洗滤饼,将滤饼干燥即得到70mg化合物C13-4。.Ms[M+H]+178.1
4、化合物C13-5的合成
将化合物B(80mg,0.15mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C13-4(60mg,0.30mmol),醋酸铜(27mg,0.15mmol)和吡啶(24mg,0.30mmol),氧气氛围下25℃搅拌过夜。反应结束后,反应液用乙酸乙酯稀释, 饱和食盐水洗涤,分液,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得70mg化合物C13-5。Ms[M+H]+658.4
5、化合物C13的合成
将化合物C13-5(70mg,0.11mmol)溶于3mL甲醇中,加入4mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min后,再将反应液加热至55oC搅拌5h。反应结束后,反应液冷至室温,减压浓缩后经纯化得7mg化合物TYK-00745的三氟乙酸盐。Ms[M+H]+450.3.
化合物C13的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.24(s,1H),7.23(t,J=7.9Hz,1H),7.07(d,J=8.0Hz,1H),6.62(d,J=7.8Hz,1H),4.83(s,2H),4.36-4.28(m,1H),3.97(d,J=9.1Hz,1H),3.87(d,J=9.2Hz,1H),3.60-3.50(m,2H),3.49-3.47(m,1H),3.38-3.33(m,2H),3.10-2.94(m,4H),2.82(s,3H),2.09-1.99(m,2H),1.98-1.92(m,1H),1.81-1.74(m,1H),1.33(d,J=6.5Hz,3H).
实施例13
本发明合成的化合物:
化合物C14的合成路线如下:
1、化合物C14-2的合成
将化合物B(70mg,0.13mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C14-1(46mg,0.26mmol),醋酸铜(24mg,0.13mmol)和2,2'-联吡啶(42mg,0.26mmol),氧气氛围下,于25℃搅拌2小时。反应结束后,用乙酸乙酯稀释,饱和食盐水洗涤,分出有机相,无水硫酸钠干燥,过滤,滤液 减压浓缩后经纯化得74mg化合物C14-2.Ms[M+H]+657.4
2、化合物C14的合成
将化合物C14-2(74mg,0.11mmol)溶于5mL甲醇中,再加入5mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min后,然后将反应液加热至55℃搅拌6h。反应结束后,冷却至室温,减压浓缩后经纯化得23mg化合物C14的三氟乙酸盐.Ms[M+H]+449.2
化合物C14的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.55(s,1H),8.27-8.26(m,2H),8.06(dd,J=9.1,1.8Hz,1H),7.86(d,J=9.1Hz,1H),4.90(s,2H),4.36-4.28(m,1H),4.25(s,3H),3.98(d,J=9.2Hz,1H),3.87(d,J=9.1Hz,1H),3.65-3.51(m,2H),3.49(d,J=4.1Hz,1H),3.10-2.98(m,2H),2.11-2.00(m,2H),1.95(d,J=13.4Hz,1H),1.78(d,J=12.8Hz,1H),1.34(d,J=6.4Hz,3H).
实施例14
本发明合成的化合物:
化合物C15的合成路线如下:
1、化合物C15-2的合成
将化合物C15-1(2.0g,10.15mmol)溶于50mL的1,4-二氧六环中,然后依次加入联硼酸频那醇酯(3.10g,12.18mmol),1,1'-双(二-苯基膦基)二茂铁 氯化钯二氯甲烷复合物(414mg,0.51mmol)和无水乙酸钾(3g,30.45mmol),氮气保护下,将反应液加热至95℃并搅拌20小时。反应结束后,将反应液冷至室温,加入饱和食盐水稀释反应,乙酸乙酯萃取,分液,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到3.0g化合物C15-2。Ms[M+H]+245.1
2、化合物C15-3的合成
将化合物C15-2(1g,4.10mmol)溶于50mL甲醇中,然后向反应液中加入氟氢化钾(1.6g,20.5mmol)的水溶液(50mL),室温搅拌1小时。反应结束后,直接减压蒸干反应液,残渣用乙腈稀释溶解,然后石油醚萃取出杂质,分液,乙腈相减压浓缩后经纯化得到400mg化合物C15-3。Ms[M+H]+163.0
3、化合物C15-4的合成
将化合物C15-3(400mg,2.47mmol)溶于15mL四氢呋喃中,依次向反应液中加入4-N,N-二甲胺基吡啶(30mg,0.25mmol)和二碳酸二叔丁酯(1.1g,4.94mmol),反应液室温搅拌3小时。反应结束后,加入饱和食盐水稀释反应,乙酸乙酯萃取,分液,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到80mg化合物C15-4A和C15-4B的混合物。Ms[M+H]+263.1
4、化合物C15-5的合成
将化合物B(80mg,0.15mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C15-4A和C15-4B的混合物(80mg,0.30mmol),醋酸铜(27mg,0.15mmol)和2,2'-联吡啶(50mg,0.30mmol),氧气氛围下,于25oC搅拌20小时。反应结束后,反应液用乙酸乙酯稀释,饱和氯化钠洗涤,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得90mg化合物C15-5A和C15-5B的混合物。Ms[M+H]+743.4
5、化合物C15的合成
将化合物C15-5A和C15-5B的混合物(90mg,0.12mmol)溶于3mL甲醇中,再加入4mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min,然后升温至55℃搅拌5h。反应结束后,将反应液冷却至室温,减压浓缩后经纯化得化合物C15的三氟乙酸盐。Ms[M+H]+435.2.
化合物C15的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),8.29(s,1H),8.19(dd,J=8.8,1.8Hz,1H),8.10(s,1H),7.92(d,J=8.8Hz, 1H),4.91(s,2H),4.36-4.27(m,1H),3.98(d,J=9.2Hz,1H),3.88(d,J=9.2Hz,1H),3.65-3.47(m,3H),3.10-2.97(m,2H),2.10-2.00(m,2H),1.99-1.91(m,1H),1.82-1.75(m,1H),1.34(d,J=6.5Hz,3H).
实施例15
本发明合成的化合物:
化合物C16的合成路线如下:
1、化合物C16-1的合成
将化合物中间体10(600mg,1.1mmol)溶于30mL二氯甲烷中,加入戴斯马丁氧化剂(1.2g,2.76mmol),氮气保护下,反应液于室温搅拌2小时。反应结束后,加入饱和碳酸氢钠和饱和硫代硫酸钠水溶液淬灭反应,二氯甲烷萃取,合并有机相,饱和碳酸氢钠水溶液洗涤,无水硫酸钠干燥,减压浓缩后经纯化得到500mg化合物C16-1.Ms[M+H]+541.3
化合物C16-1的核磁数据:1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.28(s,1H),7.24(d,J=8.7Hz,1H),6.87(d,J=8.7Hz,1H),5.61(s,2H),5.14(d,J=10.7Hz,1H),4.19-4.12(m,1H),3.82(d,=8.7Hz,1H),3.7(s,3H),3.63-3.60(m,1H),3.55-3.5(m,2H),3.44(dd,J=10.8,5.8Hz,1H),3.13-3.00(m,2H),1.97-1.91(m,2H),1.70-1.61(m,2H),1.16(s,9H),1.10(d,J=6.3Hz,3H).
2、化合物C16-2的合成
将化合物C16-1(300mg,0.56mmol)溶于30mL二氯甲烷中,氮气保护冰浴冷却下,缓慢滴加二乙氨基三氟化硫(267mg,1.67mmol),滴加完毕后,将反应液转移至室温搅拌10小时。反应结束后,加饱和碳酸氢钠水溶液淬灭反应,二氯甲烷萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到189mg化合物C16-3.Ms[M+H]+563.3
3、化合物C16-3的合成
将化合物C16-2(180mg,0.32mmol)溶于2mL三氟乙酸中,冰浴冷却下向反应液中加入三氟甲磺酸(0.2mL),氮气保护下搅拌5分钟后转移至室温,再搅拌2小时。反应结束后将反应液倒入冰水中,然后加入饱和碳酸氢钠水溶液淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到141mg化合物C16-3.Ms[M+H]+443.2
4、化合物C16-5的合成
将化合物C16-3(107mg,0.24mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C16-4(85mg,0.48mmol),醋酸铜(44mg,0.24mmol)和吡啶(33mg,0.48mmol),氧气氛围下,于25℃搅拌16小时。反应结束后,用乙酸乙酯稀释,饱和氯化钠溶液洗涤,分出有机相,无水硫酸钠干燥,减压浓缩后经纯化得159mg化合物C16-5.Ms[M+H]+573.3
5、化合物C16的合成
将化合物C16-5(150mg,0.27mmol)溶于5mL甲醇中,再加入5mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min后,再将反应液加热至55℃搅拌6h。反应结束后,冷却至室温,减压浓缩后经纯化得159mg化合物C16的三氟乙酸盐.Ms[M+H]+469.3
化合物C16的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.47(s,1H),8.43(s,1H),8.19(dd,J=8.8,1.7Hz,1H),8.07(s,1H),7.93(d,J=8.8Hz,1H),7.17(t,J=53.7Hz,1H),4.35-4.29(m,1H),4.13(s,3H),3.99(d,J=9.2Hz,1H),3.89(d,J=9.2Hz,1H),3.61-3.41(m,3H),3.20-3.04(m,2H),2.16-2.02(m,2H),1.97(d,J=13.4Hz,1H),1.80(d,J=12.9Hz,1H),1.34(d,J=6.5Hz,3H).
实施例16
本发明合成的化合物:
化合物C17的合成路线如下:
1、化合物C17-2的合成
将化合物C17-1(1.0g,4.7mmol)溶于25mL 1,4-二氧六环中,然后依次加入联硼酸频那醇酯(1.8g,7.07mmol),1,1'-双(二-苯基膦基)二茂铁氯化钯二氯甲烷复合物(200mg,0.24mmol)和乙酸钾(1.4g,14.1mmol),氮气保护下,将反应液加热至95℃搅拌20小时。反应结束后,反应液冷至室温,加入饱和食盐水稀释反应液,乙酸乙酯萃取,分液,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到1.6g化合物C17-2。Ms[M+H]+260.1
2、化合物C17-3的合成
将化合物C17-2(300mg,1.23mmol)溶于20mL甲醇中,然后向反应液中加入氟氢化钾(480mg,6.15mmol)的水溶液(20mL),室温搅拌1小时。反应结束后,直接减压蒸干反应液,残渣用乙腈稀释溶解,用石油醚萃取出杂质,分液,乙腈相减压浓缩后经纯化得到90mg化合物C17-3。Ms[M+H]+178.0
化合物C17-3的核磁数据:1H NMR(400MHz,DMSO-d6)δ8.30(s,2H),8.09-8.00(m,1H),7.98-7.93(m,1H),7.83-7.77(m,1H),4.32(s,3H).
3、化合物C17-4的合成
将化合物B(80mg,0.15mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C17-3(60mg,0.30mmol),醋酸铜(27mg,0.15mmol)和2,2'-联吡啶(24mg,0.30mmol),氧气氛围下于25℃搅拌过夜。反应结束后,将反应液用乙酸乙酯稀释,饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后经纯化得90mg化合物C17-4。Ms[M+H]+658.3
化合物C17-4的核磁数据:1H NMR(400MHz,DMSO-d6)δ8.69-8.65(m,1H),8.63(s,1H),8.44-8.38(m,1H),8.24-8.20(m,1H),5.40(s,2H),5.16(d,J=10.7Hz,1H),4.38(s,3H),4.21-4.13(m,1H),3.87-3.82(m,1H),3.57-3.52(m,1H),3.51-3.44(m,1H),3.43-3.38(m,2H),3.04-2.90(m,2H),2.04-1.95(m,2H),1.76-1.64(m,2H),1.18(s,9H),1.15(s,9H),1.12(d,J=6.4Hz,3H).
4、化合物C17的合成
将化合物C17-4(90mg,0.14mmol)溶于3mL甲醇中,再加入4mL盐酸甲醇(4M),氮气保护下,于25℃搅拌30min后,再将反应液加热至55℃搅拌5h。反应结束后,将反应液冷至室温,减压浓缩后经纯化得到C17的三氟乙酸盐。Ms[M+H]+450.2
化合物C17的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.76(s,1H),8.55(dd,J=9.1,1.9Hz,1H),8.33(s,1H),8.13(d,J=9.1Hz,1H),4.94(s,2H),4.42(s,3H),4.36-4.29(m,1H),3.98(d,J=9.2Hz,1H),3.88(d,J=9.1Hz,1H),3.62-3.51(m,2H),3.51-3.47(m,1H),3.10-2.98(m,2H),2.10-2.01(m,2H),2.00-1.93(m,1H),1.83-1.75(m,1H),1.34(d,J=6.5Hz,3H).
实施例17
本发明合成的化合物:
化合物C18的合成路线如下:
1、化合物C18-2的合成
将化合物B(80mg,0.15mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C18-1(60mg,0.30mmol),醋酸铜(27mg,0.15mmol)和2,2'-联吡啶(47mg,0.30mmol),氧气氛围下,于25℃搅拌过夜。反应结束后,用乙酸乙酯稀释反应液,饱和氯化钠洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得100mg化合物C18-2.Ms[M+H]+671.4
2、化合物C18的合成
将化合物C18-2(100mg,0.15mmol)溶于3mL甲醇中,再加入4mL的4M氯化氢甲醇溶液,氮气保护下,于25℃搅拌30min后,再将反应液加热至55℃搅拌5h。反应结束后,冷至室温,减压浓缩后经纯化得C18的三氟乙酸盐.Ms[M+H]+463.2.
化合物C18的核磁数据:1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),8.30(s,1H),8.21-8.16(m,1H),8.07(s,1H),7.91(d,J=8.8Hz,1H),4.93(s,2H),4.55(q,J=7.3Hz,2H),4.36-4.28(m,1H),3.98(d,J=9.1Hz,1H),3.88(d,J=9.1Hz,1H),3.62-3.47(m,3H),3.11-2.98(m,2H),2.12-2.01(m,2H),2.00-1.92(m,1H),1.83-1.75(m,1H),1.53(t,J=7.2Hz,3H),1.34(d,J=6.5Hz,3H).
实施例18
本发明合成的化合物:
化合物C19的合成路线如下:
1、化合物C19-2的合成
将化合物C19-1(1.0g,5.08mmol)溶于10mL N,N-二甲基甲酰胺中,加入碳酸铯(5.0g,15.24mmol),室温搅拌0.5小时后,加入三氟碘乙烷(2.13g,10.2mmol),然后加热至50℃搅拌5小时。反应结束后,将反应液冷至室温,加水淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到552mg化合物C19-2.Ms[M+H]+278.9
化合物C19-2的核磁数据:1H NMR(90MHz,CDCl3)δ8.04(s,1H),7.67-7.57(m,2H),7.38-7.2(m,1H),4.90(q,3H).
2、化合物C19-3的合成
将化合物C19-2(500mg,1.8mmol)溶于30mL 1,4-二氧六环中,依次加入联硼酸频那醇酯(914mg,3.6mmol),1,1'-双(二-苯基膦基)二茂铁氯化钯(73mg,0.09mmol)和醋酸钾(529mg,5.4mmol),氮气保护下,反应液于95℃搅拌20小时。反应结束后,将反应液冷至室温,加水稀释反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到930mg化合物C19-3.Ms[M+H]+327.1
3、化合物C19-4的合成
将化合物C19-3(400mg,1.22mmol)溶于40mL甲醇中,向反应液中 加入氟氢化钾(478mg,6.13mmol)的水溶液(40mL),室温搅拌1h。反应结束后,将反应液直接减压蒸干,残渣用乙腈稀释溶解,然后用石油醚萃取出杂质,分液,乙腈相减压浓缩后得到80mg化合物C19-4.Ms[M+H]+245.04、化合物C19的合成
参考化合物C18的合成,数据见表一。
实施例19
本发明合成的化合物:
化合物C20、C21的合成路线如下:
1、化合物C20-2的合成
将化合物C20-1(5g,23.87mmol)溶于25mL四氢呋喃中,然后移至干冰浴下,降至-62℃,缓慢加入LDA(26.3mL,26.26mmol),-62℃下搅拌1小时,再缓慢滴加DMF(2.617g,35.81mmol),反应液移自然升至室温,氮气保护下搅拌3h。反应结束后,将反应液置于冰水浴下,缓慢加饱和氯化 铵水溶液淬灭反应,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到2.559g化合物C20-2.Ms[M+H]+236.9
2、化合物C20-3的合成
将化合物C20-2(2.459g,10.36mmol)溶于25mL四氢呋喃中,然后依次加入碳酸钾(1.714g,12.43mmol),甲氧基氨(951mg,11.39mmol),氮气保护下,反应液于45℃搅拌12小时。反应结束后,将反应液冷至室温,加水淬灭反应液,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到2.250g化合物C20-3.Ms[M+H]+265.9
3、化合物C20-4的合成
将化合物C20-3(1.45g,5.44mmol)溶于15mL二甲基亚砜中,然后加入水合肼(544mg,10.88mmol),氮气保护下,反应液于100℃搅拌12小时。反应结束后,将反应液冷至室温,加水淬灭反应液,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到1.22g化合物C20-4.Ms[M+H]+230.9
4、化合物C20-5和C21-5的合成
将化合物C20-4(1.220g,5.27mmol)溶于15mL四氢呋喃中,然后移至冰水浴下,缓慢加入氢化钠(253mg,6.32mmol),0℃下搅拌60分钟,再缓慢滴加碘甲烷(1.123g,7.91mmol),反应液移至室温,氮气保护下搅拌过夜。反应结束后,将反应液置于冰水浴下,缓慢加水淬灭反应,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到化合物C20-5和C21-5。
5、化合物C20-7和C21-7的合成
化合物C20-7和C21-7的合成参考化合物C19-4的合成方法。
6、化合物C20和C21的合成
参考化合物C18的合成,数据见表一。
实施例20
本发明合成的化合物:
化合物C22、C23的合成路线如下:
1、化合物C22-2的合成
将化合物C22-1(3.0g,13.5mmol)溶于60mL四氢呋喃中,然后依次加入碳酸钾(2.2g,16.3mmol),甲氧基氨盐酸盐(1.3g,14.9mmol),氮气保护下,反应液于45℃搅拌3小时。反应结束后,将反应液冷至室温后通过硅藻土过滤,乙酸乙酯淋洗滤饼,滤液减压浓缩后经纯化得到3.0g化合物C22-2.Ms[M+H]+250.0
2、化合物C22-3的合成
将化合物C22-2(3.0g,12.1mmol)溶于15mL二甲基亚砜中,然后加入7mL水合肼,氮气保90护下,反应液于℃搅拌36小时。反应结束后,将反应液冷至室温,加水淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得到2.2g化合物C22-3.Ms[M+H]+215.0
3、化合物C22-4和C23-4的合成
将化合物C22-3(2.2g,10.1mmol)溶于40mL四氢呋喃中,冰水浴冷却下,分批加入含量为60%的氢化钠(489mg,12.2mmol),加毕,将反应液缓慢升至室温搅拌1h后,降温至0℃,缓慢滴加碘甲烷(2.2g,15.3mmol),加毕,反应液移至室温搅拌。反应结束后,将反应液置于冰水浴下,缓慢加水淬灭反应,用乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得到710mg化合物C22-4和1.44g化合物C23-4.Ms[M+H]+229.0
4、化合物C22-5和C23-5的合成
将化合物C22-4(900mg,3.95mmol)溶于10mL 1,4-二氧六环中,然后依次加入联硼酸频那醇酯(1.2g,4.74mmol),1,1'-双(二-苯基膦基)二茂铁氯化钯,二氯甲烷复合物(144mg,0.2mmol)和醋酸钾(1.16g,11.85mmol),氮气保护下,反应液于95℃搅拌20小时。反应结束后,将反应液冷至室温,加水淬灭反应液,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到996mg化合物C22-5.Ms[M+H]+277.1
将化合物C23-4(1.84g,8.07mmol)溶于20mL 1,4-二氧六环中,然后依次加入联硼酸频那醇酯(2.46g,9.68mmol),1,1'-双(二-苯基膦基)二茂铁氯化钯(295mg,0.4mmol)和醋酸钾(2.37g,24.21mmol),氮气保护下,反应液于95℃搅拌12小时。反应结束后,将反应液冷至室温,加水淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到1.98g化合物C23-5.Ms[M+H]+277.1
5、化合物C22-6和C23-6的合成
将化合物C22-5(996mg,3.6mmol)溶于100mL甲醇中,然后向反应液中加入氟氢化钾(254mg,3.44mmol)的水溶液(100mL),室温搅拌30 分钟。反应结束后,直接旋干反应液,加乙腈溶解,加石油醚萃取,然后保留乙腈相,乙腈相过滤除去残渣,滤液减压浓缩得392mg化合物C22-6.Ms[M+H]+195.0
将化合物C23-5(500mg,1.8mmol)溶于50mL甲醇中,然后向反应液中加入氟氢化钾(700mg,9mmol)的水溶液(50mL),室温搅拌30分钟。反应结束后,直接旋干反应液,加乙腈溶解,加石油醚萃取,然后保留乙腈相,过滤残渣,减压浓缩得102mg化合物C23-6.Ms[M+H]+195.0
6、化合物C22和C23的合成
参考化合物C18的合成,数据见表一。
实施例21
本发明合成的化合物:
化合物C24的合成路线如下:
1、化合物C24-2的合成
将化合物B(80mg,0.15mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C24-1(192mg,0.75mmol),醋酸铜(27mg,0.15mmol)和2,2'-联吡啶(47mg,0.30mmol),氧气氛围下,于90℃搅拌反应7小时。反应结束后,用乙酸乙酯稀释反应液,饱和氯化钠洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩后经纯化得化合物C24-2。Ms[M+H]+656.3
2、化合物C24的合成
化合物C24的合成参考化合物C18的合成,数据见表一。
实施例22
本发明合成的化合物:
化合物C25、C26的合成路线如下:
1、化合物C25-2和C26-2的合成
将化合物C25-1(5.0g,20.3mmol)溶于200mL乙腈中,然后依次加入碳酸钾(10.75g,40.6mmol),溴二氟甲基磷酸二乙酯(8.15g,24.3mmol),氮气保护下,反应液于室温搅拌12小时。反应结束后,加水淬灭反应,反应液用乙酸乙酯萃取,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后经纯化得到3.29g化合物C25-2和化合物C26-2的混合物.Ms[M+H]+246.9
2、化合物C25-3和C26-3的合成
将化合物C25-2和C26-2的混合物(1.2g,4.8mmol)溶于60mL 1,4-二氧六环中,然后依次加入联硼酸频那醇酯(2.48g,9.7mmol),1,1'-双(二-苯基膦基)二茂铁氯化钯(175mg,0.24mmol)和醋酸钾(1.4g,14.4mmol), 氮气保护下,反应液于95℃搅拌12小时。反应结束后,将反应液冷至室温,加水淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到120mg化合物C25-3和1.165g化合物C26-3。
化合物C25-3:Ms[M+H]+295.1
化合物C26-3:Ms[M+H]+295.1
化合物C26-3的核磁数据:1H NMR(400MHz,DMSO-d6)δ8.90(d,J=1.0Hz,1H),8.17(t,J=60Hz,1H),8.05(d,J=1.3Hz,1H),7.78(dd,J=8.6,1.1Hz,1H),7.36(d,J=8.5Hz,1H),1.32(s,12H).
3、化合物C25和C26的合成
化合物C25和化合物C26的合成参考化合物C22和C23的合成,数据见表一。
实施例23
本发明合成的化合物:
化合物C27和化合物C28的合成路线如下:
化合物C27和化合物C28的合成参考化合物C22的合成,数据见表一。
实施例24
本发明合成的化合物:
化合物C29合成路线如下:
1、化合物C29-2的合成:
将化合物C29-1(2.0g,10.15mmol)溶于20mL N,N-二甲基甲酰胺中, 在冰浴下加入含量60%的氢化钠(609mg,15.23mmol),在氮气保护下于室温搅拌0.5小时后,冰水浴冷却下滴加碘甲烷(1.86g,13.2mmol),加毕,将反应液移至室温搅拌2小时。反应结束后,加水淬灭反应,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到1.29g化合物C29-2.Ms[M+H]+210.9
2、化合物C29-3的合成:
将化合物C29-2(700mg,3.33mmol)溶于7mL四氢呋喃中,氮气保护下,将反应液冷却至-78℃,然后滴加正丁基锂(2.5M,2mL,5mmol)的四氢呋喃溶液,保持温度搅拌0.5h后,再滴加异丙氧基硼酸脂(930mg,5mmol),然后-78℃条件下再搅拌1h。反应结束后,-78℃条件下滴加水淬灭反应,将反应液升至室温,乙酸乙酯萃取,合并有机相,无水硫酸钠干燥,减压浓缩后经纯化得到170mg化合物C29-3.Ms[M+H]+259.1
3、化合物C29-4的合成:
将化合物B(80mg,0.155mmol)溶于5mL N,N-二甲基甲酰胺中,依次加入化合物C29-3(120mg,0.46mmol),醋酸铜(42mg,0.23mmol)和吡啶(72mg,0.465mmol),氧气氛围下,将反应液加热至95℃并搅拌16小时。反应结束后,用乙酸乙酯稀释,饱和氯化钠溶液洗涤,分出有机相,无水硫酸钠干燥,减压浓缩后经纯化得化合物C29-4.Ms[M+H]+657.3
4、化合物C29的合成:
参考化合物C22的合成,数据见表一。
实施例25
本发明合成的化合物:
化合物C30合成路线如下:
C30的合成参考化合物C22的合成,数据见表一。
实施例26
本发明合成的化合物:
化合物C31合成路线如下:
C31的合成参考化合物C22的合成,数据见表一。
实施例27
本发明合成的化合物:
化合物C32合成路线如下:
C32的合成参考化合物C22的合成,数据见表一。
实施例28
本发明合成的化合物:
化合物C33合成路线如下:
C33的合成参考化合物C22的合成,数据见表一。
实施例29
本发明合成的化合物:
化合物C34合成路线如下:
C34的合成参考化合物C22的合成,数据见表一。
实施例30
本发明合成的化合物:
化合物C35和C36的合成路线如下:
C35和C36的合成参考化合物C22的合成,数据见表一。
表一
下面对所合成的部分化合物进行生物活性测试实验。
实施例1:体外评价
1、实验试剂及材料
a)纯化的全长SHP2蛋白(卡梅德生物-天津)
b)SHP2激活肽(BPS Bioscience);
c)DiFMUP;
d)反应缓冲液(120mM HEPES pH 7.2,200mM NaCl,1mM EDTA,0.002%Brij35),热压处理后加入0.04%BSA,储存在4℃,临用前稀释至1×,并加入2mM的DTT。
2、实验步骤
a)384孔板中加入10uL 2号待测化合物溶液,3倍梯度稀释,共8个浓度;
b)待测样品孔加入5uL 4,号Niv激活肽(2uM)和5uL 4×全长SHP2蛋白(0.88nM),对照孔不加抑制剂,空白孔不加SHP2激活肽和抑制剂;
c)密封384孔板,混匀后室温孵育1hr;
d)加入5uL 5×DiFMUP(125uM),密封384孔板,混匀后室温孵育1hr,用EnVision检测;
3、数据分析及结果
抑制率计算公式如下:
%Inhibition=[1-(RFU
sample-RFU
blank)/(RFU
total-RFU
blank)]X100
用Graphpad 8.0进行非线性回归分析,通过Y=Bottom+(Top-Bottom)/(1+10^((LogIC
50-X)*Hill Slope))方程拟合出酶活性随化合物浓度变化得曲线求得各化合物得IC
50值。化合物抑制SHP2酶活性的IC
50如表二:
(在下表中,使用以下名称:<50nM=A;50-500nM=B;>500nM=C。)
表二
实施例2:化合物MV4-11细胞活性评价
生物活性测试实验过程如下:
取对数生长期的MV4-11细胞,制成细胞悬液,以160uL/孔接种于96孔板,接种密度为5000个细胞/孔,37℃细胞培养箱中过夜培养。配制5×待测化合物溶液,4倍梯度稀释,共8个浓度,双复孔。将待测化合物溶液以40uL/孔加入96孔板,空白孔和对照孔加入相应体积的溶剂,振摇混匀后于37℃细胞培养箱中孵育72hr,CTG方法检测细胞活力。
利用方程式(Sample-blank)/(control-blank)*100%将原始数据换算成抑制率,IC
50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出),结果见表三。(在下表中,使用以下名称:<100nM=A;100-500nM=B;>500nM=C。)
表三
从上表可知,通过体外生物活性筛选,以RMC-4630为对照品(结构式为
),我们所合成的化合物SHP2有很好的抑制能力。有望进一步开发成为用于调节SHP2活性或治疗SHP2相关疾病方面的药物。在专利WO2021148010A1中实施例5报道的结构式为
和该化合物对比发现,我们的化合物对SHP2有更好的抑制能力。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
- 一种式I’化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药,其中:R 1选自下组:双环的C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、C6-C10芳基杂环烷基;R 1上的任意氢原子任选地被一个或多个以下取代基取代:氘、羟基、卤素、氰基、=O、酯基、酰胺基、酮羰基、氨基、羟基取代的C1-C4烷基、-C(O)OR a、-NHC(O)R a、-NHC(O)OR a、-C(O)(C1-C4亚烷基)OH、C1~C6烷基、C1~C6卤代烷基、C1~C6硫代烷基、C1~C6烷氧基、C1~C6杂烷基、C1~C6烷胺基、C3~C6环烷基、C3~C8环烷胺基、C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基;R a为C1-C4烷基;所述C6-C10芳基杂环烷基为-(C6-C10芳基)并(含1-3个选自N、O、S的杂原子的饱和或不饱和的3-8元杂环烷基);R 1为双环结构且为并环结构;R 2选自下组:H、氘、氨基、氰基、卤素、羟基、甲基、CH 2OH、CH(CH 3)OH、C(CH 3) 2OH、卤代甲基、氘代甲基、CONH 2、CF 2OH、NHSO 2Me、CH 2NHSO 2Me;R 3选自下组:氢、氘、羟基、氨基、氰基、卤素、甲基、氘代甲基、卤代甲基;A环选自下组:单环或双环的含1-3个选自N、O、S的杂原子的3-11元杂环烷基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、-(含1-3个选自N、O、S的杂原子的3-8元亚杂环烷基)-(含1-3个选自N、O、S的杂原子的3-8元杂环烷基)、含1-3个选自N、O、S的杂原子的4-8元杂桥环烷基;A环上的任意氢原子未被取代或被以下取代基单取代、双取代或三取代:(CH 2) nNHR’ 1、(CH 2) nCONH 2、(CH 2) nCF 2H、(CH 2) nCF 3、(CH 2) nOH、=O、C1-C6烷基、卤素、氨基、羟基、-N-(C1-C6烷基)、-(C1-C6亚烷基)-NH 2,其中烷基上的氢未被取代或被OR’ 1单取代或双取代;R’ 1选自下组:H、C1-C4烷基、羟基取代的C1-C4烷基;n选自下组:0、1、2、3。
- 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药,其特征在于,R 1为B环并C环,其中,B环、C环各自独立地选自下组:C5-C6芳基、含1-3个选自N、O、S的杂原子的5-6元杂芳基、C5-C6环烷基、含1-3个选自N、O、S的杂原子的饱和的5-6元杂环烷基;R 1上的任意氢原子任选地被一个或多个以下取代基取代:氘、羟基、卤素、氰基、=O、氨基、羟基取代的C1-C4烷基、C1~C6烷基、C1~C6卤代烷基、C1~C6硫代烷基、C1~C6烷氧基、C3~C6环烷基、C1~C6烷胺基、C6-C10芳基、含1-3个选自N、O、S的杂原子的6-10元杂芳基、-COC(CH 3) 2OH。
- 一种药物组合物,其特征在于,包含药学上可接受的载体和一种或多种安全有效量的权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或 前药。
- 一种权利要求7所述的药物组合物的用途,其特征在于,用于制备用作SHP2抑制剂的药物。
- 一种权利要求7所述的药物组合物的用途,其特征在于,用于制备用于调节SHP2活性或治疗SHP2相关疾病的药物。
- 如权利要求9所述用途,其特征在于,所述SHP2相关疾病选自下组:努南综合征、豹综合征、青少年骨髓单核细胞性白血病、急性髓样白血病、神经母细胞瘤、黑色素瘤、乳腺癌、食道癌、肺癌、胃癌、头癌、间变性大细胞淋巴瘤、成神经细胞瘤、成胶质细胞瘤、头颈的鳞状细胞癌、结肠癌、肝癌。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202280006674.5A CN116323616A (zh) | 2021-07-07 | 2022-07-07 | 用作shp2抑制剂的化合物及其应用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110768781 | 2021-07-07 | ||
CN202110768781.9 | 2021-07-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023280283A1 true WO2023280283A1 (zh) | 2023-01-12 |
Family
ID=84800372
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/104449 WO2023280283A1 (zh) | 2021-07-07 | 2022-07-07 | 用作shp2抑制剂的化合物及其应用 |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN116323616A (zh) |
TW (1) | TW202304927A (zh) |
WO (1) | WO2023280283A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023230205A1 (en) | 2022-05-25 | 2023-11-30 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016203404A1 (en) * | 2015-06-19 | 2016-12-22 | Novartis Ag | Compounds and compositions for inhibiting the activity of shp2 |
WO2019183364A1 (en) * | 2018-03-21 | 2019-09-26 | Relay Therapeutics, Inc. | Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof |
WO2021033153A1 (en) * | 2019-08-20 | 2021-02-25 | Otsuka Pharmaceutical Co., Ltd. | Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors |
-
2022
- 2022-07-07 WO PCT/CN2022/104449 patent/WO2023280283A1/zh active Application Filing
- 2022-07-07 CN CN202280006674.5A patent/CN116323616A/zh active Pending
- 2022-07-07 TW TW111125565A patent/TW202304927A/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016203404A1 (en) * | 2015-06-19 | 2016-12-22 | Novartis Ag | Compounds and compositions for inhibiting the activity of shp2 |
WO2019183364A1 (en) * | 2018-03-21 | 2019-09-26 | Relay Therapeutics, Inc. | Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof |
WO2021033153A1 (en) * | 2019-08-20 | 2021-02-25 | Otsuka Pharmaceutical Co., Ltd. | Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023230205A1 (en) | 2022-05-25 | 2023-11-30 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
Also Published As
Publication number | Publication date |
---|---|
TW202304927A (zh) | 2023-02-01 |
CN116323616A (zh) | 2023-06-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11046697B2 (en) | Compounds and compositions useful for treating disorders related to NTRK | |
WO2023280283A1 (zh) | 用作shp2抑制剂的化合物及其应用 | |
CN109843873B (zh) | 炔代杂环化合物、其制备方法及其在医药学上的应用 | |
TWI518085B (zh) | 經取代之多環胺甲醯基吡啶酮衍生物之前藥 | |
WO2020156285A1 (zh) | 一种苯并吡啶酮杂环化合物及其用途 | |
WO2019001572A1 (zh) | Rho 相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途 | |
WO2019000682A1 (zh) | Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途 | |
CN108473497B (zh) | Ep4拮抗剂 | |
CN114127053A (zh) | 一种取代吡嗪化合物、其制备方法和用途 | |
TWI753918B (zh) | 作為jak抑制劑的吡咯並嘧啶化合物的結晶 | |
CN113748114A (zh) | 一种喹唑啉化合物及其在医药上的应用 | |
WO2019157879A1 (zh) | 作为trk抑制剂的杂环化合物 | |
WO2022012510A1 (zh) | 一种作为btk抑制剂的化合物及其制备方法与用途 | |
WO2023280280A1 (zh) | 作为KRas G12D抑制剂的稠环化合物 | |
TW201734020A (zh) | 布魯頓氏酪胺酸激酶抑制劑及其使用方法 | |
CN110041253B (zh) | 吡啶类n-氧化衍生物及其制备方法和应用 | |
WO2019085916A1 (zh) | P2x3和/或p2x2/3受体拮抗剂、包含其的药物组合物及其用途 | |
CN114685531A (zh) | 四并环化合物及其药物组合物和应用 | |
WO2022268230A1 (zh) | 作为kif18a抑制剂的化合物 | |
WO2022253101A1 (zh) | 作为parp7抑制剂的哒嗪酮类化合物 | |
WO2022199599A1 (zh) | 丙烯酰基取代的化合物、包含其的药物组合物及其用途 | |
CN110198941B (zh) | 吡咯并吡啶类n-氧化衍生物及其制备方法和应用 | |
WO2021129841A1 (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
WO2023041055A1 (zh) | Kif18a抑制剂 | |
WO2021197467A1 (zh) | 多靶点的抗肿瘤化合物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: 22837028 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 18577261 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |