WO2023025324A1 - 作为p53调节剂的化合物 - Google Patents
作为p53调节剂的化合物 Download PDFInfo
- Publication number
- WO2023025324A1 WO2023025324A1 PCT/CN2022/115635 CN2022115635W WO2023025324A1 WO 2023025324 A1 WO2023025324 A1 WO 2023025324A1 CN 2022115635 W CN2022115635 W CN 2022115635W WO 2023025324 A1 WO2023025324 A1 WO 2023025324A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- cycloalkyl
- optionally substituted
- hydrogen
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 360
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 8
- 230000003287 optical effect Effects 0.000 claims abstract description 7
- 239000000651 prodrug Substances 0.000 claims abstract description 7
- 229940002612 prodrug Drugs 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 121
- 125000000623 heterocyclic group Chemical group 0.000 claims description 104
- 229910052739 hydrogen Inorganic materials 0.000 claims description 71
- 239000001257 hydrogen Substances 0.000 claims description 71
- 150000002431 hydrogen Chemical class 0.000 claims description 58
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 44
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- 125000003342 alkenyl group Chemical group 0.000 claims description 39
- 229910052760 oxygen Inorganic materials 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- -1 C(O)R d Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000006413 ring segment Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 150000001924 cycloalkanes Chemical class 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000012634 fragment Substances 0.000 claims description 8
- 125000004437 phosphorous atom Chemical group 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 150000004677 hydrates Chemical class 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 3
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 208000005234 Granulosa Cell Tumor Diseases 0.000 claims description 3
- 208000017604 Hodgkin disease Diseases 0.000 claims description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000008601 Polycythemia Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 206010041660 Splenomegaly Diseases 0.000 claims description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 3
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 3
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 3
- 206010057644 Testis cancer Diseases 0.000 claims description 3
- 206010043515 Throat cancer Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000006491 bone marrow cancer Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 3
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 3
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 3
- 201000007450 intrahepatic cholangiocarcinoma Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 3
- 201000005243 lung squamous cell carcinoma Diseases 0.000 claims description 3
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 206010028537 myelofibrosis Diseases 0.000 claims description 3
- 208000025113 myeloid leukemia Diseases 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 206010038038 rectal cancer Diseases 0.000 claims description 3
- 201000001275 rectum cancer Diseases 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 201000003120 testicular cancer Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 206010046885 vaginal cancer Diseases 0.000 claims description 3
- 208000013139 vaginal neoplasm Diseases 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 206010024305 Leukaemia monocytic Diseases 0.000 claims description 2
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 2
- 125000000232 haloalkynyl group Chemical group 0.000 claims description 2
- 201000006894 monocytic leukemia Diseases 0.000 claims description 2
- 206010014950 Eosinophilia Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 230000002518 glial effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 329
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 276
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 254
- 238000006243 chemical reaction Methods 0.000 description 150
- 239000012043 crude product Substances 0.000 description 127
- 235000019439 ethyl acetate Nutrition 0.000 description 110
- 239000000243 solution Substances 0.000 description 95
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 88
- 239000007787 solid Substances 0.000 description 85
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 82
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 78
- 238000004809 thin layer chromatography Methods 0.000 description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
- 238000005481 NMR spectroscopy Methods 0.000 description 70
- 239000012074 organic phase Substances 0.000 description 69
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 68
- 238000010898 silica gel chromatography Methods 0.000 description 68
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 67
- 239000011541 reaction mixture Substances 0.000 description 64
- 239000012299 nitrogen atmosphere Substances 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- 239000000706 filtrate Substances 0.000 description 52
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 50
- 239000003208 petroleum Substances 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- 238000001914 filtration Methods 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- 229910000024 caesium carbonate Inorganic materials 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- 239000007788 liquid Substances 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 230000035772 mutation Effects 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 238000000926 separation method Methods 0.000 description 12
- 125000003367 polycyclic group Chemical group 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 10
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 10
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 10
- 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 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- 235000008504 concentrate Nutrition 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 239000001301 oxygen Chemical group 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000011593 sulfur Chemical group 0.000 description 8
- LNTIKAHDNWYAGL-UHFFFAOYSA-N Br.CC#C Chemical compound Br.CC#C LNTIKAHDNWYAGL-UHFFFAOYSA-N 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 5
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 230000004568 DNA-binding Effects 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 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 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 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
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- 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 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 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 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 229940126657 Compound 17 Drugs 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-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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 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 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 2
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 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 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000002252 acyl group Chemical group 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
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 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
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000004637 cellular stress Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose 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
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 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 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 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
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 1
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- KCKYDPXAKVBJHE-UHFFFAOYSA-N 2-(fluoromethylsulfonyl)pyridine Chemical compound FCS(=O)(=O)c1ccccn1 KCKYDPXAKVBJHE-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 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
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- DJKPQYBFSAJUBS-UHFFFAOYSA-N 4-bromo-2-methoxy-1-nitrobenzene Chemical compound COC1=CC(Br)=CC=C1[N+]([O-])=O DJKPQYBFSAJUBS-UHFFFAOYSA-N 0.000 description 1
- ABEUJUYEUCCZQF-UHFFFAOYSA-N 4-chloro-2-methoxy-1-nitrobenzene Chemical compound COC1=CC(Cl)=CC=C1[N+]([O-])=O ABEUJUYEUCCZQF-UHFFFAOYSA-N 0.000 description 1
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 101001053401 Arabidopsis thaliana Acid beta-fructofuranosidase 3, vacuolar Proteins 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 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
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000031448 Genomic Instability Diseases 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
- 239000004471 Glycine Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 201000011062 Li-Fraumeni syndrome Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 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
- 101150080074 TP53 gene Proteins 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 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
- 239000003655 absorption accelerator Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000008649 adaptation response Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 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
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 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
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- QARVLSVVCXYDNA-IDEBNGHGSA-N bromobenzene Chemical group Br[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 QARVLSVVCXYDNA-IDEBNGHGSA-N 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
- 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
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 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
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- UHKPOGGUWJGGID-UHFFFAOYSA-N carbonic acid;cesium Chemical compound [Cs].OC(O)=O UHKPOGGUWJGGID-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 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
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- YOXHCYXIAVIFCZ-UHFFFAOYSA-N cyclopropanol Chemical compound OC1CC1 YOXHCYXIAVIFCZ-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 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
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- NSSMTQDEWVTEKN-UHFFFAOYSA-N diethoxy(methyl)phosphane Chemical compound CCOP(C)OCC NSSMTQDEWVTEKN-UHFFFAOYSA-N 0.000 description 1
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 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
- 150000002148 esters Chemical class 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
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose 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
- 230000003179 granulation Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 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
- 150000003949 imides Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 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
- 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 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
- 208000032839 leukemia Diseases 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VFZXMEQGIIWBFJ-UHFFFAOYSA-M magnesium;cyclopropane;bromide Chemical compound [Mg+2].[Br-].C1C[CH-]1 VFZXMEQGIIWBFJ-UHFFFAOYSA-M 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- NLXXVSKHVGDQAT-UHFFFAOYSA-N o-(oxan-2-yl)hydroxylamine Chemical compound NOC1CCCCO1 NLXXVSKHVGDQAT-UHFFFAOYSA-N 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
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- QMLWSAXEQSBAAQ-UHFFFAOYSA-N oxetan-3-ol Chemical compound OC1COC1 QMLWSAXEQSBAAQ-UHFFFAOYSA-N 0.000 description 1
- 108700025694 p53 Genes Proteins 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 230000019491 signal transduction Effects 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 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
- 239000011550 stock solution Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 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
- 239000012588 trypsin Substances 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a new type of derivative containing tricyclic heteroaryl, its synthesis method and its use as a p53 regulator in the preparation of medicines for the treatment of tumors and other related diseases in the application.
- TP53 mutations are closely related to poor prognosis of various tumors, and germline TP53 mutations can lead to a rare familial cancer-prone disease: Li Fraumeni syndrome.
- p53 provides an important barrier to tumor transformation and progression.
- p53 is very sensitive to cellular stress and coordinates a complex signaling pathway to maintain cellular homeostasis and genome stability.
- Most of the TP53 mutations are missense mutations, where the codon encoding a certain amino acid becomes the codon encoding another amino acid after base substitution.
- mutated p53 may support tumor progression by promoting adaptive responses to tumor-associated stress.
- cancer cells are exposed to a variety of internal and external stressors. Mutated p53 can sense a variety of cellular stresses and induce cellular adaptive mechanisms to exert cancer-promoting effects.
- the p53Y220C mutation is one of the common missense mutation types of p53. This mutation exists in cancer types such as breast cancer, lung cancer, colon cancer, gastric cancer, and head and neck cancer. There are about 100,000 new cancer patients with this mutation every year worldwide. people. Therefore, the development of compounds targeting this mutation to reactivate the function of wild-type p53 is crucial for cancer therapy.
- the purpose of the present invention is to provide a new class of p53 regulators.
- the first aspect of the present invention provides a compound with the structure shown in the following formula (I), or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate :
- Ring A is selected from aryl or heteroaryl
- Ring B is selected from aryl or heteroaryl
- C ring is selected from C 3-8 cycloalkyl or 4- to 12-membered heterocyclyl
- D is selected from a chemical bond, -C ⁇ C-, -CR a ⁇ CR a -, or a C 3-6 cyclic group;
- E is selected from chemical bonds, -(CR a R a ) q -, -O-, -NR b -, C 3-6 cyclic groups, or 3- to 6-membered heterocyclic groups;
- F is selected from a chemical bond, -NR b -, -O-, or -(CR a R a ) q -;
- U is selected from a chemical bond, -NR c -, -O-, -NR c C(O)R c -, -NR c C(O)-;
- Each R 2 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3- to 6-membered heterocyclyl, CN, OR b , SR b , or NR b R b ; R b is as defined above;
- R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , C(O) )N(OR b )R b , NR b C(O)R d , NR b S(O) 2 R d , S(O) 2 R d , S(O)(NR b )R d , S(O )R d , NR b S(O) 2 R d , S(O)(NR b )R d , S(O )R d , NR b S
- Each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl , C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl , C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, C 2-4 alkenyl -O-, C 2-4 haloalkenyl-O-, C 2-4 alkynyl-O-, C 2-4 haloalkynyl-O-, C 3-6 cycloalkyl-O-, 3 - to 8-membered heterocyclyl-O-, CN, SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b ; the alkyl , alk
- R 4 and R in E and the ring atoms on the F and B rings connected to it together form an optionally substituted 6- to 8-membered ring structure
- R 5 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered Heterocyclyl, CN, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , C(O)NR b (OR b ) , NR b C(O)R d , NR b S(O) 2 R d , S(O) 2 R d , S(O)(NR b )R d , S(O)R d , NR b S( O) 2 R d , S(O) 2 NR b R b ; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;
- Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base, 3- to 6-membered heterocyclyl, CN, SR b , NR b R b ; each R b is defined as above; m is selected from 0, 1, 2, 3, or 4;
- n is selected from 0, 1, 2, 3, or 4;
- p is selected from 0, 1, 2, 3, or 4;
- q is selected from 0, 1, 2, or 3;
- each of the above-mentioned alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups is optionally and independently replaced by 1-3 substituents independently selected from the following group Substitution: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, Aryl, Heteroaryl, CN, NO2, OR b , SR b , NR b R b , C(O)R d , C(O)OR b , C(O)NR b R b , NR b C(O )R d , NR b S(O) 2 R d , or S(O) 2 R d , provided that the formed chemical structure is stable and meaningful; wherein each R b is
- the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms;
- the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group;
- the ring structure is Single ring, parallel ring, condensed ring or heterocyclic ring, said ring structure may be saturated or partially unsaturated (but not aromatic).
- the ring B is selected from phenyl or 5-7 membered heteroaryl.
- the C ring is selected from C 5-7 cycloalkyl or 5- to 8-membered heterocyclyl.
- R 3 is selected from C(O)NR b (OR b ), P(O)R f R f , P(O)(NR b R b )R f , or P(O)( OR b ) R f ; each R f is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, OR b , NR b R b ; or two R f together with the phosphorus atom connected to them together form a 4- to 8-membered ring structure optionally substituted, this ring structure can additionally contain 0-1 optional selected from N, O , a heteroatom of S; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; or two R b together with the nitrogen atom connected to them form any substituted 4 - to 8-membered ring structure, which may additionally contain 0-1 hetero
- R3 is selected from: Wherein, "—" represents the position where R 3 is connected to other parts of the compound of formula (I); the definition of R b is as above.
- formula (I) is formula (II):
- R 1 is selected from the following groups:
- Each R 2 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, CN, OR b , SR b , or NR b R b ; m is selected from 0, 1, or 2; R b is as defined above;
- R 3 is selected from the following groups:
- R 4 is selected from the following groups:
- fragment Groups selected from the following groups:
- F is selected from -NH-, -NMe-, or -O-.
- R3 is selected from the following groups:
- fragment Groups selected from the following groups:
- R is selected from the following groups:
- R 4 is selected from the following groups:
- formula (I) is formula (III):
- each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by C(O) in formula (III) NH(OR b ) is substituted, H on other CH is optionally substituted by R 4 ; R b is selected from hydrogen or C 1-4 alkyl;
- R 1 , R 2 , m, F, ring C, R 5 , R 6 , p are as defined above.
- formula (I) is formula (IV):
- each X is independently selected from CH or N, provided that at least two Xs are selected from CH, and the formed structure is stable; wherein the H on one CH is replaced by P(O) in formula (IV) Rf is substituted with Rf , and H on other CHs are optionally substituted with R4 ; each Rf is independently selected from C1-4 alkyl, C3-6 cycloalkyl, 3- to 8-membered heterocycle group, aryl group, heteroaryl group, OR b , NR b R b ; or two R f together with the phosphorus atom connected to them form an optionally substituted 4- to 8-membered ring structure, the ring structure May additionally contain 0-1 heteroatoms optionally selected from N, O, S; the alkyl, cycloalkyl, heterocyclyl, or ring structure described in R f are optionally substituted by the following substituents: Hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C
- R 1 , R 2 , m, F, ring C, R 4 , R 5 , R 6 , p, R b are as defined above.
- formula (I) is formula (V):
- R 1 , R 2 , m, R 4 , R 5 , R 6 , p, R b are as defined above.
- each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, OR b , SR b , or NR b R b ;
- Each R 4 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base-O-, 3- to 8-membered heterocyclyl-O-; said alkyl, alkoxy, cycloalkyl, heterocyclyl are optionally replaced by one or more groups selected from the following group Substitution: halogen, CN, OR b , SR b , NR b R b ;
- Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkane Base, 3- to 6-membered heterocyclic group, CN, SR b , NR b R b ; each R b is as defined above;
- n is selected from 0, 1, 2, or 3;
- p is selected from 0, 1, 2, 3, or 4;
- formula (I) is formula (VI):
- T is selected from a chemical bond or -NR c -;
- R c is selected from hydrogen or C 1-4 alkyl;
- Z is selected from N or CR k ;
- R k is selected from hydrogen or C 1-4 alkyl;
- Each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group in the R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ;
- R 1 , R 2 , m, R 4 , R 5 , R 6 , p, R b are as defined above.
- formula (I) is formula (VIIa) or (VIIb):
- Each R e is independently selected from hydrogen, fluorine, or C 1-4 alkyl; the alkyl group in the R e is optionally substituted by the following substituents: CN, OR b , SR b , NR b R b , C(O)OR b ; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl;
- R 3 is selected from the following groups:
- Rf is as defined above;
- R 1 , R 2 , m, R 4 , R 6 , p, R b , R d are as defined above.
- the compound of formula (I) is selected from the following group:
- "*" represents a chiral center, which can be optionally R configuration or S configuration, or a mixture of R configuration and S configuration; use
- the bonded carbon atom may optionally be in the R or S configuration, or optionally in cis or trans.
- the second aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
- the third aspect of the present invention provides a compound as described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate The use of it for the preparation of a pharmaceutical composition for treating a disease, disease or condition related to the p53 Y220C mutation.
- the disease, disease or condition is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, Granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, Head and neck squamous cell carcinoma, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma , Non-Hodgkin's lymphoma, monocytic leukemia,
- the inventors unexpectedly discovered a class of p53 modulators with novel structures and their preparation methods and applications.
- the compound of the present invention can be applied to the treatment of various diseases related to the activity of the transcription factor. Based on the above findings, the inventors have accomplished the present invention.
- each chiral carbon atom may optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
- alkyl refers to a straight chain (i.e., unbranched) or branched chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight chain and branched chain groups .
- the alkyl group is defined by the number of carbon atoms (such as C 1-10 ), it means that the said alkyl group contains 1-10 carbon atoms.
- C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar groups.
- alkenyl refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms (eg C 2- 8 ) is limited before the alkenyl group, it means that the alkenyl group contains 2-8 carbon atoms.
- C 2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups group.
- alkynyl alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
- the alkynyl group can be straight or branched, or a combination thereof. When the number of carbon atoms is limited before the alkynyl group (such as C 2-8 alkynyl group), it means that the alkynyl group contains 2-8 carbon atoms.
- C2-8 alkynyl refers to a straight or branched chain alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
- cycloalkyl alone or as part of another substituent, refers to a monocyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated ring .
- a cycloalkyl group is preceded by a restriction on the number of carbon atoms (such as C 3- 10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
- C 3-8 cycloalkyl refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo Pentyl, cycloheptyl, or similar groups.
- Spirocycloalkyl means a bicyclic or polycyclic group in which the single rings share a single carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has fully conjugated pi electrons system.
- “Fused cycloalkyl” means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more bicyclic bonds, but none of the rings have a fully conjugated ⁇ -electron system.
- “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system .
- the atoms contained in the cycloalkyl group are all carbon atoms.
- the following are some examples of cycloalkyl groups, and the present invention is not limited only to the cycloalkyl groups described below.
- Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, eg, phenyl and naphthyl.
- the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ -electron system on the carbon atoms in the ring.
- Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited only to the aryl groups described below.
- Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group (containing one to more heteroatoms optionally A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the connection point is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited only to the heteroaryl groups described below.
- Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
- a polycyclic heterocyclic group refers to a heterocyclic group including spiro rings, fused rings and bridged rings.
- “Spirocyclic heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, with the remaining ring atoms being carbon.
- “fused ring heterocyclyl” means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none A ring has a fully conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- “Bridged heterocyclyl” means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system , and wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated and aromatic rings in the heterocyclic group (for example, the saturated ring and the aromatic ring are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of connection to the parent is on the aromatic ring, it is called heteroaryl, not heterocyclic. The following are some examples of heterocyclic groups, and the present invention is not limited only to the following heterocyclic groups.
- C 3-6 cyclic group refers to a saturated or partially unsaturated monocyclic or bicyclic cyclic group having 3-6 carbon atoms.
- Heterocyclic group means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group (non-aromatic) in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- Ring structure refers to a ring system group having a saturated or partially saturated single ring, bicyclic or polycyclic rings (fused rings, bridged rings or spiro rings) and no heteroatoms in the ring skeleton.
- the cyclic group may be a monovalent, divalent, trivalent or other valent group, preferably a divalent or trivalent group.
- a restriction on the number of carbon atoms such as C 3-10 ) it means that the cycloalkyl group contains 3-10 carbon atoms.
- halogen refers to F, Cl, Br and I, alone or as part of another substituent.
- substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
- the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
- an optionally substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
- a cyclic substituent, such as a heterocyclyl may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, ie, two rings that share a single carbon atom.
- substituents contemplated by this invention are those that are stable or chemically feasible.
- the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , Aryl, heteroaryl, halogen, hydroxyl, alkoxy, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
- a pharmaceutically acceptable salt of a compound of the present invention refers to a salt that is suitable for contact with the tissues of a subject (eg, a human) without undue side effects.
- a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or having a basic Salts (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates) of compounds of the invention.
- the present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereoisomers, if present), hydrates , the use of a pharmaceutically acceptable carrier or excipient for regulating p53.
- the compounds of the present invention are useful as modulators of p53.
- the invention is a p53 regulator, which can prevent, alleviate or cure diseases by regulating the activity of p53.
- the diseases referred to include but are not limited to: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma , intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, osteosarcoma , esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphom
- compositions can be mixed with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
- Compositions can be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections. Sterile powder, etc.
- pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicate and macromolecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants (such as magnesium stearate, glycerin, and talc).
- disintegrants such as starch, croscarmellose sodium, complex silicate and macromolecular polyethylene glycol
- granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic
- lubricants such as magnesium stearate, glycerin, and talc
- the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.
- the amount of the compound or pharmaceutical composition of the present invention administered to the patient is not fixed, and is usually administered in a pharmaceutically effective amount.
- the amount of the compound to be actually administered can be determined by the physician according to the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like. Dosage of the compounds of this invention will depend on the particular use for the treatment, the mode of administration, the state of the patient, and the judgment of the physician.
- the ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration and the like.
- compositions and methods of administration are provided.
- the pharmaceutical composition of the invention can be used for treating, preventing and alleviating diseases related to p53 activity or expression.
- the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
- safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
- Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
- cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- gelatin such as talc
- solid lubricants such as stearic acid , magnesium stearate
- calcium sulfate such
- the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- Examples of usable embedding components are polymeric substances and waxy substances.
- the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
- inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
- compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
- the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
- the dosage is usually 1-2000 mg, preferably 5-500 mg.
- factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
- p53 Y220C regulator with a novel structure, its preparation and application, the inhibitor can activate the activity of p53 Y220C at very low concentration.
- a class of pharmaceutical compositions for treating diseases related to p53 Y220C activity is provided.
- Some representative compounds of the present invention can be prepared by the following synthetic methods.
- the reagents and conditions of each step can be selected from the conventional reagents or conditions of this type of preparation method in the art.
- the above selection can be made by those skilled in the art based on the knowledge in the art.
- DIPEA N,N-diisopropylamine
- HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)
- MgCl 2 magnesium chloride
- PE petroleum ether
- Some compounds of the present invention can be prepared by the following methods:
- Compound IIa-1 was prepared by the method in patent WO2021061643.
- Compound IIa-2 can be prepared by a suitable method.
- Compound IIa-1 and Compound IIa-2 were metal-catalyzed coupling reaction to obtain compound IIa-3, and then the target compound IIa was obtained through deprotection reaction.
- Compound 2 and Compound 3 in the present invention were prepared by the method of Scheme 1.
- the compound of formula (III) can be prepared by the following method.
- Compound III-1 was prepared by the method in patent WO2021061643. Compound III-1 is hydrolyzed to obtain compound III-2, and then subjected to condensation to obtain the compound of formula (III).
- the compound of formula (V) can be prepared by the following method.
- V-4 The key step in the synthesis of these compounds is the synthesis of intermediate V-4.
- V-1 dialkylphosphine oxide
- V-2 can be reduced to obtain V-4 (route A);
- V-4 prepared by reacting phosphinate V-3 with Grignard reagent can be used (route B).
- V-4 was alkylated with bromopropyne and protected by Boc to obtain compound V-5 with a terminal triple bond and different phosphorocarbonyl substitutions.
- V-5 was coupled with different 2-position OTf substituted indole compounds to obtain V-6. Then carry out Buchward condensation and deprotection with substituted piperidine amino compound to obtain compound V.
- the compound of formula (VI) can be prepared by the following method.
- Compound VI-1 was prepared by the method in patent WO2021061643, VI-2 was synthesized from tetracyclic carbonyl as raw material, VI-1 and VI-2 were condensed to obtain VI-3, and then deprotected to obtain compound VI.
- the compound of formula (VII) can be prepared by the following method.
- Compound VII-1 was prepared by the method in patent WO2021061643, and was subjected to Buchward condensation with piperidine derivatives VII-2-a and VII-2-b with exocyclic double bonds to obtain the precursor, and then deprotected to obtain the target Compounds VII-a and VII-b.
- Embodiment 1 the preparation of compound 1
- compound 1-g 80 mg, 0.13 mmol was dissolved in anhydrous 1,4-dioxane, and 2-(dicyclohexylphosphine) 3,6-dimethoxy-2' was added in sequence, 4',6'-triisopropyl-1,1'-biphenyl (8.37mg, 0.0091mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'- Biphenyl (8.5 mg, 0.018 mmol), cesium carbonate (169 mg, 0.52 mmol) and compound 1-h (35 mg, 0.17 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h.
- Embodiment 2 the preparation of compound 2
- Embodiment 3 the preparation of compound 3
- reaction solution was warmed to zero, and water (0.15mL), 15% aqueous sodium hydroxide solution (0.15mL), and water (0.3mL) were added dropwise in sequence, and the reaction mixture was warmed to room temperature and stirred for 15 minutes, and an appropriate amount of anhydrous sodium sulfate was added, and stirred After 15 minutes, it was filtered and the filtrate was concentrated under reduced pressure.
- the resulting crude product was separated and purified by silica gel column chromatography to obtain compound 3-c (250 mg, 85%).
- compound 2-d (15 mg, 0.024 mmol), compound 3-f (6 mg, 0.029 mmol), cesium carbonate (31.8 mg, 0.097 mmol), Brettphos Pd G4 (2.2 mg, 0.0024 mmol), 2- Dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (2.2mg, 0.0048mmol) and 1,4-dioxane solution (1mL) in a sealed tube at 110°C React for 16 hours.
- Embodiment 4 the preparation of compound 4
- Embodiment 5 the preparation of compound 5
- Embodiment 6 the preparation of compound 6
- Embodiment 7 the preparation of compound 7
- Embodiment 8 the preparation of compound 8
- Embodiment 9 the preparation of compound 9
- Embodiment 10 the preparation of compound 10
- Embodiment 11 Preparation of compound 11
- Embodiment 12 the preparation of compound 12
- 12-a (19.7g, 91mmol) was dissolved in tetrahydrofuran (25mL), and added dropwise to a tetrahydrofuran solution (75mL) containing magnesium chips (5g, 208mmol), stirred at room temperature for 2h, and then poured into the reaction solution
- Diethyl phosphate (6.4g, 46mmol) in tetrahydrofuran (20mL) continue stirring at room temperature for 1h, add potassium carbonate aqueous solution (30g potassium carbonate dissolved in 50mL water) to the reaction solution to form a large amount of white precipitate, filter The precipitate was washed with ethanol, and the filtrate was collected and concentrated, then added dichloromethane, and dried over anhydrous magnesium sulfate.
- Embodiment 13 Preparation of compound 13
- Embodiment 14 the preparation of compound 14
- Embodiment 15 Preparation of compound 15
- Embodiment 16 Preparation of compound 16
- Embodiment 17 the preparation of compound 17
- Embodiment 18 Preparation of compound 18
- compound 18-b (105 mg, 0.280 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL), and 2-(dicyclohexylphosphine)-3,6-dimethoxy -2',4',6'-triisopropyl-1,1'-biphenyl (20mg, 0.020mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1, 1'-biphenyl 20 mg, 0.04 mmol), cesium carbonate (459 mg, 1.41 mmol) and compound 7-f (167 mg, 0.337 mmol). The reaction mixture was warmed up to 100°C and stirred for 16h.
- Example 19 In vitro p53 Y220C and DNA binding activity test.
- the HTRF method was used to detect the activation of p53 Y220C protein activity by the compound.
- Compounds were dissolved in DMSO to make 10 mM stock solutions and further diluted to 100 ⁇ M. Transfer 60 ⁇ L of the compound to a 384-well plate, and perform serial dilution according to the multiple of 1:4, with a total of 10 concentrations. Use the Echo to transfer 0.1 ⁇ L of the diluted compound to a 384-well plate, and duplicate each compound. Add 2.5 ⁇ L of p53 Y220C protein solution to the 384-well plate, centrifuge at 1000 rpm for 1 min, and incubate for 10 min.
- activation rate (% activator) 100*(ave Low control-ave cpd well)/(ave Low control-ave High control).
- ave High control is the average reading value of wild-type p53 wells added with equal concentration of DMSO
- ave cpd well is the average reading value of compound wells
- ave Low control is the average reading value of p53 Y220C wells added with equal concentration of DMSO.
- EC 50 is used to represent the concentration required for the compound to restore p53 Y220C DNA-binding function to 50% of the wild type.
- the activity data of representative compounds to activate p53 Y220C protein and DNA binding are shown in Table 1.
- the positive drug Ref-A has an EC 50 value in the range of 60-120nM under the test conditions.
- Example 20 Inhibition of compound on proliferation of p53 Y220C mutated liver cancer cell line Huh7.
- Huh7 cells in good growth state were selected and digested with trypsin. Add fresh medium, mix well, and centrifuge at 800rpm for 3 minutes. According to the seed plate density of 2000 Huh7 cells per well, they were seeded in 96-well plates and cultured overnight in a 37°C incubator. The next day, the culture plate was taken out, and the compound was diluted in a five-fold gradient for administration. Among them, the blank control wells only added normal medium, no cells, and no DMSO; the DMSO wells contained cells and contained 0.5% DMSO. The 96-well plate was placed in a 37°C incubator for 144 hours.
- Chromatographic column ACQUITY UPLC BEH C18 (2.1mm ⁇ 50mm, 1.7 ⁇ m); column temperature 40°C; mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, the flow rate is 0.350 ml/min, using gradient elution , the elution gradient is 0.50min: 10%B; 1.50min: 90%B; 2.50min: 90%B; 2.51min: 10%B; 3.50min: stop. Injection volume: 1 ⁇ L.
- Animals 3 SD male rats, with a weight range of 200-220g, were used after being raised in the laboratory of the Experimental Animal Center for 2 days after purchase, fasted for 12 hours before administration and within 4 hours after administration, and free to drink water during the test. After the rats were gavaged, blood samples were collected within a predetermined period of time.
- Drug samples generally take multiple samples with similar structures (the difference in molecular weight is more than 2 units), weigh them accurately, and administer them together (cassette PK). This allows multiple compounds to be screened simultaneously and their oral absorption rates compared. Pharmacokinetics of drug samples in rats were also studied using single administration.
- Blood was collected from the orbit at 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours after intragastric administration. Take 50 ⁇ L of plasma sample, add 200 ⁇ L of acetonitrile (containing internal standard verapamil 2ng/mL), vortex for 3 min, centrifuge at 20000 rcf, 4 °C for 10 min, and take the supernatant for LC-MS/MS analysis.
- acetonitrile containing internal standard verapamil 2ng/mL
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (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
本发明提供了作为p53调节剂的化合物,具体地,本发明提供了一种如下式(I)所示结构的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物。所述的化合物可以用于治疗或预防与p53的活性或表达量相关的疾病或病症。
Description
本发明涉及药物化学领域;具体地说,本发明涉及一类新型含有三环杂芳基的衍生物,其合成方法及其作为一种p53调节剂在制备药物用于***等相关多种疾病中的应用。
在人类肿瘤中,最常见的突变为TP53基因突变,此基因编码p53蛋白。TP53突变和多种肿瘤的不良预后密切相关,胚系TP53突变可导致一种罕见的家族性癌症倾向疾病:Li Fraumeni综合征。p53作为抑癌因子,为肿瘤的转化和进展提供了一个重要的屏障。p53对细胞压力非常敏感,并且可以协调一个复杂的信号通路来维持细胞的稳态和基因组的稳定性。大部分的TP53突变都为错义突变,编码某种氨基酸的密码子经过碱基替换后,成为编码另一种氨基酸的密码子。这种突变通常导致p53蛋白抑癌功能的失活,丧失激活其下游基因的功能,有些突变也会反过来抑制其正常的p53蛋白发挥功能,起到显性抑制作用。另外,发生突变的p53可以通过促进对肿瘤相关的压力的适应性响应来支持肿瘤的进展。在一个处于生长状态的肿瘤中,癌症细胞会暴露于多种内部和外部压力环境下。突变的p53可以感应多种细胞压力,诱导细胞的适应性机制来发挥促癌效果。
p53Y220C突变是p53常见的的错义突变类型之一,在乳腺癌、肺癌、结肠癌、胃癌和头颈癌等癌症类型中都存在此突变,全球范围内每年新增此突变的癌症患者约10万人。因此,开发针对此突变的化合物,重新激活野生型p53的功能,对癌症治疗至关重要。
发明内容
本发明的目的是提供一类新型的p53调节剂。
本发明的第一方面,提供了一种如下式(I)所示结构的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物:
式(I)中:
A环选自芳基或杂芳基;
B环选自芳基或杂芳基;
C环选自C
3-8环烷基或4-至12-元杂环基;
D选自化学键、-C≡C-、-CR
a=CR
a-、或C
3-6环状基团;
E选自化学键、-(CR
aR
a)
q-、-O-、-NR
b-、C
3-6环状基团、或3-至6-元杂环状基团;
F选自化学键、-NR
b-、-O-、或-(CR
aR
a)
q-;
U选自化学键、-NR
c-、-O-、-NR
cC(O)R
c-、-NR
cC(O)-;
上述各个R
a各自独立地选自氢、卤素、C
1-4烷基、OR
b、CN、NR
bR
b;各个R
b和R
c各自独立地选自氢、C
1-4烷基、或C
1-4卤代烷基、C
3-6环烷基、3-至8-元杂环基;除一股取代基外,所述的环烷基或杂环基任选地被=M取代;M选自O或CR
eR
e;或二个R
b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;
R
1选自氢、C
1-4烷基、C
1-4卤代烷基、C
3-6环烷基、3-至8-元杂环基、芳基、杂芳基、C(O)R
d、或S(O)
2R
d;所述的烷基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR
b、SR
b、NR
bR
b;或所述的环烷基、杂环基任选地被=M取代;M选自O或CR
eR
e;各个R
e各自独立地选自氢、氟、或C
1-4烷基;所述R
e中的烷基任选地被下组取代基取代:CN、OR
b、SR
b、NR
bR
b、C(O)OR
b;R
d选自C
1-4烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至8-元杂环基、芳基、或杂芳基;除一般取代基外,所述的环烷基或杂环基任选地被=M取代;M选自O或CR
eR
e;R
b的定义如上所述;
各个R
2各自独立地选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
1-4卤代烷氧基、C
2-4烯基、C
2-
4炔基、C
3-6环烷基、3-至6-元杂环基、CN、OR
b、SR
b、或NR
bR
b;R
b的定义如上所述;
R
3选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、OR
b、SR
b、NR
bR
b、C(O)R
d、C(O)OR
b、C(O)NR
bR
b、C(O)N(OR
b)R
b、NR
bC(O)R
d、NR
bS(O)
2R
d、S(O)
2R
d、S(O)(NR
b)R
d、S(O)R
d、NR
bS(O)
2R
d、S(O)
2NR
bR
b、NR
bS(O)
2NR
bR
b、P(O)R
fR
f、P(O)(NR
bR
b)R
f、或P(O)(OR
b)R
f;各个R
b和R
d的定义如上所述;或二个R
b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;所述的环状结构任选地被=M取代;M选自O或CR
eR
e;各个R
f各自独立地选自C
1-4烷基、C
3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR
b、NR
bR
b;或二个R
f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R
f中所述的烷基、环烷基、杂环基、或环状结构任选地被下组取代基取代:氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至6-元杂环基、CN、OR
b、SR
b、NR
bR
b、=O;R
b的定义如上所述;
各个R
4各自独立地选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、羟基、C
1-4烷氧基、C
1-4卤代烷氧基、C
2-4烯基、C
2-4卤代烯基、C
2-4炔基、C
2-4卤代炔基、C
3-6环烷基、3-至8-元杂环基、C
2-4烯基-O-、C
2-4卤代烯基-O-、C
2-4炔基-O-、C
2-4卤代炔基-O-、C
3-6环烷基-O-、3-至8-元杂环基-O-、CN、SR
b、NR
bR
b、C(O)R
d、C(O)OR
b、C(O)NR
bR
b;所述的烷基、烷氧基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR
b、SR
b、NR
bR
b;或所述的环烷基、杂环基任选地被=M取代;M选自O或CR
eR
e;各个R
e各自独立地选自氢、氟、或C
1-4烷基;所述R
e的烷基任选地被下组取代基取代:CN、OR
b、SR
b、NR
bR
b、C(O)OR
b;各个R
b和R
d的定义如上所述;
或R
4和E中的R
a与与其相连接的F和B环上的环原子一起共同形成任意取代的6-至8-元的环状结构;
或R
4和F中的R
b与与其相连接的B环上的环原子一起共同形成任意取代的6-至8-元的环状结 构;
R
5选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至8-元杂环基、CN、OR
b、SR
b、NR
bR
b、C(O)R
d、C(O)OR
b、C(O)NR
bR
b、C(O)NR
b(OR
b)、NR
bC(O)R
d、NR
bS(O)
2R
d、S(O)
2R
d、S(O)(NR
b)R
d、S(O)R
d、NR
bS(O)
2R
d、S(O)
2NR
bR
b;各个R
b各自独立地选自氢、C
1-4烷基、或C
1-4卤代烷基;或二个R
b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R
d选自C
1-4烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至6-元杂环基;上述R
5、R
b、R
d中的烷基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、C
1-4烷基、C
3-6环烷基、3-至6-元杂环基、CN、OR
b、SR
b、NR
bR
b;或上述R
5中的环烷基、杂环基任选地被C=M取代;M选自O或CR
eR
e;各个R
e各自独立地选自氢、氟、或C
1-4烷基;所述R
e的烷基任选地被下组取代基取代:CN、OR
b、SR
b、NR
bR
b、C(O)OR
b;各个R
b的定义如上所述;
各个R
6各自独立地选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、羟基、C
1-4烷氧基、C
1-4卤代烷氧基、C
3-6环烷基、3-至6-元杂环基、CN、SR
b、NR
bR
b;各个R
b的定义如上所述;m选自0、1、2、3、或4;
n选自0、1、2、3、或4;
p选自0、1、2、3、或4;
q选自0、1、2、或3;
其中,各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代:卤素、C
1-4烷基、C
1-4卤代烷基、C
2-4烯基、C
2-4炔基、C
3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO2、OR
b、SR
b、NR
bR
b、C(O)R
d、C(O)OR
b、C(O)NR
bR
b、NR
bC(O)R
d、NR
bS(O)
2R
d、或S(O)
2R
d,前提条件是所形成的化学结构是稳定的和有意义的;其中,各个R
b各自独立地选自氢、C
1-4烷基、或C
1-4卤代烷基;或二个R
b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;各个R
d各自独立选自C
1-4烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至8-元杂环基、芳基、或杂芳基;
除非特别说明,上述的芳基为含有6-12个碳原子的芳香基团;杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团;环状结构为单环、并环、稠环或杂环,所述的环状结构可以是饱和或者部分不饱和的(但并非芳香性的)。
在另一优选例中,所述的B环选自苯基或5-7元杂芳基。
在另一优选例中,所述的C环选自C
5-7环烷基或5-至8-元杂环基。
在另一优选例中,R
3选自C(O)NR
b(OR
b)、P(O)R
fR
f、P(O)(NR
bR
b)R
f、或P(O)(OR
b)R
f;各个R
f各自独立地选自C
1-4烷基、C
3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR
b、NR
bR
b;或二个R
f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;各个R
b各自独立地选自氢、C
1-4烷基、或C
1-4卤代烷基;或二个R
b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;
其中,R
f中所述的烷基、环烷基、杂环基、或环状结构任意地被选自下组的基团取代:氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至6-元杂环基、CN、OR
b、SR
b、NR
bR
b、=O;R
b的定义如上所述;
在另一优选例中,式(I)为式(II):
其中,
R
1选自下组基团:
各个R
2各自独立地选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
1-4卤代烷氧基、C
2-4烯基、C
2-
4炔基、CN、OR
b、SR
b、或NR
bR
b;m选自0、1、或2;R
b的定义如上文中所述;
R
3选自下组基团:
其中,“—”表示R
3与式(II)化合物其它部分连接的位点;R
b、R
d、和R
f的定义如上文所述;
R
4选自下组基团:
其中,“---”表示R
4与式(II)化合物其它部分连接的位点;
其中,“*”表示手性中心;
F选自-NH-、-NMe-、或-O-。
在另一优选例中,R
3选自下组基团:
其中,“—”表示R
3与式(II)化合物其它部分连接的位点;R
b和R
f的定义如上文中所述;
其中,“*”表示手性中心;
在另一优选例中,R
1选自下组基团:
在另一优选例中,R
4选自下组基团:
其中,“---”表示R
4与式(II)化合物其它部分连接的位点。
在另一优选例中,式(I)为式(III):
其中,各个X各自独立地选自CH或N,前提条件是至少二个X选自CH,且所形成的结构是稳定的;其中一个CH上的H被式(III)中的C(O)NH(OR
b)取代,其它CH上的H任选地被R
4取代;R
b选自氢或C
1-4烷基;
R
1、R
2、m、F、C环、R
5、R
6、p的定义如上文中所述。
在另一优选例中,式(I)为式(IV):
其中,各个X各自独立地选自CH或N,前提条件是至少二个X选自CH,且所形成的结构是稳定的;其中一个CH上的H被式(IV)中的P(O)R
fR
f取代,其它CH上的H任选地被R
4取代;各个R
f各自独立地选自C
1-4烷基、C
3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR
b、NR
bR
b;或二个R
f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R
f中所述的烷基、环烷基、杂环基、或环状结构任选地被下组取代基取代:氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至6-元杂环基、CN、OR
b、SR
b、NR
bR
b、=O;
R
1、R
2、m、F、C环、R
4、R
5、R
6、p、R
b的定义如上文中所述。
在另一优选例中,式(I)为式(V):
其中,各个R
f各自独立地选自C
1-4烷基、C
3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR
b、NR
bR
b;或二个R
f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R
f中所述的烷基、环烷基、杂环基、或环状结构任选地被下组取代基取代:氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至6-元杂环基、CN、OR
b、SR
b、NR
bR
b、=O;
R
1、R
2、m、R
4、R
5、R
6、p、R
b的定义如上文中所述。
在另一优选例中,式(V)中:
R
1选自C
1-4烷基、C
1-4卤代烷基、C
3-6环烷基、3-至8-元杂环基;所述的烷基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR
b、SR
b、NR
bR
b;或所述的环烷基、杂环基任选地被=M取代;M选自O或CR
eR
e;各个R
e各自独立地选自氢、氟、或C
1-4烷基;所述R
e中的烷基任选地被下组取代基取代:CN、OR
b、SR
b、NR
bR
b、C(O)OR
b;
各个R
2各自独立地选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、C
1-4卤代烷氧基、CN、OR
b、SR
b、或NR
bR
b;
各个R
4各自独立地选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、羟基、C
1-4烷氧基、C
1-4卤代烷氧基、C
3-6环烷基-O-、3-至8-元杂环基-O-;所述的烷基、烷氧基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR
b、SR
b、NR
bR
b;
R
5选自氢、C
1-4烷基、C
3-6环烷基、3-至8-元杂环基、C(O)R
d、S(O)
2R
d;所述环烷基、杂环基任选地被C=M取代;M选自O或CR
eR
e;各个R
e各自独立地选自氢、氟、或C
1-4烷基;
各个R
6各自独立地选自氢、卤素、C
1-4烷基、C
1-4卤代烷基、羟基、C
1-4烷氧基、C
1-4卤代烷氧基、C
3-6环烷基、3-至6-元杂环基、CN、SR
b、NR
bR
b;各个R
b的定义如上所述;
上述各个R
b各自独立地选自氢、C
1-4烷基、C
1-4卤代烷基、或C
3-6环烷基;所述环烷基任选地被=M取代;
上述各个R
d各自独立地选自C
1-4烷基、C
2-4烯基、C
2-4炔基、C
3-6环烷基、3-至8-元杂环基、芳基、或杂芳基;所述环烷基、杂环基任选地被=M取代;
m选自0、1、2、或3;
p选自0、1、2、3、或4;
在另一优选例中,式(I)为式(VI):
T选自化学键或-NR
c-;R
c选自氢或C
1-4烷基;
Z选自N或CR
k;R
k选自氢或C
1-4烷基;
各个R
e各自独立地选自氢、氟、或C
1-4烷基;所述R
e中的烷基任选地被下组取代基取代:CN、OR
b、SR
b、NR
bR
b、C(O)OR
b;
R
1、R
2、m、R
4、R
5、R
6、p、R
b的定义如上文中所述。
在另一优选例中,式(I)为式(VIIa)或(VIIb):
各个R
e各自独立地选自氢、氟、或C
1-4烷基;所述R
e中的烷基任选地被下组取代基取代:CN、OR
b、SR
b、NR
bR
b、C(O)OR
b;各个R
b各自独立地选自氢、C
1-4烷基、或C
1-4卤代烷基;
R
3选自下组基团:
其中,“—”表示R
3与式(VIIa)或(VIIb)化合物其它部分连接的位点;
R
f的定义如上文中所述;
R
1、R
2、m、R
4、R
6、p、R
b、R
d的定义如上文中所述。
在另一优选例中,所述的式(I)化合物选自下组:
本发明的第二方面,提供了一种药物组合物,所述药物组合物包含本发明第一方面所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,以及药学上可接受的载体。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物的用途,其用于制备治疗与p53 Y220C突变相关的疾病,病症或病状的药物组合物。
在另一优选例中,所述疾病,病症或病状选自下组:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝细胞癌、肝内胆管癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、***癌、***癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、骨肉瘤、食管癌、肾癌、皮肤癌、胃癌、髓系白血病、淋巴系白血病、骨髓纤维化、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
本发明人经过长期而深入的研究,意外地发现了一类结构新颖的p53调节剂以及它们的制备方法和应用。本发明化合物可以应用于与所述转录因子的活性相关的各种疾病的治疗。基于上述发现,发明人完成了本发明。
术语
除特别说明之处,本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处,本发明的所有化合物之中,各手性碳原子(手性中心)可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,在单独或作为其他取代基一部分时,术语“烷基”指只含碳原子的直链(即,无支链)或支链饱和烃基,或直链和支链组合的基团。当烷基前具有碳原子数限定(如C
1-10)时,指所述的烷基含有1-10个碳原子。例如,C
1-8烷基指含有1-8个碳原子的烷基,包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“烯基”是指直链或支链,具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C
2-
8)时,指所述的烯基含有2-8个碳原子。例如,C
2-8烯基指含有2-8个碳原子烯基,包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的,或其组合。当炔基前具有碳原子数限定(如C
2-8炔基)时,指所述的炔基含有2-8个碳原子。例如,术语“C
2-8炔基”指具有2-8个碳原子的直链或支链炔基,包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“环烷基”指具有饱和的或部分饱和 的单元环,二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C
3-
10)时,指所述的环烷基含有3-10个碳原子。在一些优选实施例中,术语“C
3-8环烷基”指具有3-8个碳原子的饱和或部分不饱和的单环或二环烷基,包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子,本发明并不仅局限下述的环烷基。
除非有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子,本发明并不仅局限下述的芳基。
“杂芳基”指包含一个到多个杂原子(任选自氮、氧和硫)的具有芳香性的单环或多环基团,或者包含杂环基(含一个到多个杂原子任选自氮、氧和硫)与芳基稠合形成的多环基团,且连接位点位于芳基上。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子,本发明并不仅局限下述的杂芳基。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指***中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。“稠环杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***,而且其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***,而且其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起),连接到母体的点一定是在饱和的环上。注:当连接到母体的点在芳环上时,称为杂芳基,不称为杂环基。如下是杂环基的一些例子,本发明并不仅局限下述的杂环基。
“C
3-6环状基团”指具有3-6个碳原子的饱和或部分不饱和的单环或二环环状基团。
“杂环状基团”指饱和或部分不饱和单环或多环环状烃基团(非芳香性),其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。
“环状结构”指具有饱和的或部分饱和的单元环,二环或多环(稠环、桥环或螺环),且环骨架上不含杂原子的环系基团。所述的环状基团可以是一价、二价、三价或其他价态基团,优选为二价或三价基团。当某个环状基团前具有碳原子数限定(如C
3-10)时,指所述的环烷基含有3-10个碳原子。
如本文所用,在单独或作为其他取代基一部分时,术语“卤素”指F、Cl、Br和I。
如本文所用,术语“取代”(在有或无“任意地”修饰时)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,某个任意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。环状取代基,例如杂环基,可以与另一个环相连,例如环烷基,从而形成螺二环系,即两个环具有一个共用碳原子。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):C
1-8烷基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、3-至12-元杂环基,芳基、杂芳基、卤素、羟基、烷氧基、羧基(-COOH)、C
1-8醛基、C
2-10酰基、C
2-10酯基、氨基。
为了方便以及符合常规理解,术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点,而不包括那些化学上不能实现的取代。
如本文所用,除非特别说明,术语“药学上可接受的盐”指适合与对象(例如,人)的组织接触,而不会产生不适度的副作用的盐。在一些实施例中,本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如,钾盐,钠盐,镁盐,钙盐)或具有碱性基团的本发明的化合物的盐(例如,硫酸盐,盐酸盐,磷酸盐,硝酸盐,碳酸盐)。
用途:
本发明提供了一类式(I)化合物,或它们的氘代衍生物、它们的盐、异构体(对映异构体或非对映异构体,如果存在的情况下)、水合物、可药用载体或赋形剂用于调节p53的用途。
本发明化合物可用作一种p53调节剂。
本发明是一种p53调节剂,通过调节p53的活性达到预防、缓解或治愈疾病的目的。所指疾病包括但不限于:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝细胞癌、肝内胆管癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、***癌、***癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、骨肉瘤、食管癌、肾癌、皮肤癌、胃癌、髓系白血病、淋巴系白血病、骨髓纤维化、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
可将本发明化合物及其氘代衍生物,以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起,得到的组合物可在体内给予哺乳动物,例如男人、妇女和动物,用于治疗病症、症状和疾病。组合物可以是:片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液。无菌粉末等。一些实施例中,药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇),造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和***胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中,所述药物组合物是适于口服的剂 型,包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定,通常按药用有效量给药。同时,实际给予的化合物的量可由医师根据实际情况决定,包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素,包括剂量、理化性质、给药途径等。
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。
药物组合物和施用方法
由于本发明化合物具有优异的对p53调节的活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与p53活性或表达量相关的疾病。
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5-200mg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
)、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。
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***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化合物联合给药。
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5~500mg。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。
本发明的主要优点包括:
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的p53 Y220C调节剂,及其制备和应用,所述的抑制剂在极低浓度下即可激活p53 Y220C的活性。
3.提供了一类治疗与p53 Y220C活性相关疾病的药物组合物。
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,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。
本发明的部分代表性化合物可以通过下面合成方法制备而得,下述各反应式中,各步骤的试剂和条件可以选用本领域进行该类制备方法常规的试剂或条件,在本发明的化合物结构公开后,上述选择可以由本领域技术人员根据本领域知识进行。
化合物的通用合成方法
缩写
Boc
2O=二碳酸二叔丁酯
Cs
2CO
3=碳酸铯
DCM=二氯甲烷
DIPEA=N,N-二异丙基胺
DMAP=4-二甲基氨基吡啶
DMF=N,N-二甲基甲酰胺
DMSO=二甲基亚砜
e.e.=对映体过量百分数
EtOAc or EA=乙酸乙酯
HATU=(1-[双(二甲基氨基)亚甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化六氟磷酸盐)
MgCl
2=氯化镁
NH
4HCO
3=碳酸氢铵
Pd(OAc)
2=乙酸钯(II)
Pd
2dba
3=三(二亚苄基丙酮)钯(0)
PE=石油醚
RT=室温
TEA=三乙胺
TFA=三氟乙酸
本发明的部分化合物可以通过以下方法制备得到:
方案1:
式(II)部分化合物可采用下面的方法制备得到。
化合物IIa-1采用专利WO2021061643中的方法制备得到。化合物IIa-2可以通过合适的方法制备得到。化合物IIa-1和化合物IIa-2通过金属催化的偶联反应得到化合物IIa-3,再经脱保护反应得到目标化合物IIa。本发明中的化合物2和化合物3采用方案1的方法制备得到。
方案2:
式(III)化合物可采用下面的方法制备得到。
化合物III-1采用专利WO2021061643中的方法制备得到。化合物III-1经过水解反应得到化合物III-2,再经缩合反应得到式(III)化合物。
方案3:
式(V)化合物可采用下面的方法制备得到。
此类化合物的合成的关键步骤为合成中间体V-4。方法有二,当相应的二烷基氧化磷V-1是商业化可购买时,其于溴苯取代物通过金属催化偶合得到V-2,V-2还原得V-4(路线A);当V-1不能购买时,可以利用次膦酸酯V-3与格氏试剂反应而制的V-4(路线B)。V-4经溴丙炔烷基化及Boc保护得到带有末端三键和不同磷羰基取代的化合物V-5,V-5与不同的2-位OTf取代吲哚化合物偶合得到V-6,再与取代的哌啶氨基化合物进行Buchward缩合及脱保护得到化合物V。
方案4:
式(VI)化合物可采用下面的方法制备得到。
化合物VI-1采用专利WO2021061643中的方法制备得到,VI-2由四圆环羰基为原料而合成,VI-1与VI-2缩合得到VI-3,然后脱保护得到化合物VI。
方案5:
式(VII)化合物可采用下面的方法制备得到。
化合物VII-1采用专利WO2021061643中的方法制备得到,与带有环外双键的哌啶类衍生物VII-2-a,VII-2-b进行Buchward缩合得到前体,之后脱保护而得到目标化合物VII-a和VII-b。
实施例:
实施例1:化合物1的制备
氮气氛围下,将5-氯-2-硝基苯甲醚(100mg,0.534mmol)溶解在DMF(2mL)中,依次加入K
3PO
4(125mg,0.586mmol)、Pd(OAc)
2(6mg,0.0026mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(18.4mg,0.032mmol)和二甲基氧化膦(46mg,0.586mmol),反应混合液升温至150℃微波反应50分钟。反应液冷却至室温,加水(5mL),用乙酸乙酯(3×5mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)得到黑色液体化合物1-b(70mg,收率:57%)。MS(ES
+,m/z):230.3[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.86(dd,J=8.1,3.2Hz,1H),7.66(dd,J=12.6,1.0Hz,1H),7.17(m 1H),4.02(s,3H),1.78(s,3H),1.76(s,3H)。
将化合物1-b(500mg,2.18mmol)和Pd/C(50mg)加入甲醇(30mL)中,反应混合物在1大气压的氢气氛围下于25℃反应4小时。加入甲醇(20mL)稀释反应液,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1-15∶1)得到黑色液体化合物1-c(115mg,收率44%)。MS(ES
+,m/z):200.3[M+H]
+。
1H NMR(500MHz,CD
3OD)δ7.16-7.09(m,2H),6.80(m,1H),3.90(s,3H),1.72(s,3H),1.69(s,3H)。
将化合物1-c(8mg,0.067mmol)溶解在(Boc)
2O(1mL)中,反应混合液升温至80℃搅拌三小时。反应液冷却至室温后减压浓缩,粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=10∶1)得 到黑色液体化合物1-d(3mg,收率15%)。MS(ES
+,m/z):300.4[M+H]
+。
1H NMR(500MHz,CDCl
3)δ8.20(bs,1H),7.37(dd,J=12.3,1.1Hz,1H),7.23(s,1H),7.09(m,1H),3.94(s,3H),1.72(s,3H),1.69(s,3H),1.52(s,9H)。
将化合物1-d(50mg,0.167mmol)溶解在DMF(4mL)中,加入碳酸铯(162.9mg,0.5mmol)和丙炔溴(60mg,0.5mmol)。反应混合液在室温中搅拌2小时。加水(5mL),用乙酸乙酯(3×5mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)得到红褐色液体化合物1-e(50mg,收率88.8%)。MS(ES
+,m/z):338.4[M+H]
+。
1H NMR(500MHz,CDCl
3)δ8.01(s,1H),7.42(m,2H),7.11(m,1H),4.27(bs,2H),3.90(s,3H),2.17(s,1H),1.75(s,3H),1.73(s,3H),1.35(m,9H)。
氮气氛围下,化合物1-e(150mg,0.44mmol)溶解在DMF(3mL)和三乙胺(3mL)中,加入碘化亚铜(12.56mg,0.066mmol)、(Ph
3P)
2PdCl
2(15mg,0.022mmol)和化合物1-f(227mg,0.533mmol,合成参见WO 2021/061643),反应混合物在室温搅拌2小时。加水(10mL),用乙酸乙酯(3×10mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压浓缩滤液得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)得到浅黄色固体化合物1-g(260mg,收率96%)。MS(ES
+,m/z):615.4[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.48(d,J=13.1Hz,1H),7.38(s,1H),7.33(d,J=7.5Hz,1H),7.23(d,J=8.3Hz,1H),7.17-7.08(m,2H),6.79(s,1H),4.64(q,J=8.4Hz,4H),3.92(s,3H),1.76(s,3H),1.73(s,3H),1.46(m,9H)。
氮气氛围下,化合物1-g(80mg,0.13mmol)溶解在无水1,4-二氧六环中,依次加入2-(二环己基膦)3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯(8.37mg,0.0091mmol)、2-二环己基磷-2′,6′-二异丙氧基-1,1′-联苯(8.5mg,0.018mmol)、碳酸铯(169mg,0.52mmol)和化合物1-h(35mg,0.17mmol)。反应混合液升温至100℃,搅拌16h。加水(10mL),用乙酸乙酯(3×10mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)后再经硅胶薄层层析纯化(二氯甲烷∶甲醇=20∶1)得到浅黄色固体化合物1-i(6mg,收率7%)。MS(ES
+,m/z):665.8[M+H]
+。
化合物1-i(6mg,0.009mmol)溶解在4M HCl的1,4-二氧六环(3mL)中,25℃搅拌0.5小时。反应液减压浓缩,滴加NH
3/MeOH(0.5mL)调pH值为8,加水(5mL),用乙酸乙酯(5mL×3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=15∶1)。硅胶薄层层析纯化(二氯甲烷∶甲醇=20∶1)得到浅黄色固体化合物1(1.6mg,收率31.5%)。MS(ES
+,m/z):565.7[M+H]
+。
1H NMR(500MHz,DMSO-d
6)δ7.21(m,1H),7.17(s,1H),7.13(dd,J=11.9,1.4Hz,1H),7.00(t,J=8.0Hz,1H),6.84(m,1H),6.73(d,J=8.3Hz,1H),6.23(d,J=7.9Hz,1H),6.04(t,J=6.4Hz,1H),5.50(d,J=8.7Hz,1H),4.90(q,J
H,F=8.8Hz,2H),4.80(d,J=50.1Hz,1H),4.31(d,J=6.4Hz,2H),3.84(s,3H),3.61-3.50(m,1H),3.02(m,1H),2.80(d,J=10.6Hz,1H),2.18(s,3H),2.07(m,1H),2.01(m,1H),1.92(m,1H),1.69(m,1H),1.59(s,3H),1.56(s,3H)。
实施例2:化合物2的制备
氮气氛围下,t-BuOK(168mg,1.5mmol)溶解在DMF(2mL)中,降温至-55℃,依次加入化合物2-a(213mg,1mmol)和化合物2-[(二氟甲基)磺酰基]-吡啶(61mg,0.83mmol)。反应混合液保持-55℃搅拌15分钟,加入饱和氯化铵水溶液(0.5mL),再加入3M盐酸水溶液(1.3mL)。加水(5mL),用甲基叔丁基醚(5mL×3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=8∶1)得到白色固体化合物2-b(100mg,收率40%)。MS(ES
+,m/z):247.4[M+H]
+。
1H NMR(500MHz,CDCl
3)δ4.43(s,1H),3.52(s,1H),2.41(dt,J=15.1,4.0Hz,2H),1.99(dd,J=11.9,2.8Hz,2H),2.00-1.80(m,2H),1.44(s,9H),1.24-1.12(m,2H).
19F NMR(471MHz,CDCl
3)δ-97.85(s)。
化合物2-b(100mg,0.4mmol)溶解在4M HCl的1,4-二氧六环(5mL)中,25℃搅拌1小时。反应液减压浓缩得到白色固体化合物2-c(73mg,收率99%)。
1H NMR(500MHz,DMSO-d
6)δ8.25(s,3H),3.10(s,1H),2.40(d,J=14.5Hz,2H),2.01(d,J=12.1Hz,2H),1.96-1.84(m,2H),1.42-1.30(m,2H)。
将化合物2-d(50mg,0.08mmol,合成参见WO 2021/061643)化合物2-c(17.9mg,0.096mmol)、碳酸铯(106mg,0.32mmol)、Brettphos Pd G4(7.3mg,0.008mmol)和2-双环己基膦-2′,6′-二异丙氧基联苯(7.3mg,0.016mmol)依次加入到微波反应管中,然后加入无水1,4-二氧六环溶液(2mL),氮气氛围下于110℃反应16小时。加水(2mL)和乙酸乙酯(3×5mL)萃取,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到粗品。该粗品经Prep-TLC分离纯化(二氯甲烷∶甲醇=15∶1)。得到浅黄色固体化合物2-e(40mg,72.2%)。MS(ES
+,m/z):682.8[M+H]
+。
1H NMR(500MHz,DMSO-d
6)δ7.53(d,J=8.0Hz,1H),7.32-7.50(m,2H),7.15(t,J=8.0Hz,1H),6.65(d,J=8.2Hz,1H),6.62(s,1H),6.31(d,J=7.8Hz,1H),4.95-4.36(m,4H),3.93(s,3H),3.89-3.63(m,1H),3.57-3.44(m,1H),3.08(s,3H),2.56-2.44(m,2H),2.22-2.15(m,2H),2.05-1.97(m,2H),1.44-1.28(m,11H)。
将化合物2-e(20mg,0.029mmol)溶解在4M HCl的1,4-二氧六环(2mL)中,25℃搅拌0.5小时。TLC监测反应完毕,反应液减压浓缩。冷冻干燥后得到浅黄色固体化合物2的盐酸盐(16mg,85.7%)。MS(ES
+,m/z):582.7[M+H]
+。
1H NMR(500MHz,DMSO-d
6)δ7.39(dd,J=8.4,1.9Hz,1H),7.26(d,J=1.9Hz,1H),7.23-7.16(m,1H),7.16-7.12(m,1H),6.90(d,J=8.4Hz,1H), 6.82-6.43(m,2H),5.09-5.01(m,2H),4.38(s,2H),4.32(s,1H),3.90(s,3H),3.82(m,2H),3.39(s,1H),3.10(s,3H),2.44-2.39(m,2H),2.05-1.99(m,2H),1.98-1.89(m,2H),1.47-1.38(m,2H)。
实施例3:化合物3的制备
氮气氛围下,氢化钠(60%,48mg,1.2mmol)分散在THF(3mL)中,降温至-78℃,缓慢滴加化合物磷酰基乙酸三乙酯(250mg,1.2mmol),滴加结束后升至室温搅拌0.5小时。反应混合液冷却至零度,加入化合物3-a(213mg,1mmol),室温搅拌2小时,加饱和碳酸氢钠水溶液(5mL),乙酸乙酯(5mLx3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=3∶1)。得到白色固体化合物3-b(260mg,收率92%)。
1H NMR(500MHz,CDCl
3)δ5.62(s,1H),4.45(s,1H),4.13(m,2H),3.68(s,1H),3.62(d,J=14.1Hz,1H),2.27(dd,J=18.7,14.7Hz,2H),2.17(dd,J=22.0,9.3Hz,1H),2.07(t,J=11.8Hz,2H),1.43(s,9H),1.35-1.28(m,2H),1.25(d,J=7.1Hz,3H)。
氮气氛围下,化合物3-b(347mg,1.225mmol)溶解在无水四氢呋喃(5mL)中,降温至-78℃,缓慢滴加二异丁基氢化铝(2.55mL,2.55mmol),滴加完毕,反应混合液保持-78℃搅拌1小时。反应液升温至零度,依次滴加水(0.15mL)、15%氢氧化钠水溶液(0.15mL)、水(0.3mL),再将反应混合物升温至室温搅拌15分钟,加入适量无水硫酸钠,搅拌15分钟,过滤、滤液减压浓缩,所得粗品经硅胶柱层析分离纯化得化合物3-c(250mg,85%)。
1H NMR(500MHz,CDCl
3)δ5.40(t,J=7.0Hz,1H),4.43(s,1H),4.14(d,J=3.0Hz,2H),3.62(s,1H),2.60-2.51(m,1H),2.23(m,1H),2.14(t,J=12.7Hz,1H),2.06-1.97(m,2H),1.97-1.89(m,1H),1.44(s,9H),1.24-1.19(m,2H)。
将化合物3-c(242mg,1.0mmol)溶解在二氯甲烷(8mL)中,冰浴下滴加二异丙基乙基胺(390mg,3mmol),甲磺酰氯(173mg,1.5mmol),反应液升温至室温搅拌2小时。反应液中加入饱和食盐水,以二氯甲烷(20mL x 3)萃取,有机层合并后经无水硫酸钠干燥、过滤、减压浓缩,所得粗品化合物3-d(319mg)直接用于下一步反应。
将化合物3-d(319mg,1.0mmol)、碘化钠(15mg,0.1mmol)、二甲胺(1.0M in THF,5.5mL,5.5mmol)溶于乙腈(6mL)中。反应混合物于封管中60℃加热搅拌3小时。将反应混合物减压浓缩,经硅胶柱层析分离纯化(二氯甲烷∶甲醇=15∶1),得白色固体化合物3-e(200mg,75%)。MS(ES
+,m/z):269.5[M+H]
+。
1H NMR(500MHz,DMSO-d
6)δ6.79(d,J=7.7Hz,1H),5.27(t,J= 7.7Hz,1H),3.64(d,J=7.7Hz,2H),2.65(s,6H),2.59(d,J=14.3Hz,1H),2.25(d,J=13.6Hz,1H),2.10(t,J=12.5Hz,1H),1.88(t,J=13.2Hz,1H),1.82(d,J=8.8Hz,2H),1.37(s,10H),1.27-1.16(m,2H)。
将化合物3-e(20mg,0.074mmol)溶解于4M HCl的1,4-二氧六环(3mL)中,室温搅拌1小时。将反应液减压浓缩,冷冻干燥得到白色固体化合物3-f(10mg,收率66%)。
1H NMR(500MHz,DMSO-d
6)δ10.81(s,1H),δ8.31(s,3H),5.34(t,J=7.7Hz,1H),3.66(d,J=5.2Hz,2H),3.56(s,1H),3.24-3.12(m,1H),2.69(m,1H),2.65(s,6H),2.32(m,1H),2.14(m,1H),2.04(m,2H),1.95-1.85(m,1H),1.50-1.34(m,2H)。
在氮气氛围下,化合物2-d(15mg,0.024mmol)、化合物3-f(6mg,0.029mmol)、碳酸铯(31.8mg,0.097mmol)、Brettphos Pd G4(2.2mg,0.0024mmol)、2-二环己基磷-2′,6′-二异丙氧基-1,1′-联苯(2.2mg,0.0048mmol)和1,4-二氧六环溶液(1mL)于封管中110℃反应16小时。反应液冷却后加水(2mL),用乙酸乙酯(3x5mL)萃取,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到粗品。该粗品经制备薄层色谱分离纯化(二氯甲烷∶甲醇=15∶1)得到浅黄色固体化合物3-g(8mg,46.7%)。MS(ES
+,m/z):703.8[M+H]
+。
1H NMR(500MHz,DMSO-d
6)δ7.58(s,1H),7.53(s,2H),7.09(s,1H),7.03(t,J=8.0Hz,1H),6.70(d,J=8.4Hz,1H),6.22(d,J=7.9Hz,1H),5.50(d,J=8.0Hz,1H),5.20(t,J=7.2Hz,1H),4.93-4.83(m,2H),4.80-4.50(m,2H),3.92(s,3H),3.62-3.51(m,1H),3.27(s,3H),3.01-2.88(m,2H),2.32-2.12(m,8H),2.10-2.03(m,2H),1.96-1.88(m,1H),1.46-1.24(m,12H)。
将化合物3-g(8mg,0.011mmol)溶于二氯甲烷(0.5mL)中,加入4M盐酸的1,4-二氧六环溶液(0.1mL,0.4mmol)。混合物在25℃下搅拌2个小时。浓缩反应液,用氨的甲醇溶液调节pH>7。经制备薄层色谱分离纯化(二氯甲烷∶甲醇=15∶1)得到棕色固体化合物3(1.3mg,19%)。MS(ES
+,m/z):603.7[M+H]
+。
1H NMR(500MHz,DMSO-d
6)δ8.26(s,1H),7.39(dd,J=8.3,1.8Hz,1H),7.25(d,J=1.8Hz,1H),7.08(s,1H),7.01(t,J=8.0Hz,1H),6.89(d,J=8.4Hz,1H),6.68(d,J=8.2Hz,1H),6.50(t,J=6.2Hz,1H),6.20(d,J=7.9Hz,1H),5.48(d,J=8.0Hz,1H),5.19(t,J=7.0Hz,1H),4.93(q,J=9.0Hz,2H),4.36(d,J=6.2Hz,2H),3.90(s,3H),3.10(s,3H),2.87(d,J=7.1Hz,2H),2.15(s,6H),2.05-1.95(m,4H),1.94-1.86(m,2H),1.34-1.27(m,2H)。
实施例4:化合物4的制备
化合物4-a(171mg,1mmol)溶解在DMF(2.5mL)中,加入NaSMe(140mg,2mmol)。反应混合液在25℃搅拌2小时。TLC监测反应完毕,反应液加水(5mL),MTBE(5mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=10∶1),得到黄色固体化合物4-b(150mg,收率75%)。MS(ES
+,m/z):200.3[M+H]
+。
1H NMR(500MHz,MeOD)δ7.83(d,J=8.6Hz,1H),7.04(d,J=1.8Hz,1H),6.91(dd,J=8.6,1.9Hz,1H),3.96(s,3H),2.57(s,3H)。
化合物4-b(40mg,0.2mmol)溶解在甲醇(3mL)中,加入NaIO
4(35mg,0.16mmol)的水(1mL)溶液。反应混合液在25℃搅拌16小时。TLC监测反应完毕,反应液加水(5mL),乙酸乙酯(5mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=3∶2),得到黄色固体化合物4-c(25mg,收率58%)。MS(ES
+,m/z):216.3[M+H]
+。
1H NMR(500MHz,MeOD)δ7.97(d,J=8.3Hz,1H),7.62(d,J=1.6Hz,1H),7.37(dd,J=8.3,1.7Hz,1H),4.04(s,3H),2.87(s,3H)。
氮气氛围下,化合物4-c(30mg,0.14mmol)溶解在二氯甲烷(2mL)中,加入MgO(23mg,0.56mmol),搅拌两分钟后,依次加入三氟乙酰胺(32mg,0.28mmol),PhI(OAc)
2(68mg,0.21mmol),Rh
2(OAc)
4(1.6mg,0.035mmol)。反应混合液在25℃搅拌16小时。TLC监测反应完毕,反应液加水(5mL),二氯甲烷(5mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1)。得到黄色固体化合物4-d(24mg,收率52%)。MS(ES
+,m/z):327[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.99(d,J=8.4Hz,1H),7.72(d,J=1.8Hz,1H),7.61(dd,J=8.4,1.8Hz,1H),4.07(s,3H),3.49(s,3H)。
氢气氛围下,化合物4-d(30mg,0.1mmol)溶在甲醇(10mL)中,加入Pd/C(5mg)。反应混合液在25℃下搅拌4小时。TLC监测反应完毕,加入甲醇(2mL)稀释反应液,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1)。得到灰色固体化合物4-e(20mg,收率67%)。MS(ES
+,m/z):297.3[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.39(dd,J=8.4,2.1Hz,1H),7.25(d,J=2.1Hz,1H),6.74(d,J=8.4Hz,1H),4.54(s,2H),3.90(s,3H),3.40(s,3H)。
化合物4-e(150mg,0.5mmol)溶解在(Boc)
2O(2mL)中,反应混合液升温至90℃搅拌16小时。TLC监测反应完毕,冷却至室温,硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1)。得到白色固体化合物4-f(160mg,收率81%)。MS(ES
+,m/z):397.4[M+H]
+。
1H NMR(500MHz,CDCl
3)δ8.38(d,J=8.7Hz,1H),7.54(dd,J=8.7,2.1Hz,1H),7.40(d,J=2.1Hz,1H),7.34(s,1H),3.97(s,3H),3.43(s,3H),1.53(s,9H)。
化合物4-f(600mg,1.5mmol)溶解在DMF(20mL)中,加入碳酸铯(975mg,3mmol),溴丙炔(360mg,3mmol)。反应混合液在室温中搅拌16小时。TLC监测反应完毕,加水(20mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=1∶1)。得到无色液体化合物4-g(420mg,收率82.8%)。MS(ES
+,m/z):339.5[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.63-7.57(m,1H),7.54(t,J=2.2Hz,1H),7.46(bs,1H),7.29(d,J=8.1Hz,1H),4.29(bs,2H),3.90(m,3H),3.11(m,3H),2.18(t,J=2.3Hz,1H),1.42(s,9H)。
化合物4-g(280mg,0.83mmol)溶解在(Boc)
2O(3mL)中,反应混合液升温至90℃搅拌16小时。TLC监测反应完毕,冷却至室温,硅胶柱层析分离纯化(石油醚∶乙酸乙酯=1∶1)。得到白色固体化合物4-i(350mg,收率94%)。MS(ES
+,m/z):439.5[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.57-7.53(m,1H),7.49(d,J=1.7Hz,1H),7.32(d,J=8.2Hz,1H),4.32(bs,2H),3.91(s,3H),3.25(s,3H),2.18(t,J=2.3Hz,1H),1.40(s,9H),1.39(s,9H)。
氮气氛围下,化合物4-i(200mg,0.456mmol)溶解在DMF(3mL)和三乙胺(3mL)中,加入CuI(13mg,0.68mmol),(Ph
3P)
2PdCl
2(16mg,0.023mmol),化合物1-f(240mg,0.563mmol),反应混合液在室温中搅拌2小时。TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=3∶2)。得到浅黄色固体化合物4-J(250mg,收率71.5%)。MS(ES
+,m/z):716.7[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.54-7.49(m,3H),7.33(d,J=7.8Hz,1H),7.23(d,J=8.4Hz,1H),7.14(t,J=7.9Hz,1H),6.79(s,1H),5.04-4.37(m,4H),3.92(d,J=11.7Hz,3H),3.25(d,J=8.4Hz,3H),1.43-1.36(m,18H)。
氮气氛围下,化合物4-J(50mg,0.07mmol)溶解在无水二氧六环中,依次加入Brettphos(4.5mg,0.0049mmol),Ruphos(4.5mg,0.0098mmol),碳酸铯(91mg,0.28mmol),化合物1-h(17mg,0.085mmol)。反应混合液升温至100℃,搅拌16h。TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)。再次用硅胶薄层层析纯化(二氯甲烷∶甲醇=20∶1)得到浅黄色固体化合物4-k(15mg,收率28%)。MS(ES
+,m/z):766.9[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.59-7.44(m,3H),7.14(t,J=8.0Hz,1H),6.71-6.69(m,2H),6.29(d,J=7.7Hz,1H),4.87(d,J=48.6Hz,1H),4.64-4.56(m,4H),4.19(s,1H),3.93(s,3H),3.61-3.56(m,1H),3.33-3.26(m,1H),3.23(s,3H),2.99(m,1H),2.40(s,3H),2.32-2.23(m,1H),2.12-1.90(m,3H),1.38(s,18H).
化合物4-k(15mg,0.019mmol)溶解在4M HCl/dioxane(2mL)中,25℃搅拌1h。TLC监测反应完毕,反应液减压浓缩,滴加NH
3/MeOH(0.5mL)调pH值为8,加水(5mL),乙酸乙酯(5mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=15∶1)。硅胶薄层层析纯化(二氯甲烷∶甲醇=15∶1),冷冻干燥后得到浅黄色固体化合物4(8mg,收率72.1%)。MS(ES
+,m/z):566.6[M+H]
+。
1HNMR(500MHz,DMSO-d
6)δ7.42(dd,J=8.3,2.0Hz,1H),7.30(d,J=2.0Hz,1H),7.19(s,1H),7.01(t,J=8.0Hz,1H),6.87(d,J=8.4Hz,1H),6.74(d,J=8.2Hz,1H),6.33(t,J=6.3Hz,1H),6.24(d,J=7.8Hz,1H),5.52(d,J=8.7Hz,1H),4.93(q,J=9.2Hz,2H),4.82(d,J=49.3Hz,1H),4.35(d,J=6.3Hz,2H),3.88(s,3H),3.82(bs,1H),3.60-3.51(m,1H),3.05(m,1H),2.99(s,3H),2.82(d,J=10.8Hz,1H),2.20(s,3H),2.11(m,1H),1.95-1.91(m,2H),1.70(d,J=12.6Hz,1H).
实施例5:化合物5的制备
环丙醇(200mg,3.42mmol)溶于四氢呋喃(10mL)中,在0℃下分批加入氢化钠(140mg,3.42mmol),在0℃下搅拌30分钟,然后加入化合物5-a(500mg,2.28mmol)的四氢呋喃溶液,TLC监测反应完毕。加冰水淬灭反应,乙酸乙酯(3 x 10mL)萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=5∶1)得到黄色固体化合物5-b(450mg,76.7%)。
1HNMR(500MHz,CDCl
3)δ8.02(d,J=1.8Hz,1H),7.92(d,J=8.3Hz,1H),7.62(dd,J=8.3,1.8Hz,1H),4.00-3.97(m,1H),3.12(s,3H),0.97-0.92(m,4H)。
在氮气氛围下,将化合物5-b(450mg,1.75mmol)溶于乙酸乙酯(20mL)中,加入Pd/C(100mg),置换瓶中氮气为氢气。反应混合液在25℃下搅拌4小时。TLC监测反应完毕,加入硅藻土和乙酸乙酯过滤,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1)得到灰色固体化合物5-c(350mg,88.1%)。MS(ES
+,m/z):228.3[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.61(d,J=2.1Hz,1H),7.39(dd,J=8.2,2.0Hz,1H),6.73(d,J=8.2Hz,1H),4.25(s,2H),3.85-3.81(m,1H),3.03(s,3H),0.90-0.82(m,2H),0.84-0.77(m,2H)。
在氮气氛围下,化合物5-c(320mg,1.47mmol)溶于无水四氢呋喃(5mL)中,依次加入二碳酸二叔丁酯(642mg,2.94mmol),DMAP(180mg,1.47mmol)。反应混合液在70℃下搅拌4小时。LCMS监测反应完毕,待反应混合物冷却后,加入水(5mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1)得到白色固体化合物5-d(520mg,86.4%)。MS(ES
+,m/z):428.4[M+H]
+。
1HNMR(500MHz,CDCl
3)δ7.81(d,J=2.0Hz,1H),7.54(dd,J=8.1,2.0Hz,1H),7.29(d,J=8.1Hz,1H),3.85(m,1H),3.08(s,3H),1.41(s,18H),0.88-0.84(m,2H),0.80-0.75(m,2H)。
将化合物5-d(320mg,0.75mmol)溶于甲醇溶液(30mL)中,然后加入无水碳酸钾(518mg,3.75mmol),室温搅拌过夜。LCMS检测反应完毕。减压蒸馏甲醇溶液,加入水(10mL)和乙酸乙酯(3 x 20mL)萃取。有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓 缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=4∶1)得到无色油状化合物5-e(230mg,93.9%)。MS(ES
+,m/z):272.3[M-(t-Bu)+H]
+。
1HNMR(500MHz,CDCl
3)δ8.30(d,J=8.6Hz,1H),7.71(d,J=2.1Hz,1H),7.55(dd,J=8.5,2.0Hz,1H),7.13(s,1H),3.88-3.83(m,1H),3.05(s,3H),1.53(s,9H),0.94-0.89(m,2H),0.88-0.85(m,2H)。
在氮气氛围下将化合物5-e(230mg,0.7mmol)溶于无水DMF(5mL)中,依次加入碳酸铯(682mg,2.1mmol),溴丙炔(250mg,2.1mmol)。反应混合液在室温下搅拌3h。LCMS监测反应完毕,反应液中加入水(5mL)和乙酸乙酯(3 x 10mL)萃取,有机相用饱和食盐水洗涤3次,无水硫酸钠干燥,过滤减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=4∶1)。得到黄色固体化合物5-f(250mg,97.3%)。MS(ES
+,m/z):310.3[M-(t-Bu)+H]
+。
1HNMR(500MHz,CDCl
3)δ7.81(d,J=1.9Hz,1H),7.54(dd,J=8.2,2.0Hz,1H),7.45(s,1H),4.24(s,2H),3.84(s,1H),3.09(s,3H),2.17(s,1H),1.41(s,9H),0.88-0.85(m,2H),0.81-0.78(m,2H)。
在氮气氛围下将化合物5-f(100mg,0.27mmol)化合物1-f(128mg,0.3mmol),碘化亚铜(10mg,0.05mmol),二(三苯基膦)二氯化钯(10mg,0.014mmol)溶于DMF(2mL)和三乙胺(1mL)中,该混合液在室温下搅拌1小时,LCMS监测反应完毕,反应液加水(3mL)和乙酸乙酯(3 x 5mL)萃取,有机相用饱和的食盐水洗涤三次,然后用无水硫酸钠干燥,过滤减压浓缩得到粗品,该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=3∶1)。得到黄色固体化合物5-g(95mg,54.8%)。LCMS(ES,m/z):MS(ES
+,m/z):585.4,587.4[M-(t-Bu)+H]
+。
1HNMR(500MHz,DMSO-d6)δ7.85-7.82(m,1H),7.64(d,J=8.3Hz,1H),7.56(s,2H),7.37(d,J=7.5Hz,1H),7.26-7.20(m,1H),6.77(s,1H),5.09(d,J=9.2Hz,2H),4.62(s,2H),4.06(s,1H),3.27(s,3H),1.37(s,9H),0.85(m,2H),0.67(m,2H)。
将化合物5-g(40mg,0.062mmol)化合物1-h(16mg,0.074mmol),碳酸铯(60mg,0.186mmol),Brettphos(4mg,0.004mmol),Ruphos(4mg,0.08mmol)依次加入到微波管中,然后加入无水二氧六环溶液(2mL),使用长针头深入溶液里通入氮气搅拌10分钟,然后密封微波管。反应混合液在110℃下搅拌16小时。LCMS监测反应完毕。加水(2mL)和乙酸乙酯(3 x 5mL)萃取,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到粗品,该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)。得到黄色固体化合物5-h(10mg,23.1%)。MS(ES
+,m/z):693.8[M+H]
+。
1HNMR(500MHz,CDCl
3)δ7.84(s,1H),7.54(d,J=7.8Hz,1H),7.44(s,1H),7.14(t,J=8.0Hz,1H),6.74-6.66(m,2H),6.29(d,J=7.8Hz,1H),4.85(d,J=48.9Hz,1H),4.60-4.54(m,4H),3.85(s,1H),3.56(dd,J=28.4,11.6Hz,1H),3.29-3.20(m,1H),3.08(s,3H),2.97(d,J=12.0Hz,1H),2.35(s,3H),2.28-2.13(m,2H),1.94-1.88(m,2H),1.37(s,9H),0.87-0.86(m,2H),0.84-0.76(m,2H)。
将化合物5-h(10mg,0.014mmol)溶于氯化氢二氧六环溶液中,室温搅拌1小时,LCMS监测反应完毕。浓缩反应液,加入乙酸乙酯和三乙胺,经Prep-TLC分离得到化合物5(3mg,35.1%)。MS(ES
+,m/z):593.7[M+H]
+。
1HNMR(500MHz,CDCl
3)δ7.62(d,J=2.0Hz,1H),7.53(dd,J=8.4,2.0Hz,1H),7.14(t,J=8.0Hz,1H),6.80(d,J=8.4Hz,1H),6.76(s,1H),6.70(d,J=8.2Hz,1H),6.29(d,J=7.7Hz,1H),5.02(t,J=6.3Hz,1H),4.89(d,J=46.7Hz,2H),4.59(q,J
H,F=8.5Hz,2H),4.32(d,J=6.3Hz,2H),3.88-3.81(m,1H),3.66-3.61(m,1H),3.31-3.28(m,1H),3.04(s,3H),2.44(s,3H),3.03-3.01(m,1H),2.08-1.97(m,4H),0.89-0.85(m,2H),0.84-0.80(m,2H)。
实施例6:化合物6的制备
氮气氛围下,化合物6-a(507mg,6.84mmol)溶解在THF(20mL)中,加入NaH(280mg,6.84mmol),冰水浴搅拌十分钟,加入oxetan-3-ol(1g,4.56mmol)。反应混合液室温搅拌十六小时。TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1)。得到白色固体化合物6-b(1g,收率80%)。MS(ES
+,m/z):274[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.99(d,J=8.3Hz,1H),7.66(dd,J=8.3,1.7Hz,1H),7.20(d,J=1.6Hz,1H),5.45-5.39(m,1H),5.07-5.02(m,2H),4.83(m,2H),3.09(s,3H)。
氢气氛围下,化合物6-b(30mg,0.109mmol)溶在甲醇(5mL)中,加入Pd/C(10mg)。反应混合液在25℃下搅拌4小时。TLC监测反应完毕,加入甲醇(10mL)稀释反应液,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=1∶1)。得到白色固体化合物6-c(22mg,收率74%)。MS(ES
+,m/z):244[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.40(dd,J=8.3,1.9Hz,1H),6.83(d,J=1.8Hz,1H),6.78(m,1H),5.32-5.25(m,1H),5.03(m,2H),4.76(m,2H),4.44(s,2H),2.99(s,3H)。
化合物6-c(350mg,1.44mmol)溶解在(Boc)2O(10mL)中,反应混合液升温至80℃搅拌三小时。TLC监测反应完毕,冷却至室温,湿法上样硅胶柱层析分离纯化(石油醚∶乙酸乙酯=1∶1)。得到白色固体化合物6-d(300mg,收率61%)。MS(ES
+,m/z):344[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.99(d,J=7.8Hz,1H),7.48(d,J=2.1Hz,1H),7.44(dd,J=8.7,2.2Hz,1H),4.33-4.27(m,1H),4.16(m,1H),3.88-3.80(m,2H),3.59(m,1H),3.03(s,3H),1.55(s,9H)。
化合物6-d(270mg,0.786mmol)溶解在DMF(5mL)中,加入碳酸铯(770mg,2.36mmol),溴丙炔(290mg,2.36mmol)。反应混合液在室温中搅拌2小时。TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1)。得到浅黄色固体化合物6-e(100mg,收率33%)。MS(ES
+,m/z):326[M+H]
+。
1H NMR(500MHz,CDCl
3)δ8.01(d,J=8.8Hz,1H),7.48(d,J=2.3Hz,1H),7.44(dd,J=8.7,2.3Hz,1H),4.37(m,1H),4.24(t,J=1.9Hz,2H),4.20(m,1H),3.80(m,1H),3.73(m,1H),3.54(m,1H),3.02(s,3H),2.48(t,J=2.4Hz,1H),1.56(s,9H)。
在氮气氛围下将化合物6-e(95mg,0.25mmol),化合物1-f(128mg,0.3mmol),碘化亚铜(9.5mg,0.05mmol),二(三苯基膦)二氯化钯(9mg,0.013mmol)溶于DMF(2mL)和三乙胺(2mL)中,该混合液在室温下搅拌2小时,LCMS监测反应完毕,反应液加水(3mL)和乙 酸乙酯(3x10mL)萃取,有机相用饱和的食盐水洗涤三次,然后用无水硫酸钠干燥,过滤减压浓缩得到粗品,该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=4∶1)。得到黄色固体化合物6-f(130mg,79.4%)。MS(ES,m/z):601.3,603.3[M-tBu+H]
+。
1HNMR(500MHz,CDCl
3)δ7.49(d,J=2.3Hz,1H),7.44(dd,J=8.7,2.2Hz,1H),7.35(d,J=7.6Hz,1H),7.26(s,2H),7.18(t,J=7.9Hz,1H),6.91(s,1H),4.77(q,J=8.4Hz,2H),4.56(d,J=1.6Hz,2H),4.40(m,1H),4.24(m,1H),3.88(m,1H),3.81(m,1H),3.55(m,1H),3.00(s,3H),1.54(s,9H)。
将化合物6-f(115mg,0.175mmol)化合物1-h(43mg,0.21mmol),碳酸铯(228mg,0.7mmol),Brettphos(11.3mg,0.012mmol),Ruphos(11.4mg,0.024mmol)依次加入到微波管中,然后加入无水二氧六环溶液(2mL),使用长针头深入溶液里通入氮气搅拌10分钟,然后密封微波管。反应混合液在110℃下搅拌16小时。LCMS监测反应完毕。加水(2mL),乙酸乙酯(3x10mL)萃取,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到粗品,该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)。得到黄色固体化合物6-g(34mg,27.4%)。MS(ES,m/z):709.8[M+H]
+。
1HNMR(500MHz,CDCl
3)δ8.02(d,J=8.7Hz,1H),7.50(d,J=2.2Hz,1H),7.44(dd,J=8.8,2.2Hz,1H),7.17(t,J=8.0Hz,1H),6.83(s,1H),6.73(d,J=8.3Hz,1H),6.31(d,J=7.7Hz,1H),4.86(d,J=49.1Hz,1H),4.72(q,J=8.5Hz,2H),4.55(s,2H),4.42-4.38(m,1H),4.23(d,J=13.7Hz,1H),3.88(m,1H),3.81(m,1H),3.63-3.51(m,2H),3.30-3.21(m,1H),3.01(s,3H),2.35(s,3H),2.28-2.12(m,2H),2.02-1.87(m,2H),1.54(s,9H)。
将化合物6-g(10mg,0.014mmol)溶于二氯甲烷(0.5mL)中,滴加(0.5mL)三氟乙酸,室温搅拌1小时,LCMS监测反应完毕。滴加氨甲醇溶液调节反应液pH=8,浓缩后经Prep-TLC分离得到化合物6(3mg,35.1%)。MS(ES,m/z):609.7[M+H]
+。
1HNMR(500MHz,CDCl
3)δ7.37(S,1H),7.33(d,J=8.4Hz,1H),7.17(t,J=8.0Hz,1H),6.83(s,1H),6.73(d,J=8.3Hz,1H),6.63(d,J=8.3Hz,1H),6.31(d,J=7.7Hz,1H),4.87(d,J=49.1Hz,1H),4.70(q,J=8.5Hz,2H),4.55(s,2H),4.36-4.34(m,2H),4.24(bs,1H),3.87(m,1H),3.80(m,1H),3.64-3.55(m,1H),3.52(d,J=12.0Hz,1H),3.40(m,1H),3.26(t,J=11.2Hz,1H),2.97(s,3H),2.36(s,3H),2.33-2.23(m,1H),2.18(t,J=11.4Hz,1H),2.05-2.03(m,1H),1.93(q,J=12.1Hz,1H)。
实施例7:化合物7的制备
将化合物7-a(2.53g,13.96mmol,1.0eq)溶于(Boc)
2O(30mL),在110℃下搅拌3小时。TLC监测反应完毕,柱层析分离纯化(石油醚∶乙酸乙酯=10∶1)得到白色固体化合物7-b-1/7-b-2(4.74g),直接用于下一步反应。
将化合物7-b-1/7-b-2(3.74g,1.0eq),K
2CO
3(3.86g,27.92mmol,2.0eq)溶于甲醇(30mL)中,41℃反应16h。DCM萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。柱层析分离纯化(石油醚∶乙酸乙酯=10∶1)得到化合物7-c(3.74g,95%)。LC-MS(ES
+,m/z):282.1[M+H]
+。
1H NMR(500MHz,CDCl
3)δ8.16(d,J=8.4Hz,1H)7.67(dd,J=8.5,1.5Hz,1H),7.52(d,J=1.5Hz,1H),7.26(s,1H),3.93(s,3H),3.89(s,3H),1.35(s,9H)。
将化合物7-c(2.74g,9.74mmol,1.0eq),Cs
2CO
3(9.52g,29.22mmol,3.0eq),3-溟丙炔(3.48g,29.22mmol。3.0eq)溶于DMF(50mL)中,室温搅拌2h。TLC监测反应完毕,水/MTBE萃取,旋干,柱层析分离纯化(石油醚∶乙酸乙酯=10∶1)得到白色固体化合物7-d(2.89g,93%)。LC-MS(ES
+,m/z):319.2[M+H]
+。
1H NMR(500MHz,CDCl3)δ7.63(dd,J=8.0,1.55Hz,1H),7.58(s,1H),7.33(s,1H),4.27(s,2H),3.91(s,3H),3.87(s,3H),2.15(s,1H),1.38(s,9H)。
将化合物7-d(400mg,1.25mmol,1.0eq),1-f(640mg,1.50mmol,1.2eq),CuI(36mg,0.188mmol,0.15eq),(PPh
3)
2PdCl
2(44mg,0.063mmol,0.05eq)溶于三乙胺(10mL)和DMF(5mL)的混合溶剂中,于氮气氛围下室温反应16h。TLC监测反应完毕,旋干三乙胺,水/MTBE萃取旋干,柱层析分离纯化(石油醚∶乙酸乙酯=5∶1)得到黄色固体化合物7-e(398mg,54%)。LC-MS(ES
+,m/z):539.4541.3[M+H-56]
+。
1H NMR(500MHz,CDCl3)δ7.66(d,J=8.1Hz,1H),7.63(s,1H),7.34-7.29(m,2H),7.22(d,J=8.2Hz,1H),7.14(t,J=7.9Hz,1H),6.78(s,1H),4.73(bs,2H),4.60(q,J=8.5Hz,2H),3.93(s,3H),3.91(s,3H),1.39(s,9H)。
将化合物7-e(300mg,0.504mmol,1.0eq),1-h(205mg,0.68mmol,1.3eq),Cs
2CO
3(654mg,2.02mmol,4eq),BrettPhos(44mg,0.063mmol,0.05eq),RuPhos(33mg,0.07mmol,0.14eq)溶于二氧六环(5mL)于氮气氛围下110℃反应16h。TLC监测反应完毕,水/MTBE萃取旋干,柱层层析分离纯化(DCM∶MeOH=50∶1)得到黄色固体化合物7-f(210mg,64%)。LC-MS(ES
+,m/z):647.6[M+H]
+。直接用于下一步反应。
化合物7-f(100mg,0.155mmol,1.0eq)溶解在甲醇(10mL)中,加入LiOH(H
2O合物)(32mg,0.77mmol,5.0eq)。45℃搅拌反应16小时。TLC监测反应完毕,旋干甲醇,C-18柱纯化得到黄色固体化合物7-g(48mg,48%)。LC-MS(ES
+,m/z):633.3[M-Li+2H]
+。
化合物7-g(10.2mg,0.016mmol,1.0eq)溶解在DMF(2mL)中,加入HATU(25mg,0.080mmol,5eq),甲氧胺盐酸盐(7mg,0.080mmol,5eq),DIPEA(21mg,0.16mmol,110eq),室温反应16h。TLC反应结束,THF萃取,有机相干燥,过滤,减压浓缩,PTLC分离纯化(DCM∶MeOH=20∶1),得到黄色固体7-h(6.3mg,60%)。
氮气氛围下,7-h(6.2mg,00094mmol,1.0eq)在DCM(1mL)和TFA(1mL)中搅拌,反应30min.LC-MS监测反应完毕,旋干反应液。NH
3/MeOH(5mL)游离,PTLC分离纯化(DCM∶MeOH=15∶1),得到黄色固体7(2.6mg,49%).LC-MS(ES
+,m/z):562.5[M+H]
+。
1H NMR(500MHz,CDCl3)δ8.57(s,1H),7.32(s,1H),7.24(d,J=8.6Hz,1H),7.14(t,J=8.0Hz,1H),6.75(s,1H),6.70(t,J=8.3Hz,2H),6.29(d,J=7.7Hz,1H),5.00(m,1H),4.86(d,J=48.5Hz,1H),4.57(q,J=8.5Hz,2H),4.32(d,J=6.1Hz,2H),4.18(m,1H),3.82(s,3H),3.88(s,3H).3.57(m,1H),3.28(t,J=11.0Hz,1H),3.00(d,J=10.0Hz,1H),2.39(s,3H),1.91-2.07(m,3H)。
实施例8:化合物8的制备
化合物7-g(33mg,0.052mmol,1.0eq)溶解在DMF(2mL)中,加入HATU(80mg,0.258mmol,5eq),O-(四氢-2H-吡喃-2-基)羟基胺(30mg,0.258mmol,5eq),DIPEA(67mg,0.52mmol,10eq)室温反应16h。TLC反应结束,THF萃取,有机相干燥,过滤,减压浓缩,PTLC分离纯化(DCM∶MeOH=20∶1),得到黄色固体8-a(27mg,71%)。LC-MS(ES
+,m/z):732.4[M+H]
+。
氮气氛围下,8-a(27mg,0.0368mmol 1.0eq)在DCM(5mL)和TFA(2mL)中搅拌,反应30min.LC-MS监测反应完毕,旋干反应液。NH
3/MeOH(5mL)游离,PTLC分离纯化(DCM∶MeOH=15∶1),得到黄色固体8(3.0mg,14%)。LC-MS(ES
+,m/z):548.30[M+H]
+。
实施例9:化合物9的制备
氮气氛围下,化合物9-a(232mg,1mmol)溶解在DMF(3.5mL)中,依次加入K
3PO
4(255mg,1.2mmol),Pd(OAc)2(12mg,0.05mmol),Xantphos(58mg,0.1mmol),POEt
2(160mg,1.5mmol),反应混合液升温至150℃微波反应五十分钟。TLC监测反应完毕,反应液冷却至室温,加水(5mL),乙酸乙酯(5mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=15∶1)。得到黑色液体化合物9-b(200mg,收率77.8%)。MS(ES
+,m/z):258.4[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.86(dd,J=8.1,3.1Hz,1H),7.64(d,J=11.5Hz,1H),7.10(dd,J=13.0,4.6Hz,1H),4.03(s,3H),2.11-1.98(m,2H),1.92-1.81(m,2H),1.15(t,J=7.7Hz,3H),1.11(t,J=7.7Hz,3H)。
氢气氛围下,化合物9-b(1.3g,5.054mmol)溶在甲醇(50mL)中,加入Pd/C(300mg)。反应混合液在25℃下搅拌4小时。TLC监测反应完毕,加入甲醇(20mL)稀释反应液,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1-15∶1)。得到黑色液体化合物9-c(1.1g,收率96%)。MS(ES
+,m/z):228.44[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.17(d,J=11.4Hz,1H),6.94-6.88(m,1H),6.72(dd,J=7.8,3.3Hz,1H),4.41 -3.95(m,2H),3.87(s,3H),1.97-1.85(m,2H),1.85-1.74(m,2H),1.09(t,J=7.9Hz,3H),1.06(t,J=7.8Hz,3H)。
化合物9-c(1.1g,4.84mmol)溶解在(Boc)
2O(10mL)中,反应混合液升温至80℃搅拌三小时。TLC监测反应完毕,冷却至室温,湿法上样硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)。得到黑色液体化合物D(1.5g,收率95%)。MS(ES
+,m/z):328.45[M+H]
+。
1H NMR(500MHz,CDCl
3)δ8.19(d,J=6.0Hz,1H),7.35(d,J=11.4Hz,1H),7.23(s,1H),7.02(t,J=9.3Hz,1H),3.93(s,3H),1.95(m,2H),1.84(m,2H),1.51(s,9H),1.11(t,J=7.8Hz,3H),1.08(t,J=8.0Hz,3H)。
化合物9-d(1.2g,3.65mmol)溶解在DMF(20mL)中,加入碳酸铯(3.6g,10.97mmol),溴丙炔(1.4g,10.97mmol)。反应混合液在室温中搅拌2小时。TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)。得到浅黄色固体化合物9-e(1.3g,收率97%)。MS(ES
+,m/z):366.46[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.40(d,J=11.4Hz,1H),7.36(s,1H),7.08-7.00(m,1H),4.25(bs,2H),3.88(s,3H),2.17(s,1H),1.99(m,2H),1.87(m,2H),1.56-1.20(m,9H),1.13(t,J=8.0Hz,3H),1.09(d,J=7.6Hz,3H)。
氮气氛围下,化合物9-e(50mg,0.137mmol)溶解在DMF(1mL)和三乙胺(2mL)中,加入CuI(4mg,0.02mmol),(Ph
3P)
2PdCl
2(5mg,0.0068mmol),化合物1-f(70mg,0.164mmol),反应混合液在室温中搅拌2小时。TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=25∶1)。得到浅黄色固体化合物9-f(60mg,收率68%)。MS(ES
+,m/z):641.6[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.46(dd,J=7.6,4.4Hz,1H),7.36(d,J=8.0Hz,1H),7.32(d,J=7.7Hz,1H),7.23(d,J=8.2Hz,1H),7.14(t,J=7.9Hz,1H),7.05(t,J=9.0Hz,1H),6.78(s,1H),4.66(m,4H),3.92(s,3H),2.00(m,2H),1.93-1.84(m,2H),1.34(m,9H),1.13(t,J=8.1Hz,3H),1.10(t,J=7.9Hz,3H)。
氮气氛围下,化合物9-f(100mg,0.156mmol)溶解在无水二氧六环中,依次加入Brettphos(10mg,0.011mmol),Ruphos(10mg,0.02184mmol),碳酸铯(202mg,0.624mmol),化合物1-h(45mg,0.202mmol)。反应混合液升温至100℃,搅拌16h。TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=15∶1)。硅胶薄层层析纯化(二氯甲烷∶甲醇=15∶1)得到浅黄色固体化合物9-g(25mg,收率23%)。MS(ES
+,m/z):693.6[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.46(d,J=9.0Hz,1H),7.36(s,1H),7.14(t,J=8.0Hz,1H),7.09-7.00(m,1H),6.69(m,2H),6.29(d,J=7.7Hz,1H),4.84(d,J=49.0Hz,1H),4.61(m,4H),4.19(bs,1H),3.92(s,3H),3.55(m,1H),3.24(t,J=10.6Hz,1H),2.95(d,J=11.0Hz,1H),2.33(s,3H),2.32-2.20(m,1H),2.15(t,J=11.6Hz,1H),2.06-1.86(m,6H),1.58-1.31(m,9H),1.16-1.12(m,3H),1.12-1.07(m,3H)。
化合物9-g(10mg,0.0144mmol)溶解在DCM/TFA(1mL/1mL)中,25℃搅拌1h。TLC监测反应完毕,反应液减压浓缩,滴加NH
3/MeOH(0.5mL)调pH值为8,加水(5mL),乙酸乙酯(5mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=12∶1)。硅胶薄层层析纯化(二氯甲烷∶甲醇=12∶1),冷冻干燥后得到浅黄色固体化合物9(5mg,收率59%)。MS(ES
+, m/z):593.6[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.23(d,J=11.4Hz,1H),7.13(t,J=8.0Hz,1H),7.10-7.04(m,1H),6.82(dd,J=8.0,3.1Hz,1H),6.76(s,1H),6.68(d,J=8.2Hz,1H),6.29(d,J=7.8Hz,1H),4.93(t,J=6.1Hz,1H),4.85(d,J=49.0Hz,1H),4.57(dd,J=17.1,8.6Hz,2H),4.32(d,J=6.2Hz,2H),4.19(s,1H),3.93(s,3H),3.53(m,1H),3.25(m,1H),2.95(m,1H),2.36(s,3H),2.24-1.78(m,8H),1.14(t,J=8.0Hz,3H),1.10(d,J=7.7Hz,3H)。
实施例10:化合物10的制备
将化合物10-a(3.90g,26.32mmol,1.0eq)溶于(Boc)
2O(40mL),在100℃下搅拌48小时。TLC监测反应完毕,柱层析分离纯化(石油醚∶乙酸乙酯=30∶1)得到白色固体化合物10-b(5.38g,83%)。LC-MS(ES
+,m/z):249.3[M+H]
+
将化合物10-b(4.07g,16.39mmol,1.0eq),NaN
3(5.33g,81.96mmol,5.0eq),NH
4Cl(4.38g,81.96mmol,5.0eq)溶于DMF(50mL)中,120℃反应16h。TLC监测反应完毕,加水稀释,1M HCl调pH=1,THF萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。柱层析分离纯化(DCM∶THF=5∶1)得到化合物10-c(3.86g,81%)。LC-MS(ES
+,m/z):292.4[M+H]
+;
1H NMR(500MHz,DMSO)δ8.23(s,1H),7.98(d,J=8.3Hz,1H),7.64(s,1H),7.61(d,J=8.4Hz,1H),3.92(s,3H),1.48(s,9H)。
将化合物10-c(720mg,2.56mmol,1.0eq),DHP(323mg,3.8mmol,1.5eq),PPTS(65mg,0.256mmol,0.1eq)溶于THF(15mL)中,室温反应16h。TLC监测反应完毕,浓缩。柱层析分离纯化(PE∶EA=5∶1)得到无色液体化合物10-d(800mg,83%)。LC-MS(ES
+,m/z):376.2[M+H]
+;
1H NMR(500MHz,CDCl
3),δ8.20(s,1H),7.80(dd,J=8.4,1.25Hz,1H),7.67(d,J=1.3Hz,1H),7.22(s,1H),6.03(dd,J=8.0,2.45Hz,1H),4.05(m,1H),3.97(s,3H),3.83(m,1H),2.51(m,1H),2.18(m,2H),1.71-1.83(m,3H),1.54(s,9H)。
将化合物10-d(400mg,1.06mmol,1.0eq),Cs
2CO
3(1.0g,3.2mmol,3.0eq),3-溴丙炔(380mg,3.2mmol,3.0eq)溶于DMF(5mL)中,室温搅拌16h。TLC监测反应完毕,水/MTBE萃取旋干,柱层析分离纯化(PE∶EA=5∶1)得到无色液体化合物10-e(400mg,91%)。LC-MS(ES
+,m/z):430.2[M+H]
+;
1H NMR(500MHz,CDCl
3)δ7.78(d,J=8.0Hz,1H),7.74(s,1H),7.37(s,1H),6.05(dd,J=7.8,2.6Hz,1H),4.04(m,1H),3.92(s,3H),3.83(m,1H),4.3(bs,2H)2.51(m,1H),2.18(m,3H),1.71-1.83(m,3H),1.54(s,2H)1.34(s,7H)。
将化合物10-e(80mg,0.188mmol,1.0eq),1-f(124mg,0.288mmol,1.2eq),CuI(6mg,0.029mmol,0.15eq),(PPh
3)
2PdCl
2(7mg,0.010mmol,0.05eq)溶于三乙胺(2mL)和DMF(1mL)的混合溶剂中,于氮气氛围下室温反应16h。TLC监测反应完毕,旋干三乙胺,水/MTBE萃取,旋干,Prep-TLC分离纯化(石油醚∶乙酸乙酯=2∶1)得到黄色固体化合物10-f(42mg,32%) LC-MS(ES
+,m/z):689.5[M+H]
+,691.6[M+H+2]
+;1H NMR(500MHz,CDCl3)δ7.80(d,J=8.0Hz,1H),7.39(t,J=7.8Hz,1H),7.27-7.33(m,2H),7.22(d,J=8.2Hz,1H),7.13(t,J=7.9Hz,1H),6.79(s,1H)6.07(dd,J=7.7,2.4Hz,1H),4.23-5.19(s,2H)4.61(q,J=8.5Hz,2H),4.04(m,1H),3.94(s,3H),3.83(m,1H),2.52(m,1H),2.19(m,3H),1.71-1.82(m,3H),1.34(s,9H)
将化合物10-f(69mg,0.10mmol,1.0eq),1-h(27mg,0.13mmol,1.3eq),Cs
2CO
3(130mg,0.40mmol,4eq),BrettPhos(7mg,0.007mmol,0.07eq),RuPhos(7mg,0.014mmol,0.14eq)溶于二氧六环(2mL)于氮气氛围下110℃反应16h。TLC监测反应完毕,水/MTBE萃取旋干,柱层析分离纯化(DCM∶MeOH=50∶1)得到黄色固体化合物(30mg),C-18反相柱纯化黄色固体化合物10-g(3mg,3%)。LC-MS(ES
+,m/z):741.6[M+H]
+。
氮气氛围下,10-g(3mg,0.0041mmol,1.0eq)在DCM(2mL)和TFA(1mL)中搅拌,反应30min.LC-MS监测反应完毕,旋干反应液。NH
3/MeOH(5mL)游离,Prep-TLC分离纯化(DCM∶MeOH=10∶1),得到黄色固体10(1.0mg,44%)。LC-MS(ES
+,m/z):557.5[M+H]
+。
实施例11:化合物11的制备
在氮气氛围和-50℃下,向t-BuOK(4.64g,27.58mmol)的无水DMF(35mL)溶液中滴加化合物11-a(4.86g,27.58mmol)和二氟甲基(2-吡啶基)砜(4.44g,22.98mmol)的DMF(15mL)溶液,混合物-45℃搅拌60分钟。滴加饱和氯化铵15ml和3M盐酸15ml,后缓慢升至室温,并反应16h用水(60mL)和MTBE(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚∶乙酸乙酯=5∶1)得到无色液体化合物11-b,2.98g,收率62%,LC-MS(ES
+,m/z):211.35[M+H]
+。
在氮气氛围和-78℃下,将化合物11-b(2.98g,14.3mmol)溶于DCM(50mL)中,然后加入三溴化硼(7.15g,28.54mmol),于-78℃搅拌30min。用饱和碳酸氢钠溶液(5mL)淬灭。水相用DCM萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤。残留物用柱层析纯化出去苄溴,化合物11-c溶于THF,直接用于下一步。
在氮气氛围和冰浴0℃下,向氢化钠(1.14g,28.54mmol)的无水四氢呋喃(25mL)混悬溶液中滴加化合物11-c(198mg,1.65mmol)的无水四氢呋喃(25mL)溶液,混合物0℃搅拌30分钟。滴加TsCl(3.26g,17.12mmol)的无水四氢呋喃(5mL)溶液,混合物升至25℃搅拌过夜。用水(100mL)淬灭反应,用乙酸乙酯(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚∶乙酸乙酯=20∶1)得到白色固体化合物11-d,2.53g,收率65%(两步),LC-MS(ES
+,m/z):275.53[M+H]
+。
在氮气氛围和冰浴0℃下,向化合物11-e(3.58g,15.82mmol)的无水HMPA(70mL)混悬溶液中分批加氢化钠(696mg,17.40mmol),混合物0℃搅拌30分钟。加11-d(5.20g,18.98mmol),混合物升至78℃搅拌16h。用水(100mL)淬灭反应,用乙酸乙酯(3x100mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚∶乙酸乙酯=15∶1)得到淡黄色固体化合物11-f,513mg,收率9.9%。LC-MS(ES
+,m/z):327.93,330.08[M+H]
+。
在氮气氛围下,将化合物11-f(513mg,1.56mmol)溶于THF(15mL)中,然后加入TiCl4(890mg,4.69mmol),Zn粉(612mg,9.36mmol),于70℃回流搅拌2h。用1M HCl溶液(50mL)淬灭。水相用MTBE(3x30mL)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,残留物用柱层析分离纯化(石油醚∶乙酸乙酯=10∶1),得到淡黄色固体化合物11-g,371mg,收率76%。LC-MS(ES
+,m/z):314.08,315.91[M+H]
+。
在氮气氛围和-78℃下,向11-g(423mg,1.34mmol)的无水四氢呋喃(10mL)溶液中滴加化合物KHMDS(2.7mL,2.69mmol),混合物在-78℃下搅拌45分钟。滴加N-苯基双(三氟甲烷磺酰)亚胺(961mg,2.69mmol)的无水四氢呋喃(5mL)溶液,混合物-78℃搅拌1h。用水(20mL)淬灭反应,用乙酸乙酯(3x20mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚∶乙酸乙酯=20∶1)得到白色固体化合物11-h,518mg,收率86%,
1H NMR(500MHz,CDCl
3),δ7.50(d,J=8.4Hz,1H),7.39(d,J=7.8Hz,1H),7.18(t,J=8.2,7.9Hz,1H),6.42(s,1H),5.06(m,1H),3.55(m,2H),3.33(m,2H)。
于氮气氛围下,化合物11-h(134mg,0.30mmol)溶解在DMF(2mL)和三乙胺(2mL)中,加入CuI(12mg,0.06mmol),(Ph
3P)
2PdCl
2(11mg,0.015mmol),化合物11-i(122mg,0.36mmol,合成参见WO 2021/061643),反应混合液在室温中搅拌2小时。TLC监测反应完毕,加水(20mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=5∶1-3∶1)。得到类白色固体化合物11-j(140mg,收率73%)。LC-MS(ES
+,m/z):636.71[M+H]
+。
在氮气氛围下,化合物11-j(64mg,0.10mmol)溶解在无水二氧六环中,依次加入Brettphos(10mg,0.01mmol),Ruphos(10mg,0.02mmol),碳酸铯(130mg,0.40mmol),化合物1-h(27mg,0.13mmol)。反应混合液升温至100℃,搅拌16h,TLC监测反应完毕,加水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=15∶1)。硅胶薄层层析纯化(二氯甲烷∶甲醇=20∶1)得到浅黄色固体化合物11-k(34mg,收率50%)。LC-MS(ES
+,m/z):687.84[M+H]
+。
在氮气氛围下,将化合物11-k(34mg,0.50mmol)溶解在DCM(10mL)和TFA(1mL)中,于25℃搅拌2小时。反应液旋干,NH
3/MeOH游离后,PTLC分离纯化(二氯甲烷∶甲醇= 25∶1)得到类白色固体化合物11(6.0mg,收率21%)。LC-MS(ES
+,m/z):587.83[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.53(dd,J=1.8,8.3Hz,1H),7.28(d,J=1.8Hz,1H),7.10(t,J=8.3Hz,1H),6.85(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),6.72(s,1H),6.26(d,J=7.7Hz,1H),5.20(m,1H),5.14(t,J=6.0Hz,1H),4.84(d,J
H,F=48.9Hz,1H),4.35(d,J=6.1Hz,2H),4.17(bs,1H),3.94(s,3H),3.62(m,2H),3.55(m,1H),3.23(m,1H),3.15(m,2H),3.03(s,3H),2.94(d,J=11Hz 1H),2.34(s,3H),2.22(m,1H),2.58(m,2H),2.14(m,1H),2.02(m,1H),1.90(m,1H),
实施例12:化合物12的制备
氮气氛围下,将12-a(19.7g,91mmol)溶解在四氢呋喃(25mL)中,逐滴加入到含有镁屑(5g,208mmol)的四氢呋喃溶液(75mL)中,室温搅拌2h后向反应液中加入磷酸二乙酯(6.4g,46mmol)的四氢呋喃溶液(20mL),室温继续搅拌1h,反应完毕向反应液中加入碳酸钾水溶液(30g碳酸钾溶解在50mL水中)形成大量的白色沉淀物,过滤沉淀物并用乙醇洗涤,收集滤液浓缩后加入二氯甲烷,无水硫酸镁干燥。过滤浓缩后经减压蒸馏(160℃)得到无色透明液体12-b(900mg,收率18.6%)。LCMS(ES,m/z)=105.1[M+1]。
1H NMR(500MHz,CDCl
3)δ7.44(d,J=458.6Hz,1H),2.02-1.99(m,2H),1.82-1.71(m,6H)。
氮气氛围下,化合物12-b(156mg,1.5mmol),5-溴-2-硝基苯甲醚(232mg,1mml),磷酸钾(233mg,1.1mmol),醋酸钯(11.2mg,0.05mmol),Xantphos(35mg,0.06mmol)加入到DMF(3mL)中,升温到90℃搅拌16h。LCMS监测反应完毕,冷却至室温,加水(5mL)乙酸乙酯(3x10mL)萃取,有机相用饱和食盐水洗涤3次,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=30∶1)得到黄色油状物12-c(150mg,收率58.8%)。LCMS(ES,m/z)=256.1[M+1],
1H NMR(500MHz,CDCl3)δ7.88(dd,J=8.1,3.2Hz,1H),7.71(dd,J=12.3,1.4Hz,1H),7.13(ddd,J=10.4,8.1,1.4Hz,1H),4.04(s,3H),2.31-2.19(m,2H),2.17-2.09(m,2H),2.04-1.96(m,4H)。
在氮气氛围下,将化合物12-c(150mg,0.588mmol)溶于乙酸乙酯(20mL)中,加入钯碳(50mg),置换瓶中氮气为氢气。反应混合液在25℃下搅拌4小时。LCMS监测反应完毕,加入硅藻土和乙酸乙酯过滤,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=30∶1)得到浅黄色固体化合物12-d(130mg,98.5%),LCMS(ES,m/z)=226.1[M+1],
1H NMR(500MHz,CDCl3)δ7.26(dd,J=12.0,1.6Hz,1H),6.97(ddd,J=11.4,7.9,1.5Hz,1H),6.74(dd,J=7.9,3.4Hz,1H),4.12(s,2H),3.91(s,3H),2.22-2.09(m,2H),2.08-1.86(m,6H)。
在氮气氛围下,化合物12-d(130mg,0.578mmol)溶于甲醇(2mL)中,加入二碳酸二叔丁酯(3mL)。反应混合液在70℃下搅拌16小时。LCMS监测反应完毕,待反应混合物冷却后,加入水(10mL),乙酸乙酯(20mLx3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=40∶1)得到黄色油状物12-e(180mg,95.8%),LCMS(ES,m/z)=326.1[M+1],
1H NMR(500MHz,CDCl
3)δ8.20(d,J=6.4Hz,1H),7.42(dd,J=12.0,1.6Hz,1H),7.24(s,1H),7.08-7.02(m,1H),3.94(s,3H),2.23-2.11(m,2H),2.10-1.88(m,6H),1.53(s,9H)。
在氮气氛围下将化合物12-e(180mg,0.554mmol)溶于无水DMF(5mL)中,依次加入碳酸铯(541mg,1.62mmol),溴丙炔(193mg,1.62mmol)。反应混合液在30℃下搅拌2h。LCMS监测反应完毕,反应液中加入水(5mL)和乙酸乙酯(3x10mL)萃取,有机相用饱和食盐水洗涤3次,无水硫酸钠干燥,过滤减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=40∶1)。得到黄色固体化合物12-f(180mg,收率89.5%)。LCMS(ES,m/z)=364.1[M+1],
1HNMR(500MHz,CDCl
3)δ7.48(d,J=12.2Hz,1H),7.38(s,1H),7.12-7.04(m,1H),4.28(s,2H),3.90(s,3H),2.27-2.14(m,3H),2.13-1.87(m,6H),1.34(s,9H)。
在氮气氛围下将化合物12-f(100mg,0.275mmol)化合物1f(142mg,0.33mmol),碘化亚铜(10mg,0.055mmol),二(三苯基膦)二氯化钯(10mg,0.014mmol)溶于DMF(2mL)和三乙胺(3mL)中,该混合液在室温下搅拌2小时,LCMS监测反应完毕,反应液加水(10mL)和乙酸乙酯(3x20mL)萃取,有机相用饱和的食盐水洗涤三次,无水硫酸钠干燥,过滤减压浓缩得到粗品,该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=40∶1)。得到黄色油状物12-g(120mg,收率68.2%)。LCMS(ES,m/z)=638.9,640.9[M+1],
1H NMR(500MHz,CDCl
3)δ7.52(d,J=12.3Hz,1H),7.42-7.31(m,2H),7.23(d,J=8.3Hz,1H),7.17-7.12(m,1H),7.11-7.05(m,1H),6.79(s,1H),4.91-4.43(m,4H),3.92(s,3H),2.25-2.14(m,2H),2.14-1.89(m,6H),1.37(s,9H)。
将化合物12-g(60mg,0.094mmol),化合物1-h(27mg,0.132mmol),碳酸铯(122mg,0.376mmol),BrettphosPd G4(6mg,0.0066mmol),Ruphos(6mg,0.0132mmol)依次加入到微波管中,然后加入无水二氧六环溶液(2mL),通入氮气搅拌10分钟,然后密封微波管。反应混合液在100℃下搅拌16小时。LCMS监测反应完毕。加水(5mL)和乙酸乙酯(3x10mL)萃取,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到粗品,该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1)。得到黄色固体化合物12-h(20mg,30.86%)。LCMS(ES,m/z)=691.1[M+1],
1H NMR(500MHz,CDCl
3)δ7.58-7.49(m,1H),7.46-7.32(m,1H),7.14(t,J=8.0Hz,1H),7.11-7.04(m,1H),6.76-6.66(m,2H),6.29(d,J=7.8Hz,1H),4.85(d,J=49.1Hz,1H), 4.75-4.44(m,4H),4.20(s,1H),3.92(s,3H),3.62-3.50(m,1H),3.24(t,J=11.6Hz,1H),2.99-2.91(m,1H),2.35(s,3H),2.28-2.06(m,6H),2.04-1.87(m,6H),1.37(s,9H)。
将化合物12-h(10mg,0.0145mmol)溶于二氯甲烷溶液(1mL)中,加入三氟乙酸(0.4mL),反应室温搅拌30分钟,LCMS监测反应完毕。浓缩反应液,加入氨甲醇溶液调节反应液pH=8,然后经Prep-TLC(二氯甲烷∶甲醇=15∶1)分离得到化合物12(2.8mg,42.8%)。LCMS(ES,m/z)=591.2[M+1],
1H NMR(500MHz,CDCl
3)δ7.31-7.27(m,1H),7.16-7.08(m,2H),6.82(dd,J=8.0,3.2Hz,1H),6.76(s,1H),6.68(d,J=8.3Hz,1H),6.29(d,J=7.7Hz,1H),4.95(t,J=6.3Hz,1H),4.85(d,J=49.0Hz,1H),4.57(q,J=8.5Hz,2H),4.32(d,J=6.3Hz,2H),4.19(s,1H),3.93(s,3H),3.61-3.50(m,1H),3.29-3.21(m,1H),2.99-2.92(m,1H),2.35(s,3H),2.26-2.10(m,4H),2.09-1.85(m,8H)。
实施例13:化合物13的制备
将化合物13-a(1g,4.31mmol),甲基二乙氧基膦(0.88g,6.46mmol),醋酸钯(96.8mg,0.43mmol),Xantphos(249.2mg,0.43mmol)和磷酸钾(1.37g,6.46mol)依次加入到微波管中,然后加入无水DMF溶液(3mL),使用长针头深入溶液里通入氮气搅拌10分钟,然后密封微波管。反应混合液150℃微波反应2小时。TLC监测反应完毕。上述操作重复5次,反应液合并后加水(40mL),乙酸乙酯(3 x 50mL)萃取,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1-0∶100)。得到红色液体化合物13-b(2.5g,收率44.7%)。LC-MS(ES
+,m/z):260.2[M+H]
+;
1H NMR(500MHz,CDCl
3)δ7.88(dd,J=8.1,3.6Hz),7.63(d,J=12.9Hz),7.35(dd,J=10.6,8.6Hz),4.14-4.08(m,1H),4.03(s,3H),3.91-3.81(m,1H),1.69(s,3H),1.32(t,J=7.1Hz,3H)。
氢气氛围化合物13-b(900mg,3.47mmol)溶在乙酸乙酯(20mL)中,加入Pd/C(90mg)。反应混合液在25℃下搅拌3小时。TLC监测反应完毕,加入乙酸乙酯(20mL)稀释反应液,过滤后滤液减压浓缩得到黄色化合物13-c(700mg,收率87.9%)。LC-MS(ES
+,m/z):230.1[M+H]
+。
在氮气氛围下,化合物13-c(700mg,3.05mmol)溶于(Boc)
2O(4mL)中,80℃搅拌16小时。TLC监测反应完毕,冷却至室温,湿法上样硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1-0∶100)。得到浅黄色液体化合物13-d(700mg,收率76.6%)。LC-MS(ES
+,m/z):430.4[M+H]
+。
将化合物13-d(700mg,1.63mmol)溶于无水乙醇(10mL)中,加入无水碳酸钾(1.12g,8.15mmol)。反应混合液在78℃下搅拌8小时。TLC监测反应完毕。加入水(30mL),乙酸乙酯(3 x 50mL)萃取。有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1-0∶100)。得到淡黄色液体化合物13-e(350mg,收率65.2%)。LC-MS(ES
+,m/z):330.3[M+H]
+;
1H NMR(500MHz,CDCl
3)δ7.34(d,J=12.6Hz,1H),7.30-7.27(m,1H),7.25-7.22(m,1H),4.39(s,1H),4.13-4.00(m,1H),3.94(s,3H),3.87-3.73(m,1H),1.65(d,J=14.5Hz,3H),1.46(s,9H),1.40(t,J=9.1Hz,3H).
化合物13-e(350mg,1.06mmol)溶解在DMF(3mL)中,加入碳酸铯(1.04g,3.19mmol),溴丙炔(379.4mg,3.19mmol)。反应混合液在80℃下搅拌16小时。TLC监测反应完毕,加水(15mL),乙酸乙酯(3 x 15mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1-0∶100)。得到浅黄色液体化合物13-f(290mg,收率74.2%)。LC-MS(ES
+,m/z):368.3[M+H]
+;
1H NMR(500MHz,CDCl
3)δ7.38-7.30(m,2H),7.24-7.20(m,1H),4.30-4.13(m,1H),4.08-3.98(m,2H),3.82(s,3H),3.80-3.75(m,1H),2.11(t,J=2.5Hz,1H),1.62(d,J=14.5Hz,3H),1.31-1.18(m,12H)。
氮气氛围下,化合物13-f(290mg,0.79mmol)溶解在DMF(4mL)和三乙胺(2mL)中,加入CuI(22.5mg,0.12mmol),Pd(PPh
3)
2Cl
2(27.7mg,0.04mmol),化合物1f(437.3mg,1.03mmol),反应混合液在室温中搅拌2小时。TLC监测反应完毕,加水(15mL),乙酸乙酯(3 x 20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=2∶1-0∶100),得到浅黄色固体化合物13-g(370mg,收率72.8%)。LC-MS(ES
+,m/z):643.4[M+H]
+,645.5[M+2+H];
1H NMR(500MHz,CDCl
3)δ7.49-7.40(m,1H),7.39-7.31(m,2H),7.31-7.28(m,1H),7.23(d,J=8.4Hz,1H),7.15(t,J=7.9Hz,1H),6.79(s,1H),4.95-4.43(m,2H),4.65(q,J=8.1Hz,2H),4.09-4.02(m,1H),3.91(s,3H),3.89-3.75(m,1H),1.68(d,J=14.5Hz,3H),1.45-1.34(m,9H),1.28(t,J=6.9Hz,3H).
氮气氛围下,化合物13-g(370mg,0.57mmol)溶解在无水二氧六环(4mL)中,依次加入Brettphos Pd G4(52.9mg,0.058mmol),Ruphos(53.6mg,0.115mmol),碳酸铯(750mg,2.30mmol),化合物1h(153.3mg,0.75mmol)。反应混合液升温至100℃,搅拌16h。TLC监测反应完毕,加水(10mL),乙酸乙酯(3 x 15mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=15∶1)。得到浅黄色固体化合物13-h(150mg,收率37.5%)。LC-MS(ES
+,m/z):695.5[M+H]
+;
1H NMR(500MHz,CDCl
3)δ7.48-7.34(m,2H),7.14(t,J=8.0Hz,1H),6.72(s,1H),6.70(d,J=8.5Hz,1H),6.29(d,J=7.7Hz,1H),4.85(d,J=48.9Hz,1H),4.60(q,J=8.5Hz,2H),4.77-4.27(m,2H),4.26-4.11(m,1H),4.11-4.02(m,1H),3.91(s,3H),3.88-3.78(m,1H),3.56(dd,J=29.1,11.6Hz,1H),3.24(t,J=11.5Hz,1H),2.95(d,J=11.5Hz,1H),2.34(s,3H),2.26-2.20(m,1H),2.15(t,J=11.8Hz,1H),2.05-1.99(m,2H),1.96-1.89(m,1H),1.67(d,J=15.0Hz,3H),1.41-1.20(m,12H).
化合物13-h(5mg,0.007mmol)溶解在DCM(1mL)中,加入三氟乙酸(0.25mL)。25℃搅拌3h。TLC监测反应完毕,反应液减压浓缩,滴加NH
3/MeOH(0.5mL)调pH值为8,加水(3mL),乙酸乙酯(3 x 5mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶薄层层析分离纯化(二氯甲烷∶甲醇=10∶1),冷冻干燥后得到浅黄色固体化合物13(2mg,收率,46.7%)。LC-MS(ES
+,m/z):595.4[M+H]
+;
1H NMR(500MHz,CD
3CN)δ7.22(ddd,J=12.1,8.1,1.6Hz,1H),7.07-6.99(m,2H),6.81(dd,J=8.1,3.6Hz,1H),6.77(s,1H),6.65(d,J=8.3Hz,1H),6.23(d,J=7.7Hz,1H),5.30(t,J=6.6Hz,1H),4.75(d,J=49.1Hz,1H),4.66(q,J=8.9Hz,2H),4.47(d,J=9.2Hz,1H),4.26(d,J=6.5Hz,2H),3.86-3.81(m,1H),3.81(s,3H),3.79-3.62(m,1H),3.59-3.45(m,1H),3.05(t,J=11.5Hz,1H),2.81(d,J=11.6Hz,1H),2.19(s,3H),1.82-1.77(m,1H),1.47(d,J=14.5Hz,3H),1.14(t,J=7.1Hz,3H).
实施例14:化合物14的制备
氮气氛围下,将环丙基溴化镁(0.5M,18mL,9mmol)加入到化合物14-a(260mg,1.13mmol)的四氢呋喃溶液(5mL)中。反应混合液在70℃搅拌16小时。反应液冷却至室温,加入饱和氯化铵溶液(5mL)淬灭,乙酸乙酯(3x30mL)萃取。合并的有机相经饱和食盐水(3×15mL)洗涤、无水硫酸钠干燥、过滤后滤液减压浓缩。得到粗品经硅胶柱层析纯化(二氯甲烷∶甲醇=20∶1)得到黄色油状化合物14-b(240mg,收率93.9%)。LCMS(ES,m/z):226.1[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.21-7.17(m,1H),7.09-7.03(m,1H),6.73(dd,J=7.8,3.4Hz,1H),4.13(s,2H),3.89(s,3H),1.68(d,J=12.9Hz,3H),1.01-0.74(m,5H)。
在氮气氛围下,将化合物14-b(180mg,0.799mmol)溶于甲醇(2mL)中,加入二碳酸二叔丁酯(4mL)。反应混合液在70℃下搅拌16小时。LCMS监测反应完毕,待反应混合物冷却后,加入水(10mL),乙酸乙酯(20mLx3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=40∶1)得到黄色油状物14-c(160mg,61.6%)。LCMS(ES,m/z):326.1[M+1],
1H NMR(500 MHz,CDCl
3)δ8.19(d,J=8.1Hz,1H),7.35-7.30(m,1H),7.23(s,1H),7.20-7.15(m,1H),3.93(s,3H),1.71(d,J=12.9Hz,3H),1.52(s,9H),1.03-0.80(m,5H)。
在氮气氛围下将化合物14-c(160mg,0.49mmol)溶于无水DMF(3mL)中,依次加入碳酸铯(479mg,1.47mmol),溴丙炔(175mg,1.47mmol),反应混合液在30℃下搅拌2h,LCMS监测反应完毕,反应液中加入水(5mL),乙酸乙酯(3x10mL)萃取,有机相用饱和食盐水洗涤三次,无水硫酸钠干燥,过滤减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=40∶1),得到黄色固体化合物14-d(150mg,收率83.9%)。LCMS(ES,m/z):364.1[M+1],
1H NMR(500MHz,CDCl
3)δ7.47-7.31(m,2H),7.24-7.17(m,1H),4.27(s,2H),3.89(s,3H),2.19-2.15(m,1H),1.74(d,J=12.6Hz,3H),1.34(s,9H),1.05-0.79(m,5H)。
在氮气氛围下将化合物14-d(100mg,0.275mmol),1f(176mg,0.412mmol),碘化亚铜(10mg,0.055mmol),二(三苯基膦)二氯化钯(10mg,0.014mmol)溶于DMF(2mL)和三乙胺(2mL)中,该混合液在室温下搅拌2小时,LCMS监测反应完毕,反应液加水(10mL),用乙酸乙酯(3x20mL)萃取,有机相用饱和的食盐水洗涤三次,无水硫酸钠干燥,过滤减压浓缩得到粗品,该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=40∶1)。得到黄色油状物14-e(60mg,收率34.1%)。LCMS(ES,m/z):639.1,[M+1],
1HNMR(500MHz,CDCl
3)δ7.50-7.35(m,2H),7.34-7.31(m,1H),7.25-7.18(m,2H),7.17-7.12(m,1H),6.79(s,1H),4.77-4.51(m,4H),3.92(s,3H),1.75(d,J=12.7Hz,3H),1.37(s,9H),1.06-0.86(m,5H)。
将化合物14-e(55mg,0.086mmol),化合物1h(26mg,0.129mmol),碳酸铯(112mg,0.344mmol),BrettphosPd G4(8mg,0.009mmol),Ruphos(8mg,0.018mmol)依次加入到微波管中,然后加入无水二氧六环溶液(3mL),通入氮气搅拌10分钟,然后密封微波管,反应混合液在100℃下搅拌16小时。LCMS监测反应完毕。加水(5mL),用乙酸乙酯(3x10mL)萃取,有机相用饱和的食盐水洗涤,无水硫酸钠干燥,过滤浓缩得到粗品,该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=20∶1),得到黄色固体化合物14-f(20mg,33.7%)。LCMS(ES,m/z):691.3[M+1]。
1H NMR(500MHz,CDCl
3)δ7.46-7.32(m,2H),7.23-7.17(m,1H),7.14(t,J=8.0Hz,1H),6.75-6.66(m,2H),6.29(d,J=7.7Hz,1H),4.85(d,J=49.7Hz,1H),4.73-4.41(m,4H),4.20(s,1H),3.91(s,3H),3.62-3.47(m,1H),3.29-3.20(m,1H),2.99-2.91(m,1H),2.34(s,3H),2.25-2.19(m,1H),2.15(t,J=11.8Hz,1H),2.06-2.02(m,1H),1.96-1.88(m,1H),1.74(d,J=12.7Hz,4H),1.36(s,9H),1.06-0.89(m,5H)。
将化合物14-f(10mg,0.015mmol)溶于二氯甲烷溶液(1mL)中,加入三氟乙酸(0.5mL),反应室温搅拌1小时,LCMS监测反应完毕,浓缩反应液,加入氨甲醇溶液调节反应液pH=8,然后经制备TLC(二氯甲烷∶甲醇=15∶1)分离得到化合物14(2mg,23.4%)。LCMS(ES,m/z):591.3[M+1]。
1HNMR(500MHz,CDCl
3)δ7.25-7.18(m,2H),7.13(t,J=8.0Hz,1H),6.82(dd,J=8.0,3.3Hz,1H),6.76(s,1H),6.68(d,J=8.3Hz,1H),6.29(d,J=7.7Hz,1H),4.94(t,J=6.3Hz,1H),4.84(d,J=49.1Hz,1H),4.56(q,J=8.5Hz,2H),4.32(d,J=6.3Hz,2H),4.20(br,1H),3.92(s,3H),3.62-3.49(m,1H),3.24(t,J=10.7Hz,1H),2.99-2.91(m,1H),2.34(s,3H),2.31-2.20(m,1H),2.15(t,J=9.6Hz,1H),2.06-1.99(m,1H),1.95-1.85(m,1H),1.71(d,J=12.9Hz,3H),1.02-0.91(m,2H),0.91-0.85(m,2H),0.84-0.76(m,1H)。
实施例15:化合物15的制备
氮气氛围下,叔丁醇钾(0.99g,8.7mmol)溶解于DMF(10mL)中,降温至-45℃,缓慢滴加化合物15-a(1g,5.39mmol)的DMF(5mL)溶液和二氟甲基(2-吡啶基)砜(0.87g,4.5mmol)的DMF(5mL)溶液,缓慢升至室温搅拌过夜。TLC监测反应完毕,加入饱和氯化铵水溶液(10mL),3M盐酸水溶液(3mL)室温搅拌一小时。乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=10∶1)。得到白色固体化合物15-b(300mg,收率25.4%)。MS(ES
+,m/z):220.1[M+H]
+。
化合物15-b(7mg,0.031mmol)溶解于DCM(1mL)中,加入4M盐酸1,4-二氧六环溶液(1mL)。室温搅拌反应1h。TLC原料消失,浓缩得到黄色液体化合物15-c(3.8mg,收率100%)。MS(ES
+,m/z):120.1[M+H]
+。
化合物7-g(10mg,0.0156mmol)溶解于DCM(1mL)中,加入化合物15-c(3.8mg,0.031mmol),DIPEA(8mg,0.0624mmol),HATU(8.9mg,0.0234mmol),反应混合液于室温搅拌二小时。TLC监测反应完毕,加入水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=18∶1)。得到黄色固体化合物15-d(7mg,收率61%)。MS(ES
+,m/z):734.3[M+H]
+。
化合物15-d(7mg,0.0095mmol)溶解于DCM(2mL)中,加入三氟乙酸(0.5mL)。室温搅拌反应1h。TLC原料消失,浓缩得到粗品,加氨甲醇调pH至弱碱性,硅胶薄层层析纯化(二氯甲烷∶甲醇=18∶1),冷冻干燥后得白色固体化合物15(2.9mg,收率48%)。MS(ES
+,m/z):634.3[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.37(d,J=1.8Hz,1H),7.25-7.21(m,1H),7.14(t,J=8.0Hz,1H),6.81-6.60(m,3H),6.29(d,J=7.7Hz,1H),6.24(d,J=7.4Hz,1H),4.95(t,J=6.4Hz,1H),4.84(d,J=49.1Hz,1H),4.68(q,J=7.5Hz,1H),4.56(q,J=8.5Hz,2H),4.33(d,J=6.3Hz,2H),4.19(s,1H),3.92(s,3H),3.60(m,1H),3.28(m,1H),3.23-3.13(m,2H),3.00(s,1H),2.74-2.63(m,2H),2.38(s,3H),2.22(t,J=7.6Hz,1H),1.95(m,3H)。
实施例16:化合物16的制备
化合物16-a(2g,10.8mmol)溶解于乙腈(100mL)中,加入三苯基膦(14g,54mmol),反应液降温至0℃,分批加入四溴化碳(8.9g,27mmol),反应混合液升至室温反应十六小时。TLC监测反应完毕,过滤,收集滤液,减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚∶乙酸乙酯=5∶1)。得到白色固体化合物16-b(350mg,收率9.5%)。MS(ES
+,m/z):339.8[M+H]
+。
化合物16-b(30mg,0.088mmol)溶解于乙腈(2mL)中,加入二碳酸二叔丁酯(40mg,0.176mmol),三乙胺(18mg,0.176mmol),4-二甲氨基吡啶(2.15mg,0.0176mmol)。反应混合液于室温搅拌十六小时。TLC监测反应完毕,加入水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶薄层层析分离纯化(石油醚∶乙酸乙酯=10∶1)。得到白色固体化合物16-c(20mg,收率51.5%)。MS(ES
+,m/z):440[M+H]
+。
氮气氛围下,将碘化亚铜(425mg,2.27mmol)分散于无水四氢呋喃(2.2mL)中,于0℃滴加甲基锂的四氢呋喃溶液(1.5M,1.8mL)。加入化合物16-c(100mg,0.227mmol)的四氢呋喃溶液(2.6mL)。反应混合液于室温搅拌十六小时。TLC监测反应完毕,加入饱和氯化铵水溶液(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶薄层层析分离纯化(石油醚∶乙酸乙酯=10∶1)。得到无色透明液体化合物16-d(25mg,收率35.4%)。MS(ES
+,m/z):312.2[M+H]
+。
化合物16-d(10mg,0.032mmol)溶解于DCM(1mL)中,加入三氟乙酸(54mg,0.48mmol)。室温搅拌反应1h。TLC原料消失,硅胶柱层析纯化(二氯甲烷∶甲醇=10∶1),得无色液体化合物16-e(3mg,收率84%)。MS(ES
+,m/z):112.1[M+H]
+。
化合物7-f(30mg,0.046mmol)溶解于DCM(5mL)中,加入三氟乙酸(0.3mL)。室温搅拌反应1h。TLC原料消失,减压浓缩得到粗品,加氨甲醇调pH至弱碱性,硅胶薄层层析纯化(二 氯甲烷∶甲醇=30∶1),得黄色固体化合物16-g(8mg,收率32%)。MS(ES
+,m/z):547.3[M+H]
+。
化合物16-g(25mg,0.046mmol)溶解于甲醇(3mL)中,加入氢氧化锂水合物(10mg,0.232mmol),反应混合液升温至50℃搅拌十六小时。TLC原料消失,减压浓缩得到粗品,硅胶薄层层析纯化(二氯甲烷∶甲醇=10∶1),得黄色固体化合物16-h(10mg,收率41%)。MS(ES
+,m/z):533.2[M+H]
+。
化合物16-h(11mg,0.02mmol)溶解于DMF(1.5mL)中,加入化合物16-e(5mg,0.04mmol),DIPEA(10.32mg,0.08mmol),HATU(11mg,0.03mmol),反应混合液于室温搅拌二小时。TLC监测反应完毕,加入水(10mL),乙酸乙酯(10mL x 3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=18∶1)。冷冻干燥后得到黄色固体化合物16(4.1mg,收率32.7%)。MS(ES
+,m/z):626.3[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.41-7.36(m,1H),7.26-7.20(m,1H),7.13(t,J=8.0Hz,1H),6.75(s,1H),6.72(d,J=8.2Hz,1H),6.68(d,J=8.3Hz,1H),6.28(d,J=7.7Hz,1H),6.23(d,J=7.1Hz,1H),4.98-4.90(m,1H),4.84(d,J=49.3Hz,1H),4.60-4.47(m,3H),4.32(d,J=5.5Hz,2H),4.27-4.10(m,1H),3.91(s,3H),3.56(m,1H),3.25(t,J=11.4Hz,1H),3.19-3.07(m,2H),2.96(d,J=11.8Hz,1H),2.59-2.50(m,2H),2.35(s,3H),2.24-2.19(m,1H),2.15(d,J=15.1Hz,1H),2.07-2.02(m,1H),1.96-1.89(m,1H),1.54(s,6H).
实施例17:化合物17的制备
化合物7-g(10mg,0.0156mmol)和17-a(5.3mg,0.0312mmol)溶解在N,N-甲基甲酰胺(1mL)中,依次加入2-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯(8.9mg,0.0234mmol)和N,N-二异丙基乙胺(8.1mg,0.0628mmol)。反应混合液在室温搅拌2h,LCMS监测反应完毕,反应液冷却至室温,加水(10mL),乙酸乙酯(3 x 15mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经制备层析硅胶板分离纯化(二氯甲烷∶甲醇=18∶1)。得到浅黄色固体化合物17-b(7mg,收率59.7%)。LC-MS(ES
+,m/z):748.4[M+H]
+;
1H NMR(500MHz,CDCl
3)δ7.40-7.26(m,1H),7.13(t,J=8.0Hz,1H),7.05-6.98(m,1H),6.96-6.90(m,1H),6.75-6.65(m,2H),6.28(d,J=7.7Hz,1H),4.84(d,J=49.0Hz,1H),4.75-4.31(m,4H),3.86(s,3H),3.80-3.68(m,2H),3.60-3.52(m,1H),3.47-3.33(m,2H),3.24(t,J= 11.4Hz,1H),3.02-2.86(m,2H),2.34(s,3H),2.32-2.27(m,2H),2.24-2.20(m,1H),2.18-2.12(m,2H),2.05-2.00(m,2H),1.95-1.90(m,1H),1.31(d,J=57.8Hz,9H)。
化合物17-b(6mg,0.008mmol)溶解在二氯甲烷(1mL)中,加入三氟乙酸(0.25mL)。反应混合液在室温搅拌1h。LCMS监测反应完毕,反应液用二氯甲烷稀释,氨的甲醇溶液调节pH=8,减压浓缩得到粗品。该粗品经制备层析硅胶板分离纯化(DCM∶MeOH=18∶1)。得到浅黄色固体化合物17(3.1mg,收率59.6%)。LC-MS(ES
+,m/z):648.4[M+H]
+;
1H NMR(500MHz,CDCl
3)δ7.14(t,J=8.0Hz,1H),7.00(dd,J=8.0,1.8Hz,1H),6.98-6.95(m,1H),6.75(s,1H),6.73(d,J=8.0Hz,1H),6.69(d,J=8.3Hz,1H),6.29(d,J=7.7Hz,1H),4.99-4.72(m,2H),4.59(q,J=8.5Hz,2H),4.31(s,2H),3.82-3.40(m,6H),3.62(s,6H),3.27(t,J=11.5Hz,,1H),2.99(d,J=11.6Hz,1H),2.38(s,3H),2.28-2.18(m,5H),2.09-2.00(m,2H),1.96-1.92(m,1H)。
实施例18:化合物18的制备
氮气氛围下,取微波管加入11-d(1.53g,5.58mmol),4-叔丁氧羰基氨基哌啶(1.68g,8.37mmol)和DIPEA(3.61g,27.9mmol)的无水DMF(25mL),混合物于110℃搅拌48h。用水(100mL)淬灭反应,用乙酸乙酯(3 x 50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚∶乙酸乙酯=10∶1-2∶1)得到白色固体化合物18-a,280mg,收率17%。LC-MS(ES
+,m/z):303.23[M+H]
+。
氮气氛围下化合物18-a(280mg,0.926mmol)溶解在4M HCl的1,4-二氧六环(15mL)中,于25℃搅拌1小时。反应液用EA(20mL)稀释,过滤得白色固体18-b,215mg,收率84%。LC-MS(ES
+,m/z):203.1[M+H]
+。
氮气氛围下,化合物18-b(105mg,0.280mmol)溶解在无水1,4-二氧六环(5mL)中,依次加入2-(二环己基膦)-3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯(20mg,0.020mmol)、2-二环己基磷-2′,6′-二异丙氧基-1,1′-联苯20mg,0.04mmol)、碳酸铯(459mg,1.41mmol)和化合物7-f(167 mg,0.337mmol)。反应混合液升温至100℃,搅拌16h。加水(10mL),用乙酸乙酯(3x10mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=30∶1)得到浅黄色固体化合物18-c(153mg,收率76%)。LC-MS(ES
+,m/z):717.7[M+H]
+。
在氮气氛围下,化合物18-c(153mg,0.213mmol)溶解在5mL甲醇和1mL水混合溶剂中,加入LiOH·H2O(45mg,1.07mmol)、反应混合液室温搅拌16h,该粗品经C-18硅胶柱层析分离纯化得到类白色固体化合物18-d(128mg,收率85%)。LC-MS(ES
+,m/z):709.9[M+H]
+。
在氮气氛围下,化合物18-d(58mg,0.818mmol)溶解在5mL DMF溶剂中,加入甲胺盐酸盐(11mg,0.164mmol),HATU(62mg,0.164mmol),DIPEA(42mg,0.327mmol),反应混合液于室温搅拌16h。加水(20mL),MTBE(3x10mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷∶甲醇=30∶1)得到浅黄色固体化合物18-e(53mg,收率91%)。LC-MS(ES
+,m/z):716.8[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.47(s,1H),7.18(dd,J=1.6,8.0Hz,1H),7.13(t,J=8.0Hz,1H),6.65(d,J=7.8Hz,1H),6.64(s,1H),6.29(d,J=7.8Hz,1H),6.11(s,1H),5.02-4.10(s,2H),4.55(q,JH,F=8.6Hz,2H),3.90(s,3H),3.48(m,1H),3.03(d,J=4.9Hz,3H),2.88(m,1H),2.83(m,2H),2.75(m,2H),2.59(m,2H),2.15(m,2H),2.02(m,2H),1.35(s,9H),1.31(m,2H)。
在氮气氛围下,将化合物18-e(53mg,074mmol)溶解在DCM(10mL)和TFA(1mL)中,于25℃搅拌2小时。反应液旋干后,用NH
3/MeOH游离,后经PTLC分离纯化(二氯甲烷∶甲醇=25∶1)得到类白色固体化合物18(35.6mg,收率78.1%)。LC-MS(ES
+,m/z):616.8[M+H]
+。
1H NMR(500MHz,CDCl
3)δ7.38(d,J=1.5Hz,1H),7.24(dd,J=1.5,8.2Hz,1H),7.13(t,J=8.0Hz,1H),6.72(d,J=8.2Hz,1H),6.68(s,1H),6.64(d,J=8.2Hz,1H),6.29(d,J=7.8Hz,1H),6.03(d,J=4.1Hz,1H),4.90(t,J=6.3Hz,1H),4.56(q,J
H,F=8.6Hz,2H),4.31(d,J=6.3Hz,2H),3.92(s,3H),3.47(m,1H),3.00(d,J=4.9Hz,3H),2.87(m,1H),2.83(m,2H),2.75(m,2H),2.58(m,2H),2.14(m,2H),2.02(m,2H),1.53(m,2H)。
实施例19:体外p53 Y220C和DNA结合活性测试。
采用HTRF的方法检测化合物对p53 Y220C蛋白活性的激活。用DMSO将化合物溶解,制成10mM的储存液,并继续稀释到100μM。转移60μL的化合物到384孔板中,按照1∶4的倍数进行梯度稀释,共10个浓度。使用Echo转移0.1μL稀释好的化合物到384孔板中,每个化合物重复两次。加入2.5μL的p53 Y220C蛋白溶液到384孔板中,1000rpm离心1min,孵育10min。加入2.5μL MAb-Anti-His-Tb工作液,30℃条件下孵育60min。加入5μL的Streptavidin-d2&dsDNA起始反应,30℃条件下孵育60min。使用BMG读取665nM/620nM的荧光数值。按下列公式计算:激活率(%acticator)=100*(ave Low control-ave cpd well)/(ave Low control-ave High control)。其中ave High control为野生型p53孔加入等浓度DMSO的平均读值,ave cpd well为化合物孔的平均读值,ave Low control为p53 Y220C孔加入等浓度DMSO的平均读值。用EC
50代表化合物将p53 Y220C结合DNA功能恢复到野生型的50%需要的浓度。各化合物的EC
50值用XLFit 5.5.0软件的非线性回归方法分析,公式为:Y=Bottom+(Top-Bottom)/(1+10^((LogEC
50-X)*HillSlope))。代表性化合物激活p53 Y220C蛋白和DNA结合的活性数据如表1所示。
表1:化合物在体外对p53 Y220C和DNA结合的活性
备注:A<100nM;100nM≤B<500nM;500nM≤C<1000nM。阳性药Ref-A在该测试条件下的EC
50值范围为60-120nM。
实施例20:化合物对p53 Y220C突变的肝癌细胞系Huh7增殖的抑制。
选择生长状态良好的Huh7细胞,用胰酶消化。加入新鲜的培养基,充分混合均匀后,800rpm离心3分钟。按照每孔2000个Huh7细胞的种板密度接种于96孔板中,37℃培养箱中培养过夜。第二天,取出培养板,将化合物按照五倍的梯度稀释,给药处理。其中空白对照孔为只加正常培养基,不加细胞,不含DMSO;DMSO孔为有细胞,含0.5%DMSO。将96孔板放入37℃培养箱中培养144小时。
将细胞培养板放置室温中平衡30分钟;每孔加入100μL CellTiter Glo检测试剂,在振板机上混匀2分钟,诱导细胞裂解;将96孔板在室温中放置10分钟,使其发光信号稳定;粘贴白色的底膜于培养板底部,使用Enspire检测化学发光值按下列公式计算:抑制率(%)=(1-(化合物读数-空白对照读数)/(DMSO对照读数-空白对照读数))×100%。各化合物的IC
50值用XLFit软件的非线性回归方法分析。代表性化合物抑制细胞增殖的活性数据如表2所示。
表2:化合物对Huh7细胞增殖的抑制活性
化合物 | Huh7 IC 50 |
Ref-A | B |
1 | B |
4 | C |
5 | C |
6 | D |
7 | C |
8 | C |
9 | A |
12 | B |
14 | B |
15 | C |
16 | D |
18 | D |
备注:A<500nM;500nM≤B<1000nM;1000nM≤C<5000nM;5000nM≤D<10000nM。
化合物Ref-A的化学结构如下:
实施例21:大鼠体内的药物动力学研究
仪器:Waters生产的XEVO TQ-S液质联用仪,所有的测定数据由Masslynx V4.1软件采集并处理,用Microsoft Excel计算和处理数据。用WinNonLin 8.0软件,采用统计矩法进行药代动学参数计算。主要包括动力学参数Tmax、T
1/2、Cmax、AUC
0-24h等。色谱柱:ACQUITY UPLC BEH C18(2.1mm×50mm,1.7μm);柱温40℃;流动相A为水(0.1%甲酸),流动相B为乙腈,流速为0.350毫升/分钟,采用梯度洗脱,洗脱梯度为0.50min:10%B;1.50min:90%B;2.50min:90%B;2.51min:10%B;3.50min:stop。进样量:1μL。
动物:SD雄性大鼠3只,体重范围200-220g,购入后在实验动物中心实验室饲养2天后使用,给药前12小时及给药后4小时内禁食,试验期间自由饮水。大鼠灌胃后按既定的时间内点取血样。
溶媒:0.4%乙醇+0.4%Tween 80+99.2%(0.5%甲基纤维素M450)。灌胃给药溶液的配制:精密称量化合物,加入溶媒中,常温下超声5分钟使药品完全溶解,配制成0.3毫克/毫升的药液。
药物样品:一般采取多个结构类似的样品(分子量相差在2个单位以上),准确称量,一起给药(cassette PK)。这样可以同时筛选多个化合物,比较它们的口服吸收率。也采用单一给药来研究药物样品在大鼠体内的药物动力学。
灌胃给药后分别于0.25、0.5、1、2、4、8、10和24小时眼眶取血。取血浆样品50μL,加入200μL的乙腈(含内标维拉帕米2ng/mL),涡旋振荡3min后,20000rcf,4℃离心10min,取上清液进行LC-MS/MS分析。
准确称量化合物配制成不同的浓度,在质谱上进行定量分析,从而建立起标准曲线,然后测试上述血浆里化合物的浓度,得出不同时间点的化合物浓度。所有的测定数据由相关的软件采集并处理,采用统计矩法进行药代动学参数计算(主要包括动力学参数Tmax、T
1/2、Cmax、AUC
0-24h等)。
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 (17)
- 一种如下式(I)所示结构的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物:式(I)中:A环选自芳基或杂芳基;B环选自芳基或杂芳基;C环选自C 3-8环烷基或4-至12-元杂环基;D选自化学键、-C≡C-、-CR a=CR a-、或C 3-6环状基团;E选自化学键、-(CR aR a) q-、-O-、-NR b-、C 3-6环状基团、或3-至6-元杂环状基团;F选自化学键、-NR b-、-O-、或-(CR aR a) q-;U选自化学键、-NR c-、-O-、-NR cC(O)R c-、-NR cC(O)-;上述各个R a各自独立地选自氢、卤素、C 1-4烷基、OR b、CN、NR bR b;各个R b和R c各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基、C 3-6环烷基、3-至8-元杂环基;除一般取代基外,所述的环烷基或杂环基任选地被=M取代;M选自O或CR eR e;或二个R b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R 1选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、C(O)R d、或S(O) 2R d;所述的烷基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR b、SR b、NR bR b;或所述的环烷基、杂环基任选地被=M取代;M选自O或CR eR e;各个R e各自独立地选自氢、氟、或C 1-4烷基;所述R e中的烷基任选地被下组取代基取代:CN、OR b、SR b、NR bR b、C(O)OR b;R d选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基;除一般取代基外,所述的环烷基或杂环基任选地被=M取代;M选自O或CR eR e;R b的定义如上所述;各个R 2各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、CN、OR b、SR b、或NR bR b;R b的定义如上所述;R 3选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、OR b、SR b、NR bR b、C(O)R d、C(O)OR b、C(O)NR bR b、C(O)N(OR b)R b、NR bC(O)R d、NR bS(O) 2R d、S(O) 2R d、S(O)(NR b)R d、S(O)R d、NR bS(O) 2R d、S(O) 2NR bR b、NR bS(O) 2NR bR b、P(O)R fR f、P(O)(NR bR b)R f、或P(O)(OR b)R f;各个R b和R d的定义如上所述;或二个R b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;所述的环状结构任选 地被=M取代;M选自O或CR eR e;各个R f各自独立地选自C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR b、NR bR b;或二个R f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R f中所述的烷基、环烷基、杂环基、或环状结构任选地被下组取代基取代:氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、CN、OR b、SR b、NR bR b、=O;R b的定义如上所述;各个R 4各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、羟基、C 1-4烷氧基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基、3-至8-元杂环基、C 2-4烯基-O-、C 2-4卤代烯基-O-、C 2-4炔基-O-、C 2-4卤代炔基-O-、C 3-6环烷基-O-、3-至8-元杂环基-O-、CN、SR b、NR bR b、C(O)R d、C(O)OR b、C(O)NR bR b;所述的烷基、烷氧基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR b、SR b、NR bR b;或所述的环烷基、杂环基任选地被=M取代;M选自O或CR eR e;各个R e各自独立地选自氢、氟、或C 1-4烷基;所述R e的烷基任选地被下组取代基取代:CN、OR b、SR b、NR bR b、C(O)OR b;各个R b和R d的定义如上所述;或R 4和E中的R a与与其相连接的F和B环上的环原子一起共同形成任意取代的6-至8-元的环状结构;或R 4和F中的R b与与其相连接的B环上的环原子一起共同形成任意取代的6-至8-元的环状结构;R 5选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、CN、OR b、SR b、NR bR b、C(O)R d、C(O)OR b、C(O)NR bR b、C(O)NR b(OR b)、NR bC(O)R d、NR bS(O) 2R d、S(O) 2R d、S(O)(NR b)R d、S(O)R d、NR bS(O) 2R d、S(O) 2NR bR b;各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基;或二个R b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R d选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基;上述R 5、R b、R d中的烷基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、C 1-4烷基、C 3-6环烷基、3-至6-元杂环基、CN、OR b、SR b、NR bR b;或上述R 5中的环烷基、杂环基任选地被C=M取代;M选自O或CR eR e;各个R e各自独立地选自氢、氟、或C 1-4烷基;所述R e的烷基任选地被下组取代基取代:CN、OR b、SR b、NR bR b、C(O)OR b;各个R b的定义如上所述;各个R 6各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、羟基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至6-元杂环基、CN、SR b、NR bR b;各个R b的定义如上所述;m选自0、1、2、3、或4;n选自0、1、2、3、或4;p选自0、1、2、3、或4;q选自0、1、2、或3;其中,各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代:卤素、C 1-4烷基、C 1-4卤代烷基、C 2- 4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR b、SR b、NR bR b、C(O)R d、C(O)OR b、C(O)NR bR b、NR bC(O)R d、NR bS(O) 2R d、或S(O) 2R d,前提条件是所形成的化学结构是稳定的和有意义的;其中,各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基;或二个R b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;各个R d各自独立选 自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基;除非特别说明,上述的芳基为含有6-12个碳原子的芳香基团;杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团;环状结构为单环、并环、稠环或杂环,所述的环状结构可以是饱和或者部分不饱和的(但并非芳香性的)。
- 如权利要求1所述的化合物,其特征在于,R 3选自C(O)NR b(OR b)、P(O)R fR f、P(O)(NR bR b)R f、或P(O)(OR b)R f;各个R f各自独立地选自C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR b、NR bR b;或二个R f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基;或二个R b与和它们连接的氮原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;其中,R f中所述的烷基、环烷基、杂环基、或环状结构任意地被选自下组的基团取代:氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、CN、OR b、SR b、NR bR b、=O;R b的定义如上所述;
- 如权利要求1所述的化合物,其特征在于,式(I)为式(II):其中,R 1选自下组基团:各个R 2各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4烯基、C 2-4炔基、CN、OR b、SR b、或NR bR b;m选自0、1、或2;R b的定义如权利要求1所述;R 3选自下组基团:R 4选自下组基团:其中,“*”表示手性中心;F选自-NH-、-NMe-、或-O-。
- 如权利要求1所述的化合物,其特征在于,式(I)为式(IV):其中,各个X各自独立地选自CH或N,前提条件是至少二个X选自CH,且所形成的结构是稳定的;其中一个CH上的H被式(IV)中的P(O)R fR f取代,其它CH上的H任选地被R 4取代;各个R f各自独立地选自C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR b、NR bR b;或二个R f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R f中所述的烷基、环烷基、杂环基、或环状结构任选地被下组取代基取代:氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、CN、OR b、SR b、NR bR b、=O;R 1、R 2、m、F、C环、R 4、R 5、R 6、p、R b的定义如权利要求1所述。
- 如权利要求1所述的化合物,其特征在于,式(I)为式(V):其中,各个R f各自独立地选自C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、OR b、NR bR b;或二个R f与和它们连接的磷原子一起共同形成任意取代的4-至8-元的环状结构,此环状结构可额外含有0-1个任选自N、O、S的杂原子;R f中所述的烷基、环烷基、杂环基、或环状结构任选地被下组取代基取代:氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、CN、OR b、SR b、NR bR b、=O;R 1、R 2、m、R 4、R 5、R 6、p、R b的定义如权利要求1所述。
- 如权利要求10所述的化合物,其特征在于,式(V)中:R 1选自C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、3-至8-元杂环基;所述的烷基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR b、SR b、NR bR b;或所述的环烷基、杂环基任选地被=M取代;M选自O或CR eR e;各个R e各自独立地选自氢、氟、或C 1-4烷基;所述R e中的烷基任选地被下组取代基取代:CN、OR b、SR b、NR bR b、C(O)OR b;各个R 2各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、CN、OR b、SR b、或NR bR b;各个R 4各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、羟基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基-O-、3-至8-元杂环基-O-;所述的烷基、烷氧基、环烷基、杂环基任选地被一个或多个选自下组的基团取代:卤素、CN、OR b、SR b、NR bR b;R 5选自氢、C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、C(O)R d、S(O) 2R d;所述环烷基、杂环基任选地被C=M取代;M选自O或CR eR e;各个R e各自独立地选自氢、氟、或C 1-4烷基;各个R 6各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、羟基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至6-元杂环基、CN、SR b、NR bR b;各个R b的定义如上所述;上述各个R b各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、或C 3-6环烷基;所述环烷基任选地被=M取代;上述各个R d各自独立地选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基;所述环烷基、杂环基任选地被=M取代;m选自0、1、2、或3;p选自0、1、2、3、或4。
- 一种药物组合物,其特征在于,包含权利要求1至14中任一项所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,以及药学上可接受的载体。
- 一种权利要求1至14中任一项的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物的用途,其特征在于,用于制备治疗与p53活性或表达量相关的疾病,病症或病状的药物组合物。
- 如权利要求16所述的用途,其特征在于,所述疾病,病症或病状选自下组:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝细胞癌、肝内胆管癌、直肠癌、膀胱癌、咽 喉癌、乳腺癌、***癌、***癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、骨肉瘤、食管癌、肾癌、皮肤癌、胃癌、髓系白血病、淋巴系白血病、骨髓纤维化、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202280058585.5A CN117916230A (zh) | 2021-08-27 | 2022-08-29 | 作为p53调节剂的化合物 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110998240.5A CN115724784A (zh) | 2021-08-27 | 2021-08-27 | 作为p53调节剂和/或hdac抑制剂的化合物 |
CN202110998240.5 | 2021-08-27 | ||
CN202111165274.2 | 2021-09-30 | ||
CN202111165274.2A CN115894328A (zh) | 2021-09-30 | 2021-09-30 | 作为p53调节剂和/或hdac抑制剂的化合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023025324A1 true WO2023025324A1 (zh) | 2023-03-02 |
Family
ID=85322495
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/115635 WO2023025324A1 (zh) | 2021-08-27 | 2022-08-29 | 作为p53调节剂的化合物 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN117916230A (zh) |
WO (1) | WO2023025324A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11963953B2 (en) | 2022-01-27 | 2024-04-23 | Pmv Pharmaceuticals, Inc. | Deuterated compounds for restoring mutant p53 function |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109069481A (zh) * | 2016-02-19 | 2018-12-21 | 皮姆维制药公司 | 用于恢复突变p53功能的方法和化合物 |
WO2021061643A1 (en) * | 2019-09-23 | 2021-04-01 | Pmv Pharmaceuticals, Inc. | METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION |
WO2021262484A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Combination therapy for treatment of cancer |
WO2021262541A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Companion diagnostic tool for mutant p53 reactivating compounds |
WO2021262483A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION |
WO2022213975A1 (en) * | 2021-04-08 | 2022-10-13 | Jacobio Pharmaceuticals Co., Ltd. | Compounds targeting y220c mutant of p53 |
-
2022
- 2022-08-29 WO PCT/CN2022/115635 patent/WO2023025324A1/zh active Application Filing
- 2022-08-29 CN CN202280058585.5A patent/CN117916230A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109069481A (zh) * | 2016-02-19 | 2018-12-21 | 皮姆维制药公司 | 用于恢复突变p53功能的方法和化合物 |
WO2021061643A1 (en) * | 2019-09-23 | 2021-04-01 | Pmv Pharmaceuticals, Inc. | METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION |
WO2021262484A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Combination therapy for treatment of cancer |
WO2021262541A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | Companion diagnostic tool for mutant p53 reactivating compounds |
WO2021262483A1 (en) * | 2020-06-24 | 2021-12-30 | Pmv Pharmaceuticals, Inc. | METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION |
WO2022213975A1 (en) * | 2021-04-08 | 2022-10-13 | Jacobio Pharmaceuticals Co., Ltd. | Compounds targeting y220c mutant of p53 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11963953B2 (en) | 2022-01-27 | 2024-04-23 | Pmv Pharmaceuticals, Inc. | Deuterated compounds for restoring mutant p53 function |
Also Published As
Publication number | Publication date |
---|---|
CN117916230A (zh) | 2024-04-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2021175199A1 (zh) | 一类芳香杂环类化合物及其在药物中的应用 | |
TWI476199B (zh) | 用於治療疾病之巨環衍生物 | |
CN106892924B (zh) | 短效苯并二氮*衍生物、其制备方法及其用途 | |
WO2021129824A1 (zh) | 新型K-Ras G12C抑制剂 | |
WO2020259432A1 (zh) | Kras-g12c抑制剂 | |
WO2021027911A1 (zh) | 新型螺环类K-Ras G12C抑制剂 | |
WO2020011246A1 (zh) | 含苯环的化合物、其制备方法及应用 | |
WO2022268230A1 (zh) | 作为kif18a抑制剂的化合物 | |
WO2021249563A1 (zh) | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 | |
WO2023280136A1 (zh) | 氘甲基取代吡嗪并吡嗪并喹啉酮类衍生物、其制备方法及其在医药上的应用 | |
CN112300153A (zh) | 一种杂环化合物、药物组合物和用途 | |
WO2022063297A1 (zh) | 喹唑啉衍生物及其制备方法和用途 | |
WO2023011513A1 (zh) | Shp2抑制剂、包含其的药物组合物及其用途 | |
WO2023025324A1 (zh) | 作为p53调节剂的化合物 | |
WO2021129841A1 (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
CA3128917A1 (en) | Acryl-containing nuclear transport modulators and uses thereof | |
WO2023217064A1 (zh) | 一种喜树碱衍生物,基于其的抗体-药物偶联物和药物组合物,及其应用 | |
WO2022222911A1 (zh) | 嘧啶酮化合物及其用途 | |
WO2022171088A1 (zh) | 吡唑并[3,4-d]嘧啶-3-酮衍生物 | |
WO2022122044A1 (zh) | 作为gls1抑制剂的杂环化合物 | |
WO2022174765A1 (zh) | 作为Wee-1抑制剂的稠环化合物 | |
WO2022002100A1 (zh) | 新型苯并咪唑化合物 | |
CN115894328A (zh) | 作为p53调节剂和/或hdac抑制剂的化合物 | |
EP2699580B1 (en) | Diazonamide analogs | |
CN115724784A (zh) | 作为p53调节剂和/或hdac抑制剂的化合物 |
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: 22860670 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202280058585.5 Country of ref document: CN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |