CN117050073A - Polysubstituted phenyl bisimidazopyridine compound and synthetic method and application thereof - Google Patents
Polysubstituted phenyl bisimidazopyridine compound and synthetic method and application thereof Download PDFInfo
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- CN117050073A CN117050073A CN202210480499.5A CN202210480499A CN117050073A CN 117050073 A CN117050073 A CN 117050073A CN 202210480499 A CN202210480499 A CN 202210480499A CN 117050073 A CN117050073 A CN 117050073A
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- CN
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- Prior art keywords
- phenyl
- compound
- fluoro
- target
- phenylbiimidazopyridine
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- 230000005764 inhibitory process Effects 0.000 claims abstract description 10
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 42
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 238000003786 synthesis reaction Methods 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 229940125763 bromodomain inhibitor Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- -1 polysubstituted phenyl bisimidazopyridine compound Chemical class 0.000 abstract description 184
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 108091052242 Bromo- and Extra-Terminal domain (BET) family Proteins 0.000 abstract 2
- 238000006243 chemical reaction Methods 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000002994 raw material Substances 0.000 description 51
- 239000000047 product Substances 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 12
- 108091005625 BRD4 Proteins 0.000 description 12
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 102000001805 Bromodomains Human genes 0.000 description 5
- 108050009021 Bromodomains Proteins 0.000 description 5
- 229940124639 Selective inhibitor Drugs 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- RSOJSFYJLQADDM-UHFFFAOYSA-N ethanesulfonamide Chemical compound [CH2]CS(N)(=O)=O RSOJSFYJLQADDM-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- 229910002027 silica gel Inorganic materials 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- JPJGNZQDELRZGE-UHFFFAOYSA-N (phenyl-$l^{2}-phosphanyl)benzene Chemical compound C=1C=CC=CC=1[P]C1=CC=CC=C1 JPJGNZQDELRZGE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000008827 biological function Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- QTZSKHCRRPXONC-UHFFFAOYSA-N 1,3-dibromo-2,5-difluorobenzene Chemical compound FC1=CC(Br)=C(F)C(Br)=C1 QTZSKHCRRPXONC-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- DEFSPWZHYXXHLB-UHFFFAOYSA-N 7-bromo-1h-imidazo[4,5-b]pyridine Chemical compound BrC1=CC=NC2=C1NC=N2 DEFSPWZHYXXHLB-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 102100029894 Bromodomain testis-specific protein Human genes 0.000 description 1
- 102100033641 Bromodomain-containing protein 2 Human genes 0.000 description 1
- 102100033642 Bromodomain-containing protein 3 Human genes 0.000 description 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000794028 Homo sapiens Bromodomain testis-specific protein Proteins 0.000 description 1
- 101000871850 Homo sapiens Bromodomain-containing protein 2 Proteins 0.000 description 1
- 101000871851 Homo sapiens Bromodomain-containing protein 3 Proteins 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
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- 239000012738 dissolution medium Substances 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- YSNVSVCWTBLLRW-UHFFFAOYSA-N oxan-4-ylmethanol Chemical compound OCC1CCOCC1 YSNVSVCWTBLLRW-UHFFFAOYSA-N 0.000 description 1
- SWYHWLFHDVMLHO-UHFFFAOYSA-N oxetan-3-ylmethanol Chemical compound OCC1COC1 SWYHWLFHDVMLHO-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- PCPUMGYALMOCHF-UHFFFAOYSA-N oxolan-3-ylmethanol Chemical compound OCC1CCOC1 PCPUMGYALMOCHF-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域Technical field
本发明属于药物化学领域，具体涉及一种多取代苯基联咪唑并吡啶类化合物及合成方法与用途。The invention belongs to the field of medicinal chemistry, and specifically relates to a multi-substituted phenylbiimidazopyridine compound and its synthesis method and use.
背景技术Background technique
表观遗传靶点溴结构域和超末端结构域(BET)蛋白家族在肿瘤及炎症治疗中是一个极其重要的靶点。BET蛋白家族包含4种亚型，分别是BRD2、BRD3、BRD4和BRDT，其中BRD4相关的研究最为广泛。BET家族蛋白都包含了两个高度保守的N端串联溴构域BD1和BD2。每个溴结构域由四个反平行的α螺旋(αZ、αA、αB和αC)和两个疏水的环(ZA环和BC环)组成。选择性抑制两种溴结构域之一成为人们关注的重点，因为这有助于我们了解每个溴结构域发挥的生物功能，从而合理地评估疗效和毒性。The epigenetic target bromodomain and ultra-terminal domain (BET) protein family is an extremely important target in the treatment of tumors and inflammation. The BET protein family includes 4 subtypes, namely BRD2, BRD3, BRD4 and BRDT, among which BRD4 has been the most extensively studied. BET family proteins all contain two highly conserved N-terminal tandem bromodomains, BD1 and BD2. Each bromodomain consists of four antiparallel α-helices (αZ, αA, αB, and αC) and two hydrophobic loops (ZA loop and BC loop). Selective inhibition of one of the two bromodomains is of interest because it helps us understand the biological function exerted by each bromodomain and thereby rationally assess efficacy and toxicity.
由于BD1和BD2是串联在同一个蛋白上的两个BD，很难通过常规的生物学手段考察单个BD的生物学功能。而BD1和BD2的非选择性抑制剂在基础研究和临床试验中已经表现出一定的局限性。目前，BD2选择性抑制剂相较于BD1选择性抑制剂报道更多，且已报道的BD1选择性抑制剂的活性和选择性有待进一步提升。较少的BD1选择性抑制剂限制了理解选择性抑制BD1的生物学功能和治疗价值，因此开发BD1高选择性抑制剂并探索其潜在的治疗效应也是急需解决的问题。Since BD1 and BD2 are two BDs connected in series on the same protein, it is difficult to examine the biological function of a single BD through conventional biological means. Non-selective inhibitors of BD1 and BD2 have shown certain limitations in basic research and clinical trials. Currently, there are more reports on BD2-selective inhibitors than BD1-selective inhibitors, and the activity and selectivity of the reported BD1-selective inhibitors need to be further improved. Fewer BD1 selective inhibitors limit the understanding of the biological functions and therapeutic value of selective inhibition of BD1. Therefore, developing highly selective inhibitors of BD1 and exploring their potential therapeutic effects are also urgent issues to be solved.
发明内容Contents of the invention
本发明的目的在于克服现有技术的不足，提供一种多取代苯基联咪唑并吡啶类化合物及合成方法与用途。The object of the present invention is to overcome the shortcomings of the prior art and provide a multi-substituted phenylbiimidazopyridine compound and its synthesis method and application.
本发明上述目的通过如下技术方案实现：The above objects of the present invention are achieved through the following technical solutions:
一种多取代苯基联咪唑并吡啶类化合物，为式Ⅰ或式Ⅱ所示化合物，或式Ⅰ、式Ⅱ化合物药学上可接受的盐：A multi-substituted phenylbiimidazopyridine compound, which is a compound represented by formula I or formula II, or a pharmaceutically acceptable salt of a compound of formula I or formula II:
其中：in:
A环选自苯基或5-10元芳杂基；Ra独立选自氢、C1-3烷基、n＝1-5；Ring A is selected from phenyl or 5-10 membered aromatic hetero group; R a is independently selected from hydrogen, C 1-3 alkyl, n=1-5;
R1、R2、R3独立选自氢、卤素；R 1 , R 2 and R 3 are independently selected from hydrogen and halogen;
Y独立选自-CH2-、-(CH2)mO-、-NR*-、-(CH2)mS-；其中，m＝0、1、2、3或4；R*为氢、C1-3烷基或C2-4烯基；Y is independently selected from -CH 2 -, -(CH 2 ) m O-, -NR*-, -(CH 2 ) m S-; where, m=0, 1, 2, 3 or 4; R* is hydrogen , C 1-3 alkyl or C 2-4 alkenyl;
R4独立选自氢、4-10元杂环烷烃、R3-和R4-Y-基团与苯环形成5-10元骈合环；R 4 is independently selected from hydrogen, 4-10 membered heterocycloalkanes, R 3 - and R 4 -Y- groups and the benzene ring form a 5-10 membered parallel ring;
其中：in:
X为N或CH；X is N or CH;
C环独立选自5-6元芳杂环、4-7元杂环烷烃；Rc独立选自氢、卤素、C1-3烷烃、C1-3烷氧基，m＝1-2；C ring is independently selected from 5-6 membered aromatic heterocycles and 4-7 membered heterocycloalkanes; R c is independently selected from hydrogen, halogen, C 1-3 alkane, C 1-3 alkoxy group, m=1-2;
R5独立选自氢、C1-5烷烃、C1-3烷氧基。R 5 is independently selected from hydrogen, C 1-5 alkane, C 1-3 alkoxy.
R6和R7独立选自氢、卤素。R 6 and R 7 are independently selected from hydrogen and halogen.
优选地，所述药学上可接受的盐为式Ⅰ、式Ⅱ化合物的酸加成盐，其中用于成盐的酸包括氯化氢、硫酸、溴化氢、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、马来酸、甲磺酸、苯磺酸和对甲苯磺酸。Preferably, the pharmaceutically acceptable salt is an acid addition salt of a compound of Formula I or Formula II, wherein the acid used to form the salt includes hydrogen chloride, sulfuric acid, hydrogen bromide, oxalic acid, citric acid, succinic acid, tartaric acid, Phosphoric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
一种上述多取代苯基联咪唑并吡啶类化合物的合成方法，化合物结构如目标1所示，合成路线如下：A method for synthesizing the above-mentioned multi-substituted phenylbiimidazopyridine compounds. The compound structure is as shown in Target 1, and the synthesis route is as follows:
一种上述多取代苯基联咪唑并吡啶类化合物的合成方法，化合物结构如目标2～目标3所示，合成路线如下：A method for synthesizing the above-mentioned multi-substituted phenylbiimidazopyridine compounds. The structure of the compound is as shown in target 2 to target 3. The synthesis route is as follows:
一种上述多取代苯基联咪唑并吡啶类化合物的合成方法，化合物结构如目标4～目标6所示，合成路线如下：A method for synthesizing the above-mentioned multi-substituted phenylbiimidazopyridine compounds. The structure of the compound is as shown in Target 4 to Target 6. The synthesis route is as follows:
一种上述多取代苯基联咪唑并吡啶类化合物的合成方法，化合物结构如目标7～目标8所示，合成路线如下：A method for synthesizing the above-mentioned multi-substituted phenylbiimidazopyridine compounds. The structure of the compound is as shown in Target 7 to Target 8. The synthesis route is as follows:
一种上述多取代苯基联咪唑并吡啶类化合物的合成方法，化合物结构如目标9～目标17所示，合成路线如下：A method for synthesizing the above-mentioned multi-substituted phenylbiimidazopyridine compounds. The structure of the compound is as shown in Target 9 to Target 17. The synthesis route is as follows:
上述多取代苯基联咪唑并吡啶类化合物用于制备BET抑制剂药物的用途。The use of the above-mentioned multi-substituted phenylbiimidazopyridine compounds for preparing BET inhibitor drugs.
优选地，所述抑制为选择性抑制BET蛋白的BD1结构域。Preferably, the inhibition is selective inhibition of the BD1 domain of BET protein.
上述多取代苯基联咪唑并吡啶类化合物用于制备抗肿瘤药物或抗炎症药物的用途。The above-mentioned multi-substituted phenylbiimidazopyridine compounds are used for preparing anti-tumor drugs or anti-inflammatory drugs.
有益效果：Beneficial effects:
本发明提供的多取代苯基联咪唑并吡啶类化合物结构新颖，对BET蛋白具有优异的抑制作用，且这种抑制存在明显的选择性，具体为选择性抑制BET蛋白的BD1结构域。本领域技术人员知道，BET蛋白为肿瘤或炎症治疗的靶点，因此，本发明提供的多取代苯基联咪唑并吡啶类化合物可以用于制备抗肿瘤药物或抗炎症药物。The multi-substituted phenylbiimidazopyridine compounds provided by the present invention have a novel structure and have excellent inhibitory effect on BET protein, and this inhibition has obvious selectivity, specifically selectively inhibiting the BD1 domain of BET protein. Those skilled in the art know that BET protein is a target for tumor or inflammation treatment. Therefore, the multi-substituted phenylbiimidazopyridine compounds provided by the present invention can be used to prepare anti-tumor drugs or anti-inflammatory drugs.
具体实施方式Detailed ways
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。下列实施例中未注明具体条件的实验方法，按照行业现有方法和条件实施。The substantive content of the present invention will be described in detail below with reference to the examples, but this does not limit the scope of the present invention. Experimental methods without specifying specific conditions in the following examples were implemented in accordance with existing methods and conditions in the industry.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-300核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured using a Bruker AVANCE-300 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane ( TMS).
MS的测定用MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)。HRMS使用Aglient 6230。MS was measured using a MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS). HRMS uses Aglient 6230.
薄层层析硅胶板使用青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。其他本发明公开的起始原料可以按照本领域已知的方法来合成，或者来自市售产品。Thin layer chromatography silica gel plates use Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm~0.2mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Other starting materials disclosed herein may be synthesized according to methods known in the art, or may be derived from commercially available products.
实施例中无特殊说明，反应能够均在氩气气氛或氮气气氛下进行。There are no special instructions in the examples, and the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There are no special instructions in the examples. The reaction temperature is room temperature, which is 20°C to 30°C.
合成路线1：Synthesis route 1:
实施例1按照Scheme 1合成。Example 1 was synthesized according to Scheme 1.
Scheme 1.Reagents and conditions：(a)Cs2CO3,Pd(dppf)Cl2·CH2Cl2,1,4-Dioxane,H2O,100℃,3h；(b)AcOK,Pd(dppf)Cl2·CH2Cl2,dry 1,4-Dioxane,100℃,3h；(c)Cs2CO3,Pd(dppf)Cl2·CH2Cl2,1,4-Dioxane,H2O,100℃,7h。Scheme 1.Reagents and conditions: (a)Cs 2 CO 3 ,Pd(dppf)Cl 2 ·CH 2 Cl 2 ,1,4-Dioxane,H 2 O,100℃,3h;(b)AcOK,Pd(dppf )Cl 2 ·CH 2 Cl 2 ,dry 1,4-Dioxane,100℃,3h; (c)Cs 2 CO 3 ,Pd(dppf)Cl 2 ·CH 2 Cl 2 ,1,4-Dioxane,H 2 O ,100℃,7h.
4-(7-溴-2,3-二氢苯并呋喃-5-基)-3,5-二甲基异噁唑(34e)4-(7-bromo-2,3-dihydrobenzofuran-5-yl)-3,5-dimethylisoxazole (34e)
4-(7-bromo-2,3-dihydrobenzofuran-5-yl)-3,5-dimethylisoxazole(34e)4-(7-bromo-2,3-dihydrobenzofuran-5-yl)-3,5-dimethylisoxazole(34e)
常规合成路线A:将33e(600mg，2.11mmol)，19b(512.54mg,2.30mmol)，碳酸铯(1.15g,3.53mmol)，和[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(143.90mg，0.177mmol)加入到史莱克管中，随后加入9mL二氧六环和3mL水作为反应溶剂。用氩气充分置换史莱克管中的空气，100℃反应3h后TLC监测反应完全结束。待反应冷却至室温后，加入等体积的乙酸乙酯和水分液萃取3次，合并有机层并低压浓缩除去溶剂，残留物经过柱层析得到目标产物34e(461mg，产率：84.9％)。Conventional synthesis route A: combine 33e (600mg, 2.11mmol), 19b (512.54mg, 2.30mmol), cesium carbonate (1.15g, 3.53mmol), and [1,1-bis(diphenylphosphorus)ferrocene] Palladium dichloride dichloromethane complex (143.90 mg, 0.177 mmol) was added to the Shrek tube, and then 9 mL of dioxane and 3 mL of water were added as the reaction solvent. The air in the Shrek tube was fully replaced with argon gas, and TLC monitored the complete completion of the reaction after 3 hours of reaction at 100°C. After the reaction was cooled to room temperature, equal volumes of ethyl acetate and water were added for liquid extraction three times. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was subjected to column chromatography to obtain the target product 34e (461 mg, yield: 84.9%).
5-(3,5-二甲基异噁唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,3-二氢呋喃[2,3-c]吡啶(35e)5-(3,5-Dimethylisoxazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-2,3-dihydrofuran[2,3-c]pyridine (35e)
5-(3,5-dimethylisoxazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[2,3-c]pyridine(35e)5-(3,5-dimethylisoxazol-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[2,3- c]pyridine(35e)
常规合成路线B:将34e(500mg，1.98mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼烷)21(438.07mg，1.73mmol)，乙酸钾(260.47mg，2.65mmol)和[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(108.79mg，0.13mmol)加入到史莱克管中，随后加入10mL无水二氧六环作为反应溶剂。用氩气充分置换史莱克管中的空气，100℃反应3h后TLC监测反应完全结束。待反应冷却至室温后，加入等体积的乙酸乙酯和水分液萃取3次，合并有机层并低压浓缩除去溶剂，得到残留物35e(466mg，产率：80.1％)。未经进一步纯化，直接投下一步。Conventional synthesis route B: 34e (500mg, 1.98mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2 -dioxaborane) 21 (438.07 mg, 1.73 mmol), potassium acetate (260.47 mg, 2.65 mmol) and [1,1-bis(diphenylphosphorus)ferrocene]palladium dichloride dichloromethane complex The substance (108.79 mg, 0.13 mmol) was added to the Shrek tube, and then 10 mL of anhydrous dioxane was added as the reaction solvent. The air in the Shrek tube was fully replaced with argon gas, and TLC monitored the complete completion of the reaction after 3 hours of reaction at 100°C. After the reaction was cooled to room temperature, equal volumes of ethyl acetate and water were added for liquid extraction three times. The organic layers were combined and concentrated under low pressure to remove the solvent to obtain residue 35e (466 mg, yield: 80.1%). Without further purification, it was used directly in the next step.
实施例1：Example 1:
7-(5-(1,3,5-三甲基-1H-吡唑-4-基)-2,3-二氢苯并呋喃-7-基)-1H-咪唑并[4,5-b]吡啶(实施例1)7-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)-1H-imidazo[4,5- b] Pyridine (Example 1)
7-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)-1H-imidazo[4,5-b]pyridine(实施例1)7-(5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)-1H-imidazo[4,5-b]pyridine (Example 1)
常规合成路线C:将7-溴-1H-咪唑并[4,5-b]吡啶23(258mg，1.3mmol)，35e(400mg，1.13mmol)，碳酸铯(848.66mg，2.60mmol)和[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷复合物(106.38mg，0.13mmol)加入到史莱克管中，随后加入9mL二氧六环和3mL水作为反应溶剂。用氩气充分置换史莱克管中的空气，100℃反应7h后TLC监测反应完全结束。待反应冷却至室温后，加入等体积的乙酸乙酯和水分液萃取3次，合并有机层并低压浓缩除去溶剂，残留物经过柱层析得到得到实施例1(124mg，产率：41.5％)。1H NMR(300MHz,Chloroform-d)δ8.57(d,J＝5.2Hz,1H),8.41(s,1H),7.74(s,1H),7.65(d,J＝5.2Hz,1H),7.23(s,1H),4.80(t,J＝8.7Hz,2H),3.82(s,3H),3.41(t,J＝8.7Hz,2H),2.32(d,J＝1.7Hz,6H).HRMS(ESI):calcd for C20H19N5O[M+H]+346.16,found 346.1672纯度：96.72％by HPLC(MeOH/H2O＝65:35,tR＝8.795min).Conventional synthesis route C: 7-bromo-1H-imidazo[4,5-b]pyridine 23 (258mg, 1.3mmol), 35e (400mg, 1.13mmol), cesium carbonate (848.66mg, 2.60mmol) and [1 , 1-Bis(diphenylphosphorus)ferrocene]palladium dichloride dichloromethane complex (106.38mg, 0.13mmol) was added to the Shrek tube, and then 9mL of dioxane and 3mL of water were added as the reaction solvent . The air in the Shrek tube was fully replaced with argon gas, and TLC monitored the complete completion of the reaction after 7 hours of reaction at 100°C. After the reaction was cooled to room temperature, equal volumes of ethyl acetate and water were added for liquid extraction three times. The organic layers were combined and concentrated under low pressure to remove the solvent. The residue was subjected to column chromatography to obtain Example 1 (124 mg, yield: 41.5%). . 1 H NMR(300MHz,Chloroform-d)δ8.57(d,J＝5.2Hz,1H),8.41(s,1H),7.74(s,1H),7.65(d,J＝5.2Hz,1H), 7.23(s,1H),4.80(t,J＝8.7Hz,2H),3.82(s,3H),3.41(t,J＝8.7Hz,2H),2.32(d,J＝1.7Hz,6H). HRMS (ESI):calcd for C 20 H 19 N 5 O[M+H] + 346.16, found 346.1672 Purity: 96.72% by HPLC (MeOH/H 2 O=65:35, t R =8.795min).
合成路线2：Synthesis route 2:
实施例2～3按照Scheme 2合成。Examples 2 to 3 were synthesized according to Scheme 2.
Scheme 3.Reagents and conditions：(a)Pd2(dba)3,Xantphos,t-BuONa,toluene,100℃,5h(b)MeI,NaH,DMF,r.t.,overnight；(c)AcOK,Pd(dppf)Cl2·CH2Cl2,dry1,4-Dioxane,100℃,3h；(d)Cs2CO3,Pd(dppf)Cl2·CH2Cl2,1,4-Dioxane,H2O,100℃,7h.Scheme 3.Reagents and conditions: (a)Pd 2 (dba) 3 ,Xantphos,t-BuONa,toluene,100℃,5h(b)MeI,NaH,DMF,rt,overnight; (c)AcOK,Pd(dppf )Cl 2 ·CH 2 Cl 2 ,dry1,4-Dioxane,100℃,3h; (d)Cs 2 CO 3 ,Pd(dppf)Cl 2 ·CH 2 Cl 2 ,1,4-Dioxane,H 2 O, 100℃,7h.
N-(3-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑-4-胺(41)N-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole-4-amine (41)
N-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazol-4-amine(41)N-(3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazol-4-amine(41)
室温下，将25a(500mg,1.97mmol)、40(271.16mg,2.17mmol)、Pd2(dba)3(90.1mg,0.09mmol)、Xantphos(113.8mg,0.197mmol)和叔丁醇钠(378.63mg,3.94mmol)加入到史莱克管中，加入15mL甲苯作为反应溶剂，氩气充分置换反应体系中的空气后，在100℃中反应5h，TLC检测反应原料完全反应，加入等体积水和乙酸乙酯萃取反应液三次，合并有机层以饱和氯化钠溶液萃取一次，取有机层以无水硫酸钠干燥2h，抽滤后滤液减压浓缩除去溶剂得到残留物，经硅胶出层析后得到目标产物41(337mg，产率：57.4％)。At room temperature, 25a (500mg, 1.97mmol), 40 (271.16mg, 2.17mmol), Pd 2 (dba) 3 (90.1mg, 0.09mmol), Xantphos (113.8mg, 0.197mmol) and sodium tert-butoxide (378.63 mg, 3.94 mmol) into the Shrek tube, add 15 mL toluene as the reaction solvent, fully replace the air in the reaction system with argon, and react at 100°C for 5 hours. TLC detects that the reaction raw materials are completely reacted. Add equal volumes of water and acetic acid. Extract the reaction solution three times with ethyl ester, combine the organic layers and extract once with saturated sodium chloride solution. Dry the organic layer over anhydrous sodium sulfate for 2 hours. After suction filtration, the filtrate is concentrated under reduced pressure to remove the solvent to obtain a residue, which is obtained after silica gel chromatography. Target product 41 (337 mg, yield: 57.4%).
N-(3-溴-2-氟苯基)-N,1,3,5-四甲基-1H-吡唑-4-胺(42)N-(3-bromo-2-fluorophenyl)-N,1,3,5-tetramethyl-1H-pyrazole-4-amine (42)
N-(3-bromo-2-fluorophenyl)-N,1,3,5-tetramethyl-1H-pyrazol-4-amine(42)N-(3-bromo-2-fluorophenyl)-N,1,3,5-tetramethyl-1H-pyrazol-4-amine(42)
室温下，将41(300mg,1.01mmol)溶于DMF中，在搅拌下缓慢加入氢化钠(120.7mg,3.02mmol)，继续搅拌30分钟后，滴加碘甲烷(157.1mg,1.11mmol)，室温反应过夜后，TLC检测反应原料完全反应，加入等体积水和乙酸乙酯萃取反应液三次，合并有机层以饱和氯化钠溶液萃取一次，取有机层以无水硫酸钠干燥2h，抽滤后滤液减压浓缩除去溶剂得到残留物，经硅胶出层析后得到目标产物42(337mg，产率：57.4％)。Dissolve 41 (300 mg, 1.01 mmol) in DMF at room temperature, slowly add sodium hydride (120.7 mg, 3.02 mmol) under stirring, continue stirring for 30 minutes, add methyl iodide (157.1 mg, 1.11 mmol) dropwise, and stir at room temperature. After reacting overnight, TLC detects that the reaction raw materials have completely reacted. Add equal volumes of water and ethyl acetate to extract the reaction solution three times. The combined organic layers are extracted once with saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate for 2 hours and filtered with suction. The filtrate was concentrated under reduced pressure to remove the solvent to obtain a residue, which was chromatographed on silica gel to obtain the target product 42 (337 mg, yield: 57.4%).
N-(2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑-4-胺(43a)N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5- Trimethyl-1H-pyrazole-4-amine (43a)
N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazol-4-amine(43a)N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazol-4-amine (43a)
按常规路线B，以41(400.0mg，1.34mmol)为反应原料，得到目标产物43a(312mg，产率：67.4％)。According to conventional route B, using 41 (400.0 mg, 1.34 mmol) as the reaction raw material, the target product 43a (312 mg, yield: 67.4%) was obtained.
N-(2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-N,1,3,5-四甲基-1H-吡唑-4-胺(43b)N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,1,3, 5-Tetramethyl-1H-pyrazole-4-amine (43b)
N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,1,3,5-tetramethyl-1H-pyrazol-4-amine(43b)N-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,1,3,5-tetramethyl-1H-pyrazol-4 -amine(43b)
按常规路线B，以42(400.0mg，1.28mmol)为反应原料，得到目标产物43b(377mg，产率：81.9％)。According to conventional route B, using 42 (400.0 mg, 1.28 mmol) as the reaction raw material, the target product 43b (377 mg, yield: 81.9%) was obtained.
实施例2：Example 2:
N-(2-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)苯基)-1,3,5-三甲基-1H-吡唑-4-胺(实施例2)N-(2-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole-4-amine ( Example 2)
N-(2-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-1,3,5-trimethyl-1H-pyrazol-4-amine(实施例2)N-(2-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-1,3,5-trimethyl-1H-pyrazol-4-amine (Example 2)
按常规路线C，以43a(600mg,1.74mmol)为反应原料，得到实施例2(178mg，产率：39.6％)。1H NMR(300MHz,DMSO-d6)δ13.25(s,1H),8.59–8.38(m,2H),7.44–7.29(m,1H),7.18–6.74(m,3H),6.48–6.32(m,1H),3.73(s,3H),2.12(d,J＝2.2Hz,3H),2.01(d,J＝2.9Hz,3H).HRMS(ESI):calcd for C18H17FN6[M+Na]+359.14,found 359.1392纯度：97.08％by HPLC(MeOH/H2O＝80:20,tR＝3.878min).According to the conventional route C, using 43a (600 mg, 1.74 mmol) as the reaction raw material, Example 2 (178 mg, yield: 39.6%) was obtained. 1 H NMR (300MHz, DMSO-d 6 ) δ13.25(s,1H),8.59–8.38(m,2H),7.44–7.29(m,1H),7.18–6.74(m,3H),6.48–6.32 (m,1H),3.73(s,3H),2.12(d,J＝2.2Hz,3H),2.01(d,J＝2.9Hz,3H).HRMS(ESI):calcd for C 18 H 17 FN 6 [M+Na] + 359.14, found 359.1392 Purity: 97.08% by HPLC (MeOH/H 2 O = 80:20, t R = 3.878min).
实施例3：Example 3:
N-(2-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)苯基)-N,1,3,5-四甲基-1H-吡唑-4-胺(实施例17)N-(2-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-N,1,3,5-tetramethyl-1H-pyrazole-4- Amines (Example 17)
N-(2-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-N,1,3,5-tetramethyl-1H-pyrazol-4-amine(实施例17)N-(2-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)phenyl)-N,1,3,5-tetramethyl-1H-pyrazol-4-amine (Example 17 )
按常规路线C，以43b(600mg,1.67mmol)为反应原料，得到目标产物实施例3(219mg，产率：48.7％)。1H NMR(300MHz,Chloroform-d)δ8.53(d,J＝5.2Hz,1H),8.41(s,1H),7.45(d,J＝4.9Hz,1H),7.28(s,1H),7.16(t,J＝7.9Hz,1H),6.93(t,J＝8.4Hz,1H),3.74(s,3H),3.30(d,J＝2.5Hz,3H),2.12(s,6H).HRMS(ESI):calcd for C19H19FN6[M+Na]+373.15,found 373.1553纯度：94.37％by HPLC(MeOH/H2O＝80:20,tR＝6.250min).According to conventional route C, using 43b (600 mg, 1.67 mmol) as the reaction raw material, the target product Example 3 (219 mg, yield: 48.7%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.53(d,J＝5.2Hz,1H),8.41(s,1H),7.45(d,J＝4.9Hz,1H),7.28(s,1H), 7.16(t,J＝7.9Hz,1H),6.93(t,J＝8.4Hz,1H),3.74(s,3H),3.30(d,J＝2.5Hz,3H),2.12(s,6H). HRMS (ESI): calcd for C 19 H 19 FN 6 [M+Na] + 373.15, found 373.1553 Purity: 94.37% by HPLC (MeOH/H 2 O = 80:20, t R = 6.250min).
合成路线3：Synthesis route 3:
实施例4～6按照Scheme 3合成。Examples 4 to 6 were synthesized according to Scheme 3.
Scheme 3.Reagents and conditions：(a)Isopropylmagnesium chloridelithium chloride complex(CAS:745038-86-2),dry THF,Ar,-40℃to 0℃,overnight；(b)MeI,t-BuOK,DMF,0℃to r.t.,6h；(c)AcOK,Pd(dppf)Cl2·CH2Cl2,dry 1,4-Dioxane,100℃,3h；(d)Cs2CO3,Pd(dppf)Cl2·CH2Cl2,1,4-Dioxane,H2O,100℃,7h.Scheme 3.Reagents and conditions: (a) Isopropylmagnesium chloridelithium chloride complex (CAS:745038-86-2),dry THF,Ar,-40℃to 0℃,overnight; (b)MeI,t-BuOK,DMF,0 ℃ to rt, 6h; (c) AcOK, Pd(dppf)Cl 2 ·CH 2 Cl 2 ,dry 1,4-Dioxane, 100℃, 3h; (d) Cs 2 CO 3 ,Pd(dppf)Cl 2 · CH 2 Cl 2 ,1,4-Dioxane,H 2 O,100℃,7h.
(3-溴-2-氟苯基)(氧杂环丁烷-3-基)甲醇(45a)(3-Bromo-2-fluorophenyl)(oxetan-3-yl)methanol (45a)
(3-bromo-2-fluorophenyl)(oxetan-3-yl)methanol(45a)(3-bromo-2-fluorophenyl)(oxetan-3-yl)methanol(45a)
将44a(372.98g,4.33mmol)加入到100mL双颈圆底烧瓶中，以40mL无水四氢呋喃作为溶剂，以氩气充分置换反应体系中的空气，将反应体系降温至-40℃并维持30分钟，在氮气流下缓慢滴加预冷的异丙基氯化镁-氯化锂(CAS:745038-86-2)2M四氢呋喃溶液(5.1mmol)，维持-40℃继续反应2h后，将预冷的25a(1.0g,3.94mmol)的四氢呋喃溶液缓慢滴加到上述体系，并将反应移至冰浴中反应4h，TLC检测反应原料几乎完全反应，加入饱和氯化铵淬灭反应，随后加入等体积水和乙酸乙酯萃取反应液三次，合并有机层以饱和氯化钠溶液萃取一次，取有机层以无水硫酸钠干燥2h，抽滤后滤液减压浓缩除去溶剂得到淡黄色油状物45a，未经进一步纯化直接投下一步。Add 44a (372.98g, 4.33mmol) into a 100mL double-neck round-bottom flask, use 40mL anhydrous tetrahydrofuran as the solvent, fully replace the air in the reaction system with argon, cool the reaction system to -40°C and maintain it for 30 minutes , slowly drop pre-cooled isopropyl magnesium chloride-lithium chloride (CAS: 745038-86-2) 2M tetrahydrofuran solution (5.1mmol) under nitrogen flow, maintain -40°C and continue the reaction for 2 hours, add the pre-cooled 25a ( 1.0g, 3.94mmol) of tetrahydrofuran solution was slowly added dropwise to the above system, and the reaction was moved to an ice bath to react for 4 hours. TLC detected that the reaction raw materials were almost completely reacted. Add saturated ammonium chloride to quench the reaction, and then add an equal volume of water and The reaction solution was extracted three times with ethyl acetate. The combined organic layers were extracted once with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate for 2 hours. After filtration, the filtrate was concentrated under reduced pressure to remove the solvent to obtain light yellow oily substance 45a, which was obtained without further treatment. Directly pass to the next step for purification.
(3-溴-2-氟苯基)(四氢呋喃-3-基)甲醇(45b)(3-Bromo-2-fluorophenyl)(tetrahydrofuran-3-yl)methanol (45b)
(3-bromo-2-fluorophenyl)(tetrahydrofuran-3-yl)methanol(45b)(3-bromo-2-fluorophenyl)(tetrahydrofuran-3-yl)methanol(45b)
按45a的制备方法，以44b(433.75mg,4.33mmol)为反应原料，得到淡黄色油状物目标产物45b。According to the preparation method of 45a, using 44b (433.75 mg, 4.33 mmol) as the reaction raw material, the target product 45b was obtained as a light yellow oil.
(3-溴-2-氟苯基)(四氢-2H-吡喃-4-基)甲醇(45c)(3-Bromo-2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol (45c)
(3-bromo-2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol(45c)(3-bromo-2-fluorophenyl)(tetrahydro-2H-pyran-4-yl)methanol(45c)
按45a的制备方法，以44c(494.5mg,4.33mmol)为反应原料，得到淡黄色油状物目标产物45c。According to the preparation method of 45a, using 44c (494.5 mg, 4.33 mmol) as the reaction raw material, the target product 45c was obtained as a light yellow oil.
3-((3-溴-2-氟苯基)(甲氧基)甲基)氧杂环丁烷(46a)3-((3-bromo-2-fluorophenyl)(methoxy)methyl)oxetane (46a)
3-((3-bromo-2-fluorophenyl)(methoxy)methyl)oxetane(46a)3-((3-bromo-2-fluorophenyl)(methoxy)methyl)oxetane(46a)
室温下，将45a(300mg,1.15mmol)溶于10mLDMF中，在搅拌状态缓慢加入叔丁醇钾，室温下搅拌10分钟后，滴加碘甲烷(212.3mg,1.495mmol)后继续反应6h，TLC检测反应原料几乎完全反应，加入等体积水和乙酸乙酯萃取反应液三次，合并有机层以饱和氯化钠溶液萃取一次，取有机层以无水硫酸钠干燥2h，抽滤后滤液减压浓缩除去溶剂得到残留油状物，经硅胶柱层析得到目标产物46a(310mg，产率：98.1％)。Dissolve 45a (300 mg, 1.15 mmol) in 10 mL DMF at room temperature, slowly add potassium tert-butoxide under stirring, stir at room temperature for 10 minutes, add methyl iodide (212.3 mg, 1.495 mmol) dropwise, and continue the reaction for 6 hours, TLC Check that the reaction raw materials are almost completely reacted. Add equal volumes of water and ethyl acetate to extract the reaction solution three times. Combine the organic layers and extract once with saturated sodium chloride solution. Dry the organic layer with anhydrous sodium sulfate for 2 hours. After suction filtration, the filtrate is concentrated under reduced pressure. The solvent was removed to obtain residual oil, and the target product 46a (310 mg, yield: 98.1%) was obtained through silica gel column chromatography.
3-((3-溴-2-氟苯基)(甲氧基)甲基)四氢呋喃(46b)3-((3-bromo-2-fluorophenyl)(methoxy)methyl)tetrahydrofuran (46b)
3-((3-bromo-2-fluorophenyl)(methoxy)methyl)tetrahydrofuran(46b)3-((3-bromo-2-fluorophenyl)(methoxy)methyl)tetrahydrofuran(46b)
按46a制备方法，以45b(300mg,1.09mmol)为反应原料，得到目标产物46b(302mg，产率：95.8％)。According to the preparation method of 46a, using 45b (300 mg, 1.09 mmol) as the reaction raw material, the target product 46b (302 mg, yield: 95.8%) was obtained.
4-((3-溴-2-氟苯基)(甲氧基)甲基)四氢-2H-吡喃(46c)4-((3-bromo-2-fluorophenyl)(methoxy)methyl)tetrahydro-2H-pyran (46c)
4-((3-bromo-2-fluorophenyl)(methoxy)methyl)tetrahydro-2H-pyran(46c)4-((3-bromo-2-fluorophenyl)(methoxy)methyl)tetrahydro-2H-pyran(46c)
按46a制备方法，以45c(300mg,1.04mmol)为反应原料，得到目标产物46c(303mg，产率：96.3％)。According to the preparation method of 46a, using 45c (300 mg, 1.04 mmol) as the reaction raw material, the target product 46c (303 mg, yield: 96.3%) was obtained.
2-(2-氟-3-(甲氧基(氧杂环丁烷-3-基)甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(47a)2-(2-Fluoro-3-(methoxy(oxetan-3-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-di Oxyborane(47a)
2-(2-fluoro-3-(methoxy(oxetan-3-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(47a)2-(2-fluoro-3-(methoxy(oxetan-3-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(47a)
按常规路线B，以46a(400mg,1.45mmol)为反应原料，得到目标产物47a(413mg，产率：88.2％)。According to conventional route B, using 46a (400 mg, 1.45 mmol) as the reaction raw material, the target product 47a (413 mg, yield: 88.2%) was obtained.
2-(2-氟-3-(甲氧基(四氢呋喃-3-基)甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(47b)2-(2-Fluoro-3-(methoxy(tetrahydrofuran-3-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane( 47b)
2-(2-fluoro-3-(methoxy(tetrahydrofuran-3-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(47b)2-(2-fluoro-3-(methoxy(tetrahydrofuran-3-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(47b)
按常规路线B，以46b(400mg,1.38mmol)为反应原料，得到目标产物47a(401mg，产率：86.2％)。According to conventional route B, using 46b (400 mg, 1.38 mmol) as the reaction raw material, the target product 47a (401 mg, yield: 86.2%) was obtained.
2-(2-氟-3-(甲氧基(四氢-2H-吡喃-4-基)甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷(47c)2-(2-Fluoro-3-(methoxy(tetrahydro-2H-pyran-4-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2 -Dioxoborane (47c)
2-(2-fluoro-3-(methoxy(tetrahydro-2H-pyran-4-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(47c)2-(2-fluoro-3-(methoxy(tetrahydro-2H-pyran-4-yl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(47c)
按常规路线B，以46c(400mg,1.32mmol)为反应原料，得到目标产物47c(409mg，产率：88.5％)。According to conventional route B, using 46c (400 mg, 1.32 mmol) as the reaction raw material, the target product 47c (409 mg, yield: 88.5%) was obtained.
实施例4：Example 4:
7-(2-氟-3-(甲氧基(氧杂环丁烷-3-基)甲基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例4)7-(2-fluoro-3-(methoxy(oxetan-3-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 4)
7-(2-fluoro-3-(methoxy(oxetan-3-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例4)7-(2-fluoro-3-(methoxy(oxetan-3-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 4)
按常规路线C，以47a(400mg,1.24mmol)为反应原料，得到实施例4(138mg，产率：46.1％)。1H NMR(300MHz,DMSO-d6)δ8.60–8.36(m,2H),7.85(t,J＝7.3Hz,1H),7.62–7.48(m,2H),7.38(d,J＝6.5Hz,1H),4.91(d,J＝7.9Hz,1H),4.63(d,J＝6.9Hz,2H),4.51(t,J＝7.0Hz,1H),4.38(q,J＝7.2,6.2Hz,1H),3.48–3.36(m,1H),3.27(s,3H).HRMS(ESI):calcdfor C17H16FN3O2[M+H]+314.12,found 314.1283纯度：95.51％by HPLC(MeOH/H2O＝80:20,tR＝3.876min).According to the conventional route C, using 47a (400 mg, 1.24 mmol) as the reaction raw material, Example 4 (138 mg, yield: 46.1%) was obtained. 1 H NMR (300MHz, DMSO-d 6 ) δ8.60–8.36(m,2H),7.85(t,J＝7.3Hz,1H),7.62–7.48(m,2H),7.38(d,J＝6.5 Hz,1H),4.91(d,J＝7.9Hz,1H),4.63(d,J＝6.9Hz,2H),4.51(t,J＝7.0Hz,1H),4.38(q,J＝7.2,6.2 Hz,1H),3.48–3.36(m,1H),3.27(s,3H).HRMS(ESI):calcdfor C 17 H 16 FN 3 O 2 [M+H] + 314.12,found 314.1283Purity: 95.51%by HPLC (MeOH/H 2 O=80:20, t R =3.876min).
实施例5：Example 5:
7-(2-氟-3-(甲氧基(四氢呋喃-3-基)甲基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例5)7-(2-fluoro-3-(methoxy(tetrahydrofuran-3-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 5)
7-(2-fluoro-3-(methoxy(tetrahydrofuran-3-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例5)7-(2-fluoro-3-(methoxy(tetrahydrofuran-3-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 5)
按常规路线C，以47b(400mg,1.14mmol)为反应原料，得到实施例5(113mg，产率：37.8％)。1H NMR(300MHz,Chloroform-d)δ8.58(dd,J＝5.1,3.0Hz,1H),8.42(s,1H),7.95(tdd,J＝6.9,4.6,1.7Hz,1H),7.61–7.50(m,2H),7.45–7.34(m,1H),4.58(dd,J＝8.1,4.3Hz,1H),4.01–3.58(m,4H),3.30(d,J＝4.9Hz,3H),2.73(dp,J＝11.9,4.8,4.1Hz,1H),2.17–1.96(m,1H),1.88–1.60(m,1H).HRMS(ESI):calcd for C18H18FN3O2[M+H]+328.14,found 328.1454纯度：98.62％by HPLC(MeOH/H2O＝80:20,tR＝3.874min).According to conventional route C, using 47b (400 mg, 1.14 mmol) as the reaction raw material, Example 5 (113 mg, yield: 37.8%) was obtained. 1 H NMR (300MHz, Chloroform-d) δ8.58 (dd, J＝5.1, 3.0Hz, 1H), 8.42 (s, 1H), 7.95 (tdd, J＝6.9, 4.6, 1.7Hz, 1H), 7.61 –7.50(m,2H),7.45–7.34(m,1H),4.58(dd,J＝8.1,4.3Hz,1H),4.01–3.58(m,4H),3.30(d,J＝4.9Hz,3H ),2.73(dp,J＝11.9,4.8,4.1Hz,1H),2.17–1.96(m,1H),1.88–1.60(m,1H).HRMS(ESI):calcd for C 18 H 18 FN 3 O 2 [M+H] + 328.14, found 328.1454 Purity: 98.62% by HPLC (MeOH/H 2 O = 80:20, t R = 3.874min).
实施例6：Example 6:
7-(2-氟-3-(甲氧基(四氢-2H-吡喃-4-基)甲基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例6)7-(2-fluoro-3-(methoxy(tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 6)
7-(2-fluoro-3-(methoxy(tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例6)7-(2-fluoro-3-(methoxy(tetrahydro-2H-pyran-4-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 6)
按常规路线C，以47c(400mg,1.13mmol)为反应原料，得到实施例6(132mg，产率：44.0％)。1H NMR(300MHz,Chloroform-d)δ8.56(d,J＝5.1Hz,1H),8.41(d,J＝8.4Hz,1H),7.93(td,J＝7.3,1.9Hz,1H),7.57–7.48(m,2H),7.38(t,J＝7.5Hz,1H),4.43(d,J＝6.9Hz,1H),4.11–3.87(m,2H),3.48–3.31(m,2H),3.29(s,3H),1.90(d,J＝12.6Hz,2H),1.58–1.51(m,2H),1.33(d,J＝13.7Hz,1H).HRMS(ESI):calcd for C19H20FN3O2[M+H]+342.16,found342.1618纯度：95.47％by HPLC(MeOH/H2O＝80:20,tR＝3.524min).According to the conventional route C, using 47c (400 mg, 1.13 mmol) as the reaction raw material, Example 6 (132 mg, yield: 44.0%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.56(d,J＝5.1Hz,1H),8.41(d,J＝8.4Hz,1H),7.93(td,J＝7.3,1.9Hz,1H), 7.57–7.48(m,2H),7.38(t,J＝7.5Hz,1H),4.43(d,J＝6.9Hz,1H),4.11–3.87(m,2H),3.48–3.31(m,2H) ,3.29(s,3H),1.90(d,J＝12.6Hz,2H),1.58–1.51(m,2H),1.33(d,J＝13.7Hz,1H).HRMS(ESI):calcd for C 19 H 20 FN 3 O 2 [M+H] + 342.16, found342.1618 purity: 95.47% by HPLC (MeOH/H 2 O = 80:20, t R = 3.524min).
合成路线4：Synthesis route 4:
实施例7～8按照Scheme 4合成。Examples 7 to 8 were synthesized according to Scheme 4.
Scheme 4.Reagents and conditions：(a)t-BuOK,DMF,r.t.,overnight；(b)AcOK,Pd(dppf)Cl2·CH2Cl2,dry 1,4-Dioxane,100℃,3h；(c)Cs2CO3,Pd(dppf)Cl2·CH2Cl2,1,4-Dioxane,H2O,100℃,7h.Scheme 4.Reagents and conditions: (a) t-BuOK, DMF, rt, overnight; (b) AcOK, Pd(dppf)Cl 2 ·CH 2 Cl 2 ,dry 1,4-Dioxane, 100℃, 3h; ( c)Cs 2 CO 3 ,Pd(dppf)Cl 2 ·CH 2 Cl 2 ,1,4-Dioxane,H 2 O,100℃,7h.
N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-N-甲基乙磺酰胺(49a)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-methylethanesulfonamide (49a)
N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-methylethanesulfonamide(49a)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-methylethanesulfonamide(49a)
室温下，将N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺31b(600mg,1.54mmol)溶于20mLDMF中，在搅拌状态下缓慢加入叔丁醇钾(345.03mg,3.07mmol)。室温下继续搅拌30min后，滴加碘甲烷(283.7mg,2.0mmol)。室温下反应5h后，TLC检测，反应完全结束。加入等体积的乙酸乙酯和水分液萃取3次，合并有机层，以饱和氯化钠溶液再次分液萃取，取有机层，用无水硫酸钠干燥1h后，浓缩除去溶剂。经柱层析分离后得到棕色粉末(587mg，产率：94.4％)。At room temperature, N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide 31b (600 mg, 1.54 mmol) Dissolve in 20 mL of DMF, and slowly add potassium tert-butoxide (345.03 mg, 3.07 mmol) under stirring. After continuing to stir at room temperature for 30 min, methyl iodide (283.7 mg, 2.0 mmol) was added dropwise. After reacting for 5 hours at room temperature, TLC detected that the reaction was completely completed. Add equal volumes of ethyl acetate and water for liquid extraction three times, combine the organic layers, and extract again with saturated sodium chloride solution. Take the organic layer, dry it with anhydrous sodium sulfate for 1 hour, and then concentrate to remove the solvent. After separation by column chromatography, brown powder (587 mg, yield: 94.4%) was obtained.
N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺(49b)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide (49b)
N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(49b)N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(49b)
按49a制备方法，以碘乙烷(311.7mg,2.0mmol)为反应原料，得到目标产物49b(569mg,88.47％)。According to the preparation method of 49a, using ethyl iodide (311.7 mg, 2.0 mmol) as the reaction raw material, the target product 49b (569 mg, 88.47%) was obtained.
N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-N-甲基乙基磺酰胺(50a)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-5-(1,3,5-tri Methyl-1H-pyrazol-4-yl)phenyl)-N-methylethylsulfonamide (50a)
N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-methylethanesulfonamide(50a)N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4- yl)phenyl)-N-methylethanesulfonamide(50a)
按常规路线B，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)甲磺酰胺49a(500mg,1.24mmol)为反应原料，得到目标产物50a(421mg，产率：75.4％)。According to conventional route B, use N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide 49a (500 mg, 1.24 mmol) as the reaction raw material, the target product 50a (421 mg, yield: 75.4%) was obtained.
N-乙基-N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺(50b)N-ethyl-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-5-(1, 3,5-Trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide (50b)
N-ethyl-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(50b)N-ethyl-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(1,3,5-trimethyl-1H- pyrazol-4-yl)phenyl)ethanesulfonamide(50b)
按常规路线B，以N-(3-溴-4-氟-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺49b(500mg,1.20mmol)为反应原料，得到目标产物50b(432mg，产率：77.7％)。According to the conventional route B, use N-(3-bromo-4-fluoro-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide 49b (500 mg, 1.20 mmol) as the reaction raw material, the target product 50b (432 mg, yield: 77.7%) was obtained.
实施例7：Example 7:
N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-N-甲基乙烷磺酰胺(实施例7)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl) Phenyl)-N-methylethanesulfonamide (Example 7)
N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-methylethanesulfonamide(实施例7)N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N -methylethanesulfonamide (Example 7)
按常规路线C，以N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-N-甲基乙基磺酰胺50a(659.5mg,0.66mmol)为反应原料，得到实施例7(98mg，产率：43.85％)。1H NMR(300MHz,Chloroform-d)δ8.57(d,J＝17.3Hz,1H),8.39(s,1H),7.98(dd,J＝5.9,2.8Hz,1H),7.55(d,J＝5.2Hz,1H),7.40(dd,J＝6.0,2.9Hz,1H),3.84(s,3H),3.48(s,3H),3.20(q,J＝7.4Hz,2H),2.28(dd,J＝3.1,1.0Hz,6H),1.47(t,J＝7.4Hz,3H).HRMS(ESI):calcd for C21H23FN6O2S[M+H]+443.16,found 443.1665纯度：96.99％by HPLC(MeOH/H2O＝80:20,tR＝3.659min).According to the conventional route C, use N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-5-(1 , 3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-N-methylethylsulfonamide 50a (659.5mg, 0.66mmol) was used as the reaction raw material to obtain Example 7 (98mg, product rate: 43.85%). 1 H NMR (300MHz, Chloroform-d) δ8.57(d,J＝17.3Hz,1H),8.39(s,1H),7.98(dd,J＝5.9,2.8Hz,1H),7.55(d,J ＝5.2Hz,1H),7.40(dd,J＝6.0,2.9Hz,1H),3.84(s,3H),3.48(s,3H),3.20(q,J＝7.4Hz,2H),2.28(dd ,J＝3.1,1.0Hz,6H),1.47(t,J＝7.4Hz,3H).HRMS(ESI):calcd for C 21 H 23 FN 6 O 2 S[M+H] + 443.16,found 443.1665Purity :96.99% by HPLC (MeOH/H 2 O=80:20, t R =3.659min).
实施例8：Example 8:
N-乙基-N-(4-氟-3-(1H-咪唑并[4,5-b]吡啶-7-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙烷磺酰胺(实施例8)N-ethyl-N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazole) -4-yl)phenyl)ethanesulfonamide (Example 8)
N-ethyl-N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide(实施例8)N-ethyl-N-(4-fluoro-3-(1H-imidazo[4,5-b]pyridin-7-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl) phenyl)ethanesulfonamide (Example 8)
按常规路线C，以N-乙基-N-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-5-(1,3,5-三甲基-1H-吡唑-4-基)苯基)乙磺酰胺50b(305.5mg,0.66mmol)为反应原料，得到实施例8(103mg，产率：44.68％)。1H NMR(300MHz,Chloroform-d)δ8.62(d,J＝5.1Hz,1H),8.54(s,1H),7.95(s,1H),7.60(d,J＝4.3Hz,1H),7.39(d,J＝4.6Hz,1H),3.91(d,J＝7.0Hz,2H),3.87(s,3H),3.20(q,J＝7.3Hz,2H),2.30(s,6H),1.49(t,J＝7.2Hz,3H),1.31(t,J＝7.0Hz,3H).HRMS(ESI):calcd for C22H25FN6O2S[M+H]+457.17,found457.1751纯度：94.08％by HPLC(MeOH/H2O＝80:20,tR＝4.408min).According to the conventional route C, use N-ethyl-N-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl) -5-(1,3,5-Trimethyl-1H-pyrazol-4-yl)phenyl)ethanesulfonamide 50b (305.5 mg, 0.66 mmol) was used as the reaction raw material to obtain Example 8 (103 mg, yield :44.68%). 1 H NMR(300MHz,Chloroform-d)δ8.62(d,J＝5.1Hz,1H),8.54(s,1H),7.95(s,1H),7.60(d,J＝4.3Hz,1H), 7.39(d,J＝4.6Hz,1H),3.91(d,J＝7.0Hz,2H),3.87(s,3H),3.20(q,J＝7.3Hz,2H),2.30(s,6H), 1.49(t,J＝7.2Hz,3H),1.31(t,J＝7.0Hz,3H).HRMS(ESI):calcd for C 22 H 25 FN 6 O 2 S[M+H] + 457.17, found457. 1751 Purity: 94.08% by HPLC (MeOH/H 2 O = 80:20, t R = 4.408 min).
合成路线5：Synthesis route 5:
实施例9～17按照Scheme 5合成。Examples 9 to 17 were synthesized according to Scheme 5.
Scheme 5.Reagents and conditions：(a)Cs2CO3,Pd(dppf)Cl2·CH2Cl2,1,4-Dioxane,H2O,100℃,3h；(b)t-BuOK,DMSO,r.t.,overnight；(c)AcOK,Pd(dppf)Cl2·CH2Cl2,dry 1,4-Dioxane,100℃,3h；(d)Cs2CO3,Pd(dppf)Cl2·CH2Cl2,1,4-Dioxane,H2O,100℃,7h.Scheme 5.Reagents and conditions: (a)Cs 2 CO 3 ,Pd(dppf)Cl 2 ·CH 2 Cl 2 ,1,4-Dioxane,H 2 O,100℃,3h; (b)t-BuOK,DMSO ,rt,overnight;(c)AcOK,Pd(dppf)Cl 2 ·CH 2 Cl 2 ,dry 1,4-Dioxane,100℃,3h;(d)Cs 2 CO 3 ,Pd(dppf)Cl 2 ·CH 2 Cl 2 ,1,4-Dioxane,H 2 O,100℃,7h.
4-(3-溴-2,5-二氟苯基)-1,3,5-三甲基吡唑(52)4-(3-bromo-2,5-difluorophenyl)-1,3,5-trimethylpyrazole (52)
4-(3-bromo-2,5-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole(52)4-(3-bromo-2,5-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole(52)
按常规路线A，以1,3-二溴-2,5-二氟苯51(500mg，1.84mmol)和19b(513.1mg，2.29mmol)为反应原料，得到目标产物52(497mg，产率：89.8％)。According to conventional route A, using 1,3-dibromo-2,5-difluorobenzene 51 (500 mg, 1.84 mmol) and 19b (513.1 mg, 2.29 mmol) as reaction raw materials, the target product 52 (497 mg, yield: 89.8%).
4-(3-溴-2-氟-5-(氧杂环丁烷-3-基氧基)苯基)-1,3,5-三甲基-1H-吡唑(54a)4-(3-bromo-2-fluoro-5-(oxetan-3-yloxy)phenyl)-1,3,5-trimethyl-1H-pyrazole (54a)
4-(3-bromo-2-fluoro-5-(oxetan-3-yloxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54a)4-(3-bromo-2-fluoro-5-(oxetan-3-yloxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54a)
常规反应路线D：室温下，将52(450mg,1.49mmol)53a(110mg,1.49mmol)加入到100mL圆底烧瓶中并以30mLDMSO作为反应溶剂，在搅拌状态下缓慢加入叔丁醇钾(217.99mg，1.94mmol)继续在室温下反应过夜，经TLC检测反应原料大部分已反应。加入等体积饱和氯化铵溶液和乙酸乙酯进行分液萃取三次，合并有机层后以饱和氯化钠溶液萃取一次，取有机层经无水硫酸钠干燥1h后，抽滤后的滤液减压浓缩除去溶剂，残留物经硅胶柱层析分离得到目标化合物54a(329mg，产率：62.0％)。Conventional reaction route D: At room temperature, add 52 (450 mg, 1.49 mmol) 53a (110 mg, 1.49 mmol) into a 100 mL round-bottom flask and use 30 mL DMSO as the reaction solvent. Slowly add potassium tert-butoxide (217.99 mg) under stirring. , 1.94 mmol) continued to react at room temperature overnight, and TLC detected that most of the reaction raw materials had reacted. Add equal volumes of saturated ammonium chloride solution and ethyl acetate for liquid separation extraction three times. Combine the organic layers and extract once with saturated sodium chloride solution. Dry the organic layer over anhydrous sodium sulfate for 1 hour, and then decompress the filtrate after suction filtration. The solvent was concentrated to remove, and the residue was separated by silica gel column chromatography to obtain target compound 54a (329 mg, yield: 62.0%).
4-(3-溴-2-氟-5-((四氢呋喃-3-基)氧基)苯基)-1,3,5-三甲基-1H-吡唑(54b)4-(3-bromo-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole (54b)
4-(3-bromo-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54b)4-(3-bromo-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54b)
按常规路线D，以52(450mg,1.49mmol)和19b(131.66mg，1.49mmol)为反应原料，得到目标产物52(318mg，产率：57.6％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 19b (131.66 mg, 1.49 mmol) as reaction raw materials, the target product 52 (318 mg, yield: 57.6%) was obtained.
4-(3-溴-2-氟-5-((四氢-2H-吡喃-4-基)氧基)苯基)-1,3,5-三甲基-1H-吡唑(54c)4-(3-bromo-2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole (54c )
4-(3-bromo-2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54c)4-(3-bromo-2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54c)
按常规路线D，以52(450mg,1.49mmol)和53c(152.62mg，1.49mmol)为反应原料，得到目标产物54c(281mg，产率：49.1％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 53c (152.62 mg, 1.49 mmol) as reaction raw materials, the target product 54c (281 mg, yield: 49.1%) was obtained.
4-(5-(氮杂环丁烷-3-基氧基)-3-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑(54d)4-(5-(azetidin-3-yloxy)-3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole (54d)
4-(5-(azetidin-3-yloxy)-3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(54d)4-(5-(azetidin-3-yloxy)-3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(54d)
按常规路线D，以52(450mg,1.49mmol)和53d(109.23mg，1.49mmol)为反应原料，得到目标产物54d(260mg，产率：49.1％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 53d (109.23 mg, 1.49 mmol) as reaction raw materials, the target product 54d (260 mg, yield: 49.1%) was obtained.
4-(3-溴-2-氟-5-((3-甲基氧杂环丁烷-3-基)氧基)苯基)-1,3,5-三甲基-1H-吡唑(54e)4-(3-bromo-2-fluoro-5-((3-methyloxetan-3-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole (54e)
4-(3-bromo-2-fluoro-5-((3-methyloxetan-3-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54e)4-(3-bromo-2-fluoro-5-((3-methyloxetan-3-yl)oxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54e)
按常规路线D，以52(450mg,1.49mmol)和53e(131.66mg，1.49mmol)为反应原料，得到目标产物54e(252mg，产率：45.7％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 53e (131.66 mg, 1.49 mmol) as reaction raw materials, the target product 54e (252 mg, yield: 45.7%) was obtained.
4-(3-溴-2-氟-5-(氧杂环丁烷-3-基甲氧基)苯基)-1,3,5-三甲基-1H-吡唑(54f)4-(3-bromo-2-fluoro-5-(oxetan-3-ylmethoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole (54f)
4-(3-bromo-2-fluoro-5-(oxetan-3-ylmethoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54f)4-(3-bromo-2-fluoro-5-(oxetan-3-ylmethoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54f)
按常规路线D，以52(450mg,1.49mmol)和53f(131.66mg，1.49mmol)为反应原料，得到目标产物54f(330mg，产率：59.8％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 53f (131.66 mg, 1.49 mmol) as reaction raw materials, the target product 54f (330 mg, yield: 59.8%) was obtained.
4-(5-((2-氧杂螺[3.3]庚-6-基)氧基)-3-溴-2-氟苯基)-1,3,5-三甲基-1H-吡唑(54g)4-(5-((2-oxaspiro[3.3]hept-6-yl)oxy)-3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole (54g)
4-(5-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(54g)4-(5-((2-oxaspiro[3.3]heptan-6-yl)oxy)-3-bromo-2-fluorophenyl)-1,3,5-trimethyl-1H-pyrazole(54g)
按常规路线D，以52(450mg,1.49mmol)和53g(170.57mg，1.49mmol)为反应原料，得到目标产物54g(279mg，产率：47.2％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 53 g (170.57 mg, 1.49 mmol) as reaction raw materials, the target product 54 g (279 mg, yield: 47.2%) was obtained.
4-(3-溴-2-氟-5-((3-甲基氧杂环丁烷-3-基)甲氧基)苯基)-1,3,5-三甲基-1H-吡唑(54h)4-(3-bromo-2-fluoro-5-((3-methyloxetan-3-yl)methoxy)phenyl)-1,3,5-trimethyl-1H-pyra Azole(54h)
4-(3-bromo-2-fluoro-5-((3-methyloxetan-3-yl)methoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54h)4-(3-bromo-2-fluoro-5-((3-methyloxetan-3-yl)methoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54h)
按常规路线D，以52(450mg,1.49mmol)和53h(152.62mg，1.49mmol)为反应原料，得到目标产物54h(306mg，产率：53.4％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 53h (152.62 mg, 1.49 mmol) as reaction raw materials, the target product 54h (306 mg, yield: 53.4%) was obtained.
4-(3-溴-2-氟-5-((四氢呋喃-2-基)甲氧基)苯基)-1,3,5-三甲基-1H-吡唑(54i)4-(3-bromo-2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole (54i)
4-(3-bromo-2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54i)4-(3-bromo-2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)phenyl)-1,3,5-trimethyl-1H-pyrazole(54i)
按常规路线D，以52(450mg,1.49mmol)和53i(152.62mg，1.49mmol)为反应原料，得到目标产物54i(361mg，产率：63.0％)。According to conventional route D, using 52 (450 mg, 1.49 mmol) and 53i (152.62 mg, 1.49 mmol) as reaction raw materials, the target product 54i (361 mg, yield: 63.0%) was obtained.
4-(2-氟-5-(氧杂环丁烷-3-氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(55a)4-(2-Fluoro-5-(oxetane-3-oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55a)
4-(2-fluoro-5-(oxetan-3-yloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55a)4-(2-fluoro-5-(oxetan-3-yloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5 -trimethyl-1H-pyrazole(55a)
按常规路线B，以54a(600mg,1.61mmol)为反应原料，得到目标产物55a(503mg，产率：74.0％)。According to conventional route B, using 54a (600 mg, 1.61 mmol) as the reaction raw material, the target product 55a (503 mg, yield: 74.0%) was obtained.
4-(2-氟-5-((四氢呋喃-3-基)氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1，3,5-三甲基-1H-吡唑(55b)4-(2-fluoro-5-((tetrahydrofuran-3-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55b)
4-(2-fluoro-5-((tetrahydrofuran-3-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55b)4-(2-fluoro-5-((tetrahydrofuran-3-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1, 3,5-trimethyl-1H-pyrazole(55b)
按常规路线B，以54b(600mg,1.58mmol)为反应原料，得到目标产物55b(527mg，产率：77.9％)。According to conventional route B, using 54b (600 mg, 1.58 mmol) as the reaction raw material, the target product 55b (527 mg, yield: 77.9%) was obtained.
4-(2-氟-5-((四氢-2H-吡喃-4-基)氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(55c)4-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxo Borol-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55c)
4-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55c)4-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl )-1,3,5-trimethyl-1H-pyrazole(55c)
按常规路线B，以54c(600mg,1.57mmol)为反应原料，得到目标产物55c(551mg，产率：81.8％)。1H NMR(300MHz,Chloroform-d)δ8.56(d,J＝5.1Hz,1H),8.41(s,1H),7.54(s,1H),7.47(s,1H),6.89(s,1H),4.54(s,1H),4.10–3.99(m,2H),3.84(s,3H),3.62(t,J＝9.2Hz,2H),2.28(s,3H),2.26(s,3H),2.11(s,2H),1.96–1.82(m,2H).According to conventional route B, using 54c (600 mg, 1.57 mmol) as the reaction raw material, the target product 55c (551 mg, yield: 81.8%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.56(d,J＝5.1Hz,1H),8.41(s,1H),7.54(s,1H),7.47(s,1H),6.89(s,1H ),4.54(s,1H),4.10–3.99(m,2H),3.84(s,3H),3.62(t,J＝9.2Hz,2H),2.28(s,3H),2.26(s,3H) ,2.11(s,2H),1.96–1.82(m,2H).
4-(5-(氮杂环丁烷-3-氧基)-2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(55d)4-(5-(azetidine-3-oxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55d)
4-(5-(azetidin-3-yloxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55d)4-(5-(azetidin-3-yloxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5 -trimethyl-1H-pyrazole(55d)
按常规路线B，以54d(600mg,1.63mmol)为反应原料，得到目标产物55d(522mg，产率：76.8％)。According to conventional route B, using 54d (600 mg, 1.63 mmol) as the reaction raw material, the target product 55d (522 mg, yield: 76.8%) was obtained.
4-(2-氟-5-((3-甲基氧杂环丁烷-3-基)氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(55e)4-(2-fluoro-5-((3-methyloxetan-3-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55e)
4-(2-fluoro-5-((3-methyloxetan-3-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55e)4-(2-fluoro-5-((3-methyloxetan-3-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 1,3,5-trimethyl-1H-pyrazole(55e)
按常规路线B，以54e(600mg,1.59mmol)为反应原料，得到目标产物55e(551mg，产率：76.4％)。According to conventional route B, using 54e (600 mg, 1.59 mmol) as the reaction raw material, the target product 55e (551 mg, yield: 76.4%) was obtained.
4-(5-(环丁基甲氧基)-2-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(55f)4-(5-(cyclobutylmethoxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene methyl)-1,3,5-trimethyl-1H-pyrazole (55f)
4-(5-(cyclobutylmethoxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55f)4-(5-(cyclobutylmethoxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H -pyrazole(55f)
按常规路线B，以54f(600mg,1.63mmol)为反应原料，得到目标产物55f(551mg，产率：81.4％)。According to conventional route B, using 54f (600 mg, 1.63 mmol) as the reaction raw material, the target product 55f (551 mg, yield: 81.4%) was obtained.
4-(5-((2-氧杂螺[3.3]庚烷-6-基)氧代)-2-f氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(55g)4-(5-((2-oxaspiro[3.3]heptan-6-yl)oxo)-2-ffluoro-3-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55g)
4-(5-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55g)4-(5-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)-1,3,5-trimethyl-1H-pyrazole(55g)
按常规路线B，以54g(600mg,1.49mmol)为反应原料，得到目标产物55g(534mg，产率：79.5％)。According to conventional route B, 54g (600mg, 1.49mmol) was used as the reaction raw material to obtain 55g of the target product (534mg, yield: 79.5%).
4-(2-氟-5-((1-甲基环丁基)甲氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1,3,5-三甲基-1H-吡唑(55h)4-(2-Fluoro-5-((1-methylcyclobutyl)methoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle Pentan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55h)
4-(2-fluoro-5-((1-methylcyclobutyl)methoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55h)4-(2-fluoro-5-((1-methylcyclobutyl)methoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3, 5-trimethyl-1H-pyrazole(55h)
按常规路线B，以54h(600mg,1.57mmol)为反应原料，得到目标产物55h(510mg，产率：75.7％)。1H NMR(300MHz,Chloroform-d)δ8.53(s,1H),8.43(s,1H),7.49(s,1H),7.43(s,1H),6.88(s,1H),4.67(d,J＝5.9Hz,2H),4.48(d,J＝5.9Hz,2H),4.11(s,2H),3.81(s,3H),2.24(d,J＝6.0Hz,6H),1.46(s,3H).According to conventional route B, using 54h (600 mg, 1.57 mmol) as the reaction raw material, the target product 55h (510 mg, yield: 75.7%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.53(s,1H),8.43(s,1H),7.49(s,1H),7.43(s,1H),6.88(s,1H),4.67(d ,J＝5.9Hz,2H),4.48(d,J＝5.9Hz,2H),4.11(s,2H),3.81(s,3H),2.24(d,J＝6.0Hz,6H),1.46(s ,3H).
4-(2-氟-5-((四氢呋喃-2-基)甲氧基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-1，3,5-三甲基-1H-吡唑(55i)4-(2-Fluoro-5-((tetrahydrofuran-2-yl)methoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole (55i)
4-(2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-trimethyl-1H-pyrazole(55i)4-(2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1, 3,5-trimethyl-1H-pyrazole(55i)
按常规路线B，以54i(600mg,1.57mmol)为反应原料，得到目标产物55i(503mg，产率：74.7％)。According to conventional route B, using 54i (600 mg, 1.57 mmol) as the reaction raw material, the target product 55i (503 mg, yield: 74.7%) was obtained.
实施例9：Example 9:
7-(2-氟-5-(氧杂环丁烷-3-氧基)3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例9)7-(2-fluoro-5-(oxetane-3-oxy)3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazole Para[4,5-b]pyridine (Example 9)
7-(2-fluoro-5-(oxetan-3-yloxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例9)7-(2-fluoro-5-(oxetan-3-yloxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 9)
按常规路线C，以55a(528.18mg,1.31mmol)为反应原料，得到实施例9(182mg，产率：45.8％)。1H NMR(300MHz,Chloroform-d)δ8.65(s,1H),8.48(s,1H),7.59(s,1H),7.36(s,1H),6.71(dd,J＝5.3,2.8Hz,1H),5.32(m,1H),5.05(t,J＝6.6Hz,2H),4.89(t,J＝6.1Hz,2H),3.86(s,3H),2.28(d,J＝5.3Hz,6H).HRMS(ESI):calcd for C21H20FN5O2[M+H]+394.16,found 394.1678纯度：95.90％by HPLC(MeOH/H2O＝80:20,tR＝4.876min).According to conventional route C, using 55a (528.18 mg, 1.31 mmol) as the reaction raw material, Example 9 (182 mg, yield: 45.8%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.65(s,1H),8.48(s,1H),7.59(s,1H),7.36(s,1H),6.71(dd,J＝5.3,2.8Hz ,1H),5.32(m,1H),5.05(t,J＝6.6Hz,2H),4.89(t,J＝6.1Hz,2H),3.86(s,3H),2.28(d,J＝5.3Hz ,6H).HRMS(ESI):calcd for C 21 H 20 FN 5 O 2 [M+H] + 394.16, found 394.1678 Purity: 95.90% by HPLC (MeOH/H 2 O＝80:20, t R ＝4.876 min).
实施例10：Example 10:
7-(2-氟-5-((四氢呋喃-3-基)氧基)-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例10)7-(2-fluoro-5-((tetrahydrofuran-3-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazole Para[4,5-b]pyridine (Example 10)
7-(2-fluoro-5-((tetrahydrofuran-3-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例10)7-(2-fluoro-5-((tetrahydrofuran-3-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5- b]pyridine (Example 10)
按常规路线C，以55b(546.88mg,1.31mmol)为反应原料，得到实施例10(199mg，产率：48.4％)。1H NMR(300MHz,Chloroform-d)δ8.62(d,J＝5.8Hz,2H),7.65(t,J＝4.8Hz,1H),7.55(d,J＝8.3Hz,1H),7.11–7.03(m,1H),3.99(s,1H),3.87(s,3H),3.50–3.33(m,2H),3.24(dd,J＝10.1,4.4Hz,1H),2.99(p,J＝8.2Hz,1H),2.31(t,J＝3.2Hz,6H),1.46–1.40(m,2H).HRMS(ESI):calcd for C22H22FN5O2[M+H]+408.18,found 408.1825纯度：97.41％by HPLC(MeOH/H2O＝80:20,tR＝6.565min).According to conventional route C, using 55b (546.88 mg, 1.31 mmol) as the reaction raw material, Example 10 (199 mg, yield: 48.4%) was obtained. 1 H NMR (300MHz, Chloroform-d) δ8.62(d,J＝5.8Hz,2H),7.65(t,J＝4.8Hz,1H),7.55(d,J＝8.3Hz,1H),7.11– 7.03(m,1H),3.99(s,1H),3.87(s,3H),3.50–3.33(m,2H),3.24(dd,J＝10.1,4.4Hz,1H),2.99(p,J＝ 8.2Hz,1H),2.31(t,J＝3.2Hz,6H),1.46–1.40(m,2H).HRMS(ESI):calcd for C 22 H 22 FN 5 O 2 [M+H] + 408.18, Found 408.1825 Purity: 97.41% by HPLC (MeOH/H 2 O = 80:20, t R = 6.565min).
实施例11：Example 11:
7-(2-氟-5-((四氢-2H-吡喃-4-基)氧基)-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑[4,5-b]吡啶(实施例11)7-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzene base)-1H-imidazole[4,5-b]pyridine (Example 11)
7-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例11)7-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[ 4,5-b]pyridine (Example 11)
按常规路线C，以55c(565.01mg,1.31mmol)为反应原料，得到实施例11(215mg，产率：50.5％)。1H NMR(300MHz,Chloroform-d)δ8.56(d,J＝5.1Hz,1H),8.41(s,1H),7.54(s,1H),7.47(s,1H),6.89(s,1H),4.54(s,1H),4.10–3.99(m,2H),3.84(s,3H),3.62(t,J＝9.2Hz,2H),2.28(s,3H),2.26(s,3H),2.11(s,2H),1.96–1.82(m,2H).HRMS(ESI):calcdfor C23H24FN5O2[M+H]+422.20,found 422.2012纯度：94.88％by HPLC(MeOH/H2O＝80:20,tR＝4.805min).According to the conventional route C, using 55c (565.01 mg, 1.31 mmol) as the reaction raw material, Example 11 (215 mg, yield: 50.5%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.56(d,J＝5.1Hz,1H),8.41(s,1H),7.54(s,1H),7.47(s,1H),6.89(s,1H ),4.54(s,1H),4.10–3.99(m,2H),3.84(s,3H),3.62(t,J＝9.2Hz,2H),2.28(s,3H),2.26(s,3H) ,2.11(s,2H),1.96–1.82(m,2H).HRMS(ESI):calcdfor C 23 H 24 FN 5 O 2 [M+H] + 422.20,found 422.2012Purity: 94.88% by HPLC(MeOH/ H 2 O = 80:20, t R = 4.805 min).
实施例12：Example 12:
7-(5-(氮杂环丁烷-3-氧基)-2-氟-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例12)7-(5-(azetidine-3-oxy)-2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H- Imidazo[4,5-b]pyridine (Example 12)
7-(5-(azetidin-3-yloxy)-2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例12)7-(5-(azetidin-3-yloxy)-2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 12)
按常规路线C，以55d(526.88mg,1.31mmol)为反应原料，得到实施例12(201mg，产率：50.7％)。1H NMR(300MHz,DMSO-d6)δ8.48(s,1H),8.42(d,J＝5.0Hz,1H),7.38(dd,J＝5.0,1.7Hz,1H),7.26(dd,J＝5.5,3.1Hz,1H),6.77(dd,J＝5.7,3.2Hz,1H),5.06(d,J＝7.1Hz,1H),3.77–3.82(m,2H),3.73(s,3H),3.60(d,J＝7.0Hz,2H),2.23–2.19(m,3H),2.12(s,3H).HRMS(ESI):calcd for C21H21FN6O[M+H]+393.18,found 393.1832.纯度：99.25％byHPLC(MeOH/H2O＝80:20,tR＝4.082min).According to the conventional route C, using 55d (526.88 mg, 1.31 mmol) as the reaction raw material, Example 12 (201 mg, yield: 50.7%) was obtained. 1 H NMR (300MHz, DMSO-d 6 ) δ8.48 (s, 1H), 8.42 (d, J = 5.0Hz, 1H), 7.38 (dd, J = 5.0, 1.7Hz, 1H), 7.26 (dd, J＝5.5,3.1Hz,1H),6.77(dd,J＝5.7,3.2Hz,1H),5.06(d,J＝7.1Hz,1H),3.77–3.82(m,2H),3.73(s,3H ),3.60(d,J＝7.0Hz,2H),2.23–2.19(m,3H),2.12(s,3H).HRMS(ESI):calcd for C 21 H 21 FN 6 O[M+H] + 393.18, found 393.1832. Purity: 99.25% by HPLC (MeOH/H 2 O = 80:20, t R = 4.082min).
实施例13：Example 13:
7-(2-氟-5-((3-甲基氧杂环丁烷-3-基)氧基)-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑[4,5-b]吡啶(实施例13)7-(2-fluoro-5-((3-methyloxetan-3-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl )phenyl)-1H-imidazole[4,5-b]pyridine (Example 13)
7-(2-fluoro-5-((3-methyloxetan-3-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例13)7-(2-fluoro-5-((3-methyloxetan-3-yl)oxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4, 5-b]pyridine (Example 13)
按常规路线C，以55e(546.59mg,1.31mmol)为反应原料，得到实施例13(191mg，产率：46.4％)。1H NMR(300MHz,Chloroform-d)δ8.68(d,J＝43.7Hz,2H),8.47(s,1H),7.57(s,1H),6.61(s,1H),5.06(d,J＝6.4Hz,2H),4.65(d,J＝6.4Hz,2H),3.86(s,3H),2.28(d,J＝5.7Hz,6H),1.88(s,3H).HRMS(ESI):calcd for C22H22FN5O2[M+H]+408.19,found408.1942纯度：99.35％by HPLC(MeOH/H2O＝80:20,tR＝4.064min).According to conventional route C, using 55e (546.59 mg, 1.31 mmol) as the reaction raw material, Example 13 (191 mg, yield: 46.4%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.68(d,J＝43.7Hz,2H),8.47(s,1H),7.57(s,1H),6.61(s,1H),5.06(d,J ＝6.4Hz,2H),4.65(d,J＝6.4Hz,2H),3.86(s,3H),2.28(d,J＝5.7Hz,6H),1.88(s,3H).HRMS(ESI): calcd for C 22 H 22 FN 5 O 2 [M+H] + 408.19, found408.1942 Purity: 99.35% by HPLC (MeOH/H 2 O=80:20, t R =4.064min).
实施例14：Example 14:
7-(2-氟-5-(氧杂环丁烷-3-基甲氧基)-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑[4,5-b]吡啶(实施例14)7-(2-fluoro-5-(oxetan-3-ylmethoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)- 1H-imidazole[4,5-b]pyridine (Example 14)
7-(2-fluoro-5-(oxetan-3-ylmethoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例14)7-(2-fluoro-5-(oxetan-3-ylmethoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine (Example 14)
按常规路线C，以55f(546.59mg,1.31mmol)为反应原料，得到实施例14(237mg，产率：57.6％)。1H NMR(300MHz,Chloroform-d)δ8.65–8.45(m,1H),8.36(s,1H),7.54–7.44(m,2H),6.85(dd,J＝5.5,3.1Hz,1H),4.91(dd,J＝7.8,6.2Hz,2H),4.60(t,J＝6.1Hz,2H),4.26(d,J＝6.7Hz,2H),3.80(s,3H),3.47(p,J＝6.9Hz,1H),2.24(s,3H),2.20(s,3H).13CNMR(75MHz,DMSO-d6)δ154.47,148.87,144.65,144.35,144.18,137.69,134.13,132.90,125.27,125.04,123.35,118.36,117.92,116.82,112.40,73.65,70.17,36.38,34.29,12.79,10.53.HRMS(ESI):calcd for C22H22FN5O2[M+H]+408.18,found 408.1837纯度：99.25％by HPLC(MeOH/H2O＝80:20,tR＝4.327min).According to the conventional route C, using 55f (546.59 mg, 1.31 mmol) as the reaction raw material, Example 14 (237 mg, yield: 57.6%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.65–8.45(m,1H),8.36(s,1H),7.54–7.44(m,2H),6.85(dd,J＝5.5,3.1Hz,1H) ,4.91(dd,J＝7.8,6.2Hz,2H),4.60(t,J＝6.1Hz,2H),4.26(d,J＝6.7Hz,2H),3.80(s,3H),3.47(p, J＝6.9Hz,1H),2.24(s,3H),2.20(s,3H). 13 CNMR(75MHz,DMSO-d 6 )δ154.47,148.87,144.65,144.35,144.18,137.69,134.13,132.90,125.27, 125.04,123.35,118.36,117.92,116.82,112.40,73.65,70.17,36.38,34.29,12.79,10.53.HRMS(ESI):calcd for C 22 H 22 FN 5 O 2 [M+H] + 408.18,found 40 8.1837 purity :99.25% by HPLC (MeOH/H 2 O=80:20, t R =4.327min).
实施例15：Example 15:
7-(5-((2-氧杂螺[3.3]庚-6-基)氧基)-2-氟-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑并[4,5-b]吡啶(实施例15)7-(5-((2-oxaspiro[3.3]hept-6-yl)oxy)-2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl )phenyl)-1H-imidazo[4,5-b]pyridine (Example 15)
7-(5-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例15)7-(5-((2-oxaspiro[3.3]heptan-6-yl)oxy)-2-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H- imidazo[4,5-b]pyridine (Example 15)
按常规路线C，以55g(580.78mg,1.31mmol)为反应原料，得到实施例15(182mg，产率：41.6％)。1H NMR(300MHz,Chloroform-d)δ8.55(s,1H),8.33(s,1H),7.53(s,1H),7.39(s,1H),6.71(dd,J＝5.5,3.2Hz,1H),4.97–5.02(m,1H),4.35(dd,J＝9.7,6.4Hz,2H),4.10(dd,J＝9.8,4.2Hz,2H),3.83(s,3H),2.26(s,3H),2.25–2.24(m,3H),1.65–1.88(m,4H).13CNMR(75MHz,DMSO-d6)δ152.24,150.14,148.89,144.68,144.38,144.20,137.78,133.81,132.86,125.53,118.34,117.68,116.89,115.24,112.24,77.23,70.87,36.37,31.47,22.58,14.47,12.76,10.51.HRMS(ESI):calcd for C24H24FN5O2[M+H]+434.20,found434.1994纯度：92.86％by HPLC(MeOH/H2O＝80:20,tR＝6.250min).According to the conventional route C, using 55g (580.78mg, 1.31mmol) as the reaction raw material, Example 15 (182mg, yield: 41.6%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.55(s,1H),8.33(s,1H),7.53(s,1H),7.39(s,1H),6.71(dd,J＝5.5,3.2Hz ,1H),4.97–5.02(m,1H),4.35(dd,J＝9.7,6.4Hz,2H),4.10(dd,J＝9.8,4.2Hz,2H),3.83(s,3H),2.26( s,3H),2.25–2.24(m,3H),1.65–1.88(m,4H). 13 CNMR(75MHz,DMSO-d 6 )δ152.24,150.14,148.89,144.68,144.38,144.20,137.78,133.81,132.86 ,125.53,118.34,117.68,116.89,115.24,112.24,77.23,70.87,36.37,31.47,22.58,14.47,12.76,10.51.HRMS(ESI):calcd for C 24 H 24 FN 5 O 2 [M+H] + 434.20, found 434.1994 Purity: 92.86% by HPLC (MeOH/H 2 O = 80:20, t R = 6.250min).
实施例16：Example 16:
7-(2-氟-5-((3-甲基氧杂环丁烷-3-基)甲氧基)-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑[4,5-b]吡啶(实施例16)7-(2-Fluoro-5-((3-methyloxetan-3-yl)methoxy)-3-(1,3,5-trimethyl-1H-pyrazole-4- (base)phenyl)-1H-imidazole[4,5-b]pyridine (Example 16)
7-(2-fluoro-5-((3-methyloxetan-3-yl)methoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例16)7-(2-fluoro-5-((3-methyloxetan-3-yl)methoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4, 5-b]pyridine (Example 16)
按常规路线C，以55h(565.32mg,1.31mmol)为反应原料，得到实施例16(205mg，产率：48.2％)。1H NMR(300MHz,Chloroform-d)δ8.53(s,1H),8.43(s,1H),7.49(s,1H),7.43(s,1H),6.88(s,1H),4.67(d,J＝5.9Hz,2H),4.48(d,J＝5.9Hz,2H),4.11(s,2H),3.81(s,3H),2.24(d,J＝6.0Hz,6H),1.46(s,3H).HRMS(ESI):calcd for C23H24FN5O2[M+H]+422.20,found 422.1993纯度：98.90％by HPLC(MeOH/H2O＝80:20,tR＝3.606min).According to the conventional route C, using 55h (565.32 mg, 1.31 mmol) as the reaction raw material, Example 16 (205 mg, yield: 48.2%) was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.53(s,1H),8.43(s,1H),7.49(s,1H),7.43(s,1H),6.88(s,1H),4.67(d ,J＝5.9Hz,2H),4.48(d,J＝5.9Hz,2H),4.11(s,2H),3.81(s,3H),2.24(d,J＝6.0Hz,6H),1.46(s ,3H).HRMS(ESI):calcd for C 23 H 24 FN 5 O 2 [M+H] + 422.20, found 422.1993 Purity: 98.90% by HPLC (MeOH/H 2 O＝80:20, t R ＝3.606 min).
实施例17：Example 17:
7-(2-氟-5-((四氢呋喃-2-基)甲氧基)-3-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-1H-咪唑[4,5-b]吡啶(实施例17)7-(2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H- Imidazole[4,5-b]pyridine (Example 17)
7-(2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5-b]pyridine(实施例17)7-(2-fluoro-5-((tetrahydrofuran-2-yl)methoxy)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)-1H-imidazo[4,5- b]pyridine (Example 17)
按常规路线C，以55i(565.32mg,1.31mmol)为反应原料，得到实施例17(221mg，产率：51.9％)。1H NMR(300MHz,Chloroform-d)δ8.58(d,J＝5.0Hz,1H),8.41(s,1H),7.52(d,J＝5.0Hz,1H),7.45(t,J＝4.3Hz,1H),6.90(dd,J＝5.7,3.1Hz,1H),4.35(p,J＝6.1Hz,1H),4.07(d,J＝5.1Hz,2H),3.99(q,J＝7.1Hz,1H),3.90(t,J＝7.0Hz,1H),3.83(s,3H),2.25(s,3H),2.22(s,3H),2.13(dt,J＝11.7,6.7Hz,1H),2.06–1.94(m,2H),1.85(s,1H).HRMS(ESI):calcd for C23H24FN5O2[M+H]+422.20,found 422.1989.纯度：97.85％by HPLC(MeOH/H2O＝80:20,tR＝3.103min).According to the conventional route C, using 55i (565.32 mg, 1.31 mmol) as the reaction raw material, Example 17 (221 mg, yield: 51.9%) was obtained. 1 H NMR (300MHz, Chloroform-d) δ8.58 (d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 7.52 (d, J = 5.0 Hz, 1H), 7.45 (t, J = 4.3 Hz,1H),6.90(dd,J＝5.7,3.1Hz,1H),4.35(p,J＝6.1Hz,1H),4.07(d,J＝5.1Hz,2H),3.99(q,J＝7.1 Hz,1H),3.90(t,J＝7.0Hz,1H),3.83(s,3H),2.25(s,3H),2.22(s,3H),2.13(dt,J＝11.7,6.7Hz,1H ),2.06–1.94(m,2H),1.85(s,1H).HRMS(ESI):calcd for C 23 H 24 FN 5 O 2 [M+H] + 422.20,found 422.1989.Purity: 97.85% by HPLC (MeOH/H 2 O=80:20, t R =3.103min).
药理活性评价： Pharmacological activity evaluation :
1、MST方法测试实施例化合物对BRD4(1)和BRD4(2)的亲和力1. MST method to test the affinity of the example compounds for BRD4(1) and BRD4(2)
以MonolithTM RED-NHS二代蛋白标记试剂盒(Nano Temper)置换蛋白缓冲液，并用荧光标记BRD4(1)及BRD4(2)蛋白。使用不含一级氨基(比如Tris或glycine)、咪唑(乐研)或β-巯基乙醇(阿拉丁)的溶液作为分析buffer，荧光标记蛋白与不同浓度的化合物以1:1的比例混合，在Monolith NT.115(NanoTemper)分析仪上由红外激光设置微观温度梯度场，以荧光染料标记、色氨酸自发荧光及荧光融合蛋白等信号跟踪分子在微观温度梯度场中的移动。通过PR.ThermControl软件分析小分子与BRD4(1)或BRD4(2)的亲和力。The protein buffer was replaced with MonolithTM RED-NHS second-generation protein labeling kit (Nano Temper), and BRD4(1) and BRD4(2) proteins were labeled with fluorescence. Use a solution that does not contain primary amino groups (such as Tris or glycine), imidazole (Leyan) or β-mercaptoethanol (Aladdin) as the analysis buffer. Fluorescently labeled proteins are mixed with compounds of different concentrations in a ratio of 1:1. The Monolith NT.115 (NanoTemper) analyzer uses an infrared laser to set up a microscopic temperature gradient field, and uses signals such as fluorescent dye labeling, tryptophan autofluorescence and fluorescent fusion proteins to track the movement of molecules in the microscopic temperature gradient field. Analyze the affinity of small molecules to BRD4(1) or BRD4(2) by PR.ThermControl software.
表1实施例对BRD4(1)和BRD4(2)的结合亲和力Table 1 Binding affinity of examples to BRD4(1) and BRD4(2)
表1中，a Selectivty指化合物对BRD4(2)的KD值/BRD4(1)的KD值。In Table 1, a Selectivty refers to the K D value of the compound against BRD4(2)/the K D value of BRD4(1).
2、细胞水平活性评价2. Cell-level activity evaluation
人髓性单核细胞白血病细胞MV-4-11、人慢性髓系白血病细胞K562、人卵巢癌细胞SKOV3、人结直肠癌细胞HCT-116、人胰腺癌细胞MIAPaca-2、人前列腺癌细胞PC-3从中科院上海细胞库购得，人非小细胞肺癌细胞A549购自碧云天生物技术(BeyotimeBiotechnology)公司。MV-4-11细胞培养在IMDM培养基中，K562与HCT-116细胞培养在RPMI-1640培养基中，A549和MIA Paca-2细胞培养在DMEM培养基中，SKOV3细胞培养自McCoy’s 5A培养基中，PC-3细胞培养在Ham’s F-12培养基中。培养时各类培养基添加10％胎牛血清，1％的100×青霉素链霉素双抗(15140-122,Gibco ThermoFisher,USA)，在37℃，5％CO2条件下培养。将处于对数生长期的细胞以每孔5000个的密度接种与96孔板中，培养基体积为100μL，于37℃，5％CO2的孵箱内过夜培养。次日，加入100μL培养基配制的不同浓度的药物溶液，每个浓度设三个复孔(记为RLUtest)，并设置对照孔和空白孔。对照孔为细胞、培养液与相同浓度的药物溶解介质(记为RLUcontrol),空白孔为培养液(记为RLUblank)。96h后，悬浮细胞每孔吸出100μL至96孔黑板中，每孔再加入100μL的CellTiter-Lumi发光法细胞活力检测试剂盒(Beyotime Biotechnology)检测试剂，放置在摇床上避光孵育10min后检测。贴壁细胞每孔吸出100μL培养基丢弃，在96孔板中各加入100μL的检测试剂，放置摇床上裂解2min后，将孔中溶液吸出至96孔黑板中，放置在摇床上避光孵育8min后检测。通过Thermoscientific varioskanflash上的化学发光模块检测化学发光值。通过如下计算公式计算细胞的存活百分比，采用Graphpad Prism 8.0软件计算IC50。Human myeloid leukemia cells MV-4-11, human chronic myeloid leukemia cells K562, human ovarian cancer cells SKOV3, human colorectal cancer cells HCT-116, human pancreatic cancer cells MIAPaca-2, human prostate cancer cells PC -3 was purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences, and human non-small cell lung cancer cells A549 were purchased from Beyotime Biotechnology. MV-4-11 cells were cultured in IMDM medium, K562 and HCT-116 cells were cultured in RPMI-1640 medium, A549 and MIA Paca-2 cells were cultured in DMEM medium, and SKOV3 cells were cultured in McCoy's 5A medium. , PC-3 cells were cultured in Ham's F-12 medium. During culture, various culture media were added with 10% fetal bovine serum and 1% 100× penicillin-streptomycin double antibody (15140-122, Gibco ThermoFisher, USA), and cultured at 37°C and 5% CO2 . Cells in the logarithmic growth phase were seeded into a 96-well plate at a density of 5,000 cells per well, with a medium volume of 100 μL, and cultured overnight in a 37°C, 5% CO2 incubator. The next day, add 100 μL of drug solutions of different concentrations prepared in culture medium. Set up three duplicate wells for each concentration (recorded as RLU test ), and set up control wells and blank wells. The control wells are cells, culture medium and drug dissolution medium of the same concentration (denoted as RLU control ), and the blank wells are culture medium (denoted as RLU blank ). After 96 hours, 100 μL of suspended cells were aspirated from each well into a 96-well black plate, and 100 μL of CellTiter-Lumi luminescence cell viability detection kit (Beyotime Biotechnology) detection reagent was added to each well, placed on a shaking table in the dark and incubated for 10 min before detection. Aspirate 100 μL of culture medium from each well of the adherent cells and discard, add 100 μL of detection reagent to each well of the 96-well plate, place on a shaker for lysing for 2 minutes, then suck the solution in the well into a 96-well black plate, place on the shaker to avoid light, and incubate for 8 minutes. detection. Chemiluminescence values were detected by the chemiluminescence module on the Thermoscientific varioskanflash. Calculate the survival percentage of cells using the following calculation formula, and use Graphpad Prism 8.0 software to calculate IC 50 .
细胞存活率(％)＝(RLUtest-RLUblank)/(RLUcontrol-RLUblank)×100％Cell survival rate (%)=(RLU test -RLU blank )/(RLU control -RLU blank )×100%
表2实施例14对不同肿瘤细胞的增殖抑制活性Table 2 Example 14 Proliferation Inhibitory Activity on Different Tumor Cells
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。The function of the above embodiments is to specifically introduce the essential content of the present invention, but those skilled in the art should know that the protection scope of the present invention should not be limited to these specific embodiments.
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| WO2016057500A1 (en) * | 2014-10-06 | 2016-04-14 | Merck Patent Gmbh | Heteroaryl compounds as btk inhibitors and uses thereof |
| WO2018035080A1 (en) * | 2016-08-16 | 2018-02-22 | Merck Patent Gmbh | 2-oxo-imidazopyridines as reversible btk inhibitors and uses thereof |
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| WO2007040438A2 (en) * | 2005-10-03 | 2007-04-12 | Astrazeneca Ab | Novel imidazo [4,5 -b] pyridine derivatives as inhibitors of glycogen synthase kinase 3 for use in the treatment of dementia and neurodegenerative disorders |
| WO2016057500A1 (en) * | 2014-10-06 | 2016-04-14 | Merck Patent Gmbh | Heteroaryl compounds as btk inhibitors and uses thereof |
| WO2018035080A1 (en) * | 2016-08-16 | 2018-02-22 | Merck Patent Gmbh | 2-oxo-imidazopyridines as reversible btk inhibitors and uses thereof |
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