WO2024183756A1 - Benzene ring-containing compound, and preparation method therefor and use thereof - Google Patents
Benzene ring-containing compound, and preparation method therefor and use thereof Download PDFInfo
- Publication number
- WO2024183756A1 WO2024183756A1 PCT/CN2024/080324 CN2024080324W WO2024183756A1 WO 2024183756 A1 WO2024183756 A1 WO 2024183756A1 CN 2024080324 W CN2024080324 W CN 2024080324W WO 2024183756 A1 WO2024183756 A1 WO 2024183756A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- independently
- alkyl
- substituted
- benzene ring
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 274
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 82
- 239000012453 solvate Substances 0.000 claims abstract description 80
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 35
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 119
- 125000000217 alkyl group Chemical group 0.000 claims description 89
- 125000005842 heteroatom Chemical group 0.000 claims description 88
- 125000001072 heteroaryl group Chemical group 0.000 claims description 54
- 229910052736 halogen Inorganic materials 0.000 claims description 52
- 150000002367 halogens Chemical class 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 51
- 150000002500 ions Chemical class 0.000 claims description 45
- 229910052760 oxygen Inorganic materials 0.000 claims description 44
- 229910052717 sulfur Inorganic materials 0.000 claims description 44
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 40
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 230000002285 radioactive effect Effects 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 239000000126 substance Substances 0.000 claims description 30
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 229940126062 Compound A Drugs 0.000 claims description 27
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 27
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 24
- 230000001225 therapeutic effect Effects 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 19
- -1 hydroxy, amino Chemical group 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052805 deuterium Inorganic materials 0.000 claims description 15
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002738 chelating agent Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 9
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 6
- XOYLJNJLGBYDTH-UHFFFAOYSA-M chlorogallium Chemical compound [Ga]Cl XOYLJNJLGBYDTH-UHFFFAOYSA-M 0.000 claims description 5
- 150000002739 metals Chemical class 0.000 claims description 5
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 229910052755 nonmetal Inorganic materials 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 229940121653 pd-1/pd-l1 inhibitor Drugs 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 150000002843 nonmetals Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229910052738 indium Inorganic materials 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052745 lead Inorganic materials 0.000 claims description 2
- 229910052702 rhenium Inorganic materials 0.000 claims description 2
- 229910052712 strontium Inorganic materials 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- 150000001923 cyclic compounds Chemical class 0.000 claims 1
- 102000008096 B7-H1 Antigen Human genes 0.000 abstract description 19
- 108010074708 B7-H1 Antigen Proteins 0.000 abstract description 19
- 201000010099 disease Diseases 0.000 abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 199
- 238000006243 chemical reaction Methods 0.000 description 174
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 86
- 230000015572 biosynthetic process Effects 0.000 description 81
- 238000003786 synthesis reaction Methods 0.000 description 81
- 230000002829 reductive effect Effects 0.000 description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 238000000746 purification Methods 0.000 description 23
- 238000004440 column chromatography Methods 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 239000000872 buffer Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- 239000007853 buffer solution Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 7
- 230000008685 targeting Effects 0.000 description 7
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229940126142 compound 16 Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 5
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 5
- 229940126657 Compound 17 Drugs 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000002146 bilateral effect Effects 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- HHVUFPUWPWOWOA-UHFFFAOYSA-N 3-bromo-2-methylbenzaldehyde Chemical compound CC1=C(Br)C=CC=C1C=O HHVUFPUWPWOWOA-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 230000003698 anagen phase Effects 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 238000002591 computed tomography Methods 0.000 description 4
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- AEDROEGYZIARPU-UHFFFAOYSA-K lutetium(iii) chloride Chemical compound Cl[Lu](Cl)Cl AEDROEGYZIARPU-UHFFFAOYSA-K 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000011775 sodium fluoride Substances 0.000 description 4
- 235000013024 sodium fluoride Nutrition 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- RVUXZXMKYMSWOM-UHFFFAOYSA-N 2-[4,7,10-tris[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound CC(C)(C)OC(=O)CN1CCN(CC(O)=O)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1 RVUXZXMKYMSWOM-UHFFFAOYSA-N 0.000 description 3
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
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- 208000005017 glioblastoma Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- APCHKWZTSCBBJX-RGMNGODLSA-N methyl (2s)-piperidine-2-carboxylate;hydrochloride Chemical compound [Cl-].COC(=O)[C@@H]1CCCC[NH2+]1 APCHKWZTSCBBJX-RGMNGODLSA-N 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- VVBSXSVVMNGQIN-NUBCRITNSA-N methyl (3r)-pyrrolidine-3-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCNC1 VVBSXSVVMNGQIN-NUBCRITNSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000005025 nuclear technology Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 229940127044 therapeutic radiopharmaceutical Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0463—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
Definitions
- the invention relates to a benzene ring-containing compound and a preparation method and application thereof.
- Radiopharmaceuticals refer to a special class of drugs containing radioactive nuclides for medical diagnosis and treatment. They are compounds or biological agents labeled with radioactive nuclides used for medical diagnosis or treatment in the body. They are divided into diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals. These two types of drugs include radioactive non-metallic drugs and radioactive metal drugs. The former include radioactive non-metallic nuclide drugs represented by 131 I and 18 F, while the latter include radioactive metal nuclide drugs represented by 68 Ga, 177 Lu, 186 Re, etc.
- theranostics refers to the diagnosis and treatment of specific diseases using molecularly targeted molecules labeled with diagnostic radioisotopes (such as positron or gamma emitters) or therapeutic radiometals (such as beta emitters).
- diagnostic radioisotopes such as positron or gamma emitters
- therapeutic radiometals such as beta emitters.
- the most advanced platforms are based on radiolabeling of targeting molecules with high affinity for receptors expressed on tumor cells, with 18 F and 68 Ga for diagnostic purposes, or with 177 Lu for therapeutic purposes.
- PD-1 programmed death 1
- CD28 CD28 superfamily
- Immune regulation targeting PD-1 is of great significance for anti-tumor, anti-infection, anti-autoimmune diseases and organ transplant survival.
- ligand PD-L1 can also be used as a target, and the corresponding antibodies and small molecule drugs can also inhibit the binding of PD-1 and PD-L1, thereby activating the immune response to eliminate tumor cells.
- the present invention provides a benzene ring-containing compound with a completely new structure and a preparation method and application thereof.
- the benzene ring-containing compound has inhibitory activity on PD-1/PD-L1 binding and can be used to diagnose or treat tumors and other related diseases.
- the present invention provides a benzene ring-containing compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
- R 1 and R 2 are independently hydrogen, halogen, cyano, C 1-4 alkyl, or C 1-4 alkyl substituted by one or more Ra ;
- Ra is each independently deuterium, halogen, hydroxyl , amino, C1-4 alkyl, C1-4 alkoxy or -COOH;
- R 3g and R 3h are each independently hydrogen or C 1-4 alkyl
- R 3i are each independently hydroxy, amino, C 1-4 alkyl or -COOH;
- R 3e and R 3f are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C( ⁇ O)- substituted by one or more R c2 ;
- R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S; R c3 and R c4 are each independently hydroxyl, amino, C 1-4 alkyl or -COOH;
- R4 and R5 are independently hydrogen, deuterium, C1-4 alkyl, 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- R b1 , R b2 and R b3 are each independently deuterium, halogen , hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy or -COOH;
- Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- X is -O-, -S- or -N(R X )-;
- RX is hydrogen or C1-4 alkyl
- R6 and R7 are independently hydrogen, halogen, C1-4 alkyl or C1-4 alkyl substituted by one or more halogens; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more Rd , wherein the number of heteroatoms in the 5-6 membered heteroaryl is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- R d are each independently deuterium, halogen, hydroxyl , amino, C 1-4 alkyl or C 1-4 alkoxy;
- L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
- n 1, 2, 3, 4, 5, 6, 7 or 8;
- L4 is a chemical bond or a 5-12 membered heterocycloalkyl group; in the 5-12 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- L2 is a group containing a diagnostic radionuclide.
- the compound as shown in Formula I its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any scheme of the present invention (this paragraph is hereinafter referred to as "certain preferred embodiments of the present invention"),
- R 1 and R 2 are independently hydrogen, halogen, cyano, C 1-4 alkyl, or C 1-4 alkyl substituted by one or more Ra ;
- Ra is each independently deuterium, halogen, hydroxyl , amino, C1-4 alkyl, C1-4 alkoxy or -COOH;
- R 3g and R 3h are each independently hydrogen or C 1-4 alkyl
- R 3i are each independently hydroxy, amino, C 1-4 alkyl or -COOH;
- R 3e and R 3f are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C( ⁇ O)- substituted by one or more R c2 ;
- R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S; R c3 and R c4 are each independently hydroxyl, amino, C 1-4 alkyl or -COOH;
- R4 and R5 are independently hydrogen, deuterium, C1-4 alkyl, 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3,
- the heteroatoms are independently one or more of N, O and S;
- R b1 , R b2 and R b3 are each independently deuterium, halogen , hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy or -COOH;
- Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- X is -O-, -S- or -N(R X )-;
- RX is hydrogen or C1-4 alkyl
- R6 and R7 are independently hydrogen, halogen or C1-4 alkyl; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more Rd , wherein the number of heteroatoms in the 5-6 membered heteroaryl is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- R d are each independently deuterium, halogen, hydroxyl , amino, C 1-4 alkyl or C 1-4 alkoxy;
- L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
- n 1, 2, 3, 4, 5, 6, 7 or 8;
- L4 is a chemical bond or a 5-7 membered heterocycloalkyl group; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- L2 is a group containing a diagnostic radionuclide.
- the halogen is fluorine, chlorine, bromine or iodine.
- the C 1-4 alkoxy group and the C 1-4 alkoxy group substituted by one or more R 3c are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example n-propoxy.
- the C 2-4 alkenyl group and the C 2-4 alkenyl group substituted by one or more R 3d are independently vinyl or
- the 5-12 membered heteroaryl and the 5-12 membered heteroaryl in the 5-12 membered heteroaryl substituted by one or more R 3e are bicyclic; preferably, both rings in the bicyclic are aromatic or one ring is aromatic and the other ring is not aromatic.
- the 5-12 membered heteroaryl and the 5-12 membered heteroaryl in the 5-12 membered heteroaryl substituted by one or more R 3e are a condensed ring.
- the 5-12 membered heteroaryl in R 3 and ring A, is independently an 8-10-membered fused ring heteroaryl, for example
- the 5-12 membered heterocycloalkyl is a monocyclic or bicyclic ring, and the bicyclic ring is preferably a spiro ring.
- the 5-12 membered heterocycloalkyl group is a 5-7 membered heterocycloalkyl group or an 8-12 membered heterocycloalkyl group.
- the 8-12 membered heterocycloalkyl is a bicyclic ring, preferably a spirocyclic ring, more preferably
- the 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R 3i , and the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R c4 is a monocyclic ring.
- the 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R 3i , and the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R c4 are independently morpholinyl, tetrahydropyrrolyl, piperazinyl or piperidinyl.
- R 4 , R 5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl group or a 5-7 membered heterocycloalkyl group substituted by one or more R b3 , wherein the 5-7 membered heterocycloalkyl group is a monocyclic ring.
- R 4 , R 5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl group or a 5-7 membered heterocycloalkyl group substituted by one or more R b3 , wherein the 5-7 membered heterocycloalkyl group is independently morpholinyl, tetrahydropyrrolyl, piperazinyl or piperidinyl.
- the 6-10 membered aryl group is a monocyclic or bicyclic ring.
- the 6-10 membered aryl group is phenyl or naphthyl.
- the halogen in the C 1-4 alkyl substituted by one or more halogens is fluorine, chlorine, bromine or iodine, for example fluorine.
- the C 1-4 alkyl substituted by one or more halogens is preferably a fluorine-substituted C 1-4 alkyl, such as trifluoromethyl.
- R 6 , R 7 and the atoms between them together form a 5-6 membered heteroaryl group, wherein The 5-6 membered heteroaryl is a monocyclic ring.
- R 6 , R 7 and the atoms therebetween together form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is furyl, oxazolyl, isoxazolyl, thiazolyl or pyrrolyl, such as oxazolyl or thiazolyl.
- R 1 and R 2 are each independently hydrogen, halogen or C 1-4 alkyl.
- R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl , 5-12 membered heteroaryl , C 1-4 alkyl substituted by one or more R 3a, C 1-4 alkoxy substituted by one or more R 3c, C 2-4 alkenyl substituted by one or more R 3d , or 5-12 membered heteroaryl substituted by one or more R 3e .
- R3 is wherein p1, p2, p3, p4, p5 and p6 are each independently 1, 2 or 3, for example 1 or 2.
- R3 is
- R 3a , R 3c and R 3d are each independently 5-7 membered heterocycloalkyl, or 5-7 membered heterocycloalkyl substituted with one or more hydroxyl groups.
- R c3 and R c4 are each independently hydroxy, C 1-4 alkyl or -COOH.
- one of R4 and R5 is hydrogen, and the other is C1-4 alkyl, 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 .
- R b1 , R b2 and R b3 are each independently hydroxy, C 1-4 alkyl or -COOH.
- X is -O- or -S-.
- R 6 and R 7 are independently hydrogen, halogen or C 1-4 alkyl substituted by one or more halogens; or R 6 , R 7 and the atoms between them together form a 5-6 membered heteroaryl.
- R 6 and R 7 are independently hydrogen or halogen; or R 6 , R 7 and the atoms therebetween together form a 5-6 membered heteroaryl group.
- m is 2 or 6.
- L3 is -O( CH2 ) n1O ( CH2 ) m1- or -O( CH2 ) n2- , wherein the oxygen atom is connected to the benzene ring, and n1, n2 and m1 are independently 1, 2, 3, 4, 5 or 6, for example, n1 is 2, n2 is 1 or 5, and m1 is 2.
- L1 is -O( CH2 ) n1O ( CH2 ) m1- , -O( CH2 ) n2- ,
- the oxygen atom end is connected to the benzene ring, n1 is 2 or 4, n2 is 1 or 5, and m1 is 2.
- L1 is -O( CH2 ) n1O ( CH2 ) m1- , -O( CH2 ) n2- or The oxygen atom end is connected to the benzene ring, n1 is 2, n2 is 1 or 5, and m1 is 2.
- L2 consists of an ion containing a diagnostic radionuclide and a chelating group, and the ion containing the diagnostic radionuclide is chelated with the chelating group.
- the diagnostic radionuclide is 18 F, 68 Ga, 99m Tc, 123 I, 124 I, 111 In or 64 Cu.
- the valence state of the ions containing the diagnostic radionuclide is monovalent, divalent, trivalent or tetravalent, such as divalent or trivalent.
- the ions containing diagnostic radionuclides are ions containing diagnostic radioactive metals or ions containing diagnostic radioactive non-metals.
- the ions containing diagnostic radioactive metals are [ 68 GaCl] 2+ or 68 Ga 3+ .
- the diagnostic radioactive non-metal-containing ion is [Al 18 F] 2+ .
- the chelating group is A end and
- R1 and R2 are each independently hydrogen, halogen or C1-4 alkyl
- R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, 5-12 membered heteroaryl, C 1-4 alkyl substituted by one or more R 3a , C 1-4 alkoxy substituted by one or more R 3c , C 2-4 alkenyl substituted by one or more R 3d , or 5-12 membered heteroaryl substituted by one or more R 3e ; wherein the 5-12 membered heteroaryl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- R 3a , R 3c and R 3d are each independently a 5-7 membered heterocycloalkyl group, or a 5-7 membered heterocycloalkyl group substituted by one or more R 3i ; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- R 3i are each independently hydroxyl
- R 3e are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C( ⁇ O)- substituted by one or more R c2 ;
- R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- R c3 and R c4 are each independently hydroxy, C 1-4 alkyl or -COOH;
- R4 and R5 are independently hydrogen, C1-4 alkyl , 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- R b1 , R b2 and R b3 are each independently hydroxy, C 1 - 4 alkyl or -COOH;
- Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- X is -O- or -S-;
- R6 and R7 are independently hydrogen, halogen or C1-4 alkyl substituted by one or more halogens; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl, wherein the number of heteroatoms in the 5-6 membered heteroaryl is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
- n 2 or 6;
- L4 is a chemical bond or a 5-12 membered heterocycloalkyl group; in the 5-12 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- L2 is a group containing a diagnostic radionuclide.
- R1 and R2 are each independently hydrogen, halogen or C1-4 alkyl
- R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, 5-12 membered heteroaryl, C 1-4 alkyl substituted by one or more R 3a , C 1-4 alkoxy substituted by one or more R 3c , C 2-4 alkenyl substituted by one or more R 3d , or 5-12 membered heteroaryl substituted by one or more R 3e ; wherein the 5-12 membered heteroaryl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- R 3a , R 3c and R 3d are each independently a 5-7 membered heterocycloalkyl group, or a 5-7 membered heterocycloalkyl group substituted by one or more R 3i ; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- R 3i are each independently hydroxyl
- R 3e are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C( ⁇ O)- substituted by one or more R c2 ;
- R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- R c3 and R c4 are each independently hydroxy, C 1-4 alkyl or -COOH;
- R4 and R5 are independently hydrogen, C1-4 alkyl , 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the number of heteroatoms is 2 or 3.
- the substituents are independently one or more of N, O and S;
- R b1 , R b2 and R b3 are each independently hydroxy, C 1 - 4 alkyl or -COOH;
- Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
- X is -O- or -S-;
- R6 and R7 are independently hydrogen or halogen; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl group, wherein the number of heteroatoms in the 5-6 membered heteroaryl group is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
- n 2 or 6;
- L4 is a chemical bond or a 5-7 membered heterocycloalkyl group; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
- L2 is a group containing a diagnostic radionuclide.
- ring A is phenyl or The b end is connected to L.
- R 1 is methyl or bromine.
- R2 is hydrogen, methyl or chlorine.
- R 3 is hydrogen
- R 3a , R 3c and R 3d are each independently
- R4 is hydrogen
- R 5 is (For example ),
- R6 is chloro or trifluoromethyl.
- R6 is chlorine
- R 7 is hydrogen
- R 6 , R 7 and the atoms between them together form The C-terminus is fused with a benzene ring.
- L3 is The oxygen atom end is connected to the benzene ring.
- L3 is The oxygen atom end is connected to the benzene ring.
- L4 is a chemical bond, (For example ), the d end is connected to L2 .
- L4 is a chemical bond or The d end is connected to L2 .
- L 1 is The oxygen atom end is connected to the benzene ring.
- L 1 is The oxygen atom end is connected to the benzene ring.
- L2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with the ion containing the diagnostic radionuclide (such as [Al 18 F] 2+ , [ 68 GaCl] 2+ or 68 Ga 3+ ), and the structure of compound A is shown in any of the following:
- the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with [Al 18 F] 2+ , and the compound A is as described above.
- the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with [ 68GaCl ] 2+ , and the compound A is as described above.
- the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with 68 Ga 3+ , and the compound A is as described above.
- the benzene ring-containing compound as shown in Formula I is selected from any of the following structures:
- the benzene ring-containing compound as shown in Formula I is selected from any of the following structures:
- the present invention provides a benzene ring-containing compound as shown in Formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
- L5 is a group containing a therapeutic radionuclide
- ring A, L, L1 , X, R1 , R2 , R3 , R4 , R5 , R6 and R7 are The definitions are as above.
- L5 consists of an ion containing a therapeutic radionuclide and a chelating group, and the ion containing the therapeutic radionuclide is chelated with the chelating group.
- the therapeutic radionuclide is 177 Lu, 90 Y, 89 Sr, 188 Re, 225 Ac, 213 Bi or 212 Pb.
- the valence state of the ions containing the therapeutic radionuclide is monovalent, divalent, trivalent or tetravalent, such as trivalent.
- the ions containing therapeutic radionuclides are ions containing therapeutic radiometals.
- the therapeutic radioactive metal-containing ions are [ 177 LuCl] 2+ or 177 Lu 3+ .
- the chelating group is as described above.
- L5 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the benzene ring-containing compound as shown in Formula II is a compound formed by chelating compound A with an ion containing a therapeutic radionuclide, and the structure of compound A is as described above.
- the benzene ring-containing compound as shown in Formula II is a compound formed by chelating compound A with 177 Lu 3+ , and the structure of compound A is as described above.
- the benzene ring-containing compound as shown in Formula II is selected from any of the following structures:
- the present invention provides a benzene ring-containing compound as shown in formula III, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
- L 6 is a group containing a non-radioactive nuclide
- the definitions of ring A, L, L 1 , X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are As mentioned above.
- L6 is composed of an ion containing a non-radioactive nuclide and a chelating group, and the ion containing the non-radioactive nuclide is chelated with the chelating group.
- the non-radioactive nuclide is Lu, Ga, F, Y, Sr, Re, Ac, Bi, Pb, Cu, Tc or In.
- the chelating group is as described above.
- the non-radioactive nuclide-containing ions are [AlF] 2+ , [GaCl] 2+ , Ga 3+ , Lu 3+ or [LuCl] 2+ .
- L 6 is
- the benzene ring-containing compound as shown in Formula III is a compound formed by chelating compound A with the ion containing the non-radioactive nuclide (such as [AlF] 2+ , [GaCl] 2+ , Ga 3+ , Lu 3+ or [LuCl] 2+ ), and the compound A is as described above.
- the non-radioactive nuclide such as [AlF] 2+ , [GaCl] 2+ , Ga 3+ , Lu 3+ or [LuCl] 2+
- the benzene ring-containing compound as shown in Formula III is selected from any of the following structures:
- the present invention provides a method for preparing a benzene ring-containing compound as shown in formula I, a benzene ring-containing compound as shown in formula II, or a benzene ring-containing compound as shown in formula III, which comprises the following steps: chelating one of ions containing diagnostic radionuclides, ions containing therapeutic radionuclides, or ions containing non-radioactive nuclides with a compound as shown in formula IV;
- L7 is a chelating group
- ring A, L, L1 , X, R1 , R2 , R3 , R4 , R5 , R6 and R7 are defined as above.
- L 7 is The a end is connected to L1 .
- the present invention provides a benzene ring-containing compound as shown in formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
- Ring A, L, L 1 , L 7 , X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
- the compound represented by formula IV is selected from any one of the above-mentioned compounds A.
- the present invention provides a compound V, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the structure of the compound V is shown as any one of the following:
- the present invention provides a pharmaceutical composition, comprising a substance B and a pharmaceutical excipient, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III, Formula IV or Formula V as described above.
- the present invention provides a pharmaceutical composition, comprising a substance B and a pharmaceutical excipient, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III or Formula IV as described above.
- the present invention also provides an application of a substance B in the preparation of a PD-1/PD-L1 inhibitor, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III, Formula IV, or Formula V as described above.
- the PD-1/PD-L1 The inhibitors can be used in mammals in vivo; they can also be used in vitro, mainly for experimental purposes, for example: as standard samples or control samples for comparison, or prepared into kits according to conventional methods in the art to provide rapid detection of the effect of inhibiting PD-1/PD-L1.
- the present invention also provides an application of a substance B in the preparation of a PD-1/PD-L1 inhibitor, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III, or Formula IV as described above.
- the PD-1/PD-L1 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PD-1/PD-L1.
- the present invention also provides a use of the benzene ring-containing compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for diagnosing tumors.
- the present invention also provides a use of the benzene ring-containing compound shown in Formula II as described above, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors.
- the present invention also provides a benzene ring-containing compound as shown in formula III as described above, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, or a benzene ring-containing compound as shown in formula IV as described above, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and/or preventing tumors.
- the present invention also provides a use of the compound as shown in Formula V, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and/or preventing tumors.
- the tumor is a PD-1/PD-L1-related or mediated tumor, such as lung cancer, gastric cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, skin cancer, melanoma, glioma, glioblastoma, leukemia or lymphoma, and for example colorectal cancer.
- PD-1/PD-L1-related or mediated tumor such as lung cancer, gastric cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, skin cancer, melanoma, glioma, glioblastoma, leukemia or lymphoma, and for example colorectal cancer.
- the present invention also provides a compound as shown below:
- substituted or “substituent” means that the hydrogen atom in the group is replaced by a specified group.
- substitution position is not specified, the substitution can be at any position, but it is allowed only if a stable or chemically feasible chemical is formed.
- An example is as follows: a 5-12 membered heteroaryl substituted with one or more R 3g means that the hydrogen atom on the 5-12 membered heteroaryl is replaced with one or more R 3g , and when there are multiple R 3g , each R 3g is the same or different.
- any variable appears more than once in the composition or structure of a compound its definition in each case is independent.
- the group may be optionally substituted with up to two R 3c , and each case of R 3c has independent options.
- combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.
- connection direction of the linking groups listed in the present invention can be arbitrary, including connection from left to right and connection from right to left.
- the linking group L is -C-D-
- -A-L-B includes -A-C-D-B and -A-D-C-B.
- alkyl refers to a saturated linear or branched monovalent hydrocarbon group.
- C1-4 alkyl refers to an alkyl group having 1 to 4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
- alkylene refers to a saturated straight or branched divalent hydrocarbon group.
- C1-4 alkylene refers to an alkylene group having 1 to 4 carbon atoms, specifically methylene, ethylene (e.g., -CH2CH2- , -CH( CH3 )-), propylene (e.g. , -CH2CH2CH2- , -C( CH3 ) 2- , -CH2CH ( CH3 ) - ), butylene (e.g. , -CH2CH2CH2CH2- , -CH( CH3 )CH( CH3 )-, -CH2CH ( CH3 ) CH2- ).
- halogen refers to F, Cl, Br or I.
- alkoxy refers to the group R X -O-, wherein R X is alkyl as defined above.
- cycloalkyl refers to a saturated monocyclic ring group consisting only of carbon atoms, having a specified number of carbon atoms (eg, C 3 to C 6 ). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- heterocycloalkyl refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated.
- Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, and the like.
- aryl refers to a cyclic group consisting only of carbon atoms with a specified number of carbon atoms (e.g., C 6 to C 10 ), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule).
- the aryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring.
- Aryl groups include, but are not limited to, phenyl, naphthyl, etc.
- heteroaryl refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule).
- the heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring.
- Heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
- the "-" at the end of a group means that the group is connected to other fragments in the molecule through this site.
- the structural fragment is connected to other fragments in the molecule through this site.
- the morpholinyl group Connect to other fragments in the molecule.
- pharmaceutically acceptable salt solvate refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base, and a solvent (including but not limited to: water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable
- the salt has the same meaning as the term "pharmaceutically acceptable salt” above, and the solvent is stoichiometric or non-stoichiometric.
- the solvate of the pharmaceutically acceptable salt includes but is not limited to hydrochloride monohydrate.
- therapeutically effective amount refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease.
- the therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
- pharmaceutical excipients refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
- treat refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.
- prevention refers to reducing the risk of developing a disease.
- patient refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
- the reagents and raw materials used in the present invention are commercially available.
- the positive progress of the present invention is that the present invention provides a benzene ring-containing compound with a completely new structure and a preparation method and application thereof.
- the benzene ring-containing compound of the present invention has inhibitory activity on PD-1/PD-L1 binding, and can be used to diagnose or treat tumors and other related diseases.
- the mixture 1-f (330 mg, 0.572 mmol), compound 1-1 (260.25 mg, 0.630 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (41.88 mg, 0.057 mmol) and potassium carbonate (158.23 mg, 1.145 mmol) were dissolved in dioxane (0.5 mL) and water (0.6 mL), and the reaction solution was stirred at 100 ° C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (10 mL), and the mixed solution was extracted with dichloromethane (20 mL).
- LC-MS (ESI): m/z 358.5 (M+H) + .
- reaction solution was extracted with dichloromethane (50 mL), and the organic phase was washed with 5% sodium thiosulfate solution (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL) in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-h (3000 mg, yield: 88.31%).
- LC-MS (ESI): m/z 363.2(M+H) + .
- Buffer system pH 4.0, 0.5 M sodium acetate-acetic acid buffer solution (freshly prepared).
- Dissolve compound 5 in buffer solution wash the germanium gallium generator with 0.1M HCl in sections, take the part with the highest activity, add sodium acetate-acetic acid buffer solution to obtain 300uL 68 Ga 3+ solution, add it to the buffer solution of compound 5, seal the plastic centrifuge tube, and heat for 15min at a heating temperature of 100°C.
- Buffer system pH 4.0, 0.5 M sodium acetate-acetic acid buffer solution (freshly prepared).
- QMA column activation 5 mL of water, 5 mL of freshly prepared sodium acetate-acetic acid buffer solution with a pH of about 4.0 and a concentration of 0.5 M.
- Precursor solution 100 ⁇ L buffer, 6 ⁇ L 10 mM AlCl 3 buffer solution, 300 ⁇ L acetonitrile (reaction-promoting solvent), 20 ⁇ L precursor solution (3 mg/mL).
- N,N-diisopropylethylamine (0.16 mL, 0.9 mmol)
- compound (S,E)-1-(2-(4-aminobutoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid tert-butyl ester (186.83 mg, 0.3 mmol), 81-e (90 mg, 0.3 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) were dissolved in N,N-dimethylformamide (0.3 mL), and the reaction solution was stirred at room temperature for 30 minutes.
- HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
- compound 81-c (40.0 mg, 0.05 mmol) and compound (10- ⁇ 1-[(2-methylpropan-2-yl)oxy]-1-oxoethyl-2-yl ⁇ -4,7-bis ⁇ 2-[(2-methylpropyl-2-yl)oxy]-2-oxoethyl ⁇ -1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (28.49 mg, 0.05 mmol) were added to a mixture of 1% ethyl acetate and 1% ethyl acetate.
- Gallium trichloride (47.33 mg, 0.269 mmol) was added to an aqueous solution (3 mL) of compound 81-a (61.0 mg, 0.054 mmol), and the reaction solution was reacted at 40°C for 18 hours, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was purified by Pre-HPLC to obtain compound 83 (37.51 mg, yield: 58%).
- LC-MS (ESI): m/z 1202.39 (M+H) + .
- HTRF Homogenous time-resolved fluorescence
- the purchased kit (CisBio, #64CUS000C-1) contains reagents required for the experiment, such as PD-1, PD-L1, anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer and Detection Buffer.
- the compound was prepared with 100% DMSO to form 10 concentrations with a 3-fold concentration gradient.
- the biological activity of the disclosed compounds was determined by the above test.
- the disclosed compounds have good inhibitory activity on PD-1/PD-L1 binding.
- the measured results are as follows (Table 1):
- the KD values of the in vitro interactions between PD-L1, PD1 and the compounds were determined using biacore S200.
- MC-38-hPD-L1 cells Human PD-L1 gene knock-in MC-38 cells (MC-38-hPD-L1 cells) were cultured in vitro in the presence of 10% heat-inactivated fetal bovine serum in DMEM medium and hygromycin B (final concentration 100 ⁇ L/mL) at 37°C and 5% CO 2. The cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the left side of the mouse.
- Mouse MC-38 cells were cultured in vitro in DMEM medium with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO 2. Cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the right side of the mouse.
- mice 100 ⁇ L of 1 ⁇ 10 6 MC-38-hPD-L1 cell suspension was inoculated subcutaneously on the left dorsal flank of C57BL/6J mice. On the second day, 100 ⁇ L of 1 ⁇ 10 6 MC-38 cell suspension was inoculated subcutaneously on the right dorsal flank of the same mouse. After inoculation, the mice were raised normally, and after a certain number of days, tumor-bearing mice with bilateral transplanted tumors in the range of 150 mm 3 -350 mm 3 were selected for the experiment.
- the quality-controlled compound 16 was diluted with 10% ethanol in normal saline (pH about 4.5), the drug was extracted, and injected into the tail vein of each animal.
- the volume of administration was 100 ⁇ L/mouse, and the dosage was 100-200 ⁇ Ci/mouse;
- Micro-PET/CT scans were performed at 0.5 h, 1.5 h, 2.5 h, and 3.5 h after injection of compound 16 to collect the original imaging data of the animals.
- MC-38-hPD-L1 cells Human PD-L1 gene knock-in MC-38 cells (MC-38-hPD-L1 cells) were cultured in vitro in the presence of 10% heat-inactivated fetal bovine serum in DMEM medium and hygromycin B (final concentration 100 ⁇ L/mL) at 37°C and 5% CO 2. The cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the left side of the mouse.
- Mouse MC-38 cells were cultured in vitro in DMEM medium with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO 2. Cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the right side of the mouse.
- mice 100 ⁇ L of 1 ⁇ 10 6 MC-38-hPD-L1 cell suspension was inoculated subcutaneously on the left dorsal flank of C57BL/6J mice. On the second day, 100 ⁇ L of 1 ⁇ 10 6 MC-38 cell suspension was inoculated subcutaneously on the right dorsal flank of the same mouse. After inoculation, the mice were raised normally, and after a certain number of days, tumor-bearing mice with bilateral transplanted tumors in the range of 150 mm 3 -350 mm 3 were selected for the experiment.
- the quality-controlled compound 17 is diluted with 10% ethanol in saline (pH about 4.5).
- the drug was extracted and injected into each animal through the tail vein, with a volume of 100 ⁇ L/animal and a dose of 100-200 ⁇ Ci/animal;
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Abstract
Description
本申请要求申请日为2023/3/7的中国专利申请2023102126094的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application No. 2023102126094 filed on March 7, 2023. This application cites the entire text of the above Chinese patent application.
本发明涉及一种含苯环类化合物及其制备方法和应用。The invention relates to a benzene ring-containing compound and a preparation method and application thereof.
核医学是现代医学的一个重要分支,主要是以放射性核素及其标记化合物为基础,将核技术应用于疾病的研究、诊断和治疗。放射性药物指含有放射性核素供医学诊断和治疗用的一类特殊药物,用于机体内进行医学诊断或治疗的含放射性核素标记的化合物或生物制剂,又分为诊断放射性药物和治疗放射性药物。而这二类药物又包含了放射性非金属药物和放射性金属药物,前者有131I、18F等代表的放射性非金属核素药物,而后者有68Ga、177Lu、186Re等代表的放射性金属核素药物。Nuclear medicine is an important branch of modern medicine. It is mainly based on radioactive nuclides and their labeled compounds, and applies nuclear technology to the research, diagnosis and treatment of diseases. Radiopharmaceuticals refer to a special class of drugs containing radioactive nuclides for medical diagnosis and treatment. They are compounds or biological agents labeled with radioactive nuclides used for medical diagnosis or treatment in the body. They are divided into diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals. These two types of drugs include radioactive non-metallic drugs and radioactive metal drugs. The former include radioactive non-metallic nuclide drugs represented by 131 I and 18 F, while the latter include radioactive metal nuclide drugs represented by 68 Ga, 177 Lu, 186 Re, etc.
在核医学的背景下,治疗诊断学是指使用标记有诊断性放射性同位素(例如正电子或γ发射体)或治疗性放射性金属(例如β发射体)的分子靶向性分子来诊断和治疗特定疾病。最先进的平台基于对靶向性分子进行放射性标记,该靶向性分子对肿瘤细胞上表达的受体具有高亲和力,用18F和68Ga用于诊断,或用177Lu用于治疗目的。In the context of nuclear medicine, theranostics refers to the diagnosis and treatment of specific diseases using molecularly targeted molecules labeled with diagnostic radioisotopes (such as positron or gamma emitters) or therapeutic radiometals (such as beta emitters). The most advanced platforms are based on radiolabeling of targeting molecules with high affinity for receptors expressed on tumor cells, with 18 F and 68 Ga for diagnostic purposes, or with 177 Lu for therapeutic purposes.
PD-1(programmed death 1)程序性死亡受体1,是一种重要的免疫抑制分子。其为CD28超家族成员,最初是从凋亡的小鼠T细胞杂交瘤2B4.11克隆出来。以PD-1为靶点的免疫调节对抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等均有重要的意义。其配体PD-L1也可作为靶点,相应的抗体和小分子药物也可以抑制PD-1与PD-L1的结合,从而起到激活免疫反应消灭肿瘤细胞的作用。PD-1 (programmed death 1) is an important immunosuppressive molecule. It is a member of the CD28 superfamily and was originally cloned from the apoptotic mouse T cell hybridoma 2B4.11. Immune regulation targeting PD-1 is of great significance for anti-tumor, anti-infection, anti-autoimmune diseases and organ transplant survival. Its ligand PD-L1 can also be used as a target, and the corresponding antibodies and small molecule drugs can also inhibit the binding of PD-1 and PD-L1, thereby activating the immune response to eliminate tumor cells.
目前现有技术中还未出现含有放射性核素的含苯环类衍生化合物作为靶向PD-L1的小分子核素药物上市,并且也没有此类化合物通过PET肿瘤显像用于诊断以及用于治疗肿瘤的有关技术报道。Currently, there are no radioactive nuclide-containing benzene ring-derived compounds on the market as small molecule nuclide drugs targeting PD-L1, and there are no technical reports on the use of such compounds for diagnosis and treatment of tumors through PET tumor imaging.
发明内容Summary of the invention
本发明提供了一种全新结构的含苯环类化合物及其制备方法和应用。该类含苯环类化合物对PD-1/PD-L1结合具有抑制活性,能够用于诊断或治疗肿瘤等相关疾病。The present invention provides a benzene ring-containing compound with a completely new structure and a preparation method and application thereof. The benzene ring-containing compound has inhibitory activity on PD-1/PD-L1 binding and can be used to diagnose or treat tumors and other related diseases.
本发明提供了一种如式I所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物:
The present invention provides a benzene ring-containing compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
L为化学键、-NH-或-C(=O)NH-,-C(=O)NH-中羰基端与R3连接;L is a chemical bond, -NH- or -C(=O)NH-, in which the carbonyl end of -C(=O)NH- is connected to R 3 ;
R1和R2独立地为氢、卤素、氰基、C1-4烷基或被一个或多个Ra取代的C1-4烷基;R 1 and R 2 are independently hydrogen, halogen, cyano, C 1-4 alkyl, or C 1-4 alkyl substituted by one or more Ra ;
Ra各自独立地为氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基或-COOH; Ra is each independently deuterium, halogen, hydroxyl , amino, C1-4 alkyl, C1-4 alkoxy or -COOH;
R3为氢、氘、卤素、羟基、氨基、C1-4烷基、C1-4烷基-S-、C1-4烷氧基、C2-4烯基、-C(=O)NH2、-C(=O)OC1-4烷基、5-12元杂芳基、4-14元杂环烷基、被一个或多个R3a取代的C1-4烷基、被一个或多个R3b取代的C1-4烷基-S-、被一个或多个R3c取代的C1-4烷氧基、被一个或多个R3d取代的C2-4烯基、被一个或多个R3e取代的5-12元杂芳基或被一个或多个R3f取代的4-14元杂环烷基,其中所述的5-12元杂芳基和所述的4-14元杂环烷基中,杂原子个数独立地为1、2或3个,杂原子独立地为N、O和S中的一种或多种;R 3 is hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkyl-S-, C 1-4 alkoxy , C 2-4 alkenyl, -C(=O)NH 2 , -C(=O)OC 1-4 alkyl, 5-12 membered heteroaryl, 4-14 membered heterocycloalkyl, C 1-4 alkyl substituted by one or more R 3a , C 1-4 alkyl-S- substituted by one or more R 3b , C 1-4 alkoxy substituted by one or more R 3c, C 2-4 alkenyl substituted by one or more R 3d , 5-12 membered heteroaryl substituted by one or more R 3e , or 4-14 membered heterocycloalkyl substituted by one or more R 3f , wherein the number of heteroatoms in the 5-12 membered heteroaryl and the 4-14 membered heterocycloalkyl is independently 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
R3a、R3b、R3c和R3d各自独立地为C1-4烷基-S-、卤素、C1-4烷基、C1-4烷氧基、-COOH、-(C1-4亚烷基)-COOH、-C(=O)OC1-4烷基、-C(=O)NH2、-C(=O)NHC1-4烷基、5-7元杂环烷基、-NR3gR3h、或被一个或多个R3i取代的5-7元杂环烷基;所述的5-7元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种;R 3a , R 3b , R 3c and R 3d are each independently C 1 - 4 alkyl-S-, halogen, C 1 - 4 alkyl, C 1 - 4 alkoxy, -COOH, -(C 1 - 4 alkylene)-COOH, -C(=O)OC 1 - 4 alkyl, -C(=O)NH 2 , -C(=O)NHC 1 - 4 alkyl, 5-7 membered heterocycloalkyl, -NR 3g R 3h , or 5-7 membered heterocycloalkyl substituted by one or more R 3i ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
R3g和R3h各自独立地为氢或C1-4烷基;R 3g and R 3h are each independently hydrogen or C 1-4 alkyl;
R3i各自独立地为羟基、氨基、C1-4烷基或-COOH;R 3i are each independently hydroxy, amino, C 1-4 alkyl or -COOH;
R3e和R3f各自独立地为C1-4烷基、被一个或多个Rc1取代的C1-4烷基、或被一个或多个Rc2取代的C1-4烷基-C(=O)-;R 3e and R 3f are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C(═O)- substituted by one or more R c2 ;
Rc1和Rc2各自独立地为卤素、3-8元环烷基、5-7元杂环烷基、被一个或多个Rc3取代的3-8元环烷基、或被一个或多个Rc4取代的5-7元杂环烷基,所述5-7元杂环烷基中,杂原子个数为1,2或3个,杂原子独立地为N、O和S中的一种或多种;Rc3和Rc4各自独立地为羟基、氨基、C1-4烷基或-COOH;R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S; R c3 and R c4 are each independently hydroxyl, amino, C 1-4 alkyl or -COOH;
R4和R5独立地为氢、氘、C1-4烷基、3-8元环烷基、被一个或多个Rb1取代的C1-4烷基、或被一个或多个Rb2取代的3-8元环烷基;或者,R4、R5以及与它们连接的氮原子共同形成5-7元杂环烷基或被一个或多个Rb3取代的5-7元杂环烷基;所述5-7元杂环烷基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种; R4 and R5 are independently hydrogen, deuterium, C1-4 alkyl, 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
Rb1、Rb2和Rb3各自独立地为氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基或-COOH;R b1 , R b2 and R b3 are each independently deuterium, halogen , hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy or -COOH;
环A为6-10元芳基或5-12元杂芳基,所述的5-12元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种;Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
X为-O-、-S-或-N(RX)-;X is -O-, -S- or -N(R X )-;
RX为氢或C1-4烷基; RX is hydrogen or C1-4 alkyl;
R6和R7独立地为氢、卤素、C1-4烷基或被一个或多个卤素取代的C1-4烷基;或者,R6、R7以及与它们之间的原子共同形成5-6元杂芳基或被一个或多个Rd取代的5-6元杂芳基,所述的5-6元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种; R6 and R7 are independently hydrogen, halogen, C1-4 alkyl or C1-4 alkyl substituted by one or more halogens; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more Rd , wherein the number of heteroatoms in the 5-6 membered heteroaryl is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
Rd各自独立地为氘、卤素、羟基、氨基、C1-4烷基或C1-4烷氧基; R d are each independently deuterium, halogen, hydroxyl , amino, C 1-4 alkyl or C 1-4 alkoxy;
L1为-L3-L4-,其中L4与L2连接;L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
L3为-(CH2)m-,其中的1、2、3、4或5个非相邻的CH2独立地被-Y1-所代替,每个Y1独立地为-C(=O)-、-C(=O)O-、-O-、-NH-、-C(=O)NH-或-NHC(=O)NH-;L 3 is -(CH 2 ) m -, wherein 1, 2, 3, 4 or 5 non-adjacent CH 2 groups are independently replaced by -Y 1 -, and each Y 1 is independently -C(=O)-, -C(=O)O-, -O-, -NH-, -C(=O)NH- or -NHC(=O)NH-;
m为1、2、3、4、5、6、7或8;m is 1, 2, 3, 4, 5, 6, 7 or 8;
L4为化学键或5-12元杂环烷基;所述的5-12元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种; L4 is a chemical bond or a 5-12 membered heterocycloalkyl group; in the 5-12 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
L2为含有诊断性放射性核素的基团。 L2 is a group containing a diagnostic radionuclide.
在本发明的某些优选实施方案中,所述的如式I所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,某些基团具有如下定义,未提及的基团的定义如本发明中任一方案所述(本段内容以下简称为“在本发明的某些优选实施方案中”),In certain preferred embodiments of the present invention, the compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any scheme of the present invention (this paragraph is hereinafter referred to as "certain preferred embodiments of the present invention"),
L为化学键、-NH-或-C(=O)NH-,-C(=O)NH-中羰基端与R3连接;L is a chemical bond, -NH- or -C(=O)NH-, in which the carbonyl end of -C(=O)NH- is connected to R 3 ;
R1和R2独立地为氢、卤素、氰基、C1-4烷基或被一个或多个Ra取代的C1-4烷基;R 1 and R 2 are independently hydrogen, halogen, cyano, C 1-4 alkyl, or C 1-4 alkyl substituted by one or more Ra ;
Ra各自独立地为氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基或-COOH; Ra is each independently deuterium, halogen, hydroxyl , amino, C1-4 alkyl, C1-4 alkoxy or -COOH;
R3为氢、氘、卤素、羟基、氨基、C1-4烷基、C1-4烷基-S-、C1-4烷氧基、C2-4烯基、-C(=O)NH2、-C(=O)OC1-4烷基、5-12元杂芳基、4-14元杂环烷基、被一个或多个R3a取代的C1-4烷基、被一个或多个R3b取代的C1-4烷基-S-、被一个或多个R3c取代的C1-4烷氧基、被一个或多个R3d取代的C2-4烯基、被一个或多个R3e取代的5-12元杂芳基或被一个或多个R3f取代的4-14元杂环烷基,其中所述的5-12元杂芳基和所述的4-14元杂环烷基中,杂原子个数独立地为1、2或3个,杂原子独立地为N、O和S中的一种或多种;R 3 is hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkyl-S-, C 1-4 alkoxy , C 2-4 alkenyl, -C(=O)NH 2 , -C(=O)OC 1-4 alkyl, 5-12 membered heteroaryl, 4-14 membered heterocycloalkyl, C 1-4 alkyl substituted by one or more R 3a , C 1-4 alkyl-S- substituted by one or more R 3b , C 1-4 alkoxy substituted by one or more R 3c, C 2-4 alkenyl substituted by one or more R 3d , 5-12 membered heteroaryl substituted by one or more R 3e , or 4-14 membered heterocycloalkyl substituted by one or more R 3f , wherein the number of heteroatoms in the 5-12 membered heteroaryl and the 4-14 membered heterocycloalkyl is independently 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
R3a、R3b、R3c和R3d各自独立地为C1-4烷基-S-、卤素、C1-4烷基、C1-4烷氧基、-COOH、-(C1-4亚烷基)-COOH、-C(=O)OC1-4烷基、-C(=O)NH2、-C(=O)NHC1-4烷基、5-7元杂环烷基、-NR3gR3h、或被一个或多个R3i取代的5-7元杂环烷基;所述的5-7元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种;R 3a , R 3b , R 3c and R 3d are each independently C 1 - 4 alkyl-S-, halogen, C 1 - 4 alkyl, C 1 - 4 alkoxy, -COOH, -(C 1 - 4 alkylene)-COOH, -C(=O)OC 1 - 4 alkyl, -C(=O)NH 2 , -C(=O)NHC 1 - 4 alkyl, 5-7 membered heterocycloalkyl, -NR 3g R 3h , or 5-7 membered heterocycloalkyl substituted by one or more R 3i ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
R3g和R3h各自独立地为氢或C1-4烷基;R 3g and R 3h are each independently hydrogen or C 1-4 alkyl;
R3i各自独立地为羟基、氨基、C1-4烷基或-COOH;R 3i are each independently hydroxy, amino, C 1-4 alkyl or -COOH;
R3e和R3f各自独立地为C1-4烷基、被一个或多个Rc1取代的C1-4烷基、或被一个或多个Rc2取代的C1-4烷基-C(=O)-;R 3e and R 3f are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C(═O)- substituted by one or more R c2 ;
Rc1和Rc2各自独立地为卤素、3-8元环烷基、5-7元杂环烷基、被一个或多个Rc3取代的3-8元环烷基、或被一个或多个Rc4取代的5-7元杂环烷基,所述5-7元杂环烷基中,杂原子个数为1,2或3个,杂原子独立地为N、O和S中的一种或多种;Rc3和Rc4各自独立地为羟基、氨基、C1-4烷基或-COOH;R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S; R c3 and R c4 are each independently hydroxyl, amino, C 1-4 alkyl or -COOH;
R4和R5独立地为氢、氘、C1-4烷基、3-8元环烷基、被一个或多个Rb1取代的C1-4烷基、或被一个或多个Rb2取代的3-8元环烷基;或者,R4、R5以及与它们连接的氮原子共同形成5-7元杂环烷基或被一个或多个Rb3取代的5-7元杂环烷基;所述5-7元杂环烷基中,杂原子的个数为1、2或3个, 杂原子独立地为N、O和S中的一种或多种; R4 and R5 are independently hydrogen, deuterium, C1-4 alkyl, 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, The heteroatoms are independently one or more of N, O and S;
Rb1、Rb2和Rb3各自独立地为氘、卤素、羟基、氨基、C1-4烷基、C1-4烷氧基或-COOH;R b1 , R b2 and R b3 are each independently deuterium, halogen , hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy or -COOH;
环A为6-10元芳基或5-12元杂芳基,所述的5-12元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种;Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
X为-O-、-S-或-N(RX)-;X is -O-, -S- or -N(R X )-;
RX为氢或C1-4烷基; RX is hydrogen or C1-4 alkyl;
R6和R7独立地为氢、卤素或C1-4烷基;或者,R6、R7以及与它们之间的原子共同形成5-6元杂芳基或被一个或多个Rd取代的5-6元杂芳基,所述的5-6元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种; R6 and R7 are independently hydrogen, halogen or C1-4 alkyl; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl or a 5-6 membered heteroaryl substituted by one or more Rd , wherein the number of heteroatoms in the 5-6 membered heteroaryl is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
Rd各自独立地为氘、卤素、羟基、氨基、C1-4烷基或C1-4烷氧基;R d are each independently deuterium, halogen, hydroxyl , amino, C 1-4 alkyl or C 1-4 alkoxy;
L1为-L3-L4-,其中L4与L2连接;L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
L3为-(CH2)m-,其中的1、2、3、4或5个非相邻的CH2独立地被-Y1-所代替,每个Y1独立地为-C(=O)-、-C(=O)O-、-O-、-NH-、-C(=O)NH-或-NHC(=O)NH-;L 3 is -(CH 2 ) m -, wherein 1, 2, 3, 4 or 5 non-adjacent CH 2 groups are independently replaced by -Y 1 -, and each Y 1 is independently -C(=O)-, -C(=O)O-, -O-, -NH-, -C(=O)NH- or -NHC(=O)NH-;
m为1、2、3、4、5、6、7或8;m is 1, 2, 3, 4, 5, 6, 7 or 8;
L4为化学键或5-7元杂环烷基;所述的5-7元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种; L4 is a chemical bond or a 5-7 membered heterocycloalkyl group; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
L2为含有诊断性放射性核素的基团。 L2 is a group containing a diagnostic radionuclide.
在本发明的某些优选实施方案中,R1、R2、Rc1、Rc2、R6和R7中,所述的卤素为氟、氯、溴或碘。In certain preferred embodiments of the present invention, in R 1 , R 2 , R c1 , R c2 , R 6 and R 7 , the halogen is fluorine, chlorine, bromine or iodine.
在本发明的某些优选实施方案中,R1、R2、R3、R3e、Rc3、Rc4、R4、R5、Rb1、Rb2和Rb3中,所述的C1-4烷基、被一个或多个R3a取代的C1-4烷基中的C1-4烷基、被一个或多个Rc1取代的C1-4烷基中的C1-4烷基、被一个或多个Rc2取代的C1-4烷基-C(=O)-中的C1-4烷基、和被一个或多个Rb1取代的C1-4烷基中的C1-4烷基各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In certain preferred embodiments of the present invention, in R 1 , R 2 , R 3 , R 3e , R c3 , R c4 , R 4 , R 5 , R b1 , R b2 and R b3 , the C 1-4 alkyl, the C 1-4 alkyl in the C 1-4 alkyl substituted by one or more R 3a , the C 1-4 alkyl in the C 1-4 alkyl substituted by one or more R c1 , the C 1-4 alkyl in the C 1-4 alkyl-C(=O)- substituted by one or more R c2 , and the C 1-4 alkyl in the C 1-4 alkyl substituted by one or more R b1 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在本发明的某些优选实施方案中,R3中,所述的C1-4烷氧基、和被一个或多个R3c取代的C1-4烷氧基中的C1-4烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,例如正丙氧基。In certain preferred embodiments of the present invention, in R 3 , the C 1-4 alkoxy group and the C 1-4 alkoxy group substituted by one or more R 3c are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example n-propoxy.
在本发明的某些优选实施方案中,R3中,所述的C2-4烯基、和被一个或多个R3d取代的C2-4烯基中的C2-4烯基独立地为乙烯基或 In certain preferred embodiments of the present invention, in R 3 , the C 2-4 alkenyl group and the C 2-4 alkenyl group substituted by one or more R 3d are independently vinyl or
在本发明的某些优选实施方案中,R3和环A中,所述的5-12元杂芳基和被一个或多个R3e取代的5-12元杂芳基中的5-12元杂芳基为双环;优选地,所述的双环中两个环均具有芳香性或者一个环具有芳香性,另一个环不具有芳香性。In certain preferred embodiments of the present invention, in R 3 and ring A, the 5-12 membered heteroaryl and the 5-12 membered heteroaryl in the 5-12 membered heteroaryl substituted by one or more R 3e are bicyclic; preferably, both rings in the bicyclic are aromatic or one ring is aromatic and the other ring is not aromatic.
在本发明的某些优选实施方案中,R3和环A中,所述的5-12元杂芳基和被一个或多个R3e取代的5-12元杂芳基中的5-12元杂芳基为稠环。In certain preferred embodiments of the present invention, in R 3 and ring A, the 5-12 membered heteroaryl and the 5-12 membered heteroaryl in the 5-12 membered heteroaryl substituted by one or more R 3e are a condensed ring.
在本发明的某些优选实施方案中,R3和环A中,所述的5-12元杂芳基、和被一个或多个R3e取 代的5-12元杂芳基中的5-12元杂芳基独立地为8-10元稠环杂芳基,例如 In certain preferred embodiments of the present invention, in R 3 and ring A, the 5-12 membered heteroaryl, and replaced by one or more R 3e The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is independently an 8-10-membered fused ring heteroaryl, for example
在本发明的某些优选实施方案中,L4中,所述的5-12元杂环烷基为单环或双环。所述的双环优选为螺环。In certain preferred embodiments of the present invention, in L 4 , the 5-12 membered heterocycloalkyl is a monocyclic or bicyclic ring, and the bicyclic ring is preferably a spiro ring.
在本发明的某些优选实施方案中,L4中,所述的5-12元杂环烷基为5-7元杂环烷基或8-12元杂环烷基。In certain preferred embodiments of the present invention, in L 4 , the 5-12 membered heterocycloalkyl group is a 5-7 membered heterocycloalkyl group or an 8-12 membered heterocycloalkyl group.
在本发明的某些优选实施方案中,L4中,所述的8-12元杂环烷基为双环,优选为螺环,更优选为 In certain preferred embodiments of the present invention, in L 4 , the 8-12 membered heterocycloalkyl is a bicyclic ring, preferably a spirocyclic ring, more preferably
在本发明的某些优选实施方案中,R3a、R3c、R3d、Rc1、Rc2和L4中,所述的5-7元杂环烷基、被一个或多个R3i取代的5-7元杂环烷基中的5-7元杂环烷基、和被一个或多个Rc4取代的5-7元杂环烷基中的5-7元杂环烷基为单环。In certain preferred embodiments of the present invention, in R 3a , R 3c , R 3d , R c1 , R c2 and L 4 , the 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R 3i , and the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R c4 is a monocyclic ring.
在本发明的某些优选实施方案中,R3a、R3c、R3d、Rc1、Rc2和L4中,所述的5-7元杂环烷基、被一个或多个R3i取代的5-7元杂环烷基中的5-7元杂环烷基、和被一个或多个Rc4取代的5-7元杂环烷基中的5-7元杂环烷基独立地为吗啉基、四氢吡咯基、哌嗪基或哌啶基。In certain preferred embodiments of the present invention, in R 3a , R 3c , R 3d , R c1 , R c2 and L 4 , the 5-7 membered heterocycloalkyl, the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R 3i , and the 5-7 membered heterocycloalkyl in the 5-7 membered heterocycloalkyl substituted by one or more R c4 are independently morpholinyl, tetrahydropyrrolyl, piperazinyl or piperidinyl.
在本发明的某些优选实施方案中,R4、R5以及与它们连接的氮原子共同形成5-7元杂环烷基或被一个或多个Rb3取代的5-7元杂环烷基中,所述的5-7元杂环烷基为单环。In certain preferred embodiments of the present invention, R 4 , R 5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl group or a 5-7 membered heterocycloalkyl group substituted by one or more R b3 , wherein the 5-7 membered heterocycloalkyl group is a monocyclic ring.
在本发明的某些优选实施方案中,R4、R5以及与它们连接的氮原子共同形成5-7元杂环烷基或被一个或多个Rb3取代的5-7元杂环烷基中,所述的5-7元杂环烷基独立地为吗啉基、四氢吡咯基、哌嗪基或哌啶基。In certain preferred embodiments of the present invention, R 4 , R 5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl group or a 5-7 membered heterocycloalkyl group substituted by one or more R b3 , wherein the 5-7 membered heterocycloalkyl group is independently morpholinyl, tetrahydropyrrolyl, piperazinyl or piperidinyl.
在本发明的某些优选实施方案中,环A中,所述的6-10元芳基为单环或双环。In certain preferred embodiments of the present invention, in ring A, the 6-10 membered aryl group is a monocyclic or bicyclic ring.
在本发明的某些优选实施方案中,环A中,所述的6-10元芳基为苯基或萘基。In certain preferred embodiments of the present invention, in ring A, the 6-10 membered aryl group is phenyl or naphthyl.
在本发明的某些优选实施方案中,R6和R7中,所述的被一个或多个卤素取代的C1-4烷基中的卤素为氟、氯、溴或碘,例如氟。In certain preferred embodiments of the present invention, in R 6 and R 7 , the halogen in the C 1-4 alkyl substituted by one or more halogens is fluorine, chlorine, bromine or iodine, for example fluorine.
在本发明的某些优选实施方案中,R6和R7中,所述的被一个或多个卤素取代的C1-4烷基优选为氟取代的C1-4烷基,例如三氟甲基。In certain preferred embodiments of the present invention, in R 6 and R 7 , the C 1-4 alkyl substituted by one or more halogens is preferably a fluorine-substituted C 1-4 alkyl, such as trifluoromethyl.
在本发明的某些优选实施方案中,R6、R7以及与它们之间的原子共同形成5-6元杂芳基中,所述 的5-6元杂芳基为单环。In certain preferred embodiments of the present invention, R 6 , R 7 and the atoms between them together form a 5-6 membered heteroaryl group, wherein The 5-6 membered heteroaryl is a monocyclic ring.
在本发明的某些优选实施方案中,R6、R7以及与它们之间的原子共同形成5-6元杂芳基中,所述的5-6元杂芳基为呋喃基、噁唑基、异噁唑基、噻唑基或吡咯基,例如噁唑基或噻唑基。In certain preferred embodiments of the present invention, R 6 , R 7 and the atoms therebetween together form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is furyl, oxazolyl, isoxazolyl, thiazolyl or pyrrolyl, such as oxazolyl or thiazolyl.
在本发明的某些优选实施方案中,R1和R2各自独立地为氢、卤素或C1-4烷基。In certain preferred embodiments of the present invention, R 1 and R 2 are each independently hydrogen, halogen or C 1-4 alkyl.
在本发明的某些优选实施方案中,R3为氢、C1-4烷基、C1-4烷氧基、C2-4烯基、5-12元杂芳基、被一个或多个R3a取代的C1-4烷基、被一个或多个R3c取代的C1-4烷氧基、被一个或多个R3d取代的C2- 4烯基、或被一个或多个R3e取代的5-12元杂芳基。In certain preferred embodiments of the present invention, R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl , 5-12 membered heteroaryl , C 1-4 alkyl substituted by one or more R 3a, C 1-4 alkoxy substituted by one or more R 3c, C 2-4 alkenyl substituted by one or more R 3d , or 5-12 membered heteroaryl substituted by one or more R 3e .
在本发明的某些优选实施方案中,R3为 其中p1、p2、p3、p4、p5和p6各自独立地为1、2或3,例如1或2。In certain preferred embodiments of the present invention, R3 is wherein p1, p2, p3, p4, p5 and p6 are each independently 1, 2 or 3, for example 1 or 2.
在本发明的某些优选实施方案中,R3为 In certain preferred embodiments of the present invention, R3 is
在本发明的某些优选实施方案中,R3a、R3c和R3d各自独立地为5-7元杂环烷基、或被一个或多个羟基取代的5-7元杂环烷基。In certain preferred embodiments of the present invention, R 3a , R 3c and R 3d are each independently 5-7 membered heterocycloalkyl, or 5-7 membered heterocycloalkyl substituted with one or more hydroxyl groups.
在本发明的某些优选实施方案中,Rc3和Rc4各自独立地为羟基、C1-4烷基或-COOH。In certain preferred embodiments of the present invention, R c3 and R c4 are each independently hydroxy, C 1-4 alkyl or -COOH.
在本发明的某些优选实施方案中,R4和R5中的一个为氢,另一个为C1-4烷基、3-8元环烷基、被一个或多个Rb1取代的C1-4烷基、或被一个或多个Rb2取代的3-8元环烷基;或者,R4、R5以及与它们连接的氮原子共同形成5-7元杂环烷基或被一个或多个Rb3取代的5-7元杂环烷基。In certain preferred embodiments of the present invention, one of R4 and R5 is hydrogen, and the other is C1-4 alkyl, 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 .
在本发明的某些优选实施方案中,Rb1、Rb2和Rb3各自独立地为羟基、C1-4烷基或-COOH。In certain preferred embodiments of the present invention, R b1 , R b2 and R b3 are each independently hydroxy, C 1-4 alkyl or -COOH.
在本发明的某些优选实施方案中,X为-O-或-S-。In certain preferred embodiments of the present invention, X is -O- or -S-.
在本发明的某些优选实施方案中,R6和R7独立地为氢、卤素或被一个或多个卤素取代的C1-4烷基;或者R6、R7以及与它们之间的原子原子共同形成5-6元杂芳基。 In certain preferred embodiments of the present invention, R 6 and R 7 are independently hydrogen, halogen or C 1-4 alkyl substituted by one or more halogens; or R 6 , R 7 and the atoms between them together form a 5-6 membered heteroaryl.
在本发明的某些优选实施方案中,R6和R7独立地为氢或卤素;或者R6、R7以及与它们之间的原子原子共同形成5-6元杂芳基。In certain preferred embodiments of the present invention, R 6 and R 7 are independently hydrogen or halogen; or R 6 , R 7 and the atoms therebetween together form a 5-6 membered heteroaryl group.
在本发明的某些优选实施方案中,m为2或6。In certain preferred embodiments of the present invention, m is 2 or 6.
在本发明的某些优选实施方案中,L3为-O(CH2)n1O(CH2)m1-、-O(CH2)n2-、-O(CH2)n1NH-、-O(CH2)n1-OC(=O)-、-O(CH2)n1O(CH2)m1NH-或-O(CH2)n1NHC(=O)-,其中氧原子端与苯环连接,n1、n2和m1独立地为1、2、3、4、5或6,例如n1为2或4,n2为1或5,m1为2。In certain preferred embodiments of the present invention, L3 is -O( CH2 ) n1O ( CH2 ) m1- , -O( CH2 ) n2- , -O(CH2)n1NH-, -O( CH2 ) n1 -OC(= O )-, -O ( CH2 )n1O( CH2 ) m1NH- or -O( CH2 ) n1NHC (=O)-, wherein the oxygen atom terminal is connected to the benzene ring, and n1, n2 and m1 are independently 1, 2, 3, 4, 5 or 6, for example, n1 is 2 or 4, n2 is 1 or 5, and m1 is 2.
在本发明的某些优选实施方案中,L3为-O(CH2)n1O(CH2)m1-、-O(CH2)n2-、-O(CH2)n1NH-、-O(CH2)n1-OC(=O)-或-O(CH2)n1O(CH2)m1NH-,其中氧原子端与苯环连接,n1、n2和m1独立地为1、2、3、4、5或6,例如n1为2或4,n2为1或5,m1为2。In certain preferred embodiments of the present invention, L3 is -O( CH2 ) n1O ( CH2 ) m1- , -O( CH2 )n2-, -O(CH2) n1NH- , -O( CH2 ) n1 -OC(=O)- or -O( CH2 ) n1O ( CH2 ) m1NH- , wherein the oxygen atom terminal is connected to the benzene ring, n1 , n2 and m1 are independently 1, 2, 3, 4 , 5 or 6, for example, n1 is 2 or 4, n2 is 1 or 5, and m1 is 2.
在本发明的某些优选实施方案中,L3为-O(CH2)n1O(CH2)m1-、-O(CH2)n2-或-O(CH2)n1NHC(=O)-,其中氧原子端与苯环连接,n1、n2和m1独立地为1、2、3、4、5或6,例如n1为2或4,n2为1或5,m1为2。In certain preferred embodiments of the present invention, L3 is -O( CH2 ) n1O ( CH2 ) m1- , -O( CH2 ) n2- or -O( CH2 ) n1NHC (=O)-, wherein the oxygen atom terminal is connected to the benzene ring, and n1, n2 and m1 are independently 1, 2, 3, 4, 5 or 6, for example, n1 is 2 or 4, n2 is 1 or 5, and m1 is 2.
在本发明的某些优选实施方案中,L3为-O(CH2)n1O(CH2)m1-或-O(CH2)n2-,其中氧原子端与苯环连接,n1、n2和m1独立地为1、2、3、4、5或6,例如n1为2,n2为1或5,m1为2。In certain preferred embodiments of the present invention, L3 is -O( CH2 ) n1O ( CH2 ) m1- or -O( CH2 ) n2- , wherein the oxygen atom is connected to the benzene ring, and n1, n2 and m1 are independently 1, 2, 3, 4, 5 or 6, for example, n1 is 2, n2 is 1 or 5, and m1 is 2.
在本发明的某些优选实施方案中,L1为-O(CH2)n1O(CH2)m1-、-O(CH2)n2-、 其中氧原子端与苯环连接,n1为2或4,n2为1或5,m1为2。In certain preferred embodiments of the present invention, L1 is -O( CH2 ) n1O ( CH2 ) m1- , -O( CH2 ) n2- , The oxygen atom end is connected to the benzene ring, n1 is 2 or 4, n2 is 1 or 5, and m1 is 2.
在本发明的某些优选实施方案中,L1为-O(CH2)n1O(CH2)m1-、-O(CH2)n2-或其中氧原子端与苯环连接,n1为2,n2为1或5,m1为2。In certain preferred embodiments of the present invention, L1 is -O( CH2 ) n1O ( CH2 ) m1- , -O( CH2 ) n2- or The oxygen atom end is connected to the benzene ring, n1 is 2, n2 is 1 or 5, and m1 is 2.
在本发明的某些优选实施方案中,L2由含诊断性放射性核素的离子与螯合基团组成,所述的含诊断性放射性核素的离子与所述的螯合基团螯合。In certain preferred embodiments of the present invention, L2 consists of an ion containing a diagnostic radionuclide and a chelating group, and the ion containing the diagnostic radionuclide is chelated with the chelating group.
在本发明的某些优选实施方案中,所述的诊断性放射性核素为18F,68Ga,99mTc,123I,124I,111In或64Cu。In certain preferred embodiments of the present invention, the diagnostic radionuclide is 18 F, 68 Ga, 99m Tc, 123 I, 124 I, 111 In or 64 Cu.
在本发明的某些优选实施方案中,所述的含诊断性放射性核素的离子的价态为一价、二价、三价或四价,例如二价或三价。In certain preferred embodiments of the present invention, the valence state of the ions containing the diagnostic radionuclide is monovalent, divalent, trivalent or tetravalent, such as divalent or trivalent.
在本发明的某些优选实施方案中,所述的含诊断性放射性核素的离子为含诊断性放射性金属的离子或含诊断性放射性非金属的离子。In certain preferred embodiments of the present invention, the ions containing diagnostic radionuclides are ions containing diagnostic radioactive metals or ions containing diagnostic radioactive non-metals.
在本发明的某些优选实施方案中,所述的含诊断性放射性金属的离子为[68GaCl]2+或68Ga3+。 In certain preferred embodiments of the present invention, the ions containing diagnostic radioactive metals are [ 68 GaCl] 2+ or 68 Ga 3+ .
在本发明的某些优选实施方案中,所述的含诊断性放射性非金属的离子为[Al18F]2+。In certain preferred embodiments of the present invention, the diagnostic radioactive non-metal-containing ion is [Al 18 F] 2+ .
在本发明的某些优选实施方案中,所述的螯合基团为 a端与In certain preferred embodiments of the present invention, the chelating group is A end and
L1连接。L 1 connection.
在本发明的某些优选实施方案中,L为化学键、-NH-或-C(=O)NH-,-C(=O)NH-中羰基端与R3连接;In certain preferred embodiments of the present invention, L is a chemical bond, -NH- or -C(=O)NH-, wherein the carbonyl end of -C(=O)NH- is connected to R 3 ;
R1和R2各自独立地为氢、卤素或C1-4烷基; R1 and R2 are each independently hydrogen, halogen or C1-4 alkyl;
R3为氢、C1-4烷基、C1-4烷氧基、C2-4烯基、5-12元杂芳基、被一个或多个R3a取代的C1-4烷基、被一个或多个R3c取代的C1-4烷氧基、被一个或多个R3d取代的C2-4烯基、或被一个或多个R3e取代的5-12元杂芳基;其中所述的5-12元杂芳基中,杂原子个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种;R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, 5-12 membered heteroaryl, C 1-4 alkyl substituted by one or more R 3a , C 1-4 alkoxy substituted by one or more R 3c , C 2-4 alkenyl substituted by one or more R 3d , or 5-12 membered heteroaryl substituted by one or more R 3e ; wherein the 5-12 membered heteroaryl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
R3a、R3c和R3d各自独立地为5-7元杂环烷基、或被一个或多个R3i取代的5-7元杂环烷基;所述的5-7元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种;R 3a , R 3c and R 3d are each independently a 5-7 membered heterocycloalkyl group, or a 5-7 membered heterocycloalkyl group substituted by one or more R 3i ; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
R3i各自独立地为羟基;R 3i are each independently hydroxyl;
R3e各自独立地为C1-4烷基、被一个或多个Rc1取代的C1-4烷基、或被一个或多个Rc2取代的C1-4烷基-C(=O)-;R 3e are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C(═O)- substituted by one or more R c2 ;
Rc1和Rc2各自独立地为卤素、3-8元环烷基、5-7元杂环烷基、被一个或多个Rc3取代的3-8元环烷基、或被一个或多个Rc4取代的5-7元杂环烷基,所述5-7元杂环烷基中,杂原子个数为1,2或3个,杂原子独立地为N、O和S中的一种或多种;R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
Rc3和Rc4各自独立地为羟基、C1-4烷基或-COOH;R c3 and R c4 are each independently hydroxy, C 1-4 alkyl or -COOH;
R4和R5独立地为氢、C1-4烷基、3-8元环烷基、被一个或多个Rb1取代的C1-4烷基、或被一个或多个Rb2取代的3-8元环烷基;或者,R4、R5以及与它们连接的氮原子共同形成5-7元杂环烷基或被一个或多个Rb3取代的5-7元杂环烷基;所述5-7元杂环烷基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种; R4 and R5 are independently hydrogen, C1-4 alkyl , 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
Rb1、Rb2和Rb3各自独立地为羟基、C1-4烷基或-COOH;R b1 , R b2 and R b3 are each independently hydroxy, C 1 - 4 alkyl or -COOH;
环A为6-10元芳基或5-12元杂芳基,所述的5-12元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种;Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
X为-O-或-S-;X is -O- or -S-;
R6和R7独立地为氢、卤素或被一个或多个卤素取代的C1-4烷基;或者,R6、R7以及与它们之间的原子共同形成5-6元杂芳基,所述的5-6元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种; R6 and R7 are independently hydrogen, halogen or C1-4 alkyl substituted by one or more halogens; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl, wherein the number of heteroatoms in the 5-6 membered heteroaryl is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
L1为-L3-L4-,其中L4与L2连接;L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
L3为-(CH2)m-,其中的1、2、3、4或5个非相邻的CH2独立地被-Y1-所代替,每个Y1独立地为-O-、-C(=O)O-、-NH-或-C(=O)NH-;L 3 is -(CH 2 ) m -, wherein 1, 2, 3, 4 or 5 non-adjacent CH 2 groups are independently replaced by -Y 1 -, and each Y 1 is independently -O-, -C(=O)O-, -NH- or -C(=O)NH-;
m为2或6;m is 2 or 6;
L4为化学键或5-12元杂环烷基;所述的5-12元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种; L4 is a chemical bond or a 5-12 membered heterocycloalkyl group; in the 5-12 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
L2为含有诊断性放射性核素的基团。 L2 is a group containing a diagnostic radionuclide.
在本发明的某些优选实施方案中,L为化学键、-NH-或-C(=O)NH-,-C(=O)NH-中羰基端与R3连接;In certain preferred embodiments of the present invention, L is a chemical bond, -NH- or -C(=O)NH-, wherein the carbonyl end of -C(=O)NH- is connected to R 3 ;
R1和R2各自独立地为氢、卤素或C1-4烷基; R1 and R2 are each independently hydrogen, halogen or C1-4 alkyl;
R3为氢、C1-4烷基、C1-4烷氧基、C2-4烯基、5-12元杂芳基、被一个或多个R3a取代的C1-4烷基、被一个或多个R3c取代的C1-4烷氧基、被一个或多个R3d取代的C2-4烯基、或被一个或多个R3e取代的5-12元杂芳基;其中所述的5-12元杂芳基中,杂原子个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种;R 3 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, 5-12 membered heteroaryl, C 1-4 alkyl substituted by one or more R 3a , C 1-4 alkoxy substituted by one or more R 3c , C 2-4 alkenyl substituted by one or more R 3d , or 5-12 membered heteroaryl substituted by one or more R 3e ; wherein the 5-12 membered heteroaryl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
R3a、R3c和R3d各自独立地为5-7元杂环烷基、或被一个或多个R3i取代的5-7元杂环烷基;所述的5-7元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种;R 3a , R 3c and R 3d are each independently a 5-7 membered heterocycloalkyl group, or a 5-7 membered heterocycloalkyl group substituted by one or more R 3i ; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
R3i各自独立地为羟基;R 3i are each independently hydroxyl;
R3e各自独立地为C1-4烷基、被一个或多个Rc1取代的C1-4烷基、或被一个或多个Rc2取代的C1-4烷基-C(=O)-;R 3e are each independently C 1-4 alkyl, C 1-4 alkyl substituted by one or more R c1 , or C 1-4 alkyl-C(═O)- substituted by one or more R c2 ;
Rc1和Rc2各自独立地为卤素、3-8元环烷基、5-7元杂环烷基、被一个或多个Rc3取代的3-8元环烷基、或被一个或多个Rc4取代的5-7元杂环烷基,所述5-7元杂环烷基中,杂原子个数为1,2或3个,杂原子独立地为N、O和S中的一种或多种;R c1 and R c2 are each independently halogen, 3-8 membered cycloalkyl, 5-7 membered heterocycloalkyl, 3-8 membered cycloalkyl substituted by one or more R c3 , or 5-7 membered heterocycloalkyl substituted by one or more R c4 , wherein the 5-7 membered heterocycloalkyl has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
Rc3和Rc4各自独立地为羟基、C1-4烷基或-COOH;R c3 and R c4 are each independently hydroxy, C 1-4 alkyl or -COOH;
R4和R5独立地为氢、C1-4烷基、3-8元环烷基、被一个或多个Rb1取代的C1-4烷基、或被一个或多个Rb2取代的3-8元环烷基;或者,R4、R5以及与它们连接的氮原子共同形成5-7元杂环烷基或被一个或多个Rb3取代的5-7元杂环烷基;所述5-7元杂环烷基中,杂原子的个数为1、2或3个,杂原 子独立地为N、O和S中的一种或多种; R4 and R5 are independently hydrogen, C1-4 alkyl , 3-8 membered cycloalkyl, C1-4 alkyl substituted by one or more Rb1 , or 3-8 membered cycloalkyl substituted by one or more Rb2 ; or, R4 , R5 and the nitrogen atom to which they are attached together form a 5-7 membered heterocycloalkyl or a 5-7 membered heterocycloalkyl substituted by one or more Rb3 ; in the 5-7 membered heterocycloalkyl, the number of heteroatoms is 1, 2 or 3, and the number of heteroatoms is 2 or 3. The substituents are independently one or more of N, O and S;
Rb1、Rb2和Rb3各自独立地为羟基、C1-4烷基或-COOH;R b1 , R b2 and R b3 are each independently hydroxy, C 1 - 4 alkyl or -COOH;
环A为6-10元芳基或5-12元杂芳基,所述的5-12元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种;Ring A is a 6-10 membered aryl group or a 5-12 membered heteroaryl group, wherein the 5-12 membered heteroaryl group has 1, 2 or 3 heteroatoms, and the heteroatoms are independently one or more of N, O and S;
X为-O-或-S-;X is -O- or -S-;
R6和R7独立地为氢或卤素;或者,R6、R7以及与它们之间的原子共同形成5-6元杂芳基,所述的5-6元杂芳基中,杂原子的个数为1、2或3个,杂原子独立地为N、O和S中的一种或多种; R6 and R7 are independently hydrogen or halogen; or, R6 , R7 and the atoms between them together form a 5-6 membered heteroaryl group, wherein the number of heteroatoms in the 5-6 membered heteroaryl group is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
L1为-L3-L4-,其中L4与L2连接;L 1 is -L 3 -L 4 -, wherein L 4 is connected to L 2 ;
L3为-(CH2)m-,其中的1、2、3、4或5个非相邻的CH2独立地被-Y1-所代替,每个Y1独立地为-O-、-C(=O)O-、-NH-或-C(=O)NH-;L 3 is -(CH 2 ) m -, wherein 1, 2, 3, 4 or 5 non-adjacent CH 2 groups are independently replaced by -Y 1 -, and each Y 1 is independently -O-, -C(=O)O-, -NH- or -C(=O)NH-;
m为2或6;m is 2 or 6;
L4为化学键或5-7元杂环烷基;所述的5-7元杂环烷基中,杂原子的个数为1个、2个或3个,杂原子独立地为N、O和S中的一种或多种; L4 is a chemical bond or a 5-7 membered heterocycloalkyl group; in the 5-7 membered heterocycloalkyl group, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are independently one or more of N, O and S;
L2为含有诊断性放射性核素的基团。 L2 is a group containing a diagnostic radionuclide.
在本发明的某些优选实施方案中,环A为苯基或其中b端与L连接。In certain preferred embodiments of the present invention, ring A is phenyl or The b end is connected to L.
在本发明的某些优选实施方案中,R1为甲基或溴。In certain preferred embodiments of the present invention, R 1 is methyl or bromine.
在本发明的某些优选实施方案中,R2为氢、甲基或氯。In certain preferred embodiments of the present invention, R2 is hydrogen, methyl or chlorine.
在本发明的某些优选实施方案中,R3为氢、 In certain preferred embodiments of the present invention, R 3 is hydrogen,
在本发明的某些优选实施方案中,R3a、R3c和R3d各自独立地为 In certain preferred embodiments of the present invention, R 3a , R 3c and R 3d are each independently
在本发明的某些优选实施方案中,R4为氢。In certain preferred embodiments of the present invention, R4 is hydrogen.
在本发明的某些优选实施方案中,R5为(例如)、 In certain preferred embodiments of the present invention, R 5 is (For example ),
在本发明的某些优选实施方案中,为 In certain preferred embodiments of the present invention, for
在本发明的某些优选实施方案中,R6为氯或三氟甲基。In certain preferred embodiments of the present invention, R6 is chloro or trifluoromethyl.
在本发明的某些优选实施方案中,R6为氯。In certain preferred embodiments of the present invention, R6 is chlorine.
在本发明的某些优选实施方案中,R7为氢。In certain preferred embodiments of the present invention, R 7 is hydrogen.
在本发明的某些优选实施方案中,R6、R7以及与它们之间的原子共同形成 其中c端与苯环稠合。In certain preferred embodiments of the present invention, R 6 , R 7 and the atoms between them together form The C-terminus is fused with a benzene ring.
在本发明的某些优选实施方案中,L3为 其中氧原子端与苯环连接。In certain preferred embodiments of the present invention, L3 is The oxygen atom end is connected to the benzene ring.
在本发明的某些优选实施方案中,L3为其中氧原子端与苯环连接。In certain preferred embodiments of the present invention, L3 is The oxygen atom end is connected to the benzene ring.
在本发明的某些优选实施方案中,L4为化学键、(例如),d端与L2连接。In certain preferred embodiments of the present invention, L4 is a chemical bond, (For example ), the d end is connected to L2 .
在本发明的某些优选实施方案中,L4为化学键或d端与L2连接。In certain preferred embodiments of the present invention, L4 is a chemical bond or The d end is connected to L2 .
在本发明的某些优选实施方案中,L1为 其中氧原子端与苯环连接。In certain preferred embodiments of the present invention, L 1 is The oxygen atom end is connected to the benzene ring.
在本发明的某些优选实施方案中,L1为 其中氧原子端与苯环连接。 In certain preferred embodiments of the present invention, L 1 is The oxygen atom end is connected to the benzene ring.
在本发明的某些优选实施方案中,L2为 In certain preferred embodiments of the present invention, L2 is
在本发明的某些优选实施方案中,所述的如式I所示的含苯环类化合物为化合物A与所述的含诊断性放射性核素的离子(例如[Al18F]2+、[68GaCl]2+或68Ga3+)螯合形成的化合物,所述的化合物A的结构如下任一所示:
In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with the ion containing the diagnostic radionuclide (such as [Al 18 F] 2+ , [ 68 GaCl] 2+ or 68 Ga 3+ ), and the structure of compound A is shown in any of the following:
在本发明的某些优选实施方案中,所述的如式I所示的含苯环类化合物为化合物A与[Al18F]2+螯合形成的化合物,所述的化合物A如前所述。In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with [Al 18 F] 2+ , and the compound A is as described above.
在本发明的某些优选实施方案中,所述的如式I所示的含苯环类化合物为化合物A与[68GaCl]2+螯合形成的化合物,所述的化合物A如前所述。In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with [ 68GaCl ] 2+ , and the compound A is as described above.
在本发明的某些优选实施方案中,所述的如式I所示的含苯环类化合物为化合物A与68Ga3+螯合形成的化合物,所述的化合物A如前所述。In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula I is a compound formed by chelating compound A with 68 Ga 3+ , and the compound A is as described above.
在本发明的某些优选实施方案中,所述的如式I所示的含苯环类化合物选自如下任一结构:
In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula I is selected from any of the following structures:
在本发明的某些优选实施方案中,所述的如式I所示的含苯环类化合物选自如下任一结构:
In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula I is selected from any of the following structures:
本发明提供了一种如式II所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,
The present invention provides a benzene ring-containing compound as shown in Formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
其中,L5为含有治疗性放射性核素的基团,环A、L、L1、X、R1、R2、R3、R4、R5、R6和R7的 定义如上所述。Wherein, L5 is a group containing a therapeutic radionuclide, and ring A, L, L1 , X, R1 , R2 , R3 , R4 , R5 , R6 and R7 are The definitions are as above.
在本发明的某些优选实施方案中,L5由含治疗性放射性核素的离子与螯合基团组成,所述的含治疗性放射性核素的离子与所述的螯合基团螯合。In certain preferred embodiments of the present invention, L5 consists of an ion containing a therapeutic radionuclide and a chelating group, and the ion containing the therapeutic radionuclide is chelated with the chelating group.
在本发明的某些优选实施方案中,所述的治疗性放射性核素为177Lu,90Y,89Sr,188Re,225Ac,213Bi或212Pb。In certain preferred embodiments of the present invention, the therapeutic radionuclide is 177 Lu, 90 Y, 89 Sr, 188 Re, 225 Ac, 213 Bi or 212 Pb.
在本发明的某些优选实施方案中,所述的含治疗性放射性核素的离子的价态为一价、二价、三价或四价,例如三价。In certain preferred embodiments of the present invention, the valence state of the ions containing the therapeutic radionuclide is monovalent, divalent, trivalent or tetravalent, such as trivalent.
在本发明的某些优选实施方案中,所述的含治疗性放射性核素的离子为含治疗性放射性金属的离子。In certain preferred embodiments of the present invention, the ions containing therapeutic radionuclides are ions containing therapeutic radiometals.
在本发明的某些优选实施方案中,所述的含治疗性放射性金属的离子为[177LuCl]2+或177Lu3+。In certain preferred embodiments of the present invention, the therapeutic radioactive metal-containing ions are [ 177 LuCl] 2+ or 177 Lu 3+ .
在本发明的某些优选实施方案中,L5中,所述的螯合基团如上所述。In certain preferred embodiments of the present invention, in L 5 , the chelating group is as described above.
在本发明的某些优选实施方案中,L5为 In certain preferred embodiments of the present invention, L5 is
在本发明的某些优选实施方案中,所述的如式II所示的含苯环类化合物为化合物A与含治疗性放射性核素的离子螯合形成的化合物,所述的化合物A的结构如前所述。In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula II is a compound formed by chelating compound A with an ion containing a therapeutic radionuclide, and the structure of compound A is as described above.
在本发明的某些优选实施方案中,所述的如式II所示的含苯环类化合物为化合物A与177Lu3+螯合形成的化合物,所述的化合物A的结构如前所述。In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula II is a compound formed by chelating compound A with 177 Lu 3+ , and the structure of compound A is as described above.
在本发明的某些优选实施方案中,所述的如式II所示的含苯环类化合物选自如下任一结构:
In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula II is selected from any of the following structures:
本发明提供了一种如式III所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,
The present invention provides a benzene ring-containing compound as shown in formula III, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
其中,L6为含有非放射性核素的基团,环A、L、L1、X、R1、R2、R3、R4、R5、R6和R7的定义 如上所述。Wherein, L 6 is a group containing a non-radioactive nuclide, and the definitions of ring A, L, L 1 , X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are As mentioned above.
在本发明的某些优选实施方案中,L6由含非放射性核素的离子与螯合基团组成,所述的含非放射性核素的离子与所述的螯合基团螯合。In certain preferred embodiments of the present invention, L6 is composed of an ion containing a non-radioactive nuclide and a chelating group, and the ion containing the non-radioactive nuclide is chelated with the chelating group.
在本发明的某些优选实施方案中,所述的非放射性核素为Lu,Ga,F,Y,Sr,Re,Ac,Bi,Pb,Cu,Tc或In。In certain preferred embodiments of the present invention, the non-radioactive nuclide is Lu, Ga, F, Y, Sr, Re, Ac, Bi, Pb, Cu, Tc or In.
在本发明的某些优选实施方案中,L6中,所述的螯合基团如上所述。In certain preferred embodiments of the present invention, in L 6 , the chelating group is as described above.
在本发明的某些优选实施方案中,所述的含非放射性核素的离子为[AlF]2+、[GaCl]2+、Ga3+、Lu3+或[LuCl]2+。In certain preferred embodiments of the present invention, the non-radioactive nuclide-containing ions are [AlF] 2+ , [GaCl] 2+ , Ga 3+ , Lu 3+ or [LuCl] 2+ .
在本发明的某些优选实施方案中,L6为 In certain preferred embodiments of the present invention, L 6 is
在本发明的某些优选实施方案中,所述的如式III所示的含苯环类化合物为化合物A与所述的含非放射性核素的离子(例如[AlF]2+、[GaCl]2+、Ga3+、Lu3+或[LuCl]2+)螯合形成的化合物,所述的化合物A如前所述。In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula III is a compound formed by chelating compound A with the ion containing the non-radioactive nuclide (such as [AlF] 2+ , [GaCl] 2+ , Ga 3+ , Lu 3+ or [LuCl] 2+ ), and the compound A is as described above.
在本发明的某些优选实施方案中,所述的如式III所示的含苯环类化合物选自如下任一结构:
In certain preferred embodiments of the present invention, the benzene ring-containing compound as shown in Formula III is selected from any of the following structures:
本发明提供了一种如上所述的如式I所示的含苯环类化合物、如式II所示的含苯环类化合物或如式III所示的含苯环类化合物的制备方法,其包括如下步骤:将含诊断性放射性核素的离子、含治疗性放射性核素的离子或含非放射性核素的离子中的一种与如式IV所示的化合物螯合,即可;
The present invention provides a method for preparing a benzene ring-containing compound as shown in formula I, a benzene ring-containing compound as shown in formula II, or a benzene ring-containing compound as shown in formula III, which comprises the following steps: chelating one of ions containing diagnostic radionuclides, ions containing therapeutic radionuclides, or ions containing non-radioactive nuclides with a compound as shown in formula IV;
所述的如式IV所示的化合物中,L7为螯合基团,环A、L、L1、X、R1、R2、R3、R4、R5、R6和R7的定义如上所述。In the compound of formula IV, L7 is a chelating group, and ring A, L, L1 , X, R1 , R2 , R3 , R4 , R5 , R6 and R7 are defined as above.
在本发明的某些优选实施方案中,L7为 其中a端与L1连接。In certain preferred embodiments of the present invention, L 7 is The a end is connected to L1 .
本发明提供了一种如式IV所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,
The present invention provides a benzene ring-containing compound as shown in formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
其中,环A、L、L1、L7、X、R1、R2、R3、R4、R5、R6和R7的定义如上所述。wherein Ring A, L, L 1 , L 7 , X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
在本发明的某些优选实施方案中,所述的如式IV所示的化合物选自上述化合物A中的任一种。In certain preferred embodiments of the present invention, the compound represented by formula IV is selected from any one of the above-mentioned compounds A.
本发明提供了一种化合物V、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合 物,所述化合物V的结构如下任一所示: The present invention provides a compound V, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof. The structure of the compound V is shown as any one of the following:
本发明提供了一种药物组合物,其包含物质B以及药用辅料,所述的物质B为物质C、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,所述的物质C为如上所述的如式I、如式II、如式III、如式IV或如式V所示的含苯环类化合物。The present invention provides a pharmaceutical composition, comprising a substance B and a pharmaceutical excipient, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III, Formula IV or Formula V as described above.
本发明提供了一种药物组合物,其包含物质B以及药用辅料,所述的物质B为物质C、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,所述的物质C为如上所述的如式I、如式II、如式III或如式IV所示的含苯环类化合物。The present invention provides a pharmaceutical composition, comprising a substance B and a pharmaceutical excipient, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III or Formula IV as described above.
本发明还提供了一种物质B在制备PD-1/PD-L1抑制剂中的应用,所述物质B为物质C、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,所述的物质C为如上所述的如式I、如式II、如式III、如式IV或如式V所示的含苯环类化合物。在所述的应用中,所述的PD-1/PD-L1 抑制剂可用于哺乳动物生物体内;也可用于生物体外,主要作为实验用途,例如:作为标准样或对照样提供比对,或按照本领域常规方法制成试剂盒,为抑制PD-1/PD-L1的效果提供快速检测。The present invention also provides an application of a substance B in the preparation of a PD-1/PD-L1 inhibitor, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III, Formula IV, or Formula V as described above. In the application, the PD-1/PD-L1 The inhibitors can be used in mammals in vivo; they can also be used in vitro, mainly for experimental purposes, for example: as standard samples or control samples for comparison, or prepared into kits according to conventional methods in the art to provide rapid detection of the effect of inhibiting PD-1/PD-L1.
本发明还提供了一种物质B在制备PD-1/PD-L1抑制剂中的应用,所述物质B为物质C、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,所述的物质C为如上所述的如式I、如式II、如式III或如式IV所示的含苯环类化合物。在所述的应用中,所述的PD-1/PD-L1抑制剂可用于哺乳动物生物体内;也可用于生物体外,主要作为实验用途,例如:作为标准样或对照样提供比对,或按照本领域常规方法制成试剂盒,为抑制PD-1/PD-L1的效果提供快速检测。The present invention also provides an application of a substance B in the preparation of a PD-1/PD-L1 inhibitor, wherein the substance B is a substance C, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and the substance C is a benzene ring-containing compound as shown in Formula I, Formula II, Formula III, or Formula IV as described above. In the application, the PD-1/PD-L1 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PD-1/PD-L1.
本发明还提供了一种如上所述的如式I所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物在制备用于诊断肿瘤的药物中的应用。The present invention also provides a use of the benzene ring-containing compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for diagnosing tumors.
本发明还提供了一种如上所述的如式II所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物在制备用于治疗肿瘤的药物中的应用。The present invention also provides a use of the benzene ring-containing compound shown in Formula II as described above, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors.
本发明还提供了一种如上所述的如式III所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物,或如如上所述的如式IV所示的含苯环类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物在制备治疗和/或预防肿瘤的药物中的应用。The present invention also provides a benzene ring-containing compound as shown in formula III as described above, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, or a benzene ring-containing compound as shown in formula IV as described above, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and/or preventing tumors.
本发明还提供了一种如上所述的如式V所示的化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物在制备治疗和/或预防肿瘤的药物中的应用。The present invention also provides a use of the compound as shown in Formula V, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and/or preventing tumors.
在本发明的某些优选实施方案中,所述肿瘤为PD-1/PD-L1相关或介导的肿瘤,例如肺癌、胃癌、结直肠癌、宫颈癌、卵巢癌、前列腺癌、乳腺癌、胰腺癌、肝癌、膀胱癌、肾癌、骨癌、皮肤癌、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、白血病或淋巴瘤,又例如结直肠癌。In certain preferred embodiments of the present invention, the tumor is a PD-1/PD-L1-related or mediated tumor, such as lung cancer, gastric cancer, colorectal cancer, cervical cancer, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, liver cancer, bladder cancer, kidney cancer, bone cancer, skin cancer, melanoma, glioma, glioblastoma, leukemia or lymphoma, and for example colorectal cancer.
本发明还提供了一种如下所示的化合物:
The present invention also provides a compound as shown below:
定义和说明Definition and Description
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.
在本发明中,术语“取代”或“取代基”是基团中的氢原子被指定的基团所代替。当没有指明取代位置时,取代可以在任何位置,但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。举例说明如下:被一个或多个R3g取代的5-12元杂芳基表示5-12元杂芳基上的氢原子被一个或多个R3g所取代,当存在多个R3g时,每个R3g相同或不同。In the present invention, the term "substituted" or "substituent" means that the hydrogen atom in the group is replaced by a specified group. When the substitution position is not specified, the substitution can be at any position, but it is allowed only if a stable or chemically feasible chemical is formed. An example is as follows: a 5-12 membered heteroaryl substituted with one or more R 3g means that the hydrogen atom on the 5-12 membered heteroaryl is replaced with one or more R 3g , and when there are multiple R 3g , each R 3g is the same or different.
当任何变量在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R3c所取代,则所述基团可以任选地至多被两个R3c所取代,并且每种情况下的R3c都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When any variable appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R 3c , the group may be optionally substituted with up to two R 3c , and each case of R 3c has independent options. In addition, combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.
本发明所列举的连接基团没有指明其连接方向时,其连接方向可以是任意的,既包括从左到右连接,也包括从右到左连接。举例说明如下,-A-L-B中连接基团L为-C-D-,在没有指明L的连接方向时,-A-L-B包括-A-C-D-B和-A-D-C-B。When the connection direction of the linking groups listed in the present invention is not specified, the connection direction can be arbitrary, including connection from left to right and connection from right to left. For example, in -A-L-B, the linking group L is -C-D-, and when the connection direction of L is not specified, -A-L-B includes -A-C-D-B and -A-D-C-B.
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
在本发明中,术语“烷基”是指饱和的直链或支链的一价烃基。C1-4烷基是指具有1-4个碳原子的烷基,其具体为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In the present invention, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. C1-4 alkyl refers to an alkyl group having 1 to 4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在本发明中,术语“亚烷基”是指饱和的直链或支链的二价烃基。C1-4亚烷基是指具有1-4个碳原子的亚烷基,其具体为亚甲基、亚乙基(例如-CH2CH2-、-CH(CH3)-)、亚丙基(例如-CH2CH2CH2-、-C(CH3)2-、-CH2CH(CH3)-)、亚丁基(例如-CH2CH2CH2CH2-、-CH(CH3)CH(CH3)-、-CH2CH(CH3)CH2-)。In the present invention, the term "alkylene" refers to a saturated straight or branched divalent hydrocarbon group. C1-4 alkylene refers to an alkylene group having 1 to 4 carbon atoms, specifically methylene, ethylene (e.g., -CH2CH2- , -CH( CH3 )-), propylene (e.g. , -CH2CH2CH2- , -C( CH3 ) 2- , -CH2CH ( CH3 ) - ), butylene (e.g. , -CH2CH2CH2CH2- , -CH( CH3 )CH( CH3 )-, -CH2CH ( CH3 ) CH2- ).
在本发明中,卤素是指F、Cl、Br或I。In the present invention, halogen refers to F, Cl, Br or I.
术语“烷氧基”是指基团RX-O-,其中,RX为上文所定义的烷基。The term "alkoxy" refers to the group R X -O-, wherein R X is alkyl as defined above.
术语“环烷基”是指具有指定的碳原子数(例如C3~C6)的、仅由碳原子组成的、饱和的单环环状基团。环烷基包括但不限于环丙基、环丁基、环戊基、环己基等。The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms, having a specified number of carbon atoms (eg, C 3 to C 6 ). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
术语“杂环烷基”是指具有指定环原子数(例如5~12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团,其为单环、桥环或螺环,且每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基、哌啶基、哌嗪基等。The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, and the like.
术语“芳基”是指具有指定的碳原子数(例如C6~C10)的、仅由碳原子组成的环状基团,其为单环或多环,且至少一个环具有芳香性(符合休克尔规则)。芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。芳基包括但不限于苯基、萘基等。The term "aryl" refers to a cyclic group consisting only of carbon atoms with a specified number of carbon atoms (e.g., C 6 to C 10 ), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The aryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Aryl groups include, but are not limited to, phenyl, naphthyl, etc.
术语“杂芳基”是指具有指定环原子数(例如5~12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团,其为单环或多环,且至少一个环具有芳香性(符合休克尔规则)。杂芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。杂芳基包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、吲哚基等。The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
基团末端的“-”是指该基团通过该位点与分子中的其他片段连接。The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site.
结构片段中的是指该结构片段通过该位点与分子中的其他片段连接。例如,是指吗啉基通过与分子中的其他片段连接。In the structure fragment It means that the structural fragment is connected to other fragments in the molecule through this site. For example, The morpholinyl group Connect to other fragments in the molecule.
术语“多个”是指2个、3个、4个或5个。The term "plurality" refers to 2, 3, 4 or 5.
术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱、溶剂(包括但不限于:水、甲醇、乙醇等)结合形成的物质,其中,药学上可接受 的盐与上文术语“药学上可接受的盐”的含义相同,溶剂为化学计量的或非化学计量的。药学上可接受的盐的溶剂合物包括但不限于盐酸盐一水合物。The term "pharmaceutically acceptable salt solvate" refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base, and a solvent (including but not limited to: water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable The salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent is stoichiometric or non-stoichiometric. The solvate of the pharmaceutically acceptable salt includes but is not limited to hydrochloride monohydrate.
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化,但可由本领域技术人员视情况调整。The term "therapeutically effective amount" refers to the amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
术语“治疗”是指下述任一情形:(1)缓解疾病的一种或多种生物学表现;(2)干扰引发疾病的生物级联中的一个或多个点;(3)减缓疾病的一种或多种生物学表现发展。The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.
术语“预防”是指降低发生疾病的风险。The term "prevention" refers to reducing the risk of developing a disease.
术语“患者”是指已经或即将接受治疗的任何动物,优选哺乳动物,最优选人类。哺乳动物包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。The term "patient" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.
本发明的积极进步效果在于:本发明提供了一种全新结构的含苯环类化合物及其制备方法和应用。本发明的含苯环类化合物对PD-1/PD-L1结合具有抑制活性,从而能够用于诊断或治疗肿瘤等相关疾病。The positive progress of the present invention is that the present invention provides a benzene ring-containing compound with a completely new structure and a preparation method and application thereof. The benzene ring-containing compound of the present invention has inhibitory activity on PD-1/PD-L1 binding, and can be used to diagnose or treat tumors and other related diseases.
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.
实施例1
Example 1
化合物1-l的合成Synthesis of compound 1-1
将8-[(3-溴-2-甲基苯基)氨基]吡啶并[3,4-b]吡啶-3-甲醛(680mg,1.987mmol)、(3R)-四氢-1H-吡咯-3-醇(346.24mg,3.974mmol)和乙酸(0.228mL,3.974mmol)溶解在甲醇(10.0mL)中,加入氰 基硼氢化钠(0.057mL,3.974mmol),将反应液在60℃搅拌1.0小时。将反应液冷却至室温,减压浓缩,残余物依次用水(5mL×1)和乙醇(5mL×2)洗涤后得1-l(440mg,收率:53.57%),无需纯化直接用于下一步。LC-MS(ESI):m/z=414.5(M+H)+。8-[(3-bromo-2-methylphenyl)amino]pyrido[3,4-b]pyridine-3-carbaldehyde (680 mg, 1.987 mmol), (3R)-tetrahydro-1H-pyrrol-3-ol (346.24 mg, 3.974 mmol) and acetic acid (0.228 mL, 3.974 mmol) were dissolved in methanol (10.0 mL) and cyanogen was added. Sodium borohydride (0.057 mL, 3.974 mmol) was added, and the reaction solution was stirred at 60°C for 1.0 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was washed with water (5 mL×1) and ethanol (5 mL×2) in sequence to obtain 1-1 (440 mg, yield: 53.57%), which was used directly in the next step without purification. LC-MS (ESI): m/z=414.5(M+H) + .
化合物1-k的合成Synthesis of compound 1-k
将2,4-二羟基-5-硝基苯甲酸甲酯(2131.50mg,10mmol),Pd/C(212.84mg,0.200mmol)溶解在甲醇(20mL)中,将反应液在氢气球下室温搅拌3小时,反应液经硅藻土过滤,滤液减压浓缩,得1-k(1800mg,收率:98.27%),无需纯化直接进行下一步。LC-MS(ESI):m/z=184.73(M+H)+。Methyl 2,4-dihydroxy-5-nitrobenzoate (2131.50 mg, 10 mmol) and Pd/C (212.84 mg, 0.200 mmol) were dissolved in methanol (20 mL), and the reaction solution was stirred at room temperature for 3 hours under a hydrogen balloon, and the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 1-k (1800 mg, yield: 98.27%), which was directly carried out to the next step without purification. LC-MS (ESI): m/z = 184.73 (M+H) + .
化合物1-j的合成Synthesis of compound 1-j
将化合物1-k(1800mg,9.827mmol)和3-溴-2-甲基苯-1-甲醛(2151.77mg,10.810mmol)溶于乙醇(40mL)中,将反应液在80℃搅拌2小时。将反应液冷却至室温,减压浓缩,残余物溶解于二氯甲烷(40mL)中,加入二氧化锰(5126.16mg,58.962mmol),将反应液在室温搅拌1小时。反应液硅藻土过滤,滤液依次用7%次亚硫酸钠溶液(100mL×1)、碳酸氢钠溶液(100mL×2)洗涤。有机相无水硫酸钠干燥,过滤,减压浓缩,残余物经层析柱(乙酸乙酯:石油醚=1:1)纯化,得1-j(2700mg,收率:75.86%)。LC-MS(ESI):m/z=363.2(M+H)+。Compound 1-k (1800 mg, 9.827 mmol) and 3-bromo-2-methylbenzene-1-carboxaldehyde (2151.77 mg, 10.810 mmol) were dissolved in ethanol (40 mL), and the reaction solution was stirred at 80 ° C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (40 mL), and manganese dioxide (5126.16 mg, 58.962 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was washed with 7% sodium hyposulfite solution (100 mL×1) and sodium bicarbonate solution (100 mL×2) in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography column (ethyl acetate: petroleum ether = 1:1) to obtain 1-j (2700 mg, yield: 75.86%). LC-MS (ESI): m/z=363.2(M+H) + .
化合物1-i的合成Synthesis of compound 1-i
将化合物1-j(543.27mg,1.5mmol),2-甲基丙-2-基4-(碘甲基)六氢吡啶-1-羧酸酯(975.57mg,3.000mmol),碳酸钾(414.63mg,3.000mmol)溶解在N,N-二甲基甲酰胺(5.0mL)中,将反应液在80℃加热搅拌16小时。将反应液冷却至室温,加水(30mL)稀释,用乙酸乙酯(40mL×2)萃取。分出的有机相无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析(石油醚:乙酸乙酯=3:1)纯化,得1-i(620mg,收率:73.88%)。LC-MS(ESI):m/z=560.3(M+H)+。Compound 1-j (543.27 mg, 1.5 mmol), 2-methylpropan-2-yl 4-(iodomethyl)piperidin-1-carboxylate (975.57 mg, 3.000 mmol), potassium carbonate (414.63 mg, 3.000 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), and the reaction solution was heated and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (40 mL×2). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 1-i (620 mg, yield: 73.88%). LC-MS (ESI): m/z = 560.3 (M+H) + .
化合物1-h的合成Synthesis of compound 1-h
化合物1-i(620mg,1.108mmol)溶于四氢呋喃(7.0mL),将反应液降至-78℃,滴加二异丁基氢化铝(3.0mL,3.000mmol)。滴加完毕,将反应液在-78℃搅拌2小时。将反应液加温至0℃,加水(114mL)淬灭,依次加入15%NaOH溶液(114mL)和水(340mL)。过滤,滤液加压浓缩,得1-h(450mg,收率:76.41%),粗品无需纯化,直接进行下一步。LC-MS(ESI):m/z=532.5(M+H)+。Compound 1-i (620 mg, 1.108 mmol) was dissolved in tetrahydrofuran (7.0 mL), the reaction solution was cooled to -78 °C, and diisobutylaluminum hydride (3.0 mL, 3.000 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at -78 °C for 2 hours. The reaction solution was heated to 0 °C, quenched with water (114 mL), and 15% NaOH solution (114 mL) and water (340 mL) were added in sequence. Filtered, the filtrate was concentrated under pressure to obtain 1-h (450 mg, yield: 76.41%), the crude product did not need to be purified, and was directly carried out to the next step. LC-MS (ESI): m/z = 532.5 (M+H) + .
化合物1-g的合成Synthesis of compound 1-g
将化合物1-h(450mg,0.847mmol)溶解在二氯甲烷(20mL)中,加入二氧化锰(1030.62mg,11.854mmol)。将反应液在室温搅拌96小时,过滤,将滤液减压浓缩,残余物柱层析(石油醚:乙酸乙酯=3:1)纯化,得1-g(413mg,收率:92.13%)。LC-MS(ESI):m/z=530.5(M+H)+。Compound 1-h (450 mg, 0.847 mmol) was dissolved in dichloromethane (20 mL), and manganese dioxide (1030.62 mg, 11.854 mmol) was added. The reaction solution was stirred at room temperature for 96 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 1-g (413 mg, yield: 92.13%). LC-MS (ESI): m/z = 530.5 (M+H) + .
化合物1-f的合成Synthesis of compound 1-f
将化合物1-g(413mg,0.780mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1,3,2-二氧硼烷(396.19mg,1.560mmol)、二氯[1,1'-二(二苯基膦)二茂铁]钯(57.08mg,0.078mmol)、醋酸钾(153.11mg,1.560mmol)溶解在二氧六环(5.0mL)中,将反应液在氮气保护下90℃加热16小时。将反应液冷却至室温,反应液二氯甲烷(40mL)稀释,用水(10mL×1)洗。有机相无水硫酸 钠干燥,过滤,减压浓缩,残余物柱层析(石油醚:乙酸乙酯=5:1)纯化,得1-f(220mg,收率:84.86%)。LC-MS(ESI):m/z=577.6(M+H)+。Compound 1-g (413 mg, 0.780 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (396.19 mg, 1.560 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (57.08 mg, 0.078 mmol), potassium acetate (153.11 mg, 1.560 mmol) were dissolved in dioxane (5.0 mL), and the reaction solution was heated at 90 ° C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with dichloromethane (40 mL), and washed with water (10 mL × 1). The organic phase was anhydrous sulfuric acid Dry over sodium, filter, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 1-f (220 mg, yield: 84.86%). LC-MS (ESI): m/z=577.6 (M+H) + .
化合物1-e的合成Synthesis of compound 1-e
将混合物1-f(330mg,0.572mmol)、化合物1-l(260.25mg,0.630mmol)、二氯[1,1'-二(二苯基膦)二茂铁]钯(41.88mg,0.057mmol)和碳酸钾(158.23mg,1.145mmol)溶解在二氧六环(0.5mL)和水(0.6mL)中,将反应液在氮气保护下100℃搅拌16小时。将反应液冷却至室温,加水(10mL)稀释,混合液用二氯甲烷(20mL)萃取。分出的有机相,无水硫酸钠干燥,过滤,减压浓缩,得1-e(448mg,收率:99.96%),无需纯化直接进行下一步。LC-MS(ESI):m/z=783.9(M+H)+。The mixture 1-f (330 mg, 0.572 mmol), compound 1-1 (260.25 mg, 0.630 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (41.88 mg, 0.057 mmol) and potassium carbonate (158.23 mg, 1.145 mmol) were dissolved in dioxane (0.5 mL) and water (0.6 mL), and the reaction solution was stirred at 100 ° C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (10 mL), and the mixed solution was extracted with dichloromethane (20 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-e (448 mg, yield: 99.96%), which was directly carried out to the next step without purification. LC-MS (ESI): m/z = 783.9 (M+H) + .
化合物1-d的合成Synthesis of compound 1-d
将化合物1-e(448mg,0.572mmol)、(3R)-四氢-1H-吡咯-3-羧酸甲酯盐酸盐(189.54mg,1.144mmol)和三乙胺(0.159mL,1.144mmol)溶解在甲醇(2mL)和四氢呋喃(4mL)中,加入氰基硼氢化钠(71.91mg,1.144mmol)。将反应液在60℃搅拌1小时。将反应液冷却至室温,减压浓缩,残余物柱层析(乙酸乙酯:乙醇=10:1,乙醇中添加1%氨水)纯化,得1-d(315mg,收率:61.43%)。LC-MS(ESI):m/z=897.2(M+H)+。Compound 1-e (448 mg, 0.572 mmol), (3R)-tetrahydro-1H-pyrrole-3-carboxylic acid methyl ester hydrochloride (189.54 mg, 1.144 mmol) and triethylamine (0.159 mL, 1.144 mmol) were dissolved in methanol (2 mL) and tetrahydrofuran (4 mL), and sodium cyanoborohydride (71.91 mg, 1.144 mmol) was added. The reaction solution was stirred at 60°C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: ethanol = 10: 1, 1% ammonia water was added to ethanol) to obtain 1-d (315 mg, yield: 61.43%). LC-MS (ESI): m/z = 897.2 (M+H) + .
化合物1-c的合成Synthesis of compound 1-c
将化合物1-d(315mg,0.352mmol)溶解在甲醇(2.0mL)中,加入将盐酸二氧六环溶液(2.0mL),将反应液室温搅拌2小时,将反应液减压浓缩,得1-c(318mg,收率:99.78%),无需纯化直接进行下一步反应。LC-MS(ESI):m/z=796.9(M+H)+。Compound 1-d (315 mg, 0.352 mmol) was dissolved in methanol (2.0 mL), and dioxane hydrochloride solution (2.0 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain 1-c (318 mg, yield: 99.78%), which was directly used for the next step without purification. LC-MS (ESI): m/z = 796.9 (M+H) + .
化合物1-b的合成Synthesis of compound 1-b
将化合物1-c(318mg,0.351mmol)、(4,7,10-三{2-[(2-甲基丙-2-基)氧基]-2-氧乙基}-1,4,7,10-四氮杂环十二烷-1-基)乙酸(201.17mg,0.351mmol)和乙基二异丙胺(0.290mL,1.756mmol)溶解在二甲基甲酰胺(4.0mL)中,将反应液在室温下搅拌10分钟。加入O-(IH-苯并三唑-1-基)-N,N,N’,N’-四甲基异脲六氟化磷(266.41mg,0.702mmol),继续室温搅拌1小时。将反应液减压浓缩,残余物柱层析(二氯甲烷:甲醇(2%氨水)=5:1)纯化,得1-b(370mg,收率:77.99%)。LC-MS(ESI):m/z=1351.7(M+H)+。Compound 1-c (318 mg, 0.351 mmol), (4,7,10-tri{2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (201.17 mg, 0.351 mmol) and ethyldiisopropylamine (0.290 mL, 1.756 mmol) were dissolved in dimethylformamide (4.0 mL), and the reaction solution was stirred at room temperature for 10 minutes. O-(IH-benzotriazole-1-yl)-N,N,N',N'-tetramethylisourea phosphorus hexafluoride (266.41 mg, 0.702 mmol) was added, and stirring was continued at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol (2% ammonia water) = 5:1) to obtain 1-b (370 mg, yield: 77.99%). LC-MS (ESI): m/z=1351.7(M+H) + .
化合物1-a的合成Synthesis of compound 1-a
将化合物1-b(180mg,0.133mmol)溶解在二氯甲烷(2.0mL)中,加入三氟乙酸(2.0mL,0.133mmol),将反应液在室温搅拌16小时,减压浓缩,得1-a(248mg,收率:99.90%),无需纯化直接进行下一步。LC-MS(ESI):m/z=1183.4(M+H)+。Compound 1-b (180 mg, 0.133 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.0 mL, 0.133 mmol) was added, the reaction solution was stirred at room temperature for 16 hours, and concentrated under reduced pressure to obtain 1-a (248 mg, yield: 99.90%), which was directly carried out to the next step without purification. LC-MS (ESI): m/z = 1183.4 (M+H) + .
化合物1的合成Synthesis of compound 1
将化合物1-a(248mg,0.133mmol)溶解在甲醇(1.0mL)、四氢呋喃(1.0mL)和水(0.5mL)中,加入氢氧化锂(111.50mg,2.657mmol),将反应液在室温搅拌1小时。将反应液用乙酸中和至pH=6,经Pre-HPLC制备纯化(TFA条件),得1(130mg,收率:56.22%)。LC-MS(ESI):m/z=1169.3(M+H)+。Compound 1-a (248 mg, 0.133 mmol) was dissolved in methanol (1.0 mL), tetrahydrofuran (1.0 mL) and water (0.5 mL), lithium hydroxide (111.50 mg, 2.657 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was neutralized with acetic acid to pH = 6, and purified by Pre-HPLC (TFA conditions) to obtain 1 (130 mg, yield: 56.22%). LC-MS (ESI): m/z = 1169.3 (M+H) + .
实施例2
Example 2
化合物2的合成Synthesis of compound 2
将化合物1(11.68mg,0.01mmol)溶解在0.2M乙酸/乙酸钠缓冲溶液(pH=4.5,0.6mL)中,加入三氯化镥(5.63mg,0.020mmol),将反应液在90℃加热10分钟。反应液反相制备,得2(11.5mg,收率:85.82%)。LC-MS(ESI):m/z=1341.3(M+H)+。Compound 1 (11.68 mg, 0.01 mmol) was dissolved in 0.2 M acetic acid/sodium acetate buffer solution (pH=4.5, 0.6 mL), lutetium trichloride (5.63 mg, 0.020 mmol) was added, and the reaction solution was heated at 90°C for 10 minutes. The reaction solution was prepared by reverse phase to obtain 2 (11.5 mg, yield: 85.82%). LC-MS (ESI): m/z=1341.3 (M+H) + .
实施例3
Example 3
化合物3-o的合成Synthesis of compound 3-o
将4-羟基-3-(三氟甲基)苯-1-甲醛(3000mg,15.780mmol)溶解在硫酸(30mL)中,将反应液降低至0℃,向反应液中滴加硝酸(1835.57mg,18.935mmol)。反应液在0℃搅拌1小时。将反应液倒入剧烈搅拌的冰水(100mL)中。将析出的固体过滤,滤饼用水(30mL×1)洗涤,干燥得黄色固体3-o(3300mg,收率:88.95%)。LC-MS(ESI):m/z=236.2(M+H)+。Dissolve 4-hydroxy-3-(trifluoromethyl)benzene-1-carboxaldehyde (3000 mg, 15.780 mmol) in sulfuric acid (30 mL), lower the reaction solution to 0°C, and add nitric acid (1835.57 mg, 18.935 mmol) dropwise to the reaction solution. Stir the reaction solution at 0°C for 1 hour. Pour the reaction solution into vigorously stirred ice water (100 mL). Filter the precipitated solid, wash the filter cake with water (30 mL×1), and dry to obtain a yellow solid 3-o (3300 mg, yield: 88.95%). LC-MS (ESI): m/z=236.2(M+H) + .
化合物3-n的合成Synthesis of compound 3-n
将化合物3-o(3000mg,12.759mmol)和四氢-1H-吡咯(2.096mL,25.519mmol)溶解在甲醇(30.0mL)中,加入氰基硼氢化钠(1603.61mg,25.519mmol),将反应液在室温搅拌3小时。减压浓缩,残余物加水(20mL),二氯甲烷(50mL×2)萃取。合并的有机相无水硫酸钠干燥,过滤,减压浓缩。用乙酸乙酯(20mL)洗涤,干燥得黄色固体状3-n(2270mg,收率:61.30%)。LC-MS(ESI):m/z=291.3(M+H)+。Compound 3-o (3000 mg, 12.759 mmol) and tetrahydro-1H-pyrrole (2.096 mL, 25.519 mmol) were dissolved in methanol (30.0 mL), sodium cyanoborohydride (1603.61 mg, 25.519 mmol) was added, and the reaction solution was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue, and extracted with dichloromethane (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was washed with ethyl acetate (20 mL) and dried to obtain 3-n as a yellow solid (2270 mg, yield: 61.30%). LC-MS (ESI): m/z=291.3 (M+H) + .
化合物3-m的合成Synthesis of compound 3-m
将化合物3-n(1980mg,6.822mmol)溶解在甲醇(50.0mL)中,加入Pd/C 10%(217.80mg,0.205mmol),将反应液在氢气球下室温搅拌6小时。将反应液过滤,减压浓缩,得棕色固体3-m(1775mg,收率:99.97%)。无需纯化直接进行下一步。LC-MS(ESI):m/z=261.3(M+H)+。Compound 3-n (1980 mg, 6.822 mmol) was dissolved in methanol (50.0 mL), Pd/C 10% (217.80 mg, 0.205 mmol) was added, and the reaction solution was stirred at room temperature for 6 hours under a hydrogen balloon. The reaction solution was filtered and concentrated under reduced pressure to obtain a brown solid 3-m (1775 mg, yield: 99.97%). The next step was carried out directly without purification. LC-MS (ESI): m/z = 261.3 (M+H) + .
化合物3-l的合成Synthesis of compound 3-1
将化合物3-m(1041.04mg,4.0mmol)和3-溴-2-甲基苯-1-甲醛(796.20mg,4.000mmol)溶解在甲醇(20mL)中,将反应液在80℃加热搅拌3小时,将反应液冷却至室温,减压浓缩。残余物用二氯甲烷(20mL)溶解,分批加入二氧化锰(4100mg,47.159mmol)。将反应液室温搅拌16小时,反应液过滤,滤液减压浓缩,残余物柱层析(石油醚:乙酸乙酯(乙酸乙酯中添加5%7M甲醇氨溶液)=1:1)得红色固体3-l(634mg,收率:36.08%)。LC-MS(ESI):m/z=440.5(M+H)+。Compound 3-m (1041.04 mg, 4.0 mmol) and 3-bromo-2-methylbenzene-1-carboxaldehyde (796.20 mg, 4.000 mmol) were dissolved in methanol (20 mL), the reaction solution was heated and stirred at 80 ° C for 3 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), and manganese dioxide (4100 mg, 47.159 mmol) was added in batches. The reaction solution was stirred at room temperature for 16 hours, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate (5% 7M methanolic ammonia solution in ethyl acetate) = 1: 1) to obtain a red solid 3-1 (634 mg, yield: 36.08%). LC-MS (ESI): m/z = 440.5 (M+H) + .
化合物3-k的合成Synthesis of compound 3-k
将2,4-二羟基-5-硝基苯甲酸甲酯(2900mg,13.605mmol)溶解在甲醇(20mL)中,加入Pd/C 10%(289.58mg,0.272mmol),将反应液在氢气球下室温搅拌3小时,反应液经硅藻土过滤,将滤液减压浓缩,得灰色固体3-k(2480mg,收率:99.52%),无需纯化直接进行下一步。LC-MS(ESI):m/z=184.3(M+H)+。Methyl 2,4-dihydroxy-5-nitrobenzoate (2900 mg, 13.605 mmol) was dissolved in methanol (20 mL) and Pd/C was added. 10% (289.58 mg, 0.272 mmol), the reaction solution was stirred at room temperature for 3 hours under a hydrogen balloon, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a gray solid 3-k (2480 mg, yield: 99.52%), which was directly carried out to the next step without purification. LC-MS (ESI): m/z=184.3 (M+H) + .
化合物3-j的合成Synthesis of compound 3-j
将化合物3-k(2480mg,13.540mmol)和3-溴-2-甲基苯-1-甲醛(2964.67mg,14.894mmol)溶于甲醇(40mL)中,将反应液回流搅拌2小时。将反应液冷却至室温,将反应液减压浓缩,残余物重新溶于二氯甲烷(40mL)中,加入二氧化锰(7063.04mg,81.240mmol),反应液在室温搅拌1小时。反应液硅藻土过滤,滤液依次用7%硫代硫酸钠溶液(100mL×1)、碳酸氢钠溶液(100mL×2)洗涤。有机相无水硫酸钠干燥,过滤,减压浓缩,残余物乙酸乙酯:石油醚=1:1(50mL)洗涤,减压浓缩得淡灰色固体3-j(4200mg,收率:85.65%)。LC-MS(ESI):m/z=363.5(M+H)+。Compound 3-k (2480 mg, 13.540 mmol) and 3-bromo-2-methylbenzene-1-carboxaldehyde (2964.67 mg, 14.894 mmol) were dissolved in methanol (40 mL), and the reaction solution was refluxed and stirred for 2 hours. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was redissolved in dichloromethane (40 mL), and manganese dioxide (7063.04 mg, 81.240 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was washed with 7% sodium thiosulfate solution (100 mL×1) and sodium bicarbonate solution (100 mL×2) in turn. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with ethyl acetate: petroleum ether = 1:1 (50 mL), and concentrated under reduced pressure to obtain a light gray solid 3-j (4200 mg, yield: 85.65%). LC-MS (ESI): m/z=363.5(M+H) + .
化合物3-i的合成Synthesis of compound 3-i
将化合物3-j(2500mg,6.903mmol)和2-甲基丙-2-基4-(碘甲基)六氢吡啶-1-羧酸酯(4489.34mg,13.805mmol)溶解在N,N-二甲基甲酰胺(25.0mL)中,加入碳酸钾(1908.03mg,13.805mmol),将反应液在80℃加热搅拌16小时。将反应液冷却至室温,加水(30mL)稀释,用乙酸乙酯(40mL×2)萃取。将有机相无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析(石油醚:乙酸乙酯=3:1)得白色泡沫状3-i(2500mg,收率:64.74%)。LC-MS(ESI):m/z=560.5(M+H)+。Compound 3-j (2500 mg, 6.903 mmol) and 2-methylpropan-2-yl 4-(iodomethyl)piperidin-1-carboxylate (4489.34 mg, 13.805 mmol) were dissolved in N,N-dimethylformamide (25.0 mL), potassium carbonate (1908.03 mg, 13.805 mmol) was added, and the reaction solution was heated and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (40 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain white foam 3-i (2500 mg, yield: 64.74%). LC-MS (ESI): m/z = 560.5 (M+H) + .
化合物3-h的合成Synthesis of compound 3-h
将化合物3-i(1678.38mg,3.0mmol)溶于四氢呋喃(20.0mL)中,-78℃下滴加二异丁基氢化铝,1.0M(6.600mL,6.600mmol)。滴加完毕,-78℃搅拌2小时,将反应液升至0℃,加水(114mg)淬灭,依次加入15%氢氧化钠溶液(114mL)和水(340mL)。过滤,滤液减压浓缩,得白色泡沫3-h(1594mg,收率:99.98%),无需纯化直接进行下一步。LC-MS(ESI):m/z=532.6(M+H)+。Compound 3-i (1678.38 mg, 3.0 mmol) was dissolved in tetrahydrofuran (20.0 mL), and diisobutylaluminum hydride, 1.0 M (6.600 mL, 6.600 mmol) was added dropwise at -78 °C. After the addition was completed, the mixture was stirred at -78 °C for 2 hours, the reaction solution was raised to 0 °C, water (114 mg) was added to quench, and 15% sodium hydroxide solution (114 mL) and water (340 mL) were added in sequence. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain white foam 3-h (1594 mg, yield: 99.98%), which was directly carried out to the next step without purification. LC-MS (ESI): m/z = 532.6 (M+H) + .
化合物3-g的合成Synthesis of compound 3-g
将化合物3-h(1594mg,2.999mmol)溶于二氯甲烷(30mL)中,加入二氧化锰(4100mg,47.159mmol)。将反应液室温搅拌96小时,过滤,将滤液减压浓缩,残余物柱层析(石油醚:乙酸乙酯=3:1)得白色固体3-g(1100mg,收率:69.27%)。LC-MS(ESI):m/z=530.2(M+H)+。Compound 3-h (1594 mg, 2.999 mmol) was dissolved in dichloromethane (30 mL), and manganese dioxide (4100 mg, 47.159 mmol) was added. The reaction solution was stirred at room temperature for 96 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid 3-g (1100 mg, yield: 69.27%). LC-MS (ESI): m/z = 530.2 (M+H) + .
化合物3-f的合成Synthesis of compound 3-f
将化合物3-g(1000mg,1.889mmol)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1,3,2-二氧硼烷(959.30mg,3.778mmol)溶解在二氧六环(5.0mL)中,加入二氯[1,1'-二(二苯基膦)二茂铁]钯(138.21mg,0.189mmol)和醋酸钾(370.74mg,3.778mmol),将反应液在氮气保护下90℃加热16小时。将反应液冷却至室温,二氯甲烷(40mL)稀释,水(10mL×1)洗涤。有机相无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析(石油醚:乙酸乙酯=5:1)得白色固体3-f(220mg,收率:84.86%)。LC-MS(ESI):m/z=577.5(M+H)+。Compound 3-g (1000 mg, 1.889 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (959.30 mg, 3.778 mmol) were dissolved in dioxane (5.0 mL), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (138.21 mg, 0.189 mmol) and potassium acetate (370.74 mg, 3.778 mmol) were added, and the reaction solution was heated at 90°C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with dichloromethane (40 mL), and washed with water (10 mL×1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain a white solid 3-f (220 mg, yield: 84.86%). LC-MS (ESI): m/z=577.5 (M+H) + .
化合物3-e的合成Synthesis of compound 3-e
将化合物3-f(345.90mg,0.6mmol)和化合物3-l(260.25mg,0.630mmol)溶解于二氧六环(0.5 mL)和水(0.6mL)中,加入二氯[1,1'-二(二苯基膦)二茂铁]钯(43.90mg,0.060mmol)和碳酸钾(165.85mg,1.200mmol),将反应液在氮气保护下100℃搅拌4小时。将反应液冷却至室温,加水(10mL)稀释,二氯甲烷(20mL)萃取。合并有机相无水硫酸钠干燥,过滤,减压浓缩,得3-e(448mg,收率:99.96%),无需纯化直接进行下一步。LC-MS(ESI):m/z=809.6(M+H)+。Compound 3-f (345.90 mg, 0.6 mmol) and compound 3-1 (260.25 mg, 0.630 mmol) were dissolved in dioxane (0.5 mL) and water (0.6 mL), add dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (43.90 mg, 0.060 mmol) and potassium carbonate (165.85 mg, 1.200 mmol), and stir the reaction solution at 100°C for 4 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-e (448 mg, yield: 99.96%), which was directly carried out to the next step without purification. LC-MS (ESI): m/z=809.6(M+H) + .
化合物3-d的合成Synthesis of compound 3-d
将化合物3-e(550mg,0.476mmol)、(2S)-四氢-1H-吡咯-2-羧酸甲酯(122.96mg,0.95mmol)和三乙胺(0.132mL,0.952mmol)溶解在甲醇(5.0mL)和四氢呋喃(5.0mL)中,加入氰基硼氢化钠(59.82mg,0.952mmol),将反应液在60℃加热1小时。将反应液冷却至室温,减压浓缩,残余物柱层析(石油醚:乙酸乙酯:三乙胺=100:100:1)得3-d(377mg,收率:85.90%)。LC-MS(ESI):m/z=923.1(M+H)+。Compound 3-e (550 mg, 0.476 mmol), (2S)-tetrahydro-1H-pyrrole-2-carboxylic acid methyl ester (122.96 mg, 0.95 mmol) and triethylamine (0.132 mL, 0.952 mmol) were dissolved in methanol (5.0 mL) and tetrahydrofuran (5.0 mL), sodium cyanoborohydride (59.82 mg, 0.952 mmol) was added, and the reaction solution was heated at 60°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate: triethylamine = 100: 100: 1) to obtain 3-d (377 mg, yield: 85.90%). LC-MS (ESI): m/z = 923.1 (M+H) + .
化合物3-c的合成Synthesis of compound 3-c
将化合物3-d(377mg,0.409mmol)溶于甲醇(2.0mL),加入盐酸二氧六环溶液(2.0mL)。将反应液室温搅拌2小时,反应液减压浓缩,得黄色固体3-c(380mg,收率:99.79%)。无需纯化直接进行下一步反应。LC-MS(ESI):m/z=822.9(M+H)+。Compound 3-d (377 mg, 0.409 mmol) was dissolved in methanol (2.0 mL), and dioxane hydrochloride solution (2.0 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain a yellow solid 3-c (380 mg, yield: 99.79%). The next step reaction was carried out directly without purification. LC-MS (ESI): m/z = 822.9 (M+H) + .
化合物3-b的合成Synthesis of compound 3-b
将化合物3-c(380mg,0.408mmol)、(4,7,10-三{2-[(2-甲基丙-2-基)氧基]-2-氧乙基}-1,4,7,10-四氮杂环十二烷-1-基)乙酸(280.43mg,0.490mmol)和O-(IH-苯并三唑-1-基)-N,N,N’,N’-四甲基异脲六氟化磷(232.11mg,0.612mmol)溶于N,N-二甲基甲酰胺(5.0mL)中,加入乙基二异丙胺(0.337mL,2.040mmol)。将反应液在室温搅拌1小时。反应液减压浓缩,柱层析(二氯甲烷:甲醇(含5%7M甲醇氨溶液)=2:1)得黄色泡沫状3-b(480mg,收率:53.84%)。LC-MS(ESI):m/z=1377.7(M+H)+。Compound 3-c (380 mg, 0.408 mmol), (4,7,10-tri{2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (280.43 mg, 0.490 mmol) and O-(IH-benzotriazole-1-yl)-N,N,N',N'-tetramethylisourea phosphorus hexafluoride (232.11 mg, 0.612 mmol) were dissolved in N,N-dimethylformamide (5.0 mL), and ethyl diisopropylamine (0.337 mL, 2.040 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and column chromatography (dichloromethane: methanol (containing 5% 7M methanolic ammonia solution) = 2:1) was performed to obtain yellow foam 3-b (480 mg, yield: 53.84%). LC-MS (ESI): m/z=1377.7(M+H) + .
化合物3-a的合成Synthesis of compound 3-a
将化合物3-b(480mg,0.220mmol)溶于二氯甲烷(5.0mL),加入三氟乙酸(5.0mL,0.220mmol)。将反应液在室温搅拌24小时,将反应液减压浓缩得3-a(167mg,收率:62.92)。无需纯化直接进行下一步。LC-MS(ESI):m/z=1209.3(M+H)+。Compound 3-b (480 mg, 0.220 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (5.0 mL, 0.220 mmol) was added. The reaction solution was stirred at room temperature for 24 hours, and the reaction solution was concentrated under reduced pressure to obtain 3-a (167 mg, yield: 62.92). The next step was carried out directly without purification. LC-MS (ESI): m/z = 1209.3 (M+H) + .
化合物3的合成Synthesis of compound 3
将化合物3-a(167mg,0.138mmol)溶解在甲醇(2.0mL)、四氢呋喃(2.0mL)和水(1.0mL)中,加入氢氧化锂(86.99mg,2.073mmol),室温下搅拌1小时。反应液反相制备色谱分离得白色固体3(130mg,收率:78.76%)。LC-MS(ESI):m/z=1195.6(M+H)+。Compound 3-a (167 mg, 0.138 mmol) was dissolved in methanol (2.0 mL), tetrahydrofuran (2.0 mL) and water (1.0 mL), lithium hydroxide (86.99 mg, 2.073 mmol) was added, and stirred at room temperature for 1 hour. The reaction solution was separated by reverse phase preparative chromatography to obtain a white solid 3 (130 mg, yield: 78.76%). LC-MS (ESI): m/z = 1195.6 (M+H) + .
实施例4
Example 4
化合物4的合成Synthesis of compound 4
将化合物3(11.94mg,0.01mmol)溶于0.2M醋酸钠/醋酸缓冲溶液(pH=4.5,0.5mL),加入三氯化镥(5.63mg,0.020mmol)。将反应液在90℃加热10分钟,将反应液冷却至室温,反相制备色谱纯化得4(13.2mg,收率:96.63%)。LC-MS(ESI):m/z=1367.2(M+H)+。Compound 3 (11.94 mg, 0.01 mmol) was dissolved in 0.2 M sodium acetate/acetic acid buffer solution (pH = 4.5, 0.5 mL), and lutetium trichloride (5.63 mg, 0.020 mmol) was added. The reaction solution was heated at 90°C for 10 minutes, cooled to room temperature, and purified by reverse phase preparative chromatography to obtain 4 (13.2 mg, yield: 96.63%). LC-MS (ESI): m/z = 1367.2 (M+H) + .
实施例5
Example 5
化合物5-d的合成Synthesis of compound 5-d
在0℃下,将2-甲基丙-2-基溴乙酸酯(3019.14mg,15.478mmol)溶解于乙腈(40mL)的溶液,滴加进1,4,7-三氮烷(1000mg,7.739mmol)溶解于乙腈(10mL)溶液中,滴加完毕将反应液在室温搅拌24小时,将反应液减压浓缩,用纯水(5mL)稀释。将混合液用1M盐酸将反应液调节至pH=3。将反应液用甲基叔丁基醚(15mL×3)萃取,混合液用1M氢氧化钠溶液调节pH=8,用二氯甲烷(20mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩得5-d(1200mg,收率:43.37%)。LC-MS(ESI):m/z=358.5(M+H)+。At 0°C, 2-methylpropan-2-yl bromoacetate (3019.14 mg, 15.478 mmol) was dissolved in acetonitrile (40 mL), and 1,4,7-triazine (1000 mg, 7.739 mmol) was dissolved in acetonitrile (10 mL) and added dropwise. After the addition was completed, the reaction solution was stirred at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure, and diluted with pure water (5 mL). The mixed solution was adjusted to pH = 3 with 1M hydrochloric acid. The reaction solution was extracted with methyl tert-butyl ether (15 mL × 3), the mixed solution was adjusted to pH = 8 with 1M sodium hydroxide solution, extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-d (1200 mg, yield: 43.37%). LC-MS (ESI): m/z = 358.5 (M+H) + .
化合物5-c的合成Synthesis of compound 5-c
将化合物5-d(715.00mg,2.0mmol)和碳酸钾(552.84mg,4.00mmol)溶解于甲醇(10mL)和水(10mL)中,加入溴乙酸(383.48mg,2.76mmol)。将反应液在室温搅拌过夜,用盐酸(1mol/L)调节pH值至6,反应液用二氯甲烷(50mL×2)萃取。合并有机相,无水硫酸钠干燥,过滤,减压浓缩得5-c(610mg,收率:73.40%)。LC-MS(ESI):m/z=416.7(M+H)+。Compound 5-d (715.00 mg, 2.0 mmol) and potassium carbonate (552.84 mg, 4.00 mmol) were dissolved in methanol (10 mL) and water (10 mL), and bromoacetic acid (383.48 mg, 2.76 mmol) was added. The reaction solution was stirred at room temperature overnight, and the pH value was adjusted to 6 with hydrochloric acid (1 mol/L). The reaction solution was extracted with dichloromethane (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-c (610 mg, yield: 73.40%). LC-MS (ESI): m/z=416.7(M+H) + .
化合物5-b的合成Synthesis of compound 5-b
将化合物1-c(181mg,0.200mmol)、化合物5-c(99.69mg,0.240mmol)和二异丙基乙胺(0.363mL,2.199mmol)溶解于N,N-二甲基甲酰胺(2.0mL)中,将反应液在室温搅拌10分钟,加入O-苯并三氮唑-四甲基脲六氟磷酸酯(151.63mg,0.40mmol),将反应液继续搅拌1小时,将反应液减压浓缩,残余物直接Pre-HPLC纯化得5-b(90mg,收率:37.72%)。LC-MS(ESI):m/z=1194.3(M+H)+。Compound 1-c (181 mg, 0.200 mmol), compound 5-c (99.69 mg, 0.240 mmol) and diisopropylethylamine (0.363 mL, 2.199 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), the reaction solution was stirred at room temperature for 10 minutes, O-benzotriazole-tetramethyluronium hexafluorophosphate (151.63 mg, 0.40 mmol) was added, the reaction solution was stirred for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was directly purified by Pre-HPLC to obtain 5-b (90 mg, yield: 37.72%). LC-MS (ESI): m/z = 1194.3 (M+H) + .
化合物5-a的合成Synthesis of compound 5-a
将化合物5-b(90mg,0.055mmol)溶解于二氯甲烷(2.0mL)中,加入三氟乙酸(2.5mL,0.055mmol),将反应液在室温搅拌20小时,减压浓缩得5-a(103mg,收率:99.64%),无须纯化,直接进行下一步反应。LC-MS(ESI):m/z=1082.3(M+H)+。Compound 5-b (90 mg, 0.055 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (2.5 mL, 0.055 mmol) was added, the reaction solution was stirred at room temperature for 20 hours, and concentrated under reduced pressure to obtain 5-a (103 mg, yield: 99.64%), which was directly used for the next step without purification. LC-MS (ESI): m/z = 1082.3 (M+H) + .
化合物5的合成Synthesis of compound 5
将化合物5-a(103mg,0.055mmol)溶解于四氢呋喃(0.6mL)、甲醇(0.6mL)和水(0.3mL) 中,加入一水合氢氧化锂(45.99mg,1.096mmol),将反应液在室温搅拌1小时,直接Pre-HPLC纯化得5(41mg,收率:69.85%)。LC-MS(ESI):m/z=1067.89(M+H)+.Compound 5-a (103 mg, 0.055 mmol) was dissolved in tetrahydrofuran (0.6 mL), methanol (0.6 mL) and water (0.3 mL) Lithium hydroxide monohydrate (45.99 mg, 1.096 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour, and directly purified by Pre-HPLC to obtain 5 (41 mg, yield: 69.85%). LC-MS (ESI): m/z = 1067.89 (M+H) + .
1H NMR(400MHz,MeOD)δ:8.92(s,1H),8.23(s,1H),8.18(d,J=7.9Hz,1H),8.06(d,J=7.6Hz,1H),7.96(d,J=5.8Hz,1H),7.85(s,1H),7.51–7.23(m,4H),7.08(d,J=5.9Hz,1H),6.96(d,J=7.2Hz,1H),4.61–4.38(m,4H),4.20(dd,J=28.2,13.1Hz,2H),4.09–3.87(m,3H),3.82–3.67(m,2H),3.67–3.34(m,8H),3.24–2.59(m,19H),2.45(s,3H),2.41–2.31(m,1H),2.31–2.15(m,3H),2.08(s,3H),1.98–1.80(m,3H),1.43–1.15(m,2H). 1 H NMR (400MHz, MeOD) δ: 8.92 (s, 1H), 8.23 (s, 1H), 8.18 (d, J = 7.9Hz, 1H), 8.06 (d, J = 7.6Hz, 1H), 7.96 ( d,J=5.8Hz,1H),7.85(s,1H),7.51–7.23(m,4H),7.08(d,J=5.9Hz,1H),6.96(d,J=7.2Hz,1H), 4.61–4.38(m,4H) ,4.20(dd,J=28.2,13.1Hz,2H),4.09–3.87(m,3H),3.82–3.67(m,2H),3.67–3.34(m,8H),3.24–2.59(m,19H) ,2.45(s,3H),2.41–2.31(m,1H),2.31–2.15(m,3H),2.08(s,3H),1.98–1.80(m,3H),1.43–1.15(m,2H) .
实施例6
Example 6
化合物6的合成Synthesis of compound 6
将氯化铝(0.80mg,0.006mmol)溶解于乙酸钠-乙酸缓冲液(pH=4.6,0.6mL)中,加入氟化钠(0.31mg,0.008mmol),将反应液在室温搅拌5分钟。加入乙醇(0.3mL)和化合物5(5.34mg,0.005mmol),将反应液在100℃加热搅拌30分钟,将反应液冷却至室温。直接Pre-HPLC纯化得6(2.61mg,收率:46.94%)。LC-MS(ESI):m/z=1112.3(M+H)+。Aluminum chloride (0.80 mg, 0.006 mmol) was dissolved in sodium acetate-acetic acid buffer (pH = 4.6, 0.6 mL), sodium fluoride (0.31 mg, 0.008 mmol) was added, and the reaction solution was stirred at room temperature for 5 minutes. Ethanol (0.3 mL) and compound 5 (5.34 mg, 0.005 mmol) were added, and the reaction solution was heated and stirred at 100 ° C for 30 minutes, and the reaction solution was cooled to room temperature. Direct Pre-HPLC purification gave 6 (2.61 mg, yield: 46.94%). LC-MS (ESI): m/z = 1112.3 (M+H) + .
实施例7
Example 7
化合物7-f的合成Synthesis of compound 7-f
将化合物3-f(288.25mg,0.50mmol)和溴苯(0.105mL,1.000mmol)溶解在二氧六环(3.0mL)和水(0.6mL)中,加入碳酸钾(138.21mg,1.00mmol)和(1,1'-双(二苯基膦基)二茂铁)二氯化钯(36.59mg,0.050mmol),在氮气保护下,将反应液在90℃加热搅拌20小时,将反应液冷却至室温,减压浓缩,残余物柱层析(石油醚:乙酸乙酯=3:1)得7-f(190mg,收率:72.16%)。LC-MS(ESI):m/z=527.7(M+H)+。Compound 3-f (288.25 mg, 0.50 mmol) and bromobenzene (0.105 mL, 1.000 mmol) were dissolved in dioxane (3.0 mL) and water (0.6 mL), potassium carbonate (138.21 mg, 1.00 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (36.59 mg, 0.050 mmol) were added, and the reaction solution was heated and stirred at 90°C for 20 hours under nitrogen protection, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 7-f (190 mg, yield: 72.16%). LC-MS (ESI): m/z = 527.7 (M+H) + .
化合物7-e的合成Synthesis of compound 7-e
将化合物7-f(190mg,0.361mmol)、2-甲基丙-2-基(2S)-六氢吡啶-2-羧酸盐(103.8mg,0.722mmol)和醋酸(0.021mL,0.361mmol)溶于甲醇(3.0mL)。加入氰基硼氢化钠(90.69mg,1.443 mmol)。将反应液在60℃加热搅拌1小时。将反应液冷却至室温,减压浓缩,残余物用二氯甲烷(30mL)溶解,溶液用水(10mL)洗涤。分出的有机相,用无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析纯化(石油醚:乙酸乙酯=3:1,然后二氯甲烷:甲醇=5:1)得7-e(92mg,收率:48.21%)。LC-MS(ESI):m/z=529.8(M+H)+。Compound 7-f (190 mg, 0.361 mmol), 2-methylpropan-2-yl (2S)-piperidinium-2-carboxylate (103.8 mg, 0.722 mmol) and acetic acid (0.021 mL, 0.361 mmol) were dissolved in methanol (3.0 mL). Sodium cyanoborohydride (90.69 mg, 1.443 mmol). The reaction solution was heated and stirred at 60°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and the solution was washed with water (10 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1, then dichloromethane: methanol = 5: 1) to obtain 7-e (92 mg, yield: 48.21%). LC-MS (ESI): m/z = 529.8 (M+H) + .
化合物7-d的合成Synthesis of compound 7-d
将化合物7-e(92mg,0.174mmol)溶解于甲醇(1.0mL)中,加入盐酸二氧六环溶液(1.0mL)。将反应液在室温搅拌2小时,减压浓缩,得7-d(81mg,收率:100.10%),无须纯化直接进行下一步反应。LC-MS(ESI):m/z=429.5(M+H)+。Compound 7-e (92 mg, 0.174 mmol) was dissolved in methanol (1.0 mL), and dioxane hydrochloride solution (1.0 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain 7-d (81 mg, yield: 100.10%), which was directly used for the next step without purification. LC-MS (ESI): m/z = 429.5 (M+H) + .
化合物7-c的合成Synthesis of compound 7-c
将化合物7-d(81mg,0.174mmol)、(10-{1-[(2-甲基丙-2-基)氧基]-1-氧代乙基-2-基}-4,7-双{2-[(2-乙基丙-2-基氧基]-2-氧代乙基}-1,4,7,10-四氮杂环十二烷-1-基)乙酸(99.77mg,0.174mmol)和二异丙基乙胺(0.144mL,0.871mmol)溶解于N,N-二甲基甲酰胺(1.0mL)中,加入O-苯并三氮唑-四甲基脲六氟磷酸酯(132.13mg,0.348mmol)。将反应液在室温搅拌1小时。减压浓缩,残余物柱层析(二氯甲烷:甲醇=10:1)得7-c(171mg,收率:99.84%)。LC-MS(ESI):m/z=984.3(M+H)+。Compound 7-d (81 mg, 0.174 mmol), (10-{1-[(2-methylpropan-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-ethylpropan-2-yloxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (99.77 mg, 0.174 mmol) and diisopropylethylamine (0.144 mL, 0.87 1mmol) was dissolved in N,N-dimethylformamide (1.0mL), and O-benzotriazole-tetramethyluronium hexafluorophosphate (132.13mg, 0.348mmol) was added. The reaction solution was stirred at room temperature for 1 hour. It was concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane: methanol = 10: 1) to obtain 7-c (171mg, yield: 99.84%). LC-MS (ESI): m/z = 984.3 (M+H) + .
化合物7-b的合成Synthesis of compound 7-b
将化合物7-c(171mg,0.174mmol)溶解于二氯甲烷(3.0mL)中,加入二氧化锰(423.36mg,4.87mmol)。将反应液室温搅拌72小时。将反应液过滤,滤液减压浓缩得7-b(170mg,收率:99.62%),无须纯化直接进行下一步反应。LC-MS(ESI):m/z=982.5(M+H)+。Compound 7-c (171 mg, 0.174 mmol) was dissolved in dichloromethane (3.0 mL), and manganese dioxide (423.36 mg, 4.87 mmol) was added. The reaction solution was stirred at room temperature for 72 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 7-b (170 mg, yield: 99.62%), which was directly used for the next step without purification. LC-MS (ESI): m/z = 982.5 (M+H) + .
化合物7-a的合成Synthesis of compound 7-a
将化合物7-b(170mg,0.173mmol)和(2S)-六氢吡啶-2-羧酸(67.13mg,0.520mmol)溶解于甲醇(2.0mL)和四氢呋喃(1.0mL)中,加入氰基硼氢化钠(43.55mg,0.693mmol),将反应液在60℃加热搅拌1小时,将反应液冷却至室温,直接Pre-HPLC纯化得7-a(70mg,收率:36.92%)。LC-MS(ESI):m/z=1095.5(M+H)+。Compound 7-b (170 mg, 0.173 mmol) and (2S)-piperidine-2-carboxylic acid (67.13 mg, 0.520 mmol) were dissolved in methanol (2.0 mL) and tetrahydrofuran (1.0 mL), sodium cyanoborohydride (43.55 mg, 0.693 mmol) was added, the reaction solution was heated and stirred at 60°C for 1 hour, the reaction solution was cooled to room temperature, and 7-a (70 mg, yield: 36.92%) was directly purified by Pre-HPLC. LC-MS (ESI): m/z = 1095.5 (M+H) + .
化合物7的合成Synthesis of compound 7
将化合物7-a(105mg,0.096mmol)溶解于二氯甲烷(2.0mL)中,加入三氟乙酸(2.0mL)。将反应液室温搅拌24小时。直接Pre-HPLC纯化得7(44.0mg,收率:49.52%)。LC-MS(ESI):m/z=927.3(M+H)+。Compound 7-a (105 mg, 0.096 mmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (2.0 mL) was added. The reaction solution was stirred at room temperature for 24 hours. 7 (44.0 mg, yield: 49.52%) was obtained by direct Pre-HPLC purification. LC-MS (ESI): m/z = 927.3 (M+H) + .
1HNMR(400MHz,MeOD)δ:8.08-8.01(m,1H),7.96(s,1H),7.53(s,1H),7.50-7.29(m,7H),4.70(d,J=13.1Hz,1H),4.62(d,J=14.8Hz,1H),4.53(d,J=12.2Hz,1H),4.10(t,J=6.2Hz,2H),3.95–3.84(m,2H),3.83-3.35(m,17H),3.19-2.90(m,10H),2.72(t,J=11.7Hz,1H),2.55(s,3H),2.33–2.15(m,2H),2.05-1.81(m,4H),1.81-1.67(m,2H),1.67-1.50(m,2H),1.50-1.36(m,1H). 1 HNMR(400MHz,MeOD)δ:8.08-8.01(m,1H),7.96(s,1H),7.53(s,1H),7.50-7.29(m,7H),4.70(d,J=13.1Hz, 1H),4.62(d,J=14.8Hz,1H),4.53(d,J=12.2Hz,1H),4.10(t,J=6.2Hz,2H),3.95 –3.84(m,2H),3.83-3.35(m,17H),3.19-2.90(m,10H),2.72(t,J=11.7Hz,1H),2.55(s,3H),2.33–2.15(m ,2H),2.05-1.81(m,4H),1.81-1.67(m,2H),1.67-1.50(m,2H),1.50-1.36(m,1H).
实施例8
Example 8
化合物8-b的合成Synthesis of compound 8-b
将化合物3-c(182mg,0.195mmol)、化合物5-c(105.56mg,0.254mmol)和O-苯并三氮唑-四甲基脲六氟磷酸酯(111.17mg,0.293mmol)溶解于乙腈(3.0mL)中,加入二异丙基乙胺(0.323mL,1.954mmol),将反应液在室温搅拌1小时,反应液直接Pre-HPLC制备得8-b(173mg,收率:72.59%)。LC-MS(ESI):m/z=1220.5(M+H)+。Compound 3-c (182 mg, 0.195 mmol), compound 5-c (105.56 mg, 0.254 mmol) and O-benzotriazole-tetramethyluronium hexafluorophosphate (111.17 mg, 0.293 mmol) were dissolved in acetonitrile (3.0 mL), diisopropylethylamine (0.323 mL, 1.954 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was directly subjected to Pre-HPLC to prepare 8-b (173 mg, yield: 72.59%). LC-MS (ESI): m/z = 1220.5 (M+H) + .
化合物8-a的合成Synthesis of compound 8-a
将化合物8-b(173mg,0.111mmol)溶解于二氯甲烷(2.0mL)中,加入三氟乙酸(3.0mL,0.111mmol),将反应液在室温搅拌20小时,将反应液减压浓缩,残余物Pre-HPLC纯化得8-a(50mg,收率:40.76%)。LC-MS(ESI):m/z=1108.3(M+H)+。Compound 8-b (173 mg, 0.111 mmol) was dissolved in dichloromethane (2.0 mL), trifluoroacetic acid (3.0 mL, 0.111 mmol) was added, the reaction solution was stirred at room temperature for 20 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain 8-a (50 mg, yield: 40.76%). LC-MS (ESI): m/z = 1108.3 (M+H) + .
化合物8的合成Synthesis of compound 8
将化合物8-a(50mg,0.045mmol)溶解于甲醇(1.0mL)、四氢呋喃(1.00mL),水(0.50mL) 和一水合氢氧化锂(18.95mg,0.452mmol)中,将反应液在室温下搅拌1小时,反应液直接Pre-HPLC制备得8(41mg,收率:83.05%)。LC-MS(ESI):m/z=1094.5(M+H)+。Dissolve compound 8-a (50 mg, 0.045 mmol) in methanol (1.0 mL), tetrahydrofuran (1.00 mL), and water (0.50 mL). and lithium hydroxide monohydrate (18.95 mg, 0.452 mmol), the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was directly subjected to Pre-HPLC to obtain 8 (41 mg, yield: 83.05%). LC-MS (ESI): m/z = 1094.5 (M+H) + .
1H NMR(400MHz,MeOD)δ:8.23(d,J=6.8Hz,2H),8.15-8.06(m,1H),7.86(d,J=12.2Hz,2H),7.54(t,J=7.7Hz,1H),7.51-7.41(m,3H),7.40-7.32(m,1H),4.65-4.46(m,3H),4.43-4.34(m,2H),4.17-3.87(m,4H),3.86–3.70(m,2H),3.69-3.53(m,5H),3.29-2.83(m,18H),2.81-2.67(m,1H),2.50(d,J=4.0Hz,3H),2.48-2.40(m,4H),2.40-2.29(m,1H),2.28-2.08(m,2H),2.08-2.00(m,4H),2.00-1.87(m,3H),1.44-1.12(m,2H). 1 H NMR (400MHz, MeOD) δ: 8.23 (d, J = 6.8 Hz, 2H), 8.15-8.06 (m, 1H), 7.86 (d, J = 12.2 Hz, 2H), 7.54 (t, J = 7.7 Hz,1H),7.51-7.41(m,3H),7.40-7.32(m,1H),4.65-4.46(m,3H),4.43-4.34(m,2H),4.17-3.87(m,4H), 3.86 –3.70(m,2H),3.69-3.53(m,5H),3.29-2.83(m,18H),2.81-2.67(m,1H),2.50(d,J=4.0Hz,3H),2.48-2.40 (m,4H),2.40-2.29(m,1H),2.28-2.08(m,2H),2.08-2.00(m,4H),2.00-1.87(m,3H),1.44-1.12(m,2H) .
实施例9
Example 9
化合物9的合成Synthesis of compound 9
将氯化铝(1.28mg,0.010mmol)、氟化钠(0.40mg,0.010mmol)加入乙酸钠-乙酸缓冲液(pH=4.6,1.0mL)和乙醇(0.5mL)中,加入化合物8(8.75mg,0.008mmol),将反应液在100℃加热搅拌30分钟,将反应液冷却至室温,直接Pre-HPLC制备得9(6.0mg,收率:65.93%)。LC-MS(ESI):m/z=1138.3(M+H)+。Aluminum chloride (1.28 mg, 0.010 mmol) and sodium fluoride (0.40 mg, 0.010 mmol) were added to sodium acetate-acetic acid buffer (pH=4.6, 1.0 mL) and ethanol (0.5 mL), and compound 8 (8.75 mg, 0.008 mmol) was added. The reaction solution was heated and stirred at 100°C for 30 minutes, and the reaction solution was cooled to room temperature, and 9 (6.0 mg, yield: 65.93%) was directly prepared by Pre-HPLC. LC-MS (ESI): m/z=1138.3 (M+H) + .
实施例10
Example 10
化合物10的合成Synthesis of compound 10
将化合物7(7mg,0.008mmol)加入水(0.5mL)中,加入三氯化镓(2.66mg,0.015mmol),将反应液在90℃加热搅拌10分钟,将反应液冷却至室温,直接Pre-HPLC制备得10(6mg,收率:79.96%)。LC-MS(ESI):m/z=993.9(M+H)+。Compound 7 (7 mg, 0.008 mmol) was added to water (0.5 mL), and gallium trichloride (2.66 mg, 0.015 mmol) was added. The reaction solution was heated and stirred at 90°C for 10 minutes, and the reaction solution was cooled to room temperature and directly prepared by Pre-HPLC to obtain 10 (6 mg, yield: 79.96%). LC-MS (ESI): m/z = 993.9 (M+H) + .
实施例11
Embodiment 11
化合物11-j的合成Synthesis of compound 11-j
将4-{3-[(3-溴-2-甲基苯基)氧基]丙基}-1,4-恶嗪烷(3850mg,12.253mmol)溶解于二氧六环(50mL)中,加入4,4,5,5-四甲基-2-(4,4,5,5--四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧化氮硼烷(4667.12mg,18.379mmol)、(1,1'-双(二苯基膦基)二茂铁)二氯化钯(896.52mg,1.225mmol)和醋酸钾(3607.40mg,36.758mmol),将反应液在80℃加热搅拌过夜,将反应液冷却至室温,用乙酸乙酯(50mL×3)萃取,依次用水(30mL×2)和饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得11-j(3981mg,收率:89.93%),无须纯化直接进行下一步。LC-MS(ESI):m/z=362(M+H)+。LC-MS(ESI):m/z=362.3(M+H)+。4-{3-[(3-bromo-2-methylphenyl)oxy]propyl}-1,4-oxazinane (3850 mg, 12.253 mmol) was dissolved in dioxane (50 mL), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxadiazine borane (4667.12 mg, 18.379 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloro Palladium chloride (896.52 mg, 1.225 mmol) and potassium acetate (3607.40 mg, 36.758 mmol) were added, the reaction solution was heated and stirred at 80°C overnight, the reaction solution was cooled to room temperature, extracted with ethyl acetate (50 mL×3), washed with water (30 mL×2) and saturated brine (50 mL×1) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-j (3981 mg, yield: 89.93%), which was directly carried out to the next step without purification. LC-MS (ESI): m/z=362(M+H) + . LC-MS (ESI): m/z=362.3(M+H) + .
化合物11-i的合成 Synthesis of compound 11-i
将2,4-二羟基-5-硝基苯甲酸甲酯(500mg,2.346mmol)溶解于甲醇(10mL)中,加入钯碳10%(49.93mg,0.469mmol)。将反应液在氢气氛围下室温搅拌过夜,将反应液用硅藻土过滤,滤饼用二氯甲烷(10mL×3)洗涤,将滤液减压浓缩得11-i(429mg,收率:99.85%),无须纯化直接进行下一步。LC-MS(ESI):m/z=184.5(M+H)+。Dissolve methyl 2,4-dihydroxy-5-nitrobenzoate (500 mg, 2.346 mmol) in methanol (10 mL), add palladium carbon 10% (49.93 mg, 0.469 mmol). Stir the reaction solution at room temperature overnight under hydrogen atmosphere, filter the reaction solution with diatomaceous earth, wash the filter cake with dichloromethane (10 mL×3), and concentrate the filtrate under reduced pressure to obtain 11-i (429 mg, yield: 99.85%), which is directly carried out to the next step without purification. LC-MS (ESI): m/z=184.5(M+H) + .
化合物11-h的合成Synthesis of compound 11-h
将3-溴-2-甲基苯-1-甲醛(1867.04mg,9.380mmol)溶解于甲醇(50mL)中,加入化合物11-i(1718mg,9.380mmol),将反应液在回流温度加热搅拌1小时,将反应液冷却至室温,减压浓缩,残余物用二氯甲烷(50mL)溶解,加入2,3-二氯-5,6-二氰基-1,4-苯醌(3193.81mg,14.070mmol),将反应液在室温搅拌1小时,反应液用二氯甲烷(50mL)萃取,有机相依次用5%硫代硫酸钠溶液(100mL)和饱和碳酸氢钠水溶液(100mL)洗涤,合并有机相,无水硫酸钠干燥,过滤,减压浓缩得11-h(3000mg,收率:88.31%)。LC-MS(ESI):m/z=363.2(M+H)+。3-Bromo-2-methylbenzene-1-carboxaldehyde (1867.04 mg, 9.380 mmol) was dissolved in methanol (50 mL), and compound 11-i (1718 mg, 9.380 mmol) was added. The reaction solution was heated and stirred at reflux temperature for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3193.81 mg, 14.070 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane (50 mL), and the organic phase was washed with 5% sodium thiosulfate solution (100 mL) and saturated sodium bicarbonate aqueous solution (100 mL) in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-h (3000 mg, yield: 88.31%). LC-MS (ESI): m/z=363.2(M+H) + .
化合物11-g的合成Synthesis of compound 11-g
将化合物11-h(1000mg,2.761mmol)溶解于N,N-二甲基甲酰胺(10mL)中,加入2-甲基丙烷-2-基4-(碘甲基)六氢吡啶-1-羧酸盐(1795.74mg,5.522mmol)和碳酸钾(763.21mg,5.522mmol),将反应液在80℃加热搅拌过夜,将反应液冷却至室温,用乙酸乙酯(20mL)萃取,依次用水(20mL×3)和饱和食盐水(20mL×1)洗涤,合并有机相,无水硫酸钠干燥,过滤,减压浓缩得11-g(930mg,收率:60.21%)。LC-MS(ESI):m/z=600.5(M+H)+。Compound 11-h (1000 mg, 2.761 mmol) was dissolved in N,N-dimethylformamide (10 mL), 2-methylpropane-2-yl 4-(iodomethyl)piperidinium-1-carboxylate (1795.74 mg, 5.522 mmol) and potassium carbonate (763.21 mg, 5.522 mmol) were added, the reaction solution was heated and stirred at 80°C overnight, the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL), washed with water (20 mL×3) and saturated brine (20 mL×1) in turn, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-g (930 mg, yield: 60.21%). LC-MS (ESI): m/z=600.5(M+H) + .
化合物11-f的合成Synthesis of compound 11-f
将化合物11-g(930mg,1.662mmol)溶解于无水四氢呋喃(10mL)中,将反应液降温至0℃,加入二异丁基氢化铝(4.488mL,4.488mmol),将反应液在0℃搅拌2小时,反应液用乙酸乙酯(30mL)萃取,加入水(20mL)淬灭,加入酒石酸钾钠(2g,9.52mmol),将溶液剧烈搅拌15分钟,收集有机相,无水硫酸钠干燥,过滤,减压浓缩得11-f(727mg,收率:82.29%)。LC-MS(ESI):m/z=532.9(M+H)+。Compound 11-g (930 mg, 1.662 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), the reaction solution was cooled to 0°C, diisobutylaluminum hydride (4.488 mL, 4.488 mmol) was added, the reaction solution was stirred at 0°C for 2 hours, the reaction solution was extracted with ethyl acetate (30 mL), water (20 mL) was added to quench, potassium sodium tartrate (2 g, 9.52 mmol) was added, the solution was vigorously stirred for 15 minutes, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-f (727 mg, yield: 82.29%). LC-MS (ESI): m/z=532.9 (M+H) + .
化合物11-e的合成Synthesis of compound 11-e
将化合物11-f(727mg,1.368mmol)溶解于二氯甲烷(10mL)中,加入戴斯-马丁试剂(754.27mg,1.778mmol),将反应液在室温搅拌30分钟,将反应液用水(30mL)淬灭,混合液用乙酸乙酯萃取,有机相依次用5%硫代硫酸钠溶液(30mL)和碳酸氢钠溶液(30mL)洗涤,合并有机相,无水硫酸钠干燥,过滤,减压浓缩得11-e(615mg,收率:84.92%)。LC-MS(ESI):m/z=530.8(M+H)+。Compound 11-f (727 mg, 1.368 mmol) was dissolved in dichloromethane (10 mL), Dess-Martin reagent (754.27 mg, 1.778 mmol) was added, the reaction solution was stirred at room temperature for 30 minutes, the reaction solution was quenched with water (30 mL), the mixed solution was extracted with ethyl acetate, the organic phase was washed with 5% sodium thiosulfate solution (30 mL) and sodium bicarbonate solution (30 mL) in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-e (615 mg, yield: 84.92%). LC-MS (ESI): m/z=530.8 (M+H) + .
化合物11-d的合成Synthesis of compound 11-d
将化合物11-j(503.62mg,1.394mmol)溶解于二氧六环(20mL)和水(1mL)中,加入化合物11-e(615mg,1.162mmol)、(1,1'-双(二苯基膦基)二茂铁)二氯化钯(85.00mg,0.116mmol)和碳酸钠(307.80mg,2.904mmol),将反应液在80℃加热搅拌过夜,将反应液冷却至室温,反应液用乙酸乙酯(30mL)萃取,有机相依次用水(30mL×1)和饱和食盐水(30mL)洗涤,合并有机相,无水硫酸钠干燥,过滤,减压浓缩得11-d(693mg,收率:87.24%)。LC-MS(ESI):m/z=684.9(M+H)+。 Compound 11-j (503.62 mg, 1.394 mmol) was dissolved in dioxane (20 mL) and water (1 mL), and compound 11-e (615 mg, 1.162 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (85.00 mg, 0.116 mmol) and sodium carbonate (307.80 mg, 2.904 mmol) were added, and the reaction solution was heated and stirred at 80°C overnight, and the reaction solution was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (30 mL), and the organic phase was washed with water (30 mL×1) and saturated brine (30 mL) in turn, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-d (693 mg, yield: 87.24%). LC-MS (ESI): m/z=684.9(M+H) + .
化合物11-c的合成Synthesis of compound 11-c
将化合物11-d(693mg,1.013mmol)和(S)哌啶-2-羧酸叔丁酯(375.5mg,2.027mmol)溶解于甲醇(10mL)和二氯甲烷(10mL)中,加入醋酸(121.71mg,2.027mmol),将反应液在室温搅拌1小时,加入氰基硼氢酸钠(318.40mg,5.067mmol),将反应液在室温搅拌过夜,将反应液减压浓缩,残余物柱层析(石油醚:乙酸乙酯=3:1,然后,二氯甲烷:甲醇=15:1)得11-c(138.8mg,收率:16.06%)。LC-MS(ESI):m/z=853(M+H)+。Compound 11-d (693 mg, 1.013 mmol) and (S) piperidine-2-carboxylic acid tert-butyl ester (375.5 mg, 2.027 mmol) were dissolved in methanol (10 mL) and dichloromethane (10 mL), acetic acid (121.71 mg, 2.027 mmol) was added, the reaction solution was stirred at room temperature for 1 hour, sodium cyanoborohydride (318.40 mg, 5.067 mmol) was added, the reaction solution was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 3: 1, then, dichloromethane: methanol = 15: 1) to obtain 11-c (138.8 mg, yield: 16.06%). LC-MS (ESI): m/z = 853 (M+H) + .
化合物11-b的合成Synthesis of compound 11-b
将化合物11-c(138.8mg,0.163mmol)溶解于二氧六环(5mL)中,加入盐酸二氧六环(5mL),将反应液在室温搅拌30分钟,减压浓缩得11-b(120mg,收率:97.95%)。LC-MS(ESI):m/z=753(M+H)+。Compound 11-c (138.8 mg, 0.163 mmol) was dissolved in dioxane (5 mL), dioxane hydrochloride (5 mL) was added, the reaction solution was stirred at room temperature for 30 minutes, and concentrated under reduced pressure to obtain 11-b (120 mg, yield: 97.95%). LC-MS (ESI): m/z = 753 (M+H) + .
化合物11-a的合成Synthesis of compound 11-a
将化合物11-b(120mg,0.159mmol)溶解于N,N-二甲基甲酰胺(5mL)中,加入5-c(66.22mg,0.159mmol)、O-苯并三氮唑-四甲基脲六氟磷酸酯(78.57mg,0.207mmol)和二异丙基乙胺(0.053mL,0.319mmol),将反应液在室温搅拌过夜,反应液用二氯甲烷(10mL)萃取,有机相依次用水(5mL×3)和饱和食盐水(5mL×1)洗涤,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物直接prep-HPLC制备得11-a(146mg,收率:79.63%)。LC-MS(ESI):m/z=1150(M+H)+。Compound 11-b (120 mg, 0.159 mmol) was dissolved in N,N-dimethylformamide (5 mL), 5-c (66.22 mg, 0.159 mmol), O-benzotriazole-tetramethyluronium hexafluorophosphate (78.57 mg, 0.207 mmol) and diisopropylethylamine (0.053 mL, 0.319 mmol) were added, and the reaction solution was stirred at room temperature overnight, and the reaction solution was extracted with dichloromethane (10 mL), and the organic phase was washed with water (5 mL × 3) and saturated brine (5 mL × 1) in turn, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly prep-HPLC to prepare 11-a (146 mg, yield: 79.63%). LC-MS (ESI): m/z = 1150 (M+H) + .
化合物11的合成Synthesis of compound 11
将化合物11-a(146mg,0.127mmol)溶解于二氯甲烷(5mL)中,加入三氟乙酸(5mL,0.440mmol),将反应液在室温搅拌2小时,将反应液减压浓缩,残余物直接prep-HPLC制备得11(39.15mg,收率:31.41%)。LC-MS(ESI):m/z=982(M+H)+。Compound 11-a (146 mg, 0.127 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL, 0.440 mmol) was added, the reaction solution was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was directly prep-HPLC to prepare 11 (39.15 mg, yield: 31.41%). LC-MS (ESI): m/z = 982 (M+H) + .
实施例12
Example 12
化合物12的合成Synthesis of compound 12
将化合物11(10mg,0.010mmol)溶解于乙醇(0.50mL)中,加入0.2M乙酸钠-乙酸缓冲液(pH=4.5,1mL)、氯化铝(2mL,0.006mmol)和氟化钠(1mL,0.006mmol),将反应液在100℃加热搅拌30分钟,将反应液降至室温,减压浓缩,残余物直接prep-HPLC制备得12(3.75mg,收率:35.89%)。LC-MS(ESI):m/z=1026(M+H)+。Compound 11 (10 mg, 0.010 mmol) was dissolved in ethanol (0.50 mL), 0.2 M sodium acetate-acetic acid buffer (pH = 4.5, 1 mL), aluminum chloride (2 mL, 0.006 mmol) and sodium fluoride (1 mL, 0.006 mmol) were added, the reaction solution was heated and stirred at 100 ° C for 30 minutes, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was directly prep-HPLC to prepare 12 (3.75 mg, yield: 35.89%). LC-MS (ESI): m/z = 1026 (M+H) + .
实施例13
Example 13
化合物13-a的合成Synthesis of compound 13-a
将化合物11-b(117mg,0.155mmol)溶解于N,N-二甲基甲酰胺(5mL)中,加入(4,7,10-三{2-[(2-甲基丙-2-基)氧基]-2-氧代乙基}-1,4,7,10-四氮杂环十二烷-1-基)乙酸(106.79mg,0.186mmol)、O-苯并三氮唑-四甲基脲六氟磷酸酯(76.60mg,0.202mmol)和二异丙基乙胺(0.051mL,0.311mmol),将反应液在室温搅拌过夜,反应液用二氯甲烷(10mL)萃取,有机相依次用水(5mL×3)和饱和食盐水(5mL×1)洗涤,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物直接prep-HPLC制备得13-a(115mg,收率:56.60%)。LC-MS(ESI):m/z=1308(M+H)+。Compound 11-b (117 mg, 0.155 mmol) was dissolved in N,N-dimethylformamide (5 mL), and (4,7,10-tri{2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (106.79 mg, 0.186 mmol), O-benzotriazole-tetramethyluronium hexafluorophosphate (76.60 mg, 0. 202mmol) and diisopropylethylamine (0.051mL, 0.311mmol), the reaction solution was stirred at room temperature overnight, the reaction solution was extracted with dichloromethane (10mL), the organic phase was washed with water (5mL×3) and saturated brine (5mL×1) in turn, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the residue was directly prep-HPLC prepared to give 13-a (115mg, yield: 56.60%). LC-MS (ESI): m/z=1308(M+H) + .
化合物13的合成Synthesis of compound 13
将化合物13-a(115mg,0.088mmol)溶解于二氯甲烷(5mL)中,加入三氟乙酸(5mL,0.440mmol),将反应液在室温搅拌2小时,减压浓缩,残余物直接prep-HPLC制备得13(29.8mg,收率:31.28%)。LC-MS(ESI):m/z=1083(M+H)+。Compound 13-a (115 mg, 0.088 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL, 0.440 mmol) was added, the reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was directly prep-HPLC to prepare 13 (29.8 mg, yield: 31.28%). LC-MS (ESI): m/z = 1083 (M+H) + .
实施例14
Embodiment 14
化合物14的合成Synthesis of compound 14
将化合物13(20mg,0.016mmol)加入乙酸钠-乙酸缓冲液(3mL)中,加入三氯化镥(2.60mg,0.009mmol),将反应液在室温搅拌10分钟,减压浓缩,残余物直接prep-HPLC制备得14(4.67mg,收率:80.66%)。LC-MS(ESI):m/z=1255(M+H)+。Compound 13 (20 mg, 0.016 mmol) was added to sodium acetate-acetic acid buffer (3 mL), and lutetium trichloride (2.60 mg, 0.009 mmol) was added, and the reaction solution was stirred at room temperature for 10 minutes, concentrated under reduced pressure, and the residue was directly prep-HPLC to prepare 14 (4.67 mg, yield: 80.66%). LC-MS (ESI): m/z = 1255 (M+H) + .
实施例15
Embodiment 15
化合物15的合成Synthesis of compound 15
将化合物13(5mg,0.005mmol)加入水(2mL)中,加入三氯化镓(0.181mL,0.009mmol),将反应液在90℃加热搅拌10分钟,将反应液冷却至室温,减压浓缩,残余物直接prep-HPLC制备得15(2.62mg,收率:49.34%)。LC-MS(ESI):m/z=1149(M+H)+。Compound 13 (5 mg, 0.005 mmol) was added to water (2 mL), and gallium trichloride (0.181 mL, 0.009 mmol) was added. The reaction solution was heated and stirred at 90°C for 10 minutes, and then cooled to room temperature and concentrated under reduced pressure. The residue was directly prep-HPLC to prepare 15 (2.62 mg, yield: 49.34%). LC-MS (ESI): m/z = 1149 (M+H) + .
实施例16(68Ga标记的化合物5)
Example 16 ( 68Ga -labeled compound 5)
化合物16的合成Synthesis of compound 16
1.缓冲体系:pH 4.0左右,浓度0.5M的乙酸钠-乙酸缓冲溶液(新鲜配制)。1. Buffer system: pH 4.0, 0.5 M sodium acetate-acetic acid buffer solution (freshly prepared).
2.将化合物5用缓冲溶液溶解,用0.1M的HCl分段淋洗锗镓发生器,取活度最高部分,加入乙酸钠-乙酸缓冲溶液得到300uL68Ga3+溶液,加入到化合物5的缓冲溶液中,将塑料离心管密封,加热15min,加热温度为100℃。2. Dissolve compound 5 in buffer solution, wash the germanium gallium generator with 0.1M HCl in sections, take the part with the highest activity, add sodium acetate-acetic acid buffer solution to obtain 300uL 68 Ga 3+ solution, add it to the buffer solution of compound 5, seal the plastic centrifuge tube, and heat for 15min at a heating temperature of 100°C.
3.C18Light小柱纯化:用5mL水稀释反应液,然后上样到C18Light小柱上,用1mL浓度为50%(v/v)的乙醇-水溶液洗脱产品得到化合物16。3. C18 Light column purification: dilute the reaction solution with 5 mL of water, then load it onto a C18 Light column, and elute the product with 1 mL of 50% (v/v) ethanol-water solution to obtain compound 16.
实施例17(Al18F标记的化合物5)
Example 17 (Compound 5 labeled with Al 18 F)
化合物17的合成Synthesis of compound 17
1.缓冲体系:pH4.0左右,浓度0.5M的乙酸钠-乙酸缓冲溶液(新鲜配制)。1. Buffer system: pH 4.0, 0.5 M sodium acetate-acetic acid buffer solution (freshly prepared).
2.QMA柱活化:5mL水,5mL新鲜配制的pH4.0左右,浓度0.5M的乙酸钠-乙酸缓冲溶液。2. QMA column activation: 5 mL of water, 5 mL of freshly prepared sodium acetate-acetic acid buffer solution with a pH of about 4.0 and a concentration of 0.5 M.
3.F-18离子纯化:靶水通过QMA柱,依次用0.3mL缓冲液淋洗。3. F-18 ion purification: The target water passed through the QMA column and was eluted with 0.3 mL of buffer in sequence.
4.前体溶液:100μL缓冲液,6μL浓度为10mM的AlCl3缓冲液溶液,300μL乙腈(促反应溶剂),20μL前体溶液(3mg/mL)。4. Precursor solution: 100 μL buffer, 6 μL 10 mM AlCl 3 buffer solution, 300 μL acetonitrile (reaction-promoting solvent), 20 μL precursor solution (3 mg/mL).
5.前体溶液混匀静置平衡5min。5. Mix the precursor solution and let it stand for 5 minutes.
6.向反应溶液中加入300μL含有F-18的QMA柱淋洗液。6. Add 300 μL of QMA column eluent containing F-18 to the reaction solution.
7.将塑料离心管密封,加热15min,加热温度为100℃。7. Seal the plastic centrifuge tube and heat for 15 minutes at 100°C.
8.C18Light小柱纯化:用5mL水稀释反应液,然后上样到C18Light小柱上,用1mL浓度为50%(v/v)的乙醇-水溶液洗脱产品。洗脱液进样HPLC分析。8. Purification by C18 Light column: dilute the reaction solution with 5 mL of water, then load it onto a C18 Light column, and elute the product with 1 mL of 50% (v/v) ethanol-water solution. Inject the eluate into HPLC for analysis.
9.色谱条件如下
9. Chromatographic conditions are as follows
实施例18
Embodiment 18
化合物18-j的合成Synthesis of compound 18-j
向2-溴-1-碘-3-甲苯(1484.65mg,5.0mmol)、过氧化二苯甲酰(363.00mg,1.50mmol)和四氯化碳(20.0mL)的回流混合液中缓慢加入N-溴代琥珀酰亚胺(1156.87mg,6.50mmol)。加入后,将反应液回流16小时。将反应液冷却至室温,过滤,减压浓缩滤液。残余物柱层析(100%石油醚)纯化得18-j(1150mg,收率:61.20%)。LC-MS(ESI):m/z=376.8(M+H)+。N-bromosuccinimide (1156.87 mg, 6.50 mmol) was slowly added to a refluxing mixture of 2-bromo-1-iodo-3-toluene (1484.65 mg, 5.0 mmol), dibenzoyl peroxide (363.00 mg, 1.50 mmol) and carbon tetrachloride (20.0 mL). After addition, the reaction solution was refluxed for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% petroleum ether) to obtain 18-j (1150 mg, yield: 61.20%). LC-MS (ESI): m/z=376.8 (M+H) + .
化合物18-i的合成Synthesis of compound 18-i
将化合物18-j(1150mg,3.060mmol)和5-氯-2,4-二羟基苯-1-甲醛(528.05mg,3.06mmol)溶解于乙腈(20.0mL)中,加入碳酸氢钠(771.19mg,9.180mmol),将反应液回流44小时。将反应液冷却至室温并用水(30mL)稀释。过滤悬浮固体。依次用水(10mL×3)和乙腈(10mL)洗涤滤饼,得18-i(1300mg,收率:90.88%)。LC-MS(ESI):m/z=467.5(M+H)+。Compound 18-j (1150 mg, 3.060 mmol) and 5-chloro-2,4-dihydroxybenzene-1-carboxaldehyde (528.05 mg, 3.06 mmol) were dissolved in acetonitrile (20.0 mL), sodium bicarbonate (771.19 mg, 9.180 mmol) was added, and the reaction solution was refluxed for 44 hours. The reaction solution was cooled to room temperature and diluted with water (30 mL). The suspended solid was filtered. The filter cake was washed with water (10 mL×3) and acetonitrile (10 mL) in turn to obtain 18-i (1300 mg, yield: 90.88%). LC-MS (ESI): m/z=467.5 (M+H) + .
化合物18-h的合成Synthesis of compound 18-h
将化合物18-i(467.48mg,1.0mmol)、(2S)-六氢吡啶-2-羧酸甲酯盐酸盐(0.556mL,4.000mmol)和三乙胺(0.556mL,4.000mmol)加入四氢呋喃(10.0mL)和甲醇(10.0mL)中,加入氰基硼氢化钠(502.72mg,8.00mmol),将反应液在60℃加热搅拌30分钟,将反应液冷却至室温,将反应液用水(20mL)稀释,然后用二氯甲烷(40mL)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析(石油醚:乙酸乙酯=5:1)得18-h(170mg,收率:28.59%)。LC-MS(ESI):m/z=595.6(M+H)+。Compound 18-i (467.48 mg, 1.0 mmol), (2S)-piperidine-2-carboxylic acid methyl ester hydrochloride (0.556 mL, 4.000 mmol) and triethylamine (0.556 mL, 4.000 mmol) were added to tetrahydrofuran (10.0 mL) and methanol (10.0 mL), sodium cyanoborohydride (502.72 mg, 8.00 mmol) was added, the reaction solution was heated and stirred at 60°C for 30 minutes, the reaction solution was cooled to room temperature, the reaction solution was diluted with water (20 mL), and then extracted with dichloromethane (40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 18-h (170 mg, yield: 28.59%). LC-MS (ESI): m/z = 595.6 (M+H) + .
化合物18-g的合成Synthesis of compound 18-g
将4-溴-1H-吲唑(1970.30mg,10.0mmol)和1-溴-3-氯丙烷(2361.60mg,15.000mmol)溶解于乙腈(20.0mL)中,加入碳酸钾(2764.00mg,20.00mmol),将反应液在60℃加热搅拌16小时,将反应液冷却至室温,减压浓缩,残余物用水(30mL)稀释,然后用乙酸乙酯(40mL)萃取,合并有机相,依次用水(30mL×3)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析(石油醚:乙酸乙酯=10:1)得18-g(1400mg,收率:51.18%)。LC-MS(ESI):m/z=274.9(M+H)+。4-Bromo-1H-indazole (1970.30 mg, 10.0 mmol) and 1-bromo-3-chloropropane (2361.60 mg, 15.000 mmol) were dissolved in acetonitrile (20.0 mL), potassium carbonate (2764.00 mg, 20.00 mmol) was added, the reaction solution was heated and stirred at 60°C for 16 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was diluted with water (30 mL), and then extracted with ethyl acetate (40 mL), the organic phases were combined, washed with water (30 mL×3) and saturated brine (30 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 18-g (1400 mg, yield: 51.18%). LC-MS (ESI): m/z = 274.9 (M+H) + .
化合物18-f的合成Synthesis of compound 18-f
将化合物18-g(1400mg,5.118mmol)、(3R)-四氢-1H-吡咯-3-醇(891.71mg,10.235mmol)溶解于乙腈(15.0mL)中,加入碳酸钾(1414.64mg,10.235mmol)和碘化钾(254.86mg,1.535mmol),将反应液在60℃加热搅拌16小时,将反应液冷却至室温,减压浓缩,残余物用乙酸乙酯(50mL) 稀释,然后依次用水(30mL×3)和饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩得18-f(1720mg,收率:100%)。LC-MS(ESI):m/z=325.3(M+H)+。Compound 18-g (1400 mg, 5.118 mmol) and (3R)-tetrahydro-1H-pyrrol-3-ol (891.71 mg, 10.235 mmol) were dissolved in acetonitrile (15.0 mL), potassium carbonate (1414.64 mg, 10.235 mmol) and potassium iodide (254.86 mg, 1.535 mmol) were added, and the reaction solution was heated and stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was washed with ethyl acetate (50 mL). The mixture was diluted, washed with water (30 mL×3) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 18-f (1720 mg, yield: 100%). LC-MS (ESI): m/z=325.3 (M+H) + .
化合物18-e的合成Synthesis of compound 18-e
将化合物18-f(1720mg,5.305mmol)和4,4,5,5-四甲基-2-(4,4,5,5--四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧化氮硼烷(2694.32mg,10.610mmol)溶解于二氧六环(20.0mL)中,加入醋酸钾(1561.91mg,15.915mmol)和(1,1'-双(二苯基膦基)二茂铁)二氯化钯(388.17mg,0.531mmol),氮气保护下将反应液在90℃加热搅拌20小时,将反应液冷却至室温,用水(20mL)稀释,混合液用二氯甲烷(40mL×10)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析(二氯甲烷:甲醇=2:1)得到粗产品18-e(1300mg,收率:66.00%)。LC-MS(ESI):m/z=372.4(M+H)+。Compound 18-f (1720 mg, 5.305 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxadiazine borane (2694.32 mg, 10.610 mmol) were dissolved in dioxane (20.0 mL), potassium acetate (1561.91 mg, 15.915 mmol) and (1,1'-bis(diphenylamine)) were added. Phosphino)ferrocene)palladium dichloride (388.17 mg, 0.531 mmol), the reaction solution was heated and stirred at 90°C for 20 hours under nitrogen protection, the reaction solution was cooled to room temperature, diluted with water (20 mL), the mixed solution was extracted with dichloromethane (40 mL×10), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane: methanol = 2: 1) to obtain the crude product 18-e (1300 mg, yield: 66.00%). LC-MS (ESI): m/z = 372.4 (M+H) + .
化合物18-d的合成Synthesis of compound 18-d
将化合物18-h(170mg,0.286mmol)和化合物18-e(106.14mg,0.286mmol)溶解于二氧六环(2mL)和水(0.4mL)中,加入(1,1'-双(二苯基膦基)二茂铁)二氯化钯(20.92mg,0.029mmol)和碳酸钾(39.51mg,0.286mmol),氮气保护下,将反应液在90℃加热搅拌20小时,将反应液冷却至室温,减压浓缩,残余物柱层析(二氯甲烷:甲醇:氨=70:30:2)得18-d(107mg,收率:52.56%)。LC-MS(ESI):m/z=713.1(M+H)+。Compound 18-h (170 mg, 0.286 mmol) and compound 18-e (106.14 mg, 0.286 mmol) were dissolved in dioxane (2 mL) and water (0.4 mL), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (20.92 mg, 0.029 mmol) and potassium carbonate (39.51 mg, 0.286 mmol) were added, and the reaction solution was heated and stirred at 90°C for 20 hours under nitrogen protection, and the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to column chromatography (dichloromethane: methanol: ammonia = 70: 30: 2) to obtain 18-d (107 mg, yield: 52.56%). LC-MS (ESI): m/z = 713.1 (M+H) + .
化合物18-c的合成Synthesis of compound 18-c
将化合物18-d(105mg,0.147mmol)和1,5-二碘戊烷(95.53mg,0.295mmol)溶解于N,N-二甲基甲酰胺(1.0mL)中,加入碳酸钾(40.76mg,0.295mmol),将反应液在室温搅拌20小时,将反应液用水(10mL)稀释,然后用二氯甲烷(20mL)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,残余物柱层析(二氯甲烷:乙醇=5:1)得18-c(84mg,收率:31.36%)。LC-MS(ESI):m/z=909.3(M+H)+。Compound 18-d (105 mg, 0.147 mmol) and 1,5-diiodopentane (95.53 mg, 0.295 mmol) were dissolved in N,N-dimethylformamide (1.0 mL), potassium carbonate (40.76 mg, 0.295 mmol) was added, and the reaction solution was stirred at room temperature for 20 hours, and the reaction solution was diluted with water (10 mL), and then extracted with dichloromethane (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (dichloromethane: ethanol = 5:1) to obtain 18-c (84 mg, yield: 31.36%). LC-MS (ESI): m/z = 909.3 (M+H) + .
化合物18-b的合成Synthesis of compound 18-b
将化合物18-c(84mg,0.092mmol)和化合物5-d(42.76mg,0.120mmol)溶解于乙腈(1.0mL)中,加入碳酸钾(25.43mg,0.184mmol),将反应液在室温搅拌20小时,将反应液用水(1.0mL)稀释,然后用二氯甲烷(20.0mL)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得18-b(100mg,收率:95.54%)。LC-MS(ESI):m/z=1138.9(M+H)+。Compound 18-c (84 mg, 0.092 mmol) and compound 5-d (42.76 mg, 0.120 mmol) were dissolved in acetonitrile (1.0 mL), potassium carbonate (25.43 mg, 0.184 mmol) was added, and the reaction solution was stirred at room temperature for 20 hours, and the reaction solution was diluted with water (1.0 mL), and then extracted with dichloromethane (20.0 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18-b (100 mg, yield: 95.54%). LC-MS (ESI): m/z = 1138.9 (M+H) + .
化合物18-a的合成Synthesis of compound 18-a
将化合物18-b(100mg,0.088mmol)溶解于四氢呋喃(2.0mL)中,加入盐酸(2.0mL,12.00mmol),将反应液在50℃加热搅拌20小时,将反应液冷却至室温,减压浓缩得18-a(108mg,收率:99%)。LC-MS(ESI):m/z=1026.5(M+H)+。Compound 18-b (100 mg, 0.088 mmol) was dissolved in tetrahydrofuran (2.0 mL), hydrochloric acid (2.0 mL, 12.00 mmol) was added, the reaction solution was heated and stirred at 50°C for 20 hours, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain 18-a (108 mg, yield: 99%). LC-MS (ESI): m/z = 1026.5 (M+H) + .
化合物18的合成Synthesis of compound 18
将化合物18-a(108mg,0.087mmol)溶解于四氢呋喃(1.0mL)、甲醇(1.0mL)和水(1.0mL)中,加入氢氧化锂(72.84mg,1.74mmol),将反应液在室温搅拌1小时,直接Pre-HPLC制备得18(12.5mg,收率:14.2%)。LC-MS(ESI):m/z=1012.3(M+H)+。 Compound 18-a (108 mg, 0.087 mmol) was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (1.0 mL), lithium hydroxide (72.84 mg, 1.74 mmol) was added, the reaction solution was stirred at room temperature for 1 hour, and 18 (12.5 mg, yield: 14.2%) was directly prepared by Pre-HPLC. LC-MS (ESI): m/z=1012.3 (M+H) + .
实施例19
Embodiment 19
化合物19的合成Synthesis of compound 19
将化合物18(4.0mg,0.004mmol)、氯化铝(0.64mg,0.005mmol)和氟化钠(0.20mg,0.005mmol)加入乙醇(0.3mL)和0.2M乙酸钠-乙酸缓冲液(pH=4.6,0.6mL),将反应液在100℃加热搅拌15分钟,将反应液冷却至室温,直接Pre-HPLC制备得19(1.4mg,收率:33.57%)。LC-MS(ESI):m/z=1056.23(M+H)+。Compound 18 (4.0 mg, 0.004 mmol), aluminum chloride (0.64 mg, 0.005 mmol) and sodium fluoride (0.20 mg, 0.005 mmol) were added to ethanol (0.3 mL) and 0.2 M sodium acetate-acetic acid buffer (pH = 4.6, 0.6 mL), and the reaction solution was heated and stirred at 100 ° C for 15 minutes, and the reaction solution was cooled to room temperature, and 19 (1.4 mg, yield: 33.57%) was directly prepared by Pre-HPLC. LC-MS (ESI): m/z = 1056.23 (M+H) + .
实施例20
Embodiment 20
化合物81-e的合成Synthesis of compound 81-e
向4-(叔丁基)9-乙基-1-氧-4-氮杂螺[5.5]十一碳-4,9-二羧酸酯(98.23mg,0.30mmol)干燥的四氢呋喃溶液中(3.0mL)中滴加LiOH溶液(28.74mg,1.20mmol),滴加完毕后,反应液在室温条件下搅拌3小时,TLC监测反应进程,反应结束后,用盐酸溶液(1M)调节pH=6-8,减压浓缩除去四氢呋喃,并通过冷冻干燥纯化得到白色固体化合物81-e(85mg,收率95%)。LC-MS(ESI):m/z=300.3(M+H)+。LiOH solution (28.74 mg, 1.20 mmol) was added dropwise to a solution (3.0 mL) of 4-(tert-butyl)-9-ethyl-1-oxo-4-azaspiro[5.5]undecane-4,9-dicarboxylate (98.23 mg, 0.30 mmol) in dried tetrahydrofuran. After the addition was complete, the reaction solution was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After the reaction was completed, the pH was adjusted to 6-8 with hydrochloric acid solution (1 M), the tetrahydrofuran was removed by concentration under reduced pressure, and the white solid compound 81-e (85 mg, yield 95%) was obtained by freeze drying and purification. LC-MS (ESI): m/z=300.3 (M+H) + .
化合物81-d的合成Synthesis of compound 81-d
将N,N-二异丙基乙胺(0.16mL,0.9mmol)、化合物(S,E)-1-(2-(4-氨基丁氧基)-4-(2-(2-甲基-[1,1'-联苯]-3-基)乙烯基)-5-(三氟甲基)苄基)哌啶-2-羧酸叔丁酯(186.83mg,0.3mmol),81-e(90mg,0.3mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)溶解于N,N-二甲基甲酰胺(0.3mL)中,将反应液在室温下搅拌30分钟。将反应液加入乙酸乙酯(20mL)稀释,依次用水(20mL×2)和饱和食盐水(10mL)洗涤。有机相无水硫酸钠干燥,过滤,减压浓缩,残余物经Pre-HPLC纯化得81-d(234mg,收率86%)。LC-MS(ESI):m/z=905.1(M+H)+。N,N-diisopropylethylamine (0.16 mL, 0.9 mmol), compound (S,E)-1-(2-(4-aminobutoxy)-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid tert-butyl ester (186.83 mg, 0.3 mmol), 81-e (90 mg, 0.3 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) were dissolved in N,N-dimethylformamide (0.3 mL), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (20 mL), and washed with water (20 mL×2) and saturated brine (10 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain 81-d (234 mg, yield 86%). LC-MS (ESI): m/z = 905.1 (M+H) + .
化合物81-c的合成Synthesis of compound 81-c
氮气保护下,向化合物81-d(160mg,0.18mmol)中加入盐酸-1,4二氧六环溶(0.8mL)和干燥的四氢呋喃溶液(1.6mL),室温条件下,反应2小时,减压浓缩,残余物经Pre-HPLC纯化得81-c(74mg,收率52%)。LC-MS(ESI):m/z=805.0(M+H)+。Under nitrogen protection, hydrochloric acid-1,4-dioxane solution (0.8 mL) and dry tetrahydrofuran solution (1.6 mL) were added to compound 81-d (160 mg, 0.18 mmol), reacted for 2 hours at room temperature, concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain 81-c (74 mg, yield 52%). LC-MS (ESI): m/z=805.0 (M+H) + .
化合物81-b的合成Synthesis of compound 81-b
在0℃,氮气保护下,向化合物81-c(40.0mg,0.05mmol)和化合物(10-{1-[(2-甲基丙-2-基)氧基]-1-氧代乙基-2-基}-4,7-双{2-[(2-甲丙基-2-基)氧化基]-2-氧代乙基}-1,4,7,10-四氮杂环十二烷-1-基)乙酸(28.49mg,0.05mmol)的无水N,N-二甲基甲酰胺溶液(3.0mL)中加入苯并三氮唑-N,N,N,N-四甲基脲六氟磷酸酯(HBTU,37.73mg,0.10mmol)和三乙胺(25.12mg,0.25mmol),升至室温,反应液在室温条件下反应12小时,减压浓缩,残余物通过柱色谱(洗脱液:二氯甲烷:甲醇=100-20:1) 纯化得到81-b(60mg,收率:89%)。LC-MS(ESI):m/z=1359.2(M+H)+。At 0°C, under nitrogen protection, compound 81-c (40.0 mg, 0.05 mmol) and compound (10-{1-[(2-methylpropan-2-yl)oxy]-1-oxoethyl-2-yl}-4,7-bis{2-[(2-methylpropyl-2-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (28.49 mg, 0.05 mmol) were added to a mixture of 1% ethyl acetate and 1% ethyl acetate. Benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU, 37.73 mg, 0.10 mmol) and triethylamine (25.12 mg, 0.25 mmol) were added to anhydrous N,N-dimethylformamide solution (3.0 mL), and the temperature was raised to room temperature. The reaction solution was reacted at room temperature for 12 hours, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane: methanol = 100-20:1) Purification afforded 81-b (60 mg, yield: 89%). LC-MS (ESI): m/z=1359.2 (M+H) + .
化合物81-a的合成Synthesis of compound 81-a
将化合物81-b(60mg,0.04mmol)溶解在二氯甲烷(4mL)中,将反应液冷却至0℃,加入三氟乙酸(3mL)。将反应液在室温下搅拌16小时。将反应液减压浓缩,残余物经Pre-HPLC纯化得白色固体81-a(21.8mg,收率:43.6%)。LC-MS(ESI):m/z=1135.3(M+H)+。Compound 81-b (60 mg, 0.04 mmol) was dissolved in dichloromethane (4 mL), the reaction solution was cooled to 0°C, and trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Pre-HPLC to obtain a white solid 81-a (21.8 mg, yield: 43.6%). LC-MS (ESI): m/z = 1135.3 (M+H) + .
化合物81的合成Synthesis of compound 81
将化合物81-a(21.8mg,0.019mmol)和三氯化镥(16.2mg,0.058mmol)溶于甲醇(1.0mL)和乙酸钠-乙酸缓冲液(pH=4.5)(0.5mL)中。将反应液在室温下搅拌20分钟,然后在90℃搅拌5分钟,将反应液冷却至室温。反应液直接经Pre-HPLC制备分别得化合物81(4.1mg,收率:16.33%),LC-MS(ESI):m/z=1307.3(M+H)+,和化合物82(3.0mg,收率12.0%),LC-MS(ESI):m/z=1307.3(M+H)+。Compound 81-a (21.8 mg, 0.019 mmol) and lutetium trichloride (16.2 mg, 0.058 mmol) were dissolved in methanol (1.0 mL) and sodium acetate-acetic acid buffer (pH = 4.5) (0.5 mL). The reaction solution was stirred at room temperature for 20 minutes, then stirred at 90°C for 5 minutes, and the reaction solution was cooled to room temperature. The reaction solution was directly prepared by Pre-HPLC to obtain compound 81 (4.1 mg, yield: 16.33%), LC-MS (ESI): m/z = 1307.3 (M+H) + , and compound 82 (3.0 mg, yield 12.0%), LC-MS (ESI): m/z = 1307.3 (M+H) + .
实施例21Embodiment 21
化合物83的合成
Synthesis of compound 83
将三氯化镓(47.33mg,0.269mmol)加入到化合物81-a(61.0mg,0.054mmol)的水溶液(3mL)中,反应液在40℃下反应18小时,停止反应,减压浓缩,残余物经Pre-HPLC纯化得到化合物83(37.51mg,收率:58%)。LC-MS(ESI):m/z=1202.39(M+H)+。Gallium trichloride (47.33 mg, 0.269 mmol) was added to an aqueous solution (3 mL) of compound 81-a (61.0 mg, 0.054 mmol), and the reaction solution was reacted at 40°C for 18 hours, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was purified by Pre-HPLC to obtain compound 83 (37.51 mg, yield: 58%). LC-MS (ESI): m/z=1202.39 (M+H) + .
效果实施例1Effect Example 1
采用均相时间分辨荧光(Homogenouse Time-Resolved Fluorescence,HTRF)结合试验来检测本公开的化合物对PD-1/PD-L1的结合能力。Homogenous time-resolved fluorescence (HTRF) binding assay was used to detect the binding ability of the compounds disclosed in the present invention to PD-1/PD-L1.
购买来的试剂盒(CisBio,#64CUS000C-1)中包含有PD-1、PD-L1、anti-tag1-Eu、Anti-tag2-XL665、Dilute Buffer和Detection Buffer等实验所需的试剂。 The purchased kit (CisBio, #64CUS000C-1) contains reagents required for the experiment, such as PD-1, PD-L1, anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer and Detection Buffer.
实验步骤Experimental procedures
1.将化合物用100%DMSO配置成浓度梯度为3倍的10个浓度。1. The compound was prepared with 100% DMSO to form 10 concentrations with a 3-fold concentration gradient.
2.将化合物的DMSO溶液加入到稀释缓冲溶液(Dilute Buffer)中,混合均匀后转移到96孔板中。2. Add the DMSO solution of the compound into the dilute buffer, mix well and transfer to a 96-well plate.
3.将PD-L1用稀释缓冲溶液(Dilute Buffer)稀释,然后加入到上述96孔板中。3. Dilute PD-L1 with dilute buffer and add it to the above 96-well plate.
4.将PD-1用稀释缓冲溶液(Dilute Buffer)稀释,然后加入到上述96孔板中,并在室温下培养30分钟。4. Dilute PD-1 with dilute buffer, add it to the above 96-well plate, and incubate at room temperature for 30 minutes.
5.将一份anti-tag1-Eu和一份Anti-tag2-XL665加入到检测缓冲溶液(Detection Buffer)中,混合均匀后转移到上述96孔板中。5. Add one part anti-tag1-Eu and one part Anti-tag2-XL665 into the detection buffer solution (Detection Buffer), mix well and transfer to the above 96-well plate.
6.此96孔板中的混合液在室温下培养1到24小时。6. Incubate the mixture in the 96-well plate at room temperature for 1 to 24 hours.
7.用Envision读取HTRF数值。7. Use Envision to read the HTRF value.
实验结果Experimental Results
本公开化合物的生物学活性通过以上的试验进行测定,本公开化合物对PD-1/PD-L1结合具有较好的抑制活性,测得的结果如下(表1):The biological activity of the disclosed compounds was determined by the above test. The disclosed compounds have good inhibitory activity on PD-1/PD-L1 binding. The measured results are as follows (Table 1):
表1.本公开化合物对PD-1/PD-L1结合的IC50值
Table 1. IC50 values of compounds disclosed herein for PD-1/PD-L1 binding
效果实施例2Effect Example 2
使用biacore S200测定PD-L1、PD1与化合物体外相互作用的KD值。The KD values of the in vitro interactions between PD-L1, PD1 and the compounds were determined using biacore S200.
实验步骤Experimental Procedure
1.PD-L1、PD1蛋白偶联CM5芯片。1.PD-L1 and PD1 protein coupled to CM5 chip.
1.1.Biacore S200设置及实验条件:
1.1.Biacore S200 setup and experimental conditions:
2.化合物与PD-L1、PD1相互作用2. Compounds interact with PD-L1 and PD1
2.1.化合物的倍比稀释:以10uM为起始点,8个稀释梯度2.1. Compound dilution: 10uM as the starting point, 8 dilution gradients
2.2.Biacore S200设置及实验条件:
2.2.Biacore S200 settings and experimental conditions:
实验结果Experimental Results
本公开化合物的生物学活性通过以上的试验进行测定,测得的结果如下(表2):The biological activities of the disclosed compounds were determined by the above test, and the results were as follows (Table 2):
表2.本公开部分化合物对PD-1/PD-L1结合的KD值
Table 2. KD values of some compounds of the present disclosure for binding to PD-1/PD-L1
效果实施例3Effect Example 3
化合物16进行Micro-PET/CT扫描肿瘤靶向研究Micro-PET/CT scanning tumor targeting study of compound 16
1.实验动物信息:C57BL/6J小鼠,SPF级;15-21g;模型鼠构建:双侧肿瘤1. Experimental animal information: C57BL/6J mice, SPF grade; 15-21g; Model mouse construction: bilateral tumors
2.双侧肿瘤模型鼠构建(MC-38小鼠肿瘤模型)。2. Construction of bilateral tumor model mice (MC-38 mouse tumor model).
2.1细胞培养2.1 Cell culture
人源PD-L1基因敲入MC-38细胞(MC-38-hPD-Ll细胞)体外贴壁培养,培养条件为DMEM培养基中加10%热灭活胎牛血清,并加入hygromycinB(终浓度100μL/mL),37℃5%CO2培养。一周2-3次传代处理。当细胞呈指数生长期时,收取细胞,计数,小鼠左侧皮下接种。Human PD-L1 gene knock-in MC-38 cells (MC-38-hPD-L1 cells) were cultured in vitro in the presence of 10% heat-inactivated fetal bovine serum in DMEM medium and hygromycin B (final concentration 100 μL/mL) at 37°C and 5% CO 2. The cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the left side of the mouse.
鼠源MC-38细胞体外贴壁培养,培养条件为DMEM培养基中加10%热灭活胎牛血清,37℃5%CO2培养。一周2-3次传代处理。当细胞呈指数生长期时,收取细胞,计数,小鼠右侧皮下接种。Mouse MC-38 cells were cultured in vitro in DMEM medium with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO 2. Cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the right side of the mouse.
2.2肿瘤细胞接种2.2 Tumor cell inoculation
100μL 1×106MC-38-hPD-Ll细胞混悬液接种于C57BL/6J小鼠左背侧皮下。于第二天同一只小鼠右背侧皮下接种100μL 1×106MC-38细胞混悬液。接种后正常饲养小鼠,一定天数后选双侧移植瘤体积在150mm3-350mm3范围的荷瘤鼠用于试验。100 μL of 1×10 6 MC-38-hPD-L1 cell suspension was inoculated subcutaneously on the left dorsal flank of C57BL/6J mice. On the second day, 100 μL of 1×10 6 MC-38 cell suspension was inoculated subcutaneously on the right dorsal flank of the same mouse. After inoculation, the mice were raised normally, and after a certain number of days, tumor-bearing mice with bilateral transplanted tumors in the range of 150 mm 3 -350 mm 3 were selected for the experiment.
3.实验过程:3. Experimental process:
(1)按照Micro-PET/CT操作规程开机,打开扫描软件,进行日校正; (1) Turn on the machine according to the Micro-PET/CT operating procedures, open the scanning software, and perform daily calibration;
(2)动物麻醉准备,使用异氟烷麻醉荷瘤鼠;(2) Animal anesthesia preparation: tumor-bearing mice were anesthetized using isoflurane;
(3)待荷瘤鼠翻正反射消失,质控后的化合物16用10%乙醇的生理盐水(pH约为4.5)稀释,抽取药物,尾静脉注射至各动物体内,给药容量为100μL/只,给药剂量为100-200μCi/只;(3) After the righting reflex of the tumor-bearing mice disappeared, the quality-controlled compound 16 was diluted with 10% ethanol in normal saline (pH about 4.5), the drug was extracted, and injected into the tail vein of each animal. The volume of administration was 100 μL/mouse, and the dosage was 100-200 μCi/mouse;
(4)于注射化合物16后0.5h,1.5h,2.5h,3.5h进行Micro-PET/CT扫描,收集动物显像原始数据。(4) Micro-PET/CT scans were performed at 0.5 h, 1.5 h, 2.5 h, and 3.5 h after injection of compound 16 to collect the original imaging data of the animals.
4.实验结果表明:化合物16扫描模型鼠左侧肿瘤(MC38-PDL1)的摄取值明显高于右侧(MC-38),见表3。4. The experimental results show that the uptake value of compound 16 in the left tumor (MC38-PDL1) of the model mouse is significantly higher than that in the right tumor (MC-38), see Table 3.
表3.肿瘤靶向摄取值(单位:ID%/g)
Table 3. Tumor targeting uptake values (unit: ID%/g)
效果实施例4Effect Example 4
化合物17进行Micro-PET/CT扫描肿瘤靶向研究Micro-PET/CT scanning tumor targeting study of compound 17
1.实验动物信息:CD57小鼠,SPF级;15-21g;1. Experimental animal information: CD57 mice, SPF grade; 15-21g;
2.双侧肿瘤模型鼠构建(MC-38小鼠肿瘤模型):2. Construction of bilateral tumor model mice (MC-38 mouse tumor model):
2.1细胞培养2.1 Cell culture
人源PD-L1基因敲入MC-38细胞(MC-38-hPD-Ll细胞)体外贴壁培养,培养条件为DMEM培养基中加10%热灭活胎牛血清,并加入hygromycinB(终浓度100μL/mL),37℃5%CO2培养。一周2-3次传代处理。当细胞呈指数生长期时,收取细胞,计数,小鼠左侧皮下接种。Human PD-L1 gene knock-in MC-38 cells (MC-38-hPD-L1 cells) were cultured in vitro in the presence of 10% heat-inactivated fetal bovine serum in DMEM medium and hygromycin B (final concentration 100 μL/mL) at 37°C and 5% CO 2. The cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the left side of the mouse.
鼠源MC-38细胞体外贴壁培养,培养条件为DMEM培养基中加10%热灭活胎牛血清,37℃5%CO2培养。一周2-3次传代处理。当细胞呈指数生长期时,收取细胞,计数,小鼠右侧皮下接种。Mouse MC-38 cells were cultured in vitro in DMEM medium with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO 2. Cells were subcultured 2-3 times a week. When the cells were in the exponential growth phase, the cells were harvested, counted, and inoculated subcutaneously on the right side of the mouse.
2.2肿瘤细胞接种2.2 Tumor cell inoculation
100μL 1×106MC-38-hPD-Ll细胞混悬液接种于C57BL/6J小鼠左背侧皮下。于第二天同一只小鼠右背侧皮下接种100μL 1×106MC-38细胞混悬液。接种后正常饲养小鼠,一定天数后选双侧移植瘤体积在150mm3-350mm3范围的荷瘤鼠用于试验。100 μL of 1×10 6 MC-38-hPD-L1 cell suspension was inoculated subcutaneously on the left dorsal flank of C57BL/6J mice. On the second day, 100 μL of 1×10 6 MC-38 cell suspension was inoculated subcutaneously on the right dorsal flank of the same mouse. After inoculation, the mice were raised normally, and after a certain number of days, tumor-bearing mice with bilateral transplanted tumors in the range of 150 mm 3 -350 mm 3 were selected for the experiment.
3.实验过程:3. Experimental process:
(1)按照Micro-PET/CT操作规程开机,打开扫描软件,进行日校正;(1) Turn on the machine according to the Micro-PET/CT operating procedures, open the scanning software, and perform daily calibration;
(2)动物麻醉准备,使用异氟烷麻醉荷瘤鼠;(2) Animal anesthesia preparation: tumor-bearing mice were anesthetized using isoflurane;
(3)待荷瘤鼠翻正反射消失,质控后的化合物17用10%乙醇的生理盐水(pH约为4.5)稀释, 抽取药物,尾静脉注射至各动物体内,给药容量为100μL/只,给药剂量为100-200μCi/只;(3) After the righting reflex of the tumor-bearing mice disappears, the quality-controlled compound 17 is diluted with 10% ethanol in saline (pH about 4.5). The drug was extracted and injected into each animal through the tail vein, with a volume of 100 μL/animal and a dose of 100-200 μCi/animal;
(4)于注射化合物17后0.5h,1.5h,2.5h,3.5h进行Micro-PET/CT扫描,收集动物显像原始数据,结果见表4。(4) Micro-PET/CT scans were performed at 0.5 h, 1.5 h, 2.5 h, and 3.5 h after injection of compound 17, and the raw imaging data of the animals were collected. The results are shown in Table 4.
表4.肿瘤靶向摄取值(单位:ID%/g)
Table 4. Tumor targeting uptake values (unit: ID%/g)
4.实验结果表明:化合物17扫描模型鼠左侧肿瘤(MC38-PDL1)的摄取值明显高于右侧(MC-38)。 4. The experimental results showed that the uptake value of compound 17 in the left tumor (MC38-PDL1) of the model mouse was significantly higher than that in the right tumor (MC-38).
Claims (23)
A benzene ring-containing compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
The benzene ring-containing compound as shown in formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, characterized in that the benzene ring-containing compound as shown in formula I is a compound formed by chelating compound A with the ion containing the diagnostic radionuclide as described in claim 4, and the structure of compound A is any one of the following:
A benzene ring-containing compound as shown in formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
A benzene ring-containing compound as shown in formula III, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
Preferably, the benzene ring-containing compound as shown in Formula III is selected from any of the following structures:
A method for preparing a benzene ring-containing compound as shown in formula I as described in any one of claims 1 to 8, a benzene ring-containing compound as shown in formula II as described in any one of claims 9 to 11, or a benzene ring-containing compound as shown in formula III as described in any one of claims 12 to 14, comprising the following steps: chelating one of the ions containing diagnostic radionuclides as described in claim 4, the ions containing therapeutic radionuclides as described in claim 10, or the ions containing non-radioactive nuclides as described in claim 13 with the compound as shown in formula IV;
A benzene ring-containing compound as shown in formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof,
A compound as shown below:
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