CN119013270A - Nitrogen-containing heterocyclic derivative, composition thereof and pharmaceutical application thereof - Google Patents
Nitrogen-containing heterocyclic derivative, composition thereof and pharmaceutical application thereof Download PDFInfo
- Publication number
- CN119013270A CN119013270A CN202380030090.6A CN202380030090A CN119013270A CN 119013270 A CN119013270 A CN 119013270A CN 202380030090 A CN202380030090 A CN 202380030090A CN 119013270 A CN119013270 A CN 119013270A
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- CN
- China
- Prior art keywords
- alkyl
- membered
- substituted
- cycloalkyl
- heterocyclyl
- Prior art date
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- 239000000203 mixture Substances 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 239000002207 metabolite Substances 0.000 claims abstract description 43
- 239000000651 prodrug Substances 0.000 claims abstract description 43
- 229940002612 prodrug Drugs 0.000 claims abstract description 43
- 239000012453 solvate Substances 0.000 claims abstract description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 22
- -1 said-CH 2 - Chemical group 0.000 claims description 513
- 125000000623 heterocyclic group Chemical group 0.000 claims description 431
- 125000000217 alkyl group Chemical group 0.000 claims description 418
- 229910052760 oxygen Inorganic materials 0.000 claims description 271
- 125000003545 alkoxy group Chemical group 0.000 claims description 265
- 229910052740 iodine Inorganic materials 0.000 claims description 248
- 229910052731 fluorine Inorganic materials 0.000 claims description 245
- 229910052717 sulfur Inorganic materials 0.000 claims description 208
- 125000005842 heteroatom Chemical group 0.000 claims description 204
- 229910052757 nitrogen Inorganic materials 0.000 claims description 203
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 192
- 125000001424 substituent group Chemical group 0.000 claims description 188
- 125000001072 heteroaryl group Chemical group 0.000 claims description 148
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 129
- 125000000304 alkynyl group Chemical group 0.000 claims description 126
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 124
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 118
- 229910052736 halogen Inorganic materials 0.000 claims description 110
- 125000003118 aryl group Chemical group 0.000 claims description 97
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 96
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 94
- 125000002393 azetidinyl group Chemical group 0.000 claims description 92
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 87
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 83
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 80
- 150000002367 halogens Chemical class 0.000 claims description 80
- 229910052799 carbon Inorganic materials 0.000 claims description 79
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 75
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 72
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 66
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 65
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 62
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 62
- 125000003342 alkenyl group Chemical group 0.000 claims description 61
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 52
- 125000003386 piperidinyl group Chemical group 0.000 claims description 50
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 49
- 125000003566 oxetanyl group Chemical group 0.000 claims description 49
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 48
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 42
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 42
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 42
- 239000013078 crystal Substances 0.000 claims description 41
- 229910052805 deuterium Inorganic materials 0.000 claims description 40
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 39
- 125000004076 pyridyl group Chemical group 0.000 claims description 39
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 38
- 229910052794 bromium Inorganic materials 0.000 claims description 37
- 229910052801 chlorine Inorganic materials 0.000 claims description 37
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 36
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 36
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 35
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 34
- 125000005843 halogen group Chemical group 0.000 claims description 33
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 32
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 31
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 31
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 30
- 125000000335 thiazolyl group Chemical group 0.000 claims description 29
- 125000001544 thienyl group Chemical group 0.000 claims description 29
- 125000001425 triazolyl group Chemical group 0.000 claims description 28
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 27
- 125000002971 oxazolyl group Chemical group 0.000 claims description 27
- 125000002541 furyl group Chemical group 0.000 claims description 26
- 125000002883 imidazolyl group Chemical group 0.000 claims description 26
- 125000002757 morpholinyl group Chemical group 0.000 claims description 26
- 125000004414 alkyl thio group Chemical group 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 229920002554 vinyl polymer Polymers 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
- 125000005475 oxolanyl group Chemical group 0.000 claims description 23
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 23
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 22
- 125000001624 naphthyl group Chemical group 0.000 claims description 21
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 21
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 16
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 15
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 15
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 13
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 13
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 13
- 239000012634 fragment Substances 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 10
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 9
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 9
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- 125000004306 triazinyl group Chemical group 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 7
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 6
- GXPBBJPLXAOLTM-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.0]hexane Chemical class C1NC2CNC21 GXPBBJPLXAOLTM-UHFFFAOYSA-N 0.000 claims description 6
- FOGGMWDTLLXUTO-UHFFFAOYSA-N 4,7-diazabicyclo[3.2.0]heptane Chemical class C1CNC2CNC21 FOGGMWDTLLXUTO-UHFFFAOYSA-N 0.000 claims description 6
- KNLOUXALILBKPY-UHFFFAOYSA-N 5,8-diazabicyclo[4.2.0]octane Chemical class C1CCNC2CNC21 KNLOUXALILBKPY-UHFFFAOYSA-N 0.000 claims description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 6
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 6
- 150000001539 azetidines Chemical class 0.000 claims description 6
- 230000015556 catabolic process Effects 0.000 claims description 6
- 238000006731 degradation reaction Methods 0.000 claims description 6
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 claims description 6
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 6
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000003776 cleavage reaction Methods 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 230000007017 scission Effects 0.000 claims description 5
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000002785 azepinyl group Chemical group 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000014509 gene expression Effects 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- 125000001620 monocyclic carbocycle group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000169 tricyclic heterocycle group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000004161 1,4-diazepinyl group Chemical group 0.000 claims description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 3
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 3
- 125000006450 cyclopropyl cyclopropyl group Chemical group 0.000 claims description 3
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 3
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 239000000543 intermediate Substances 0.000 abstract description 15
- 239000000126 substance Substances 0.000 abstract description 8
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- 238000002360 preparation method Methods 0.000 description 73
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 54
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 51
- 239000012043 crude product Substances 0.000 description 50
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 14
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
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- GQIRIWDEZSKOCN-UHFFFAOYSA-N 1-chloro-n,n,2-trimethylprop-1-en-1-amine Chemical compound CN(C)C(Cl)=C(C)C GQIRIWDEZSKOCN-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
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- WOPSKXFEWNXZRP-UHFFFAOYSA-N 2-(4-iodopyrazol-1-yl)-2-methylpropanoic acid Chemical compound IC=1C=NN(C=1)C(C(=O)O)(C)C WOPSKXFEWNXZRP-UHFFFAOYSA-N 0.000 description 4
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- UENGYBYGCXKNRF-UHFFFAOYSA-N tert-butyl 3-ethynylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(C#C)C1 UENGYBYGCXKNRF-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SGADHBKDBASSPN-UHFFFAOYSA-N tert-butyl-(1,3-dibromopropan-2-yloxy)-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](OC(CBr)CBr)(C(C)(C)C)C1=CC=CC=C1 SGADHBKDBASSPN-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体，以及在AR相关疾病如癌症中的用途。B‑L‑K (I)。The present invention relates to a compound described by general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates thereof, as well as use thereof in AR-related diseases such as cancer. B-L-K (I).
Description
The present invention relates to a compound of general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, as well as intermediates and preparation methods thereof, and uses thereof in AR related diseases such as cancer diseases.
Androgen receptor (Androgen receptor, AR) is a hormone nuclear receptor, structurally divided into an N-terminal activation region (NTD), a DNA binding region (DBD) and a ligand binding region (LTD), capable of modulating gene expression that induces prostate cancer, and thus, inhibition of androgen receptor is an effective method for treating prostate cancer. Androgen receptor inhibitors such as enzalutamide, bicalutamide and the like which are currently marketed mainly exert an inhibitory effect through the action with a ligand binding domain (LTD) of an androgen receptor, but a drug resistance phenomenon caused by androgen receptor cleavage mutants (Androgen receptor SPLICE VARIANTS, AR-Vs) in which LTD fragments are deleted occurs in some patients during the course of treatment. Preclinical studies indicate that androgen receptor cleavage mutants can accelerate the progression of enzalutamide resistant prostate cancer, and how to solve the drug resistance problem becomes a concern of clinical medicine.
The small molecule degradation agent is a medicine for carrying out directional degradation on target protein by utilizing an organism ubiquitin-proteinase system (UPS). The small molecule degrading agent can target the target point which is difficult to be formed into medicine by virtue of a unique catalytic mechanism, solves the medicine resistance problem, and is a great hot spot in the medicine research and development fields of tumors, autoimmune diseases and the like at present.
PROTAC (proteolysis TARGETING CHIMERA) is a bifunctional compound capable of simultaneously combining a target protein and E3 ubiquitin ligase, and the compound can be recognized by a proteasome of a cell to cause degradation of the target protein, so that the content of the target protein in the cell can be effectively reduced. By introducing ligands capable of binding to different targeting proteins at PROTAC molecules, the PROTAC technology is enabled to be applied to the treatment of various diseases, and has received wide attention in recent years.
Molecular glue (molecular glue) is a class of small molecules that promote the contact of a target protein with the E3 ubiquitin ligase, inducing interactions between the two, and thus leading to degradation of the target protein. From a functional point of view, molecular gums promote strong interactions between the target protein and the E3 ubiquitin ligase by filling the gap between them, enhancing their binding interface (nat. Commun.,2022,13,815). Compared with the traditional small molecule inhibitor, the molecular gel has the advantages of driving the degradation of target protein in a catalytic mode and no need of having a binding pocket on the target protein, and has the potential of acting on a non-patent drug target.
Accordingly, there is a need to develop novel androgen receptor cleavage mutant (Androgen receptor SPLICE VARIANTS, AR-Vs, particularly AR-V7 mutant) inhibitors and PROTAC or other small molecule degradant drugs of E3 ubiquitin ligase for the treatment of neoplastic diseases associated with androgen receptor cleavage mutants.
Disclosure of Invention
The invention aims to provide a compound which has novel structure, good drug effect, high bioavailability, safer property and can inhibit and degrade AR or/and AR-Vs (especially AR-V7) and is used for treating diseases related to AR such as prostate cancer.
The invention provides a compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K (I)；
In certain embodiments, L is selected from a bond or-C 1-50 hydrocarbyl-, of which 1 to 20 methylene units are optionally replaced by-Ak-, -Cy-;
In certain embodiments, L is selected from a bond or-C 1-20 hydrocarbyl-, of which 1 to 20 methylene units are optionally replaced by-Ak-, -Cy-;
In certain embodiments, L is selected from a bond or-C 1-10 hydrocarbyl-, of which 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) methylene units are optionally replaced by-Ak-, -Cy-; in certain embodiments, each-Ak-is independently selected from Ak1, ak2, ak3, ak4, or Ak5;
In certain embodiments, each-Ak-is independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 (e.g., 1 or 2) substituents selected from halogen, OH, CN, NH 2、C1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl;
In certain embodiments, each-Cy-is independently selected from Cy1, cy2, cy3, cy4, or Cy5;
In certain embodiments, each-Cy-is independently selected from a bond or one of the following optionally substituted groups: 4-8 membered heteromonocyclic ring, 4-10 membered heteromonocyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, substituted when substituted with 1 to 4R L2, said heterocyclyl, heteroaryl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring containing 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following optionally substituted groups: 4-7 membered heteromonocyclic ring, 4-10 membered heteromonocyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, substituted when substituted with 1 to 4R L2 substituents, said heterocyclyl, heteroaryl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring containing 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
in certain embodiments, each R L2 is independently selected from deuterium, F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-4 alkylene-O-C 1-4 alkyl, -O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -O-C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I. OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen substituted C 1-4 alkyl, Hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, each R L2 is independently selected from deuterium, F, cl, br, I, OH, NH 2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-2 alkylene-O-C 1-2 alkyl, -O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 1-2 alkyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -O-C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6 membered heterocyclyl, The alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, Halogen substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R L2 is each independently selected from deuterium, F, cl, br, = O, COOH, CN, NHCH 3、N(CH3)2、OH、NH2, or one of the following optionally substituted groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2CH2 -O-methyl, -OCH 2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -O-methyl, -CH 2OCH2CH2 -O-cyclopropyl, when substituted, being substituted with 1 to 4 substituents selected from F, CHF 2、CF3、-OCHF2、-OCF3, methyl, methoxy, =o, hydroxymethyl, COOH, CN, NHCH 3、N(CH3)2、OH、NH2;
In certain embodiments, each R L2 is independently selected from deuterium, F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, -N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, or C 1-4 alkoxy;
In certain embodiments, each R L2 is independently selected from deuterium, F, cl, br, I, OH, NH 2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, or C 1-4 alkoxy;
In certain embodiments, R L2 are each independently selected from deuterium, F, CF 3, OH, methyl, methoxy, =o, hydroxymethyl, COOH, NHCH 3、N(CH3)2, CN, or NH 2;
In certain embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
In certain embodiments, L is selected from the group consisting of a bond 、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-;
In certain embodiments, L is selected from the group consisting of a bond 、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-;
In certain embodiments, L is selected from-Cy 1-Cy2-, preferably Cy1 is selected from C 6-10 aryl, benzoc 4-6 carbocycle, benzo4 to 6 membered heterocycle, 5 to 6 membered heteroaryl, or 8 to 10 membered heteroaryl, cy2 is selected from 4 to 6 membered nitrogen containing heterocycloalkyl, cy2 is selected from 4-7 membered nitrogen containing heteromonocyclic ring, 4-10 membered nitrogen containing heterobicyclic ring, 5-12 membered nitrogen containing heterospiro ring, 7-10 membered nitrogen containing heterobridged ring, said heterocyclyl, heteromonocyclic ring, heterobicyclic ring, heterobridged ring, heterospiro ring, or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N, optionally substituted with 1 or 2 = O when the heteroatom is selected from S;
in certain embodiments, L is selected from
In certain embodiments, L is selected from a bond or a group shown in Table L-1, the left side of which is attached to B;
In certain embodiments, L is selected from the group shown in Table L-2, the left side of which is attached to B;
In certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 (e.g., 1 or 2) substituents selected from halogen, OH, CN, NH 2、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl;
in certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from -O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH- or-NHC (=o) -;
In certain embodiments, ak1, ak2, ak3, ak4 are each independently selected from -C(＝O)-、-O-、NH、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-NHCO-;
In certain embodiments, each R L is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R L is independently selected from H or C 1-6 alkyl;
In certain embodiments, each R L is independently selected from H or C 1-4 alkyl;
In certain embodiments, R L are each independently selected from H, methyl, or ethyl;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following optionally substituted groups: a 4-7 membered nitrogen containing heteromonocyclic ring, 4-10 membered nitrogen containing heteromonocyclic ring, 5-12 membered nitrogen containing heterospiro ring, 7-10 membered nitrogen containing heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, which when substituted is substituted with 1 to 4R L2, said heterocyclyl, heteromonocyclic ring, heterofused ring, heterobridged ring, heterospiro ring or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N, which when heteroatom is selected from S is optionally substituted with 1 or 2 = O;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazepinyl, phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyrimidine, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl, benzofuranyl, benzoxazolyl, and combinations thereof triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiazinyl, triazolooxazolyl, triazolopyrazinyl, triazolyl, triazolopyrazinyl, triazolyl, triazoloimidazolyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spiropropyl, cyclopropyl-spirobutyl, cyclopropyl-spiropentyl, cyclopropyl-spirohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl-spiropentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-azetidinyl, cyclopropyl-pyrrolidyl, cyclopropyl-piperidyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidyl, cyclobutyl-azetidinyl, cyclopentyl-piperidyl, cyclohexyl-azetidinyl-yl-spirocyclohexyl, cyclohexyl-pyrrolidinyl, cyclohexyl-piperidinyl, azetidinyl-azetidinyl, azetidinyl-pyrrolidinyl, azetidinyl-piperidinyl, pyrrolidinyl-azetidinyl, pyrrolidinyl-pyrrolidinopyrrolidinyl pyrrolidinyl-piperidinyl, piperidinyl-azetidinyl, piperidinyl-pyrrolidinyl, piperidinyl-piperidinyl, and cyclobutylspiroazetidine, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, and cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinyl cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, and azetidinyl spiroazetidinyl, When substituted, are substituted with 1 to 4R L2;
In certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: When substituted, are substituted with 1 to 4R L2;
In certain embodiments, cy1, cy2, cy3 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, are substituted with 1 to 4R L2;
in certain embodiments, L is selected from
In certain embodiments, cy1 is selected from a 4-12 membered nitrogen containing heterocycle, preferably a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heteromonocyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, said nitrogen containing heterocycle containing from 1 to 4 (e.g. 1,2,3 or 4) heteroatoms selected from O, S, N, optionally substituted with 0, 1 or 2 = O when the heteroatom is selected from S;
In certain embodiments, cy1 is selected from 4-6 membered nitrogen containing heterocycles;
in certain embodiments, L is selected from
In certain embodiments, L is selected from-Cy 1-Cy2-, cy1 is selected from phenyl, naphthyl, benzoc 4-6 carbocyclyl, benzo4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 8 to 10 membered benzocyclic heteroaryl, cy2 is selected from 4-6 membered nitrogen containing heterocycles, preferably azetidinyl, pyrrolidinyl, or piperidinyl, said Cy1 or Cy2 being optionally substituted with 1 to 4 substituents selected from R L2;
in certain embodiments, L is selected from The left side is directly connected with B, cy2 is selected from 4-6 membered nitrogen-containing heterocycle, preferably nitrogen-containing heterocycle butyl, pyrrolidinyl or piperidinyl;
in certain embodiments, rr is selected from 0,1, 2, 3, or 4;
in certain embodiments, B is selected from
In certain embodiments, V is selected from
In certain embodiments, V is selected from
In certain embodiments, V is selected from -N(Rb5a)C(＝W)-(CRb3Rb4)-、-C(＝W)-(CRb3Rb4)-、-C(＝W)-(CRb3Rb4)v2-、-(CRb3Rb4)C(＝W)(CRb3Rb4)-、-(CRb3Rb4)C(＝W)-、-N(Rb5a)C(＝W)N(Rb5a)-、-N(Rb5a)C(＝W)-、-N(Rb5a)C(＝W)-(CRb3Rb4)-N(Rb5a)-、-N(Rb5a)C(＝W)-(CRb3Rb4)-O-、-N(Rb5a)C(＝W)-(CRb3Rb4)2-N(Rb5a)-、-N(Rb5a)C(＝W)-(CRb3Rb4)2-O-、-N(Rb5a)C(＝W)-(CRb3Rb4)2-N(Rb5a)C(＝W)-、-N(Rb5a)C(＝W)-(CRb3Rb4)-N(Rb5a)C(＝W)-、-NHC(＝W)-(CRb6Rb7)-、-C(＝W)-、-C(＝W)-C(＝W)-、-(CRb3Rb4)v1-N(Rb5a)C(＝W)-(CRb3Rb4)v2-、-N(Rb5a)C(＝W)-(CRb3Rb4)-C(＝W)-、-N(Rb5a)C(＝W)-C(＝W)-(CRb3Rb4)-、-N(Rb5a)C(＝W)-C(＝W)-、-C(＝W)-C(＝W)-、-C(＝W)-(CRb3Rb4)-C(＝W)-、-C(＝W)-N(Rb5a)-(CRb3Rb4)-、-C(＝W)-(CRb6Rb7)-C(＝W)-、-N(Rb5a)C(＝W)-C(＝W)-(CRb3Rb4)-、-N(Rb5a)C(＝W)-、-C(＝W)N(Rb5a)-、-N(Rb5a)C(＝W)N(Rb5a)-;
In certain embodiments, V is selected from -NH(C＝O)(CRb3Rb4)-、-NH(C＝O)(CRb6Rb7)-、-N(Rb5)(C＝O)(CRb3Rb4)-、-N(Rb5)(C＝O)(CRb6Rb7)-、-NH(C＝O)(CRb3Rb4)-NH-、-NH(C＝O)(CRb3Rb4)-O-、-NH(C＝O)(CRb3Rb4)-NH(C＝O)-、-NH(C＝O)(CRb3Rb4)-(C＝O)NH-、-NH(C＝O)(CRb3Rb4)-(C＝O)-、-NH(C＝O)-(C＝O)-、-NH(C＝O)-(C＝O)-、-(C＝O)-(C＝O)、-(C＝O)(CRb3Rb4)-、-NH(C＝O)-、-(C＝O)NH-、-NH(C＝O)NH-、-(C＝O)(CRb3Rb4)-、-NH(C＝O)(CRb3Rb4)-CH2-、-NH(C＝O)-CH2-(CRb3Rb4)-、-(C＝O)-;
In certain embodiments, Y 1、Y2、Y3 is each independently selected from a bond, O, S, NR b5a、C(＝S)、C(＝O)、CONRb5a、NRb5a CO;
In certain embodiments, each P 1、P2 is independently selected from
In certain embodiments, v 2 is each independently selected from 0, 1,2, 3, or 4;
In certain embodiments, v 1 is each independently selected from 0,1, or 2;
In certain embodiments, v 3 is selected from 0, 1,2, or 3;
in certain embodiments, v 4 is selected from 0, 1,2, or 3;
in certain embodiments, z is selected from 0,1, 2, or 3;
in certain embodiments, B is selected from
In certain embodiments, B is selected fromIn certain embodiments, B is selected from
In certain embodiments, B is selected fromR b6 is selected from- (CH 2)m1-C3-6 cycloalkyl) and R b7 is selected from H, F, cl, CN, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl or-CH 2-C3-6 cycloalkyl, said alkyl, alkynyl or cycloalkyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl;
in certain embodiments, B is selected from R b7 is preferably H, F, cl, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, B 4 is preferably phenyl or 5-to 6-membered heteroaryl, B 2 is preferably pyrazole, said B 4 is optionally substituted with 1 to 4R b1, said B 2 is optionally substituted with 1 to 4R b2;
in certain embodiments, B is selected from V is selected from-NHC (=o) -, -NH (c=o) (CR b3Rb4)-O-、-NH(C＝O)(CRb3Rb4)-,B1 is preferably phenyl or a5 to 6 membered heteroaryl, said B 1 being optionally substituted with 1 to 4R b1;
in certain embodiments, B is selected from B 1 is preferably phenyl or 5-to 6-membered heteroaryl, said B 1 being optionally substituted with 1 to 4R b1; in certain embodiments, B is selected fromB 1 is preferably phenyl or 5-to 6-membered heteroaryl, said B 1 being optionally substituted with 1 to 4R b1;
in certain embodiments, B is selected from B 5 is selected fromA6 membered heteroaryl (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl), 8 to 10 membered heteroaryl (e.g., quinolinyl, isoquinolinyl, quinazolinyl), B 1 is preferably phenyl or a5 to 6 membered heteroaryl, said B 1 is optionally substituted with 1 to 4R b1, said B 5 is optionally substituted with 1 to 4R b2;
In some embodiments of the present invention, in some embodiments, Selected from the group consisting ofPreferably
In certain embodiments, B is selected fromB 1 is preferably phenyl or 5-to 6-membered heteroaryl, said B 1 being optionally substituted with 1 to 4R b1;
in certain embodiments, B is selected from Y1 is selected from 0,1, 2 or 3;
in certain embodiments, B is selected from (Preferably v1=0 or 1, v2=1),
Is as defined for B 1;
in certain embodiments, B is selected from
In some embodiments of the present invention, in some embodiments,Selected from the group consisting of
In certain embodiments, B is selected from
In certain embodiments, B is selected fromIn certain embodiments, B is selected fromIn certain embodiments, B is selected fromIn certain embodiments, B is selected fromIn certain embodiments, B is selected fromIn certain embodiments, B is selected fromIn certain embodiments, B is selected fromIn certain embodiments, B is selected from
In certain embodiments, B is selected from
In certain embodiments, W is selected from O or S;
in certain embodiments, W is selected from O;
In certain embodiments, ring S is selected from 4 to 9 membered nitrogen containing heterocyclyl, ring S optionally substituted with 1 to 4R s;
in certain embodiments, ring S is selected from a 5-, 6-, or 7-membered ring containing 1 or 2 nitrogen atoms, ring S optionally being substituted with 1 to 4R s;
In certain embodiments, ring S is selected from the group consisting of an azacyclopentyl, an azacyclohexyl, ring S optionally substituted with 1 to 4R s;
In certain embodiments, B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, said B 1 optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to4 heteroatoms selected from O, S, N;
In certain embodiments, B 1、B4 is each independently selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl, said B 1、B4 being optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, B 1、B4 is each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10-14 tricyclic carbocyclyl, 12-14 membered tricyclic heterocyclyl, said B 1、B4 is optionally substituted with 1 to 4R b1, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each B 1、B4 is independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 3-isoquinolinyl, quinazolinyl, 3, 4-dihydro-1H-benzopyranyl, 1,2,3, 4-tetrahydroquinolinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, Said B 1、B4 is optionally substituted with 1 to 4R b1;
In certain embodiments, B 1 is selected from substituted or unsubstituted phenyl or pyridinyl, optionally substituted with 1 to 4R b1 when substituted;
in certain embodiments, B 1 is selected from Y1 is selected from 0,1, 2 or 3;
in certain embodiments, B 1 is selected from Ba is selected from N, CR b1, bb is selected from N, CR b1, bc is selected from N, CR b1, bd is selected from N, CR b1, And up to 2 of Ba, bb, bc, bd are N, R b1A is selected from C 3-6 cycloalkyl, C 2-6 alkynyl, phenyl or 5-to 6-membered heteroaryl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, Phenyl, pyrazolyl, said cycloalkyl, alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, phenyl, heteroaryl, pyrazolyl optionally substituted with 1 to 4C 1-4 alkyl groups selected from F, cl, br, I, OH, =o, -CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen, Cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, preferably optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、NHCH3、N(CH3)2, Substituents for methyl, ethyl, isopropyl, ethynyl, -CH 2-CN、-CH2OH、-CH2OMe、-CH2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl;
In certain embodiments, B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, said B 2 optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl, or B 5, said B 2 being optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterobicyclic, 5-10 membered heterobridged ring, said B 2 optionally substituted with 1 to 4R b2, said heteroaryl, heterocyclyl, heterobicyclic, heterobridged ring containing 1 to4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from a 5-7 membered heterocyclyl, a 5-6 membered heteroaryl, or a 9-10 membered heteroacene, said B 2 being optionally substituted with 1 to 4R b2, said heteroaryl, heterocyclyl, heteroacene containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 2 is selected from B 5;
In certain embodiments, B 2 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridonyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, Or B 5, when substituted, is substituted with 1 to 4R b2;
In certain embodiments, B 2 is selected from pyrazolyl, said B 2 is optionally substituted with 1 to 4R b2;
In certain embodiments, B 2 is selected from pyrazolyl, said B 2 is substituted with 1R b2a, optionally with 1 to 3R b2;
In certain embodiments, B 2 is selected from The right side is directly connected with L;
In certain embodiments, B 2 is selected from The right side is directly connected with L;
In certain embodiments, B 3 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 3 is selected from the group consisting of 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl, 4-7 membered monocyclic heterocyclyl, 7-14 membered heteroacene, 7-14 membered heterospiro, said B 3 being optionally substituted with 1 to 4R b1, said heteroaryl, heterocyclyl, heteroacene, heterospiro containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 3 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzopyrrolidinyl, benzopiperidinyl, benzopyranyl, 3-pyridazinonyl, 2-pyridonyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, pyridoimidazolyl, pyridopyrrolyl, carbazolyl, 2, 3-indolinyl, benzomorpholinyl, When substituted, are substituted with 1 to 4R b1;
In certain embodiments, B 3 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, Benzopyridyl, benzothienyl, benzofuranyl, and a process for preparing the same,Thienyl, furyl, pyrrolyl, when substituted, are substituted with 1 to 4R b1;
In certain embodiments, B 4 is selected from phenyl, a 5-6 membered heteroaryl, said phenyl or heteroaryl optionally substituted with 1 to 4R b1, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, B 4 is selected from one of the following substituted or unsubstituted groups: phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, when substituted, are substituted with 1 to 4R b1;
In certain embodiments, B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said B 4 is substituted with 1R b1a, optionally with 1 to 3R b1;
In certain embodiments, B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said B 4 is substituted with 1R b1a, optionally substituted with 1 to 3 substituents selected from F, cl, br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
In certain embodiments, B 4 is selected from phenyl, pyridinyl, said B 4 is substituted with 1R b1a, optionally with 1 to 3R b1;
in certain embodiments, B 5 is selected from C 12-18 tri-ring, 12 to 18 membered hetero-tri-ring, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, phenyl, benzoc 4-6 carbocycle, benzo4 to 6 membered heterocycle, pyrazoloc 4-6 carbocycle, pyrazolo4 to 6 membered heterocycle, triazolo C 4-6 carbocycle, triazolo 4 to 6 membered heterocycle, imidazo C 4-6 carbocycle, imidazo 4 to 6 membered heterocycle, thieno C 4-6 carbocycle, thieno 4 to 6 membered heterocycle, furo C 4-6 carbocycle, furo 4 to 6 membered heterocycle, 4-7 membered nitrogen containing heteromonocyclic alkyl (e.g., azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl), 4-10 membered nitrogen containing heterocycloalkyl, 5-12 membered nitrogen containing heterospirocycloalkyl, 7-10 membered nitrogen containing heterobridged cycloalkyl, 3-7 membered monocyclic alkyl, 4-10 membered heterocycloalkyl, 5-12 membered alkyl, 7-10 membered bridged cycloalkyl, said B is optionally substituted with 1 to 6 membered cycloalkyl, said 1 to 25 heteroatoms;
B 5 is selected from Said B 5 is optionally substituted with 1 to 4R b2;
In certain embodiments, R b1 is each independently selected from H, F, cl, br, I, = O, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, c 1-4 alkoxy, C 1-4 alkylthio 、-(CH2)n-Rb22、-ORb22、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-12 cycloalkyl (preferably C 3-6 cycloalkyl), C 6-10 aryl, 5-10 membered heteroaryl (preferably 5-6 membered heteroaryl) or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, a 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituted with 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R b1 is independently selected from H、F、Cl、Br、I、＝O、OH、NH2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3 or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, cyclopentyl-cyclopentyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-cyclopentyl, azetidinyl-spirohexyl, cyclobutylspirocyclohexyl, cyclobutylspiropiperidinyl, cyclopropyl-spirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl-spirocyclohexyl, Optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-OH, -C 1-2 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 4-6 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R b1 is independently selected from H、F、Cl、Br、I、＝O、OH、NH2、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)2(CH3)2、-S(＝O)2CH3 or one of the following optionally substituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl spirospirocyclohexyl, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、NHCH3、N(CH3)2, methyl, ethyl, isopropyl, ethynyl, -CH 2-CN、-CH2OH、-CH2OMe、-CH2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl;
In certain embodiments, R b1 is selected from F, cl, CN, CF 3、-OCF3, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclobutyl, or R b1a;
In certain embodiments, R b1 is selected from R b1a;
In certain embodiments, each R b2 is independently selected from H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4 alkyl, -C (=O) N (C 1-4 alkyl )2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5-to 10-membered heteroaryl, 4-to 10-membered heterocyclyl, -C 1-4 -alkylene-4-to 10-membered heterocyclyl, said alkylene, CH 2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, halogen substituted C 3-6 cycloalkyl, halogen substituted C 3-6 Cycloalkyloxy, 5-6 membered heteroaryl or 4-8 membered heterocyclyl groups substituted with 1 to 4 substituents selected from O, s, N heteroatoms;
In certain embodiments, each R b2 is independently selected from H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4 alkyl, -C (=O) N (C 1-4 alkyl )2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5-to 6-membered heteroaryl, 4-to 8-membered heterocyclyl, -C 1-4 -alkylene-4-to 8-membered heterocyclyl, said alkylene, CH 2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、-NHC1-4 alkyl, -N (C 1-4 alkyl) 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, A halogen substituted C 3-6 cycloalkyloxy, a 5-6 membered heteroaryl or a 4-8 membered heterocyclyl substituent, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R b2 is independently selected from H、F、Cl、Br、I、＝O、OH、NH2、NH(CH3)、N(CH3)2、CN、NO2、COOH、-C(＝O)NH2 or one of the following optionally substituted groups: -CH 2OCH2CH3, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, being 1 to 4 groups selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、NHCH3、N(CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxacyclohexyl, cyclopropyl, Cyclobutyl group,Cyclopropyloxy group, Is substituted by a substituent of (2);
In certain embodiments, R b2 is selected from R b2a;
in certain embodiments, R b21 is each independently selected from H or C 1-4 alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;
In certain embodiments, each R b21 is independently selected from H, methyl, ethyl, isopropyl;
In certain embodiments, R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-4 alkoxy;
In certain embodiments, each R b22 is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;
In certain embodiments, n is each independently selected from 0, 1, 2, 3, or 4;
in certain embodiments, n is each independently selected from 0,1, 2;
In certain embodiments, n is each independently selected from 0, 1;
In certain embodiments, each R b3、Rb4、Rb6、Rb7 is independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-6 alkyl, halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
Optionally, R b3、Rb4 is not simultaneously H;
optionally, R b6、Rb7 is not simultaneously H;
In certain embodiments, R b3、Rb4 together with the carbon atoms to which it is attached form a C 3-8 cycloalkyl or a 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b3、Rb4 is each independently selected from H, OH, NH 2、C1-4 alkyl, C 2-4 alkynyl, C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 3 to 8 heteromonocyclic ring, said alkyl, alkynyl, cycloalkyl or heteromonocyclic ring being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 2-4 alkynyl or 3 to 8 heterocyclyl, said heteromonocyclic ring, heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R b3、Rb4 is independently selected from H, OH, NH 2, or one of the following optionally substituted groups: methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、CF3、CHF2, methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, cyclobutylspirocyclobutyl; ;
In certain embodiments, R b3、Rb4 taken together with the carbon atoms to which it is attached form a C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or a 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 carbocyclyl, or 3 to 8 heterocyclyl, said heteromonocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b3、Rb4 taken together with the carbon atoms to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxetanyl, said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, oxolanyl optionally substituted with 1 to 4 (e.g., 1,2, 3, or 4) substituents selected from deuterium, F, cl, br, I, OH, NH 2、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4 to 6 heterocyclyl, said heteromonocyclic or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b3、Rb4 taken together with the carbon atom to which it is attached form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxycyclohexyl, cyclobutylspirocyclobutyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, cyclobutylspirocyclobutyl optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、N(CH3)、CN、CF3、CHF2, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl;
In certain embodiments, R b3 and R b5a、Rb1 are directly linked to R b5a to form a ring S selected from 4 to 9 membered nitrogen containing heterocyclyl, ring S optionally substituted with 1 to 4 substituents selected from R s;
In certain embodiments, R s is each independently selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl, or 3 to 8 heterocyclyl, said alkyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R s is each independently selected from F, cl, br, I, OH, NH 2、-NHC1-4 alkyl, -N (C 1-4 alkyl) 2、CN、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy, or cycloalkyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl or C 1-4 alkoxy;
in certain embodiments, each R s is independently selected from \F、Cl、Br、I、OH、NH2, CN, methyl, ethyl, methoxy, ethoxy, or cyclopropyl;
In certain embodiments, R b5a is selected from H or R b5;
In certain embodiments, R b5 is selected from OH, NH 2、C1-4 alkyl, - (CH 2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b5 is selected from OH, NH 2, methyl, ethyl, propyl, isopropyl, - (CH 2)n -cyclopropyl, - (CH 2)n -cyclobutyl, - (CH 2)n -cyclopentyl, - (CH 2)n -cyclohexyl, phenyl, pyridinyl), said-CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b5 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, phenyl, pyridinyl, said-CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl;
in certain embodiments, R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-6 alkyl, halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, said alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 and cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5-10 membered heterobridged ring, 5-12 membered heterospiro, 5-12 membered heteroacene, said alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospiro, or heteroacene optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl, heterocyclyl, heterobridged ring, heterospiro, or heterofused ring containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, azetenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptyl, phenyl, pyridinyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-cyclohexyl, cyclobutyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-spirocyclopropyl-, cyclopropyl-spirocyclohexyl, cyclobutyl-spirocyclopentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-and-azetidinyl, cyclopropyl-and-pyrrolidinyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl cyclohexylazetidinyl, cyclohexylpyrrolidyl, cyclohexylpiperidyl, azetidinazetidinyl, azetidinopyrrolidinyl, azetidinopiperidyl a cyclohexylazetidinyl group, a cyclohexylopyrrolidinyl group, a cyclohexylopiperidyl group, a azetidinoazetidines, azetidinopyrrolidines, azetidinopiperidines, azetidines, azetidin, cyclohexyl spiropiperidinyl, azetidinyl, and the like azetidinyl spiropyrrolidinyl azetidinyl spiropiperidinyl pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b3、Rb4、Rb7 is each independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, said alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, each R b3、Rb4、Rb7 is independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 bridged cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5-10 membered heterobridged ring, 5-12 membered heterospiro, 5-12 membered heterofused ring, said alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospiro or fused ring optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, said heteroaryl, heterocyclyl, heterobridged ring or fused ring containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R b3、Rb4、Rb7 is independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、CHF2、CF3、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptanyl, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl-cyclohexyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirocyclobutyl-spirocyclohexyl, cyclobutyl-spirocyclohexyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spiropyrrolidinyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl cyclohexylazetidinyl, cyclohexylpyrrolidyl, cyclohexylpiperidyl, azetidinazetidinyl, azetidinopyrrolidinyl, azetidinopiperidyl a cyclohexylazetidinyl group, a cyclohexylopyrrolidinyl group, a cyclohexylopiperidyl group, a azetidinoazetidines, azetidinopyrrolidines, azetidinopiperidines, azetidines, azetidin, cyclohexyl spiropiperidinyl, azetidinyl, and the like azetidinyl spiropyrrolidinyl azetidinyl spiropiperidinyl pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, is substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl (preferably with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、CF3、CHF2, methyl, ethyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxacyclopentyl, oxacyclohexyl, cyclobutylspirocyclobutyl), said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In some embodiments of the present invention, in some embodiments, Selected from the group consisting of
In certain embodiments, each X is independently selected from NH, O, or S;
in certain embodiments, each X is independently selected from NH, O;
In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4-10 membered heterocyclyl, said cycloalkyl, alkenyl, alkynyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4-8 membered heterocyclyl, said cycloalkyl, alkenyl, alkynyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b23 is each independently selected from vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxolanyl, cyclohexyl, piperidine, or morpholine, said vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxolanyl, cyclohexyl, piperidine, or morpholine optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy;
In certain embodiments, R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, or 4-10 membered heterocyclyl, said alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, or a 4-8 membered heterocyclyl, said alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, each R b24 is independently selected from methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azexenyl, oxetanyl, oxolanyl, cyclohexyl, piperidine, or morpholine, said methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepinyl, oxetanyl, oxolanyl, oxetanyl, cyclohexyl, piperidine, or morpholine being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy;
in certain embodiments, m1 are each independently selected from 0,1, 2, or 3;
in certain embodiments, m2 is each independently selected from 0,1, 2, or 3;
In certain embodiments, m2 is each independently selected from 0,1, 2;
In certain embodiments, R b7 is selected from H, F, cl, br, I, OH, NH 2、CN、NO2、CHF2、CF3, methyl, ethyl, ethynyl, propynyl, propargyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxolanyl, -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2O(CH2)2OCH3、-CH2 O-cyclobutyl, -CH 2 O-cyclopropyl, -CH 2OCH2 -cyclobutyl, -CH 2OCH2 -cyclopropyl, -CH 2 NH-cyclobutyl, -CH 2 NH-cyclopropyl, -CH 2OCH2 -oxetanyl, -CH 2OCH2 -oxetanyl, Said methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, piperidinyl or morpholinyl optionally substituted with 1 to 4C 1-4 alkyl groups selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl groups, halogen substituted, cyano substituted C 1-4 alkyl groups, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents substituted with C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b7 is selected from one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholinyl, phenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirobutyl, cyclopropyl-spiropentyl, cyclopropyl-spirocyclohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl-spiropentyl, cyclopentyl-spirohexyl, cyclohexyl-spirohexyl, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b6 is selected from F, cl, br, I, OH, NH 2、CN、NO2 or one of the following optionally substituted groups: ethynyl, propynyl, propargyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxolanyl, -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2O(CH2)2OCH3、-CH2 O-cyclobutyl, -CH 2 O-cyclopropyl, -CH 2OCH2 -cyclobutyl, -CH 2OCH2 -cyclopropyl, -CH 2 NH-cyclobutyl, -CH 2 NH-cyclopropyl, -CH 2OCH2 -oxetanyl, -CH 2OCH2 -oxetanyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopentylcyclopentyl, morpholinyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopentylcyclopentyl, and pyrimidinyl cyclopentyl cyclohexyl, cyclopropyl spiropropyl, cyclopropyl spirobutyl, cyclopropyl spiropentyl, cyclopropyl spirohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl spiropentyl, cyclopentyl spirohexyl, cyclohexyl spirohexyl, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b6 is selected from C 3-8 cycloalkyl, -CH 2-C3-8 cycloalkyl, or-CH 2CH2-C3-8 cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said R b6 is optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In some embodiments of the present invention, in some embodiments, Selected from the group consisting of
In some embodiments of the present invention, in some embodiments,Selected from the group consisting ofB 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, said B 1 being substituted with 1R b1a, optionally with 1 to 3R b1, B 2 is selected from 5-10 membered heterocyclyl, said B 2 being optionally substituted with 1 to 3R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In some embodiments of the present invention, in some embodiments, Selected from the group consisting ofB 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, said B 1 optionally being substituted with 1 to 4R b1, B 2 is selected from 5-10 membered heterocyclyl, said B 2 is substituted with 1R b2a, optionally being substituted with 1 to 3R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
In some embodiments of the present invention, in some embodiments, Selected from the group consisting ofSelected from the group consisting ofOr C 5-10 spirocycles, ofSubstituted with 1 to 3 substituents selected from R b3a, said spiro optionally substituted with 1 to 3 substituents selected from halogen or R b3a;
In certain embodiments, B 1 is selected from phenyl, said phenyl being substituted with 3 to 5R b1;
In certain embodiments, R b3a is each independently substituted with a substituent selected from OH, NH 2、CN、N(C1-4 alkyl) 2、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, or C 1-4 alkoxy;
In certain embodiments, R b3a is each independently substituted with a substituent selected from OH, NH 2、CN、N(CH3)2、CF3、-CH2 CN, methyl, ethyl, methoxy, or ethoxy;
In certain embodiments, R b1a is selected from the group consisting of-C 1-4 alkylene- (C.ident.C) -H, -C 1-4 alkylene-NH 2、-C1-4 alkylene-N (C 1-4 alkyl) 2、-C1-4 alkylene-NHC 1-4 alkyl, N (C 1-4 alkyl) 2、C5-6 cycloalkyl, C 5-9 spirocyclic, 5-to 6-membered heteroaryl, - (C.ident.C) -CH 3, cyclopropyl, cyclobutyl, Phenyl, said- (C.ident.C) -CH 3 being substituted by 1 to 3 groups selected from F, cl, br, I, OH, NH 2、CN、COOH、N(C1-4 alkyl) 2、C1-4 alkyl, C 1-4 alkoxy, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl substituted with 1 to4 substituents selected from NH 2、CN、COOH、N(C1-4 alkyl) 2、C1-4 alkyl, c 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkyl, A C 3-6 cycloalkyl group substituted with 1 to4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, a C 3-6 cycloalkyl group optionally substituted with 1 to4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, Cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b1a is selected from -CH2NH2、-CH2N(CH3)2、-CH2CH2N(CH3)2、N(CH3)2、C(CH3)2NH2、-(C≡C)-CH3、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, cyclopropyl spirobutyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl spirohexyl, Phenyl, said- (C.ident.C) -CH 3 being substituted by 1 to 3 groups selected from F, cl, br, I, OH, NH 2、CN、COOH、N(C1-4 alkyl) 2、C1-4 alkyl, C 1-4 alkoxy, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl substituted with 1 to4 substituents selected from NH 2、CN、COOH、N(C1-4 alkyl) 2、C1-4 alkyl, c 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkyl, A substituent of C 3-6 cycloalkyl is substituted, the cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, C 1-4 alkyl substituted with 1 to 4 groups selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkoxy, halogen, Cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, cyclopropyl spirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl spirohexyl or phenyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, The heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b1a is selected from -CH2NH2、-CH2N(CH3)2、-CH2CH2N(CH3)2、N(CH3)2、C(CH3)2NH2、
In certain embodiments, R b2a is selected from the group consisting of-COOH, -CONH 2、-(CH2)n-NH2、-(CH2)n-N(C1-4 alkyl) 2、-(CH2)n-NHC1-4 alkyl, N (C 1-4 alkyl) 2、-(CH2)n-OH、-(CH2)n-C2-4 alkynyl, - (CH 2)nOC1-4 alkyl, - (CH 2)nO(CH2)nOC1-4 alkyl, - (CH 2)n-O(CH2)nOC3-6 cycloalkyl, -C 1-4 alkylene-4 to 6 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, said alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, alkynyl being optionally substituted with 1 to 3 substituents selected from the group consisting of F, cl, br, I, OH, NH 2、CN、COOH、NHC1-4 alkyl, N (C 1-4 alkyl) 2、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
In certain embodiments, R b2a is selected from -COOH、-CONH2、-CH2NH2、C(CH3)2OH、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2OCH3、-CH2OCH2CH2O- cyclopropyl, -CH 2N(CH3)2、-CH2CH2N(CH3)2, phenyl,
Optionally, B is not
In certain embodiments, B is selected from one of the structural fragments shown in Table B-1:
Table B-1
In certain embodiments, B is selected from one of the structures shown in Table B-2;
Table B-2
In certain embodiments, q is each independently selected from 0, 1,2, 3, 4, 5, or 6;
In certain embodiments, q is each independently selected from 0, 1, 2, 3, or 4;
In certain embodiments, q is each independently selected from 0,1, or 2;
In certain embodiments, n1, n2, n3 are each independently selected from 0, 1,2, or 3;
in certain embodiments, p1 or p2 are each independently selected from 0, 1, 2,3, 4, or 5;
in certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, or 3;
in certain embodiments, p1 or p2 are each independently selected from 0, 1, or 2;
in certain embodiments, K is selected from K1, K2, K3, K4;
in certain embodiments, K1 is selected from
In certain embodiments, K1 is selected from
In certain embodiments, K2 is selected from
In certain embodiments, K2 is selected from
In certain embodiments, K3 is selected from
In certain embodiments, K3 is selected from
In certain embodiments, K4 is selected from In certain embodiments, K4 is selected from
In certain embodiments, each E is independently selected from a C 3-10 carbocycle, a C 6-10 aromatic ring, a 3-12 membered heterocycle, or a 5-12 membered heteroaryl ring containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, E is each independently selected from a C 3-10 carbocycle, a benzene ring, a 4-12 membered heterocycle, a 5-12 membered heteroaryl ring containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each E is independently selected from a benzene ring, a 5-6 membered heteroaromatic ring containing 1 to 3 (e.g., 1,2, 3) heteroatoms selected from O, S, N;
In certain embodiments, each E is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, an oxazole ring, an indoline ring, an isoindoline ring, a1, 2,3, 4-tetrahydroquinoline ring, or a1, 2,3, 4-tetrahydroisoquinoline ring;
in certain embodiments, each E is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;
in certain embodiments, each E is independently selected from the group consisting of a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring;
in certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;
In certain embodiments, a is selected from a C 3-10 carbocycle, a C 6-10 aromatic ring, a 3-10 membered heterocycle, or a 5-10 membered heteroaryl ring containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, N;
In certain embodiments, a is selected from a C 3-8 carbocycle, a benzene ring, a 4-7 membered heterocycle, or a 5-6 membered heteroaryl ring containing 1 to 4 (e.g., 1,2, 3, or 4) heteroatoms selected from O, S, N;
In certain embodiments, a is selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;
In certain embodiments, a is selected from a benzene ring or a pyridine ring;
in certain embodiments, each F is independently selected from a C 3-20 carbocycle, a C 6-20 aromatic ring, a 3-20 membered heterocycle, or a 5-20 membered heteroaryl ring containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each F is independently selected from the group consisting of a C 3-7 monocyclic carbocycle, a C 4-10 fused ring carbocycle, a C 5-12 spiro carbocycle, a C 5-10 bridged carbocycle, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterofused ring, a 8-15 membered heterotricyclic ring, a 5-12 membered heterospiro ring, a 5-10 membered heterobridged ring, a C 6-14 aryl, a 5-10 membered heteroaryl, a, The heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaromatic ring contains 1 to 4 (e.g., 1, 2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each F is independently selected from the group consisting of a C 3-7 monocyclic carbocycle, a C 4-10 fused ring carbocycle, a C 5-12 spiro carbocycle, a C 5-10 bridged carbocycle, a 4-7 membered heteromonocyclic ring, a 4-10 membered heterofused ring, a 8-15 membered heterotricyclic ring, a 5-12 membered heterospiro ring, a 5-10 membered heterobridged ring, a C 6-14 aryl, a 5-10 membered heteroaryl, a, The heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;
In certain embodiments, each F is independently selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, and a pyrimidine ring,
In certain embodiments, each F is independently selected from the group consisting of a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, and a pyrimidine ring,
In some embodiments of the present invention, in some embodiments, F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrrolyl, pyrrolopyridinyl, and pyrrolopyridinyl, imidazolyl, and pyrrolyl pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidinopyridinyl, pyrimidinopyrazinyl, pyrimidinopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrazolyl, pyridazinopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, pyrimidinopyrazinyl, and pyrimidinyl, and pyrazinyl are obtained from the composition containing the composition, The left side of the connecting rod is directly connected with L;
In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-CO-、-NRqCO-、-CONRq -, or a 3-12 membered heterocycle, said heterocycle optionally being substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, said heterocycle containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each Q is independently selected from-O-, -S-, -CH 2-、-NRq-、-CO-、-NRqCO-、-CONRq -or a 4-7 membered heterocycle, said heterocycle optionally being substituted with 1 to 4 (e.g., 1, 2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocycle containing 1 to 4 (e.g., 1, 2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each Q is independently selected from a bond, C (=o), Q1, or Q2;
In certain embodiments, Q1 is selected from the group consisting of a bond, CH 2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3),
In certain embodiments, Q2 is selected from a bond, CH 2、O、S、C(＝O)、NHC(＝O)、N(CH3) C (=o);
In certain embodiments, R q is selected from H or C 1-6 alkyl;
in certain embodiments, R q is selected from H or C 1-4 alkyl;
In certain embodiments, R q is selected from H, methyl, ethyl;
In certain embodiments, each R k2 is independently selected from a bond, -CO-, -SO 2 -, -SO-, or-C (R k3)2 -;
In some embodiments of the present invention, in some embodiments, R k2 is each independently selected from-CO-, -SO 2 -, or-C (R k3)2 -;
In certain embodiments, R k1 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, R k7a, said alkyl, alkoxy, cycloalkyl optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
In certain embodiments, R k1 is selected from R k7a;
In certain embodiments, R k3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, or a 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, or heterocyclyl being optionally substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, R k1、Rk3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, optionally substituted with 1 to4 (e.g., 1,2, 3, or 4) substituents selected from F, cl, br, I, OH, NH 2;
In certain embodiments, R k1、Rk3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy, optionally substituted with 1 to 4 (e.g., 1, 2,3, or 4) substituents selected from F, cl, br, I, OH, NH 2;
In certain embodiments, two R k3 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocycle or a 3-8 membered heterocycle, two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocycle or a 3-8 membered heterocycle, the carbocycle or heterocycle optionally being substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, the heterocycle containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, two R k3 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocycle or a 3-7 membered heterocycle, two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocycle or a 3-7 membered heterocycle, the carbocycle or heterocycle optionally being substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, the heterocycle containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, R k4 is each independently selected from H, OH, NH 2、CN、CONH2、C1-6 alkyl, C 3-8 cycloalkyl, or a 3-8 membered heterocyclyl, optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, each R k4 is independently selected from H, OH, NH 2、CF3、CN、C1-4 alkyl;
In certain embodiments, each R k5 is independently selected from C(CH3)2、CO、CH2、SO2、
In certain embodiments, each R k5 is independently selected from CO, CH 2、SO2, or
In certain embodiments, each R k6 is independently selected from CO, CH, SO, SO 2、CH2 or N;
in certain embodiments, each R k7 is independently selected from C(CH3)2、CO、CH、N、CH2、O、S、NRk7a；
In certain embodiments, each R k7 is independently selected fromC (CH 3)2、CO、CH、N、CH2、O、S、N(CH3)、N(CH2CH3), N (cyclopropyl) or NH;
In certain embodiments, each R k7 is independently selected from CO, CH, N, CH 2、O、S、N(CH3) or NH;
In certain embodiments, each R k7 is independently selected from CH 2、O、N(CH3) or NH;
In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl;
in certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;
In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, said alkyl or cycloalkyl optionally substituted with 1 to 4 substituents selected from halogen, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;
In certain embodiments, R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF 3、C1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 cycloalkyl;
In certain embodiments, R k7a is selected from H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2CF3、-CH(CH3)CF3、-CH(CH3) -cyclopropyl, -CH 2 -cyclopropyl, -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2CH2 -methoxy;
In certain embodiments, R k7a is selected from H, CF 3, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl;
In certain embodiments, R k7a is selected from H, CH 3、CH2CH3, cyclopropyl;
in certain embodiments, each R k8 is independently selected from C, N or CH;
in certain embodiments, each R k9 is independently selected from a bond, C (CH 3)2、CO、CH2、CH2CH2 or SO 2;
In certain embodiments, each R k9 is independently selected from CO, SO 2, or CH 2;
In certain embodiments, M 1 is selected from the group consisting of a bond, -CH 2 -C (=o) NH-, or-C (=o) CH 2 NH-;
in certain embodiments, M 2 is selected from-NHC (=o) -C 1-6 alkyl, -NHC (=o) -C 3-6 cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
In certain embodiments, M 3 is selected from-NH-or-O-;
In certain embodiments, R k10 is selected from C 1-6 alkyl optionally substituted with 1 to 4 (e.g., 1, 2,3, 4) substituents selected from F, cl, br, I, =o, OH, C 1-6 alkyl, or C 3-6 cycloalkyl;
in certain embodiments, G is selected from a C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring, optionally substituted with 1 to 4 (e.g., 1,2,3, 4) substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl, the heteroaromatic ring containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from N, O, S;
In certain embodiments, R k11 is each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, or-O-C (=o) -C 1-6 alkyl, said alkyl, alkoxy, or alkylthio being optionally substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from F, cl, br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
In certain embodiments, R k12、Rk13 is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted with 1 to4 (e.g., 1, 2,3, 4) substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl, or C 1-4 alkoxy;
In certain embodiments, R k14 is selected from a 5-6 membered heteroaryl optionally substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl, the heteroaryl containing 1 to 4 (e.g., 1,2, 3, 4) heteroatoms selected from N, O, S; in certain embodiments, R k14 is selected from thiazoles optionally substituted with 1 to 4 (e.g., 1,2, 3, 4) substituents selected from methyl; in certain embodiments, R k14 is selected from
In certain embodiments, K is selected from one of the structural fragments shown in Table K-1:
Table K-1
In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;
Table K-2
In certain embodiments, K is selected from one of the structural fragments shown in Table K-3:
K-3
in certain embodiments, K is selected from
As a first embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
L is selected from a bond or a-C 1-50 hydrocarbyl-, of which 1 to 20 methylene units are optionally replaced by-Ak-, -Cy-;
each-Ak-is independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 substituents selected from halogen, OH, CN, NH 2、C1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl; q is each independently selected from 0, 1,2, 3, 4, 5 or 6;
R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
each-Cy-is independently selected from a bond or one of the following optionally substituted groups: 4-8 membered heteromonocyclic ring, 4-10 membered heteromonocyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4 to6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, substituted with 1 to 4R L2, said heterocyclyl, heteroaryl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring containing 1 to4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally substituted with 1 or 2 = O;
R L2 is each independently selected from deuterium, F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-4 alkylene-O-C 1-4 alkyl, -O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -O-C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I. OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen substituted C 1-4 alkyl, Hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
b is selected from
B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, said B 1 being optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, said B 2 optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
V is selected from
W is selected from O or S;
Y 1、Y2、Y3 are each independently selected from a bond, O, S, NR b5a、C(＝S)、C(＝O)、CONRb5a、NRb5a CO;
p 1、P2 are each independently selected from
V 2 are each independently selected from 0, 1,2,3 or 4;
v 1 are each independently selected from 0, 1 or 2;
R b1 is independently selected from H, F, cl, br, I, = O, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio 、-(CH2)n-Rb22、-ORb22、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy), Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, a 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituted with 1 to 4 heteroatoms selected from O, S, N;
R b21 are each independently selected from H or C 1-4 alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;
R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
n is each independently selected from 0,1, 2, 3 or 4;
R b2 is each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4 alkyl, -C (=O) N (C 1-4 alkyl )2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C 1-4 alkylene-4 to 10 membered heterocyclyl, said alkylene, CH 2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, halogen substituted C 3-6 cycloalkyl, halogen substituted C 3-6 Cycloalkyloxy, 5-6 membered heteroaryl or 4-8 membered heterocyclyl groups substituted with 1 to 4 substituents selected from O, s, N heteroatoms;
r b3、Rb4、Rb6、Rb7 is each independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-6 alkyl, halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
Or R b3、Rb4 taken together with the carbon atom to which it is attached form C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
Alternatively, R b3 and R b5a、Rb1 are directly linked to R b5a to form a ring S selected from 4 to 9 membered nitrogen containing heterocyclyl, ring S optionally substituted with 1 to 4 substituents selected from R s;
R s is independently selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl, or 3 to 8 heterocyclyl, said alkyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R b5a is selected from H or R b5;
R b5 is selected from OH, NH 2、C1-4 alkyl, - (CH 2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =O, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
x is independently selected from NH, O or S;
m1 is independently selected from 0,1, 2 or 3;
m2 is each independently selected from 0,1, 2 or 3;
R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, said cycloalkyl, alkenyl, alkynyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, or a 4-10 membered heterocyclyl, said alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
k is selected from K1, K2, K3 and K4;
K1 is selected from
K2 is selected from
K3 is selected from
K4 is selected from
Each Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-CO-、-NRqCO-、-CONRq -, or a 3-12 membered heterocyclic ring, said heterocyclic ring being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S or N;
R q is selected from H or C 1-6 alkyl;
A is selected from a C 3-10 carbocycle, a C 6-10 aromatic ring, a 3-10 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;
F is each independently selected from a C 3-20 carbocycle, a C 6-20 aromatic ring, a 3-20 membered heterocycle or a 5-20 membered heteroaryl ring containing 1 to 4 heteroatoms selected from O, S or N;
R k2 is each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-, or-C (R k3)2 -;
R k1 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, R k7a, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl;
Each R k3 is independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
Or two R k3 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocycle or a 3-8 membered heterocycle, and two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocycle or a 3-8 membered heterocycle, said carbocycle or heterocycle being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
Each R k4 is independently selected from H, OH, NH 2、CN、CONH2、C1-6 alkyl, C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
M 1 is selected from the group consisting of bond, -CH 2 -C (=O) NH-, or-C (=O) CH 2 NH-;
M 2 is selected from-NHC (=o) -C 1-6 alkyl, -NHC (=o) -C 3-6 cycloalkyl or a 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;
M 3 is selected from-NH-or-O-;
R k10 is selected from C 1-6 alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, C 1-6 alkyl or C 3-6 cycloalkyl;
R k11 is each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or-O-C (=o) -C 1-6 alkyl, said alkyl, alkoxy or alkylthio being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;
R k12、Rk13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy;
R k14 is selected from a 5-6 membered heteroaryl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;
G is selected from a C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O or S;
n1, n2, n3 are each independently selected from 0,1, 2 or 3;
p1 or p2 are each independently selected from 0,1, 2, 3, 4 or 5.
As a second embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
B is selected from
V 2 are each independently selected from 1,2, 3 or 4;
v 1 are each independently selected from 0, 1 or 2;
v 3 is selected from 0, 1,2 or 3;
v 4 is selected from 0, 1,2 or 3;
z is selected from 0,1, 2 or 3;
W is selected from O or S;
Is as defined for B 1;
B 1、B4 are each independently selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, said B 1、B4 being optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl, or B 5, said B 2 being optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to4 heteroatoms selected from O, S, N;
B 3 is selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl, said B 3 optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
b 5 is selected from the group consisting of C 12-18 tricyclo, 12 to 18 membered hetero tricyclo, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, phenyl, benzoc 4-6 carbocycle, benzo4 to 6 membered heterocycle, pyrazoloc 4-6 carbocycle, pyrazolo4 to 6 membered heterocycle, triazolo C 4-6 carbocycle, triazolo 4 to 6 membered heterocycle, imidazo C 4-6 carbocycle, imidazo 4 to 6 membered heterocycle, thieno C 4-6 carbocycle, thieno 4 to 6 membered heterocycle, furo C 4-6 carbocycle, furo 4 to 6 membered heterocycle, 4-7 membered nitrogen containing heteromonocyclic alkyl, 4-10 membered nitrogen containing heterocycloalkyl, 5-12 membered nitrogen containing heterospirocycloalkyl, 7-10 membered nitrogen containing heterobridged cycloalkyl, 3-7 membered monocyclic alkyl, 4-10 membered heterocycloalkyl, 5-12 membered alkyl, 7-10 membered bridged cycloalkyl, said B 5 being optionally substituted with 1 to 4R b2, said heterocycle, heterocycloalkyl, spirocycloalkyl, and spirocycloalkyl containing a heteroatom selected from the group consisting of 861 to O, S, N heteroatoms;
R b5 is selected from OH, NH 2、C1-4 alkyl, - (CH 2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =O, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, said alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b3、Rb4、Rb7 is each independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, said alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
Or R b3、Rb4 taken together with the carbon atom to which it is attached form C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
the remaining groups are as defined in the first embodiment of the invention.
As a third embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
B is selected from
Ring S is selected from 5-, 6-or 7-membered rings containing 1 or 2 nitrogen atoms, ring S optionally being substituted with 1 to 4R s;
R s is independently selected from F, cl, br, I, OH, NH 2、-NHC1-4 alkyl, -N (C 1-4 alkyl) 2、CN、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl or C 1-4 alkoxy;
b 1、B4 is independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10-14 tricyclic carbocyclyl, 12-14 membered tricyclic heterocyclyl, said B 1、B4 is optionally substituted with 1 to 4R b1, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heteroacene, 5-10 membered heterobridged ring, said B 2 optionally being substituted with 1 to 4R b2, said heteroaryl, heterocyclyl, heteroacene, heterobridged ring containing 1 to 4 heteroatoms selected from O, S, N;
B 3 is selected from the group consisting of 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl, 4-7 membered monocyclic heterocyclyl, 7-14 membered heteroacene, 7-14 membered heterospiro, said B 3 being optionally substituted with 1 to 4R b1, said heteroaryl, heterocyclyl, heteroacene, heterospiro containing 1 to 4 heteroatoms selected from O, S, N;
R b2 is each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4 alkyl, -C (=O) N (C 1-4 alkyl )2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5-to 6-membered heteroaryl, 4-to 8-membered heterocyclyl, -C 1-4 -alkylene-4-to 8-membered heterocyclyl, said alkylene, CH 2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、-NHC1-4 alkyl, -N (C 1-4 alkyl) 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, A halogen substituted C 3-6 cycloalkyloxy, a 5-6 membered heteroaryl or a 4-8 membered heterocyclyl substituent, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 and cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5-10 membered heterobridged ring, 5-12 membered heterospiro, 5-12 membered heterofused ring, said alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospiro or fused ring optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
r b3、Rb4、Rb7 is each independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 and cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5-10 membered heterobridged ring, 5-12 membered heterospiro, 5-12 membered heterofused ring, said alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospiro or fused ring optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, said heteroaryl, heterocyclyl, heterobridged ring, heterospiro or fused ring containing 1 to 4 heteroatoms selected from O, S, N;
Or R b3、Rb4 taken together with the carbon atom to which it is attached form C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or a 4-8 membered heterocyclyl, said cycloalkyl, alkenyl, alkynyl, heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, or a 4-8 membered heterocyclyl, said alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
optionally, B is selected from When R b3、Rb4 cannot be simultaneously selected from H;
The remaining groups are as defined in the first or second embodiment of the invention.
As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q- or a bond, said-CH 2 -, -CH=CH-optionally substituted with 1 to 2 substituents selected from F, cl, br, I, OH, CN, NH 2、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl;
Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following optionally substituted groups: 4-7 membered heteromonocyclic ring, 4-10 membered heteromonocyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, substituted with 1 to 4R L2, said heterocyclyl, heteroaryl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally substituted with 1 or 2 = O; q is each independently selected from 0, 1, 2,3 or 4;
R L is independently selected from H or C 1-6 alkyl;
K2 is selected from
K3 is selected from
A is selected from a C 3-8 carbocycle, a benzene ring, a 4-7 membered heterocycle or a 5-6 membered heteroaryl ring containing 1 to 4 heteroatoms selected from O, S or N;
F is each independently selected from the group consisting of C 3-7 monocyclic carbocycle, C 4-10 bicyclic carbocycle, C 5-12 spirocyclic carbocycle, C 5-10 bridged cyclic carbocycle, 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 8-15 membered heterotricyclic ring, 5-12 membered heterospirocyclic ring, 5-10 membered heterobridged ring, C 6-14 aryl, 5-10 membered heteroaryl, The heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;
represents a ring selected from aromatic or non-aromatic rings;
E is each independently selected from a C 3-10 carbocycle, a benzene ring, a 4-12 membered heterocycle, a 5-12 membered heteroaryl ring containing 1 to4 heteroatoms selected from O, S or N;
Each Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-CO-、-NRqCO-、-CONRq -, or a 4-7 membered heterocyclic ring, said heterocyclic ring being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S or N;
R q is selected from H or C 1-4 alkyl;
R k1、Rk3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH 2;
or two R k3 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocycle or a 3-7 membered heterocycle, and two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocycle or a 3-7 membered heterocycle, said carbocycle or heterocycle being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;
R k4 is independently selected from H, OH, NH 2、CF3, CN or C 1-4 alkyl;
R k5 are each independently selected from C(CH3)2、CO、CH2、SO2、
Each R k6 is independently selected from CO, CH, SO, SO 2、CH2 or N;
r k7 are each independently selected from C(CH3)2、CO、CH、N、CH2、O、S、NRk7a；
Each R k8 is independently selected from C, N or CH;
r k9 are each independently selected from the group consisting of a bond, C (CH 3)2、CO、CH2、CH2CH2 or SO 2;
R ka is selected from O, S or NH;
R k7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;
R k14 is selected from
P1 is selected from 0,1, 2 or 3;
p2 is selected from 0,1, 2 or 3;
The remaining groups are as defined in the first, second or third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following optionally substituted groups: a 4-7 membered nitrogen containing heteromonocyclic ring, 4-10 membered nitrogen containing heteromonocyclic ring, 5-12 membered nitrogen containing heterospiro ring, 7-10 membered nitrogen containing heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, which when substituted is substituted with 1 to 4R L2, said heterocyclyl, heteromonocyclic ring, heterofused ring, heterobridged ring, heterospiro ring or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N, which when heteroatom is selected from S is optionally substituted with 1 or 2 = O;
R L is independently selected from H or C 1-4 alkyl;
K1 is selected from
K4 is selected from
Q is selected from a bond, C (=o);
Q1 is selected from the group consisting of a bond, CH 2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3),
Q2 is selected from a bond, CH 2、O、S、C(＝O)、NHC(＝O)、N(CH3) C (=o);
E. each a is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;
F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrol-namidinyl, pyrrol-n-yl, pyrrol pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, and imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, The left side of the connecting rod is directly connected with L;
R ka is selected from O, S or NH;
r k7 are each independently selected from C (CH 3)2、CH2、O、N(CH3)、N(CH2CH3), N (cyclopropyl) or NH;
r k1、Rk3 are each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2;
R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF 3、C1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 cycloalkyl;
p1 or p2 are each independently selected from 0,1 or 2;
the remaining groups are as defined in any of the second, third, or fourth embodiments of the invention.
As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
R L is selected from H, methyl or ethyl;
q is each independently selected from 0,1 or 2;
Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazepinyl, phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyrimidine, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl, benzofuranyl, benzoxazolyl, and combinations thereof triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiazinyl, triazolooxazolyl, triazolopyrazinyl, triazolyl, triazolopyrazinyl, triazolyl, triazoloimidazolyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spiropropyl, cyclopropyl-spirobutyl, cyclopropyl-spiropentyl, cyclopropyl-spirohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl-spiropentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-azetidinyl, cyclopropyl-pyrrolidyl, cyclopropyl-piperidyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidyl, cyclobutyl-azetidinyl, cyclopentyl-piperidyl, cyclohexyl-azetidinyl-yl-spirocyclohexyl, cyclohexyl-pyrrolidinyl, cyclohexyl-piperidinyl, azetidinyl-azetidinyl, azetidinyl-pyrrolidinyl, azetidinyl-piperidinyl, pyrrolidinyl-azetidinyl, pyrrolidinyl-pyrrolidinopyrrolidinyl pyrrolidinyl-piperidinyl, piperidinyl-azetidinyl, piperidinyl-pyrrolidinyl, piperidinyl-piperidinyl, and cyclobutylspiroazetidine, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, and cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinyl cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, and azetidinyl spiroazetidinyl, When substituted, are substituted with 1 to 4R L2;
r L2 is each independently selected from deuterium, F, cl, br, I, OH, NH 2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-2 alkylene-O-C 1-2 alkyl, -O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 1-2 alkyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -O-C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6 membered heterocyclyl, The alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, Halogen substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;
B 1、B4 is each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 3-isoquinolinyl, quinazolinyl, 3, 4-dihydro-1H-benzopyranyl, 1,2,3, 4-tetrahydroquinolinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, Said B 1、B4 is optionally substituted with 1 to 4R b1;
B 2 is selected from one of the following substituted or unsubstituted: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridonyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, Or B 5, when substituted, is substituted with 1 to 4R b2;
B 5 is selected from Said B 5 is optionally substituted with 1 to 4R b2;
B 3 is selected from one of the following substituted or unsubstituted: phenyl, naphthyl, Benzopyridyl, benzothienyl, benzofuranyl, thienyl, furyl, pyrrolyl, when substituted, are substituted with 1 to 4R b1;
R b1 are each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3 or one of the following optionally substituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl spirospirocyclohexyl, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、NHCH3、N(CH3)2, methyl, ethyl, isopropyl, ethynyl, -CH 2-CN、-CH2OH、-CH2OMe、-CH2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl;
R b2 are each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、NH(CH3)、N(CH3)2、CN、NO2、COOH、-C(＝O)NH2 or one of the following optionally substituted groups: -CH 2OCH2CH3, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, being 1 to 4 groups selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、NHCH3、N(CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxacyclohexyl, cyclopropyl, Cyclobutyl group,Cyclopropyloxy group, Is substituted by a substituent of (2);
R b3、Rb4 are each independently selected from H, OH, NH 2 or optionally substituted one of the following groups: methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、CF3、CHF2, methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, cyclobutylspirocyclobutyl;
Or R b3、Rb4 together with the carbon atom to which it is attached form one of the optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, cyclobutylspirocyclobutyl, when substituted, substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、N(CH3)、CN、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
r b5 is selected from OH, NH 2, methyl, ethyl, propyl, isopropyl, - (CH 2)n -cyclopropyl, - (CH 2)n -cyclobutyl, - (CH 2)n -cyclopentyl, - (CH 2)n -cyclohexyl, phenyl, pyridinyl), said-CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl being optionally substituted by 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
n is independently selected from 0 and 1;
r b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, azetenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptyl, phenyl, pyridinyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-cyclohexyl, cyclobutyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-spirocyclopropyl-, cyclopropyl-spirocyclohexyl, cyclobutyl-spirocyclopentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-and-azetidinyl, cyclopropyl-and-pyrrolidinyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl cyclohexylazetidinyl, cyclohexylpyrrolidyl, cyclohexylpiperidyl, azetidinazetidinyl, azetidinopyrrolidinyl, azetidinopiperidyl a cyclohexylazetidinyl group, a cyclohexylopyrrolidinyl group, a cyclohexylopiperidyl group, a azetidinoazetidines, azetidinopyrrolidines, azetidinopiperidines, azetidines, azetidin, cyclohexyl spiropiperidinyl, azetidinyl, and the like azetidinyl spiropyrrolidinyl azetidinyl spiropiperidinyl pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b7 is selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、CHF2、CF3、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptanyl, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl-cyclohexyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirocyclobutyl-spirocyclohexyl, cyclobutyl-spirocyclohexyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spiropyrrolidinyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl cyclohexylazetidinyl, cyclohexylpyrrolidyl, cyclohexylpiperidyl, azetidinazetidinyl, azetidinopyrrolidinyl, azetidinopiperidyl a cyclohexylazetidinyl group, a cyclohexylopyrrolidinyl group, a cyclohexylopiperidyl group, a azetidinoazetidines, azetidinopyrrolidines, azetidinopiperidines, azetidines, azetidin, cyclohexyl spiropiperidinyl, azetidinyl, and the like azetidinyl spiropyrrolidinyl azetidinyl spiropiperidinyl pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
x is independently selected from NH, O or S;
m2 is each independently selected from 0,1 or 2;
R b23 is each independently selected from the group consisting of vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetenyl, oxetanyl, oxolanyl, piperidinyl, or morpholin, said vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetenyl, oxetanyl, oxolanyl, oxetanyl, piperidine, or morpholin optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy;
R b24 is each independently selected from methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropyloxy, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azexenyl, oxetanyl, oxolanyl, cyclohexyl, piperidine, or morpholine, said methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxolanyl, piperidine, or morpholine being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy;
K is selected from one of the structural fragments shown in the table K-1;
the remaining groups are as defined in any of the second, third, fourth or fifth embodiments of the invention.
As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: When substituted, are substituted with 1 to 4R L2;
R L2 are each independently selected from deuterium, F, cl, br, = O, COOH, CN, NHCH 3、N(CH3)2、OH、NH2 or one of the following optionally substituted groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2CH2 -O-methyl, -OCH 2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -O-methyl, -CH 2OCH2CH2 -O-cyclopropyl, when substituted, being substituted with 1 to 4 substituents selected from F, CHF 2、CF3、-OCHF2、-OCF3, methyl, methoxy, =o, hydroxymethyl, COOH, CN, NHCH 3、N(CH3)2、OH、NH2;
b is selected from one of the structural fragments shown in the table B-1 or the table B-2;
k is selected from one of the structural fragments shown in the table K-2;
The remaining groups are as defined in any of the second, third, fourth, fifth or sixth embodiments of the invention.
As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
L is selected from a bond or one of the structural fragments shown in Table L-1 or Table L-2, wherein the left side of the group is linked to B;
the remaining groups are as defined in any of the second, third, fourth, fifth, sixth or seventh embodiments of the invention.
As a ninth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
L is as defined in any one of the third, fourth, fifth, sixth or seventh embodiments of the invention;
K is as defined in any one of the third, fourth, fifth, sixth or seventh embodiments of the invention;
b is as defined for the seventh embodiment of the invention.
As a tenth embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
L is selected from bond 、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from -O-、-OCH2-、-CH2O-、-OCH2CH2-、-CH2CH2O-、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-N(CH3)-、-NH-、-CH2N(CH3)-、-CH2NH-、-NHCH2-、-CH2CH2N(CH3)-、-CH2CH2NH-、-NHCH2CH2-、-C(＝O)-、-C(＝O)CH2NH-、-CH2C(＝O)NH-、-C(＝O)NH- or-NHC (=O) -;
the remaining groups are as defined in any of the second, third, fourth, fifth, sixth, seventh, eighth or nine embodiments of the present invention.
As an eleventh embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein,
L is selected from bond 、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-;
Ak1, ak2, ak3, ak4 are each independently selected from the group consisting of -C(＝O)-、-O-、NH、-CH＝CH-、-CH＝C(CN)-、-CH＝C(F)-、-C(CN)＝CH-、-C(F)＝CH-、-C≡C-、-C(CH3)2-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-NHCO-;
Cy1, cy2, cy3 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, are substituted with 1 to 4R L2;
B. k is as defined in any one of the second, third, fourth, fifth, sixth and seventh embodiments of the invention.
As a twelfth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, wherein,
L is selected from-Cy 1-Cy2-;
Cy1 is selected from one of the following optionally substituted groups: phenyl group, The Cy1 is optionally substituted with 1 to 3R L2;
Cy2 is selected from The Cy2 is optionally substituted with 1 to 2R L2;
The remaining groups are as defined in any of the second, third, fourth, fifth, sixth and seventh embodiments of the invention.
The present invention relates to a compound selected from one of the structures of table E-1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
Table E-1
Table L-1L groups
TABLE L-2
The present invention relates to a pharmaceutical composition comprising a compound of the invention described above or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention described above or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
In some embodiments, the pharmaceutical compositions of the present invention may be in unit dosage form (the amount of the primary drug in a unit dosage form is also referred to as "formulation specification").
By "effective amount" or "therapeutically effective amount" in the present application is meant that a sufficient amount of a compound of the present disclosure is administered that will alleviate to some extent one or more symptoms of the disease or disorder being treated (e.g., inhibiting or degrading AR or an AR shear mutant-related disease such as prostate cancer). In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is that amount of a composition comprising a compound of the present disclosure that is required to provide clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to 1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg.
In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof.
A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of the invention, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease preferably inhibiting or degrading AR or an AR-shear mutant related disease (e.g., prostate cancer).
A method for treating a disease in a mammal comprising administering a pharmaceutical compound of the invention or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof to a subject at a daily dose of 1-1000 mg/day, which may be a single dose or divided doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 600 mg/day, 1000 mg/day.
The present invention relates to a kit comprising a single or multiple dose form of a composition comprising a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in an amount equivalent to the amount of the compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic or the pharmaceutical composition in preparing medicaments for treating diseases related to activity or expression quantity of AR or AR shear mutant.
The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal of the compound or the stereoisomer, the solvate, the metabolite, the pharmaceutically acceptable salt or eutectic crystal of the compound or the prodrug in preparation of medicines for treating and inhibiting or degrading diseases related to AR or AR shear mutants.
The invention relates to the application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal or the pharmaceutical composition of the invention, wherein the disease is selected from prostate cancer.
The amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof is in each case converted in the form of the free base.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the present invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12C、13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), the isotopes of oxygen include 16O、17 O and 18 O, the isotopes of sulfur include 32S、33S、34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.
"Halogen" means F, cl, br or I.
"Halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".
"Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.
"Hydrocarbyl" refers to a substituted or unsubstituted, straight or branched, saturated or unsaturated group consisting of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent, or tetravalent.
"Alkylene" refers to substituted or unsubstituted straight and branched chain divalent saturated hydrocarbon radicals including- (CH 2)v - (v being an integer from 1 to 10), with alkylene embodiments including but not limited to methylene, ethylene, propylene, butylene, and the like.
"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.
"Heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group including, but not limited to, 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group being oxidizable to various oxidation states. Heterocycloalkyl groups can be attached to heteroatoms or carbon atoms, heterocycloalkyl groups can be attached to aromatic or non-aromatic rings, and heterocycloalkyl groups can be attached to bridged or spiro rings, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group may be monovalent, divalent, trivalent, or tetravalent.
"Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1,2 or 3 carbon-carbon double bonds, the backbone including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, alkenyl examples including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like; alkenyl groups appear herein, the definition of which is consistent with the definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.
"Alkynyl" refers to substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, typically 1,2 or 3 carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, alkynyl embodiments including but not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-decynyl, 4-decynyl, and the like; alkynyl groups may be monovalent, divalent, trivalent or tetravalent.
"Alkoxy" refers to a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.
"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system, to which carbocyclyl may be attached, optionally in the form of a monocyclic, bridged, or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.
"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system and that contains 1 or more (including but not limited to 2,3, 4, or 5) heteroatoms selected from N, O or S, and C, N, S optionally substituted in the heterocyclyl ring may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged ring or a spiro ring, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxacyclyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [ 2.3.5 ] dioxanyl, 2.1.5 [ 2.5 ] dioxanyl, 2.5.5 ] oxazinyl, 573.5.5 [ 2.5 ] oxazinyl, and adamantyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent, or tetravalent.
"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spiro system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1,2, 3, or 4) double bonds, and optionally may contain 0 to 5 heteroatoms selected from N, O or S (=o) n (n is 0, 1, or 2). Non-limiting examples include:
"Spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.
"Fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1,2,3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) n or O, n being 0,1, or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.
"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=o) n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane and adamantane. "bridged ring" or "bridged ring radical" can be monovalent, divalent, trivalent, or tetravalent.
"Carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms.
"Carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms.
"Carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms.
"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic group" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system.
"Heterobicyclic", "heterobicyclic group", "fused heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing a heteroatom.
"Heterospiro", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spiro" containing a heteroatom.
"Heterobridged ring", "heterobridged ring radical", "bridged ring heterocyclyl" or "bridged heterocyclic radical" refers to a "bridged ring" that contains a heteroatom.
"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is an aryl ring, non-limiting examples of which include benzene rings, naphthalene rings,The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.
"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) n, n being 0, 1, 2), the number of ring atoms in the heteroaryl ring including but not limited to5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include
Heteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.
"Substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate 、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m- alkenyl-R a、ORd, or- (CH 2)m -alkynyl-R a (where m, n is 0, 1, or 2), arylthio, thiocarbonyl, silane, or-NR bRc, and the like, wherein R b and R c are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively R b and R c may form a five-or six-membered cycloalkyl or heterocyclyl, each of R a and R d is independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, bridged ring, or spirocyclic, and the like.
"Containing 1 to 5 heteroatoms selected from O, S, N" means containing 1,2, 3,4, or 5 heteroatoms selected from O, S, N.
"0 To X substituents selected from …" means substituted with 0, 1,2,3 … X substituents selected from … and X is selected from any integer between 1 and 10. The term "substituted with 0 to 4 substituents selected from …" means substituted with 0, 1,2,3 or 4 substituents selected from …. For example, "0 to 5 substituents selected from …" means substituted with 0, 1,2,3,4, or 5 substituents selected from …. By "optionally substituted with 1 to 4 substituents selected from F" is meant that the heterobridge ring is optionally substituted with 0, 1,2,3 or 4 substituents selected from F.
The X-Y membered ring (X is selected from an integer of 3 or less and Y is selected from any integer of 4 to 12) includes X, X +1, X+2, X+3, X+4 …. Y membered rings. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"Pharmaceutical composition" refers to one or more compounds of the present invention, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and mixtures of other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
"Formulation specification" refers to the weight of the principal drug contained in each individual, tablet or other unit of formulation.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"Stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"Tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.
"IC 50" is the concentration of drug or inhibitor required to inhibit a given biological process (or a component of the process such as an enzyme, receptor, cell, etc.) in half.
The following describes the technical scheme of the present invention in detail with reference to examples, but the scope of the present invention includes but is not limited thereto.
The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and include: taitan technology, an Naiji chemistry, shanghai de moer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, ming Kangde and Budweiser technologies.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 -6 (ppm). NMR was performed using a (Bruker AVANCE III and Bruker Avance 300) magnetonuclear instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and an internal standard of Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
SEM:THP:Boc: a tert-butoxycarbonyl group; ms:TBS: MTBE methyl tert-butyl ether; bn is benzyl; DIPEA: n, N-diisopropylethylamine; DMAc: n, N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane; cbz: NMP: n-methylpyrrolidone; TCFH: tetramethyl chlorourea hexafluorophosphate esters;
Synthesis of intermediate 1:
the first step: preparation of 1B hydrochloride
1A (90 g,0.50 mol) was dissolved in 500mL of 2mol/L ethyl acetate hydrochloride solution and reacted at room temperature for 5 hours. The reaction system was concentrated under reduced pressure to give crude hydrochloride salt of 1B (59 g).
LCMS m/z＝82.3[M+1]+
And a second step of: preparation of intermediate 1
The hydrochloride (59 g) of the crude product 1B was dissolved in 500mL of DMSO, sodium hydrogencarbonate (42 g,0.50 mol) was added, and after stirring at room temperature for 10min, 100mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO2017197056 for synthesis) (165.6 g,0.60 mol) were added and reacted at 85℃for 5h. The reaction solution was cooled to room temperature, 5L of water was added, and the solid was collected by filtration, washed with 500mL of water and dried by air blast to give crude intermediate 1 (40 g).
Synthesis of intermediate 2:
The hydrochloride salt of crude 1B (0.72 g) was dissolved in 20mL of DMSO, and 2mL of DIPEA and 2A (see WO2020239103 for synthesis) (1.80 g,6.12 mmol) were added and reacted at 80℃for 3h. The reaction solution was cooled to room temperature, 200mL of water was added, and the solid was collected by filtration, washed with 50mL of water and dried by air blast to give crude intermediate 2 (1.3 g).
Example 1: preparation of Compound 1
The first step: 1b preparation
1A (4.1 g,19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g,21.75 mmol) were dissolved in 40mL acetonitrile, cesium carbonate (9.68 g,29.70 mmol) was added and reacted at 80℃for 3H. The reaction solution was cooled to room temperature, 30mL of water and 100mL of ethyl acetate were added, the solution was separated, the organic phase was washed with 30mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:9) to give 1b (2.40 g, yield: 38%).
And a second step of: 1c preparation
1B (2.30 g,7.18 mmol) was dissolved in 20mL tetrahydrofuran, 4mL water was added, and lithium hydroxide monohydrate (0.6 g,14.3 mmol) was added and reacted at room temperature for 30min. To the reaction solution was added dropwise 1mol/L diluted hydrochloric acid to adjust pH to 6, 50mL of ethyl acetate was added, the solution was separated, the organic phase was washed with 20mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (2.0 g). The crude product (0.5 g) was dissolved in 10mL of DCM, 1-chloro-N, N, 2-trimethylpropenamine (0.34 g,2.54 mmol) was added, and after 2h at room temperature, triethylamine (0.52 g,5.14 mmol) and 5-trifluoromethylindole (0.38 g,2.03 mmol) were added in sequence and reacted at room temperature for 18h. To the reaction solution was added 30mL of methylene chloride, 40mL of saturated aqueous sodium hydrogencarbonate solution was added, the organic phase was separated, washed with 100mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 1c (0.51 g, yield: 54%).
LCMS m/z＝462.1[M+1]+
And a third step of: preparation of Compound 1
1C (0.22 g,0.48 mmol) was dissolved in 5mL DMF, and the crude intermediate 1 (0.19 g), TEA (0.15 g,1.48 mmol), cuI (18 mg,0.095 mmol) and PdCl 2(PPh3)2 (67 mg,0.095 mmol) were added sequentially, nitrogen was replaced three times, and reacted at 80℃for 18h. The reaction solution was cooled to room temperature, 50mL of water was added, solids were precipitated, the mixture was filtered, the cake was washed with 20mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation on a silica gel column (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 1 (0.1 g, yield: 31%).
1H NMR(400MHz,CDCl3)δ8.26(d,1H),8.08(s,1H),7.72–7.56(m,3H),7.51–7.34(m,2H),6.84–6.75(m,1H),6.54(dd,1H),5.20–5.06(m,1H),4.99–4.86(m,1H),4.44–4.26(m,2H),4.13–3.67(m,6H),3.26–3.11(m,2H),2.97–2.63(m,4H),2.53–2.23(m,2H),2.20–2.00(m,2H).
LCMS m/z＝671.1[M+1]+
Example 2: preparation of Compound 2
The first step: 2b preparation
2A (4.1 g,19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g,21.75 mmol) were dissolved in 40mL acetonitrile, cesium carbonate (9.68 g,29.70 mmol) was added and reacted at 80℃for 3H. The reaction solution was cooled to room temperature, 30mL of water and 100mL of ethyl acetate were added, the solution was separated, the organic phase was washed with 30mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:9) to give 2b (2.40 g, yield: 38%).
And a second step of: 2c preparation
2B (2.30 g,7.18 mmol) was dissolved in 20mL tetrahydrofuran, 4mL of water was added, lithium hydroxide monohydrate (0.6 g,14.3 mmol) was added, the reaction was carried out at room temperature for 30min, 1mol/L diluted hydrochloric acid was added dropwise to adjust pH to 6, 50mL of ethyl acetate was added, the solution was separated, the organic phase was washed with 20mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (2.0 g). The crude product (0.51 g) was dissolved in 10mL of methylene chloride, and 1-chloro-N, N, 2-trimethylpropenamine (0.35 g,2.62 mmol) was slowly added dropwise and reacted at room temperature for 2 hours. Triethylamine (0.53 g,5.24 mmol) and 2-chloro-4- (trifluoromethyl) aniline (0.34 g,1.74 mmol) were added to the reaction mixture, and reacted at room temperature for 3 hours. To the reaction solution was added 20mL of saturated aqueous sodium hydrogencarbonate solution, extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (ethyl acetate/petroleum ether (v/v) =1:3) to give 2c (0.45 g, yield: 52%).
And a third step of: preparation of 2d
2C (0.5 g,1.06 mmol) was dissolved in 5mL DMF, cooled to 0deg.C with ice bath, 0.08g of 60% sodium hydride was added, and after 30min reaction at 0deg.C, methyl iodide (0.3 g,2.11 mmol) was added and reaction was carried out at 0deg.C for 1h. To the reaction solution was added 50mL of water, extracted twice with 50mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =20:1) to give 2d (0.4 g, yield: 78%).
LCMS m/z＝484.0[M+1]+
Fourth step: preparation of Compound 2
2D (0.2 g,0.41 mmol), the crude intermediate 1 (0.14 g), TEA (0.25 g,2.47 mmol), cuI (16 mg,0.084 mmol) and PdCl 2(PPh3)2 (29 mg,0.041 mmol) were reacted for 3h under nitrogen with 5mL of DMF under nitrogen with three substitutions. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the filter cake was washed with 10mL of water, the filter cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was purified by separation with a silica gel column (petroleum ether/ethyl acetate (v/v) =100:1-1:5), and the obtained crude product was subjected to chiral resolution (instrument and preparation column: preparation of liquid phase using Waters 150 SFC, preparation column model CHIRALPAK COLUMN). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: supercritical carbon dioxide/methanol and acetonitrile. The gradient elution method comprises the following steps: the mixed solvent of methanol and acetonitrile was eluted with a 65% isocratic gradient) and lyophilized to give chiral isomer 1 of compound 2) (13.1 mg, yield: 5%) and chiral isomer 2 (11.1 mg, yield: 4%).
Chiral analysis method of compound 2
Instrument: SHIMADZU LC-30AD sf, column: CHIRALCEL AD-3, specification: 50mm by 4.6mm,3 μm
Mobile phase a: supercritical CO 2, mobile phase B: methanol and acetonitrile mixed solution containing 0.05% diethylamine, column temperature: 35 DEG C
Flow rate: 3mL/min, wavelength: 220nm, elution procedure: mobile phase a, b=50:50.
Retention time of chiral isomer 1 of compound 2: 0.871min
Retention time of chiral isomer 2 of compound 2: 1.863min
Nuclear magnetic spectrum of chiral isomer 1 of compound 2
1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.83–6.50(m,8H),5.00–4.85(m,1H),4.42–4.31(m,2H),4.14–3.99(m,2H),3.90–3.73(m,1H),3.30–2.64(m,9H),2.39–1.80(m,4H).
LCMS m/z＝693.1[M+1]+
Nuclear magnetic spectrum of chiral isomer 2 of compound 2
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.83–6.50(m,8H),4.99–4.85(m,1H),4.42–4.30(m,2H),4.13–3.99(m,2H),3.90–3.73(m,1H),3.30–2.64(m,9H),2.37–1.80(m,4H).
LCMS m/z＝693.2[M+1]+
Example 3: preparation of Compound 3
Compound 3 chiral isomer 1 and chiral isomer 2 of compound 3 were obtained by the synthetic method of reference example 2 starting from compound 2 c.
Chiral analysis method of Compound 3
Instrument: SHIMADZU LC-30AD sf, column: CHIRALCEL AD-3, specification: 50mm by 4.6mm,3 μm
Mobile phase a: supercritical CO 2, mobile phase B: methanol and acetonitrile mixed solution containing 0.05% diethylamine, column temperature: 35 DEG C
Flow rate: 3mL/min, wavelength: 220nm, elution procedure: mobile phase a, b=50:50.
Retention time of chiral isomer 1 of compound 3: 0.839min
Retention time of chiral isomer 2 of compound 3: 2.053min
Nuclear magnetic spectrum of chiral isomer 1 of compound 3
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.81–6.43(m,8H),5.00–4.88(m,1H),4.42–3.29(m,6H),3.20–2.63(m,7H),2.40–0.90(m,7H).
LCMS m/z＝707.2[M+1]+
Nuclear magnetic spectrum of chiral isomer 2 of compound 3
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.81–6.43(m,8H),5.00–4.88(m,1H),4.44–3.29(m,6H),3.20–2.63(m,7H),2.40–0.90(m,7H).
LCMS m/z＝707.2[M+1]+
Example 4: preparation of Compound 4
The first step: 4b preparation
4A (2 g,9.66 mmol) and 4-iodopyrazole (1.8 g,9.28 mmol) were dissolved in 30mL acetonitrile, cesium carbonate (9.44 g,28.97 mmol) was added and reacted at 80℃for 4h. The reaction solution was cooled to room temperature, washed with 40mL of saturated sodium chloride solution, the aqueous phase was extracted with 50mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether/ethyl acetate (v/v) =5:1) to give 4b (2.8 g, yield: 94%).
LCMS m/z＝321.1[M+1]+
And a second step of: 4c preparation
4B (1.4 g,4.37 mmol) was dissolved in 5mL ethanol and lithium hydroxide monohydrate (0.70 g,16.68 mmol) and 3mL water were added and reacted at 40℃for 2h. The reaction solution was cooled to room temperature, adjusted to pH 3 with 1mol/L dilute hydrochloric acid, extracted with 30mL ethyl acetate, the combined organic phases dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was dissolved in10 mL DCM, 1-chloro-N, N, 2-trimethylpropenamine (0.88 g,6.60 mmol) was added, and after 2h at room temperature, triethylamine (1.33 g,13.14 mmol) and 3-chloro-4-aminotrifluorotoluene (1.11 g,5.68 mmol) were added in sequence and reacted at room temperature for 18h. To the reaction solution was added 50mL of methylene chloride, 40mL of saturated aqueous sodium hydrogencarbonate solution was added, the organic phase was separated, washed with 100mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate (v/v) =5:1) to give 4c (0.62 g, yield: 23%).
LCMS m/z＝470.0[M+1]+
And a third step of: preparation of Compound 4
4C (0.30 g,0.64 mmol) was dissolved in 5mL DMF and the crude intermediate 1 (0.26 g), TEA (0.19 g,1.88 mmol), cuI (24 mg,0.13 mmol) and PdCl 2(PPh3)2 (90 mg,0.13 mmol) were added sequentially, nitrogen was replaced three times and reacted at 80℃for 18h. The reaction solution was cooled to room temperature, 50mL of water was added to precipitate a solid, the solid was filtered, the cake was collected, the cake was washed with 20mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 4 (0.12 g, yield: 28%).
1H NMR(400MHz,CDCl3)δ9.49(s,1H),8.55(d,1H),8.11(s,1H),7.82–7.59(m,4H),7.55–7.48(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.17(d,1H),4.12–4.03(m,2H),3.88–3.74(m,1H),2.96–2.64(m,3H),2.20–2.07(m,1H),1.83–1.67(m,1H),1.00–0.88(m,1H),0.81–0.65(m,2H),0.55–0.40(m,1H).
LCMS m/z＝679.1[M+1]+
Example 5: preparation of Compound 5
The first step: 5a preparation
4B (1.25 g,3.90 mmol) was dissolved in 20mL tetrahydrofuran, the reaction system was cooled to-78℃and LDA solution (2.0 mol/L tetrahydrofuran/n-heptane (v/v) =12/25) (2.34 mL,4.68 mmol) was slowly added dropwise, stirring was continued at-78℃for 30min, then methyl iodide (0.92 g,6.48 mmol) was added and the mixture was allowed to react at room temperature for 3h. To the reaction solution was added 40mL of saturated aqueous sodium chloride solution, extracted with 50mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 5a (0.88 g, yield: 67%).
And a second step of: 5b preparation
5A (0.87 g,2.60 mmol) was dissolved in 8mL ethanol, and lithium hydroxide monohydrate (0.42 g,10.00 mmol) and 4mL water were added and reacted at 40℃for 2h. The reaction solution was cooled to room temperature, pH was adjusted to 3 with 1mol/L dilute hydrochloric acid, extracted with 40mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was dissolved in 8mL of DCM, 1-chloro-N, N, 2-trimethylpropenamine (0.53 g,3.97 mmol) was added, and after 2h at room temperature, triethylamine (0.80 g,7.91 mmol) and 3-chloro-4-aminotrifluorotoluene (0.67 g,3.43 mmol) were sequentially added and reacted at room temperature for 19h. To the reaction solution was added 40mL of methylene chloride, 40mL of saturated aqueous sodium hydrogencarbonate solution was added, the organic phase was separated, washed with 80mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 5b (0.32 g, yield: 19%).
LCMS m/z＝484.0[M+1]+
And a third step of: preparation of Compound 5
5B (0.32 g,0.66 mmol) was dissolved in 9mL DMF and the crude intermediate 1 (0.27 g), TEA (0.20 g,1.98 mmol), cuI (24 mg,0.13 mmol) and PdCl 2(PPh3)2 (90 mg,0.13 mmol) were added sequentially, nitrogen was replaced three times and reacted at 80℃for 18h. The reaction solution was cooled to room temperature, 50mL of water was added to precipitate a solid, the solid was filtered, the cake was collected, the cake was washed with 20mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 5 (0.21 g, yield: 46%).
1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.53(d,1H),8.03–7.90(m,2H),7.77(s,1H),7.67(d,1H),7.63–7.58(m,1H),7.54–7.47(m,1H),6.85–6.78(m,1H),6.56(dd,1H),4.99–4.89(m,1H),4.43–4.30(m,2H),4.15–4.03(m,2H),3.90–3.75(m,1H),2.96–2.64(m,3H),2.20–2.06(m,1H),1.80–1.68(m,4H),0.86–0.79(m,2H),0.74–0.58(m,2H).
LCMS m/z＝693.2[M+1]+
Example 6: preparation of Compound 6
The first step: 6b preparation
6A (4.06 g,20.00 mmol) was dissolved in 50mL acetonitrile and cesium carbonate (9.77 g,30.00 mmol) was added and reacted at 80℃for 3h. The reaction system was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, 80mL of THF was added to the residue and dissolved with 20mL of water, lithium hydroxide monohydrate (0.98 g,23.36 mmol) was added, and the reaction was carried out at room temperature for 0.5h. The reaction was adjusted to pH 4 with concentrated hydrochloric acid, concentrated under reduced pressure, the residue was lyophilized, the lyophilized residue was dissolved with 80mL DCM/MeOH (v/v) =10:1, filtered, and the filtrate was concentrated under reduced pressure to give crude product (2.7 g). The crude product (0.80 g) was dissolved in 10mL DCM and 1-chloro-N, N, 2-trimethylpropenamine (0.51 g,3.82 mmol) was added and reacted at room temperature for 2h. To the reaction mixture were added 2-chloro-4-trifluoromethylaniline (0.5 g,2.56 mmol) and triethylamine (0.77 g,7.61 mmol), and the mixture was reacted at room temperature for 16 hours. To the reaction solution was added 80mL of ethyl acetate, 30mL of saturated aqueous sodium hydrogencarbonate solution was added, the organic phase was separated, washed with 30mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 6b (0.22 g, yield: 18%).
And a second step of: preparation of Compound 6
6B (0.20 g,0.43 mmol) was dissolved in 5mL DMF and the crude intermediate 1 (0.16 g), TEA (0.13 g,1.28 mmol), cuI (0.008 g,0.042 mmol) and PdCl 2(PPh3)2 (0.030 g,0.043 mmol) were added sequentially, nitrogen was replaced three times and reacted at 55℃for 1h. The reaction solution was cooled to room temperature, 50mL of water was added to precipitate a solid, the solid was filtered, the cake was washed with 10mL of water, the cake was collected, the cake was dissolved with 30mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 6 (0.10 g, yield: 35%).
1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.54(d,1H),8.04(s,1H),8.00(s,1H),7.82–7.55(m,4H),6.86–6.78(m,1H),6.56(dd,1H),5.00–4.88(m,1H),4.45–4.30(m,2H),4.15–4.02(m,2H),3.90–3.75(m,1H),3.00–2.62(m,3H),2.21–2.08(m,1H).
LCMS m/z＝673.0[M-1]-
Example 7: preparation of Compound 7
The first step: 7b preparation
2- (4-Iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid (0.5 g,1.78 mmol) (see WO 2019074962) was dissolved in 10mL of DCM, 1-chloro-N, N, 2-trimethylpropenamine (0.36 g,2.69 mmol) was added, and after reacting at room temperature for 2 hours, triethylamine (1.09 g,10.77 mmol) and 7a (0.34 g,1.82 mmol) were added in this order and reacted at room temperature for 12 hours. To the reaction solution was added 50mL of methylene chloride, 50mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-3:1) to give 7b (0.5 g, yield: 63%).
And a second step of: preparation of Compound 7
7B (0.42 g,0.93 mmol), crude intermediate 1 above (0.32 g), TEA (0.57 g,5.63 mmol), cuI (36 mg,0.18 mmol) and PdCl 2(PPh3)2 (66 mg,0.094 mmol) were added to 5mL DMF and reacted under nitrogen at 55deg.C for 1.5h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/dichloromethane/ethyl acetate (v/v) =1:1:2) to give compound 7 (0.1 g, yield: 16%).
1H NMR(400MHz,CDCl3)δ8.36(d,1H),7.95(s,1H),7.72–7.60(m,3H),7.52–7.44(m,1H),7.42–7.34(m,1H),6.85–6.75(m,1H),6.55(dd,1H),5.00–4.87(m,1H),4.44–4.30(m,2H),4.15–4.00(m,2H),3.89–3.73(m,1H),3.25–3.12(m,2H),3.06–2.62(m,5H),2.20–2.04(m,1H),1.89(s,6H).
LCMS m/z＝659.2[M+1]+
Example 8: preparation of Compound 8
Compound 8 was obtained in reference example 1 starting from compound 8 a.
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.73–7.17(m,6H),6.82–6.75(m,1H),6.53(dd,1H),4.99–4.85(m,3H),4.40–4.28(m,2H),4.27–4.16(m,2H),4.10–4.00(m,2H),3.86–3.72(m,1H),3.08–2.63(m,7H),2.19–1.88(m,3H).
LCMS m/z＝671.8[M+1]+
Example 9: preparation of Compound 9
Compound 9 was obtained in reference example 7 starting from compound 9 a.
1H NMR(400MHz,CDCl3)δ8.35(d,1H),8.08–7.99(m,1H),7.74–7.60(m,3H),7.56–7.48(m,1H),7.39(s,1H),6.84–6.76(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.12–4.00(m,2H),3.86–3.74(m,1H),3.24–3.12(m,2H),3.04–2.65(m,5H),2.19–2.08(m,1H),1.89(s,6H).
LCMS m/z＝616.2[M+1]+
Example 10: preparation of Compound 10
Compound 10 was obtained in reference example 1 starting from compound 10 a.
1H NMR(400MHz,CDCl3)δ8.40–8.25(m,1H),7.98(s,1H),7.71–7.60(m,3H),7.58–7.49(m,1H),7.40(s,1H),6.83–6.76(m,1H),6.54(dd,1H),4.98–4.88(m,1H),4.40–4.26(m,2H),4.10–3.98(m,2H),3.85–3.72(m,1H),3.57–3.43(m,2H),3.12–2.65(m,9H),2.19–1.90(m,3H).
LCMS m/z＝628.7[M+1]+
Example 11: preparation of Compound 11
Starting with compounds 11a and 2b, compound 11 (0.38 g) was obtained according to the synthesis method of example 1
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.74–7.45(m,5H),7.25–7.17(m,2H),6.85–6.77(m,1H),6.56(dd,1H),5.01–4.66(m,2H),4.42–4.28(m,2H),4.16–3.98(m,2H),3.89–3.65(m,2H),3.15–2.55(m,10H),2.20–1.80(m,4H),1.70–1.50(m,2H),1.11–0.92(m,1H).
LCMS m/z＝713.8[M+1]+
Example 12: preparation of Compound 12
Using the compound 12a as a starting material, compound 12 (0.10 g) was obtained as a result of referential example 11.
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.73–7.48(m,5H),7.31–7.22(m,1H),7.16–7.08(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.43–4.30(m,2H),4.13–3.69(m,4H),3.68–3.07(m,3H),3.05–2.57(m,8H),2.34–1.77(m,5H).
LCMS m/z＝699.2[M+1]+
Example 13: preparation of Compound 13
From compound 13a as a starting material, compound 13 (0.16 g) was obtained in referential example 11.
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.72–7.64(m,2H),7.60–7.42(m,3H),7.22–6.96(m,2H),6.86–6.78(m,1H),6.62–6.51(m,1H),5.22–5.11(m,1H),5.00–4.86(m,1H),4.45–4.27(m,2H),4.15–3.96(m,2H),3.92–3.68(m,1H),3.30–2.53(m,9H),2.34–1.64(m,7H).
LCMS m/z＝699.2[M+1]+
Example 14: preparation of Compound 14
Using the compound 14a as a starting material, compound 14 (0.17 g) was obtained in referential example 1.
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.72–6.90(m,6H),6.84–6.74(m,1H),6.59–6.49(m,1H),4.99–4.87(m,1H),4.84–4.20(m,4H),4.10–3.95(m,2H),3.92–3.68(m,2H),3.52–3.36(m,1H),3.10–2.63(m,8H),2.54–2.40(m,1H),2.18–1.81(m,3H).
LCMS m/z＝685.2[M+1]+
Example 15: preparation of Compound 15
Starting from 15a and 2b, compound 15 (0.15 g) was obtained in referential example 1
And a second step of: preparation of Compound 15
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.69(s,1H),8.63(s,1H),8.37–8.30(m,1H),8.08–8.00(m,1H),7.83–7.72(m,1H),7.72–7.59(m,2H),7.53–7.36(m,3H),6.89–6.78(m,1H),6.69(dd,1H),5.12–5.02(m,1H),4.42–4.28(m,2H),4.04–3.93(m,2H),3.92–3.77(m,1H),3.28–2.98(m,4H),2.97–2.80(m,1H),2.68–2.44(m,2H),2.14–1.84(m,3H).
Example 16: preparation of Compound 16
The first step: 16B preparation
To the reaction flask were successively added 16A (2.00 g,10.15 mmol), cyclopropylboronic acid (1.31 g,15.25 mmol), anhydrous potassium phosphate (8.62 g,40.61 mmol), tricyclohexylphosphine (1.14 g,4.07 mmol) and palladium acetate (0.46 g,2.05 mmol), and 1, 4-dioxane (25 mL) and water (2.5 mL) were added under nitrogen atmosphere to react at 90℃for 16h. The reaction solution was cooled to room temperature, ethyl acetate was then added to extract (40 mL. Times.3), the organic phase was washed with 20mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (ethyl acetate/petroleum ether (v/v) =1:5) to give 16B (1.32 g, yield: 82%).
LCMS m/z＝159.1[M+1]+
And a second step of: 16b preparation
16A (1.5 g,13.87 mmol) was added to a 100mL three-necked flask, 50% concentrated sulfuric acid (40 mL) was added, the mixture was cooled to0℃and N-iodosuccinimide (4.6 g,20.45 mmol) was slowly added and reacted at room temperature for 16h. The reaction system was slowly added to 40mL of saturated aqueous sodium carbonate, extracted with ethyl acetate (80 mL. Times.2), the organic phase was washed with saturated aqueous sodium thiosulfate (80 mL. Times.2) and saturated aqueous sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =81:19) to give 16b (2.3 g, yield: 71%).
LCMS m/z＝235.1[M+1]+
And a third step of: 16c preparation
16B (0.8 g,3.42 mmol) was added to a 100mL single port flask, 20mL acetonitrile was added, followed by ethyl 1-bromocyclobutane-1-carboxylate (698 mg,3.37 mmol) and cesium carbonate (2.2 g,6.75 mmol) and reacted at 90℃for 3h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =89:11) to give 16c (0.9 g, yield: 73%).
LCMS m/z＝361.1[M+1]+
Fourth step: 16d preparation
16C (0.9 g,2.5 mmol) was dissolved in 15mL tetrahydrofuran, 5mL water was added, cooled to 0deg.C, lithium hydroxide monohydrate (315 mg,7.51 mmol) was added and reacted at room temperature for 2h. The reaction solution was adjusted to pH 4 with 0.5mol/L hydrochloric acid, extracted with ethyl acetate (60 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (60 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane: methanol (v/v) =95:5) to give a crude product (0.6 g). The above crude product (200 mg) was put into a 50mL single-necked flask, 15mL of methylene chloride was added, 1-chloro-N, N, 2-trimethylpropenamine (120 mg,0.9 mmol) was added, and after reacting at room temperature for 1 hour, triethylamine (182 mg,1.8 mmol) and 16B (95 mg,0.6 mmol) were added in this order, and reacting at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =85:15) to give 16d (120 mg, yield: 42%).
LCMS m/z＝473.1[M+1]+
Fifth step, the method comprises the following steps; preparation of Compound 16
16D (120 mg,0.25 mmol) was added to a 50mL single port flask, DMF (10 mL) was added, crude intermediate 1 (126 mg), TEA (76 mg,0.75 mmol), pdCl 2(PPh3)2 (17 mg,0.024 mmol) and CuI (10 mg,0.053 mmol) were added, nitrogen was replaced three times, reaction was carried out at 50℃for 2h, the reaction system was cooled to room temperature, saturated aqueous ammonium chloride solution (120 mL) was added, extraction (50 mL. Times.3) was carried out with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride solution (60 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =37:63) to give compound 16 (90 mg, yield: 53%).
1H NMR(400MHz,CDCl3)δ8.53(s,1H),8.40(d,1H),7.94(s,1H),7.67(d,1H),7.59(s,1H),7.49(dd,1H),7.37–7.32(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.44–4.30(m,2H),4.10–4.00(m,2H),3.88–3.76(m,1H),3.10–2.60(m,7H),2.30–1.90(m,4H),1.53–1.40(m,1H),1.06–0.81(m,6H),0.59–0.50(m,2H).
LCMS m/z＝680.1[M-1]-
Example 17: preparation of Compound 17
Starting with compounds 17B and 16c, compound 17 (60 mg) was obtained according to the synthesis method of example 16
1H NMR(400MHz,CDCl3)δ8.44(d,1H),8.31(s,1H),7.93(s,1H),7.73–7.45(m,4H),6.84–6.77(m,1H),6.56(dd,1H),4.98–4.87(m,1H),4.44–4.30(m,2H),4.10–3.97(m,2H),3.90–3.76(m,1H),3.07–2.61(m,7H),2.26–1.94(m,7H),1.11–1.03(m,2H),1.01–0.93(m,2H).
LCMS m/z＝723.8[M+1]+
Example 18: preparation of Compound 18
The first step: 18b preparation
18A (5.0 g,30.1 mmol), 4-fluoro-1H-pyrazole (4.11 g,47.75 mmol) and potassium carbonate (6.60 g,47.76 mmol) were added to 80mL of DMF and reacted at 80℃for 16H. The reaction solution was cooled to room temperature, 100mL of water was then added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to give 18b (4.0 g, yield: 57%).
And a second step of: 18c preparation
18B (1.5 g,6.46 mmol) was dissolved in 30mL of methanol, 0.2g of 10% Pd/C was added, the hydrogen was replaced three times, and the mixture was allowed to react at room temperature under a hydrogen balloon atmosphere for 2 hours. The reaction system was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to give crude product 18c (0.8 g).
LCMS m/z＝203.1[M+1]+
And a third step of: 18d preparation
The crude 18c (0.4 g) above was dissolved with 2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid (0.67 g,2.39 mmol) in 15mL DCM, TCFH (0.83 g,2.96 mmol) was added, and N-methylimidazole (0.65 g,7.92 mmol) was slowly added dropwise and reacted at room temperature for 16H. The reaction system was concentrated under reduced pressure, the crude product was dissolved with 50mL of methylene chloride, the organic phase was washed with 20mL of water, dried over anhydrous sulfuric acid, and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =5:1) to give 18d (0.78 g, yield: 70%).
LCMS m/z＝465.4[M+1]+
Fourth step: preparation of Compound 18
18D (0.23 g,0.50 mmol), intermediate 1 (0.25 g), TEA (0.15 g,1.48 mmol), cuI (10 mg,0.0525 mmol) and PdCl 2(PPh3)2 (35 mg,0.0499 mmol) were added to 5mL DMF and reacted under nitrogen at 50℃for 1h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:1), to give compound 18 (0.05 g, yield: 15%).
1H NMR(400MHz,CDCl3)δ10.29(s,1H),8.72(d,1H),8.02(s,1H),7.74(s,1H),7.72–7.65(m,1H),7.65–7.58(m,3H),7.56–7.52(m,1H),7.50–7.46(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.45–4.34(m,2H),4.17–4.04(m,2H),3.92–3.78(m,1H),2.96–2.65(m,3H),2.19–2.07(m,1H),1.88(s,6H).
LCMS m/z＝674.3[M+1]+
Example 19: preparation of Compound 19
Starting from compound 19b and 2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid, compound 19 (0.33 g) was obtained by the method of synthesis example 18
1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.49(d,1H),8.05(s,1H),7.80(s,1H),7.74(s,1H),7.67(d,1H),7.59–7.54(m,1H),7.54–7.47(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.95–2.65(m,3H),2.22–2.06(m,4H),1.93(s,6H).
LCMS m/z＝628.6[M+1]+
Example 20: preparation of Compound 20
Using the compound 20b as a starting material, a compound 20 (0.02 g) was obtained in referential example 18.
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.77(s,1H),7.74–7.64(m,3H),7.61(s,1H),7.50–7.44(m,1H),6.84–6.77(m,1H),6.56(dd,1H),5.48(q,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.15–4.03(m,2H),3.89–3.76(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.98(s,6H).
LCMS m/z＝725.2[M+1]+
Example 21: preparation of Compound 21
Using the compound 21a as a starting material, compound 21 (0.20 g) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.43(d,1H),8.08(s,1H),7.78(s,1H),7.71(s,1H),7.67(d,1H),7.62–7.56(m,1H),7.47(dd,1H),6.83–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.96–2.64(m,4H),2.17–2.07(m,1H),1.94(s,6H),1.33(d,6H).
LCMS m/z＝699.2[M+1]+
Example 22: preparation of Compound 22
Reference compound 17, preparation method, yield compound 22 (85 mg)
1H NMR(400MHz,CDCl3)δ8.37–8.22(m,2H),8.03(br.s,1H),7.81–7.61(m,3H),7.36–7.28(m,1H),7.22–7.12(m,1H),6.85–6.74(m,1H),6.55(dd,1H),4.99–4.87(m,1H),4.42–4.28(m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H),3.45–3.30(m,2H),3.15–3.00(m,2H),2.97–2.65(m,5H),2.28–1.95(m,9H).
LCMS m/z＝668.3[M+1]+
Example 23: preparation of trifluoroacetate salt of Compound 23
The first step: preparation of 23B
23A (2.8 g,10.02 mmol) (see WO 2019074962), tert-butyl 3-ethynylazetidine-1-carboxylate (2.17 g,11.97 mmol), TEA (3.04 g,30.04 mmol), cuI (190 mg,1.00 mmol) and PdCl 2(PPh3)2 (700 mg,1.00 mmol) were added to 60mL of dichloromethane and reacted at room temperature under nitrogen for 18h. 150mL of water was added to the reaction system, the pH of the system was adjusted to 2 with 1mol/L hydrochloric acid, the mixture was extracted with 100mL of methylene chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methylene chloride/methanol (v/v) =20:1) to give 23B (3.3 g, yield: 99%).
LCMS m/z＝334.5[M+1]+。
And a second step of: preparation of 23d
23C (0.15 g,1.00 mmol) and 23B (0.40 g,1.20 mmol) were dissolved in 15mL DCM and TCFH (0.42 g,1.50 mmol) was added and N-methylimidazole (0.33 g,4.02 mmol) was slowly added dropwise and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 23d (0.2 g, yield: 43%).
And a third step of: preparation of p-toluenesulfonate salt of 23e
23D (200 mg,0.43 mmol) was dissolved in 4mL of acetonitrile, and p-toluenesulfonic acid monohydrate (0.22 g,1.05 mmol) was added and reacted at room temperature for 2h. The reaction solution was concentrated under reduced pressure to give p-toluenesulfonate (0.44 g) as crude product 23 e.
LCMS m/z＝367.4[M+1]+
Fourth step: preparation of trifluoroacetate salt of Compound 23
The crude 23e p-toluenesulfonate (0.44 g) was dissolved in 5mL DMSO, DIPEA (0.34 g,2.63 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.12 g,0.43 mmol) were added and reacted at 80℃for 3h. The reaction solution was cooled to room temperature, 40mL of water was added, filtration was carried out, the cake was washed with 10mL of water, the cake was dissolved with 50mL of DCM, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was subjected to Pre-HPLC (apparatus and preparative column: preparation of liquid phase using Glison GX-281, preparative column model is Sunfire C18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% tfa). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 5% gradient (elution time 15 min) and lyophilized to give the trifluoroacetate salt of compound 23 (0.05 g).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.01(s,1H),8.30(s,1H),7.87–7.77(m,2H),7.68(d,1H),7.63–7.58(m,1H),7.44(dd,1H),6.90–6.84(m,1H),6.71(dd,1H),5.11–5.02(m,1H),4.45–4.32(m,2H),4.28(s,1H),4.06–3.96(m,2H),3.95–3.83(m,1H),2.95–2.80(m,1H),2.71–2.51(m,2H),2.08–1.95(m,1H),1.84(s,6H).
LCMS m/z＝623.1[M+1]+
Example 24: preparation of Compound 24
Starting from 24b and 2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid, compound 24 (0.05 g) was obtained according to the preparation method of compound 18.
1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.33(d,1H),8.00(s,1H),7.86–7.76(m,2H),7.67(d,1H),7.62–7.56(m,1H),7.56–7.45(m,1H),6.83–6.76(m,1H),6.54(dd,1H),4.98–4.87(m,1H),4.40–4.30(m,2H),4.10–4.00(m,2H),3.86–3.72(m,1H),2.95–2.64(m,3H),2.18–2.08(m,1H),1.97(s,6H),1.69(s,6H).
Example 25: preparation of Compound 25
The first step: 25c preparation
25B (1.5 g,5.10 mmol) was dissolved in 20mL tetrahydrofuran, cooled to-78deg.C, and LDA in tetrahydrofuran/n-hexane (v/v) =12:25 solution (2.0 mol/L) (3.05 mL,6.10 mmol) was slowly added dropwise, and after reaction at-78deg.C for 30min, bromomethylcyclopropane (1.38 g,10.2 mmol) was added and the mixture was allowed to react at room temperature for 3h. To the reaction solution was added 40mL of saturated sodium chloride solution, which was washed, extracted with 60mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =5:1), to give 25c (288 mg, yield: 16%).
Using 25c and 2-chloro-4- (trifluoromethyl) aniline as raw materials, compound 25 (81 mg) was obtained in referential example 5.
1H NMR(400MHz,CDCl3)δ9.64(s,1H),8.55–8.47(m,1H),7.99(s,1H),7.86–7.76(m,2H),7.71–7.63(m,1H),7.62–7.57(m,1H),7.53–7.45(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.44–4.30(m,2H),4.15–4.00(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.50–2.35(m,1H),2.20–2.05(m,2H),2.00(s,3H),0.60–0.30(m,3H),0.20–0.07(m,1H),0.02–-0.10(m,1H).
LCMS m/z＝707.6[M+1]+
Example 26: preparation of trifluoroacetate salt of Compound 26
The first step: 26c preparation
60% Sodium hydride (2.45 g) was added to 300mL of DMSO, cooled to0℃and 40mL of a solution of tert-butyl ((1, 3-dibromopropan-2-yl) oxy) diphenylsilane (20.4 g,44.7 mmol) (see WO2013173720 for synthesis) and 26b (10.5 g,34.08 mmol) in DMSO was added dropwise to the solution and reacted at room temperature for 12h. 1L of purified water was added to the reaction system, extracted with 300mL of ethyl acetate, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give 26c (3.5 g, yield: 17%).
LCMS m/z＝603.2[M+1]+。
And a second step of: 26d preparation
26C (3.5 g,5.81 mmol) was added to 60mL of methylene chloride, 20mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 3h. The reaction solution was concentrated under reduced pressure, 100mL of methylene chloride was added, the pH was adjusted to 9 with a saturated aqueous sodium carbonate solution, the pH was adjusted to 5 with 2mol/L hydrochloric acid, and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (2.5 g). The crude product (2.5 g) was dissolved with 2-chloro-4- (trifluoromethyl) aniline (0.88 g,4.5 mmol) in 100mL DCM and TCFH (1.96 g,7.0 mmol) was added and N-methylimidazole (1.5 g,18.27 mmol) was slowly added dropwise and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 26d (2.3 g, yield: 71%).
And a third step of: 26e preparation
26D (2.3 g,3.2 mmol) was dissolved in 60mL THF, TBAF (2.6 g,9.94 mmol) was added and the reaction was refluxed for 5h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 50mL of ethyl acetate was added to the residue, and the organic phase was washed with 100mL of purified water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 26e (0.6 g, yield: 39.0%).
LCMS m/z＝485.9[M+1]+。
Fourth step: preparation of trifluoroacetate salt of Compound 26
26E (0.1 g,0.21 mmol), intermediate 1 (0.1 g,0.3 mmol), TEA (0.1 g,1.0 mmol), cuI (3.6 mg,0.019 mmol) and PdCl 2(PPh3)2 (14 mg,0.02 mmol) were added to 5mL of DMF and reacted under nitrogen at 60℃for 3h. The reaction solution was cooled to room temperature, filtered, and subjected to Pre-HPLC (apparatus and preparative column: preparative liquid phase using Glison GX-281, type of preparative column being Sunfire C18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% tfa). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 5% gradient (elution time 15 min) and lyophilized to give the trifluoroacetate salt of compound 26 (0.08 g).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.05–8.91(m,1H),8.48–8.27(m,1H),8.23–8.12(m,1H),7.94–7.84(m,2H),7.78–7.64(m,2H),6.90–6.83(m,1H),6.76–6.67(m,1H),5.11–5.01(m,1H),4.45–4.32(m,2H),4.28–4.07(m,1H),4.05–3.95(m,2H),3.95–3.83(m,1H),3.28–3.05(m,2H),2.97–2.70(m,2H),2.65–2.51(m,3H),2.08–1.95(m,1H).
LCMS m/z＝695.2[M+1]+
Example 27: preparation of trifluoroacetate salt of Compound 27
The first step: 27b preparation
27A (2.7 g,10 mmol), (E) -2- (2-ethoxyvinyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (3.0 g,15.15 mmol), pd (dppf) Cl 2 (725.7 mg,1.0 mmol) and CsF (4.6 g,30.28 mmol) were added to 80mL of 1, 4-dioxane and 20mL of water and reacted at 85℃for 12h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 100mL of ethyl acetate was added, washed with 100mL of purified water, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give 27b (2.3 g, yield: 88%).
And a second step of: 27c preparation
27B (2.3 g,8.81 mmol) was added to 50mL tetrahydrofuran, 4mL concentrated hydrochloric acid was added and reacted at room temperature for 16h. The reaction solution was concentrated under reduced pressure, 100mL of methylene chloride was added, the pH was adjusted to 10 with a saturated aqueous sodium carbonate solution, and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 27c (1.5 g).
And a third step of: 27d preparation
The crude product 27c (1.5 g) was dissolved in 30mL of methanol, potassium carbonate (2.0 g,14.47 mmol) was added, cooled to 0℃and dimethyl (1-diazo-2-oxopropyl) phosphonate (1.93 g,10 mmol) was added dropwise, nitrogen was replaced three times, and the reaction was carried out at room temperature for 16h. The reaction system was concentrated under reduced pressure, 100mL of ethyl acetate was added, the organic phase was separated by washing with 100mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =4:1) to give 27d (0.47 g, two-step yield from compound 27 b: 23%).
Fourth step: 27e preparation
27D (0.47 g,2.05 mmol) was added to 8mL of ethanol, and reduced iron powder (0.56 g,10 mmol) and 2mL of saturated aqueous ammonium chloride solution were added and reacted under reflux for 2h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 40mL of ethyl acetate was added, and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 27e (0.36 g).
LCMS m/z＝200.1[M+1]+
The trifluoroacetate salt of compound 27 was prepared by acidic method using compound 27e+23b as starting material, according to the preparation method of example 23 [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 27 (50 mg).
1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.47(d,1H),8.09(s,1H),7.81(s,1H),7.75(s,1H),7.67(d,1H),7.59–7.43(m,2H),6.83–6.78(m,1H),6.55(dd,1H),4.98–4.90(m,1H),4.42–4.30(m,2H),4.11–4.00(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.08(m,4H),1.94(s,6H).
Example 28: preparation of Compound 28
The first step: 28B preparation
28A (5.00 g,24.15 mmol), 2mol/L aqueous sodium hydroxide (25 mL) and 25mL ethanol were added to the flask, respectively, and the mixture was stirred at room temperature for 2h. The reaction solution was cooled to 0℃and 1mol/L hydrochloric acid was then added thereto to adjust the pH to 2, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was washed with 20mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (4.6 g). To the crude product (4.6 g) was added 1-chloro-N, N, 2-trimethylpropenamine (5.14 g,38.55 mmol) and DCM (100 mL), and after stirring at room temperature for 1h, TEA (10.67 mL,76.55 mmol) and 2-chloro-4-trifluoromethylaniline (5.02 g,25.67 mmol) were added and reacted at room temperature for 16h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:5) to give 28B (6.05 g, yield: 70%).
And a second step of: 28b preparation
28A (5.0 g,39.64 mmol) was dissolved in 25mL trifluoroacetic acid and N-iodosuccinimide (9.82 g,43.65 mmol) was added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the residue was slowly dropped into 100mL of a saturated aqueous sodium hydrogencarbonate solution to precipitate a product, which was filtered, and a cake was collected, washed with 20mL of water, and dried under reduced pressure to give crude 28b (4.0 g, yield: 40%).
LCMS m/z＝252.9[M+1]+
And a third step of: 28c preparation
The crude 28B (1.0 g) was dissolved with 28B (1.7 g,4.77 mmol) in 25mL acetonitrile, cesium carbonate (2.59 g,7.95 mmol) was added and reacted at 50℃for 6h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 28c (350 mg, yield: 14%).
LCMS m/z＝528.4[M+1]+
Fourth step: 28d preparation
28C (110 mg,0.21 mmol) was dissolved in 3mL of DMF, 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (57 mg,0.31 mmol) and TEA (64 mg,0.63 mmol), cuI (5 mg,0.026 mmol) and PdCl 2(PPh3)2 (15 mg,0.021 mmol) were added, nitrogen was replaced three times, and reacted at 50℃for 2h. The reaction solution was cooled to room temperature, 10mL of water was added, extraction was performed with 30mL of ethyl acetate, the organic phase was washed with 20mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =3:1), to give crude product 28d (0.12 g).
Fifth step: 28e preparation
The crude 28d (120 mg) was dissolved in 5mL tetrahydrofuran and 1mL water, lithium hydroxide monohydrate (27 mg,0.64 mmol) was added and reacted at room temperature for 3h. The reaction was adjusted to pH 3 with 2mol/L hydrochloric acid, extracted with 50mL of DCM, the organic phase dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (dichloromethane/methanol (v/v) =15:1) to give crude product 28e (0.12 g).
Sixth step: preparation of p-toluenesulfonate salt of 28f
The crude 28e (120 mg) was dissolved in 4mL of acetonitrile, and p-toluenesulfonic acid monohydrate (0.16 g,0.84 mmol) was added and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give p-toluenesulfonate (300 mg) as crude 28 f.
LCMS m/z＝467.1[M+1]+
Seventh step: preparation of Compound 28
The crude 28f p-toluenesulfonate (300 mg) was dissolved in 5mL DMSO, 0.25mL DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (100 mg,0.36 mmol) were added and reacted at 80℃for 3h. The reaction solution was cooled to room temperature, 50mL of water was added, the mixture was filtered, the cake was collected, the cake was washed with 10mL of water, the cake was dissolved with 30mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane/methanol (v/v) =15:1) to give compound 28 (15 mg, yield: 6%).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.57(s,1H),8.45(s,1H),7.98–7.87(m,2H),7.78–7.65(m,2H),6.92–6.87(m,1H),6.80–6.71(m,2H),5.11–5.02(m,1H),4.43–4.30(m,2H),4.24–4.12(m,2H),4.08–3.96(m,1H),3.12–2.97(m,2H),2.97–2.80(m,3H),2.72–2.50(m,2H),2.10–1.95(m,3H).
Example 29: preparation of Compound 29
The first step: 29b preparation
29A (2 g,7.63 mmol) was added to 40mL acetonitrile, followed by methyl 2-bromo-2-methylpropionate (1.5 g,8.29 mmol) and cesium carbonate (4.9 g,15.04 mmol) and reacted at 90℃for 16h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =17:3) to give 29b (2.7 g, yield: 98%).
1H NMR(400MHz,CDCl3)δ7.70–7.66(m,1H),3.73(s,3H),1.86(s,6H).
And a second step of: 29c preparation
29B (2.7 g,7.46 mmol) was dissolved in 40mL tetrahydrofuran, 10mL water was added, cooled to 0deg.C, lithium hydroxide monohydrate (1.5 g,35.75 mmol) was added and reacted at room temperature for 2h. The reaction system was adjusted to pH 4 with 0.5mol/L hydrochloric acid, extracted with ethyl acetate (80 mL. Times.3), and the organic phase was washed with saturated aqueous sodium chloride (80 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (2.1 g). The crude product (200 mg) was put into a 50mL single-necked flask, 15mL of methylene chloride was added, 1-chloro-N, N, 2-trimethylpropenamine (115 mg,0.86 mmol) was added, and after 1 hour of reaction at room temperature, triethylamine (172 mg,1.70 mmol) and 16B (90 mg,0.57 mmol) were added in this order, and the reaction was carried out at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =91:9) to give 29c (190 mg, yield: 68%).
LCMS m/z＝489.1[M+1]+
Thirdly, performing the following steps; preparation of Compound 29
29C (90 mg,0.18 mmol) was added to 10mL of DMF, crude intermediate 1 (93 mg) and triethylamine (55 mg,0.54 mmol), pdCl 2(PPh3)2 (13 mg,0.019 mmol) and CuI (7 mg,0.037 mmol) were added, nitrogen was replaced three times, and reacted at 50℃for 2h. The reaction system was cooled to room temperature, 10mL of saturated aqueous ammonium chloride solution was slowly added, extraction was performed with ethyl acetate (50 ml×3), the organic phase was washed with saturated aqueous sodium chloride solution (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =22:78) to give compound 29 (52 mg, yield: 41%).
1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.36(d,1H),7.96–7.82(m,2H),7.74–7.63(m,1H),7.54–7.46(m,1H),7.42–7.35(m,1H),6.83–6.78(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–3.97(m,2H),3.90–3.75(m,1H),2.98–2.64(m,3H),2.18–2.07(m,1H),1.99(s,6H),1.59–1.46(m,1H),1.06–0.98(m,2H),0.62–0.55(m,2H).
Example 30: preparation of Compound 30
Compound 30 (60 mg) was obtained in referential example 29 using 29B and 17B as raw materials.
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.40(d,1H),7.96(s,1H),7.88–7.82(m,1H),7.68(d,1H),7.61–7.56(m,1H),7.53–7.46(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.10–4.00(m,2H),3.88–3.75(m,1H),2.97–2.65(m,3H),2.18–2.07(m,4H),1.97(s,6H).
Example 31: preparation of Compound 31
The first step: 31b preparation
(Methoxymethyl) triphenylphosphine chloride (1.65 g,4.81 mmol) was added to the flask, 30mL of anhydrous tetrahydrofuran was added under nitrogen, the mixture was cooled to 0℃and potassium tert-butoxide (0.57 g,5.08 mmol) was added thereto, and after stirring at 0℃for 0.5h, 31a (0.5 g,3.21 mmol) was added thereto, and the mixture was reacted at room temperature for 19h. 70mL of water was added to the reaction mixture, the mixture was extracted with ethyl acetate (80 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-5:1) to give 31b (0.12 g, yield: 20%).
LCMS m/z＝184.1[M+1]+
And a second step of: 31c preparation
31B (0.11 g,0.60 mmol) was dissolved in 3mL THF, 3mL 6mol/L hydrochloric acid was added and reacted at room temperature for 2h. To the reaction solution was added 10mL of water, the pH was adjusted to 7 with a saturated aqueous sodium hydrogencarbonate solution, extraction was performed with 20mL of ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 31c (0.11 g).
Compound 31 Using the compound 31c as a starting material, compound 31 (5 mg) was obtained in referential example 22.
1H NMR(400MHz,CDCl3)δ8.37–8.22(m,2H),7.80–7.42(m,4H),7.22–7.17(m,1H),7.13–7.05(m,1H),6.85–6.77(m,1H),6.64–6.52(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H),3.13–2.67(m,9H),2.59(s,6H),2.30–1.96(m,5H).
LCMS m/z＝682.2[M+1]+
Example 32: preparation of Compound 32
Using the compound 32b as a starting material, compound 32 (60 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.46(d,1H),8.05(s,1H),7.80(s,1H),7.72(s,1H),7.67(d,1H),7.60–7.56(m,1H),7.51–7.45(m,1H),6.83–6.79(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.44–4.30(m,2H),4.10–3.97(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.52(q,2H),2.18–2.08(m,1H),1.94(s,6H),1.29(t,3H).
Example 33: preparation of Compound 33
Starting from 33b, compound 33 (11 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.49(d,1H),8.03–7.95(m,1H),7.80(s,1H),7.74(s,1H),7.70–7.59(m,2H),7.56–7.48(m,1H),6.83–6.76(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.28(m,2H),4.12–3.99(m,2H),3.88–3.75(m,1H),3.59(s,2H),2.95–2.65(m,3H),2.39(s,6H),2.18–2.08(m,1H),1.94(s,6H).
LCMS m/z＝714.2[M+1]+
Example 34: preparation of Compound 34
Starting from compound 34a+2-bromo-2-methylpropionate, compound 34 (70 mg) was obtained in reference example 29.
1H NMR(400MHz,CDCl3)δ8.55–8.37(m,2H),7.92(s,1H),7.72–7.65(m,2H),7.60–7.45(m,2H),6.84–6.78(m,1H),6.60–6.52(m,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.10–4.00(m,2H),3.90–3.77(m,1H),2.96–2.64(m,3H),2.20–1.95(m,5H),1.86(s,6H),1.09–1.02(m,2H),1.00–0.92(m,2H).
LCMS m/z＝711.2[M+1]+
Example 35: preparation of Compound 35
Starting from compound 34b+16b, compound 35 (50 mg) was obtained in referential example 29.
1H NMR(400MHz,CDCl3)δ8.86(s,1H),8.36(d,1H),7.97(s,1H),7.72–7.64(m,2H),7.49(dd,1H),7.38–7.32(m,1H),6.84–6.77(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.10–4.00(m,2H),3.90–3.75(m,1H),2.97–2.62(m,3H),2.22–1.82(m,8H),1.66–1.46(m,1H),1.06–0.78(m,6H),0.60–0.50(m,2H).
LCMS m/z＝670.3[M+1]+
Example 36: preparation of Compound 36
Starting from compound 36b, compound 36 (34 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.32(d,1H),8.03(s,1H),7.80(s,1H),7.73(s,1H),7.67(d,1H),7.34–7.20(m,2H),7.02–6.95(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.99–4.88(m,1H),4.42–4.30(m,2H),4.10–4.00(m,2H),3.88–3.73(m,1H),2.95–2.64(m,3H),2.18–2.08(m,4H),1.94(s,6H).
Example 37: preparation of Compound 37
The first step: 37b preparation
37A (1.00 g,6.32 mmol) (see Bioorganic & MEDICINAL CHEMISTRY,2012,20,1188-1200) was dissolved in 15mL dichloromethane, triethylamine (1.92 g,18.97 mmol) was added, cooled to 0deg.C, msCl (0.87 g,7.59 mmol) was added dropwise and reacted at room temperature for 3h. To the reaction solution was added 20mL of water, extracted with dichloromethane (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-5:1) to give 37b (1.1 g, yield: 74%).
And a second step of: 37c preparation
37B (0.7 g,2.96 mmol) was dissolved in 15mL DMF and cesium carbonate (2.89 g,8.87 mmol) and 4-iodopyrazole (0.86 g,4.43 mmol) were added and reacted at 80℃for 12h. The reaction system was cooled to room temperature, 30mL of water was added, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-5:1) to give 37c (0.3 g, yield: 30%).
And a third step of: 37d preparation
37C (0.38 g,1.14 mmol) was dissolved in 3mL of a mixed solvent of THF/H 2 O (v/v) =4:1, lithium hydroxide monohydrate (72 mg,1.72 mmol) was added and reacted at 40℃for 3H. The reaction system was cooled to room temperature, 10mL of water was added, pH was adjusted to 3 with 1mol/L hydrochloric acid, extraction was performed with ethyl acetate (25 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (0.34 g). The crude product (0.34 g) was dissolved in 10mL of DCM, 1-chloro-N, N, 2-trimethylpropenamine (0.22 g,1.65 mmol) was added, and after 2h at room temperature, triethylamine (0.34 g,3.36 mmol) and 2-chloro-4- (trifluoromethyl) aniline (0.22 g,1.12 mmol) were added in sequence and reacted at room temperature for 19h. To the reaction solution was added 15mL of methylene chloride, 20mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 37d (0.305 g, yield: 56%).
Fourth step: preparation of Compound 37
37D (305 mg,0.63 mmol), crude intermediate 1 (320 mg), TEA (190 mg,1.88 mmol), cuI (24 mg,0.126 mmol) and PdCl 2(PPh3)2 (88 mg,0.125 mmol) were added to 10mL DMF and reacted at 55deg.C under nitrogen for 4h. The reaction solution was cooled to room temperature, 25mL of water was added, suction filtration was performed, the cake was washed with 5mL of water, the cake was dissolved with 100mL of a mixed solvent of DCM/MeOH (v/v) =5:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane/methanol (v/v) =10:1-5:1) to give compound 37 (51 mg, yield: 12%).
1H NMR(400MHz,CDCl3)δ8.46(d,1H),8.27(s,1H),8.04(s,1H),7.77–7.40(m,5H),6.83–6.77(m,1H),6.54(dd,1H),4.98–4.89(m,1H),4.40–4.26(m,2H),4.07–3.96(m,2H),3.84–3.70(m,1H),3.28(s,2H),2.98–2.49(m,7H),2.18–1.96(m,3H).
Example 38: preparation of Compound 38
The first step: 38b preparation
38A (1.5 g,9.15 mmol) was added to a 100mL single port flask, 30mL DMF was added, 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (2.5 g,13.8 mmol) and triethylamine (2.7 g,26.7 mmol) were added, nitrogen was replaced three times, pdCl 2(PPh3)2 (640 mg,0.92 mmol) and CuI (350 mg,1.84 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 50℃for 2h. The reaction was cooled to room temperature, 200mL of saturated aqueous ammonium chloride solution was slowly added, extraction was performed with ethyl acetate (100 ml×3), the organic phase was washed with saturated aqueous sodium chloride solution (150 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =87:13) to give 38b (2 g, yield: 83%).
LCMS m/z＝265.1[M+1]+
And a second step of: 38c preparation
38B (1.0 g,3.79 mmol) was added to a 100mL three-necked flask, 20mL tetrahydrofuran was added, nitrogen was replaced three times, the flask was cooled to-78℃and a 2mol/L lithium diisopropylamide in tetrahydrofuran (3.8 mL,7.6 mmol) was slowly added to react at-78℃for 20min, and then the temperature was raised to0℃to react for 1h. The reaction was cooled to-78℃and 38A (986 mg,5.69 mmol) was added (see WO2014045031 for synthesis) and reacted at room temperature for 16h. To the reaction system was added 50mL of saturated aqueous ammonium chloride, extracted with ethyl acetate (70 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (80 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =78:22) to give 38c (0.35 g, yield: 21%).
LCMS m/z＝438.1[M+1]+
And a third step of: preparation of the hydrochloride salt of 38d
38C (0.335 g,0.77 mmol) was dissolved in 15mL of methanol, cooled to 0deg.C, and a 0.5mol/L solution of hydrogen chloride in ethyl acetate (10 mL,5 mmol) was added and reacted at 0deg.C for 1h. The reaction system was concentrated under reduced pressure to give crude 38d hydrochloride (210 mg).
Fourth step: 38e preparation
2-Chloro-4- (trifluoromethyl) benzoic acid (67 mg,0.3 mmol) was added to a 50mL single-necked flask, 10mL of methylene chloride was added, 1-chloro-N, N, 2-trimethylpropenamine (58 mg,0.43 mmol) was added, and after 1 hour of reaction at room temperature, triethylamine (88 mg,0.87 mmol) and hydrochloride (110 mg) of the above crude product 38d were added in this order, and reaction was carried out at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =72:28) to give 38e (80 mg, yield: 49%).
LCMS m/z＝540.1[M+1]+
Fifth step, the method comprises the following steps; preparation of p-toluenesulfonate salt of 38f
38E (80 mg,0.15 mmol) was added to a 50mL single-necked flask, 20mL acetonitrile was added, and p-toluenesulfonic acid (103 mg,0.6 mmol) was added to react at 30℃for 2h. The reaction system was concentrated under reduced pressure to give p-toluenesulfonate (70 mg) as crude product 38 f.
LCMS m/z＝440.1[M+1]+
Sixth step; preparation of Compound 38
The crude 38f p-toluenesulfonate (70 mg) was added to a 50mL single-necked flask, 6mL DMSO and DIPEA (103 mg,0.80 mmol) were added, and after stirring for 20min, 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (66 mg,0.24 mmol) was added and reacted at 80℃for 2h. The reaction system was cooled to room temperature, 80mL of water was slowly added, extraction was performed with ethyl acetate (50 ml×3), the organic phase was washed with saturated aqueous sodium chloride (60 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =28:72) to give compound 38 (25 mg, yield: 15%).
1H NMR(400MHz,CDCl3)δ8.15–8.00(m,1H),7.84–7.54(m,5H),7.14–7.02(m,1H),6.88–6.75(m,1H),6.65–6.50(m,1H),4.99–4.87(m,1H),4.45–4.30(m,2H),4.17–4.03(m,2H),3.95–3.80(m,1H),2.97–2.65(m,7H),2.31–2.05(m,3H).
Example 39: preparation of Compound 39
The first step: 39b preparation
2-Chloro-4-trifluoromethylbenzoic acid (0.1 g,0.45 mmol) was dissolved in 2mL of DCM, 1-chloro-N, N, 2-trimethylpropenamine (0.09 g,0.67 mmol) was added, and after 2h at room temperature, triethylamine (0.27 g,2.67 mmol) and 39a (see WO 2016116061) (0.1 g,0.40 mmol) were added in sequence and reacted at room temperature for 12h. To the reaction solution was added 50mL of dichloromethane, 50mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =20:1-5:1) to give 39b (0.06 g, yield: 33%).
LCMS m/z＝455.0[M+1]+
And a second step of: preparation of Compound 39
39B (0.06 g,0.13 mmol), crude intermediate 1 (0.044 g), TEA (0.079 g,0.78 mmol), cuI (5 mg,0.026 mmol) and bis triphenylphosphine palladium dichloride (9 mg,0.013 mmol) were added to 5mL DMF and reacted under nitrogen at 50℃for 0.5h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on silica gel column (petroleum ether/dichloromethane/ethyl acetate (v/v) =1:1:2) to give compound 39 (0.015 g, yield: 17%).
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.77–7.56(m,3H),7.52–7.40(m,1H),6.84–6.70(m,2H),6.58–6.48(m,1H),6.17–5.82(m,1H),5.04–4.80(m,2H),4.54–3.45(m,10H),2.99–2.62(m,3H),2.20–2.06(m,1H).
LCMS m/z＝664.2[M+1]+
Example 40: preparation of trifluoroacetate salt of Compound 40
The first step: 40b preparation
40A (2.2 g,9.9 mmol) was added to 50mL DMF, 28B (4.3 g,12 mmol) and cesium carbonate (6.5 g,19.95 mmol) were added and reacted at 85℃for 3h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate and 200mL of purified water were added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =4:1) to give 40b (1.5 g, yield: 30%).
And a second step of: 40c preparation
40B (0.5 g,1.0 mmol) was added to 30mL of 1, 2-dichloroethane, morpholine (0.2 g,2.3 mmol) was added, sodium triacetoxyborohydride (0.42 g,1.98 mmol) was added and the reaction was carried out at room temperature for 12h. To the reaction solution was added 20mL of methylene chloride, 50mL of purified water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =3:1) to give 40c (0.38 g, yield: 67%).
LCMS m/z＝569.1[M+1]+
And a third step of: 40d preparation
40C (0.38 g,0.67 mmol), tert-butyl 3-ethynylazatidine-1-carboxylate (0.18 g,0.99 mmol), TEA (0.3 g,2.96 mmol), cuI (11 mg,0.058 mmol) and PdCl 2(PPh3)2 (42 mg,0.06 mmol) were added to 5mL DMF and reacted at 90℃under nitrogen for 3h. The reaction solution was cooled to room temperature, 30mL of purified water was added, filtration was performed, the cake was dissolved with 30mL of methylene chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =3:1), to give 40d (0.32 g, yield: 77%).
LCMS m/z＝622.3[M+1]+
Starting from compound 40d, reference example 23 preparation, acidic preparation [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 40 (10 mg).
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),9.21(s,1H),8.52(s,1H),7.98–7.87(m,2H),7.80–7.65(m,2H),6.92–6.86(m,1H),6.73(dd,1H),5.12–5.01(m,1H),4.48–4.28(m,4H),4.15–3.02(m,11H),3.02–2.70(m,5H),2.67–2.46(m,2H),2.08–1.92(m,3H).
LCMS m/z＝778.2[M+1]+
Example 41: preparation of trifluoroacetate salt of Compound 41
The first step: 41a preparation
40B (0.5 g,1.0 mmol) was added to 30mL of methylene chloride, DAST (0.48 g,2.98 mmol) was added, and the reaction was carried out at room temperature for 3h. 2mL of methanol was added to the reaction system, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give 41a (0.31 g, yield: 60%).
And a second step of: 41b preparation
41A (0.38 g,0.73 mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.18 g,0.99 mmol), TEA (0.3 g,2.96 mmol), cuI (11 mg,0.058 mmol) and PdCl 2(PPh3)2 (42 mg,0.06 mmol) were reacted under nitrogen at 95℃for 3h. The reaction solution was cooled to room temperature, 30mL of purified water was added, filtration was performed, the cake was dissolved with 30mL of methylene chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =4:1), to give 41b (0.32 g, yield: 77%).
The trifluoroacetate salt of compound 41 was prepared by acidic method using compound 41b as a starting material, according to the preparation method of example 23 [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 41 (50 mg).
1H NMR(400MHz,CDCl3)δ8.60–8.50(m,2H),8.07–7.98(m,1H),7.73(s,1H),7.67(d,1H),7.62–7.56(m,1H),7.55–7.48(m,1H),6.92–6.60(m,2H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–4.00(m,2H),3.90–3.76(m,1H),3.15–3.02(m 2H),2.95–2.66(m,5H),2.30–2.02(m,3H).
LCMS m/z＝727.1[M-1]-
Example 42: preparation of trifluoroacetate salt of Compound 42
The first step: 42a preparation
40B (0.5 g,1.0 mmol) was added to 30mL of 1, 2-dichloroethane, dimethylamine (0.2 g,4.44 mmol) and sodium triacetoxyborohydride (0.42 g,1.98 mmol) were added and reacted at room temperature for 12h. To the reaction solution was added 20mL of methylene chloride, 50mL of purified water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =1:1) to give 42a (0.27 g, yield: 51%).
LCMS m/z＝527.1[M+1]+
And a second step of: 42b preparation
42A (0.27 g,0.51 mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.18 g,0.99 mmol), TEA (0.3 g,2.96 mmol), cuI (11 mg,0.058 mmol) and PdCl 2(PPh3)2 (42 mg,0.06 mmol) were added to 5mL DMF and reacted under nitrogen at 95℃for 3h. The reaction solution was cooled to room temperature, 30mL of purified water was added, filtration was performed, the cake was dissolved with 30mL of methylene chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =1:1) to give 42b (0.25 g, yield: 85%).
The trifluoroacetate salt of compound 42 was prepared by acidic method using compound 42b as a starting material, according to the preparation method of example 23 [ mobile phase system: acetonitrile/water (with 0.1% tfa) ], to afford the trifluoroacetate salt of compound 42 (6 mg).
1H NMR(400MHz,DMSO-d6)δ11.06(br.s,1H),9.29(s,1H),8.59(s,1H),7.98–7.90(m,1H),7.89–7.81(m,1H),7.78–7.65(m,2H),6.92–6.84(m,1H),6.73(dd,1H),5.14–5.00(m,1H),4.57(s,2H),4.47–4.35(m,2H),4.13–4.02(m,2H),4.01–3.89(m,1H),3.10(s,6H),3.01–2.72(m,5H),2.71–2.50(m,2H),2.08–1.93(m,3H).
Example 43: preparation of Compound 43
The first step: preparation of Compound 43b
43A (0.19 g,0.73 mmol) (see Bioorganic & MEDICINAL CHEMISTRY LETTERS,2021,33,127749) was dissolved in 2mL DCM, 1-chloro-N, N, 2-trimethylpropenamine (0.19 g,1.42 mmol) was added and after 2h reaction at room temperature triethylamine (0.58 g,5.73 mmol) and 16B (0.25 g,1.58 mmol) were added sequentially and reacted at room temperature for 12h. To the reaction solution was added 50mL of methylene chloride, 50mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =20:1-5:1) to give 43b (0.2 g, yield: 69%).
And a second step of: preparation of Compound 43
43B (0.092 g,0.23 mmol), crude intermediate 1 (0.078 g), TEA (0.14 g,1.38 mmol), cuI (8.8 mg,0.046 mmol) and PdCl 2(PPh3)2 (16 mg,0.023 mmol) were added to 2mL of DMF and reacted under nitrogen at 55℃for 1h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on silica gel column (petroleum ether/dichloromethane/ethyl acetate (v/v) =1:1:2) to give compound 43 (0.005 g, yield: 3%).
1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.52(d,1H),7.97(s,1H),7.72–7.62(m,1H),7.60–7.51(m,1H),7.51–7.42(m,1H),7.39–7.32(m,2H),6.94–6.87(m,2H),6.84–6.77(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.43–4.32(m,2H),4.13–4.02(m,2H),3.89–3.77(m,1H),2.96–2.64(m,3H),2.19–2.08(m,1H),1.70–1.48(m,7H),0.92–0.78(m,2H),0.58–0.47(m,2H).
LCMS m/z＝656.3[M+1]+
Example 44: preparation of Compound 44
The first step: 44b preparation
44A (0.90 g,3.63 mmol) and 1-chloro-N, N, 2-trimethylpropenamine (0.73 g,5.46 mmol) were added to dichloromethane (10 mL), stirred at room temperature for 1h, triethylamine (1.51 mL) was added and reacted with 2-chloro-4- (trifluoromethyl) aniline (0.85 g,4.35 mmol) at room temperature for 16h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20) to give 44b (0.50 g, yield: 32%).
LCMS m/z＝426.0[M+1]+
And a second step of: preparation of Compound 44
44B (0.17 g,0.4 mmol), crude intermediate 1 (0.20 g), pdCl 2(PPh3)2 (27 mg,0.038 mmol), cuI (15 mg,0.079 mmol) and DIPEA (0.15 g,1.16 mmol) were added to DMF (5 mL) and reacted at 60℃under nitrogen for 5h. The reaction system was cooled to room temperature, added to water (20 mL), extracted with a mixed solvent of ethyl acetate/methanol (v/v) =5:1 (20 ml×3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:2), and the obtained crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 44 (13 mg, yield: 5%).
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),10.36(s,1H),8.09(s,1H),8.02–7.93(m,2H),7.92–7.85(m,1H),7.82–7.74(m,1H),7.74–7.65(m,2H),7.62–7.53(m,1H),6.93–6.85(m,1H),6.74(dd,1H),5.12–5.01(m,1H),4.50–4.36(m,2H),4.17–3.90(m,3H),3.00–2.80(m,1H),2.67–2.50(m,2H),2.10–1.92(m,1H).
LCMS m/z＝635.0[M+1]+
Example 45: preparation of Compound 45
Using the compound 45a as a starting material, compound 45 (15 mg) was obtained in referential example 43.
1H NMR(400MHz,CDCl3)δ8.45(d,1H),7.94(s,1H),7.74(s,1H),7.68(d,1H),7.53–7.40(m,5H),7.36–7.32(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.45–4.32(m,2H),4.17–4.07(m,2H),3.94–3.80(m,1H),2.96–2.66(m,3H),2.18–2.08(m,1H),1.69(s,6H),1.20–1.10(m,1H),0.56–0.47(m,2H),0.36–0.28(m,2H).
LCMS m/z＝640.3[M+1]+
Example 46: preparation of Compound 46
Starting from compound 46 a+2-chloro-4- (trifluoromethyl) aniline, compound 46 (12 mg) was obtained in referential example 43.
1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.93(s,1H),7.72–7.64(m,1H),7.57(s,1H),7.54–7.46(m,4H),7.38–7.30(m,2H),6.84–6.80(m,1H),6.57(dd,1H),4.98–4.90(m,1H),4.44–4.32(m,2H),4.18–4.07(m,2H),3.93–3.80(m,1H),3.00–2.66(m,5H),2.64–2.51(m,2H),2.30–2.07(m,2H),2.03–1.90(m,1H).
Example 47: preparation of trifluoroacetate salt of Compound 47
The first step: 47b preparation
47A (0.7 g,2.27 mmol) (see WO 2012074951) was dissolved in10 mL of methanol and an aqueous solution (5 mL) of lithium hydroxide monohydrate (0.29 g,6.91 mmol) was added and reacted at room temperature for 2h. 50mL of water was added to the reaction system, the pH was adjusted to 2 with 1mol/L hydrochloric acid, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (0.7 g). The crude product (0.2 g) was dissolved in 2mL DCM and 16B (0.11 g,0.70 mmol), TCFH (0.38 g,1.36 mmol) and N-methylimidazole (0.28 g,3.41 mmol) were added and reacted at room temperature for 12h. To the reaction solution was added 50mL of dichloromethane, 50mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =20:1-5:1) to give 47b (0.2 g, yield: 66%).
And a second step of: preparation of trifluoroacetate salt of Compound 47
47B (0.1 g,0.23 mmol), crude intermediate 1 (0.12 g), TEA (0.14 g,1.38 mmol), cuI (8.8 mg,0.046 mmol) and PdCl 2(PPh3)2 (16 mg,0.023 mmol) were added to 2mL of DMF and reacted under nitrogen at 55deg.C for 1h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 20mL of DCM, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was subjected to Pre-HPLC (apparatus and preparative column: preparation of liquid phase using Glison GX-281, preparative column model is Sunfire C18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% tfa). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 5% gradient (elution time 15 min) and lyophilized to give the trifluoroacetate salt of compound 47 (0.05 g).
1H NMR(400MHz,CDCl3)δ8.44–8.32(m,2H),8.12(s,1H),7.67(d,1H),7.58–7.50(m,3H),7.48–7.43(m,1H),6.83–6.75(m,1H),6.54(dd,1H),4.98–4.89(m,1H),4.41–4.27(m,4H),4.08–3.98(m,2H),3.83–3.71(m,1H),2.97–2.64(m,3H),2.19–2.08(m,1H),1.69–1.52(m,1H),1.40(s,6H),1.06–0.96(m,2H),0.67–0.58(m,2H).
LCMS m/z＝644.8[M+1]+
Example 48: preparation of Compound 48
The first step: 48B-A and 48B-B preparation
28B (0.4 g,1.12 mmol), 28a (0.22 g,1.13 mmol) and cesium carbonate (0.73 g,2.24 mmol) were added to acetonitrile (10 mL) and reacted at 50℃for 4h. The reaction system was cooled to room temperature, filtered, the solvent was removed from the filtrate under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20) to give 48B-a (0.14 g, yield: 26%) and 48B-B (65 mg, yield: 12%) respectively.
48B-A nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.57(d,1H),7.64–7.56(m,1H),7.55–7.46(m,1H),7.46–7.40(m,1H),6.62–6.56(m,1H),3.15–3.00(m,2H),2.84–2.72(m,2H),2.32–2.01(m,2H).
48B-B nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ8.64–8.55(m,1H),7.72–7.64(m,1H),7.60–7.56(m,3H),6.64–6.58(m,1H),3.20–2.99(m,4H),2.33–2.16(m,1H),2.09–1.93(m,1H).
And a second step of: preparation of Compound 48
48B-A (0.14 g,0.30 mmol), intermediate 1 (0.15 g), pdCl 2(PPh3)2 (21 mg,0.030 mmol), cuI (11 mg,0.060 mmol) and DIPEA (0.12 g,0.93 mmol) were added to DMF (5 mL) and reacted at 60℃under nitrogen for 3h. The reaction system was cooled to room temperature, added to water (20 mL), extracted with a mixed solvent of ethyl acetate/methanol (v/v) =5:1 (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:2), and the obtained crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 48 (101 mg, yield: 50%).
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.55(dd,1H),7.95(s,1H),7.68(d,1H),7.61–7.54(m,2H),7.54–7.47(m,1H),6.86–6.80(m,1H),6.57(dd,1H),6.54–6.50(m,1H),4.99–4.89(m,1H),4.45–4.34(m,2H),4.19–4.10(m,2H),3.94–3.81(m,1H),3.15–3.01(m,2H),2.95–2.65(m,5H),2.34–2.02(m,3H).
LCMS m/z＝679.2[M+1]+
Example 49: preparation of Compound 49
Using the compound 48B-B as a starting material, compound 49 (12 mg) was obtained in referential example 48.
1H NMR(400MHz,CDCl3)δ8.54(d,1H),7.91(s,1H),7.73(s,1H),7.71–7.64(m,2H),7.57–7.53(m,1H),7.48–7.42(m,1H),6.82–6.76(m,1H),6.58–6.51(m,2H),4.99–4.89(m,1H),4.37–4.26(m,2H),4.08–3.97(m,2H),3.84–3.72(m,1H),3.12–2.96(m,4H),2.95–2.66(m,3H),2.32–1.99(m,3H).
LCMS m/z＝679.1[M+1]+
Example 50: preparation of Compound 50
The first step: 50b preparation
50A (see WO2014086316)(45mg,0.13mmol)、2c(61mg,0.13mmol)、Pd(dppf)Cl2·CH2Cl2(CAS:95464-05-4)(11mg,0.0136mmol)、 for synthesis) was added to a mixed solution of 1, 4-dioxane and water (6 mL, v/v=5:1), reacted at 90℃under nitrogen for 16h, the reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 50b (42 mg, yield: 56%).
LCMS m/z＝575.1[M+1]+
Using the compound 50b as a starting material, compound 50 (22 mg) was obtained in referential example 23.
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.58(d,1H),8.01(s,2H),7.83(s,1H),7.69(d,1H),7.59–7.47(m,4H),7.40–7.34(m,2H),6.89–6.83(m,1H),6.61(dd,1H),4.98–4.90(m,1H),4.54–4.42(m,2H),4.14–3.98(m,3H),3.19–3.05(m,2H),2.96–2.65(m,5H),2.43–1.95(m,3H).
Example 51: preparation of Compound 51
The first step: 51b preparation
51A (2.0 g,8.51 mmol) was dissolved in 25mL of dichloromethane and 1-chloro-N, N, 2-trimethylpropenamine (1.71 g,12.80 mmol) was added and reacted at room temperature for 2h. The reaction system was slowly added dropwise to 10mL of concentrated aqueous ammonia and reacted at room temperature for 30min. To the reaction system was added 50mL of saturated aqueous sodium hydrogencarbonate solution, extracted with 50mL of methylene chloride, and the organic phase was washed with 30mL of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product 51b (1.5 g).
And a second step of: 51c preparation
The crude product 51b (1.5 g) was dissolved in20 mL of tetrahydrofuran, and L.sub.complex reagent (CAS: 19172-47-5) (2.59 g,6.40 mmol) was added thereto and reacted at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 51c (1.5 g, yield: 94%).
And a third step of: 51d preparation
51C (250 mg,1.00 mmol) was dissolved in 5mL 1, 4-dioxane, 1-bromo-3-methylbutan-2-one (200 mg,1.21 mmol) was added and reacted in a lock tube at 100℃for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 51d (0.18 g, yield: 57%).
LCMS m/z＝317.0[M+1]+.
Fourth step: 51e preparation
Compound 51d (180 mg,0.57 mmol) was dissolved in 10mL of methanol, 0.1g of 10% palladium on carbon was added to replace hydrogen three times, and the mixture was reacted at room temperature under a hydrogen balloon atmosphere for 16 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to give crude 51e (0.14 g).
LCMS m/z＝287.3[M+1]+
Using the compound 51e as a starting material, a compound 51 (0.08 g) was obtained in referential example 18.
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.28–8.22(m,1H),8.20–8.15(m,1H),8.07–8.00(m,1H),7.97(s,1H),7.81–7.75(m,2H),7.67(d,1H),6.92–6.87(m,1H),6.84–6.79(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.41–4.31(m,2H),4.14–4.02(m,2H),3.88–3.76(m,1H),3.22–3.08(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.95(s,6H),1.35(d,6H).
Example 52: preparation of Compound 52
The first step: 52d preparation
Potassium tert-butoxide (2.0 g,17.82 mmol) and CuI (1.13 g,5.93 mmol) were dissolved in 30mL of ultra-dry DMF, cooled to 0℃under nitrogen protection, and (difluoromethyl) trimethylsilane (1.48 g,11.92 mmol) was added, replaced with nitrogen three times, stirred at 0℃for 15min, phenanthrene-9, 10-dione (1.48 g,7.11 mmol) was added, and a solution of 52c (1.098 g,5.93 mmol) in DMF (10 mL) was slowly added dropwise, reacted at 0℃for 1h, and at room temperature for 16h. To the reaction system was added 80mL of saturated aqueous ammonium chloride, followed by filtration through celite, the filtrate was extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =8:1) to give 52d (0.35 g, yield: 25%).
Using the compound 52d as a starting material, compound 52 (30 mg) was obtained in referential example 23.
1H NMR(400MHz,CDCl3)δ9.31(s,1H),8.53(d,1H),8.03(s,1H),7.82–7.76(m,2H),7.74–7.59(m,3H),6.85–6.77(m,1H),6.70–6.35(m,2H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.74(m,1H),2.97–2.64(m,3H),2.19–2.05(m,1H),1.94(s,6H).
LCMS m/z＝707.2[M+1]+.
Example 53: preparation of Compound 53
The first step: 53B preparation
53A (1.0 g,5.99 mmol) was added to a 100mL single-necked flask, dried dichloromethane (20 mL), 16B (952 mg,6.02 mmol) and TCFH (2.5 g,8.91 mmol) were added sequentially, N-methylimidazole (2.46 g,29.96 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 3h. The reaction system was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =93:7) to give 53B (1.5 g, yield: 82%).
LCMS m/z＝307.1[M+1]+
And a second step of: 53b preparation
3-Acetylylazetidine hydrochloride (540 mg,4.59 mmol) and potassium carbonate (1.3 g,9.41 mmol) were added to a 100mL single port flask, 20mL of dried dimethyl sulfoxide was added, and after stirring at room temperature for 20min, 53a (1.0 g,3.08 mmol) was added, cuI (88 mg, 0.460 mmol) and L-proline (106 mg,0.92 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 100℃for 16h. The reaction system was cooled to room temperature, slowly poured into a saturated aqueous ammonium chloride solution (220 mL), extracted with ethyl acetate (50 ml×2), the organic phase was washed with a saturated aqueous sodium chloride solution (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =58:42) to give 53b (0.27 g, yield: 32%).
LCMS m/z＝278.1[M+1]+
And a third step of: 53c preparation
53B (0.27 g,0.97 mmol) was dissolved in 10mL dichloromethane and trifluoroacetic acid (3 mL) was added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, saturated aqueous sodium carbonate (30 mL) was added, extraction was performed with ethyl acetate (30 ml×3), the organic phase was washed with saturated aqueous sodium chloride (30 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =42:58) to give 53c (100 mg, yield: 70%).
LCMS m/z＝148.1[M+1]+
Fourth step: 53d preparation
53C (100 mg,0.68 mmol) was added to dry acetonitrile (10 mL), cesium carbonate (442 mg,1.36 mmol) and 53B (250 mg,0.82 mmol) were added and reacted at 90℃for 16h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =1:99) to give 53d (90 mg, yield: 35%).
LCMS m/z＝374.1[M+1]+
Fifth step: preparation of Compound 53
53D (90 mg,0.24 mmol) was added to dry DMF (10.0 mL), 53C (67 mg,0.2 mmol) and triethylamine (61 mg,0.6 mmol) were added, nitrogen was replaced three times, pdCl 2(PPh3)2 (14 mg,0.02 mmol) and CuI (6 mg,0.031 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 60℃for 3h. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (80.0 mL) was slowly added, extraction was performed with ethyl acetate (50 ml×3), the organic phase was washed with a saturated aqueous sodium chloride solution (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =22:78) to give compound 53 (50 mg, yield: 40%).
1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.43–8.34(m,1H),7.98(s,1H),7.89–7.78(m,2H),7.76–7.71(m,1H),7.51–7.45(m,1H),7.38–7.33(m,1H),7.24–7.21(m,1H),7.15–7.11(m,1H),5.01–4.93(m,1H),4.19–4.06(m,2H),3.84–3.70(m,3H),2.98–2.67(m,3H),2.21–2.11(m,1H),1.98–1.90(m,6H),1.54–1.45(m,1H),1.05–0.96(m,2H),0.63–0.52(m,2H).
LCMS m/z＝630.2[M+1]+
Example 54: preparation of Compound 54
Starting from compound 54a, compound 54 (45 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.56(s,1H),8.11(dd,1H),8.08–7.97(m,1H),7.81(s,1H),7.75–7.62(m,2H),7.24–7.15(m,1H),7.11–7.06(m,1H),7.04–6.97(m,1H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H),2.95–2.63(m,3H),2.18–2.07(m,1H),2.02–1.90(m,6H),1.56–1.45(m,1H),0.92–0.80(m,2H),0.60–0.45(m,2H).
LCMS m/z＝605.3[M+1]+
Example 55: preparation of Compound 55
The first step: 55b preparation
2-Iodobenzoic acid (0.45 g,1.81 mmol), 1-chloro-N, N, 2-trimethylpropenamine (0.36 g,2.69 mmol) were added to dichloromethane (10 mL), stirred at room temperature for 1h, triethylamine (0.75 mL) was added and reacted with 2-chloro-4- (trifluoromethyl) aniline (0.42 g,2.15 mmol) at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20) to give 55b (0.33 g, yield: 43%).
LCMS m/z＝425.9[M+1]+
And a second step of: 55c preparation
55B (0.20 g,0.47 mmol), tert-butyl 3-ethynylazatidine-1-carboxylate (0.13 g,0.72 mmol), pdCl 2(PPh3)2 (33 mg,0.047 mmol), cuI (18 mg,0.095 mmol) and DIPEA (0.18 g,1.39 mmol) were added to DMF (5 mL) and reacted under nitrogen at 60℃for 5h. The reaction system was cooled to room temperature, added to water (20 mL), extracted with a mixed solvent of ethyl acetate/methanol (v/v) =5:1 (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give 55c (0.22 g, yield: 98%).
Using the compound 55c as a starting material, compound 55 (18 mg) was obtained in referential example 23.
1H NMR(400MHz,CDCl3)δ8.07–7.97(m,2H),7.93–7.80(m,2H),7.79–7.69(m,2H),7.68–7.61(m,2H),7.58–7.50(m,1H),6.79(d,1H),6.54(dd,1H),4.98–4.87(m,1H),4.55–4.32(m,3H),3.92–3.80(m,2H),2.95–2.63(m,3H),2.19–2.07(m,1H).
Example 56: preparation of Compound 56
Using the compound 56a as a starting material, compound 56 (50 mg) was obtained in referential example 22.
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.44(d,1H),7.96(s,1H),7.85–7.73(m,3H),7.72–7.63(m,2H),6.81(d,1H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H),3.12–2.98(m,2H),2.96–2.64(m,5H),2.30–2.20(m,3H).
Example 57: preparation of Compound 57
The first step: 57b preparation
57A (1.95 g,10.05 mmol) was added to 30mL of super-dry DMF, cooled to 5℃and 60% sodium hydride (0.29 g) was added, and after 1h reaction at 5℃2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (3.0 g,10.87 mmol) was added and reacted at 60℃for 3h. The reaction system was cooled to room temperature, 100mL of water was added, solids were precipitated, filtration was performed, and the cake was dried under reduced pressure to give crude 57b (2.1 g).
LCMS m/z＝451.3[M+1]+
And a second step of: 57d preparation
2C (4.7 g,10 mmol) was dissolved in 100mL of dichloromethane, and ethynyl trimethylsilane (1.96 g,20 mmol), TEA (2.0 g,19.8 mmol), cuI (0.19 g,1 mmol) and PdCl 2(PPh3)2 (0.7 g,1 mmol) were added in this order, nitrogen was replaced three times, and reacted at room temperature for 4h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 57d (4.3 g, yield: 98%).
And a third step of: 57e preparation
57D (4.3 g,9.77 mmol) was added to 60mL tetrahydrofuran, and 20mL of a 1mol/L tetrahydrofuran solution of tetrabutylammonium fluoride was added and reacted at room temperature for 2 hours. To the reaction mixture was added 100mL of ethyl acetate, and the mixture was washed three times with 100mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 57e (3.5 g).
Fourth step: preparation of Compound 57
The crude product 57e (0.22 g) was dissolved in 5mL of DMF, and the crude product 57b (0.27 g), TEA (0.2 g,1.98 mmol), cuI (0.019 g,0.1 mmol) and PdCl 2(PPh3)2 (0.07 g,0.1 mmol) were added in this order, nitrogen was replaced three times, and reacted at 65℃for 4 hours. The reaction solution was cooled to room temperature, 20mL of saturated aqueous ammonium chloride solution was added, filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 50mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 57 (150 mg, two-step yield from compound 57 d: 35%).
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.20–9.08(m,2H),8.50(s,1H),8.45–8.32(m,2H),8.23–8.04(m,3H),8.04–7.87(m,2H),7.80–7.71(m,1H),5.26–5.12(m,1H),3.05–2.73(m,5H),2.70–2.50(m,2H),2.18–1.92(m,3H).
Example 58: preparation of Compound 58
The first step: 58a preparation
The above crude 57e (0.74 g) was added to 12mL of tetrahydrofuran, 1-Boc-3-azidoazetidine (CAS: 429672-02-6) (0.4 g,2.02 mmol) was added, copper sulfate pentahydrate (1.0 g,4.0 mmol) and sodium L-ascorbate (CAS: 134-03-2) (0.4 g,2.02 mmol) were added, and the mixture was reacted at room temperature for 16h. 50mL of water was added to the reaction system to precipitate a solid, which was extracted with 50mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give 58a (0.9 g, yield: 79%).
LCMS m/z＝566.2[M+1]+
And a second step of: preparation of p-toluenesulfonate salt of 58b
58A (0.28 g, 0.495mmol) was added to 5mL of acetonitrile, p-toluenesulfonic acid monohydrate (0.38 g,2.0 mmol) was added, and the reaction was carried out at room temperature for 3h. The reaction system was concentrated under reduced pressure to give p-toluenesulfonate (0.23 g) of crude 58 b.
And a third step of: preparation of Compound 58
The crude product 58b p-toluenesulfonate (0.23 g) was dissolved in 5mL of DMSO, 1.0mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (280 mg,1.01 mmol) were added and reacted at 95℃for 3h. The reaction solution was cooled to room temperature, 20mL of water was added, a solid was precipitated, suction filtration was performed, the cake was dissolved with 50mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane/methanol (v/v) =15:1) to give compound 58 (110 mg, yield: 15%).
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.12(s,1H),8.63(s,1H),8.47(s,1H),8.23(d,1H),8.10(s,1H),7.94–7.88(m,1H),7.78–7.68(m,2H),6.98(d,1H),6.82(dd,1H),5.82–5.70(m,1H),5.14–5.02(m,1H),4.73–4.60(m,2H),4.48–4.37(m,2H),3.05–2.73(m,5H),2.71–2.50(m,2H),2.10–1.95(m,3H).
LCMS m/z＝722.6[M+1]+
Example 59: synthesis of Compound 59
The first step: 59b preparation
59A (2.26 g,9.96 mmol) was added to 40mL of 1, 4-dioxane, pinacol vinylborate (3.1 g,20.1 mmol) and cesium fluoride (3.0 g,19.75 mmol) were added, pd (dppf) Cl 2 (0.7 g,0.96 mmol) and 10mL of water were added and reacted at 85℃for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 100mL of ethyl acetate and 50mL of water were added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =10:1) to give 59b (1.0 g, yield: 58%).
And a second step of: 59c preparation
59B (1.0 g,5.74 mmol) was added to 20mL tetrahydrofuran, sodium iodide (0.15 g,1.0 mmol) and trifluoromethyl trimethylsilane (3.3 g,23.2 mmol) were added and reacted at 65℃for 5h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =1:1) to give 59c (0.5 g, yield: 39%).
And a third step of: 59d preparation
59C (0.22 g,0.98 mmol) was added to 10mL of ethanol, iron powder (0.34 g,6.07 mmol) and 2mL of saturated aqueous ammonium chloride solution were added and the mixture was refluxed for 2h. The reaction solution was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 59d (0.16 g).
LCMS m/z＝195.1[M+1]+
Using the compound 59d as a starting material, compound 59 (0.19 g) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ9.30(s,1H),8.29(d,1H),8.09(s,1H),7.80(s,1H),7.75(s,1H),7.67(d,1H),7.58(dd,1H),7.49(s,1H),6.80(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H),2.95–2.62(m,3H),2.54–2.41(m,1H),2.04–1.88(m,7H),1.70–1.50(m,2H).
Example 60: preparation of Compound 60
Using the compound 60a as a starting material, compound 60 (55 mg) was obtained in referential example 59.
1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.28–8.14(m,2H),7.81(s,1H),7.75(s,1H),7.67(d,1H),7.54(d,1H),7.45(s,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.01(m,2H),3.86–3.74(m,1H),2.94–2.62(m,3H),2.60–2.46(m,1H),2.18–2.06(m,1H),2.00–1.86(m,7H),1.62–1.49(m,1H).
Example 61: preparation of trifluoroacetate salt of Compound 61
The first step: 61b preparation
61A (2.41 g,9.88 mmol) and ethyl 1-bromocyclobutane-1-carboxylate (1.5 g,7.24 mmol) were dissolved in 40mL acetonitrile, cesium carbonate (4.39 g,13.47 mmol) was added and reacted at 80℃for 18h. The reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 61b (1.1 g, yield: 41%).
LCMS m/z＝371.4[M+1]+
And a second step of: 61c preparation
61B (1.1 g,2.97 mmol) was dissolved in10 mL tetrahydrofuran/water (v/v) =4:1, lithium hydroxide monohydrate (0.62 g,14.78 mmol) was added and reacted at 40℃for 5h. The reaction solution was cooled to room temperature, 5mL of water was added, pH was adjusted to 3 with 1mol/L hydrochloric acid solution, extraction was performed three times with 20mL of ethyl acetate, and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (0.99 g). The crude product (0.99 g) was dissolved in10 mL DCM, TCFH (1.22 g,4.35 mmol) and 2-chloro-4- (trifluoromethyl) aniline (0.73 g,3.73 mmol) were added, N-methylimidazole (0.95 g,11.57 mmol) was added and reacted at room temperature for 19h. To the reaction solution was added 30mL of methylene chloride, 30mL of water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =5:1-1:1) to give 61c (650 mg, yield: 42%).
And a third step of: preparation of trifluoroacetate salt of Compound 61
61C (0.40 g,0.77 mmol), crude intermediate 1 above (0.39 g), TEA (0.23 g,2.27 mmol), cuI (29 mg,0.15 mmol) and PdCl 2(PPh3)2 (110 mg,0.157 mmol) were added to 5mL DMF and reacted under nitrogen at 55℃for 5h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 50mL of a mixed solvent of methylene chloride/methanol (v/v) =5:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation with a silica gel column (petroleum ether/ethyl acetate (v/v) =1:1.5), and the obtained crude product was subjected to Pre-HPLC (instrument and preparation column: preparation of liquid phase using Glison GX-281, preparation column model: sunfire C18,5 μm, inner diameter×length=30mm×150mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% tfa). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 5% gradient (elution time 15 min) and lyophilized to give the trifluoroacetate salt of compound 61 (210 mg).
1H NMR(400MHz,CDCl3)δ9.16(s,1H),8.63(d,1H),7.96(s,1H),7.83–7.75(m,1H),7.70(d,1H),7.55–7.38(m,4H),7.30–7.20(m,1H),6.86(d,1H),6.61(dd,1H),5.24–5.10(m,1H),5.01–4.87(m,1H),4.53–4.41(m,2H),4.30–4.17(m,2H),4.17–3.93(m,2H),2.97–2.36(m,6H),2.36–2.21(m,1H),2.21–2.07(m,1H).
Example 62: preparation of trifluoroacetate salt of Compound 62
The first step: 62b preparation
62A (0.65 g,2.90 mmol) was dissolved in 10mL DCM and DMAP (71 mg,0.58 mmol) and (Boc) 2 O (0.69 g,3.16 mmol) were added and reacted at room temperature for 4h. To the reaction solution were added 20mL of methylene chloride and 30mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1-1:1) to give 62b (0.8 g, yield: 85%).
And a second step of: 62c preparation
62B (0.4 g,1.23 mmol), zinc cyanide (0.14 g,1.19 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (CAS: 161265-03-8) (71 mg,0.12 mmol) and bis (dibenzylacetone) palladium (CAS: 32005-36-0) (71 mg,0.125 mmol) were dissolved in 5mL DMF and N, N, N ', N' -tetramethyl ethylenediamine (0.57 g,4.91 mmol) was added and reacted at 100℃for 18h. The reaction solution was cooled to room temperature, 50mL of saturated aqueous sodium chloride solution was then added, extraction was performed with 60mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 62c (0.22 g, yield: 68%).
LCMS m/z＝271.4[M+1]+
And a third step of: 62d preparation
62C (0.22 g,0.81 mmol) was dissolved in 2mL DCM and 2mL trifluoroacetic acid was added and reacted at room temperature for 3.5h. To the reaction solution was added 5mL of water, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extraction was performed three times with 20mL of methylene chloride, and the organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 62d (0.11 g).
The synthesis of example 7 was followed to give the trifluoroacetate salt of compound 62 (19 mg) starting from 62d+2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid.
1H NMR(400MHz,CDCl3)δ8.35(d,1H),8.00(s,1H),7.72–7.59(m,3H),7.48(dd,1H),6.82(dd,2H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.27(m,2H),4.13–4.01(m,2H),3.88–3.72(m,1H),3.10(s,2H),2.95–2.69(m,3H),2.18–2.07(m,1H),1.87(s,6H),1.04–0.84(m,4H).
LCMS m/z＝642.3[M+1]+
Example 63: preparation of trifluoroacetate salt of Compound 63
Starting from compound 63a+2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid, reference example 19 gave trifluoroacetate salt of compound 63 (110 mg)
1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.10–8.02(m,1H),7.91(s,1H),7.76(s,1H),7.71(s,1H),7.60(d,1H),7.21–7.13(m,2H),6.77–6.70(m,1H),6.48(dd,1H),4.91–4.81(m,1H),4.33–4.22(m,2H),4.05–3.95(m,2H),3.80–3.67(m,1H),2.90–2.57(m,3H),2.12–2.00(m,1H),1.87(s,6H),1.83–1.73(m,1H),0.97–0.88(m,2H),0.61–0.54(m,2H).
LCMS m/z＝630.2[M+1]+
Example 64: preparation of Compound 64
The first step: 64b preparation
64A (3.52 g,20.0 mmol), triphenylphosphine (15.73 g,59.97 mmol) and potassium iodide (6.64 g,40.0 mmol) were added to 60mL of acetonitrile, reacted at 70℃for 30min under nitrogen atmosphere, cooled to room temperature, slowly added dropwise a solution of methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (6.72 g,34.98 mmol) in 20mL of acetonitrile, and reacted at 70℃for 3h under nitrogen atmosphere. The reaction system was cooled to room temperature, 80mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (pure petroleum ether) to give 64b (0.34 g, yield: 7%).
And a second step of: 64c preparation
64B (0.2 g,0.87 mmol) was dissolved in 5mL of ethanol, and 2mL of a saturated aqueous ammonium chloride solution and reduced iron powder (0.49 g,8.75 mmol) were added and reacted under reflux for 2h. The reaction system was cooled to room temperature, filtered, the filtrate was extracted with 100mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =5:1) to give 64c (0.16 g, yield: 92%).
LCMS m/z＝201.1[M+1]+
Using the compound 64c as a starting material, compound 64 (0.110 g) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ9.25(s,1H),8.15(d,1H),7.98(s,1H),7.83–7.75(m,2H),7.71–7.60(m,2H),7.58–7.52(m,1H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.12–4.01(m,2H),3.88–3.75(m,1H),3.30(q,2H),2.95–2.65(m,3H),2.17–2.06(m,1H),1.93(s,6H).
Example 65: preparation of Compound 65 trifluoroacetate salt
Starting from 65b, reference example 19 preparation, acidic preparation [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 65 (20 mg).
Free base of compound 65 starting from compound 65b, reference is made to the preparation method of example 19, neutral preparation [ mobile phase system: acetonitrile/water (containing 10mmol/L ammonium bicarbonate) was lyophilized.
Compound 65 free base nuclear magnetic data:
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.02(s,1H),7.96(d,1H),7.80(s,1H),7.70(s,1H),7.67(d,1H),6.88(dd,1H),6.84–6.77(m,2H),6.55(dd,1H),4.99–4.88(m,1H),4.40–4.30(m,2H),4.13–4.00(m,2H),3.88–3.73(m,1H),2.94–2.64(m,3H),2.20–2.05(m,1H),1.94(s,6H),1.85–1.73(m,1H),1.53–1.41(m,1H),0.95–0.77(m,4H),0.65–0.55(m,2H),0.55–0.47(m,2H).
LCMS m/z＝645.3[M+1]+
example 66: preparation of Compound 66
The first step: 66c preparation
To the reaction flask were added 1-chloro-N, N, 2-trimethylpropenamine (0.72 g,5.39 mmol), 2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid (1.00 g,3.57 mmol) and DCM (20 mL), and after stirring at room temperature for 1H, TEA (1.48 mL,10.65 mmol) and 66b (0.56 g,3.54 mmol) were added in this order, and reacted at room temperature for 1H. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:5) to give 66c (1.05 g, yield: 71%).
LCMS m/z＝421.0[M+1]+
And a second step of: 66e preparation
66D (7.6 g,49.96 mmol) was dissolved in 100mL DMSO and DIPEA (16.15 g,125.00 mmol) and 3-ethynylazetidine hydrochloride (8.82 g,75.01 mmol) were added and reacted at 120℃for 3h. The reaction solution was cooled to room temperature, the reaction system was slowly poured into 800mL of water, filtered, the cake was collected, washed with 20mL of water, and the cake was air-dried to give crude 66e (6.9 g).
And a third step of: preparation of 66f
The crude 66e (6.5 g) was suspended in a mixed solvent of 100mL THF, 50mL methanol and 50mL water, and lithium hydroxide monohydrate (3.84 g,91.52 mmol) was added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, 100mL of water was added to the residue, the pH of the system was adjusted to 3 with concentrated hydrochloric acid, solids were precipitated, filtration was performed, a cake was collected, the cake was washed with 20mL of water, and the cake was air-dried to give crude 66f (5.8 g).
LCMS m/z＝232.2[M+1]+
Fourth step: preparation of 66g
The crude 66f (5.8 g) was dissolved in 200mL DCM, imidazole (5.13 g,75.35 mmol) was added, cooled to 0deg.C, TBSCl (5.67 g,37.62 mmol) was added slowly in portions and reacted at room temperature for 16h. 200mL of water was added to the reaction system, the pH of the system was adjusted to 3 with concentrated hydrochloric acid, the mixture was extracted with 100mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane/methanol (v/v) =15:1) to give 66g (8.5 g, three-step yield from compound 66 d: 52%).
LCMS m/z＝346.2[M+1]+
Fifth step: preparation for 66h
66G (7.5 g,21.73 mmol) was dissolved in 80mL DMF, HATU (0.51 g,1.34 mmol) and DIPEA (11.22 g,86.81 mmol) were added and after 30min at RT 3-aminopiperidine-2, 6-dione hydrochloride (4.29 g,26.06 mmol) was added and reacted at RT for 16h. 250mL of water was added to the reaction system, extracted with 200mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (dichloromethane/methanol (v/v) =15:1) to give 66h (6.2 g, yield: 63%).
LCMS m/z＝456.3[M+1]+
Sixth step: preparation of 66i
66H (6.2 g,13.62 mmol) was dissolved in 100mL THF and tetrabutylammonium fluoride trihydrate (6.44 g,20.41 mmol) was added and reacted at room temperature for 0.5h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:2) to give 66i (4.0 g, yield: 86%).
Seventh step: preparation of 66j
66I (4.0 g,11.72 mmol) was dissolved in 200mL DCM and triethylamine (4.74 g,46.84 mmol) was added and p-toluenesulfonyl chloride (2.9 g,15.21 mmol) was added and reacted at 40℃for 16h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) =15:1) to give 66j (3.3 g, yield: 87%).
LCMS m/z＝324.1[M+1]+
Eighth step: preparation of Compound 66
66J (0.2 g,0.62 mmol) and 66c (0.39 g,0.93 mmol) were dissolved in 8mL DMF, TEA (0.19 g,1.88 mmol) was added, nitrogen was replaced three times, cuI (12 mg,0.063 mmol) and PdCl 2(PPh3)2 (44 mg,0.063 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 50℃for 1.5h. The reaction solution was cooled to room temperature, 60mL of water was then added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:2), to give compound 66 (0.065 g, yield: 17%).
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.37(d,1H),7.87–7.76(m,2H),7.71(s,1H),7.49(dd,1H),7.40–7.35(m,1H),6.47(dd,1H),6.32–6.26(m,1H),5.41–5.24(m,2H),4.77–4.69(m,1H),4.37–4.24(m,2H),4.07–3.94(m,2H),3.84–3.70(m,1H),3.02–2.87(m,1H),2.73–2.15(m,3H),1.95(s,6H),1.57–1.44(m,1H),1.03–0.92(m,2H),0.61–0.54(m,2H).
LCMS m/z＝616.8[M+1]+
Example 67: preparation of Compound 67
The first step: 67c preparation
67A (2.95 g,10.68 mmol) was dissolved in 50mL DMSO, the above crude 67b hydrochloride (1.7 g) was added, DIPEA (4.14 g,32.03 mmol) was added and reacted at 80℃for 3h. The reaction was cooled to room temperature, slowly poured into 400mL of water, filtered, the filter cake was washed with 20mL of water, and the filter cake was dried under reduced pressure to give crude 67c (1.7 g).
And a second step of: preparation of Compound 67
The crude 67c (0.2 g), 2c (0.32 g,0.68 mmol) and TEA (0.17 g,1.68 mmol) were added to 5mL of DMF, nitrogen was replaced three times, and CuI (11 mg,0.058 mmol) and PdCl 2(PPh3)2 (40 mg,0.057 mmol) were added and reacted under nitrogen atmosphere at 50℃for 1.5h. The reaction solution was cooled to room temperature, 60mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:2) to give compound 67 (110 mg, yield: 23%).
1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.54(d,1H),8.02(s,1H),7.71(s,1H),7.64(d,1H),7.61–7.55(m,2H),7.50(dd,1H),6.79(d,1H),6.52(dd,1H),4.97–4.89(m,1H),4.24–4.12(m,2H),3.89–3.80(m,2H),3.12–2.98(m,3H),2.94–2.65(m,7H),2.28–1.98(m,3H).
Example 68: preparation of Compound 68
The first step: 68c preparation
To the reaction flask were added 1-chloro-N, N, 2-trimethylpropenamine (0.72 g,5.38 mmol), 2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanoic acid (1.00 g,3.58 mmol) and DCM (20 mL), and after stirring at room temperature for 1H, TEA (1.48 mL,10.65 mmol) and 68b (0.56 g,3.54 mmol) were added in this order, and reacted at room temperature for 1H. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:5) to give 68c (1.05 g, yield: 71%).
LCMS m/z＝421.0[M+1]+。
Using the compound 68c+67c as a starting material, compound 68 (130 mg) was obtained in referential example 67.
1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.36(d,1H),8.02(s,1H),7.71–7.60(m,3H),7.48(dd,1H),7.40–7.33(m,1H),6.82–6.76(m,1H),6.56–6.48(m,1H),4.98–4.88(m,1H),4.24–4.12(m,2H),3.90–3.79(m,2H),3.14–3.00(m,1H),2.95–2.65(m,5H),2.17–2.07(m,1H),1.93(s,6H),1.53–1.42(m,1H),1.00–0.90(m,2H),0.61–0.51(m,2H).
Example 69: preparation of Compound 69
Using this compound 69a as a starting material, compound 69 (0.20 g) was obtained in referential example 22.
1H NMR(400MHz,CDCl3)δ8.12(s,1H),7.94(s,1H),7.76(s,1H),7.72–7.62(m,2H),7.44–7.37(m,2H),7.32–7.23(m,2H),7.08(t,1H),6.80(s,1H),6.58–6.52(m,1H),4.93(dd,1H),4.40–4.30(m,2H),4.12–4.01(m,2H),3.87–3.74(m,1H),3.14–2.97(m,2H),2.95–2.64(m,5H),2.27–1.96(m,3H).
LCMS m/z＝577.2[M+1]+
Example 70: preparation of Compound 70
The first step: 70b preparation
2C (1.0 g,2.13 mmol), 70a (1.30 g,10.63 mmol) (see WO 2018052949) and triethylamine (1.05 g,10.38 mmol) were dissolved in 20mL DCM, nitrogen was replaced three times, cuI (40.6 mg,0.213 mmol) and PdCl 2(PPh3)2 (150 mg,0.214 mmol) were added and reacted at room temperature under nitrogen for 16h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to give 70b (0.3 g, yield: 30%).
And a second step of: 70c preparation
70B (0.15 g,0.32 mmol) was dissolved in 5mL THF and tetrabutylammonium fluoride trihydrate (0.20 g,0.63 mmol) was added and reacted at room temperature for 0.5h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1) to give 70c (0.12 g, yield: 96%).
And a third step of: preparation of Compound 70
70C (0.12 g,0.31 mmol), 70A (0.16 g,0.47 mmol) and TEA (0.10 g,0.99 mmol) were added to 5mL of DMF, nitrogen was replaced three times, cuI (6 mg,0.032 mmol) and PdCl 2(PPh3)2 (22 mg,0.031 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 50℃for 1.5h. The reaction solution was cooled to room temperature, 60mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:2) to give compound 70 (30 mg, yield: 15%).
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.55(d,1H),8.02–7.80(m,6H),7.64–7.57(m,1H),7.56–7.48(m,1H),5.04–4.92(m,1H),3.18–3.03(m,2H),2.99–2.67(m,5H),2.34–1.99(m,3H).
Example 71: preparation of Compound 71
The first step: 71b preparation
71A (5.0 g,20.49 mmol) was dissolved in 80mL THF, cooled to 0deg.C under nitrogen, 60% sodium hydride (1.23 g) was slowly added in portions, stirred at room temperature for 1h, then SEMCl (5.12 g,30.71 mmol) was added and reacted at room temperature for 16h. 200mL of saturated aqueous ammonium chloride was added, extracted with 200mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether) to give 71b (7.0 g, yield: 91%).
LCMS m/z＝375.3[M+1]+
And a second step of: 71c preparation
71B (7.0 g,18.7 mmol) was dissolved in 80mL of DMSO, 3-ethynylazetidine hydrochloride (5.02 g,42.69 mmol) and potassium carbonate (8.86 g,64.11 mmol) were added, nitrogen was replaced three times, cuI (0.81 g,4.25 mmol) and L-proline (0.98 g,8.51 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 100℃for 16h. The reaction system was cooled to room temperature, added to 60mL of water, extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether/ethyl acetate (v/v) =10:1) to give 71c (3.7 g, yield: 60%).
LCMS m/z＝328.2[M+1]+
And a third step of: 71d preparation
71C (1.5 g,4.58 mmol) was dissolved in 20mL THF and tetrabutylammonium fluoride trihydrate (14.45 g,45.81 mmol) was added and reacted at 70℃for 16h. The reaction solution was cooled to room temperature, 50mL of water was added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane/methanol (v/v) =15:1), to give 71d (800 mg, yield: 89%).
LCMS m/z＝198.3[M+1]+
Fourth step: 71e-1 and 71e-2
71D (0.8 g,4.05 mmol) was dissolved in 20mL DMF and cooled to 0deg.C under nitrogen, 60% sodium hydride (0.32 g) was added slowly in portions and after stirring at room temperature for 1h 3-bromopiperidine-2, 6-dione (1.00 g,5.21 mmol) was added and reacted at room temperature for 16h. 200mL of saturated aqueous ammonium chloride solution was added to the reaction system, extracted with 200mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by separation with a silica gel column (dichloromethane/methanol (v/v) =15:1), and the obtained crude product was subjected to Pre-HPLC (instrument and preparation column: preparation of liquid phase using Glison GX-281, preparation column model was Sunfire C18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05mol/L ammonium acetate). The gradient elution method comprises the following steps: acetonitrile was eluted by a gradient of 10% (elution time 15 min), and lyophilized to give 71e-1 (0.14 g, yield: 11%) and 71e-2 (0.18 g, yield: 14%) respectively.
Elution time of 71 e-1: 13min;
elution time of 71 e-2: 14min.
Fifth step: preparation of Compound 71
71E-1 (0.07 g,0.23 mmol), 2c (0.13 g,0.28 mmol) and TEA (0.07 g,0.69 mmol) were added to 5mL of DMF, nitrogen was replaced three times, and CuI (5 mg,0.026 mmol) and PdCl 2(PPh3)2 (16 mg,0.023 mmol) were added and reacted under nitrogen atmosphere at 50℃for 1.5h. The reaction solution was cooled to room temperature, 60mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 50mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:2) to give compound 71 (35 mg, yield: 23.41%).
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.54(d,1H),8.00(s,1H),7.83(s,1H),7.77(s,1H),7.68(s,1H),7.63–7.55(m,2H),7.53–7.47(m,1H),6.83–6.70(m,1H),6.51(s,1H),5.29–5.18(m,1H),4.29–4.17(m,2H),3.94–3.83(m,2H),3.79–3.65(m,1H),3.14–3.00(m,3H),2.94–2.70(m,4H),2.60–2.47(m,1H),2.30–2.15(m,1H),2.15–2.02(m,1H).
Example 72: preparation of Compound 72
Using the compound 71e-2 as a starting material, a compound 72 (85 mg) was obtained in referential example 71.
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.54(d,1H),8.10(s,1H),7.91(s,1H),7.77(s,1H),7.68(s,1H),7.60–7.55(m,1H),7.53–7.46(m,1H),7.29–7.23(m,1H),6.79–6.67(m,2H),5.32–5.22(m,1H),4.30–4.18(m,2H),3.93–3.82(m,2H),3.80–3.67(m,1H),3.14–2.98(m,3H),2.91–2.67(m,4H),2.52–2.38(m,1H),2.30–2.01(m,2H).
Example 73: preparation of Compound 73
The first step: 73b synthesis
73A (375 mg,2.00 mmol) was dissolved in 10mL dichloromethane, 73A (0.59 g,2.43 mmol) and TCFH (0.85 g,3.03 mmol) were added, NMI (0.66 g,8.04 mmol) was added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, 50mL of saturated aqueous sodium hydrogencarbonate solution was added, extraction was performed with 100mL of methylene chloride, the organic phase was washed with 25mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give 73b (800 mg, yield: 97%).
LCMS m/z＝412.0[M+1]+
Using the compound 73b as a starting material, compound 73 (50 mg) was obtained in referential example 45.
1H NMR(400MHz,CDCl3)δ8.39(d,1H),8.09(s,1H),7.67(d,1H),7.52–7.38(m,3H),7.34(s,1H),7.30–7.21(m,2H),6.85–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.17–4.05(m,2H),3.92–3.77(m,1H),3.48–3.36(m,2H),2.95–2.65(m,5H),2.18–2.05(m,1H),1.63(s,6H).
Example 74: preparation of Compound 74
Starting with compound 74a, reference example 44 gave the compound 74(0.065g).1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.50(s,1H),8.07–7.97(m,3H),7.89–7.75(m,3H),7.69(d,1H),6.89(d,1H),6.74(dd,1H),5.12–5.02(m,1H),4.49–4.37(m,2H),4.17–4.06(m,2H),4.04–3.92(m,1H),2.98–2.81(m,1H),2.65–2.45(m,2H),2.08–1.96(m,1H).
Example 75: preparation of Compound 75
Starting from compound 75a, compound 75 (0.06 g) was obtained in referential example 44.
1H NMR(400MHz,CDCl3)δ8.70(d,1H),8.45(s,1H),7.95–7.86(m,1H),7.77–7.55(m,4H),7.52–7.31(m,2H),6.88–6.80(m,1H),6.64–6.53(m,1H),4.99–4.89(m,1H),4.48–4.33(m,2H),4.20–4.06(m,2H),3.95–3.81(m,1H),2.97–2.65(m,3H),2.18–2.07(m,1H).
Example 76: preparation of Compound 76
Starting from compound 76c, compound 76 (10 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.32(d,1H),7.99(s,1H),7.82–7.76(m,2H),7.67(d,1H),7.29–7.23(m,1H),7.21–7.13(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.40–4.30(m,2H),4.13–4.00(m,2H),3.88–3.75(m,1H),3.28(q,2H),2.95–2.65(m,3H),2.18–2.07(m,1H),1.94(s,6H).
Example 77: preparation of Compound 77
Using the compound 71e-2 as a starting material, compound 77 (80 mg) was obtained in referential example 71.
1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.37(d,1H),8.02(s,1H),7.91(s,1H),7.78(s,1H),7.70(s,1H),7.48(dd,1H),7.39–7.34(m,1H),7.31–7.24(m,1H),6.81–6.67(m,2H),5.33–5.22(m,1H),4.30–4.18(m,2H),3.94–3.83(m,2H),2.99–3.67(m,1H),3.13–3.00(m,1H),2.92–2.72(m,2H),2.53–2.40(m,1H),1.95(s,6H),1.55–1.42(m,1H),1.04–0.92(m,2H),0.60–0.52(m,2H).
Example 78: preparation of Compound 78
Using the compound 71e-1 as a starting material, a compound 78 (40 mg) was obtained in referential example 71.
1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.37(d,1H),8.16(s,1H),7.82(s,1H),7.78(s,1H),7.70(s,1H),7.60(d,1H),7.48(dd,1H),7.40–7.33(m,1H),6.75(dd,1H),6.47(s,1H),5.28–5.19(m,1H),4.28–4.17(m,2H),3.93–3.81(m,2H),3.77–3.64(m,1H),3.14–3.01(m,1H),2.94–2.70(m,2H),2.59–2.47(m,1H),1.95(s,6H),1.55–1.43(m,1H),1.02–0.92(m,2H),0.60–0.52(m,2H).
Example 79: preparation of Compound 79
Using the compound 79b as a starting material, compound 79 (380 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.15(s,1H),7.87(d,1H),7.78(s,1H),7.74(s,1H),7.67(d,1H),7.30–7.23(m,1H),7.19(dd,1H),6.83–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.14–4.02(m,2H),3.89–3.74(m,1H),2.94–2.65(m,3H),2.19–2.06(m,1H),1.98–1.82(m,7H),1.04–0.92(m,2H),0.72–0.62(m,2H).
LCMS m/z＝673.2[M+1]+
Example 80: preparation of Compound 80
Using the compound 80b as a starting material, compound 80 (150 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.13(d,1H),8.04(s,1H),7.82–7.74(m,2H),7.67(d,1H),7.04–6.99(m,1H),6.94(dd,1H),6.81(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.64(m,3H),2.20–2.06(m,1H),1.94(s,6H),1.87–1.75(m,1H),0.98–0.87(m,2H),0.67–0.57(m,2H).
LCMS m/z＝639.2[M+1]+
Example 81: preparation of Compound 81
The first step: 81b preparation
60% Sodium hydride (3.4 g) was added to 60mL of DMF under nitrogen, cooled to 0℃and diethyl malonate (6.8 g,42.45 mmol) was slowly added dropwise, and after 30min of reaction at 0℃the reaction was allowed to proceed at room temperature for 30min. 81a (6.0 g,28.7 mmol) was slowly added dropwise at 0deg.C and reacted at room temperature for 3h. 10mL of water was added to the reaction system at 0deg.C, extracted with ethyl acetate (80 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (60 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give crude product 81b (10.5 g).
And a second step of: 81c preparation
The crude 81b (10.5 g) was dissolved in a mixed solvent of 60mL glacial acetic acid and 30mL concentrated hydrochloric acid, and reacted at 100℃for 16h. The reaction system was cooled to room temperature, water (400 mL) was added, extraction was performed with ethyl acetate (90 ml×2), the organic phase was washed with saturated aqueous sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give a crude product (5.2 g). The crude product (5.2 g) was dissolved in 80mL of methanol, thionyl chloride (3 mL) was slowly added dropwise at 0℃and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give 81c (3.3 g, two-step yield from compound 81 a: 44%).
LCMS m/z＝264.1[M+1]+
And a third step of: 81d preparation
81C (3.3 g,12.5 mmol) was dissolved in 40mL DMF under nitrogen, 60% sodium hydride (2.0 g) was added slowly in portions at 0deg.C, after 30min at 0deg.C, 1h at RT, methyl iodide (6.1 g,42.98 mmol) was added slowly at 0deg.C, and the reaction was carried out at RT for 3h. Water (150 mL) was added to the reaction system, extracted with ethyl acetate (60 mL. Times.2), the organic phase was washed with saturated aqueous sodium chloride (80 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give 81d (2.6 g, yield: 71%).
LCMS m/z＝292.1[M+1]+
Fourth step: 81e preparation
81D (2.6 g,8.93 mmol) was added to a 250mL single-necked flask, ethanol (50 mL), water (10 mL), ammonium chloride (2.4 g,44.9 mmol) and reduced iron powder (2.5 g,44.64 mmol) were sequentially added and reacted at 70℃for 4h. The reaction system was cooled to room temperature, filtered through celite, water (200 mL) was added to the filtrate, extracted with ethyl acetate (80 mL. Times.2), the organic phase was washed with saturated aqueous sodium chloride (60 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =73:27) to give 81e (2.2 g, yield: 94%).
LCMS m/z＝262.1[M+1]+
Fifth step: 81f preparation
81E (1.2 g,4.59 mmol) was dissolved in toluene (10 mL) and water (10 mL), concentrated hydrochloric acid (3 mL) was added at 0deg.C, sodium nitrite (380 mg,5.51 mmol) was slowly added after stirring for 10min, and reacted at 0-5deg.C for 30min, 10mL aqueous potassium iodide (1.5 g,9.04 mmol) was added and reacted at room temperature for 2h. Water (50 mL) was added to the reaction system, extracted with ethyl acetate (40 mL. Times.2), the organic phase was washed with saturated sodium thiosulfate solution (40 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =92:8) to give 81f (1.5 g, yield: 88%).
LCMS m/z＝373.1[M+1]+
Sixth step: preparation of 81g
81F (1.5 g,4.03 mmol) was added to a 100mL single-necked flask, tetrahydrofuran (60 mL), water (6 mL) and lithium hydroxide monohydrate (850 mg,20.26 mmol) were added in this order, and the mixture was reacted at room temperature for 16h. The reaction system was adjusted to pH 5 with 0.5mol/L hydrochloric acid, extracted with ethyl acetate (30 mL. Times.2), the organic phase was washed with saturated aqueous sodium chloride (40 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =72:28) to give a crude product (1.1 g). The crude product (0.1 g) was dissolved in10 mL of methylene chloride, and 66b (45 mg,0.28 mmol), TCFH (118 mg,0.42 mmol) and N-methylimidazole (92 mg,1.12 mmol) were added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =84:16) to give 81g (90 mg, yield: 65%).
LCMS m/z＝499.1[M+1]+
Seventh step: preparation of Compound 81
81G (90 mg,0.18 mmol) was added to a 50mL single-necked flask, dried DMF (12 mL), crude intermediate 1 (91 mg) above and TEA (54 mg,0.53 mmol) were added sequentially, nitrogen was replaced three times, pdCl 2(PPh3)2 (13 mg,0.019 mmol) and CuI (6 mg,0.032 mmol) were added, nitrogen was replaced three times, and the reaction was carried out at 60℃for 2 hours. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (150 mL) was slowly added, extraction was performed with ethyl acetate (30 ml×2), the organic phase was washed with a saturated aqueous sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =23:77) to give compound 81 (60 mg, yield: 47%).
1H NMR(400MHz,CDCl3)δ8.43(d,1H),7.93(s,1H),7.78–7.66(m,3H),7.63–7.56(m,2H),7.56–7.48(m,1H),7.41–7.35(m,1H),6.86–6.80(m,1H),6.58(dd,1H),4.98–4.89(m,1H),4,47–4.35(m,2H),4.18–4.06(m,2H),3.97–3.84(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.73(s,6H),1.28–1.17(m,1H),0.62–0.53(m,2H),0.40–0.32(m,2H).
LCMS m/z＝706.8[M-1]-
Example 82: preparation of Compound 82
LCMS m/z＝271.1[M+1]+
The first step: 82c preparation
82B (0.3 g,1.11 mmol) was dissolved in 15mL acetonitrile, 28B (390 mg,1.094 mmol) and cesium carbonate (719mg, 2.19 mmol) were added sequentially and reacted at 90℃for 16h. The reaction system was cooled to room temperature, 150mL of water was added, extraction was performed with ethyl acetate (50 ml×2), the organic phase was washed with saturated aqueous sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =80:20) to give 82c (50 mg, yield: 8%).
LCMS m/z＝546.1[M+1]+
Starting from 82c and intermediate 1, compound 82 (35 mg) was obtained according to the seventh preparation method of compound 81.
1H NMR(400MHz,CDCl3)δ9.02(s,1H),8.59–8.52(m,1H),8.17–8.09(m,2H),7.93(s,1H),7.79(s,1H),7.73–7.65(m,1H),7.54–7.34(m,5H),6.84–6.79(m,1H),6.56(dd,1H),4.99–4.89(m,1H),4.43–4.32(m,2H),4.14–4.04(m,2H),3.94–3.81(m,1H),3.17–3.03(m,2H),2.95–2.63(m,5H),2.32–2.05(m,3H).
Examples 83 and 84: preparation of Compound 83 and Compound 84
The first step: 83a preparation
To the reaction flask were added 2-bromo-2-methylpropanoic acid (1.5 g,8.98 mmol) and 10mL of dichloromethane, 1-chloro-N, N, 2-trimethylpropenamine (1.80 g,13.47 mmol) and, after stirring at room temperature for 1h, TEA (2.72 g,26.88 mmol) and 16B (1.70 g,10.75 mmol) were added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20) to give 83a (1.46 g, yield: 53%).
And a second step of: 83b-1 and 83b-2 preparation
To the reaction flask were added 3-iodo-1H-pyrazole (1.0 g,5.16 mmol), 83a (1.91 g,6.22 mmol), cesium carbonate (3.37 g,10.34 mmol) and 15mL acetonitrile, respectively, and reacted at 50℃for 4 hours. The reaction system was cooled to room temperature, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20) to give a mixture (1.0 g) of crude products 83b-1 and 83 b-2.
And a third step of: preparation of Compound 83 and Compound 84
A mixture (0.50 g) of the above crude products 83b-1 and 83b-2, the above crude intermediate 1 (0.60 g), pdCl 2(PPh3)2 (83 mg,0.12 mmol), cuI (45 mg,0.24 mmol) and DIPEA (0.46 g,3.56 mmol) were added separately to the reaction flask under nitrogen atmosphere, and 10mL of DMF was added and reacted at 60℃for 5 hours. The reaction system was cooled to room temperature, added to 40mL of water, filtered, and the filter cake was subjected to SFC (instrument and preparation column: preparation of liquid phase using SFC Prep 150AP, preparation column model: torus DEA, inner diameter. Times. Length=19 mm. Times. 250 mm). The preparation method comprises the following steps: the crude DMF solution was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: carbon dioxide/methanol. The elution method comprises the following steps: isocratic elution, mobile phase methanol content 35%, flow 30mL/min. Thus, compound 83 (elution time: 8.12 min) (25 mg, two-step yield: 13% from compound 83 a) and compound 84 (elution time: 9.87 min) (60 mg, two-step yield: 31% from compound 83 a) were obtained.
Nuclear magnetic data of compound 83:
1H NMR(400MHz,CDCl3)δ8.32(d,1H),7.96(d,2H),7.71(d,1H),7.59(d,1H),7.36–7.30(m,1H),7.22(dd,1H),6.67(d,1H),6.57(d,1H),6.46(dd,1H),4.96(dd,1H),4.23–4.16(m,2H),3.86–3.77(m,2H),3.73–3.64(m,1H),2.97–2.65(m,3H),2.25–2.15(m,1H),1.97(s,6H),1.36–1.26(m,1H),0.70–0.60(m,2H),0.45–0.34(m,2H).
LCMS m/z＝630.5[M+1]+
nuclear magnetic data of compound 84:
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.39(d,1H),7.98(s,1H),7.69(d,1H),7.66(d,1H),7.48(dd,1H),7.38–7.34(m,1H),6.83(d,1H),6.58(dd,1H),6.49(d,1H),4.95(dd,1H),4.43–4.35(m,2H),4.14–4.07(m,2H),3.89–3.78(m,1H),2.98–2.65(m,3H),2.19–2.10(m,1H),1.97(s,6H),1.58–1.46(m,1H),1.08–1.02(m,2H),0.60–0.54(m,2H).
LCMS m/z＝630.5[M+1]+
Example 85: preparation of Compound 85
Using the compound 85d as a starting material, reference example 81 gave compound 85 (13 mg).
1H NMR(400MHz,CDCl3)δ8.48(d,1H),7.97(s,1H),7.90(s,1H),7.69(d,1H),7.56–7.28(m,4H),7.15(dd,1H),6.85–6.80(m,1H),6.58(dd,1H),5.00–4.90(m,1H),4.44–4.34(m,2H),4.17–4.05(m,2H),3.92–3.80(m,1H),2.97–2.65(m,3H),2.21–2.07(m,1H),1.69(s,6H),1.34–1.22(m,1H),0.57–0.48(m,2H),0.41–0.33(m,2H).
Example 86: preparation of Compound 86
Using the compound 88b as a starting material, referential example 50 gave compound 86 (0.07 g).
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.41(d,1H),8.02(s,1H),7.96–7.90(m,2H),7.69(d,1H),7.54–7.42(m,3H),7.39–7.34(m,1H),7.32–7.26(m,2H),7.03–6.96(m,1H),6.73(dd,1H),4.99–4.89(m,1H),3.94–3.82(m,1H),3.74–3.43(m,4H),2.95–2.66(m,3H),2.60–2.44(m,1H),2.31–2.08(m,2H),2.02(s,6H),1.59–1.46(m,1H),1.02–0.90(m,2H),0.60–0.52(m,2H).
Example 87: preparation of Compound 87
Starting from compound 90b, reference example 50 gave compound 87 (0.06 g).
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.58(d,1H),8.10–7.96(m,2H),7.81(s,1H),7.71(d,1H),7.60–7.41(m,4H),7.36(s,1H),7.27–7.21(m,2H),7.16(d,1H),5.00–4.91(m,1H),4.18–4.02(m,2H),3.20–3.00(m,4H),2.98–2.65(m,6H),2.35–1.77(m,7H).
Example 88: preparation of Compound 88
Using the compound 88b as a starting material, compound 88 (0.07 g) was obtained in referential example 50.
1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.58(d,1H),8.01(s,2H),7.83(s,1H),7.69(d,1H),7.62–7.42(m,4H),7.32–7.26(m,2H),7.03–6.95(m,1H),6.73(dd,1H),5.00–4.88(m,1H),3.93–3.80(m,1H),3.73–3.42(m,4H),3.19–3.05(m,2H),2.96–2.64(m,5H),2.58–2.44(m,1H),2.38–2.02(m,4H).
Example 89: preparation of Compound 89
Using the compound 89c as a starting material, referential example 81 gave compound 89 (75 mg).
1H NMR(400MHz,CDCl3)δ9.89(s,1H),8.64–8.58(m,1H),8.42(d,1H),7.95(s,1H),7.80–7.63(m,2H),7.52–7.35(m,3H),6.87–6.80(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.45–4.35(m,2H),4.18–4.07(m,2H),3.94–3.82(m,1H),2.96–2.66(m,3H),2.19–2.08(m,1H),1.77(s,6H),1.73–1.63(m,1H),1.13–1.02(m,2H),0.70–0.62(m,2H).
LCMS m/z＝641.2[M+1]+
Example 90: preparation of Compound 90
Using the compound 90b as a starting material, referential example 50 gave compound 90 (0.085 g).
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.41(d,1H),8.11(s,1H),7.91(d,2H),7.70(d,1H),7.53–7.40(m,3H),7.39–7.30(m,2H),7.27–7.20(m,2H),7.11(dd,1H),5.00–4.90(m,1H),4.18–4.02(m,2H),3.20–3.02(m,2H),2.97–2.65(m,4H),2.20–2.08(m,1H),2.08–1.93(m,8H),1.92–1.75(m,2H),1.57–1.45(m,1H),1.02–0.90(m,2H),0.60–0.51(m,2H).
Example 91: preparation of Compound 91
The first step: 91b preparation
To the reaction flask were successively added 91A (0.20 g,1.14 mmol), 91A hydrochloride (0.16 g), cesium carbonate (1.08 g,3.31 mmol) and DMF (5 mL) and reacted at room temperature for 15h. To the reaction solution were added 30mL of ethyl acetate and 20mL of water, and the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20-1:10) to give 91b (0.22 g, yield: 84%).
And a second step of: 91c preparation
To the reaction flask were added 91b (0.22 g,0.95 mmol), zinc powder (0.62 g,9.54 mmol), ammonium chloride (0.51 g,9.53 mmol), tetrahydrofuran (9 mL) and water (3 mL), and the mixture was reacted at room temperature for 1h. The reaction system was filtered through celite, the filter cake was washed with 50mL of ethyl acetate, 50mL of water and 50mL of ethyl acetate were added to the filtrate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 91c (0.19 g).
Using the compound 91c as a starting material, compound 91 (0.12 g) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.15(s,1H),8.00(d,1H),7.82–7.74(m,2H),7.67(d,1H),6.83–6.78(m,1H),6.55(dd,1H),6.44–6.38(m,1H),6.33(dd,1H),5.52–5.25(m,1H),4.98–4.87(m,1H),4.42–4.30(m,2H),4.22–4.02(m,4H),3.98–3.73(m,3H),2.95–2.66(m,3H),2.18–2.07(m,1H),1.93(s,6H).
Example 92: preparation of Compound 92 trifluoroacetate salt
Starting from compound 92b, reference example 19 preparation, acidic preparation [ mobile phase system: acetonitrile/water (with 0.1% tfa) ], to afford the trifluoroacetate salt of compound 92 (255 mg).
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.16(d,1H),7.98(s,1H),7.83–7.74(m,2H),7.67(d,1H),7.20–7.14(m,1H),7.13–7.05(m,1H),6.84–6.76(m,1H),6.60–6.50(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.14–4.00(m,2H),3.88–3.75(m,1H),2.97–2.65(m,4H),2.20–2.07(m,1H),1.94(s,6H),1.19(d,6H).
LCMS m/z＝641.1[M+1]+
Example 93: preparation of Compound 93 trifluoroacetate salt
Starting from compound 93a, reference example 19 preparation, acidic preparation [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 93 (220 mg).
1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.16(d,1H),8.05–7.95(m,1H),7.83–7.75(m,2H),7.67(d,1H),7.13–7.07(m,1H),7.01(dd,1H),6.83–6.77(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.66(m,3H),2.39(d,2H),2.18–2.07(m,1H),1.94(s,6H),1.87–1.73(m,1H),0.86(d,6H).
LCMS m/z＝655.1[M+1]+
Example 94: preparation of Compound 94
The first step: 94b preparation
94A (0.2 g,0.9 mmol) was dissolved in 5mL toluene, 94A (0.2 g,0.91 mmol) and TEA (0.14 g,1.38 mmol) were added and reacted at 55℃for 2h. The reaction system was cooled to room temperature, suction filtered, and the cake was collected to give crude 94b (0.21 g).
LCMS m/z＝441.2[M+1]+
And a second step of: preparation of Compound 94
The crude 94b (0.289 g), crude intermediate 1 (0.33 g), TEA (0.20 g,1.98 mmol), cuI (25 mg,0.13 mmol) and PdCl 2(PPh3)2 (93 mg,0.13 mmol) were added to a reaction flask, 8mL DMF was added and reacted at 55℃under nitrogen for 3h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of a mixed solvent of DCM/MeOH (v/v) =5:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =5:1-1:1) to give compound 94 (120 mg, two-step yield from compound 94 a: 15%).
1H NMR(400MHz,CDCl3)δ8.47–8.40(m,1H),8.15(s,1H),7.68–7.57(m,2H),7.54–7.47(m,1H),7.44–7.27(m,6H),6.68–6.64(m,1H),6.51(dd,1H),5.01–4.92(m,1H),4.38–4.27(m,2H),4.14–4.01(m,2H),3.91–3.77(m,1H),2.99–2.67(m,3H),2.19–2.10(m,1H).
LCMS m/z＝650.2[M+1]+
Example 95: preparation of Compound 95 trifluoroacetate salt
Using 95b as a raw material, the preparation method of reference example 19, prepared by acidity [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 95 (215 mg).
1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.37(d,1H),7.98(s,1H),7.85–7.77(m,2H),7.67(d,1H),7.60–7.30(m,7H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.14–4.02(m,2H),3.88–3.75(m,1H),2.97–2.63(m,3H),2.18–2.08(m,1H),1.97(s,6H).
LCMS m/z＝675.3[M+1]+
Example 96: preparation of Compound 96
Using 96a as a starting material, compound 96 (0.20 g) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.43(d,1H),8.13(d,1H),7.95(s,1H),7.84(s,2H),7.80(d,1H),7.75(d,1H),7.67(d,1H),7.59–7.53(m,1H),7.49–7.43(m,1H),6.84–6.78(m,1H),6.55(dd,1H),4.97–4.89(m,1H),4.40–4.32(m,2H),4.12–4.04(m,2H),3.88–3.77(m,1H),2.95–2.62(m,3H),2.18–2.08(m,1H),1.99(s,6H).
Example 97: preparation of Compound 97
Using compound 97b as a starting material, compound 97 (220 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.91(s,1H),8.42(d,1H),7.94(s,1H),7.86(d,1H),7.83–7.74(m,3H),7.73–7.62(m,2H),7.52(dd,1H),6.84–6.77(m,1H),6.55(dd,1H),6.50–6.43(m,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.87–3.76(m,1H),2.96–2.62(m,3H),2.18–2.08(m,1H),1.96(s,6H).
Example 98: preparation of compound 98 trifluoroacetate salt
The first step: 98b preparation
98A (1.1 g,5 mmol) was added to 20mL of DMF, 28B (2.2 g,6.17 mmol) and cesium carbonate (3.3 g,10.1 mmol) were added and reacted at 85℃for 3h. The reaction solution was cooled to room temperature, 100mL of ethyl acetate and 200mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =3:1) to give 98b (0.6 g, yield: 24%).
And a second step of: preparation of compound 98 trifluoroacetate salt
98B (0.2 g,0.4 mmol) was dissolved in 5mL DMF and the crude intermediate 1 (0.17 g), TEA (0.1 g,0.99 mmol), cuI (0.019 g,0.1 mmol) and PdCl 2(PPh3)2 (0.07 g,0.1 mmol) were added sequentially and reacted under nitrogen at 95℃for 1h. The reaction solution was cooled to room temperature, 20mL of water was added, filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 30mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:3), and the obtained crude product was subjected to Pre-HPLC (instrument and preparative column: preparation of liquid phase using Glison GX-281, preparative column model is Sunfire C18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% tfa). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 5% gradient (elution time 15 min) and lyophilized to give the trifluoroacetate salt of compound 98 (0.02 g).
1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.51(d,1H),8.09(s,1H),7.98(s,1H),7.70(d,1H),7.65–7.58(m,1H),7.57–7.49(m,1H),6.88–6.80(m,1H),6.59(dd,1H),4.99–4.89(m,1H),4.48–4.37(m,2H),4.23–4.11(m,2H),3.98–3.87(m,1H),3.20–2.66(m,7H),2.33–2.04(m,3H).
Example 99: preparation of Compound 99 trifluoroacetate salt
Using 99b as a raw material, the preparation method of reference example 92, prepared by acidity [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 99 (185 mg).
1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.19–8.08(m,2H),7.84–7.75(m,2H),7.67(d,1H),7.17–7.12(m,1H),7.09–7.03(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.40–4.30(m,2H),4.13–4.02(m,2H),3.87–3.75(m,1H),2.95–2.65(m,3H),2.57(q,2H),2.20–2.05(m,1H),1.94(s,6H),1.18(t,3H).
LCMS m/z＝627.0[M+1]+
Examples 100 and 101: preparation of Compounds 100 and 101
Starting from compound 100a, reference examples 83 and 84 gave compound 100 and compound 101
The purification method of the final product comprises the following steps: SFC (instrument and preparation column: preparation of liquid phase using SFC Prep 150 AP, preparation column model was xylonite Torrs 2-pic, inner diameter. Times. Length=19 mm. Times.250 mm). The preparation method comprises the following steps: the crude methanol solution was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: carbon dioxide/methanol. The elution method comprises the following steps: isocratic elution, mobile phase methanol content 20%, flow 40mL/min, respectively obtained compound 100 (elution time 7.57 min) (50 mg) and compound 101 (elution time 11.53 min) (190 mg).
Nuclear magnetic hydrogen spectrum of compound 100:
1H NMR(400MHz,CDCl3)δ8.34(d,1H),8.05–7.95(m,2H),7.71(d,1H),7.47–7.41(m,1H),7.35–7.30(m,1H),7.22(dd,1H),6.71–6.65(m,1H),6.47(dd,1H),5.00–4.91(m,1H),4.26–4.18(m,2H),3.85–3.67(m,3H),2.96–2.66(m,3H),2.25–2.14(m,1H),2.10(s,3H),1.94(s,6H),1.36–1.23(m,1H),0.69–0.61(m,2H),0.44–0.35(m,2H).
LCMS m/z＝644.1[M+1]+
nuclear magnetic hydrogen spectrum of compound 101:
1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.39(d,1H),7.96(s,1H),7.70(d,1H),7.54–7.43(m,2H),7.38–7.33(m,1H),6.86–6.81(m,1H),6.58(dd,1H),5.00–4.90(m,1H),4.47–4.36(m,2H),4.17–4.05(m,2H),3.94–3.80(m,1H),2.97–2.65(m,3H),2.21–2.07(m,4H),1.94(s,6H),1.59–1.46(m,1H),1.10–0.99(m,2H),0.62–0.54(m,2H).
LCMS m/z＝644.0[M+1]+
Example 102: preparation of Compound 102
The first step: 102b preparation
102A (4.7 g,22.6 mmol) was dissolved in 80mL DCM, TEA (4.58 g,45.26 mmol) and DMAP (0.28 g,2.29 mmol) were added and trifluoroacetic anhydride (5.70 g,27.14 mmol) was slowly added dropwise at 0deg.C and reacted for 3h at room temperature. To the reaction was added 100mL of saturated aqueous sodium bicarbonate solution, extracted with 200mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =3:1) to give 102b (6.5 g, yield: 95%).
And a second step of: 102c preparation
102B (6.08 g,20.00 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (6.79 g,23.98 mmol) were dissolved in 80mL DMA, zinc powder (7.85 g,120.8 mmol) was added, and 2-amidinopyridine hydrochloride (CAS: 51285-26-8) (0.63 g,4.0 mmol) was added under nitrogen to react with nickel chloride ethylene glycol dimethyl ether complex (CAS: 29046-78-4) (0.88 g,4.00 mmol) at 100deg.C under nitrogen for 16h. The reaction system was cooled to room temperature, 200mL of water and 100mL of ethyl acetate were added, the filtrate was separated by filtration, the aqueous phase was extracted with 200mL of ethyl acetate, the organic phase was washed with 100mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =4:1) to give 102c (4.3 g, yield: 57%).
And a third step of: 102d preparation
102C (4.3 g,11.31 mmol) was dissolved in 80mL of methanol, potassium carbonate (9.38 g,67.87 mmol) was added and reacted with cesium carbonate (7.37 g,22.62 mmol) at 60℃for 16h. The reaction was cooled to room temperature, 150mL of DCM was added, filtration was performed, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =2:1) to give 102d (2.4 g, yield: 75%).
Fourth step: 102e preparation
102D (1.8 g,6.33 mmol) was dissolved in 60mL of acetonitrile, KI (1.58 g,9.52 mmol) was added to react with CuI (1.81 g,9.50 mmol) and I 2 (2.41 g,9.50 mmol) slowly dropwise with isoamyl nitrite (1.11 g,9.48 mmol) at 0deg.C under nitrogen atmosphere at room temperature for 16h. To the reaction system was added 100mL of saturated aqueous sodium thiosulfate, and the mixture was filtered, the filtrate was extracted with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =3:1) to give 102e (1.2 g, yield: 48%).
Fifth step: 102f preparation
102E (1.2 g,3.04 mmol), 4-pyrazolopinacol ester (CAS: 269410-08-4) (0.88 g,4.54 mmol), potassium carbonate (0.84 g,6.08 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (250 mg,0.31 mmol) were added under nitrogen and reacted at 100deg.C under nitrogen for 4h. The reaction solution was cooled to room temperature, 80mL of water was then added, extraction was performed with 100mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3:1), to give 102f (520 mg, yield: 51%).
LCMS m/z＝336.1[M+1]+
Sixth step: preparation of 102g
102F (0.072 g,0.21 mmol) was dissolved in 8mL acetonitrile, cesium carbonate (0.14 g,0.43 mmol) was added and reacted with 53B (0.32 g,1.04 mmol) at 80℃for 8h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 102g (90 mg, yield: 76%).
LCMS m/z＝562.2[M+1]+
Starting from compound 102g, compound 102 (40 mg) was obtained in referential example 23.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.40(d,1H),8.09–8.05(m,1H),8.00(s,1H),7.92(s,1H),7.70(d,1H),7.49(dd,1H),7.40–7.32(m,1H),7.27–7.14(m,2H),6.90–6.84(m,1H),6.62(dd,1H),5.00–4.86(m,1H),4.56–4.44(m,2H),4.33–4.20(m,1H),4.16–4.05(m,2H),2.96–2.65(m,3H),2.20–2.08(m,1H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.91(m,2H),0.62–0.52(m,2H).
Example 103: preparation of Compound 103
The first step: 103b preparation
103A (450 mg,2.0 mmol) was dissolved in 10mL of dichloromethane, 103A (0.53 g,2.42 mmol) and TCFH (0.85 g,3.03 mmol) were added, NMI (0.66 g,8.04 mmol) was added and reacted at room temperature for 16h. To the reaction system was added 50mL of saturated aqueous sodium bicarbonate solution, extracted with 100mL of dichloromethane, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether: ethyl acetate (v/v) =5:1) to give 103b (800 mg, yield: 94%).
LCMS m/z＝426.1[M+1]+
And a second step of: preparation of Compound 103
103B (0.21 g,0.49 mmol), crude intermediate 1 above (0.25 g), TEA (0.15 g,1.48 mmol), cuI (10 mg,0.053 mmol) and PdCl 2(PPh3)2 (35 mg,0.05 mmol) were added to the reaction flask and reacted for 2h under nitrogen with 4mL DMF. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:2) to give compound 103 (0.21 g, yield: 68%).
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.94(s,1H),7.88–7.78(m,2H),7.72(s,1H),7.70–7.60(m,2H),7.58–7.50(m,1H),7.37–7.29(m,1H),7.27–7.21(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.43–4.32(m,2H),4.17–4.06(m,2H),3.93–3.78(m,1H),2.95–2.64(m,3H),2.19–2.07(m,1H).
Example 104: preparation of Compound 104
The first step: 104b preparation
104A (1.00 g,7.57 mmol) was dissolved in 15mL of dichloromethane and a solution of bromine (1.21 g,7.57 mmol) in 5mL of dichloromethane was slowly added dropwise at-15℃under nitrogen atmosphere and reacted at-15℃for 0.5h. To the reaction solution was added 30mL of saturated aqueous sodium bicarbonate solution at-15 ℃, the aqueous phase was extracted with dichloromethane (10 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether: ethyl acetate (v/v) =5:1) to give 104b (1.30 g, yield: 81%).
LCMS m/z＝211.1[M+1]+
And a second step of: referring to the preparation of 16B from 16A, 104c (0.74 g) was obtained starting from 104a
LCMS m/z＝173.2[M+1]+
Starting from compound 104c, compound 104 (0.11 g) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.97(s,1H),7.84(s,1H),7.75(s,1H),7.68(d,1H),7.37–7.30(m,1H),7.18–7.10(m,1H),6.85–6.77(m,1H),6.56(dd,1H),4.99–4.87(m,1H),4.42–4.32(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.07(m,4H),1.97(s,6H),1.70–1.58(m,1H),0.92–0.80(m,2H),0.57–0.47(m,2H).
LCMS m/z＝644.3[M+1]+
Example 105: preparation of Compound 105
Starting from compound 105a, compound 105 (0.24 g) was obtained in referential example 104.
1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.44(dd,1H),7.97(s,1H),7.81(s,1H),7.73(s,1H),7.67(d,1H),7.37–7.25(m,2H),6.84–6.78(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.88–3.74(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.95(s,6H),1.68–1.55(m,1H),1.18–1.08(m,2H),0.74–0.65(m,2H).
LCMS m/z＝630.2[M+1]+
Example 106: preparation of Compound 106
Starting from compound 106b, compound 106 (150 mg) was obtained in referential example 104.
1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.56–8.50(m,1H),8.24(s,1H),7.82(s,1H),7.72(s,1H),7.67(d,1H),7.38–7.24(m,1H),7.18–7.10(m,1H),6.85–6.75(m,1H),6.55(dd,1H),4.99–4.90(m,1H),4.43–4.30(m,2H),4.12–4.00(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.96(s,6H),1.61–1.49(m,1H),1.04–0.94(m,2H),0.64–0.56(m,2H).
Example 107: preparation of Compound 107
Starting with compound 107a, reference example 104 gave the compound 107(20mg).1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.06(s,1H),8.35(s,1H),7.94–7.86(m,1H),7.84(s,1H),7.79–7.71(m,1H),7.68(d,1H),6.90–6.83(m,1H),6.72(dd,1H),5.12–5.02(m,1H),4.47–4.32(m,2H),4.07–3.96(m,2H),3.96–3.82(m,1H),2.97–2.80(m,1H),2.67–2.51(m,2H),2.10–1.96(m,1H),1.86(s,6H),1.56–1.44(m,1H),0.98–0.85(m,2H),0.56–0.45(m,2H).
LCMS m/z＝646.5[M-1]-
Example 108: preparation of Compound 108
Starting from compound 108a, compound 108 (300 mg) was obtained in referential example 104.
1H NMR(400MHz,CDCl3)δ8.50–8.30(m,2H),7.84(s,1H),7.76(s,1H),7.67(d,1H),7.23(dd,1H),7.09(s,1H),6.85–6.75(m,1H),6.56(dd,1H),4.99–4.88(m,1H),4.43–4.30(m,2H),4.14–4.00(m,2H),3.88–3.75(m,1H),2.94–2.65(m,3H),2.18–2.07(m,1H),1.96(s,6H),1.77–1.64(m,1H),1.02–0.91(m,2H),0.65–0.55(m,2H).
Example 109: preparation of Compound 109
Using the compound 109d as a starting material, compound 109 (0.15 g) was obtained in referential example 59.
1H NMR(400MHz,CDCl3)δ9.94(s,1H),8.28(d,1H),7.95(s,1H),7.74–7.65(m,3H),7.62(d,1H),7.59(s,1H),7.03(dd,1H),6.99–6.95(m,1H),6.85–6.80(m,1H),6.57(dd,1H),6.14(t,1H),4.99–4.87(m,1H),4.43–4.32(m,2H),4.15–4.05(m,2H),3.92–3.78(m,1H),2.98–2.66(m,3H),2.19–2.08(m,1H),1.95–1.79(m,7H),1.02–0.92(m,2H),0.71–0.62(m,2H).
Example 110: preparation of Compound 110
Starting from compound 110a, compound 110 (50 mg) was obtained in referential example 102.
1H NMR(400MHz,CDCl3)δ9.18(s,1H),8.41(d,1H),8.10–7.94(m,3H),7.70(d,1H),7.58–7.46(m,2H),7.39–7.32(m,1H),7.21–7.12(m,2H),6.90–6.84(m,1H),6.62(m,1H),5.00–4.86(m,1H),4.55–4.40(m,2H),4.14–3.95(m,3H),2.96–2.65(m,3H),2.23–2.07(m,1H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.90(m,2H),0.60–0.51(m,2H).
Example 111: preparation of Compound 111
Using the compound 111a as a starting material, compound 111 (100 mg) was obtained in referential example 102.
1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.41(d,1H),8.03–7.88(m,3H),7.68(d,1H),7.49(dd,1H),7.42–7.28(m,4H),6.90–6.85(m,1H),6.62(dd,1H),4.98–4.87(m,1H),4.55–4.44(m,2H),4.34–4.21(m,1H),4.15–4.05(m,2H),2.95–2.66(m,3H),2.33(s,3H),2.18–2.08(m,1H),2.02(s,6H),1.58–1.45(m,1H),1.00–0.92(m,2H),0.58–0.51(m,2H).
LCMS m/z＝696.2[M+1]+
Example 112: preparation of Compound 112 trifluoroacetate salt
Starting from compound 80b, reference example 22 preparation, acidic preparation [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 112 (90 mg).
1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.14(d,1H),8.04(s,1H),7.77(s,1H),7.72–7.64(m,2H),7.03–6.98(m,1H),6.94(dd,1H),6.84–6.76(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.86–3.76(m,1H),3.13–2.99(m,2H),2.96–2.65(m,5H),2.31–1.97(m,3H),1.87–1.75(m,1H),0.97–0.90(m,2H),0.68–0.58(m,2H).
Example 113: preparation of Compound 113 trifluoroacetate salt
Starting from compound 80c and intermediate 2, reference is made to the preparation method of example 19, acidic preparation [ mobile phase system: acetonitrile/water (containing 0.1% tfa) ], to afford the trifluoroacetate salt of compound 113.
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.11(d,1H),8.04(s,1H),7.82–7.75(m,2H),7.39(d,1H),7.05–6.99(m,1H),6.94(dd,1H),6.88–6.81(m,1H),4.97–4.87(m,1H),4.55–4.42(m,2H),4.27–4.15(m,2H),3.85–3.74(m,1H),2.97–2.64(m,3H),2.18–2.07(m,1H),1.94(s,6H),1.86–1.76(m,1H),0.98–0.90(m,2H),0.67–0.58(m,2H).
Example 114: preparation of Compound 114
Using the compound 28B as a starting material, referential example 101 gave compound 114 (0.17 g).
1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.59–8.52(m,1H),8.01(s,1H),7.69(d,1H),7.60–7.54(m,1H),7.53–7.46(m,1H),7.40–7.34(m,1H),6.86–6.80(m,1H),6.57(dd,1H),4.99–4.89(m,1H),4.48–4.35(m,2H),4.19–4.08(m,2H),3.98–3.85(m,1H),3.10–2.96(m,2H),2.96–2.65(m,5H),2.31–2.03(m,6H).
LCMS m/z＝693.1[M+1]+
Example 115: preparation of Compound 115
The first step: 115a preparation
60% Sodium hydride (1.06 g) was added to 20mL of DMSO under nitrogen, a solution of 85a (2.0 g,8.80 mmol) and 1, 3-dibromopropane (2.66 g,13.2 mmol) in 5mL of dichloromethane was slowly added and reacted at 30℃for 19h. Water (80 mL) was added to the reaction system, extracted with dichloromethane (80 mL. Times.2), the organic phase was washed with saturated aqueous sodium chloride (60 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =10:1) to give 115a (0.65 g, yield: 28%).
LCMS m/z＝268.4[M+1]+
And a second step of: 115b
115A (0.65 g,2.43 mmol) was dissolved in 10mL of methanol, 10% Pd/C (300 mg) was added and the mixture was reacted at room temperature under a hydrogen balloon atmosphere for 5 hours. The reaction system was filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to give 115b (0.38 g, yield: 66%).
LCMS m/z＝238.2[M+1]+
And a third step of: 115c preparation
115B (0.38 g,1.60 mmol) was dissolved in a mixed solvent of toluene (4 mL) and water (0.4 mL), concentrated hydrochloric acid (1 mL) was added at 0deg.C, and after stirring for 30min, sodium nitrite (150 mg,2.17 mmol) was slowly added, and the mixture was reacted at 0-5deg.C for 30min, and 2mL of an aqueous solution of potassium iodide (0.53 g,3.2 mmol) was added and reacted at room temperature for 4h. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (30 mL. Times.2), the organic phase was washed with saturated sodium thiosulfate solution (20 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =91:9) to give 115c (0.35 g, yield: 63%).
LCMS m/z＝349.0[M+1]+
Fourth step: 115d preparation
115C (0.35 g,1.01 mmol) was added to a 100mL single-necked flask, methanol (4 mL), water (0.4 mL) and potassium hydroxide (0.21 g,3.74 mmol) were sequentially added, and reacted at 60℃for 5h. The reaction system was cooled to room temperature, pH was adjusted to 3 with 1mol/L hydrochloric acid, extraction was performed with ethyl acetate (30 mL. Times.2), the organic phase was washed with saturated aqueous sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =1:1) to give a crude product (0.15 g). The crude product (0.1 g) was dissolved in 1mL of acetonitrile, thionyl chloride (55 mg,0.46 mmol) was added, and after reacting at 60℃for 1 hour, it was cooled to room temperature, TEA (0.2 mL) was added, and 2-chloro-4- (trifluoromethyl) aniline (61 mg,0.31 mmol) was added and reacted at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give 115d (86 mg, yield: 56%).
Fifth step: preparation of Compound 115
115D (130 mg,0.26 mmol) was added to the flask, dried DMF (3 mL), crude intermediate 1 (130 mg) above, and TEA (79 mg,0.78 mmol) were added sequentially, nitrogen was replaced three times, pdCl 2(PPh3)2 (36 mg,0.051 mmol) and CuI (9 mg,0.047 mmol) were added and reacted at 55℃under nitrogen for 3h. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (150 mL) was slowly added, extraction was performed with ethyl acetate (30 ml×2), the organic phase was washed with a saturated aqueous sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =1:2) to give compound 115 (21 mg, yield: 11%).
1H NMR(400MHz,CDCl3)δ8.59(d,1H),8.04–7.82(m,2H),7.68(d,1H),7.60–7.44(m,2H),7.37–7.25(m,2H),7.21–7.11(m,1H),6.87–6.77(m,1H),6.57(dd,1H),4.98–4.87(m,1H),4.44–4.32(m,2H),4.17–4.04(m,2H),3.93–3.76(m,1H),3.04–2.54(m,7H),2.36–2.19(m,1H),2.19–2.08(m,1H),2.06–1.90(m,1H).
Example 116: preparation of Compound 116
Compound 116 was obtained by the synthesis method of reference example 102, starting from compound 116 a.
1H NMR(400MHz,CDCl3)δ9.43(s,1H),8.45(d,1H),8.22–8.08(m,2H),7.96–7.82(m,3H),7.73–7.35(m,7H),6.93–6.87(m,1H),6.64(dd,1H),4.98–4.87(m,1H),4.87–4.62(m,3H),4.35–4.21(m,2H),2.94–2.62(m,3H),2.18–2.02(m,7H),1.68–1.52(m,1H),1.07–0.96(m,2H),0.66–0.56(m,2H).
Example 117: preparation of Compound 117
The first step: 117b preparation
117A (5.3 g,39.79 mmol) was dissolved in 100mL DCM, TEA (6.1 g,60.3 mmol) was added and trifluoroacetic anhydride (10.5 g,50 mmol) was slowly added dropwise at 0deg.C and reacted for 2h at room temperature. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 117b (9.0 g, yield: 99%).
And a second step of: 117c preparation
117B (9.0 g,39.27 mmol) was dissolved in 100mL acetonitrile, NBS (7.7 g,43.26 mmol) was added at 0deg.C and reacted at room temperature for 12h. The reaction system was concentrated under reduced pressure, 200mL of ethyl acetate and 200mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =4:1) to give 117c (12.0 g, yield: 99%).
Starting from compound 117c, compound 117 (120 mg) was obtained in referential example 102.
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.48–8.34(m,2H),7.94–7.84(m,2H),7.67(d,1H),7.48(dd,1H),7.39–7.20(m,3H),6.91–6.83(m,1H),6.60(dd,1H),5.00–4.87(m,1H),4.55–4.40(m,2H),4.24–4.05(m,3H),3.10–2.98(m,2H),2.98–2.65(m,5H),2.23–2.07(m,3H),2.03(s,6H),1.58–1.46(m,1H),1.00–0.90(m,2H),0.60–0.52(m,2H).
Example 118: preparation of Compound 118
The first step: 118b preparation
118A (0.4 g,1.51 mmol) (see WO 2022187588) was dissolved in 20mL DCM and dess-Martin oxidant (0.77 g,1.82 mmol) was added and reacted at room temperature for 10min. To the reaction system were added 10mL of water and 20mL of methylene chloride, and after stirring for 2min, the solution was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to give 118b (0.3 g, yield: 76%).
And a second step of: 118c preparation
118B (0.15 g,0.57 mmol), dimethyl (1-diazo-2-oxopropyl) phosphonate (0.17 g,0.88 mmol) and potassium carbonate (0.16 g,1.16 mmol) were added to 5mL of methanol and reacted at 30℃for 12h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to give 118c (0.05 g, yield: 34%).
And a third step of: 118d preparation
118C (0.05 g,0.19 mmol) was dissolved in 5mL ethanol, and 5mL aqueous sodium hydroxide (0.023 g,0.58 mmol) was added and reacted at 80℃for 2h. The reaction system was cooled to room temperature, concentrated under reduced pressure, pH was adjusted to 2 with 1mol/L hydrochloric acid, extracted with ethyl acetate (20 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (0.02 g). The crude product (0.02 g) was dissolved in 5mL of acetonitrile, and 3-amino-2, 6-piperidinedione hydrochloride (0.014 g,0.085 mmol) and N, N' -carbonyldiimidazole (0.028 g,0.17 mmol) were added and reacted at 90℃for 3 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) =50:1) to give 118d (0.01 g, yield: 37%).
LCMS m/z＝323.4[M+1]+
Fourth step: preparation of Compound 118
118d(0.01g,0.031mmol)、2c(0.15g,0.032mmol)、PdCl2(PPh3)2(2.2mg,0.003mmol)、CuI(1.2mg,0.0063mmol) And TEA (0.019 g,0.19 mmol) were added to the flask and reacted at 55℃for 2h under nitrogen. The reaction was cooled to room temperature, added to 20mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (10 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by prep-TLC (dichloromethane: petroleum ether: ethyl acetate (v/v) =2:2:1) to give compound 118 (6 mg, yield: 29%).
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.54(d,1H),8.05(s,1H),7.80–7.62(m,4H),7.61–7.55(m,1H),7.54–7.45(m,1H),5.00–4.92(m,1H),3.60–3.47(m,1H),3.46–3.32(m,2H),3.25–3.13(m,2H),3.12–2.97(m,2H),2.97–2.65(m,5H),2.30–1.95(m,3H).
Example 119: preparation of Compound 119
Compound 119 was obtained by the synthesis method of reference example 118, starting from compounds 118d and 68 c.
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.37(d,1H),7.99(s,1H),7.77(s,1H),7.74–7.65(m,3H),7.49(dd,1H),7.41–7.34(m,1H),5.02–4.90(m,1H),3.60–3.47(m,1H),3.47–3.33(m,2H),3.26–3.12(m,2H),2.97–2.65(m,3H),2.20–2.09(m,1H),1.94(s,6H),1.54–1.44(m,1H),1.03–0.92(m,2H),0.63–0.52(m,2H).
Examples 120 and 121: preparation of trifluoroacetate salts of Compounds 120 and 121
The first step: 120b-1 and 120b-2
120A (0.32 g,1.51 mmol) was added to each of the reaction bottles (see WO2022199503 for synthesis), 28B (0.52 g,1.46 mmol), cesium carbonate (0.98 g,3.01 mmol) and 6mL acetonitrile, and reacted at 60℃for 4h. The reaction system was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20) to give a mixture (0.50 g) of crude products 120b-1 and 120 b-2.
And a second step of: preparation of trifluoroacetate salts of Compounds 120 and 121
To the reaction flask were added a mixture of crude 120b-1 and 120b-2 (0.50 g), crude intermediate 1 (0.52 g,1.53 mmol), pdCl 2(PPh3)2 (72 mg,0.10 mmol), cuI (39 mg,0.20 mmol) and DIPEA (0.40 g,3.09 mmol), respectively, under nitrogen atmosphere, 10mL DMF was added and reacted at 60℃for 5h. The reaction was cooled to room temperature, added to water (40 mL), filtered and the filter cake was subjected to Pre-HPLC (apparatus and preparation column: preparation of liquid phase using Waters 2767, preparation column model SunFire@PrepC18, 5 μm, inner diameter×length=19 mm×250 mm). The preparation method comprises the following steps: the crude DMSO solution was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile. The gradient elution method comprises the following steps: acetonitrile was eluted 90% by a 50% gradient and lyophilized to give the trifluoroacetate salt of compound 120 (elution time 16.90 min) (5 mg) and the trifluoroacetate salt of compound 121 (elution time 16.02 min) (10 mg), respectively.
Characterization data for compound 120 trifluoroacetate salt:
LCMS m/z＝697.1[M+1]+
characterization data for compound 121 trifluoroacetate salt:
LCMS m/z＝697.1[M+1]+
the trifluoroacetate salt of compound 121 was free with aqueous ammonia to give the free base of compound 121.
Compound 121 free base nuclear magnetism:
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.53(d,1H),8.03(s,1H),7.69(d,1H),7.62–7.57(m,1H),7.55–7.44(m,2H),6.83(d,1H),6.58(dd,1H),4.99–4.90(m,1H),4.47–4.34(m,2H),4.22–4.10(m,2H),3.97–3.85(m,1H),3.12–2.97(m,2H),2.96–2.66(m,5H),2.30–2.02(m,3H).
Examples 122 and 123: preparation of trifluoroacetate salts of Compounds 122 and 123
The first step: 122a-1 and 122a-2
120A (0.31 g,1.46 mmol) was added to each of the reaction vessels (see WO2022199503 for synthesis), 53B (0.46 g,1.50 mmol), cesium carbonate (0.94 g,2.89 mmol) and 6mL acetonitrile, and reacted at 60℃for 4h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) =1:20) to give a mixture (0.52 g) of crude products 122a-1 and 122 a-2.
And a second step of: preparation of trifluoroacetate salts of Compounds 122 and 123
A mixture (0.52 g) of the above crude products 122a-1 and 122a-2, crude intermediate 1 (0.61 g), pdCl 2(PPh3)2 (84 mg,0.12 mmol), cuI (46 mg,0.24 mmol) and DIPEA (0.47 g,3.64 mmol) were added separately to the flask under nitrogen, and 10mL of DMF was added to react for 5h at 60 ℃. The reaction was cooled to room temperature, added to water (40 mL), filtered and the filter cake was subjected to Pre-HPLC (apparatus and preparation column: preparation of liquid phase using Waters 2767, preparation column model SunFire@PrepC18, 5 μm, inner diameter×length=19 mm×250 mm). The preparation method comprises the following steps: the crude DMSO solution was filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile. The gradient elution method comprises the following steps: acetonitrile was eluted at a gradient of 50% and lyophilized to give the trifluoroacetate salt of compound 122 (elution time 15.88 min) (6 mg) and the trifluoroacetate salt of compound 123 (elution time 14.58 min) (20 mg), respectively.
Characterization data for compound 122 trifluoroacetate salt:
LCMS m/z＝648.2[M+1]+、
Trifluoroacetate characterization data for compound 123:
LCMS m/z＝648.2[M+1]+
the trifluoroacetate salt of the compound 123 is dissociated with ammonia to obtain the free base of the compound 123.
Compound 123 free base nuclear magnetism:
1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.37(d,1H),8.12(s,1H),7.69(d,1H),7.58(d,1H),7.49(dd,1H),7.40–7.36(m,1H),6.88–6.80(m,1H),6.58(dd,1H),5.00–4.91(m,1H),4.46–4.35(m,2H),4.17–4.06(m,2H),3.95–3.81(m,1H),2.96–2.66(m,3H),2.20–2.07(m,1H),1.94(s,6H),1.58–1.45(m,1H),1.14–1.02(m,2H),0.65–0.56(m,2H)
Example 124: preparation of Compound 124
The first step: 124b preparation
124A (1.0 g,4.11 mmol) and 124A (0.88 g,4.50 mmol) were dissolved in 40mL DCM and TCFH (1.72 g,6.14 mmol) and NMI (1.34 g,16.32 mmol) were added and reacted for 16h at room temperature. To the reaction was added 50mL of water, extracted with 200mL of DCM, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1) to give 124b (1.3 g, yield: 75%).
And a second step of: 124c preparation
124B (0.1 g,0.24 mmol), 50a (102 mg,0.28 mmol), sodium carbonate (76 mg,0.72 mmol) were added to 5mL of 1, 4-dioxane and 1mL of water, and tetrakis triphenylphosphine palladium (28 mg,0.024 mmol) was added under nitrogen atmosphere, and reacted at 100℃under nitrogen atmosphere for 4 hours. The reaction solution was cooled to room temperature, 20mL of water was then added, extraction was performed with 50mL of ethyl acetate, the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =5:1), to give 124c (50 mg, yield: 36%).
Using the compound 124c as a starting material, compound 124 (25 mg) was obtained in referential example 23.
1H NMR(400MHz,CDCl3)δ8.56(d,1H),7.91(s,1H),7.75–7.58(m,6H),7.58–7.48(m,4H),7.48–7.40(m,2H),6.90–6.85(m,1H),6.62(dd,1H),4.99–4.90(m,1H),4.57–4.45(m,2H),4.17–4.02(m,3H),2.96–2.66(m,3H),2.19–2.08(m,1H),1.75(s,6H).
Example 125: preparation of Compound 125
Starting from 65c and intermediate 2, reference example 19 gave the compound 125(10mg).1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.00–7.90(m,2H),7.80(s,1H),7.70(s,1H),7.39(d,1H),6.91–6.79(m,3H),4.95–4.87(m,1H),4.53–4.42(m,2H),4.24–4.15(m,2H),3.85–3.73(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),1.95(s,6H),1.86–1.74(m,1H),1.53–1.42(m,1H),0.94–0.80(m,4H),0.63–0.57(m,2H),0.55–0.48(m,2H).
LCMS m/z＝663.1[M+1]+
Example 126: preparation of Compound 126
Starting from 65b, compound 126 (8 mg) was obtained in referential example 22.
1H NMR(400MHz,CDCl3)δ8.12(s,1H),8.00(d,1H),7.96(s,1H),7.71–7.64(m,3H),6.92–6.85(m,1H),6.83–6.77(m,2H),6.55(dd,1H),4.97–4.89(m,1H),4.39–4.30(m,2H),4.10–4.02(m,2H),3.87–3.74(m,1H),3.13–3.02(m,2H),2.96–2.65(m,5H),2.30–1.96(m,3H),1.84–1.74(m,1H),1.48–1.37(m,1H),0.93–0.79(m,4H),0.63–0.57(m,2H),0.53–0.46(m,2H).
LCMS m/z＝657.1[M+1]+
Example 127: preparation of Compound 127
The first step: 127b preparation
To the reaction flask were added 127a hydrochloride (0.30 g) (see WO2022187588 for synthesis), bromopropyne (0.12 g,1.01 mmol), DIPEA (0.46 g,3.56 mmol) and 5mL DMF, respectively, and reacted at 40℃for 4h. The reaction system was cooled to room temperature, poured into 50mL of water, extracted with ethyl acetate (50 ml×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was slurried with 10mL of a mixed solvent of dichloromethane/methanol (v/v) =5:1, filtered, and the cake was dried under reduced pressure to give crude product 127b (70 mg).
LCMS m/z＝338.1[M+1]+
And a second step of: preparation of Compound 127
To the reaction flask were added the crude product 127b(70mg)、68c(88mg,0.21mmol)、PdCl2(PPh3)2(15mg,0.021mmol)、CuI(8mg,0.042mmol) and DIPEA (81 mg,0.63 mmol), respectively, under nitrogen, and 5mL of DMF was added and reacted at 60℃for 5h. The reaction system was cooled to room temperature, added to 50mL of water, filtered, the cake was dissolved with a mixed solvent of dichloromethane/methanol (v/v) =2:1, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:2), and the obtained crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =1:1) to give compound 127 (2 mg, yield: 2%).
1H NMR(400MHz,CDCl3)δ9.09(s,1H),8.36(d,1H),8.10(s,1H),7.83–7.77(m,1H),7.73–7.67(m,3H),7.53–7.45(m,1H),7.40–7.34(m,1H),5.00–4.92(m,1H),4.22(s,4H),3.85(s,2H),2.97–2.67(m,3H),2.20–2.10(m,1H),1.95(s,6H),1.54–1.44(m,1H),1.00–0.92(m,2H),0.60–0.52(m,2H).
LCMS m/z＝630.2[M+1]+
Example 128: preparation of Compound 128
Starting with 128b, compound 128 (110 mg) was obtained in referential example 19.
1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.17(d,1H),7.95(s,1H),7.82–7.74(m,2H),7.67(d,1H),7.24–7.19(m,1H),7.11(dd,1H),6.84–6.78(m,1H),6.55(dd,1H),4.97–4.88(m,1H),4.40–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.94–2.57(m,3H),2.46(d,2H),2.18–2.07(m,1H),1.94(s,6H),0.97–0.84(m,1H),0.54–0.45(m,2H),0.20–0.12(m,2H).
LCMS m/z＝653.1[M+1]+
Example 129: preparation of Compound 129
Using the compounds 89g and 50a as a starting material, compound 129 (36 mg) was obtained in referential example 124.
1H NMR(400MHz,CDCl3)δ9.95(s,1H),8.81(s,1H),8.44(d,1H),8.02–7.86(m,2H),7.74–7.67(m,1H),7.66–7.54(m,3H),7.54–7.44(m,3H),7.42–7.37(m,1H),6.92–6.84(m,1H),6.62(dd,1H),5.00–4.90(m,1H),4.58–4.45(m,2H),4.18–4.02(m,3H),2.98–2.65(m,3H),2.20–2.07(m,1H),1.85(s,6H),1.80–1.70(m,1H),1.13–1.04(m,2H),0.70–0.63(m,2H).
LCMS m/z＝693.1[M+1]+
Example 130: preparation of Compound 130
Starting from compound 68c, reference example 124 gave compound 130 (48 mg).
1H NMR(400MHz,CDCl3)δ9.22(s,1H),8.41(d,1H),7.98–7.88(m,3H),7.69(d,1H),7.53–7.45(m,3H),7.41–7.33(m,3H),6.90–6.84(m,1H),6.62(dd,1H),5.00–4.87(m,1H),4.55–4.42(m,2H),4.17–3.99(m,3H),2.98–2.65(m,3H),2.22–2.08(m,1H),2.03(s,6H),1.58–1.47(m,1H),1.00–0.90(m,2H),0.60–0.52(m,2H).
Example 131: preparation of Compound 131
Compound 131 was obtained by the synthesis method of reference example 110, starting from compound 131 a.
Nuclear magnetic data of compound 131:
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.41(d,1H),8.18–8.11(m,2H),7.98(s,1H),7.70(d,1H),7.49(dd,1H),7.38–7.34(m,1H),7.06–6.96(m,2H),6.87(d,1H),6.62(dd,1H),4.99–4.91(m,1H),4.52–4.43(m,2H),4.10–3.93(m,3H),2.96–2.67(m,3H),2.19–2.09(m,1H),2.04(s,6H),1.57–1.47(m,1H),1.01–0.92(m,2H),0.60–0.52(m,2H).
Example 132: preparation of Compound 132
Compound 132 was obtained by the synthesis method of reference example 110, starting from compound 132 a.
Nuclear magnetic data of compound 132:
1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.41(d,1H),8.07(s,1H),8.02(s,1H),7.97(s,1H),7.69(d,1H),7.50(dd,1H),7.40–7.35(m,1H),7.35–7.27(m,1H),7.21–7.13(m,1H),6.87(d,1H),6.62(dd,1H),4.99–4.90(m,1H),4.56–4.46(m,2H),4.38–4.25(m,1H),4.18–4.08(m,2H),2.96–2.66(m,3H),2.18–2.09(m,1H),2.03(s,6H),1.59–1.48(m,1H),1.00–0.92(m,2H),0.60–0.53(m,2H).
Example 133: preparation of Compound 133
Compound 133 was obtained by the method of example 127 using compounds 127b and 2c as starting materials.
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.53(d,1H),7.97(s,1H),7.77(s,1H),7.73–7.67(m,3H),7.59–7.56(m,1H),7.53–7.46(m,1H),5.01–4.91(m,1H),4.24(s,4H),3.86(s,2H),3.13–2.99(m,2H),2.96–2.65(m,5H),2.30–1.98(m,3H).
Example 134: preparation of Compound 134
Compound 134 was obtained by the synthesis method of example 66, starting from 80c and 66 j.
1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.12(d,1H),7.82–7.65(m,4H),7.04–6.99(m,1H),6.94(dd,1H),6.46(dd,1H),6.34–6.26(m,1H),5.34–5.17(m,2H),4.73(t,1H),4.33–4.22(m,2H),4.03–3.93(m,2H),3.83–3.70(m,1H),3.00–2.86(m,1H),2.71–2.56(m,1H),2.30–2.12(m,2H),1.93(s,6H),1.87–1.75(m,1H),0.99–0.89(m,2H),0.67–0.56(m,2H).
Example 135: preparation of compound 135 trifluoroacetate salt
Compound 135 was obtained by the method of example 23 using p-toluenesulfonate and 2A as raw materials.
1H NMR(400MHz,CDCl3)δ8.96(s,1H),8.32(d,1H),8.08(s,1H),7.79(s,2H),7.45(s,1H),7.42–7.31(m,2H),6.84(d,1H),4.98–4.85(m,1H),4.55–4.40(m,2H),4.27–4.13(m,2H),3.85–3.72(m,1H),3.06(s,1H),2.97–2.65(m,3H),2.20–2.06(m,1H),1.94(s,6H).
Example 136: preparation of Compound 136
The first step: 136b preparation
136A (2.0 g,5.01 mmol) (see WO 2022187588) was dissolved in 5mL DCM and 4mol/L ethyl acetate hydrochloride solution (50 mL) was added and reacted at room temperature for 3h. The reaction system was concentrated under reduced pressure, the residue was dissolved with 30mL of methylene chloride and 5mL of methanol, pH was adjusted to 7 by adding potassium hydrogencarbonate, and the filtrate was filtered and concentrated under reduced pressure to give crude 136b (1.4 g).
LCMS m/z＝300.3[M+1]+
And a second step of: 136c preparation
2C (2.0 g,4.26 mmol) was dissolved in 30mL of DMSO and azetidin-3-ylmethanol hydrochloride (480 mg,6.39 mmol), cuI (160 mg,0.84 mmol), L-proline (200 mg,1.74 mmol) and potassium carbonate (1.77 g,12.81 mmol) were added in sequence and reacted at 90℃for 16h under nitrogen. The reaction solution was cooled to room temperature, 150mL of water and 50mL of ethyl acetate were added, the aqueous phase was extracted with 50mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel column (petroleum ether/ethyl acetate (v/v) =1:1-0:1) to give 136c (300 mg, yield: 16%).
LCMS m/z＝429.1[M+1]+
And a third step of: 136d preparation
136C (60 mg,0.14 mmol) was dissolved in 15mL DMSO and IBX (180 mg,0.64 mmol) was added and reacted at 50℃for 4h. The reaction system was cooled to room temperature, 15mL of saturated aqueous sodium hydrogencarbonate solution was added, after stirring at room temperature for 10min, 40mL of water and 40mL of ethyl acetate were added, and the organic phase was washed with 20mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 136d (70 mg).
Fourth step: preparation of Compound 136
The crude 136b (63 mg) and the crude 136d (70 mg) were dissolved in 10mL of DCM and 2mL of DMF, 1mL of acetic acid was added, and after reaction at 40℃for 16h, sodium triacetoxyborohydride (89 mg,0.42 mmol) was added in portions and reacted at room temperature for 2h. To the reaction solution were added 30mL of methylene chloride and 30mL of saturated aqueous sodium hydrogencarbonate, the organic phase was washed with 30mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:1-0:1) to give compound 136 (10 mg, two-step yield from compound 136 c: 10%).
1H NMR(400MHz,CDCl3)δ8.57(d,1H),8.52(s,1H),8.10(s,2H),7.99(s,1H),7.61–7.54(m,1H),7.54–7.46(m,1H),7.41(s,2H),5.07–4.98(m,1H),4.70–4.50(m,2H),4.00–3.80(m,2H),3.75–3.50(m,2H),3.34–3.15(m,1H),3.08–2.68(m,10H),2.30–1.95(m,4H).
Example 137: preparation of Compound 137
Compound 137 was obtained by the synthesis method of example 44, starting from compound 137 a.
1H NMR(400MHz,CDCl3)δ8.72(d,1H),8.49(s,1H),7.95(s,1H),7.74–7.53(m,6H),6.89–6.80(m,1H),6.59(dd,1H),4.99–4.89(m,1H),4.48–4.36(m,2H),4.23–4.10(m,2H),4.00–3.86(m,1H),3.00–2.62(m,3H),2.20–2.08(m,1H).
LCMS m/z＝653.0[M+1]+
Example 138: preparation of Compound 138
Compound 138 was obtained by the synthesis method of example 44, starting with compound 138 a.
1H NMR(400MHz,CDCl3)δ10.81(s,1H),8.82(d,1H),8.63(s,1H),8.28(s,1H),7.92(s,1H),7.74–7.66(m,2H),7.64–7.56(m,1H),7.56–7.46(m,1H),6.86–6.82(m,1H),6.60(dd,1H),4.99–4.89(m,1H),4.48–4.37(m,2H),4.22–4.10(m,2H),3.98–3.85(m,1H),3.00–2.63(m,3H),2.22–2.08(m,1H).
LCMS m/z＝636.1[M+1]+
Example 139: preparation of Compound 139
Compound 139 was obtained by the synthesis method of reference example 44, starting from compounds 139A and 139A.
1H NMR(400MHz,CDCl3)δ8.73(s,1H),8.59(d,1H),7.97(s,2H),7.82(d,1H),7.72–7.56(m,3H),7.55–7.44(m,2H),6.87–6.80(m,1H),6.58(dd,1H),4.99–4.88(m,1H),4.47–4.35(m,2H),4.18–4.07(m,2H),3.95–3.81(m,1H),2.96–2.65(m,3H),2.18–2.08(m,1H),1.90–1.78(m,1H),1.18–1.10(m,2H),0.83–0.72(m,2H).
Example 140: preparation of Compound 140
The first step: 140c preparation
To 140b (2.0 g,6.02 mmol) and lithium hydroxide (0.69 g,28.81 mmol) were added 10mL of water and 10mL of methanol and reacted at room temperature for 16h. The reaction solution was added to 50mL of water, pH was adjusted to2 with 1mol/L hydrochloric acid, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (1.5 g). The crude product (410 mg) was dissolved in 20mL of methylene chloride with 5- (trifluoromethyl) indoline (0.2 g,1.07 mmol), TCFH (0.45 g,1.60 mmol) and NMI (0.35 g,4.26 mmol) were added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to give 140c (450 mg, yield: 86%).
LCMS m/z＝488.0[M+1]+
And a second step of: preparation of Compound 140
140C (0.20 g,0.41 mmol), crude intermediate 1 above (0.21 g), TEA (0.12 g,1.19 mmol), cuI (8 mg,0.042 mmol) and PdCl 2(PPh3)2 (29 mg,0.041 mmol) were added to the reaction flask, and 4mL of DMF was added under nitrogen protection and reacted at 50℃for 2h. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:2) to give compound 140 (0.18 g, yield: 63%).
1H NMR(400MHz,CDCl3)δ8.31(d,1H),8.01(s,1H),7.66(d,1H),7.50–7.38(m,2H),7.36–7.29(m,2H),6.90–6.83(m,2H),6.81–6.77(m,1H),6.54(dd,1H),4.97–4.88(m,1H),4.48–4.16(m,5H),4.10–4.02(m,2H),3.86–3.75(m,1H),3.32–3.07(m,2H),2.95–2.63(m,3H),2.18–2.08(m,1H),1.51–1.39(m,1H),0.83–0.66(m,3H),0.66–0.56(m,1H).
LCMS m/z＝697.1[M+1]+
Example 141: preparation of Compound 141
The first step: 141b preparation
CuI (1.72 g,9.03 mmol) and KI (1.5 g,9.04 mmol) were added to 60mL of acetonitrile, isoamyl nitrite (1.26 g,10.76 mmol) was added at 75℃and 141a (1.5 g,6.05 mmol) was added and reacted at 75℃for 2h. The reaction system was cooled to room temperature, 200mL of water and 150mL of ethyl acetate were added, the mixture was filtered through celite, the separated liquid was extracted with ethyl acetate (60 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (80 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =35:65) to obtain 141b (0.8 g, yield: 37%).
LCMS m/z＝360.1[M+1]+
And a second step of: 141c preparation
141B (200 mg,0.56 mmol) was dissolved in 10mL of dichloromethane, 2mL of trifluoroacetic acid was added and reacted at room temperature for 2h. The reaction was concentrated under reduced pressure, 10mL of toluene and TEA (56 mg,0.55 mmol) were added, 141A (124 mg,0.56 mmol) was added, and the mixture was reacted at 55℃for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =91:8) to give 141c (100 mg, yield: 38%).
And a third step of: preparation of Compound 141
Compound 141 was obtained by the synthesis method of example 18, starting with compound 141 c.
1H NMR(400MHz,CDCl3)δ8.44(d,1H),7.96(s,1H),7.72–7.65(m,1H),7.64–7.60(m,1H),7.51(dd,1H),7.33–7.26(m,2H),7.23(s,1H),7.19–7.12(m,1H),6.82(d,1H),6.61(dd,1H),4.98–4.90(m,1H),4.68(s,2H),4.43–4.34(m,2H),4.17–4.06(m,2H),3.92–3.80(m,1H),3.80–3.73(m,2H),3.03–2.94(m,2H),2.94–2.65(m,3H),2.18–2.08(m,1H).
LCMS m/z＝690.2[M+1]+
Example 142: preparation of Compound 142
Compound 142 was obtained by the synthesis method of example 80, starting with compound 142 c.
1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.13(s,1H),8.01(d,1H),7.82–7.74(m,2H),7.67(d,1H),7.07(d,1H),6.82–6.79(m,1H),6.55(dd,1H),4.99–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.99–2.60(m,7H),2.18–2.00(m,3H),1.94(s,6H).
LCMS m/z＝639.3[M+1]+
Example 143: preparation of Compound 143
The first step: 143b preparation
143A (0.45 g,2.0 mmol) and 143A (530 mg,2.24 mmol) were dissolved in 20mL of dichloromethane, TCFH (0.85 g,3.03 mmol) was added, NMI (0.67 g,8.16 mmol) was added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =5:1) to give 143b (820 mg, yield: 93%).
LCMS m/z＝444.2[M+1]+
And a second step of: preparation of Compound 143
143B (0.22 g,0.50 mmol), crude intermediate 1 above (0.25 g), TEA (0.15 g,1.48 mmol), cuI (10 mg,0.053 mmol) and PdCl 2(PPh3)2 (35 mg,0.050 mmol) were added to the reaction flask and reacted at 50℃for 2h under nitrogen with 4mL of DMF. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 100mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:2) to give compound 143 (0.18 g, yield: 55%).
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.98(s,1H),7.85(d,1H),7.73(s,1H),7.70–7.60(m,2H),7.58–7.48(m,1H),7.43(s,1H),6.99–6.90(m,1H),6.86–6.77(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.44–4.32(m,2H),4.17–4.05(m,2H),3.92–3.77(m,1H),2.95–2.63(m,3H),2.19–2.07(m,1H).
LCMS m/z＝653.0[M+1]+
Example 144: preparation of Compound 144
Compound 144 was obtained by the synthesis method of reference example 18, starting from compound 144 a.
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.83(s,1H),7.75(s,1H),7.67(d,1H),7.58(s,1H),6.84–6.78(m,1H),6.77–6.69(m,2H),6.59(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.17–4.02(m,2H),3.88–3.75(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),2.05(s,6H),1.95(s,6H).
LCMS m/z＝611.2[M+1]+
Example 145: preparation of Compound 145
Compound 145 was obtained by the synthesis method of reference example 18, starting from compound 145 a.
1H NMR(400MHz,CDCl3)δ8.14(s,1H),8.09(s,1H),7.80(s,1H),7.76(s,1H),7.70(d,1H),7.67(d,1H),7.00–6.95(m,1H),6.95–6.91(m,1H),6.83–6.78(m,1H),6.55(dd,1H),4.97–4.89(m,1H),4.40–4.31(m,2H),4.13–4.02(m,2H),3.87–3.75(m,1H),2.95–2.65(m,3H),2.26(s,3H),2.17–2.07(m,1H),2.06–2.02(m,3H),1.94(s,6H).
LCMS m/z＝593.2[M+1]+
Example 146: preparation of Compound 146
Compound 146 was obtained by the synthesis method of reference example 110, starting from compound 146 d.
Nuclear magnetic data of compound 146:
1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.65(s,1H),8.22(s,1H),8.05(d,1H),7.73–7.62(m,2H),7.62–7.46(m,5H),6.91–6.86(m,1H),6.75(dd,1H),5.11–5.02(m,1H),4.55–4.44(m,2H),4.32–4.20(m,1H),4.18–4.08(m,2H),2.95–2.80(m,1H),2.70–2.45(m,2H),2.07–1.97(m,1H),1.92(s,6H),1.68–1.58(m,1H),0.88–0.76(m,2H),0.62–0.53(m,2H).
Example 147: preparation of Compound 147
The first step: 147b preparation
147A (1.42 g,4.98 mmol) was dissolved in 50mL of 1, 4-dioxane and 10mL of purified water, and cyclopropylboric acid (0.81 g,9.43 mmol), potassium phosphate (2.2 g,10.36 mmol), palladium acetate (0.23 g,1.02 mmol) and tricyclohexylphosphine (0.56 g,2.0 mmol) were added sequentially under nitrogen atmosphere and reacted at 95℃for 16h. The reaction system was cooled to room temperature, 80mL of ethyl acetate and 50mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =4:1) to give 147b (0.8 g, yield: 78%).
LCMS m/z＝208.1[M+1]+
Compound 147 was obtained by the synthesis method of reference example 18, starting from compound 147 b.
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.83(s,1H),7.79–7.71(m,2H),7.67(d,1H),6.92–6.85(m,1H),6.83–6.77(m,1H),6.66–6.60(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.31(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.94–2.63(m,3H),2.17–2.04(m,1H),1.96(s,6H),1.84–1.64(m,2H),0.97–0.88(m,2H),0.84–0.75(m,2H),0.66–0.58(m,2H),0.55–0.47(m,2H).
LCMS m/z＝679.1[M+1]+
Example 148: preparation of Compound 148
Compound 148 was obtained by the synthesis method of reference example 147, starting from compound 148 a.
1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.93(s,1H),7.84(s,1H),7.74(s,1H),7.68(d,1H),7.15(s,2H),6.85–6.77(m,1H),6.56(dd,1H),4.98–4.89(m,1H),4.44–4.30(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),2.96–2.66(m,3H),2.19–2.07(m,1H),1.97(s,6H),1.77–1.65(m,2H),0.94–0.78(m,4H),0.58–0.49(m,4H).
LCMS m/z＝670.7[M+1]+
Example 149: preparation of Compound 149
The first step: preparation of 149b
149A (2 g,6.06 mmol) was dissolved in a mixed solvent of 100mL of 1, 4-dioxane and 20mL of water, and cyclopropylboric acid (4.7 g,54.7 mmol), potassium phosphate (19 g,89.51 mmol), pd (OAc) 2 (410 mg,1.83 mmol) and tricyclohexylphosphine (512 mg,1.83 mmol) were added and reacted at 100℃under nitrogen atmosphere for 16h. The reaction system was cooled to room temperature, water (120 mL) and ethyl acetate (160 mL) were added, celite was added to filter the mixture, the filtrate was separated, the aqueous phase was extracted with ethyl acetate (100 ml×2), the organic phase was washed with saturated aqueous sodium chloride solution (100 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =87:13) to give 149b (700 mg, yield: 54%).
LCMS m/z＝214.3[M+1]+
Compound 149 was obtained by the synthesis method of example 18, starting from compound 149 b.
1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.83(s,1H),7.75–7.70(m,2H),7.67(d,1H),6.84–6.78(m,1H),6.60–6.50(m,3H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),1.97(s,6H),1.83–1.72(m,1H),1.72–1.60(m,2H),0.93–0.83(m,2H),0.80–0.70(m,4H),0.62–0.55(m,2H),0.54–0.45(m,4H).
LCMS m/z＝685.3[M+1]+
Example 150: preparation of Compound 150
Compound 150 was obtained by the synthesis method of example 18, starting with compound 150 a.
1H NMR(400MHz,CDCl3)δ8.58(s,1H),8.08–7.99(m,2H),7.77(s,2H),7.67(d,1H),6.86–6.78(m,2H),6.72(dd,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.12–4.00(m,2H),3.88–3.72(m,1H),2.95–2.63(m,3H),2.18–2.05(m,1H),1.92(s,6H),1.88–1.75(m,1H),0.96–0.88(m,2H),0.66–0.58(m,2H).
LCMS m/z＝623.3[M+1]+
Example 151: preparation of Compound 151
The first step: 151b preparation
151A (1.0 g,5.11 mmol) was dissolved in 20mL of DMF and 3-fluoro-5-iodoaniline (1.2 g,5.06 mmol) and N, N' -carbonyldiimidazole (0.91 g,5.61 mmol) were added and reacted at 80℃for 12h. The reaction system was cooled to room temperature, added to 100mL of ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was slurried with 20mL of diethyl ether, filtered, and the cake was dried under vacuum to give crude product 151b (1.0 g).
And a second step of: preparation of Compound 151
The crude 151b (0.11 g) and crude intermediate 1 (0.12 g), TEA (0.14 g,1.38 mmol), cuI (8.8 mg,0.046 mmol) and PdCl 2(PPh3)2 (16 mg,0.023 mmol) were added to a reaction flask, and 2mL of DMF was added under nitrogen protection, and reacted at 55℃for 3h. The reaction solution was cooled to room temperature, added to 50mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (20 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-10:7) to give compound 151 (0.05 g, two-step yield from compound 151 a: 13%).
1H NMR(400MHz,CDCl3)δ8.38(d,1H),8.14(s,1H),7.67–7.56(m,2H),7.50(d,1H),7.44–7.27(m,2H),7.23–7.12(m,2H),6.88–6.80(m,1H),6.76–6.68(m,1H),6.54–6.46(m,1H),5.02–4.90(m,1H),4.40–4.27(m,2H),4.10–3.97(m,2H),3.88–3.72(m,1H),2.97–2.65(m,3H),2.21–2.08(m,1H).
Example 152: preparation of Compound 152
Compound 152 was obtained by the synthesis method of example 18, starting from compound 152b+152a.
1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.95(s,1H),7.90(d,1H),7.80(s,1H),7.72–7.64(m,2H),6.98–6.92(m,1H),6.81(d,1H),6.74(dd,1H),6.55(dd,1H),4.98–4.87(m,1H),4.40–4.30(m,2H),4.12–4.02(m,2H),3.88–3.73(m,1H),2.95–2.62(m,3H),2.18–2.07(m,1H),1.95(s,6H),1.91–1.80(m,1H),1.49–1.39(m,1H),0.95–0.77(m,4H),0.73–0.62(m,2H),0.55–0.44(m,2H).
LCMS m/z＝645.3[M+1]+
Example 153: preparation of Compound 153
Compound 153 was obtained by the synthesis method of example 44, starting from compound 74b and intermediate 2.
1H NMR(400MHz,CDCl3)δ8.69(d,1H),8.43(s,1H),7.93(s,1H),7.84(s,1H),7.80(s,1H),7.71(s,1H),7.67–7.57(m,2H),7.41(d,1H),6.87(d,1H),4.98–4.85(m,1H),4.58–4.46(m,2H),4.34–4.20(m,2H),3.94–3.77(m,1H),2.97–2.65(m,3H),2.21–2.07(m,1H).
Example 154: preparation of Compound 154
Compound 154 was obtained by the synthesis method of example 147, starting with compound 154 a.
1H NMR(400MHz,CDCl3)δ8.38(s,1H),7.98(s,1H),7.83(s,1H),7.75(s,1H),7.67(d,1H),7.55–7.49(m,1H),7.23–7.18(m,1H),6.84–6.78(m,1H),6.56(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.06(m,1H),1.97(s,6H),1.83–1.70(m,1H),0.96–0.84(m,2H),0.62–0.52(m,2H).
Example 156: preparation of Compound 156
The first step: 156b
156A (140 mg,0.53 mmol) was dissolved in 15mL of dry dichloromethane, 1-chloro-N, N, 2-trimethylpropenamine (100 mg,0.75 mmol) was added, and after 1.5h at room temperature, TEA (151 mg,1.49 mmol) and 156A (94 mg,0.5 mmol) were added and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =9:1) to give 156b (100 mg, yield: 46%).
LCMS m/z＝436.1[M+1]+
Compound 156 was obtained by the synthesis method of example 44, starting with compound 156 b.
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.40–7.40(m,7H),6.92–6.84(m,1H),6.73(dd,1H),5.11–4.98(m,1H),4.47–4.35(m,2H),4.15–3.90(m,5H),3.23–3.09(m,2H),2.96–2.79(m,1H),2.70–2.45(m,2H),2.07–1.96(m,1H).
LCMS m/z＝645.6[M+1]+
Example 157: preparation of Compound 157
Compound 157 was obtained by the synthesis method of example 44, starting from compounds 157a and 65 b.
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.15(d,1H),7.90(s,1H),7.72–7.57(m,3H),7.57–7.50(m,1H),7.02–6.92(m,2H),6.87–6.81(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.48–4.36(m,2H),4.20–4.12(m,2H),3.97–3.86(m,1H),2.96–2.64(m,3H),2.18–2.08(m,1H),1.93–1.77(m,2H),1.07–0.98(m,2H),0.98–0.90(m,2H),0.76–0.70(m,2H),0.70–0.63(m,2H).
Example 158: preparation of Compound 158
Compound 158 was obtained by the synthesis method of example 44, starting from compounds 158a and 65 b.
1H NMR(400MHz,CDCl3)δ10.62(s,1H),8.57(d,1H),8.35–8.26(m,2H),7.94(s,1H),7.69(d,1H),7.47–7.41(m,1H),7.02–6.89(m,2H),6.88–6.81(m,1H),6.59(dd,1H),4.98–4.90(m,1H),4.47–4.36(m,2H),4.20–4.10(m,2H),3.97–3.83(m,1H),2.96–2.66(m,3H),2.18–2.08(m,1H),1.95–1.81(m,2H),1.12–1.03(m,2H),0.98–0.82(m,2H),0.75–0.63(m,4H).
Example 159: preparation of Compound 159
The first step: 159b preparation
159A (1.00 g,7.51 mmol) was dissolved in 10mL acetonitrile, cooled to 0deg.C, NCS (2.01 g,15.05 mmol) was added and reacted at 40deg.C for 5h. The reaction solution was cooled to room temperature, 90mL of ethyl acetate, 100mL of water and 20mL of a 10% aqueous solution of sodium thiosulfate were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-2:1) to give 159b (0.22 g, yield: 15%).
LCMS m/z＝202.1[M+1]+
Compound 159 was obtained by the synthesis method of example 18, starting with compound 159 b.
1H NMR(400MHz,CDCl3)δ7.94(s,2H),7.83(s,1H),7.74(s,1H),7.67(d,1H),7.23(d,1H),6.87(d,1H),6.81(d,1H),6.56(dd,1H),4.99–4.88(m,1H),4.44–4.28(m,2H),4.15–4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.18–2.07(m,1H),1.96(s,6H),1.77–1.66(m,1H),0.92–0.80(m,2H),0.60–0.50(m,2H).
LCMS m/z＝673.2[M+1]+
Example 160: preparation of Compound 160
Compound 160 was obtained by the synthesis method of example 147, starting with compound 160 a.
1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.97(s,1H),7.77(d,2H),7.67(d,1H),6.94–6.86(m,2H),6.84–6.78(m,1H),6.60–6.48(m,2H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.95–2.65(m,3H),2.18–2.06(m,1H),1.90(s,6H),1.85–1.74(m,2H),0.96–0.82(m,4H),0.70–0.60(m,4H).
LCMS m/z＝645.3[M+1]+
Example 161: preparation of Compound 161
Compound 161 was obtained by the synthesis method of reference example 160, starting from compound 161 a.
1H NMR(400MHz,CDCl3)δ8.26(s,1H),7.96(s,1H),7.80–7.74(m,2H),7.67(d,1H),7.12–7.06(m,1H),7.04–7.00(m,1H),6.87(d,1H),6.83–6.77(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.32(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.24–2.05(m,3H),1.90(s,6H),1.00–0.82(m,4H),0.70–0.55(m,4H).
LCMS m/z＝645.2[M+1]+
Example 162: preparation of Compound 162
Compound 162 was obtained by the synthesis method of reference example 74, starting from compounds 74b and 66 j.
1H NMR(400MHz,CDCl3)δ8.68(d,1H),8.43(s,1H),7.94–7.77(m,3H),7.74–7.68(m,1H),7.66–7.56(m,2H),6.58–6.48(m,1H),6.33(s,1H),5.66–5.35(m,2H),4.84–4.66(m,1H),4.50–4.33(m,2H),4.24–4.06(m,2H),3.97–3.77(m,1H),3.04–2.87(m,1H),2.85–2.50(m,2H),2.48–2.27(m,1H).
LCMS m/z＝655.0[M+1]+
Example 163: preparation of Compound 163
The first step: preparation of 163b
163A (1.0 g,4.84 mmol) was dissolved in 30mL 1, 4-dioxane and 10mL water, and 163A (1.01 g,7.22 mmol), potassium carbonate (1.07 g,7.74 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (0.39 g,0.48 mmol) were added under nitrogen and reacted at 86℃for 12h. The reaction system was cooled to room temperature, added to 50mL of water, extracted three times with 50mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =1:0-10:7) to give 163b (1.0 g, yield: 93%).
LCMS m/z＝222.1[M+1]+
Compound 163 was obtained by the synthesis method of example 104, starting with compound 163 b.
1H NMR(400MHz,CDCl3)δ8.66(s,1H),8.20(d,1H),7.92(s,1H),7.82(s,1H),7.73(s,1H),7.67(d,1H),7.51–7.42(m,2H),7.37(dd,1H),7.27–7.23(m,1H),7.13–7.04(m,2H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H),3.88–3.75(m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.97(s,6H),1.62–1.50(m,1H),1.00–0.78(m,2H),0.64–0.54(m,2H).
Example 164: preparation of Compound 164
Compound 164 was obtained by the synthesis method of reference example 165 starting from compound 164a (synthesis method see WO 2022143489).
1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.38–8.32(m,1H),8.29–8.24(m,1H),8.23–8.18(m,1H),8.07–7.97(m,1H),7.83(s,2H),7.70–7.57(m,2H),7.49–7.40(m,1H),7.39–7.30(m,1H),6.88–6.82(m,1H),6.74–6.64(m,1H),5.12–5.02(m,1H),4.47–4.35(m,2H),4.10–3.97(m,2H),3.95–3.80(m,1H),2.99–2.80(m,1H),2.68–2.52(m,2H),2.10–2.00(m,1H),1.92(s,6H),1.77–1.65(m,1H),0.96–0.84(m,2H),0.68–0.58(m,2H).
Example 165: preparation of Compound 165
Compound 165 was obtained by the synthesis method of example 147, starting with compound 165 a.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.82(s,1H),7.73(s,1H),7.67(d,1H),7.49(s,1H),6.83–6.79(m,1H),6.72(s,2H),6.56(dd,1H),4.98–4.88(m,1H),4.42–4.31(m,2H),4.13–4.02(m,2H),3.87–3.76(m,1H),2.96–2.66(m,3H),2.18–2.07(m,1H),2.02(s,6H),1.95(s,6H),1.83–1.72(m,1H),0.92–0.84(m,2H),0.66–0.57(m,2H).
LCMS m/z＝633.2[M+1]+
Example 166: preparation of Compound 166
Compound 166 was obtained by the synthesis method of reference example 44, starting from compounds 166a and 65 b.
1H NMR(400MHz,CDCl3)δ8.35(s,1H),8.11(d,1H),7.92(s,1H),7.74–7.65(m,2H),7.60–7.51(m,1H),7.34–7.26(m,1H),7.02–6.92(m,2H),6.86–6.79(m,1H),6.58(dd,1H),4.99–4.89(m,1H),4.45–4.35(m,2H),4.18–4.07(m,2H),3.94–3.80(m,1H),2.96–2.66(m,3H),2.20–2.08(m,1H),1.94–1.76(m,2H),1.08–0.98(m,2H),0.98–0.90(m,2H),0.77–0.69(m,2H),0.69–0.63(m,2H).
Example 167: preparation of Compound 167
Compound 167 was obtained by the synthesis method of example 44, starting from compounds 167a and 65 b.
1H NMR(400MHz,CDCl3)δ8.33(s,1H),8.09(d,1H),7.95(s,1H),7.83–7.77(m,2H),7.69(d,1H),7.61–7.55(m,1H),7.02–6.90(m,2H),6.86–6.80(m,1H),6.58(dd,1H),4.98–4.90(m,1H),4.45–4.35(m,2H),4.18–4.07(m,2H),3.93–3.80(m,1H),2.96–2.65(m,3H),2.20–2.08(m,1H),1.92–1.76(m,2H),1.08–0.98(m,2H),0.98–0.90(m,2H),0.78–0.69(m,2H),0.69–0.62(m,2H).
Example 168: preparation of Compound 168
Compound 168 was obtained by the synthesis method of example 166, starting from compound 168 a.
1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.35–8.27(m,2H),8.02–7.90(m,3H),7.84–7.62(m,5H),7.41–7.34(m,1H),6.84–6.76(m,1H),6.57(dd,1H),4.98–4.88(m,1H),4.48–4.35(m,2H),4.20–4.07(m,2H),3.95–3.82(m,1H),2.95–2.63(m,3H),2.18–2.07(m,1H).
LCMS m/z＝624.2[M-1]-
Example 169: preparation of Compound 169
Compound 169 was obtained by the method of synthesis of reference example 151 using compound 65b as a starting material.
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.59(d,1H),7.29(d,1H),7.25–7.19(m,1H),7.07–7.02(m,1H),6.86–6.77(m,1H),6.77–6.63(m,4H),6.57–6.40(m,2H),4.92–4.80(m,1H),4.34–4.22(m,2H),4.04–3.92(m,2H),3.79–3.62(m,1H),2.88–2.55(m,3H),2.12–2.00(m,1H),1.87–1.72(m,2H),0.94–0.80(m,4H),0.64–0.52(m,4H).
Example 170: preparation of Compound 170
Compound 170 was obtained by the synthesis method of example 153, starting from compound 75b and intermediate 2.
1H NMR(400MHz,CDCl3)δ11.07(s,1H),10.47(s,1H),8.02–7.97(m,1H),7.97–7.93(m,1H),7.91–7.83(m,1H),7.83–7.74(m,2H),7.69–7.59(m,2H),7.03(d,1H),5.12–5.02(m,1H),4.60–4.47(m,2H),4.28–4.17(m,2H),4.03–3.88(m,1H),2.96–2.79(m,1H),2.67–2.44(m,2H),2.10–1.95(m,1H).
LCMS m/z＝669.0[M-1]-
Example 171: preparation of Compound 171
Compound 171 was obtained by the synthesis method of example 66, starting from compounds 75b and 66 j.
1H NMR(400MHz,CDCl3)δ8.70(d,1H),8.44(s,1H),7.80–7.66(m,4H),7.66–7.52(m,2H),7.38–7.28(m,1H),6.53–6.45(m,1H),6.33(s,1H),5.34–5.20(m,2H),4.78–4.69(m,1H),4.38–4.27(m,2H),4.10–3.98(m,2H),3.90–3.75(m,1H),3.02–2.85(m,1H),2.72–2.55(m,1H),2.28–2.10(m,2H).
LCMS m/z＝639.1[M+1]+
Example 172: preparation of Compound 172
Compound 172 was obtained by the synthesis method of example 154, starting with compound 172 a.
1H NMR(400MHz,CDCl3)δ8.50(s,1H),8.38(s,1H),8.03–7.95(m,1H),7.82(s,1H),7.72(s,1H),7.66(d,1H),6.94–6.83(m,1H),6.83–6.78(m,1H),6.78–6.72(m,1H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.00(m,2H),3.87–3.72(m,1H),2.93–2.65(m,3H),2.17–2.07(m,1H),1.95(s,6H),1.56–1.46(m,1H),0.94–0.84(m,2H),0.58–0.49(m,2H).
LCMS m/z＝623.2[M+1]+
Example 173: preparation of Compound 173
Compound 173 was obtained by the synthesis method of reference example 44 starting from compounds 173a (see WO2021173917 for synthesis method) and 65 b.
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.12(d,1H),7.96(s,1H),7.68(d,1H),7.58(d,1H),7.53(d,1H),6.99–6.92(m,2H),6.82(d,1H),6.57(dd,1H),4.98–4.89(m,1H),4.44–4.32(m,2H),4.17–4.05(m,2H),3.91–3.77(m,1H),2.98–2.64(m,3H),2.18–2.08(m,1H),1.92–1.76(m,2H),1.10–1.00(m,2H),0.99–0.82(m,2H),0.76–0.69(m,2H),0.69–0.62(m,2H).
Example 174: preparation of Compound 174
Compound 174 was obtained by the synthesis method of example 154, starting with compound 174 b.
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.06(s,1H),7.95(d,1H),7.80(s,1H),7.74–7.63(m,2H),7.03–6.95(m,1H),6.92–6.84(m,1H),6.80(d,1H),6.55(dd,1H),4.99–4.88(m,1H),4.42–4.30(m,2H),4.12–4.01(m,2H),3.87–3.75(m,1H),2.95–2.66(m,3H),2.25(s,3H),2.18–2.06(m,1H),1.95(s,6H),1.55–1.40(m,1H),0.89–0.79(m,2H),0.56–0.46(m,2H).
LCMS m/z＝619.2[M+1]+
Example 175: preparation of Compound 175
Compound 175 was obtained by the method of example 81 using compounds 65b and 81f as starting materials.
1H NMR(400MHz,CDCl3)δ7.99(d,1H),7.93(s,1H),7.76–7.73(m,1H),7.68(d,1H),7.64–7.55(m,2H),7.52(s,1H),6.96(d,1H),6.83(d,1H),6.72(dd,1H),6.58(dd,1H),4.99–4.89(m,1H),4.44–4.35(m,2H),4.17–4.06(m,2H),3.95–3.82(m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.93–1.80(m,1H),1.72(s,6H),1.30–1.15(m,1H),0.97–0.80(m,2H),0.73–0.65(m,2H),0.53–0.43(m,2H),0.37–0.28(m,2H).
LCMS m/z＝723.3[M+1]+
Example 176: preparation of Compound 176
Compound 176 was obtained by the synthesis method of example 66, starting from compounds 65c and 66 j.
1H NMR(400MHz,CDCl3)δ8.43(s,1H),7.99–7.88(m,2H),7.79(s,1H),7.73–7.67(m,2H),6.87(dd,1H),6.83–6.77(m,1H),6.45(dd,1H),6.33–6.27(m,1H),5.32–5.18(m,2H),4.76–4.69(m,1H),4.33–4.22(m,2H),4.02–3.92(m,2H),3.83–3.70(m,1H),2.99–2.85(m,1H),2.70–2.55(m,1H),2.24–2.12(m,2H),1.94(s,6H),1.86–1.74(m,1H),1.53–1.41(m,1H),0.92–0.80(m,4H),0.64–0.56(m,2H),0.54–0.46(m,2H).
LCMS m/z＝631.7[M+1]+
Example 177: preparation of Compound 177
Compound 177 was obtained by the synthesis method of example 174, starting from compound 177 a.
1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.05(d,1H),7.99(s,1H),7.82–7.73(m,2H),7.67(d,1H),7.16(d,1H),6.80(d,1H),6.74(dd,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.32(m,2H),4.12–4.02(m,2H),3.87–3.75(m,1H),2.94–2.64(m,3H),2.18–2.08(m,1H),1.94(s,6H),1.90–1.80(m,1H),0.98–0.90(m,2H),0.72–0.62(m,2H).
Example 178: preparation of Compound 178
Compound 178 was obtained by the synthesis method of example 177, starting from compound 178 a.
1H NMR(400MHz,CDCl3)δ8.08–8.00(m,1H),7.90(s,1H),7.84(s,1H),7.74(s,1H),7.67(d,1H),7.22(dd,1H),7.10(t,1H),6.94–6.86(m,1H),6.81(d,1H),6.56(dd,1H),4.98–4.89(m,1H),4.42–4.31(m,2H),4.12–4.03(m,2H),3.88–3.74(m,1H),2.98–2.64(m,3H),2.18–2.07(m,1H),1.98(s,6H),1.80–1.68(m,1H),0.88–0.78(m,2H),0.58–0.49(m,2H).
LCMS m/z＝639.2[M+1]+
Example 179: preparation of Compound 179
The first step: preparation of 179b
179A (2.00 g,9.69 mmol) was dissolved in a mixed solvent of 20mL of toluene and 2mL of water, cyclopropylboric acid (4.15 g,48.3 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (0.79 g,1.92 mmol), pd (OAc) 2 (0.22 g,0.98 mmol) and potassium phosphate (8.20 g,38.63 mmol) were added, and after reacting at 75℃for 19 hours under nitrogen atmosphere, cyclopropylboric acid (1.66 g,19.32 mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (0.79 g,1.92 mmol) and palladium acetate (0.22 g,0.98 mmol) were added and reacted at 75℃for 5 hours under nitrogen atmosphere. The reaction system was cooled to room temperature, 100mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 179b (0.62 g, yield: 37%).
LCMS m/z＝174.1[M+1]+
Compound 179 was obtained by the synthesis method of example 80, starting with compound 179 b.
1H NMR(400MHz,CDCl3)δ8.18(s,1H),7.88–7.80(m,2H),7.73(s,1H),7.67(d,1H),7.08(t,1H),6.88–6.77(m,3H),6.55(dd,1H),4.98–4.89(m,1H),4.42–4.30(m,2H),4.13–4.03(m,2H),3.88–3.75(m,1H),2.94–2.64(m,3H),2.18–2.05(m,1H),1.98(s,6H),1.77–1.63(m,2H),0.84–0.74(m,4H),0.56–0.47(m,4H).
LCMS m/z＝645.3[M+1]+
Example 180: preparation of Compound 180
Compound 180 was obtained by the synthesis method of example 44, starting from compounds 65b and 180A.
1H NMR(400MHz,CDCl3)δ8.60–8.45(m,2H),8.24–8.10(m,2H),8.02–7.92(m,2H),7.70(d,1H),7.04–6.92(m,2H),6.88–6.80(m,1H),6.60(dd,1H),5.00–4.89(m,1H),4.48–4.38(m,2H),4.28–4.18(m,2H),4.03–3.92(m,1H),2.96–2.64(m,3H),2.18–2.07(m,1H),1.93–1.80(m,2H),1.09–1.00(m,2H),0.98–0.91(m,2H),0.78–0.63(m,4H).
Example 181: preparation of Compound 181
The first step: 181b preparation
181A (1.35 g,10.00 mmol) was dissolved in 20mL acetonitrile, NBS (2.14 g,12.02 mmol) was slowly added at 0deg.C, and after stirring at 0deg.C for 1h, the reaction was carried out at room temperature for 2h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to give 181b (1.2 g, yield: 56%).
LCMS m/z＝213.9[M+1]+
Compound 181 was obtained by the synthesis method of reference example 104, starting from compound 181 b.
1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.04(s,1H),7.82–7.72(m,2H),7.67(d,1H),7.28(s,1H),6.81(d,1H),6.67(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.63–4.53(m,2H),4.43–4.31(m,2H),4.12–4.02(m,2H),3.88–3.75(m,1H),3.01–2.65(m,5H),2.18–2.07(m,1H),1.96–1.82(m,7H),0.90–0.82(m,2H),0.70–0.62(m,2H).
Example 182: preparation of Compound 182
The first step: 182b preparation
182A (0.3 g,5.45 mmol) was dissolved in 5mL DMSO and TEA (2.21 g,21.84 mmol) and 182A (1.96 g,7.10 mmol) were added and reacted at 80℃for 3h. The reaction system was cooled to room temperature, 50mL of ethyl acetate and 50mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 182b (0.11 g, yield: 6%).
LCMS m/z＝312.1[M+1]+
And a second step of: preparation of Compound 182
182B (0.11 g,0.35 mmol), 2c (0.16 g,0.34 mmol), TEA (0.10 g,0.99 mmol), cuI (13 mg,0.068 mmol) and PdCl 2(PPh3)2 (48 mg,0.068 mmol) were added to the reaction flask and reacted at 55℃for 2h under nitrogen atmosphere with 5mL of DMF. The reaction solution was cooled to room temperature, 50mL of water was added, suction filtration was performed, the cake was washed with 10mL of water, the cake was dissolved with 60mL of DCM/MeOH (v/v) =5:1, dried over anhydrous sodium sulfate, and the crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate (v/v) =1:1.5) to give compound 182 (32 mg, yield: 14%).
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.53(d,1H),8.16(s,1H),7.77(s,1H),7.70(s,1H),7.66(d,1H),7.60–7.55(m,1H),7.53–7.46(m,1H),7.09(d,1H),6.86(dd,1H),4.99–4.74(m,2H),4.22(s,2H),3.13–2.98(m,2H),2.94–2.64(m,5H),2.30–1.98(m,3H).
LCMS m/z＝653.2[M+1]+
Example 183: preparation of Compound 183
Compound 183 was obtained by the synthesis method of reference example 44 starting from compounds 183a (see Australian Journal of Chemistry,1965,18,1351-1364) and 65 b.
1H NMR(400MHz,CDCl3)δ8.45–8.33(m,1H),8.30–8.18(m,1H),8.13(s,1H),8.06(s,1H),7.93(s,1H),7.88–7.81(m,1H),7.77(s,1H),7.69(d,1H),7.63–7.53(m,2H),7.07–6.97(m,1H),6.94(s,1H),6.84(d,1H),6.59(dd,1H),4.98–4.89(m,1H),4.47–4.35(m,2H),4.22–4.11(m,2H),3.98–3.85(m,1H),2.96–2.64(m,3H),2.20–2.08(m,1H),1.94–1.70(m,2H),1.00–0.80(m,4H),0.72–0.62(m,4H).
Example 184: preparation of Compound 184
Compound 184 was obtained by the synthesis method of reference example 183, starting from compound 184a (see Australian Journal of Chemistry,1965,18,1351-1364 for synthesis methods).
1H NMR(400MHz,CDCl3)δ8.75(d,1H),8.34–8.17(m,2H),8.04(s,1H),7.98–7.85(m,1H),7.85–7.76(m,1H),7.76–7.70(m,1H),7.68–7.48(m,5H),6.80–6.74(m,1H),6.52(dd,1H),4.92–4.81(m,1H),4.42–4.30(m,2H),4.15–4.05(m,2H),3.90–3.76(m,1H),2.90–2.55(m,3H),2.12–2.00(m,1H).
Example 185: preparation of Compound 185
The first step: 185b preparation
185A (2 g,7.52 mmol) was dissolved in 30mL of methanol, thionyl chloride (2 mL) was slowly added dropwise and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =92:8) to give 185b (1.9 g, yield: 90%).
And a second step of: 185c preparation
185B (1.9 g,6.79 mmol) was added to a 100mL single port flask, DMF (30.0 mL), tert-butyl 3-ethynylazetidine-1-carboxylate (1.8 g,9.93 mmol) and TEA (2.1 g,20.75 mmol) were added and PdCl 2(PPh3)2 (497 mg,0.71 mmol) and CuI (194 mg,1.02 mmol) were added under nitrogen and reacted at 50℃for 2h. The reaction system was cooled to room temperature, a saturated aqueous ammonium chloride solution (200 mL) was slowly added, extraction was performed with ethyl acetate (150 ml×3), the organic phase was washed with a saturated aqueous sodium chloride solution (200 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =67:33) to give 185c (1.3 g, yield: 57%).
LCMS m/z＝334.1[M+1]+
And a third step of: 185d preparation
185C (1.3 g,3.90 mmol) was added to a mixed solvent of tetrahydrofuran (30 mL) and water (10 mL), and lithium hydroxide monohydrate (819 mg,19.5 mmol) was added and reacted at room temperature for 16h. The reaction system was adjusted to pH 7 with 0.5mol/L hydrochloric acid, extracted with ethyl acetate (70 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (70 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =72:28) to give crude product 185d (700 mg). The crude 185d (130 mg) was added to a 500mL single-necked flask, dried DCM (10 mL) was added, 23c (62 mg,0.41 mmol) and TCFH (173 mg,0.62 mmol) were added, N-methylimidazole (174 mg,2.12 mmol) was slowly added dropwise and reacted at room temperature for 16h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =67:33) to give 185d (45 mg, yield: 24%).
LCMS m/z＝453.1[M+1]+
Fourth step: 185e preparation of p-toluenesulfonate salt
185D (45 mg,0.1 mmol) was added to a 500mL single-port flask, acetonitrile (5 mL) was added, and p-toluenesulfonic acid (69 mg,0.4 mmol) was added and reacted at 35℃for 4h. Concentrated under reduced pressure to give crude 185f of p-toluenesulfonate (40 mg).
LCMS m/z＝353.1[M+1]+
Fifth step: preparation of Compound 185
The crude 185f p-toluenesulfonate (40 mg) was added to a 25mL single port flask, dried DMSO (5 mL) was added, DIPEA (64 mg,0.49 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (41 mg,0.15 mmol) were added and reacted at 80℃for 2h. The reaction was cooled to room temperature, water (60 mL) was slowly added, extracted with ethyl acetate (30 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by separation on a silica gel column (petroleum ether: ethyl acetate (v/v) =23:77), the crude product was prepared by Prep-HPLC (apparatus: WATERS AUTOP preparation liquid phase; column: sunFire@PrepC18 (19X 250 nm), mobile phase A: acetonitrile; mobile phase B: water (containing 5mmol/L ammonium acetate)), gradient elution: mobile phase A content from 25-80%, flow rate: 17mL/min; column temperature: room temperature; detection wavelength: 210nm; sample was dissolved with DMF, filtered with 0.45 μm filter head, prepared into sample liquid, elution time: 15min, and freeze-dried to give compound 185 (3 mg, yield: 3%).
1H NMR(400MHz,CDCl3)δ8.50(d,1H),8.37(s,1H),7.98(s,1H),7.73–7.65(m,2H),7.62–7.53(m,2H),7.46(dd,1H),7.36–7.30(m,1H),6.84(d,1H),6.59(dd,1H),4.98–4.90(m,1H),4.48–4.35(m,2H),4.20–4.07(m,2H),3.95–3.82(m,1H),3.11(s,1H),2.96–2.65(m,3H),2.18–2.08(m,1H).
LCMS m/z＝609.7[M+1]+
Example 186: preparation of Compound 186
The first step: 186b preparation
70% Nitric acid (1.1 mL) was added dropwise to a solution of 186a (5.4 g,33.29 mmol) in TFA (60 mL) at 0deg.C for 30min, and reacted at 0deg.C for 2h. The reaction was poured into 400mL of ice water, stirred for 20min, extracted with dichloromethane (200 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =7:3) to give 186b (4.2 g, yield: 61%).
LCMS m/z＝206.1[M-1]-
And a second step of: 186c preparation
186B (1 g,4.83 mmol) was dissolved in 20mL of methanol, 10% palladium on carbon (200 mg) was added, and the mixture was reacted at room temperature under a hydrogen balloon atmosphere for 16h. The reaction system was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude 186c (800 mg).
LCMS m/z＝178.2[M+1]+
And a third step of: 186d preparation
The crude 186c (800 mg) was added to a mixed solvent of toluene (10 mL) and water (10 mL), concentrated hydrochloric acid (1.2 mL) was added, sodium nitrite (372 mg,5.39 mmol) was added at 0℃and after 30min of reaction at 0℃a solution of KI (1.6 g,9.64 mmol) in water (10 mL) was slowly added and the reaction was carried out at room temperature for 2h. Water (100 mL) was added to the reaction system, extracted with ethyl acetate (60 mL. Times.3), the organic phase was washed with saturated aqueous sodium chloride (60 mL. Times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =67:33) to give 186d (500 mg, yield: 32%).
Compound 186 was obtained by the synthesis method of example 44, starting with compound 186 d.
1H NMR(400MHz,CDCl3)δ8.65–8.54(m,1H),7.95(s,1H),7.88–7.78(m,1H),7.76–7.60(m,2H),7.58–7.50(m,1H),7.50–7.12(m,3H),6.82(d,1H),6.56(dd,1H),4.99–4.88(m,1H),4.45–4.32(m,2H),4.18–4.03(m,2H),3.95–3.77(m,1H),3.50–3.20(m,5H),2.97–2.64(m,3H),2.19–2.07(m,1H).
Example 187: preparation of Compound 187
Compound 187 was obtained by the synthesis method of example 147, starting from compound 187 a.
1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.83(s,1H),7.75–7.61(m,3H),6.83–6.78(m,1H),6.73–6.67(m,1H),6.59–6.52(m,2H),4.98–4.88(m,1H),4.42–4.30(m,2H),4.13–4.02(m,2H)3.88–3.76(m,1H),2.95–2.65(m,3H),2.18–2.08(m,1H),2.05(s,3H),1.96(s,6H),1.83–1.73(m,1H),1.65–1.55(m,1H),0.93–0.84(m,2H),0.81–0.71(m,2H),0.63–0.57(m,2H),0.54–0.45(m,2H).
LCMS m/z＝659.3[M+1]+
Example 188: preparation of Compound 188
The first step: 188b preparation
2B (2.30 g,7.18 mmol) was dissolved in 20mL tetrahydrofuran, 4mL water was added, and lithium hydroxide monohydrate (0.6 g,14.3 mmol) was added and reacted at room temperature for 30min. To the reaction solution was added dropwise 1mol/L diluted hydrochloric acid to adjust pH to 6, 50mL of ethyl acetate was added, the solution was separated, the organic phase was washed with 20mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (2.0 g). The crude product (0.56 g) was dissolved in 20mL of methylene chloride, 1-chloro-N, N, 2-trimethylpropenamine (0.34 g,2.54 mmol) was added dropwise, and after reacting at room temperature for 2 hours, 188a (0.25 g,1.18 mmol) and TEA (0.71 g,7.02 mmol) were added in this order, and reacted at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give 188b (0.45 g, yield: 79%).
And a second step of: preparation of Compound 188
188B (0.45 g,0.93 mmol) was dissolved in 10mL DMF and the crude intermediate 1 (0.5 g), TEA (0.25 g,2.47 mmol), cuI (0.032 g,0.17 mmol) and PdCl 2(PPh3)2 (0.058 g,0.083 mmol) were added sequentially and reacted at 60℃for 2h. The reaction system was cooled to room temperature, 40mL of saturated ammonium chloride solution was added, filtration was performed, the cake was dissolved with 20mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =1:2) to give compound 188 (0.33 g, yield: 51%).
1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.40(d,1H),8.06(s,1H),7.82–7.63(m,3H),7.24–7.19(m,1H),7.17–7.09(m,1H),6.80(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.43–4.30(m,2H),4.14–4.00(m,2H),3.88–3.74(m,1H),3.14–2.99(m,2H),2.96–2.65(m,5H),2.30–2.00(m,3H).
LCMS m/z＝693.1[M-1]-
Example 189: preparation of Compound 189
The first step: 189b
189A (3.00 g,12.69 mmol) was dissolved in a mixed solvent of 30mL of ethanol and 10mL of water, and reduced iron powder (2.12 g,37.86 mmol) and 10mL of acetic acid were added and reacted at room temperature for 19 hours. The reaction solution was adjusted to pH7 with 5mol/L aqueous sodium hydroxide solution, 100mL of water and 100mL of ethyl acetate were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 189b (2.3 g, yield: 88%).
LCMS m/z＝206.0[M+1]+
Compound 189 was obtained by the synthesis method of example 174, starting from compound 189 b.
1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.15–8.07(m,2H),7.83–7.75(m,2H),7.65(d,1H),7.12(t,1H),6.79(d,1H),6.74–6.67(m,1H),6.54(dd,1H),4.97–4.87(m,1H),4.40–4.29(m,2H),4.12–4.01(m,2H),3.88–3.73(m,1H),2.97–2.63(m,3H),2.18–2.02(m,2H),1.94(s,6H),1.00–0.90(m,2H),0.67–0.57(m,2H).
LCMS m/z＝639.8[M+1]+
Example 190: preparation of Compound 190
The first step: 190b
190A (1.0 g,6.80 mmol) was dissolved in 20mL DMF and NBS (1.21 g,6.80 mmol) was added at 0deg.C and reacted for 0.5h at 0deg.C. To the reaction solution were added 50mL of ethyl acetate and 50mL of water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 190b (700 mg, yield: 46%).
And a second step of: 190c preparation
190B (600 mg,2.65 mmol) was dissolved in 5mL trifluoroacetic acid and triethylsilane (3.08 g,26.49 mmol) was added and reacted at 60℃for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, the residue was adjusted to pH 9 with saturated aqueous sodium bicarbonate, 50mL of ethyl acetate and 50mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on a silica gel column (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 190c (510 mg, yield: 91%).
Compound 190 was obtained by the synthesis method of reference example 165, starting from compound 190 c.
1H NMR(400MHz,CDCl3)δ8.42(s,1H),8.00(s,1H),7.88(d,1H),7.80(s,1H),7.72–7.64(m,2H),7.07(d,1H),6.81(d,1H),6.55(dd,1H),4.98–4.89(m,1H),4.40–4.32(m,2H),4.12–4.02(m,2H),3.87–3.75(m,1H),2.97–2.64(m,7H),2.18–2.07(m,1H),2.06–1.90(m,8H),1.51–1.40(m,1H),0.92–0.80(m,2H),0.45–0.37(m,2H).
LCMS m/z＝645.4[M+1]+
Example 191: preparation of Compound 191
Compound 191 was obtained by the synthesis method of example 180 using compounds 191A and 191A as starting materials.
1H NMR(400MHz,CDCl3)δ8.76(d,1H),8.62(s,1H),8.51(d,1H),8.18(d,1H),8.06–7.96(m,2H),7.75–7.67(m,2H),7.65–7.59(m,1H),6.84(d,1H),6.60(dd,1H),4.99–4.90(m,1H),4.49–4.40(m,2H),4.28–4.17(m,2H),4.05–3.92(m,1H),2.98–2.65(m,3H),2.20–2.03(m,1H).
Example 192: preparation of Compound 192
The first step: 192b preparation
192A (3.00 g,13.04 mmol) was dissolved in a mixed solvent of 30mL of toluene and 3mL of water, and cyclopropylboric acid (1.76 g,20.49 mmol), tricyclohexylphosphine (0.89 g,3.17 mmol), palladium acetate (0.35 g,1.56 mmol) and potassium phosphate (11.73 g,55.26 mmol) were added and reacted at 100℃under nitrogen for 19 hours. The reaction system was cooled to room temperature, 100mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 192b (2.05 g, yield: 82%).
And a second step of: 192c preparation
192B (1.00 g,5.23 mmol) was dissolved in 10mL acetonitrile, KI (1.30 g,7.83 mmol) and CuI (1.49 g,7.82 mmol) were added, nitrosoisoamyl ester (1.10 g,9.39 mmol) was added at 75deg.C and reacted at 75deg.C for 2h. The reaction system was cooled to room temperature, 80mL of ethyl acetate and 100mL of water were added, the filtrate was separated by suction filtration, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 192c (0.65 g, yield: 41%).
And a third step of: 192d preparation
192C (0.65 g,2.15 mmol) was dissolved in 5mL of methanol and 1mL of water, and lithium hydroxide monohydrate (0.45 g,10.72 mmol) was added and reacted at room temperature for 2h. The reaction solution was adjusted to pH 3 with 1mol/L hydrochloric acid, 20mL of ethyl acetate was added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =5:1-1:1) to give 192d (0.45 g, yield: 73%).
Compound 192 was obtained by the synthesis method of example 44, starting with compound 192 d.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.81(s,1H),7.76(s,1H),7.68(d,1H),7.58–7.43(m,3H),7.29(s,1H),7.17(s,1H),6.82(d,1H),6.57(dd,1H),4.99–4.87(m,1H),4.44–4.32(m,2H),4.17–4.03(m,2H),3.90–3.78(m,1H),2.96–2.66(m,3H),2.19–2.06(m,1H),1.89–1.72(m,1H),1.04–0.91(m,2H),0.72–0.52(m,2H).
Example 193: preparation of Compound 193
Compound 193 was obtained by the synthesis method of reference example 81, starting from compound 80 b.
1H NMR(400MHz,CDCl3)δ8.12(d,1H),7.93(s,1H),7.78–7.64(m,2H),7.62–7.54(m,2H),7.34(s,1H),7.01–6.93(m,2H),6.83(d,1H),6.57(dd,1H),4.98–4.89(m,1H),4.45–4.32(m,2H),4.17–4.06(m,2H),3.93–3.82(m,1H),2.95–2.65(m,3H),2.18–2.05(m,1H),1.90–1.77(m,1H),1.70(s,6H),0.98–0.80(m,2H),0.67–0.57(m,2H).
Example 194: preparation of Compound 194
Compound 194 was obtained by the synthesis method of reference example 168, starting from compound 80 b.
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.17(s,1H),7.93(s,1H),7.80–7.72(m,1H),7.69(d,1H),7.63–7.55(m,1H),7.38(d,1H),7.26(d,1H),7.08(dd,1H),6.89(d,1H),6.74(dd,1H),5.11–5.02(m,1H),4.48–4.37(m,2H),4.17–4.05(m,2H),4.05–3.92(m,1H),2.98–2.80(m,1H),2.68–2.46(m,2H),2.10–1.90(m,2H),1.03–0.94(m,2H),0.77–0.69(m,2H).
Example 195: preparation of Compound 195
The first step: 195b
Pyrazole (0.75 g,11.02 mmol) was dissolved in 30mL of tetrahydrofuran, 60% sodium hydride (0.29 g) was added at 0deg.C, and after 30min at room temperature, 195a (2.2 g,10 mmol) was added and reacted at 60deg.C for 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =3:1) to give 195b (2.1 g, yield: 79%).
LCMS m/z＝268.1[M+1]+
And a second step of: 195c preparation
195B (2.1 g,7.86 mmol) was dissolved in 50mL of ethanol, and reduced iron powder (2.24 g,40 mmol) and 10mL of saturated aqueous ammonium chloride solution were added and reacted under reflux for 1h. The reaction system was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, 80mL of ethyl acetate and 50mL of purified water were added, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 195c (1.64 g).
Compound 195 was obtained by the synthesis method of reference example 165, starting from compound 195 c.
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.38(s,1H),8.22(d,1H),7.90–7.80(m,2H),7.77–7.60(m,3H),7.53–7.37(m,2H),6.80(s,1H),6.54(d,1H),6.43(s,1H),5.01–4.86(m,1H),4.44–4.27(m,2H),4.15–3.96(m,2H),3.90–3.70(m,1H),2.96–2.62(m,3H),2.20–2.04(m,1H),1.97(s,6H),1.64–1.47(m,1H),1.02–0.82(m,2H),0.70–0.54(m,2H).
Example 196: preparation of Compound 196
Compound 196 was obtained by the method of example 164 using compound 196a (CN 111138307) as a starting material.
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.30(s,1H),8.27(s,2H),7.91(s,1H),7.86–7.74(m,2H),7.66(d,1H),7.57–7.48(m,1H),7.36–7.29(m,1H),7.29–7.21(m,1H),6.88–6.83(m,1H),6.70(dd,1H),5.12–5.01(m,1H),4.45–4.33(m,2H),4.10–3.97(m,2H),3.95–3.80(m,3H),2.98–2.80(m,1H),2.65–2.52(m,2H),2.10–1.98(m,1H),1.88(s,6H),1.75–1.65(m,1H),0.90–0.75(m,2H),0.65–0.57(m,2H).
Example 197: preparation of Compound 197
Compound 197 was obtained by the synthesis method of example 163, starting from compound 197 a.
1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.39(d,1H),8.12(s,1H),7.85–7.77(m,2H),7.68(d,1H),7.58–7.51(m,1H),7.48–7.26(m,3H),7.24–7.07(m,2H),6.84–6.77(m,1H),6.55(dd,1H),4.99–4.88(m,1H),4.43–4.28(m,2H),4.14–4.02(m,2H),3.88–3.75(m,1H),2.98–2.65(m,3H),2.20–2.05(m,1H),1.97(s,6H).
Example 198: preparation of Compound 198
The first step: 198b preparation
198A (3.16 g,12.68 mmol) was dissolved in a mixed solvent of 30mL of ethanol and 10mL of water, and reduced iron powder (2.13 g,38.04 mmol) and ammonium chloride (3.39 g,63.38 mmol) were added and reacted at 80℃for 3 hours. The reaction system was cooled to room temperature, 100mL of ethyl acetate and 100mL of water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =10:1-1:1) to give 198b (1.4 g, yield: 50%).
Compound 198 was obtained by the synthesis method of example 192, starting with compound 198 b.
1H NMR(400MHz,CDCl3)δ8.00(br.s,1H),7.86–7.78(m,2H),7.74–7.60(m,2H),7.57–7.51(m,1H),7.39–7.32(m,1H),7.28–7.23(m,1H),7.01(d,1H),6.86–6.80(m,1H),6.58(dd,1H),5.00–4.87(m,1H),4.47–4.35(m,2H),4.18–4.07(m,2H),3.95–3.80(m,1H),2.97–2.68(m,3H),2.20–2.05(m,1H).
Example 199: preparation of Compound 199
Compound 199 was obtained by the synthesis method of example 198 using compound 199a as a starting material.
1H NMR(400MHz,CDCl3)δ8.78–8.72(m,1H),8.29–8.21(m,1H),8.05–7.46(m,8H),7.43–7.32(m,1H),6.88–6.80(m,2H),6.64–6.55(m,1H),4.99–4.87(m,1H),4.49–4.36(m,2H),4.23–4.10(m,2H),3.99–3.85(m,1H),2.98–2.65(m,3H),2.20–2.07(m,1H).
Example 200: preparation of Compound 200
Compound 200 was obtained by the synthesis method of example 159, starting with compound 80 b.
1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.96(s,1H),7.82(s,1H),7.75(s,1H),7.67(d,1H),7.01(s,2H),6.84–6.77(m,1H),6.55(dd,1H),4.98–4.88(m,1H),4.43–4.30(m,2H),4.14–4.02(m,2H),3.88–3.75(m,1H),2.96–2.62(m,3H),2.20–2.06(m,1H),1.95(s,6H),1.88–1.74(m,1H),1.06–0.94(m,2H),0.72–0.60(m,2H)
Example 201: preparation of Compound 201
The first step: 201b preparation
201A (0.5 g,1.39 mmol) was added to 10mL of DMSO under nitrogen (see WO2017036968 for synthesis), methyl 3-piperidinecarboxylate (0.24 g,1.68 mmol), cuI (0.082 g,0.43 mmol), L-proline (0.19 g,1.65 mmol) and potassium carbonate (0.39 g,2.82 mmol) and reacted at 70℃for 18h. The reaction system was cooled to room temperature, added to 50mL of water, extracted with ethyl acetate (50 ml×3), the organic phase was washed with saturated aqueous sodium chloride (50 ml×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to give 201b (0.1 g, yield: 19%).
LCMS m/z＝375.4[M+1]+
And a second step of: 201c preparation
201B (0.1 g,0.27 mmol) was dissolved in 2mL of methanol, the pH was adjusted to 10 with 2mol/L aqueous sodium hydroxide solution, and the reaction was carried out at room temperature for 2h. To the reaction solution was added 20mL of water, the pH was adjusted to 3 with 2mol/L hydrochloric acid, extraction was performed with ethyl acetate (30 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product (0.05 g). The crude product (0.05 g) was dissolved in 2mL DCM and 16B (0.022 g,0.14 mmol), TCFH (0.059 g,0.21 mmol) and N-methylimidazole (0.046 g,0.56 mmol) were added and reacted at room temperature for 12h. To the reaction solution were added 50mL of methylene chloride and 50mL of water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =1:0-3:1) to give 201c (0.04 g, yield: 57%).
LCMS m/z＝501.2[M+1]+
And a third step of: preparation of 201d trifluoroacetate salt
201C (0.04 g,0.08 mmol) was dissolved in 6mL of dichloromethane, 2mL of trifluoroacetic acid was added and stirred at room temperature for 1h. The reaction system was concentrated under reduced pressure to give crude trifluoroacetate salt 201d (0.032 g).
LCMS m/z＝401.5[M+1]+
Fourth step: preparation of Compound 201
The crude product 201d trifluoroacetate salt (0.032 g) was dissolved in 5mL DMSO, DIPEA (0.062 g,0.48 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.044 g,0.16 mmol) were added and reacted at 90℃for 1.5h. The reaction system was cooled to room temperature, added to 40mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (40 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: dichloromethane: ethyl acetate (v/v) =1:1:0-1:1:1) to give compound 201 (0.005 g, yield: 5%).
1H NMR(400MHz,CDCl3)δ9.67(s,1H),8.51(d,1H),7.99(s,1H),7.68(d,1H),7.51(dd,1H),7.38–7.26(m,3H),7.10–6.95(m,2H),6.90–6.80(m,1H),6.59(dd,1H),5.00–4.86(m,1H),4.54–4.37(m,2H),4.10–3.90(m,3H),3.77–3.65(m,1H),3.54–3.37(m,1H),3.28–3.15(m,1H),3.10–2.65(m,5H),2.22–1.76(m,5H),1.62–1.47(m,1H),0.82–0.44(m,4H).
LCMS m/z＝657.2[M+1]+
Example 202: preparation of Compound 202
The first step: 202a preparation
146F (0.3 g,0.95 mmol), ethyl 1-bromocyclobutanoate (0.2 g,0.97 mmol) and cesium carbonate (0.62 g,1.9 mmol) are dissolved in 10mL acetonitrile and reacted at 50℃for 16h. The reaction was cooled to room temperature, filtered, the filtrate was added to 50mL of water, extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was isolated and purified by prep-TLC (petroleum ether: ethyl acetate (v/v) =5:1), yielding 202a (70 mg, yield: 17%).
LCMS m/z＝444.2[M+1]+
And a second step of: 202b preparation
202A (0.07 g,0.158 mmol) was dissolved in 2mL of methanol, the pH was adjusted to 10 with 2mol/L aqueous sodium hydroxide solution, and the reaction was carried out at room temperature for 2 hours. The reaction system was added to 50mL of water, pH was adjusted to 2 with 2mol/L hydrochloric acid, extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product (50 mg). The crude product (50 mg) was dissolved in 2mL of DCM, 3-chloro-4-aminotrifluorotoluene (0.023 g,0.12 mmol), TCFH (0.051 g,0.182 mmol) and N-methylimidazole (0.039 g,0.475 mmol) were added and reacted at room temperature for 12h. To the reaction solution were added 50mL of methylene chloride and 50mL of water, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether: ethyl acetate (v/v) =1:0-3:1) to give 202b (0.04 g, yield: 56%).
And a third step of: preparation of 202c trifluoroacetate salt
202B (0.04 g,0.067 mmol) was dissolved in 6mL of dichloromethane, 2mL of trifluoroacetic acid was added and reacted at room temperature for 1h. The reaction system was concentrated under reduced pressure to give crude 202c trifluoroacetate salt (0.033 g).
Fourth step: preparation of Compound 202
The crude 202c trifluoroacetate salt (0.033 g) was dissolved in 5mL DMSO, DIPEA (0.053 g,0.41 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.044 g,0.16 mmol) were added and reacted at 90℃for 1.5h. The reaction system was cooled to room temperature, added to 40mL of ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride (40 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: dichloromethane: ethyl acetate (v/v) =1:1:0-1:1:1) to give compound 202 (5 mg, yield: 4%).
Biological test case
1. Inhibition of 22RV1 cell proliferation assay
Prostate cancer cells 22RV1 were purchased from ATCC and cultured in RPMI 1640+10% FBS at 37℃in 5% CO 2 incubator. Cells in exponential growth phase were collected on the first day, cell suspensions were adjusted to the corresponding concentrations with 1% css-FBS phenol red free medium, plated, cells were 2000 cells/well, and incubated overnight. The next day, different concentrations of the compound were added and placed in incubator for further incubation for 7 days. After the incubation, 50. Mu.L of CellTiter-Glo reagent, which had been melted and equilibrated to room temperature in advance, was added to each well according to the protocol of CellTiter-Glo kit (Promega, G7573), and the mixture was homogenized for 2 minutes with a microplate shaker, and after 10 minutes of standing at room temperature, the fluorescence signal value was measured with an enzyme-labeled instrument (PHERASTAR FSX). As a result, the inhibition ratios of the respective concentrations of the compounds were calculated by the process of the formula (1), and IC 50 values having 50% inhibition ratios of the compounds were calculated using DoseResp functions using origin9.2 software. Where RLU compound is a readout of the drug-treated group and RLU control is an average of the DMSO solvent control group. Inhibit% = [1-RLU compound/RLUcontrol ] ×100% formula (1)
The results of IC 50 values inhibiting 22RV1 cell proliferation are shown in Table 1.
TABLE 1 IC50 values for compounds of the invention to inhibit 22RV1 cells
Conclusion: the compounds of the present invention, such as the compounds of examples, have good inhibitory effect on prostate cell 22RV1, as shown in table 1.
Degradation experiments of AR cleavage mutant 7 (AR-V7) in 2.22RV1 cells
Prostate cancer cells 22RV1 were purchased from ATCC with 1640+10% fbs as cell culture medium and cultured in 5% co 2 incubator at 37 ℃. Cells in exponential growth phase were collected on the first day, cell suspensions were plated at corresponding concentrations with 1% css-FBS phenol red free medium, 1mL per well in 6-well plates, and the number of cells was 300000 cells/well. The following day 1% css-FBS phenol red free medium containing the test compound was added, one well was added with 0.2% DMSO 1% css-FBS phenol red free medium as DMSO vehicle control, and 6 well plates were incubated in 5% CO 2 incubator at 37 ℃. After 24 or 48 hours, the cells were trypsinized, collected in 1.5mL centrifuge tubes, 15. Mu.L of RIPA lysate (containing 1 Xprotease inhibitor cocktail (Protease Inhibitor cocktail)) was added to each well, and after 15 minutes of lysis on ice, 12000g was centrifuged at 4℃for 10 minutes. The supernatant protein samples were collected and protein quantification was performed by BCA method. AR-V7 was detected using full-automatic protein expression quantitative analysis, the experimental procedure was as follows, with the protein concentration to be measured diluted to 2mg/mL. mu.L of the diluted protein sample was taken and added to 1. Mu.L of 5 XMaster Mix (provided by the kit), and the prepared sample was denatured at 95℃for 5 minutes and placed on ice for use. The primary antibodies were diluted with Antibody Diluent II (kit provided) in the ratio of 1:10 and 1:500 for AR V7 (CST, 19672S) and beta-actin (CST, 3700), respectively. The secondary antibody is a 1:1 mixed goat anti-mouse and goat anti-rabbit secondary antibody, and the color developing solution is Lumino-S and Peroxide mixed in a 1:1. And sequentially adding the prepared reagents into a detection plate according to the instruction of the kit, and detecting on the machine. Western banding processing the Western bands were automatically simulated according to signal values using the full automatic protein expression quantitative analysis software "Compass for SW". The degradation rate of AR-V7 (2) relative to vehicle control at different drug concentrations was calculated according to formula (2). Wherein AR-V7 compound is the relative peak area of AR-V7 in the administration group, and AR-V7 solvent is the relative peak area of AR-V7 in the vehicle control group. AR-V7% = (1-AR-V7 compound/AR-V7solvent). Times.100% formula (2)
DC 50 calculation: compound concentration DC 50 values at 50% AR-V7 degradation were calculated using Graphpad software and analyzed using log (inhibitor) vs. response-Variable slope (four parameters) functions, following the procedure of formula (2).
TABLE 2 48 hours degradation of DC of AR-V7 50
Conclusion: the compounds of the present invention, e.g., the compounds of the examples, have good degradation of AR-V7 in prostate cell 22RV 1.
3. Rat pharmacokinetic testing
The purpose of the experiment is as follows: the test evaluates the in vivo pharmacokinetic profile of the test agent in rats by administering the test agent to SD rats intravenously and intragastrically, and determining the concentration of the test agent in the plasma of the rats.
Test animals: male SD rats, 200-250 g, 6-8 weeks old, 6/compound. Purchased from Chengdu laboratory animals Inc.
The test method comprises the following steps: on the day of the test, 6 SD rats were randomly grouped by body weight. The water is not forbidden for 12-14 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
TABLE 3 Table 3
* The dosages are calculated as the free base.
Sampling: isoflurane was anesthetized before and after dosing by orbital blood extraction of 0.1mL and placed in EDTAK centrifuge tubes. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min.
Plasma time points for IV & PO group collection: 0,5min,15min,30min,1,2,4,6,8,24h.
All samples were stored at-60 ℃ prior to analytical testing. The samples were quantitatively analyzed by LC-MS/MS.
TABLE 4 pharmacokinetic parameters of the compounds of the invention in rat plasma
* And (3) injection: (lavage) administering the compound; N/A: unmeasured test
Conclusion: the compounds of the invention, such as the examples, have better oral absorption in rats.
4. Mouse pharmacokinetic test
4.1 Test animals: male ICR mice, 25-30 g, 6/compound. Purchased from Chengdu laboratory animals Inc.
4.2 Test design: on the day of the test, 6 ICR mice were randomly grouped by body weight. The water is not forbidden for 12-14 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
TABLE 5 dosing information
Note that: intravenous vehicle 5% dma +5% solutol +90% saline;
Orally (lavage) administered vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
* The dosages are calculated as the free base.
Before and after administration, 0.1mL of isoflurane was anesthetized and collected via orbit, placed in EDTAK centrifuge tube, centrifuged at 5000rpm at 4℃for 10min, and plasma was collected. Blood sampling time points of the venous group and the gastric lavage group are: 0,5,15,30min,1,2,4,7,24h. All samples were subjected to quantitative analysis by LC-MS/MS at-60 ℃ prior to analytical detection.
Conclusion: the compounds of the invention, such as the examples, have better oral absorption in mice.
5. Beagle pharmacokinetic testing
Test animals: male beagle, about 8-10 kg, 6 compounds per unit, purchased from Beijing Mas Biotechnology Co., ltd.
The test method comprises the following steps: on the day of the trial, 6 beagle dogs were randomly grouped by body weight. The water is not forbidden for 14-18 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
TABLE 6 dosing information
Note that: intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
Orally (lavage) administered vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
* The dosages are calculated as the free base.
Blood 1mL was taken through the jugular vein or the limb vein before and after administration and placed in EDTAK centrifuge tubes. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min. Blood sampling time points of the venous group and the gastric lavage group are: 0,5,15,30min,1,2,4,6,8,10,12,24,48h. All samples were subjected to quantitative analysis by LC-MS/MS at-80 ℃.
Conclusion: the compounds of the invention, such as the examples, have better oral absorption in dogs.
6. Monkey pharmacokinetic testing
Test animals: male cynomolgus monkey, 3-5 kg, 3-6 age, 4/compound. Purchased from western mountain biotechnology limited, su.
The test method comprises the following steps: on the day of the experiment, 4 monkeys were randomized by body weight. The water is not forbidden for 14-18 h after 1 day of feeding, and the feed is fed for 4h after the feeding.
TABLE 7 dosing information
Note that: intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;
Orally (lavage) administered vehicle: 5% DMSO+5% Solutol+30% PEG400+60% (20% SBE-CD);
* The dosages are calculated as the free base.
1.0ML of blood was taken through the vein of the extremities before and after administration and placed in a EDTAK centrifuge tube. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min. Blood sampling time points of the venous group and the gastric lavage group are: 0,5,15,30min,1,2,4,6,8,10,12,24h. All samples were subjected to quantitative analysis by LC-MS/MS at-80 ℃.
Conclusion: with the compounds of the invention, for example, the compounds of the examples have better oral absorption in monkeys.
HERG Potassium ion channel action test
Experiment platform: electrophysiological manual patch clamp system
Cell line: chinese Hamster Ovary (CHO) cell lines stably expressing hERG potassium ion channels
The experimental method comprises the following steps: CHO (CHINESE HAMSTER Ovary) cells stably expressing hERG potassium channels hERG potassium channel currents were recorded using whole cell patch clamp technique at room temperature. The glass microelectrode is formed by drawing a glass electrode blank (BF 150-86-10, sutter) through a drawing instrument, the tip resistance after the electrode inner liquid is poured is about 2-5MΩ, and the glass microelectrode can be connected to a patch clamp amplifier after being inserted into an amplifier probe. The clamp voltage and data recording are controlled and recorded by pClamp 10 software through a computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz. After whole cell recordings were obtained, the cells were clamped at-80 mV and the step voltage inducing hERG potassium current (I hERG) was applied from-80 mV to a depolarization voltage of 2s to +20mV, repolarized to-50 mV for 1s and back to-80 mV. This voltage stimulus was administered every 10s, and the administration was started after the hERG potassium current had stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells were tested per concentration (n.gtoreq.2).
And (3) data processing: the data analysis was performed using pClamp 10,GraphPad Prism 5 and Excel software. The extent of inhibition of hERG potassium current (-peak hERG tail current induced at 50 mV) by different compound concentrations was calculated using the following formula: inhibition% = [1- (I/Io) ] ×100%
Wherein Inhibition% represents the percent Inhibition of the compound on hERG potassium current, and I and Io represent the magnitude of hERG potassium current after and before dosing, respectively.
Compound IC 50 was calculated using GRAPHPAD PRISM 5 software by fitting the following equation: y=bottom+ (Top-Bottom)/(1+10 ((LogIC 50 -X) × HillSlope))
Wherein X is the Log value of the detection concentration of the sample, Y is the inhibition percentage under the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages respectively.
Conclusion: the compounds of the invention, e.g., the example compounds, do not have significant inhibitory effects on hERG potassium channel current.
8. Liver microsome stability test
The experiment adopts five hepatic microsomes of human, canine, rat and mouse as in vitro models to evaluate the metabolic stability of the test subjects.
At 37 ℃,1 mu M of the test substance is incubated with microsomal protein and coenzyme NADPH together, the reaction is stopped after a certain time (5, 10,20,30,60 min), ice-cold acetonitrile containing an internal standard is added, the concentration of the test substance in a sample is detected by adopting an LC-MS/MS method, T 1/2 is obtained according to the ln value of the drug residual rate in an incubation system and the incubation time, and the intrinsic clearance CL int(mic) of the liver microsome and the intrinsic clearance CL int(Liver) of the liver are further calculated.
Conclusion: the compounds of the present invention, e.g., the example compounds, have good liver microsomal stability.
CYP450 enzyme inhibition test
The objective of this study was to evaluate the effect of the test substances on the activity of 5 isoenzymes (CYP 1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A 4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. The specific probe substrate of CYP450 isozymes is respectively incubated with human liver microsomes and test substances with different concentrations, reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) is added to start the reaction, after the reaction is finished, the metabolic products generated by the specific substrates are quantitatively detected by processing the samples and adopting liquid chromatography-tandem mass spectrometry (LC-MS/MS), the change of the CYP enzyme activity is measured, the IC 50 value is calculated, and the inhibition potential of the test substances on each CYP enzyme subtype is evaluated.
Conclusion: the compounds of the present invention, such as the example compounds, have no significant inhibitory effect on the 5 isozymes of human liver microsomal cytochrome P450.
Caco2 permeability test
The assay uses a monolayer of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES,pH 7.4.+ -. 0.05) containing the compound of the invention (2. Mu.M) or the control compound digoxin (10. Mu.M), nadolol (2. Mu.M) and metoprolol (2. Mu.M) was added to the apical or basal side dosing wells. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation for 2 hours at 37±1 ℃, the cell plates were removed and appropriate amounts of samples were taken from each of the top and bottom ends into a new 96-well plate. The protein was then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC MS/MS and the concentrations of the compounds of the invention and control compounds were determined. The concentration data were used to calculate apparent permeability coefficients from the apical to basal side of the monolayer cells, and basal to apical transport, and thus the efflux rate. The integrity of the monolayer after incubation for 2 hours was assessed by leakage of fluorescein.
Conclusion: the compounds of the present invention, such as the example compounds, have some Caco2 permeability.
11. Experiment of inhibiting growth of mouse 22RV1 subcutaneous transplantation tumor model by the compound
Cell culture: 22RV1 cells (from ATCC) were cultivated in vitro by addition of 10% foetal calf serum and of a medium containing 10. Mu.g/mL recombinant insulin, 37℃and 5% CO 2. Passaging is routinely performed 2 times a week. Cells were harvested, counted and inoculated while the cells remained in the exponentially growing phase.
Animals: BALB/c nude mice, male, 4-6 weeks old, weight 14-20 g. Is provided by Beijing Vitolihua laboratory animal technology Co.
Tumor inoculation: experimental mice were inoculated subcutaneously on the right back with 5 x 10 6 RV1 cells, resuspended in PBS and matrigel (1:1), and tumor growth was observed periodically and castrated until the tumor had grown to an average volume of 80mm 3: mice were anesthetized with isoflurane, surgical castration was performed through a scrotal midline incision, bilateral access was allowed, after each testis was exposed, the spermatic cord was ligated with 5-0vicryl sutures, then the testes were excised, then scrotum and skin were sutured with 5-0Vicyryl, respectively, and the animals were observed continuously after surgery until complete recovery. After castration, the tumor may shrink (tumor regression), beginning the grouping and treatment when the average tumor volume regrows to around 100mm 3, day 0.
Administration: the compounds of the invention were dosed orally (PO), once daily (QD), 10 mice per group, and all groups were dosed for 28 days.
Experimental observation and end: mice body weight and tumor measurements were measured 3 times a week. The experiment was ended 28 days after dosing, and all mice were euthanized. Tumor volume calculation formula: tumor volume (mm 3)＝1/2×(a×b2) (where a represents the long diameter and b represents the short diameter), raw data were measured by balance and vernier caliper.
Conclusion: the compound disclosed by the invention, such as an example compound, has a certain inhibition effect on the growth of a mouse 22RV1 subcutaneous transplantation tumor model.
HEK293 cell proliferation assay
Human embryonic kidney 293 cells HEK293 were purchased from ATCC, and the complete medium was EMEM+10% FBS, and cultured in 5% CO 2 incubator at 37 ℃. Cells in exponential growth phase were collected, cell suspensions were adjusted to the corresponding concentrations with complete medium and plated to give 1000 cells/well and a volume of 180 μl per well. The next day 20. Mu.L of the compound was added and the incubation in incubator continued for 7 days. After the completion of the incubation, 50. Mu.L of CTG solution previously melted and equilibrated to room temperature was added to each well according to the protocol of CellTiter-Glo kit (Promega, G7573), and the mixture was homogenized for 2 minutes with a microplate shaker, and after 10 minutes at room temperature, the fluorescence signal value was measured with an enzyme-labeled instrument (PHERASTAR FSX). Chemiluminescence readings were plotted using GRAPHPAD PRIM 8.0.0 software using a four parameter nonlinear regression model to plot S-type concentration curves and calculate IC 50 values. As a result, the proliferation rate Growth of each concentration of the compound was calculated by the treatment of the formula (3), and the concentration IC 50 value of the compound at a proliferation rate of 50% was calculated by using GRAPHPAD PRIM 8.0.0 software. Where RLU compound is a readout of the drug-treated group and RLU control is an average of the solvent control group. Growth% = RLU compound/RLUcontrol ×100% formula (3)
The results of IC 50 values inhibiting HEK293 cell proliferation are shown in table 8.
TABLE 8 IC50 values for compounds of the invention to inhibit HEK293 cells
Conclusion: the compounds of the present invention, such as the example compounds, have weak inhibitory effect on HEK293, a human embryonic kidney 293 cell, as shown in Table 8.
Claims (14)
- A compound or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of compounds of formula (I), B-L-K (I);L is selected from a bond or a-C 1-50 hydrocarbyl-, of which 1 to 20 methylene units are optionally replaced by-Ak-, -Cy-;each-Ak-is independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-NRL(CH2)qC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-(C≡C)q-、-CH＝CH-、-Si(RL)2-、-Si(OH)(RL)-、-Si(OH)2-、-P(＝O)(ORL)-、-P(＝O)(RL)-、-S-、-S(＝O)-、-S(＝O)2- or a bond, said-CH 2 -, -ch=ch-optionally substituted with 1 to 2 substituents selected from halogen, OH, CN, NH 2、C1-6 alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl;q is each independently selected from 0,1, 2, 3,4, 5 or 6;R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;each-Cy-is independently selected from a bond or one of the following optionally substituted groups: 4-8 membered heteromonocyclic ring, 4-10 membered heteromonocyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4 to6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, substituted with 1 to 4R L2, said heterocyclyl, heteroaryl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring containing 1 to4 heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally substituted with 1 or 2 = O;R L2 is each independently selected from deuterium, F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-4 alkylene-O-C 1-4 alkyl, -O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkylene-O-C 3-10 carbocyclyl, -O-C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl optionally being substituted with 1 to 4 groups selected from F, cl, br, I. OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, halogen substituted C 1-4 alkyl, Hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;b is selected fromB 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, said B 1 being optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, said B 2 optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;V is selected fromW is selected from O or S;Y 1、Y2、Y3 are each independently selected from a bond, O, S, NR b5a、C(＝S)、C(＝O)、CONRb5a、NRb5a CO;p 1、P2 are each independently selected fromV 2 are each independently selected from 0, 1,2,3 or 4;v 1 are each independently selected from 0, 1 or 2;R b1 is independently selected from H, F, cl, br, I, = O, OH, CN, NO 2、COOH、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio 、-(CH2)n-Rb22、-ORb22、-N(Rb21)2、-C(＝O)N(Rb21)2、-C(＝O)ORb21、-C(＝O)Rb22、-S(＝O)2Rb22、-P(＝O)(Rb22)2、-S(＝O)2N(Rb21)2、-NRb21C(＝O)Rb22、-NRb21S(＝O)2Rb22、C3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, =o, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy), Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene-C 3-6 cycloalkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-O-C 1-4 alkyl, C 3-6 cycloalkyl, a 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituted with 1 to 4 heteroatoms selected from O, S, N;R b21 are each independently selected from H or C 1-4 alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy;R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;n is each independently selected from 0,1, 2, 3 or 4;R b2 is each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4 alkyl, -C (=O) N (C 1-4 alkyl )2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C 1-4 alkylene-4 to 10 membered heterocyclyl, said alkylene, CH 2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, Halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, halogen substituted C 3-6 cycloalkyl, halogen substituted C 3-6 Cycloalkyloxy, 5-6 membered heteroaryl or 4-8 membered heterocyclyl groups substituted with 1 to 4 substituents selected from O, s, N heteroatoms;r b3、Rb4、Rb6、Rb7 is each independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-6 alkyl, halogen substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;Or R b3、Rb4 taken together with the carbon atom to which it is attached form C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;Alternatively, R b3 and R b5a、Rb1 are directly linked to R b5a to form a ring S selected from 4 to 9 membered nitrogen containing heterocyclyl, ring S optionally substituted with 1 to 4 substituents selected from R s;R s is independently selected from F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl, or 3 to 8 heterocyclyl, said alkyl, alkoxy, cycloalkyl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;R b5a is selected from H or R b5;R b5 is selected from OH, NH 2、C1-4 alkyl, - (CH 2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =O, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;x is independently selected from NH, O or S;m1 is independently selected from 0,1, 2 or 3;m2 is each independently selected from 0,1, 2 or 3;R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, said cycloalkyl, alkenyl, alkynyl, heterocyclyl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, or a 4-10 membered heterocyclyl, said alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;k is selected from K1, K2, K3 and K4;K1 is selected fromK2 is selected fromK3 is selected fromK4 is selected fromEach Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-CO-、-NRqCO-、-CONRq -, or a 3-12 membered heterocyclic ring, said heterocyclic ring being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S or N;R q is selected from H or C 1-6 alkyl;A is selected from a C 3-10 carbocycle, a C 6-10 aromatic ring, a 3-10 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring containing 1 to 4 heteroatoms selected from O, S or N;F is each independently selected from a C 3-20 carbocycle, a C 6-20 aromatic ring, a 3-20 membered heterocycle or a 5-20 membered heteroaryl ring containing 1 to 4 heteroatoms selected from O, S or N;R k2 is each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-, or-C (R k3)2 -;R k1 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, R k7a, said alkyl, alkoxy or cycloalkyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;R k7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl;Each R k3 is independently selected from H, F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;Or two R k3 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocycle or a 3-8 membered heterocycle, and two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-8 carbocycle or a 3-8 membered heterocycle, said carbocycle or heterocycle being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;Each R k4 is independently selected from H, OH, NH 2、CN、CONH2、C1-6 alkyl, C 3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;M 1 is selected from the group consisting of bond, -CH 2 -C (=O) NH-, or-C (=O) CH 2 NH-;M 2 is selected from-NHC (=o) -C 1-6 alkyl, -NHC (=o) -C 3-6 cycloalkyl or a 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;M 3 is selected from-NH-or-O-;R k10 is selected from C 1-6 alkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, C 1-6 alkyl or C 3-6 cycloalkyl;R k11 is each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or-O-C (=o) -C 1-6 alkyl, said alkyl, alkoxy or alkylthio being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;R k12、Rk13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, =o, OH, NH 2、C1-4 alkyl or C 1-4 alkoxy;R k14 is selected from a 5-6 membered heteroaryl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaryl containing 1 to 4 heteroatoms selected from N, O or S;G is selected from a C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, CF 3、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl, said heteroaromatic ring containing 1 to 4 heteroatoms selected from N, O or S;n1, n2, n3 are each independently selected from 0,1, 2 or 3;p1 or p2 are each independently selected from 0,1, 2, 3, 4 or 5.
- The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,B is selected fromV 2 are each independently selected from 1,2, 3 or 4;v 1 are each independently selected from 0, 1 or 2;v 3 is selected from 0, 1,2 or 3;v 4 is selected from 0, 1,2 or 3;z is selected from 0,1, 2 or 3;W is selected from O or S;Is as defined for B 1;B 1、B4 are each independently selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, said B 1、B4 being optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl, or B 5, said B 2 being optionally substituted with 1 to 4R b2, said heterocyclyl containing 1 to4 heteroatoms selected from O, S, N;B 3 is selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl, said B 3 optionally substituted with 1 to 4R b1, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;b 5 is selected from the group consisting of C 12-18 tricyclo, 12 to 18 membered hetero tricyclo, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, phenyl, benzoc 4-6 carbocycle, benzo4 to 6 membered heterocycle, pyrazoloc 4-6 carbocycle, pyrazolo4 to 6 membered heterocycle, triazolo C 4-6 carbocycle, triazolo 4 to 6 membered heterocycle, imidazo C 4-6 carbocycle, imidazo 4 to 6 membered heterocycle, thieno C 4-6 carbocycle, thieno 4 to 6 membered heterocycle, furo C 4-6 carbocycle, furo 4 to 6 membered heterocycle, 4-7 membered nitrogen containing heteromonocyclic alkyl, 4-10 membered nitrogen containing heterocycloalkyl, 5-12 membered nitrogen containing heterospirocycloalkyl, 7-10 membered nitrogen containing heterobridged cycloalkyl, 3-7 membered monocyclic alkyl, 4-10 membered heterocycloalkyl, 5-12 membered alkyl, 7-10 membered bridged cycloalkyl, said B 5 being optionally substituted with 1 to 4R b2, said heterocycle, heterocycloalkyl, spirocycloalkyl, and spirocycloalkyl containing a heteroatom selected from the group consisting of 861 to O, S, N heteroatoms;R b5 is selected from OH, NH 2、C1-4 alkyl, - (CH 2)n-Rb22、-C(＝O)N(Rb21)2、-C(＝O)Rb22、C3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said-CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally being substituted with 1 to 4 substituents selected from F, cl, br, I, OH, =O, -N (R b21)2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, said alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;R b3、Rb4、Rb7 is each independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, or 4-12 membered heterocyclyl, said alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl being optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;Or R b3、Rb4 taken together with the carbon atom to which it is attached form C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N.
- The compound of claim 2, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,B is selected fromRing S is selected from 5-, 6-or 7-membered rings containing 1 or 2 nitrogen atoms, ring S optionally being substituted with 1 to 4R s;R s is independently selected from F, cl, br, I, OH, NH 2、-NHC1-4 alkyl, -N (C 1-4 alkyl) 2、CN、C1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, said alkyl, alkoxy or cycloalkyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl or C 1-4 alkoxy;b 1、B4 is independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10-14 tricyclic carbocyclyl, 12-14 membered tricyclic heterocyclyl, said B 1、B4 is optionally substituted with 1 to 4R b1, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heteroacene, 5-10 membered heterobridged ring, said B 2 optionally being substituted with 1 to 4R b2, said heteroaryl, heterocyclyl, heteroacene, heterobridged ring containing 1 to 4 heteroatoms selected from O, S, N;B 3 is selected from the group consisting of 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl, 4-7 membered monocyclic heterocyclyl, 7-14 membered heteroacene, 7-14 membered heterospiro, said B 3 being optionally substituted with 1 to 4R b1, said heteroaryl, heterocyclyl, heteroacene, heterospiro containing 1 to 4 heteroatoms selected from O, S, N;R b2 is each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、-N(Rb21)2、CN、NO2、COOH、-C(＝O)NH2、-C(＝O)NH-C1-4 alkyl, -C (=O) N (C 1-4 alkyl )2、-(CH2)n-Rb22、-(CH2)nO(CH2)n-Rb22、-(CH2)nO(CH2)nO-Rb22、C1-4 alkyl), C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5-to 6-membered heteroaryl, 4-to 8-membered heterocyclyl, -C 1-4 -alkylene-4-to 8-membered heterocyclyl, said alkylene, CH 2, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, NH 2、-NHC1-4 alkyl, -N (C 1-4 alkyl) 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, A halogen substituted C 3-6 cycloalkyloxy, a 5-6 membered heteroaryl or a 4-8 membered heterocyclyl substituent, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;R b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 and cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5-10 membered heterobridged ring, 5-12 membered heterospiro, 5-12 membered heterofused ring, said alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospiro or fused ring optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;r b3、Rb4、Rb7 is each independently selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、-(CH2)m1-Rb23、-(CH2)m1-X-(CH2)m2-Rb24、C1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 and cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5-10 membered heterobridged ring, 5-12 membered heterospiro, 5-12 membered heterofused ring, said alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospiro or fused ring optionally substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, said heteroaryl, heterocyclyl, heterobridged ring, heterospiro or fused ring containing 1 to 4 heteroatoms selected from O, S, N;Or R b3、Rb4 taken together with the carbon atom to which it is attached form C 3-8 cycloalkyl or 3 to 8 membered heteromonocyclic ring, said cycloalkyl or heteromonocyclic ring optionally being substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、-N(Rb21)2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteromonocyclic, heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or a 4-8 membered heterocyclyl, said cycloalkyl, alkenyl, alkynyl, heterocyclyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl, or a 4-8 membered heterocyclyl, said alkoxy, cycloalkyl, cycloalkyloxy, heterocyclyl optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、CF3、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;optionally, B is selected from In this case, R b3、Rb4 cannot be selected from H at the same time.
- The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;Ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH2)q-、-(CH2)q-O-、-O-(CH2)q-、-(CH2)q-NRL-、-NRL-(CH2)q-、-(CH2)q-NRLC(＝O)-、-(CH2)q-C(＝O)NRL-、-C(＝O)-、-C(＝O)-(CH2)q-NRL-、-CH＝CH-、-(C≡C)q- or a bond, said-CH 2 -, -CH=CH-optionally substituted with 1 to 2 substituents selected from F, cl, br, I, OH, CN, NH 2、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl;Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following optionally substituted groups: 4-7 membered heteromonocyclic ring, 4-10 membered heteromonocyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, substituted with 1 to 4R L2, said heterocyclyl, heteroaryl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring containing 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally substituted with 1 or 2 = O; q is each independently selected from 0, 1, 2,3 or 4;R L is independently selected from H or C 1-6 alkyl;K2 is selected fromK3 is selected fromA is selected from a C 3-8 carbocycle, a benzene ring, a 4-7 membered heterocycle or a 5-6 membered heteroaryl ring containing 1 to 4 heteroatoms selected from O, S or N;F is each independently selected from the group consisting of C 3-7 monocyclic carbocycle, C 4-10 bicyclic carbocycle, C 5-12 spirocyclic carbocycle, C 5-10 bridged cyclic carbocycle, 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 8-15 membered heterotricyclic ring, 5-12 membered heterospirocyclic ring, 5-10 membered heterobridged ring, C 6-14 aryl, 5-10 membered heteroaryl, The heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl groups contain 1 to 4 heteroatoms selected from O, S or N;represents a ring selected from aromatic or non-aromatic rings;E is each independently selected from a C 3-10 carbocycle, a benzene ring, a 4-12 membered heterocycle, a 5-12 membered heteroaryl ring containing 1 to4 heteroatoms selected from O, S or N;Each Q is independently selected from a bond, -O-, -S-, -CH 2-、-NRq-、-CO-、-NRqCO-、-CONRq -, or a 4-7 membered heterocyclic ring, said heterocyclic ring being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocyclic ring containing 1 to 4 heteroatoms selected from O, S or N;R q is selected from H or C 1-4 alkyl;R k1、Rk3 is each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH or NH 2;or two R k3 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocycle or a 3-7 membered heterocycle, and two R k1 and the carbon atom or ring backbone directly attached to both together form a C 3-6 carbocycle or a 3-7 membered heterocycle, said carbocycle or heterocycle being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、CONH2、C1-4 alkyl or C 1-4 alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;R k4 is independently selected from H, OH, NH 2、CF3, CN or C 1-4 alkyl;R k5 are each independently selected from C(CH3)2、CO、CH2、SO2、Each R k6 is independently selected from CO, CH, SO, SO 2、CH2 or N;r k7 are each independently selected from C(CH3)2、CO、CH、N、CH2、O、S、NRk7a；Each R k8 is independently selected from C, N or CH;r k9 are each independently selected from the group consisting of a bond, C (CH 3)2、CO、CH2、CH2CH2 or SO 2;R ka is selected from O, S or NH;R k7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、CF3、C1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;R k14 is selected fromP1 is selected from 0,1, 2 or 3;p2 is selected from 0,1, 2 or 3.
- The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following optionally substituted groups: a 4-7 membered nitrogen containing heteromonocyclic ring, 4-10 membered nitrogen containing heteromonocyclic ring, 5-12 membered nitrogen containing heterospiro ring, 7-10 membered nitrogen containing heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzoc 4-6 carbocyclyl, benzo4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, which when substituted is substituted with 1 to 4R L2, said heterocyclyl, heteromonocyclic ring, heterofused ring, heterobridged ring, heterospiro ring or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N, which when heteroatom is selected from S is optionally substituted with 1 or 2 = O;R L is independently selected from H or C 1-4 alkyl;K1 is selected fromK4 is selected fromQ is selected from a bond, C (=o);Q1 is selected from the group consisting of a bond, CH 2、NH、N(CH3)、O、S、C(＝O)、NHC(＝O)、C(＝O)NH、N(CH3)C(＝O)、C(＝O)N(CH3),Q2 is selected from a bond, CH 2、O、S、C(＝O)、NHC(＝O)、N(CH3) C (=o);E. each a is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxazole ring;F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridinyl benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrol-namidinyl, pyrrol-n-yl, pyrrol pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, and imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, The left side of the connecting rod is directly connected with L;R ka is selected from O, S or NH;r k7 are each independently selected from C (CH 3)2、CH2、O、N(CH3)、N(CH2CH3), N (cyclopropyl) or NH;r k1、Rk3 are each independently selected from H, F, cl, br, I, OH, = O, NH 2、CF3、CN、COOH、CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2;R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, said methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CF 3、C1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 cycloalkyl;p1 or p2 are each independently selected from 0,1 or 2.
- The compound of claim 5, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,R L is selected from H, methyl or ethyl;q is each independently selected from 0,1 or 2;Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazepinyl, phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyrimidine, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl, benzofuranyl, benzoxazolyl, and combinations thereof triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiazinyl, triazolooxazolyl, triazolopyrazinyl, triazolyl, triazolopyrazinyl, triazolyl, triazoloimidazolyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spiropropyl, cyclopropyl-spirobutyl, cyclopropyl-spiropentyl, cyclopropyl-spirohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl-spiropentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-azetidinyl, cyclopropyl-pyrrolidyl, cyclopropyl-piperidyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidyl, cyclobutyl-azetidinyl, cyclopentyl-piperidyl, cyclohexyl-azetidinyl-yl-spirocyclohexyl, cyclohexyl-pyrrolidinyl, cyclohexyl-piperidinyl, azetidinyl-azetidinyl, azetidinyl-pyrrolidinyl, azetidinyl-piperidinyl, pyrrolidinyl-azetidinyl, pyrrolidinyl-pyrrolidinopyrrolidinyl pyrrolidinyl-piperidinyl, piperidinyl-azetidinyl, piperidinyl-pyrrolidinyl, piperidinyl-piperidinyl, and cyclobutylspiroazetidine, cyclobutylspiropyrrolidinyl, cyclobutylspiropiperidinyl, and cyclopentyl spiroazetidinyl, cyclopentyl spiropyrrolidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiroazetidinyl cyclohexylspiropyrrolidinyl, cyclohexylspiropiperidinyl, azetidinyl cyclohexyl spiropyrrolidinyl, cyclohexyl spiropiperidinyl, and azetidinyl spiroazetidinyl, When substituted, are substituted with 1 to 4R L2;r L2 is each independently selected from deuterium, F, cl, br, I, OH, NH 2、NHCH3、N(CH3)2、COOH、CN、＝O、C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 1-2 alkylene-O-C 1-2 alkyl, -O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 1-2 alkyl, -C 1-2 alkylene-O-C 1-2 alkylene-O-C 3-6 carbocyclyl, -O-C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6 membered heterocyclyl, The alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 groups selected from F, cl, br, I, OH, COOH, CN, NH 2、NHC1-4 alkyl, N (C 1-4 alkyl) 2、＝O、C1-4 alkyl, Halogen substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;B 1、B4 is each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 3-isoquinolinyl, quinazolinyl, 3, 4-dihydro-1H-benzopyranyl, 1,2,3, 4-tetrahydroquinolinyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, Said B 1、B4 is optionally substituted with 1 to 4R b1;B 2 is selected from one of the following substituted or unsubstituted: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridonyl, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, Or B 5, when substituted, is substituted with 1 to 4R b2;B 5 is selected from Said B 5 is optionally substituted with 1 to 4R b2;B 3 is selected from one of the following substituted or unsubstituted: phenyl, naphthyl, Benzopyridyl, benzothienyl, benzofuranyl, thienyl, furyl, pyrrolyl, when substituted, are substituted with 1 to 4R b1;R b1 are each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、N(CH3)2、CN、NO2、-C(＝O)CH3、-C(＝O)NH2、-C(＝O)NH-CH3、-C(＝O)N(CH3)2、-S(＝O)2NH2、-P(＝O)(CH3)2、-S(＝O)2CH3 or one of the following optionally substituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, morpholine, pyrrolidinyl cyclopentyl, azetidinyl spirocyclohexyl, cyclopropyl spirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl spirospirocyclohexyl, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、NHCH3、N(CH3)2, methyl, ethyl, isopropyl, ethynyl, -CH 2-CN、-CH2OH、-CH2OMe、-CH2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl;R b2 are each independently selected from H、F、Cl、Br、I、＝O、OH、NH2、NH(CH3)、N(CH3)2、CN、NO2、COOH、-C(＝O)NH2 or one of the following optionally substituted groups: -CH 2OCH2CH3, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, being 1 to 4 groups selected from F, cl, br, I, OH, CN, CHF 2、CF3、NH2、NHCH3、N(CH3)2, methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxacyclohexyl, cyclopropyl, Cyclobutyl group,Cyclopropyloxy group, Is substituted by a substituent of (2);R b3、Rb4 are each independently selected from H, OH, NH 2 or optionally substituted one of the following groups: methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、CN、CF3、CHF2, methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, cyclobutylspirocyclobutyl;Or R b3、Rb4 together with the carbon atom to which it is attached form one of the optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, cyclobutylspirocyclobutyl, when substituted, substituted with 1 to 4 substituents selected from deuterium, F, cl, br, I, OH, NH 2、N(CH3)、CN、C1-4 alkyl, halo-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;r b5 is selected from OH, NH 2, methyl, ethyl, propyl, isopropyl, - (CH 2)n -cyclopropyl, - (CH 2)n -cyclobutyl, - (CH 2)n -cyclopentyl, - (CH 2)n -cyclohexyl, phenyl, pyridinyl), said-CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl being optionally substituted by 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;n is independently selected from 0 and 1;r b6 is selected from F、Cl、Br、I、OH、NH2、CN、NO2、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, azetenyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptyl, phenyl, pyridinyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-cyclohexyl, cyclobutyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-spirocyclopropyl-, cyclopropyl-spirocyclohexyl, cyclobutyl-spirocyclopentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, cyclopropyl-and-azetidinyl, cyclopropyl-and-pyrrolidinyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl cyclohexylazetidinyl, cyclohexylpyrrolidyl, cyclohexylpiperidyl, azetidinazetidinyl, azetidinopyrrolidinyl, azetidinopiperidyl a cyclohexylazetidinyl group, a cyclohexylopyrrolidinyl group, a cyclohexylopiperidyl group, a azetidinoazetidines, azetidinopyrrolidines, azetidinopiperidines, azetidines, azetidin, cyclohexyl spiropiperidinyl, azetidinyl, and the like azetidinyl spiropyrrolidinyl azetidinyl spiropiperidinyl pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;R b7 is selected from H、F、Cl、Br、I、OH、NH2、CN、NO2、CHF2、CF3、-CH2-Rb23、-CH2-X-(CH2)m2-Rb24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-diazaheptanyl, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl, cyclopropyl-spirocyclobutyl-cyclohexyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirocyclobutyl-spirocyclohexyl, cyclobutyl-spirocyclohexyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spiropyrrolidinyl cyclopropyl-piperidinyl, cyclobutyl-azetidinyl, cyclobutyl-pyrrolidinyl, cyclobutyl-piperidinyl, cyclopentyl-azetidinyl, cyclopentyl-pyrrolidinyl, cyclopentyl-piperidinyl cyclohexylazetidinyl, cyclohexylpyrrolidyl, cyclohexylpiperidyl, azetidinazetidinyl, azetidinopyrrolidinyl, azetidinopiperidyl a cyclohexylazetidinyl group, a cyclohexylopyrrolidinyl group, a cyclohexylopiperidyl group, a azetidinoazetidines, azetidinopyrrolidines, azetidinopiperidines, azetidines, azetidin, cyclohexyl spiropiperidinyl, azetidinyl, and the like azetidinyl spiropyrrolidinyl azetidinyl spiropiperidinyl pyrrolidinyl spiroazetidinyl pyrrolidinyl spiropyrrolidinyl pyrrolidinyl spiro pyrrolidinyl group, When substituted, is substituted with 1 to 4 substituents selected from F, cl, br, I, OH, NH 2、CN、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl, or 3 to 8 heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;x is independently selected from NH, O or S;m2 is each independently selected from 0,1 or 2;R b23 is each independently selected from the group consisting of vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetenyl, oxetanyl, oxolanyl, piperidinyl, or morpholin, said vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetenyl, oxetanyl, oxolanyl, oxetanyl, piperidine, or morpholin optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy;R b24 is each independently selected from methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclopropyloxy, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azexenyl, oxetanyl, oxolanyl, cyclohexyl, piperidine, or morpholine, said methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxolanyl, piperidine, or morpholine being optionally substituted with 1 to 4 substituents selected from F, cl, br, I, OH, = O, NH 2、CN、COOH、C1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy;K is selected from one of the structural fragments shown in Table K-1.
- The compound of claim 6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,Cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: When substituted, are substituted with 1 to 4R L2;R L2 are each independently selected from deuterium, F, cl, br, = O, COOH, CN, NHCH 3、N(CH3)2、OH、NH2 or one of the following optionally substituted groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2CH2 -O-methyl, -OCH 2CH2 -O-cyclopropyl, -CH 2OCH2CH2 -O-methyl, -CH 2OCH2CH2 -O-cyclopropyl, when substituted, being substituted with 1 to 4 substituents selected from F, CHF 2、CF3、-OCHF2、-OCF3, methyl, methoxy, =o, hydroxymethyl, COOH, CN, NHCH 3、N(CH3)2、OH、NH2;b is selected from one of the structural fragments shown in the table B-1 or the table B-2;k is selected from one of the structural fragments shown in Table K-2.
- The compound of claim 7, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,L is selected from a bond or one of the structural fragments shown in Table L-1 or Table L-2, wherein the left side of the group is linked to B.
- The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures shown in table E-1.
- A pharmaceutical composition comprising a compound according to any one of claims 1-9 or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, preferably comprising 1-1500mg of a compound according to any one of claims 1-9 or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
- Use of a compound according to any one of claims 1-9, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with AR or AR cleavage mutant activity or expression level.
- Use of a compound according to any one of claims 1-9, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment and inhibition or degradation of an AR or AR shear mutant related disease.
- The use according to claim 11 or 12, wherein the disease is selected from prostate cancer.
- A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-9, or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease preferably being AR or an AR splice mutant activity or expression level-related disease.
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| CN2022106660762 | 2022-06-14 | ||
| CN202211017939 | 2022-08-24 | ||
| CN202211017939X | 2022-08-24 | ||
| CN2022113665756 | 2022-11-10 | ||
| CN202211366575 | 2022-11-10 | ||
| CN202310062221 | 2023-01-13 | ||
| CN2023100622210 | 2023-01-13 | ||
| PCT/CN2023/091444 WO2023208165A1 (en) | 2022-04-29 | 2023-04-28 | Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical application thereof |
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