CN113788827B - Phthalazinone compound, preparation method and medical application thereof - Google Patents
Phthalazinone compound, preparation method and medical application thereof Download PDFInfo
- Publication number
- CN113788827B CN113788827B CN202111212595.3A CN202111212595A CN113788827B CN 113788827 B CN113788827 B CN 113788827B CN 202111212595 A CN202111212595 A CN 202111212595A CN 113788827 B CN113788827 B CN 113788827B
- Authority
- CN
- China
- Prior art keywords
- nmr
- compound
- cancer
- preparation
- chloroform
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- -1 Phthalazinone compound Chemical class 0.000 title claims abstract description 51
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 claims abstract description 24
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 claims abstract description 24
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 claims abstract description 14
- 102000015087 Poly (ADP-Ribose) Polymerase-1 Human genes 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 70
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- 206010018338 Glioma Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 239000007821 HATU Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical class C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- KJFMBFZCATUALV-UHFFFAOYSA-N Phenolphthalein Natural products C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 abstract description 7
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 113
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 75
- 230000015572 biosynthetic process Effects 0.000 description 49
- 238000003786 synthesis reaction Methods 0.000 description 49
- 125000005842 heteroatom Chemical group 0.000 description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 35
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 30
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 30
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 27
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 26
- 229950006238 nadide Drugs 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 14
- 239000002207 metabolite Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 11
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 125000001188 haloalkyl group Chemical group 0.000 description 8
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- ZQLZNGUJOGWVCB-UHFFFAOYSA-N imidazo[1,2-a]pyridine-7-carboxamide Chemical compound C1=C(C(=O)N)C=CN2C=CN=C21 ZQLZNGUJOGWVCB-UHFFFAOYSA-N 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 235000005152 nicotinamide Nutrition 0.000 description 7
- 239000011570 nicotinamide Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 108010021809 Alcohol dehydrogenase Proteins 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229960003966 nicotinamide Drugs 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- PWJFNRJRHXWEPT-UHFFFAOYSA-N ADP ribose Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)C=O)C(O)C1O PWJFNRJRHXWEPT-UHFFFAOYSA-N 0.000 description 3
- 102000007698 Alcohol dehydrogenase Human genes 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 230000005778 DNA damage Effects 0.000 description 3
- 231100000277 DNA damage Toxicity 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- QSYTWBKZNNEKPN-UHFFFAOYSA-N tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCN)CC1 QSYTWBKZNNEKPN-UHFFFAOYSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- PQGCEDQWHSBAJP-TXICZTDVSA-N 5-O-phosphono-alpha-D-ribofuranosyl diphosphate Chemical compound O[C@H]1[C@@H](O)[C@@H](O[P@](O)(=O)OP(O)(O)=O)O[C@@H]1COP(O)(O)=O PQGCEDQWHSBAJP-TXICZTDVSA-N 0.000 description 2
- SRNWOUGRCWSEMX-TYASJMOZSA-N ADP-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1OC(O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-TYASJMOZSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FWODHXRPGFXKIG-UHFFFAOYSA-N C(=O)(OC(C)(C)C)N1CCNCC1.N1CCNCC1 Chemical compound C(=O)(OC(C)(C)C)N1CCNCC1.N1CCNCC1 FWODHXRPGFXKIG-UHFFFAOYSA-N 0.000 description 2
- 230000033616 DNA repair Effects 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101000996052 Homo sapiens Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 102100034451 Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 Human genes 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 101800000628 PDH precursor-related peptide Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000001793 charged compounds Chemical class 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000005782 double-strand break Effects 0.000 description 2
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 description 2
- 230000037149 energy metabolism Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical group [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004529 1,2,3-triazinyl group Chemical group N1=NN=C(C=C1)* 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 1
- CKFADRWPUYOHOZ-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-pyrrolo[3,2-b]pyridine Chemical compound N1C=CC=C2NCCC21 CKFADRWPUYOHOZ-UHFFFAOYSA-N 0.000 description 1
- BOIPLTNGIAPDBY-UHFFFAOYSA-N 2-[6-(4-chlorophenoxy)hexyl]-1-cyano-3-pyridin-4-ylguanidine Chemical compound C1=CC(Cl)=CC=C1OCCCCCCN=C(NC#N)NC1=CC=NC=C1 BOIPLTNGIAPDBY-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 108091007743 BRCA1/2 Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 102000011724 DNA Repair Enzymes Human genes 0.000 description 1
- 108010076525 DNA Repair Enzymes Proteins 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 101710148290 DNA ligase 3 Proteins 0.000 description 1
- 102100033688 DNA ligase 3 Human genes 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920002430 Fibre-reinforced plastic Polymers 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 101001113440 Homo sapiens Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 1
- 101000735456 Homo sapiens Protein mono-ADP-ribosyltransferase PARP3 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100020870 La-related protein 6 Human genes 0.000 description 1
- 108050008265 La-related protein 6 Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100034935 Protein mono-ADP-ribosyltransferase PARP3 Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
- 102000011990 Sirtuin Human genes 0.000 description 1
- 108050002485 Sirtuin Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WFIHKLWVLPBMIQ-UHFFFAOYSA-N [1,3]thiazolo[5,4-b]pyridine Chemical compound C1=CN=C2SC=NC2=C1 WFIHKLWVLPBMIQ-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- KYIKRXIYLAGAKQ-UHFFFAOYSA-N abcn Chemical compound C1CCCCC1(C#N)N=NC1(C#N)CCCCC1 KYIKRXIYLAGAKQ-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000033590 base-excision repair Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012084 conversion product Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 125000000597 dioxinyl group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000005303 dithiazolyl group Chemical group S1SNC(=C1)* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000294 dose-dependent toxicity Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000011151 fibre-reinforced plastic Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 230000023611 glucuronidation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 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
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940101270 nicotinamide adenine dinucleotide (nad) Drugs 0.000 description 1
- 235000020956 nicotinamide riboside Nutrition 0.000 description 1
- 239000011618 nicotinamide riboside Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000005783 single-strand break Effects 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a phenolphthalein ketone compound with a structure shown in a general formula I, a pharmaceutical composition, a preparation method and application thereof. The phenolphthalein ketone compound has remarkable inhibitory activity on NAMPT and PARP1 and has good therapeutic effect on tumors.
Description
Technical Field
The invention belongs to the field of innovative pharmaceutical chemistry, and in particular relates to a phenolphthalein ketone compound shown in a formula I or pharmaceutically acceptable salts, solvates, prodrugs, isomers or metabolites thereof, a preparation method, a pharmaceutical composition containing the compound, and application of the compound or the pharmaceutical composition in preparing antitumor drugs.
Background
Cancer is a serious disease which afflicts human health, and research and development of novel antitumor drugs are important subjects and long-term tasks in the field of biological medicine. Poly ADP-ribose polymerase, PARP, is a multifunctional protein post-translational modification enzyme that is widely found in eukaryotic cells. In mammalian cells, the PARP family has 17 members, whereas the members involved in DNA damage repair processes are only three of PARP1, PARP2, and PARP3, wherein PARP1 is a major member involved in DNA repair processes, when DNA damage is single-stranded broken, cells initiate DNA damage response procedures, PARP1 can sense DNA single-stranded damage gaps, and Nicotinamide Adenine Dinucleotide (NAD) is catalyzed by self-glycosylation of its zinc finger DNA binding domain located at the site of DNA damage + ) Decomposing into nicotinamide and ADP ribose, and using ADP ribose as substrate to make receptor protein and PARP1 form poly ADP-ribose polymer to form PARP-ADP ribose branched chain, avoiding recombination of DNA molecule around damaged part and damaged DNA, and simultaneously attracting DNA repair protein, histone H1, a series of transcription factors and other DNA repair enzymes such as X-ray repair cross complementary gene 1, DNA ligase 3, DNA guide polymerase beta and the like to be combined at the damaged part to repair the damaged part. When PARP function is impaired or inhibited, single strand breaks persist, which can easily lead to stalling of replication forks and DNA double strand breaks, and thus impaired DNA replicas appear and accumulate gradually, eventually leading to replication fork breakdown. In cells with normal functional homologous recombination repair pathways, the DNA double strand breaks are immediately repaired, which can compensate for the loss of function in the base excision repair pathway; however, in tumor cells lacking homologous recombination repair, such as breast cancer carrying BRCA1/2 mutations, there is a lack of compensatory mechanisms, and the tumor cells fail to repair DNA damage, ultimately leading to cell death.
Nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide, NAD for short) + ) Is an indispensable substance in the electron transfer process and plays an important role in the energy metabolism and signal transduction processes. In addition, NAD + NADH in the form of its reduced form is important for maintaining a reducing environment within the cell and thereby protecting the cell from oxidative stress. Thus, intracellular NAD + Is a critical factor in determining cell fate. Tumor cells have uncontrolled proliferation rates, rapid metabolic rates, and significantly increased oxidative stress levels relative to normal cells, and thus tumor cells are resistant to NAD + The change in level is sensitive. NAD (NAD) + Key enzymes of the in vivo biosynthetic pathway have become important targets for anticancer drugs. NAD (NAD) + In vivo synthetic pathwayIncluding de novo and salvage synthetic pathways.
NAD + The salvage synthesis route is to use nicotinic acid, nicotinamide or nicotinamide ribose as a starting material. Due to a plurality of NADs + Consumable enzymes such as poly (adenosine diphosphate) ribose polymerase (PARP) and deacetylase (Sirtuis, SIRT) can rapidly re-release nicotinamide, thereby NAD starting from nicotinamide + The salvage pathway is the most economical and dominant NAD + Biosynthetic pathways (gali U.S. et al J.Med. Chem.2013, 22, 56 (16): 6279-96). Whereas nicotinamide riboside transferase (nicotinamide phosphoribosyltransferase, NAMPT) controls nicotinamide to NAD + And (3) a speed-limiting enzyme for transformation. In view of the abnormal energy metabolism of tumor cells, NAD is more required + Rapid and timely supplementation, tumor cells are more dependent on NAMPT and are more sensitive to NAMPT inhibition. Therefore, NAMPT is considered as an effective anticancer target, and NAMPT inhibitors have become a hotspot for extensive research. Currently, two NAMPT inhibitors CHS-828 and FK866 have entered the clinical trial phase (Montecocco Fet al. Curr. Drug targets.2013,1, 14 (6): 637-43). However, the clinical trial results of these two compounds were not ideal and did not show significant therapeutic effect after administration to patients. Furthermore, these two compounds have poor pharmacokinetic properties and also show dose-dependent toxicity such as thrombocytopenia and gastrointestinal toxic side effects. Therefore, NAMPT inhibitors with novel structure and good pharmaceutical property are required to be further researched and developed.
Disclosure of Invention
The invention aims to: the invention aims to provide a phenolphthalein ketone compound and a pharmaceutical composition thereof, which have the advantages of good curative effect of anticancer drugs, overcoming drug resistance and the like.
The invention obtains PARP/NAMPT double-target inhibitor, and can reduce NAD through inhibiting nicotinamide phosphoribosyl transferase + To increase the level of chemical combinationThe competitive inhibition of poly (adenosine diphosphate) ribose polymerase by the compound is expected to solve the current drug resistance problem of PARP inhibitors.
The invention also aims to provide a preparation method and application of the phenolphthalein ketone compound with the advantages of good curative effect of the anticancer drug, overcoming drug resistance and the like, and a pharmaceutical composition thereof.
The invention provides phthalazinone compounds with a structure shown in a general formula I, or pharmaceutically acceptable salts, solvates, prodrugs, isomers or metabolites thereof,
in formula I:
l is-CH 2 OCH 2 CH 2 OCH 2 -, or, unsubstituted or R 1 Substituted C 2-10 An alkyl group;
R 1 independently hydroxy, amino, halogen, C 1-6 Alkyl, C of (2) 1-6 Alkoxy, C 1-6 A haloalkyl group;
e is O, S or N-C.ident.N;
x is a single bond, C 2-4 Olefinic bond, C 1-4 Alkyl, cyclopropyl, -NHCH 2 -；
R is unsubstituted or R 2 Substituted C 6-10 Aryl, unsubstituted or R 3 The substituted hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-3, 5-10 membered hetero aryl, unsubstituted or R 4 The substituted hetero atom is selected from one or more of N, O and S, and the hetero atom number is 5-10 membered heterocyclic alkyl of 1-3;
R 2 、R 3 and R is 4 Independently deuterium, halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 A haloalkyl group.
Further, when L is unsubstituted or R 1 Substituted C 2-10 In the case of alkyl, said R 1 Is one or more, when there are a plurality of R 1 In the time-course of which the first and second contact surfaces,said R is 1 May be the same or different;
and/or when L is unsubstituted or R 1 Substituted C 2-10 In the case of alkyl, said C 2-10 Alkyl is C 2-8 An alkyl group;
and/or when R 1 Is C 1-6 When alkyl is said C 1-6 Alkyl is C 1-3 An alkyl group;
and/or when R 1 When halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or, when E is O, X is a single bond, C 1-4 Alkyl, C 2-4 Alkenyl, cyclopropyl or-NHCH 2 -, or, when E is S, X is-NHCH 2 -or, when E is N-c≡n, X is a single bond;
and/or when R is unsubstituted or R 3 The substituted hetero atom is one or more of N, O and S, and when the hetero atom number is 1-3, the hetero atom is 5-10 membered heteroaryl, the R 3 Is one or more, when there are a plurality of R 3 When said R is 3 May be the same or different;
and/or when R is unsubstituted or R 3 When the heteroatom is selected from one or more of N, O and S and the heteroatom number is 1-3, the heteroaryl is one or more of N, O and S, the heteroatom number is 1-3 and the heteroatom number is at least 1, and the heteroatom number is 5-10;
and/or when R is unsubstituted or R 4 The substituted hetero atom is one or more of N, O and S, and when the hetero atom number is 1-3, the hetero atom is 5-10 membered heterocyclic alkyl, the R 4 Is one or more, when there are a plurality of R 4 When said R is 4 May be the same or different;
and/or when R is unsubstituted or R 4 When the heteroatom is selected from one or more of N, O and S and the 5-to 10-membered heterocycloalkyl group with 1-3 heteroatoms, the heterocycloalkyl group is one or more of N, O and S, the heteroatom is 1-3, and the 5-to 10-membered heterocycloalkyl group with at least 1N atom;
and/or when R 3 Halogen, wherein the halogen is fluorine, chlorine, bromine or iodine;
and/or when R 3 Is C 1-6 In the case of alkyl, said C 1-6 Alkyl is C 1-3 An alkyl group;
and/or when R 3 Is C 1-6 In the case of alkoxy, said C 1-6 Alkoxy is C 1-3 An alkoxy group;
and/or when R 3 Is C 1-6 When haloalkyl, said C 1-6 Haloalkyl is C 1-3 A haloalkyl group;
and/or when R 4 Is C 1-6 In the case of alkyl, said C 1-6 Alkyl is C 1-3 An alkyl group;
and/or when R 4 Is C 1-6 When haloalkyl, said C 1-6 Haloalkyl is C 1-3 A haloalkyl group.
Further, when L is unsubstituted or R 1 Substituted C 2-10 In the case of alkyl, said R 1 Is 1,2 or 3;
and/or when L is unsubstituted or R 1 Substituted C 2-10 In the case of alkyl, said unsubstituted or R 1 Substituted C 2-10 Alkyl is C 2-6 An alkyl group;
and/or when R is unsubstituted or R 3 The substituted hetero atom is one or more of N, O and S, and when the hetero atom number is 1-3, the hetero atom is 5-10 membered heteroaryl, the R 3 Is 1,2 or 3;
and/or when R is unsubstituted or R 3 When the heteroatom is selected from one or more of N, O and S and the heteroatom is 5-10 membered heteroaryl with 1-3 heteroatoms, the heteroaryl is pyridyl, pyridopyrrolyl, pyridoimidazolyl, pyridofuryl, pyrazolothienyl or pyrazolopyrazolyl;
and/or when R is unsubstituted or R 4 The substituted hetero atom is one or more of N, O and S, and when the hetero atom number is 5-10 membered heterocycloalkyl, the R is 1-3 4 The number of (2) is 1,2 or 3；
And/or when R is unsubstituted or R 4 The substituted hetero atom is one or more of N, O and S, and when the hetero atom number is 5-10 membered heterocycloalkyl of 1-3, the heterocycloalkyl is
And/or when R 3 Halogen, wherein the halogen is fluorine;
and/or when R 3 Is C 1-6 When alkyl is said C 1-6 Alkyl of (2) is methyl, ethyl, propyl or isopropyl, preferably methyl;
and/or when R 3 Is C 1-6 When alkoxy is said C 1-6 Alkoxy of (a) is methoxy, ethoxy or propoxy, preferably methoxy;
and/or when R 3 Is C 1-6 When haloalkyl, said C 1-6 Haloalkyl is-CF 3 ；
And/or when R 4 Is C 1-6 In the case of alkyl, said C 1-6 Alkyl is methyl, ethyl or propyl, preferably methyl;
and/or when R 4 Is C 1-6 When haloalkyl, said C 1-6 Haloalkyl is-CF 3 。
Further, when R is unsubstituted or R 3 The substituted hetero atom is one or more of N, O and S, and when the hetero atom number is 5-10 membered heteroaryl of 1-3, the unsubstituted or R 3 Substituted heteroaryl groups are:
and/or when R is unsubstituted or R 4 The substituted hetero atom is one or more of N, O and S, and when the hetero atom number is 1-3' 5-10 membered heterocyclic alkyl group, the unsubstituted or R 4 Substituted heterocycloalkyl is
And/or when E is O, X is a single bond, R is
Alternatively, when E is O, X is-NHCH 2 -、C 2-4 Alkenyl or cyclopropyl, R is
Alternatively, when E is S, X is-NHCH 2 -, R is
Alternatively, when E is N-C≡N, X is a single bond and R is
Further, L is unsubstituted C 2-10 An alkyl group;
and/or E is O, S or N-C≡N;
and/or X is a single bond, C 2-4 Olefinic bond, C 1.4 Alkyl, cyclopropyl, -NHCH 2 -；
And/or R is unsubstituted or R 3 The substituted hetero atom is selected from one or more of N, O and S, the hetero atom number is 1-3 '5-10 membered heteroaryl, or the unsubstituted or R4 substituted hetero atom is selected from one or more of N, O and S, and the hetero atom number is 1-3' 5-10 membered heterocycloalkyl;
and/or R 3 Is halogen, amino or C 1-6 An alkyl group;
and/or R 4 Is amino or C 1-6 An alkyl group.
Further, the method comprises the steps of,
the phenolphthalein ketone compound or pharmaceutically acceptable salts, solvates, prodrugs, isomers or metabolites thereof is any one of the following:
further, the preparation method of the phenolphthalein ketone compound is characterized by comprising the following steps of: the method comprises the following steps:
and (3) in a solvent, under the action of alkali and a condensing agent, carrying out condensation reaction on the compound shown in the formula II and the compound shown in the formula III, wherein L, E, X and R are defined as above.
A pharmaceutical composition comprising an effective amount of a compound of formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, prodrug, isomer or metabolite thereof, and a pharmaceutically acceptable carrier. The invention also provides application of the pharmaceutical composition in preparing medicines for preventing and/or treating tumors, including but not limited to breast cancer, ovarian cancer, prostatic cancer, colon cancer, gastric cancer, non-small cell lung cancer, glioma, kidney cancer, pancreatic cancer, liver cancer, melanoma, leukemia and cervical cancer, preferably breast cancer, ovarian cancer, prostate cancer, colon cancer, gastric cancer, non-small cell lung cancer, melanoma, leukemia and cervical cancer.
The application of phenolphthalone compounds with the structure shown in the general formula I or pharmaceutically acceptable salts, solvates, prodrugs, isomers or metabolites thereof in preparing medicines for preventing and/or treating tumors or NAMPT and PARP1 inhibitors.
Further, the tumor is one or more of breast cancer, ovarian cancer, prostate cancer, colon cancer, gastric cancer, non-small cell lung cancer, glioma, renal cancer, pancreatic cancer, liver cancer, melanoma, leukemia and cervical cancer. Preferred are breast, prostate, colon, non-small cell lung, leukemia and kidney cancers.
The pharmaceutically acceptable carrier can be those excipients widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts. Preferably, the salt is contacted with a base or acid in a conventional manner to isolate the parent compound, thereby regenerating the neutral form of the compound. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
The term "isomer" refers to two or more compounds that have the same molecular composition but different structures and properties.
The term "solvate" refers to a mixture of a compound and a solvent, e.g., crystalline is a solvate.
The term "metabolite" refers to a pharmaceutically active product of a compound of formula I or a salt thereof produced by in vivo metabolism. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation (glucorination), enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain the metabolites thereof.
The identification of metabolites is typically accomplished by preparing radiolabeled compounds of the invention (e.g., 14 c or 3 H) Isotope, parenteral administration thereof to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg/kg), allows forAllowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and for its conversion products to be isolated from urine, blood or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
"substitution" in the present invention may be one or more, and when there are plural "substitution", the "substitution" may be the same or different.
The term "plurality" refers to 2,3, 4, or 5. For example, the term "alkyl" refers to a straight or branched saturated hydrocarbon group having the indicated number of carbon atoms. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, t-butyl, neopentyl, n-hexyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 4-methyl-2-pentyl. It should be noted that when the number of carbon atoms thereof is not particularly limited, it means only the number of carbon atoms of the alkyl moiety indicated therein, and does not include the number of carbon atoms on the substituent of the alkyl group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkoxy" refers to the group-O-R Y Wherein R is Y Are alkyl groups as defined above.
The term "cycloalkyl" refers to a saturated, monocyclic or polycyclic alkyl group. The monocyclic cycloalkyl group is preferably a monovalent saturated cyclic alkyl group having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Each ring of the polycyclic cycloalkyl is saturated and may be a bicyclic or tricyclic cycloalkyl having 4 to 10 carbon atoms.
In the present invention, "heterocycloalkyl" means a saturated monocyclic ring having a heteroatom or a bicyclic ring formed by fusing a saturated monocyclic ring having a heteroatom with a heteroaryl, and when "heterocycloalkyl" is a bicyclic ring formed by fusing a saturated monocyclic ring having a heteroatom with a heteroaryl, the "heterocycloalkyl" is linked to other fragments or groups in the compound represented by formula I through a saturated monocyclic ring having a heteroatom.
The term "aryl" refers to an aromatic group having the indicated number of carbon atoms, preferably a monocyclic, bicyclic or tricyclic aromatic group, and when bicyclic or tricyclic, each ring satisfies the shock rule. C of the invention 6-10 Aryl of (a) refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring containing 1,2 or 3 atoms independently selected from nitrogen, oxygen and sulfur. The 5-to 6-membered monocyclic ring includes, but is not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, furazanyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl or tetrazinyl. The 9-10 membered bicyclic ring includes, but is not limited to, benzimidazolyl, benzisothiazolyl, benzoxazolyl, imidazopyridine, thiazolopyridine, furopyridine, tetrahydropyrrolopyridine.
The beneficial effects are that: compared with the prior art, the invention has the following advantages:
1. the compounds of the invention have good inhibitory activity on VEGFR, especially VEGFR 2.
2. The compound has good inhibitory activity on NAMPT.
3. The compound has dual inhibition activities of VEGFR and NAMPT, has good treatment effect on tumors, has fewer toxic and side effects and can solve the problem of drug resistance compared with a single-target inhibitor.
Detailed Description
Example 1: synthetic route of the compound of formula I (Synthesis of A series of compounds)
Preparation of 4- (4-aminoethyl) -1-t-butoxycarbonylpiperazine
Into a 25ml round bottom flask was charged compound 1 (2.0 g,10.8 mmol), compound 2 (3.0 g,10.8 mmol), triethylamine (3.0 ml,21.6 mmol), o-xylene (70 ml) and LThe reaction was carried out at 120℃for 24 hours. After the reaction, the mixture was filtered, the filtrate was concentrated, and column chromatography (EA/pe=1:4 to 2:1) was performed to obtain compound 3. To a 250ml round bottom flask was added compound 3 (3.7 g,9.6 mmol), hydrazine hydrate (1.0 ml,19.2 mmol), ethanol (80 ml), and the mixture was refluxed at 80℃for 10 hours. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and the mixture was chromatographed (DCM/MeOH/Et 3 N=90:8:2) to give 4- (4-aminoethyl) -1-t-butoxycarbonylpiperazine (1.9 g, 80%).
Preparation of 4- (4- (imidazo [1,2-a ] pyridine-7-carboxamide) n-butyl) piperazine-1-t-butoxycarbonyl piperazine
In a 25ml round bottom flask was added compound 4 (1.5 g,5.3 mmol), compound 5 (850 mg,5.3 mmol), HBTU (3.0 g,8.0 mmol), DIPEA (2.7 ml,16.0 mmol), DMF (25 ml) and reacted at room temperature for 14 h. After the reaction was completed, DMF was dried by spin-drying, and column chromatography (MeOH/DCM=1:30.about.1:10) gave 4- (4- (imidazo [1,2-a ] pyridine-7-carboxamide) n-butyl) piperazine-1-t-butoxycarbonyl piperazine (1.0 g, 47%).
Preparation of N- (4- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) butyl) imidazo [1,2-a ] pyridine-7-carboxamide
A25 ml round bottom flask was charged with Compound 6 (1.0 g,2.5 mmol), ethyl acetate (10 ml), and a saturated solution of ethyl acetate in hydrogen chloride (4 ml) was prepared and reacted at room temperature for 4 hours. After the reaction is finished, filtering to obtain solid, and drying for later use. A25 ml round bottom flask was charged with the solid from the previous step, compound 7 (1.1 g,3.8 mmol), HATU (1.4 g,3.8 mmol), DIPEA (2.1 ml,12.5 mmol), DMF (20 ml) and reacted at room temperature for 10 hours. After the reaction, spin-drying DMF, column chromatography (MeOH/DCM=1:20-1:8) gives N- (4- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazinyl-1-yl) methyl) benzoyl) piperazin-1-yl) butyl) imidazo [1,2-a]pyridine-7-carboxamide (500 mg, 43%). 1 H NMR(500MHz，Chloroform-d)δ8.83(d，J＝9.0Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，8.08(t，J＝4.4Hz，1H)，8.02(d，J＝1.6Hz，1H)，7.80(ddt，J＝5.0，2.0，1.1Hz，1H)，7.78-7.72(m，1H)，7.72-7.65(m，3H)，7.65(s，1H)，7.44(dddt，J＝7.9，4.9，1.9，1.0Hz，1H)，7.36(dd，J＝9.0，1.5Hz，1H)，7.21(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.74(dt，J＝11.7，5.3Hz，2H)，3.45-3.34(m，4H)，2.58(t，J＝5.4Hz，4H)，2.46(t，J＝6.3Hz，2H)，1.69-1.60(m，2H)，1.56(pd，J＝6.3，1.0Hz，2H). 13 C NMR(125MHz，Chloroform-d)δ166.97，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，142.28，132.79-132.48(m)，132.42-132.03(m)，130.76，129.93-129.68(m)，129.24，127.35，125.74，125.58，123.91，123.33，115.59，115.43，112.00，111.06，109.28，56.03，53.41，45.21，39.75，36.72，26.61，24.99.
Example 2: preparation of N- (4- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) ethyl) imidazo [1,2-a ] pyridine-7-carboxamide
The synthesis was as in example 1, with only the corresponding starting materials being replaced. 1 H NMR(500MHz，Chloroform-d)δ8.79(d，J＝8.9Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，8.00(d，J＝1.5Hz，1H)，7.86(t，J＝4.4Hz，1H)，7.78-7.62(m，6H)，7.49(dddt，J＝8.6，4.9，1.9，0.9Hz，1H)，7.39(dd，J＝9.0，1.5Hz，1H)，7.24(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.76-3.68(m，2H)，3.52(td，J＝5.6，4.4Hz，2H)，3.44-3.35(m，2H)，2.68(t，J＝5.6Hz，2H)，2.62-2.51(m，4H). 13 C NMR(125MHz，DMSO-d6)δ166.51，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.85，142.29，132.79-132.03(m)，130.75，130.00-129.70(m)，129.24，127.35，125.74，125.58，123.91，123.33，115.59，115.43，112.22，111.06，109.27，55.86，52.46，45.21，37.56，36.72.
Example 3: preparation of N- (4- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) propyl) imidazo [1,2-a ] pyridine-7-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.68(d，J＝8.9Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，8.17(t，J＝4.4Hz，1H)，8.06(d，J＝1.6Hz，1H)，7.78-7.64(m，5H)，7.61(ddt，J＝4.9，1.9，1.0Hz，1H)，7.50(dddt，J＝8.1，5.1，2.0，1.1Hz，1H)，7.35(dd，J＝9.0，1.5Hz，1H)，7.25(t，J＝8.2Hz，1H)，4.30(t，J＝1.0Hz，2H)，3.73(dt，J＝11.7，5.3Hz，2H)，3.39-3.28(m，4H)，2.64-2.55(m，4H)，2.46(t，J＝6.4Hz，2H)，1.78(p，J＝6.4Hz，2H). 13 C NMR(125MHz，Chloroform-d)δ166.63，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.85，142.28，132.79-132.03(m)，130.75，129.81(d，J＝8.2Hz)，129.24，127.35，125.74，125.58，123.91，123.33，115.59，115.43，112.00，111.06，109.27，53.26(d，J＝6.9Hz)，45.21，38.13，36.72，25.71.
Example 4: preparation of N- (4- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) imidazo [1,2-a ] pyridine-7-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.79(d，J＝8.9Hz，1H)，8.26-8.18(m，2H)，8.01(d，J＝1.5Hz，1H)，7.78-7.72(m，1H)，7.72-7.67(m，3H)，7.67-7.63(m，2H)，7.52(dddt，J＝7.9，5.1，2.0，1.1Hz，1H)，7.33(dd，J＝9.0，1.5Hz，1H)，7.24(t，J＝8.2Hz，1H)，4.25(t，J＝1.0Hz，2H)，3.81-3.72(m，2H)，3.27(dtd，J＝11.9，6.0，4.6Hz，4H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.63(dp，J＝22.2，6.5Hz，4H)，1.44-1.34(m，2H). 13 C NMR(125MHz，Chloroforrm-d)δ166.75，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，142.28，132.82-132.48(m)，132.42-132.03(m)，130.76，129.93-129.59(m)，129.33，127.35，125.74，125.58，123.91，123.33，115.59，115.43，112.00，111.06，109.28，56.16，53.41，45.21，39.86，36.72，28.56，26.50，25.02.
Example 5: preparation of N- (4- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) imidazo [1,2-a ] pyridine-7-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.79(d，J＝8.9Hz，2H)，8.29-8.23(m，2H)，8.15(t，J＝4.4Hz，2H)，8.02(d，J＝1.5Hz，2H)，7.76(d，J＝1.8Hz，1H)，7.75-7.67(m，7H)，7.65(s，2H)，7.56(ddt，J＝5.0，2.0，1.0Hz，2H)，7.48(dddt，J＝8.6，4.9，1.9，0.9Hz，2H)，7.33(dd，J＝9.0，1.5Hz，2H)，7.23(t，J＝8.2Hz，2H)，4.27(t，J＝1.0Hz，4H)，3.74(ddd，J＝11.7，6.0，4.6Hz，4H)，3.32(ddd，J＝11.7，6.0，4.5Hz，4H)，3.24(td，J＝6.3，4.3Hz，4H)，2.63-2.51(m，8H)，2.37(t，J＝6.4Hz，4H)，1.64(p，J＝6.6Hz，4H)，1.45(p，J＝6.6Hz，4H)，1.37-1.23(m，8H). 13 C NMR(125MHz，Chloroform-d)δ166.75，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，142.28，132.82-132.48(m)，132.42-132.03(m)，130.76，129.88(d，J＝7.9Hz)，129.67，129.32，127.35，125.74，125.58，123.91，123.33，115.59，115.43，112.00，111.06，109.28，56.16，53.41，45.21，39.77，36.72，28.48，27.33，27.11，26.71.
Example 6: (E) Preparation of (E) -N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) ethyl) -3- (pyridin-3-yl) acrylamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.65(t，J＝1.9Hz，1H)，8.58(dt，J＝3.7，1.8Hz，1H)，8.29-8.23(m，1H)，7.97(dt，J＝7.8，1.9Hz，1H)，7.83(t，J＝4.4Hz，1H)，7.82-7.75(m，2H)，7.75-7.64(m，2H)，7.62-7.50(m，3H)，7.25(t，J＝8.2Hz，1H)，6.59(d，J＝15.9Hz，1H)，4.24(t，J＝1.0Hz，2H)，3.83-3.75(m，2H)，3.43-3.38(m，2H)，3.38-3.30(m，2H)，2.68(t，J＝5.6Hz，2H)，2.61-2.52(m，4H). 13 C NMR(125MHz，Chloroform-d)δ167.27，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.85，150.23，149.57，138.69，134.34，132.71，132.37-132.03(m)，130.75，129.83(dd，J＝18.6，6.7Hz)，129.16，127.27，125.74，125.58，123.91，123.33，120.46，115.59，115.43，55.78，52.46，45.21，38.41.36.72.
Example 7: (E) Preparation of (E) -N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) propyl) -3- (pyridin-3-yl) acrylamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.90(t，J＝1.8Hz，1H)，8.58(dt，J＝3.6，1.8Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，7.98(dt，J＝7.9，1.8Hz，1H)，7.78-7.72(m，2H)，7.68(dtd，J＝14.8，7.5，1.7Hz，2H)，7.64-7.56(m，3H)，7.49(dddt，J＝8.7，4.9，1.9，0.9Hz，1H)，7.24(t，J＝8.2Hz，1H)，6.59(d，J＝15.9Hz，1H)，4.28(t，J＝1.0Hz，2H)，3.76(dt，J＝11.7，5.3Hz，2H)，3.38-3.29(m，2H)，3.17(td，J＝6.3，4.3Hz，2H)，2.64-2.55(m，4H)，2.45(t，J＝6.4Hz，2H)，1.72(p，J＝6.4Hz，2H). 13 C NMR(125MHz，Chloroform-d)δ167.67，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.85，150.23，149.56，138.69，134.33，132.71，132.37-132.03(m)，130.75，130.00-129.66(m)，129.16，127.35，125.74，125.58，123.91，123.33，120.74，115.59，115.43，53.33(d，J＝11.0Hz)，45.16，39.19，36.72，25.95.
Example 8: (E) Preparation of (E) -N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) butyl) -3- (pyridin-3-yl) acrylamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.88(t，J＝1.9Hz，1H)，8.64(dt，J＝3.6，1.8Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，7.96(dt，J＝7.8，1.8Hz，1H)，7.78-7.45(m，8H)，7.24(t，J＝8.2Hz，1H)，6.59(d，J＝15.9Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.60(dt，J＝11.7，5.3Hz，2H)，3.26(dt，J＝11.7，5.3Hz，2H)，3.20(td，J＝6.3，4.4Hz，2H)，2.59(t，J＝5.3Hz，4H)，2.46(t，J＝6.3Hz，2H)，1.68-1.59(m，2H)，1.56-1.46(m，2H). 13 C NMR(125MHz，Chloroform-d)δ167.37，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.85，150.23，149.56，138.69，134.33，132.71，132.42-132.03(m)，130.75，129.94-129.66(m)，129.24，127.35，125.74，125.58，123.91，123.33，120.74，115.59，115.43，56.03，53.37，45.21，39.60，36.72，26.67，24.95.
Example 9: (E) Preparation of (E) -N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -3- (pyridin-3-yl) acrylamide
Synthetic prescriptionThe procedure is as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.93(t，J＝1.9Hz，1H)，8.64(dt，J＝3.6，1.8Hz，1H)，8.29-8.23(m，1H)，8.03(dt，J＝7.9，1.8Hz，1H)，7.79-7.64(m，4H)，7.63-7.54(m，3H)，7.50(dddt，J＝8.2，5.1，2.0，1.0Hz，1H)，7.24(t，J＝8.2Hz，1H)，6.60(d，J＝15.9Hz，1H)，4.28(t，J＝1.0Hz，2H)，3.67-3.59(m，2H)，3.26-3.15(m，4H)，2.58(t，J＝5.3Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.59-1.47(m，4H)，1.47-1.44(m，1H)，1.44-1.38(m，1H). 13 C NMR(125MHz，Chloroform-d)δ167.37，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，150.23，149.58，138.69，134.33，132.74，132.42-132.03(m)，130.76，129.93-129.64(m)，129.24，127.35，125.74，125.58，123.91，123.26，120.72，115.59，115.43，56.16，53.33，45.21，39.73，36.72，28.70，26.50，25.03.
Example 10: (E) Preparation of (E) -N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) -3- (pyridin-3-yl) acrylamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.98(t，J＝1.9Hz，1H)，8.64(dt，J＝3.6，1.8Hz，1H)，8.29-8.23(m，1H)，8.13(dt，J＝7.9，1.9Hz，1H)，7.79(t，J＝4.4Hz，1H)，7.76-7.64(m，3H)，7.61(dd，J＝7.9，3.5Hz，1H)，7.54-7.45(m，2H)，7.30(d，J＝15.9Hz，1H)，7.23(t，J＝8.1Hz，1H)，6.60(d，J＝15.9Hz，1H)，4.29(t，J＝1.0Hz，2H)，3.66(ddd，J＝11.7，6.0，4.6Hz，2H)，3.27-3.16(m，4H)，2.63-2.51(m，4H)，2.37(t，J＝6.4Hz，2H)，1.57(p，J＝6.5Hz，2H)，1.46(p，J＝6.6Hz，2H)，1.38-1.22(m，4H). 13 C NMR(125MHz，Chloroform-d)δ167.37，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，150.23，149.58，138.69，134.33，132.74，132.42-132.03(m)，130.76，129.76(dd，J＝13.6，8.1Hz)，129.33，127.35，125.74，125.58，123.91，123.26，120.72，115.59，115.43，56.16，53.41，45.21，39.72，36.72，28.51，27.30，27.11，26.71.
Example 11: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) butyl) -1H-pyrrolo [3,2-c ] pyridine-3-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.31(d，J＝1.8Hz，1H)，8.59(t，J＝4.4Hz，1H)，8.34(dd，J＝5.7，1.5Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，8.10(d，J＝2.6Hz，1H)，7.787.65(m，3H)，7.62(ddt，J＝5.0，2.0，1.0Hz，1H)，7.52-7.42(m，2H)，7.26-7.19(m，1H)，4.27(t，J＝1.0Hz，2H)，3.68-3.59(m，2H)，3.38(td，J＝6.2，4.4Hz，2H)，3.30-3.22(m，2H)，2.63-2.53(m，4H)，2.46(t，J＝6.3Hz，2H)，1.68-1.60(m，2H)，1.55(pd，J＝6.3，1.1Hz，2H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，165.54，160.15，158.42，158.13，151.88，143.76(d，J＝8.1Hz)，138.80，132.71，132.42-132.03(m)，130.76，130.10，129.93-129.68(m)，129.24，127.35，125.74，125.58，123.91，122.11，115.59，115.43，108.41，108.07，56.03，53.41，45.21，39.81，36.72，26.78，24.99.
Example 12: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -1H-pyrrolo [3,2-c ] pyridine-3-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.43(d，J＝1.6Hz，1H)，8.51(t，J＝4.4Hz，1H)，8.34(dd，J＝5.7，1.6Hz，1H)，8.29-8.23(m，1H)，8.08(d，J＝2.6Hz，1H)，7.78-7.64(m，3H)，7.61(ddt，J＝5.0，2.0，1.0Hz，1H)，7.51-7.42(m，2H)，7.24(t，J＝8.2Hz，1H)，4.19(t，J＝1.0Hz，2H)，3.86-3.78(m，2H)，3.36-3.24(m，4H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.56(dp，J＝34.0，6.5Hz，4H)，1.44-1.34(m，2H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，165.61，160.15，158.42，158.13，151.88，143.80(d，J＝3.3Hz)，138.80，132.74，132.42-132.03(m)，130.76，130.15，129.93-129.59(m)，129.33，127.35，125.74，125.58，123.91，122.11，115.59，115.43，108.43，108.07，56.16，53.41，45.21，39.99，36.72，28.70，26.50，25.02.
Example 13: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) -1H-pyrrolo [3,2-c ] pyridine-3-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.43(d，J＝1.8Hz，1H)，8.55(t，J＝4.3Hz，1H)，8.34(dd，J＝5.7，1.6Hz，1H)，8.29-8.23(m，1H)，7.78-7.68(m，4H)，7.67(dd，J＝7.4，1.7Hz，1H)，7.56-7.45(m，2H)，7.45(dd，J＝5.6，2.1Hz，1H)，7.24(t，J＝8.2Hz，1H)，4.29(t，J＝1.0Hz，2H)，3.67-3.58(m，2H)，3.34-3.25(m，4H)，2.58(dd，J＝5.7，5.0Hz，4H)，2.37(t，J＝6.4Hz，2H)，1.62(p，J＝6.6Hz，2H)，1.45(p，J＝6.6Hz，2H)，1.38-1.22(m，4H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，165.63，160.15，158.42，158.13，151.88，144.05，143.79，138.80，132.74，132.42-132.03(m)，130.76，130.15，129.88(d，J＝7.9Hz)，129.67，129.32，127.35，125.74，125.58，123.91，122.11，115.59，115.43，108.43，108.07，56.16，53.41，45.21，39.94，36.72，28.60，27.33，27.11，26.75.
Example 14: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) ethyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.61(d，J＝1.8Hz，1H)，8.40(dd，J＝5.6，1.7Hz，1H)，8.26(dd，J＝7.7，1.8Hz，1H)，7.72(dtd，J＝22.5，7.4，1.8Hz，2H)，7.68-7.61(m，2H)，7.49(dddt，J＝8.6，4.9，1.9，0.9Hz，1H)，7.37(d，J＝5.7Hz，1H)，7.24(t，J＝8.2Hz，1H)，6.48(t，J＝4.4Hz，1H)，4.86(s，2H)，4.30(s，2H)，4.26(t，J＝1.0Hz，2H)，3.69(ddd，J＝11.7，5.9，4.7Hz，2H)，3.48-3.41(m，2H)，3.41-3.35(m，2H)，2.67(t，J＝5.6Hz，2H)，2.59-2.48(m，4H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.13，157.77，151.85，146.68，145.95，143.08，132.71，132.57-132.03(m)，130.75，130.00-129.70(m)，129.24，127.35，125.74，125.58，123.91，116.96，115.59，115.43，55.79，52.71，52.49，52.15，45.21，38.03，36.72.
Example 15: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) propyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.62(d，J＝1.8Hz，1H)，8.40(dd，J＝5.7，1.8Hz，1H)，8.26(dd，J＝7.7，1.8Hz，1H)，7.78-7.63(m，3H)，7.55(ddt，J＝5.0，2.0，1.0Hz，1H)，7.50(dddt，J＝8.7，4.9，1.9，0.9Hz，1H)，7.36(d，J＝5.6Hz，1H)，7.24(t，J＝8.2Hz，1H)，6.68(t，J＝4.4Hz，1H)，4.86(s，2H)，4.40(d，J＝13.4Hz，1H)，4.33-4.26(m，3H)，3.65(dt，J＝11.7，5.2Hz，2H)，3.35(td，J＝6.3，4.4Hz，2H)，3.26(dt，J＝11.7，5.3Hz，2H)，2.59(t，J＝5.3Hz，4H)，2.45(t，J＝6.4Hz，2H)，1.76(p，J＝6.4Hz，2H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.13，157.90，151.85，146.68，145.95，143.08，132.71，132.48-132.03(m)，130.75，129.81(d，J＝8.2Hz)，129.24，127.35，125.74，125.58，123.91，117.04，115.59，115.43，53.26(d，J＝7.9Hz)，52.49，52.15，45.21，38.86，36.72，25.79.
Example 16: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) butyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.60(d，J＝1.8Hz，1H)，8.40(dd，J＝5.7，1.8Hz，1H)，8.29-8.23(m，1H)，7.78-7.64(m，3H)，7.63(ddt，J＝5.0，2.0，1.0Hz，1H)，7.50(dddt，J＝8.0，5.1，2.0，1.1Hz，1H)，7.37(d，J＝5.7Hz，1H)，7.24(t，J＝8.2Hz，1H)，6.46(t，J＝4.4Hz，1H)，4.86(s，2H)，4.31(s，2H)，4.26(t，J＝1.0Hz，2H)，3.73(dt，J＝11.7，5.3Hz，2H)，3.34(dt，J＝11.7，5.3Hz，2H)，3.18(td，J＝6.2，4.4Hz，2H)，2.59(t，J＝5.3Hz，4H)，2.46(t，J＝6.4Hz，2H)，1.64(p，J＝6.7Hz，2H)，1.55-1.46(m，2H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.11(d，J＝4.5Hz)，151.88，146.68，145.95，143.08，132.71(d，J＝7.2Hz)，132.42-132.03(m)，130.76，129.93-129.68(m)，129.24，127.35，125.74，125.58，123.91，117.04，115.59，115.43，56.03，53.41，52.49，52.18，45.21，39.43，36.72，26.62，24.99.
Example 17: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -1, 3-dihydro-2H-pyrrole [3,4-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.60(d，J＝1.8Hz，1H)，8.40(dd，J＝5.5，1.8Hz，1H)，8.29-8.23(m，1H)，7.78-7.61(m，4H)，7.50(dddt，J＝8.2，5.1，2.0，1.0Hz，1H)，7.37(d，J＝5.7Hz，1H)，7.24(t，J＝8.2Hz，1H)，6.70(t，J＝4.4Hz，1H)，4.86(s，2H)，4.31(s，2H)，4.26(t，J＝1.0Hz，2H)，3.78-3.69(m，2H)，3.38-3.29(m，2H)，3.16(td，J＝6.3，4.4Hz，2H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.59-1.44(m，4H)，1.43-1.33(m，2H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.11(d，J＝4.5Hz)，151.88，146.68，145.95，143.08，132.74，132.50-132.03(m)，130.76，129.93-129.59(m)，129.33，127.35，125.74，125.58，123.91，117.04，115.59，115.43，56.16，53.41，52.49，52.18，45.21，39.50，36.72，28.39，26.50，25.01.
Example 18: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.61(d，J＝1.8Hz，1H)，8.40(dd，J＝5.7，1.8Hz，1H)，8.29-8.23(m，1H)，7.78-7.65(m，3H)，7.62(ddt，J＝4.9，2.0，1.0Hz，1H)，7.49(dddt，J＝8.8，5.1，2.0，1.0Hz，1H)，7.36(d，J＝5.6Hz，1H)，7.24(t，J＝8.2Hz，1H)，6.58(t，J＝4.4Hz，1H)，4.86(s，2H)，4.30(s，2H)，4.26(t，J＝1.0Hz，2H)，3.71(ddd，J＝11.7，5.9，4.8Hz，2H)，3.37(ddd，J＝11.7，5.9，4.8Hz，2H)，3.16(td，J＝6.3，4.4Hz，2H)，2.63-2.52(m，4H)，2.37(t，J＝6.4Hz，2H)，1.52-1.40(m，4H)，1.37-1.22(m，4H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.11(d，J＝4.5Hz)，151.88，146.70，145.95，143.08，132.74，132.50-132.03(m)，130.76，129.88(d，J＝7.9Hz)，129.67，129.32，127.35，125.74，125.58，123.91，117.04，115.59，115.43，56.16，53.41，52.49，52.18，45.21，39.56，36.72，28.76，27.33，27.11，26.60.
Example 19: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) imidazo [1,2-a ] pyrimidine-7-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.38(d，J＝8.9Hz，1H)，8.34(t，J＝4.4Hz，1H)，8.29-8.22(m，1H)，8.08(s，1H)，7.79-7.63(m，4H)，7.47(dddt，J＝7.9，4.9，1.9，1.0Hz，1H)，7.36(s，1H)，7.28-7.15(m，2H)，4.26(t，J＝1.0Hz，2H)，3.78-3.68(m，2H)，3.42-3.31(m，4H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.58(dp，J＝14.9，6.6Hz，4H)，1.46-1.34(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.73(d，J＝7.9Hz)，163.51，158.23，151.89，145.53，143.19，132.54-132.28(m)，132.07(d，J＝2.9Hz)，130.82，129.87(d，J＝7.9Hz)，129.54(d，J＝3.1Hz)，129.32，129.14，127.36，123.89，115.58，115.42，113.57，111.37，56.23，53.50，45.22，40.13，36.72，28.57，26.49，25.00.
Example 20: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -3a,7 a-dihydro-1H-pyrazolo [3,4-b ] pyridine-6-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.28-8.23(m，1H)，7.80-7.72(m，2H)，7.72-7.64(m，2H)，7.52(t，J＝4.3Hz，1H)，7.46(dddt，J＝8.6，5.0，1.9，0.9Hz，1H)，7.36(d，J＝5.5Hz，1H)，7.22(t，J＝8.2Hz，1H)，6.97(d，J＝6.6Hz，1H)，6.89(dd，J＝9.3，1.0Hz，1H)，6.08(dd，J＝9.2，5.7Hz，1H)，5.26(dd，J＝6.6，5.1Hz，1H)，4.40(dt，J＝11.4，1.0Hz，1H)，4.11(dt，J＝11.3，1.0Hz，1H)，3.76-3.68(m，2H)，3.49(qd，J＝5.6，1.1Hz，1H)，3.41-3.33(m，2H)，3.27(dtdJ＝14.3，6.2，4.3Hz，1H)，3.12(dtd，J＝14.4，6.2，4.4Hz，1H)，2.58(t，J＝5.4Hz，4H)，2.43(dt，J＝11.9，6.4Hz，1H)，2.32(dt，J＝12.0，6.3Hz，1H)，1.64-1.28(m，6H). 13 C NMR(125MHz，Common NMR Solvents)δ166.64，165.76，165.70，159.83，158.23，157.81，153.23，151.89，134.56，132.46，132.42，132.36，132.09，132.06，130.82，129.90，129.84，129.52，129.14，128.57，127.48，127.36，125.65，125.49，123.89，115.58，115l42，74.73，56.23，53.50，45.22，43.28，40.29，36.72，28.65，26.49.25.00.
Example 21: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) furo [2,3-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.85(d，J＝1.7Hz，1H)，8.72(dd，J＝5.7，1.6Hz，1H)，8.30-8.23(m，2H)，7.91(d，J＝2.1Hz，1H)，7.79(ddt，J＝5.0，2.0，1.0Hz，1H)，7.78-7.65(m，4H)，7.46(dddt，J＝8.6，4.9，1.9，0.9Hz，1H)，7.22(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.72(dt，J＝11.7，5.2Hz，2H)，3.42-3.31(m，4H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.57(dp，J＝19.4，6.5Hz，4H)，1.44-1.35(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.76，165.70，161.31，159.83，158.23，157.81，151.89，151.31，151.18，144.55，134.40，132.69，132.46，132.42，132.36，132.09，132.06，130.82，129.90，129.84，129.52，129.14，127.36，125.65，125.49，123.89，117.65，115.58，115.42，110.56，56.23，53.50，45.22，39.93，36.72，28.69，26.49，25.00.
Example 22: preparation of 4-fluoro-N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) nicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.92(dd，J＝5.0，1.8Hz，1H)，8.65-8.59(m，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，8.10(t，J＝4.4Hz，1H)，7.78-7.64(m，3H)，7.63(ddt，J＝5.0，2.0，1.0Hz，1H)，7.50(dddt，J＝8.0，5.0，2.0，1.1Hz，1H)，7.28-7.20(m，2H)，4.26(t，J＝1.0Hz，2H)，3.71(dt，J＝11.7，5.2Hz，2H)，3.42-3.33(m，2H)，3.19(td，J＝6.2，4.4Hz，2H)，2.58(t，J＝5.3Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.57(dp，J＝11.1，6.5Hz，4H)，1.41(q，J＝7.0Hz，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.73(dJ＝7.9Hz)，164.60-164.34(m)，162.40，159.83，158.23，157.81，152.01-151.61(m)，132.57-132.30(m)，132.07(d，J＝2.9Hz)，130.82，129.93(d，J＝8.1Hz)，129.59，129.06，127.36，125.65，125.49，123.89，120.91，120.75，115.58，115.42，110.08，109.92，56.23，53.46，45.22，40.10，36.72，28.79，26.50，25.00.
Example 23: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.92(s，1H)，9.01(t，J＝1.7Hz，1H)，8.40-8.31(m，2H)，8.29-8.23(m，1H)，7.78-7.64(m，3H)，7.63(ddt，J＝4.9，2.0，0.9Hz，1H)，7.54-7.46(m，2H)，7.39(d，J＝1.4Hz，1H)，7.24(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.76-3.68(m，2H)，3.44-3.32(m，4H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.58(dp，J＝22.7，6.5Hz，4H)，1.45-1.35(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.73(d，J＝7.9Hz)，162.74，159.83，158.23，157.81，151.89，143.59，142.86，140.02，132.54-132.28(m)，132.07(d，J＝2.9Hz)，130.82，129.87(d，J＝7.9Hz)，129.52，129.14，127.36，125.65，125.49，124.82，123.89，115.58，115.42，108.41，104.28，56.23，53.50，45.22，40.26，36.72，28.69，26.49，25.00.
Example 24: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) thieno [2,3-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.03(d，J＝1.6Hz，1H)，8.76(dd，J＝5.6，1.7Hz，1H)，8.44(t，J＝4.4Hz，1H)，8.29-8.23(m，1H)，8.17-8.07(m，2H)，7.80(ddt，J＝4.9，2.0，1.0Hz，1H)，7.77-7.64(m，3H)，7.44(dddt，J＝8.0，5.1，2.0，1.0Hz，1H)，7.21(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.78-3.70(m，2H)，3.44-3.33(m，4H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.58(dp，J＝19.5，6.5Hz，4H)，1.41(q，J＝7.0Hz，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.76，165.70，164.56，159.83，158.23，157.81，151.89，146.13，144.48，143.16，139.02，136.76，132.53，132.42，132.36，132.09，132.06，130.82，129.99，129.93，129.52，129.14，127.36，125.65，125.49，124.49，123.89，119.96，115.58，115.42，56.23，53.50，45.22，40.08，36.72，28.70，26.49，25.00.
Example 25: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -6-methylnicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.01(d，J＝1.9Hz，1H)，8.29-8.18(m，2H)，7.89(ddJ＝8.4，1.8Hz，1H)，7.81-7.65(m，4H)，7.46(dddt，J＝8.6，4.9，1.9，0.9Hz，1H)，7.30(dq，J＝8.4，0.8Hz，1H)，7.22(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.76-3.67(m，2H)，3.42-3.34(m，2H)，3.24(td，J＝6.2，4.3Hz，2H)，2.62-2.53(m，7H)，2.38(t，J＝6.4Hz，2H)，1.56(dp，J＝10.3，6.5Hz，4H)，1.40(q，J＝7.0Hz，2H). 13 C NMR(125MHz，Common NMR Solvents)δ166.86，165.76，165.70，159.83，158.23，157.81，156.77，151.89，148.29，134.96，132.49，132.45，132.38，132.09，132.06，130.82，129.97，129.90，129.59，129.06，128.32，127.36，125.65，125.49，123.89，122.76，115.58，115.42，56.23，53.46，45.22，39.79，36.72，28.75，26.50，25.00.23.95.
Example 26: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) nicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.14(t，J＝1.8Hz，1H)，8.77(ddd，J＝4.6，2.6，1.8Hz，1H)，8.29-8.21(m，2H)，8.11(t，J＝4.4Hz，1H)，7.78-7.63(m，4H)，7.50(dddt，J＝7.9，4.9，1.9，1.0Hz，1H)，7.43(dd，J＝7.9，4.8Hz，1H)，7.24(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.75-3.66(m，2H)，3.42-3.33(m，2H)，3.25(td，J＝6.2，4.4Hz，2H)，2.62-2.53(m，4H)，2.38(t，J＝6.4Hz，2H)，1.57(dp，J＝11.3，6.6Hz，4H)，1.41(q，J＝7.0Hz，2H).13C NMR(125MHz，Common NMR Solvents)δ166.61，165.76，165.70，159.83，158.23，157.81，151.89，150.73，149.53，135.48，132.51，132.42，132.35，132.11，132.08，130.82，130.25，129.99，129.93，129.59，129.07，127.36，125.65，125.49，123.89，123.62，115.58，115.42，56.23，53.56，45.19，39.79，36.72，28.78，26.54，25.00.
Example 27: preparation of 6-amino-N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) nicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.83(d，J＝1.9Hz，1H)，8.29-8.21(m，2H)，7.78-7.63(m，5H)，7.48(dddt，J＝7.9，4.9，1.9，1.0Hz，1H)，7.23(t，J＝8.2Hz，1H)，6.32(d，J＝8.4Hz，1H)，5.92(d，J＝6.2Hz，1H)，5.80(d，J＝6.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.71(dt，J＝11.7，5.2Hz，2H)，3.42-3.33(m，2H)，3.30-3.13(m，2H)，2.58(t，J＝5.3Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.58(dp，J＝28.9，6.5Hz，4H)，1.44-1.34(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ166.76，165.76，165.70，160.35，159.83，158.23，157.81，151.89，149.18，136.09，132.49，132.45，132.38，132.09，132.06，130.82，129.97，129.90，129.59，129.06，127.36，125.65，125.49，123.89，122.06，115.58，115.42，107.59，56.23，53.46，45.22，39.79，36.72，28.75，26.50，25.00.
Example 28: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) isonicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.73-8.62(m，2H)，8.26(dd J＝7.6，1.7Hz，1H)，7.89(t，J＝4.4Hz，1H)，7.78-7.62(m，6H)，7.50(dddt，J＝8.0，4.9，2.0，1.1Hz，1H)，7.24(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.70(dt，J＝11.7，5.3Hz，2H)，3.42-3.33(m，4H)，2.62-2.53(m，4H)，2.38(t，J＝6l3Hz，2H)，1.57(dp，J＝13.1，6.5Hz，4H)，1.41(q，J＝7.0Hz，2H). 13 C NMR(125MHz，Common NMR Solvents)δ167.71，165.76，165.70，159.83，158.23，157.81，151.89，150.28，139.57，132.51，132l42，132l35，132.11，132.08，130.82，129.99，129.93，129.59，129.07，127l36，125.65，125.49，123.89，121.22，115.58，115.42，56.23，53.56，45.19，39.70，36.72，28.75，26.54，25.00.
Example 29: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -6- (trifluoromethyl) nicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ9.07(d，J＝1.9Hz，1H)，8.29-8.23(m，1H)，8.15(t，J＝4.3Hz，1H)，8.00(dd，J＝8.4，1.8Hz，1H)，7.78-7.64(m，4H)，7.63(ddt，J＝5.0，2.0，1.1Hz，1H)，7.50(dddt，J＝7.9，4.9，1.9，1.0Hz，1H)，7.24(t，J＝8.2Hz，1H)，4.26(t，J＝0.9Hz，2H)，3.72(dt，J＝11.7，5.3Hz，2H)，3.41-3.32(m，2H)，3.15(td，J＝6.3，4.4Hz，2H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.57(dp，J＝13.0，6.5Hz，4H)，1.40(q，J＝7.0Hz，2H). 13 C NMR(125MHz，Common NMR Solvents)δ166.69，165.76，165.70，159.83，158.23，157.81，151.89，149.48，149.22，148.77，148.75，148.74，148.72，136.06，136.04，136.02，136.01，132.53，132.42，132.36，132.09，132.06，130.82，130.08，129.99，129.93，129.52，129.07，127.36，125.65，125.49，123.91，122.76，120.61，119.84，119.81，119.78，119.75，115.58，115.42，56.23，53.50，45.22，39.79，36.72，28.72，26.49，24.98.
Example 30: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -2-methyl isonicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.65(d，J＝5.7Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，7.96(t，J＝4.3Hz，1H)，7.83-7.64(m，6H)，7.44(dddt，J＝8.6，5.0，1.8，0.9Hz，1H)，7.21(t，J＝8.2Hz，1H)，4.26(t，J＝0.9Hz，2H)，3.77-3.69(m，2H)，3.45-3.36(m，2H)，3.28(td，J＝6.3，4.4Hz，2H)，2.62-2.53(m，7H)，2.38(t，J＝6.3Hz，2H)，1.57(pd，J＝6.6，3.0Hz，4H)，1.45-1.36(m，2H). 13 C NMR(125MHz，CommonNMR Solvents)δ167.42，165.76，165.70，159.83，159.35，158.23，157.81，151.89，146.12，138.74，132.49，132.45，132.38，132.09，132.06，130.82，129.97，129.90，129.59，129.06，127.36，125.65，125.49，123.89，120.45，119.13，115.58，115.42，56.23，53.46，45.22，39.70，36.72，28.73，26.50，25.00，23.75.
Example 31: preparation of 2-fluoro N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) isonicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.52(d，J＝5.6Hz，1H)，8.26(dd，J＝7.6，1.7Hz，1H)，8.03(t，J＝4.3Hz，1H)，7.80(ddt，J＝5.0，2.0，1.0Hz，1H)，7.77-7.63(m，4H)，7.50(dd，J＝5.7，1.8Hz，1H)，7.44(dddt，J＝8.0，4.9，2.0，1.1Hz，1H)，7.21(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.73(dt，J＝11.7，5.2Hz，2H)，3.45-3.36(m，2H)，3.27(td，J＝6.3，4.4Hz，2H)，2.58(t，J＝5.3Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.57(dp，J＝8.2，6.6Hz，4H)，1.45-1.36(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ167.83，167.80，165.76，165.70，163.29，161.27，159.83，158.23，157.81，151.89，147.68，147.57，141.24，141.18，132.49，132.45，132.38，132.09，132.06，130.82，129.97，129.90，129.59，129.06，127.36，125.65，125.49，123.89，118.66，118.64，115.58，115.42，106.51，106.35，56.23，53.46，45.22，39.74，36.72，28.75，26.50，25.00.
Example 32: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -2- (trifluoromethyl) isonicotinamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.80(d，J＝5.6Hz，1H)，8.29-8.23(m，1H)，8.12-8.03(m，2H)，7.80(ddt，J＝5.0，2.0，0.9Hz，1H)，7.77-7.64(m，3H)，7.48-7.40(m，2H)，7.21(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.74(dt，J＝11.7，5.2Hz，2H)，3.44-3.36(m，2H)，3.23(td，J＝6.3，4.4Hz，2H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.65(p，J＝6.5Hz，2H)，1.56(p，J＝6.6Hz，2H)，1.45-1.36(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ168.03，165.76，165.70，159.83，158.23，157.81，151.89，149.23，148.98，147.33，147.31，147.30，147.28，140.03，140.02，132.53，132.42，132.36，132.09，132.06，130.82，129.99，129.93，129.52，129.07，127.36，125.65，125.49，123.91，123.20，122.11，121.06，117.61，117.58，117.55，117.51，115.58，115.42，56.23，53.50，45.22，39.71，36.72，28.72，26.49，24.98.
Example 33: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) imidazo [1,2-a ] pyridine-6-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.65(d，J＝1.4Hz，1H)，8.33-8.23(m，2H)，7.95(dd，J＝9.1，1.6Hz，1H)，7.83-7.63(m，7H)，7.44(dddt，J＝7.9，4.9，1.9，1.0Hz，1H)，7.21(t，J＝8.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.74(dt，J＝11.7，5.3Hz，2H)，3.44-3.36(m，2H)，3.20(td，J＝6.3，4.4Hz，2H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.58(dp，J＝19.8，6.6Hz，4H)，1.41(q，J＝7.0Hz，2H). 13 C NMR(125MHz，Common NMR Solvents)δ166.74，165.76，165.70，159.83，158.23，157.81，151.89，140.68，134.40，132.46，132.42，132.36，132.09，132.06，130.90，130.82，129.90，129.84，129.52，129.14，127.36，125.65，125.49，123.89，122.17，118.43，115.58，115.42，113.21，112.79，56.23，53.50，45.22，40.07，36.72，28.58，26.49，25.00.
Example 34: preparation of 6-amino-N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -1H-pyrrolo [3,2-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ10.00(s，1H)，8.69(d，J＝1.5Hz，1H)，8.53(t，J＝4.4Hz，1H)，8.29-8.23(m，1H)，7.78-7.64(m，4H)，7.46(dddt，J＝7.9，4.9，1.9，1.0Hz，1H)，7.28-7.20(m，2H)，6.68(s，1H)，5.84(d，J＝6.0Hz，1H)，5.77(d，J＝6.0Hz，1H)，4.21(t，J＝1.0Hz，2H)，3.77-3.68(m，2H)，3.44-3.35(m，4H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.59(dp，J＝17.5，6.6Hz，4H)，1.41(q.J＝6.9Hz，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.76，165.70，162.72，159.83，158.23，157.81，154.72，151.89，144.53，143.14，132.51，132.42，132.36，132.16，132.09，132.06，130.82，129.99，129.93，129.52，129.13，127.36，125.65，125.49，123.89，115.64，115.58，115.42，104.21，89.88，56.23，53.50，45.22，40.26，36.72，28.69，26.49，24.98.
Example 35: preparation of 5-amino N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) furo [2,3-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.49(s，1H)，8.35(t，J＝4.4Hz，1H)，8.29-8.23(m，1H)，7.80(ddt，J＝5.0，2.0，1.0Hz，1H)，7.77-7.64(m，3H)，7.50-7.40(m，2H)，7.21(t，J＝8.2Hz，1H)，7.03(d，J＝2.3Hz，1H)，5.35(d，J＝6.2Hz，1H)，5.23(d，J＝6.2Hz，1H)，4.26(t，J＝1.0Hz，2H)，3.79-3.70(m，2H)，3.45-3.37(m，2H)，3.34(td，J＝6.3，4.4Hz，2H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.58(dp，J＝15.0，6.6Hz，4H)，1.45-1.36(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.76，165.70，161.27，159.83，158.23，157.81，152.75，151.89，150.20，143.41，133.99，133.20，132.51，132.42，132.36，132.09，132.06，130.82，129.99，129.93，129.52，129.13，127.36，125.65，125.49，123.89，115.58，115.42，109.00，98.52，56.23，53.50，45.22，39.93，36.72，28.69，26.49，24.98.
Example 36: preparation of 6-amino N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.37-8.17(m，1H)，8.11(s，1H)，7.79-7.64(m，4H)，7.47(dddt，J＝8.7，4.9，1.9，0.9Hz，1H)，7.22(t，J＝8.2Hz，1H)，6.74(t，J＝4.4Hz，1H)，6.52(s，1H)，5.32(d，J＝6.0Hz，1H)，5.22(d，J＝6.0Hz，1H)，4.33-4.23(m，6H)，3.76-3.67(m，2H)，3.42-3.33(m，2H)，3.14(td，J＝6.2，4.4Hz，2H)，2.58(t，J＝5.4Hz，4H)，2.38(t，J＝6.4Hz，2H)，1.59-1.53(m，2H)，1.53-1.45(m，3H)，1.45-1.35(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.73(d，J＝7.9Hz)，159.83，158.42，158.23(d，J＝1.1Hz)，157.81，151.89，148.75，140.58，132.59-132.28(m)，132.07(d，J＝2.9Hz)，130.82，129.96(d，J＝7.9Hz)，129.52，129.13，127.36，125.65，125.49，123.89，121.12，115.58，115.42，101.83，56.23，53.50，52.11，51.90，45.22，39.63，36.72，28.35，26.49，24.97.
Example 37: preparation of N- (5- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -6-methyl-1, 3-dihydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.49(s，1H)，8.29-8.23(m，1H)，7.78-7.61(m，4H)，7.49(dddt，J＝8.2，5.1，2.0，1.0Hz，1H)，7.29(s，1H)，7.24(t，J＝8.2Hz，1H)，6.74(t，J＝4.4Hz，1H)，4.82(s，2H)，4.42(d， J＝13.5Hz，1H)，4.35-4.24(m，3H)，3.76-3.67(m，2H)，3.42-3.33(m，2H)，3.16(td，J＝6.2，4.4Hz，2H)，2.62-2.53(m，7H)，2.38(t，J＝6.3Hz，2H)，1.59-1.45(m，4H)，1.45-1.36(m，2H). 13 C NMR(125MHz，Common NMR Solvents)δ165.76，165.70，159.83，158.23，158.12，157.81，157.66，151.89，147.88，142.02，132.51，132.42，132.36，132.09，132.06，130.82，130.18，129.99，129.93，129.52，129.13，127.36，125.65，125.49，123.89，117.17，115.58，115.42，56.23，53.50，52.12，52.07，45.22，39.63，36.72，28.35，26.49，24.97，24.47.
Example 38: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -2- (pyridin-3-yl) cyclopropyl-1-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.56(dt，J＝4.8，1.8Hz，1H)，8.33-8.23(m，2H)，7.78-7.64(m，3H)，7.59(ddt，J＝5.0，2.0，1.0Hz，1H)，7.56-7.46(m，2H)，7.31(dd，J＝7.8，4.7Hz，1H)，7.24(t，J＝8.2HZ，1H)，7.03(t，J＝4.4Hz，1H)，4.40(dt，J＝11.5，1.1Hz，1H)，4.13(dt，J＝11.3，0.9Hz，1H)，3.85-3.77(m，2H)，3.42-3.33(m，2H)，3.19(dtd，J＝14.3，6.2，4.3Hz，1H)，2.98(dtd，J＝14.3，6.2，4.3Hz，1H)，2.63-2.52(m，5H)，2.47-2.38(m，1H)，2.37-2.24(m，2H)，1.66-1.21(m，8H). 13 C NMR(125MHz，Chloroform-d)δ173.48，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，149.37，148.19，135.03，132.74，132.53-132.03(m)，130.76，129.93-129.59(m)，129.33，127.35，125.74，125.58，123.87(d，J＝11.0Hz)，115.59，115.43，56.16，53.41，45.21，39.56，36.72，28.70，27.33，26.53，25.02，23.95，17.27.
Example 39: preparation of N- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) -2- (pyridin-3-yl) cyclopropyl-1-carboxamide
The synthesis was as in example 1. 1 H NMR(500MHz，Chloroform-d)δ8.56(dt，J＝4.8，1.8Hz，2H)，8.32(t，J＝1.9Hz，2H)，8.29-8.23(m，2H)，7.78-7.68(m，6H)，7.67(dd，J＝7.4，1.7Hz，1H)，7.52-7.44(m，4H)，7.30-7.19(m，4H)，7.06(t，J＝4.3Hz，2H)，4.41(dt，J＝11.3，1.0Hz，2H)，4.11(dt，J＝11.3，0.9Hz，2H)，3.72-3.63(m，4H)，3.39-3.31(m，4H)，3.23(dtd，J＝14.3，6.2，4.2Hz，2H)，2.97(dtd，J＝14.3，6.4，4.4Hz，2H)，2.63-2.52(m，9H)，2.43(dt，J＝11.9，6.3Hz，2H)，2.38-2.27(m，4H)，1.66-1.58(m，2H)，1.58-1.31(m，10H)，1.31-1.16(m，6H). 13 C NMR(125MHz，Chloroform-d)δ173.48，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，149.37，148.19，135.13，132.74，132.53-132.03(m)，130.76，129.88(d，J＝7.9Hz)，129.67，129.32，127.35，125.74，125.58，123.87(d，J＝11.0Hz)，115.59，115.43，56.16，53.41，45.21，39.46，36.72，28.57，27.33，27.11，26.71，23.95，17.27.
Example 40: synthetic route of the compound of formula I (Synthesis of B series Compound)
Preparation of methyl-N' -cyano-N- (pyridin-4-yl) amidinothio
NaH (60%, 5g,127.4 mmol), DMF (100 ml) and Compound 8 (10.0g,106.2mmol,in 50ml DMF) were added dropwise at 0deg.C, after the completion of the dropwise addition, the mixture was stirred at 0deg.C for half an hour, compound 9 (15.6g,106.2mmol,in 50ml DMF) was added dropwise, after the completion of the dropwise addition, the reaction solution was allowed to stand at room temperature and reacted for 16 hours. After the reaction, the reaction mixture was washed three times with diethyl ether/petroleum ether=1:5, and the pH was adjusted to 8 with glacial acetic acid, and the reaction mixture was suction-filtered to give methyl-N' -cyano-N- (pyridin-4-yl) carbamimidothioide (14.1 g, 69%).
Preparation of tert-butyl-4- (2- (2-cyano-3- (pyridin-4-yl) guanidino) ethyl) piperazine-1-carboxylate
Into a 50ml round bottom flask was charged compound 10 (1.0 g,5.2 mmol), 4- (2-aminoethyl) -1-t-butoxycarbonylpiperazine (1.2 g,5.2 mmol), triethylamine (1.4 ml,10.4 mmol), DMAP (122 mg,1.0 mmol), pyridine 20ml, and reacted at 50℃for 12 hours. After the reaction, the pyridine was dried by spin, water was added, ethyl acetate was added, the organic phase was separated, the aqueous phase was extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and column-chromatographed to give tert-butyl-4- (2- (2-cyano-3- (pyridin-4-yl) guanidino) ethyl) piperazine-1-carboxylate (1.0 g, 52%).
Preparation of 2-cyano-1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) ethyl) -3- (piperidin-4-yl) guanidine
1 H NMR(500MHz，Chloroform-d)δ9.10(s，1H)，8.40-8.35(m，2H)，8.26(dd，J＝7.6，1.7Hz，1H)，8.02(t，J＝4.4Hz，1H)，7.96(ddt，J＝4.9，2.0，1.1Hz，1H)，7.78-7.63(m，3H)，7.47(dddt，J＝8.6，4.9，1.9，0.9Hz，1H)，7.21(t，J＝8.2Hz，1H)，7.03-6.98(m，2H)，4.25(t，J＝1.0Hz，2H)，3.76(dt，J＝11.7，5.3Hz，2H)，3.60(td，J＝5.5，4.2Hz，2H)，3.38-3.29(m，2H)，2.58(dt，J＝14.2，5.5Hz，6H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.13，154.49，151.85，149.78，144.41，132.71，132.37-132.03(m)，130.75，130.00-129.70(m)，129.16，127.35，125.74，125.58，123.91，118.00，115.59，115.43，112.92，55.70，52.46，45.21，40.41，36.72.
Example 41: preparation of 2-cyano-1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) propyl) -3- (piperidin-4-yl) guanidine
The synthesis was as in example 40. 1 H NMR(500MHz，Chloroform-d)δ8.81(s，1H)，8.40-8.35(m，2H)，8.26(dd，J＝7.6，1.7Hz，1H)，7.74(ddd，J＝15.3，7.6，1.8Hz，2H)，7.71-7.63(m，3H)，7.59(ddt，J＝4.9，2.0，1.0Hz，1H)，7.50(dddt，J＝8.0，4.9，2.0，1.1Hz，1H)，7.24(t，J＝8.2Hz，1H)，7.03-6.98(m，2H)，4.28(t，J＝1.0Hz，2H)，3.69(ddd，J＝11.7，6.0，4.7Hz，2H)，3.39(td，J＝6.3，4.3Hz，2H)，3.22(ddd，J＝11.7，6.0，4.7Hz，2H)，2.64-2.53(m，4H)，2.45(t，J＝6.4Hz，2H)，1.77(p，J＝6.3Hz，2H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.13，154.86，151.85，149.80，144.65，132.71，132.42-132.03(m)，130.75，129.94-129.70(m)，129.24，127.35，125.74，125.58，123.91，118.00，115.59，115.43，112.92，53.44，53.23，45.21，39.91，36.72，26.24.
Example 42: preparation of 2-cyano-1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) butyl) -3- (piperidin-4-yl) guanidine
The synthesis was as in example 40. 1 H NMR(500MHz，Chloroform-d)δ9.29(s，1H)，8.40-8.35(m，2H)，8.26(dd，J＝7.6，1.7Hz，1H)，7.80(t，J＝4.4Hz，1H)，7.78-7.68(m，3H)，7.68-7.63(m，1H)，7.49(dddt，J＝8.6，5.0，1.8，0.9Hz，1H)，7.23(t，J＝8.2Hz，1H)，7.03-6.98(m，2H)，4.26(t，J＝1.0Hz，2H)，3.69(dt，J＝11.5，5.3Hz，2H)，3.51(td，J＝6.2，4.4Hz，2H)，3.37(dt，J＝11.7，5.3Hz，2H)，2.58(t，J＝5.4Hz，4H)，2.46(t，J＝6.2Hz，2H)，1.68-1.52(m，4H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.13，154.85，151.88，149.96，144.65，132.71，132.42-132.03(m)，130.76，129.93-129.68(m)，129.24，127.35，125.74，125.58，123.91，118.00，115.59，115.43，112.92，56.06，53.33，45.21，41.39，36.72，26.79，24.97.
Example 43: preparation of 2-cyano-1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -3- (piperidin-4-yl) guanidine
The synthesis was as in example 40. 1 H NMR(500MHz，Chloroform-d)δ8.95(s，1H)，8.40-8.35(m，2H)，8.29-8.23(m，1H)，7.78-7.64(m，3H)，7.64-7.58(m，2H)，7.49(dddt，J＝7.9，5.1，2.0，1.1Hz，1H)，7.27-7.19(m，1H)，7.03-6.98(m，2H)，4.27(t，J＝1.0Hz，2H)，3.71(ddd，J＝11.5，6.0，4.5Hz，2H)，3.45(td，J＝6.2，4.4Hz，2H)，3.27(ddd，J＝11.7，6.0，4.5Hz，2H)，2.63-2.51(m，4H)，2.38(t，J＝6.3Hz，2H)，1.56-1.46(m，4H)，1.45-1.35(m，2H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.13，154.85，151.88，149.96，144.65，132.74，132.42-132.03(m)，130.76，129.93-129.59(m)，129.33，127.35，125.74，125.58，123.91，118.00，115.59，115.43，112.92，56.16，53.41，45.21，41.56，36.72，27.88，26.54，25.02.
Example 44: preparation of 2-cyano-1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-oxazin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) -3- (piperidin-4-yl) guanidine
The synthesis was as in example 40. 1 H NMR(500MHz，Chloroform-d)δ8.89(s，1H)，8.40-8.35(m，2H)，8.29-8.23(m，1H)，7.80(t，J＝4.4Hz，1H)，7.78-7.68(m，3H)，7.68-7.64(m，1H)，7.48(dddt，J＝8.6，4.9，1.9，0.9Hz，1H)，7.22(t，J＝8.2Hz，1H)，7.03-6.98(m，2H)，4.25(t，J＝1.0Hz，2H)，3.77-3.69(m，2H)，3.45(td，J＝6.3，4.4Hz，2H)，3.41-3.33(m，2H)，2.58(dd，J＝5.7，4.9Hz，4H)，2.37(t，J＝6.4Hz，2H)，1.48(dp，J＝33.0，6.5Hz，4H)，1.37-1.22(m，4H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.42，158.13，154.85，151.88，149.96，144.25，132.74，132.42-132.03(m)，130.76，129.88(d，J＝7.9Hz)，129.67，129.32，127.35，125.74，125.58，123.91，118.00，115.59，115.43，112.92，56.16，53.41，45.21，41.56，36.72，28.56，27.30，27.11，26.63.
Example 45: synthetic route of the compound of formula I (Synthesis of C series Compound)
Preparation of tert-butyl 4- (2- (3- (pyridin-4-methyl) ureido) ethyl) piperazine-1-carboxylate
BCT (294 mg,1.0 mmol), nitrogen-protected, anhydrous tetrahydrofuran (10 ml) was added to a 25ml round bottom flask, compound 12 (216 mg,2.0mmol, dissolved in 5ml THF) was added at 0deg.C, after the addition was completed, the reaction was carried out at 70deg.C for 12 hours, after the reaction was completed, compound 4 (4- (2-aminoethyl) -1-t-butoxycarbonylpiperazine) (230 mg,1.0mmol, dissolved in 5ml THF) was added at 0deg.C, after the addition was completed, the reaction was carried out at 70deg.C for 12 hours. After the reaction, water was added to spin-dry tetrahydrofuran, ethyl acetate was added, the organic phase was separated, the aqueous phase was extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, washed with saturated saline water three times, dried over anhydrous sodium sulfate, concentrated, and column chromatographed to give tert-butyl 4- (2- (3- (pyridin-4-methyl) ureido) ethyl) piperazine-1-carboxylate (127 mg, 35%).
Preparation of 1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -3- (pyridin-3-methyl) urea
The synthesis was as in example 16. 1 H NMR(500MHz，Chloroform-d)δ8.61(t，J＝1.7Hz，1H)，8.49(ddd，J＝3.6，2.2，1.5Hz，1H)，8.29-8.23(m，1H)，7.78-7.64(m，4H)，7.63(ddt，J＝4.9，2.0，1.1Hz，1H)，7.50(dddt，J＝8.6，4.9，1.9，0.9Hz，1H)，7.31-7.20(m，2H)，6.37(t，J＝6.1Hz，1H)，5.97(t，J＝4.4Hz，1H)，4.53(d，J＝6.2Hz，2H)，4.26(t，J＝1.0Hz，2H)，3.76-3.68(m，2H)，3.41-3.33(m，2H)，3.09(td，J＝6.2，4.4Hz，2H)，2.58(t，J＝5.3Hz，4H)，2.38(t，J＝6.3Hz，2H)，1.57-1.38(m，6H).13C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.86，158.42，158.13，151.88，148.44(d，J＝11.2Hz)，135.20，133.78，132.74，132.42-132.03(m)，130.76，129.93-129.68(m)，129.32，127.35，125.74，125.58，123.93(d，J＝5.7Hz)，115.59，115.43，56.16，53.33，45.21，42.02，39.06，36.72，28.33，26.50，25.02.
Example 46: preparation of 1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) -3- (pyridin-3-methyl) urea
The synthesis was as in example 45. 1 H NMR(500MHz，Chloroform-d)δ8.51-8.46(m，2H)，8.29-8.23(m，1H)，7.78-7.64(m，4H)，7.53-7.44(m，2H)，7.30-7.22(m，2H)，6.39(t，J＝6.1Hz，1H)，6.08(t，J＝4.3Hz，1H)，4.54(d，J＝6.0Hz，2H)，4.09(t，J＝1.0Hz，2H)，3.68(ddd，J＝11.7，5.8，4.7Hz，2H)，3.28(ddd，J＝11.7，5.9，4.8Hz，2H)，3.14(td，J＝6.3，4.3Hz，2H)，2.63-2.52(m，4H)，2.37(t，J＝6.4Hz，2H)，1.50-1.40(m，4H)，1.37-1.22(m，4H). 13 C NMR(125MHz，Chloroform-d)δ166.29(d，J＝8.1Hz)，160.15，158.86，158.42，158.13，151.88，148.44(d，J＝11.4Hz)，135.20，133.78，132.74，132.42-132.03(m)，130.76，129.93-129.59(m)，129.33，127.35，125.74，125.58，123.93(d，J＝5.7Hz)，115.59，115.43，56.16，53.41，45.21，42.02，38.85，36.72，28.73，27.30，27.11，26.60.
Example 47: synthetic route of the compound of formula I (Synthesis of D series Compound)
Preparation of tert-butyl-4- (2- (3- (pyridin-3-methyl) thiourea) ethyl) piperazine-1-carboxylate
Into a 25ml round bottom flask was charged thiophosgene (115 mg,1.0 mmol), nitrogen gas was used to protect, anhydrous toluene (10 ml) was added at 0℃and after the completion of the dropwise addition, compound 12 (108 mg,1.0mmol, dissolved in 5ml THF) was heated to 70℃for 5 hours, after the completion of the reaction, compound 4 (4- (2-aminoethyl) -1-t-butoxycarbonylpiperazine) (230 mg,1.0mmol, dissolved in 5ml THF) was added at 0℃without any post-treatment, and after the completion of the dropwise addition, the temperature was raised to 70℃for 5 hours. After the completion of the reaction, toluene was dried by spin-drying, water was added, ethyl acetate was added, the organic phase was separated, the aqueous phase was extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, washed with saturated saline water three times, dried over anhydrous sodium sulfate, concentrated, and column-chromatographed to give tert-butyl-4- (2- (3- (pyridin-3-methyl) thiourea) ethyl) piperazine-1-carboxylate (135 mg, 33%).
Preparation of 1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) pentyl) -3- (piperazine-3-methyl) thiourea
1 H NMR(500MHz，Chloroform-d)δ8.49-8.43(m，4H)，8.29-8.23(m，2H)，7.78-7.75(m，1H)，7.75-7.64(m，9H)，7.53(dddt，J＝8.2，5.1，2.0，1.0Hz，2H)，7.33-7.21(m，6H)，7.06(t，J＝4.4Hz，2H)，4.86(d，J＝6.2Hz，4H)，4.25(t，J＝1.0Hz，4H)，3.71(dt，J＝11.7，5.3Hz，4H)，3.38-3.29(m，8H)，2.58(t，J＝5.3Hz，8H)，2.38(t，J＝6.4Hz，4H)，1.52(dp，J＝25.5，6.5Hz，8H)，1.34(q，J＝7.0Hz，4H). 13 C NMR(125MHz，Chloroform-d)δ180.76，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，148.43(d，J＝8.3Hz)，135.55，135.20，132.74，132.42-132.03(m)，130.76，129.88(d，J＝7.9Hz)，129.67，129.32，127.35，125.74，125.58，123.93(d，J＝5.7Hz)，115.59，115.43，56.16，53.33，45.21，44.84，42.88，36.72，28.12，26.55，25.03.
Example 48: preparation of 1- (2- (4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-azin-1-yl) methyl) benzoyl) piperazin-1-yl) hexyl) -3- (piperazin-3-methyl) thiourea
The synthesis was as in example 47. 1 H NMR(500MHz，Chloroform-d)δ8.56(t，J＝1.8Hz，1H)，8.46(dt，J＝3.7，1.9Hz，1H)，8.29-8.23(m，1H)，7.77(dt，J＝7.8，2.0Hz，1H)，7.75-7.65(m，3H)，7.62(ddt，J＝5.0，2.0，1.0Hz，1H)，7.31-7.23(m，3H)，7.23-7.16(m，1H)，7.03(t，J＝4.4Hz，1H)，4.89(d，J＝6.2Hz，2H)，4.16(t，J＝1.0Hz，2H)，3.84-3.75(m，2H)，3.46-3.37(m，2H)，3.32(td，J＝6.3，4.4Hz，2H)，2.58(dd，J＝5.7，4.9Hz，4H)，2.39(t，J＝6.4Hz，2H)，1.48(dp，J＝22.7，6.5Hz，4H)，1.38-1.22(m，4H). 13 C NMR(125MHz，Chloroform-d)δ180.76，166.29(d，J＝8.1Hz)，160.15，158.42，158.13，151.88，148.43(d，J＝8.3Hz)，135.55，135.20，132.74，132.42-132.03(m)，130.76，129.88(d，J＝7.9Hz)，129.67，129.32，127.35，125.74，125.58，123.94(d，J＝4.8Hz)，115.59，115.43，56.15，53.41，45.21，44.84，42.70，36.72，28.36，27.30，27.11，26.63.
Example 49: determination of PARP and NAMPT enzyme inhibitory Activity
PARP1 enzyme inhibition activity test method
PARP1 enzyme inhibition activity adopts a PARP homogeneous assay kit. The test system included 1 ng/. Mu.L PARP-1, 20 ng/. Mu.L activated DNA (Sigma), 500nM NAD dissolved in the following reaction buffer: 100mM Tris-HCl (pH 8.0), 100mM NaCl and 20mM MgCl 2 . PARP-1 protein (1 ng/. Mu.L) was pre-incubated with various concentrations of test compound for 30min at room temperature, followed by addition of 500nM NAD to initiate the PARylation reaction. The remaining unreacted NAD was incubated with the circulating test solution (1% ethanol, 25. Mu.M resazurin, 0.30U/mL alcohol dehydrogenase and 0.25U/mL diaphorase) and the concentration of NAD was proportional to the fluorescent signal of Ex 540nm/Em 590 nm. Assessment of the rate of decrease in NAD under the action of different concentrations of Compounds IC for PARP1 inhibitory Activity 50 Is a numerical value of (2).
NAMPT inhibition activity assays were performed according to the procedure provided by the CycLex NAMPT colorimetric assay kit (MBL International Corp.) manufacturer. The basic principle is as follows: NAM and PRPP produce NMN under the action of NAMPT, NMN and ATP produce NAD under the action of NMNAT1, NAD under the action of alcohol dehydrogenase (alcohol dehydrogenase, ADH) produces NADH, which returns to NAD under the action of diaphorase. WST-1 forms orange-yellow formazan in the enzymatic cycling of NAD/NADH, and the effect of a compound on NAMPT enzyme activity can be detected by detecting a change in absorbance at OD 450 nM.
The specific experimental operation steps are as follows:
(1) preparing a compound solution to be tested: all compounds were dissolved in DMSO at a stock concentration of 10mM, formulated to the required concentration as required for the test, and diluted 2-fold from the initial concentration, 8 concentration gradients were set, each concentration repeated three times.
(2) Taking ddH 2 O (10. Mu.L) and NAM (5. Mu.L) were added to 96-well assay plates;
(3) adding 5 mu L of a compound to be tested or DMSO into a 96-well detection plate;
(4) preparing a mixture I, including: 20 XNAMPT assay buffer (5. Mu.L), PRPP (5. Mu.L), ATP (5. Mu.L), recombinant NMNAT1 (5. Mu.L), ddH 2 O (35. Mu.L) and NAMPT (5. Mu.L) for a total of 60. Mu.L. Adding the mixture I into a 96-well detection plate;
(5) placing the 96-well detection plate into a 30 ℃ incubator for incubation for 60min;
(6) configuring the texture I includes: WST-1 (5. Mu.L), ADH (5. Mu.L), diaphorase (5. Mu.L), ethanol (5. Mu.L), and a total of 20. Mu.L. After incubation, the 96-well assay plate was removed and the mix II was added to the 96-well assay plate;
(7) dynamically monitoring the absorbance value of each hole at the OD 450nm in 30min on an enzyme-labeled instrument, and detecting every 5 min;
(8) and selecting a time period in which the absorbance and the time are linearly changed, and calculating the reaction rate. Treatment with GraphPad Prism5 software. To compensate for NAMPT inhibitory activity of DMSO, values were corrected using DMSO as a solvent control.
The specific experimental results are shown in table 1: the compound cells of the examples have better inhibitory activity on NAMPT and PARP 1.
Table 1: NAMPT and PARP1 inhibitory Activity
Example 50: antitumor Activity test
The data of the inhibiting activity of the compound cancer cells are detected by an MTT method, which is also called MTT colorimetric method, and is a method for detecting the survival and growth of the cells. MTT (yellow thiazole blue) can penetrate through cell membranes and enter cells, amber dehydrogenase in mitochondria of living cells can reduce exogenous MTT into bluish purple needle-shaped Formazan crystals which are difficult to dissolve in water and deposit in the cells, the crystals can be dissolved by dimethyl sulfoxide (DMSO), and the light absorption value of the crystals can be detected by an enzyme-linked immunosorbent assay (ELISA) at the wavelength of 490nm/570nm, so that the number of the living cells can be indirectly reflected. The cancer cell lines used were MCF-7 (human breast cancer cells), K562 (human chronic granulocytic leukemia cells), HT29 (human prostate cancer cells), A549 (human non-small cell lung cancer cells) and ACHN (renal cell carcinoma cells)
The specific experimental results are shown in table 1:
(1) collecting cells in logarithmic growth phase, regulating the concentration of the cell suspension, and adding 100 mu L of the cell suspension into each well of a 96-well plate; the number of cells per well was about 7000, at 5% CO 2 Incubating overnight at 37 ℃ until the cells are fully adherent;
(2) setting medicine concentration gradients, setting 3 compound holes for each concentration gradient, diluting medicine into corresponding culture medium to required final concentration, sucking out original culture medium in 96-well plate, adding 100 μl of prepared culture medium containing medicine with required final concentration, adding 5% CO 2 Incubating at 37 ℃; and a blank group (containing only 100. Mu.L of culture medium, no cells, and the subsequent treatment is the same as that of other wells) and a control group (containing cells and culture medium) are simultaneously set;
(3) the drug treatment was continued for 4 hours by adding 10. Mu. LMTT solution (5 mg/ml) per well at 44 hours (drug treated cells for 48 hours);
(4) the culture medium in the wells was blotted off (if the cells were suspended, the medium was aspirated after centrifugation at 2500rpm for 5 min). 150 μl of dimethyl sulfoxide was added to each well, and the mixture was shaken until the crystals were sufficiently dissolved. Detecting the absorbance value of each hole at the OD490nm on an enzyme-labeled instrument;
(5) calculating the inhibition rate: inhibition ratio = 1- (dosing OD value-blank OD value)/(control OD value-blank OD value) = (control OD value-dosing OD value)/(control OD value-blank OD value);
(6) repeating the above experimental steps for three times to obtain average value of three inhibition rates, and using IC 50 IC for calculating medicine by calculator 50 Values.
The specific experimental results are shown in table 2 below: the compound of the embodiment has better antiproliferative activity on various tumor cells.
Table 2: anti-cell proliferation Activity (IC) of the Compounds of examples 50 nM)
Claims (7)
1. A phthalazinone compound having a structure represented by formula i, or a pharmaceutically acceptable salt thereof:
in formula I:
l is C 2-8 An alkyl group;
e is O or S;
x isSingle bond, vinyl bond, cyclopropyl or-NHCH 2 -；
R is
When E is O, X is a single bond, R is
When E is O, X is a vinyl bond, cyclopropyl, -NH-CH 2 -, R is
When E is S, X is-NH-CH 2 -, R is
2. The phthalazinone compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein when L is C 2-8 In the case of alkyl, said C 2-8 Alkyl is C 2-6 An alkyl group.
3. The phthalazinone compound of claim 1, or a pharmaceutically acceptable salt thereof, being any one of the following:
4. a process for the preparation of phthalazinone compounds in accordance with any one of claims 1 to 3, characterised in that: the method comprises the following steps:
in a solvent, under the action of alkali and condensing agent, performing condensation reaction on a compound shown in a formula II and a compound shown in a formula III, wherein L, E, X and R are defined as above; the solvent is DMF, the base is DIPEA, and the condensing agent is HATU.
5. A pharmaceutical composition comprising an effective amount of a phthalazinone compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 3, and a pharmaceutically acceptable carrier.
6. The use of a phthalazinone compound of the structure shown in the general formula i or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a medicament for preventing and/or treating tumors or NAMPT and PARP1 inhibitor.
7. The use according to claim 6, wherein the tumor is one or more of breast cancer, ovarian cancer, prostate cancer, colon cancer, gastric cancer, non-small cell lung cancer, glioma, renal cancer, pancreatic cancer, liver cancer, melanoma, leukemia and cervical cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111212595.3A CN113788827B (en) | 2021-10-18 | 2021-10-18 | Phthalazinone compound, preparation method and medical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111212595.3A CN113788827B (en) | 2021-10-18 | 2021-10-18 | Phthalazinone compound, preparation method and medical application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113788827A CN113788827A (en) | 2021-12-14 |
| CN113788827B true CN113788827B (en) | 2023-04-25 |
Family
ID=78878159
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111212595.3A Active CN113788827B (en) | 2021-10-18 | 2021-10-18 | Phthalazinone compound, preparation method and medical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113788827B (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0305681D0 (en) * | 2003-03-12 | 2003-04-16 | Kudos Pharm Ltd | Phthalazinone derivatives |
| WO2012074840A2 (en) * | 2010-11-22 | 2012-06-07 | The General Hospital Corporation | Compositions and methods for in vivo imaging |
| CN102898377B (en) * | 2012-02-14 | 2016-01-20 | 南京圣和药业股份有限公司 | One class phthalazinone derivatives and uses thereof |
| US10179775B2 (en) * | 2014-08-11 | 2019-01-15 | The General Hospital Corporation | Cyclooctenes for bioorthogonol reactions |
| CN110194762B (en) * | 2018-02-27 | 2021-09-10 | 中国科学院上海药物研究所 | Phthalazinone derivatives, preparation method and application thereof |
| CN113811333B (en) * | 2019-05-14 | 2024-03-12 | 诺维逊生物股份有限公司 | Compounds targeting anti-cancer nuclear hormone receptors |
-
2021
- 2021-10-18 CN CN202111212595.3A patent/CN113788827B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113788827A (en) | 2021-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI748539B (en) | Cot modulators and methods of use thereof | |
| CN105960405B (en) | Glutaminase inhibitors | |
| TW202144345A (en) | Kras mutant protein inhibitors | |
| EP3753937B1 (en) | Atr inhibitor and application thereof | |
| TWI627174B (en) | P2x7 modulators | |
| HU228195B1 (en) | Lactam derivatives having a pyrazolo-pyridine ring and pharmaceutical compositions thereof as factor xa inhibitors | |
| BR112017003312B1 (en) | INDAZOLE COMPOUNDS AS FGFR KINASE INHIBITORS, PREPARATION AND USE THEREOF | |
| WO2016210330A1 (en) | Glucose uptake inhibitors | |
| TW201838981A (en) | Pyrimidinyl-pyridyloxy-naphthyl compounds and methods of treating ire1-related diseases and disorders | |
| CN103224496B (en) | Tricyclic antidepressants PI3K and/or mTOR inhibitors | |
| AU2014367283B2 (en) | Maleimide derivatives as modulators of WNT pathway | |
| EP3845527A1 (en) | Multi-substituted pyridone derivatives and medical use thereof | |
| WO2021115401A1 (en) | Fluorine-containing heterocyclic derivatives with macrocyclic structure and use thereof | |
| CN108530444A (en) | A kind of novel NAMPT and IDO double inhibitors and preparation method thereof and medical usage | |
| KR20240134943A (en) | Six-membered ring thiazole compounds and their applications | |
| CN115417867A (en) | Substituted naphthalimide derivative and medical application thereof | |
| CN103665042B (en) | Optically active 2-hydroxy tetrahydro thienopyridine derivative and its production and use | |
| EP4273146A1 (en) | Tricyclic compound and use thereof | |
| WO2005058315A1 (en) | Novel heterocyclic compounds as ikk2 inhibitors with anti-hbv activity | |
| WO2022052924A1 (en) | Preparation method for class of nitrogen-containing fused ring compounds and use thereof | |
| CN113788827B (en) | Phthalazinone compound, preparation method and medical application thereof | |
| CN117105936A (en) | Imidazo [1,2-a ] pyridine compound serving as FLT3 inhibitor, and preparation method and application thereof | |
| Tang et al. | Design, development and evaluation of a prodrug-type TrkA-selective inhibitor with antinociceptive effects in vivo | |
| TW201504239A (en) | Protein tyrosine kinase inhibitor and application thereof | |
| CN102827160B (en) | PI3K or PI3K/m-TOR pathway inhibitor and the purposes in pharmacy thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |