CN116987066A - Pyrimidine compound and preparation method and application thereof - Google Patents
Pyrimidine compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN116987066A CN116987066A CN202310736832.9A CN202310736832A CN116987066A CN 116987066 A CN116987066 A CN 116987066A CN 202310736832 A CN202310736832 A CN 202310736832A CN 116987066 A CN116987066 A CN 116987066A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- aminobenzoic acid
- pyrimidine compound
- reaction
- 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.)
- Pending
Links
- -1 Pyrimidine compound Chemical class 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 45
- 239000000047 product Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical class NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 34
- 238000005576 amination reaction Methods 0.000 claims description 34
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 22
- 150000001408 amides Chemical class 0.000 claims description 22
- 238000006482 condensation reaction Methods 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 20
- 150000005417 aminobenzoic acid derivatives Chemical class 0.000 claims description 19
- 238000007069 methylation reaction Methods 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 108091008605 VEGF receptors Proteins 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical class ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 claims description 13
- 230000011987 methylation Effects 0.000 claims description 11
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- PVNVSSNARYHLRF-UHFFFAOYSA-N 2,3-dimethylindazol-6-amine Chemical compound C1=C(N)C=CC2=C(C)N(C)N=C21 PVNVSSNARYHLRF-UHFFFAOYSA-N 0.000 claims description 9
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-aminobenzoic acid Chemical class NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 claims description 9
- 229940124674 VEGF-R inhibitor Drugs 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 9
- 239000013067 intermediate product Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000012022 methylating agents Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 5
- 239000012661 PARP inhibitor Substances 0.000 claims description 5
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 150000001448 anilines Chemical class 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 239000007859 condensation product Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 230000001681 protective effect Effects 0.000 claims description 5
- 150000003230 pyrimidines Chemical class 0.000 claims description 4
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 claims description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 80
- 238000001228 spectrum Methods 0.000 description 42
- 239000001257 hydrogen Substances 0.000 description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- 229910052799 carbon Inorganic materials 0.000 description 20
- 238000001514 detection method Methods 0.000 description 20
- 206010028980 Neoplasm Diseases 0.000 description 19
- 238000004896 high resolution mass spectrometry Methods 0.000 description 19
- 239000003112 inhibitor Substances 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 14
- 229940126657 Compound 17 Drugs 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 13
- 229960000572 olaparib Drugs 0.000 description 13
- 229960000639 pazopanib Drugs 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 12
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 206010006187 Breast cancer Diseases 0.000 description 10
- 208000026310 Breast neoplasm Diseases 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 206010027476 Metastases Diseases 0.000 description 10
- 230000009401 metastasis Effects 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 8
- 238000011580 nude mouse model Methods 0.000 description 8
- 241000699660 Mus musculus Species 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 5
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- 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 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 229940125810 compound 20 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- NAWJZCSEYBQUGY-UHFFFAOYSA-N 2,3-diaminobenzamide Chemical compound NC(=O)C1=CC=CC(N)=C1N NAWJZCSEYBQUGY-UHFFFAOYSA-N 0.000 description 3
- 230000005778 DNA damage Effects 0.000 description 3
- 231100000277 DNA damage Toxicity 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- RZYUIHNYUYKPOQ-UHFFFAOYSA-N 4-amino-2,6-difluorobenzoic acid Chemical compound NC1=CC(F)=C(C(O)=O)C(F)=C1 RZYUIHNYUYKPOQ-UHFFFAOYSA-N 0.000 description 2
- AMVHEVZYTGHASE-UHFFFAOYSA-N 4-amino-2-(trifluoromethyl)benzoic acid Chemical group NC1=CC=C(C(O)=O)C(C(F)(F)F)=C1 AMVHEVZYTGHASE-UHFFFAOYSA-N 0.000 description 2
- MBDUKNCPOPMRJQ-UHFFFAOYSA-N 4-amino-2-chlorobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C(Cl)=C1 MBDUKNCPOPMRJQ-UHFFFAOYSA-N 0.000 description 2
- JSKXHTHMCCDEGD-UHFFFAOYSA-N 4-amino-3-fluorobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1F JSKXHTHMCCDEGD-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 239000006180 TBST buffer Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 210000001365 lymphatic vessel Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical group NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- NTGHNRIGJCKMIL-UHFFFAOYSA-N 2,4-dichloro-4-methyl-1H-pyrimidine Chemical compound N1=C(NC(C=C1)(Cl)C)Cl NTGHNRIGJCKMIL-UHFFFAOYSA-N 0.000 description 1
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 description 1
- DQXNTSXKIUZJJS-UHFFFAOYSA-N 2,4-dichloro-5-methylpyrimidine Chemical compound CC1=CN=C(Cl)N=C1Cl DQXNTSXKIUZJJS-UHFFFAOYSA-N 0.000 description 1
- FDGAEAYZQQCBRN-UHFFFAOYSA-N 3-amino-4-methoxybenzoic acid Chemical group COC1=CC=C(C(O)=O)C=C1N FDGAEAYZQQCBRN-UHFFFAOYSA-N 0.000 description 1
- PPWRHKISAQTCCG-UHFFFAOYSA-N 4,5-difluorobenzene-1,2-diamine Chemical compound NC1=CC(F)=C(F)C=C1N PPWRHKISAQTCCG-UHFFFAOYSA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- OLJXRTRRJSMURJ-UHFFFAOYSA-N 4-amino-2-methoxybenzoic acid Chemical compound COC1=CC(N)=CC=C1C(O)=O OLJXRTRRJSMURJ-UHFFFAOYSA-N 0.000 description 1
- FSXVZWAWYKMFMX-UHFFFAOYSA-N 5-amino-2-methylbenzoic acid Chemical group CC1=CC=C(N)C=C1C(O)=O FSXVZWAWYKMFMX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 108050009527 Hypoxia-inducible factor-1 alpha Proteins 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000015087 Poly (ADP-Ribose) Polymerase-1 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
- 102000002490 Rad51 Recombinase Human genes 0.000 description 1
- 108010068097 Rad51 Recombinase Proteins 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229940123429 VEGFR tyrosine kinase inhibitor Drugs 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000005073 lymphatic endothelial cell Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 230000024121 nodulation Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 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 1
- 238000011160 research Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a pyrimidine compound, a preparation method and application thereof.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a pyrimidine compound, and a preparation method and application thereof.
Background
The nutrition supply of the tumor neovascularization is not separated in the continuous growth and invasion and metastasis processes of the tumor, and researches show that the neovascularization is closely related to the growth, infiltration and metastasis of solid tumors and obviously related to prognosis. Different angiogenic factors are preferentially expressed at different stages in the process, and vascular endothelial growth factors (Vascular endothelial growth factors, VEGFs) are used as key factors with strongest tumor angiogenesis promoting activity and are expressed in the whole process of tumor development. Furthermore, vascular endothelial growth factor receptors (Vascular endothelial growth factors, VEGFRs) are one of the important molecules mediating tumor-associated vascular and lymphatic vessel production, and are aberrantly expressed in breast cancer. An anti-angiogenic drug represented by a VEGF monoclonal antibody and a VEGFR tyrosine kinase inhibitor acts on tumor vascular or lymphatic endothelial cells to inhibit formation of new blood vessels or lymphatic vessels, thereby blocking the nutrition supply of tumors and suppressing malignant progress of tumors. Drug discovery for VEGFR has been of interest to large pharmaceutical enterprises and researchers, and pan-VEGFR inhibitors have also played a good role in the treatment of many solid tumors. VEGFR inhibitors have shown varying degrees of clinical benefit in the clinical treatment of different types of tumors by inhibiting tumor-associated angiogenesis. However, the drawbacks of pan VEGFR inhibitors are also very pronounced, including severe adverse effects caused by inhibition of physiological angiogenesis (e.g. bleeding, delayed wound healing, perforation of the gastrointestinal tract, hypertension, thromboembolic complications, proteinuria, etc.), short duration of anti-tumor effect, therapeutic resistance caused by activation of the angiogenesis compensation signal pathway, which have largely limited the clinical applications of such inhibitors.
In order to increase the curative effect of the VEGFR inhibitor and reduce toxic and side effects, the VEGFR inhibitor is clinically combined with the schemes of chemotherapy, radiotherapy, operation, endocrine treatment and the like to achieve the maximum synergistic effect. Among them, many preclinical and clinical data demonstrate that VEGFR inhibitors have synergistic effects in combination with many tumor-associated target inhibitors, including epigenetic drugs (HDAC inhibitors), immunotherapeutic drugs (PD-1 and PD-L1 inhibitors and mab) and other RTK inhibitors (EGFR inhibitors, FGFR inhibitors, BRAF inhibitors and c-Met inhibitors), and the like. Although combination therapy is a clinically effective strategy for tumor treatment, this strategy also requires consideration of drug combination doses, complex pharmacokinetic profiles of both drugs, and potential toxic side effects. Currently, aiming at a double-target inhibitor with synergistic effect, the double-target inhibitor is attracting more and more attention in the development of anti-tumor drugs. As an alternative strategy to combination therapy, dual-target drugs have certain advantages. First, the dual-target drug not only largely retains the advantages of the combination therapy, but also partly overcomes the disadvantages of the combination therapy. Because of being an integrated molecule, the risk of drug-drug adverse interaction of the double-target drug is low, the pharmacokinetic parameters are stable, the occurrence probability of target drug resistance is low, and the compliance of patients is high. Therefore, a novel and efficient VEGFR double-target inhibitor is designed and discovered, and a novel method and a novel idea are hopefully provided for the application of the VEGFR related inhibitor in TNBC treatment.
In a VEGFR inhibitor-related combination strategy, the pan-VEGFR inhibitor cediranib was also used in combination with the poly adp-ribose diphosphate polymerase (poly adp-ribose polymerase, PARP) inhibitor olaharib to treat recurrent ovarian and breast cancer patients (NCT 02484404). Mechanical studies indicate that VEGFR inhibitors form an anoxic environment by inhibiting angiogenesis, resulting in down-regulation of the expression of key homologous recombination repair HRR factors (RAD 51, BRCA 1/2) and reduced DNA repair capacity. Development of a small molecule inhibitor of dual targeting VEGFR/PARP may be an effective strategy for treating non-BRCA mutant breast cancers, and no small molecule inhibitor of dual targeting VEGFR/PARP has been reported at present.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a pyrimidine compound, which has a structure shown in a formula I:
in the formula I, R 1 Is CH 3 Or H; r is R 2 H, CF of a shape of H, CF 3 、CH 3 Or OCH (optical wavelength) 3 ；
R 3 Is that
Rx, rn, rm, ry and Rz are independently F, cl, H, OCH 3 、CF 3 Or CH (CH) 3 ；
R 4 Is thatOr H; r is R 5 Is F or H; r is R 6 Is F or H.
Preferably, the structure is represented by the formulas 1 to 20:
the invention also provides a preparation method of the pyrimidine compound, which comprises the following steps:
after a 2, 4-dichloropyrimidine derivative with a structure shown in a formula II and 2, 3-dimethyl-6-amino-2H-indazole are first dissolved, carrying out a first substitution reaction under alkaline conditions to obtain an intermediate product III with a formula III;
after the intermediate product III and the methylation reagent are dissolved for the second time, methylation reaction is carried out under the protective atmosphere and alkaline conditions, and a methylation compound with a structure shown in a formula IV is obtained;
after the methylated compound and the aminobenzoic acid derivative are dissolved for the third time, carrying out a second substitution reaction under an acidic condition to obtain an amination product; the aminobenzoic acid derivatives include p-aminobenzoic acid derivatives having the structure of formula V-1 and m-aminobenzoic acid derivatives having the structure of formula V-2;
when the aminobenzoic acid derivative is a para-aminobenzoic acid derivative, the amination product has a structure shown in a formula VI-1, and when the aminobenzoic acid derivative is a meta-aminobenzoic acid derivative, the amination product has a structure shown in a formula VI-2;
the amination product with the formula VI-1, a first condensing agent and a benzimidazole compound with the structure of the formula VII are dissolved for the fourth time, and then a first amide condensation reaction is carried out under alkaline conditions to obtain a first pyrimidine compound;
the first pyrimidine compound has a structure shown in formula I and R 3 Is that
The amination product with the structure of a formula VI-1 or the amination product with the structure of a formula VI-2, a second condensing agent and the aniline derivative with the structure of a formula VIII are subjected to a fifth dissolution, then a second amide condensation reaction is carried out, the obtained second condensation product is mixed with acetic acid, and a first cyclization reaction is carried out, so that a second pyrimidine compound and a third pyrimidine compound are respectively obtained;
the second pyrimidine compound has a structure shown in formula I, and R 3 Is that
The third pyrimidine compound has a structure shown in formula I, and R 3 Is that
Preferably, the molar ratio of the 2, 4-dichloropyrimidine derivative to the 2, 3-dimethyl-6-amino-2H-indazole is 1:1.2 to 2; the temperature of the first substitution reaction is 80-90 ℃ and the time is 12-15 h.
Preferably, the methylating agent is CH 3 I, a step of I; the molar ratio of intermediate III to the methylating agent is 1:1.1 to 1.5; the temperature of the methylation reaction is 25-30 ℃ and the time is 6-18 h.
Preferably, the molar ratio of the methylated compound to the aminobenzoic acid derivative is 1:1.2 to 1.5; the temperature of the second substitution reaction is 80-90 ℃ and the time is 15-20 h.
Preferably, the first condensing agent is 1-hydroxybenzotriazole and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide; the temperature of the first amide condensation reaction is between-5 and 0 ℃ and the time is between 15 and 20 hours.
Preferably, the second condensing agent is 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, the temperature of the second amide condensation reaction is 25-30 ℃ and the time is 24-30 h; the temperature of the first cyclization reaction is 110-130 ℃ and the time is 15-20 h.
Preferably, the temperature of the third amide condensation reaction is 25-30 ℃ and the time is 24-30 h.
The invention also provides application of the pyrimidine compound or the preparation method in preparation of the dual-targeting VEGFR/PARP inhibitor.
The invention provides a pyrimidine compound, which has a structure shown in a formula I, wherein a 2, 3-dimethyl-6-amino-2H-indazole fragment in the formula I occupies a key hydrophobic pocket of VEGFR2, a 2-aminopyrimidine part and a Cys917 residue of a hinge region form two key hydrogen bonds, and the indazole and the aminopyrimidine fragment are key pharmacophores combined with the VEGFR2 by small molecules. In addition, the 1H-benzo [ d ] imidazole fragment in formula I forms a key hydrogen bond with Gly863 and Ser904 residues in the nicotinamide binding pocket of target PARP1 and forms pi-pi stacking interactions with Tyr907, which is a key pharmacophore for binding of formula I to PARP 1. Therefore, the pyrimidine compound provided by the invention has the effect of double-targeting inhibition on VEGFR and PARP.
Drawings
FIG. 1 is a graph showing the results of a test for the mechanism of DNA damage induced by a positive control Olaparib (Ola), pazopanib (Paz) and its combination to BRCA wild-type breast cancer cells using an immunoblot assay to explore Compound 17;
FIG. 2 is a graph showing the change in tumor volume of nude mice treated with a combination of compounds 17, olaparib, pazopanib, olaparib and Pazopanib for 15 days in a nude mouse MDA-MB-231 xenograft tumor model;
FIG. 3 is a graph of lung metastasis in nude mice 15 days after treatment of a model of lung metastasis in nude mice with a combination of compounds 17, olaparib, pazopanib, olaparib and Pazopanib.
Detailed Description
The invention provides a pyrimidine compound, which has a structure shown in a formula I:
in the formula I, R 1 Is CH 3 Or H; r is R 2 H, CF of a shape of H, CF 3 、CH 3 Or OCH (optical wavelength) 3 ；
R 3 Is thatRx, rn, rm, ry and Rz are independently F, cl, H, OCH 3 、CF 3 Or CH (CH) 3 ；
R 4 Is thatOr H; r is R 5 Is F or H; r is R 6 Is F or H.
In the present invention, the pyrimidine compound preferably has a structure represented by formulae 1 to 20:
the invention also provides a preparation method of the pyrimidine compound, which comprises the following steps:
after a 2, 4-dichloropyrimidine derivative with a structure shown in a formula II and 2, 3-dimethyl-6-amino-2H-indazole are first dissolved, carrying out a first substitution reaction under alkaline conditions to obtain an intermediate product III with a formula III;
after the intermediate product III and the methylation reagent are dissolved for the second time, methylation reaction is carried out under the protective atmosphere and alkaline conditions, and a methylation compound with a structure shown in a formula IV is obtained;
after the methylated compound and the aminobenzoic acid derivative are dissolved for the third time, carrying out a second substitution reaction under an acidic condition to obtain an amination product; the aminobenzoic acid derivatives include p-aminobenzoic acid derivatives having the structure of formula V-1 and m-aminobenzoic acid derivatives having the structure of formula V-2;
when the aminobenzoic acid derivative is a para-aminobenzoic acid derivative, the amination product has a structure shown in a formula VI-1, and when the aminobenzoic acid derivative is a meta-aminobenzoic acid derivative, the amination product has a structure shown in a formula VI-2;
the amination product with the formula VI-1, a first condensing agent and a benzimidazole compound with the structure of the formula VII are dissolved for the fourth time, and then a first amide condensation reaction is carried out under alkaline conditions to obtain a first pyrimidine compound;
the first pyrimidine compound has a structure shown in formula I and R 3 Is that
The amination product with the structure of a formula VI-1 or the amination product with the structure of a formula VI-2, a second condensing agent and the aniline derivative with the structure of a formula VIII are subjected to a fifth dissolution, then a second amide condensation reaction is carried out, the obtained second condensation product is mixed with acetic acid, and a first cyclization reaction is carried out, so that a second pyrimidine compound and a third pyrimidine compound are respectively obtained;
the second pyrimidine compound has a structure shown in formula I, and R 3 Is that
The third pyrimidine compound has a structure shown in formula I, and R 3 Is that
The first pyrimidine compound, the second pyrimidine compound and the third pyrimidine compound form the pyrimidine compound of claim 1;
the invention carries out a first substitution reaction under alkaline condition after a 2, 4-dichloropyrimidine derivative with a structure shown in a formula II and 2, 3-dimethyl-6-amino-2H-indazole are first dissolved, so as to obtain an intermediate product III with a formula III.
In the present invention, the first solvent of the first dissolution is preferably C 2 H 5 OH and THF; the ratio of the 2, 4-dichloropyrimidine derivative to the first solvent is preferably 1mmol:16 to 20mL, more preferably 1mmol: 17-18 mL. In the present invention, the alkaline conditions are preferably defined by NaHCO 3 Adjusted to 10. In the present invention, the molar ratio of the 2, 4-dichloropyrimidine derivative to the 2, 3-dimethyl-6-amino-2H-indazole is preferably 1:1.2 to 2, more preferably 1:1.5.
in the present invention, the temperature of the first substitution reaction is preferably 80 to 90 ℃, more preferably 85 ℃; the time is preferably 12 to 15 hours, more preferably 13 to 14 hours.
After obtaining an intermediate product III, the intermediate product III and a methylation reagent are dissolved for the second time, and then methylation reaction is carried out under a protective atmosphere and alkaline conditions, so that the methylation compound with the structure of the formula IV is obtained.
In the present invention, the methylating agent is preferably CH 3 I. In the present invention, the second solvent for the second dissolution is preferably DMF. In the present invention, the alkaline condition of the methylation reaction is preferably represented by CsCO 3 The pH was adjusted to 10. In the present invention, the protective atmosphere is preferably nitrogen.
In the present invention, the ratio of the intermediate III to the second solvent is preferably 1mmol:8 to 10mL, more preferably 1mmol:9mL. In the present invention, the molar ratio of intermediate III to methylating agent is preferably 1:1.1 to 1.5, more preferably 1:1.2. in the present invention, the temperature of the methylation reaction is preferably 25 to 30 ℃, more preferably 25 ℃, and the time is preferably 6 to 18 hours, more preferably 7 to 12 hours.
After obtaining the methylated compound, the invention carries out a second substitution reaction under an acidic condition after the methylated compound and the aminobenzoic acid derivative are dissolved for the third time, so as to obtain an amination product.
In the present invention, the third solvent for the third dissolution is preferably isopropyl alcohol. In the present invention, the acidic condition is preferably adjusted to a pH of 2 by hydrochloric acid. In the present invention, the aminobenzoic acid derivative includes a p-aminobenzoic acid derivative having a structure of formula V-1 and a m-aminobenzoic acid derivative having a structure of formula V-2.
In the present invention, the ratio of the amount of the methylated compound to the second solvent is preferably 1 to 1.2mmol:15 to 20mL, more preferably 1.1 mmol: 17-18 mL. In the present invention, the molar ratio of the methylated compound to the aminobenzoic acid derivative is preferably 1:1.2 to 1.5, more preferably 1:1.3 to 1.4.
In the present invention, the temperature of the second substitution reaction is preferably 80 to 90 ℃, more preferably 85 ℃, and the time is preferably 15 to 20 hours, more preferably 17 to 18 hours.
In the present invention, when the aminobenzoic acid derivative is a para-aminobenzoic acid derivative, the amination product has a structure represented by formula VI-1, and when the aminobenzoic acid derivative is a meta-aminobenzoic acid derivative, the amination product has a structure represented by formula VI-2.
After an amination product with a structure shown in a formula VI-1 is obtained, the amination product with the structure shown in the formula VI-1, a first condensing agent and a benzimidazole compound with a structure shown in a formula VII are dissolved for the fourth time, and then a first amide condensation reaction is carried out under alkaline conditions to obtain a first pyrimidine compound.
In the present invention, the fourth solvent for the fourth dissolution is preferably DMF. In the present invention, the first condensing agent is 1-Hydroxybenzotriazole (HOBT) and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI); the molar ratio of HOBT to EDCI is preferably 1:1.1 to 1.5, more preferably 1:1.2 to 1.3. In the present invention, the basic condition of the first amide condensation reaction is preferably Et 3 N is provided, and the pH value of the alkaline condition is preferably 9-10.
In the present invention, the ratio of the amount of the aminated product having the structure of formula VI-1 to the fourth solvent is preferably 1mmol:10 to 15mL, more preferably 1:12mL. In the present invention, the molar ratio of the amination product having the structure of formula VI-1 to the benzimidazole compound is preferably 1:1.2 to 1.5, more preferably 1:1.3. in the present invention, the molar ratio of the amination product having the structure of formula V-1 to the first condensing agent is preferably 1:1 to 1.2, more preferably 1:1.1.
in the present invention, the temperature of the first amide condensation reaction is preferably-5 to 0 ℃, more preferably-1 to-3 ℃, and the time is preferably 15 to 20 hours, more preferably 17 to 18 hours.
In the present invention, after the first amide condensation reaction, the method preferably further comprises extracting the first amide condensation reaction system, and drying the extracted organic phase with a drying agent, concentrating under reduced pressure, and performing silica gel column chromatography.
In the invention, the extracted reagent is preferably ethyl acetate, the drying agent is preferably anhydrous sodium sulfate, and the developing agent for silica gel column chromatography is preferably a methylene chloride-methanol system with the volume ratio of methylene chloride to methanol being 15:1.
In the invention, the first pyrimidine compound has a structure shown in a formula I and R 3 Is thatSpecifically: the compounds having the structures of formulas 2 to 3 and formulas 12 to 15 belong to the first pyrimidine compounds.
After an amination product is obtained, the amination product with a structure of a formula VI-1 or the amination product with a structure of a formula VI-2, a second condensing agent and an aniline derivative with a structure of a formula VIII are dissolved in a fifth mode, then a second amide condensation reaction is carried out, the obtained second condensation product is mixed with acetic acid, and a first cyclization reaction is carried out to obtain a second pyrimidine compound and a third pyrimidine compound respectively.
In the present invention, the fifth solvent for the fifth dissolution is preferably DMF. In the present invention, the second condensing agent is preferably 2- (7-azabenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU).
In the present invention, the molar ratio of the amination product having the structure of formula V-1 and the second condensing agent is preferably 1:2 to 5, more preferably 1:2 to 4. In the present invention, the molar ratio of the amination product having the structure of formula V-1 to the aniline derivative is preferably 1:1.2 to 1.5, more preferably 1:1.3. in the present invention, the ratio of the amount of the aminated product having the structure of formula V-1 to the fifth solvent is preferably 1mmol:10 to 15mL, more preferably 1mol: 12-13 mL.
In the present invention, the temperature of the second amide condensation reaction is preferably 25 to 30 ℃, more preferably 25 ℃; the time is preferably 24 to 30 hours, more preferably 25 hours.
In the present invention, the molar ratio of the second condensation product to acetic acid is preferably 1mmol:18 to 20mL, more preferably 1:19mL. In the present invention, the temperature of the first cyclization reaction is preferably 110 to 130 ℃, more preferably 120 ℃; the time is preferably 15 to 20 hours, more preferably 17 to 18 hours.
In the present invention, it is preferable that after the first cyclization reaction, the first cyclization reaction is extracted, and the extracted organic phase is subjected to drying with a desiccant, concentration and separation by a silica gel column.
In the invention, the extracted reagent is preferably ethyl acetate, the drying agent is preferably anhydrous sodium sulfate, and the developing agent for silica gel column chromatography is preferably a methylene chloride-methanol system with the volume ratio of methylene chloride to methanol being 10:1.
In the present invention, the second pyrimidine compound has a structure represented by formula I, and R 3 Is thatSpecifically: the compounds with the structures of the formulas 1 and 4-11 belong to second pyrimidine compounds.
In the present invention, the ratio of the amount of the amination product of formula V-2 to the fifth solvent is preferably 1mmol:12 to 15mL, more preferably 1mmol: 13-14 mL. In the present invention, the molar ratio of the amination product of formula V-2 to the aniline compound is preferably 1:1 to 1.5, more preferably 1:1.3 to 1.4.
In the invention, the third pyrimidine compound has a structure shown in formula I, and R 3 Is thatSpecifically, compounds having the formulas 16 to 20The compound belongs to a third pyrimidine compound.
The invention also provides application of the pyrimidine compound or the pyrimidine compound prepared by the preparation method of any one of the above to preparation of a dual-targeting VEGFR/PARP inhibitor.
In the invention, the dual-targeting VEGFR/PARP inhibitor comprises the pyrimidine compounds and pharmaceutically acceptable salts. In the present invention, the pharmaceutically acceptable salt preferably includes nitrate, hydrochloride, sulfate or phosphate.
In the present invention, the form of the dual-targeted VEGFR/PARP inhibitor preferably comprises a tablet, capsule, aqueous or oily solution, suspension, emulsion, cream, ointment, gel, suppository, powder or aerosol.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Compound 1 has the following structure:
the preparation process comprises the following steps:
(1) 1mmol of 2, 4-dichloropyrimidine, 1.5mmol of 2, 3-dimethyl-6-amino-2H-indazole are dissolved in 20mL of C 2 H 5 OH and THF (C) 2 H 5 The volume ratio of OH to THF is 4: 1) After that, naHCO is used 3 The pH was adjusted to 10 and a first substitution reaction (85 ℃ C. For 12 h) was performed to give an intermediate.
(2) 1mmol of the intermediate obtained in step (1), 1.1mmol of CH 3 I was dissolved in 10mL DMF and CsCO 3 And (3) regulating the pH value to 10, and carrying out methylation under the protection of nitrogen, wherein the temperature of the methylation is 25 ℃ and the time is 18 hours, so as to obtain the methylated compound.
(3) After 0.5mmol of the methylation product obtained in the step (2) and 0.75mmol of p-aminobenzoic acid were dissolved in 25mL of isopropanol, the pH was adjusted to 2 with hydrochloric acid, and a second substitution reaction was performed at a temperature of 85℃to obtain an aminated product.
(4) 0.5mmol of the amination product obtained in the step (3), 1mmol of HATU and 0.51mmol of 2, 3-diaminobenzamide are dissolved in DMF, the pH is adjusted to 10 by DIPE, then the amide condensation reaction is carried out at 25 ℃, the obtained product is dissolved in 30mL of acetic acid, then reflux (cyclization) is carried out at 120 ℃ for 12h, the cyclization reaction obtained system is poured into 200mL of water and extracted with ethyl acetate (3X 40 mL), the obtained organic phase is added into anhydrous sodium sulfate for drying, and after decompression concentration, separation is carried out through a silica gel column, the developing agent is methylene dichloride-methanol system (volume ratio of methylene dichloride to methanol is 10:1), and finally the compound 1 is obtained.
The results of the high resolution mass spectrometry detection of compound 1 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 28 H 25 N 9 NaO 526.2074,found 526.2074。
The nuclear magnetic resonance hydrogen spectrum of the compound 1 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.00(s,1H),8.82(s,1H),8.58–8.27(m,1H),8.13–7.99(m,1H),7.97–7.55(m,5H),7.45(d,J＝12.1Hz,1H),7.22(t,J＝7.7Hz,1H),6.88(t,J＝9.1Hz,1H),5.92–7.84(m,1H),4.06(s,3H),3.47(s,3H),2.63(s,3H)。
the nuclear magnetic resonance carbon spectrum of compound 1 has the following map information: 13 C NMR(151MHz,DMSO-d 6 )δ172.81,166.80,162.91,159.46,156.33,150.63,147.49,144.42,142.33,132.65,132.38,132.15,123.12,122.58(2),122.35(2),120.32(2),120.09(2),119.33,117.36,114.48,97.89,38.58,37.84,9.88。
example 2
Compound 2 has the following structure:
steps (1) to (3) are the same as in example 1.
(4) 0.5mmol of the amination product obtained in step (3), 1mmol of HOBT, 1.01mmol of EDCI, 0.75mmol of 2-amino-1H-benzimidazole-4-formylDissolving amine in DMF and Et 3 N is adjusted to pH 10, then amide condensation reaction is carried out under the condition of 0 ℃, the system obtained by the amide condensation reaction is poured into 200mL of water, ethyl acetate (3X 40 mL) is used for extraction, the obtained organic phase is added with anhydrous sodium sulfate for drying, after decompression concentration, separation is carried out through a silica gel column, the developing agent is a methylene dichloride-methanol system (the volume ratio of methylene dichloride to methanol is 15:1), and finally the compound 2 is obtained.
The results of the high resolution mass spectrometry detection of compound 2 are as follows: HRMS (ESI) (M/z) [ M+H ]] + calcd for C 29 H 27 N 10 O 2 547.2313,found 547.2323.
The nuclear magnetic resonance hydrogen spectrum of the compound 2 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.44(s,1H),8.63(s,1H),7.98(dd,J＝8.2,1.3Hz,1H),7.89(d,J＝6.0Hz,1H),7.82–7.64(m,5H),7.47(d,J＝1.0Hz,1H),7.37(t,J＝7.9Hz,1H),7.22(t,J＝7.8Hz,1H),6.90(dd,J＝8.8,1.6Hz,1H),5.82(d,J＝6.0Hz,1H),4.06(s,3H),3.53(s,3H),2.62(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 2 is shown in the graph information: 13 C NMR(151MHz,DMSO-d 6 )δ167.22,162.87,159.89,156.28,147.45,142.37,141.96,132.65(2),128.87(2),122.97(2),122.25(2),120.66(2),120.13(2),119.95(2),119.07(2),114.35(2),97.27,38.49,37.82,9.86.
example 3
Compound 3 has the following structure:
the difference from example 2 is that: substitution of 2, 4-dichloropyrimidine: 5-trifluoromethyl-2, 4-dichloropyrimidine.
The results of the high resolution mass spectrometry detection of compound 3 are as follows: HRMS (ESI) (M/z) [ M+H ]] + calcd for C 30 H 26 F 3 N 10 O 2 615.2187,found 615.2194.
The nuclear magnetic resonance hydrogen spectrum of the compound 3 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.68(s,1H),9.62(s,1H),7.98–7.80(m,5H),7.68(d,J＝8.7Hz,1H),7.51(d,J＝8.2Hz,1H),7.36–7.24(m,1H),7.14(s,1H),6.88(dd,J＝8.8,1.6Hz,1H),4.03(s,3H),3.48(s,3H),2.60(s,3H),1.41(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 3 is shown in the graph information: 13 C NMR(151MHz,DMSO-d 6 )δ167.34,166.59,163.13,158.42,147.21,146.45,146.04,143.34,132.57,130.72(2),130.60,128.16,126.09,124.13,122.48,121.79,121.19,119.80,119.18,117.63,117.54,111.85(2),110.60,52.08,41.66,37.76,16.68,9.88.
example 4
Compound 4 has the following structure:
/>
the only difference from example 1 is that: substitution of 2, 4-dichloropyrimidine: 5-methyl-2, 4-dichloropyrimidine.
The results of the high resolution mass spectrometry detection of compound 4 are as follows:
HRMS(ESI)(m/z):[M+Na] + calcd for C 29 H 27 N 9 NaO 540.2231,found540.2227。
the nuclear magnetic resonance hydrogen spectrum of compound 4 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.68(s,1H),9.62(s,1H),7.98–7.80(m,5H),7.68(d,J＝8.7Hz,1H),7.51(d,J＝8.2Hz,1H),7.36–7.24(m,1H),7.14(s,1H),6.88(dd,J＝8.8,1.6Hz,1H),4.03(s,3H),3.48(s,3H),2.60(s,3H),1.41(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 4 has the following map information: 13 C NMR(151MHz,DMSO-d 6 )δ167.34,166.59,163.13,158.42,147.21,146.45,146.04,143.34,132.57,130.72,130.60,128.16,126.09,124.13,122.48,121.79,121.19(2),119.80,119.18,117.63,117.54,111.85,110.60,52.08,41.66,37.76,16.68,9.88.
example 5
The only difference from example 1 is that: substitution of 2, 4-dichloropyrimidine: 4-methyl-2, 4-dichloropyrimidine.
The results of the high resolution mass spectrometry detection of compound 5 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 29 H 27 N 9 NaO 540.2231,found 540.2227.
The nuclear magnetic resonance hydrogen spectrum of the compound 5 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.54(s,1H),9.49(s,1H),9.17(s,1H),8.17(d,J＝8.7Hz,1H),8.00(d,J＝8.5Hz,1H),7.91–7.60(m,6H),7.27–7.19(m,1H),7.12(d,J＝16.5Hz,1H),6.92–6.83(m,1H),4.03(s,3H),3.51(s,3H),3.46(s,3H),2.60(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 5 has the following map information: 13 C NMR(151MHz,DMSO-d 6 )δ167.14,163.15,158.53,150.48,147.47,144.93,144.81,136.48,132.56(2),130.00(2),127.98(2),121.79(2),119.19(2),118.44(2),111.85(2),102.52(2),99.68,37.76,24.80,16.67,9.89.
example 6
The difference from example 1 is that: substitution of 2, 4-dichloropyrimidine: 4-methoxy-2, 4-dichloropyrimidine.
The results of the high resolution mass spectrometry detection of compound 6 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 29 H 27 N 9 NaO 2 556.2180,found 556.2179.
The nuclear magnetic resonance hydrogen spectrum of the compound 6 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.48(s,1H),9.28(s,1H),8.06(d,J＝8.6Hz,1H),7.96–7.86(m,2H),7.82(d,J＝7.6Hz,1H),7.74–7.65(m,3H),7.59(dd,J＝8.7,5.7Hz,1H),7.32–7.24(m,1H),7.19(d,J＝7.9Hz,1H),6.81(t,J＝9.4Hz,1H),4.02(s,3H),3.51(s,3H),3.48(s,3H),2.60(s,3H).
the nuclear magnetic resonance carbon spectrum of the compound 6 has the following map information: 13 C NMR(151MHz,DMSO-d 6 )δ169.14,167.01,162.84,159.65,156.56,153.23,153.01,147.49,143.80,142.69,141.69,128.10(2),128.03(2),127.83(2),127.35,122.81(2),121.96(2),119.45,118.70,97.02,38.39,33.59,24.58,24.37.
example 7
The difference from example 1 is that: the para aminobenzoic acid is replaced with: 4-amino-3-fluoro-benzoic acid.
The results of the high resolution mass spectrometry detection of compound 7 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 28 H 24 FN 9 NaO 544.1980,found 544.1980.
The nuclear magnetic resonance hydrogen spectrum of the compound 7 has the following map information: 1 H NMR(400MHz,CDCl 3 )δ10.95(s,1H),9.87(s,1H),8.55(s,1H),8.30–8.06(m,1H),7.95–7.45(m,5H),7.39–7.28(m,1H),6.88(d,J＝8.6Hz,1H),5.92(d,J＝8.1Hz,1H),4.13(s,3H),3.54(s,3H),2.65(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 7 has the following map information: 13 C NMR(151MHz,DMSO-d 6 )δ167.76,167.71,162.90,159.55,156.34,153.60,147.46,142.27,132.62(2),125.57,122.23(2),121.86(2),120.12(2),119.97,115.77,114.44(2),97.87,97.72,38.29,38.20,37.84,21.78,9.88.
example 8
Compound 8 has the following structure:
the only difference from example 1 is that: the para aminobenzoic acid is replaced with: 4-amino-2-chlorobenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of the compound 8 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.74(s,1H),8.27(s,1H),8.03–7.66(m,7H),7.49(d,J＝0.6Hz,1H),7.34(t,J＝7.8Hz,1H),6.92(dd,J＝8.8,1.5Hz,1H),5.91(d,J＝6.0Hz,1H),4.06(s,3H),3.52(s,3H),2.63(s,3H).
compounds of formula (I)8, the spectrum information of the nuclear magnetic resonance carbon spectrum is as follows: 13 C NMR(151MHz,DMSO-d 6 )δ162.94,159.50,156.32,150.63,147.50,144.46,142.34,132.65(2),132.39(2),122.34(2),120.35(2),120.15(2),119.35(2),117.35(2),114.47(2),97.86,38.58,37.85,9.89.
the high resolution mass spectrum detection results of compound 8 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 28 H 24 ClN 9 NaO 560.1685,found 560.1684.
Example 9
Compound 9 has the following structure:
the difference from example 1 is that: the para-aminobenzoic acid was replaced with 4-amino-2-trifluoromethylbenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of the compound 9 has the following map information: 1 H NMR(600MHz,DMSO-d 6 )δ9.87(s,1H),9.37(s,1H),8.66(s,1H),8.25–7.59(m,7H),7.50(s,1H),7.32(s,1H),6.92(d,J＝6.5Hz,1H),5.87(s,1H),4.06(s,3H),3.53(s,3H),2.63(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 9 has the following map information: 13 C NMR(151MHz,DMSO-d 6 )δ173.60,168.47,166.90,164.62,162.89,159.55,156.29,151.58,151.53,147.44,143.38,142.19,132.92(2),132.69,122.74(2),122.40,122.21,121.12,120.05,116.49(2),114.54,97.97,38.41,37.85,23.52,9.88.
the results of the high resolution mass spectrometry detection of compound 9 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 29 H 24 F 3 N 9 NaO 594.1948,found 594.1950.
Example 10
Compound 10 has the following structure:
the difference from example 1 is that: the para aminobenzoic acid is replaced with: 4-amino-2, 6-difluorobenzoic acid.
Compounds of formula (I)The spectrum information of the nuclear magnetic resonance hydrogen spectrum of 10 is as follows: 1 H NMR(400MHz,CDCl 3 )δ9.82(s,1H),8.20(d,J＝7.5Hz,1H),7.86(d,J＝6.0Hz,1H),7.70(d,J＝7.9Hz,1H),7.62(d,J＝8.7Hz,1H),7.55–7.41(m,2H),7.35(d,J＝2.3Hz,1H),7.17–6.96(m,3H),6.89(d,J＝8.3Hz,1H),5.95(d,J＝6.2Hz,1H),4.12(s,2H),3.53(s,3H),2.64(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 10 has the following profile information: 13 C NMR(151MHz,DMSO-d 6 )δ166.79,162.86,160.07,156.31,155.08,153.45,152.26,150.60,147.41,142.24,133.52,132.67,127.54,125.73,123.18,122.23,121.67,120.09,119.92,115.75(2),114.35,111.45,111.31,97.48,38.09,37.82,9.86.
the results of the high resolution mass spectrometry detection of compound 10 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 28 H 23 F 2 N 9 NaO 562.1886,found 562.1885.
Example 11
Compound 11 has the following structure:
the difference from example 1 is that: the para aminobenzoic acid is replaced with: 4-amino-2-methoxybenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of compound 11 has the following profile information: 1 H NMR(400MHz,DMSO-d 6 )δ9.44(s,1H),8.55(d,J＝8.4Hz,1H),7.92(d,J＝5.8Hz,2H),7.84–7.66(m,6H),7.50–7.32(m,2H),7.26(t,J＝7.7Hz,1H),6.91(d,J＝8.9Hz,1H),5.90(d,J＝5.9Hz,1H),4.07(s,3H),4.04(s,3H),3.51(s,3H),2.65(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 11 is shown in the figure: 13 C NMR(151MHz,DMSO-d 6 )δ167.08,162.94,159.19,156.38,153.45,147.89,142.47,132.69,131.86,129.64,129.58,122.75,122.63,122.24,121.83,120.39,120.16,119.99,118.23,117.49,117.34,114.41,101.19,103.94,97.78,56.62,38.55,37.87,9.91.
the results of the high resolution mass spectrometry detection of compound 11 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 29 H 27 N 9 NaO 2 556.2180,found 556.2182.
Example 12
Compound 12 has the following structure:
the difference from example 2 is that: the para aminobenzoic acid is replaced with: 4-amino-3-fluoro-benzoic acid.
The nuclear magnetic resonance hydrogen spectrum of the compound 12 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ8.83(s,1H),8.37(t,J＝8.4Hz,1H),8.07–7.64(m,7H),7.47(d,J＝0.9Hz,1H),7.23(t,J＝7.8Hz,1H),6.90(dd,J＝8.8,1.6Hz,1H),5.92(d,J＝6.0Hz,1H),4.07(s,3H),3.48(s,3H),2.64(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 12 is shown in the graph information: 13 C NMR(151MHz,DMSO-d 6 )δ168.40,167.29,162.89,159.61,156.33,153.70,153.17,152.08,151.55,147.43(2),142.28,142.20,132.71,122.30,122.22,120.12(2),120.08,120.00,114.42(2),114.38,98.21,97.61,38.31,38.17,37.84,9.87.
the results of the high resolution mass spectrometry detection of compound 12 are as follows: HRMS (ESI) (M/z) [ M+H ]] + calcd for C 29 H 26 FN 10 O 2 565.2219,found 565.2230.
Example 13
Compound 13 has the following structure:
the only difference from example 2 is that: the para aminobenzoic acid is replaced with: 4-amino-2-chlorobenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of the compound 13 has the following map information:
1 H NMR(400MHz,DMSO-d 6 )δ9.65(d,J＝25.1Hz,1H),8.01–7.78(m,6H),7.68(d,J＝8.9Hz,1H),7.54(d,J＝8.3Hz,1H),7.41–7.24(m,2H),7.14(d,J＝1.9Hz,1H),6.87(dt,J＝8.8,1.7Hz,1H),4.03(s,3H),2.60(s,3H),1.41(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 13 has the following map information:
13 C NMR(151MHz,DMSO-d 6 )δ162.89,159.91,156.28,147.47,142.40,141.97,133.82,132.64,128.86,123.00(2),122.55,122.24(2),121.22,120.68(2),120.13,119.95,119.10,118.25,114.35(2),112.34,97.28,49.08,38.48,37.81,9.85.
the results of the high resolution mass spectrometry detection of compound 13 are as follows:
HRMS(ESI)(m/z):[M+H] + calcd for C 29 H 26 ClN 10 O 2 581.1923,found581.1935.
example 14
Compound 14 has the following structure:
the difference from example 2 is that: the para-aminobenzoic acid was replaced with 4-amino-2-trifluoromethylbenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of compound 14 has the following profile information: 1 H NMR(400MHz,DMSO-d 6 )δ9.92(s,1H),9.84(s,1H),8.50(d,J＝10.2Hz,1H),8.08–7.87(m,2H),7.83–7.66(m,2H),7.62(d,J＝8.3Hz,1H),7.52–7.27(m,2H),6.90(d,J＝8.8Hz,1H),5.88(t,J＝6.3Hz,1H),4.07(s,3H),3.50(s,3H),2.63(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 14 has the following profile information: 13 C NMR(151MHz,DMSO-d 6 )δ167.42,166.24,162.87,159.33,156.28,147.44(2),145.17,142.17,132.68(2),132.45(2),124.75(2),122.38(2),120.51(2),120.05(2),114.58(2),110.21(2),98.19,52.83,38.41,37.85,9.86.
the results of the high resolution mass spectrometry detection of compound 14 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 30 H 25 F 3 ClN 10 NaO 2 637.2006,found 637.2002.
Example 15
Compound 15 has the following structure:
the difference from example 2 is that: the para aminobenzoic acid is replaced with: 4-amino-2, 6-difluorobenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of compound 15 has the following profile information: 1 H NMR(600MHz,DMSO-d 6 )δ12.77(s,1H),8.96(s,1H),8.80(s,1H),8.01(s,1H),7.88–7.57(m,5H),7.44(s,1H),7.26(s,1H),7.13(s,1H),6.88(s,1H),5.81(s,1H),4.06(s,3H),3.42(s,3H),2.63(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 15 is shown in the figure: 13 C NMR(151MHz,DMSO-d 6 )δ162.87(2),160.09(2),156.31,155.06,153.48,152.24,150.57,147.42(2),142.25(2),132.65(2),125.65,122.22,120.09(2),119.93(2),114.36(2),111.42,111.27,97.47,38.09,37.83,9.87.
the results of the high resolution mass spectrometry detection of compound 15 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 29 H 24 F 2 N 10 NaO 2 605.1944,found 605.1942.
Example 16
Compound 16 has the following structure:
the only difference from example 1 is that: the para-aminobenzoic acid is replaced with meta-aminobenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of compound 16 has the following profile information: 1 H NMR(400MHz,CDCl 3 )δ9.86(s,1H),8.46(s,1H),8.12(d,J＝6.9Hz,1H),7.85(d,J＝5.3Hz,1H),7.71(d,J＝7.7Hz,1H),7.59–7.28(m,6H),6.90(d,J＝8.8Hz,1H),6.06(s,1H),5.92(d,J＝4.4Hz,1H),4.05(s,3H),3.53(s,3H),2.51(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 16 has the following profile information: 13 C NMR(151MHz,DMSO-d 6 )δ169.14,167.01,162.84,159.65,156.56,153.23,153.01,147.49,143.80,142.69,141.69,128.10(2),128.03(2),127.83,127.35,122.81(2),121.96(2),119.45(2),118.70,97.02,38.39,33.59,24.37.
the results of the high resolution mass spectrometry detection of compound 16 are as follows: HRMS (ESI) (m/z):[M+Na] + calcd for C 28 H 25 N 9 NaO 526.2074,found 526.2068.
Example 17
Compound 17 has the following structure:
the only difference from example 1 is that: the para-aminobenzoic acid is replaced with 3-amino-6-methylbenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of compound 17 has the following map information: 1 H NMR(400MHz,CDCl 3 )δ9.84(s,1H),8.23–8.09(m,2H),7.80(d,J＝5.9Hz,1H),7.56(dd,J＝19.5,8.2Hz,2H),7.48–7.30(m,4H),7.24(d,J＝8.4Hz,1H),6.88(d,J＝8.9Hz,1H),6.00–5.84(m,2H),4.07(s,3H),3.50(s,3H),2.63(s,3H),2.55(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 17 is shown in the figure: 13 C NMR(151MHz,DMSO-d 6 )δ173.41,166.86,162.86,159.99,156.30,153.68,147.44,142.38,139.76,132.58,131.69,129.72,129.16,122.98,122.43,122.12,120.74,120.38,120.15(2),119.90,114.31(2),96.90,38.38,37.81,22.85,20.49,9.83.
the results of the high resolution mass spectrometry detection of compound 17 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 29 H 27 N 9 NaO 540.2231,found 540.2227.
Example 18
Compound 18 has the following structure:
the only difference from example 1 is that: the para-aminobenzoic acid was replaced with 3-amino-4 methoxybenzoic acid.
The nuclear magnetic resonance hydrogen spectrum of the compound 18 has the following map information: 1 H NMR(400MHz,CDCl 3 )δ9.44(s,1H),7.82(dd,J＝28.1,16.7Hz,2H),7.70(dd,J＝8.5,2.0Hz,1H),7.62(d,J＝8.7Hz,1H),7.56–7.47(m,1H),7.38–7.27(m,1H),7.14–7.05(m,1H),7.03–6.95(m,1H),6.90(d,J＝8.6Hz,2H),5.83(d,J＝6.1Hz,1H),4.12(s,3H),3.96(s,3H),3.87(s,3H),2.64(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 18 has the following profile information: 13 C NMR(151MHz,DMSO-d 6 )δ172.73,162.94,159.63,156.33,153.23,150.43,147.44,142.18,142.08,132.63(2),130.23(2),122.21(2),121.07,120.07(2),119.98,118.18,114.47(2),111.21,97.56,56.67,38.41,37.85,21.94,9.85.
the results of the high resolution mass spectrometry detection of compound 18 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 29 H 27 N 9 NaO 2 556.2180,found 556.2187.
Example 19
Compound 19 has the following structure:
the preparation process differs from example 17 only in that: 2, 3-diaminobenzamide was replaced with "4, 5-difluorobenzene-1, 2-diamine".
The nuclear magnetic resonance hydrogen spectrum of compound 19 has the following profile information: 1 H NMR(400MHz,DMSO-d 6 )δ9.29(s,1H),8.28(s,1H),7.95–7.54(m,5H),7.44(s,1H),7.18(d,J＝8.3Hz,1H),6.86(dd,J＝8.7,1.4Hz,1H),5.78(d,J＝5.9Hz,1H),4.04(s,3H),3.47(s,3H),2.58(s,3H),2.47(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 19 is shown in the figure: 13 C NMR(151MHz,DMSO-d 6 )δ172.79,162.86,160.01,156.21,155.00,147.46,142.40,139.64,132.55,131.51,130.13,129.07,122.09,120.47,120.32(2),120.13(2),119.90(2),114.30(2),96.92,38.34,37.77,21.81,20.35,9.80.
the results of the high resolution mass spectrometry detection of compound 19 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 28 H 24 F 2 N 8 Na 533.1984,found 533.1977.
Example 20
Compound 20 has the following structure:/>
the only difference from example 17 is that: 2, 3-diaminobenzamide is replaced with "o-phenylenediamine".
The nuclear magnetic resonance hydrogen spectrum of the compound 20 has the following map information: 1 H NMR(400MHz,DMSO-d 6 )δ9.27(s,1H),8.25(s,1H),7.94–7.38(m,6H),7.20(dd,J＝5.9,3.0Hz,3H),6.99–6.78(m,1H),5.91–5.67(m,1H),4.06(s,3H),3.47(s,3H),2.61(s,3H),2.48(s,3H).
the nuclear magnetic resonance carbon spectrum of compound 20 is shown in the figure: 13 C NMR(151MHz,DMSO-d 6 )δ172.91,162.88,160.05,156.25,152.98,147.46,142.42,139.56,132.59,131.40,130.76,129.10,122.16,120.46,120.22,120.16(2),119.92(2),114.32(2),96.89,38.35,37.81,23.97,22.15,20.39,9.85.
the results of the high resolution mass spectrometry detection of compound 20 are as follows: HRMS (ESI) (M/z) [ M+Na ]] + calcd for C 28 H 26 N 8 Na 497.2173,found 497.2177.
The invention tests the anti-proliferation activity of the compounds 1-20 in enzymology, namely the anti-BRCA wild breast cancer cells MDA-MB-231 and MCF-7, and the test method comprises the following steps:
enzymatic inhibition activity: the VEGFR2 and PARP1 enzyme inhibitory activities were supported by technical services provided by Shanghai Rui Corp and were measured by enzyme-linked immunosorbent assay (ELISA) kit.
Anti-proliferative Activity test of anti-BRCA wild-type breast cancer cells MDA-MB-231 and MCF-7 cells: compounds 1 to 20 and a positive control (PARP inhibitor- -Olaparib, VEGFR inhibitor- -Pazopanib) were prepared as DMSO solutions at a concentration of 1 mM/L. BRCA wild-type breast cancer cells MDA-MB-231 and MCF-7 were inoculated into 96-well plates at 6000 cells per well using the cell counting plate technique after digestion of the cell suspensions with pancreatin. After 24h incubation at 37℃cells were treated with various concentrations of test compound for 48h, after which 20. Mu. LMTT solution (5 mg/L) was added to each well and incubated in a cell incubator. After 4 hours, the culture medium in each well is sucked out from the 96-well plate, 200 mu L of DMSO is added into each well to dissolve the bottom bluish-violet formazan crystals, the mixture is placed on a shaking table to oscillate for 15 minutes at a low speed to promote the dissolution of the crystals, and the mixture is placed on an enzyme-labeled instrument to measure the absorbance (OD value) at 570 nm.
Using the formula: inhibition ratio = (negative control OD-experimental OD) ×100%/(negative control OD-blank OD), inhibition ratio of test compound to tumor cells was calculated, and IC of each test compound was calculated using GraphPad Prism 8.0 software 50 Values.
a IC 50 The values were tested 3 times (standard deviation).
b N.d=undetected.
As can be seen from table 1: the compound has inhibiting activity on VEGFR2 and PARP1 and anti-BRCA wild type breast cancer cell proliferation activity, wherein the compound 17 has the strongest inhibiting activity on PARP1 and VEGFR2 and BRCA wild type breast cancer inhibiting activity, and the cell activity is obviously superior to that of a positive control.
Test example 2
Compound 17, positive control Olaparib (Ola), pazopanib (Paz), and combinations thereof induced BRCA wild-type breast cancer cell DNA damage mechanisms were explored using immunoblot assays.
The immunoblotting test was: MDA-MB-231 and MCF-7 cells were seeded into six well plates (3X 10 per well) 5 Individual cells), and placed in an incubator at 37 ℃ overnight. Compound 17, positive control Olaparib (abbreviated as Ola), pazopanib (abbreviated as Paz) and combinations thereof (ola+Paz) at various concentrations were used to treat cells for 48h, washed with PBS 2 times, and centrifuged at 13000rpm for 20min to quantify protein concentration using BCA protein assay kit. After separation by 15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the total protein at equivalent concentration was transferred to nitrocellulose (PVDF) membrane. After blocking with 5% skim milk-TBST solution for 1h at room temperature, the membranes were incubated with the corresponding primary antibodies overnight at 4 ℃, after 2 washes with TBST solution, the membranes were incubated with horseradish peroxidase (HRP) -conjugated secondary antibodies and observed with ECL as HRP substrate.
The test results are shown in fig. 1, and it can be seen from fig. 1: the use of compound 17 in combination with Pazopanib+olaparib positively regulates the expression of hypoxia inducible factor-1α (HIF-1α), a key molecule that mediates hypoxia. In addition, 17 induces increased HIF-1α expression compared to the combination treatment group. 17 significantly inhibited expression of homologous recombination repair pathway factors (FOXM 1, RAD51 and BRCA 1) in MDA-MB-231 and MCF-7 cells at a concentration of 8 μm, thereby inducing DNA damage in tumor cells.
Test example 3
Compound 17 (50 mg/kg or 25 mg/kg), olaparib (50 mg/kg), pazopanib (50 mg/kg) or an olaparib+Pazopanib combination (50 mg/kg+50 mg/kg) was orally administered to treat a model of a xenograft tumor of MDA-MB-231 in nude mice for 15 days, and the tumor volume of the nude mice was changed.
The test results are shown in fig. 2, and it can be seen from fig. 2: compound 17 can significantly inhibit tumor size and weight. Compound 17 (50 mg/kg) showed more significant tumor inhibition compared to the combination group, with a tumor inhibition (TGI) of 72.1%.
Test example 4
Compound 17 (50 mg/kg or 25 mg/kg), olaparib (50 mg/kg), pazopanib (50 mg/kg) or an olaparib+Pazopanib combination (50 mg/kg+50 mg/kg) were orally administered to treat a model of pulmonary metastasis of nude mice MDA-MB-231 for 15 days and a graph of pulmonary metastasis of nude mice is shown in FIG. 3, wherein the arrows represent pulmonary metastasis nodules.
As can be seen from fig. 3: the combination of group and compound 17 was effective in inhibiting lung metastasis nodule formation by visualizing the number of metastasis nodules on the lung metastasis tissue.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A pyrimidine compound, characterized by having a structure represented by formula I:
in the formula I, R 1 is-CH 3 Or H; r is R 2 H, CF of a shape of H, CF 3 、CH 3 Or OCH (optical wavelength) 3 ；
R 3 Is that
Rx, rn, rm, ry and Rz are independently-F, -Cl, -H, -OCH 3 、-CF 3 or-CH 3 ；
R 4 Is thatOr H; r is R 5 Is F or H; r is R 6 Is F or H.
2. The pyrimidine compound according to claim 1, having a structure represented by the formula 1 to formula 20:
3. the method for preparing pyrimidine compounds according to claim 1, comprising the steps of:
after a 2, 4-dichloropyrimidine derivative with a structure shown in a formula II and 2, 3-dimethyl-6-amino-2H-indazole are first dissolved, carrying out a first substitution reaction under alkaline conditions to obtain an intermediate product III with a formula III;
after the intermediate product III and the methylation reagent are dissolved for the second time, methylation reaction is carried out under the protective atmosphere and alkaline conditions, and a methylation compound with a structure shown in a formula IV is obtained;
after the methylated compound and the aminobenzoic acid derivative are dissolved for the third time, carrying out a second substitution reaction under an acidic condition to obtain an amination product; the aminobenzoic acid derivatives include p-aminobenzoic acid derivatives having the structure of formula V-1 and m-aminobenzoic acid derivatives having the structure of formula V-2;
when the aminobenzoic acid derivative is a para-aminobenzoic acid derivative, the amination product has a structure shown in a formula VI-1, and when the aminobenzoic acid derivative is a meta-aminobenzoic acid derivative, the amination product has a structure shown in a formula VI-2;
the amination product with the formula VI-1, a first condensing agent and a benzimidazole compound with the structure of the formula VII are dissolved for the fourth time, and then a first amide condensation reaction is carried out under alkaline conditions to obtain a first pyrimidine compound;
the first pyrimidine compound has a structure shown in formula I and R 3 Is that
The amination product with the structure of a formula VI-1 or the amination product with the structure of a formula VI-2, a second condensing agent and the aniline derivative with the structure of a formula VIII are subjected to a fifth dissolution, then a second amide condensation reaction is carried out, the obtained second condensation product is mixed with acetic acid, and a first cyclization reaction is carried out, so that a second pyrimidine compound and a third pyrimidine compound are respectively obtained;
the second pyrimidine compound has a structure shown in formula I, and R 3 Is that
The third pyrimidine compound has a structure shown in formula I, and R 3 Is that
4. The method of claim 3, wherein the molar ratio of the 2, 4-dichloropyrimidine derivative to the 2, 3-dimethyl-6-amino-2H-indazole is 1:1.2 to 2; the temperature of the first substitution reaction is 80-90 ℃ and the time is 12-15 h.
5. The method according to claim 3, wherein the methylating agent is CH 3 I, a step of I; the molar ratio of intermediate III to the methylating agent is 1:1.1 to 1.5; the temperature of the methylation reaction is 25-30 ℃ and the time is 6-18 h.
6. A process according to claim 3, wherein the molar ratio of methylated compound to aminobenzoic acid derivative is 1:1.2 to 1.5; the temperature of the second substitution reaction is 80-90 ℃ and the time is 15-20 h.
7. A method of preparation according to claim 3 wherein the first condensing agent is 1-hydroxybenzotriazole and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide; the temperature of the first amide condensation reaction is between-5 and 0 ℃ and the time is between 15 and 20 hours.
8. The method according to claim 3, wherein the second condensing agent is 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate, and the second amide condensation reaction is carried out at a temperature of 25 to 30 ℃ for a time of 24 to 30 hours; the temperature of the first cyclization reaction is 110-130 ℃ and the time is 15-20 h.
9. The process according to claim 3, wherein the temperature of the third amide condensation reaction is 25 to 30℃for 24 to 30 hours.
10. Use of a pyrimidine compound according to claims 1-2 or obtainable by a method according to any one of claims 3-9 for the preparation of a dual-targeting VEGFR/PARP inhibitor.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310736832.9A CN116987066A (en) | 2023-06-20 | 2023-06-20 | Pyrimidine compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310736832.9A CN116987066A (en) | 2023-06-20 | 2023-06-20 | Pyrimidine compound and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116987066A true CN116987066A (en) | 2023-11-03 |
Family
ID=88530954
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310736832.9A Pending CN116987066A (en) | 2023-06-20 | 2023-06-20 | Pyrimidine compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116987066A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
| US12006322B2 (en) | 2022-04-28 | 2024-06-11 | Xin Thera, Inc. | Substituted pyridines as PARP1 inhibitors |
-
2023
- 2023-06-20 CN CN202310736832.9A patent/CN116987066A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
| US12006322B2 (en) | 2022-04-28 | 2024-06-11 | Xin Thera, Inc. | Substituted pyridines as PARP1 inhibitors |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN116987066A (en) | Pyrimidine compound and preparation method and application thereof | |
| JP5524343B2 (en) | Benzodiazepine bromodomain inhibitor | |
| KR101896599B1 (en) | Tetrahydroquinoline derivatives useful as bromodomain inhibitors | |
| JP2015129193A (en) | Heteroaryl derivatives as cftr modulators | |
| CN107266425A (en) | It is used as the base benzsulfamide of pyrazoles 1 of CCR9 antagonists | |
| TW200403060A (en) | Inhibitors of tyrosine kinases | |
| CN110563703B (en) | Compound for inducing PARP-1 degradation based on CRBN ligand, preparation method and application | |
| CN110194762B (en) | Phthalazinone derivatives, preparation method and application thereof | |
| CN111303121A (en) | 4-phenoxypyridine compound containing quinoxalinone and application thereof | |
| CN107879975A (en) | Histon deacetylase (HDAC) inhibitor and its application | |
| CN103382182B (en) | Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage | |
| CN115703761A (en) | Compound as WWP1 inhibitor and application thereof | |
| CN106565612B (en) | Diphenylethyllene pyrimidines, composition and application thereof | |
| US11236112B2 (en) | Crystal form and salt form of TGF-βRI inhibitor and preparation method therefor | |
| US20050222186A1 (en) | Substituted diaminopyrimidines | |
| CN111471048B (en) | Compound with nitrogen-containing bridged ring, spiro ring or fused ring structure and application thereof | |
| CN110357852B (en) | Benzopyrimidine compounds, preparation method and application | |
| CN116496219A (en) | Six-membered and five-membered heterocyclic compound, and pharmaceutical composition and application thereof | |
| CN104211682A (en) | pyridine compounds and applications thereof | |
| CN114133397A (en) | Evodiamine compound and preparation method and application thereof | |
| CN112876457A (en) | Novel 4-phenoxypyridine derivative and application thereof | |
| CN112110864A (en) | 4-amide substituted pyrimidine targeted DDR1 inhibitor, preparation method thereof and application of inhibitor in antitumor activity | |
| JP2005524671A (en) | New azepane derivatives | |
| CN115340502B (en) | BCL-XL inhibitor and preparation method and application thereof | |
| CN108047132A (en) | Diphenylamines yl pyridines anti-tumor compounds and preparation method thereof and purposes |
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 |