CN113354622A - 对苯二胺类lsd1抑制剂及其制备方法 - Google Patents
对苯二胺类lsd1抑制剂及其制备方法 Download PDFInfo
- Publication number
- CN113354622A CN113354622A CN202010150110.1A CN202010150110A CN113354622A CN 113354622 A CN113354622 A CN 113354622A CN 202010150110 A CN202010150110 A CN 202010150110A CN 113354622 A CN113354622 A CN 113354622A
- Authority
- CN
- China
- Prior art keywords
- methyl
- pharmaceutically acceptable
- alkyl
- general formula
- acceptable salts
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 18
- 229940123628 Lysine (K)-specific demethylase 1A inhibitor Drugs 0.000 title description 12
- CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000003112 inhibitor Substances 0.000 claims abstract description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000004472 Lysine Substances 0.000 claims abstract description 5
- -1 hydrogen Chemical class 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- GVWISOJSERXQBM-UHFFFAOYSA-N n-methylpropan-1-amine Chemical compound CCCNC GVWISOJSERXQBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- FXWOAMWXZDFVTM-UHFFFAOYSA-N 1-(diaminomethylideneamino)-1-hydrazinylguanidine Chemical compound NNN(C(N)=N)NC(N)=N FXWOAMWXZDFVTM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 claims description 2
- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012964 benzotriazole Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 6
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 150000004989 p-phenylenediamines Chemical class 0.000 abstract description 11
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 150000001875 compounds Chemical class 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 34
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 150000007522 mineralic acids Chemical class 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 238000000227 grinding Methods 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 description 4
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 description 4
- 239000011714 flavin adenine dinucleotide Substances 0.000 description 4
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- SZTYQQYYIMVETL-UHFFFAOYSA-N n-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 SZTYQQYYIMVETL-UHFFFAOYSA-N 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- OLWAQODFEQGTLK-UHFFFAOYSA-N 1-N-[2-(dimethylamino)ethyl]-1-N-methyl-4-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-2-nitrobenzene-1,4-diamine Chemical compound CN(CCN(C1=C(C=C(C=C1)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)[N+](=O)[O-])C)C OLWAQODFEQGTLK-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- JBPAZBJDPWVSRT-UHFFFAOYSA-N O(C)C1=C(NC2=NC(C=3C4=CC=CC=C4N(C=3)C)=CC=N2)C=C(N(=O)=O)C(N2CCC(CC2)N)=C1 Chemical compound O(C)C1=C(NC2=NC(C=3C4=CC=CC=C4N(C=3)C)=CC=N2)C=C(N(=O)=O)C(N2CCC(CC2)N)=C1 JBPAZBJDPWVSRT-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000004663 cell proliferation Effects 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
- 239000010408 film Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- HVOYZOQVDYHUPF-UHFFFAOYSA-N n,n',n'-trimethylethane-1,2-diamine Chemical compound CNCCN(C)C HVOYZOQVDYHUPF-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
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- 230000002441 reversible effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- OYRBDGKUVUVWRI-UHFFFAOYSA-N 1-phenylcyclopropan-1-amine Chemical compound C=1C=CC=CC=1C1(N)CC1 OYRBDGKUVUVWRI-UHFFFAOYSA-N 0.000 description 2
- AAZYJKNISGEWEV-UHFFFAOYSA-N 2-chloro-4-phenylpyrimidine Chemical class ClC1=NC=CC(C=2C=CC=CC=2)=N1 AAZYJKNISGEWEV-UHFFFAOYSA-N 0.000 description 2
- IIBWXYHPBMUNJP-UHFFFAOYSA-N 3-(2-chloropyrimidin-4-yl)-1-methylindole Chemical compound C12=CC=CC=C2N(C)C=C1C1=CC=NC(Cl)=N1 IIBWXYHPBMUNJP-UHFFFAOYSA-N 0.000 description 2
- PKEPAQKEINNCAB-UHFFFAOYSA-N 4-n-[2-(dimethylamino)ethyl]-2-methoxy-4-n-methyl-1-n-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine Chemical compound COC1=CC(N(C)CCN(C)C)=C([N+]([O-])=O)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 PKEPAQKEINNCAB-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 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
- 108010010803 Gelatin Proteins 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
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- HACMLTQTHAZCLX-UHFFFAOYSA-N n-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine Chemical compound [O-][N+](=O)C=1C=C(NC=2N=C(C=CN=2)C=2C3=CC=CC=C3N(C)C=2)C(OC)=CC=1N1CCN(C)CC1 HACMLTQTHAZCLX-UHFFFAOYSA-N 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 230000036961 partial effect Effects 0.000 description 1
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- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 230000002103 transcriptional effect Effects 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- XBBRLCXCBCZIOI-DLBZAZTESA-N vafidemstat Chemical compound O1C(N)=NN=C1CN[C@H]1[C@H](C=2C=CC(OCC=3C=CC=CC=3)=CC=2)C1 XBBRLCXCBCZIOI-DLBZAZTESA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
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Abstract
本发明属于药物合成领域,提供了如通式(Ⅰ)所示的对苯二胺类衍生物及其药学上可接受的盐、其立体异构体,其中,R1、R2、R3、R4、m和n如权利要求和说明书所述。所述通式(Ⅰ)的对苯二胺类衍生物及其药学上可接受的盐、其立体异构体可单独或联合用药,作为赖氨酸特异性脱甲基酶‑1(LSD1)抑制剂,用于肿瘤类疾病的治疗。
Description
技术领域
本发明属于化学合成药物技术领域,涉及一类新型对苯二胺类衍生物以及所述衍生物的药学可接受的盐、它们的制备方法及其作为赖氨酸特异性去甲基酶-1(LSD1)抑制剂的用途。
背景技术
组蛋白赖氨酸去甲基化酶在开发表观遗传学领域的药物中占据着非常重要的地位,直到2004年,Shi Yang课题组第一次发现了组蛋白赖氨酸特异性去甲基化酶1,揭示了组蛋白甲基化过程是一个可逆、可控的过程(Cell 2004,119,941–953.)。研究发现LSD1在辅因子黄素腺嘌呤二核苷酸(FAD)的辅助下可以特异性地去除组蛋白赖氨酸的单甲基或双甲基,通过作用于甲基化的赖氨酸可以分别发挥基因转录激活和转录抑制的作用。进而调控下游信号通路,发挥调节作用。通过去除H3K4的双甲基化修饰,LSD1可以与转录共阻遏物诱导抑癌基因的沉默,从而促进肿瘤细胞的生长。研究者相继报道了LSD1作为肿瘤治疗靶标,其抑制剂与其他药物(如激酶抑制剂)联合用药可发挥更好的肿瘤治疗效果。因此,LSD1抑制剂的开发有利于抗肿瘤药物的研发,可以单独或者与其他药物组合用于癌症的治疗。
已报道的LSD1抑制剂有六百多个,其中尚无用于肿瘤治疗的上市LSD1抑制剂。目前处于临床研究阶段的LSD1抑制剂共有11个,可分为不可逆性抑制剂和可逆性抑制剂两类。不可逆性抑制剂可以与辅因子FAD形成共价结合,阻断FAD参与去甲基的循环,从而发挥LSD1抑制活性。目前处于临床研究阶段的代表性LSD1抑制剂ORY-1001、ORY-2001、GSK-2879552、IMG-7289均以反苯基环丙胺为结构母核的不可逆抑制剂。目前已公布结构的抑制剂中只有Utah大学原研、Salarius制药公司推进临床试验的Seclidemstat mesylate和Celgene制药公司开发的CC-90011作为可逆性LSD1抑制剂处于临床研究阶段,适应症均为肿瘤。
目前对于LSD1抑制剂的研发多数以反苯基环丙胺类化合物展开,开发更多新骨架LSD1抑制剂是目前抗肿瘤领域的研究热点。本发明所述通式Ⅰ化合物作为LSD1抑制剂,在体外酶水平表现出较好的活性。
发明内容
本发明的目的在于提供一种通式I所示的对苯二胺类衍生物,以及所述衍生物的药学可接受的盐和立体异构体,用于制备LSD1抑制剂,
其中:
R1、R2独立地选自氢、C1-C3烷基、(CH2)pNR5R6,其中,所述C1-C3烷基可含有0-4个选自F、Cl或Br的卤原子取代,其中p为1-6的整数,R5、R6为氢或甲基;
或R1、R2与和它们所连接的氮原子一起形成3-6元环烷基或5-6元杂环基,所述环烷基或杂环基可以被多个R7取代,所述的杂环基可含有1-3个N、O或S的杂原子;
R7为氢、C1-C4烷基、氨基、硝基、氰基、卤素、羟基;
R3选自氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、硝基、氰基、氨基、羟基、卤原子;
m为0、1、2或3;
X=C或N;
R4选自卤原子、C6-C10芳基、C4-C10芳杂环;其中C6-C10芳基、C4-C10芳杂环可被一个或多个Ra取代,且所述C4-C10芳杂环含有1~3个选自N、O或S的杂原子;
Ra选自C1~C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、甲酰胺、乙酰胺;
n为0、1、2或3;
本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体,
其中,R1、R2独立地选自氢、C1-C3烷基、(CH2)pNR5R6,其中,所述C1-C3烷基可含有0-4个选自F、Cl或Br的卤原子取代;p为2-5的整数;优选为氢、C1-C3烷基、丙胺、N-甲基丙胺、N,N-二甲基丙胺;
或R1、R2与和它们所连接的氮原子一起形成3-6元环烷基或5-6元杂环基,所述环烷基或杂环基可以被多个R7取代,所述的杂环基可含有1-3个N、O或S的杂原子;R7优选氢、氨基;所述杂环基为:
进一步地,本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体,
其中,
R3选自氢、甲基、三氟甲基、甲氧基、三氟甲氧基、乙基、乙氧基、丙基、异丙基、硝基、氰基、氨基、羟基、卤原子,优选氨基、羟基、甲氧基活性、三氟甲氧基;
进一步地,本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体,
其中,
m为0、1、2或3,优选0、1、2;
进一步地,本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体,
其中,
X=C或N;
进一步地,本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体,
其中,
R4选自H、呋喃、噻吩、吡咯、噁唑、异恶唑、吡唑、咪唑、三氮唑、苯基、吡啶、嘧啶、吲哚、苯并呋喃、苯并噻吩、苯并噻唑、苯并噁唑、苯并异噁唑、苯并咪唑、苯并吡唑、苯并三氮唑、萘、喹啉、喹唑啉;且所述基团可被一个或多个Ra取代;
进一步地,本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体,
其中,
Ra选自C1~C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺;优选甲基、乙基、氟;
进一步地,本发明优选涉及通式(I)所示的对苯二胺类衍生物及其药学可接受的盐和立体异构体,
其中,
n为0、1、2或3,优选0、1;
本发明通式I化合物及其药学上可接受的盐优选以下化合物,但这些化合物并不意味着对本发明的任何限制:
N-[2-(二甲氨基)乙基]-5-甲氧基-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基-1,4-苯二胺
2-甲氧基-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-N’-[2-(甲氨基)乙基]-5-硝基-1,4-苯二胺
N-[2-甲氧基-5-硝基-4-(哌嗪-1-基)苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-[2-甲氧基-4-(4-甲基哌嗪-1-基)-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-[4-(4-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
2-甲氧基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-5-硝基-N’-(哌啶-4-甲基)-1,4-苯二胺
(S)-N-[4-(3-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
(R)-N-[4-(3-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-(4-氨基环己基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
2-甲氧基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-N’-(1-甲基哌啶-4-基)-5-硝基苯-1,4-二胺
2-甲氧基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-5-硝基-N’-(哌啶-3-基)-1,4-苯二胺
N-[4-(3-氨基吡咯啉-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺
N-(3-氨基丙基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
2-甲氧基-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-N’-[3-(甲氨基)丙基]-5-硝基苯-1,4-二胺
N-(2-氨基乙基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-(4-氨基丁基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-(5-氨基戊基)-5-甲氧基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,2,4-三胺
N’-[2-(二甲氨基)乙基]-2-甲氧基-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N,2-二甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
N’-[2-(二甲氨基)乙基]-N’,2-二甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
2-氯-N’-[2-(二甲氨基)乙基]-N’-甲基-N-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
2-氯-N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-(三氟甲基)苯基-1,4-二胺
2-[(2-(二甲氨基)乙基)(甲基)氨基]-5-[(4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基)氨基]苯腈
N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-(三氟甲基)苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-(4-苯基嘧啶-2-基)苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-(5-苯基嘧啶-2-基)苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(萘乙酰胺-2-基)-2-嘧啶基]苯基-1,4-二胺
N-[5-(苯并呋喃-3-基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
N-[5-(苯并[b]噻吩-3-基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(噻吩-3-基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(5-(呋喃-3-基)-2-嘧啶基)-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(5-(3-甲氧基苯基)-2-嘧啶基)-N-甲基苯基-1,4-二胺
N-[5-(3-氯苯基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
3-[2-((4-((2-(二甲氨基)乙基)(甲基)氨基)苯基)氨基)-5-嘧啶基]苯腈
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(3-(三氟甲氧基)苯基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(3-氟苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(3,5-二甲基苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(4-氟-3-甲基苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(3-氟-4-甲氧基苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N-甲基-N’-[5-(甲苯基)-2-嘧啶基]苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(2-氟苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-[5-(4-氟苯基)-2-嘧啶基]-N-甲基苯基-1,4-二胺
N-[5-(3,4-二甲氧基苯基)-2-嘧啶基]-N’-[2-(二甲氨基)乙基]-N’-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(5-(5-异丙基-2-甲氧基苯基)-2-嘧啶基)-N-甲基苯基-1,4-二胺
N-[2-(二甲氨基)乙基]-N’-(4-(2-氟-4-甲基苯基)-2-吡啶基)-N-甲基苯基-1,4-二胺。
而且,按照本发明所属领域的一些通常方法,本发明中通式I的化合物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐,与酸加成的盐是特别优选的酸为:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸。
本发明中“卤素”是指氟、氯、溴或碘;“烷基”是指直链或支链的烷基;“芳杂环”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,该环状体系是指具有芳香性的,并且除去环状体系中的一个或不同位置的多个氢原子而得到的有机基团,如噻唑基,咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基,吲哚基,苯并噻唑基,噁唑基,异噁唑基,萘基,喹啉基,异喹啉基,苯并咪唑基,苯并噁唑基等;脂肪伯胺、脂肪仲胺、脂肪叔胺是指含有一个或多个氮原子的链状或环状脂肪体系,如乙胺、N-甲基乙胺、N,N-二甲基乙胺、丙胺、丁胺、环丁胺、四氢吡咯、哌嗪基、哌啶基、四氢吡唑烷基、四氢咪唑、N-甲基哌啶等。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。按照本发明的式(I)化合物,可按照路线1的方法或路线2方法制备得来。
如路线1所示,其中应用的全部可变因数如权利要求中的定义。
起始原料I与取代的脂肪胺发生亲核取代反应得到中间体II,反应条件a为一种有机碱(如:三乙胺、N,N-二异丙基乙胺等)或无机碱(如:碳酸钠、碳酸钾、碳酸铯、磷酸钠、氢氧化钠、氢氧化钾等)做缚酸剂的情况下,于室温或加热条件下进行;反应溶剂可以是甲醇、乙醇、丙醇、丙酮、N,N-二甲基甲酰胺、二甲基亚砜等极性溶剂;优选碳酸钾做缚酸剂,N,N-二甲基甲酰胺做溶剂,80℃反应。
中间体II经还原反应得中间体III,反应条件b可以为各种钯类催化剂催化下的氢化还原、还原性金属与无机酸组合(如:铁粉/氯化铵、铁粉/盐酸、锌粉/醋酸,等);反应溶剂可以是四氢呋喃、甲醇、乙醇、二氯甲烷、水等,溶剂可以是单一溶剂也可以是混合溶剂;催化氢化条件优选10%Pd/C做催化剂、甲醇做溶剂、反应温度优选室温。还原性金属与无机酸组合进行还原时,优选铁粉/氯化铵体系,水和乙醇的混合溶剂作为反应溶剂,温度为60–80℃。
中间体IV与取代的芳基硼酸经铃木反应得中间体V,反应条件c为钯配合物催化、无机碱和无氧条件下加热反应;钯配合物可以为Pd(PPh3)4、PdCl2、PdCl2(dppf)、Pd(OAc)2和Pd(PPh3)2Cl2等,优选Pd(PPh3)4;无机碱可以为碳酸钾、碳酸钠、碳酸锂、碳酸铯等,优选碳酸钠;溶剂可以为乙醇、1,4-二氧六环、四氢呋喃、甲苯、N,N-二甲基甲酰胺、二甲基亚砜、水和乙二醇二甲醚等,也可以是两种溶剂组成的混合溶剂,溶剂优选乙二醇二甲醚和水(体积比为10:1)的混合溶剂;反应温度可以为80–140℃,优选110℃。
中间体III和中间体V发生亲核取代反应得到目标产物,反应条件d为有机酸或无机酸催化下,加热10–48小时;有机酸可以为苯磺酸、对甲苯磺酸和乙酸等,无机酸可以是稀硫酸、稀盐酸、稀硝酸等,酸的用量为催化量,优选对甲苯磺酸、稀盐酸;溶剂可以为甲醇、乙醇、异丙醇、N,N-二甲基甲酰胺和二甲基亚砜等,优选乙醇、异丙醇;反应温度可以为60–130℃,优选80℃;反应时间优选24小时。
路线2所示,其中应用的全部可变因数如权利要求中的定义。
中间体VI和中间体VII发生亲核取代反应得中间体VIII,反应条件e为有机酸或无机酸催化下,加热48–96小时;有机酸可以为苯磺酸、对甲苯磺酸和乙酸等,无机酸可以是稀硫酸、稀盐酸、稀硝酸等,酸的用量为催化量或摩尔量,优选对甲苯磺酸、稀盐酸;溶剂可以为甲醇、乙醇、异丙醇、N,N-二甲基甲酰胺和二甲基亚砜等,优选乙醇、异丙醇;反应温度可以为80–150℃,优选110℃;反应时间优选72小时;根据反应进程,可以选择封管加热反应。
中间体VIII与脂肪胺发生亲核取代反应得到目标产物;反应条件f为一种有机碱(如:三乙胺、N,N-二异丙基乙胺等)或无机碱(如:碳酸钠、碳酸钾、碳酸铯、磷酸钠、氢氧化钠、氢氧化钾等)做缚酸剂的情况下,于室温或加热条件下进行;反应溶剂可以是甲醇、乙醇、丙醇、丙酮、N,N-二甲基甲酰胺、二甲基亚砜等极性溶剂;优选碳酸钾做缚酸剂,N,N-二甲基甲酰胺做溶剂,80℃反应。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定,质谱用Agilent 1100 LC/MSD测定;所用试剂均为分析纯或化学纯。
表1.实施例结构式、化学名、相对分子质量
实施例1:N-[2-(二甲氨基)乙基]-5-甲氧基-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基-1,4-苯二胺的合成
步骤A-1:3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚的制备
将2,4-二氯嘧啶(3.0g,20.4mmol)和三氯化铝(2.6g,20.4mmol)加入100mL反应瓶中,加入30mL乙二醇二甲醚,室温搅拌5min。将N-甲基吲哚(2.7g,20.4mmol)滴加到反应液中,加毕,升温至80℃继续反应6h。冷却反应液至室温,将反应液减压浓缩,加入50mL乙酸乙酯溶解粗品。乙酸乙酯相依次水洗(10mL×3)、饱和食盐水洗(10mL×3),无水硫酸钠干燥后浓缩,经硅胶柱层析纯化(石油醚:乙酸乙酯=4:1)得浅黄色固体3.07g,收率62.0%。1HNMR(600MHz,DMSO)δ8.53(d,J=5.4Hz,1H),8.51(s,1H),8.43–8.40(m,1H),7.83(d,J=5.5Hz,1H),7.58(d,J=7.9Hz,1H),7.30(dtd,J=14.8,7.1,1.1Hz,2H),3.90(s,3H)。
步骤A-2:N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺的制备
将3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(2.4g,10.0mmol)和对甲苯磺酸(1.7g,10.0mmol)加入100mL反应瓶中,加入无水乙醇40mL,回流反应30min。加入4-氟-2-甲氧基-5-硝基苯胺(1.9g,10.0mmol),继续回流反应10h。将反应液减压浓缩后,加入40mL水、40mL乙酸乙酯,剧烈搅拌5min后,用饱和氢氧化钠溶液调节PH=8。分出乙酸乙酯相,以无水硫酸钠干燥后浓缩得粗品,经硅胶柱层析(石油醚:乙酸乙酯=8:1)后得橘红色固体2.2g,收率56.1%。1H NMR(600MHz,DMSO)δ9.12(d,J=8.5Hz,1H),8.41–8.38(m,2H),8.37(s,1H),8.30(s,1H),7.54(d,J=8.2Hz,1H),7.37(d,J=13.3Hz,1H),7.32(d,J=5.4Hz,1H),7.29–7.24(m,1H),7.15(t,J=7.1Hz,1H),4.03(s,3H),3.89(s,3H)。
步骤A-3:N-[2-(二甲氨基)乙基]-5-甲氧基-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基-1,4-苯二胺的合成
将N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺(2.0g,5.1mmol)、N,N,N'-三甲基乙二胺(0.5g,5.1mmol)和N,N-二异丙基乙胺(0.7g,5.1mmol)加入100mL反应瓶,加入4mLN,N-二甲基甲酰胺,80℃反应12h。冷却反应液,将反应液冷却后加入到100mL水中,乙酸乙酯(10mL×3)萃取,饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥,减压浓缩。经硅胶柱层析纯化得橘红色固体1.4g,收率58.5%。1H NMR(600MHz,DMSO)δ8.63(s,1H),8.35(d,J=7.8Hz,1H),8.32(d,J=5.3Hz,2H),8.08(s,1H),7.52(d,J=8.2Hz,1H),7.27–7.23(m,1H),7.21(dd,J=5.3,2.8Hz,1H),7.12(t,J=7.4Hz,1H),6.85(s,1H),3.96(d,J=2.2Hz,3H),3.88(s,3H),3.27(t,J=6.9Hz,2H),2.86(s,3H),2.48(d,J=6.8Hz,2H),2.16(s,6H)。
实施例2-4、实施例10和实施例14的合成,以N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺和不同的脂肪胺按照实施例1相同的合成方法得到。
实施例5:N-[4-(4-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺的合成步骤A-4:叔丁基[1-(5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基)氨基)-2-硝基苯基)哌啶-4-基]氨基甲酸酯的制备
将N-(4-氟-2-甲氧基-5-硝基苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺(2.0g,5.1mmol)、N,N-二异丙基乙胺(0.7g,5.1mmol)和4-叔丁氧羰基氨基哌啶(1.0g,5.1mmol)加入100mL反应瓶,加入4mLN,N-二甲基甲酰胺,80℃反应12h。冷却反应液,将反应液冷却后加入到100mL水中,乙酸乙酯(10mL×3)萃取,饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥,减压浓缩。经硅胶柱层析纯化得橘红色固体1.9g,收率64.1%。
步骤A-5:N-[4-(4-氨基哌啶-1-基)-2-甲氧基-5-硝基苯基]-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺的合成
将叔丁基[1-(5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基)氨基)-2-硝基苯基)哌啶-4-基]氨基甲酸酯(1.2g,2.1mmol)加入5ml 6N HCl/MeOH中,室温搅拌反应2h。减压浓缩溶剂,加入5ml水,用饱和氢氧化钠溶液调节PH=10。乙酸乙酯(10mL×3)萃取,合并乙酸乙酯并用饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥,减压浓缩,得橘红色固体0.86g,收率86.8%。1H NMR(600MHz,DMSO)δ8.79(s,1H),8.36(d,J=7.9Hz,1H),8.33(d,J=4.4Hz,2H),8.11(s,1H),7.52(d,J=8.2Hz,1H),7.25(dd,J=16.7,6.6Hz,2H),7.12(t,J=7.5Hz,1H),6.84(s,1H),3.98(s,3H),3.88(s,3H),3.24(d,J=12.1Hz,2H),2.87(t,J=10.6Hz,2H),2.74(t,J=9.8Hz,1H),1.82(d,J=10.3Hz,2H),1.65(s,2H),1.44(td,J=13.5,3.5Hz,2H)。
实施例6-9、实施例11-13和实施例15-17采用不同的脂肪胺底物按照实施例5的合成方法得到。
实施例18:N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺的合成步骤A-6:N-[2-(二甲氨基)乙基]-N-甲基-2-硝基苯基-1,4-二胺的制备
将4-氟-3-硝基苯胺(1.6g,10.2mmol)、N,N,N'-三甲基乙二胺(1.1g,10.2mmol)和N,N-二异丙基乙胺(1.4g,10.2mmol)加入100mL反应瓶,加入4mL N,N-二甲基甲酰胺,80℃反应12h。冷却反应液,将反应液冷却后加入到100mL水中,乙酸乙酯(10mL×3)萃取,饱和食盐水(10mL×3)洗涤。将乙酸乙酯相用无水硫酸钠干燥,减压浓缩。经硅胶柱层析纯化得黄色固体1.6g,收率66.3%。
步骤A-7:N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺的合成
将中间体N-[2-(二甲氨基)乙基]-N-甲基-2-硝基苯基-1,4-二胺和3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚按照步骤A-2的操作方法合成N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺。1H NMR(600MHz,DMSO)δ9.62(s,1H),8.54(d,J=7.1Hz,1H),8.45(d,J=2.6Hz,1H),8.36(d,J=5.4Hz,1H),8.33(s,1H),7.81(dd,J=9.0,2.5Hz,1H),7.55(d,J=8.2Hz,1H),7.36(d,J=9.0Hz,1H),7.31–7.26(m,1H),7.24(d,J=5.4Hz,1H),7.19(t,J=7.4Hz,1H),3.89(s,3H),3.15-3.09(m,2H),2.76(s,3H),2.43(t,J=7.0Hz,2H),2.17(s,6H)。
实施例19:N-[2-(二甲氨基)乙基]-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]苯基-1,2,4-三胺的合成
步骤A-8:将N-(2-(二甲氨基)乙基)-N-甲基-N’-[4-(1-甲基-1H-吲哚-3-基)-2-嘧啶基]-2-硝基苯-1,4-二胺(0.5g,1.1mmol)和10%钯碳(0.1g)加入50ml反应瓶中,加入20ml甲醇。氢气条件下,室温反应12h。过滤,将滤液浓缩得浅黄色固体0.4g,收率89.0%。1HNMR(600MHz,DMSO)δ9.04(s,1H),8.63(d,J=7.9Hz,1H),8.30(s,1H),8.27(d,J=5.3Hz,1H),7.53(d,J=8.2Hz,1H),7.26(dd,J=11.6,4.5Hz,1H),7.22-7.16(m,2H),7.13(d,J=5.3Hz,1H),6.97-6.90(m,2H),3.89(s,3H),3.10(s,4H),2.66(s,6H),2.53(s,3H)。
实施例20-27的合成按照实施例18的合成方法得到。
实施例28:N-[2-(二甲氨基)乙基]-N-甲基-N’-(4-苯基嘧啶-2-基)苯基-1,4-二胺的合成步骤A-9:2-氯-4-苯基嘧啶的制备
将苯硼酸(1.2g,10.0mmol)、2-氯-4-溴嘧啶(1.9g,10.0mmol)、碳酸钠(2.1g,20.0mmol)和四三苯基膦钯(0.6g,0.5mmol)加入50ml反应瓶中,加入30ml乙二醇二甲醚,氮气保护下,升温至110℃反应12h。反应液冷却减压浓缩得油状物,用40ml乙酸乙酯溶解油状物,并依次用水和饱和食盐水洗涤。无水硫酸钠干燥后浓缩,经硅胶柱层析纯化得白色固体1.0g,收率50.0%。1H NMR(600MHz,DMSO)δ9.13(d,J=1.8Hz,2H),7.87–7.79(m,2H),7.60–7.53(m,2H),7.51(dd,J=8.1,6.5Hz,1H)。
步骤A-10:N,N,N’-三甲基-N’-(4-硝基苯基)乙烷-1,2-二胺的制备
以对氟硝基苯和N,N,N'-三甲基乙二胺为原料,按照步骤A-6的操作制备,收率60.7%。
步骤A-11:N-[2-(二甲氨基)乙基]-N-甲基苯-1,4-二胺的制备
以N,N,N’-三甲基-N’-(4-硝基苯基)乙烷-1,2-二胺为原料按照步骤A-8的操作制备得到,收率92.6%。
步骤A-12:N-[2-(二甲氨基)乙基]-N-甲基-N’-(4-苯基嘧啶-2-基)苯基-1,4-二胺的合成
以2-氯-4-苯基嘧啶和N-[2-(二甲氨基)乙基]-N-甲基苯-1,4-二胺为原料按照步骤A-2的操作合成,收率55.3%。1H NMR(600MHz,DMSO)δ9.39(s,1H),8.73(s,2H),7.68(d,J=7.5Hz,2H),7.53(d,J=8.9Hz,2H),7.46(t,J=7.6Hz,2H),7.35(t,J=7.3Hz,1H),6.69(d,J=8.9Hz,2H),3.40(d,J=7.1Hz,2H),2.87(s,3H),2.47-2.40(m,2H),2.23(s,6H)。
实施例29-48的合成按照实施例28的合成方法得到。
本发明部分产物的体外药理测试
本发明采购Cayman公司的700120试剂盒对部分化合物的LSD1抑制活性进行检测,具体操作步骤如下:
(1)检测设置100%活性孔、背景孔、阳性对照孔和化合物孔。每组设三个复孔。
(2)100%活性孔:依次加入120μL LSD1 Buffer溶液、10μL溶液(与溶解化合物和阳性药相同成分的溶液)、20μLLSD1酶、20μLLSD1检测肽。
(3)测试孔和阳性对照孔:依次加入120μL LSD1 Buffer溶液、10μL待测化合物溶液、20μLLSD1酶、20μLLSD1检测肽。
(4)背景孔:依次加入140μLLSD1 Buffer溶液、10μL溶液(与溶解化合物和阳性药相同成分的溶液)、20μLLSD1酶。
(5)加溶液过程中将96孔板置于冰袋上降温,防止酶促反应的进行。加毕,避光,室温孵育30min。
(6)孵育30min后,依次向每个孔加入20μL辣根过氧化物酶溶液、10μL荧光底物溶液。避光,室温孵育10min。
(7)酶标仪530nM波长下激发,检测590nM的发射荧光的强弱。
抑制率%=(100%活性孔–样品孔)/100%活性孔*100
表2.实施例核磁氢谱、酶抑制活性数据
注:体外酶水平活性测试IC50被指定为在以下范围内:
A:<1μΜ
B:>1μΜ至<10μΜ
C:>10μΜ至<50μΜ
D:>50μΜ
我们选择酶活性较优的几个化合物,采用CCK-8检测试剂盒进行细胞增殖抑制能力评估,选取U87、H460和THP-1三个肿瘤细胞株进行评估。具体步骤和结果如下:
1、将待测细胞接种于96孔板中,每孔接种3×103个细胞,然后加入0.1μL不同浓度的待测化合物溶液,每个浓度梯度的测试孔设置三个复孔,每孔终体积为100μL。
2、将96孔板置于二氧化碳恒温培养箱中,孵育72h。
3、每孔加入10μL CCK8溶液,吹打混匀后,孵育2-4h。
4、使用酶标仪读取450nm波长下的吸光度值,计算细胞存活率。
表3.实施例细胞增殖抑制活性数据
Compd. | U87 | H460 | THP-1 |
X26 | A | A | A |
X42 | C | C | C |
X43 | D | B | B |
X44 | C | A | A |
注:体外细胞增殖抑制活性测试IC50被指定为在以下范围内:
A:<5μΜ
B:>5μΜ至<10μΜ
C:>10μΜ至<50μΜ
D:>50μΜ
本发明中通式I的化合物及其药学上可接受的盐或前药可单独施用,但通常是和药用载体混合物给予,所述药用载体的选择要根据所需用药途径和标准药物实践,下面分别用该类化合物的各种药物剂型,例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法,说明其在制药领域中的新应用。
实施例49:片剂用含有权利要求1中化合物的化合物(以实施例1化合物为例)10g,按照药剂学一般压片法加辅料20g混匀后,压制成100片,每片重300mg。
实施例50:胶囊剂用含有权利要求1中化合物的化合物(以实施例2化合物为例)10g,按照药剂学胶囊剂的要求将辅料20g混匀后,装入空心胶囊,每个胶囊重300mg。
实施例51:注射剂用含有权利要求1中化合物的化合物(以实施例3化合物为例)10g,按照药剂学常规方法,进行活性炭吸附,经0.65μm微孔滤膜过滤后,填入氮气罐制成水针制剂,每只装2mL,共灌装100瓶。
实施例52:气雾剂用含有权利要求1中化合物的化合物(以实施例5化合物为例)10g,用适量丙二醇溶解后,加入蒸馏水及其他辐料后,制成500mL的澄清溶液即得。
实施例53:栓剂用含有权利要求1中化合物的化合物(以实施例9化合物为例)10g,将之研细加入甘油适量,研匀后加入已熔化的甘油明胶,研磨均匀,倾入已涂润滑剂的模型中,制得栓剂50颗
实施例54:膜剂用含有权利要求1中化合物的化合物(以实施例23化合物为例)10g,将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解,80目筛网过滤,再将实施例18化合物加入到滤液中搅拌溶解,涂膜机制膜100片。
实施例55:滴丸剂用含有权利要求1中化合物的化合物(以实施例30化合物为例)10g,与明胶等基质50g加热熔化混匀后,滴入低温液体石蜡中,共制得滴丸1000丸。
实施例56:外用搽剂用含有权利要求1中化合物的化合物(以实施例35化合物为例)10g,按照常规药剂学方法与乳化剂等辅料2.5g混合研磨,再加蒸馏水至200mL制得。
实施例57:软膏剂用含有权利要求1中化合物的化合物(以实施例40化合物为例)10g,研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明,但修改和等价变化对于精通此领域的技术人员而言是显见的,且它们都包含在本发明范围。
Claims (10)
1.通式(Ⅰ)所示的衍生物,及其药学上可接受的盐、立体异构体:
其中:
R1、R2独立地选自氢、C1-C3烷基、(CH2)pNR5R6,其中,所述C1-C3烷基可含有0-4个选自F、Cl或Br的卤原子取代,其中p为1-6的整数,R5、R6为氢或甲基;
或R1、R2与和它们所连接的氮原子一起形成3-6元环烷基或5-6元杂环基,所述环烷基或杂环基可以被多个R7取代,所述的杂环基可含有1-3个N、O或S的杂原子;
R7为氢、C1-C4烷基、氨基、硝基、氰基、卤素、羟基;
R3选自氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、硝基、氰基、氨基、羟基、卤原子;
m为0、1、2或3,优选为0、1或2;
X=C或N;
R4选自卤原子、苯、萘、C4-C10芳杂环;其中苯、萘、C4-C10芳杂环可被一个或多个Ra取代,且所述C4-C10芳杂环含有1~3个选自N、O或S的杂原子;
Ra选自C1~C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺;
n为0、1、2或3,优选为0或1。
4.权利要求1-3任何一项所述的通式(Ⅰ)所示的衍生物,及其药学上可接受的盐、立体异构体,
其中,
R3选自氢、甲基、三氟甲基、甲氧基、三氟甲氧基、乙基、乙氧基、丙基、异丙基、硝基、氰基、氨基、卤原子,优选氨基、甲氧基。
5.权利要求1-4任何一项所述的通式(Ⅰ)所示的衍生物,及其药学上可接受的盐、立体异构体,
其中,
R4选自H、呋喃、噻吩、吡咯、噁唑、异恶唑、吡唑、咪唑、三氮唑、苯基、吡啶、嘧啶、吲哚、苯并呋喃、苯并噻吩、苯并噻唑、苯并噁唑、苯并异噁唑、苯并咪唑、苯并吡唑、苯并三氮唑、萘、喹啉、喹唑啉;且所述基团可被一个或多个Ra取代。
6.权利要求1-5任何一项所述的通式(Ⅰ)所示的衍生物,及其药学上可接受的盐、立体异构体,
其中,
Ra选自C1~C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺,优选甲基、氟。
8.药物组合物,包含权利要求1-6中任何一项所述的通式(Ⅰ)所示的衍生物,及其药学上可接受的盐、立体异构体和药学上可接受的载体或赋形剂。
9.权利要求1-6中任何一项所述的通式(Ⅰ)所示的衍生物,及其药学上可接受的盐、立体异构体在制备赖氨酸特异性去甲基化酶1抑制剂中的应用。
10.权利要求1-6中任何一项所述的通式(Ⅰ)所示的衍生物,及其药学上可接受的盐、立体异构体与其它抗肿瘤药物联合用药。
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CN113387935A (zh) * | 2021-07-23 | 2021-09-14 | 苏州雅深智慧科技有限公司 | 抑制三突变表皮生长因子受体酪氨酸激酶的化合物及用途 |
CN113387935B (zh) * | 2021-07-23 | 2022-06-10 | 苏州雅深智慧科技有限公司 | 抑制三突变表皮生长因子受体酪氨酸激酶的化合物及用途 |
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