CN107074866B - 嘧啶并吡咯类化合物、其制备方法、药用组合物及其应用 - Google Patents
嘧啶并吡咯类化合物、其制备方法、药用组合物及其应用 Download PDFInfo
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- CN107074866B CN107074866B CN201680003385.4A CN201680003385A CN107074866B CN 107074866 B CN107074866 B CN 107074866B CN 201680003385 A CN201680003385 A CN 201680003385A CN 107074866 B CN107074866 B CN 107074866B
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- Prior art keywords
- phenyl
- pyrimidine
- pyrrolo
- base
- diamines
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 150000003851 azoles Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- -1 N- methyl -4- piperidyl Chemical group 0.000 claims description 355
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 155
- 229910052757 nitrogen Inorganic materials 0.000 claims description 131
- 238000006243 chemical reaction Methods 0.000 claims description 110
- 125000002252 acyl group Chemical group 0.000 claims description 108
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 100
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 98
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 59
- 229950002366 nafoxidine Drugs 0.000 claims description 53
- 125000005936 piperidyl group Chemical group 0.000 claims description 49
- 125000004193 piperazinyl group Chemical group 0.000 claims description 46
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 40
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 38
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 38
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 22
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 21
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 19
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims description 19
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 17
- NZGAPXNPIZCGPW-UHFFFAOYSA-N C(=O)N1CCNCC1.[O] Chemical compound C(=O)N1CCNCC1.[O] NZGAPXNPIZCGPW-UHFFFAOYSA-N 0.000 claims description 16
- 125000003368 amide group Chemical group 0.000 claims description 16
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- VHORTMLFSRMOMV-KOJHFSGDSA-N N1=CC=CC2=CC=CC=C12.CC1(CC=C2C[C@@H]3[C@@H]4C=C[C@@H]([C@]5([C@@]4(C2=C1O5)CCN3C)C)O)O Chemical compound N1=CC=CC2=CC=CC=C12.CC1(CC=C2C[C@@H]3[C@@H]4C=C[C@@H]([C@]5([C@@]4(C2=C1O5)CCN3C)C)O)O VHORTMLFSRMOMV-KOJHFSGDSA-N 0.000 claims description 12
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 12
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 11
- 125000006308 propyl amino group Chemical group 0.000 claims description 11
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 125000003047 N-acetyl group Chemical group 0.000 claims description 10
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
- 125000006606 n-butoxy group Chemical group 0.000 claims description 7
- 201000006845 reticulosarcoma Diseases 0.000 claims description 7
- 208000029922 reticulum cell sarcoma Diseases 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 5
- 125000005429 oxyalkyl group Chemical group 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 4
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 206010029260 Neuroblastoma Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 4
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 4
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 3
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- OHUMKYGINIODOY-UHFFFAOYSA-N 1-(1-methylpiperidin-4-yl)piperazine Chemical compound C1CN(C)CCC1N1CCNCC1 OHUMKYGINIODOY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 2
- QRUONQPZJNDVTF-UHFFFAOYSA-N CNC(C(C)(N(NC=O)NCCC)NC=O)(NCC)NC=O Chemical compound CNC(C(C)(N(NC=O)NCCC)NC=O)(NCC)NC=O QRUONQPZJNDVTF-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 2
- XCAXUOCZIYVBRX-UHFFFAOYSA-N N1(CCCCC1)C1N(CCC(C1)O)NC(C)=O Chemical compound N1(CCCCC1)C1N(CCC(C1)O)NC(C)=O XCAXUOCZIYVBRX-UHFFFAOYSA-N 0.000 claims description 2
- MTIGEZYTLWKGDO-UHFFFAOYSA-N N1(CCNCC1)C1N(CCOC1)NC(C)=O Chemical compound N1(CCNCC1)C1N(CCOC1)NC(C)=O MTIGEZYTLWKGDO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 2
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- LNPTUKQSJYQXMT-UHFFFAOYSA-N 4-[6-[(3-ethyloxetan-3-yl)methoxy]hexyl]-n-[4-[4-[4-[6-[(3-ethyloxetan-3-yl)methoxy]hexyl]-n-(4-methoxyphenyl)anilino]phenyl]phenyl]-n-(4-methoxyphenyl)aniline Chemical compound C=1C=C(N(C=2C=CC(OC)=CC=2)C=2C=CC(=CC=2)C=2C=CC(=CC=2)N(C=2C=CC(CCCCCCOCC3(CC)COC3)=CC=2)C=2C=CC(OC)=CC=2)C=CC=1CCCCCCOCC1(CC)COC1 LNPTUKQSJYQXMT-UHFFFAOYSA-N 0.000 claims 101
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 36
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 claims 29
- IFFLKGMDBKQMAH-UHFFFAOYSA-N 2,4-diaminopyridine Chemical class NC1=CC=NC(N)=C1 IFFLKGMDBKQMAH-UHFFFAOYSA-N 0.000 claims 26
- QHDUEZNODTXHCY-UHFFFAOYSA-N C(C)(C)S(=O)(=O)C1=C(C=CC=C1)N1C=CC=2N=C(N=C(C=21)N)N Chemical class C(C)(C)S(=O)(=O)C1=C(C=CC=C1)N1C=CC=2N=C(N=C(C=21)N)N QHDUEZNODTXHCY-UHFFFAOYSA-N 0.000 claims 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 16
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 claims 14
- GKXQZKVXOCTMIW-UHFFFAOYSA-N CCN1C=CC2=C1C(=NC(=N2)N)N Chemical class CCN1C=CC2=C1C(=NC(=N2)N)N GKXQZKVXOCTMIW-UHFFFAOYSA-N 0.000 claims 12
- XDUQAJLLUUDWKV-UHFFFAOYSA-N CS(=O)(=O)C1=C(C=CC=C1)CN1C=CC=2N=C(N=C(C=21)N)N Chemical class CS(=O)(=O)C1=C(C=CC=C1)CN1C=CC=2N=C(N=C(C=21)N)N XDUQAJLLUUDWKV-UHFFFAOYSA-N 0.000 claims 10
- CARFXAYOIWUTHO-UHFFFAOYSA-N CS(=O)(=O)C1=CC=CC=C1N2C=CC3=C2C(=NC(=N3)N)N Chemical class CS(=O)(=O)C1=CC=CC=C1N2C=CC3=C2C(=NC(=N3)N)N CARFXAYOIWUTHO-UHFFFAOYSA-N 0.000 claims 10
- WSRMIDGHFUYDPJ-UHFFFAOYSA-N CSC1=C(CN(C=C2)C3=C2N=C(N)N=C3N)C=CC=C1 Chemical class CSC1=C(CN(C=C2)C3=C2N=C(N)N=C3N)C=CC=C1 WSRMIDGHFUYDPJ-UHFFFAOYSA-N 0.000 claims 10
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 7
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 6
- FWEFPHCXXXKAKG-UHFFFAOYSA-N CC(C)S(C1=C(CN(C=C2)C3=C2N=C(N)N=C3N)C=CC=C1)(=O)=O Chemical class CC(C)S(C1=C(CN(C=C2)C3=C2N=C(N)N=C3N)C=CC=C1)(=O)=O FWEFPHCXXXKAKG-UHFFFAOYSA-N 0.000 claims 6
- HYMPCJMYTQXVMB-UHFFFAOYSA-N CSC(C=CC=C1)=C1N(C=C1)C2=C1N=C(N)N=C2N Chemical class CSC(C=CC=C1)=C1N(C=C1)C2=C1N=C(N)N=C2N HYMPCJMYTQXVMB-UHFFFAOYSA-N 0.000 claims 6
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims 6
- MRYYJGQKVGZGSB-UHFFFAOYSA-N 1-methyl-4-piperidin-4-ylpiperazine Chemical class C1CN(C)CCN1C1CCNCC1 MRYYJGQKVGZGSB-UHFFFAOYSA-N 0.000 claims 4
- PKVBGLXWHVWKSE-UHFFFAOYSA-N 4-[[5-methyl-4-(2-methylsulfanylanilino)pyrrolo[3,2-d]pyrimidin-2-yl]amino]benzenesulfonamide Chemical class CN1C=CC=2N=C(N=C(C=21)NC1=C(C=CC=C1)SC)NC1=CC=C(C=C1)S(=O)(=O)N PKVBGLXWHVWKSE-UHFFFAOYSA-N 0.000 claims 4
- IMCQIJWKVSVKKG-UHFFFAOYSA-N NS(=O)(=O)C1=CC=C(C=C1)C=1C2=C(N=C(N=1)N)C=CN2 Chemical compound NS(=O)(=O)C1=CC=C(C=C1)C=1C2=C(N=C(N=1)N)C=CN2 IMCQIJWKVSVKKG-UHFFFAOYSA-N 0.000 claims 4
- UJYCFKXEXYUSKY-UHFFFAOYSA-N S(=O)(=O)(C)C1=C(CC2=NCC=C2)C=CC=C1 Chemical class S(=O)(=O)(C)C1=C(CC2=NCC=C2)C=CC=C1 UJYCFKXEXYUSKY-UHFFFAOYSA-N 0.000 claims 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 3
- HBWGDGHGYGHWKD-UHFFFAOYSA-N 1-methyl-4-pyridin-3-ylpiperazine Chemical compound C1CN(C)CCN1C1=CC=CN=C1 HBWGDGHGYGHWKD-UHFFFAOYSA-N 0.000 claims 2
- ZOAMZFNAPHWBEN-UHFFFAOYSA-N 2-$l^{1}-oxidanylpropane Chemical compound CC(C)[O] ZOAMZFNAPHWBEN-UHFFFAOYSA-N 0.000 claims 2
- YAMSVLWOGCBDCA-UHFFFAOYSA-N 2-methyl-5h-pyrrolo[3,2-d]pyrimidine Chemical compound CC1=NC=C2NC=CC2=N1 YAMSVLWOGCBDCA-UHFFFAOYSA-N 0.000 claims 2
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Landscapes
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Abstract
本发明涉及一种下面通式I表示的化合物、其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其制备方法、含有它的药用组合物及其在制备预防和治疗肿瘤的药物中的用途,其中所述取代基定义见说明书。
Description
技术领域
本发明涉及药物化学领域,具体地,涉及一类具有ALK和/或c-Met选择性抑制活性的化合物,其制备方法、包含该化合物的药物组合物,以及这些化合物在制备用于预防或治疗与生物体内渐变性淋巴瘤酶相关的疾病的药物中的用途,以及在制备用于预防或治疗与血管新生或癌转移相关的疾病的药物中的用途,尤其是在制备用于预防或治疗肿瘤生长与转移的药物中的用途。
背景技术
渐变性淋巴瘤酶(ALK)是一种受体酪氨酸激酶,隶属于胰岛素受体超家族。蛋白结构从N端到C端依次为胞外受体结构域、跨膜区和胞内酪氨酸激酶结构域。正常的ALK蛋白主要在中枢神经和末梢神经系统中表达,人体中ALK基因的表达水平随脑部发育程度呈现下降趋势,尤其在成熟脑组织中的量很少。而在其他系统尤其是造血体统中尚未发现ALK的表达,证明其表达和分布具有一定的区域性。
正常情况下,人源的ALK基因可以编码1602个氨基酸、200kDa的I型穿膜蛋白ALK,但该基因通常处于休眠状态。在与其他基因发生融合的情况下,ALK基因可以成为非常强力的致癌基因。目前已经发现的可以与ALK基因发生融合的基因有核磷蛋白基因(NPM,渐变性大细胞淋巴瘤ALCL),棘皮动物微管相关蛋白样4基因(EML4,非小细胞肺癌NSCLC),原肌球蛋白3基因(TPM3,炎性肌纤维母细胞瘤IMT)等等(Nat.Rev.Cancer,2008,8,11-23.;Nat.Rev.Cancer,2013,13,685-700.;Expert Opin.Ther.Pat.,2014.24(4):p.417-42.)。
在非小细胞肺癌中,主要是与EML4基因发生融合,该融合基因(EML4-ALK)在NSCLC中的发生率为4%-7%。随着对非小细胞肺癌(NSCLC)在分子生物学上的研究不断深入,基于分子标记物(biomarker)的个性化治疗已经从实验室走向了临床,并在对晚期非小细胞肺癌患者的治疗上取得了较大的临床进展。这意味着除了对NSCLC可以进行传统的病理组织学分类外,还可以根据具体患者的不同分子标记物的不同表达水平进行分子表型分类。NSCLC患者在接受治疗前进行相关分子标记物检测。在临床上医生可以根据其肿瘤分子表型特征进行有针对性的治疗,从而提高治疗效果。在这样的背景下,以与肿瘤发生、发展密切相关的驱动基因或其编码蛋白为靶点研究开发新药物已经成为抗肿瘤药物研究的热点。
目前,美国食品和药物管理局已经批准辉瑞(Pfizer)公司开发的小分子抑制剂Crizotlnib(J.Thorac.Oncol.,2010.5(12):p.2044-6.)、诺华(Novartis)公司开发的Ceritinib(J.Med.Chem.,2013.56(14):p.5675-90.)上市,而Chugai PharmaceutlCal开发的Alectinib(Cancer Lett.,2014.351(2):p.215-21.)也在日本获批上市。但是,也有临床研究表明有部分患者对Crizotinib已经出现了耐药性,同时,Crizotinib的生物利用度也有待提高。Ceritinib可以针对对Crizotinib出现耐药性或不耐受的患者,而Alectinib仅在日本获批上市,在欧美地区仍处于临床试验阶段。因此,临床实践中非常需要它们的替代化合物。
发明内容
本发明发明人为了寻找新ALK抑制剂,经过广泛深入的研究,设计、合成了一系列结构新颖、安全性高、对多种酪氨酸激酶(EGFR、PDGFR、c-Met等),尤其是对ALK具有较高的活性的多取代嘧啶并吡咯(吡咯[3,2-d]嘧啶)衍生物,并且研究了这一类新型衍生物的抗肿瘤活性。
化合物的通式:
其中取代基和符号的定义下面详细说明。
本发明的一个目的是提供一类具有ALK和/或c-Met选择性抑制活性的化合物及其药学上可接受的盐或药学上可接受的溶剂合物;
本发明的另一个目的是提供一种上述化合物的制备方法;
本发明的另一个目的是提供一种包含上述化合物的药物组合物;
本发明的另一个目的是提供上述化合物在制备用于预防或治疗与生物体内渐变性淋巴瘤酶相关的伴随细胞异常增殖、形态变化以及运动功能亢进等的疾病的药物中的用途,以及在制备用于预防或治疗与血管新生或癌转移相关的疾病的药物中的用途,尤其是在制备用于预防或治疗肿瘤生长与转移的药物中的用途。
本发明是通过下面技术方案实现的。
一方面,本发明提供了一种下面通式I表示的化合物、其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,
其中:
R’为氢,氯或溴;
R1任选自:
1)C1-C6烷基,2-N,N-二甲基氨基乙基,2-羟基乙基,2-N,N-二乙基氨基乙基,2-N,N-二异丙基氨基乙基,2-吗啡啉基乙基,2-(4-N-甲基哌嗪基)乙基,3-N,N-二甲基氨基丙基,3-N,N-二乙基氨基丙基,3-N,N-二异丙基氨基丙基,3-吗啡啉基丙基,3-(4-N-甲基哌嗪)基丙基,4-N,N-二甲基氨基环己基,4-N,N-二乙基氨基环己基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,1,3-二甲基-5-吡唑基,1-甲基-4-吡唑基,3-甲基-5-异噁唑啉基,1-(N-甲基-4-哌啶基)-4-吡唑基,1-(N-叔丁氧甲酰基-4-哌啶基)-4-吡唑基;
2)其中Z1,Z2,Z3,Z4,Z5各自独立地任选自:
(1)氢,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,N-甲基-4-哌啶基,
(3)N,N-二甲基氨基,N,N-二乙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基氨基,2-吗啡啉基乙基氨基,2-(4-N-甲基哌嗪基)乙基氨基,3-N,N-二甲基氨基丙基氨基,3-N,N-二乙基氨基丙基氨基,3-N,N-二异丙基氨基丙基氨基,3-吗啡啉基丙基氨基,3-(4-N-甲基哌嗪基)丙基氨基,N-甲基哌啶-4-氨基,N-乙基哌啶-4-氨基,N-异丙基哌啶-4-氨基,
(4)2-N,N-二甲基氨基乙氧基,2-N,N-二乙基氨基乙氧基,2-N,N-二异丙基氨基乙氧基,2-(N-甲基哌嗪基)乙氧基,2-(N-乙酰基哌嗪基)乙氧基,2-吗啡啉基乙氧基,2-硫啡啉基乙氧基,2-哌啶基乙氧基,3-N,N-二甲基氨基丙氧基,3-N,N-二乙基氨基丙氧基,3-N,N-二异丙基氨基丙氧基,3-(N-甲基哌嗪基)丙氧基,3-(N-乙酰基哌嗪基)丙氧基,3-吗啡啉基丙氧基,3-硫啡啉基丙氧基,3-哌啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,单卤素取代苯基甲氧基,偕二卤素取代苯基甲氧基,杂二卤素取代苯基甲氧基,
(5)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,吗啡啉基,3,5-二甲基吗啡啉基,硫啡啉基,四氢吡咯基,3-N,N-二甲基四氢吡咯基,3-N,N-二乙基四氢吡咯基,N-甲基哌嗪基,N-乙基哌嗪基,N-异丙基哌嗪基,N-乙酰基哌嗪基,N-叔丁氧甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-(3-羟基丙基)哌嗪基,N-(2-N,N-二甲基乙基)哌嗪基,N-(2-N,N-二乙基乙基)哌嗪基,N-(3-N,N-二甲基丙基)哌嗪基,N-(3-N,N-二乙基丙基)哌嗪基,2-氧代-哌嗪-4-基,咪唑基,4-甲基咪唑基,
(6)4-(N-甲基哌嗪基)哌啶基,4-(N-乙基哌嗪基)哌啶基,4-(N-异丙基哌嗪基)哌啶基,4-(N-乙酰基哌嗪基)哌啶基,4-(N-叔丁氧甲酰基哌嗪基)哌啶基,4-(N-甲磺酰基哌嗪基)哌啶基,4-(N-(2-羟基乙基)哌嗪基)哌啶基,4-(N-(2-氰基乙基)哌嗪基)哌啶基,4-(N-(3-羟基丙基)哌嗪基)哌啶基,4-(N-(2-N,N-二甲基乙基)哌嗪基)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪基)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪基)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪基)哌啶基,4-(四氢吡咯基)哌啶基,4-(3-N,N-二甲基四氢吡咯基)哌啶基,N-(N-甲基-4-哌啶基)哌嗪基,N-(N-乙基-4-哌啶基)哌嗪基,
(7)羟基磺酰基,氨基磺酰基,甲胺基磺酰基,乙胺基磺酰基,丙胺基磺酰基,异丙胺基磺酰基,环丙基胺基磺酰基,环丁基胺基磺酰基,环戊基胺基磺酰基,哌啶基-1-磺酰基,4-羟基哌啶基-1-磺酰基,4-N,N-二甲基哌啶基-1-磺酰基,4-N,N-二乙基哌啶基-1-磺酰基,四氢吡咯基-1-磺酰基,3-N,N-二甲基四氢吡咯基-1-磺酰基,3-N,N-二乙基四氢吡咯基-1-磺酰基,N-甲基哌嗪基-1-磺酰基,N-乙基哌嗪基-1-磺酰基,N-乙酰基哌嗪基-1-磺酰基,N-叔丁氧甲酰基哌嗪基-1-磺酰基,N-(2-羟基乙基)哌嗪基-1-磺酰基,N-(2-氰基乙基)哌嗪基-1-磺酰基,N-(2-N,N-二甲基乙基)哌嗪基-1-磺酰基,N-(2-N,N-二乙基乙基)哌嗪基-1-磺酰基,N-(3-羟基丙基)哌嗪基-1-磺酰基,N-(3-N,N-二甲基丙基)哌嗪基-1-磺酰基,N-(3-N,N-二乙基丙基)哌嗪基-1-磺酰基,吗啡啉基-1-磺酰基,3,5-二甲基吗啡啉基-1-磺酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-磺酰基,N-(N-甲基-4-哌啶基)哌嗪基-1-磺酰基,
(8)羟基甲酰基,氨基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,哌啶基-1-甲酰基,4-羟基哌啶基-1-甲酰基,4-N,N-二甲基哌啶基-1-甲酰基,4-N,N-二乙基哌啶基-1-甲酰基,四氢吡咯基-1-甲酰基,3-N,N-二甲基四氢吡咯基-1-甲酰基,3-N,N-二乙基四氢吡咯基-1-甲酰基,N-甲基哌嗪基-1-甲酰基,N-乙基哌嗪基-1-甲酰基,N-乙酰基哌嗪基-1-甲酰基,N-叔丁氧甲酰基哌嗪基-1-甲酰基,N-(2-羟基乙基)哌嗪基-1-甲酰基,N-(2-氰基乙基)哌嗪基-1-甲酰基,N-(2-N,N-二甲基乙基)哌嗪基-1-甲酰基,N-(2-N,N-二乙基乙基)哌嗪基-1-甲酰基,N-(3-羟基丙基)哌嗪基-1-甲酰基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰基,吗啡啉基-1-甲酰基,3,5-二甲基吗啡啉基-1-甲酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰基,
(9)甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,
(10)氨基甲酰胺基,甲胺基甲酰胺基,乙胺基甲酰胺基,丙胺基甲酰胺基,异丙胺基甲酰胺基,环丙基胺基甲酰胺基,环丁基胺基甲酰胺基,环戊基胺基甲酰胺基,哌啶基-1-甲酰胺基,4-羟基哌啶基-1-甲酰胺基,4-N,N-二甲基哌啶基-1-甲酰胺基,4-N,N-二乙基哌啶基-1-甲酰胺基,四氢吡咯基-1-甲酰胺基,3-N,N-二甲基四氢吡咯基-1-甲酰胺基,3-N,N-二乙基四氢吡咯基-1-甲酰胺基,N-甲基哌嗪基-1-甲酰胺基,N-乙基哌嗪基-1-甲酰胺基,N-乙酰基哌嗪基-1-甲酰胺基,N-叔丁氧甲酰基哌嗪基-1-甲酰胺基,N-(2-羟基乙基)哌嗪基-1-甲酰胺基,N-(2-氰基乙基)哌嗪基-1-甲酰胺基,N-(2-N,N-二甲基乙基)哌嗪基-1-甲酰胺基,N-(2-N,N-二乙基乙基)哌嗪基-1-甲酰胺基,N-(3-羟基丙基)哌嗪基-1-甲酰胺基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰胺基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰胺基,吗啡啉基-1-甲酰胺基,3,5-二甲基吗啡啉基-1-甲酰胺基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰胺基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰胺基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰胺基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰胺基;或
(11)氨基乙酰胺基,N-叔丁氧甲酰基乙酰胺基,N-乙酰基氨基乙酰胺基,丙烯酰胺基,环丙酰胺基,氯乙酰胺基,哌啶基乙酰胺基,4-羟基哌啶基乙酰胺基,4-N,N-二甲基哌啶基乙酰胺基,4-N,N-二乙基哌啶基乙酰胺基,四氢吡咯基乙酰胺基,3-N,N-二甲基四氢吡咯基乙酰胺基,3-N,N-二乙基四氢吡咯基乙酰胺基,N-甲基哌嗪基乙酰胺基,N-乙基哌嗪基乙酰胺基,N-乙酰基哌嗪基乙酰胺基,N-叔丁氧甲酰基哌嗪基乙酰胺基,N-(2-羟基乙基)哌嗪基乙酰胺基,N-(2-氰基乙基)哌嗪基乙酰胺基,N-(2-N,N-二甲基乙基)哌嗪基乙酰胺基,N-(2-N,N-二乙基乙基)哌嗪基乙酰胺基,N-(3-羟基丙基)哌嗪基乙酰胺基,N-(3-N,N-二甲基丙基)哌嗪基乙酰胺基,N-(3-N,N-二乙基丙基)哌嗪基乙酰胺基,吗啡啉基乙酰胺基,3,5-二甲基吗啡啉基乙酰胺基,4-(N-甲基-1-哌嗪基)哌啶基乙酰胺基,4-(N-乙基-1-哌嗪基)哌啶基乙酰胺基,4-(N-乙酰基-1-哌嗪基)哌啶基乙酰胺基,N-(N-甲基-4-哌啶基)哌嗪基乙酰胺基,4-(四氢吡咯-1-基)哌啶基乙酰胺基;2-甲基氨基乙酰胺基,2-(1-甲基乙基)氨基乙酰胺基;N-苄氧基甲酰基-2甲基氨基乙酰胺基;
(12)Z2与Z3可以形成含氧的取代或未取代的五元环或六元环;取代基可以选自与Z1相同的上述取代基,
(13)Z2与Z3可以形成含氮的取代或未取代的五元环或六元环;取代基可以选自与Z1相同的上述取代基,
3)其中Z2,Z3,Z4,Z5与上述2)中定义相同;
4)其中Z1,Z3,Z4,Z5与上述2)中定义相同;
A为直接键或亚甲基;
X为直接键,NH,S或O原子;
R2任选自:
1)C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C6环烷基;
2)其中A1,A2,A3,A4,A5各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲硫基,乙硫基,异丙硫基,甲亚磺酰基,乙亚磺酰基,异丙亚磺酰基,甲磺酰基,乙磺酰基,异丙磺酰基,甲磺酰胺基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,二甲基次磷酰基,二乙基次磷酰基,二异丙基次磷酰基,
3)
其中,Y为NH,S或O原子,
A6,A7,A8,A9,A10,A11各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基;
4)
其中A12任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,甲基亚磺酰基,乙基亚磺酰基,异丙基亚磺酰基,甲基磺酰基,乙基磺酰基,异丙基磺酰基;
Y2,Y3,Y4选自以下组合:
Y2为N,Y3为N-A13,Y4为CH或N;
Y2为N,Y3为C-A13,Y4为N,O或S;
Y2为O或S,Y3为N-A13,Y4为CH;
Y2为O或S,Y3为C-A13,Y4为N;和
Y2为C,Y3为N-A13,Y4为O或S;
其中A13为氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C6环烷基;
5)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,吗啡啉基,3,5-二甲基吗啡啉基,硫啡啉基,四氢吡咯基,3-N,N-二甲基四氢吡咯基,3-N,N-二乙基四氢吡咯基,N-甲基哌嗪基,N-乙基哌嗪基,N-异丙基哌嗪基,N-乙酰基哌嗪基,N-叔丁氧甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-(3-羟基丙基)哌嗪基,N-(2-N,N-二甲基乙基)哌嗪基,N-(2-N,N-二乙基乙基)哌嗪基,N-(3-N,N-二甲基丙基)哌嗪基,N-(3-N,N-二乙基丙基)哌嗪基,
R3为氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,或C3-C6环烷基。
除非特殊说明,上述基团和取代基具有药物化学领域的普通含义。需要说明的是,含氧烷基是指烷基骨架的中间有一个或多个氧取代的基团,例如,甲氧基乙基,甲氧基乙氧基甲基。
按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物具有式II结构:
其中:
W为氧代,硫代,或氢,
n=0,或1,
R4,R5,R6各自独立地任选自:
(1)氢,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基;
R7任选自:
(1)氢,C1-C6烷基,乙酰基,丙酰基,正丁酰基,异丁酰基,
(2)氨基乙酰基,2-N,N-二甲基乙酰基,2-N,N-二乙基乙酰基,2-N,N-二异丙基乙酰基,哌啶基乙酰基,4-羟基哌啶基乙酰基,4-N,N-二甲基哌啶基乙酰基,4-N,N-二乙基哌啶基乙酰基,四氢吡咯基乙酰基,3-N,N-二甲基四氢吡咯基乙酰基,3-N,N-二乙基四氢吡咯基乙酰基,N-甲基哌嗪基乙酰基,N-乙基哌嗪基乙酰基,N-乙酰基哌嗪基乙酰基,N-叔丁氧甲酰基哌嗪基乙酰基,N-(2-羟基乙基)哌嗪基乙酰基,N-(2-氰基乙基)哌嗪基乙酰基,N-(2-N,N-二甲基乙基)哌嗪基乙酰基,N-(2-N,N-二乙基乙基)哌嗪基乙酰基,N-(3-羟基丙基)哌嗪基乙酰基,N-(3-N,N-二甲基丙基)哌嗪基乙酰基,N-(3-N,N-二乙基丙基)哌嗪基乙酰基,吗啡啉基乙酰基,3,5-二甲基吗啡啉基乙酰基,4-(N-甲基-1-哌嗪基)哌啶基乙酰基,4-(N-乙基-1-哌嗪基)哌啶基乙酰基,4-(N-乙酰基-1-哌嗪基)哌啶基乙酰基,N-(N-甲基-4-哌啶基)哌嗪基乙酰基;
A,X,R2,R3与上述技术方案中定义相同。
按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物具有式III结构:
其中:
X,R1,R2,R3与通式I结构的化合物中定义相同。相当于通式I结构表示的化合物中A为直接键,R’为氢。
按照本发明的一种具体技术方案,所述的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物具有式IV结构:
其中:
R1,R3与通式I结构的化合物中定义相同,
R2任选自:
1)C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C6环烷基,
2)其中A1,A2,A3,A4,A5各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲硫基,乙硫基,异丙基硫基,甲亚磺酰基,乙亚磺酰基,异丙亚磺酰基,甲磺酰基,乙磺酰基,异丙磺酰基,甲磺酰胺基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,二甲基次磷酰基,二乙基次磷酰基,二异丙基次磷酰基,
3)其中A6,A7,A8,A9,A10,A11各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基。
按照本发明的一种具体技术方案,所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物,
其中优选下面至少一项:
(1)R1中Z1选自甲氧基、乙氧基、异丙氧基或三氟甲氧基,和/或Z3选自4-N,N-二甲基氨基哌啶基、4-羟基哌啶基、吗啡啉基、四氢吡咯基、3-N,N-二甲基四氢吡咯基、N-甲基哌嗪基、N-乙基哌嗪基、N-乙酰基哌嗪基、N-(2-羟基乙基)哌嗪基、N-(2-氰基乙基)哌嗪基、N-(3-羟基丙基)哌嗪基、4-(N-甲基哌嗪基)哌啶基、4-(N-乙基哌嗪基)哌啶基、4-(N-乙酰基哌嗪基)哌啶基、4-(N-叔丁氧甲酰基哌嗪基)哌啶基、4-(N-(2-羟基乙基)哌嗪基)哌啶基、4-(N-(2-氰基乙基)哌嗪基)哌啶基、4-(四氢吡咯基)哌啶基、N-(N-甲基-4-哌啶基)哌嗪基、N-(N-乙基-4-哌啶基)哌嗪基、氨基磺酰基、甲胺基磺酰基、环丙基胺基磺酰基、哌啶基-1-磺酰基、4-羟基哌啶基-1-磺酰基、4-N,N-二甲基哌啶基-1-磺酰基、四氢吡咯基-1-磺酰基、3-N,N-二甲基四氢吡咯基-1-磺酰基、N-甲基哌嗪基-1-磺酰基、N-乙基哌嗪基-1-磺酰基、吗啡啉基-1-磺酰基、甲酸基、氨基甲酰基、甲胺基甲酰基、乙胺基甲酰基、异丙胺基甲酰基、环丙基胺基甲酰基、哌啶基-1-甲酰基、4-羟基哌啶基-1-甲酰基、4-N,N-二甲基哌啶基-1-甲酰基、四氢吡咯基-1-甲酰基、3-N,N-二甲基四氢吡咯基-1-甲酰基、N-甲基哌嗪基-1-甲酰基、N-乙基哌嗪基-1-甲酰基、N-乙酰基哌嗪基-1-甲酰基、吗啡啉基-1-甲酰基、4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基、4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基、4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰基、N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰基;
(2)R2选自2-甲磺酰基苯基、2-乙磺酰基苯基、2-异丙磺酰基苯基、2-甲磺酰胺基苯基或2-二甲基次磷酰基苯基;
(3)R3选自氢或甲基;
(4)化合物为药学上可接受的盐,其中所述药学上可接受的盐为无机酸盐或有机酸盐,其中,所述无机酸盐为盐酸盐、氢溴酸盐、硝酸盐、硫酸盐或磷酸盐,所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、烷基磺酸盐或芳基磺酸盐;优选地,所述烷基磺酸盐为甲基磺酸盐或乙基磺酸盐;所述芳基磺酸盐为苯磺酸盐或对甲苯磺酸盐。
按照本发明的一种具体技术方案,所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物,其中所述化合物为下面实施例中所述化合物之一。
另一方面,本发明提供了一种药物组合物,其包含上述任一技术方案所述的化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物,和药学上可接受的载体、稀释剂或赋形剂。
另一方面,本发明还提供了一种上述任一技术方案所述化合物的制备方法,包括下面步骤:
该反应的起始原料可以市购得到。
反应条件:(a)碱性条件(如二异丙基乙基胺,三乙胺,碳酸钾等)或酸性条件(三氟乙酸,盐酸等)的取代反应;(b)酸性条件(三氟乙酸,盐酸等)或钯催化的胺化反应;或者
反应条件:(a)卤代烷,碱性条件(NaH等)取代反应或硫酸二甲酯的甲基化;(b)碱性条件(如二异丙基乙基胺,三乙胺,碳酸钾等)或酸性条件(三氟乙酸,盐酸等)的取代反应;(c)酸性条件(三氟乙酸,盐酸等)或钯催化的胺化反应。
另一方面,本发明还提供了一种上述任一技术方案所述化合物、其立体异构体、其前药、或者其药学上可接受的盐或药学上可接受的溶剂合物在制备预防和治疗肿瘤的药物中的用途。优选地,其中所述肿瘤为渐变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌、成神经母细胞瘤、小细胞肺癌、肺腺癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴瘤、鼻咽癌中的任意一种;更优选地,其中所述肿瘤为渐变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌或成神经母细胞瘤。
具体实施方式
下面通过具体实施例详细描述本发明的实施方式,但是无论如何它们不能解释为对本发明的限制。
上述通式化合物分成几类合成制备。
化合物I的通式
实施例1
化合物IA的合成通式
化合物3的制备
将化合物1(200mg,1.06mmol)、化合物2(163mg,1.17mmol)溶于10mL叔丁醇中,再向该溶液中加入三氟乙酸(0.393mL,5.3mmol)。所得反应液置于预热至100℃的油浴中加热搅拌,至化合物1反应完全(LC-MS和TLC跟踪)。停止反应,向反应液中加饱和碳酸氢钠溶液并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(石油醚/乙酸乙酯=1/2)得化合物3(白色固体,147.3mg,产率为47.8%),直接用于下一步反应。
MS(ESI)m/z:291[M+H]+.
化合物IA的制备
方法A:
将化合物3(18.3mg,0.063mmol)、芳胺(0.044mmol)溶于1mL叔丁醇中,再向该溶液中加入三氟乙酸(23.4μL,0.32mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS和TLC跟踪)。停止反应,将反应液中加饱和碳酸氢钠溶液并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇)得化合物IA。
方法B:
将化合物3(18.3mg,0.063mmol)、芳胺(0.044mmol)溶于1mL叔丁醇中,再向该溶液中加入三氟乙酸(23.4μL,0.32mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS和TLC跟踪)。停止反应,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IA。
化合物IB、IC、ID、IE、IF均可使用类似的方法合成。
下表列出了具体化合物及结构鉴定数据。
表1.化合物IA-IF结构及表征
实施例2
化合物IG的合成通式
化合物4的制备
将化合物1(435mg,2.3mmol)、邻氨基苯甲酸甲酯(419mg,2.7mmol)溶于10ml叔丁醇中,再向该溶液中加入三氟乙酸(0.256mL,3.45mmol)。所得反应液置于预热至85℃的油浴中加热搅拌,至化合物1反应完全(LC-MS跟踪)。停止反应,将反应液中加饱和碳酸氢钠溶液40mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇=1/25)得化合物4(白色固体,424mg,产率为61%),直接用于下一步反应。
MS(ESI)m/z:303[M+H]+.
化合物IG的制备
方法A:
将化合物4(30.3mg,0.1mmol)、芳胺(0.1mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(45μL,0.6mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,将反应液中加饱和碳酸氢钠溶液10mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇)得化合物IH。
方法B:
将化合物4(10.0mg,0.03mmol)、芳胺(0.03mmol)溶于1ml叔丁醇中,再向该溶液中加入4N HCl溶液(16.5μL)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IH。
方法C:
将化合物4(25.0mg,0.08mmol)、芳胺(0.08mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(36.8μL,0.24mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IH。
化合物IH、II、IJ、IK均可使用类似方法合成。
表2.化合物IG-IK结构及表征
实施例3
化合物IL的合成通式
化合物5的制备
将化合物1(170mg,1.11mmol)、2-甲硫基苄胺(224mg,1.11mmol)溶于10mL叔丁醇中,再向该溶液中加入N,N-二异丙基乙胺(0.55mL,3.33mmol)。所得反应液置于预热至120℃的油浴中加热搅拌,至化合物1反应完全(LC-MS跟踪)。停止反应,将反应液浓缩,硅胶柱层析(乙酸乙酯/石油醚=2/5)得化合物5(白色固体,238mg,产率为70%),直接用于下一步反应。
MS(ESI)m/z:305[M+H]+.
化合物IL的制备
方法A:
将化合物5(45mg,0.15mmol)、芳胺(0.12mmol)溶于2mL仲丁醇中,再向该溶液中加入三氟乙酸(56μL,0.75mmol)。所得反应液置于预热至120℃的油浴中加热搅拌,至化合物5反应完全(LC-MS跟踪)。停止反应,向反应液中加饱和碳酸氢钠溶液10mL,二氯甲烷50mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩,硅胶柱层析(二氯甲烷/甲醇=5/2),得化合物IL。
方法B:
将化合物5(59mg,0.19mmol)、芳胺(0.15mmol)溶于2ml仲丁醇中,再向该溶液中加入三氟乙酸(70μL,0.95mmol)。所得反应液置于微波反应器,120℃反应2小时。停止反应,向反应液中加饱和碳酸氢钠溶液10mL,二氯甲烷50mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IL。
方法C:
将化合物5(45mg,0.15mmol)、芳胺(0.12mmol)溶于2ml仲丁醇中,再向该溶液中加入三氟乙酸(56μL,0.75mmol)。所得反应液置于预热至120℃的油浴中加热搅拌,至化合物2反应完全(LC-MS跟踪)。停止反应,向反应液中加饱和碳酸氢钠溶液10mL,二氯甲烷50mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),真空浓缩得化合物IL。
化合物IM、IN、IO、IP均可使用类似方法合成。
表3.化合物IL-IP结构及表征
实施例4
化合物IQ的合成通式
化合物6的制备
将化合物1(200mg,1.06mmol)、甲胺(33%wt IN EtOH,2.34mmol)溶于4ml叔丁醇中。所得反应液置于预热至45℃的油浴中加热搅拌,至化合物1反应完全(LC-MS跟踪),浓缩,硅胶柱层析(二氯甲烷/甲醇=50/1)得化合物6(黄色固体,165mg,产率为85.2%),直接用于下一步反应。
MS(ESI)m/z:183[M+H]+.
化合物IQ的制备
将化合物6(15.0mg,0.08mmol)、芳胺(0.08mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(36.7μL,0.49mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,将反应液中加饱和碳酸氢钠溶液10mL,二氯甲烷50mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇)得化合物IQ。
化合物IR、IS、IT均使用类似方法合成。
表4.化合物IQ-IT结构及表征
实施例5
化合物IU的合成通式
化合物7的制备
将化合物1(200mg,1.06mmol)、硫代水杨酸甲酯(179mg,1.06mmol)溶于4ml 1,4-二氧六环中,再向该溶液中加入N,N-二异丙基乙胺(0.35mL,2.12mmol)。所得反应液置于预热至50℃的油浴中加热搅拌,反应10h停止反应,向反应液中加饱和氯化钠溶液40mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇=50/1)得化合物7(黄色固体,299.6mg,产率为88.4%),直接用于下一步反应。
MS(ESI)m/z:320[M+H]+.
化合物IU的制备
方法A:
将化合物7(20.0mg,0.06mmol)、芳胺(0.06mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(14μL,0.18mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,反应36h,停止反应,将反应液中加饱和碳酸氢钠溶液10mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇)得化合物IU。
方法B:
将化合物7(20.0mg,0.06mmol)、芳胺(0.06mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(14μL,0.18mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,反应36h,停止反应,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IU。
表5.化合物IU结构及表征
实施例6
化合物IV的合成通式
化合物8的制备
在冰浴下,将氢化钠(480mg,20mmol,60%)、化合物1(940mg,5mmol)加于10ml干燥二氯甲烷中,并在冰浴中搅拌半小时。再向所得反应液中加入Boc酸酐(1.29mL,6mmol)。所得反应液置于冰浴中搅拌,温度缓慢升至室温,反应4h停止反应,向反应液中加饱和氯化铵溶液40mL、二氯甲烷20mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩得化合物8(黄色固体,1.41g,产率为97.9%),直接用于下一步反应。
MS(ESI)m/z:289[M+H]+.
化合物9的制备
将化合物8(300mg,1.04mmol)、水杨酸甲酯(237.6mg,1.56mmol)溶于5ml DMF中,再向该溶液中加入碳酸铯(1.02g,3.12mmol)。所得反应液置于预热至60℃的油浴中加热搅拌,反应16h停止反应,向反应液中加饱和氯化钠溶液40mL、乙酸乙酯20mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇=50/1)得化合物9(黄色固体,65mg,产率为20.5%),直接用于下一步反应。
MS(ESI)m/z:304[M+H]+.
化合物IV的制备
将化合物9(15.0mg,0.05mmol)、芳胺(0.05mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(11μL,0.15mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,反应24h,停止反应,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IV。
表6.化合物IV结构及表征
2化合物II的通式
实施例7
化合物IIA的合成通式
化合物10的制备
将化合物1(100mg,0.53mmol)、碳酸铯(350mg,1.06mmol)溶于1mL DMF中,在氮气气氛下向该溶液中加入硫酸二甲酯(1mL)。所得反应液置于室温搅拌5h。停止反应,将反应液中缓慢加水50mL,待体系冷却后加入乙酸乙酯并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(石油醚/乙酸乙酯=2/1)得化合物10(白色固体,76.3mg,产率为70%),直接用于下一步反应。
MS(ESI)m/z:203[M+H]+.
化合物11的制备
将化合物10(101mg,0.5mmol)溶于N,N-二甲基甲酰胺中(4mL),在冰浴条件下加入氢化钠(60mg,2.5mmol)搅拌5-10mlN,然后加入2-甲硫基苯胺(69.6mg,0.5mmol),在室温下搅拌,反应过夜。直至化合物10反应完全(LC-MS和TLC跟踪)后停止反应。向体系中加入冰块淬灭氢化钠,加入乙酸乙酯并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(石油醚/乙酸乙酯=2/1)得化合物11(固体,64.7mg,产率为42.5%),直接用于下一步反应。
MS(ESI)m/z:305[M+H]+.
化合物IIA的制备
方法A:
将化合物11(30.0mg,0.09mmol)、芳胺(0.072mmol)溶于1mL叔丁醇中,再向该溶液中加入2-二环己基磷-2,4,6-三异丙基联苯(7.7mg,0.016mmol),三(二亚苄基丙酮)二钯(9.9mg,0.011mmol),碳酸钾(37mg,0.27mmol),在氮气的保护下,将所得反应液置于预热至120℃的油浴中加热搅拌,至芳胺反应完全(LC-MS和TLC跟踪)停止反应。向反应液中加甲醇和二氯甲烷,把体系过滤,直接浓缩硅胶柱层析(二氯甲烷/甲醇)得化合物IIA。
方法B:
将化合物11(30.0mg,0.09mmol)、芳胺(0.072mmol)溶于1mL叔丁醇中,再向该溶液中加入2-二环己基磷-2,4,6-三异丙基联苯(7.7mg,0.016mmol),三(二亚苄基丙酮)二钯(9.9mg,0.011mmol),碳酸钾(37mg,0.27mmol),在氮气的保护下,将所得反应液置于预热至120℃的油浴中加热搅拌,至芳胺反应完全(LC-MS和TLC跟踪)停止反应。向反应液中加甲醇和二氯甲烷,把体系过滤,直接浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IIA。
化合物IIB、IIC、IID、IIE、IIF均使用类似方法合成。
表7.化合物IIA-IIF结构及表征
实施例8
化合物IIG的合成通式
化合物12的制备
将化合物10(76.3mg,0.38mmol)、邻氨基苯甲酸甲酯(62.7mg,0.42mmol)溶于3ml叔丁醇中,再向该溶液中加入三氟乙酸(0.085mL,1.14mmol)。所得反应液置于预热至85℃的油浴中加热搅拌,至化合物10反应完全(LC-MS跟踪)。停止反应,将反应液中加饱和碳酸氢钠溶液40mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇=1/25)得化合物12(白色固体,43.2mg,产率为56.2%),直接用于下一步反应。
MS(ESI)m/z:317[M+H]+.
化合物IIG的制备
方法A:
将化合物12(20.0mg,0.06mmol)、芳胺(0.06mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(28μL,0.36mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,将反应液中加饱和碳酸氢钠溶液10mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩硅胶柱层析(二氯甲烷/甲醇)得化合物IIG。
方法B:
将化合物12(20.0mg,0.06mmol)、芳胺(0.06mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(28μL,0.36mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IIG。
化合物IIH使用类似方法合成。
表8.化合物IIG、IIH结构及表征
实施例9
化合物III的合成通式
化合物13的制备
将化合物10(66mg,0.33mmol)、2-甲硫基苄胺(50mg,0.33mmol)溶于2ml叔丁醇中,再向该溶液中加入N,N-二异丙基乙胺(0.74mL,4.47mmol)。所得反应液置于预热至120℃的油浴中加热搅拌,至化合物10反应完全(LC-MS跟踪)。停止反应,将反应液浓缩,硅胶柱层析(乙酸乙酯/石油醚=1/1)得化合物13(白色固体,60mg,产率为57%),直接用于下一步反应。
MS(ESI)m/z:319[M+H]+.
化合物III的制备
方法A:
将化合物13(20mg,0.06mmol)、芳胺(0.05mmol)溶于2ml叔丁醇中,再向该溶液中加入2-双环己基膦-2′,4′,6′-三异丙基联苯(9.6mg,0.05mmol),三(二亚苄基丙酮)二钯(5.1mg,0.01mmol),碳酸钾(24.8mg,0.18mmol),在N2保护条件下将所得反应液置于预热至120℃的油浴中加热搅拌,至化合物13反应完全(LC-MS跟踪)。停止反应,一段硅胶柱过滤,浓缩,硅胶柱层析(二氯甲烷/甲醇=20/3),得化合物III。
方法B:
将化合物13(20mg,0.06mmol)、芳胺(0.05mmol)溶于2ml叔丁醇中,再向该溶液中加入2-双环己基膦-2′,4′,6′-三异丙基联苯(9.6mg,0.05mmol),三(二亚苄基丙酮)二钯(5.1mg,0.01mmol),碳酸钾(24.8mg,0.18mmol),在N2保护条件下将所得反应液置于预热至120℃的油浴中加热搅拌,至化合物13反应完全(LC-MS跟踪)。停止反应,一段硅胶柱过滤,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物III。
化合物IIJ、IIK、IIL均使用类似方法制备。
表9.化合物III-IIL结构及表征
实施例10
化合物IIM的合成通式
化合物14的制备
将化合物10(150mg,0.74mmol)、2,6-二氯苄胺(130mg,0.74mmol)溶于5ml DMF中,再向该溶液中加入碳酸钾(308mg,2.23mmol)。所得反应液置于预热至60℃的油浴中加热搅拌,反应16h停止反应,向反应液中加饱和氯化钠溶液40mL、乙酸乙酯20mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩得化合物14(黄色固体,175.3mg,产率为74.3%),直接用于下一步反应。
MS(ESI)m/z:318[M+H]+.
化合物IIM的制备
方法A:
将化合物14(25.0mg,0.08mmol)、芳胺(0.08mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(35μL,0.47mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,向反应液中加饱和氯化钠溶液40mL、乙酸乙酯20mL并分液,有机相用饱和氯化钠溶液洗涤两次,无水硫酸钠干燥,浓缩、硅胶柱层析(二氯甲烷/甲醇=40/1)得化合物IIM。
方法B:
将化合物14(25.0mg,0.08mmol)、芳胺(0.08mmol)溶于1ml叔丁醇中,再向该溶液中加入三氟乙酸(35μL,0.47mmol)。所得反应液置于预热至110℃的油浴中加热搅拌,至芳胺反应完全(LC-MS跟踪)。停止反应,浓缩,经反相制备型HPLC纯化(以含0.35%三氟乙酸的水溶液和甲醇为流动相),经真空浓缩得化合物IIM。
表10.化合物IIM-IIN结构及表征
试验例
生物活性测试:
化合物对激酶稳转细胞系的生长抑制活性
化合物对激酶ALK的活性通过其抑制激酶稳转细胞系EML4-ALK-BaF3,EML4-ALK(L1196M)-BaF3,NPM-ALK-BaF3,和野生型BaF3的生长进行评价(Proc.Natl.Acad.Sci.USA.,2006,103,3153-8.)。激酶稳转的细胞系EML4-ALK-BaF3,EML4-ALK(L1196M)-BaF3和NPM-ALK-BaF3的生长依赖其激酶活性,化合物若能抑制激酶ALK自身活性或ALK信号通路的活性就能抑制其稳转BaF3细胞的生长。而野生型BaF3的细胞生长不依赖ALK和ALK信号通路的活性,测定化合物对野生型BaF3细胞的生长的影响可以评价其广谱毒性。因此化合物对野生型BaF3和激酶稳转的EML4-ALK-BaF3,EML4-ALK(L1196M)-BaF3,NPM-ALK-BaF3间IC50的比值越大表明具有更好的靶向性。
具体试验方法如下:
1)培养基:DMEM(Dulbecco′s modified eagle medium)或RPMI1640(含10%胎牛血清,100μg/mL氨苄青霉素,100μg/mL链霉素)。
2)试剂:MTS反应液(含2mg/mL的MTS[3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4磺苯基)-2H-四唑,内盐](3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt);100μg/mL的PES(phenazine methosulfate))。
3)化合物测试:将激酶稳转的细胞(EML4-ALK-BaF3,或EML4-ALK(L1196M)-BaF3或NPM-ALK-BaF3)(2×104个/孔)接入96-孔培养板,细胞液体积为90μL,然后加入各梯度浓度化合物10μL(最高浓度为10μM,依次按1/3逐级稀释,共设置8个浓度点,体系中含0.1%DMSO(二甲基亚砜))。混匀化合物的细胞板置于细胞培养箱中(37℃;5%CO2)培养48h,再加入20μL的MTS反应液,混匀后置于细胞培养箱中(37℃;5%CO2)孵育1-4hr;采用酶标仪(VARIOSKAN FLASH,Thermo)测量490nm波长下的OD值。每组实验设置三个平行,以终浓度为0.1%DMSO为阴性对照,以不含细胞及化合物的培养基为空白对照。细胞生长抑制率由如下公式计算:
细胞抑制率%=1-(OD实验组-OD空白组)/(OD阴性组-OD空白组)*100%
4)IC50值计算:根据测量的细胞抑制率利用GradPad Prism 5软件计算化合物作用于细胞的半抑制浓度。
表11.化合物I系列对激酶稳转细胞系的生长抑制活性
*Crizotinib(克唑替尼)做为阳性对照,ND指未测定。
表12.化合物II系列对激酶稳转细胞系的生长抑制活性
*Crizotinib(克唑替尼)做为阳性对照,ND指未测定。
由以上活性数据可以看出,对于活性较好的化合物如ID-3,II-5,IID-2,IIL-2,均具有较好的靶向选择性。
化合物对肿瘤细胞的生长抑制活性
若测试的肿瘤细胞为悬浮细胞,参照上述(1)的方法进行测定。
若测试的肿瘤细胞为贴壁细胞,以1000-10000细胞/孔加入96-孔培养板中,孵育至贴壁后加化合物。其它参照上述(1)的方法进行。
化合物ID-3对肺癌细胞H3122,A549,DFCI076(克唑替尼耐药肿瘤细胞株),黑色素瘤A375,肝癌HepG2,乳腺癌MCF7均有较好的生长抑制活性,其中对激酶ALK阳性的肺癌细胞株H3122和DFCI076最为敏感。
表13.化合物ID-3对肿瘤细胞的生长抑制活性
以上所述的仅是本发明的一些实施方式。对于本领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。
Claims (12)
1.一种下面通式I表示的化合物、其立体异构体或其药学上可接受的盐,
其中:
R’为氢,氯或溴;
R1任选自:
1)C1-C6烷基,2-N,N-二甲基氨基乙基,2-羟基乙基,2-N,N-二乙基氨基乙基,2-N,N-二异丙基氨基乙基,2-吗啡啉基乙基,2-(4-N-甲基哌嗪基)乙基,3-N,N-二甲基氨基丙基,3-N,N-二乙基氨基丙基,3-N,N-二异丙基氨基丙基,3-吗啡啉基丙基,3-(4-N-甲基哌嗪)基丙基,4-N,N-二甲基氨基环己基,4-N,N-二乙基氨基环己基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,1,3-二甲基-5-吡唑基,1-甲基-4-吡唑基,3-甲基-5-异噁唑啉基,1-(N-甲基-4-哌啶基)-4-吡唑基,1-(N-叔丁氧甲酰基-4-哌啶基)-4-吡唑基;
2)其中Z1,Z2,Z3,Z4,Z5各自独立地任选自:
(1)氢,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,N-甲基-4-哌啶基,
(3)N,N-二甲基氨基,N,N-二乙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基氨基,2-吗啡啉基乙基氨基,2-(4-N-甲基哌嗪基)乙基氨基,3-N,N-二甲基氨基丙基氨基,3-N,N-二乙基氨基丙基氨基,3-N,N-二异丙基氨基丙基氨基,3-吗啡啉基丙基氨基,3-(4-N-甲基哌嗪基)丙基氨基,N-甲基哌啶-4-氨基,N-乙基哌啶-4-氨基,N-异丙基哌啶-4-氨基,
(4)2-N,N-二甲基氨基乙氧基,2-N,N-二乙基氨基乙氧基,2-N,N-二异丙基氨基乙氧基,2-(N-甲基哌嗪基)乙氧基,2-(N-乙酰基哌嗪基)乙氧基,2-吗啡啉基乙氧基,2-硫啡啉基乙氧基,2-哌啶基乙氧基,3-N,N-二甲基氨基丙氧基,3-N,N-二乙基氨基丙氧基,3-N,N-二异丙基氨基丙氧基,3-(N-甲基哌嗪基)丙氧基,3-(N-乙酰基哌嗪基)丙氧基,3-吗啡啉基丙氧基,3-硫啡啉基丙氧基,3-哌啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,单卤素取代苯基甲氧基,偕二卤素取代苯基甲氧基,杂二卤素取代苯基甲氧基,
(5)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,吗啡啉基,3,5-二甲基吗啡啉基,硫啡啉基,四氢吡咯基,3-N,N-二甲基四氢吡咯基,3-N,N-二乙基四氢吡咯基,N-甲基哌嗪基,N-乙基哌嗪基,N-异丙基哌嗪基,N-乙酰基哌嗪基,N-叔丁氧甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-(3-羟基丙基)哌嗪基,N-(2-N,N-二甲基乙基)哌嗪基,N-(2-N,N-二乙基乙基)哌嗪基,N-(3-N,N-二甲基丙基)哌嗪基,N-(3-N,N-二乙基丙基)哌嗪基,2-氧代-哌嗪-4-基,咪唑基,4-甲基咪唑基,
(6)4-(N-甲基哌嗪基)哌啶基,4-(N-乙基哌嗪基)哌啶基,4-(N-异丙基哌嗪基)哌啶基,4-(N-乙酰基哌嗪基)哌啶基,4-(N-叔丁氧甲酰基哌嗪基)哌啶基,4-(N-甲磺酰基哌嗪基)哌啶基,4-(N-(2-羟基乙基)哌嗪基)哌啶基,4-(N-(2-氰基乙基)哌嗪基)哌啶基,4-(N-(3-羟基丙基)哌嗪基)哌啶基,4-(N-(2-N,N-二甲基乙基)哌嗪基)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪基)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪基)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪基)哌啶基,4-(四氢吡咯基)哌啶基,4-(3-N,N-二甲基四氢吡咯基)哌啶基,N-(N-甲基-4-哌啶基)哌嗪基,N-(N-乙基-4-哌啶基)哌嗪基,
(7)羟基磺酰基,氨基磺酰基,甲胺基磺酰基,乙胺基磺酰基,丙胺基磺酰基,异丙胺基磺酰基,环丙基胺基磺酰基,环丁基胺基磺酰基,环戊基胺基磺酰基,哌啶基-1-磺酰基,4-羟基哌啶基-1-磺酰基,4-N,N-二甲基哌啶基-1-磺酰基,4-N,N-二乙基哌啶基-1-磺酰基,四氢吡咯基-1-磺酰基,3-N,N-二甲基四氢吡咯基-1-磺酰基,3-N,N-二乙基四氢吡咯基-1-磺酰基,N-甲基哌嗪基-1-磺酰基,N-乙基哌嗪基-1-磺酰基,N-乙酰基哌嗪基-1-磺酰基,N-叔丁氧甲酰基哌嗪基-1-磺酰基,N-(2-羟基乙基)哌嗪基-1-磺酰基,N-(2-氰基乙基)哌嗪基-1-磺酰基,N-(2-N,N-二甲基乙基)哌嗪基-1-磺酰基,N-(2-N,N-二乙基乙基)哌嗪基-1-磺酰基,N-(3-羟基丙基)哌嗪基-1-磺酰基,N-(3-N,N-二甲基丙基)哌嗪基-1-磺酰基,N-(3-N,N-二乙基丙基)哌嗪基-1-磺酰基,吗啡啉基-1-磺酰基,3,5-二甲基吗啡啉基-1-磺酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-磺酰基,N-(N-甲基-4-哌啶基)哌嗪基-1-磺酰基,
(8)羟基甲酰基,氨基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,哌啶基-1-甲酰基,4-羟基哌啶基-1-甲酰基,4-N,N-二甲基哌啶基-1-甲酰基,4-N,N-二乙基哌啶基-1-甲酰基,四氢吡咯基-1-甲酰基,3-N,N-二甲基四氢吡咯基-1-甲酰基,3-N,N-二乙基四氢吡咯基-1-甲酰基,N-甲基哌嗪基-1-甲酰基,N-乙基哌嗪基-1-甲酰基,N-乙酰基哌嗪基-1-甲酰基,N-叔丁氧甲酰基哌嗪基-1-甲酰基,N-(2-羟基乙基)哌嗪基-1-甲酰基,N-(2-氰基乙基)哌嗪基-1-甲酰基,N-(2-N,N-二甲基乙基)哌嗪基-1-甲酰基,N-(2-N,N-二乙基乙基)哌嗪基-1-甲酰基,N-(3-羟基丙基)哌嗪基-1-甲酰基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰基,吗啡啉基-1-甲酰基,3,5-二甲基吗啡啉基-1-甲酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰基,
(9)甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,
(10)氨基甲酰胺基,甲胺基甲酰胺基,乙胺基甲酰胺基,丙胺基甲酰胺基,异丙胺基甲酰胺基,环丙基胺基甲酰胺基,环丁基胺基甲酰胺基,环戊基胺基甲酰胺基,哌啶基-1-甲酰胺基,4-羟基哌啶基-1-甲酰胺基,4-N,N-二甲基哌啶基-1-甲酰胺基,4-N,N-二乙基哌啶基-1-甲酰胺基,四氢吡咯基-1-甲酰胺基,3-N,N-二甲基四氢吡咯基-1-甲酰胺基,3-N,N-二乙基四氢吡咯基-1-甲酰胺基,N-甲基哌嗪基-1-甲酰胺基,N-乙基哌嗪基-1-甲酰胺基,N-乙酰基哌嗪基-1-甲酰胺基,N-叔丁氧甲酰基哌嗪基-1-甲酰胺基,N-(2-羟基乙基)哌嗪基-1-甲酰胺基,N-(2-氰基乙基)哌嗪基-1-甲酰胺基,N-(2-N,N-二甲基乙基)哌嗪基-1-甲酰胺基,N-(2-N,N-二乙基乙基)哌嗪基-1-甲酰胺基,N-(3-羟基丙基)哌嗪基-1-甲酰胺基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰胺基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰胺基,吗啡啉基-1-甲酰胺基,3,5-二甲基吗啡啉基-1-甲酰胺基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰胺基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰胺基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰胺基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰胺基;或
(11)氨基乙酰胺基,N-叔丁氧甲酰基乙酰胺基,N-乙酰基氨基乙酰胺基,丙烯酰胺基,环丙酰胺基,氯乙酰胺基,哌啶基乙酰胺基,4-羟基哌啶基乙酰胺基,4-N,N-二甲基哌啶基乙酰胺基,4-N,N-二乙基哌啶基乙酰胺基,四氢吡咯基乙酰胺基,3-N,N-二甲基四氢吡咯基乙酰胺基,3-N,N-二乙基四氢吡咯基乙酰胺基,N-甲基哌嗪基乙酰胺基,N-乙基哌嗪基乙酰胺基,N-乙酰基哌嗪基乙酰胺基,N-叔丁氧甲酰基哌嗪基乙酰胺基,N-(2-羟基乙基)哌嗪基乙酰胺基,N-(2-氰基乙基)哌嗪基乙酰胺基,N-(2-N,N-二甲基乙基)哌嗪基乙酰胺基,N-(2-N,N-二乙基乙基)哌嗪基乙酰胺基,N-(3-羟基丙基)哌嗪基乙酰胺基,N-(3-N,N-二甲基丙基)哌嗪基乙酰胺基,N-(3-N,N-二乙基丙基)哌嗪基乙酰胺基,吗啡啉基乙酰胺基,3,5-二甲基吗啡啉基乙酰胺基,4-(N-甲基-1-哌嗪基)哌啶基乙酰胺基,4-(N-乙基-1-哌嗪基)哌啶基乙酰胺基,4-(N-乙酰基-1-哌嗪基)哌啶基乙酰胺基,N-(N-甲基-4-哌啶基)哌嗪基乙酰胺基,4-(四氢吡咯-1-基)哌啶基乙酰胺基;2-甲基氨基乙酰胺基,2-(1-甲基乙基)氨基乙酰胺基;N-苄氧基甲酰基-2甲基氨基乙酰胺基;
(12)Z2与Z3可以形成含氧的取代或未取代的五元环或六元环;取代基可以选自与Z1相同的上述取代基;
(13)Z2与Z3可以形成含氮的取代或未取代的五元环或六元环;取代基可以选自与Z1相同的上述取代基;
3)其中Z2,Z3,Z4,Z5与上述2)中定义相同;
4)其中Z1,Z3,Z4,Z5与上述2)中定义相同;
A为直接键或亚甲基;
X为NH,S或O原子;
R2任选自:
1)C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C6环烷基;
2)其中A1,A2,A3,A4,A5各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲硫基,乙硫基,异丙基硫基,甲亚磺酰基,乙亚磺酰基,异丙亚磺酰基,甲磺酰基,乙磺酰基,异丙磺酰基,甲磺酰胺基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,二甲基次磷酰基,二乙基次磷酰基,二异丙基次磷酰基,
3)
其中,Y为NH,S或O原子,
A6,A7,A8,A9,A10,A11各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基;
4)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,吗啡啉基,3,5-二甲基吗啡啉基,硫啡啉基,四氢吡咯基,3-N,N-二甲基四氢吡咯基,3-N,N-二乙基四氢吡咯基,N-甲基哌嗪基,N-乙基哌嗪基,N-异丙基哌嗪基,N-乙酰基哌嗪基,N-叔丁氧甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-(3-羟基丙基)哌嗪基,N-(2-N,N-二甲基乙基)哌嗪基,N-(2-N,N-二乙基乙基)哌嗪基,N-(3-N,N-二甲基丙基)哌嗪基,N-(3-N,N-二乙基丙基)哌嗪基,
R3为氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,或C3-C6环烷基。
2.根据权利要求1所述的化合物、其立体异构体或者其药学上可接受的盐,具有式II结构:
其中:
W为氧代,硫代,或氢,
n=0,或1,
R4,R5,R6各自独立地任选自:
(1)氢,氟,氯,溴,碘,硝基,氰基,
(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基;
R7任选自:
(1)氢,C1-C6烷基,乙酰基,丙酰基,正丁酰基,异丁酰基,
(2)氨基乙酰基,2-N,N-二甲基乙酰基,2-N,N-二乙基乙酰基,2-N,N-二异丙基乙酰基,哌啶基乙酰基,4-羟基哌啶基乙酰基,4-N,N-二甲基哌啶基乙酰基,4-N,N-二乙基哌啶基乙酰基,四氢吡咯基乙酰基,3-N,N-二甲基四氢吡咯基乙酰基,3-N,N-二乙基四氢吡咯基乙酰基,N-甲基哌嗪基乙酰基,N-乙基哌嗪基乙酰基,N-乙酰基哌嗪基乙酰基,N-叔丁氧甲酰基哌嗪基乙酰基,N-(2-羟基乙基)哌嗪基乙酰基,N-(2-氰基乙基)哌嗪基乙酰基,N-(2-N,N-二甲基乙基)哌嗪基乙酰基,N-(2-N,N-二乙基乙基)哌嗪基乙酰基,N-(3-羟基丙基)哌嗪基乙酰基,N-(3-N,N-二甲基丙基)哌嗪基乙酰基,N-(3-N,N-二乙基丙基)哌嗪基乙酰基,吗啡啉基乙酰基,3,5-二甲基吗啡啉基乙酰基,4-(N-甲基-1-哌嗪基)哌啶基乙酰基,4-(N-乙基-1-哌嗪基)哌啶基乙酰基,4-(N-乙酰基-1-哌嗪基)哌啶基乙酰基,N-(N-甲基-4-哌啶基)哌嗪基乙酰基;
A,X,R2,R3与权利要求1中定义相同。
3.根据权利要求1所述的化合物、其立体异构体或者其药学上可接受的盐,具有式III结构:
其中:
X,R1,R2,R3与权利要求1中定义相同。
4.根据权利要求1所述的化合物、其立体异构体或者其药学上可接受的盐,具有式IV结构:
其中:
R1,R3与权利要求1中定义相同,
R2任选自:
1)C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C6环烷基,
2)其中A1,A2,A3,A4,A5各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲硫基,乙硫基,异丙基硫基,甲亚磺酰基,乙亚磺酰基,异丙亚磺酰基,甲磺酰基,乙磺酰基,异丙磺酰基,甲磺酰胺基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,二甲基次磷酰基,二乙基次磷酰基,二异丙基次磷酰基,
3)其中A6,A7,A8,A9,A10,A11各自独立地任选自:
(1)氢,氟,氯,溴,碘,氰基,三氟甲基,三氟甲氧基,硝基,
(2)甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,甲胺基甲酰基,乙胺基甲酰基,丙胺基甲酰基,异丙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基。
5.根据权利要求1-4项任一所述化合物、其立体异构体或者其药学上可接受的盐,
其中任选下面至少一项:
(1)R1中Z1选自甲氧基、乙氧基、异丙氧基或三氟甲氧基,和/或Z3选自4-N,N-二甲基氨基哌啶基、4-羟基哌啶基、吗啡啉基、四氢吡咯基、3-N,N-二甲基四氢吡咯基、N-甲基哌嗪基、N-乙基哌嗪基、N-乙酰基哌嗪基、N-(2-羟基乙基)哌嗪基、N-(2-氰基乙基)哌嗪基、N-(3-羟基丙基)哌嗪基、4-(N-甲基哌嗪基)哌啶基、4-(N-乙基哌嗪基)哌啶基、4-(N-乙酰基哌嗪基)哌啶基、4-(N-叔丁氧甲酰基哌嗪基)哌啶基、4-(N-(2-羟基乙基)哌嗪基)哌啶基、4-(N-(2-氰基乙基)哌嗪基)哌啶基、4-(四氢吡咯基)哌啶基、N-(N-甲基-4-哌啶基)哌嗪基、N-(N-乙基-4-哌啶基)哌嗪基、氨基磺酰基、甲胺基磺酰基、环丙基胺基磺酰基、哌啶基-1-磺酰基、4-羟基哌啶基-1-磺酰基、4-N,N-二甲基哌啶基-1-磺酰基、四氢吡咯基-1-磺酰基、3-N,N-二甲基四氢吡咯基-1-磺酰基、N-甲基哌嗪基-1-磺酰基、N-乙基哌嗪基-1-磺酰基、吗啡啉基-1-磺酰基、甲酸基、氨基甲酰基、甲胺基甲酰基、乙胺基甲酰基、异丙胺基甲酰基、环丙基胺基甲酰基、哌啶基-1-甲酰基、4-羟基哌啶基-1-甲酰基、4-N,N-二甲基哌啶基-1-甲酰基、四氢吡咯基-1-甲酰基、3-N,N-二甲基四氢吡咯基-1-甲酰基、N-甲基哌嗪基-1-甲酰基、N-乙基哌嗪基-1-甲酰基、N-乙酰基哌嗪基-1-甲酰基、吗啡啉基-1-甲酰基、4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基、4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基、4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰基、N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰基;
(2)R2自选2-甲基磺酰基苯基、2-乙基磺酰基苯基、2-异丙基磺酰基苯基、2-甲基磺酰胺基苯基或2-二甲基次磷酰基苯基;
(3)R3选自氢或甲基;
(4)化合物为药学上可接受的盐,其中所述药学上可接受的盐为无机酸盐或有机酸盐,其中,所述无机酸盐为盐酸盐、氢溴酸盐、硝酸盐、硫酸盐或磷酸盐,所述有机酸盐为甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、烷基磺酸盐或芳基磺酸盐。
6.根据权利要求1所述化合物、其立体异构体或者其药学上可接受的盐,其中所述化合物为下列化合物之一:
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-异丙氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(吡啶-2-基甲氧基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(N,N-二甲基氨基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(6-(4-羟基哌啶-1-基)吡啶-3-基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(6-吗啡啉基吡啶-3-基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(N-(2-N,N-二甲基氨基乙酰基)-5-甲氧基吲哚啉-6-基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3,4二氢喹啉-2(1H)-酮-6-基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-三氟甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-丙烯酰胺基苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-吗啡啉基乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-(4-甲基哌嗪-1-基)乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-(4-(N,N-二甲基氨基)哌啶-1-基)乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-(4-(四氢吡咯-1-基)哌啶-1-基)乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(环丙基甲酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,N2-(3-胺基苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-叔丁氧基甲酰胺基乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-乙酰胺基乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(3-(2-胺基乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
(S)-N2-(3-(2-苄氧基甲酰胺基-2-甲基乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
(S)-N2-(3-(2-甲基-2-胺基乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
(S)-N2-(3-(2-异丙基-2-胺基乙酰胺基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰胺基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰胺基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-N4-(2-(甲磺酰胺基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰胺基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-吗啡啉苯基)-N4-(2-(甲磺酰胺基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-吗啡啉苯基)-N4-(2-(甲磺酰胺基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(N,N-二甲基氨基)哌啶-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-吗啡啉苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(吡啶-2-基甲氧基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-异丙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基磺酰基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-异丙氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-吗啡啉苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-吗啡啉甲酰基苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(6-(4-羟基哌啶-1-基)吡啶-3-基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-乙氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-吗啡啉苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(N-甲基胺基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(2-(N-甲基胺基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(N-甲基胺基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)噻吩-3-基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)噻吩-3-基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-吗啡啉甲酰基苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-溴-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-溴-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-溴-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-氯-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-氯-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-氯-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-溴-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-溴-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-溴-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-氯-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-氯-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
7-氯-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-4-吗啡啉基-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(4-(4-羟基哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(4-氨基磺酰基苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(4-(4-羟基哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(4-氨基磺酰基苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺;
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-异丙氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰胺基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-N4-(2-(二甲基次磷酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2,6-二氯苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,或
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(4-氨基磺酰基苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺。
7.根据权利要求6所述化合物、其立体异构体或者其药学上可接受的盐,其中所述化合物为下列化合物之一:
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-异丙氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-吗啡啉苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(吡啶-2-基甲氧基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-异丙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基磺酰基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-异丙氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-吗啡啉苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-吗啡啉甲酰基苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(6-(4-羟基哌啶-1-基)吡啶-3-基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(2-(异丁氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-吗啡啉苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(N-甲基胺基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-N4-(2-(N-甲基胺基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(N-甲基胺基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)噻吩-3-基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)噻吩-3-基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-吗啡啉甲酰基苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-甲基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-乙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-甲基哌嗪-1-基甲酰基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-(4-羟基哌啶-1-基)苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
N2-(4-氨基磺酰基苯基)-N4-环丙基-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(4-(4-羟基哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(4-氨基磺酰基苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)硫基)-N2-(2-甲氧基-4-(4-(四氢吡咯-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(4-(4-羟基哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-N2-(4-氨基磺酰基苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺;
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲硫基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-异丙氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-5-甲基-(4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙磺酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(3-(甲氧基甲酰基)苯基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(异丙硫基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基甲酰基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-乙氧基-4-(4-羟基哌啶-1-基)苯基)-N4-(2-(甲磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-氨基磺酰基苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
5-甲基-N2-(4-(4-甲基哌嗪-1-基)苯基)-N4-(2-(异丙磺酰基)苄基)-5H-吡咯并[3,2-d]嘧啶-2,4二胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(4-(4-羟基哌啶-1-基)苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺,或
4-((2-(甲氧基甲酰基)苯基)氧基)-5-甲基-N2-(4-氨基磺酰基苯基)-5H-吡咯并[3,2-d]嘧啶-2-胺。
8.一种药物组合物,其包含权利要求1-7任一项所述化合物、其立体异构体或者其药学上可接受的盐,和药学上可接受的载体、稀释剂或赋形剂。
9.一种权利要求1-7任一项所述化合物的制备方法,包括下面步骤:
反应条件:(a)碱性条件或酸性条件的取代反应;(b)酸性条件或钯催化的胺化反应;或者
反应条件:(a)卤代烷,碱性条件取代反应或硫酸二甲酯的甲基化;(b)碱性条件或酸性条件的取代反应;(c)酸性条件或钯催化的胺化反应。
10.根据权利要求1-7任一项所述化合物、其立体异构体或者其药学上可接受的盐在制备预防和治疗肿瘤的药物中的用途。
11.根据权利要求10所述的用途,其中所述肿瘤为渐变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌、成神经母细胞瘤、小细胞肺癌、肺腺癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴瘤、鼻咽癌中的任意一种。
12.根据权利要求11所述的用途,其中所述肿瘤为渐变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌或成神经母细胞瘤。
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CN107531725B (zh) * | 2015-08-13 | 2021-03-19 | 北京韩美药品有限公司 | Irak4抑制剂及其应用 |
CN108276410B (zh) * | 2017-01-06 | 2021-12-10 | 首药控股(北京)股份有限公司 | 一种间变性淋巴瘤激酶抑制剂及其制备方法和用途 |
CN107312006B (zh) * | 2017-06-28 | 2019-11-15 | 郑州大学第一附属医院 | 吡咯并嘧啶类衍生物及其应用 |
CN109384782A (zh) * | 2017-08-04 | 2019-02-26 | 厦门大学 | 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途 |
CN109575045B (zh) * | 2017-09-28 | 2021-02-12 | 南京红云生物科技有限公司 | 噻吩并嘧啶类化合物、其制备方法、药用组合物及其应用 |
KR101992621B1 (ko) * | 2017-12-07 | 2019-09-27 | 주식회사 온코빅스 | 암세포 성장 억제 효과를 나타내는 신규한 피리미딘 유도체 및 그를 포함하는 약제학적 조성물 |
WO2019112344A1 (ko) * | 2017-12-07 | 2019-06-13 | 주식회사 온코빅스 | 암세포 성장 억제 효과를 나타내는 신규한 피리미딘 유도체 및 그를 포함하는 약제학적 조성물 |
AU2019234574A1 (en) | 2018-03-12 | 2020-09-03 | Abbvie Inc. | Inhibitors of tyrosine kinase 2 mediated signaling |
CN110526914B (zh) * | 2018-05-25 | 2022-02-08 | 首药控股(北京)股份有限公司 | 一种alk抑制剂的多晶型物及其制备方法 |
KR102377007B1 (ko) * | 2018-09-20 | 2022-03-22 | 한미약품 주식회사 | 상피세포 성장인자 수용체 돌연변이 저해 효과를 갖는 신규 융합 피리미딘 골격 설폰아마이드 유도체 |
WO2020060268A1 (ko) * | 2018-09-20 | 2020-03-26 | 한미약품 주식회사 | 상피세포 성장인자 수용체 돌연변이 저해 효과를 갖는 신규 융합 피리미딘 골격 설폰아마이드 유도체 |
WO2020088390A1 (zh) * | 2018-10-29 | 2020-05-07 | 江苏先声药业有限公司 | 作为第四代egfr抑制剂的嘧啶吡唑类化合物 |
CN111170996B (zh) * | 2018-11-09 | 2021-12-28 | 天津大学 | 具有alk抑制活性的嘧啶衍生物及其合成方法和应用 |
CN113717156B (zh) * | 2020-05-25 | 2023-05-09 | 南京红云生物科技有限公司 | Egfr抑制剂、其制备方法及用途 |
CN114105887B (zh) * | 2021-09-16 | 2023-12-01 | 沈阳药科大学 | 一种氨基嘧啶衍生物及其制备方法和用途 |
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