CN101558046A - Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders - Google Patents
Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders Download PDFInfo
- Publication number
- CN101558046A CN101558046A CNA2007800392665A CN200780039266A CN101558046A CN 101558046 A CN101558046 A CN 101558046A CN A2007800392665 A CNA2007800392665 A CN A2007800392665A CN 200780039266 A CN200780039266 A CN 200780039266A CN 101558046 A CN101558046 A CN 101558046A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- amino
- halogen
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000002062 proliferating effect Effects 0.000 title abstract description 3
- DUIMWXDLDBNUFD-UHFFFAOYSA-N 4-pyrimidin-2-ylmorpholine Chemical class C1COCCN1C1=NC=CC=N1 DUIMWXDLDBNUFD-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 302
- 150000003839 salts Chemical class 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims abstract description 85
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 69
- 201000011510 cancer Diseases 0.000 claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- -1 heterocyclic radical Chemical class 0.000 claims description 533
- 229910052736 halogen Inorganic materials 0.000 claims description 335
- 150000002367 halogens Chemical class 0.000 claims description 334
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 219
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 153
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 151
- 239000001257 hydrogen Substances 0.000 claims description 134
- 229910052739 hydrogen Inorganic materials 0.000 claims description 134
- 150000003254 radicals Chemical group 0.000 claims description 134
- 125000002837 carbocyclic group Chemical group 0.000 claims description 122
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 118
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 108
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 99
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 78
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 69
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 68
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
- 229910052757 nitrogen Inorganic materials 0.000 claims description 52
- 239000003814 drug Substances 0.000 claims description 51
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 49
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 49
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 42
- 241001465754 Metazoa Species 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 229910052727 yttrium Inorganic materials 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- 125000004429 atom Chemical group 0.000 claims description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 19
- 125000001544 thienyl group Chemical group 0.000 claims description 19
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 125000002541 furyl group Chemical group 0.000 claims description 16
- 206010020718 hyperplasia Diseases 0.000 claims description 16
- 125000002883 imidazolyl group Chemical group 0.000 claims description 15
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 11
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- 230000001028 anti-proliverative effect Effects 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 8
- 208000018569 Respiratory Tract disease Diseases 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 230000000414 obstructive effect Effects 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 208000026278 immune system disease Diseases 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 4
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 claims description 4
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 4
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 108091007960 PI3Ks Proteins 0.000 abstract description 103
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 abstract description 63
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 abstract description 63
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 23
- 201000010099 disease Diseases 0.000 abstract description 18
- 230000008569 process Effects 0.000 abstract description 10
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 102000038030 PI3Ks Human genes 0.000 abstract description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 130
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 102
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 102
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 238000012360 testing method Methods 0.000 description 53
- 210000004027 cell Anatomy 0.000 description 50
- 239000002904 solvent Substances 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- 230000000694 effects Effects 0.000 description 47
- 150000003905 phosphatidylinositols Chemical class 0.000 description 44
- 229940067626 phosphatidylinositols Drugs 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- 239000012071 phase Substances 0.000 description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 35
- 239000000203 mixture Substances 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 239000002253 acid Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000003112 inhibitor Substances 0.000 description 18
- 230000005764 inhibitory process Effects 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 108091000080 Phosphotransferase Proteins 0.000 description 17
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 17
- 102000020233 phosphotransferase Human genes 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 16
- 150000001721 carbon Chemical group 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- 238000005516 engineering process Methods 0.000 description 16
- 239000002953 phosphate buffered saline Substances 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- 208000032839 leukemia Diseases 0.000 description 14
- 230000014759 maintenance of location Effects 0.000 description 14
- 238000006366 phosphorylation reaction Methods 0.000 description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 239000001301 oxygen Substances 0.000 description 13
- 230000026731 phosphorylation Effects 0.000 description 13
- 201000009030 Carcinoma Diseases 0.000 description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000012544 monitoring process Methods 0.000 description 12
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 230000008859 change Effects 0.000 description 11
- 238000013016 damping Methods 0.000 description 11
- 239000012530 fluid Substances 0.000 description 11
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
- 108091008611 Protein Kinase B Proteins 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 230000004913 activation Effects 0.000 description 10
- 239000011324 bead Substances 0.000 description 10
- 230000004663 cell proliferation Effects 0.000 description 10
- 229910052763 palladium Inorganic materials 0.000 description 10
- 230000002265 prevention Effects 0.000 description 10
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 10
- 229960002930 sirolimus Drugs 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 125000002524 organometallic group Chemical group 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
- 230000005284 excitation Effects 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 150000002902 organometallic compounds Chemical class 0.000 description 8
- 125000006239 protecting group Chemical class 0.000 description 8
- 206010006187 Breast cancer Diseases 0.000 description 7
- 206010009944 Colon cancer Diseases 0.000 description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 7
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 7
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 7
- 238000003016 alphascreen Methods 0.000 description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 description 7
- 201000010989 colorectal carcinoma Diseases 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 210000002751 lymph Anatomy 0.000 description 7
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 206010005003 Bladder cancer Diseases 0.000 description 6
- 206010005949 Bone cancer Diseases 0.000 description 6
- 208000018084 Bone neoplasm Diseases 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 6
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 6
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- 208000034578 Multiple myelomas Diseases 0.000 description 6
- 206010033128 Ovarian cancer Diseases 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 229920001213 Polysorbate 20 Polymers 0.000 description 6
- 206010060862 Prostate cancer Diseases 0.000 description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 6
- 102000001253 Protein Kinase Human genes 0.000 description 6
- 206010039491 Sarcoma Diseases 0.000 description 6
- 206010041067 Small cell lung cancer Diseases 0.000 description 6
- 208000033781 Thyroid carcinoma Diseases 0.000 description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
- 239000004327 boric acid Substances 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 208000006990 cholangiocarcinoma Diseases 0.000 description 6
- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 description 6
- 201000004101 esophageal cancer Diseases 0.000 description 6
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 208000014829 head and neck neoplasm Diseases 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 201000007270 liver cancer Diseases 0.000 description 6
- 208000014018 liver neoplasm Diseases 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 6
- 108060006633 protein kinase Proteins 0.000 description 6
- 208000029817 pulmonary adenocarcinoma in situ Diseases 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000012552 review Methods 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 201000000849 skin cancer Diseases 0.000 description 6
- 201000008261 skin carcinoma Diseases 0.000 description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 description 6
- 210000001550 testis Anatomy 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 201000002510 thyroid cancer Diseases 0.000 description 6
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 6
- 201000005112 urinary bladder cancer Diseases 0.000 description 6
- 208000012991 uterine carcinoma Diseases 0.000 description 6
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000005864 Sulphur Substances 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 5
- 229910052796 boron Inorganic materials 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- 229940123729 mTOR kinase inhibitor Drugs 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 208000003174 Brain Neoplasms Diseases 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 208000008770 Multiple Hamartoma Syndrome Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000003435 aroyl group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 210000000481 breast Anatomy 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 4
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 208000026037 malignant tumor of neck Diseases 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 4
- 125000005493 quinolyl group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 102000013275 Somatomedins Human genes 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000013467 fragmentation Methods 0.000 description 3
- 238000006062 fragmentation reaction Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 3
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- 201000007815 Bannayan-Riley-Ruvalcaba syndrome Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 201000002847 Cowden syndrome Diseases 0.000 description 2
- 102100034032 Cytohesin-3 Human genes 0.000 description 2
- 101710160297 Cytohesin-3 Proteins 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 102000009465 Growth Factor Receptors Human genes 0.000 description 2
- 108010009202 Growth Factor Receptors Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 101150097381 Mtor gene Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 239000012828 PI3K inhibitor Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 2
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 2
- 206010034764 Peutz-Jeghers syndrome Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 2
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 2
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 108010076089 accutase Proteins 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 2
- 230000006287 biotinylation Effects 0.000 description 2
- 238000007413 biotinylation Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000035605 chemotaxis Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000003750 conditioning effect Effects 0.000 description 2
- SFJMFSWCBVEHBA-UHFFFAOYSA-M copper(i)-thiophene-2-carboxylate Chemical compound [Cu+].[O-]C(=O)C1=CC=CS1 SFJMFSWCBVEHBA-UHFFFAOYSA-M 0.000 description 2
- 210000004292 cytoskeleton Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000009266 disease activity Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 125000005241 heteroarylamino group Chemical group 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 229940124302 mTOR inhibitor Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 2
- 229950008959 marimastat Drugs 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- OFXSXYCSPVKZPF-UHFFFAOYSA-N methoxyperoxymethane Chemical compound COOOC OFXSXYCSPVKZPF-UHFFFAOYSA-N 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012660 pharmacological inhibitor Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 229940063683 taxotere Drugs 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000009999 tuberous sclerosis Diseases 0.000 description 2
- 239000000225 tumor suppressor protein Substances 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 229950000578 vatalanib Drugs 0.000 description 2
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 2
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 2
- SFWWGMKXCYLZEG-YFKPBYRVSA-N (3s)-3-methylmorpholine Chemical compound C[C@H]1COCCN1 SFWWGMKXCYLZEG-YFKPBYRVSA-N 0.000 description 1
- ZPKSAIWDCQVXSQ-UHFFFAOYSA-N (4-aminophenoxy)boronic acid Chemical compound NC1=CC=C(OB(O)O)C=C1 ZPKSAIWDCQVXSQ-UHFFFAOYSA-N 0.000 description 1
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- 125000004825 2,2-dimethylpropylene group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[*:1])C([H])([H])[*:2] 0.000 description 1
- GMDWHBVEZCVCHU-UHFFFAOYSA-N 2-(2-methoxyethoxy)quinazolin-4-amine Chemical compound C1=CC=CC2=NC(OCCOC)=NC(N)=C21 GMDWHBVEZCVCHU-UHFFFAOYSA-N 0.000 description 1
- NQXGKSIKPATTNC-UHFFFAOYSA-N 2-amino-1,3-thiazole-5-carboxamide Chemical group NC(=O)C1=CN=C(N)S1 NQXGKSIKPATTNC-UHFFFAOYSA-N 0.000 description 1
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 108010013043 Acetylesterase Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 101710153593 Albumin A Proteins 0.000 description 1
- 208000033399 Anaphylactic responses Diseases 0.000 description 1
- 102000012936 Angiostatins Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 108010059108 CD18 Antigens Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010008354 Cervix neoplasm Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- 208000012609 Cowden disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 238000007399 DNA isolation Methods 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 229940124009 ErbB-2 tyrosine kinase inhibitor Drugs 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- 102100022466 Eukaryotic translation initiation factor 4E-binding protein 1 Human genes 0.000 description 1
- 108050000946 Eukaryotic translation initiation factor 4E-binding protein 1 Proteins 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 102100031561 Hamartin Human genes 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 1
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 1
- 101000795643 Homo sapiens Hamartin Proteins 0.000 description 1
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000864057 Homo sapiens Serine/threonine-protein kinase SMG1 Proteins 0.000 description 1
- 101000795659 Homo sapiens Tuberin Proteins 0.000 description 1
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010016648 Immunophilins Proteins 0.000 description 1
- 102000000521 Immunophilins Human genes 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 1
- 101710201824 Insulin receptor substrate 1 Proteins 0.000 description 1
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- 208000022010 Lhermitte-Duclos disease Diseases 0.000 description 1
- 206010025102 Lung infiltration Diseases 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101710170181 Metalloproteinase inhibitor Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- PRQROPMIIGLWRP-UHFFFAOYSA-N N-formyl-methionyl-leucyl-phenylalanin Chemical compound CSCCC(NC=O)C(=O)NC(CC(C)C)C(=O)NC(C(O)=O)CC1=CC=CC=C1 PRQROPMIIGLWRP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229940116355 PI3 kinase inhibitor Drugs 0.000 description 1
- 206010033848 Paramnesia Diseases 0.000 description 1
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 102100030264 Pleckstrin Human genes 0.000 description 1
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 208000007531 Proteus syndrome Diseases 0.000 description 1
- 102100024908 Ribosomal protein S6 kinase beta-1 Human genes 0.000 description 1
- 101710108924 Ribosomal protein S6 kinase beta-1 Proteins 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 102100029938 Serine/threonine-protein kinase SMG1 Human genes 0.000 description 1
- 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 1
- 101710181599 Serine/threonine-protein kinase STK11 Proteins 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 230000017274 T cell anergy Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 241000015728 Taxus canadensis Species 0.000 description 1
- 244000162450 Taxus cuspidata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 102100031638 Tuberin Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ZIQBFAAPJOGAHV-UHFFFAOYSA-N [4-(aminomethyl)phenoxy]boronic acid Chemical compound NCC1=CC=C(OB(O)O)C=C1 ZIQBFAAPJOGAHV-UHFFFAOYSA-N 0.000 description 1
- VSJVHFFAEGLOBH-UHFFFAOYSA-N [F].C1=CN=CN=C1 Chemical compound [F].C1=CN=CN=C1 VSJVHFFAEGLOBH-UHFFFAOYSA-N 0.000 description 1
- FJPVCKDSPVJGFE-UHFFFAOYSA-N [O]C(=O)C1CCCCC1 Chemical group [O]C(=O)C1CCCCC1 FJPVCKDSPVJGFE-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005910 alkyl carbonate group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- RQDXIWBZCFJVHX-UHFFFAOYSA-N boron;2,2,2-trifluoroacetic acid Chemical compound [B].OC(=O)C(F)(F)F RQDXIWBZCFJVHX-UHFFFAOYSA-N 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000000451 chemical ionisation Methods 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 210000004020 intracellular membrane Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000003394 isomerase inhibitor Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 229960001320 lapatinib ditosylate Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- CNFDGXZLMLFIJV-UHFFFAOYSA-L manganese(II) chloride tetrahydrate Chemical compound O.O.O.O.[Cl-].[Cl-].[Mn+2] CNFDGXZLMLFIJV-UHFFFAOYSA-L 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940126170 metalloproteinase inhibitor Drugs 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- XNEFVTBPCXGIRX-UHFFFAOYSA-N methanesulfinic acid Chemical compound CS(O)=O XNEFVTBPCXGIRX-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- QVNYNHCNNGKULA-UHFFFAOYSA-N methyl 2-amino-5-bromobenzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1N QVNYNHCNNGKULA-UHFFFAOYSA-N 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- JTSLALYXYSRPGW-UHFFFAOYSA-N n-[5-(4-cyanophenyl)-1h-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide Chemical compound C=1C=CN=CC=1C(=O)NC(C1=C2)=CNC1=NC=C2C1=CC=C(C#N)C=C1 JTSLALYXYSRPGW-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical group CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000003024 peritoneal macrophage Anatomy 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 229940061584 phosphoramidic acid Drugs 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 108010026735 platelet protein P47 Proteins 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000001855 preneoplastic effect Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical class C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003244 quercetin derivatives Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 229940055725 xarelto Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound of formula (I) or a pharamaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.
Description
The present invention relates to morpholino pyrimidine derivatives, their preparation method comprises their pharmaceutical composition and their purposes in treatment, for example treats hyperplasia, and cancer is for example especially treated the disease of mTOR kinases and/or one or more PI3K enzyme mediation.
At present, people recognize that fully the imbalance of oncogene and tumor suppressor gene impels the formation of malignant tumour, for example, and by improving the approach of cell proliferation or raising cell survival.Equally, the signal path of known PI3K/mTOR family mediation has central role in many cell processes (comprising propagation and survival), and the imbalance in path is the origin cause of formation of wide spectrum human cancer and other disease.
The Mammals target of macrolide antibiotic rapamycin (sirolimus (Sirolimus)) is enzyme mTOR.This kind of enzyme belongs to relevant kinases (PIKK) family of phosphatidylinositols (PI) kinases of protein kinase, and it also comprises ATM, ATR, DNA-PK and hSMG-1.Similar with other PIKK family member, mTOR does not have detectable lipid kinase activity, but plays the effect of serine-threonine kinase on the contrary.Many understanding to the mTOR signal are based on the use rapamycin.Rapamycin at first combines with 12 kDa immunophilin FK506-conjugated protein (FKBP 12), and this mixture inhibition mTOR signal (Tee and Blenis, Seminars in Cell andDevelopmental Biology, 2005,16,29-37).MTOR albumen by catalysis kinases zone (FKBP12 (rapamycin)-connection (FRB) zone), the supposition the repressor zone (near the C-end, and have 20 the continuous HEAT of repetition primitives at the most at the N-end) and FRAP-ATM-TRRAP (FAT) and FAT C-stub area composition (Huang and Houghton, Current Opinion in Pharmacology, 2003,3,371-377).
The mTOR kinases is the crucial conditioning agent of cell growth, and show and have the effect of regulating many cell functions, comprise translate, transcribe, mRNA circulation, protein stability, actin cytoskeleton reorganization and autophagy (Jacinto and Hall, Nature Reviews Molecular andCell Biology, 2005,4,117-126).The mTOR kinases will come from the signal of somatomedin (for example Regular Insulin or rhIGF-1) and nutrient substance (for example amino acid and glucose) and integrate, to regulate the cell growth.The mTOR kinases is by the PI3K-Akt path, by growth factor activation.The mTOR kinases function that fullest characterizes in mammalian cell is to regulate to translate, it is by two paths, promptly examine candy body S6K1 activation (with raising carry 5 '-mRNAs in few pyrimidine zone, end (TOP) translates) and the inhibition (translating) of 4E-BP1 with the dependent mRNA of permission CAP-carry out.
Usually, the investigator uses rapamycin and relevant forms of rapamycin analogs (based on them at the specificity of mTOR as target in the born of the same parents) to suppress, and has probed into physiology and the pathological effect of mTOR.Yet, latest data proposes, rapamycin demonstrates variable restraining effect to the mTOR semiotic function, and think, directly suppress mTOR kinases zone and can show the anticancer significantly widely disease activity of anticancer disease activity that obtains than rapamycin (people such as Edinger, Cancer Research, 2003,63,8451-8460).For this reason, can use effectively and the optionally inhibitor of mTOR kinase activity,, and provide the therapeutical agent of usefulness so that understand the mTOR kinase function more completely.
Have considerable evidence to show now, the path upstream of mTOR is the PI3K path for example, is activated (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,489-501 in cancer continually; Bjornsti and Houghton, Nature Reviews Cancer, 2004,4,335-348; People such as Inoki, Nature Genetics, 2005,37,19-24).The component in the PI3K path that for example, suddenlys change in different human tumors comprises the activation sudden change of growth factor receptors and amplification and/or the overexpression of PI3K and Akt.
Explanation on evidence in addition, endothelial cell proliferation may also depend on the mTOR signal.Endothelial cell proliferation be by the vascular endothelial growth factor of PI3K-Akt-mTOR signal path (VEGF) activation stimulated (Dancey, Expert Opinion on Investigational Drugs, 2005,14,313-328).In addition, by influence to the expression of the factor-1 α (HIF-1 α) of hypoxia inducible, think the mTOR kinase signal can partly control VEGF synthetic (people such as Hudson, Molecular and Cellular Biology, 2002,22,7004-7014).Therefore, tumor-blood-vessel growth may depend on the mTOR kinase signal in two ways: the hypoxia inducible of the VEGF by tumour and stroma cell synthetic and the VEGF excitation by endothelium propagation and survival (by the PI3K-Akt-mTOR signal).
These find expression, and the kinase whose pharmacological inhibitor of mTOR should have therapeutic value, can be used for treating various forms of cancers, comprise for example malignant tumour of cancer and sarcoma and leukemia and lymph of noumenal tumour.Especially, the mTOR kinase inhibitor should have therapeutics and be worth, and can be used for treating for example breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer, and cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
Except tumorigenicity, explanation on evidence, the mTOR kinases is played a role in a series of progonoma syndromess.Recent research shows that tumor suppressor protein for example TSC1, TSC2, PTEN and LKB1 can be controlled the mTOR kinase signal consumingly.The forfeiture of these tumor suppressor proteins can cause a large amount of progonoma illnesss, this be because the result that the mTOR kinase signal increases (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005,16,29-37).Setting up the syndromes that molecule gets in touch with the kinase whose dysregulation of mTOR comprises: Peutz-Jeghers syndrome (PJS), the Cowden disease, Bannayan-Riley-Ruvalcaba syndromes (BRRS), the Proteus syndromes, Lhermitte-Duclos disease and tuberous sclerosis (TSC) (people such as Inoki, Nature Genetics, 2005,37,19-24).Patient with these syndromess forms optimum paramnesia tumour specifically in many organs.
Up-to-date research has shown the effect (Easton﹠amp of mTOR kinases in other disease; Houghton, Expert Opinion on Therapeutic Targets, 2004,8,551-564).Show that the propagation of the antigen induction by suppressor T cell, B cell and antibody produce, rapamycin is effective immunosuppressor (Sehgal, Transplantation Proceedings, 2003,35,7S-14S) and thus the mTOR kinase inhibitor also is useful immunosuppressor.The kinase activity that suppresses mTOR also can be effective to prevention of restenosis, in the treatment of vascular system disease, this restenosis is subjected to the normal cell in the vascular system to produce the control (people such as Morice of undesirable propagation in to the response process of introducing support, New England Journal ofMedicine, 2002,346,1773-1780).In addition, forms of rapamycin analogs (everolimus) can reduce the severity of heart allograft vascular lesion and incidence (people such as Eisen, New England Journal of Medicine, 2003,349,847-858).The raising of mTOR kinase activity is relevant with cardiac hypertrophy, and this primary hazard factor as heart failure is important clinically, and is the result (Tee﹠amp of myocardial cell's cell size increase; Blenis, Seminars in Cell and Developmental Biology, 2005,16,29-37).Thus, except cancer, expectation mTOR kinase inhibitor has prevention and treats the value of multiple disease.
Believe that equally many these morpholino pyrimidine derivatives have the activity of inhibition at kinase whose phosphatidylinositols (PI) 3-kinases family.
Phosphatidylinositols (PI) 3-kinases (PI3Ks) is ubiquitous lipid kinase, and it can be as signal converter and protein transportation route in the downstream of cell surface receptor and the intracellular membrane that is constituting.All PI3Ks have an active dual specificity enzyme of lipid kinase, and it can be in the 3-hydroxy position with the phosphoinositide phosphorylation, and the protein kinase activity with less abundant characterization.The lipid products of PI3K-catalyzed reaction (comprises phosphatidylinositols 3,4,5-triguaiacyl phosphate [PI (3,4,5) P
3], phosphatidylinositols 3,4-bisphosphate [PI (3,4) P
2] and phosphatidylinositols 3-Monophosphate [PI (3) P]) in various signal transduction pathways, constitute the second messenger, comprise that on cell proliferation, adhesion, survival, cytoskeleton are reset and current those the indispensable approach of vesica.In all cells, structurally have PI (3) P, and its level can not change significantly along with the excitation of agonist.On the contrary, in most of cell, nominally there is not PI (3,4) P
2And PI (3,4,5) P
3, but they can be assembled under the excitation of agonist apace.
The 3-phosphoinositide second messenger's that PI3K-produces downstream effect is to mediate by the target molecule that comprises 3-phosphoinositide connecting zone (for example pleckstrin homology (PH) zone and definite recently FYVE and phox zone).The albumen target of the better sign of PI3K comprises PDK1 and protein kinase B (PKB).In addition, for example Btk and Itk rely on the PI3K activity to Tyrosylprotein kinase.
According to its physiology substrate specificity, (people such as Vanhaesebroeck, Trends in Biol.Sci., 1997,22,267) can be divided three classes PI3K lipid kinase family.III class PI3K enzyme is separately with the PI phosphorylation.On the contrary, II class PI3K enzyme is with PI and PI4-phosphoric acid ester [PI (4) P] phosphorylation.Although think (4, the 5) P that has only PI
2Be physiological cell matrix, I class PI3K enzyme is PI, PI (4) P and PI 4,5-bisphosphate [PI (4,5) P
2] phosphorylation.PI (4,5) P
2Phosphorylation produce lipid second messenger PI (3,4,5) P
3The farther relevant member of the super family of lipid kinase is an IV class kinases, for example mTOR (discussing above) and DNA-dependant kinase (it is with the serine/threonine residue phosphorylation in the albumen substrate).Most of research and the PI3K lipid kinase of understanding are I class PI3K enzymes.
The heterodimer that I class PI3Ks is made up of p110 catalytic subunit and regulator subunit.Based on adjusting side and regulation mechanism, this family is further divided into Ia class and Ib fermentoid.The Ia fermentoid comprises regulator subunit (the p85 α with five uniquenesses, p55 α, p50 α, p85 β and p55 γ) (the p110 α of catalytic subunit of three uniquenesses of dimerization, p110 β and p110 δ), all catalytic subunits can interact with all regulator subunits, form various heterodimers.In the response that the somatomedin to receptor tyrosine kinase encourages,, usually Ia class PI3Ks is activated by its regulator subunit SH2 zone and activated receptor or for example interaction of the concrete phosphate tyrosine residues of IRS-1 of joint albumen.In all cell types, structurally express p110 α and p110 β, and p110 δ expression more is confined to leukocytes and some epithelial cells.On the contrary, simple classification Ib enzyme comprises the catalytic subunit with the interactional p110 γ of p101 regulator subunit.In addition, as if in the response to g protein coupled receptor system (GPCRs), classification Ib enzyme is activated, and its expression is limited to white corpuscle and myocardial cell.
Have considerable evidence to show now, in multiple human cancer, Ia class PI3K enzyme can help directly or indirectly to cause tumour (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,489-501).For example, in some tumours, the p110 alpha subunit obtains amplification, for example ovarian tumor (people such as Shayesteh, Nature Genetics, 1999,21,99-102) and cervix neoplasms (people such as Ma, Oncogene, 2000,19,2739-2744).In recent years, activation in the catalytic site of p110 α catalytic subunit sudden change is relevant with various other tumours, and for example colorectum is regional and those tumours of breast and lung people such as (, Science, 2004,304,554) Samuels.In cancer for example in ovary and the colorectal carcinoma, also determined the relevant sudden change of tumour in the p85 α regulator subunit (people such as Philp, Cancer Research, 2001,61,7426-7429).Except direct influence, it is believed that, the activation of Ia class PI3Ks helps the tumorigenic situation in the appearance of signal path upstream, for example, via the ligand dependent of receptor tyrosine kinase, GPCR system or integrin or the activation of part dependent/non-dependent (people such as Vara, CancerTreatment Reviews, 2004,30,193-204).The example in this stream signal path comprises the overexpression (people such as Harari of receptor tyrosine kinase erbB2 in causing the various tumours of activatory in path that PI3K mediates, Oncogene, 2000,19,6102-6114) and the overexpression of ras oncogene (people such as Kauffmann-Zeh,, Nature, 1997,385,544-548).In addition, Ia class PI3Ks can help tumorigenicity (movable institute causes by various downstream signals) indirectly.For example, by PI (3,4,5) P that PI3K mediated
3The imbalance that generates, PTEN tumor suppression Phosphoric acid esterase (its catalysis PI (3,4,5) P
3PI (4,5) P is got back in conversion
2) the forfeiture of effect relevant with very large-scale tumour (Simpson and Parsons, Exp.Cell Res., 2001,264,29-41).In addition, it is believed that the increase of the effect of activity that other PI3K mediates will help lend some impetus to various cancers, and for example activation by Akt (Nicholson and Anderson, Cellular Signalling, 2002,14,381-395).
The effect in mediation propagation in tumour cell and survival signal, explanation on evidence, Ia class PI3K enzyme helps tumorigenicity in the relevant stroma cell of tumour.For example, know, to preceding angiogenic factor for example in the response of VEGF, the PI3K signal in the generation angiokinesis of mediation endotheliocyte, play an important role (people such as Abid, Arterioscler.Thromb.Vasc.Biol., 2004,24,294-300).Because I class PI3K enzyme also relate to reactivity and migration (Sawyer, Expert Opinion Investig.Drugs, 2004,13,1-19), invade and metastasis by suppressing tumour cell, the PI3K enzyme inhibitors should provide the treatment benefit.In addition, I class PI3K enzyme in the immunocyte of the pre-neoplastic generation effect that helps inflammatory cell is regulated, play an important role (Coussens and Werb, Nature, 2002,420,860-867).
These find expression, and the pharmacological inhibitor of I class PI3K enzyme has therapeutic value, can be used for treating various diseases, comprises the various forms Cancerous disease, comprise for example malignant tumour of cancer and sarcoma and leukemia and lymph of noumenal tumour.Especially, the inhibitor of I class PI3K enzyme should have therapeutics and be worth, and can be used for treating for example breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer, and cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
PI3K γ (Ib class PI3K) is by the GPCRs activatory, and this has obtained proof at last in the mouse that lacks enzyme.Thus, in response to various chemotaxis materials (for example IL-8, C5a, fMLP and MIP-1a) excitation, derived from lack PI3K γ-neutrophil and the scavenger cell of animal can not produce PI (3,4,5) P
3, and be intact (people such as Hirsch, Science, 2000,287 (5455), 1049-1053 by protein tyrosine kinase coupled receptor to the signal of Ia class PI3Ks; People such as Li, Science, 2002,287 (5455), 1046-1049; People such as Sasaki, Science, 2002,287 (5455), 1040-1046).In addition, in the cell of no PI3K γ, PI (3,4,5) P
3The phosphorylation of the PKB of mediation is not to originate from these GPCR parts.Combine, the result shows that in the hematopoietic cell of having a rest, PI3K γ is by the unique PI3K heterogeneous of activatory in the GPCRs body at least.When to the neutrophil that derives from mouse marrow with derive from wild-type and PI3K γ
-/-When the peritoneal macrophages of mouse carries out in vitro tests, in chemotaxis and adherence test, observe (but not eliminating fully) performance of reduction.Yet this is converted into neutrophil that IL-8 drives and is penetrated into rapid damage in the tissue (people such as Hirsch, Science, 2000,287 (5455), 1049-1053). up-to-date data propose, and PI3K γ is relevant with the path finding process, and it is irrelevant with the generation (being used for reactivity) of mechanical force, because the random migration in the cell that lacks PI3K γ does not weaken (people such as Hannigan, Proc.Nat.Acad.of Sciences of U.S.A., 2002,99 (6), 3603-8).The data of contact PI3K γ and respiratory system disease pathology show, PI3K γ is in the lung infiltration of regulating endotaxin induction and cause having central role aspect the neutrophil activation of acute lung injury (people such as Yum, J.Immunology, 2001,167 (11), 6601-8).Although PI3K γ expresses at the white cell camber, as if its forfeiture does not hinder hematopoiesis, and the mouse that does not have a PI3K γ can grow and reproducible these truely hint that this PI3K heterogeneous can be used as the potential drug targets.Research for the stunning mouse also confirms, PI3K γ be mast cell's activatory necessity toughener (people such as Laffargue, Immunity, 2002,16 (3), 441-451).
Thus, except tumorigenicity, explanation on evidence, I class PI3K enzyme in other disease, play a role (people such as Wymann, Trends in Pharmacological Science, 2003,24,366-376).In immune cell, Ia class PI3K enzyme and simple Ib fermentoid all have important effect (Koyasu, Nature Immunology, 2003,4,313-319), and they are treatment targets of inflammatory and irritated indication thus.Up-to-date report shows, the mouse that lacks PI3K γ and PI3K δ can grow, but have the inflammatory that weakens and anaphylactic response (people such as Ali, Nature, 2004,431 (7011), 1007-11).By the anti-inflammatory effect or directly influence the myocardial cell, the restraining effect of PI3K also can be used for treating cardiovascular disorder (people such as Prasad, Trends in Cardiovascular Medicine, 2003,13,206-212).Thus, except cancer, the inhibitor of expectation I class PI3K enzyme has prevention and treats the value of multiple disease.
Differentiate some compounds of the kinases (PI3KKs) that inhibition PI3Ks is relevant with phosphatidylinositols (PI) kinases, comprised wortmannin and quercetin derivative L Y294002.These compounds are rationally concrete inhibitor (surpassing other kinases) of PI3Ks and PI3KKs, but they lack usefulness, and show less selectivity in PI3K family.
Correspondingly, desirablely be, effectively mTOR and/or PI3K inhibitor are provided further, be used for the treatment of cancer, inflammatory or obstructive respiratory tract disease, immunity or cardiovascular disorder.
Morpholino pyrimidine derivatives and PI3K inhibitor are known in the art.
International Patent Application WO 2004/048365 discloses the compound that has the PI3K enzyme inhibition activity and can be used for treating cancer.These compounds are pyrimidines that virtue is amino and heteroaryl amino replaces, and with regard to their virtue amino and heteroaryl amino substituting group, it is different from compound of the present invention.These substituting groups are not equivalent to of the present invention-XR
1Substituting group.The active inhibitor of the PI3K that is used for the treatment of cancer is also disclosed in european patent application 1277738, it mentions the bicyclic heteroaryl compounds that the 4-morpholino replaces, for example quinazoline and pyrido [3,2-d] pyrimidine derivatives, with the tricyclic heteroaryl compounds of 4-morpholino replacement, rather than monocyclic pyrimidine derivatives.
On the chemical abstracts database, registered chemical compound lot; 4-morpholine-4-base-6-(phenyl sulfonyl methyl)-2-pyridin-4-yl-pyrimidine and 4-{6-[(benzene sulfonyl for example) methyl]-2-pyridine-2-yl pyrimidines-4-yl } morpholine; but do not show applicability, and do not propose these compounds and have mTOR and/or PI3K and suppress active or useful curative properties.
Unexpectedly, we find that some morpholino pyrimidine derivatives has useful curative properties.Do not wish to be bound by theory, it is believed that, the therepic use of this derivative stems from their inhibition activity at mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib fermentoid).Because the signal path of PI3K/mTOR family mediation has central role in many cell processes (comprising propagation and survival), with because the imbalance in these paths is origin causes of formation of wide spectrum human cancer and other disease, so people expect that this derivative has therepic use.Especially, people expect that this derivative has antiproliferative and/or apoptosis performance, and this is meant that they can be used for treating hyperplasia, for example cancer.Compound of the present invention also can be effective to suppress not have the cell proliferation of control, and the cell proliferation of this no control comes from various non-malignant diseases, for example inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder.
Usually, compound of the present invention has effective inhibition activity at the mTOR kinases, but this compound also can have effective inhibition activity at one or more PI3K enzymes (for example Ia fermentoid and/or Ib fermentoid).
According to one aspect of the present invention, provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R
9,-OR
9,-SR
9,-SOR
9,-SO
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15With-NR
9SO
2R
10
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-SR
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl,
Medicine as the treatment hyperplasia.
According to another aspect of the present invention, provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR8;
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R
9,-OR
9,-SR
9,-SOR
9,-SO
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15With-NR
9SO
2R
10
Or X-R
1Be-CR
6R
7OH;
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-SR
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl,
Medicine as the treatment hyperplasia.
According to another aspect of the present invention, provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R
9,-OR
9,-SR
9,-SOR
9,-SO
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15With-NR
9SO
2R
10
Or X-R
1Be-CR
6R
7OH;
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-SR
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl
Medicine as the treatment hyperplasia.
According to another aspect of the present invention, provide the compound of formula (I)
Formula (I)
Or the purposes of its pharmacologically acceptable salt in the preparation medicine, this medicine is used for the treatment of hyperplasia; Wherein m is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R
9,-OR
9,-SR
9,-SOR
9,-SO
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15With-NR
9SO
2R
10
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-SR
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
According to another aspect of the present invention, provide the compound of formula (I)
Formula (I)
Or the purposes of its pharmacologically acceptable salt in the preparation medicine, this medicine is used for the treatment of hyperplasia; Wherein m is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R
9,-OR
9,-SR
9,-SOR
9,-SO
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15With-NR
9SO
2R
10
Or X-R
1Be-CR
6R
7OH;
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-SR
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
According to another aspect of the present invention, provide the compound of formula (I)
Formula (I)
Or the purposes of its pharmacologically acceptable salt in the preparation medicine, this medicine is used for the treatment of hyperplasia; Wherein m is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R
9,-OR
9,-SR
9,-SOR
9,-SO
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15With-NR
9SO
2R
10
Or X-R
1Be-CR
6R
7OH
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-SR
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-R
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
According to further aspect of the present invention, also provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is O, 1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-(O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R
9,-OR
9,-SR
9,-SOR
9,-O
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15And NR
9SO
2R
10
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-R
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
According to further aspect of the present invention, also provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-(O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R
9,-OR
9,-SR
9,-SOR
9,-O
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15And NR
9SO
2R
10
Or X-R
1Be-CR
6R
7OH;
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-R
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
According to further aspect of the present invention, also provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R
9,-OR
9,-SR
9,-SOR
9,-O
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15And NR
9SO
2R
10
Or X-R
1Be-CR
6R
7OH;
R
2Be to be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16
When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-R
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
Can there be stereoisomeric forms in any ratio in the compound of some formula (I).Be appreciated that all how much and optically active isomer and its mixture of the formula of the present invention includes (I) compound, comprise raceme.Tautomer and its mixture also form one aspect of the present invention.Solvate and its mixture also form one aspect of the present invention.For example, the suitable solvent thing of formula (I) compound is for example hydrate, for example hydrate of semihydrate, monohydrate, two-hydrate or three-hydrate or its other number.
The compound that the present invention relates to formula defined herein (I) with and salt.The salt that is used for pharmaceutical composition is pharmacologically acceptable salt, but other salt can be used for the compound of preparation formula (I) and their pharmacologically acceptable salt.Pharmacologically acceptable salt of the present invention can for example comprise the acid salt of formula defined herein (I) compound, and formula (I) compound is fully alkaline, so that form this salt.This acid salt is including, but not limited to fumarate, mesylate, hydrochloride, hydrobromate, Citrate trianion and maleate and the salt that forms with phosphoric acid and sulfuric acid.In addition, if formula (I) compound is abundant tart, salt is alkali salt, example including, but not limited to: an alkali metal salt is sodium or sylvite for example, alkaline earth salt is calcium or magnesium salts for example, or organic amine salt triethylamine, thanomin, diethanolamine, trolamine, morpholine, N-methyl piperidine, N-ethylpiperidine, dibenzylamine or amino acid lysine salt for example for example.
The compound of formula (I) also can be provided with the form of hydrolyzable ester in the body.The ester that comprises cleavable in the body of formula (I) compound of carboxyl or hydroxyl for example is: cleavable produces the pharmaceutically acceptable ester of parent acid or alcohol in human or animal body.This ester can by for example intravenously give the experimental animal test compound and subsequently the body fluid of check test animal identified.
The suitable pharmaceutically acceptable ester of carboxyl comprises C
1-6The alkoxy methyl ester is methoxymethyl ester for example, C
1-6The alkanoyloxymethyl ester is the oxy acid methyl neopentyl ester for example, phthalidyl ester, C
3-8Cyclo alkoxy carbonyl oxygen base C
1-6Alkyl ester is 1-cyclohexyl-carbonyl oxygen base ethyl ester for example, and 1,3-dioxole-2-ketone group methyl ester is the 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl ester, and C
1-6The alkoxy-carbonyl oxy ethyl ester is 1-methoxycarbonyl oxygen base ethyl ester for example; With can on any carboxyl of The compounds of this invention, form ester.
The suitable pharmaceutically acceptable ester of hydroxyl comprises inorganic ester for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and α-acyloxyalkyl group ether and owing to the related compound that obtains parent hydroxy is decomposed in hydrolysis in the body of ester.The example of α-acyloxyalkyl group ether comprises acetoxyl group methoxy-ether and 2,2-dimethyl propylene acyloxy methoxy-ether.The option that forms the interior hydrolyzable ester of body of hydroxyl comprises C
1-10Alkyloyl, formyl radical for example, ethanoyl, benzoyl, phenylacetyl, the benzoyl of replacement and phenylacetyl; C
1-10Carbalkoxy (obtaining alkyl carbonate), for example ethoxycarbonyl; Two-C
1-4Alkyl-carbamoyl and N-(two-C
1-4The alkylamino ethyl)-N-C
1-4Alkyl-carbamoyl (obtaining carbamate); Two-C
1-4Alkylamino ethanoyl and carboxyl ethanoyl.The example of the ring substituents on phenylacetyl and the benzoyl comprise aminomethyl, C
1-4Alkylamino methyl and two-(C
1-4Alkyl) aminomethyl is with the morpholino or the piperazinyl of 3-that is connected basic shack nitrogen-atoms and benzoyl basic ring by methylene radical or 4-position.Hydrolyzable ester comprises for example R in other useful body
AC (O) OC
1-6Alkyl-CO-, wherein R
ABe benzyloxy-C for example
1-4Alkyl or phenyl.In this ester, the suitable substituent on the phenyl comprises for example 4-C
1-4Piperazinyl-C
1-4Alkyl, piperazinyl-C
1-4Alkyl and morpholino-C
1-4Alkyl.
Also can be with the compound of prodrug form giving construction (I), it decomposes in human or animal body, obtains the compound of formula (I).The various forms of prodrug is known in this area.For example, this prodrug derivatives referring to:
A) Design of Prodrugs, edited by H.Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol.42, p.309-396, people such as edited by K.Widder, (Academic Press, 1985);
b)A Textbook of Drug Design and Development,edited byKrogsgaard-Larsen and H.Bundgaard,Chapter 5“Design and Applicationof Prodrugs”,by H.Bundgaard p.113-191(1991);
c)H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992);
D) people such as H.Bundgaard, Journal of Pharmaceutical Sciences, 77,285 (1988); And
E) people such as N.Kakeya, Chem Pharm Bull, 32,692 (1984).
General terms " C in this specification sheets
P-qAlkyl " comprise straight chain and branched-chain alkyl.Yet, speak of single alkyl for example " propyl group " only specifically be used for straight chain pattern (being n-propyl and sec.-propyl), speak of single branched-chain alkyl for example " tertiary butyl " only specifically be used for the side chain pattern.
C
P-qPrefix C in alkyl and other term (wherein p and q are integers)
P-qShow the carbon atom scope that exists in the group, for example C
1-4Alkyl comprises C
1Alkyl (methyl), C
2Alkyl (ethyl), C
3Alkyl (propyl group of n-propyl and sec.-propyl form) and C
4Alkyl (normal-butyl, sec-butyl, isobutyl-and the tertiary butyl).
Term C
P-qAlkoxyl group comprises-O-C
P-qAlkyl.
Term C
P-qAlkyloyl comprises-C (O) alkyl.
Term halogen comprises fluorine, chlorine, bromine and iodine.
" carbocyclic ring " is monocycle, dicyclo or the three-loop system that comprises saturated, the unsaturated or fractional saturation of 3 to 14 annular atomses, wherein encircles CH
2Group can be replaced by the C=O group." carbocyclic ring " comprises " aryl ", " C
P-qCycloalkyl " and " C
P-qCycloalkenyl group ".
" aryl " is aromatic series monocycle, dicyclo or trinucleated carbocyclic ring system.
" C
P-qCycloalkenyl group " be monocycle, dicyclo or the three ring carbocyclic ring ring systems that comprise the unsaturated or fractional saturation of at least 1 C=C key, wherein encircle CH
2Group can be replaced by the C=O group.
" C
P-qCycloalkyl " be saturated monocycle, dicyclo or three ring carbocyclic ring ring systems, wherein encircle CH
2Group can be replaced by the C=O group.
" heterocyclic radical " is monocycle, dicyclo or the three-loop system that comprises saturated, the unsaturated or fractional saturation of 3 to 14 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, this ring can be that carbon or nitrogen connect, and wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH
2Group can be replaced by the C=O group." heterocyclic radical " comprises " heteroaryl ", " the assorted alkyl of ring " and " the assorted thiazolinyl of ring ".
" heteroaryl " is aromatic series monocycle, dicyclo or trinucleated heterocyclic radical, especially has 5 to 1O annular atomses, and wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, and wherein nuclear nitrogen or sulphur can be oxidized.
" the assorted thiazolinyl of ring " is monocycle, dicyclo or the tricyclic heterocyclic basic ring system with unsaturated or fractional saturation of 5 to 10 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, this ring can be that carbon or nitrogen connect, and wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH
2Group can be replaced by the C=O group.
" the assorted alkyl of ring " is saturated monocycle, dicyclo or the tricyclic heterocyclic system with 5 to 10 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, this ring can be that carbon or nitrogen connect, and wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH
2Group can be replaced by the C=O group.
This specification sheets can use the combination term, comprises the group of an above functional group with description.Unless this paper describes in addition, otherwise can explain this term according to what this area was understood.For example, carbocyclic ring C
P-qAlkyl comprises the C that is replaced by carbocyclic ring
P-qAlkyl, heterocyclic radical C
P-qAlkyl comprises the C that is replaced by heterocyclic radical
P-qAlkyl, two (C
P-qAlkyl) amino comprises by 2 C
P-qThe amino that alkyl (can be identical or different) replaces.
Halo C
P-qThe C that alkyl is replaced by 1 or 1 above halogenic substituent (especially 1,2 or 3 halogenic substituent)
P-qAlkyl.Equally, other general terms that comprises halogen halo C for example
P-qAlkoxyl group can comprise 1 or 1 above halogenic substituent (especially 1,2 or 3 halogenic substituent).
Hydroxyl C
P-qThe C that alkyl is replaced by 1 or 1 above hydroxyl substituent (especially 1,2 or 3 hydroxyl substituent)
P-qAlkyl.Equally, other general terms that comprises hydroxyl hydroxyl C for example
P-qAlkoxyl group can comprise 1 or 1 above hydroxyl substituent (especially 1,2 or 3 hydroxyl substituent).
C
P-qAlkoxy C
P-qAlkyl is by 1 or 1 above C
P-qAlkoxy substituent (1,2 or 3 C especially
P-qAlkoxy substituent) C of Qu Daiing
P-qAlkyl.Equally, comprise C
P-qOther general terms of alkoxyl group is C for example
P-qAlkoxy C
P-qAlkoxyl group can comprise 1 or 1 above C
P-qAlkoxy substituent (1,2 or 3 C especially
P-qAlkoxy substituent).
If optional substituting group is selected from " 1 or 2 ", " 1,2 or 3 " or " 1,2,3 or 4 " individual group or substituting group, should be appreciated that, this definition comprises and is selected from all substituting groups that specify group, promptly all substituting groups are identical, or substituting group is selected from two or more groups that specify, and promptly substituting group is inequality.
(ACD/Name version 8.0) names compound of the present invention by means of computer software.
" hyperplasia " comprises for example for example inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder of cancer and non-malignant diseases of malignant diseases.
Any part of any R group or this group or substituent suitable meaning comprise:
C
1-4Alkyl: methyl, ethyl, propyl group, butyl, 2-methyl-propyl and uncle's fourth
Base;
C
1-6Alkyl: C
1-4Alkyl, amyl group, 2, the 2-dimethylpropyl, the 3-methyl butyl and
Hexyl;
C
3-6Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
C
3-6Cycloalkyl C
1-4Alkyl: cyclopropyl methyl, cyclopropyl ethyl, cyclobutylmethyl, ring penta
Ylmethyl and cyclohexyl methyl;
Aryl: phenyl and naphthyl;
Aryl C
1-4Alkyl: benzyl, styroyl, naphthyl methyl and naphthyl ethyl;
Carbocyclic ring: aryl, cyclohexenyl and C
3-6Cycloalkyl;
Halogen: fluorine, chlorine, bromine and iodine;
C
1-4Alkoxyl group: methoxyl group, oxyethyl group, propoxy-and isopropoxy;
C
1-6Alkoxyl group: C
1-4Alkoxyl group, pentyloxy, 1-ethyl propoxy-and hexyloxy;
C
1-6Alkyloyl: ethanoyl, propionyl and 2-methylpropionyl;
Heteroaryl: pyridyl, imidazolyl, quinolyl, the cinnolines base, pyrimidyl,
Thienyl, pyrryl, pyrazolyl, thiazolyl, thiazolyl,
Triazolyl , oxazolyl , isoxazolyl, furyl, pyridazinyl,
Pyrazinyl, indyl, benzofuryl, dibenzofuran group
And benzothienyl;
Heteroaryl C
1-4Alkyl: pyrryl methyl, pyrryl ethyl, imidazolyl methyl, imidazoles
The base ethyl, pyrazolyl methyl, pyrazolyl ethyl, furyl first
Base, the furyl ethyl, thienyl methyl, thienyl ethyl,
Pyridylmethyl, pyridyl ethyl, pyrazinyl methyl, pyrazine
The base ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrimidyl third
Base, the pyrimidyl butyl, the imidazolyl propyl group, the imidazolyl butyl,
The quinolyl propyl group, 1,3,4-triazolyl propyl group is with the oxazolyl methyl;
Heterocyclic radical: heteroaryl, pyrrolidyl, isoquinolyl, quinoxalinyl, benzene
Benzothiazolyl, benzoxazolyl, piperidyl, piperazinyl, nitrogen
The heterocycle butane group, morpholinyl, tetrahydro isoquinolyl, tetrahydrochysene quinoline
The quinoline base, indolinyl, dihydro-2H-pyranyl and tetrahydrochysene furan
The base of muttering.
It should be noted that for the given example of the term that uses in the specification sheets be not restrictive.
M, X,
1Y and Y
2, R
1, R
2And R
3Concrete meaning as follows.If suitable, this meaning can be used in combination with any aspect of the present invention or its part and any definition, claim or embodiment defined herein.
m
In one aspect of the invention, m is 0,1,2 or 3.
In yet another aspect, m is 0,1 or 2.
Further, m is 0 or 1.
In yet another aspect, m is 0, like this R
3Do not exist.
In yet another aspect, m is 1, R
3It is methyl.
1
Y and Y
2
In one aspect of the invention,
1Y is N, Y
2Be CR
8
In another aspect of the present invention,
1Y is N, Y
2Be CH.
Of the present invention aspect another,
1Y is CR
8, Y
2Be N.
Further,
1Y is CH or CF, Y
2Be N.
Further,
1Y is CH, Y
2Be N.
X
In one aspect of the invention, X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-NR
4C (O)-,-C (O) NR
4-,-S (O)
2NR
4-and-NR
4S (O)
2-.
In yet another aspect, X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7,-C (O) NR
4-and-NR
4C (O)-.
Further, X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4-and-NR
4C (O)-.
Further, X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-and-S (O)
2CR
6R
7-.
In yet another aspect, X is selected from following connection base :-SCR
6R
7-,-S (O) CR
6R
7-and-S (O)
2CR
6R
7-.
In yet another aspect, X is selected from following connection base :-NR
4CH
2-,-OCH
2-,-OCH (CH
3)-,-OC (CH
3)
2-,-SCH
2-,-SCH (CH
3)-,-C (CH
3)
2-,-S (O) CH
2-,-S (O) CH (CH
3)-,-S (O) C (CH
3)
2-,-S (O)
2CH
2-,-S (O)
2CH (CH
3)-,-S (O)
2C (CH
3)
2-,-C (O) NR
4-and-NR
4C (O)-.
In yet another aspect, X is selected from following connection base :-NR
4CH
2-,-OCH
2-,-SCH
2-,-S (O) CH
2-,-S (O)
2CH
2-,-C (O) NR
4-and-NR
4C (O)-.
In yet another aspect, X is selected from following connection base :-NR
4CH
2-,-OCH
2-,-OCH (CH
3)-,-OC (CH
3)
2-,-SCH
2-,-SCH (CH
3)-,-SC (CH
3)
2-,-S (O) CH
2-,-S (O) CH (CH
3)-,-S (O) C (CH
3)
2-,-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-.
In yet another aspect, X is selected from following connection base :-NR
4CH
2-,-OCH
2-,-SCH
2-,-S (O) CH
2-and-S (O)
2CH
2-.
Further, X is selected from following connection base :-NHCH
2-,-N (CH
3) CH
2-,-OCH
2-,-OCH (CH
3)-,-OC (CH
3)
2-,-SCH
2-,-SCH (CH
3)-,-SC (CH
3)
2-,-S (O) CH
2-,-S (O) CH (CH
3)-,-S (O) C (CH
3)
2-,-S (O)
2CH
2-,-S (O)
2CH (CH
3)-,-S (O)
2C (CH
3)
2-,-C (O) NH-,-C (O) N (CH
3)-,-NHC (O)-and-N (CH
3) C (O)-.
Further, X is selected from following connection base :-NHCH
2-,-N (CH
3) CH
2-,-OCH
2-,-SCH
2-,-S (O) CH
2-,-S (O)
2CH
2-,-C (O) NH-,-C (O) N (CH
3)-,-NHC (O)-and-N (CH
3) C (O)-.
Further, X is selected from following connection base :-NHCH
2-,-N (CH
3) CH
2-,-OCH
2-,-OCH (CH
3)-,-OC (CH
3)
2-,-SCH
2-,-SCH (CH
3)-,-SC (CH
3)
2-,-S (O) CH
2-,-S (O) CH (CH
3)-,-S (O) C (CH
3)
2-,-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-.
Further, X is selected from following connection base :-NHCH
2-,-N (CH
3) CH
2-,-OCH
2-,-SCH
2-and-S (O)
2CH
2-.
In yet another aspect, X is-SCH
2-or-S (O)
2CH
2-.
In yet another aspect, X is-SCH
2-,-SCH (CH
3)-or-SC (CH
3)
2-.
In yet another aspect, X is-S (O) CH
2-,-S (O) CH (CH
3)-or-S (O) C (CH
3)
2-.
In yet another aspect, X is-S (O)
2CH
2-,-S (O)
2CH (CH
3)-or-S (O)
2C (CH
3)
2-.
In yet another aspect, X is-S (O)
2CH
2-.
In yet another aspect, X is-S (O)
2C (CH
3)
2-.
R
1
In one aspect of the invention, R
1Be to be selected from following group: C
1-4Alkyl, C
3-10Cycloalkyl, aryl, C
3-10Cycloalkyl C
1-4Alkyl, aryl C
1-4Alkyl, the assorted alkyl of ring, heteroaryl, the assorted alkyl C of ring
1-4Alkyl, heteroaryl C
1-4Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R
9,-OR
9,-COR
9,-CONR
9R
10,-NR
9R
10With-NR
9COR
10
In yet another aspect, R
1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R
9,-OR
9,-COR
9,-CONR
9R
10,-NR
9R
10With-NR
9COR
10
Further, R
1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH
3,-CONH
2With-CONHCH
3
In yet another aspect, R
1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH
2CH
2OH ,-,-CH
2CH
2NC (O) CH
3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl,, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.
In yet another aspect, R
1It is methyl.
X-R
1
In one embodiment, X-R
1Be-C (CH
3)
2OH or-CH
2OH.
In one embodiment, X-R
1Be-CH
2OH.
R
2
In one aspect of the invention, R
2Be selected from carbocyclic ring or heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In one aspect of the invention, R
2Be selected from carbocyclic ring or heterocyclic radical, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In one aspect of the invention, R
2Be selected from 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In one aspect of the invention, R
2Be selected from 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In one aspect of the invention, R
2Be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In one aspect of the invention, R
2Be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In yet another aspect, R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In yet another aspect, R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
In yet another aspect, R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH by one or more
2,-CONHCH
3With-CON (CH
3)
2
In yet another aspect, R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH by one or more
2,-CONHCH
3With-CON (CH
3)
2
In yet another aspect, R
2By-NR
17SO
2R
18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH
2,-CONHCH
3With-CON (CH
3)
2
In yet another aspect, R
2By-NHSO
2R
18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH
2,-CONHCH
3With-CON (CH
3)
2
In yet another aspect, R
2By-NHSO
2R
18Replace, also choose wantonly by one or more phenyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH
2,-CONHCH
3With-CON (CH
3)
2
In yet another aspect, R
2Be optional quilt-NR
17SO
2R
18The phenyl or the pyridyl that replace.
In yet another aspect, R
2Be optional quilt-NHSO
2R
18The phenyl or the pyridyl that replace.
In yet another aspect, R
2Be
A wherein
1And A
2Be selected from CH or N, condition is at least one A
1Or A
2Be CH.
In yet another aspect, R
2Be
A wherein
1And A
2Be selected from CH or N, condition is at least one A
1Or A
2Be CH.
R
4
In one aspect of the invention, R
4Be hydrogen or methyl.
In yet another aspect, R
4Be hydrogen.
R 4 With
R 1
In another aspect of the present invention, as X when being following :-NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-NR
4C (O)-,-NR
4C (O) NR
5-or-NR
4S (O)
2-, R
1And R
4The atom that is connected with them forms 5-to 10-unit heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In another aspect of the present invention, as X when being following :-NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-NR
4C (O)-,-NR
4C (O) NR
5-or-NR
4S (O)
2-, R
1And R
4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
R
5
In one aspect of the invention, R
5Be hydrogen or methyl.
In yet another aspect, R
5Be hydrogen.
In yet another aspect, R
5It is methyl.
R
6
In one aspect of the invention, R
6Be hydrogen or methyl.
In yet another aspect, R
6Be hydrogen.
In yet another aspect, R
6It is methyl.
R
7
In one aspect of the invention, R
7Be hydrogen or methyl.
In yet another aspect, R
7Be hydrogen.
In yet another aspect, R
7It is methyl.
R
8
In one aspect of the invention, R
8It is hydrogen or halogen.
In yet another aspect, R
8Be hydrogen or fluorine.
Further, R
8Be hydrogen.
R
9
In one aspect of the invention, R
9Be hydrogen or optional by 1,2 or 3 C that is selected from following substituted radical replacement
1-4Alkyl: halogen, cyano group, nitro, hydroxyl, C
1-4Alkoxyl group, amino, C
1-4Alkylamino and two (C
1-4Alkyl) amino.
In yet another aspect, R
9Be hydrogen or the optional C that is replaced by 1,2 or 3 halogenic substituent
1-4Alkyl.
Further, R
9Be hydrogen, methyl or trifluoromethyl.
R
10
In one aspect of the invention, R
10Be hydrogen.
R
11
In one aspect of the invention, R
11Be hydrogen or be selected from C
1-4The group of the assorted alkyl of alkyl, aryl and ring, this group is optional to be replaced by 1,2 or 3 group that is selected from halogen, hydroxyl and cyano group.
In yet another aspect, R
11Be hydrogen, optional by methyl, phenyl or the pyrrolidyl of hydroxyl or cyano group replacement.
In yet another aspect, R
11Be hydrogen or methyl.
R
12
In one aspect of the invention, R
12Be hydrogen or methyl.
R
17
In one aspect of the invention, R
17Be hydrogen or be selected from following group: C
1-4Alkyl, the assorted alkyl of aryl and ring, this group is optional to be selected from following group replacement by 1,2 or 3: halogen, hydroxyl and cyano group.
In yet another aspect, R
17Be hydrogen, optional by methyl, phenyl or the pyrrolidyl of hydroxyl or cyano group replacement.
In yet another aspect, R
17Be hydrogen or methyl.
In yet another aspect, R
17Be hydrogen.
R
18
In one aspect of the invention, R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In one aspect of the invention, R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, phenyl, naphthyl, pyrryl, imidazolyl , isoxazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, azepine (aza) indyl, indyl, quinolyl, benzimidazolyl-, benzofuryl, dibenzofuran group, benzothienyl, phenyl C
1-6Alkyl, naphthyl C
1-6Alkyl, pyrryl C
1-6Alkyl, imidazolyl C
1-6Alkyl , isoxazolyl C
1-6Alkyl, pyrazolyl C
1-6Alkyl, furyl C
1-6Alkyl, thienyl C
1-6Alkyl, pyridyl C
1-6Alkyl, pyrimidyl C
1-6Alkyl, pyridazinyl C
1-6Alkyl, azaindolyl C
1-6Alkyl, indyl C
1-6Alkyl, quinolyl C
1-6Alkyl, benzimidazolyl-C
1-6Alkyl, benzofuryl C
1-6Alkyl, dibenzofuran group C
1-6Alkyl, benzothienyl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In one aspect of the invention, R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In one aspect of the invention, R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH
2(cyclopropyl) ,-CH
2CH
2NMe
2,-CH (CH
3) CH
2OH ,-C (CH
3)
2CH
2OH ,-CH
2CH
2OH ,-CH
2CH
2CH
2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH
2(imidazoles-2-yl) ,-CH
2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl.
In one aspect of the invention, R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, butyl, cyclopropyl and 4-fluorophenyl.
Hypotype or its pharmacologically acceptable salt of formula (I) compound are provided in one aspect of the invention; M is 0,1 or 2;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-NR
4C (O)-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R
9,-OR
9,-COR
9,-CONR
9R
10,-NR
9R
10With-NR
9COR
10Or X-R
1Be-C (CH
3)
2OH or-CH
2OH;
R
2Be selected from aryl and heteroaryl, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
When existing, each R
3It is methyl;
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or, as X when being following :-NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4C (O)-or-NR
4S (O)
2-, R
1And R
4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino;
With
R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In another aspect of the present invention, provide hypotype or its pharmacologically acceptable salt of formula (I) compound; M is 0,1 or 2;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-NR
4CH
2-,-OCH
2-,-OCH (CH
3)-,-OC (CH
3)
2-,-SCH
2-,-SCH (CH
3)-,-SC (CH
3)
2-,-S (O) CH
2-,-S (O) CH (CH
3)-,-S (O) C (CH
3)
2-,-S (O)
2CH
2-,-S (O)
2CH (CH
3)-,-S (O)
2C (CH
3)
2-,-C (O) NR
4-and-NR
4C (O)-;
R
1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R
9,-OR
9,-COR
9,-CONR
9R
10,-NR
9R
10With-NR
9COR
10
Or X-R
1Be-C (CH
3)
2OH or-CH
2OH;
R
2Be selected from 5 or 6 yuan of aryl and heteroaryl, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
When existing, each R
3It is methyl;
R
4Be hydrogen or C
1-6Alkyl;
Or as X be-NR
4CH
2-or-NR
4C (O)-time, R
1And R
4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino;
R
11And R
12Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino; With
R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In another specific category of formula (I) compound or pharmaceutically acceptable salt thereof;
M is O or 1;
1Y is CH, Y
2Be N;
X is selected from following connection base :-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-;
R
1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH
3,-CONH
2With-CONHCH
3
Or-XR
1Be-C (CH
3)
2OH or-CH
2OH;
R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
When existing, R
3It is methyl;
R
11And R
12Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino; With
R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In the further specific category of formula (I) compound or pharmaceutically acceptable salt thereof;
M is 1;
X is selected from following connection base :-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-;
1Y is CH, Y
2Be N.
R
1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH
3,-CONH
2With-CONHCH
3
R
2By-NHSO
2R
18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH
2,-CONHCH
3With-CON (CH
3)
2
R
3It is methyl; With
R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In the further specific category of formula (I) compound or pharmaceutically acceptable salt thereof;
M is 1;
X is selected from following connection base :-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-;
1Y is CH, Y
2Be N.
R
1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH
2CH
2OH ,-CH
2CH
2NC (O) CH
3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base;
R
2Be
Wherein: A
1And A
2Be selected from CH or N, condition is at least one A
1Or A
2Be CH;
R
17Be hydrogen;
R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH
2(cyclopropyl) ,-CH
2CH
2NMe
2,-CH (CH
3) CH
2OH ,-C (CH
3)
2CH
2OH ,-CH
2CH
2OH ,-CH
2CH
2CH
2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH
2(imidazoles-2-yl) ,-CH
2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl;
With, R
3It is methyl.
In one aspect of the invention, the formula (Ia) or (Ib) hypotype of compound are provided
Or its pharmacologically acceptable salt;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-NR
4C (O)-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: C
1-6Alkyl, carbocyclic ring, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R
9,-OR
9,-COR
9,-CONR
9R
10,-NR
9R
10And-NR
9COR
10Or X-R
1Be-C (CH
3)
2OH or-CH
2OH;
R
2Be selected from aryl and heteroaryl, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
R
3It is methyl;
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or, as X when being following :-NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4C (O)-or-NR
4S (O)
2-, R
1And R
4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino;
With
R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In another aspect of the present invention, the formula (Ia) or (Ib) hypotype of compound are provided
Or its pharmacologically acceptable salt;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be N, another is CR
8
X is selected from following connection base :-NR
4CH
2-,-OCH
2-,-OCH (CH
3)-,-OC (CH
3)
2-,-SCH
2-,-SCH (CH
3)-,-SC (CH
3)
2-,-S (O) CH
2-,-S (O) CH (CH
3)-,-S (O) C (CH
3)
2-,-S (O)
2CH
2-,-S (O)
2CH (CH
3)-,-S (O)
2C (CH
3)
2-,-C (O) NR
4-and-NR
4C (O)-;
R
1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R
9,-OR
9,-COR
9,-CONR
9R
10,-NR
9R
10With-NR
9COR
10
Or X-R
1Be-C (CH
3)
2OH or-CH
2OH;
R
2Be selected from 5 or 6 yuan of aryl and heteroaryl, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
R
3It is methyl;
R
4Be hydrogen or C
1-6Alkyl;
Or as X be-NR
4CH
2-or-NR
4C (O)-time, R
1And R
4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino;
R
11And R
12Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino; With
R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In formula (Ia) or (Ib) in another specific category of compound or pharmaceutically acceptable salt thereof;
1Y is CH, Y
2Be N;
X is selected from following connection base :-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-;
R
1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH
3,-CONH
2With-CONHCH
3
Or-XR
1Be-C (CH
3)
2OH or-CH
2OH;
R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHSO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
R
3It is methyl;
R
11And R
12Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino and two (C
1-6Alkyl) amino; With
R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In formula (Ia) or (Ib) in the further specific category of compound or pharmaceutically acceptable salt thereof;
X is selected from following connection base :-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-;
1Y is CH, and Y
2Be N.
R
1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH
3,-CONH
2With-CONHCH
3
R
2By-NHSO
2R
18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH
2,-CONHCH
3With-CON (CH
3)
2
R
3It is methyl; With
R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
In formula (Ia) or (Ib) in the further specific category of compound or pharmaceutically acceptable salt thereof;
M is 1;
X is selected from following connection base :-S (O)
2CH
2-,-S (O)
2CH (CH
3)-and-S (O)
2C (CH
3)
2-;
1Y is CH, Y
2Be N.
R
1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH
2CH
2OH ,-CH
2CH
2NC (O) CH
3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base,, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base;
R
2Be
A wherein
1And A
2Be selected from CH or N, condition is at least one A
1Or A
2Be CH;
R
17Be hydrogen; With
R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH
2(cyclopropyl) ,-CH
2CH
2NMe
2,-CH (CH
3) CH
2OH ,-C (CH
3)
2CH
2OH ,-CH
2CH
2OH ,-CH
2CH
2CH
2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH
2(imidazoles-2-yl) ,-CH
2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl;
With, R
3It is methyl.
Another aspect of the present invention provides each a kind of compound or combination of compounds or its pharmacologically acceptable salt that is selected from embodiment.
The present invention also provides the method for preparation formula (I) compound or pharmaceutically acceptable salt thereof.
The compound of formula (I), wherein X=-S (O)
2CR
6R
7-, can be prepared as follows: at room temperature, in water and ethanol mixed solvent system, (for example) uses
With the compound oxidation of formula (I), wherein X=SCR
6R
7-.
The compound of formula (I), wherein R
1X=R
1OCR
6R
7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (I) (R wherein
1X=HOCR
6R
7-) with the compound of formula (II) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react.
The compound of formula (I), wherein R
1X=R
1R
4NCR
6R
7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (I) (R wherein
1X=HR
4NCR
6R
7-) with the compound of formula (II) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react; Or, at suitable reductive agent NaCNBH for example
3Existence under, the compound of formula (I) (R wherein
1X=HR
4NCR
6R
7-) react with the compound of formula (III).
The compound of formula (I), wherein X
1-S (O)
2CR
6R
7-,-SCR
6R
7-,-OCR
6R
7-,-R
4NCR
6R
7-,-S (O) CR
6R
7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (IV) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with the compound of formula V.
The compound of formula (I), wherein X
1=-SCR
6R
7-, can be prepared as follows: at suitable solvent for example in the ethanol, the compound of formula (IV) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with thiocarbamide; the compound of production (VI); then; at appropriate base sodium hydroxide and solvent N for example for example; under the existence of dinethylformamide, the compound of formula (VI) and the compound of formula (II) are reacted.
The compound of formula (I), wherein X=-R
4NC (O)-, can be prepared as follows: the compound of formula (VII) and formula R
1R
4The amine of NH reacts, and with known method in the document, for example uses for example HATU of coupler, or is converted into chloride of acid before this reaction, and carboxylic acid is suitably activated.
The compound of formula (I), wherein X=-S (O)
2CR
6R
7-, can be prepared as follows: appropriate base for example sodium hydride or potassium tert.-butoxide in the presence of, at suitable solvent for example tetrahydrofuran (THF) or N, in the dinethylformamide, the compound of formula (I) (X=-S (O) wherein
2CH
2-) continuously the compound with formula (VIII) react, then with the compound of formula (IX) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) reaction.
The compound of formula (I), wherein R
1X=HOCR
6R
7-, can be prepared as follows: in suitable solvent, the suitable organometallic compound of the compound of formula (X) and formula (XI) and formula (XII) for example Grignard reagent reacts.If R
6And R
7Be different, in step subsequently, can use known technology in the document so, for example the compound of formula (X) is converted into the Weinreb acid amides, and with the reaction of the organometallic reagent of formula (XI), then with the organometallic reagent reaction of formula (XII).
The compound of formula (I) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XIII) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)) with suitable organometallic reagent (boric acid R for example
2B (OH)
2Or boric acid ester R
2B (OR)
2Or the like) prepare.Perhaps, if R
2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (I) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XIII) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)), by reacting with required amine, alcohol or mercaptan.
Should be understood that utilize above-listed or document in for example oxidation of known technology, alkylation, reduction amination or the like, the compound of formula (XIII) can be transformed into the compound of another formula (XIII).
The compound of formula (XIII), wherein X
1=-S (O)
2CR
6R
7-,-SCR
6R
7-,-OCR
6R
7-,-R
4NCR
6R
7-,-S (O) CR
6R
7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (XIV) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with the compound of formula V.
The compound of formula (XIII), wherein X
1=-SCR
6R
7-, can be prepared as follows: at suitable solvent for example in the ethanol, the compound of formula (XIV) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with thiocarbamide; the compound of production (XV); then; at appropriate base sodium hydroxide and solvent N for example for example; under the existence of dinethylformamide, the compound of formula (XV) and the compound of formula (II) are reacted.
The compound of formula (XIII), wherein X-R
4NC (O)-, can be prepared as follows: the compound of formula (XVI) and formula R
1R
4The amine of NH reacts, and with known method in the document, for example uses for example HATU of coupler, or is converted into chloride of acid before this reaction, and carboxylic acid is suitably activated.
The compound of formula (XIII), wherein X=-S (O)
2CR
6R
7-, can be prepared as follows: appropriate base for example sodium hydride or potassium tert.-butoxide in the presence of, at suitable solvent for example tetrahydrofuran (THF) or N, in the dinethylformamide, the compound of formula (XIII) (X=-S (O) wherein
2CH
2-) continuously and the compound of formula (VIII) react, then with the compound of formula (IX) (L wherein
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) reaction.
The compound of formula (XIII), wherein R
1X=HOCR
6R
7-, can be prepared as follows: in suitable solvent, the suitable organometallic compound of the compound of formula (XVII) and formula (XI) and formula (XII) for example Grignard reagent reacts.If R
6And R
7Be different, in step subsequently, can use known technology in the document so, for example the compound of formula (XVII) is converted into the Weinreb acid amides, and with the reaction of the organometallic reagent of formula (XI), then with the organometallic reagent reaction of formula (XII).
The compound of formula (IV) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XIV) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like), L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) with suitable organometallic reagent (boric acid R for example
2B (OH)
2Or boron ester R
2B (OR)
2Or the like) prepare.Perhaps, if R
2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (IV) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XIV) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)), by reacting with required amine, alcohol or mercaptan.
The compound of formula (X) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XVII) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like), R is hydrogen or C
1-4Alkyl) with suitable organometallic reagent (boric acid R for example
2B (OH)
2Or boron ester R
2B (OR)
2Or the like) prepare.Perhaps, if R
2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (X) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XVII) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)), by reacting with required amine, alcohol or mercaptan.
The compound of formula (XVIII) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XIX) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)) with suitable organometallic reagent (boric acid R for example
2B (OH)
2Or boron ester R
2B (OR)
2Or the like) prepare.Perhaps, if R
2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (XVIII) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XIX) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)), by reacting with required amine, alcohol or mercaptan.
The compound of formula (XX) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XXI) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)) with suitable organometallic reagent (boric acid R for example
2B (OH)
2Or boron ester R
2B (OR)
2Or the like) prepare.Perhaps, if R
2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (XX) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XXI) (L wherein
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like)), by reacting with required amine, alcohol or mercaptan.
The compound of formula (I), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like); can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of; at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXII) and formula (XXIII) reacts.
Should be understood that utilize above-listed or document in for example oxidation of known technology, alkylation, reduction amination or the like, the compound of formula (XXII) can be become the compound of another formula (XXII).
The compound of formula (IV), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like); can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of; at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXIV) and formula (XXIII) reacts.
The compound of formula (X), wherein L
1Be that leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like) and R are hydrogen or C
1-4Alkyl can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXV) and formula (XXIII) reacts.
The compound of formula (XVIII), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like); can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of; at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXVI) and formula (XXIII) reacts.
The compound of formula (XX), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXVII) and formula (XXIII) reacts.
The compound of formula (XIII), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXVIII) and formula (XXIII) reacts.
Should be understood that utilize above-listed or document in for example oxidation of known technology, alkylation, reduction amination or the like, the compound of formula (XIII) can be transformed into the compound of another formula (XIII).
The compound of formula (XIV), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXIX) and formula (XXIII) reacts.
The compound of formula (XVII), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like) and R be hydrogen or C
1-4Alkyl can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXX) and formula (XXIII) reacts.
The compound of formula (XIX), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXXI) and formula (XXIII) reacts.
The compound of formula (XXI), wherein L
1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L
2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O)
2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXXII) and formula (XXIII) reacts.
The compound of formula (I), wherein R
1X=H
2NCH
2-, can be prepared as follows: at suitable solvent for example in the ethanol, with hydrogen and suitable catalyst for example palladium/carbon with the compound reduction of formula (XVIII), for example hydrogenation.
The compound of formula (I), wherein R
1X=H
2NC (O)-, can be prepared as follows: at suitable solvent for example in the water-ethanol admixture, with sodium hydroxide for example with the compound hydrolysis of formula (XVIII).
The compound of formula (I), wherein R
1X=H
2NCR
6R
7-, can be prepared as follows: react by the compound of formula (XVIII) and organometallic compound (XI) with (XII).
The compound of formula (XIII), wherein R
1X=H
2NCH
2-, can be prepared as follows: at suitable solvent for example in the ethanol, with hydrogen and suitable catalyst for example palladium/carbon with the compound reduction of formula (XIX), for example hydrogenation.
The compound of formula (XIII), wherein R
1X=H
2NC (O)-, can be prepared as follows: at suitable solvent for example in the water-ethanol admixture, with sodium hydroxide for example with the compound hydrolysis of formula (XIX).
The compound of formula (XIII), wherein R
1X=H
2NCR
6R
7-, can be prepared as follows: the compound of formula (XIX) and organometallic compound (XI) and (XII) react.
Should be understood that R
2Group can (be chosen wantonly and protect with nitrogen with the form of carbocyclic ring or heterocyclic amine at first; this protecting group is including, but not limited to nitro, tert.-butoxy carbamate or the like) introduce in any stage; in the presence of appropriate base; by reacting with SULPHURYL CHLORIDE (or other suitable activation species); or utilizing that known other forms the method for sulphonamide in the document, it can be converted into sulphonamide at synthetic follow-up phase (after the suitable deprotection).
Should be understood that some the various ring substituents in The compounds of this invention, can introduce or produce that immediately, this is included in the method for the present invention aspect before or after said process by the substitution reaction of standard aromatics by conventional modified with functional group.For example, utilize the substitution reaction of standard aromatics or pass through conventional modified with functional group, the compound of formula (I) can change other formula (I) compound into.This reaction and modification comprise: for example, introduce substituting group by means of aromatics substitution reaction, substituent reduction, substituent alkylation and substituent oxidation.The reagent of this method and reaction conditions are well-known at chemical field.The object lesson of aromatics substitution reaction comprises: use concentrated nitric acid to introduce nitro, under the Friedel processing condition, use for example acyl halide and Lewis acid (for example aluminum chloride) introducing acyl group; Under the Friedel processing condition, use haloalkane and Lewis acid (for example aluminum chloride) to introduce alkyl; With the introducing halogen group.The object lesson of modifying comprises: handling (in the presence of hydrochloric acid, heating) by for example catalytic hydrogenation (using nickel catalyzator) or with iron, is amino with nitroreduction; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.
Should also be understood that in some reactions that this paper mentions, may need/wish any sensitive group in the protection compound.The situation that needs or wish to protect and the appropriate method of protection are known to those skilled in the art.Can use GPF (General Protection False base (explanation for example,, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991) according to standard practices referring to T.W.Green.Thus, if reactant comprises group for example amino, carboxyl or hydroxyl, may in some reactions that this paper mentions, protect this group.
The appropriate protection base of amino or alkylamino is an acyl group for example, alkyloyl ethanoyl for example for example, carbalkoxy, for example methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyl, aryl methoxycarbonyl, for example carbobenzoxy-(Cbz), or aroyl, for example benzoyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Thus, for example, acyl group is alkyloyl or carbalkoxy or aroyl for example, can be for example by with appropriate base for example alkali metal hydroxide for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps; acyl group is tertbutyloxycarbonyl for example; can for example remove by handling with appropriate acid (for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid); for aryl methoxycarbonyl carbobenzoxy-(Cbz) for example, can be for example by with catalyzer for example carbon carry palladium hydrogenation or by with Lewis acid for example three (trifluoroacetic acid) boron handle and remove.For the suitable possible protecting group of primary amino is phthaloyl for example, and it can be by with alkylamine dimethylamino propylamine or handle with hydrazine and to remove for example.
The appropriate protection base of hydroxyl is an acyl group for example, alkyloyl ethanoyl for example for example, and aroyl is benzoyl for example, or arylmethyl benzyl for example.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Thus, for example, acyl group is alkyloyl or aroyl for example, can be for example by with appropriate base for example alkali metal hydroxide for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps, for arylmethyl benzyl for example, can be for example by with catalyzer for example carbon carry palladium hydrogenation and remove.
The appropriate protection base of carboxyl is an esterified group for example; for example methyl or ethyl; its can be for example by with alkali for example sodium hydroxide hydrolysis remove; or the tertiary butyl for example; its can be for example by with acid for example organic acid for example trifluoroacetic acid handle and remove; or benzyl for example, its can be for example by with catalyzer for example carbon carry palladium hydrogenation and remove.
In the traditional method of using chemical field to know synthetic, can be in office what easily step remove protecting group.
Many intermediates defined herein are new, and provide these intermediates as further feature of the present invention.
Biological test
Following test can be used for measuring The compounds of this invention as the mTOR kinase inhibitor, as the PI3 kinase inhibitor, as the activatory vitro inhibition agent of PI3 kinase signal path with as the effect of the vitro inhibition agent of MDA-MB-468 human breast adenocarcinoma cell propagation.
(a)
External mTOR kinase assay
This test use the AlphaScreen technology (people such as Gray, Analytical Biochemistry, 2003,313:234-245), the determination test compound suppresses the ability by recombinant chou mTOR phosphorylation.
In the HEK293 cell, the C end disappearance (EMBL accession designation number L34075) that will comprise the mTOR of mTOR amino-acid residue 1362 to 2549 stably is expressed as the fusions of FLAG mark, as people such as Vilella-Bach, at Journal of Biochemistry, 1999,274, as described in the 4266-4272.MTOR (1362-2549) stabilized cell of HEK293 FLAG mark is tied up to Dulbecco modification Eagle ' s growth medium (DMEM; InvitrogenLimited, Paisley, UK Catalogue No.41966-029) in use 5%CO
237 ℃ of conventional down maintenances, merge until reaching 70-90%, growth medium comprises the fetus calf serum (FCS of 10% heat inactivation; Sigma, Poole, Dorset, UK, Catalogue No.F0392), 1%L-glutamine (Gibco, Catalogue No.25030-024) and 2mg/mlGeneticin (G418 vitriol; Invitrogen Limited, UK Catalogue No.10131-027).After in warm-blooded animal HEK293 clone, expressing, use FLAG epi-position mark to come purifying expressed proteins (using the standard purification technology).
In DMSO, test compound is prepared as the 10mM stock solution, and is diluted to as required in the water, obtain a series of final experimental concentration.Each diluted chemical compound thing of equal portions (2 μ l) is put into the hole of the Greiner white polystyrene plates of 384 hole lower volume (LV) (Greiner Bio-one).Biotinylated peptide matrix (the Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-T yr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH of mTOR enzyme, 1 μ M with the recombinant chou purifying
2Bachem UK Ltd), ATP (20 μ M) and buffering solution [comprise Tris-HCl pH7.4 damping fluid (50mM), EGTA (0.1mM), bovine serum albumin (0.5mg/mL), DTT (1.25mM) and Manganous chloride tetrahydrate (10mM)] 30 μ l mixtures at room temperature stirred 90 minutes.
Use 5%DMSO to replace test compound, create the control wells that produces peak signal (being equivalent to maximum enzyme activity).Replace test compound by adding EDTA (83mM), create the control wells that produces minimum signal (enzyme that is equivalent to suppress fully).At room temperature, these testing liquids were cultivated 2 hours.
By adding 10 μ l EDTA (50mM), bovine serum albumin (BSA; 0.5mg/mL) and Tris-HCl pH7.4 damping fluid (50mM) (comprise p70 S6 kinases (T389) 1A5 monoclonal antibody (Cell Signalling Technology, Catalogue No.9206B) and the AlphaScreenStreptavidin donor) mixture stop each reaction, add A protein receptor bead (200ng; Perkin Elmer, Catalogue No. is respectively 6760002B and 6760137R), at room temperature, in the dark will test plate and place about 20 hours.Use Packard Envision instrument, read the signal (producing by laser excitation) that obtains at 680nm.
Because the phosphorylation of mTOR mediation, original position has formed the biotinylation peptide of phosphorylation.The biotinylation peptide of the phosphorylation relevant with AlphaScreen Streptavidin donor bead forms mixture with p70S6 kinases (T389) 1A5 monoclonal antibody (it is relevant with Alphascreen albumin A acceptor bead).In case in 680nm laser excitation, the donor bead: acceptor bead mixture just produces the signal that can measure.Correspondingly, the existence of mTOR kinase activity can produce test signal.In the presence of the mTOR kinase inhibitor, strength of signal reduces.
For the test compound that is given, the mTOR enzyme suppresses can be with IC
50Value representation.
(b)
External PI3K enzyme test
This test use the AlphaScreen technology (people such as Gray, Analytical Biochemistry, 2003,313:234-245), suppress the ability of the recombinant type I PI3K enzyme phosphorylation of lipid PI (4,5) P2 with the determination test compound.
Use standard molecular biology and PCR clone technology, separate the dna fragmentation of coding people's PI3K catalysis and regulator subunit from the cDNA storehouse.Selected dna fragmentation is used to produce rhabdovirus expression vector.Especially, with the full length DNA subclone of the human PI3K p110 heterogeneous of each p110 α, p110 β and p110 δ type Ia (the EMBLAccession Nos. for p110 α, p110 β and p110 δ is respectively HSU79143, S67334, Y10055) to pDEST10 carrier (Invitrogen Limited, Fountain Drive, Paisley, UK) in.Carrier is the inlet adaptive version that comprises the Fastbac1 of 6-His epi-position mark.With the intercepting form (being equivalent to amino-acid residue 144-1102 (EMBL Accession No.X8336A)) of the human PI3K p110 of Ib class γ heterogeneous and total length mankind's p85 α regulator subunits (EMBL Accession No.HSP13KIN) also subclone in the pFastBac1 carrier that comprises 6-His epi-position mark.With p85 α regulator subunit co expression type i a p110 structure.After use standard baculovirus expression technology is expressed, use the standard purification technology in rhabdovirus system, use His epi-position mark, the expressed proteins purifying.
Use standard molecular biology and PCR clone technology, from cDNA storehouse DNA isolation (it is equivalent to the amino acid 263 to 380 of the general acceptor in human phosphatase inositol (Grp1) PH zone).The dna fragmentation subclone that obtains (is comprised GST epi-position mark (Amersham Pharmacia Biotech, Rainham, Essex to pGEX 4T1 coli expression carrier, UK)) in, as people such as Gray, at Analytical Biochemistry, 2003, described in the 313:234-245.Express the Grp1 PH zone of GST mark, and use the standard technique purifying.
In DMSO, test compound is prepared as the 10mM stock solution, and is diluted to as required in the water, obtain a series of final experimental concentration.Each diluted chemical compound thing of equal portions (2 μ l) is put into white polystyrene plate (the Greiner Bio-one of Greiner 384 hole lower volume (LV), Brunel Way, Stonehouse, Gloucestershire, UK Catalogue No.784075) the hole in.PI3K enzyme (15ng), DiC8-PI (4,5) P2 matrix (40 μ M with each selected recombinant chou purifying; Cell Signals Inc., Kinnear Road, Columbus, USA, CatalogueNo.901), Adenosine Triphosphate (ATP; 4 μ M) and buffering solution [comprise Tris-HCl pH7.6 damping fluid (40mM, 10 μ l), 3-[(3-courage amido propyl) dimethylamino]-1-propanesulfonic acid inner salt (CHAPS; 0.04%) dithiothreitol (DTT) (DTT; 2mM) and magnesium chloride (10mM)] mixture at room temperature stirred 20 minutes.
Use 5%DMSO to replace test compound, create the control wells that produces minimum signal (being equivalent to maximum enzyme activity).Add wortmannin (6uM; Calbiochem/MerckBioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No.681675) replace test compound, establishment can produce the control wells of peak signal (enzyme that is equivalent to suppress fully).At room temperature, also these testing liquids were stirred the companion 20 minutes.
Stop each reaction by the mixture that adds 10 μ l EDTA (100mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl pH7.6 damping fluid (40mM).
Add biotinylated-DiC8-PI (3,4,5) P3 (50nM; Cell Signals Inc., Catalogue No.107), GST-Grp1 PH albumen (2.5nM) and the anti-GST donor of AlphaScreen and the acceptor bead (100ng of recombinant chou purifying; Packard BioscienceLimited, Station Road, Pangbourne, Berkshire, UK, Catalogue No.6760603M), at room temperature, in the dark will test plate and place about 5 to 20 hours.Use Packard AlphaQuest instrument, read the signal (causing by laser excitation) that obtains at 680nm.
Because the phosphorylation of the PI3K of PI (4,5) P2 mediation, original position forms PI (3,4,5) P3.GST-Grp1 PH region protein (it is relevant with the anti-GST donor of AlphaScreen bead) forms mixture with biotinylated PI (3,4,5) P3 (it is relevant with Alphascreen Streptavidn acceptor bead).Enzyme living PI (3,4,5) P3 and biotinylated PI (3,4,5) the P3 competition of hastening parturition combines with the PH region protein.In case in 680nm laser excitation, the donor bead: acceptor bead mixture produces the signal that can measure.Correspondingly, the PI3K enzymic activity forms PI (3,4,5) P3 and competes with biotinylated PI (3,4,5) P3 subsequently, causes signal to reduce.In the presence of the PI3K enzyme inhibitors, strength of signal is recovered.
For the test compound that is given, the PI3K enzyme suppresses with IC
50Value representation.
(c)
External phosphate-Ser473 Akt test
This test determination test compound suppresses Serine 473 suppresses phosphorylation in Akt ability, uses Acumen Explorer technology (Acumen Bioscience Limited), plate reader (feature that can be used for rapid determination image that laser scanning produces) to estimate.
In DMEM (FCS and the 1%L-glutamine that comprise 10% heat inactivation), (LGC Promochem, Teddington, Middlesex, UK, Catalogue No.HTB-132) uses 5%CO with MDA-MB-468 human breast gland cell system
2Routine remains on 37 ℃, until the fusion that reaches 70-90%.
For this test, use ' Accutase ' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No.AT104), uses the normal structure culture method, cell is shifted out from culturing bottle, and be resuspended in the medium, obtain every mL 1.7x10
5Individual cell.Aliquot sample (90 μ l) is seeded into black Packard 96 hole plate (PerkinElmer, Boston, MA, USA; Catalogue No.6005182) in inner 60 holes of each, obtains the density of every hole~15000 cell.Equal portions (90 μ l) substratum medium is placed in the external holes, to prevent fringing effect.With cell 5%CO
237 ℃ of following overnight incubation, make them bonding.
At the 2nd day, handle cell with test compound, and use 5% CO
2Cultivated 2 hours down at 37 ℃.In DMSO, test compound is prepared as the 10mM stock solution, and uses the growth medium serial dilution as required, obtain a series of concentration (its be required final experimental concentration 10 times).Each diluted chemical compound thing of equal portions (10 μ l) is placed on (in triplicate) in the hole, obtains the concentration of ultimate demand.As minimum response contrast, each plate comprises the have 100 μ MLY294002 hole of final concn of (Calbiochem, Beeston, UK, Catalogue No.440202).As the peak response contrast, the hole comprises 1% DMSO and replaces test compound.After the cultivation, handled 1 hour, the inclusion of plate is fixed by at room temperature using 1.6% formalin (Sigma, Poole, Dorset, UK, Catalogue No.F1635).
Use Tecan 96 holes to wash dish device (pumping velocity 10mm/sec), carry out all suction and washing steps subsequently.Remove stationary liquid, with phosphate-buffered saline (PBS; 50 μ l; Gibco, Catalogue No.10010015) inclusion of washing plate.At room temperature, with the cell permeabilization damping fluid (mixture that comprises PBS and 0.5%Tween-20) of equal portions (50 μ l) inclusion of plate was handled 10 minutes.Remove ' saturatingization ' damping fluid, at room temperature, in the mixture of PBS and 0.05%Tween-20, with comprising 5% skim-milk [' Marvel ' (registered trademark); Premier Beverages, Stafford, GB] equal portions (50 μ l) sealing damping fluid handled 1 hour, with nonspecific binding site sealing.Remove ' sealing ' damping fluid, and at room temperature with the anti-phosphate-Akt of rabbit (Ser473) antibody-solutions (every hole 50 μ l; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) (diluting 1: 500 in ' sealing ' damping fluid) with cell cultures 1 hour.Washed cell is three times in the mixture of PBS and 0.05%Tween-20.Subsequently, at room temperature, with the anti-rabbit igg of Alexafluor488 labelled goat (every hole 50 μ l; Molecular Probes Invitrogen Limited, Paisley, UK, Catalogue No.A11008) (being diluted to 1: 500 in ' sealing ' damping fluid) with cell cultures l hour.With the mixture washed cell of PBS and 0.05%Tween-20 3 times.The PBS (50 μ l) of equal portions is joined in each hole, seal plate with black plate sealer, and detection and analysis of fluorescence signal.
The fluorescent agent quantitative response data that each compound obtains are analyzed, and the inhibition kilsyth basalt of Serine 473 that will be in Akt is shown IC
50Value.
(d)
External MDA-MB-468 human breast gland cancer proliferation test
This test determination test compound suppresses the ability of cell proliferation, uses the CellomicsArrayscan technology to estimate.According to the conventional MDA-MB-468 human breast gland cell system (LGC Promochem, Catalogue No.HTB-132) that keeps that comes described in this paper biology mensuration (b).
For this proliferation test, to use Accutase that cell is removed from culturing bottle, and be seeded in 60 holes, inside of black Packard 96 hole plates, density is 8000 cells in every hole, in the complete growth medium of 100 μ l.External holes comprises the aseptic PBS of 100 μ l.With cell 5%CO
237 ℃ of following overnight incubation, make them bonding.
At the 2nd day, handle cell with test compound, and use 5%CO
2Cultivated 48 hours down at 37 ℃.In DMSO, test compound is prepared as the 10mM stock solution, and uses the growth medium serial dilution as required, obtain a series of experimental concentration.Each diluted chemical compound thing of equal portions (50 μ l) is placed in the hole, uses 5%CO
2Cultivated 2 days down at 37 ℃.Each plate comprises the control wells of no test compound.
At the 4th day, add the reagent (Sigma, Catalogue No.B9285) (finally diluting 1: 1000) of BrdU mark, 37 ℃ of culturing cells 2 hours.Remove medium,, handled 30 minutes with the mixture (90% ethanol, 5% Glacial acetic acid and 5% water) of 100 μ l ethanol and Glacial acetic acid, the cell fixation in each hole by at room temperature.Wash twice in cell in each hole with PBS (100 μ l).(2M, 100 μ l) join in each hole with aqueous hydrochloric acid.After at room temperature 20 minutes, use twice of PBS washed cell.With hydrogen peroxide (3%, 50 μ l; Sigma CatalogueNo.H1009) joins in each hole.After at room temperature 10 minutes, with PBS washing hole once more.
By at room temperature using mouse anti BrdU antibody (50 μ l; Caltag, Burlingame, CA, US; Catalogue No.MD5200) (in the PBS that comprises 1%BSA and 0.05%Tween-20, is diluted to 1: 40) and cultivates the combination that detected BrdU in 1 hour.Remove unconjugated antibody with the PBS washed twice.Visual for introducing BrdU at room temperature, handled cell 1 hour with PBS (50 μ l) and 0.05% Tween-20 damping fluid (1: 1000 dilution that comprises the anti-mouse IgG of Alexa fluor 488 labelled goat).For nuclear visual, and 1: 1000 dilution of adding Hoechst pigment (stain) (Molecular Probes, CatalogueNo.H3570).Each plate is washed with PBS successively.Subsequently, PBS (100 μ l) is joined in each hole, use the Cellomics matrix-scanning to analyze plate, thereby estimate the number of total cell number and BrdU positive cell.
The fluorescent agent quantitative response data that each compound obtains are analyzed, and with the inhibition degree of MDA-MB-468 cell growth with IC
50Value representation.
Although the pharmacology performance of formula (I) compound resemble expectation change with structural modification, people believe usually formula (I) activity that compound had can one or more above-mentioned tests (a) in (d), under following concentration or dosage, obtain the proof :-
Test (a) :-for chemical compound lot, for the kinase whose IC of mTOR
50Value especially less than 5 μ M, for embodiment 4, is measured IC less than 10 μ M under three situations
50Value, value is 3.32,2.49 and 2.25 μ M;
Test (b) :-for the IC of the human PI3K of p110 γ Ib class
50Value is less than 10 μ M; IC for the human PI3K of p110 α type i a
50Value is less than 10 μ M; For embodiment 4, under three situations, measure IC
50Value, value>134,54,>698 μ M, show that this compound may be a mTOR inhibitor optionally;
Test (c) :-for chemical compound lot, for the IC of the Serine among the Akt 473
50Value especially less than 35 μ M, for embodiment 4, is measured IC less than 100 μ M under three situations
50The value, value be 11.29,24.05 and>31.88 μ M;
Test (d) :-IC
50Value is less than 20 μ M;
Compound of the present invention is favourable, because they have pharmacological activity.Especially, The compounds of this invention is regulated (especially suppressing) mTOR kinases and/or phosphatidylinositol-3-kinase (PI3K) enzyme, for example Ia class PI3K enzyme (for example PI3K α, PI3K β and PI3K δ) and Ib class PI3K enzyme (PI3K γ).More particularly, compound adjusting of the present invention (especially suppressing) mTOR kinases.More particularly, one or more PI3K enzyme of compound adjusting of the present invention (especially suppressing).The rejection that can use test method that this paper lists and the test method in the experimental section to come proof formula (I) compound.Correspondingly, formula (I) compound can be used for handling the condition/disease of (treatment or prevention) people and inhuman animal, and this condition/disease is by mTOR kinases and/or the mediation of one or more PI3K enzymes, and is especially kinase mediated by mTOR.
The present invention also provides pharmaceutical composition, and it comprises combining of formula defined herein (I) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable diluent or carrier.
Composition of the present invention can also be the form that is suitable for an orally using (tablet for example, lozenge, hard or soft capsule, moisture or oily suspensions, emulsion, dispersible powder or particle, slurries or elixir), local type of service (emulsifiable paste for example, ointment, gelifying agent or moisture or oily solution or suspension), inhalation form (for example finely divided powder or liquid aerosol), be blown into form of medication (for example finely divided powder) or administered parenterally form (intravenously for example, subcutaneous, the aseptic aqueous solution of intraperitoneal or intramuscularly or oily solution, or be used for the suppository of rectal administration).
Can utilize conventional pharmaceutical vehicle well known in the art, obtain composition of the present invention by ordinary method.Thus, the composition for oral design can comprise for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.
Can need to change with the amount of active ingredients that produces single formulation with one or more mixed with excipients, this depends on the host and the concrete mode of administration of being treated.For example, it (more suitably is 1 to 250mg that the preparation that designs for human oral for example comprises the promoting agent of 1mg to 1g usually, for example 1 to 100mg), promoting agent and suitable and make things convenient for the vehicle of quantity to be mixed, vehicle can be total composition weight about 5 to about 98% between change.
According to character and severity, animal or patient's age and the sex and the route of administration of morbid state,, be used for the treatment of or prevent the amount nature difference of the formula I compound of purpose according to well-known medical principle.
In the process of formula (I) compound that uses treatment or prevention purpose, give per daily dose usually, scope is for example to accept 1mg/kg to 100mg/kg body weight, if necessary, with the separate dosage forms administration.Usually, when using parenteral route, give low dosage.Thus, for example, for intravenous administration, normally used dosage range is 1mg/kg to a 25mg/kg body weight for example.Equally, for inhalation, the dosage range of use is 1mg/kg to a 25mg/kg body weight for example.Typically, unit dosage comprises about 10mg to 0.5g compound of the present invention.
As this paper stated, known mTOR kinases and PI3K enzyme had effect in tumorigenicity and many other diseases.We have found that the compound of formula (I) has the effective antitumour activity, think that this anti-tumor activity obtains by suppressing mTOR kinases and/or one or more PI3K enzymes.
Correspondingly, compound of the present invention is valuable anti-tumor agents.Especially, compound of the present invention suppress and/or treatment entity and/or liquid tumor disease in as antiproliferative, apoptosis and/or anti-to invade medicament be valuable.Especially, expect that compound of the present invention can be effective to prevent or treats suppressing for example those tumours of Ia class PI3K enzyme and Ib class PI3K enzyme sensitivity of mTOR and/or one or more PI3K enzymes.Further, expect compound of the present invention can be effective to prevent treat separately or part by mTOR and/or one or more PI3K enzymes those tumours of Ia class PI3K enzyme and the mediation of Ib class PI3K enzyme for example.Thus, this compound can produce mTOR enzyme inhibition effect in the warm-blooded animal of this treatment of needs.Some compound can produce the PI3K enzyme and suppress effect in the warm-blooded animal of this treatment of needs.
As this paper statement, the inhibitor of mTOR kinases and/or one or more PI3K enzymes has therapeutic value, is used for the treatment of hyperplasia, for example cancer and sarcoma and leukemia and lymph malignant tumour of cancer, especially noumenal tumour for example is in particular for treating for example breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer, cholangiocarcinoma, the bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae, and leukemia [comprising acute lymph leukemia (ALL) and chronic myelogenic leukemia (CML)], multiple myeloma and lymphoma.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used as medicine among the people warm-blooded animal.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce anti-proliferative effect among the people warm-blooded animal.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce the apoptosis effect among the people warm-blooded animal.
According to further feature of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein warm-blooded animal for example among the people as anti-ly invading medicament, be used to suppress and/or treat for example purposes of cancer of hyperplasia.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce the purposes of anti-proliferative effect among the people warm-blooded animal.
According to the further feature of this aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein purposes in the preparation medicine is provided, this medicine be used for warm-blooded animal for example the people produce anti-proliferative effect.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce the purposes of apoptosis effect among the people warm-blooded animal.
According to the further feature of this aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein purposes in the preparation medicine is provided, this medicine be used for warm-blooded animal for example the people produce the apoptosis effect.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is for example invaded medicament as resisting among the people warm-blooded animal, is used for for example cancer of inhibition and/or treatment hyperplasia.
According to the further feature of this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs for example produces the method for anti-proliferative effect among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
Further feature according to this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs for example produces anti-method of invading effect by inhibition and/or treatment noumenal tumour disease among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
According to further aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine for example is used for prevention or treats for example cancer of hyperplasia among the people warm-blooded animal.
Further feature according to this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs is prevention or treatment hyperplasia method for cancer for example among the people for example, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
According to further aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, be used for prevention or treatment to suppressing the responsive tumour of mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib class PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability.
Further feature according to this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is used for prevention or treats suppressing the responsive tumour of mTOR kinases and/or one or more PI3K enzyme (for example Ia fermentoid and/or Ib class PI3K enzyme), and mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability.
Further feature according to this aspect of the present invention, provide prevention or treatment to suppressing the method for the responsive tumour of mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib class PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
According to further aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, be used to provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect).
Further feature according to this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, and this medicine is used to provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect).
According to further aspect of the present invention, a kind of method is provided, be used to provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect), this method comprises the formula I compound or pharmaceutically acceptable salt thereof defined herein that gives significant quantity.
According to further feature of the present invention, provide the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in treatment cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder defined herein.
According to further feature of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein in the treatment noumenal tumour purposes in cancer and sarcoma and leukemia and the lymph malignant tumour for example.
According to further feature of the present invention, provide the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in treatment breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer defined herein.
According to further feature of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, has been used for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is used for the treatment of cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is used for the treatment of noumenal tumour for example cancer and sarcoma and leukemia and lymph malignant tumour.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, and this medicine is used for the treatment of breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, and this medicine is used for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is for example treated the method for cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is the treatment noumenal tumour method of cancer and sarcoma and leukemia and lymph malignant tumour for example among the people for example, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is for example treated the method for breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is for example treated cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphadenomatous method among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
As this paper stated, after the compound of giving construction (I),, can partly bring into play the interior effect of body of formula (I) compound by one or more metabolite that within human or animal body, forms.
The invention further relates to combined therapy, wherein simultaneously or sequentially the compound or pharmaceutically acceptable salt thereof of giving construction (I) or, comprise the pharmaceutical composition or the preparation of formula (I) compound, or give with combination preparation form with employed other treatment of control tumor disease.
Especially, treatment defined herein can be used as monotherapy, or except compound of the present invention, can also comprise routine operation or radiotherapy or chemotherapy.Correspondingly, compound of the present invention can also be used in combination with the existing therapeutical agent of treatment cancer.
The suitable medicament that uses in the combination comprises:
(i) antiproliferative/antitumour drug and its combination, for example for example alkylating agent that uses of medical science oncology (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Metabolic antagonist (antifolate for example, for example 5 FU 5 fluorouracil and Tegafur of fluorine pyrimidine for example, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); Antitumor antibiotics (anthracycline antibiotics for example, Dx for example, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, actinomycin and mithramycin); Antimitotic agent (vinca alkaloids for example, vincristin for example, vincaleucoblastine, desacetyl vinblastine amide and Vinorelbine and Japanese yew class medicine, for example pure and mild taxotere of Pacific yew (taxotere)); With local isomerase inhibitors (epipodophyllotoxin for example, for example Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);
(ii) cytostatic agent, estrogen antagonist (Tamoxifen for example for example, Toremifene Citrate, Reynolds former times phenol, droloxifene and iodoxyfene), estrogen receptor is born conditioning agent (for example fulvestrant), androgen antagonist (for example bicalutamide, flutamide, Nilutamide and acetate Sai Pulong), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogen (for example megestrol), aromatase inhibitor is (for example as Anastrozole, letrozole, vorozole and Exemestane) and the inhibitor of 5 finasteride for example;
(iii) anti-intrusion medicament (for example c-Src kinases man group inhibitor, for example 4-(6-chloro-2,3-methylene dioxo group aniline base)-7-[2-(4-methylpiperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-aminomethyl phenyl)-2-{6-[4-(2-hydroxyethyl) piperazine-1-yl]-2-methylpyrimidine-4-base is amino thiazole-5-carboxylic acid amides (Dasatinib, BMS-354825; J.Med.Chem., 2004,47,6658-6661) and the inhibitors of metalloproteinase inhibitor of Marimastat (marimastat) and upar function for example);
The (iv) inhibitor of somatomedin function: for example, this inhibitor comprises growth factor antibodies and growth factor receptor antibody (for example, anti-erbB 2 antibody Herceptin [Herceptin] and anti-erbB1 antibody Cetuximab [C225]); This inhibitor also comprises for example tyrosine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example for example for example, ZD1839), N-(3-ethynyl phenyl)-6, (the dust Lip river is for the Buddhist nun for 7-two (2-methoxy ethoxy) quinazoline-4-amine, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitor, lapatinibditosylate for example), the inhibitor of pHGF family, the inhibitor of PDGF family, imatinib for example, (for example Ras/Raf signal suppressing agent of the inhibitor of serine/threonine kinase, for example farnesyl transferase inhibitor, for example Xarelto (BAY 43-9006)) and the inhibitor by MEK and/or the kinase whose cell signal of Akt;
(v) anti-angiogenic formation medicament, those medicaments that for example suppress the vascular endothelial growth factor effect, [for example anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF (Avastin) and vegf receptor tyrosine kinase inhibitor, for example 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline (ZD6474; Embodiment 2 among the WO 01/32651), 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline (AZD2171; Embodiment 240 among the WO 00/47212), Wa Talani (vatalanib) (PTK787; WO 98/35985) and SU11248 (Sutent (Sunitinib); WO 01/60814) and the compound by other mechanism work (for example linomide, the inhibitor and the angiostatin of beta 2 integrin alpha v β 3 functions)];
(vi) blood vessel injury agent, for example Combretastatin A-4 4 and the compound that is disclosed among International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and the WO 02/08213;
(vii) antisense therapy, for example at above-listed target those, for example ISIS 2503, a kind of anti-ras antisense agents;
(viii) gene therapy method, comprise the method for replacing for example unusual p53 of aberrant gene or unusual BRCA1 or BRCA2, GDEPT (the direct enzyme precursor pharmacotherapy of gene) method, for example use those methods of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, with the method for increase patient for chemotherapy or radiocurable tolerance, for example multi-drug resistant gene therapy; With
(ix) immunotherapy method, comprise method in the immunogenic external and body that improves the patient tumors cell, for example for example interleukin 2, interleukin 4 or rHuGM-CSF carry out transfection with cytokine, reduce the method for T cell anergy, the immunocyte of use transfection is the method for the dendritic cell of cytokine transfection for example, use cytokine transfection tumor cell line method and use anti-spy to answer the method for antibody.
With reference now to following illustrative embodiment, further explains the present invention.
Except as otherwise noted, starting raw material is commercially available.All solvents and commercial reagent are the laboratory grades, and can be used as it is.
In an embodiment, record on Bruker DPX 300 (300MHz), Bruker DRX 400 (400MHz) instrument or Bruker DRX 500 (500MHz) instrument
1H NMR spectrum.Chloroform-d (δ
H7.27ppm), methyl-sulphoxide-d
6(δ
H2.50ppm) or acetone-d
6(δ
H2.05ppm) central peak as interior mark.Use following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; The m multiplet; Br, broad peak.
(0.04-0.063mm Merck) carries out column chromatography to use silica gel.Usually, KromasilKR-100-5-C18 reversed-phase column (250x20mm, Akzo Nobel) is used to prepare HPLC, with the mixture of acetonitrile and water [comprising 0.1% trifluoroacetic acid (TFA)] as elutriant, flow velocity 10mL/min.
Following method is used for the analysis of liquid chromatography (LC)/mass spectrum (MS):
HPLC:Agilent 1100 or Waters Alliance HT (2790﹠amp; 2795)
Mass spectrograph: Waters ZQ ESCi
The HPLC post
The standard HPLC post that uses is Phemonenex Gemini C185 μ m, 50x2mm.
Acid HPLC method
The mobile phase of using is: mobile phase A: water
Mobile phase B: acetonitrile
Moving phase C:1% formic acid, each method back is quick balance in 50: 50 water: MeCN (v/v), uses the 5mL flow velocity, 0.45min.
Four kinds of general HPLC methods are suitable:
5 minutes monitoring acid methods
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase C: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
4 | 0 | 95 | 5 | 6 | 1.1 |
4.5 | 0 | 95 | 5 | 6 | 1.1 |
Early stage the wash-out compound acid method in early stage
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase C: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
4 | 57.5 | 37.5 | 5 | 6 | 1.1 |
4.5 | 57.5 | 37.5 | 5 | 6 | 1.1 |
Mid-term the wash-out compound acid method in mid-term
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase C: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
0.01 | 67.5 | 27.5 | 5 | 6 | 1.1 |
4.5 | 27.5 | 67.5 | 5 | 6 | 1.1 |
The later stage acid method of later stage wash-out compound
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase C: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
0.01 | 27.5 | 67.5 | 5 | 6 | 1.1 |
4.5 | 5 | 95 | 5 | 6 | 1.1 |
Alkali formula HPLC method
In some cases, need for compound ionsization or chromatographic separation, standard acid method may be not suitable for.In the case, four kinds of corresponding alkali formula HPLC methods are suitable.
The mobile phase of using is: mobile phase A: water
Mobile phase B: acetonitrile
Moving phase D:0.1% 880 ammonia/acetonitrile
Each method back is quick balance, uses the 5mL flow velocity, 0.45min.
Minute (minute) monitoring alkali formula method
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase D: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
4 | 0 | 95 | 5 | 6 | 1.1 |
4.5 | 0 | 95 | 5 | 6 | 1.1 |
Early stage the wash-out compound alkali formula method in early stage
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase D: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
4 | 57.5 | 37.5 | 5 | 6 | 1.1 |
4.5 | 57.5 | 37.5 | 5 | 6 | 1.1 |
Mid-term the wash-out compound alkali formula method in mid-term
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase D: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
0.01 | 67.5 | 27.5 | 5 | 6 | 1.1 |
4.5 | 27.5 | 67.5 | 5 | 6 | 1.1 |
The later stage alkali formula method of later stage wash-out compound
Time/minute | Mobile phase A: | Mobile phase B: | Moving phase C: | Rational curve | Flow velocity/ml/min |
0.00 | 95 | 0 | 5 | 1 | 1.1 |
0.01 | 27.5 | 67.5 | 5 | 6 | 1.1 |
4.5 | 5 | 95 | 5 | 6 | 1.1 |
Following method is used for the analysis of liquid chromatography (LC)/mass spectrum (MS):
Instrument: Agilent 1100; Post: Waters ' Symmetry ' 2.1x 30mm; Use the mass spectroscopy (APCI) of chemical ioni zation; Flow velocity: 0.7 ml/min; Absorbing wavelength: 254nm; Solvent orange 2 A: water+0.1% TFA; Solvent B: acetonitrile+0.1% TFA; Solvent gradient: 15-95% solvent B, 2.7 minutes, 95% solvent B then, 0.3 minute.
Following method is used for LC and analyzes:
Method A: instrument: Agilent 1100; Post: Kromasil C18 reverse phase silica gel, 100x3mm, 5 μ m particle diameters; Solvent orange 2 A: 0.1%TFA/ water, solvent B:0.08%TFA/ acetonitrile; Flow velocity: 1 ml/min; Solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280nm.Usually, the retention time of record product.
Method B: instrument: Agilent 1100; Post: Waters ' Xterra ' C8 reverse phase silica gel, 100x3mm, 5 μ m particle diameters; Solvent orange 2 A: 0.015M ammonia/water, solvent B: acetonitrile; Flow velocity: 1 ml/min; Solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280rm.Usually, the retention time of record product.
This paper or the following abbreviation of use in following illustrative embodiment:
The HPLC high performance liquid chromatography
HBTU O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate;
HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate;
The HOBT I-hydroxybenzotriazole;
HOAT 1-hydroxyl-7-azepine benzotriazole;
NMP N-methylpyrrolidin-2-ketone;
The DMSO methyl-sulphoxide;
DMF N, dinethylformamide;
The DMA N,N-dimethylacetamide;
The THF tetrahydrofuran (THF);
DME 1, the 2-glycol dimethyl ether;
The DCCI dicyclohexylcarbodiimide;
MeOH methyl alcohol;
The MeCN acetonitrile;
The DCM methylene dichloride;
DIPEA N, the N-diisopropylethylamine;
DBU 1,8-diazabicyclo [5.4.0] 11-7-alkene;
RT room temperature (about 17 to 25 ℃);
The tR retention time;
M/z mass ratio.
Chemical name utilizes software to produce, and this software uses Lexichem Toolkit (v.1.40) (being obtained from OpenEye Scientific Software (www.eyesopen.com)), meets the name of IUPAC with generation.
Embodiment 1:
N-[2-(methylol)-4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] first
Sulphonamide
With N-[4-bromo-2-(methylol) phenyl] mixture of Toluidrin (250mg), potassium acetate (263mg) and two (valeryls), two boron (273mg) is 1, and the degassing is 5 minutes in the 4-diox (10mL).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (44mg), reaction is heated to 80 ℃, kept 3 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (261mg), ethanol (0.75mL), 2M sodium carbonate solution (2.7mL) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (54mg) continues other 3 hours of heating.With refrigerative reaction mixture vacuum concentration, be dissolved in the methyl alcohol, and be loaded on the SCX-2 post.Use the methanol wash post, remove compound with 7N ammonia/methyl alcohol.Vacuum concentrated solution utilizes silica gel chromatography to resistates, with 0-5% methyl alcohol/DCM wash-out.The solid that obtains is ground with diethyl ether, obtain desired material, white solid (62mg).
The NMR spectrum: 1H NMR (DMSO-d
6) δ 307 (3H, s), 3.22 (3H, s), 3.74 (8H, s), 4.53 (2H, s), 4.69 (2H, s), 5.44 (1H, s), 6.89 (1H, s), 7.45 (1H, d), 8.23-8.26 (1H, m), 8.43 (1H, s), 9.10 (1H, s)
Mass spectrum:M+H
+457.
The average IC of test (a)
50Be worth 5 μ M.
N-[4-bromo-2-(methylol) phenyl] preparation of Toluidrin is described below:
N-[4-bromo-2-(methylol) phenyl] Toluidrin
5-bromo-2-methanesulfonamido-methyl benzoate (1.34g) is dissolved among the THF (30mL), and is cooled to 0 ℃.With 15 minutes lithium aluminum hydride (8.7mL, 1M THF solution) is joined in the solution at leisure.Make reaction be warming up to room temperature, stirred 2 hours, water cancellation is then filtered.Vacuum concentrated solution utilizes silica gel chromatography to resistates, with 2.5% methyl alcohol/DCM wash-out, obtains desired material, white solid (333mg).
The NMR spectrum: 1H NMR (DMSO-d
6) δ 3.01 (3H, s), 4.61 (2H, s), 5.40 (1H, s), 7.26 (1H, d), 7.45-7.48 (1H, m), 7.62 (1H, d), 9.05-9.05 (1H, m)
Mass spectrum:M-H
+280.
5-bromo-2-methanesulfonamido-methyl benzoate
At 0 ℃, sodium borohydride (659mg) is joined in the methyl alcohol (40mL) and water (4mL) stirred solution of 2-(two (methyl sulphonyl) amino)-5-bromo-methyl benzoate (168g) in the share mode.Make reaction be warming up to room temperature, stirred 2 hours.At 0 ℃ of sodium borohydride that adds other share, stirred 18 hours.Add entry (10mL) and yellow soda ash (2M) (5mL), react with quencher.The vacuum-drying reaction distributes between ethyl acetate (50mL) and water (50mL).Use the dried over mgso organism, vacuum filtration obtains desired material, white solid (1.34g) to doing.
The NMR spectrum: 1H NMR (DMSO-d
6) δ 3.14 (3H, d), 3.89 (3H, s), 7.52-7.57 (1H, m), 7.78-7.81 (1H, m), 7.99 (1H, d)
Mass spectrum:M-H
+306.
2-(two (methyl sulphonyl) amino)-5-bromo-methyl benzoate
Methyl-2-amino-5-bromo-benzoate (1g) is dissolved in THF (20mL) and the triethylamine (3.6mL).In ice bath, mixture is cooled to 0 ℃, adds methylsulfonyl chloride (1mL) at leisure.0 ℃ of stirring reaction 15 minutes, at room temperature stirred then 19 hours.Water (10mL) cancellation reaction, vacuum concentration.Between ethyl acetate (50mL) and water (50mL), distribute reactant, dry (MgSO
4) organism, filtering, vacuum concentration obtains desired material (1.68g) white solid.
The NMR spectrum: 1H NMR (DMSO-d
6) δ 3.52 (6H, s), 3.87 (3H, s), 7.58 (1H, d), 7.94-7.97 (1H, m), 8.10 (1H, d)
Mass spectrum:M+H
+386.
The preparation of 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine is described below.
2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine
With 2, DCM (230mL) suspension of 4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidines (10.56g) carries out magnetic and stirs (in nitrogen atmosphere), and is cooled to-5 ℃.Add triethylamine (6.78mL), then dropwise add DCM (30mL) solution of morpholine (3.85mL), keep temperature of reaction to be lower than-5 ℃.At room temperature stirring reaction is 1 hour, the organic mixture of water (300mL) washing then.Dry (MgSO4) organic phase is filtered, and is evaporated to brown solid, and it is utilized silica gel chromatography, with 50% ethyl acetate/DCM wash-out, obtains desired material (6.81g) white solid.
The NMR spectrum: 1H NMR (DMSO-d
6) δ 3.12 (3H, s), 3.63 (4H, s), 3.68-3.70 (4H, m), 4.45 (2H, s), 6.96 (1H, s)
Mass spectrum:MH+292.
2,4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine
With 6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2,4-diketone (12.72g) is suspended in the phosphorus oxychloride (125mL), and reflux is 14 hours in nitrogen atmosphere.With the solution cooling, and vacuum concentration.Frozen water (250mL) is joined in the resistates at leisure, use DCM (3x200mL) to extract product then.The vacuum concentration organism obtains desired material, brown solid (10.56g).
The NMR spectrum: 1H NMR (DMSO-d
6) δ 3.14 (3H, s), 4.79 (2H, s), 7.88 (1H, s)
Mass spectrum:(M-H)-239.
6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2, the 4-diketone
6-(chloromethyl) uridylic (10.00g) is dissolved among the DMF (300mL), adds methyl-sulfinic acid (methanesulphinic) sodium salt (7.64g).To be reflected at 125 ℃ of heating 1 hour.The cooling reaction is filtered, and vacuum concentrated filtrate obtains desired material, yellow solid (12.72g).
The NMR spectrum: 1H NMR (DMSO-d
6) δ 3.10 (3H, s), 4.27 (2H, s), 5.63 (1H, s), 10.94 (1H, s), 11.16 (1H, s).
Embodiment 2:
N-[[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methyl] Toluidrin
With [4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methylamine (72mg) is suspended among the DCM (4mL), and handles with triethylamine (0.056mL).Dropwise add methylsulfonyl chloride (0.024mL) then, and stirring reaction spends the night under RT.Add entry (2mL) and come the quencher reaction, separate each layer.Extract water layer with DCM (2x2mL), the dry organism that merges filters, and is evaporated to green oil, and it is prepared purifying in the HPLC system in the alkali formula.The fraction that will comprise product is loaded into methyl alcohol in advance on the SCX post of wash-out, uses methanol wash, uses 7N ammonia/methanol-eluted fractions then.The needed fraction of vacuum-evaporation obtains desired material, white solid (20mg).
The LCMS spectrum:MH+441.58, retention time 1.41 methods: monitoring acid system
The NMR spectrum: 1H NMR (300.132MHz, DMSO-d
6) δ 2.89 (s, 3H), 3.20 (s, 3H), 3.71 (s, 8H), 4.25 (d, 2H), 4.51 (s, 2H), 6.91 (s, 1H), 7.45 (m, 2H), 7.62 (m, 1H), 8.34 (m, 2H).
The average IC of test (a)
50Be worth 6.8 μ M.
Starting raw material [4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methylamine is prepared as follows.
[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methylamine
With 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (228mg), [4-(aminomethyl) phenyl] boric acid (310mg), thiophene-2-carboxylic acid copper (I) (373mg) and Pd (PPh
3)
4(35mg) join in the microwave container, add 1 then, 4-diox (5mL).Tightness system is in microwave reactor, 130 ℃ of heating 1 hour.Further add Pd (PPh
3)
4(10mg), and reaction is heated to 130 ℃, kept 20 minutes.Mixture is changed in the SCX post of using methanol-eluted fractions in advance.Use washed with methanol SCX post then, then use 7N ammonia/methanol-eluted fractions desired material.The evaporation fraction obtains needed compound, emulsifiable paste shape solid (129mg).
The LCMS spectrum:MH+363.55, retention time 0.83 method: monitoring acid system
2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine
With 2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine-4-alcohol (15g, 63.97mmol) about 1 hour of reflux in the inferior phosphorus of oxychlorination (100ml).The inferior phosphorus of evaporation oxychlorination is used in the sodium hydroxide solution and resistates, and is extracted in the ethyl acetate.Then with sal epsom with the mixture drying that obtains, filter, evaporate to dryness obtains the crude product chloro-product.Then it is dissolved among the DCM, add morpholine (319mmol, 28ml), stirring reaction at room temperature.In case finish, collect the precipitation that obtains, white solid.Concentrated filtrate obtains more solids, obtains merging productive rate 13.7g.
The NMR spectrum: 1H NMR (300.132MHz, DMSO) δ 2.45 (s, 3H), 3.49-3.74 (m, 8H), 4.37 (s, 2H), 6.66 (s, 1H) ppm..
The LCMS spectrum:MH+304.50, retention time 1.49min, method: monitoring alkaline process.
2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine-4-alcohol
(19.07g 100mmol) is suspended in the acetonitrile (400mL) with 6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol.In this stirred suspension, add the methyl-sulfinic acid sodium salt (12.255g, 120mmol) and DMF (100mL).Reaction is heated to 100 ℃ then, obtains the suspension of black, monitor with LCMS.In case finish, remove and desolvate, and products obtained therefrom is joined 1: among 1MeOH: the DCM (200ml), with acetate (10ml) acidifying.The precipitation that collection obtains, water (200ml) and MeOH (100ml) washing, vacuum-drying is spent the night, and obtains title compound, white solid 16.45g.
The NMR spectrum: 1H NMR (300.132MHz, DMSO) δ 2.50 (s, 3H), 3.12 (s, 3H), 4.39 (s, 2H), 6.25 (s, 1H), 13.09 (s, 1H) ppm..
The LCMS spectrum:MH+235.2, retention time 0.5 minute, method: 5 minutes early stages alkali formula method.
6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol
With S-methyl-2-sulfo-pseudo-urea sulfuric ester (20g, 71.85mmol), 4-chloracetyl vinyl acetic monomer (10.755mL, 79.04mmol) and yellow soda ash (13.925g 107.78mmol) in water-soluble (100mL), and at room temperature stirs and spends the night.With TLC monitoring reaction, in case finish, collect reaction precipitation, use in the 6N hydrochloric acid and supernatant liquor, obtain more reaction precipitations, equally with its collection.Water (x3) washing accumulative precipitation obtains the off-white color solid then.60 ℃ with its vacuum-drying 48 hours, obtain needed compound, light yellow/white solid 43.2g.
The NMR spectrum: 1H NMR (300.132MHz, CDCl
3) δ 2.59 (s, 3H), 4.35 (s, 2H), 6.41 (s, 1H), 12.70 (s, 1H) ppm
Mass spectrum:M
+190
Embodiment 3:
N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] cyclopropyl-sulfonylamide
To 4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] add ring third SULPHURYL CHLORIDE (53mg) in pyridine (4mL) solution of aniline (52mg), and stirring reaction spends the night under RT.In reaction mixture, add PS-Tutofusin tris resin (200mg) then, shook mixture 2 hours, filter then, use methanol wash.With the organism evaporate to dryness that merges, then be dissolved among the DMSO (1mL), with preparation HPLC purifying, use Phenomenex ' Gemini ' preparation reversed-phase column (5 microns silica gel, 21.2mm diameter, 100mm length), the polarity mixture decrescence that makes water and acetonitrile (comprising 2% formic acid) obtains title compound (33mg) as elutriant.
The LCMS spectrum:M+H
+453.45; Retention time 2.59 methods: monitoring acid system
The average IC of test (a)
50Be worth 0.88 μ M.
Use suitable SULPHURYL CHLORIDE, prepare following compounds with similar fashion.
Embodiment 3a: the average IC of test (a)
50Be worth 1.4 μ M.
Embodiment 3b: the average IC of test (a)
50Be worth 4 μ M.
Embodiment 3c: the average IC of test (a)
50Be worth 6 μ M.
Embodiment 3d: the average IC of test (a)
50Be worth 7.1 μ M.
4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] preparation of aniline is described below:
4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] aniline
With 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (1.00g, 3.3mmol), 4-aminophenyl boric acid (904mg, 6.60mmol), thiophene-2-carboxylic acid copper (I) (1.64g, 8.58mmol), Pd (PPh
3)
4(153mg, 0.04 equivalent 0.13mmol) joins in the microwave container, and adds 1,4-diox (20mL).Use N
2With the system degassing, sealing and in microwave reactor, 130 ℃ of heating 1 hour.In case cooling is poured reactant in the water into, to filter and collect the precipitation that obtains, vacuum-drying obtains title compound, off-white color solid (988mg).
The LCMS spectrum:MH+349.41, retention time 1.43, method: monitoring acid system
The NMR spectrum: 1H NMR (300.132MHz, DMSO-d
6) δ 3.20 (3H, s), 3.61-3.83 (8H, m), 4.43 (2H, s), 5.57 (1H, s), 6.60 (2H, d), 6.70 (1H, s), 8.04 (2H, d)
Embodiment 4:
N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] Toluidrin
To 4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] add in pyridine (3mL) solution of aniline (53mg, 0.15mmol)) methylsulfonyl chloride (21mg, 0.18mmol), and under RT stirring reaction 2 hours.(10mL) joins in the mixture with water, filters collecting precipitation.With this solid of preparation HPLC purifying, obtain desired material, white solid (29mg).
The LCMS spectrum:M+H
+427.4; Retention time 1.38, method: monitoring acid system
The NMR spectrum: 1H NMR (300.132MHz, DMSO-d
6) δ 3.08 (3H, s), 3.22 (3H, s), 3.75 (8H, s), 4.57 (2H, s), 6.93 (1H, s), 7.33 (2H, d), 8.30 (2H, d), 10.12 (1H, s)
The average IC of test (a)
50Be worth 2.6 μ M.
Embodiment 5:
N-[[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] first
Base] Toluidrin
With triethylamine (0.038mL, 0.27mmol) join [4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] (100mg is in DCM 0.27mmol) (5mL) solution for methylamine.Add methylsulfonyl chloride (0.021mL, 0.27mmol), and stirring reaction 2 hours at room temperature.Water (5mL) washing organism, dry (MgSO
4), vacuum concentration.Purifying crude product on silica gel with 0-5% methyl alcohol/DCM wash-out, obtains desired material, white solid (90mg).
The LCMS spectrum:M+H
+455; Retention time 1.61, method: monitoring alkaline process
The NMR spectrum: 1H NMR (400.132MHz, CDCl
3) δ 1.36 (d, 3H), 2.89 (s, 3H), 3.08 (s, 3H), 3.35 (m, 1H), 3.60 (t, 1H), 3.79 (m, 2H), 4.05 (d, 1H), 4.18 (d, 1H), 4.27 (s, 2H), 4.39 (d, 2H), 4.49 (s, 1H), 4.80 (s, 1H), 6.52 (s, 1H), 7.43 (d, 2H), 8.36 (d, 2H).
The average IC of test (a)
50Be worth 4.5 μ M.
[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] preparation of methylamine is described below.
[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] methylamine
With 2-chloro-4-[(3S)-3-methylmorpholine-4-yl]-(1.0g 3.27mmol) is dissolved in 7: 3: 2 DME of 18%DMF: water: in the mixture solution of ethanol (9mL) to 6-(sulfonyloxy methyl ylmethyl) pyrimidine.Then with 4-aminomethyl phenyl borate hydrochlorate (0.92g, 4.91mmol), (115mg 0.16mmol) joins in the solution two (triphenylphosphine) palladium catalysts of 2M sodium carbonate solution (3mL) and dichloro, in nitrogen atmosphere, refluxes 16 hours at 90 ℃.Make reaction be cooled to room temperature, between ethyl acetate and water, distribute then.Use the dried over mgso organism, filter, be concentrated into dried.Crude product oil is utilized silica gel chromatography,, obtain desired material, emulsifiable paste shape solid (400mg) with 0-5% methyl alcohol/DCM wash-out.
The LCMS spectrum:M-H-375; Retention time 1.58, method: monitoring alkaline process
NMR Spectrum: 1H NMR(400.132MHz,CDCl
3)δ1.36(d,3H),3.08(s,3H),3.34(m,1H),3.60(m,1H),3.75(m,1H),3.83(d,1H),3.94(s,2H),4.05(m,1H),4.18(m,1H),4.26(s,2H),4.49(m,1H),6.50(s,1H),7.40(d,2H),8.33(d,2H)。
2-chloro-4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine
With 2, (30g 0.13mol) is dissolved in the methylene dichloride 4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine, in-5 ℃ of stirrings (in nitrogen atmosphere).(17.4mL 0.13mol), obtains clarifying brown solution to add triethylamine.(3S)-3-methylmorpholine is dissolved in the methylene dichloride, dropwise adds, keep reaction to be lower than-5 ℃.Remove cooling bath then, stirred the mixture 1 hour.Reflux reaction mixture 2 hours washes reaction mixture then with water, drying, evaporation then.With preparation HPLC purifying crude product, obtain desired material, solid (19.3g).
The NMR spectrum: 1H NMR (400.13MHz, DMSO-d
6) δ 1.21-1.23 (m, 3H), 3.11 (s, 3H), 3.19-3.26 (m, 1H), 3.42-3.49 (m, 1H), 3.58-3.62 (1H, m), 3.73 (d, 1H), 3.92-3.96 (m, 2H), 4.27-4.31 (m, 1H), 4.45 (s, 2H), 6.92 (s, 1H)
The LCMS spectrum:MH+306, retention time 1.42 minutes, method: 5 minutes acid methods
Before described 2, the preparation of 4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine.
Embodiment 6:
N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] first
Sulphonamide
With 2-chloro-4-[(3S)-3-methylmorpholine-4-yl]-(150mg 0.49mmol) is dissolved in 7: 3: 2 DME of 18%DMF: water: in the mixture solution of ethanol (1.5mL) to 6-(sulfonyloxy methyl ylmethyl) pyrimidine.(18mg 0.02mmol) joins in the solution, in nitrogen atmosphere, refluxes 16 hours at 90 ℃ with two (triphenylphosphine) palladium catalysts of 4-aminomethyl phenyl borate hydrochlorate (0.74mmol), 2M sodium carbonate solution (0.5mL) and dichloro then.Make reaction be cooled to room temperature, between ethyl acetate and water, distribute then.Use the dried over mgso organism, filter, be concentrated into dried.The crude product solid is dissolved among the DCM, removes by filter insoluble impurities, with preparation HPLC purifying filtrate, obtain needed compound, white solid (87mg) then.
The NMR spectrum: 1H NMR (400.13MHz, DMSO-d
6) δ 1.24 (3H, d), 293 (3H, s), 3.21 (3H, s), 3.24 (1H, m), 3.50 (1H, m), 3.65 (1H, m), 3.78 (1H, d), 3.98 (1H, m), 4.16 (1H, d), 4.43 (1H, s), 4.48 (2H, s), 6.76 (1H, s), 7.17 (2H, d), 8.21 (2H, d)
The LCMS spectrum:M+H
+441; Retention time 1.45, method: monitoring acid system
The average IC of test (a)
50Be worth 1 μ M.
Claims (33)
1. the compound of formula (I):
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y
2Be N or CR independently
8, condition is,
1Y and Y
2One of be that N and another are CR
8
X is selected from following connection base :-CR
4=CR
5-,-CR
4=CR
5CR
6R
7-,-CR
6R
7CR
5=CR
4-,-C ≡ C-,-C ≡ CCR
6R
7-,-CR
6R
7C ≡ C-,-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-NR
4S (O)
2CR
6R
7-,-S (O)
2NR
4CR
6R
7-,-C (O) NR
4-,-NR
4C (O)-,-NR
4C (O) NR
5-,-S (O)
2NR
4-and-NR
4S (O)
2-;
R
1Be to be selected from following group: hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, carbocylic radical, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R
9,-OR
9,-SR
9,-SOR
9,-SO
2R
9,-COR
9,-CO
2R
9,-CONR
9R
10,-NR
9R
10,-NR
9COR
10,-NR
9CO
2R
10,-NR
9CONR
10R
15,-NR
9COCONR
10R
15With-NR
9SO
2R
10
R
2Be to be selected from following group: C
1-6Alkyl, carbocylic radical and heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-SR
11,-SOR
11,-SO
2R
11,-COR
11,-CO
2R
11,-CONR
11R
12,-NR
11R
12,-NR
11COR
12With-NR
11COCONR
12R
16When existing, each R
3Be independently selected from halogen, cyano group, nitro ,-R
13,-OR
13,-SR
13,-SOR
13,-SO
2R
13,-COR
13,-CO
2R
13,-CONR
13R
14,-NR
13R
14,-NR
13COR
14,-NR
13CO
2R
14With-NR
13SO
2R
14
R
4And R
5Be hydrogen or C independently
1-6Alkyl;
Or R
1And R
4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
6And R
7Be independently selected from hydrogen, halogen, cyano group, nitro and C
1-6Alkyl;
R
8Be selected from hydrogen, halogen, cyano group and C
1-6Alkyl;
R
9And R
10Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocylic radical, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
11, R
12And R
17Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocylic radical, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl;
R
13, R
14, R
15, R
16And R
18Be hydrogen independently or be selected from following group: C
1-6Alkyl, carbocylic radical, carbocyclic ring C
1-6Alkyl, heterocyclic radical and heterocyclic radical C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
3. according to the compound or pharmaceutically acceptable salt thereof of claim 1 or 2, R wherein
3It is methyl.
4. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 3, Y wherein
1Be CR
8, and Y
2Be N.
5. according to the compound or pharmaceutically acceptable salt thereof of claim 4, Y wherein
1Be CH, and Y
2Be N.
6. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 5, wherein X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4CR
6R
7-,-NR
4C (O) NR
5CR
6R
7-,-S (O)
2NR
4CR
6R
7,-C (O) NR
4-and-NR
4C (O)-.
7. according to the compound or pharmaceutically acceptable salt thereof of claim 6, wherein X is selected from following connection base :-NR
4CR
6R
7-,-OCR
6R
7-,-SCR
6R
7-,-S (O) CR
6R
7-,-S (O)
2CR
6R
7-,-C (O) NR
4-and-NR
4C (O)-.
8. according to the compound or pharmaceutically acceptable salt thereof of claim 7, wherein X is selected from following connection base :-NR
4CH
2-,-OCH
2-,-OCH (CH
3)-,-OC (CH
3)
2-,-SCH
2-,-SCH (CH
3)-,-SC (CH
3)
2-,-S (O) CH
2-,-S (O) CH (CH
3)-,-S (O) C (CH
3)
2-,-S (O)
2CH
2-,-S (O)
2CH (CH
3)-,-S (O)
2C (CH
3)
2-,-C (O) NR
4-and-NR
4C (O)-.
9. according to the compound or pharmaceutically acceptable salt thereof of claim 8, wherein X is-S (O)
2CH
2-,-S (O)
2CH (CH
3)-or-S (O)
2C (CH
3)
2-.
10. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 9, R wherein
1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R
9,-OR
9,-COR
9,-CONR
9R
10,-NR
9R
10With-NR
9COR
10
11. according to the compound or pharmaceutically acceptable salt thereof of claim 10, wherein R
1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH
3,-CONH
2With-CONHCH
3
12. according to the compound or pharmaceutically acceptable salt thereof of claim 11, wherein R
1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH
2CH
2OH ,-CH
2CH
2NC (O) CH
3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base,, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.
13. according to the compound or pharmaceutically acceptable salt thereof of claim 12, wherein R
1It is methyl.
14. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 13, wherein R
2Be selected from: 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
15. according to the compound or pharmaceutically acceptable salt thereof of claim 14, wherein R
2Be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
16. according to the compound or pharmaceutically acceptable salt thereof of claim 15, wherein R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more
11,-OR
11,-COR
11,-CONR
11R
12,-NR
11R
12With-NR
11COR
12
17. according to the compound or pharmaceutically acceptable salt thereof of claim 16, wherein R
2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR
17SO
2R
18Replace, and optionally be independently selected from following substituted radical and replace: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH by one or more
2,-CONHCH
3With-CON (CH
3)
2
18. according to the compound or pharmaceutically acceptable salt thereof of claim 17, wherein R
2By-NR
17SO
2R
18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH
2,-CONHCH
3With-CON (CH
3)
2
20. according to each compound or pharmaceutically acceptable salt thereof of claim 14 to 19, wherein R
17Be hydrogen.
21. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 20, wherein R
18Be hydrogen or be selected from following group: C
1-6Alkyl, C
3-6Cycloalkyl, aryl, heteroaryl, aryl C
1-6Alkyl and heteroaryl C
1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
22. according to the compound or pharmaceutically acceptable salt thereof of claim 21, wherein R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, halogen C
1-6Alkyl, halogen C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, hydroxyl C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkyl, C
1-6Alkoxy C
1-6Alkoxyl group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, amino C
1-6Alkyl, (C
1-6Alkyl) amino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, cyano group C
1-6Alkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl (C
1-6Alkyl) amino, sulfamyl, C
1-6Alkylsulfamoyl group, two (C
1-6Alkyl) sulfamyl, C
1-6Alkanoylamino, C
1-6Alkyloyl (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl and two (C
1-6Alkyl) formamyl.
23. according to the compound or pharmaceutically acceptable salt thereof of claim 22, wherein R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH
2(cyclopropyl) ,-CH
2CH
2NMe
2,-CH (CH
3) CH
2OH ,-C (CH
3)
2CH
2OH ,-CH
2CH
2OH ,-CH
2CH
2CH
2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH
2(imidazoles-2-yl) ,-CH
2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl.
24. according to the compound or pharmaceutically acceptable salt thereof of claim 23, wherein R
18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, butyl, cyclopropyl and 4-fluorophenyl.
25., be selected from each embodiment or its pharmacologically acceptable salt according to the compound or pharmaceutically acceptable salt thereof of claim 1.
26. each formula (I) compound or pharmaceutically acceptable salt thereof according to claim 1 to 25 is used as medicine in the treatment of hyperplasia.
27. the purposes of the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine, this medicine is used for the treatment of hyperplasia.
28. the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof for example produces the purposes of anti-proliferative effect among the people warm-blooded animal.
29. the purposes of the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof in medication preparation, this medicine for example is used to produce anti-proliferative effect among the people warm-blooded animal.
30. for example produce the method for anti-proliferative effect among the people the warm-blooded animal of this kind of needs treatment, this method comprises each defined formula (I) compound or pharmaceutically acceptable salt thereof of the claim 1 to 25 that gives described animal effective dose.
31. for example treat the method for cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder among the people the warm-blooded animal of this kind of needs treatment, this method comprises each defined formula (I) compound or pharmaceutically acceptable salt thereof of the claim 1 to 25 that gives significant quantity.
32. a pharmaceutical composition, each defined formula (I) compound or pharmaceutically acceptable salt thereof that it comprises claim 1 to 25 combines with pharmaceutically acceptable diluent or carrier.
33. the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof is as medicine.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0616747.2 | 2006-08-24 | ||
GB0616747A GB0616747D0 (en) | 2006-08-24 | 2006-08-24 | Novel compounds |
US60/948,537 | 2007-07-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101558046A true CN101558046A (en) | 2009-10-14 |
Family
ID=37102735
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200780039262.7A Expired - Fee Related CN101541781B (en) | 2006-08-24 | 2007-08-21 | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders |
CNA2007800392665A Pending CN101558046A (en) | 2006-08-24 | 2007-08-22 | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200780039262.7A Expired - Fee Related CN101541781B (en) | 2006-08-24 | 2007-08-21 | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders |
Country Status (7)
Country | Link |
---|---|
CN (2) | CN101541781B (en) |
BR (1) | BRPI0715609A2 (en) |
ES (1) | ES2393215T3 (en) |
GB (1) | GB0616747D0 (en) |
RU (1) | RU2440349C2 (en) |
TW (1) | TW200817384A (en) |
ZA (1) | ZA200901015B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102781931A (en) * | 2010-01-26 | 2012-11-14 | 贝林格尔.英格海姆国际有限公司 | 5-alkynyl pyrimidines and their use as kinase inhibitors |
CN103384672A (en) * | 2011-02-25 | 2013-11-06 | 武田药品工业株式会社 | N-substituted oxazinopteridines and oxazinopteridinones |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101438245B1 (en) * | 2006-08-23 | 2014-09-04 | 쿠도스 파마슈티칼스 리미티드 | 2-methylmorpholine pyrido-, pyrazo- and pyrimido-pyrimidine derivatives as MTOR inhibitors |
WO2011080568A2 (en) * | 2009-12-28 | 2011-07-07 | Development Center For Biotechnology | Novel pyrimidine compounds as mtor and p13k inhibitors |
EP2758379B1 (en) * | 2011-09-21 | 2016-10-19 | Cellzome Limited | Urea and carbamate derivatives of 2-morpholino-1,3,5-triazine as mTOR inhibitors for the treatment of immunological or proliferative diseases |
RU2659786C2 (en) | 2012-05-15 | 2018-07-04 | Кансер Ресёрч Текнолоджи Лимитед | 5-[[4-[[morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile, therapeutic uses thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19834044A1 (en) * | 1998-07-29 | 2000-02-03 | Bayer Ag | New substituted pyrazole derivatives |
DE60144322D1 (en) * | 2000-04-27 | 2011-05-12 | Astellas Pharma Inc | CONDENSED HETEROARYL DERIVATIVES |
AU2790502A (en) * | 2000-11-10 | 2002-05-21 | Hoffmann La Roche | Pyrimidine derivatives and their use as neuropeptide y receptor ligands |
KR101052482B1 (en) * | 2002-11-21 | 2011-07-28 | 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 | 2,4,6-trisubstituted pyrimidine, a phosphatidylinositol (PI) 3-kinase inhibitor, and their use in the treatment of cancer |
GB0415364D0 (en) * | 2004-07-09 | 2004-08-11 | Astrazeneca Ab | Pyrimidine derivatives |
GB0415367D0 (en) * | 2004-07-09 | 2004-08-11 | Astrazeneca Ab | Pyrimidine derivatives |
EP1819341A4 (en) * | 2004-11-10 | 2011-06-29 | Synta Pharmaceuticals Corp | Il-12 modulatory compounds |
-
2006
- 2006-08-24 GB GB0616747A patent/GB0616747D0/en not_active Ceased
-
2007
- 2007-08-21 BR BRPI0715609-0A2A patent/BRPI0715609A2/en not_active IP Right Cessation
- 2007-08-21 TW TW96130916A patent/TW200817384A/en unknown
- 2007-08-21 RU RU2009110255/04A patent/RU2440349C2/en not_active IP Right Cessation
- 2007-08-21 ES ES07789273T patent/ES2393215T3/en active Active
- 2007-08-21 CN CN200780039262.7A patent/CN101541781B/en not_active Expired - Fee Related
- 2007-08-22 CN CNA2007800392665A patent/CN101558046A/en active Pending
-
2009
- 2009-02-12 ZA ZA200901015A patent/ZA200901015B/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102781931A (en) * | 2010-01-26 | 2012-11-14 | 贝林格尔.英格海姆国际有限公司 | 5-alkynyl pyrimidines and their use as kinase inhibitors |
CN103384672A (en) * | 2011-02-25 | 2013-11-06 | 武田药品工业株式会社 | N-substituted oxazinopteridines and oxazinopteridinones |
Also Published As
Publication number | Publication date |
---|---|
RU2440349C2 (en) | 2012-01-20 |
ES2393215T3 (en) | 2012-12-19 |
TW200817384A (en) | 2008-04-16 |
ZA200901015B (en) | 2010-08-25 |
BRPI0715609A2 (en) | 2013-10-08 |
CN101541781A (en) | 2009-09-23 |
CN101541781B (en) | 2014-01-08 |
RU2009110255A (en) | 2010-09-27 |
GB0616747D0 (en) | 2006-10-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101809002B (en) | Morpholino pyrimidine derivatives used in diseases linked to MTOR kinase and/or PI3K | |
CN101796048A (en) | Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases | |
CN101801963A (en) | Trisubstituted pyrimidine derivatives for the treatment of proliferative diseases | |
US20090325957A1 (en) | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders | |
CN101563340A (en) | 2-benzimidaz0lyl-6-m0rph0lin0-4-piperidin-4-ylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders | |
CN101484438A (en) | Pyrazole derivatives and their use as PI3k inhibitors | |
CN101563339A (en) | 2 -benzimidazolyl- 6 -morpholino-4- (azetidine, pyrrolidine, piperidine or azepine) pyrimidine derivatives as PI3K and MTOR inhibitors for the treatment of proliferative disorders | |
CN101484452A (en) | Thiazole derivatives and their use as anti-tumour agents | |
CN101535296A (en) | 2-benzimidazolyl-6-morpholino-4-phenylpyrimidine derivatives as pi3k and mtor inhibitors for the treatment of proliferative disorders | |
CN101595103A (en) | Pyrimidine derivatives | |
CN101014590A (en) | 2, 4, 6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer | |
KR20080067694A (en) | Aminopyrimidines useful as kinase inhibitors | |
CN101010318A (en) | 2, 4, 6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer | |
CN101098869A (en) | 5-heteroaryl thiazoles and their use as p13k inhibitors | |
CN101558046A (en) | Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders | |
CN101010317A (en) | 2, 4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer | |
WO2024126987A1 (en) | Inhibitory compounds | |
CN101370788A (en) | Morpholino pyrimidine derivatives and their use in therapy | |
TW201002697A (en) | Morpholino pyrimidine derivative used in diseases linked to mTOR kinase and/or PI3K | |
HK1142906B (en) | Morpholino pyrimidine derivatives used in diseases linked to mtor kinase and/or pi3k |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20091014 |