CN103038643A - 作为pi3k/akt激酶途径抑制剂效能的预测性生物标记的foxo3a - Google Patents
作为pi3k/akt激酶途径抑制剂效能的预测性生物标记的foxo3a Download PDFInfo
- Publication number
- CN103038643A CN103038643A CN2011800297239A CN201180029723A CN103038643A CN 103038643 A CN103038643 A CN 103038643A CN 2011800297239 A CN2011800297239 A CN 2011800297239A CN 201180029723 A CN201180029723 A CN 201180029723A CN 103038643 A CN103038643 A CN 103038643A
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- piperazine
- hydroxy
- dihydro
- cyclopenta
- 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
- 108091008611 Protein Kinase B Proteins 0.000 title claims abstract description 106
- 239000003112 inhibitor Substances 0.000 title claims abstract description 63
- 230000037361 pathway Effects 0.000 title claims abstract description 36
- 239000000092 prognostic biomarker Substances 0.000 title 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims abstract description 100
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 44
- 230000005764 inhibitory process Effects 0.000 claims abstract description 28
- -1 imidazole radicals Chemical class 0.000 claims description 677
- 150000001875 compounds Chemical class 0.000 claims description 141
- 206010028980 Neoplasm Diseases 0.000 claims description 99
- 108091007960 PI3Ks Proteins 0.000 claims description 91
- 239000003197 protein kinase B inhibitor Substances 0.000 claims description 73
- 210000004027 cell Anatomy 0.000 claims description 67
- 229940126638 Akt inhibitor Drugs 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 56
- CWHJIJJSDGEHNS-MYLFLSLOSA-N Senegenin Chemical compound C1[C@H](O)[C@H](O)[C@@](C)(C(O)=O)[C@@H]2CC[C@@]3(C)C(CC[C@]4(CCC(C[C@H]44)(C)C)C(O)=O)=C4[C@@H](CCl)C[C@@H]3[C@]21C CWHJIJJSDGEHNS-MYLFLSLOSA-N 0.000 claims description 52
- 239000009871 tenuigenin Substances 0.000 claims description 52
- 238000011282 treatment Methods 0.000 claims description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 claims description 39
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 108091000080 Phosphotransferase Proteins 0.000 claims description 36
- 102000020233 phosphotransferase Human genes 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 230000008034 disappearance Effects 0.000 claims description 23
- 230000008859 change Effects 0.000 claims description 22
- 239000012828 PI3K inhibitor Substances 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 238000003364 immunohistochemistry Methods 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 12
- 238000009826 distribution Methods 0.000 claims description 11
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 9
- 229910005965 SO 2 Inorganic materials 0.000 claims description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 230000010261 cell growth Effects 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 238000005194 fractionation Methods 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000003566 oxetanyl group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 2
- 102000038030 PI3Ks Human genes 0.000 claims 8
- 125000005843 halogen group Chemical group 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 13
- 230000007711 cytoplasmic localization Effects 0.000 abstract description 2
- 229940043355 kinase inhibitor Drugs 0.000 abstract 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract 2
- 230000004807 localization Effects 0.000 abstract 1
- 230000030648 nucleus localization Effects 0.000 abstract 1
- 230000004565 tumor cell growth Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 227
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 88
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 88
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 61
- 125000003118 aryl group Chemical group 0.000 description 54
- 125000000217 alkyl group Chemical group 0.000 description 52
- 201000011510 cancer Diseases 0.000 description 50
- 239000003814 drug Substances 0.000 description 46
- 239000000203 mixture Substances 0.000 description 40
- 238000002360 preparation method Methods 0.000 description 38
- 239000003795 chemical substances by application Substances 0.000 description 33
- 239000000523 sample Substances 0.000 description 33
- 238000013459 approach Methods 0.000 description 32
- 125000000304 alkynyl group Chemical group 0.000 description 24
- 229910052760 oxygen Inorganic materials 0.000 description 24
- GRZXWCHAXNAUHY-NSISKUIASA-N (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1-piperazinyl]-3-(propan-2-ylamino)-1-propanone Chemical compound C1([C@H](C(=O)N2CCN(CC2)C=2C=3[C@H](C)C[C@@H](O)C=3N=CN=2)CNC(C)C)=CC=C(Cl)C=C1 GRZXWCHAXNAUHY-NSISKUIASA-N 0.000 description 21
- 201000010099 disease Diseases 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- 125000002769 thiazolinyl group Chemical group 0.000 description 21
- 229910052799 carbon Inorganic materials 0.000 description 20
- 150000003254 radicals Chemical class 0.000 description 20
- 210000001519 tissue Anatomy 0.000 description 20
- 206010006187 Breast cancer Diseases 0.000 description 19
- 208000026310 Breast neoplasm Diseases 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 15
- 239000001301 oxygen Substances 0.000 description 15
- 238000012545 processing Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 239000003513 alkali Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 241000124008 Mammalia Species 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- BEWFIPLBFJGWSR-AONZOJHOSA-N butyl (z,12r)-12-acetyloxyoctadec-9-enoate Chemical group CCCCCC[C@@H](OC(C)=O)C\C=C/CCCCCCCC(=O)OCCCC BEWFIPLBFJGWSR-AONZOJHOSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000017105 transposition Effects 0.000 description 12
- 238000007796 conventional method Methods 0.000 description 11
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 11
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 11
- 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 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 229960000575 trastuzumab Drugs 0.000 description 11
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin 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-TZSSRYMLSA-N 0.000 description 10
- 230000004913 activation Effects 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 238000004043 dyeing Methods 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 230000014509 gene expression Effects 0.000 description 10
- 238000006366 phosphorylation reaction Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 230000026731 phosphorylation Effects 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 206010060862 Prostate cancer Diseases 0.000 description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 8
- 239000005864 Sulphur Substances 0.000 description 8
- 150000001345 alkine derivatives Chemical class 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 210000004907 gland Anatomy 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- 239000000825 pharmaceutical preparation Substances 0.000 description 8
- 239000002243 precursor Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 7
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 7
- 230000002421 anti-septic effect Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 102000001253 Protein Kinase Human genes 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 230000003078 antioxidant effect Effects 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 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 6
- 229960004679 doxorubicin Drugs 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 235000003599 food sweetener Nutrition 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 6
- JZZFDCXSFTVOJY-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide;hydron;dichloride Chemical compound Cl.Cl.C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 JZZFDCXSFTVOJY-UHFFFAOYSA-N 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 108060006633 protein kinase Proteins 0.000 description 6
- 239000013074 reference sample Substances 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000000375 suspending agent Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- XRYJULCDUUATMC-CYBMUJFWSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 XRYJULCDUUATMC-CYBMUJFWSA-N 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 5
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 5
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- 208000032612 Glial tumor Diseases 0.000 description 5
- 206010018338 Glioma Diseases 0.000 description 5
- 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 5
- 206010024612 Lipoma Diseases 0.000 description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- 206010039491 Sarcoma Diseases 0.000 description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Chemical compound CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- 235000010323 ascorbic acid Nutrition 0.000 description 5
- 239000011668 ascorbic acid Substances 0.000 description 5
- 229960005070 ascorbic acid Drugs 0.000 description 5
- 239000006172 buffering agent Substances 0.000 description 5
- 229950002826 canertinib Drugs 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 201000010536 head and neck cancer Diseases 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 201000001441 melanoma Diseases 0.000 description 5
- 229960000485 methotrexate Drugs 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 150000003053 piperidines Chemical class 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 201000000498 stomach carcinoma Diseases 0.000 description 5
- 239000012749 thinning agent Substances 0.000 description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 5
- 229960005486 vaccine Drugs 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 101100322915 Caenorhabditis elegans akt-1 gene Proteins 0.000 description 4
- 206010014759 Endometrial neoplasm Diseases 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 229940124647 MEK inhibitor Drugs 0.000 description 4
- 208000008770 Multiple Hamartoma Syndrome Diseases 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 4
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003886 aromatase inhibitor Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000002981 blocking agent Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000006880 cross-coupling reaction Methods 0.000 description 4
- 230000030609 dephosphorylation Effects 0.000 description 4
- 238000006209 dephosphorylation reaction Methods 0.000 description 4
- 230000000994 depressogenic effect Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 201000003914 endometrial carcinoma Diseases 0.000 description 4
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 4
- 208000014829 head and neck neoplasm Diseases 0.000 description 4
- 201000011066 hemangioma Diseases 0.000 description 4
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000003094 microcapsule Substances 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 229960002087 pertuzumab Drugs 0.000 description 4
- 229920000728 polyester Polymers 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 125000002098 pyridazinyl group Chemical group 0.000 description 4
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 230000007480 spreading Effects 0.000 description 4
- 238000003892 spreading Methods 0.000 description 4
- 210000001768 subcellular fraction Anatomy 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 4
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 4
- 229950000578 vatalanib Drugs 0.000 description 4
- 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 4
- 238000001262 western blot Methods 0.000 description 4
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 description 3
- NZGWDASTMWDZIW-MRVPVSSYSA-N (+)-pulegone Chemical compound C[C@@H]1CCC(=C(C)C)C(=O)C1 NZGWDASTMWDZIW-MRVPVSSYSA-N 0.000 description 3
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 3
- 125000006664 (C1-C3) perfluoroalkyl group Chemical group 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 3
- 229940122815 Aromatase inhibitor Drugs 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 3
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 3
- 0 C[C@](CCC1(C(C)(C)*)Br)CC1=O Chemical compound C[C@](CCC1(C(C)(C)*)Br)CC1=O 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 108020004414 DNA Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229940122558 EGFR antagonist Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 150000001204 N-oxides Chemical class 0.000 description 3
- 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 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- 235000019483 Peanut oil Nutrition 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 206010043276 Teratoma Diseases 0.000 description 3
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical compound C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000000090 biomarker Substances 0.000 description 3
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229950006754 cedelizumab Drugs 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940126179 compound 72 Drugs 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 229940121647 egfr inhibitor Drugs 0.000 description 3
- 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 3
- 206010016629 fibroma Diseases 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 235000008191 folinic acid Nutrition 0.000 description 3
- 239000011672 folinic acid Substances 0.000 description 3
- 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 3
- 239000000499 gel Substances 0.000 description 3
- 125000001475 halogen functional group Chemical group 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 3
- 229960001691 leucovorin Drugs 0.000 description 3
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.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 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 239000000312 peanut oil Substances 0.000 description 3
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 3
- 229950010632 perifosine Drugs 0.000 description 3
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 239000010695 polyglycol Substances 0.000 description 3
- 229920000151 polyglycol Polymers 0.000 description 3
- 208000023958 prostate neoplasm Diseases 0.000 description 3
- 125000003373 pyrazinyl group Chemical group 0.000 description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 3
- 238000012113 quantitative test Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000000837 restrainer Substances 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- 125000004306 triazinyl group Chemical group 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 2
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 2
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 2
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-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
- MMFMTASDTOCTLC-UHFFFAOYSA-N 4-methylbenzene-1,2,3-tricarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(C(O)=O)=C1C(O)=O MMFMTASDTOCTLC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 206010001233 Adenoma benign Diseases 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- 101100297694 Arabidopsis thaliana PIP2-7 gene Proteins 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 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 2
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- VOZZDEROHZMDEQ-UHFFFAOYSA-N C(=O)(O)CC1=C(C=C(C(=O)O)C=C1C)C(=O)O Chemical compound C(=O)(O)CC1=C(C=C(C(=O)O)C=C1C)C(=O)O VOZZDEROHZMDEQ-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- 101100162366 Caenorhabditis elegans akt-2 gene Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 208000012609 Cowden disease Diseases 0.000 description 2
- 201000002847 Cowden syndrome Diseases 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 208000000471 Dysplastic Nevus Syndrome Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000007569 Giant Cell Tumors Diseases 0.000 description 2
- 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 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 208000002927 Hamartoma Diseases 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 2
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 2
- 102000003815 Interleukin-11 Human genes 0.000 description 2
- 108090000177 Interleukin-11 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 241000764238 Isis Species 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 239000006057 Non-nutritive feed additive Substances 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 2
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 2
- 101100456541 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) MEC3 gene Proteins 0.000 description 2
- 101100483663 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UFD1 gene Proteins 0.000 description 2
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 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
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 229940064004 antiseptic throat preparations Drugs 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 150000003974 aralkylamines Chemical class 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 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 2
- 230000005907 cancer growth Effects 0.000 description 2
- 208000035269 cancer or benign tumor Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 230000025084 cell cycle arrest Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N chembl421 Chemical compound C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 229960002806 daclizumab Drugs 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 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 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 229940030275 epigallocatechin gallate Drugs 0.000 description 2
- 229930013356 epothilone Natural products 0.000 description 2
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 2
- 229950009760 epratuzumab Drugs 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 2
- 238000013265 extended release Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940080856 gleevec Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 230000009931 harmful effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 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 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 235000014304 histidine Nutrition 0.000 description 2
- 229960002885 histidine Drugs 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 150000001261 hydroxy acids Chemical group 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 229960003685 imatinib mesylate Drugs 0.000 description 2
- 125000002636 imidazolinyl group Chemical group 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 239000003547 immunosorbent Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 229940074383 interleukin-11 Drugs 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 229950002950 lintuzumab Drugs 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229960003646 lysine Drugs 0.000 description 2
- 235000018977 lysine Nutrition 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- FBOZXECLQNJBKD-UHFFFAOYSA-N methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-UHFFFAOYSA-N 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N n-hexadecyl alcohol Natural products CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229960005027 natalizumab Drugs 0.000 description 2
- 238000013188 needle biopsy Methods 0.000 description 2
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 2
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 2
- 208000007538 neurilemmoma Diseases 0.000 description 2
- 208000004649 neutrophil actin dysfunction Diseases 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 210000004882 non-tumor cell Anatomy 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229960000470 omalizumab Drugs 0.000 description 2
- 229940035567 orencia Drugs 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 229960000402 palivizumab Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 229940080818 propionamide Drugs 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- 229960003415 propylparaben Drugs 0.000 description 2
- 210000005267 prostate cell Anatomy 0.000 description 2
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000008707 rearrangement Effects 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 229930002330 retinoic acid Natural products 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 229950009092 rovelizumab Drugs 0.000 description 2
- HHJUWIANJFBDHT-ZVTSDNJWSA-N rsa8ko39wh 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=C1NC1=CC=CC=C21 HHJUWIANJFBDHT-ZVTSDNJWSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- RODXRVNMMDRFIK-UHFFFAOYSA-N scopoletin Chemical compound C1=CC(=O)OC2=C1C=C(OC)C(O)=C2 RODXRVNMMDRFIK-UHFFFAOYSA-N 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 229950008684 sibrotuzumab Drugs 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 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 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 229940034785 sutent Drugs 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 208000001644 thecoma Diseases 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- 229960003989 tocilizumab Drugs 0.000 description 2
- 229960005267 tositumomab Drugs 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 229950003364 tucotuzumab celmoleukin Drugs 0.000 description 2
- 108700008509 tucotuzumab celmoleukin Proteins 0.000 description 2
- 210000001215 vagina Anatomy 0.000 description 2
- 229960000241 vandetanib Drugs 0.000 description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- 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 2
- 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 2
- 229960004355 vindesine Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 2
- 229960004276 zoledronic acid Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 description 1
- QYYZXEPEVBXNNA-QGZVFWFLSA-N (1R)-2-acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-5-methylsulfonyl-1,3-dihydroisoindole-1-carboxamide Chemical compound C(C)(=O)N1[C@H](C2=CC=C(C=C2C1)S(=O)(=O)C)C(=O)NC1=CC=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O QYYZXEPEVBXNNA-QGZVFWFLSA-N 0.000 description 1
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- JCZPMGDSEAFWDY-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanamide Chemical compound NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO JCZPMGDSEAFWDY-SQOUGZDYSA-N 0.000 description 1
- RIWLPSIAFBLILR-WVNGMBSFSA-N (2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s,3r)-2-[[(2r,3s)-2-[[(2s)-2-[[2-[[2-[acetyl(methyl)amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethy Chemical compound CC(=O)N(C)CC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)NCC RIWLPSIAFBLILR-WVNGMBSFSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- UIVHJEKZRQNSEB-UHFFFAOYSA-N (3-hydroxy-4-nitrophenyl)-phenylmethanone Chemical compound C1=C([N+]([O-])=O)C(O)=CC(C(=O)C=2C=CC=CC=2)=C1 UIVHJEKZRQNSEB-UHFFFAOYSA-N 0.000 description 1
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 description 1
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 1
- FEOHYDSNGHIXOM-WLDMJGECSA-N (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)-2-methyloxane-2,4,5-triol Chemical compound CC1(O)[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO FEOHYDSNGHIXOM-WLDMJGECSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-N 0.000 description 1
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- WHBMMWSBFZVSSR-GSVOUGTGSA-N (R)-3-hydroxybutyric acid Chemical compound C[C@@H](O)CC(O)=O WHBMMWSBFZVSSR-GSVOUGTGSA-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
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 1
- ZXKXJHAOUFHNAS-FVGYRXGTSA-N (S)-fenfluramine hydrochloride Chemical compound [Cl-].CC[NH2+][C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 ZXKXJHAOUFHNAS-FVGYRXGTSA-N 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- YRMCBQLZVBXOSJ-PCFSSPOYSA-N (e)-3-[(6r,6as)-4-hydroxy-6-methoxy-3-methyl-11-oxo-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enamide Chemical compound CO[C@H]1NC2=C(O)C(C)=CC=C2C(=O)N2C=C(\C=C\C(N)=O)C[C@@H]12 YRMCBQLZVBXOSJ-PCFSSPOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 1
- QOOQLKSEGVNYLA-UHFFFAOYSA-N 1-$l^{1}-oxidanylbutane Chemical compound CCCC[O] QOOQLKSEGVNYLA-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OQZGLXOADHKTDN-UHFFFAOYSA-N 1-oxidopyrimidin-1-ium Chemical compound [O-][N+]1=CC=CN=C1 OQZGLXOADHKTDN-UHFFFAOYSA-N 0.000 description 1
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-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
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 1
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- CPJAOFOWDGRJQD-NJVNFBHUSA-N 2-aminoacetic acid;(2s)-2-amino-3-phenylpropanoic acid;(2s)-2,5-diamino-5-oxopentanoic acid Chemical compound NCC(O)=O.OC(=O)[C@@H](N)CCC(N)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 CPJAOFOWDGRJQD-NJVNFBHUSA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 1
- JIZRGGUCOQKGQD-UHFFFAOYSA-N 2-nitrothiophene Chemical group [O-][N+](=O)C1=CC=CS1 JIZRGGUCOQKGQD-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- YZDXPWDZGJRWDW-UHFFFAOYSA-N 2-piperazin-1-yl-1h-cyclopenta[d]pyrimidine Chemical compound C1CNCCN1C(N1)=NC=C2C1=CC=C2 YZDXPWDZGJRWDW-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QMEQBOSUJUOXMX-UHFFFAOYSA-N 2h-oxadiazine Chemical compound N1OC=CC=N1 QMEQBOSUJUOXMX-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- FQWNGSKQHPNIQG-UHFFFAOYSA-N 3-[[bis(2-chloroethyl)amino-(2-chloroethoxy)phosphoryl]amino]propan-1-ol Chemical compound OCCCNP(=O)(OCCCl)N(CCCl)CCCl FQWNGSKQHPNIQG-UHFFFAOYSA-N 0.000 description 1
- AXPZIVKEZRHGAS-UHFFFAOYSA-N 3-benzyl-5-[(2-nitrophenoxy)methyl]oxolan-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1OCC1OC(=O)C(CC=2C=CC=CC=2)C1 AXPZIVKEZRHGAS-UHFFFAOYSA-N 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 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
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- MCGBIXXDQFWVDW-UHFFFAOYSA-N 4,5-dihydro-1h-pyrazole Chemical compound C1CC=NN1 MCGBIXXDQFWVDW-UHFFFAOYSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- VZRRCQOUNSHSGB-UHFFFAOYSA-N 4-hydroxy-4,6,6-trimethylbicyclo[3.1.1]heptan-3-one Chemical compound C1C2C(C)(C)C1CC(=O)C2(O)C VZRRCQOUNSHSGB-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- DQZVUDZSBQMLJC-UHFFFAOYSA-N 4-methylacridin-9-amine Chemical compound C1=CC=C2N=C3C(C)=CC=CC3=C(N)C2=C1 DQZVUDZSBQMLJC-UHFFFAOYSA-N 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZEWWLZDNTOZATC-UHFFFAOYSA-N 4-thieno[3,2-d]pyrimidin-4-ylmorpholine Chemical compound C1COCCN1C1=NC=NC2=C1SC=C2 ZEWWLZDNTOZATC-UHFFFAOYSA-N 0.000 description 1
- RONQPWQYDRPRGG-UHFFFAOYSA-N 5,6-bis(4-fluoroanilino)isoindole-1,3-dione Chemical compound C1=CC(F)=CC=C1NC(C(=C1)NC=2C=CC(F)=CC=2)=CC2=C1C(=O)NC2=O RONQPWQYDRPRGG-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- MJZJYWCQPMNPRM-UHFFFAOYSA-N 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine Chemical compound CC1(C)N=C(N)N=C(N)N1OCCCOC1=CC(Cl)=C(Cl)C=C1Cl MJZJYWCQPMNPRM-UHFFFAOYSA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 description 1
- YCWQAMGASJSUIP-YFKPBYRVSA-N 6-diazo-5-oxo-L-norleucine Chemical compound OC(=O)[C@@H](N)CCC(=O)C=[N+]=[N-] YCWQAMGASJSUIP-YFKPBYRVSA-N 0.000 description 1
- DOCINCLJNAXZQF-LBPRGKRZSA-N 6-fluoro-3-phenyl-2-[(1s)-1-(7h-purin-6-ylamino)ethyl]quinazolin-4-one Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=NC2=CC=C(F)C=C2C(=O)N1C1=CC=CC=C1 DOCINCLJNAXZQF-LBPRGKRZSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-UHFFFAOYSA-N 7-[(4-amino-5-hydroxy-6-methyl-2-oxanyl)oxy]-6,9,11-trihydroxy-9-(2-hydroxy-1-oxoethyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(=O)CO)CC1OC1CC(N)C(O)C(C)O1 AOJJSUZBOXZQNB-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- JGLHXBNHKQAROV-UHFFFAOYSA-N 9-methoxy-9h-fluorene Chemical compound C1=CC=C2C(OC)C3=CC=CC=C3C2=C1 JGLHXBNHKQAROV-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241001502050 Acis Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 235000007755 Annona Nutrition 0.000 description 1
- 240000006199 Annona purpurea Species 0.000 description 1
- 235000011518 Annona purpurea Nutrition 0.000 description 1
- 108020000948 Antisense Oligonucleotides 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
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 239000012664 BCL-2-inhibitor Substances 0.000 description 1
- 201000007815 Bannayan-Riley-Ruvalcaba syndrome Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 229940123711 Bcl2 inhibitor Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 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
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- JHZPNBKZPAWCJD-UHFFFAOYSA-N CCOC(C(CCC1)C1=O)=O Chemical compound CCOC(C(CCC1)C1=O)=O JHZPNBKZPAWCJD-UHFFFAOYSA-N 0.000 description 1
- CHEDBOVBQQVSEW-YHMJZVADSA-N CCOC(C([C@@H](CC1)I)C1=C(C)C)=O Chemical compound CCOC(C([C@@H](CC1)I)C1=C(C)C)=O CHEDBOVBQQVSEW-YHMJZVADSA-N 0.000 description 1
- LLVZBTWPGQVVLW-SNAWJCMRSA-N CP-724714 Chemical compound C12=CC(/C=C/CNC(=O)COC)=CC=C2N=CN=C1NC(C=C1C)=CC=C1OC1=CC=C(C)N=C1 LLVZBTWPGQVVLW-SNAWJCMRSA-N 0.000 description 1
- QVUXHRVBWYHLSM-HZSPNIEDSA-N C[C@H](C1)c2c(N(CC3)[C@@H](C)CN3C(OC(C)(C)C)=O)ncnc2[C@@H]1OC Chemical compound C[C@H](C1)c2c(N(CC3)[C@@H](C)CN3C(OC(C)(C)C)=O)ncnc2[C@@H]1OC QVUXHRVBWYHLSM-HZSPNIEDSA-N 0.000 description 1
- RYAGBIWEGMFCGP-WICQDKGNSA-N C[C@H](C=CC1=N)/C1=C(/C)\O Chemical compound C[C@H](C=CC1=N)/C1=C(/C)\O RYAGBIWEGMFCGP-WICQDKGNSA-N 0.000 description 1
- REDVLNWVZWKQLI-RXMQYKEDSA-N C[C@H](CC1)c2c1ncnc2O Chemical compound C[C@H](CC1)c2c1ncnc2O REDVLNWVZWKQLI-RXMQYKEDSA-N 0.000 description 1
- MGSFTBDRWHRHMG-FOUAAFFMSA-N C[C@H](CC1OC(C)=O)c2c1ncnc2Cl Chemical compound C[C@H](CC1OC(C)=O)c2c1ncnc2Cl MGSFTBDRWHRHMG-FOUAAFFMSA-N 0.000 description 1
- UELVKXXVJQEFRS-ZCFIWIBFSA-N C[C@H](CCc1[n+](cn2)OC)c1c2Cl Chemical compound C[C@H](CCc1[n+](cn2)OC)c1c2Cl UELVKXXVJQEFRS-ZCFIWIBFSA-N 0.000 description 1
- AUMBWDKTDZHUNN-RXMQYKEDSA-N C[C@H](CCc1ncn2)c1c2Cl Chemical compound C[C@H](CCc1ncn2)c1c2Cl AUMBWDKTDZHUNN-RXMQYKEDSA-N 0.000 description 1
- 101001059929 Caenorhabditis elegans Forkhead box protein O Proteins 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 description 1
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 1
- 201000005262 Chondroma Diseases 0.000 description 1
- 208000010126 Chondromatosis Diseases 0.000 description 1
- 208000019591 Chondromyxoid fibroma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 208000005443 Circulating Neoplastic Cells 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
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 1
- FBRAWBYQGRLCEK-AVVSTMBFSA-N Clobetasone butyrate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CCC)[C@@]1(C)CC2=O FBRAWBYQGRLCEK-AVVSTMBFSA-N 0.000 description 1
- 206010048832 Colon adenoma Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- 244000163122 Curcuma domestica Species 0.000 description 1
- 235000003392 Curcuma domestica Nutrition 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 102000000577 Cyclin-Dependent Kinase Inhibitor p27 Human genes 0.000 description 1
- 108010016777 Cyclin-Dependent Kinase Inhibitor p27 Proteins 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- 208000001154 Dermoid Cyst Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- XEHFSYYAGCUKEN-UHFFFAOYSA-N Dihydroscopoletin Natural products C1CC(=O)OC2=C1C=C(OC)C(O)=C2 XEHFSYYAGCUKEN-UHFFFAOYSA-N 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.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 MWWSFMDVAYGXBV-RUELKSSGSA-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
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 1
- 108030004793 Dual-specificity kinases Proteins 0.000 description 1
- 208000007033 Dysgerminoma Diseases 0.000 description 1
- 206010062805 Dysplastic naevus Diseases 0.000 description 1
- 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 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 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
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 1
- CITFYDYEWQIEPX-UHFFFAOYSA-N Flavanol Natural products O1C2=CC(OCC=C(C)C)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C=C1 CITFYDYEWQIEPX-UHFFFAOYSA-N 0.000 description 1
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 1
- WHZRCUIISKRTJL-YTZKRAOUSA-N Fluocortolone caproate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)CCCCC)[C@@]2(C)C[C@@H]1O WHZRCUIISKRTJL-YTZKRAOUSA-N 0.000 description 1
- 108090000852 Forkhead Transcription Factors Proteins 0.000 description 1
- 102100035421 Forkhead box protein O3 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
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 206010061968 Gastric neoplasm Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 201000005409 Gliomatosis cerebri Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 241000197195 Gonioma <angiosperm> Species 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
- 206010018691 Granuloma Diseases 0.000 description 1
- 229940125497 HER2 kinase inhibitor Drugs 0.000 description 1
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101000877681 Homo sapiens Forkhead box protein O3 Proteins 0.000 description 1
- 101000690268 Homo sapiens Proline-rich AKT1 substrate 1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-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
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010041012 Integrin alpha4 Proteins 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 102000014158 Interleukin-12 Subunit p40 Human genes 0.000 description 1
- 108010011429 Interleukin-12 Subunit p40 Proteins 0.000 description 1
- IPMYMEWFZKHGAX-UHFFFAOYSA-N Isotheaflavin Natural products OC1CC2=C(O)C=C(O)C=C2OC1C(C1=C2)=CC(O)=C(O)C1=C(O)C(=O)C=C2C1C(O)CC2=C(O)C=C(O)C=C2O1 IPMYMEWFZKHGAX-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 208000022010 Lhermitte-Duclos disease Diseases 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- MEPSBMMZQBMKHM-UHFFFAOYSA-N Lomatiol Natural products CC(=C/CC1=C(O)C(=O)c2ccccc2C1=O)CO MEPSBMMZQBMKHM-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 239000004907 Macro-emulsion Substances 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- 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 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- BTYYWOYVBXILOJ-UHFFFAOYSA-N N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}but-2-ynamide Chemical compound C12=CC(NC(=O)C#CC)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 BTYYWOYVBXILOJ-UHFFFAOYSA-N 0.000 description 1
- ULWYIVYFPIPRRK-UHFFFAOYSA-N N1C=CC=CC=C1.[S] Chemical compound N1C=CC=CC=C1.[S] ULWYIVYFPIPRRK-UHFFFAOYSA-N 0.000 description 1
- FTFRZXFNZVCRSK-UHFFFAOYSA-N N4-(3-chloro-4-fluorophenyl)-N6-(1-methyl-4-piperidinyl)pyrimido[5,4-d]pyrimidine-4,6-diamine Chemical compound C1CN(C)CCC1NC1=NC=C(N=CN=C2NC=3C=C(Cl)C(F)=CC=3)C2=N1 FTFRZXFNZVCRSK-UHFFFAOYSA-N 0.000 description 1
- 108010072915 NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt Proteins 0.000 description 1
- FSDDOQMCJBGVNM-UHFFFAOYSA-N NC=1C=C2C(=NC=NC2=CC1)NC1=CC(=CC=C1)CN Chemical compound NC=1C=C2C(=NC=NC2=CC1)NC1=CC(=CC=C1)CN FSDDOQMCJBGVNM-UHFFFAOYSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical group C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- BGGJGWFMUCTJLK-UHFFFAOYSA-N O=C1C=C(C(C(C(=O)O)=C1)C)C(=O)O Chemical compound O=C1C=C(C(C(C(=O)O)=C1)C)C(=O)O BGGJGWFMUCTJLK-UHFFFAOYSA-N 0.000 description 1
- QVAQPGHISPFIRV-UHFFFAOYSA-N OS([Pt])(=O)=O Chemical compound OS([Pt])(=O)=O QVAQPGHISPFIRV-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000000035 Osteochondroma Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 208000027067 Paget disease of bone Diseases 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- IIXHQGSINFQLRR-UHFFFAOYSA-N Piceatannol Natural products Oc1ccc(C=Cc2c(O)c(O)c3CCCCc3c2O)cc1O IIXHQGSINFQLRR-UHFFFAOYSA-N 0.000 description 1
- 101150063858 Pik3ca gene Proteins 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100024091 Proline-rich AKT1 substrate 1 Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 1
- 101710109947 Protein kinase C alpha type Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 208000005678 Rhabdomyoma Diseases 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- CIEYTVIYYGTCCI-UHFFFAOYSA-N SJ000286565 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1 CIEYTVIYYGTCCI-UHFFFAOYSA-N 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 208000000097 Sertoli-Leydig cell tumor Diseases 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- 102220497176 Small vasohibin-binding protein_T47D_mutation Human genes 0.000 description 1
- 101710188689 Small, acid-soluble spore protein 1 Proteins 0.000 description 1
- 101710188693 Small, acid-soluble spore protein 2 Proteins 0.000 description 1
- 101710166422 Small, acid-soluble spore protein A Proteins 0.000 description 1
- 101710166404 Small, acid-soluble spore protein C Proteins 0.000 description 1
- 101710174019 Small, acid-soluble spore protein C1 Proteins 0.000 description 1
- 101710174017 Small, acid-soluble spore protein C2 Proteins 0.000 description 1
- 101710174574 Small, acid-soluble spore protein gamma-type Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 229940126624 Tacatuzumab tetraxetan Drugs 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- UXRMWRBWCAGDQB-UHFFFAOYSA-N Theaflavin Natural products C1=CC(C2C(CC3=C(O)C=C(O)C=C3O2)O)=C(O)C(=O)C2=C1C(C1OC3=CC(O)=CC(O)=C3CC1O)=CC(O)=C2O UXRMWRBWCAGDQB-UHFFFAOYSA-N 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 102100036407 Thioredoxin Human genes 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 208000009311 VIPoma Diseases 0.000 description 1
- 201000003761 Vaginal carcinoma Diseases 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 206010048214 Xanthoma Diseases 0.000 description 1
- 206010048215 Xanthomatosis Diseases 0.000 description 1
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical compound [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 description 1
- IBXPAFBDJCXCDW-MHFPCNPESA-A [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O IBXPAFBDJCXCDW-MHFPCNPESA-A 0.000 description 1
- COGNCXJCCDGTDV-UHFFFAOYSA-N [O].N1C=CC=CC=C1 Chemical compound [O].N1C=CC=CC=C1 COGNCXJCCDGTDV-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 1
- 229950002684 aceglatone Drugs 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- LCJHLOJKAAQLQW-UHFFFAOYSA-N acetic acid;ethane Chemical compound CC.CC(O)=O LCJHLOJKAAQLQW-UHFFFAOYSA-N 0.000 description 1
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229940033350 aclovate Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 201000004471 adenofibroma Diseases 0.000 description 1
- 208000002718 adenomatoid tumor Diseases 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- JZMHCANOTJFLQJ-IEQBYLOXSA-A affinitac Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)[C@@H](OP([S-])(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)C1 JZMHCANOTJFLQJ-IEQBYLOXSA-A 0.000 description 1
- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000005154 alkyl sulfonyl amino alkyl group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 238000000627 alternating current impedance spectroscopy Methods 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- WLDHEUZGFKACJH-UHFFFAOYSA-K amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1N=NC1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-UHFFFAOYSA-K 0.000 description 1
- 229960003099 amcinonide Drugs 0.000 description 1
- ILKJAFIWWBXGDU-MOGDOJJUSA-N amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229960001220 amsacrine Drugs 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
- 229960004238 anakinra Drugs 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
- 229950000242 ancitabine Drugs 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 229940049595 antibody-drug conjugate Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 229950003145 apolizumab Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- NMYKBZSMOUFOJV-FJSWQEPZSA-N aprinocarsen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)[C@@H](OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)C1 NMYKBZSMOUFOJV-FJSWQEPZSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229950002882 aselizumab Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012822 autophagy inhibitor Substances 0.000 description 1
- 229960002756 azacitidine Drugs 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
- 229950011321 azaserine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 229950001863 bapineuzumab Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 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
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N beta-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229960005354 betamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-LWCNAHDDSA-L betamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-LWCNAHDDSA-L 0.000 description 1
- 229960004311 betamethasone valerate Drugs 0.000 description 1
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- HUTDDBSSHVOYJR-UHFFFAOYSA-H bis[(2-oxo-1,3,2$l^{5},4$l^{2}-dioxaphosphaplumbetan-2-yl)oxy]lead Chemical compound [Pb+2].[Pb+2].[Pb+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O HUTDDBSSHVOYJR-UHFFFAOYSA-H 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229960005522 bivatuzumab mertansine Drugs 0.000 description 1
- 229950006844 bizelesin Drugs 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
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 208000016738 bone Paget disease Diseases 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical class Br* 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 229960004436 budesonide Drugs 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
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 229950007296 cantuzumab mertansine Drugs 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 208000022033 carcinoma of urethra Diseases 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin 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=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229960003115 certolizumab pegol Drugs 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 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
- 229950008249 chlornaphazine Drugs 0.000 description 1
- HGAZMNJKRQFZKS-UHFFFAOYSA-N chloroethene;ethenyl acetate Chemical compound ClC=C.CC(=O)OC=C HGAZMNJKRQFZKS-UHFFFAOYSA-N 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)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](OC(C)=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](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229940090100 cimzia Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 229960005465 clobetasone butyrate Drugs 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000000431 corpus luteum hormone Substances 0.000 description 1
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 description 1
- FZCHYNWYXKICIO-FZNHGJLXSA-N cortisol 17-valerate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O FZCHYNWYXKICIO-FZNHGJLXSA-N 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 108010089438 cryptophycin 1 Proteins 0.000 description 1
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 1
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 235000003373 curcuma longa Nutrition 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 150000001940 cyclopentanes Chemical class 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229950004239 defosfamide Drugs 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960002344 dexamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 125000005266 diarylamine group Chemical group 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 238000011496 digital image analysis Methods 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- OBISXEJSEGNNKL-UHFFFAOYSA-N dinitrogen-n-sulfide Chemical compound [N-]=[N+]=S OBISXEJSEGNNKL-UHFFFAOYSA-N 0.000 description 1
- PPSZHCXTGRHULJ-UHFFFAOYSA-N dioxazine Chemical compound O1ON=CC=C1 PPSZHCXTGRHULJ-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- MNQDKWZEUULFPX-UHFFFAOYSA-M dithiazanine iodide Chemical compound [I-].S1C2=CC=CC=C2[N+](CC)=C1C=CC=CC=C1N(CC)C2=CC=CC=C2S1 MNQDKWZEUULFPX-UHFFFAOYSA-M 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 229940120655 eloxatin Drugs 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 208000023965 endometrium neoplasm Diseases 0.000 description 1
- 229950010213 eniluracil Drugs 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 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
- 229950004292 erlizumab Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin 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[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- QCYAXXZCQKMTMO-QFIPXVFZSA-N ethyl (2s)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]propanoate Chemical compound N([C@@H](CC=1C=CC(NC=2C3=CN=CC=C3C=CN=2)=CC=1)C(=O)OCC)C1=C(Br)C(=O)C11CCCCC1 QCYAXXZCQKMTMO-QFIPXVFZSA-N 0.000 description 1
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229960005237 etoglucid Drugs 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
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 201000001343 fallopian tube carcinoma Diseases 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229950001563 felvizumab Drugs 0.000 description 1
- 201000010255 female reproductive organ cancer Diseases 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
- 150000002206 flavan-3-ols Chemical class 0.000 description 1
- 235000011987 flavanols Nutrition 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960000785 fluocinonide Drugs 0.000 description 1
- 229960003973 fluocortolone Drugs 0.000 description 1
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 description 1
- XZBJVIQXJHGUBE-HZMVJJPJSA-N fluocortolone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)C(C)(C)C)[C@@]2(C)C[C@@H]1O XZBJVIQXJHGUBE-HZMVJJPJSA-N 0.000 description 1
- 229960005283 fluocortolone pivalate Drugs 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002376 fluorescence recovery after photobleaching Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 229960002650 fluprednidene acetate Drugs 0.000 description 1
- DEFOZIFYUBUHHU-IYQKUMFPSA-N fluprednidene acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC(=C)[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O DEFOZIFYUBUHHU-IYQKUMFPSA-N 0.000 description 1
- 229960002074 flutamide 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
- 239000004088 foaming agent Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229940064302 folacin Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 229950004923 fontolizumab Drugs 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 239000007903 gelatin capsule Substances 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
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 235000021474 generally recognized As safe (food) Nutrition 0.000 description 1
- 235000021473 generally recognized as safe (food ingredients) Nutrition 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 229960002383 halcinonide Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 201000000284 histiocytoma Diseases 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 102000045108 human EGFR Human genes 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 229960001524 hydrocortisone butyrate Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- KNOSIOWNDGUGFJ-UHFFFAOYSA-N hydroxysesamone Natural products C1=CC(O)=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1O KNOSIOWNDGUGFJ-UHFFFAOYSA-N 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000000495 immunoinflammatory effect Effects 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 229940073062 imuran Drugs 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical group 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
- 229950004101 inotuzumab ozogamicin Drugs 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 229940125798 integrin inhibitor Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- OMEUGRCNAZNQLN-UHFFFAOYSA-N isis 5132 Chemical compound O=C1NC(=O)C(C)=CN1C1OC(COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(S)(=O)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)CO)C(O)C1 OMEUGRCNAZNQLN-UHFFFAOYSA-N 0.000 description 1
- 150000002518 isoindoles Chemical class 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 229940054136 kineret Drugs 0.000 description 1
- 229950000518 labetuzumab Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- CWPGNVFCJOPXFB-UHFFFAOYSA-N lapachol Chemical compound C1=CC=C2C(=O)C(=O)C(CC=C(C)C)=C(O)C2=C1 CWPGNVFCJOPXFB-UHFFFAOYSA-N 0.000 description 1
- SIUGQQMOYSVTAT-UHFFFAOYSA-N lapachol Natural products CC(=CCC1C(O)C(=O)c2ccccc2C1=O)C SIUGQQMOYSVTAT-UHFFFAOYSA-N 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229940115286 lentinan 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
- 239000003446 ligand Substances 0.000 description 1
- 230000004576 lipid-binding Effects 0.000 description 1
- 239000008263 liquid aerosol Substances 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229950008001 matuzumab Drugs 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 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
- 239000000155 melt Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 229950009246 mepitiostane Drugs 0.000 description 1
- 229960005108 mepolizumab Drugs 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 229940100630 metacresol Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000002905 metal composite material Substances 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- QRMNENFZDDYDEF-GOSISDBHSA-N methyl (8s)-8-(bromomethyl)-2-methyl-4-(4-methylpiperazine-1-carbonyl)oxy-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-1-carboxylate Chemical compound C1([C@H](CBr)CN(C1=C1)C(=O)C=2NC3=C(OC)C(OC)=C(OC)C=C3C=2)=C2C(C(=O)OC)=C(C)NC2=C1OC(=O)N1CCN(C)CC1 QRMNENFZDDYDEF-GOSISDBHSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 229960001521 motavizumab Drugs 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- ZTFBIUXIQYRUNT-MDWZMJQESA-N mubritinib Chemical compound C1=CC(C(F)(F)F)=CC=C1\C=C\C1=NC(COC=2C=CC(CCCCN3N=NC=C3)=CC=2)=CO1 ZTFBIUXIQYRUNT-MDWZMJQESA-N 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- ZKKVUIPXPPDIRD-UHFFFAOYSA-N n-(3-chlorophenyl)quinazolin-4-amine Chemical compound ClC1=CC=CC(NC=2C3=CC=CC=C3N=CN=2)=C1 ZKKVUIPXPPDIRD-UHFFFAOYSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YCKACRNXVWJWBX-UHFFFAOYSA-N n-phenyl-7h-pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound N=1C=NC=2NC=CC=2C=1NC1=CC=CC=C1 YCKACRNXVWJWBX-UHFFFAOYSA-N 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 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
- 229950010203 nimotuzumab Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- CMUOJBJRZUHRMU-UHFFFAOYSA-N nitrourea Chemical compound NC(=O)N[N+]([O-])=O CMUOJBJRZUHRMU-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 229950005751 ocrelizumab Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin 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=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950005848 olivomycin Drugs 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 208000020717 oral cavity carcinoma Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000003388 osteoid osteoma Diseases 0.000 description 1
- AZHVQJLDOFKHPZ-UHFFFAOYSA-N oxathiazine Chemical compound O1SN=CC=C1 AZHVQJLDOFKHPZ-UHFFFAOYSA-N 0.000 description 1
- CQDAMYNQINDRQC-UHFFFAOYSA-N oxatriazole Chemical compound C1=NN=NO1 CQDAMYNQINDRQC-UHFFFAOYSA-N 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229950011485 pascolizumab Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin 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)NCCCN[C@@H](C)C=1C=CC=CC=1)[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=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 229950003203 pexelizumab Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin 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-XVVDYKMHSA-N 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229910052573 porcelain Inorganic materials 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960002794 prednicarbate Drugs 0.000 description 1
- FNPXMHRZILFCKX-KAJVQRHHSA-N prednicarbate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O FNPXMHRZILFCKX-KAJVQRHHSA-N 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000003623 progesteronic effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- PMXCMJLOPOFPBT-HNNXBMFYSA-N purvalanol A Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)C(C)C)=NC=1NC1=CC=CC(Cl)=C1 PMXCMJLOPOFPBT-HNNXBMFYSA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical compound C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 description 1
- GYBPSRGGQNUPBF-UHFFFAOYSA-N pyrimidine;thiophene Chemical compound C=1C=CSC=1.C1=CN=CN=C1 GYBPSRGGQNUPBF-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical compound N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229960003254 reslizumab Drugs 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- NSFWWJIQIKBZMJ-PAGWOCKZSA-N roridin a Chemical compound C([C@@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-PAGWOCKZSA-N 0.000 description 1
- 102200085788 rs121913279 Human genes 0.000 description 1
- 102200085789 rs121913279 Human genes 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950005374 ruplizumab Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- FWYIBGHGBOVPNL-UHFFFAOYSA-N scopoletin Natural products COC=1C=C2C=CC(OC2=C(C1)O)=O FWYIBGHGBOVPNL-UHFFFAOYSA-N 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 208000004548 serous cystadenocarcinoma Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229940068638 simponi Drugs 0.000 description 1
- 229950003804 siplizumab Drugs 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 201000001839 skull cancer Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229960003339 sodium phosphate Drugs 0.000 description 1
- SDKPSXWGRWWLKR-UHFFFAOYSA-M sodium;9,10-dioxoanthracene-1-sulfonate Chemical compound [Na+].O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)[O-] SDKPSXWGRWWLKR-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229950006551 sontuzumab Drugs 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229950001072 tadocizumab Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229950004218 talizumab Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 125000002456 taxol group Chemical group 0.000 description 1
- 229950001788 tefibazumab Drugs 0.000 description 1
- 229960001674 tegafur Drugs 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
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960000235 temsirolimus 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
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003866 tertiary ammonium salts Chemical class 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- IPMYMEWFZKHGAX-ZKSIBHASSA-N theaflavin Chemical compound C1=C2C([C@H]3OC4=CC(O)=CC(O)=C4C[C@H]3O)=CC(O)=C(O)C2=C(O)C(=O)C=C1[C@@H]1[C@H](O)CC2=C(O)C=C(O)C=C2O1 IPMYMEWFZKHGAX-ZKSIBHASSA-N 0.000 description 1
- 235000014620 theaflavin Nutrition 0.000 description 1
- 229940026509 theaflavin Drugs 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical compound C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 125000006407 thiazinanyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- DKGYESBFCGKOJC-UHFFFAOYSA-N thiophen-3-amine Chemical compound NC=1C=CSC=1 DKGYESBFCGKOJC-UHFFFAOYSA-N 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
- 229960005324 tiludronic acid Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960004631 tixocortol Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 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
- 229950001802 toralizumab Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- LZAJKCZTKKKZNT-PMNGPLLRSA-N trichothecene Chemical compound C12([C@@]3(CC[C@H]2OC2C=C(CCC23C)C)C)CO1 LZAJKCZTKKKZNT-PMNGPLLRSA-N 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- PYIHTIJNCRKDBV-UHFFFAOYSA-L trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCCCCC[N+](C)(C)C PYIHTIJNCRKDBV-UHFFFAOYSA-L 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 208000022271 tubular adenoma Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 235000013976 turmeric Nutrition 0.000 description 1
- GFNNBHLJANVSQV-UHFFFAOYSA-N tyrphostin AG 1478 Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1 GFNNBHLJANVSQV-UHFFFAOYSA-N 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229950004362 urtoxazumab Drugs 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 208000009540 villous adenoma Diseases 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229950004393 visilizumab Drugs 0.000 description 1
- 238000012800 visualization Methods 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
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin 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)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57496—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving intracellular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
- G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Cell Biology (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本发明提供预测肿瘤细胞生长对由PI3K/AKT激酶途径抑制剂产生的抑制的敏感性的方法，包括：确定FOXO3a在肿瘤细胞中的定位分布，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关且FOXO3a的细胞核定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的抗性相关。
Description
相关申请的交叉引用
本非临时专利申请根据35USC§119(e)要求2010年4月16日提交的美国临时申请61/325,190的权益，将其全文通过引用的方式并入本申请。
技术领域
本发明涉及作为PI3K/AKT途径激酶抑制剂效能的预测的FOXO3a定位、基于FOXO3a定位对患者进行分级(stratifying)以及给予PI3K/AKT途径激酶抑制剂的方法。
背景技术
蛋白激酶包括两类：蛋白酪氨酸激酶(PTK)和丝氨酸-苏氨酸激酶(STK)。蛋白激酶B/AKT酶为一类丝氨酸-苏氨酸激酶，其在多种人类肿瘤中过表达。PI3K脂质产物的最充分表征的靶标中的一种为57KD丝氨酸-苏氨酸蛋白激酶AKT，其位于在信号转导途径中PI3K的下游(Hemmings,B.A.(1997)Science 275:628；Hay N.(2005)Cancer Cell 8:179-183)。
磷酸肌醇3-激酶(PI3K)为这样的脂质激酶，其在肌醇环的3-羟基残基上对脂质进行磷酸化(Whitman et al(1988)Nature,332:664)。由PI3-激酶产生的3-磷酸化磷脂(PIP3s)作为募集具有脂质结合区域(包括锤型同源性(PH)区域)的激酶的第二信使，诸如AKT和磷酸肌醇依赖性激酶-1(PDK1)。AKT与膜PIP3的结合引起AKT向质膜的易位，这使得AKT与PDK1接触，这导致激活AKT。肿瘤抑制基因磷酸酶PTEN使得PIP3去磷酸化且因此作为AKT活化的负性调节剂。PI3-激酶AKT和PDK1对于以下而言是重要的：许多细胞进程包括细胞周期调节、增殖、存活、凋亡以及运动性的调节，且为疾病诸如癌症、糖尿病和免疫炎症的分子机制的重要组成(Vivanco et al(2002)Nature Rev.Cancer 2:489；Phillips et al(1998)Cancer 83:41)。认为AKT通过抑制凋亡且同时增强血管发生和增殖而维持其对癌症的效应(Toker et al(2006)Cancer Res.66(8):3963-3966)。癌症中的主要PI3-激酶同工型为I型PI3-激酶p110α(alpha)。AKT的三种同工型通过对一组下游靶标包括FOXO3a、TSC1/2、GSK3β和BAD的磷酸化来调节细胞进程。由AKT对FOXO3a的磷酸化导致细胞质定位(cytoplasmic localization)以及FOXO3a的负性调节，这是因为其避开了促细胞凋亡基因和细胞周期抑制基因的转录调控。其它同工型牵涉于心血管和免疫炎性疾病中。
PI3激酶/AKT途径为开发在癌症细胞中抑制增殖、逆转细胞凋亡抑制以及克服对细胞毒素剂的耐药性的抗癌药物的引人注目的靶标。
发明内容
本发明的一方面包括预测肿瘤细胞生长对由PI3K/AKT激酶途径抑制剂产生的抑制的敏感性的方法，包括：确定FOXO3a在肿瘤细胞中的定位分布，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关，且FOXO3a的细胞核定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的抗性相关。
本发明的一方面包括治疗患者中的肿瘤的方法，包括对所述患者给予治疗有效量的PI3K/AKT激酶途径抑制剂或者其立体异构体或者盐，其中治疗取决于具有细胞质FOXO3a定位分布的患者的肿瘤。
本发明的一方面包括治疗患者中的肿瘤的方法，包括对所述患者给予治疗有效量的PI3K/AKT激酶途径抑制剂或者其立体异构体或者盐，其中FOXO3a在肿瘤中的定位分布基本上为细胞质中的。
本发明的一方面包括治疗患者中的肿瘤的方法，包括选择具有细胞质定位分布的肿瘤的患者以及对所述患者给予治疗有效量的PI3K/AKT激酶途径抑制剂或者其立体异构体或者盐。
附图说明
图1示例说明了FOXO患者如何成为PI3K/AKT信号传导的直接靶标。AKT通过磷酸化负性调节FOXO3a，进而将其定位于细胞质。当AKT为失活时，FOXO3a被去磷酸化且易位至细胞核，在此其启动诱导细胞周期停滞以及细胞凋亡的基因。
图2A-B为荧光显微图像，其显示未处理的以及用式I的化合物GDC-0068处理后的BT474细胞。在图2A中，FOXO3a集中于细胞质中。在图2B中，BT474细胞显示为用式I的化合物处理后的，其中所述AKT已经失活且FOXO3a被去磷酸化且显示为易位至细胞核。
图3A-B为荧光显微图像，其显示基线FOXO3a在对AKT抑制剂GDC-0068敏感的细胞系中为在细胞质中的，且在抗性细胞系中为在细胞核中的。图像显示Hoechst细胞核染色(底部)、FOXO3a染色(中间)和合并的(叠加)图像(顶部)。图3A显示FOXO3a在一组乳腺癌细胞系中的基线定位，所述细胞系先前确定为对AKT抑制剂处理敏感的。在敏感细胞系中，FOXO3a显示为在细胞质中的，这与激活的AKT一致。图3B显示FOXO3a在一组乳腺癌细胞系中的基线定位，所述细胞系先前确定为对AKT抑制剂处理具有抗性的。在抗性细胞系中，FOXO3a主要显示为在细胞核中的。MDA-MB-468为PTEN缺失的细胞系且因此预期为使得AKT途径激活。然而，该细胞系对至少一种式I的化合物GDC-0068具有抗性。在该细胞系中，观察到FOXO3a的分布式的细胞质和细胞核染色。
图4显示使用在Cellomics平台上的细胞核易位算法进行FOXO3a定位的定量。FOXO3a细胞核vs细胞质定位使用Cellomics HCS Arrayscan、使用细胞质对细胞核易位算法进行定量。该数据作为细胞核与细胞质染色强度之间的差异呈现于图表上。FOXO3a在AKT抑制剂GDC-0068敏感细胞系中的染色在该分析中主要为在细胞质中的(负数)，而AKT抑制剂GDC-0068抗性细胞系显示细胞核信号(正数)。给出了GDC-0068在各细胞系中的IC50值(微摩尔)，这证实了该细胞系对AKT抑制剂的敏感性。给出了各细胞系的PTEN状态(PTEN缺失的细胞系显示为“-”)。
图5显示了另外的细胞系数据，其证实了FOXO3a细胞质定位预测出对式I的AKT抑制剂GDC-0068的敏感性。显示了先前确定为对至少一种式I的AKT抑制剂GDC-0068具有抗性(IC50大于约20微摩尔)但PTEN处于缺失状态的细胞系。鉴于PTEN缺失的状态，这些细胞系通常预期为对式I的AKT抑制剂诸如GDC-0068进行响应的。
相比于先前确定为PTEN缺失的敏感的且显示细胞质染色的细胞系(EVSAT、HCC70)，PTEN缺失的四种抗性细胞系中的三种仍然显示对于FOXO3a主要为细胞核染色，这与其抗性表型一致。对全部细胞系进行比较，在对AKT抑制剂具有抗性的PTEN(-)乳腺癌细胞系中，FOXO3a定位相比于细胞质而言趋向于在细胞核中更强。该数据表明了FOXO3a定位测定可用于鉴别对AKT抑制剂具有抗性的肿瘤且可为AKT抑制剂敏感性的更准确的预测剂。除了遗传改变之外，可使用该定位测定诸如作为激活的AKT途径的标记物的PTEN。此外，该数据表明了当与PTEN状态组合使用来预测AKT抑制剂效能时，FOXO3a定位分布提供了由于单独使用PTEN状态的优势。
图6显示了散布图，其在对AKT抑制剂GDC-0068具有抗性和敏感的各种细胞系中比较了对于FOXO3a的定位测定敏感性以及对于磷酸-AKT的Luminex测定敏感性。如所观察到的，对于FOXO3a测定在抗性与敏感性细胞系之间存在更清晰的差异。对于磷酸-AKT的Luminex测定结果在抗性与敏感性细胞系之间具有更多的叠加，且因此具有减弱的敏感性。因此，FOXO3a定位相比于磷酸-AKT(一种充分描述的AKT激活的标记物)而言可更有效地区分AKT抑制剂敏感性与抗性细胞系。
图7显示了在用GDC-0941(一种PI3K抑制剂)和GDC-0068(一种式I的AKT抑制剂)处理之前和之后的各种敏感性细胞系的荧光图像。这些图像表明了在对PI3K/AKT抑制剂敏感的细胞系中在用PI3K和AKT抑制剂处理后FOXO3a由细胞质易位至细胞核。
图8显示了在用GDC-0941(一种PI3K抑制剂)和GDC-0068(一种式I的AKT抑制剂)处理之前和之后的各种抗性细胞系的荧光图像。FOXO3a在PI3K/AKT抑制剂抗性细胞系中在基线为在细胞核中的且在用PI3K/AKT抑制剂处理后保留在细胞核中。在具有PI3K/AKT激活的抗性细胞系(即PTEN缺失的MB-468)中，FOXO3a同时存在于细胞核和细胞质中且用PI3K/AKT抑制剂进行处理导致了更完全的重新定位至细胞核中。
图9显示了针对在用式I的AKT抑制剂GDC-0068处理后的FOXO3a定位的图7和8的定量数据的条形图。该图下面的图表表明激活PI3K/AKT途径的遗传改变(PI3K突变或者PTEN缺失)是否存在于测试的细胞系中。此外，指出了各种细胞中的每种对于式I的AKT抑制剂的IC50值。基于测量的IC50值，各种细胞分类为敏感性组(S)或者抗性组(R)。
图10A-C显示了在用GDC-0941处理细胞系之前和之后的定位测定结果。在图10A中，在对GDC-0941敏感的细胞系中在用GDC-0941处理后FOXO3a由细胞质重新定位至细胞核中。在图10B中，在对GDC-0941具有抗性的细胞系中，FOXO3a在基线为在细胞核中的且在处理后保留在细胞核中。图10C显示了图10A-B数据的定量，这表明了在用GDC-0941处理后FOXO3a定位至细胞核中。由于FOXO3a定位变化一致性地响应于GDC-0941和式I的AKT抑制剂，该数据表明FOXO3a定位通过PI3K/AKT途径调节且对靶向该途径的抑制剂敏感。
图11A-C显示在用PD-901(一种已知的MEK抑制剂)处理细胞系之前和之后的定位测定结果。在图11A-C中，FOXO3a定位在用PD901(一种MEK1/2抑制剂)处理后未改变，这表明FOXO3a定位在这些细胞系中未被MAPK途径调节。在该施用浓度的PD901已经在该组乳腺癌细胞系中证实为具有活性的(Hoeflich KP et al,Clin Cancer Res 15(14):4649-64,2009)。
图12A-B显示在对式I的AKT抑制剂GDC-0068敏感的或者具有抗性的前列腺细胞系中的定位测定结果。在图12A中，对式I的AKT抑制剂GDC-0068敏感的细胞系具有细胞质定位分布，而抗性细胞具有细胞核定位分布。图12B显示了图12A数据的定量，这表明定位分布可用于预测式I的AKT抑制剂在前列腺细胞系中的效能。
具体实施方式
定义
“酰基”是指由式-C(O)-R所表示的含有取代基的羰基，其中R为H、烷基、环烷基、杂环基、环烷基取代的烷基或者杂环基取代的烷基，其中所述烷基、烷氧基、环烷基和杂环基如本申请所定义。酰基包括烷酰基(例如乙酰基)、芳酰基(例如苯甲酰基)和杂芳酰基(例如吡啶酰基)。
术语"烷基"是指饱和直链或者支链一价烃基，其中所述烷基可任选独立取代有本申请所述的一种或者多种取代基。在一个实例中，所述烷基含有一至十八个碳原子(C1-C18)。在其它实例中，所述烷基为C0-C6、C0-C5、C0-C3、C1-C12、C1-C10、C1-C8、C1-C6、C1-C5、C1-C4或者C1-C3。烷基的实例包括甲基(Me、-CH3)、乙基(Et、-CH2CH3)、1-丙基(n-Pr、正丙基、-CH2CH2CH3)、2-丙基(i-Pr、异丙基、-CH(CH3)2)、1-丁基(n-Bu、正丁基、-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu、异丁基、-CH2CH(CH3)2)、2-丁基(s-Bu、仲丁基、-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu、叔丁基、-C(CH3)3)、1-戊基(正戊基、-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3、1-庚基和1-辛基。
术语"烯基"是指具有至少一个不饱和位点即碳碳双键的直链或者支链一价烃基，其中所述烯基可任选独立取代有本申请所述的一种或者多种取代基，且包括具有"顺"和"反"定向或者可选择地"E"和"Z"取向的基团。在一个实例中，所述烯基含有二至十八个碳原子(C2-C18)。在其它实例中，所述烯基为C2-C12、C2-C10、C2-C8、C2-C6或者C2-C3。实例包括但不限于乙烯基(-CH=CH2)、丙-1-烯基(-CH=CHCH3)、丙-2-烯基(-CH2CH=CH2)、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯基、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基和己-1,3-二烯基。
术语“烷氧基”是指由式-OR所表示的直链或者支链一价基团，其中R为烷基、烯基、炔基或者环烷基，其可进一步任选如本申请所述取代。烷氧基包括甲氧基、乙氧基、丙氧基、异丙氧基、单氟甲氧基、二氟甲氧基和三氟甲氧基以及环丙氧基。
术语"炔基"是指具有至少一个不饱和位点即碳碳三键的直链或者支链一价烃基，其中所述炔基可任选独立取代有本申请所述的一种或者多种取代基。在一个实例中，所述炔基含有二至十八个碳原子(C2-C18)。在其它实例中，所述炔基为C2-C12、C2-C10、C2-C8、C2-C6或者C2-C3。实例包括但不限于乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH3)、丙-2-炔基(炔丙基、-CH2C≡CH)、丁-1-炔基、丁-2-炔基和丁-3-炔基。
“氨基”表示任选取代的伯氨基(即-NH2)、仲氨基(即-NRH)和叔氨基(即-NRR)，其中R为烷基、烷氧基、环烷基、杂环基、环烷基取代的烷基或者杂环基取代的烷基，其中所述烷基、烷氧基、环烷基和杂环基如本申请所定义。具体的仲胺和叔胺为烷基胺、二烷基胺、芳基胺、二芳基胺、芳烷基胺和二芳烷基胺，其中所述烷基如本申请所定义且任选取代。具体的仲胺和叔胺为甲基胺、乙基胺、丙基胺、异丙基胺、苯基胺、苄基胺、二甲基胺、二乙基胺、二丙基胺和二异丙基胺。
本申请使用的“氨基保护基”是指通常用于阻碍或者保护氨基而反应在化合物的其它官能团上进行的衍生基团。所述保护基的实例包括氨基甲酸酯基、酰氨基、烷基和芳基、亚氨基以及可移去以重新生成预期氨基的许多N-杂原子衍生基团。具体的氨基保护基为Pmb(对甲氧基苄基)、Boc(叔叔丁基氧基羰基)、Fmoc(9-芴基甲基氧基羰基)和Cbz(苄基氧基羰基)。这些基团的其它实例出现于T.W.Greene and P.G.M.Wuts,“Protective Groups inOrganic Synthesis”,2nd ed.,John Wiley & Sons,Inc.,New York,NY，1991,chapter 7；E.Haslam,“Protective Groups in Organic Chemistry”,J.G.W.McOmie,Ed.,Plenum Press,New York,NY，1973,Chapter 5以及T.W.Greene,“Protective Groups in Organic Synthesis”,John Wiley and Sons,New York,NY，1981中。术语“保护的氨基”是指取代有上述氨基保护基中的一种的氨基。
当单独使用或者作为其它术语的一部分使用时，“芳基”是指具有指定数目的碳原子或者至多14个碳原子(如果未指定数目)的碳环芳族基团(无论是否与一个或者多个基团稠合)。芳基的实例包括苯基、萘基、联苯基、菲基、并四苯基、1,2,3,4-四氢萘基、1H-茚基、2,3-二氢-1H-茚基等(参见例如Lang’sHandbook of Chemistry(Dean,J.A.,ed)13th ed.表7-2[1985])。具体的芳基为苯基。取代的苯基或者取代的芳基是指取代有一、二、三、四或者五个选自本申请所述的基团的例如1-2、1-3或者1-4个取代基的苯基或者芳基。在一个实例中，芳基上任选的取代基选自卤素(F、Cl、Br、I)、羟基、经保护的羟基、氰基、硝基、烷基(例如C1-C6烷基)、烷氧基(例如C1-C6烷氧基)、苄基氧基、羧基、经保护的羧基、羧基甲基、经保护的羧基甲基、羟基甲基、经保护的羟基甲基、氨基甲基、经保护的氨基甲基、三氟甲基、烷基磺酰基氨基、烷基磺酰基氨基烷基、芳基磺酰基氨基、芳基磺酰基氨基烷基、杂环基磺酰基氨基、杂环基磺酰基氨基烷基、杂环基、芳基或者其它所述的基团。在这些取代基上的一个或者多个次甲基(CH)和/或者亚甲基(CH2)本身可取代有如上所述的类似的基团。术语“取代的苯基”的实例包括单-或者二(卤素)苯基诸如2-氯苯基、2-溴苯基、4-氯苯基、2,6-二氯苯基、2,5-二氯苯基、3,4-二氯苯基、3-氯苯基、3-溴苯基、4-溴苯基、3,4-二溴苯基、3-氯-4-氟苯基、2-氟苯基等；单-或者二(羟基)苯基诸如4-羟基苯基、3-羟基苯基、2,4-二羟基苯基及其经保护的羟基衍生基团等；硝基苯基诸如3-或者4-硝基苯基；氰基苯基，例如4-氰基苯基；单-或者二(低级烷基)苯基诸如4-甲基苯基、2,4-二甲基苯基、2-甲基苯基、4-(异丙基)苯基、4-乙基苯基、3-(正丙基)苯基等；单-或者二(烷氧基)苯基，例如3,4-二甲氧基苯基、3-甲氧基-4-苄基氧基苯基、3-乙氧基苯基、4-(异丙氧基)苯基、4-(叔丁氧基)苯基、3-乙氧基-4-甲氧基苯基等；3-或者4-三氟甲基苯基；单-或者二羧基苯基或者(经保护的羧基)苯基诸如4-羧基苯基、单-或者二(羟基甲基)苯基或者(经保护的羟基甲基)苯基诸如3-(经保护的羟基甲基)苯基或者3,4-二(羟基甲基)苯基；单-或者二(氨基甲基)苯基或者(经保护的氨基甲基)苯基诸如2-(氨基甲基)苯基或者2,4-(经保护的氨基甲基)苯基；或者单-或者二(N-(甲基磺酰基氨基))苯基诸如3-(N-甲基磺酰基氨基))苯基。同样，术语“取代的苯基”表示二取代的苯基，其中所述取代基为不同的，例如3-甲基-4-羟基苯基、3-氯-4-羟基苯基、2-甲氧基-4-溴苯基、4-乙基-2-羟基苯基、3-羟基-4-硝基苯基、2-羟基-4-氯苯基等，以及三取代的苯基，其中所述取代基为不同的，例如3-甲氧基-4-苄基氧基-6-甲基磺酰基氨基、3-甲氧基-4-苄基氧基-6-苯基磺酰基氨基，以及四取代的苯基，其中所述取代基为不同的，诸如3-甲氧基-4-苄基氧基-5-甲基-6-苯基磺酰基氨基。具体的取代的苯基包括2-氯苯基、2-氨基苯基、2-溴苯基、3-甲氧基苯基、3-乙氧基-苯基、4-苄基氧基苯基、4-甲氧基苯基、3-乙氧基-4-苄基氧基苯基、3,4-二乙氧基苯基、3-甲氧基-4-苄基氧基苯基、3-甲氧基-4-(1-氯甲基)苄基氧基-6-甲基磺酰基氨基苯基。稠合的芳环也可以与取代的烷基相同的方式取代有本申请所述的例如1、2或者3个任何的取代基。
术语“癌症”和“癌性”、“赘生物(neoplasm)”、“肿瘤”是指或者描述哺乳动物中的生理状况，其典型特征在于未调节的细胞生长。“肿瘤”包括一种或者多种癌性细胞。肿瘤包括实体瘤和非实体瘤。
"化学治疗剂"为用于治疗给定病症例如癌症或者炎性病症的药物。化学治疗剂的实例包括NSAID；激素类，诸如糖皮质激素；皮质激素，诸如氢化可的松、乙酸氢化可的松、乙酸可的松、新戊酸替可的松、泼尼松龙、甲基泼尼松龙、泼尼松、曲安奈德、曲安西龙醇(triamcinolone alcohol)、莫米松、安西奈德、布地奈德、地奈德、醋酸氟轻松、氟轻松、哈西奈德、倍他米松、倍他米松磷酸钠、地塞米松、地塞米松磷酸钠、氟可龙、氢化可的松-17-丁酸酯、氢化可的松-17-戊酸酯、双丙酸阿氯米松、戊酸倍他米松、二丙酸倍他米松、泼尼卡酯、氯倍他松-17-丁酸酯、氯倍他索-17-丙酸酯、己酸氟考龙、特戊酸氟考龙和醋酸氟甲叉龙；免疫选择性抗炎肽(ImSAIDs)诸如苯基丙氨酸-谷氨酰胺-甘氨酸(FEG)及其D-同分异构形式(feG)(IMULANBioTherapeutics，LLC)；抗风湿药诸如硫唑嘌呤、环孢素(环孢素A)、D-青霉胺、氯金化钠(gold salts)、羟基氯喹、来氟米特、甲氨蝶呤(MTX)、米诺环素、柳氮磺吡啶、环磷酰胺、肿瘤坏死因子α(TNFα)阻断剂诸如依那西普(Enbrel)、英夫利昔单抗(Remicade)、阿达木单抗(Humira)、赛妥珠单抗(Cimzia)、戈利木单抗(Simponi)、白介素1(IL-1)阻断剂诸如阿那白滞素(Kineret)、抗B细胞单克隆抗体诸如利妥昔单抗
T细胞共同刺激阻断剂诸如阿巴西普(Orencia)、白介素6(IL-6)阻断剂诸如托珠单抗；激素拮抗剂诸如他莫昔芬、非那雄胺或者LHRH拮抗剂；放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素)；其他试验药诸如硫代铂(Thioplatin)、PS-341、丁酸苯酯、ET-18-OCH3或者法尼基转移酶抑制剂(L-739749、L-744832)；多酚类诸如槲皮素、白藜芦醇、白皮杉醇、表没食子儿茶素没食子酸酯、茶黄素、黄烷醇、原花青素、桦木酸及其衍生物；自噬抑制剂诸如氯喹；烷化剂诸如塞替派和环磷酰胺烷基磺酸酯类诸如白消安、英丙舒凡和哌泊舒凡；氮丙啶诸如硫丹、卡波醌、meturedopa和uredopa；乙撑亚胺和甲基氨基吖啶，包括六甲密胺、三亚胺嗪、三亚乙基磷酰胺、三亚乙基硫化磷酰胺和trimethylomelamine；番荔枝内酯(尤其是布拉它辛和布拉它辛酮)；δ-9-四氢大麻酚(屈大麻酚、
)；β-拉帕醌；拉帕醇；秋水仙碱；桦木酸；喜树碱(包括合成性类似物托泊替康
CPT-11(伊立替康、
)、乙酰基喜树碱、东莨菪亭和9-氨基喜树碱)；苔藓抑素；callystatin；CC-1065(包括其阿多来新、卡折来新和比折来新合成性类似物)；鬼臼毒素；鬼臼酸；替尼泊苷；cryptophycins(特别是cryptophycin 1和cryptophycin 8)；多拉司他汀；duocarmycin(包括合成性类似物KW-2189和CB1-TM1)；艾榴塞洛素；pancratistatin；sarcodictyin；spongistatin；氮芥如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀、曲磷胺、尿嘧啶氮芥；硝基脲如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫斯汀和雷莫司汀；抗生素如烯二炔抗生素(例如刺孢霉素尤其是刺孢霉素γ1I和刺孢霉素ωI1(参见例如Nicolaou et al.,Angew.Chem Intl.Ed.Engl.,33:183-186(1994))；CDP323，口服α-4整联蛋白抑制剂；蒽环类抗生素，包括蒽环类抗生素A；埃斯培拉霉素；以及新抑癌蛋白生色团和相关色蛋白烯二炔抗生素生色团、aclacinomysin、放线菌素、authramycin、偶氮丝氨酸、博来霉素、放线菌素C、carabicin、去甲柔红霉素、嗜癌素、色霉素、放线菌素D、柔红霉素、地拖比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(包括
吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星、多柔比星盐酸盐脂质体注射剂脂质体多柔比星TLCD-99
PEG化脂质体多柔比星
和去氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素诸如丝裂霉素C、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素、嘌罗霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星；抗代谢物诸如甲氨喋呤、吉西他滨
替加氟
卡培他滨
埃坡霉素和5-氟尿嘧啶(5-FU)；叶酸类似物诸如二甲叶酸、甲氨喋呤、喋罗呤、三甲曲沙；嘌呤类似物诸如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤；嘧啶类似物诸如安西他滨、阿扎胞苷、6-氮鸟苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、伊诺他滨、氟尿苷；雄激素诸如卡普睾酮、丙酸甲雄烷酮、环硫雄醇、美雄烷、睾内酯；抗肾上腺素诸如氨鲁米特、米托坦、曲洛司坦；叶酸补充剂诸如亚叶酸；醋葡醛内酯；醛磷酰胺糖苷；氨基乙酰丙酸；恩尿嘧啶；安吖啶；bestrabucil；比生群；伊达曲杀；地磷酰胺；秋水仙胺；地吖醌；elfornithine；依利醋铵；埃坡霉素；依托格鲁；硝酸镓；羟基脲；香菇多糖；氯尼达明；美登醇诸如美登素和安丝菌素；米托胍腙；米托蒽醌；mopidanmol；根瘤菌剂；喷司他丁；蛋氨氮芥；吡柔比星；洛索蒽醌；2-乙基酰肼；丙卡巴肼；多糖复合物(JHS Natural Products,Eugene,OR)；雷佐生；根霉素；西佐喃；锗螺胺；细交链孢菌酮酸；三亚胺醌；2,2’,2”-三氯三乙胺；单端孢菌毒素(尤其是T-2毒素、verracurin A、杆孢菌素A和anguidine)；乌拉坦；长春地辛(
)；达卡巴嗪；甘露莫司汀；二溴甘露醇；二溴卫矛醇；哌泊溴烷；gacytosine；阿糖胞苷("Ara-C")；塞替派；紫杉烷例如紫杉醇
紫杉醇的白蛋白工程化纳米微粒制剂(ABRAXANETM)和多西他赛
chloranbucil；6-硫代鸟嘌呤；巯嘌呤；甲氨蝶呤；铂制剂诸如顺铂、奥沙利铂(例如
)和卡铂；长春药属，其防止微管蛋白聚合以形成微管，包括长春碱
长春新碱
长春地辛(
)和长春瑞滨依托泊苷(VP-16)；异环磷酰胺；米托蒽醌；亚叶酸；诺安托；依达曲沙；柔红霉素；氨基蝶呤；伊班膦酸盐；拓扑异构酶抑制剂RFS 2000；二氟甲基鸟氨酸(DMFO)；类视黄醇诸如芬维A胺、视黄酸包括贝沙罗汀
二膦酸盐诸如氯膦酸盐(例如
或者
)、依替膦酸盐
NE-58095、唑来膦酸/唑来膦酸盐
阿伦膦酸盐
帕米膦酸盐
替鲁膦酸
或者利塞膦酸盐
曲沙他滨(1,3-二氧戊烷核苷胞嘧啶类似物)；反义寡核苷酸，特别是抑制涉及异常细胞增殖的信号转导途径中的基因表达的那些，例如PKC-α、Raf、H-Ras和表皮生长因子受体(EGF-R)；疫苗诸如
疫苗和基因治疗疫苗，例如
疫苗、
疫苗和
疫苗；拓扑异构酶1抑制剂(例如
)；rmRH(例如)；BAY439006(索拉非尼；Bayer)；SU-11248(舒尼替尼、Pfizer)；哌立福辛、COX-2抑制剂(例如塞来考昔或者艾托考昔)、蛋白体抑制剂(例如PS341)；硼替佐米CCI-779；替吡法尼(tipifarnib)(R11577)；orafenib、ABT510；Bcl-2抑制剂诸如oblimersen sodium
pixantrone；EGFR抑制剂(参见如下定义)；法尼基转移酶抑制剂诸如洛那法尼(SCH 6636、SARASARTM)；以及上述药物的药用盐、酸或者衍生物；以及上述药物中的两种或者多种的组合，诸如CHOP，其为环磷酰胺、多柔比星、长春新碱和泼尼松龙的组合治疗的缩写；和FOLFOX，其为使用奥沙利铂(ELOXATINTM)与5-FU和亚叶酸的组合治疗方案的缩写。
如本申请所定义的额外的化学治疗剂包括用于调节、降低、阻断或者抑制可促进癌症生长的激素作用的“抗激素药物”或者“内分泌治疗剂”。它们本身可为激素，包括但不限于：具有混合的激动剂/拮抗剂分布的抗雌激素药物，包括他莫昔芬
4-羟基他莫昔芬、托瑞米芬
艾多昔芬、屈洛昔芬、雷洛昔芬
曲沃昔芬、雷洛西芬，以及选择性雌激素受体调节剂(SERM)诸如SERM3；不具有激动剂性质的纯的抗雌激素药物，诸如氟维司群
和EM800(所述药物可阻断雌激素受体(ER)二聚化、抑制DNA结合、增加ER翻转和/或者抑制ER水平)；芳香酶抑制剂，包括甾体芳香酶抑制剂诸如福美坦和依西美坦
以及非类固醇类芳香酶抑制剂诸如阿那曲唑
来曲唑
和氨鲁米特，以及其它芳香酶抑制剂包括伏氯唑
醋酸甲地孕酮法倔唑和4(5)-咪唑；黄体生成激素释放激素激动剂(lutenizing hormone-releaseing hormone agonists)，包括醋酸亮丙瑞林(
和)、戈舍瑞林、布舍瑞林和tripterelin；性甾体，包括黄体激素诸如醋酸甲地孕酮和醋酸甲羟孕酮、雌激素诸如二乙基己烯雌酚和倍美力，以及雄激素/类视黄醇诸如氟甲睾酮、全反式维甲酸和芬维A胺；奥那司酮；抗黄体酮药物；雌激素受体下调剂(ERDs)；抗雄激素药物诸如氟他胺、尼鲁米特和比卡鲁胺。
另外的化学治疗剂包括治疗抗体诸如阿仑单抗(Campath)、贝伐单抗(
Genentech)；西妥昔单抗(
Imclone)；帕木单抗(
Amgen)、利妥昔单抗(
Genentech/Biogen Idec)、培妥珠单抗(
2C4、Genentech)、曲妥单抗(
Genentech)、托西莫单抗(Bexxar、Corixia)，以及抗体药物轭合物奥吉妥珠单抗(
Wyeth)。具有作为药物的治疗潜力而与本发明化合物联用的人源化单克隆抗体包括：阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、atlizumab、bapineuzumab、莫比伐珠单抗(bivatuzumabmertansine)、莫坎妥珠单抗(cantuzumab mertansine)、西利珠单抗(cedelizumab)、赛妥珠单抗(certolizumab pegol)、cidfusituzumab、cidtuzumab、达克珠单抗(daclizumab)、依库珠单抗(eculizumab)、依法珠单抗(efalizumab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、泛维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)、奥吉妥珠单抗(gemtuzumab ozogamicin)、奥英妥珠单抗(inotuzumab ozogamicin)、ipilimumab、拉贝珠单抗(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单抗(matuzumab)、美泊珠单抗(mepolizumab)、莫维珠单抗(motavizumab)、motovizumab、那他珠单抗(natalizumab)、尼妥珠单抗(nimotuzumab)、nolovizumab、numavizumab、ocrelizumab、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕考珠单抗(pascolizumab)、pecfusituzumab、pectuzumab、培妥珠单抗(pertuzumab)、培克珠单抗(pexelizumab)、ralivizumab、雷珠单抗(ranibizumab)、reslivizumab、瑞利珠单抗(reslizumab)、resyvizumab、罗维珠单抗(rovelizumab)、卢利珠单抗(ruplizumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)、索土珠单抗(sontuzumab)、他珠单抗(tacatuzumab tetraxetan)、tadocizumab、他利珠单抗(talizumab)、特非珠单抗(tefibazumab)、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、tucotuzumab西莫白介素(tucotuzumab celmoleukin)、tucusituzumab、umavizumab、乌珠单抗(urtoxazumab)、伏特克单抗(ustekinumab)、维西珠单抗(visilizumab)；以及抗白介素-12(ABT-874/J695，Wyeth Research and Abbott Laboratories)，其为通常基因修饰为识别白介素-12p40蛋白的重组体专属人类序列、全长IgG1λ抗体。
化学治疗剂也包括“EGFR抑制剂”，其是指与EGFR结合或者直接相互作用且阻止或者降低其信号转导活性的化合物，其可选择地称为“EGFR拮抗剂”。所述药物的实例包括与EGFR结合的抗体和小分子。与EGFR结合的抗体的实例包括MAb 579(ATCC CRL HB 8506)、MAb 455(ATCC CRLHB8507)、MAb 225(ATCC CRL 8508)、MAb 528(ATCC CRL 8509)(参见美国专利4,943,533,Mendelsohn et al.)及其变化形式，诸如嵌合225(C225或者西妥昔单抗；
)和重塑的人类225(H225)(参见WO 96/40210,Imclone Systems Inc.)；IMC-11F8，一种完全人类、EGFR-靶向抗体(Imclone)；结合II型突变体EGFR的抗体(美国专利5,212,290)；美国专利5,891,996所述的结合EGFR的人源化且嵌合抗体；以及结合EGFR的人类抗体，诸如ABX-EGF或者帕木单抗(参见WO98/50433,Abgenix/Amgen)；EMD 55900(Stragliotto et al.Eur.J.Cancer 32A:636-640(1996))；EMD7200(马妥珠单抗)，一种直接对抗EGFR的人源化EGFR抗体，其与EGF和TGF-α竞争结合EGFR(EMD/Merck)；人类EGFR抗体HuMax-EGFR(GenMab)；完全人类抗体，已知为E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3和E7.6.3且在US 6,235,883中有述；MDX-447(Medarex Inc)；以及mAb 806或者人源化mAb 806(Johns et al.,J.Biol.Chem.279(29):30375-30384(2004))。所述抗-EGFR抗体可与细胞毒素剂轭合，由此生成免疫交联物(参见例如EP659,439A2,Merck Patent GmbH)。EGFR拮抗剂包括小分子诸如在以下美国专利中所述的化合物：5,616,582、5,457,105、5,475,001、5,654,307、5,679,683、6,084,095、6,265,410、6,455,534、6,521,620、6,596,726、6,713,484、5,770,599、6,140,332、5,866,572、6,399,602、6,344,459、6,602,863、6,391,874、6,344,455、5,760,041、6,002,008和5,747,498，以及在以下PCT公开中所述的化合物：WO98/14451、WO98/50038、WO99/09016和WO99/24037。具体的小分子EGFR拮抗剂包括OSI-774(CP-358774,厄洛替尼,
Genentech/OSI Pharmaceuticals)；PD 183805(CI 1033,N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(4-吗啉基)丙氧基]-6-喹唑啉基]-2-丙烯酰胺二盐酸盐，Pfizer Inc.)；ZD1839,吉非替尼(IRESSATM)4-(3’-氯-4’-氟苯胺基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉,AstraZeneca)；ZM 105180((6-氨基-4-(3-甲基苯基-氨基)-喹唑啉,Zeneca)；BIBX-1382(N8-(3-氯-4-氟-苯基)-N2-(1-甲基-哌啶-4-基)-嘧啶并[5,4-d]嘧啶-2,8-二胺,Boehringer Ingelheim)；PKI-166((R)-4-[4-[(1-苯基乙基)氨基]-1H-吡咯并[2,3-d]嘧啶-6-基]-苯酚)；(R)-6-(4-羟基苯基)-4-[(1-苯基乙基)氨基]-7H-吡咯并[2,3-d]嘧啶)；CL-387785(N-[4-[(3-溴苯基)氨基]-6-喹唑啉基]-2-丁烯酰胺)；EKB-569(N-[4-[(3-氯-4-氟苯基)氨基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲基氨基)-2-丁烯酰胺)(Wyeth)；AG1478(Pfizer)；AG1571(SU5271；Pfizer)；双重EGFR/HER2酪氨酸激酶抑制剂诸如拉帕替尼(GSK572016或者N-[3-氯-4-[(3-氟苯基)甲氧基]苯基]-6[5-[[[2-甲基磺酰基)乙基]氨基]甲基]-2-呋喃基]喹唑啉-4-胺)。
化学治疗剂也包括“酪氨酸激酶抑制剂”，其包括在先前段落中有述的EGFR-靶向药物；小分子HER2酪氨酸激酶抑制剂诸如由Takeda得到的TAK165；CP-724,714，一种ErbB2受体酪氨酸激酶的口服选择性抑制剂(Pfizer and OSI)；双重-HER抑制剂诸如EKB-569(由Wyeth得到)，其优先结合EGFR但同时抑制HER2和EGFR-过表达细胞；拉帕替尼(GSK572016；由Glaxo-SmithKline得到)，一种口服HER2和EGFR酪氨酸激酶抑制剂；PKI-166(由Novartis得到)；全-HER抑制剂诸如卡奈替尼(CI-1033；Pharmacia)；Raf-1抑制剂诸如由ISIS Pharmaceuticals得到的反义药物ISIS-5132，其抑制Raf-1信号转导；非-HER靶向TK抑制剂，诸如甲磺酸伊马替尼(GLEEVECTM,由Glaxo SmithKline得到)；多重靶向的酪氨酸激酶抑制剂，诸如舒尼替尼(
由Pfizer得到)；VEGF受体酪氨酸激酶抑制剂，诸如瓦他拉尼(vatalanib)(PTK787/ZK222584,由Novartis/ScheringAG得到)；MAPK细胞外调节激酶I抑制剂CI-1040(由Pharmacia得到)；喹唑啉，诸如PD 153035,4-(3-氯苯胺基)喹唑啉；吡啶并嘧啶；嘧啶并嘧啶；吡咯并嘧啶，诸如CGP 59326、CGP 60261和CGP 62706；吡唑并嘧啶，4-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶；姜黄(二阿魏酰甲烷，4,5-二(4-氟苯胺基)酞酰亚胺)；含有硝基噻吩部分的酪氨酸磷酸化抑制剂(tyrphostines)；PD-0183805(Warner-Lamber)；反义分子(例如与HER-编码核酸结合的分子)；喹噁啉(美国专利5,804,396)；tryphostin(美国专利5,804,396)；ZD6474(AstraZeneca)；PTK-787(Novartis/Schering AG)；全-HER(pan-HER)抑制剂，诸如CI-1033(Pfizer)；Affinitac(ISIS 3521；Isis/Lilly)；甲磺酸伊马替尼(GLEEVECTM)；PKI 166(Novartis)；GW2016(Glaxo SmithKline)；CI-1033(Pfizer)；EKB-569(Wyeth)；Semaxinib(Pfizer)；ZD6474(AstraZeneca)；PTK-787(Novartis/Schering AG)；INC-1C11(Imclone)、雷帕霉素(西罗莫司,
)；或者如在以下专利公开中任一项中所述的药物：美国专利5,804,396；WO 1999/09016(American Cyanamid)；WO 1998/43960(AmericanCyanamid)；WO 1997/38983(Warner Lambert)；WO 1999/06378(WarnerLambert)；WO 1999/06396(Warner Lambert)；WO 1996/30347(Pfizer,Inc)；WO 1996/33978(Zeneca)；WO 1996/3397(Zeneca)和WO 1996/33980(Zeneca)。
此外，化学治疗剂包括本申请所述的任意的化学治疗剂的药用盐、酸或者衍生物，以及它们的两种或者多种的组合。
“环烷基”是指非芳族、饱和或者部分不饱和的烃基环基，其中所述环烷基可任选独立地取代有一个或者多个本申请所述的取代基。在一个实例中，所述环烷基含有3至12个碳原子(C3-C12)。在其它实例中，所述环烷基为C3-C8、C3-C10或者C5-C10。在其它实例中，所述环烷基作为单环可为C3-C8、C3-C6或者C5-C6。在其它实例中，所述环烷基作为二环可为C7-C12。在其它实例中，所述环烷基作为螺环系统可为C5-C12。单环环烷基的实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基。具有7至12个环原子的二环环烷基的示例性排列包括但不限于[4,4]、[4,5]、[5,5]、[5,6]或者[6,6]环系。示例性桥环二环环烷基包括但不限于二环[2.2.1]庚烷、二环[2.2.2]辛烷和二环[3.2.2]壬烷。螺环烷基的实例包括螺[2.2]戊烷、螺[2.3]己烷、螺[2.4]庚烷、螺[2.5]辛烷和螺[4.5]癸烷。
本申请使用的“羧基保护基”是指对于在分子其它位置上进行的随后反应条件稳定的基团，其可在适当时移去而不破坏分子的剩余部分，得到未经保护的羧基。羧基保护基的实例包括酯基和杂环基。羧酸基团的酯衍生基团可用于在反应在化合物的其它官能团上进行的同时阻断或者保护羧酸基团。所述酯基的实例包括经取代的芳基烷基酯，包括经取代的苄基诸如4-硝基苄基、4-甲氧基苄基、3,4-二甲氧基苄基、2,4-二甲氧基苄基、2,4,6-三甲氧基苄基、2,4,6-三甲基苄基、五甲基苄基、3,4-亚甲二氧基苄基、二苯甲基、4,4’-二甲氧基二苯甲基、2,2’,4,4’-四甲氧基二苯甲基酯；烷基酯或者经取代的烷基酯，诸如甲基、乙基、叔丁基、烯丙基或者叔戊基、三苯基甲基(三苯甲基)、4-甲氧基三苯甲基、4,4’-二甲氧基三苯甲基、4,4’,4”-三甲氧基三苯甲基、2-苯基丙-2-基酯；硫酯诸如叔丁基硫酯，甲硅烷基酯诸如三甲基甲硅烷基酯、叔丁基二甲基甲硅烷基酯、苯甲酰甲基、2,2,2-三氯乙基、β-(三甲基甲硅烷基)乙基、β-(二(正丁基)甲基甲硅烷基)乙基、对甲苯磺酰基乙基、4-硝基苄基磺酰基乙基、烯丙基、桂皮酰基、1-(三甲基甲硅烷基甲基)丙-1-烯-3-基等。羧基保护基的其它实例为杂环基，诸如1,3-噁唑啉基。这些基团的其它实例出现在T.W.Greene and P.G.M.Wuts,“Protective Groups in OrganicSynthesis”,2nd ed.,John Wiley & Sons,Inc.,New York,N.Y.,1991,chapter 5；E.Haslam,“Protective Groups in Organic Chemistry”,J.G.W.McOmie,Ed.,Plenum Press,New York,N.Y.,1973,Chapter 5,and T.W.Greene,“ProtectiveGroups in Organic Synthesis”,John Wiley and Sons,New York,NY，1981,Chapter 5中。术语“经保护的羧基”是指取代有上述羧基保护基中的一个的羧基。
本申请使用的“羟基保护基”是指通常在反应在化合物的其它官能团上进行的同时用于阻断或者保护羟基的羟基的衍生基团。所述保护基的实例包括四氢吡喃基氧基、苯甲酰基、乙酰氧基、氨甲酰基氧基、苄基和甲硅烷基醚(例如TBS、TBDPS)。这些基团的其它实例出现在T.W.Greene and P.G.M.Wuts,“Protective Groups in Organic Synthesis”,2nd ed.,John Wiley & Sons,Inc.,New York,NY，1991,chapters 2-3；E.Haslam,“Protective Groups in OrganicChemistry”,J.G.W.McOmie,Ed.,Plenum Press,New York,NY，1973,Chapter5,and T.W.Greene,“Protective Groups in Organic Synthesis”,John Wiley andSons,New York,NY，1981中。术语“经保护的羟基”是指取代有上述羟基保护基中的一个的羟基。
“杂环基团”、“杂环的”、“杂环(heterocycle)”、“杂环基”或者“杂环(heterocyclo)”在单独使用以及用作复合基团诸如杂环烷基的部分使用时，可交替使用且是指具有3至20个环原子的任何的单环、二环、三环或者螺环的、饱和或者不饱和的芳族(杂芳基)或者非芳族环系，其中所述环原子为碳，且环或者环系中的至少一个原子为选自氮、硫或者氧的杂原子。在一个实例中，杂环基包含1至4个杂原子。在其它实例中，杂环基包括具有选自氮、硫或者氧的一个或者多个杂原子的3-至7-元单环。在其它实例中，杂环基包括具有选自氮、硫或者氧的一个或者多个杂原子的4-至6-元单环。在其它实例中，杂环基包括3-元单环。在其它实例中，杂环基包括4-元单环。在其它实例中，杂环基包括5-6-元单环。杂环基包含0至3个双键，任何氮或者硫杂原子可任选被氧化(例如NO、SO、SO2)，且任何氮杂原子可任选被季铵化(例如[NR4]+Cl-、[NH4]+OH-)。杂环基的实例为环氧乙烷基、氮杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环戊基、1,3-二硫杂环戊基、吡咯烷基、二氢-1H-吡咯基、二氢呋喃基、四氢呋喃基、二氢噻吩基、四氢噻吩基、咪唑烷基、哌啶基、哌嗪基、吗啉基、硫吗啉基、1,1-二氧代-硫吗啉基、二氢吡喃基、四氢吡喃基、六氢嘧啶基、噁嗪烷基(oxazinanyl)、噻嗪烷基(thiazinanyl)、硫杂氧杂环己基、高哌嗪基、高哌啶基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、氧氮杂环庚烷基、二氮杂环庚烷基、1,4-二氮杂环庚烷基、二氮杂基、硫氮杂
基、硫氮杂环庚烷基、四氢噻喃基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧杂环戊基、吡唑啉基、吡唑烷基、二硫杂环己基、二硫杂环戊基、嘧啶酮基、吡唑烷基、咪唑啉基、3-氮杂二环[3.1.0]己基、3,6-二氮杂二环[3.1.1]庚基、6-氮杂二环[3.1.1]庚基、3-氮杂二环[3.1.1]庚基、3-氮杂二环[4.1.0]庚基、氮杂二环[2.2.2]己基、2-氮杂二环[3.2.1]辛基、8-氮杂二环[3.2.1]辛基、2-氮杂二环[2.2.2]辛基和8-氮杂二环[2.2.2]辛基。含有硫或者氧原子以及一至三个氮原子的5-元杂环的实例为噻唑基包括噻唑-2-基和N-氧化噻唑-2-基，噻二唑基包括1,3,4-噻二唑-5-基和1,2,4-噻二唑-5-基，噁唑基例如噁唑-2-基和噁二唑基，诸如1,3,4-噁二唑-5-基和1,2,4-噁二唑-5-基。含有2至4个氮原子的5-元杂环的实例包括咪唑基，诸如咪唑-2-基；三唑基，诸如1,3,4-三唑-5-基；1,2,3-三唑-5-基、1,2,4-三唑-5-基，以及四唑基，诸如1H-四唑-5-基。苯并稠合5-元杂环的实例为苯并噁唑-2-基、苯并噻唑-2-基和苯并咪唑-2-基。含有一至三个氮原子以及任选硫或者氧原子的6-元杂环的实例为例如吡啶基，诸如吡啶-2-基、吡啶-3-基和吡啶-4-基；嘧啶基，诸如嘧啶-2-基和嘧啶-4-基；三嗪基，诸如1,3,4-三嗪-2-基和1,3,5-三嗪-4-基；哒嗪基，特别是哒嗪-3-基和吡嗪基。N-氧化吡啶基和N-氧化哒嗪基以及吡啶基、嘧啶-2-基、嘧啶-4-基、哒嗪基和1,3,4-三嗪-2-基为其它杂环基的实例。“任选取代的杂环”的取代基包括羟基、烷基、烷氧基、酰基、卤素、巯基、氧代、羧基、酰基、卤素取代的烷基、氨基、氰基、硝基、脒基、胍基。
单独使用以及用作复合基团诸如杂芳烷基的部分时的“杂芳基”是指任何单环、二环或者三环环系，其中至少一个环为含有1至4个选自氮、氧和硫的杂原子的5-或者6-元芳环，且在示例性实施方案中，至少一个杂原子为氮。参见例如Lang’s Handbook of Chemistry，同上。定义中包括任何二环基团，其中上述杂芳基环中的任一个与芳环稠合。在一个实施方案中，杂芳基包括4-6元单环芳族基团，其中一个或者多个环原子为氮、硫或者氧。在其它实施方案中，杂芳基包括5-6元单环芳族基团，其中一个或者多个环原子为氮、硫或者氧。杂芳基(无论是经取代的还是未经取代的)的实例包括噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、四唑基、噻三唑基、噁三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻嗪基、噁嗪基、三嗪基、噻二嗪基、噁二嗪基、二噻嗪基、二噁嗪基、氧杂噻嗪基、四嗪基、噻三嗪基、噁三嗪基、二噻二嗪基、咪唑啉基、二氢嘧啶基、四氢嘧啶基、四唑并[1,5-b]哒嗪基和嘌呤基，以及苯并稠合衍生基团例如苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并三唑基、苯并咪唑基和吲哚基。“杂芳基”的其它实例为：1,3-噻唑-2-基、4-(羧基甲基)-5-甲基-1,3-噻唑-2-基、4-(羧基甲基)-5-甲基-1,3-噻唑-2-基钠盐、1,2,4-噻二唑-5-基、3-甲基-1,2,4-噻二唑-5-基、1,3,4-三唑-5-基、2-甲基-1,3,4-三唑-5-基、2-羟基-1,3,4-三唑-5-基、2-羧基-4-甲基-1,3,4-三唑-5-基钠盐、2-羧基-4-甲基-1,3,4-三唑-5-基、1,3-噁唑-2-基、1,3,4-噁二唑-5-基、2-甲基-1,3,4-噁二唑-5-基、2-(羟基甲基)-1,3,4-噁二唑-5-基、1,2,4-噁二唑-5-基、1,3,4-噻二唑-5-基、2-巯基-1,3,4-噻二唑-5-基、2-(甲基硫基)-1,3,4-噻二唑-5-基、2-氨基-1,3,4-噻二唑-5-基、1H-四唑-5-基、1-甲基-1H-四唑-5-基、1-(1-(二甲基氨基)乙-2-基)-1H-四唑-5-基、1-(羧基甲基)-1H-四唑-5-基、1-(羧基甲基)-1H-四唑-5-基钠盐、1-(甲基磺酸)-1H-四唑-5-基、1-(甲基磺酸)-1H-四唑-5-基钠盐、2-甲基-1H-四唑-5-基、1,2,3-三唑-5-基、1-甲基-1,2,3-三唑-5-基、2-甲基-1,2,3-三唑-5-基、4-甲基-1,2,3-三唑-5-基、N-氧化吡啶-2-基、6-甲氧基-2-(N-氧化)-哒嗪-3-基、6-羟基哒嗪-3-基、1-甲基吡啶-2-基、1-甲基吡啶-4-基、2-羟基嘧啶-4-基、1,4,5,6-四氢-5,6-二氧代-4-甲基-1,2,4-三嗪-3-基、1,4,5,6-四氢-4-(甲酰基甲基)-5,6-二氧代-1,2,4-三嗪-3-基、2,5-二氢-5-氧代-6-羟基-1,2,4-三嗪-3-基、2,5-二氢-5-氧代-6-羟基-1,2,4-三嗪-3-基钠盐、2,5-二氢-5-氧代-6-羟基-2-甲基-1,2,4-三嗪-3-基钠盐、2,5-二氢-5-氧代-6-羟基-2-甲基-1,2,4-三嗪-3-基、2,5-二氢-5-氧代-6-甲氧基-2-甲基-1,2,4-三嗪-3-基、2,5-二氢-5-氧代-1,2,4-三嗪-3-基、2,5-二氢-5-氧代-2-甲基-1,2,4-三嗪-3-基、2,5-二氢-5-氧代-2,6-二甲基-1,2,4-三嗪-3-基、四唑并[1，5-b]哒嗪-6-基和8-氨基四唑并[1,5-b]-哒嗪-6-基。杂芳基任选如针对杂环所述的被取代。
在具体的实施方案中，杂环基在杂环基的碳原子处连接。作为实例，碳键合的杂环基包含以下的键合排列(bonding arrangement)：吡啶环的2、3、4、5或者6位，哒嗪的3、4、5或者6位，嘧啶环的2、4、5或者6位，吡嗪环的2、3、5或者6位，呋喃环、四氢呋喃环、硫代呋喃环、噻吩环、吡咯环或者四氢吡咯环的2、3、4或者5位，噁唑环、咪唑环或者噻唑环的2、4或者5位，异噁唑环、吡唑环或者异噻唑环的3、4或者5位，氮杂环丙烷的2或者3位，氮杂环丁烷的2、3或者4位，喹啉环的2、3、4、5、6、7或者8位，或者异喹啉环的1、3、4、5、6、7或者8位。
在某些实施方案中，杂环基为N连接的。作为实例，氮键合的杂环基或者杂芳基包括以下的键合排列：氮杂环丙烷、氮杂环丁烷、吡咯、吡咯烷、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑烷、3-咪唑烷、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、二氢吲哚、1H-吲唑的1位，异吲哚或者异二氢吲哚的2位，吗啉的4位，以及咔唑或者β-咔啉的9位。
除非另作说明，“任选取代的”是指基团可为未经取代的或者被针对该基团所列的一个或者多个(例如0、1、2、3或者4)取代基取代，其中所述取代基可为相同或者不同的。在一个实施方案中，任选取代的基团具有1个取代基。在其它实施方案中，任选取代的基团具有2个取代基。在其它实施方案中，任选取代的基团具有3个取代基。
在某些实施方案中，二价基团为一般性描述，而无特殊键合构型，例如基团-CH2C(O)-。应该理解的是一般性描述是指包括两种键合构型，除非另作说明。例如，在基团R1-R2-R3中，如果基团R2描述为-CH2C(O)-，则应该理解的是该基团可如R1–CH2C(O)–R3以及如R1–C(O)CH2–R3进行键合，除非另作说明。
"包装说明书(package insert)"是指通常包括在治疗产品的市售包装中的说明书，其含有关于适应症、用法、剂量、给药、禁忌症和/或告诫事项的信息，这些信息涉及上述治疗产品的使用。
“药用盐”包括酸和碱加成盐。“药用酸加成盐”是指保留游离碱的生物学有效性和性质且在生物学或者在其它方面不属于不期望的那些盐，其用无机酸以及有机酸形成，所述无机酸诸如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸，且所述有机酸可选择脂族、环脂族、芳族、芳脂族、杂环、羧酸以及磺酸类有机酸，诸如甲酸、乙酸、丙酸、羟乙酸、葡糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、枸橼酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯基乙酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。
“药用碱加成盐”由无机碱衍生的盐，诸如钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。特别地碱加成盐为铵盐、钾盐、钠盐、钙盐和镁盐。由药用有机无毒碱衍生的盐包括伯胺、仲胺和叔胺盐、经取代的胺盐包括天然存在的经取代的胺盐、环状胺盐以及碱性离子交换树脂盐，所述胺诸如异丙基胺、三甲胺、二乙胺、三乙胺、三丙基胺、乙醇胺、2-二乙基氨基乙醇、氨丁三醇、二环己基胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、多胺树脂等。特别地有机无毒碱为异丙基胺、二乙胺、乙醇胺、氨丁三醇、二环己基胺、胆碱和咖啡因。
“无菌”制剂为经灭菌的或者不含所有存活的微生物和它们的孢子。
"立体异构体"是指具有相同化学组成但它们原子或者基团的排列在空间上不同的化合物。立体异构体包括非对映异构体、对映异构体、构象异构体等。
“手性”是指具有镜像配偶体(mirror image partner)不可重叠性质的分子，而术语"非手性"是指可与其镜像配偶体重叠的分子。
"非对映异构体"是指具有两个或更多手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质或生物活性。非对映异构体的混合物可通过高分辨分析操作诸如电泳和色谱诸如HPLC来分离。
"对映异构体"是指互为不可重叠镜像的化合物的两种立体异构体。
本申请使用的立体化学定义和常规通常按照S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill BookCompany,New York；以及Eliel,E.and Wilen,S.,“Stereochemistry of OrganicCompounds”,John Wiley & Sons,Inc.,New York,1994。多种有机化合物以光学活性形式存在，即它们具有旋转平面偏振光的平面的能力。在描述有光学活性的化合物时，使用前缀D和L或者R和S来表示分子围绕其一个或多个手性中心的绝对构型。前缀d和l或者(+)和(-)用于指定平面偏振光由化合物引起的旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。对于给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，所述异构体的混合物通常称作对映异构混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当化学反应或方法中没有立体选择性或立体专一性时可出现这种情况。术语"外消旋混合物"和"外消旋体"是指两种对映异构体物质的等摩尔混合物，其没有光学活性。
术语"互变异构体"或"互变异构形式"是指可通过低能垒(low energybarrier)互相转化的不同能量的结构异构体。例如，质子互变异构体(protontautomer)(也称为质子迁移互变异构体(prototropic tautomer))包括通过质子迁移进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价互变异构体(valence tautomer)包括通过一些成键电子的重组进行的互相转化。
"溶剂化物"是指一种或多种溶剂分子与本发明化合物的结合或络合。形成溶剂化物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语"水合物"是指当溶剂分子是水时的络合物。
“受试者”、“个体”或者“患者”为脊椎动物。在某些实施方案中，脊椎动物为哺乳动物。哺乳动物包括但不限于家畜(诸如牛)、运动动物、宠物(诸如猫、狗和马)、灵长类动物、小鼠和大鼠。在某些实施方案中，哺乳动物为人类。
“治疗有效量”表示(i)治疗或预防本申请描述的具体疾病、病症或障碍的本发明化合物的量，(ii)削弱、改善或消除本申请描述的具体疾病、病症或障碍的一种或多种症状的本发明化合物的量，或(iii)预防或延迟本申请描述的具体疾病、病症或障碍的一种或多种症状的发作的本发明化合物的量。在癌症的情况中，治疗有效量的药物可降低癌细胞的数量；减小肿瘤尺寸；抑制(即在一定程度上减慢以及优选停止)癌细胞浸润周围器官中；抑制(即在一定程度上减慢以及优选停止)肿瘤转移；在一定程度上抑制肿瘤生长；和/或在一定程度上缓解与癌症相关的一种或多种症状。如果药物可预防癌细胞的生长和/或杀死现存的癌细胞，其可能是细胞生长抑制性的(cytostatic)和/或细胞毒性的。对于癌症治疗而言，可例如通过评价疾病进展时间(TTP)和/或确定应答率(RR)来测量功效。
“治疗”(以及变体诸如“治疗(treat)”或者“治疗(treating)”)是指尝试改变待治疗的个体或者细胞的自然过程的临床介入，且可用于预防或者在临床病理学过程中来进行。治疗的所需作用包括预防疾病发生或者复发、缓解症状、减小疾病的任何直接或者间接的病理学结果、稳定(即不恶化)疾病状况、预防病灶转移、减小疾病进展速率、改善或者缓和疾病状况、延长存活率(相比于如果不接受治疗所预期的存活率)以及缓和或者改善的预后。在某些实施方案中，本发明化合物用于延缓疾病或者病症的发展或者减缓疾病或者病症的进程。需要治疗的个体包括已经具有病症或者障碍的个体以及倾向于具有病症或者障碍的个体(例如通过遗传突变)或者其中病症或者障碍待预防的个体。
“FOXO3a”是指叉头/翼状螺旋盒类O蛋白(forkhead/winged helix boxclass O protein)，其为PI3K/AKT激酶信号转导途径的下游靶标。活化的AKT激酶通过磷酸化直接调控FOXO3a活性，这导致其易位至细胞质，在此其被14-3-3侣伴蛋白隔离。PI3K/AKT激酶的抑制导致FOXO3a的脱磷酸化以及细胞核定位，这导致其活化。FOXO3a的细胞核定位使得其用作转录因子以通过其关键靶标基因诸如p27Kip1和Bim的上调来诱导细胞周期停滞和/或者细胞凋亡。
“定位分布"是指给定分子在一个位点的量相比于其在第二位点的量。在一个实例中，FOXO3a定位分布是指FOXO3a在细胞核中的量相比于其在细胞质中的量。所述定位分布可用比例(例如FOXO3a在细胞核中的量除以FOXO3a在细胞质中的量)或者减法(例如FOXO3a在细胞核中的量减去FOXO3a在细胞质中的量)的方式来表示。“细胞核定位分布”是指确定为在细胞核中FOXO3a水平基本高于在细胞质中的FOXO3a水平的定位分布。在一个实例中，与在细胞质中相比，细胞核定位分布在细胞核中具有大于约50%FOXO3a。在其它实例中，与在细胞质中相比，细胞核定位分布在细胞核中具有大于约70%、可选择地大于约80%、可选择地大于约90%FOXO3a。“细胞质定位分布”是指确定为在细胞质中FOXO3a水平基本高于在细胞核中的FOXO3a水平的定位分布。在一个实例中，与在细胞核中相比，细胞核定位分布在细胞质中具有大于约50%FOXO3a。在其它实例中，与在细胞核中相比，细胞核定位分布在细胞质中具有大于约70%、可选择地大于约80%、可选择地大于约90%FOXO3a。
“pAKT分布”是指在给定样品中AKT的活化或者磷酸化(“pAKT”)的水平相比于非活化或者非磷酸化的AKT水平。在一个实例中，所述样品为肿瘤细胞。pAKT分布可用比例(例如pAKT在肿瘤细胞中的量除以非磷酸化的AKT在相同类型的细胞或者在非肿瘤细胞中的量)或者减法(例如pAKT在肿瘤细胞中的量减去非磷酸化的AKT在相同类型的细胞或者在非肿瘤细胞中的量)的方式来表示。pAKT分布也可以如下方式来表示：通过测量AKT的磷酸化下游靶标(例如pGSK或者PRAS40)的量获得的活化途径的水平。“高pAKT分布”是指全部AKT在样品中的活化或者磷酸化水平高于基线值。在一个实例中，所述基线值为针对给定细胞类型的pAKT的基本水平。在其它实例中，所述基线值为在给定样品细胞群体中的pAKT的平均值或者平均水平。在其它实例中，“高pAKT分布”是指当相比于来自相同哺乳动物或者患者群体的相同类型的平均正常的、健康的(例如非肿瘤)细胞而言，过表达或者在细胞中具有增多的磷酸化或者活化的AKT的肿瘤细胞。所述pAKT分布也可用于与其它标记(例如FOXO3a定位分布)结合以预测某些PI3k/AKT激酶途径抑制剂的效能。
除非另有说明，术语"本发明化合物(compound of this invention)"和"该发明化合物(compounds of the present invention)″包括式I-VII的化合物及其立体异构体、互变异构体、溶剂化物、代谢物、盐(例如药用盐)和前药。除非另有说明，本申请所述的结构也意在包括不同之处仅在于存在一个或者多个同位素富集原子的化合物。例如，本发明的范围内也包括式I-VII的化合物，其中一个或者多个氢原子被氘或者氚所取代，或者一个或者多个碳原子被13C-或者14C-富集的碳取代。
定位测定方法
本发明产生于以下发现：FOXO3a定位可用作用于在治疗癌症患者中预测PI3K/AKT激酶途径抑制剂的效能的诊断标记。
此外，本发明产生于以下发现：FOXO3a定位可用作药效学生物标记。除了其它方面之外，作为药效学生物标记的FOXO3a定位用于测量PI3K/AKT激酶途径抑制剂对患者肿瘤的治疗效果、指导患者的剂量选择包括鉴别抑制剂的最大耐受剂量以及可将PI3K/AKT激酶途径抑制剂活性的大小与临床结果相关联，包括基于定位测定结果的药物剂量的个体化选择。
FOXO3a可用作单一标记，用于针对使用PI3K/AKT激酶途径抑制剂治疗的患者进行选择或者分级。
可选择地，FOXO3a也可与其它标记(例如PTEN)联用，用于针对使用PI3K/AKT激酶途径抑制剂治疗的患者进行选择或者分级。标记(其中FOXO3a定位分布可用于选择或者分级患者，或者用于确定肿瘤细胞生长对PI3K/AKT激酶途径抑制剂的敏感性)的实例包括但不限于PTEN状态、PI3k和AKT突变的存在以及AKT、PI3k或者HER2的表达或者活性的水平。
一个方面包括针对使用PI3K/AKT途径抑制剂的癌症治疗来分级患者的方法，其中具有对PI3K/AKT途径抑制剂的敏感性的患者包括在使用PI3K/AKT途径抑制剂治疗的患者中。
一个方面包括预测肿瘤细胞生长对由PI3K/AKT激酶途径抑制剂产生的抑制的敏感性的方法。所述方法包括确定FOXO3a在肿瘤细胞中的定位分布，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关。
在另外的方面，FOXO3a在肿瘤细胞中的细胞核定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的抗性相关。
在另外的方面，所述方法也包括预测肿瘤细胞生长对由PI3K/AKT激酶途径抑制剂产生的抑制的敏感性。
在另外的方面，所述方法包括提供肿瘤细胞的样品。
在另外的方面，所述方法包括确定肿瘤细胞是否是PTEN缺失的。
在另外的方面，所述定位分布在确定所述肿瘤细胞是否是PTEN缺失的之后确定。
PTEN缺失状态可通过本领域已知的任何适当方式来测量。在一个实例中，使用IHC。可选择地，可使用Western blot分析。对PTEN的抗体为可商购得到的(Cell Signaling Technology,Beverly,MA,Cascade Biosciences,Winchester,MA)。针对PTEN状态的IHC和Western blot分析的实例操作描述于Neshat,M.S.et al.Enhanced sensitivity of PTEN-deficient tumors toinhibition of FRAP/mTOR,Proc.Natl Acad.Sci.USA 98,10314–10319(2001)以及Perren,A.,et.al.Immunohistochemical Evidence of Loss of PTENExpression in Primary Ductal Adenocarcinomas of the Breast,American Journalof Pathology,Vol.155,No.4,October 1999中。
确定PI3K突变的存在的方法在本领域中已知。例如，使用实时PCR针对在PIK3CA基因中特异性突变(外显子9和20以及H1047R或者H1047L突变)的检测的测定是已知的(购自Qiagen,Valencia,CA)。
测量AKT活化水平以及pAKT在样品中的量的方法是本领域已知的。例如，可使用免疫沉淀测定诸如AKT活性测定试剂盒(购自
SanFrancisco,CA)。在其它实例中，可使用Western blot测定，诸如AKT WesternBlot测定试剂盒(购自Cell Signaling Technology,Danvers,MA)。已知用于测量pAKT水平的其它测定形式包括化学发光关联的免疫吸附测定，参见Cicenas,J,et.al.,“Increased level of phosphorylated akt measured bychemiluminescence-linked immunosorbent assay is a predictor of poor prognosisin primary breast cancer overexpressing ErbB-2,”Breast Can.Res.,7(4),R394,2005。可使用的其它测定为可获得的，例如获自AlphaScreen SureFire Akt 1(p-Thr308)测定试剂盒(购自Perkin Elmer,Waltham,MA)。
在另外的方面，所述方法包括首先确定患者肿瘤细胞是否是PTEN缺失的、具有高pAKT分布、过表达AKT或者具有PI3k突变。如果患者肿瘤是PTEN缺失的、具有高pAKT分布、过表达AKT或者具有PI3k突变，则所述患者更可能响应于使用PI3K/AKT抑制剂的治疗。所述方法进一步包括确定FOXO3a在肿瘤细胞(其为PTEN缺失的、具有高pAKT分布、过表达AKT或者具有PI3k突变)中的定位分布，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关，且FOXO3a在PTEN缺失的细胞中的细胞核定位分布与对由PI3K/AKT抑制剂产生的抑制的抗性相关。在一个实例中，所述肿瘤细胞为乳腺肿瘤细胞。在其它实例中，所述肿瘤细胞为前列腺肿瘤细胞。在其它实例中，所述肿瘤细胞为胰腺肿瘤细胞。在其它实例中，所述肿瘤细胞为卵巢肿瘤细胞。在其它实例中，所述肿瘤细胞为胃肿瘤细胞。在其它实例中，所述肿瘤细胞为去势难治性前列腺肿瘤(castration resistant prostate tumor)细胞。在其它实例中，所述肿瘤细胞为头和颈肿瘤细胞。在其它实例中，所述肿瘤细胞为子宫内膜肿瘤细胞。在其它实例中，所述肿瘤细胞为间皮瘤肿瘤细胞。
在另外的方面，所述方法包括首先确定患者肿瘤细胞是否是PTEN缺失的。如果患者肿瘤是PTEN缺失的，则患者更可能响应于使用PI3K/AKT抑制剂的治疗。所述方法进一步包括确定FOXO3a在PTEN缺失的肿瘤细胞中的定位分布，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关，且FOXO3a在PTEN缺失的细胞中的细胞核定位分布与对由PI3K/AKT抑制剂产生的抑制的抗性相关。因此，携带具有细胞质定位分布的PTEN缺失的肿瘤细胞的患者可响应于治疗，且因此使用PI3K/AKT抑制剂治疗。然而，携带具有细胞核定位分布的PTEN缺失的肿瘤细胞的患者可能不响应于治疗，且不使用PI3K/AKT抑制剂治疗。
因此另外的方面包括预测PTEN-缺失的肿瘤细胞对PI3K/AKT激酶途径抑制剂的敏感性的方法，包括：确定FOXO3a在PTEN-缺失的肿瘤细胞中的定位分布，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关。
在一个方面，所述PI3K/AKT抑制剂为PI3k抑制剂。在一个实例中，所述PI3k抑制剂为2-(1H-吲唑-4-基)-6-(4-甲磺酰基-哌嗪-1-基甲基)-4-吗啉-4-基-噻吩并[3,2-d]嘧啶。
在一个方面，所述PI3K/AKT抑制剂为AKT抑制剂。在一个实例中，所述AKT抑制剂为(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮。
可采用确定FOXO3a的相对定位的任何适当方法。在一个实施方案中，具体确定了FOXO3a在样品中的细胞核和细胞质水平，且计算确定的细胞核与细胞质水平的比例(″细胞核与细胞质比例")以确定相对定位。
在一个方面，确定了FOXO3a在患者样品或者患者群体样品中的相对定位。
在另外的方面，FOXO3a在患者样品中的相对定位与参考样品进行比较。参考样品可来自由已知患者或者表征的肿瘤样品或者细胞系确定的参数。所述参考可由试验进行确定或者可为来自已经存在的数据集的预先确定的数值。
在一个实例中，所述参考样品为具有已知性状的细胞群体(或者实体瘤样品)，所述性状例如对于给定PI3K/AKT途径抑制剂的已知敏感性，如由例如IC50、Ki或者EC50值所测量。在对于乳腺癌的具体实例中，所述参考样品为来自一种或者多种细胞系的细胞样品，所述细胞系包括EVSAT、HCC70、T47D、BT474、CAL120、MB231、MB468、BT549、HCC38和HCC1937。
当在患者样品中的FOXO3a确定为在细胞质隔室中的定位多于在细胞核隔室中的定位(单独或者相对于参考样品)时，所述PI3K/AKT途径为激活的，且针对PI3K/AKT途径抑制剂治疗选择患者。如果在组织样品中的FOXO3a确定为在细胞核隔室中的定位多于在细胞质隔室中的定位(单独或者相对于参考样品)，则PI3K/AKT途径中断，且将患者排除在PI3K/AKT途径抑制剂治疗之外。
FOXO3a水平可通过本领域已知的任何适当方式来测量。
患者组织样品由躯体获得且包括细胞和细胞外物质。组织样品可由人类或者非人类动物获得。组织样品可来自任何器官，包括所述器官的疾病状态、血液循环系统以及任何循环肿瘤细胞。组织样品诸如肿瘤活组织可使用已知操作获得，诸如针吸活组织检查(needle biopsy)(参见Kim,C.H.et al.J.Virol.66:3879-3882(1992))；Biswas,B.et al.Annals NY Acad.Sci.590:582-583(1990))；Biswas,B.et al.J.Clin.Microbiol.29:2228-2233(1991)。所述组织以能够精确检测和定量FOXO3a的方式进行处理。所述组织样品可以组织微点阵形式进行制备且切片或者可包括整体组织切片。切片典型地在载玻片上制备。例如，可制备石蜡包埋的福尔马林固定的样本，核心取自样本的分开的区域，每个核心排列在接受区，且切下切片并如前所述处理，例如，Konenen,J.et al.,Tissue microarrays for high-throughput molecular profiling of tumorspecimens,(1987)Nat.Med.4:844-7中所述。当由个体分析组织样品时，重要的是防止任何变化、生理学处理或者降解，特别是在组织或者细胞已经由受试者移除之后的蛋白表达。已知表达水平的变化在干扰(例如热休克或者用脂多糖(LPS)或者其它试剂的活化)后迅速改变。此外，组织和细胞中的RNA和蛋白可快速降解。因此，由受试者获得的组织在理论上立即被固定或者冷冻。组织样本也可包括异种移植物肿瘤样品，特别是来自药物剂量范围或者毒理学研究中的动物的样品。
在本发明方法中可使用定量FOXO3a定位的任何适当方法。在一个方面，免疫组织化学(IHC)用于确定FOXO3a的定位分布。IHC是指基于免疫酶反应使用单克隆或者多克隆抗体以检测细胞或者特定蛋白诸如组织抗原的染色方法。典型地，针对定性或者定量分析，免疫组织化学操作涉及至少下述步骤中的几种：1)抗原提取(例如通过压力蒸煮、蛋白酶处理、微波辐射、在适当缓冲剂中加热等)；2)初级抗体的应用和洗涤；3)与初级抗体结合的标记的次级抗体的应用(通常为进行步骤5)中的检测的第二抗体缀合物)并洗涤；4)可包括扩增步骤；5)检测试剂的应用(例如发色团、荧光标记分子或者具有实现测定所需的敏感性的水平的适当动态范围的任何分子)；6)可使用复染法以及7)使用使得蛋白存在可视(人眼或者自动分析系统可视)的检测系统的检测。用于检测FOXO3a的各种免疫酶染色法是本领域中已知的。例如，可使用如下物质可视化免疫酶相互作用：不同酶诸如过氧化物酶、碱性磷酸酶，或者不同色原诸如DAB、AEC或者Fast Red；或者荧光标记诸如FITC、Cy3、Cy5、Cy7、Alexafluors等。复染剂可包括H&E、DAPI、Hoechst，只要所述染料与其它检测试剂相容并且使用可视化方案。如本领域所已知的，扩增试剂可用于强化染色信号。例如，可使用酪胺试剂。可使用对于本领域技术人员显而易见的任何适当方法或者系统来完成本发明的染色方法，包括自动、半自动或者手动系统。
可使用本领域技术人员所了解的适当特异性抗体来分析FOXO3a水平。可确定总体蛋白水平或者特异性磷酸化蛋白水平。可使用对于本领域技术人员显而易见的用于免疫组织化学分析的适当方法或者系统来完成本发明方法，包括自动系统、定量IHC、半定量IHC和手动方法。本申请使用的"定量"免疫组织化学是指这样的方法，其可自动扫描且评分IHC染色的组织以鉴别和定量特异性生物标记诸如抗原或者其它蛋白的存在。给予样品的评分可为样品的免疫组织化学染色的强度或者光密度(OD)的数字表示，且表示存在于样品中的靶标生物标记的量。所述定量测量可为相对的或者绝对的。例如，IHC测定中的对照样本可与针对相同对照样本获得的ELISA结果相关，由此产生用于确定组织样本中的FOXO3a绝对浓度的标准曲线。所述评分可表示为染色强度或者OD/单位面积或者染色细胞百分数。本申请使用的半定量免疫组织化学是指例如由人眼获得的免疫组织化学结果的评分，其为受训操作者评级的数字化结果(例如0、1+、2+或者3+)。
适于与免疫组织化学一起使用的各种自动化样品处理、扫描和分析系统在本领域中已知。所述系统可包括自动化染色和显微镜扫描、计算机图像分析、连续切片比较(针对定向变化以及样品尺寸与对照进行比较)、数字报表生成以及样品的归档和示踪(诸如组织切片置于其上的载玻片)。细胞显像系统为可商购得到，其将常规光束、荧光或者共聚焦显微镜与数字图像处理系统组合以进行细胞和组织包括免疫染色样品的定量分析。参见，例如CAS-200系统(Becton,Dickinson & Co.)；BLISS and IHCscore of BacusLaboratories,Inc.(Lombard,111)；ACIS of Clarient,Inc.(San Juan Capistrano,Calif)；iVision and GenoMx of BioGenex(San Ramon,Calif)；ScanScope ofAperio Technologies(Vista,Calif)；Ariol SL-50 of Applied Imaging Corporation(San Jose,Calif)；LSC Laser Scanning Cytometer of CompuCyte Corporation(Cambridge,Mass)；以及
of HistoRx Inc.(New Haven,Conn)。
在某些方面中，使用
技术确定FOXO3a在染色组织切片中的水平，这允许亚细胞隔室内的蛋白表达的定量测量，得到例如与每单位面积表达的分子数目直接成比例的数值(参见Camp,R.L.,Chung,G.G.& Rimm,D.L.Automated subcellular localization and quantification of protein expression intissue microarrays.Nat Med 8,1323-7(2002))。亚细胞隔室可包括形态学定义的隔室或者分子学定义的隔室。亚细胞隔室可为细胞膜、细胞质、细胞核、溶酶体、ER、高尔基体等。
可使用适当抗体分析FOXO3a在细胞核和细胞质中的定位定量。FOXO3a的抗体为可商购得到(例如Milipore and Cell Signaling Technology)。其它抗体由
(Calbiochem General Catalog,2006-2007)获得。针对适当抗体的其它商购资源在本领域中已知。
在某些方面，通过细胞核在Cellomics平台上的易位算法确定FOXO3a的定位定量。
在其它方面，可通过FOXO3a的
技术评分确定FOXO3a的定位定量，例如通过使用
技术自动化病理学系统。
技术(对于自动化定量分析)为蛋白原位表达的绝对测量的分析方法。该方法能够测量蛋白在亚细胞隔室内的表达，这得到与每单位面积表达的分子数目直接成比例的数值。
PI3K/AKT激酶抑制剂
存在数百种激酶但并非所有激酶抑制剂也诱导FOXO3a的易位。例如，MEK激酶抑制剂并未诱导FOXO3a的易位。本申请描述了用于确定激酶抑制剂是否也诱导FOXO3a的易位的测定。诱导FOXO3a的易位的激酶抑制包括AKT (例如AKT-1、AKT-2和AKT-3)和PI3K(例如PI3Kα)的抑制剂。所述AKT激酶抑制剂可为全-AKT抑制剂、变构AKT抑制剂或者AKT-1、AKT-2或者AKT-3的选择性抑制剂。所述PI3K抑制剂可为全-PI3K抑制剂或者可为PI3Kα、β、δ的选择性抑制剂或者它们的两种或者多种的组合。
在一个实施方案中，所述AKT激酶抑制剂为式I的化合物及其互变异构体、拆分的对映异构体、拆分的非对映异构体、溶剂化物和盐：
其中
R1为H、Me、Et和CF3；
R2为H或者Me；R5为H或者Me；
A为：
其中G为任选被一至四个R9基团取代的苯基或者任选被卤素取代的5-6元杂芳基；
R6和R7独立为H、OCH3、(C3-C6环烷基)-(CH2)、(C3-C6环烷基)-(CH2CH2)、V-(CH2)0-1，其中V为5-6元杂芳基、W-(CH2)1-2，其中W为任选取代有F、Cl、Br、I、OMe、CF3或者Me的苯基、任选取代有C1-C3烷基或者O(C1-C3烷基)的C3-C6-环烷基、羟基-(C3-C6-环烷基)、氟-(C3-C6-环烷基)、CH(CH3)CH(OH)苯基、任选取代有F、OH、C1-C3烷基、环丙基甲基或者C(=O)(C1-C3烷基)的4-6元杂环基，或者任选取代有一个或者多个独立选自下述的基团的C1-C6-烷基：OH、氧代、O(C1-C6-烷基)、CN、F、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、环丙基、苯基、咪唑基、哌啶基、吡咯烷基、吗啉基、四氢呋喃基、氧杂环丁烷基或者四氢吡喃基，或者R6和R7与它们连接的氮一起形成任选取代有一个或者多个独立选自下述的基团的4-7元杂环：OH、卤素、氧代、CF3、CH2CF3、CH2CH2OH、O(C1-C3烷基)、C(=O)CH3、NH2、NHMe、N(Me)2、S(O)2CH3、环丙基甲基和C1-C3烷基；
Ra和Rb为H，或者Ra为H，且Rb和R6与它们连接的原子一起形成具有一个或者两个环氮原子的5-6元杂环；
Rc和Rd为H或者Me，或者Rc和Rd与它们连接的原子一起形成环丙基环；
R8为H、Me、F或者OH，或者R8和R6与它们连接的原子一起形成具有一个或者两个环氮原子的5-6元杂环；
每个R9独立为卤素、C1-C6-烷基、C3-C6-环烷基、O-(C1-C6-烷基)、CF3、OCF3、S(C1-C6-烷基)、CN、OCH2-苯基、CH2O-苯基、NH2、NH-(C1-C6-烷基)、N-(C1-C6-烷基)2、哌啶基、吡咯烷基、CH2F、CHF2、OCH2F、OCHF2、OH、SO2(C1-C6-烷基)、C(O)NH2、C(O)NH(C1-C6-烷基)和C(O)N(C1-C6-烷基)2；
R10为H或者Me；且
m、n和p独立为0或者1。
另外的实施方案包括式I的AKT抑制剂，其中R1为甲基；R2、R5和R10为H；G为任选取代有1-3个R9的苯基；R9为卤素、C1-C3烷基、CN、CF3、OCF3OCH3或者OCH2苯基；Rc和Rd为H或者甲基；m、n和p为0或者1；且R8为H或者甲基。
另外的实施方案包括式I的AKT抑制剂，选自：
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮二盐酸盐；
(R)-2-氨基-3-(4-氯苯基)-1-((S)-4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮二盐酸盐；
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮二盐酸盐；
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((5R,7R)-7-甲氧基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮二盐酸盐；
(S)-3-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮二盐酸盐；
(R)-2-氨基-3-(4-氯苯基)-1-((S)-4-((S)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮；
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((S)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮；
(2R)-2-氨基-3-(4-氯-3-氟苯基)-1-((3S)-4-((5R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮；
(2R)-2-氨基-3-(4-氯苯基)-1-(4-(7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-氨基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基苯基)丙-1-酮；
2-(4-氯苯基)-1-((S)-4-((R)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
2-(4-氯苯基)-1-(4-(7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮二盐酸盐；
2-(4-氯苯基)-3-(异丙基氨基)-1-(4-(7-甲氧基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
2-(4-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
2-(3,4-二氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(吡啶-3-基甲基氨基)丙-1-酮；
2-(2,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(戊-3-基氨基)丙-1-酮；
2-(4-氯苯基)-3-((1S,2R)-1-羟基-1-苯基丙-2-基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((1R,4R)-4-羟基环己基氨基)丙-1-酮；
((3S,4R)-4-(3,4-二氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮；
((3R,4S)-4-(3,4-二氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮；
2-(4-氯苯基)-2-羟基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
4-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮；
4-氨基-2-(3,4-二氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮；
(4-(4-氯-3-氟苯基)哌啶-4-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮；
(3-(4-氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮；
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-对甲苯基丙-1-酮；
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-甲氧基苯基)丙-1-酮；
3-(乙基氨基)-2-(4-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲基氨基)丙-1-酮；
(S)-3-氨基-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(吡咯烷-1-基)丙-1-酮；
(R)-2-氨基-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-1-((S)-4-((S)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(R)-2-氨基-3-(4-氯苯基)-1-((S)-4-((R)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮；
(R)-2-氨基-3-(4-氯-3-氟苯基)-1-((S)-4-((R)-7-羟基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R)-7-羟基-5,7-二甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(4-(3,4-二氯苯基)哌啶-4-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮二盐酸盐；
4-(3,4-二氯苯基)吡咯烷-3-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮二盐酸盐；
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-甲氧基苯基)-3-(吡咯烷-1-基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(2,2,2-三氟乙基氨基)丙-1-酮；
3-(叔丁基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲基(四氢-2H-吡喃-4-基)氨基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(R)-2-氨基-3-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮；
4-(1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-1-氧代丙-2-基)苄腈；
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
3-(氮杂环丁烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-羟基氮杂环丁烷-1-基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(新戊基氨基)丙-1-酮；
2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
2-(4-氯苯基)-3-(4-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-3-((S)-3-氟吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-3-(乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮；
2-(4-氯苯基)-3-(4,4-二氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-3-(3,3-二氟吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(R)-2-氨基-3-(4-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-氨基-3-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-氨基-3-(3,4-二氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-3-((R)-3-氟吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-(三氟甲氧基)苯基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(环丙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-羟基氮杂环丁烷-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-羟基氮杂环丁烷-1-基)丙-1-酮；
(R)-4-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮；
(S)-4-氨基-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-甲基戊-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-吡咯烷-3-基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((S)-吡咯烷-3-基氨基)丙-1-酮；
(S)-3-((R)-1-乙酰基吡咯烷-3-基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-((S)-1-乙酰基吡咯烷-3-基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(哌啶-4-基氨基)丙-1-酮；
(S)-3-(1-乙酰基哌啶-4-基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(2-甲氧基乙基氨基)丙-1-酮；
(R)-2-(4-氯苯基)-4-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((1r,4S)-4-羟基环己基氨基)丙-1-酮；
(S)-3-(氮杂环丁烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(氮杂环丁烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)乙酰胺；
2-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)-N,N-二甲基乙酰胺；
2-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)-N-甲基乙酰胺；
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(异丙基氨基)丁-1-酮；
(R)-2-(4-溴苯基)-4-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮；
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(异丁基氨基)丁-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-((2-甲氧基乙基)(甲基)氨基)丁-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(异丙基氨基)丁-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(3-羟基氮杂环丁烷-1-基)丁-1-酮；
2-((R)-3-(4-溴苯基)-4-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-氧代丁基氨基)-N,N-二甲基乙酰胺；
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(2-羟基乙基氨基)丁-1-酮；
(2R)-2-(4-溴苯基)-4-(2-羟基-1-(四氢-2H-吡喃-4-基)乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮；
(R)-2-氨基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-碘苯基)丙-1-酮；
4-((R)-2-氨基-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基)苄腈；
(R)-2-氨基-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(三氟甲基)苯基)丙-1-酮；
(S)-3-(4-乙酰基哌嗪-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(4-乙酰基哌嗪-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(甲基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(2-羟基乙基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(2-羟基乙基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-甲氧基氮杂环丁烷-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-4-(环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(四氢-2H-吡喃-4-基氨基)丁-1-酮；
(2R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(2-羟基丙基氨基)丁-1-酮；
(2R)-2-(4-氯苯基)-4-(2-羟基-1-(四氢-2H-吡喃-4-基)乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮；
(2R)-2-(4-氯苯基)-4-(2-羟基-1-苯基乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮；
(S)-2-(4-氯苯基)-3-(乙基(四氢-2H-吡喃-4-基)氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(2-甲氧基乙基氨基)丁-1-酮；
(2R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(3,3,3-三氟-2-羟基丙基氨基)丁-1-酮；
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-((1-羟基环丙基)甲基氨基)丁-1-酮；
2-((R)-3-(4-溴苯基)-4-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-氧代丁基氨基)乙酰胺；
(R)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-4-(四氢-2H-吡喃-4-基氨基)丁-1-酮；
(R)-4-(3-(1H-咪唑-1-基)丙基氨基)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丁-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(S)-3-(3-氨基氮杂环丁烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(3-氨基氮杂环丁烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-硫吗啉代丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-硫吗啉代丙-1-酮；
(R)-2-(4-氯苯基)-3-(4-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(4-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-甲氧基氮杂环丁烷-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(3-甲氧基氮杂环丁烷-1-基)丙-1-酮；
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氟-3-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲氧基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基哌啶-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基哌啶-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(S)-3-(4-氨基哌啶-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(4-氨基哌啶-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(甲基(四氢-2H-吡喃-4-基)氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(甲基磺酰基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(甲基氨基)哌啶-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-(甲基氨基)哌啶-1-基)丙-1-酮；
(S)-2-(4-氯-3-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-氯-3-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(R)-2-(4-氯苯基)-3-(4-乙基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(4-乙基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-3-((S)-3-(二甲基氨基)吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-((S)-3-(二甲基氨基)吡咯烷-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-四氢呋喃-3-基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-四氢呋喃-3-基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(2-氟乙基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氟-3-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(3,5-二(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(3-氟-4-甲氧基苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
4-((R)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基)哌嗪-2-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((R)-3-羟基吡咯烷-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(4-(二甲基氨基)哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-3-(4-(二甲基氨基)哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(3-氯-5-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(3-溴-4-甲氧基苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(哌啶-4-基氨基)丙-1-酮；
(R)-2-(1-乙酰基哌啶-4-基氨基)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-((R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-1-氧代丙-2-基氨基)-N-异丙基乙酰胺；
(R)-3-(4-氯苯基)-2-(二甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(2-吗啉代乙基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(异丙基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-((S)-4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)-3-甲基哌嗪-1-基)-2-(异丙基氨基)丙-1-酮；
2-((R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-1-氧代丙-2-基氨基)-N,N-二甲基乙酰胺；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(1,4-氧氮杂环庚烷-4-基)丙-1-酮；
(R)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(1,4-氧氮杂环庚烷-4-基)丙-1-酮；
(R)-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(环己基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲氧基环己基氨基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((S)-四氢呋喃-3-基氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基四氢-2H-吡喃-4-基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(2-(四氢-2H-吡喃-4-基)乙基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(3,3,3-三氟丙基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-((四氢-2H-吡喃-4-基)甲基氨基)丙-1-酮；
(R)-3-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(异丙基(甲基)氨基)丙-1-酮；
(S)-3-(叔丁基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(叔丁基氨基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(R)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮；
(R)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(R)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮；
(S)-3-氨基-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-氨基-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
3-((S)-2-(4-氯苯基)-3-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)丙酰胺；
3-((S)-2-(4-氯苯基)-3-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-氧代丙基氨基)丙酰胺；
(4-(4-氯苯基)哌啶-4-基)(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)甲酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-3-氨基-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-氨基-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-3-氨基-2-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(R)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(S)-2-(3,5-二氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-3-((R)-3-氨基吡咯烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-((R)-3-氨基吡咯烷-1-基)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮；
(R)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-吗啉代丙-1-酮；
(S)-3-(4-乙基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(4-乙基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-(4-乙酰基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-3-(4-乙酰基哌嗪-1-基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-(二(环丙基甲基)氨基)-2-(4-氯-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-溴苯基)-3-((环丙基甲基)(甲基)氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-2-(3,4-二氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)-2-(4-(三氟甲氧基)苯基)丙-1-酮；
(R)-2-(4-氯苯基)-3-((3S,5R)-3,5-二甲基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-氯苯基)-3-((2S,6R)-2,6-二甲基吗啉代)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-((2S,6R)-2,6-二甲基吗啉代)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-((3S,5R)-3,5-二甲基哌嗪-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(R)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(R)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-甲基哌嗪-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(R)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲氧基)苯基)丙-1-酮；
(S)-3-氨基-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-氨基-2-(4-溴-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(3,4-二氯苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-溴-3-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-溴-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴-3-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-异丙基哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲基)苯基)丙-1-酮；
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(R)-2-(4-溴-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(4-羟基哌啶-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮；
(S)-3-氨基-2-(4-溴-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-氨基-2-(4-溴-2-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮；
(S)-2-(4-溴-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(4-溴-2-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-3-氨基-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
2-(4-氯苯基)-3-((3S,4R)-4-(二甲基氨基)-3-氟哌啶-1-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴-2-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-(叔丁基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲基)苯基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯-2-氟苯基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯-2-氟苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(4-氯-2-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)-2-(4-(三氟甲基)苯基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-2-(4-(三氟甲基)苯基)丙-1-酮；
(S)-2-(4-溴苯基)-3-(叔丁基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丁基氨基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-3-(环戊基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯-3-氟苯基)-3-(环戊基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基(甲基)氨基)丙-1-酮；
(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-((2-羟基乙基)(异丙基)氨基)丙-1-酮；
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-3-氨基-2-(2-氟-4-(三氟甲基)苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-3-(环丙基甲基氨基)-2-(3-氟-4-(三氟甲氧基)苯基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-3-(4,4-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-溴苯基)-3-(3,3-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(4,4-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(4-氯苯基)-3-(3,3-二甲基环己基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)-2-(噻吩-2-基)丙-1-酮；
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(R)-2-(5-溴吡啶-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(5-溴吡啶-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(5-溴噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(5-溴噻吩-2-基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮；
(S)-2-(5-氯噻吩-2-基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(四氢-2H-吡喃-4-基氨基)丙-1-酮；
(S)-2-(5-氯噻吩-2-基)-3-(环丙基甲基氨基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
(S)-2-(5-氯噻吩-2-基)-3-(环丙基甲基氨基)-1-(4-((5R,7S)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)丙-1-酮；
以及它们的盐。
另外的实施方案包括式I的AKT抑制剂，包括以下化合物：
式I化合物的制备
式I的化合物可根据在美国专利公开2008/0051399(美国专利申请11/773,949，2007年7月5日提交，标题为“Hydroxylated and methoxylatedPyrimidyl Cyclopentanes as AKT Protein Kinase Inhibitors”)中所述的方法来制备，将其针对所有目的的内容通过引用的方式并入本申请。
式I的化合物可单独制备或者作为包括至少2个化合物例如5至1,000个化合物、或者10至100个化合物的化合物库来制备。式I的化合物库可通过组合的′分开和混合′方法或者通过多重并行合成法使用溶液相后者固相化学来制备。
针对示例说明的目的，方案1-4显示制备式I的化合物以及关键中间体的一般方法。本领域技术人员应该认识到可使用其它合成途径。尽管特定起始物质和试剂描述于方案中且如下讨论，但是其它起始物质和试剂可容易地替代以提供各种衍生物和/或者反应条件。此外，通过如下所述的方法制备的许多化合物可按照该公开使用本领域技术人员熟知的常规化学方法来进一步修饰。
方案1
方案1显示制备式I的化合物10的方法，其中R1为H，R2为OH且R5为H。嘧啶2的形成可通过如下来完成：使酮酯1与硫脲在碱(诸如KOH)的存在下在适当溶剂(诸如乙醇)中反应。在化合物2的巯基在标准还原条件(例如兰尼镍和NH4OH)下还原以提供化合物3之后，羟基嘧啶3可在标准条件(例如POCl3在DIEA/DCE中的溶液)下氯化以提供化合物4。然后将化合物4在标准条件(例如MCPBA在适当溶剂诸如CHCl3中)下氧化以提供嘧啶-氧化物5。将嘧啶-氧化物用乙酸酐处理得到重排产物6。化合物7通过如下获得：使化合物6与适当取代的哌啶在标准SNAr反应条件下反应得到化合物7。将化合物7水解以提供化合物8，然后将其脱保护以得到中间体9。将哌嗪基环戊二烯并[d]嘧啶9用适当氨基酸在偶联试剂(诸如HBTU)的存在下进行酰化，随后必要时进行脱保护，得到式I的化合物10。
方案2
方案2显示制备式I的化合物22、25和27的方法，其中R1、R2和R5为甲基。根据方案2，将(+)-长叶薄荷酮11用溴进行溴化得到二溴化物12。将二溴化物12用碱(诸如乙醇钠)处理得到pulegenate 13。pulegenate 13的臭氧分解得到酮酯14。将酮酯14用硫脲在碱(诸如KOH在乙醇中的溶液)的存在下处理，随后将巯基在标准条件(例如兰尼镍催化剂在氨中的溶液)下还原得到羟基嘧啶16。将羟基嘧啶16在标准条件(例如POCl3)下氯化得到4-氯嘧啶17。将4-氯嘧啶17用氧化剂(诸如MCPBA或者过氧化氢)氧化得到N-氧化物18。将N-氧化物18用乙酸酐重排得到中间体19。使化合物19与预期哌嗪根据方案1中所述的方法反应得到化合物20(其中R5为H)以及化合物23(其中R5为Me)。使用具有手性固定相的HPLC使化合物20和23进行手性分离，然后在用碱(诸如氢氧化锂)处理后水解分别得到化合物21和24。脱保护后，然后使化合物21和24与适当氨基酸反应分别得到化合物22和25。
可选择地，化合物24的7-羟基可用烷基化剂(诸如烷基卤化物)在碱(诸如NaH或者KOH)的存在下进行烷基化得到化合物26，其中R2为Me。脱保护后，然后使化合物26与适当氨基酸反应得到化合物27。
方案3
方案3显示制备化合物73和74的替代方法。根据方案3，使用氨合成子将14进行氨基化得到63。使用例如甲酸铵在甲酰胺的存在下在50°C-250°C和/或者在高压形成嘧啶得到二环单元64。使用例如POCl3或者SOCl2活化64得到活化的嘧啶65。使用适当保护/取代的哌啶在0°C至150°C将该离去基团置换得到哌啶66。使用例如间氯过氧苯甲酸(“MCPBA”或者“m-CPBA”)或者在-20°C至50°C氧化得到N-氧化物67。用酰化剂(例如乙酸酐)处理，随后加热(40°C至200°C)引起重排得到68。使用例如LiOH或者NaOH在0°C至50°C进行水解得到醇69。使用例如Swern条件MnO4或者吡啶-SO3络合物在适当温度进行氧化得到酮70。使用例如催化的手性催化剂在氢、CBS催化剂或者硼氢化物还原剂的存在下在手性配体的存在下进行不对称还原得到在醇71或者72的(R)或者(S)立体化学。可选择地，可使用非手性还原剂(例如H2、Pd/C)，使得甲基位于环戊烷单元上以得到平面选择性(facial selectivity)以及最终非对映立体选择性。如果还原得到较低的非对映立体选择性，则非对映异构体可通过(例如)色谱法、结晶或者衍生来分离。最后，使用例如酸在0°C至50°C进行Boc-基团的脱保护，使用适当官能化的氨基酸进行乙酰化并将该氨基酸的胺进行最后的官能化(例如移去任何保护基、烷基化、还原氨基化或者酰化以引入新的取代基)得到最终化合物73和74。
方案4
将手性助剂(例如Evans噁唑烷酮等)引入至化合物(1)可通过标准酰化操作来完成，得到缀合物(2)。例如，在胺碱的存在下在-20°C至100°C将酸用活化剂(例如COCl2)处理或者形成混合酸酐(例如2,2-二甲基丙酰氯)，随后用适当手性助剂(X)处理得到化合物(2)。手性助剂的立体化学和选择可确定新产生的手性中心的立体化学以及非对映立体选择性。将化合物(2)用路易斯酸(例如TiCl4)在低温(例如-20°C至-100°C)使用胺碱(例如许尼希碱)进行处理，随后使用适当取代的亚铵离子前体(3)在低温处理得到化合物(4)。所述温度、路易斯酸以及手性助剂均可认为影响加成加合物的非对映立体选择性。最后，在温和条件(例如LiOH/H2O，在-10°C至30°C)下进行皂化得到预期酸(5)。
在其它实施方案中，AKT激酶抑制剂为式II化合物及其立体异构体、互变异构体或者药用盐：
其中：
G为任选取代有一至三个Ra基团的苯基或者任选被卤素取代的5-6元杂芳基；
R1和R1a独立选自H、Me、CF3、CHF2或者CH2F；
R2为H、F或者–OH；
R2a为H；
R3为H；
R4为H或者任选取代有F、-OH或者-O(C1-C3烷基)的C1-C4烷基；
R5和R5a独立选自H和C1-C4烷基，或者R5和R5a与它们连接的原子一起形成5-6元环烷基或者5-6元杂环基，其中所述杂环具有氧杂原子；
每个Ra独立为卤素、C1-C6-烷基、C3-C6-环烷基、-O-(C1-C6-烷基)、CF3、-OCF3、S(C1-C6-烷基)、CN、-OCH2-苯基、NH2、-NO2、-NH-(C1-C6-烷基)、-N-(C1-C6-烷基)2、哌啶基、吡咯烷基、CH2F、CHF2、-OCH2F、-OCHF2、-OH、-SO2(C1-C6-烷基)、C(O)NH2、C(O)NH(C1-C6-烷基)和C(O)N(C1-C6-烷基)2；以及
J为1或者2。
另外的实施方案包括AKT抑制剂化合物，包括：
在一个实施方案中，所述AKT抑制剂为上式的化合物，选自(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮，也称为GDC-0068。
式II的化合物可根据WO 2009006567中所述的方法制备，将其针对全部目的的内容通过引用的方式并入本申请。
在一个实施方案中，所述AKT抑制剂为式III的化合物：
其中R1和R2独立为氢、C1-C5烷基、羟基、C1-5烷氧基或者氨基；p为1至6的整数；A为5-14碳环、二环或者三环芳族或者杂芳族环，其可任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基、C1-C6-烷基或者苯基，其任选取代有卤素、OH、C1-C3烷基或者环丙基甲基；且在一个实施方案中，A具有下述结构中的一种：
其中D和E独立为–CH或者N；
其中R3和R4各自独立为氢、卤素、OH、氨基、二烷基氨基、单烷基氨基或者C1-C6-烷基，其任选取代有卤素、OH、C1-C3烷基或者环丙基甲基；
R5为5或者6元芳族或者杂芳族环，其任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基或者C1-C6-烷基，其任选取代有卤素、OH、C1-C3烷基或者环丙基甲基；在一个实施方案中，R5为苯基；
B为芳族、杂芳族、环状或者杂环状环，其具有下式：
其中Q、T、X和Y各自独立选自–CH、-CH2、C=O、N或者O；
Z为-CH、-CH2、C=O、N、O或者–C=C–；
R6和R7独立选自氢、卤素、羰基和5或者6元芳族或者杂芳族环，所述环任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基或者C1-C6-烷基，其任选取代有卤素、OH、C1-C3烷基或者环丙基甲基；在一个实施方案中，R6或者R7为吡啶基，或者R6和R7一起形成5-6元芳族、杂芳族、环状或者杂环状环，其可任选取代有卤素、OH、氨基、二烷基氨基、单烷基氨基或者C1-C6-烷基，其任选取代有卤素、OH、C1-C3烷基或者环丙基甲基；在一个实施方案中，B具有下述结构中的一种：
其中X、Y、Q、R6和R7如上所述，且X’、Q’和T’为-CH或者N。
在其它实施方案中，AKT抑制剂包括具有下式的化合物：
其中a为0或者1；b为0或者1；m为0、1或者2；n为0、1或者2；p为0、1或者2；r为0或者1；s为0或者1；
Q选自：-NR7R8，
R1独立选自(C=O)aObC1-C6烷基、(C=O)aOb芳基、C2-C6烯基、C2-C6炔基、(C=O)aOb杂环基、(C=O)aObC3-C6环烷基、CO2H、卤素、CN、OH、ObC1-C6全氟烷基、Oa(C=O)bNR7R8、NRc(C=O)NR7R8、S(O)mRa、S(O)2NR7R8、NRcS(O)mRa、氧代、CHO、NO2、NRc(C=O)ObRa、O(C=O)ObC1-C6烷基、O(C=O)ObC3-C6环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环，其中所述烷基、芳基、烯基、炔基、杂环基和环烷基任选取代有一个或者多个选自Rz的取代基；
R2独立选自C1-C6烷基、芳基、杂环基、CO2H、卤素、CN、OH和S(O)2NR7R8，其中所述烷基、芳基和杂环基任选取代有一、二或者三个选自Rz的取代基；
R7和R8独立选自H、(C=O)ObC1-C10烷基、(C=O)ObC3-C8环烷基、(C=O)Ob芳基、(C=O)Ob杂环基、C1-C10烷基、芳基、C2-C10烯基、C2-C10炔基、杂环基、C3-C8环烷基、SO2Ra和(C=O)NRb 2，其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或者多个选自Rz的取代基，或者
R7和R8可与它们连接的氮一起形成单环或者二环杂环，其在每个环上具有5-7个成员且任选除了氮之外还含有一个或者两个选自N、O和S的额外的杂原子，所述单环或者二环杂环任选取代有一个或者多个选自Rz的取代基；
Rz选自：(C=O)rOs(C1-C10)烷基、Or(C1-C3)全氟烷基、(C0-C6)亚烷基-S(O)mRa、氧代、OH、卤素、CN、(C=O)rOs(C2-C10)烯基、(C=O)rOs(C2-C10)炔基、(C=O)rOs(C3-C6)环烷基、(C=O)rOs(C0-C6)亚烷基-芳基、(C=O)rOs(C0-C6)亚烷基-杂环基、(C=O)rOs(C0-C6)亚烷基-N(Rb)2、C(O)Ra、(C0-C6)亚烷基-CO2Ra、C(O)H、(C0-C6)亚烷基-CO2H、C(O)N(Rb)2、S(O)mRa和S(O)2N(Rb)2NRc(C=O)ObRa、O(C=O)ObC1-C10烷基、O(C=O)ObC3-C8环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环，其中所述烷基、烯基、炔基、环烷基、芳基和杂环基任选取代有至多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代和N(Rb)2的取代基；
Ra为(C1-C6)烷基、(C3-C6)环烷基、芳基或者杂环基；且
Rb为H、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或者S(O)2Ra；
Rc选自：H、C1-C6烷基、芳基、C2-C6烯基、C2-C6炔基、环基、C3-C8环烷基和C1-C6全氟烷基，其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或者多个选自Rz的取代基；
或者它们的药用盐或者立体异构体。
在其它实施方案中，AKT抑制剂包括：
其中a为0或者1；b为0或者1；m为0、1或者2；n为0、1、2或者3；p为0、1或者2；r为0或者1；s为0或者1；u、v、w和x独立选自CH和N，条件是仅u、v、w和x中的一个可为N；
Q选自-NR5R6,
R1独立选自(C=O)aObC1-C6烷基、(C=O)aOb芳基、C2-C6烯基、C2-C6炔基、(C=O)aOb杂环基、(C=O)aObC3-C6环烷基、CO2H、卤素、CN、OH、ObC1-C6全氟烷基、Oa(C=O)bNR7R8、NRc(C=O)NR7R8、S(O)mRa、S(O)2NR7R8、NRcS(O)mRa、氧代、CHO、NO2、NRc(C=O)ObRa、O(C=O)ObC1-C6烷基、O(C=O)ObC3-C6环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环，其中所述烷基、芳基、烯基、炔基、杂环基和环烷基任选取代有一个或者多个选自Rz的取代基；
R2独立选自C1-C6烷基、芳基、杂环基、CO2H、卤素、CN、OH和S(O)2NR7R8，其中所述烷基、芳基和杂环基任选取代有一、二或者三个选自Rz的取代基；
R7和R8独立选自H、(C=O)ObC1-C10烷基、(C=O)ObC3-C8环烷基、(C=O)Ob芳基、(C=O)Ob杂环基、C1-C10烷基、芳基、C2-C10烯基、C2-C10炔基、杂环基、C3-C8环烷基、SO2Ra和(C=O)NRb 2，其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或者多个选自Rz的取代基，或者
R7和R8可与它们连接的氮一起形成单环或者二环杂环，其在每个环上具有5-7个成员且任选除了氮之外还含有一个或者两个选自N、O和S的额外的杂原子，所述单环或者二环杂环任选取代有一个或者多个选自Rz的取代基；
Rz选自：(C=O)rOs(C1-C10)烷基、Or(C1-C3)全氟烷基、(C0-C6)亚烷基-S(O)mRa、氧代、OH、卤素、CN、(C=O)rOs(C2-C10)烯基、(C=O)rOs(C2-C10)炔基、(C=O)rOs(C3-C6)环烷基、(C=O)rOs(C0-C6)亚烷基-芳基、(C=O)rOs(C0-C6)亚烷基-杂环基、(C=O)rOs(C0-C6)亚烷基-N(Rb)2、C(O)Ra、(C0-C6)亚烷基-CO2Ra、C(O)H、(C0-C6)亚烷基-CO2H、C(O)N(Rb)2、S(O)mRa和S(O)2N(Rb)2NRc(C=O)ObRa、O(C=O)ObC1-C10烷基、O(C=O)ObC3-C8环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环，其中所述烷基、烯基、炔基、环烷基、芳基和杂环基任选取代有至多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代和N(Rb)2的取代基；
Ra为(C1-C6)烷基、(C3-C6)环烷基、芳基或者杂环基；且
Rb为H、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或者S(O)2Ra；
Rc选自：H、C1-C6烷基、芳基、C2-C6烯基、C2-C6炔基、杂环基、C3-C8环烷基和C1-C6全氟烷基，其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或者多个选自Rz的取代基；
或者它们的药用盐或者立体异构体。
在其它实施方案中，AKT抑制剂包括：
其中a为0或者1；b为0或者1；m为0、1或者2；n为0、1、2或者3；p为0、1或者2；r为0或者1；s为0或者1；u、v和x独立选自CH和N；W为化学键、CH或者N；
Q选自：-NR5R6，
R1独立选自(C=O)aObC1-C6烷基、(C=O)aOb芳基、C2-C6烯基、C2-C6炔基、(C=O)aOb杂环基、(C=O)aObC3-C6环烷基、CO2H、卤素、CN、OH、ObC1-C6全氟烷基、Oa(C=O)bNR7R8、NRc(C=O)NR7R8、S(O)mRa、S(O)2NR7R8、NRcS(O)mRa、氧代、CHO、NO2、NRc(C=O)ObRa、O(C=O)ObC1-C6烷基、O(C=O)ObC3-C6环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环，其中所述烷基、芳基、烯基、炔基、杂环基和环烷基任选取代有一个或者多个选自Rz的取代基；
R2独立选自C1-C6烷基、芳基、杂环基、CO2H、卤素、CN、OH和S(O)2NR7R8，其中所述烷基、芳基和杂环基任选取代有一、二或者三个选自Rz的取代基；
R7和R8独立选自H、(C=O)ObC1-C10烷基、(C=O)ObC3-C8环烷基、(C=O)Ob芳基、(C=O)Ob杂环基、C1-C10烷基、芳基、C2-C10烯基、C2-C10炔基、杂环基、C3-C8环烷基、SO2Ra和(C=O)NRb 2，其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或者多个选自Rz的取代基，或者
R7和R8可与它们连接的氮一起形成单环或者二环杂环，其在每个环上具有5-7个成员且任选除了氮之外还含有一个或者两个选自N、O或者S的额外的杂原子，所述单环或者二环杂环任选取代有一个或者多个选自Rz的取代基；
Rz选自：(C=O)rOs(C1-C10)烷基、Or(C1-C3)全氟烷基、(C0-C6)亚烷基-S(O)mRa、氧代、OH、卤素、CN、(C=O)rOs(C2-C10)烯基、(C=O)rOs(C2-C10)炔基、(C=O)rOs(C3-C6)环烷基、(C=O)rOs(C0-C6)亚烷基-芳基、(C=O)rOs(C0-C6)亚烷基-杂环基、(C=O)rOs(C0-C6)亚烷基-N(Rb)2、C(O)Ra、(C0-C6)亚烷基-CO2Ra、C(O)H、(C0-C6)亚烷基-CO2H、C(O)N(Rb)2、S(O)mRa和S(O)2N(Rb)2NRc(C=O)ObRa、O(C=O)ObC1-C10烷基、O(C=O)ObC3-C8环烷基、O(C=O)Ob芳基和O(C=O)Ob-杂环，其中所述烷基、烯基、炔基、环烷基、芳基和杂环基任选取代有至多三个选自Rb、OH、(C1-C6)烷氧基、卤素、CO2H、CN、O(C=O)C1-C6烷基、氧代和N(Rb)2的取代基；
Ra为(C1-C6)烷基、(C3-C6)环烷基、芳基或者杂环基；且
Rb为H、(C1-C6)烷基、芳基、杂环基、(C3-C6)环烷基、(C=O)OC1-C6烷基、(C=O)C1-C6烷基或者S(O)2Ra；
Rc选自：H、C1-C6烷基、芳基、C2-C6烯基、C2-C6炔基、杂环基、C3-C8环烷基和C1-C6全氟烷基，其中所述烷基、环烷基、芳基、杂环基、烯基和炔基任选取代有一个或者多个选自Rz的取代基；
或者它们的药用盐或者立体异构体。
示例性AKT抑制剂包括：
在一个实施方案中，所述激酶抑制剂为AKT-1选择性抑制剂，且为式IV的化合物及其药用盐：
其中
Ar选自芳基、经取代的芳基、杂芳基和经取代的杂芳基；
Q选自环烷基、经取代的环烷基、杂环烷基、经取代的杂环烷基、芳基、经取代的芳基、杂芳基和经取代的杂芳基；
R1和R2独立选自氢、烷基、经取代的烷基、环烷基、经取代的环烷基、杂环烷基、经取代的杂环烷基、芳基、经取代的芳基、杂芳基和经取代的杂芳基；或者R1和R2与R1和R2连接的氮一起形成选自杂环烷基、经取代的杂环烷基、杂芳基和经取代的杂芳基的环；
p选自2、3、4和5；且
q为0或者1。
式IV的化合物包括：
及其盐。
另外的实施方案包括AKT抑制剂诸如具有下式的哌立福辛(perifosine)：
另外的实施方案包括AKT抑制剂诸如抗-AKT抗体和抗-AKT DNA或者RNA。
另外的实施方案包括AKT抑制剂诸如寡核苷酸，包括具有以下序列的反义寡核苷酸：5′ccagcccccaccagtccact 3′、5′cgccaaggagatcatgcagc 3′、5′gctgcatgatctccttggcg 3′、5′agatagctggtgacagacag 3′、5′cgtggagagatcatctgagg 3′、5′tcgaaaaggtcaagtgctac 3′、5′tggtgcagcggcagcggcag 3′和5′ggcgcgagcgcgggcctagc 3′。
在其它实施方案中，所述PI3-k抑制剂为式V的化合物或者其药用盐：
其中：
R1和R2独立选自氢、卤素、C1-6烷基、-NRdRe、-SRd、-ORd、-C(O)ORd、-C(O)NRdRe、-C(O)Rd、-NRdC(O)Re、-OC(O)Rf、-NRdC(O)NRdRe、-OC(O)NRdRe、-C(=NORd)NRdRe、-NRdC(=N-CN)NRdRe、-NRdS(O)2NRdRe、-S(O)2Rd、-S(O)2NRdRe、-Rf、-NO2、-N3、=O、-CN、-(CH2)1-4-NRdRe、-(CH2)1-4-SRd、-(CH2)1-4-ORd、-(CH2)1-4-C(O)ORd、-(CH2)1-4-C(O)NRdRe、-(CH2)1-4-C(O)Rd、-(CH2)1-4-NRdC(O)Re、-(CH2)1-4-OC(O)Rf、-(CH2)1-4-NRdC(O)NRdRe、-(CH2)1-4-OC(O)NRdRe、-(CH2)1-4-C(=NORd)NRdRe、-(CH2)1-4-NRdC(=N-CN)NRdRe、-(CH2)1-4-NRdS(O)2NRdRe、-(CH2)1-4-S(O)2Rd、-(CH2)1-4-S(O)2NRdRe、-(CH2)1-4-NO2、-(CH2)1-4-N3或者-(CH2)1-4-CN；其中Rd和Re各自独立选自氢、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基，或者Rd和Re与它们连接的氮组合形成3-至6-元环；Rf选自C1-6烷基、C1-6卤代烷基、C3-7环烷基、C3-7杂环烷基、苯基和-(CH2)1-4-苯基；或者
R1和R2与它们连接的原子一起形成稠合的5-或者6-元杂环基或者杂芳基环，其任选被氧代、卤素、C1-C3烷基或者CF3取代。
示例性PI3-k抑制剂包括以下化合物：
在一个实施方案中，所述PI3K激酶抑制剂为式VI和VII的化合物及其立体异构体和药用盐：
其中：
R1选自H、F、Cl、Br、I、CN、-(CR14R15)mNR10R11、-C(R14R15)nNR12C(=Y)R10、-(CR14R15)nNR12S(O)2R10、-(CR14R15)mOR10、-(CR14R15)nS(O)2R10、-(CR14R15)nS(O)2NR10R11、-C(OR10)R11R14、-C(=Y)R10、-C(=Y)OR10、-C(＝Y)NR10R11、-C(＝Y)NR12OR10、-C(=O)NR12S(O)2R10、-C(=O)NR12(CR14R15)mNR10R11、-NO2、-NR12C(=Y)R11、-NR12C(=Y)OR11、-NR12C(=Y)NR10R11、-NR12S(O)2R10、-NR12SO2NR10R11、-SR10、-S(O)2R10、-S(O)2NR10R11、-SC(=Y)R10、-SC(=Y)OR10、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基；
R2选自H、F、Cl、Br、I、CN、CF3、-NO2、-C(=Y)R10、-C(=Y)OR10、-C(=Y)NR10R11、-(CR14R15)mNR10R11、-(CR14R15)nOR10、-(CR14R15)t-NR12C(=O)(CR14R15)NR10R11、-NR12C(=Y)R10、-NR12C(=Y)OR10、-NR12C(=Y)NR10R11、-NR12SO2R10、OR10、-OC(=Y)R10、-OC(=Y)OR10、-OC(=Y)NR10R11、-OS(O)2(OR10)、-OP(=Y)(OR10)(OR11)、-OP(OR10)(OR11)、SR10、-S(O)R10、-S(O)2R10、-S(O)2NR10R11、-S(O)(OR10)、-S(O)2(OR10)、-SC(=Y)R10、-SC(=Y)OR10、-SC(=Y)NR10R11、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基；
R3为碳连接的单环杂芳基、碳连接的稠合的二环C3-C20杂环基或者碳连接的稠合的二环C1-C20杂芳基，其中所述单环杂芳基、稠合的二环C3-C20杂环基以及稠合的二环C1-C20杂芳基任选取代有一个或者多个选自F、Cl、Br、I、-CN、-NR10R11、-OR10、-C(O)R10、-NR10C(O)R11、-N(C(O)R11)2、-NR10C(O)NR10R11、-NR12S(O)2R10、-C(=O)OR10、-C(=O)NR10R11、C1-C12烷基和(C1-C12烷基)-OR10的基团；
R10、R11和R12独立为H、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基或者C1-C20杂芳基，
或者R10和R11与它们连接的氮一起形成C2-C20杂环，其任选取代有一个或者多个独立选自下述的基团：氧代、(CH2)mOR12、NR12R12、CF3、F、Cl、Br、I、SO2R12、C(=O)R12、NR12C(=Y)R12、NR12S(O)2R12、C(=Y)NR12R12、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基；
R14和R15独立选自H、C1-C12烷基或者-(CH2)n-芳基，
或者R14和R15与它们连接的原子一起形成饱和的或者部分不饱和的C3-C12碳环；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选取代有一个或者多个独立选自下述的基团：F、Cl、Br、I、CN、CF3、-NO2、oxo、R10、-C(=Y)R10、-C(=Y)OR10、-C(=Y)NR10R11、-(CR14R15)nNR10R11、-(CR14R15)nOR10、-NR10R11、-NR12C(=Y)R10、-NR12C(=Y)OR11、-NR12C(=Y)NR10R11、-(CR14R15)mNR12SO2R10、=NR12、OR10、-OC(=Y)R10、-OC(=Y)OR10、-OC(=Y)NR10R11、-OS(O)2(OR10)、-OP(=Y)(OR10)(OR11)、-OP(OR10)(OR11)、-SR10、-S(O)R10、-S(O)2R10、-S(O)2NR10R11、-S(O)(OR10)、-S(O)2(OR10)、-SC(=Y)R10、-SC(=Y)OR10、-SC(=Y)NR10R11、C1-C12烷基、C2-C8烯基、C2-C8炔基、C3-C12碳环基、C2-C20杂环基、C6-C20芳基和C1-C20杂芳基；
Y为O、S或者NR12；
m为0、1、2、3、4、5或者6；且
n为1、2、3、4、5或者6。
示例性PI3k抑制剂包括下述化合物及其盐：
另外的实施方案包括PI3K抑制剂诸如抗-PI3K抗体和抗-PI3K DNA或者RNA。
式VI和VII化合物的制备
式VI和VII化合物可通过以下合成途径进行合成，其包括与本领域技术人员熟知的方法类似的方法以及WO 2006/046031的方法，将其针对全部目的的内容通过引用的方式并入本申请。起始物质通过由商购资源诸如Aldrich Chemicals(Milwaukee,WI)购得或者使用本领域技术人员熟知的方法容易地制备(例如通过Louis F.Fieser and Mary Fieser,Reagents for OrganicSynthesis,v.1-19,Wiley,N.Y.(1967-1999ed.)或者Beilsteins Handbuch derorganischen Chemie,4,Aufl.ed.Springer-Verlag,Berlin,包括附录(也经Beilstein在线数据库获得)中所述的一般方法制备)。
式VI和VII化合物可使用制备以下物质的方法来制备：其它噻吩、呋喃、嘧啶(US 6608053；US 6492383；US 6232320；US 6187777；US 3763156；US 3661908；US 3475429；US 5075305；US 2003/220365；GB 1393161；WO 93/13664)；以及其它杂环，其描述于：Comprehensive HeterocyclicChemistry,Editors Katritzky and Rees,Pergamon Press,1984。
式VI和VII化合物可通过常规方法转化为药用盐，且盐可转化为游离化合物。药用盐的实例包括与无机酸以及有机酸形成的盐，所述无机酸诸如盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸；且有机酸诸如甲磺酸、苯磺酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、枸橼酸、乙磺酸、门冬氨酸和谷氨酸。所述盐可为甲磺酸盐、盐酸盐、磷酸盐、苯磺酸盐或者硫酸盐。盐可为单盐或者二盐。例如，所述甲磺酸盐可为单甲磺酸盐或者二甲磺酸盐。
式VI和VII化合物及其盐也可呈水合物或者溶剂化物形式。
中间体的官能团的保护(例如伯胺或者仲胺)在制备式VI和VII化合物中是必要的。对于所述保护的需求将取决于远距离官能团的性质和制备方法的条件而变化。适当的氨基保护基包括乙酰基、三氟乙酰基、叔丁氧基羰基(BOC)、苄基氧基羰基、(CBz)和9-芴基亚甲氧基羰基(Fmoc)。所述保护的需求由本领域技术人员容易地确定。对于保护基及其用途的一般描述，参见T.W.Greene,Protective Groups in Organic Synthesis,John Wiley & Sons,NewYork,1991。
针对示例性的目的，方案5-11显示制备本发明化合物以及关键中间体的一般方法。为了更详细地描述单个反应步骤，参见如下实施例部分。本领域技术人员应该认识到其它合成途径可用于合成本发明化合物。尽管特定起始物质和试剂描述于方案中且如下讨论，但是其它起始物质和试剂可容易地替换以提供各种衍生物和/或者反应条件。此外，通过如下所述的方法制备的许多化合物可根据本公开使用本领域技术人员熟知的常规化学方法来进一步修饰。
方案5
方案5显示用于由2-羧基酯、3-氨基噻吩以及2-氨基、3-羧基酯噻吩试剂(分别为51和52)制备噻吩并嘧啶中间体55和56的一般方法，其中Hal为Cl、Br或者I；且R1、R2和R10如式VI和VII化合物或者其前体或者前药所定义。
方案6
方案6显示用于将来自二卤代噻吩并嘧啶中间体57和58的4-卤化物用吗啉在碱性条件下在有机溶剂中进行选择性置换以分别制备2-卤代、4-吗啉代噻吩并嘧啶化合物59和60的一般方法，其中Hal为Cl、Br或者I；且R1和R2如式VI和VII化合物或者其前体或者前药所定义。
方案7
方案7显示用于衍生2-卤代、4-吗啉代、6-氢噻吩并嘧啶化合物61和62的6-位的一般方法，其中R1为H。用锂化试剂处理61或者62以移去6位质子，随后加入酰化剂R10C(O)Z，其中Z为离去基团，诸如卤化物、NHS酯、羧酸酯或者二烷基氨基，得到2-卤代、4-吗啉、6-酰基噻吩并嘧啶化合物63和64，其中Hal为Cl、Br或者I；且R2和R10如式VI和VII化合物或者其前体或者前药所定义。制备6-甲酰基化合物(R10=H)的R10C(O)Z的实例为N,N’-二甲基甲酰胺(DMF)。
方案8
方案8显示用于使2-卤代嘧啶中间体(65和66)与单环杂芳基、稠合二环杂环基或者稠合二环杂芳基硼酸(R15=H)或者硼酸酯(R15=烷基)试剂67进行Suzuki类型偶联以制备式VI和VII的2-取代的(Hy)、4-吗啉代噻吩并嘧啶化合物(68和69)的一般方法，其中Hal为Cl、Br或者I；且R1和R2如式VI和VII化合物或者其前体或者前药所定义。对于Suzuki反应的综述，参见：Miyaura et al.(1995)Chem.Rev.95:2457-2483；Suzuki,A.(1999)J.Organomet.Chem.576:147-168；Suzuki,A.in Metal-Catalyzed Cross-CouplingReactions,Diederich,F.,Stang,P.J.,Eds.,VCH,Weinheim,DE(1998),pp49-97。钯催化剂可为典型地用于Suzuki类型交叉偶联的任何催化剂，诸如PdCl2(PPh3)2、Pd(PPh3)4、Pd(OAc)2、PdCl2(dppf)-DCM、Pd2(dba)3/Pt-Bu)3(Owens et al(2003)Bioorganic & Med.Chem.Letters 13:4143-4145；Molanderet al(2002)Organic Letters 4(11):1867-1870；US 6448433)。
方案9
方案9显示了合成炔71的一般方法，其可用于制备化合物72和73的炔基化衍生物。炔丙基胺71可通过如下来制备：使炔丙基溴70与式R10R11NH的胺(其中R10和R11独立选自H、烷基、芳基和杂芳基，或者R10和R11与它们连接的氮一起形成杂环)在适当碱(Cs2CO3等)的存在下进行反应。对于炔基胺以及相关的合成的综述参见Booker-Milburn,K.I.,ComprehensiveOrganic Functional Group Transformations(1995),2:1039-1074；以及Viehe,H.G.,(1967)Angew.Chem.,Int.Ed.Eng.,6(9):767-778。随后炔71可与中间体72(X2=溴或者碘)或者73(经Sonogashira偶联)反应以分别提供化合物74和75，其中R2和R3如式VI和VII化合物或者其前体或者前药所定义。
方案10
方案10显示合成炔77的一般方法，其可用于制备化合物72和73的炔基化衍生物。偕-二烷基炔丙基胺77可使用Zaragoza et al (2004)J.Med.Chem.,47:2833所述的方法来制备。根据方案6，偕-二烷基氯76(R14和R15独立为甲基、乙基或者其它烷基)可与式R10R11NH的胺(其中R10和R11独立选自H、烷基、芳基和杂芳基，或者R10和R11与它们连接的氮一起形成杂环)在CuCl和适当碱(例如TEA等)的存在下进行反应以提供炔77。炔77可与中间体72或者73(经Sonogashira偶联)反应以分别提供化合物78和79，其中R2和R3如式VI和VII化合物或者其前体或者前药所定义。
方案11
方案11显示合成炔81的一般方案，其可用于制备化合物72和73的炔基化衍生物。丁-3-炔-1-胺81(其中R14和R15独立为H、烷基、芳基、杂芳基，或者R14和R15与它们连接的碳原子一起形成碳环或者杂环)可通过如下来制备：使炔80(LG=甲苯磺酸酯或者其它离去基团)与式R10R11NH的胺(其中R10和R11独立选自H、烷基、芳基和杂芳基，或者R10和R11与它们连接的氮一起形成杂环)使用Olomucki M.et al(1960)Ann.Chim.5:845所述的方法进行反应。随后炔81可与中间体72或者73(经Sonogashira偶联)根据方案5和6提供的描述进行反应以分别提供化合物82和83，其中R2和R3如式VI和VII化合物或者其前体或者前药所定义。
式VI至VII的噻吩并嘧啶化合物的药用盐可使用常规技术来制备。典型地，所述方法包括用适当酸在适当溶剂中处理所述化合物。
在如上定义的本发明方法中，氨基化步骤和Pd-介导的交叉偶联步骤均在常规条件下进行。所述钯催化剂可为典型用于Suzuki-类型交叉偶联的任何催化剂，诸如PdCl2(PPh3)2。所述还原剂典型地为硼氢化物，诸如NaBH(OAc)3、NaBH4或者NaCNBH4。
给药方法
一个实施方案包括在哺乳动物中治疗癌症的方法，包括通过评估FOXO3a定位来诊断患者对PI3K/AKT途径激酶抑制剂的可能反应；以及对所述患者给予治疗有效量的PI3K/AKT途径激酶抑制剂或者其药用盐。在一个实施方案中，所述PI3K/AKT途径激酶抑制剂为式I的化合物或者其药用盐。在其它实施方案中，所述PI3K/AKT途径激酶抑制剂为2-(1H-吲唑-4-基)-6-(4-甲磺酰基-哌嗪-1-基甲基)-4-吗啉-4-基-噻吩并[3,2-d]嘧啶(GDC-0941)或者其药用盐。在其它实施方案中，所述PI3K/AKT途径激酶抑制剂为(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮(GDC-0068)或者其药用盐。在一个实例中，所述癌症为间皮瘤、子宫内膜癌、神经胶质瘤、胰腺癌、乳腺癌、肺癌、卵巢癌、前列腺癌、黑素瘤、胃癌、结肠癌、头颈癌。在一个实例中，所述癌症为乳腺癌、前列腺癌或者卵巢癌。在其它实例中，所述癌症为乳腺癌。
一个实施方案包括在哺乳动物中治疗癌症的方法，包括通过评估PTEN状态和FOXO3a定位来诊断患者对PI3K/AKT途径激酶抑制剂的可能反应；以及对所述患者给予治疗有效量的PI3K/AKT途径激酶抑制剂或者其药用盐。在一个实施方案中，所述PI3K/AKT途径激酶抑制剂为式I的化合物或者其药用盐。在其它实施方案中，所述PI3K/AKT途径激酶抑制剂为2-(1H-吲唑-4-基)-6-(4-甲磺酰基-哌嗪-1-基甲基)-4-吗啉-4-基-噻吩并[3,2-d]嘧啶(GDC-0941)或者其药用盐。在其它实施方案中，所述PI3K/AKT途径激酶抑制剂为(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮(GDC-0068)或者其药用盐。在一个实例中，所述癌症为间皮瘤、子宫内膜癌、神经胶质瘤、胰腺癌、乳腺癌、肺癌、卵巢癌、前列腺癌、黑素瘤、胃癌、结肠癌、头颈癌。在一个实例中，所述癌症为乳腺癌、前列腺癌或者卵巢癌。在其它实例中，所述癌症为乳腺癌。
另外的实施方案包括治疗患者中肿瘤的方法，包括对所述患者给予治疗有效量的PI3K/AKT激酶途径抑制剂或者其立体异构体或者盐，其中治疗取决于患者的具有细胞质FOXO3a定位分布的肿瘤。在一个实施方案中，所述PI3K/AKT激酶途径抑制剂为GDC-0941。在其它实施方案中，所述PI3K/AKT激酶途径抑制剂为式I的化合物。在一个实施方案中，所述PI3K/AKT激酶途径抑制剂为GDC-0068。
另外的实施方案包括治疗患者中肿瘤的方法，包括对所述患者给予治疗有效量的PI3K/AKT激酶途径抑制剂或者其立体异构体或者盐，其中FOXO3a在所述肿瘤中的定位分布基本上为细胞质中的。在一个实施方案中，所述PI3K/AKT激酶途径抑制剂为GDC-0941。在其它实施方案中，所述PI3K/AKT激酶途径抑制剂为式I的化合物。在一个实施方案中，所述PI3K/AKT激酶途径抑制剂为GDC-0068。
另外的实施方案包括治疗患者中肿瘤的方法，包括选择具有细胞质定位分布的肿瘤的患者且对所述患者给予治疗有效量的PI3K/AKT激酶途径抑制剂或者其立体异构体或者盐。在一个实施方案中，所述PI3K/AKT激酶途径抑制剂为GDC-0941。在其它实施方案中，所述PI3K/AKT激酶途径抑制剂为式I的化合物。在一个实施方案中，所述PI3K/AKT激酶途径抑制剂为GDC-0068。
在一个实施方案中，所述待治疗的癌症或者肿瘤包括以下类别：(1)心脏：肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤；(2)肺：支气管癌(鳞状上皮细胞癌、未分化的小细胞癌、未分化的大细胞癌、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨错构瘤、间皮瘤、非小细胞肺癌、小细胞肺癌；(3)胃肠：食道癌(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃癌(癌瘤、淋巴瘤、平滑肌肉瘤)、胰腺癌(导管腺癌、胰岛瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、舒血管肠肽瘤)、小肠癌(腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、纤维神经瘤、纤维瘤)、大肠癌(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤)；(4)生殖泌尿道癌：肾癌(腺癌、维尔姆斯瘤(Wilm′stumor)[肾胚细胞瘤]、淋巴瘤、白血球过多症)、膀胱和尿道癌(鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)、睾丸癌(精原细胞瘤、畸胎瘤、胚胎癌性细胞、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤)；(5)肝癌：肝癌(肝细胞癌)、胆管癌、肝毒细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；(6)骨癌：成骨肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤、脊索瘤、osteochronfroma(骨软骨外生骨疣)、良性软骨瘤、成软骨细胞瘤、软骨粘液样纤维瘤、骨样骨瘤和巨细胞瘤；(7)神经系统：头骨癌(骨癌、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑膜癌(脑膜瘤、脑膜肉瘤、神经胶质瘤病)、脑癌(星形细胞瘤、成神经管细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤[松果体瘤]、多形性成胶质细胞瘤、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤)；(8)妇科癌：子宫癌(子宫内膜癌)、宫颈癌(子宫颈癌、肿瘤前宫颈非典型增生)、卵巢癌(卵巢癌[浆液性囊腺癌、粘液性囊腺癌、未分类癌]、粒层-卵泡膜细胞瘤(granulosa-theca cell tumor)、塞-莱细胞瘤(Sertoli-Leydig cell tumor)、无性细胞瘤、恶性畸胎瘤)、外阴癌(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑素瘤)、阴道癌(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(环胎性横纹肌肉瘤)、输卵管癌(癌)；(9)血液学癌：血液癌(髓细胞性白血病[急性和慢性]、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤[恶性淋巴瘤]；(10)皮肤癌：晚期黑素瘤、恶性黑素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、发育不良痣(moles dysplasticnevi)、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、牛皮癣；(11)肾上腺癌：成神经细胞瘤；(12)乳腺癌：转移性乳腺癌；乳腺癌；(13)结肠癌；(14)口腔癌；(15)毛细胞性白血病；(16)头颈癌；以及(17)其它癌症，包括顽固性转移性疾病；卡波西肉瘤；Bannayan-Zonana综合征；和考登病(Cowden disease)或者Lhermitte-Duclos病，以及其它过度增殖性疾病。
在一个实施方案中，所述癌症为卵巢癌、胰腺癌、乳腺癌、脑癌、肺癌、前列腺癌或者胃癌。在一个实施方案中，所述癌症为卵巢癌、胰腺癌、乳腺癌或者前列腺癌。
在一个实施方案中，所述癌症为间皮瘤、子宫内膜癌、神经胶质瘤、胰腺癌、乳腺癌、肺癌、卵巢癌、前列腺癌、黑素瘤、胃癌、结肠癌、头颈癌。
联合治疗
本发明化合物可与一种或者多种额外药物诸如如下所述的药物联用。第二药物的剂量可基于临床采用的剂量进行适当选择。本发明化合物以及第二药物的比例可根据给药受试者、给药途径、靶标疾病、临床病症、组合以及其它因素进行适当确定。在给药受试者为人类的情况下，例如第二药物按重量计可以每份本发明化合物0.01至100份重量的量进行使用。
药物组合制剂或者给药方案中的第二化合物优选具有与本发明化合物互补的活性，以使得它们不进行相互不良影响。所述药物以针对预期目的有效的量适当存在于组合中。因此，本发明另外的方面提供组合物，其包含本发明化合物与诸如本申请所述的第二药物的组合。
本发明化合物以及额外的药物活性药物可在单一药物组合物中一起给予或者分开给予，且当分开给予时，其可以任何顺序同时或者先后给予。所述先后给予可在时间上是接近的或者在时间上是远离的。可选择本发明化合物以及第二药物的量以及给药的相关时限以实现预期的组合治疗效果。
联合治疗可提供“协同作用(synergy)”及证实是“具有协同作用的(synergistic)”，即当活性成分一起使用时实现的作用大于分别使用这些化合物所得作用的总和。当活性成分(1)在所组合的单位剂量制剂中同时配制及同时给药或递送；(2)以分开制剂的形式交替或平行递送；或(3)通过一些其它方案给药时，可达到协同作用。当在交替治疗中递送时，当化合物例如通过在分开注射器中的不同注射剂来先后给药或递送时，可得到协同作用。通常，在交替治疗期间，将有效剂量的各种活性成分先后(即顺次)给药，而在联合治疗中，将有效剂量的两种或更多种活性成分一起给药。
给药途径
本发明化合物可通过对待治疗病症合适的任意途径来给药。合适的途径包括口服、肠胃外(包括皮下、肌内、静脉内、动脉内、皮内、鞘内和硬膜外)、经皮、直肠、经鼻、局部(包括含服和舌下)、阴道、腹膜内、肺内和鼻内。应该理解的是，优选的途径可随例如受体的情况而变化。当所述化合物口服给药时，可将其与药用载体或赋形剂一起配制成丸剂、胶囊剂、片剂等。当所述化合物肠胃外给药时，如下文详述可将其与药用肠胃外媒介物一起配制且配制成单位剂量可注射形式。
药物制剂
为了使用本发明化合物用于对哺乳动物(包括人类)进行治疗性处置(包括预防性处置)，通常根据标准制药实践将其配制为药物组合物。本发明该方面提供了药物组合物，其包含本发明化合物。在某些实施方案中，所述药物组合物包含式I-VII的化合物以及药用稀释剂或者载体的组合。
本发明药物组合物将按照这样一种方式即与良好医药实践相一致的量、浓度、时间安排、过程、媒介物和给药途径来配制、确定剂量和给药。在此背景下考虑的因素包括所治疗的具体障碍、所治疗的具体哺乳动物、个体患者的临床情况、病因、药剂的递送位点、给药的方法、给药的时间安排和医药实践者已知的其它因素。待给药的所述化合物的治疗有效量将取决于所考虑的这些因素且是预防、改善或治疗障碍所需要的最小量。通常将本发明化合物配制成药物剂型以提供可容易控制的药物剂量且使患者对所开处的方案具有顺从性。
用于本申请的组合物优选是无菌的。具体地，用于体内给药的制剂必须是无菌的。这样的灭菌可容易地通过经过无菌滤膜过滤来实现。本发明化合物通常可按固体组合物、冻干制剂或水溶液剂的形式贮存。
为用于多种给药途径和类型，可制备本发明化合物的药物制剂。例如，具有所期望纯度的本发明化合物可任选与药用稀释剂、载体、赋形剂或稳定剂混合(Remington′s Pharmaceutical Sciences(1980)16th edition,Osol,A.Ed.)，呈冻干制剂、研细粉末剂或含水溶液剂的形式。配制可如下进行：在环境温度在合适的pH及在所期望的纯度与生理学可接受的载体(即在所用剂量和浓度时对接受者是无毒性的载体)混合。所述制剂的pH主要取决于具体的用途和化合物的浓度，但范围可以是约3至约8。在乙酸盐缓冲液中的pH为5的制剂是合适的实施方案。制剂可使用常规溶解和混合操作来制备。例如，将松散的(bulk)药物物质(即本发明化合物或所述化合物的经稳定形式(例如与环糊精衍生物或其它已知复合剂(complexation agent)在一起的复合物))在一种或多种上述赋形剂存在下溶于合适的溶剂中。
所用的具体载体、稀释剂或赋形剂将取决于应用本发明化合物的方式和目的。通常基于本领域技术人员认为给予哺乳动物是安全的溶剂(GRAS)来选择溶剂。通常，安全溶剂为无毒性含水溶剂如水和可在水中溶解或与水混溶的其它无毒性溶剂。合适的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG 400、PEG 300)等及它们的混合物。可接受的稀释剂、载体、赋形剂和稳定剂在所用的剂量和浓度时对接受者是无毒性的且包括缓冲剂，如磷酸盐、枸橼酸盐及其它有机酸；抗氧化剂，包括抗坏血酸和蛋氨酸(methionine)；防腐剂(如十八烷基二甲基苄基氯化铵；氯化六甲双铵(hexamethoniumchloride)；苯扎氯铵、苄索氯铵；苯酚、丁醇或苄醇；尼泊金烷基酯，如尼泊金甲酯或尼泊金丙酯；儿茶酚；间苯二酚(resorcinol)；环己醇；3-戊醇；和间甲酚)；低分子量(少于约10个残基)多肽；蛋白质，如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，如聚乙烯吡咯烷酮；氨基酸，如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸；单糖、二糖及其它碳水化合物，包括葡萄糖、甘露糖或糊精；螯合剂，如EDTA；糖，如蔗糖、甘露醇、海藻糖或山梨醇；形成盐的抗衡离子，如钠；金属复合物(例如Zn-蛋白质复合物)；和/或非离子型表面活性剂，如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。所述制剂还可包含一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、不透明剂(opaquingagent)、助流剂(glidants)、加工助剂(processing aid)、着色剂、增甜剂、芳香剂、矫味剂和提供药物(即本发明化合物或其药物组合物)优质外观或辅助药物产品(即药品)制造的其它已知添加剂。活性药物成分还可包埋在例如通过凝聚技术或通过界面聚合而制备的微囊中，例如在胶体药物递送系统(例如脂质体、白蛋白微球、微乳、纳米粒和纳米囊)中或在宏观乳液(macroemulsion)中分别为羟甲基纤维素或明胶微囊和聚(甲基丙烯酸甲酯)微囊。这样的技术披露在Remington′s Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980)中。"脂质体"为由各种类型的脂质、磷脂和/或者表面活性剂组成的小囊泡，其用于对哺乳动物递送药物(诸如式I-VII的化合物以及任选额外的治疗剂)。脂质体的组分通常排列为双层形式，其类似于生物膜的脂质排列。
可制备本发明化合物的持续释放制剂。持续释放制剂的合适实例包括固态疏水性聚合物的半透性基质，其含有式I-VII的化合物，所述基质以成形制品的形式(例如膜或微囊)存在。持续释放基质的实例包括聚酯、水凝胶(例如聚(甲基丙烯酸2-羟基乙酯)或聚(乙烯醇))、聚丙交酯(美国专利3,773,919)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-羟乙酸共聚物如LUPRON DEPOTTM(由乳酸-羟乙酸共聚物和醋酸亮丙瑞林构成的可注射微球)和聚D-(-)-3-羟基丁酸。
本发明化合物的药物组合物可呈无菌可注射制剂如无菌可注射水性或油性混悬剂的形式。所述混悬剂可根据本领域已知方法使用上文已提及的那些合适的分散剂或润湿剂和助悬剂来配制。无菌可注射制剂还可以是在无毒性的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液剂或混悬剂，如在1,3-丁二醇中的溶液剂，或制备成冻干粉末剂。可使用的可接受媒介物和溶剂包括水、林格溶液(Ringer’s solution)和等渗氯化钠溶液。另外，无菌不挥发油通常可用作溶剂或助悬介质。出于此目的，可使用任意温和的不挥发油，包括合成的甘油一酯或甘油二酯。另外，脂肪酸如油酸同样可用于制备注射剂。
适于肠胃外给药的制剂包括水性和非水性无菌注射溶液剂，其可含有抗氧化剂、缓冲剂、抑菌剂和使得所述制剂与所预期受体的血液等渗的溶质；及水性和非水性无菌混悬剂，其可包括助悬剂和增稠剂。
本发明组合物也可为适于口服使用的剂型(例如片剂、锭剂、硬或者软胶囊、含水或者含油混悬剂、可分散粉末或者颗粒、淤浆或者酏剂)、用于局部使用的剂型(例如乳膏剂、软膏剂、凝胶剂或者含水或者含油溶液剂或者混悬剂)、用于吸入给药的剂型(例如精细分散的粉末或者液体气雾剂)、用于吹入给药的剂型(例如精细分散的粉末)。
用于片剂制剂的适当药用赋形剂包括例如，惰性稀释剂，如乳糖、碳酸钠、磷酸钙或磷酸钠；制粒剂和崩解剂，如玉米淀粉或海藻酸；粘合剂，如淀粉；润滑剂，如硬脂酸镁、硬脂酸或滑石；防腐剂，如对羟基苯甲酸乙酯或者对羟基苯甲酸丙酯，以及抗氧化剂，如抗坏血酸。片剂制剂可为未包衣的或者包衣的以改变它们的崩解以及随后在胃肠道内的活性成分的吸收，或者改善它们的稳定性和/或者外观，在以上情况下，使用常规包衣剂以及本领域熟知的操作。
口服使用的组合物可为硬明胶胶囊的形式，其中将活性成分与惰性固体稀释剂混合，例如，碳酸钙、磷酸钙或者高岭土；所述组合物也可为软明胶胶囊，其中将活性成分与水或者油诸如花生油、液体石蜡或者橄榄油混合。
含水混悬剂通常含有精细分散形式的活性成分以及一种或者多种助悬剂诸如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶；分散剂或润湿剂诸如卵磷脂或者烯化氧与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)或者氧化乙烯与长链脂肪醇的缩合产物(例如十七亚乙氧基十六烷基醇)、氧化乙烯与从脂肪酸和己糖醇衍生的偏酯的缩合产物(例如聚氧乙烯山梨醇单油酸酯)或者氧化乙烯与从脂肪酸和己糖醇酐衍生的偏酯的缩合产物(例如聚乙烯失水山梨醇单油酸酯)。所述含水混悬剂还可含有一种或多种防腐剂(如对羟基苯甲酸乙酯或对羟基苯甲酸丙酯)、抗氧化剂(诸如抗坏血酸)、着色剂、矫味剂和/或者增甜剂(如蔗糖、糖精或阿司帕坦)。
油性混悬剂可通过将活性成分混悬于植物油(诸如花生油、橄榄油、麻油或者椰子油)或者矿物油(诸如液体石蜡)中来配制。所述油性混悬剂也可含有增稠剂诸如蜂蜡、固体石蜡或者鲸蜡醇。可加入如上阐述的甜味剂以及矫味剂以提供适口的口服制剂。这些组合物可通过加入抗氧化剂诸如抗坏血酸来保存。
适于通过加入水来制备含水混悬剂的可分散粉末以及颗粒通常含有活性成分以及分散剂或者润湿剂、助悬剂以及一种或者多种防腐剂。适当的分散剂或者润湿剂以及助悬剂为通过如上已经提及的那些所示例说明的。也可存在额外的赋形剂诸如甜味剂、矫味剂和着色剂。
本发明的药物组合物也可为水包油乳剂的形式。所述油相可为植物油诸如橄榄油或者花生油，或者矿物油例如液体石蜡或者它们任一种的混合物。适当的乳化剂可为例如天然存在的树胶诸如阿拉伯胶或者西黄蓍胶，天然存在的磷脂诸如大豆、卵磷脂，由脂肪酸和己糖醇酐衍生的酯或者偏酯(例如失水山梨醇单油酸酯)以及所述偏酯与氧化乙烯的缩合产物(例如聚氧乙烯失水山梨醇单油酸酯)。所述乳剂也可含有甜味剂、矫味剂和防腐剂。
淤浆和酏剂可使用甜味剂诸如丙三醇、丙二醇、山梨醇、阿司帕坦或者蔗糖来配制，且也可含有缓和剂、防腐剂、矫味剂和/或者着色剂。
栓剂制剂可通过使活性成分与适当的无刺激性赋形剂混合来制备，所述赋形剂在常温为固体但在直肠温度为液体且因此在直肠中熔化以释放药物。适当的赋形剂包括例如可可豆脂和聚乙二醇。适于阴道给药的制剂可作为含有除了活性成分之外的诸如本领域技术人员已知的适当载体的阴道栓剂、棉塞、乳膏剂、凝胶剂、糊剂、泡沫剂或者喷雾制剂而存在。
局部制剂诸如乳膏剂、软膏剂、凝胶剂以及含水或者含油溶液剂或者混悬剂通常可通过如下来获得：使用本领域熟知的常规操作将活性成分用常规、局部应用的媒介物或者稀释剂来配制。
用于经皮给药的组合物可为本领域技术人员已知的透皮贴剂的形式。
适于肺内或者鼻部给药的制剂具有例如0.1至500微米的范围的粒度(包括0.1和500微米范围内的粒度，增量为诸如0.5、1、30微米、35微米等)，其通过鼻道的快速吸入来给药或者通过口部吸入来给药，由此到达肺泡囊。适当制剂包括活性成分的含水或者含油溶液剂。适于气雾剂或者干粉给药的制剂可根据常规方法来制备且可与其它治疗剂诸如迄今为止在治疗或者预防如下所述的病症中使用的化合物来递送。
取决于用于给药药物的方法，应用的药物组合物(或制剂)可用多种方式来包装。例如，用于分配的制品包括容器，所述容器已在其中放置有合适形式的药物制剂。合适的容器是本领域技术人员公知的且包括以下容器：如瓶(塑料瓶和玻璃瓶)、小袋(sachet)、安瓿、塑料袋、金属圆筒(metal cylinders)等。所述容器还可包括防止轻率接触包装内含物的耐损包装(tamper-proofassemblage)。另外，所述容器已在其上设置有描述容器内含物的标签。所述标签还可包括合适的注意事项。所述制剂可包装在单位剂量容器或多剂量容器例如密封的安瓿或小瓶中且可在冷冻干燥(冻干)条件下贮存，仅需要恰在使用前加入无菌液态载体例如注射用水。即用的注射溶液剂和混悬剂从前述种类的无菌粉末剂、颗粒剂和片剂来制备。优选的单位剂量制剂是含有本申请上文所述的日剂量或单位日亚剂量或其合适分数的活性成分的那些制剂。
本发明还提供兽用组合物，因此其含有上文定义的至少一种活性成分及兽用载体。兽用载体是可用于给药所述组合物这一目的物质并可以是固态、液态或气态物质，这些物质在兽医领域中要么是惰性的要么是可接受的且与所述活性成分是相容的。这些兽用组合可通过肠胃外、口服或任意其它期望的途径来给药。
与一种或者多种赋形剂组合以产生单一剂型的本发明化合物的量将必要地取决于待治疗的受试者、障碍或者病症的严重性、给药途径、化合物的处置以及开具处方的医师的判断而变化。在一个实施方案中，对需要的哺乳动物给予适当量的本发明化合物。在一个实施方案中，以约0.001mg/kg体重/天至约60mg/kg体重/天之间的量进行给药。在其它实施方案中，以约0.5mg/kg体重/天至约40mg/kg体重/天之间的量进行给药。在一些情况下，低于前述范围的下限的剂量水平可为完全足够的，而在其它情况下可采用更大剂量而不引起任何有害副作用，条件是首先将所述更大剂量分为用于全天给药的若干小剂量。对于给药途径和给药方案的其它信息，参见Chapter 25.3，Volume 5，Comprehensive Medicinal Chemistry(Corwin Hansch；Chairman ofEditorial Board),Pergamon Press 1990，其通过引用的方式明确并入本申请。
制品
在本发明另外的实施方案中，提供了含有用于治疗如上所述的病症的物质的制品或者"试剂盒"。适当的容器例如瓶、小瓶、注射器、泡罩包装(blisterpack)等。所述容器可由各种物质诸如玻璃或者塑料而形成。
在一个实施方案中，所述试剂盒包括含有本发明化合物的容器。所述容器可容纳本发明化合物或者其制剂，其可有效用于治疗所述病症且可具有无菌接入口(例如，所述容器可为静脉溶液袋或者具有经皮下注射针刺透的塞子的小瓶)。
在其它实施方案中，所述试剂盒包括容器，其包括用于测定FOXO3a在肿瘤细胞中的定位的系统。在一个实例中，所述系统包括抗-FOXO3a抗体。在其它实例中，所述系统包括细胞培养板、细胞培养基以及抗-FOXO3a抗体。
所述试剂盒还可包括插入至容器上或者与容器相连的标签或者包装说明书。使用的术语"包装说明书"是指通常包括在治疗产品的商品包装中的说明书，其包含有关适应症、用法、剂量、给药、禁忌症和/或者有关使用所述治疗产品的警告的信息。在一个实施方案中，可使用表明所述组合物包含本发明化合物的标签或者包装说明书以治疗由例如AKT激酶介导的病症。所述标签或者包装说明书也可表明所述组合物可用于治疗其它病症。
在某些实施方案中，所述试剂盒适于递送本发明化合物的固体口服形式，诸如片剂或者胶囊剂。所述试剂盒优选包括众多单位剂量。所述试剂盒可以包括针对预期用途为目的的剂量卡片。这样的试剂盒的一个实例是“泡罩包装”。泡罩包装在包装工业中是公知的，并且广泛用于包装药物单位剂型。如果期望的话，可提供记忆辅助装置(memory aid)，其可呈例如数字、字母或者其它标记形式，或者具有日历插入物，所述记忆辅助装置指定在可对所述剂量进行给药的治疗时间表中的天数。
根据另外的实施方案，试剂盒可包含(a)在其中含有本发明化合物的第一个容器；以及(b)在其中含有第二种药物制剂的第二个容器，其中所述第二种药物制剂包含用于治疗由AKT激酶介导的病症的第二种化合物。可选择地或者另外地，所述试剂盒还可包含第三个容器，其包含药用缓冲液，如抑菌性注射用水(BWFI)、磷酸盐缓冲生理盐水、林格氏溶液和葡萄糖溶液。其还可包括从商用和使用者角度来看是期望的其它物质，包括其它缓冲液、稀释剂、滤器、针头和注射器。
试剂盒还可包含给药本发明化合物以及第二种药物制剂(如果存在)的说明。例如，若试剂盒包含本发明组合物和第二种药物制剂，则试剂盒还可包含将第一种和第二种药物组合物同时、先后或者分开给予需要所述制剂的患者的说明。
在试剂盒包含本发明化合物和第二种治疗药物的组合物的某些其它实施方案中，所述试剂盒可包含用于容纳分开的组合物的容器，如分开的瓶或者分开的箔包装(foil packet)，然而，分开的组合物还可容纳在单一的未分开的容器中。在某些实施方案中，试剂盒包含给药分开的组分的说明。当分开的组分优选以不同剂型(例如口服和肠胃外)给药时，当以不同剂量间隔给药时，或者当对联用的单独组分进行滴定对主治医师是期望之时，试剂盒形式是特别有益的。
因此，本发明另外的方面提供用于治疗由AKT激酶介导的病症或者疾病的试剂盒，其中所述试剂盒包括a)包含本发明化合物或者其药用盐的第一药物组合物；以及b)使用说明。
在某些实施方案中，所述试剂盒还包括(c)第二药物组合物，其中所述第二药物组合物包含适于治疗由AKT激酶介导的病症或者疾病的第二化合物。在包括第二药物组合物的某些实施方案中，所述试剂盒还包括将第一种和第二种药物组合物同时、先后或者分开给予需要所述制剂的患者的说明。在某些实施方案中，所述第一和第二药物组合物包含于分开容器中。在其它实施方案中，所述第一和第二药物组合物包含于相同容器中。
尽管式I的化合物主要用于在哺乳动物中使用的治疗剂，但是它们在需要调控AKT蛋白激酶、酪氨酸激酶、其他丝氨酸/苏氨酸激酶和/或者双重特异性激酶时也是有用的。因此，它们用作用于开发新生物学测试以及研究新药理学试剂的药理学标准物。
另外方面包括预测肿瘤细胞生长对由PI3K/AKT激酶途径抑制剂产生的抑制的敏感性的方法，包括：确定(i)FOXO3a在细胞中的定位分布，以及(ii)HER2是否在细胞中扩增，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关。在另外的方面，所述肿瘤为乳腺癌。
实施例
FOXO3a免疫荧光染色操作
在96孔板中将组织培养细胞接种于含有10%(完全)血清的培养基中。24小时后，对细胞给予1μM指定药物达6小时，此时在37°C将细胞直接在4%甲醛于不含蛋白的磷酸盐缓冲盐水(PBS)中的溶液中固定20分钟。洗涤板，然后通过10分钟孵育将细胞在冰冷的甲醇中进行透化处理(permeabilize)。洗涤板以除去甲醇并与抗-FOXO3a抗体(Cell SignalingTechnology,分类号2497,克隆75D8)以及Hoechst细胞核染料(1:10,000稀释)在初级抗体的1:20稀释的抗体稀释缓冲剂(1%BSA,0.3%Triton X-100在PBS中的溶液)中进行孵育。将细胞在4°C孵育过夜。洗涤板以除去初级抗体，然后在环境温度避光与第二抗体(与Alexa-flour 488染料(Invitrogen)结合的山羊抗-兔抗体)孵育1小时。将板用PBS洗涤，用黑色板密封器进行密封并在Cellomics HCS ArrayScan图像仪上使用Cytoplasm-to-Nucleustranslocation bioapplication(Thermo Scientific)进行分析。
Claims (20)
1.预测肿瘤细胞生长对由PI3K/AKT激酶途径抑制剂产生的抑制的敏感性的方法，包括：确定FOXO3a在肿瘤中的定位分布，其中FOXO3a的细胞质定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的敏感性相关。
2.权利要求1的方法，其中FOXO3a的细胞核定位分布与对由PI3K/AKT激酶抑制剂产生的抑制的抗性相关。
3.权利要求1-2的方法，还包括预测所述肿瘤细胞生长对由PI3K/AKT激酶途径抑制剂产生的抑制的敏感性。
4.权利要求1-3的方法，还包括提供所述肿瘤细胞的样品。
5.权利要求1-4的方法，还包括确定所述肿瘤细胞是否是PTEN缺失的、具有高pAKT分布或者具有PI3k突变。
6.权利要求5的方法，其中在确定所述肿瘤细胞是否是PTEN缺失的、具有高pAKT分布或者具有PI3k突变之后，确定所述定位分布。
7.权利要求6的方法，其中所述定位分布在PTEN缺失的、高pAKT分布或者PI3k突变的肿瘤细胞中确定。
8.权利要求7的方法，其中FOXO3a在PTEN缺失的、高pAKT分布或者PI3k突变的细胞中的细胞质定位分布与对由PI3K/AKT抑制剂产生的抑制的敏感性相关。
9.权利要求7的方法，其中FOXO3a在PTEN缺失的、高pAKT分布或者PI3k突变的细胞中的细胞核定位分布与对由PI3K/AKT抑制剂产生的抑制的抗性相关。
10.权利要求5的方法，包括确定所述肿瘤细胞是否是PTEN缺失的。
11.权利要求5的方法，包括所述肿瘤细胞是否具有高pAKT分布。
12.权利要求5的方法，包括确定所述肿瘤细胞是否具有PI3k突变。
13.权利要求1-12的方法，其中所述PI3K/AKT抑制剂为2-(1H-吲唑-4-基)-6-(4-甲磺酰基-哌嗪-1-基甲基)-4-吗啉-4-基-噻吩并[3,2-d]嘧啶。
14.权利要求1-12的方法，其中所述PI3K/AKT抑制剂为AKT抑制剂。
15.权利要求1-12和14的方法，其中所述AKT抑制剂为式I的化合物或其互变异构体、拆分的对映异构体、拆分的非对映异构体以及盐：
其中
R1为H、Me、Et和CF3；
R2为H或者Me；R5为H或者Me；
A为：
其中G为任选被一至四个R9基团取代的苯基或者任选被卤素取代的5-6元杂芳基；
R6和R7独立为H、OCH3、(C3-C6环烷基)-(CH2)、(C3-C6环烷基)-(CH2CH2)、其中V为5-6元杂芳基的V-(CH2)0-1、其中W为任选取代有F、Cl、Br、I、OMe、CF3或者Me的苯基的W-(CH2)1-2、任选取代有C1-C3烷基或者O(C1-C3烷基)的C3-C6-环烷基、羟基-(C3-C6-环烷基)、氟-(C3-C6-环烷基)、CH(CH3)CH(OH)苯基、任选取代有F、OH、C1-C3烷基、环丙基甲基或者C(=O)(C1-C3烷基)的4-6元杂环基，或者任选取代有一个或者多个独立选自下述的基团的C1-C6-烷基：OH、氧代、O(C1-C6-烷基)、CN、F、NH2、NH(C1-C6-烷基)、N(C1-C6-烷基)2、环丙基、苯基、咪唑基、哌啶基、吡咯烷基、吗啉基、四氢呋喃基、氧杂环丁烷基或者四氢吡喃基，或者R6和R7与它们连接的氮一起形成任选取代有一个或者多个独立选自下述的基团的4-7元杂环：OH、卤素、氧代、CF3、CH2CF3、CH2CH2OH、O(C1-C3烷基)、C(=O)CH3、NH2、NHMe、N(Me)2、S(O)2CH3、环丙基甲基和C1-C3烷基；
Ra和Rb为H，或者Ra为H，且Rb和R6与它们连接的原子一起形成具有一个或者两个环氮原子的5-6元杂环；
Rc和Rd为H或者Me，或者Rc和Rd与它们连接的原子一起形成环丙基环；
R8为H、Me、F或者OH，或者R8和R6与它们连接的原子一起形成具有一个或者两个环氮原子的5-6元杂环；
每个R9独立为卤素、C1-C6-烷基、C3-C6-环烷基、O-(C1-C6-烷基)、CF3、OCF3、S(C1-C6-烷基)、CN、OCH2-苯基、CH2O-苯基、NH2、NH-(C1-C6-烷基)、N-(C1-C6-烷基)2、哌啶基、吡咯烷基、CH2F、CHF2、OCH2F、OCHF2、OH、SO2(C1-C6-烷基)、C(O)NH2、C(O)NH(C1-C6-烷基)和C(O)N(C1-C6-烷基)2；
R10为H或者Me；且
m、n和p独立为0或者1。
16.权利要求1-12和14-15中任一项的方法，其中所述AKT抑制剂为(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙-1-酮或者其盐。
17.权利要求1-16的方法，其中FOXO3a在肿瘤细胞中的定位分布由免疫组织化学(IHC)测定来确定。
18.治疗患者中肿瘤的方法，包括对所述患者给予治疗有效量的式I的化合物或者其立体异构体或者盐，其中所述治疗基于具有细胞质FOXO3a定位分布的患者肿瘤。
19.治疗患者中肿瘤的方法，包括对所述患者给予治疗有效量的式I的化合物或者其立体异构体或者盐，其中FOXO3a在肿瘤中的定位分布基本上为细胞质中的。
20.治疗患者中肿瘤的方法，包括选择具有细胞质定位分布的肿瘤的患者以及对所述患者给予治疗有效量的式I的化合物或者其立体异构体或者盐。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US32519010P | 2010-04-16 | 2010-04-16 | |
| US61/325,190 | 2010-04-16 | ||
| PCT/US2011/032721 WO2011130654A1 (en) | 2010-04-16 | 2011-04-15 | Fox03a as predictive biomarker for pi3k/akt kinase pathway inhibitor efficacy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103038643A true CN103038643A (zh) | 2013-04-10 |
Family
ID=43929155
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800297239A Pending CN103038643A (zh) | 2010-04-16 | 2011-04-15 | 作为pi3k/akt激酶途径抑制剂效能的预测性生物标记的foxo3a |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US20130059859A1 (zh) |
| EP (1) | EP2558864A1 (zh) |
| JP (1) | JP2013528787A (zh) |
| KR (1) | KR20130058672A (zh) |
| CN (1) | CN103038643A (zh) |
| BR (1) | BR112012026470A2 (zh) |
| CA (1) | CA2793892A1 (zh) |
| MX (1) | MX2012011887A (zh) |
| RU (1) | RU2012148699A (zh) |
| WO (1) | WO2011130654A1 (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105492630A (zh) * | 2014-01-03 | 2016-04-13 | 皇家飞利浦有限公司 | 使用靶基因表达的数学建模评价pi3k细胞信号传导途径活性 |
| CN106715719A (zh) * | 2014-07-21 | 2017-05-24 | 诺威尔卢斯德克有限公司 | 用于确定患者特定突变的药物反应的方法 |
| CN107076727A (zh) * | 2014-07-21 | 2017-08-18 | 诺威尔卢斯德克有限公司 | 用于确定患者特定突变的致癌指数的方法和系统 |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH12012501361A1 (en) | 2009-12-31 | 2012-10-22 | Centro Nac De Investigaciones Oncologicas Cnio | Tricyclic compounds for use as kinase inhibitors |
| WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
| WO2013173811A1 (en) * | 2012-05-17 | 2013-11-21 | Genentech, Inc. | Amorphous form of an akt inhibiting pyrimidinyl - cyclopentane compound, compositions and methods thereof |
| PL3656764T3 (pl) * | 2013-11-15 | 2024-01-22 | F. Hoffmann-La Roche Ag | Sposoby przygotowania związków pirymidynylocyklopentanu |
| ES2838923T3 (es) * | 2014-10-24 | 2021-07-02 | Koninklijke Philips Nv | Pronóstico médico y predicción de la respuesta a tratamiento usando múltiples actividades de la ruta de señalización celular |
| WO2017065277A1 (ja) * | 2015-10-14 | 2017-04-20 | 日東紡績株式会社 | ２種のプロテインキナーゼの活性測定を用いる解析方法による、薬剤感受性ヒト細胞株の判定方法 |
| TW201825465A (zh) | 2016-09-23 | 2018-07-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| TW201813963A (zh) | 2016-09-23 | 2018-04-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
| TW201815787A (zh) | 2016-09-23 | 2018-05-01 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117889A1 (en) * | 2004-05-25 | 2005-12-15 | Icos Corporation | Methods for treating and/or preventing aberrant proliferation of hematopoietic |
| CN1934072A (zh) * | 2004-01-30 | 2007-03-21 | 派普林生物脂股份有限公司 | 治疗和载体分子 |
Family Cites Families (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1470356A1 (de) | 1964-01-15 | 1970-04-30 | Thomae Gmbh Dr K | Neue Thieno[3,2-d]pyrimidine und Verfahren zu ihrer Herstellung |
| US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
| BE759493A (fr) | 1969-11-26 | 1971-05-25 | Thomae Gmbh Dr K | Nouvelles 2-(5-nitro-2-furyl)-thieno(3,2-d) pyrimidines et procedes pour les fabriquer |
| US3763156A (en) | 1970-01-28 | 1973-10-02 | Boehringer Sohn Ingelheim | 2-heterocyclic amino-4-morpholinothieno(3,2-d)pyrimidines |
| RO62428A (fr) | 1971-05-04 | 1978-01-15 | Thomae Gmbh Dr K | Procede pour la preparation des thyeno-(3,2-d)-pyrimidines |
| CU22545A1 (es) | 1994-11-18 | 1999-03-31 | Centro Inmunologia Molecular | Obtención de un anticuerpo quimérico y humanizado contra el receptor del factor de crecimiento epidérmico para uso diagnóstico y terapéutico |
| US4943533A (en) | 1984-03-01 | 1990-07-24 | The Regents Of The University Of California | Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor |
| AU639726B2 (en) | 1989-09-08 | 1993-08-05 | Duke University | Structural alterations of the egf receptor gene in human gliomas |
| US5075305A (en) | 1991-03-18 | 1991-12-24 | Warner-Lambert Company | Compound, composition and use |
| WO1993013664A2 (en) | 1992-01-11 | 1993-07-22 | Schering Agrochemicals Limited | Biheterocyclic fungicidal compounds |
| GB9300059D0 (en) | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
| GB9314893D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
| EP0659439B1 (en) | 1993-12-24 | 2001-10-24 | MERCK PATENT GmbH | Immunoconjugates |
| IL112248A0 (en) | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
| US5654307A (en) | 1994-01-25 | 1997-08-05 | Warner-Lambert Company | Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
| BR9508409A (pt) | 1994-07-21 | 1997-12-23 | Akzo Nobel Nv | Composição de peróxido transportável estável em armazenagem e uso de uma formulação de peróxido orgânico |
| US5804396A (en) | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
| JP3088018B2 (ja) | 1995-03-30 | 2000-09-18 | ファイザー・インコーポレーテッド | キナゾリン誘導体 |
| GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
| GB9508565D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
| US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
| CA2222231A1 (en) | 1995-06-07 | 1996-12-19 | Imclone Systems Incorporated | Antibody and antibody fragments for inhibiting the growth of tumors |
| EA001428B1 (ru) | 1995-07-06 | 2001-02-26 | Новартис Аг | Пирролопиримидины и фармацевтические композиции, включающие эти соединения |
| US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
| GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
| CN1145614C (zh) | 1996-04-12 | 2004-04-14 | 沃尼尔·朗伯公司 | 酪氨酸激酶的不可逆抑制剂，其制药用途及药物组合物 |
| ES2186908T3 (es) | 1996-07-13 | 2003-05-16 | Glaxo Group Ltd | Compuestos heterociciclos condensados como inhibidores de pproteina-tirosina-quinasas. |
| ID18494A (id) | 1996-10-02 | 1998-04-16 | Novartis Ag | Turunan pirazola leburan dan proses pembuatannya |
| UA73073C2 (uk) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція |
| US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
| US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
| DK0980244T3 (da) | 1997-05-06 | 2003-09-29 | Wyeth Corp | Anvendelse af quinazoline forbindelser til behandling af polycystisk nyresygdom |
| ZA986732B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
| ZA986729B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
| TW436485B (en) | 1997-08-01 | 2001-05-28 | American Cyanamid Co | Substituted quinazoline derivatives |
| AUPO903897A0 (en) | 1997-09-08 | 1997-10-02 | Commonwealth Scientific And Industrial Research Organisation | Organic boronic acid derivatives |
| AU1308799A (en) | 1997-11-06 | 1999-05-31 | American Cyanamid Company | Use of quinazoline derivatives as tyrosine kinase inhibitors for treating colonic polyps |
| SK6652000A3 (en) | 1997-11-11 | 2002-05-09 | Pfizer Prod Inc | Thienopyrimidine and thienopyridine derivatives useful as anticancer agents |
| US6187777B1 (en) | 1998-02-06 | 2001-02-13 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
| US6232320B1 (en) | 1998-06-04 | 2001-05-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory compounds |
| IL143089A0 (en) | 1998-11-19 | 2002-04-21 | Warner Lambert Co | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases |
| US6608053B2 (en) | 2000-04-27 | 2003-08-19 | Yamanouchi Pharmaceutical Co., Ltd. | Fused heteroaryl derivatives |
| EP1689719A1 (en) * | 2003-11-25 | 2006-08-16 | Eli Lilly And Company | 7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (proteinkinase b) |
| MX2007003341A (es) * | 2004-09-21 | 2007-09-07 | Velacor Therapeutics Pty Ltd | Selenio inorganico para el tratamiento de cancer. |
| GB0423653D0 (en) | 2004-10-25 | 2004-11-24 | Piramed Ltd | Pharmaceutical compounds |
| JP2007116926A (ja) * | 2005-10-25 | 2007-05-17 | Reprocell Inc | 体外における幹細胞の維持と純化に関する方法、組成物およびシステム |
| US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
| KR20150041164A (ko) * | 2006-07-06 | 2015-04-15 | 어레이 바이오파마 인크. | Ａｋｔ 단백질 키나제 억제제로서의 시클로펜타〔ｄ〕피리미딘 |
| JP2008045976A (ja) * | 2006-08-14 | 2008-02-28 | Japan Found Cancer Res | Ｐｉ３キナーゼ阻害剤に対する感受性予測方法 |
| EP2118102B1 (en) * | 2006-11-28 | 2013-06-12 | Nerviano Medical Sciences S.r.l. | Tricyclic indoles and (4,5-dihydro) indoles |
| CN103396409B (zh) | 2007-07-05 | 2015-03-11 | 阵列生物制药公司 | 作为akt蛋白激酶抑制剂的嘧啶基环戊烷 |
| AU2008298948B2 (en) * | 2007-09-12 | 2014-09-04 | F. Hoffmann-La Roche Ag | Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use |
-
2011
- 2011-04-15 EP EP11716153A patent/EP2558864A1/en not_active Withdrawn
- 2011-04-15 RU RU2012148699/15A patent/RU2012148699A/ru not_active Application Discontinuation
- 2011-04-15 JP JP2013505185A patent/JP2013528787A/ja active Pending
- 2011-04-15 CN CN2011800297239A patent/CN103038643A/zh active Pending
- 2011-04-15 WO PCT/US2011/032721 patent/WO2011130654A1/en active Application Filing
- 2011-04-15 CA CA2793892A patent/CA2793892A1/en not_active Abandoned
- 2011-04-15 BR BR112012026470A patent/BR112012026470A2/pt not_active IP Right Cessation
- 2011-04-15 MX MX2012011887A patent/MX2012011887A/es not_active Application Discontinuation
- 2011-04-15 KR KR1020127026819A patent/KR20130058672A/ko not_active Withdrawn
-
2012
- 2012-10-16 US US13/653,292 patent/US20130059859A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1934072A (zh) * | 2004-01-30 | 2007-03-21 | 派普林生物脂股份有限公司 | 治疗和载体分子 |
| WO2005117889A1 (en) * | 2004-05-25 | 2005-12-15 | Icos Corporation | Methods for treating and/or preventing aberrant proliferation of hematopoietic |
Non-Patent Citations (2)
| Title |
|---|
| CHAPUIS NICOLAS ET AL: "1 kappa B Kinase Overcomes PI3K to Control FoxO3a Subcellular Localization in Acute Myeloid Leukemia", 《ANNUAL MEETING OF THE AMERICAN-SOCIETY-OFHEMATOLOGY》 * |
| LLNK WOLFGANG ET AL: ""Chemicallnterrogation of FOX03a Nuclear Translocation Identifies Potent and Selective Inhibitors of Phosphoinositide 3-Kinases", 《JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY FOR BIOCHEMISTRY ANO MOLECULAR BIOLOGY》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105492630A (zh) * | 2014-01-03 | 2016-04-13 | 皇家飞利浦有限公司 | 使用靶基因表达的数学建模评价pi3k细胞信号传导途径活性 |
| CN112795650A (zh) * | 2014-01-03 | 2021-05-14 | 皇家飞利浦有限公司 | 使用靶基因表达的数学建模评价pi3k细胞信号传导途径活性 |
| CN106715719A (zh) * | 2014-07-21 | 2017-05-24 | 诺威尔卢斯德克有限公司 | 用于确定患者特定突变的药物反应的方法 |
| CN107076727A (zh) * | 2014-07-21 | 2017-08-18 | 诺威尔卢斯德克有限公司 | 用于确定患者特定突变的致癌指数的方法和系统 |
| CN107076727B (zh) * | 2014-07-21 | 2019-11-01 | 诺威尔卢斯德克有限公司 | 用于确定患者特定突变的致癌指数的方法和系统 |
| US11015229B2 (en) | 2014-07-21 | 2021-05-25 | Novellusdx Ltd. | Methods and systems for determining oncogenic index of patient specific mutations |
| CN106715719B (zh) * | 2014-07-21 | 2022-08-02 | 福尔生物治疗有限公司 | 用于确定患者特定突变的药物反应的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20130058672A (ko) | 2013-06-04 |
| WO2011130654A1 (en) | 2011-10-20 |
| EP2558864A1 (en) | 2013-02-20 |
| RU2012148699A (ru) | 2014-05-27 |
| MX2012011887A (es) | 2012-11-30 |
| JP2013528787A (ja) | 2013-07-11 |
| US20130059859A1 (en) | 2013-03-07 |
| CA2793892A1 (en) | 2011-10-20 |
| BR112012026470A2 (pt) | 2016-08-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103038643A (zh) | 作为pi3k/akt激酶途径抑制剂效能的预测性生物标记的foxo3a | |
| Manupati et al. | Inhibiting epidermal growth factor receptor signalling potentiates mesenchymal–epithelial transition of breast cancer stem cells and their responsiveness to anticancer drugs | |
| Tryfonopoulos et al. | Src: a potential target for the treatment of triple-negative breast cancer | |
| RU2710735C2 (ru) | Композиции и способы лечения и диагностики резистентного к химиотерапии рака | |
| Koppikar et al. | Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma | |
| AU2022200059B2 (en) | Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists | |
| Li et al. | The expression of CXCR4, CXCL12 and CXCR7 in malignant pleural mesothelioma | |
| CN103889976A (zh) | 吲唑化合物、组合物及使用方法 | |
| UA127507C2 (uk) | Селективні супресори рецепторів естрогенів | |
| EP3193866A1 (en) | Use of cbp/ep300 and bet inhibitors for treatment of cancer | |
| Miao et al. | Y-box-binding protein-1 (YB-1) promotes cell proliferation, adhesion and drug resistance in diffuse large B-cell lymphoma | |
| He et al. | Knockdown of TRIM66 inhibits cell proliferation, migration and invasion in colorectal cancer through JAK2/STAT3 pathway | |
| CN109069506A (zh) | 用于治疗癌症的方法中的共济失调-毛细血管扩张突变的和Rad3-相关的蛋白激酶(ATR)抑制剂 | |
| AU2021204704B2 (en) | Process for the preparation of tricyclic PI3K inhibitor compounds and methods for using the same for the treatment of cancer | |
| CN111936857B (zh) | 预测对疗法的反应的试剂和方法 | |
| TW201803870A (zh) | 化學化合物 | |
| EP3469099A1 (en) | Diagnostic and therapeutic methods for cancer | |
| AU2017205478A1 (en) | A method of modulating survival and stemness of cancer stem cells by MDA-9/Syntenin (SDCBP) | |
| Dai et al. | HMQ‐T‐B10 induces human liver cell apoptosis by competitively targeting EphrinB2 and regulating its pathway | |
| WO2020132046A1 (en) | Methods of treating cancer comprising administration of a glucocorticoid receptor modulator and a cancer chemotherapy agent | |
| Xi et al. | Casein kinase 2 interacting Protein‐1 suppresses glioma cell proliferation via regulating the AKT/GSK3β/β‐catenin pathway | |
| Villaamil et al. | Searching for Hif1-α interacting proteins in renal cell carcinoma | |
| Satriyo et al. | A Potent EGFR Inhibitor, N-Phenyl Pyrazoline Derivative Suppresses Aggressiveness and Cancer Stem Cell-Like Phenotype of Cervical Cancer Cells | |
| CN103893182A (zh) | 一类set蛋白小分子抑制剂及其用途 | |
| HK1183940A (zh) | 作為pi3k/akt激酶途徑抑制劑效能的預測性生物標記的foxo3a |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1183940 Country of ref document: HK |
|
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20160831 |
|
| C20 | Patent right or utility model deemed to be abandoned or is abandoned | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1183940 Country of ref document: HK |