CA2778291C - Akt inhibitors - Google Patents
Akt inhibitors Download PDFInfo
- Publication number
- CA2778291C CA2778291C CA2778291A CA2778291A CA2778291C CA 2778291 C CA2778291 C CA 2778291C CA 2778291 A CA2778291 A CA 2778291A CA 2778291 A CA2778291 A CA 2778291A CA 2778291 C CA2778291 C CA 2778291C
- Authority
- CA
- Canada
- Prior art keywords
- imidazol
- ethyl
- tert
- butyl
- piperidine
- 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.)
- Expired - Fee Related
Links
- 239000003197 protein kinase B inhibitor Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 364
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 95
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 85
- -1 tetrahydropyran-4-yl Chemical group 0.000 claims description 59
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 47
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 13
- 208000005017 glioblastoma Diseases 0.000 claims description 13
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 11
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 11
- 201000005202 lung cancer Diseases 0.000 claims description 11
- 208000020816 lung neoplasm Diseases 0.000 claims description 11
- 229940124597 therapeutic agent Drugs 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- GCEGIRJJGSNKCZ-QGZVFWFLSA-N (5r)-4-[4-[4-ethyl-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidin-1-yl]-5-methyl-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1CN(C=2C=3[C@H](C)CC(=O)NC=3N=CN=2)CCC1C1=NC(CC)=CN1CCN1CCCC1 GCEGIRJJGSNKCZ-QGZVFWFLSA-N 0.000 claims 1
- QRULDXBXPXGMQS-QGZVFWFLSA-N (5r)-5-methyl-4-[4-[1-(2-pyrrolidin-1-ylethyl)-4-(3,3,3-trifluoropropyl)imidazol-2-yl]piperidin-1-yl]-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C([C@H](C=12)C)C(=O)NC2=NC=NC=1N(CC1)CCC1C1=NC(CCC(F)(F)F)=CN1CCN1CCCC1 QRULDXBXPXGMQS-QGZVFWFLSA-N 0.000 claims 1
- WABHLXQVOYVYTI-UHFFFAOYSA-N 5-methyl-4-[4-[1-(2-pyrrolidin-1-ylethyl)-4-(trifluoromethyl)imidazol-2-yl]piperidin-1-yl]-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C=12C(C)CC(=O)NC2=NC=NC=1N(CC1)CCC1C1=NC(C(F)(F)F)=CN1CCN1CCCC1 WABHLXQVOYVYTI-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 281
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 231
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 210
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 121
- 239000012141 concentrate Substances 0.000 description 115
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 109
- 238000003756 stirring Methods 0.000 description 105
- 239000000203 mixture Substances 0.000 description 90
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 84
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 83
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 82
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 81
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 77
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 73
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 59
- 239000000243 solution Substances 0.000 description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- 239000007787 solid Substances 0.000 description 52
- 229920006395 saturated elastomer Polymers 0.000 description 51
- 229910052757 nitrogen Inorganic materials 0.000 description 50
- 239000000284 extract Substances 0.000 description 48
- 238000002360 preparation method Methods 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 44
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 239000010410 layer Substances 0.000 description 36
- 239000011780 sodium chloride Substances 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 239000002904 solvent Substances 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 28
- 238000010898 silica gel chromatography Methods 0.000 description 27
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- 239000000725 suspension Substances 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 21
- 206010028980 Neoplasm Diseases 0.000 description 21
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 21
- 230000005764 inhibitory process Effects 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 20
- 238000010626 work up procedure Methods 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 108091008611 Protein Kinase B Proteins 0.000 description 18
- 239000000908 ammonium hydroxide Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 16
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- 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 14
- 229960001433 erlotinib Drugs 0.000 description 14
- AWISGSJZNFRYNE-UHFFFAOYSA-N ethanol;dihydrochloride Chemical compound Cl.Cl.CCO AWISGSJZNFRYNE-UHFFFAOYSA-N 0.000 description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 12
- 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 12
- 229960005277 gemcitabine Drugs 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 11
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000002002 slurry Substances 0.000 description 10
- UTUVUXYKFFKIKP-UHFFFAOYSA-N tert-butyl 4-(1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC=CN1 UTUVUXYKFFKIKP-UHFFFAOYSA-N 0.000 description 10
- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- FSNGFFWICFYWQC-UHFFFAOYSA-N 1-(2-chloroethyl)pyrrolidine;hydron;chloride Chemical compound Cl.ClCCN1CCCC1 FSNGFFWICFYWQC-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 8
- 229960004316 cisplatin Drugs 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 230000002829 reductive effect Effects 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 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 8
- 229960002930 sirolimus Drugs 0.000 description 8
- JYUKMAIZDJIQSG-UHFFFAOYSA-N tert-butyl 4-(4,5-diiodo-1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(I)=C(I)N1 JYUKMAIZDJIQSG-UHFFFAOYSA-N 0.000 description 8
- 239000007983 Tris buffer Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 6
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- HGBDGFXWZDTFEB-SCSAIBSYSA-N (5r)-4-chloro-5-methyl-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(Cl)=C2[C@H](C)CC(=O)NC2=N1 HGBDGFXWZDTFEB-SCSAIBSYSA-N 0.000 description 5
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 5
- KGEDUCGWJNIMDD-UHFFFAOYSA-N 5,5,5-trifluoro-2-oxopentanal Chemical compound FC(F)(F)CCC(=O)C=O KGEDUCGWJNIMDD-UHFFFAOYSA-N 0.000 description 5
- SQKDYZDLBBSUKS-UHFFFAOYSA-N 5,5,5-trifluoropentanal Chemical compound FC(F)(F)CCCC=O SQKDYZDLBBSUKS-UHFFFAOYSA-N 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 239000005695 Ammonium acetate Substances 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229930012538 Paclitaxel Natural products 0.000 description 5
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 5
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 235000019257 ammonium acetate Nutrition 0.000 description 5
- 229940043376 ammonium acetate Drugs 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000003821 enantio-separation Methods 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- XLADYKVTZFVWDT-UHFFFAOYSA-N methyl 3-(4-hydroxy-6-oxo-1h-pyrimidin-5-yl)butanoate Chemical compound COC(=O)CC(C)C1=C(O)N=CN=C1O XLADYKVTZFVWDT-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 235000009518 sodium iodide Nutrition 0.000 description 5
- 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 5
- RSEBTIYPIHACQL-GSVOUGTGSA-N (5r)-4-chloro-5-(trifluoromethyl)-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(Cl)=C2[C@H](C(F)(F)F)CC(=O)NC2=N1 RSEBTIYPIHACQL-GSVOUGTGSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- GCUOLJOTJRUDIZ-UHFFFAOYSA-N 2-(2-bromoethoxy)oxane Chemical compound BrCCOC1CCCCO1 GCUOLJOTJRUDIZ-UHFFFAOYSA-N 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 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 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 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 4
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000003016 alphascreen Methods 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 4
- 229960003668 docetaxel Drugs 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 239000012035 limiting reagent Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- BKTSPYPORGPMQE-UHFFFAOYSA-N methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate Chemical compound COC(=O)CC(C)C1=C(Cl)N=CN=C1Cl BKTSPYPORGPMQE-UHFFFAOYSA-N 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 4
- 229960005079 pemetrexed Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- JDSMVUPKXPLSFO-UHFFFAOYSA-N tert-butyl 4-[4-bromo-1-(2-hydroxyethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(Br)=CN1CCO JDSMVUPKXPLSFO-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- YWTOGDMFHVXJNA-UHFFFAOYSA-N 2,2-dibromo-1-(oxan-4-yl)ethanone Chemical compound BrC(Br)C(=O)C1CCOCC1 YWTOGDMFHVXJNA-UHFFFAOYSA-N 0.000 description 3
- FITHKHKKDWTBOK-UHFFFAOYSA-N 4-prop-2-enoxybut-1-yne Chemical compound C=CCOCCC#C FITHKHKKDWTBOK-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 229910016523 CuKa Inorganic materials 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 206010027406 Mesothelioma Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- 239000004133 Sodium thiosulphate Substances 0.000 description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 3
- 235000019797 dipotassium phosphate Nutrition 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 208000010749 gastric carcinoma Diseases 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 3
- 201000010982 kidney cancer Diseases 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- CNCMVGXVKBJYNU-UHFFFAOYSA-N methyl oxane-4-carboxylate Chemical compound COC(=O)C1CCOCC1 CNCMVGXVKBJYNU-UHFFFAOYSA-N 0.000 description 3
- NDNVSJIXYFNRDR-UHFFFAOYSA-N n-methyl-n-(methylideneamino)methanamine Chemical compound CN(C)N=C NDNVSJIXYFNRDR-UHFFFAOYSA-N 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 201000000498 stomach carcinoma Diseases 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- NZJULHWMXWORMB-UHFFFAOYSA-N tert-butyl 4-[4-(oxan-4-yl)-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C2CCOCC2)=CN1CCN1CCCC1 NZJULHWMXWORMB-UHFFFAOYSA-N 0.000 description 3
- HTCKTMUPXPTSTF-UHFFFAOYSA-N tert-butyl 4-[4-bromo-1-(2-methylsulfonyloxyethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(Br)=CN1CCOS(C)(=O)=O HTCKTMUPXPTSTF-UHFFFAOYSA-N 0.000 description 3
- LXLZQDZNMVDJPW-UHFFFAOYSA-N tert-butyl 4-[4-bromo-1-[2-(oxan-2-yloxy)ethyl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(Br)=CN1CCOC1OCCCC1 LXLZQDZNMVDJPW-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 2
- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 2
- WXMQWLKCVVKWSD-YCRREMRBSA-N (3e)-3-(dimethylhydrazinylidene)-1,1,1-trifluoropropan-2-one Chemical compound CN(C)\N=C\C(=O)C(F)(F)F WXMQWLKCVVKWSD-YCRREMRBSA-N 0.000 description 2
- GCZGQVRHZLOCDD-UHFFFAOYSA-N 1-methylcyclobutane-1-carboxylic acid Chemical compound OC(=O)C1(C)CCC1 GCZGQVRHZLOCDD-UHFFFAOYSA-N 0.000 description 2
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- GDTHVMAIBQVUMV-UHFFFAOYSA-N 2-oxopentanal Chemical compound CCCC(=O)C=O GDTHVMAIBQVUMV-UHFFFAOYSA-N 0.000 description 2
- BTXXTMOWISPQSJ-UHFFFAOYSA-N 4,4,4-trifluorobutan-2-one Chemical compound CC(=O)CC(F)(F)F BTXXTMOWISPQSJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- GOJNFUXEBVBARW-UHFFFAOYSA-N 4-amino-6-chloropyrimidine-5-carbaldehyde Chemical compound NC1=NC=NC(Cl)=C1C=O GOJNFUXEBVBARW-UHFFFAOYSA-N 0.000 description 2
- WNHMIKSCDKSJDI-UHFFFAOYSA-N 5,5,5-trifluoropentan-1-ol Chemical compound OCCCCC(F)(F)F WNHMIKSCDKSJDI-UHFFFAOYSA-N 0.000 description 2
- JJEFRTFWKFMJAY-UHFFFAOYSA-N 5-chloro-3-(2,2,2-trifluoroethyl)-1,4-dihydropyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=CN=C2NC(=O)N(CC(F)(F)F)CC2=C1Cl JJEFRTFWKFMJAY-UHFFFAOYSA-N 0.000 description 2
- BQRPZICJBRIUBO-UHFFFAOYSA-N 6-chloro-5-[(2,2,2-trifluoroethylamino)methyl]pyrimidin-4-amine Chemical compound NC1=NC=NC(Cl)=C1CNCC(F)(F)F BQRPZICJBRIUBO-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- PVYPHUYXKVVURH-UHFFFAOYSA-N boron;2-methylpropan-2-amine Chemical compound [B].CC(C)(C)N PVYPHUYXKVVURH-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- XUPYJHCZDLZNFP-UHFFFAOYSA-N butyl butanoate Chemical compound CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 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
- 229960004768 irinotecan Drugs 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- JBHPOLJTYXPOTR-UHFFFAOYSA-N methyl 3-(4,6-dichloropyrimidin-5-yl)pentanoate Chemical compound COC(=O)CC(CC)C1=C(Cl)N=CN=C1Cl JBHPOLJTYXPOTR-UHFFFAOYSA-N 0.000 description 2
- IMGDPCBVSHGKDZ-UHFFFAOYSA-N methyl 4-acetyloxane-4-carboxylate Chemical compound COC(=O)C1(C(C)=O)CCOCC1 IMGDPCBVSHGKDZ-UHFFFAOYSA-N 0.000 description 2
- WWONFUQGBVOKOF-UHFFFAOYSA-N n-(5-bromothiophen-2-yl)sulfonyl-2,4-dichlorobenzamide Chemical compound ClC1=CC(Cl)=CC=C1C(=O)NS(=O)(=O)C1=CC=C(Br)S1 WWONFUQGBVOKOF-UHFFFAOYSA-N 0.000 description 2
- QURBKRFUFINPQC-UHFFFAOYSA-N n-methoxy-n-methyloxane-4-carboxamide Chemical compound CON(C)C(=O)C1CCOCC1 QURBKRFUFINPQC-UHFFFAOYSA-N 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- AVPKHOTUOHDTLW-UHFFFAOYSA-N oxane-4-carboxylic acid Chemical compound OC(=O)C1CCOCC1 AVPKHOTUOHDTLW-UHFFFAOYSA-N 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- DGSXKCUXTPNNKE-UHFFFAOYSA-N propan-2-amine trihydrochloride Chemical compound Cl.Cl.Cl.CC(C)N DGSXKCUXTPNNKE-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229960005137 succinic acid Drugs 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 229950010853 tasisulam Drugs 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XDDVAHSPEWODOA-UHFFFAOYSA-N tert-butyl 4-(4,5-dichloro-1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(Cl)=C(Cl)N1 XDDVAHSPEWODOA-UHFFFAOYSA-N 0.000 description 2
- FCDJYJPBVIMACP-UHFFFAOYSA-N tert-butyl 4-(5-chloro-1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(Cl)=CN1 FCDJYJPBVIMACP-UHFFFAOYSA-N 0.000 description 2
- VFXNOCFHEWAGRF-UHFFFAOYSA-N tert-butyl 4-[4,5-dibromo-1-[2-(oxan-2-yloxy)ethyl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(Br)=C(Br)N1CCOC1OCCCC1 VFXNOCFHEWAGRF-UHFFFAOYSA-N 0.000 description 2
- KWQXXDPQBOWOOR-UHFFFAOYSA-N tert-butyl 4-[4,5-diiodo-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(I)=C(I)N1CCN1CCCC1 KWQXXDPQBOWOOR-UHFFFAOYSA-N 0.000 description 2
- JOEWTJZCALABGI-UHFFFAOYSA-N tert-butyl 4-[4-iodo-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(I)=CN1CCN1CCCC1 JOEWTJZCALABGI-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- BUROJSBIWGDYCN-NAPIOXJUSA-N (1R,9S,12S,15R,16E,18R,19R,21R,23S,24Z,26E,28E,30S,35R)-12-[(2R)-1-[(1S,3R,4R)-4-dimethylphosphoryloxy-3-methoxycyclohexyl]propan-2-yl]-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone Chemical compound C1C[C@@H](OP(C)(C)=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)CCC2C[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 BUROJSBIWGDYCN-NAPIOXJUSA-N 0.000 description 1
- KGJWKEMRTROKIO-RXMQYKEDSA-N (5r)-4-chloro-5-ethyl-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(Cl)=C2[C@H](CC)CC(=O)NC2=N1 KGJWKEMRTROKIO-RXMQYKEDSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 1
- BCONMNLEVXRWTI-UHFFFAOYSA-N 1-(1-methylcyclobutyl)ethanone Chemical compound CC(=O)C1(C)CCC1 BCONMNLEVXRWTI-UHFFFAOYSA-N 0.000 description 1
- SMABWJMSNURPPV-UHFFFAOYSA-N 1-(4-methyloxan-4-yl)ethanone Chemical compound CC(=O)C1(C)CCOCC1 SMABWJMSNURPPV-UHFFFAOYSA-N 0.000 description 1
- ZVVQFPGYDBUGQB-UHFFFAOYSA-N 2-(2-chloroethoxy)oxane Chemical compound ClCCOC1CCCCO1 ZVVQFPGYDBUGQB-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- HEPPAPZASXFWTB-UHFFFAOYSA-N 3,3-dibromo-1,1,1-trifluoropropan-2-one Chemical compound FC(F)(F)C(=O)C(Br)Br HEPPAPZASXFWTB-UHFFFAOYSA-N 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- RSEBTIYPIHACQL-UHFFFAOYSA-N 4-chloro-5-(trifluoromethyl)-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(Cl)=C2C(C(F)(F)F)CC(=O)NC2=N1 RSEBTIYPIHACQL-UHFFFAOYSA-N 0.000 description 1
- HGBDGFXWZDTFEB-UHFFFAOYSA-N 4-chloro-5-methyl-6,8-dihydro-5h-pyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(Cl)=C2C(C)CC(=O)NC2=N1 HGBDGFXWZDTFEB-UHFFFAOYSA-N 0.000 description 1
- HORVGVMSRMVRDH-UHFFFAOYSA-N 4-methoxy-2-oxobutanal Chemical compound COCCC(=O)C=O HORVGVMSRMVRDH-UHFFFAOYSA-N 0.000 description 1
- OPIPDUFGXKXYLW-UHFFFAOYSA-N 4-methyl-2-oxopentanal Chemical compound CC(C)CC(=O)C=O OPIPDUFGXKXYLW-UHFFFAOYSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 1
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=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 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 1
- 229940126638 Akt inhibitor Drugs 0.000 description 1
- 101001015038 Albizia kalkora Kunitz-type trypsin inhibitor alpha chain Proteins 0.000 description 1
- 125000006847 BOC protecting group Chemical group 0.000 description 1
- ZNSMNVMLTJELDZ-UHFFFAOYSA-N Bis(2-chloroethyl)ether Chemical compound ClCCOCCCl ZNSMNVMLTJELDZ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- HVZXQPMAUMJMJU-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(CC1)c1nc(c[nH]1)C(C)(C)C Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)c1nc(c[nH]1)C(C)(C)C HVZXQPMAUMJMJU-UHFFFAOYSA-N 0.000 description 1
- FAWVHCGDOJXIPZ-UHFFFAOYSA-N CCC(CC(=O)OC)c1c(O)ncnc1O Chemical compound CCC(CC(=O)OC)c1c(O)ncnc1O FAWVHCGDOJXIPZ-UHFFFAOYSA-N 0.000 description 1
- MOWVGAAEWFVPRZ-UHFFFAOYSA-N CS(=O)(=O)OCCN1C(=NC(=C1)C(F)(F)F)C1CCN(CC1)C(=O)OC(C)(C)C Chemical compound CS(=O)(=O)OCCN1C(=NC(=C1)C(F)(F)F)C1CCN(CC1)C(=O)OC(C)(C)C MOWVGAAEWFVPRZ-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 235000006481 Colocasia esculenta Nutrition 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 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
- 238000008157 ELISA kit Methods 0.000 description 1
- ZFDIRQKJPRINOQ-HWKANZROSA-N Ethyl crotonate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 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
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 238000006626 Weinreb Ketone synthesis reaction Methods 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 0.000 description 1
- 235000017957 Xanthosoma sagittifolium Nutrition 0.000 description 1
- 240000001781 Xanthosoma sagittifolium Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 238000010936 aqueous wash Methods 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-L benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphane Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-L 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- YECAJNWCKIRMJU-UHFFFAOYSA-N cyclobutanamine Chemical compound NC1C[CH]C1 YECAJNWCKIRMJU-UHFFFAOYSA-N 0.000 description 1
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- ZKRJCMKLCDWROR-ONEGZZNKSA-N ethyl (e)-4,4,4-trifluorobut-2-enoate Chemical compound CCOC(=O)\C=C\C(F)(F)F ZKRJCMKLCDWROR-ONEGZZNKSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 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 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- MCVVUJPXSBQTRZ-ONEGZZNKSA-N methyl (e)-but-2-enoate Chemical compound COC(=O)\C=C\C MCVVUJPXSBQTRZ-ONEGZZNKSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LHTGBZMVHWJBQB-UHFFFAOYSA-N n,2-diethylaniline Chemical compound CCNC1=CC=CC=C1CC LHTGBZMVHWJBQB-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- OHEDMAIVEXQCOZ-UHFFFAOYSA-N piperidine;dihydrochloride Chemical compound Cl.Cl.C1CCNCC1 OHEDMAIVEXQCOZ-UHFFFAOYSA-N 0.000 description 1
- MDZVMZTXIHCNCQ-UHFFFAOYSA-N piperidine;trihydrochloride Chemical compound Cl.Cl.Cl.C1CCNCC1 MDZVMZTXIHCNCQ-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- JCOHXVDKRMWUQP-UHFFFAOYSA-M sodium;n-(5-bromothiophen-2-yl)sulfonyl-2,4-dichlorobenzenecarboximidate Chemical compound [Na+].ClC1=CC(Cl)=CC=C1C(=O)[N-]S(=O)(=O)C1=CC=C(Br)S1 JCOHXVDKRMWUQP-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000012134 supernatant fraction Substances 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- SZVKVQUILFIMKD-UHFFFAOYSA-N tert-butyl 4-(5-cyano-1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C#N)=CN1 SZVKVQUILFIMKD-UHFFFAOYSA-N 0.000 description 1
- LXZPQDJRYRKCCL-UHFFFAOYSA-N tert-butyl 4-[1-(2-pyrrolidin-1-ylethyl)-4-(3,3,3-trifluoropropyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(CCC(F)(F)F)=CN1CCN1CCCC1 LXZPQDJRYRKCCL-UHFFFAOYSA-N 0.000 description 1
- WDVJZCFXSHENLM-UHFFFAOYSA-N tert-butyl 4-[1-[2-(oxan-2-yloxy)ethyl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC=CN1CCOC1OCCCC1 WDVJZCFXSHENLM-UHFFFAOYSA-N 0.000 description 1
- BJQMFCXVEZFQAV-UHFFFAOYSA-N tert-butyl 4-[4-bromo-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(Br)=CN1CCN1CCCC1 BJQMFCXVEZFQAV-UHFFFAOYSA-N 0.000 description 1
- BFNIIQIAMUFQTM-UHFFFAOYSA-N tert-butyl 4-[4-ethenyl-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=C)=CN1CCN1CCCC1 BFNIIQIAMUFQTM-UHFFFAOYSA-N 0.000 description 1
- XSIQQUMWCAEVQI-UHFFFAOYSA-N tert-butyl 4-[5-(2,2,2-trifluoroethyl)-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(CC(F)(F)F)=CN1 XSIQQUMWCAEVQI-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25430809P | 2009-10-23 | 2009-10-23 | |
| US61/254,308 | 2009-10-23 | ||
| PCT/US2010/053295 WO2011050016A1 (en) | 2009-10-23 | 2010-10-20 | Akt inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2778291A1 CA2778291A1 (en) | 2011-04-28 |
| CA2778291C true CA2778291C (en) | 2014-02-11 |
Family
ID=43467018
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2778291A Expired - Fee Related CA2778291C (en) | 2009-10-23 | 2010-10-20 | Akt inhibitors |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US8436002B2 (enExample) |
| EP (1) | EP2491032B1 (enExample) |
| JP (1) | JP5581390B2 (enExample) |
| KR (1) | KR101398268B1 (enExample) |
| CN (1) | CN102574852B (enExample) |
| AU (1) | AU2010310786B2 (enExample) |
| BR (1) | BR112012011328A2 (enExample) |
| CA (1) | CA2778291C (enExample) |
| EA (1) | EA020151B1 (enExample) |
| ES (1) | ES2465094T3 (enExample) |
| MX (1) | MX2012004780A (enExample) |
| WO (1) | WO2011050016A1 (enExample) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102123131B1 (ko) | 2012-05-17 | 2020-06-15 | 제넨테크, 인크. | 하이드록실화 사이클로펜타피리미딘 화합물 및 이의 염의 제조 방법 |
| JP6214636B2 (ja) | 2012-05-17 | 2017-10-18 | アレイ バイオファーマ、インコーポレイテッド | ヒドロキシル化シクロペンチルピリミジン化合物を作製するためのプロセス |
| DK2861582T3 (en) | 2012-05-17 | 2016-08-22 | Array Biopharma Inc | A process for preparing hydroxylated compounds cyclopentylpyrimidin |
| DK2858989T3 (da) | 2012-05-17 | 2020-06-02 | Genentech Inc | Amorf form af en AKT-hæmmende pyrimidinyl-cyclopentan-forbindelse, sammensætninger deraf og fremgangsmåder dertil |
| CN104520263B (zh) | 2012-05-17 | 2016-11-09 | 基因泰克公司 | 制备氨基酸化合物的方法 |
| ES2807539T3 (es) * | 2012-11-16 | 2021-02-23 | Merck Patent Gmbh | Derivados de imidazol-piperidinilo como moduladores de la actividad de quinasa |
| SG11201505999VA (en) * | 2013-03-11 | 2015-08-28 | Merck Patent Gmbh | 6-[4-(1 h-imidazol-2-yl)piperidin-1 -yl]pyrimidin-4-amine derivatives as modulators of kinase activity |
| CA2928568A1 (en) | 2013-07-26 | 2015-01-29 | Update Pharma Inc. | Combinatorial methods to improve the therapeutic benefit of bisantrene |
| CA3206628A1 (en) | 2013-09-12 | 2015-03-19 | Dana-Farber Cancer Institute, Inc. | Methods for evaluating and treating waldenstrom's macroglobulinemia |
| GB201401198D0 (en) * | 2014-01-24 | 2014-03-12 | Bial Portela & Ca Sa | Process for the syntheis of substituted urea compounds |
| US9925192B2 (en) | 2014-02-28 | 2018-03-27 | Merck Sharp & Dohme Corp. | Method for treating cancer |
| RU2713181C1 (ru) * | 2016-05-20 | 2020-02-04 | Тайхо Фармасьютикал Ко., Лтд. | Новое производное 5h-пирроло[2,3-d]пиримидин-6(7h)-она |
| PL3919491T3 (pl) * | 2019-01-29 | 2025-10-20 | Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd. | Inhibitor akt |
| PH12022553031A1 (en) * | 2020-05-08 | 2024-05-13 | Georgiamune Inc | Akt3 modulators |
| WO2021228223A1 (zh) * | 2020-05-15 | 2021-11-18 | 南京正大天晴制药有限公司 | 氘代akt激酶抑制剂 |
| US20230271958A1 (en) * | 2020-07-22 | 2023-08-31 | Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd. | SALT AND CRYSTAL FORM OF DIHYDROPYRIDO[2,3-d]PYRIMIDINE DERIVATE |
| AU2021314419B2 (en) * | 2020-07-22 | 2023-12-07 | Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd. | Salt of dihydropyrido[2,3-d]pyrimidinone derivative, preparation method therefor, and use thereof |
| CA3186565A1 (en) * | 2020-07-22 | 2022-01-27 | Lei Miao | Unit dosage composition of akt inhibitor |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4128089A (en) | 1988-09-15 | 1990-03-22 | Rorer International (Overseas) Inc. | Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same |
| GB9300059D0 (en) | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
| GB9221220D0 (en) | 1992-10-09 | 1992-11-25 | Sandoz Ag | Organic componds |
| US5362718A (en) | 1994-04-18 | 1994-11-08 | American Home Products Corporation | Rapamycin hydroxyesters |
| NL1004346C2 (nl) | 1996-10-23 | 1998-04-24 | Dsm Nv | Werkwijze voor het scheiden van een mengsel van enantiomeren in een geschikt oplosmiddel. |
| BR0307544A (pt) | 2002-02-01 | 2004-12-07 | Ariad Gene Therapeutics Inc | Compostos contendo fósforos, componentes e composição bem como, sua utilização através de métodos de tratamentos |
| US7563748B2 (en) | 2003-06-23 | 2009-07-21 | Cognis Ip Management Gmbh | Alcohol alkoxylate carriers for pesticide active ingredients |
| WO2005117909A2 (en) | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
| RU2346996C2 (ru) | 2004-06-29 | 2009-02-20 | ЮРОПИЭН НИКЕЛЬ ПиЭлСи | Усовершенствованное выщелачивание основных металлов |
| MY179032A (en) | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
| EP1828186A1 (en) * | 2004-12-13 | 2007-09-05 | Sunesis Pharmaceuticals, Inc. | Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors |
| US7994172B2 (en) * | 2004-12-28 | 2011-08-09 | Exelixis, Inc. | [1H-pyrazolo[3, 4-D]pyrimidin-4-yl]-piperidine or -piperazine compounds as serine-theoronine kinase modulators (P70s6k, Atk1 and Atk2) for the treatment of immunological, inflammatory and proliferative diseases |
| EP1895898B1 (en) | 2005-06-29 | 2011-02-16 | Compumedics Limited | Sensor assembly with conductive bridge |
| US20100016340A1 (en) * | 2006-04-25 | 2010-01-21 | Astex Therapeutics Limited | Pharmaceutical compounds |
| JP5606734B2 (ja) | 2006-04-25 | 2014-10-15 | アステックス、セラピューティックス、リミテッド | 医薬化合物 |
| TW200801513A (en) | 2006-06-29 | 2008-01-01 | Fermiscan Australia Pty Ltd | Improved process |
| AR064416A1 (es) * | 2006-12-21 | 2009-04-01 | Cancer Rec Tech Ltd | Derivados de purina, piridina y pirimidina condensadas con heterociclos, moduladores de pka y/o pkb, composiciones farmaceuticas que los contienen, y usos para el tratamiento de enfermedades hiperproliferativas. |
| UA99284C2 (ru) * | 2007-05-11 | 2012-08-10 | Елі Ліллі Енд Компані | ИНГИБИТОРЫ р70 S6-КИНАЗЫ |
| AR074072A1 (es) * | 2008-11-11 | 2010-12-22 | Lilly Co Eli | Compuesto de imidazol -piperidin -pirrol-pirimidin-6-ona, composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para tratar el glioblastoma multiforme |
-
2010
- 2010-10-20 AU AU2010310786A patent/AU2010310786B2/en not_active Ceased
- 2010-10-20 CA CA2778291A patent/CA2778291C/en not_active Expired - Fee Related
- 2010-10-20 EA EA201270590A patent/EA020151B1/ru not_active IP Right Cessation
- 2010-10-20 EP EP10774072.2A patent/EP2491032B1/en not_active Not-in-force
- 2010-10-20 ES ES10774072.2T patent/ES2465094T3/es active Active
- 2010-10-20 WO PCT/US2010/053295 patent/WO2011050016A1/en not_active Ceased
- 2010-10-20 US US13/391,895 patent/US8436002B2/en not_active Expired - Fee Related
- 2010-10-20 CN CN201080046941.9A patent/CN102574852B/zh not_active Expired - Fee Related
- 2010-10-20 JP JP2012535319A patent/JP5581390B2/ja not_active Expired - Fee Related
- 2010-10-20 BR BR112012011328A patent/BR112012011328A2/pt not_active IP Right Cessation
- 2010-10-20 KR KR1020127010282A patent/KR101398268B1/ko not_active Expired - Fee Related
- 2010-10-20 MX MX2012004780A patent/MX2012004780A/es active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013508382A (ja) | 2013-03-07 |
| CN102574852A (zh) | 2012-07-11 |
| KR101398268B1 (ko) | 2014-05-23 |
| KR20120068941A (ko) | 2012-06-27 |
| US20120149684A1 (en) | 2012-06-14 |
| CA2778291A1 (en) | 2011-04-28 |
| EP2491032A1 (en) | 2012-08-29 |
| ES2465094T3 (es) | 2014-06-05 |
| EP2491032B1 (en) | 2014-04-16 |
| JP5581390B2 (ja) | 2014-08-27 |
| BR112012011328A2 (pt) | 2016-11-22 |
| MX2012004780A (es) | 2012-08-23 |
| AU2010310786B2 (en) | 2014-03-27 |
| EA020151B1 (ru) | 2014-09-30 |
| WO2011050016A1 (en) | 2011-04-28 |
| AU2010310786A1 (en) | 2012-04-19 |
| EA201270590A1 (ru) | 2012-09-28 |
| US8436002B2 (en) | 2013-05-07 |
| CN102574852B (zh) | 2014-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2010310786B2 (en) | AKT inhibitors | |
| JP6563623B1 (ja) | ピリドピリミジノンｃｄｋ２／４／６阻害剤 | |
| CN103384670B (zh) | 取代的咪唑并[1,2-b]哒嗪 | |
| AU2014351413B2 (en) | Pyrrolopyrrolone derivatives and their use as BET inhibitors | |
| AU2022219987A1 (en) | Cdk inhibitors and methods of use thereof | |
| JP2022106953A (ja) | ユビキチン特異的プロテアーゼ７の阻害剤としてのピペリジン誘導体 | |
| AU2017348826B2 (en) | Amino pyrazolopyrimidine compound used as neurotrophic factor tyrosine kinase receptor inhibitor | |
| AU2014307437B2 (en) | Novel fused pyrimidine compound or salt thereof | |
| TW202523326A (zh) | 雜環及其用途 | |
| CA3161339A1 (en) | Cyclic compounds and methods of using same | |
| AU2014259477A1 (en) | 3-(2-aminopyrimidin-4-yl)-5-(3-hydroxypropynyl)-1H-pyrrolo[2,3-c]pyridine derivatives as NIK inhibitors for the treatment of cancer | |
| WO2023059605A1 (en) | Heterobifunctional compounds and their use in treating disease | |
| MX2011005000A (es) | Inhibidores de cinasa akt y p70 s6. | |
| AU2021265578A1 (en) | Azalactam compounds as HPK1 inhibitors | |
| EP2920154B1 (en) | Novel imidazol-piperidinyl derivatives as modulators of kinase activity | |
| CA2821777A1 (en) | Substituted pyrimido[1,2-b]indazoles and their use as modulators of the pi3k/akt pathway | |
| WO2025160079A1 (en) | Indazolo-amino-pyrimidinone compounds | |
| CA3268634A1 (en) | Cyclin-dependent kinase 7 inhibitors | |
| WO2024063670A1 (ru) | Ингибиторы циклинзависимой киназы 7 | |
| HK1185881B (en) | Substituted imidazo[1,2-b]pyridazines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20161020 |