MX2011005000A - Inhibidores de cinasa akt y p70 s6. - Google Patents
Inhibidores de cinasa akt y p70 s6.Info
- Publication number
- MX2011005000A MX2011005000A MX2011005000A MX2011005000A MX2011005000A MX 2011005000 A MX2011005000 A MX 2011005000A MX 2011005000 A MX2011005000 A MX 2011005000A MX 2011005000 A MX2011005000 A MX 2011005000A MX 2011005000 A MX2011005000 A MX 2011005000A
- Authority
- MX
- Mexico
- Prior art keywords
- imidazol
- ethyl
- phenyl
- fluoro
- piperidin
- Prior art date
Links
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 title abstract description 18
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 10
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 305
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- -1 hydroxy-substituted azetidine ring Chemical group 0.000 claims description 291
- 150000003839 salts Chemical class 0.000 claims description 55
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 12
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 208000005017 glioblastoma Diseases 0.000 claims description 11
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 10
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims description 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 9
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 264
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 261
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 185
- 238000006243 chemical reaction Methods 0.000 description 127
- 238000002360 preparation method Methods 0.000 description 126
- 239000007787 solid Substances 0.000 description 91
- 235000019439 ethyl acetate Nutrition 0.000 description 88
- 229940093499 ethyl acetate Drugs 0.000 description 87
- 239000000243 solution Substances 0.000 description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 70
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- 239000012044 organic layer Substances 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 46
- 239000012267 brine Substances 0.000 description 42
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
- 239000000543 intermediate Substances 0.000 description 40
- 239000000203 mixture Substances 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 239000000725 suspension Substances 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 108091008611 Protein Kinase B Proteins 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 206010028980 Neoplasm Diseases 0.000 description 18
- 239000007983 Tris buffer Substances 0.000 description 18
- 230000005764 inhibitory process Effects 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 13
- PKKYYNMRPXEIFE-UHFFFAOYSA-N 4-chloro-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one Chemical compound ClC1=NC=NC2=C1CC(=O)N2 PKKYYNMRPXEIFE-UHFFFAOYSA-N 0.000 description 13
- 238000003556 assay Methods 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 13
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 11
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 238000000634 powder X-ray diffraction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 229940124597 therapeutic agent Drugs 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical group 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 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
- 239000000706 filtrate Substances 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
- NCIZQRMMYUHTDP-UHFFFAOYSA-N 5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one Chemical compound N1=CN=C2NC(=O)CC2=C1 NCIZQRMMYUHTDP-UHFFFAOYSA-N 0.000 description 7
- 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 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 7
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 7
- 150000004682 monohydrates Chemical class 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229960002930 sirolimus Drugs 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 7
- 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 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 6
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 206010041067 Small cell lung cancer Diseases 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 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 6
- 239000011541 reaction mixture Substances 0.000 description 6
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 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 5
- KYMNDJBNPVFKDS-UHFFFAOYSA-N 4-chloro-7-[(2,4-dimethoxyphenyl)methyl]-5h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound COC1=CC(OC)=CC=C1CN1C(N=CN=C2Cl)=C2CC1=O KYMNDJBNPVFKDS-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 239000007995 HEPES buffer Substances 0.000 description 5
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000003016 alphascreen Methods 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000004212 difluorophenyl group Chemical group 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 5
- 239000003197 protein kinase B inhibitor Substances 0.000 description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 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 4
- 229960001433 erlotinib Drugs 0.000 description 4
- 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 4
- 229960005277 gemcitabine Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 229960005079 pemetrexed Drugs 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- OJUGVDODNPJEEC-UHFFFAOYSA-N phenylglyoxal Chemical compound O=CC(=O)C1=CC=CC=C1 OJUGVDODNPJEEC-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- WOGOXEPEEXSPAF-UHFFFAOYSA-N 1h-imidazole;piperidine Chemical compound C1=CNC=N1.C1CCNCC1 WOGOXEPEEXSPAF-UHFFFAOYSA-N 0.000 description 3
- GCUOLJOTJRUDIZ-UHFFFAOYSA-N 2-(2-bromoethoxy)oxane Chemical compound BrCCOC1CCCCO1 GCUOLJOTJRUDIZ-UHFFFAOYSA-N 0.000 description 3
- JXCIEKVLIVDZJH-UHFFFAOYSA-N 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 JXCIEKVLIVDZJH-UHFFFAOYSA-N 0.000 description 3
- BUNOSKWLVXNWEH-UHFFFAOYSA-N 2-bromo-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone Chemical compound FC1=CC=C(C(=O)CBr)C=C1C(F)(F)F BUNOSKWLVXNWEH-UHFFFAOYSA-N 0.000 description 3
- KYBINFJRIXEZGI-UHFFFAOYSA-N 4-chloro-5,5-dimethyl-7h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound C1=NC(Cl)=C2C(C)(C)C(=O)NC2=N1 KYBINFJRIXEZGI-UHFFFAOYSA-N 0.000 description 3
- IQKBJMXJOQXLEC-UHFFFAOYSA-N 4-chloro-5-ethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one Chemical compound C1=NC(Cl)=C2C(CC)C(=O)NC2=N1 IQKBJMXJOQXLEC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000017662 Hodgkin disease lymphocyte depletion type stage unspecified Diseases 0.000 description 3
- 206010049459 Lymphangioleiomyomatosis Diseases 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 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
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 3
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 3
- 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 3
- 239000006096 absorbing agent Substances 0.000 description 3
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- HUOMDSUTPKRNAE-UHFFFAOYSA-N tert-butyl 4-[1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound CN(C)CCN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCN(C(=O)OC(C)(C)C)CC1 HUOMDSUTPKRNAE-UHFFFAOYSA-N 0.000 description 3
- DLLYEBNXXOZNAR-UHFFFAOYSA-N tert-butyl 4-[5-[4-fluoro-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(C(F)=CC=2)C(F)(F)F)=CN1 DLLYEBNXXOZNAR-UHFFFAOYSA-N 0.000 description 3
- QJMZCTXXDQBKAB-UHFFFAOYSA-N tert-butyl 4-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 QJMZCTXXDQBKAB-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 2
- PPVVSBYLWRWJAF-BTQNPOSSSA-N (2r)-1-benzyl-2-(bromomethyl)piperidine;hydrochloride Chemical compound Cl.BrC[C@H]1CCCCN1CC1=CC=CC=C1 PPVVSBYLWRWJAF-BTQNPOSSSA-N 0.000 description 2
- DSKKEOXRMGSCSN-RXMQYKEDSA-N (3r)-3-aminopiperidine-1-carboxylic acid Chemical compound N[C@@H]1CCCN(C(O)=O)C1 DSKKEOXRMGSCSN-RXMQYKEDSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 2
- SYKRFCMYMHOQAJ-UHFFFAOYSA-N 2-[4-(3-chloro-4-fluorophenyl)-2-piperidin-4-ylimidazol-1-yl]-n,n-dimethylethanamine Chemical compound CN(C)CCN1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C1CCNCC1 SYKRFCMYMHOQAJ-UHFFFAOYSA-N 0.000 description 2
- BKWCCUMGBGQTHN-UHFFFAOYSA-N 2-[4-(3-chloro-4-fluorophenyl)imidazol-1-yl]-n,n-dimethylethanamine Chemical compound CN(C)CCN1C=NC(C=2C=C(Cl)C(F)=CC=2)=C1 BKWCCUMGBGQTHN-UHFFFAOYSA-N 0.000 description 2
- JCKVHXDCXAACKU-UHFFFAOYSA-N 2-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-ylimidazol-1-yl]-n,n-dimethylethanamine Chemical compound CN(C)CCN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCNCC1 JCKVHXDCXAACKU-UHFFFAOYSA-N 0.000 description 2
- LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- OOEJOCSMUZORKA-UHFFFAOYSA-N 4-(1h-imidazol-2-yl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1C1=NC=CN1 OOEJOCSMUZORKA-UHFFFAOYSA-N 0.000 description 2
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- IJONSWCCVQAUMH-UHFFFAOYSA-N 5,5-dibromo-4-chloro-7h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound ClC1=NC=NC2=C1C(Br)(Br)C(=O)N2 IJONSWCCVQAUMH-UHFFFAOYSA-N 0.000 description 2
- JJRDAGZSVMIJFP-UHFFFAOYSA-N 6-chloro-5-n-methylpyrimidine-4,5-diamine Chemical compound CNC1=C(N)N=CN=C1Cl JJRDAGZSVMIJFP-UHFFFAOYSA-N 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 2
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 2
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 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
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 2
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000002278 Ribosomal Proteins Human genes 0.000 description 2
- 108010000605 Ribosomal Proteins Proteins 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- MWAREVYCFWUDTM-UHFFFAOYSA-N [2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl]azanium;chloride Chemical compound Cl.NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 MWAREVYCFWUDTM-UHFFFAOYSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001262 acyl bromides Chemical class 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- GEYMMMXKROUBAI-UHFFFAOYSA-N chlorane Chemical compound Cl.Cl.Cl.Cl.Cl GEYMMMXKROUBAI-UHFFFAOYSA-N 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000005388 cross polarization Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 201000011523 endocrine gland cancer Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- CXFWVKQYNKXWNT-UHFFFAOYSA-N ethyl 2-(4-hydroxy-6-oxo-1h-pyrimidin-5-yl)acetate Chemical compound CCOC(=O)CC1=C(O)N=CN=C1O CXFWVKQYNKXWNT-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000002875 fluorescence polarization Methods 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000000021 kinase assay Methods 0.000 description 2
- JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- ORHWGOUAAWDYFP-UHFFFAOYSA-N methyl 2-(4,6-dichloropyrimidin-5-yl)acetate Chemical compound COC(=O)CC1=C(Cl)N=CN=C1Cl ORHWGOUAAWDYFP-UHFFFAOYSA-N 0.000 description 2
- SIJXBVAZZBKSKE-UHFFFAOYSA-N methyl 2-(4-hydroxy-6-oxo-1h-pyrimidin-5-yl)acetate Chemical compound COC(=O)CC1=C(O)N=CN=C1O SIJXBVAZZBKSKE-UHFFFAOYSA-N 0.000 description 2
- VDCLSGXZVUDARN-UHFFFAOYSA-N molecular bromine;pyridine;hydrobromide Chemical compound Br.BrBr.C1=CC=NC=C1 VDCLSGXZVUDARN-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
- PYIXYEMKFUOLDQ-UHFFFAOYSA-N n-benzyl-2-chloro-n-methylethanamine;hydrochloride Chemical compound [Cl-].ClCC[NH+](C)CC1=CC=CC=C1 PYIXYEMKFUOLDQ-UHFFFAOYSA-N 0.000 description 2
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 2
- 229920002223 polystyrene Polymers 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
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229950010853 tasisulam Drugs 0.000 description 2
- WZELTRFSUHEEHE-UHFFFAOYSA-N tert-butyl 4-[1-(2-aminoethyl)-4-(3-chloro-4-fluorophenyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(Cl)C(F)=CC=2)=CN1CCN WZELTRFSUHEEHE-UHFFFAOYSA-N 0.000 description 2
- RCHSBXCCRWSVQI-UHFFFAOYSA-N tert-butyl 4-[4-(3-chloro-4-fluorophenyl)-1-[2-(methylamino)ethyl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound CNCCN1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C1CCN(C(=O)OC(C)(C)C)CC1 RCHSBXCCRWSVQI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- BQBLWHOSZXQOGF-UHFFFAOYSA-N tert-butyl 4-[4-bromo-1-[2-(dimethylamino)ethyl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound CN(C)CCN1C=C(Br)N=C1C1CCN(C(=O)OC(C)(C)C)CC1 BQBLWHOSZXQOGF-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- TVWZLLYAJDSSCJ-UHFFFAOYSA-N triethyl ethane-1,1,2-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)C(=O)OCC TVWZLLYAJDSSCJ-UHFFFAOYSA-N 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
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-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
- SBQRCZOBCPKPIC-CYBMUJFWSA-N (2r)-1-benzyl-2-(bromomethyl)piperidine Chemical compound BrC[C@H]1CCCCN1CC1=CC=CC=C1 SBQRCZOBCPKPIC-CYBMUJFWSA-N 0.000 description 1
- LYJHYXLNDKWVBC-QGZVFWFLSA-N (2r)-2-[[4-[3-(difluoromethyl)-4-fluorophenyl]-2-piperidin-4-ylimidazol-1-yl]methyl]-1-methylpiperidine Chemical compound CN1CCCC[C@@H]1CN1C(C2CCNCC2)=NC(C=2C=C(C(F)=CC=2)C(F)F)=C1 LYJHYXLNDKWVBC-QGZVFWFLSA-N 0.000 description 1
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- ZGTFNNUASMWGTM-UHFFFAOYSA-N 1,3-thiazole-2-carbaldehyde Chemical compound O=CC1=NC=CS1 ZGTFNNUASMWGTM-UHFFFAOYSA-N 0.000 description 1
- ROUYUBHVBIKMQO-UHFFFAOYSA-N 1,4-diiodobutane Chemical compound ICCCCI ROUYUBHVBIKMQO-UHFFFAOYSA-N 0.000 description 1
- YFOOEYJGMMJJLS-UHFFFAOYSA-N 1,8-diaminonaphthalene Chemical compound C1=CC(N)=C2C(N)=CC=CC2=C1 YFOOEYJGMMJJLS-UHFFFAOYSA-N 0.000 description 1
- GDQHCHFPBSSLQY-UHFFFAOYSA-N 1-(chloromethyl)pyrrolidine Chemical compound ClCN1CCCC1 GDQHCHFPBSSLQY-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- KIABTEBJJQSDSG-UHFFFAOYSA-N 2-[4-(3-chloro-4-fluorophenyl)-2-piperidin-4-ylimidazol-1-yl]acetonitrile;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=C(Cl)C(F)=CC=C1C1=CN(CC#N)C(C2CCNCC2)=N1 KIABTEBJJQSDSG-UHFFFAOYSA-N 0.000 description 1
- SMFKBTCLCQAAOD-UHFFFAOYSA-N 2-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-ylimidazol-1-yl]-n,n-dimethylethanamine;dihydrochloride Chemical compound Cl.Cl.CN(C)CCN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCNCC1 SMFKBTCLCQAAOD-UHFFFAOYSA-N 0.000 description 1
- WOUANPHGFPAJCA-UHFFFAOYSA-N 2-[benzyl(methyl)amino]ethanol Chemical compound OCCN(C)CC1=CC=CC=C1 WOUANPHGFPAJCA-UHFFFAOYSA-N 0.000 description 1
- WZPSNPSAYYCJGX-UHFFFAOYSA-N 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone Chemical compound NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 WZPSNPSAYYCJGX-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 description 1
- UFHCMCKMHHKYLX-UHFFFAOYSA-N 2-methylpropan-2-amine;dihydrochloride Chemical compound Cl.Cl.CC(C)(C)N UFHCMCKMHHKYLX-UHFFFAOYSA-N 0.000 description 1
- DSKKEOXRMGSCSN-UHFFFAOYSA-N 3-aminopiperidine-1-carboxylic acid Chemical compound NC1CCCN(C(O)=O)C1 DSKKEOXRMGSCSN-UHFFFAOYSA-N 0.000 description 1
- KLFYPDKDZRLLHM-UHFFFAOYSA-N 4,6-dichloro-n-methylpyrimidin-5-amine Chemical compound CNC1=C(Cl)N=CN=C1Cl KLFYPDKDZRLLHM-UHFFFAOYSA-N 0.000 description 1
- NIGDWBHWHVHOAD-UHFFFAOYSA-N 4,6-dichloropyrimidin-5-amine Chemical compound NC1=C(Cl)N=CN=C1Cl NIGDWBHWHVHOAD-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- SBOBYXQZSWQRDY-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)imidazol-2-yl]piperidine-1-carboxylic acid Chemical compound ClC=1C=C(C=CC=1F)C=1N=C(N(C=1)CCO)C1CCN(CC1)C(=O)O SBOBYXQZSWQRDY-UHFFFAOYSA-N 0.000 description 1
- VWTCNCLBEHHBDY-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluorophenyl)-1-(cyanomethyl)imidazol-2-yl]piperidine-1-carboxylic acid Chemical compound ClC=1C=C(C=CC=1F)C=1N=C(N(C=1)CC#N)C1CCN(CC1)C(=O)O VWTCNCLBEHHBDY-UHFFFAOYSA-N 0.000 description 1
- VPJWDQMJLWVUOQ-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluorophenyl)-1-[2-(dimethylamino)ethyl]imidazol-2-yl]piperidin-4-ol;dihydrochloride Chemical compound Cl.Cl.CN(C)CCN1C=C(C=2C=C(Cl)C(F)=CC=2)N=C1C1(O)CCNCC1 VPJWDQMJLWVUOQ-UHFFFAOYSA-N 0.000 description 1
- VYZVKIURUVBXNH-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluorophenyl)-1-[2-(dimethylamino)ethyl]imidazol-2-yl]piperidine-1-carboxylic acid Chemical compound ClC=1C=C(C=CC=1F)C=1N=C(N(C=1)CCN(C)C)C1CCN(CC1)C(=O)O VYZVKIURUVBXNH-UHFFFAOYSA-N 0.000 description 1
- KXXMCFYJFFFIFU-UHFFFAOYSA-N 4-[4-[1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-7-[(4-methoxyphenyl)methyl]-5h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound C1=CC(OC)=CC=C1CN1C(N=CN=C2N3CCC(CC3)C=3N(C=C(N=3)C=3C=C(C(F)=CC=3)C(F)(F)F)CCN(C)C)=C2CC1=O KXXMCFYJFFFIFU-UHFFFAOYSA-N 0.000 description 1
- AQFXBZDADRNUDQ-UHFFFAOYSA-N 4-[4-bromo-1-(2-hydroxyethyl)imidazol-2-yl]piperidine-1-carboxylic acid Chemical compound OCCN1C=C(Br)N=C1C1CCN(C(O)=O)CC1 AQFXBZDADRNUDQ-UHFFFAOYSA-N 0.000 description 1
- PEOAPNBXXJLOEY-UHFFFAOYSA-N 4-[5-[4-fluoro-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1C1=NC=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N1 PEOAPNBXXJLOEY-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
- LVJZWNGTLPSUGV-UHFFFAOYSA-N 4-[[2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl]carbamoyl]piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1C(=O)NCC(=O)C1=CC=C(F)C(C(F)(F)F)=C1 LVJZWNGTLPSUGV-UHFFFAOYSA-N 0.000 description 1
- ANFITYFXKUEIJQ-UHFFFAOYSA-N 4-chloro-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one zinc Chemical compound [Zn].ClC=1C2=C(N=CN1)NC(C2)=O ANFITYFXKUEIJQ-UHFFFAOYSA-N 0.000 description 1
- ZZNRVSNEGWXTBS-UHFFFAOYSA-N 4-chloro-5-(pyridin-4-ylmethylidene)-7h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound C1=2C(Cl)=NC=NC=2NC(=O)C1=CC1=CC=NC=C1 ZZNRVSNEGWXTBS-UHFFFAOYSA-N 0.000 description 1
- NKVRBGHVUINDMZ-UHFFFAOYSA-N 4-chloro-7-[(4-methoxyphenyl)methyl]-5h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound C1=CC(OC)=CC=C1CN1C(N=CN=C2Cl)=C2CC1=O NKVRBGHVUINDMZ-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- WFQWTIDVAQNHGR-UHFFFAOYSA-N 5-(3-chloro-4-fluorophenyl)-1h-imidazole Chemical compound C1=C(Cl)C(F)=CC=C1C1=CNC=N1 WFQWTIDVAQNHGR-UHFFFAOYSA-N 0.000 description 1
- JWHGNPMDKLQJJC-UHFFFAOYSA-N 5-benzylidene-4-chloro-7h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound C1=2C(Cl)=NC=NC=2NC(=O)C1=CC1=CC=CC=C1 JWHGNPMDKLQJJC-UHFFFAOYSA-N 0.000 description 1
- FHZALEJIENDROK-UHFFFAOYSA-N 5-bromo-1h-imidazole Chemical compound BrC1=CN=CN1 FHZALEJIENDROK-UHFFFAOYSA-N 0.000 description 1
- XXMPVAZNTUAABC-UHFFFAOYSA-N 6-[4-[1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-7-ethyl-9h-purin-8-one Chemical compound N1=CN=C2NC(=O)N(CC)C2=C1N(CC1)CCC1C(N(C=1)CCN(C)C)=NC=1C1=CC=C(F)C(C(F)(F)F)=C1 XXMPVAZNTUAABC-UHFFFAOYSA-N 0.000 description 1
- QCWUATBWGYGFOP-UHFFFAOYSA-N 6-[4-[4-(3,4-difluorophenyl)-1-[2-(dimethylamino)ethyl]imidazol-2-yl]piperidin-1-yl]-7-ethyl-9h-purin-8-one Chemical compound N1=CN=C2NC(=O)N(CC)C2=C1N(CC1)CCC1C(N(C=1)CCN(C)C)=NC=1C1=CC=C(F)C(F)=C1 QCWUATBWGYGFOP-UHFFFAOYSA-N 0.000 description 1
- UJPRICFWROKUHF-UHFFFAOYSA-N 6-[4-[4-(3-chloro-4-fluorophenyl)-1-[2-(dimethylamino)ethyl]imidazol-2-yl]piperidin-1-yl]-7-ethyl-9h-purin-8-one Chemical compound N1=CN=C2NC(=O)N(CC)C2=C1N(CC1)CCC1C(N(C=1)CCN(C)C)=NC=1C1=CC=C(F)C(Cl)=C1 UJPRICFWROKUHF-UHFFFAOYSA-N 0.000 description 1
- NFPZITBMKVNLQV-UHFFFAOYSA-N 6-[4-[4-(3-chloro-4-fluorophenyl)-1-[2-(dimethylamino)ethyl]imidazol-2-yl]piperidin-1-yl]-7-propan-2-yl-9h-purin-8-one Chemical compound N1=CN=C2NC(=O)N(C(C)C)C2=C1N(CC1)CCC1C(N(C=1)CCN(C)C)=NC=1C1=CC=C(F)C(Cl)=C1 NFPZITBMKVNLQV-UHFFFAOYSA-N 0.000 description 1
- GMMWNTHAIOJBSD-UHFFFAOYSA-N 6-chloro-4-n-(2,3-dimethylphenyl)-2-n,2-n-dimethylpyrimidine-2,4-diamine Chemical compound CN(C)C1=NC(Cl)=CC(NC=2C(=C(C)C=CC=2)C)=N1 GMMWNTHAIOJBSD-UHFFFAOYSA-N 0.000 description 1
- JXWNOQTXWANKCA-UHFFFAOYSA-N 6-chloro-7,9-dihydropurin-8-one 6-chloropyrimidine-4,5-diamine Chemical compound ClC1=C(C(=NC=N1)N)N.ClC1=C2NC(NC2=NC=N1)=O JXWNOQTXWANKCA-UHFFFAOYSA-N 0.000 description 1
- FKMGLNYKCUEHNV-UHFFFAOYSA-N 6-chloro-7-ethyl-9h-purin-8-one Chemical compound N1=CN=C2NC(=O)N(CC)C2=C1Cl FKMGLNYKCUEHNV-UHFFFAOYSA-N 0.000 description 1
- LBJNNYQNAUVPGR-UHFFFAOYSA-N 6-chloro-7-methyl-9h-purin-8-one Chemical compound N1=CN=C2NC(=O)N(C)C2=C1Cl LBJNNYQNAUVPGR-UHFFFAOYSA-N 0.000 description 1
- LJRCLNWXOAJUEN-UHFFFAOYSA-N 7-[(2,4-dimethoxyphenyl)methyl]-4-[4-[1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]imidazol-2-yl]piperidin-1-yl]-5h-pyrrolo[2,3-d]pyrimidin-6-one Chemical compound COC1=CC(OC)=CC=C1CN1C(N=CN=C2N3CCC(CC3)C=3N(C=C(N=3)C=3C=C(C(F)=CC=3)C(F)(F)F)CCN(C)C)=C2CC1=O LJRCLNWXOAJUEN-UHFFFAOYSA-N 0.000 description 1
- 101100001348 AKT8 murine leukemia virus V-AKT gene Proteins 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
- 108010039627 Aprotinin Proteins 0.000 description 1
- FHFDZRWNKVIYCA-UHFFFAOYSA-M C(C)(=O)[O-].C(C)[Br+] Chemical compound C(C)(=O)[O-].C(C)[Br+] FHFDZRWNKVIYCA-UHFFFAOYSA-M 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940122644 Chymotrypsin inhibitor Drugs 0.000 description 1
- IIVVPYVZUYQICO-UHFFFAOYSA-N Cl.ClCCN(C)C.C(C)(C)(C)OC(=O)N1CCC(CC1)C=1N(C=C(N1)C1=CC(=C(C=C1)F)Cl)CCN(C)C Chemical compound Cl.ClCCN(C)C.C(C)(C)(C)OC(=O)N1CCC(CC1)C=1N(C=C(N1)C1=CC(=C(C=C1)F)Cl)CCN(C)C IIVVPYVZUYQICO-UHFFFAOYSA-N 0.000 description 1
- BPKSJCCQUGVONY-HNCPQSOCSA-N Cl.FC1=C(C=C(C=C1)C(CN[C@H]1CN(CCC1)C(=O)O)=O)C(F)(F)F Chemical compound Cl.FC1=C(C=C(C=C1)C(CN[C@H]1CN(CCC1)C(=O)O)=O)C(F)(F)F BPKSJCCQUGVONY-HNCPQSOCSA-N 0.000 description 1
- CZXMSNPUIWAQQA-UHFFFAOYSA-N ClC=1C2=C(N=CN1)N=CC21CCCC1 Chemical compound ClC=1C2=C(N=CN1)N=CC21CCCC1 CZXMSNPUIWAQQA-UHFFFAOYSA-N 0.000 description 1
- SRUWWOSWHXIIIA-UKPGNTDSSA-N Cyanoginosin Chemical compound N1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](C)[C@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C(=C)N(C)C(=O)CC[C@H](C(O)=O)N(C)C(=O)[C@@H](C)[C@@H]1\C=C\C(\C)=C\[C@H](C)[C@@H](O)CC1=CC=CC=C1 SRUWWOSWHXIIIA-UKPGNTDSSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- HVVNJUAVDAZWCB-RXMQYKEDSA-N D-prolinol Chemical compound OC[C@H]1CCCN1 HVVNJUAVDAZWCB-RXMQYKEDSA-N 0.000 description 1
- 238000002965 ELISA Methods 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
- CFNOGBSEZGRDEI-UHFFFAOYSA-N FC(C=CC(C1=CN(CCN2CCCC2)C(C2CCNCC2)=N1)=C1)=C1Cl.Cl Chemical compound FC(C=CC(C1=CN(CCN2CCCC2)C(C2CCNCC2)=N1)=C1)=C1Cl.Cl CFNOGBSEZGRDEI-UHFFFAOYSA-N 0.000 description 1
- XGCFOZBHINAGSN-UHFFFAOYSA-N FC(C=CC(C1=CN(CCN2CCCC2)C(C2CCNCC2)=N1)=C1)=C1F.Cl Chemical compound FC(C=CC(C1=CN(CCN2CCCC2)C(C2CCNCC2)=N1)=C1)=C1F.Cl XGCFOZBHINAGSN-UHFFFAOYSA-N 0.000 description 1
- UKLBGZCUFGNHLU-UHFFFAOYSA-N FC=1C=C(C=CC1F)C=1N=C(NC1)C1CCN(CC1)C(=O)O.C(C)(C)(C)OC(=O)N1CCC(CC1)C=1N(C=C(N1)C1=CC(=C(C=C1)F)F)CCN(C)C Chemical compound FC=1C=C(C=CC1F)C=1N=C(NC1)C1CCN(CC1)C(=O)O.C(C)(C)(C)OC(=O)N1CCC(CC1)C=1N(C=C(N1)C1=CC(=C(C=C1)F)F)CCN(C)C UKLBGZCUFGNHLU-UHFFFAOYSA-N 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 1
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 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 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100020870 La-related protein 6 Human genes 0.000 description 1
- 108050008265 La-related protein 6 Proteins 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 241001473279 Liatris Species 0.000 description 1
- 235000010838 Margyricarpus pinnatus Nutrition 0.000 description 1
- 240000000786 Margyricarpus pinnatus Species 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 1
- QWEVSSMPXOBHRL-UHFFFAOYSA-N NC=1C(=NC=NC1Cl)Cl.ClC1=NC=NC(=C1NC)Cl Chemical compound NC=1C(=NC=NC1Cl)Cl.ClC1=NC=NC(=C1NC)Cl QWEVSSMPXOBHRL-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 206010034962 Photopsia Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000003861 Ribosomal protein S6 Human genes 0.000 description 1
- 108090000221 Ribosomal protein S6 Proteins 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- FKMJXALNHKIDOD-LBPRGKRZSA-N TAMe Chemical compound NC(=N)NCCC[C@@H](C(=O)OC)NS(=O)(=O)C1=CC=C(C)C=C1 FKMJXALNHKIDOD-LBPRGKRZSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- KHPWHJVKPZIZRG-CYBMUJFWSA-N [(2r)-1-benzylpiperidin-2-yl]methanol Chemical compound OC[C@H]1CCCCN1CC1=CC=CC=C1 KHPWHJVKPZIZRG-CYBMUJFWSA-N 0.000 description 1
- KYIKRXIYLAGAKQ-UHFFFAOYSA-N abcn Chemical compound C1CCCCC1(C#N)N=NC1(C#N)CCCCC1 KYIKRXIYLAGAKQ-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229940110282 alimta Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 229960004754 astemizole Drugs 0.000 description 1
- SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 1
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- RGFUAJNJTBJJTL-UHFFFAOYSA-N benzonitrile;trihydrochloride Chemical compound Cl.Cl.Cl.N#CC1=CC=CC=C1 RGFUAJNJTBJJTL-UHFFFAOYSA-N 0.000 description 1
- SIONIIVXRCVHFL-OAHLLOKOSA-N benzyl (3r)-3-[(2-methylpropan-2-yl)oxycarbonylamino]piperidine-1-carboxylate Chemical compound C1[C@H](NC(=O)OC(C)(C)C)CCCN1C(=O)OCC1=CC=CC=C1 SIONIIVXRCVHFL-OAHLLOKOSA-N 0.000 description 1
- NXLHXKQZPMJMPL-UHFFFAOYSA-N benzyl 2-[(4-methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1N(C(=O)OCC=2C=CC=CC=2)CCC1 NXLHXKQZPMJMPL-UHFFFAOYSA-N 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- DHCLVCXQIBBOPH-UHFFFAOYSA-N beta-glycerol phosphate Natural products OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 1
- GHRQXJHBXKYCLZ-UHFFFAOYSA-L beta-glycerolphosphate Chemical compound [Na+].[Na+].CC(CO)OOP([O-])([O-])=O GHRQXJHBXKYCLZ-UHFFFAOYSA-L 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- JECOSSASMXAXFV-UHFFFAOYSA-N chloroethane;hydrochloride Chemical compound Cl.CCCl JECOSSASMXAXFV-UHFFFAOYSA-N 0.000 description 1
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 1
- 239000003541 chymotrypsin inhibitor Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 1
- 108010024505 crosstide peptide Proteins 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- IXTMWRCNAAVVAI-UHFFFAOYSA-N dofetilide Chemical compound C=1C=C(NS(C)(=O)=O)C=CC=1CCN(C)CCOC1=CC=C(NS(C)(=O)=O)C=C1 IXTMWRCNAAVVAI-UHFFFAOYSA-N 0.000 description 1
- 229960002994 dofetilide Drugs 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- RWLDAJMGAVDXSH-UHFFFAOYSA-N ethane-1,1,2-tricarboxylic acid Chemical compound OC(=O)CC(C(O)=O)C(O)=O RWLDAJMGAVDXSH-UHFFFAOYSA-N 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- ZMNVHLAMRJXIJK-UHFFFAOYSA-N ethyl 2-(4,6-dichloropyrimidin-5-yl)acetate Chemical compound CCOC(=O)CC1=C(Cl)N=CN=C1Cl ZMNVHLAMRJXIJK-UHFFFAOYSA-N 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- GTCCMGFBIWUBLQ-UHFFFAOYSA-N formamide;hydrochloride Chemical compound Cl.NC=O GTCCMGFBIWUBLQ-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- DWKBWEQGJORTQY-UHFFFAOYSA-N methyl 2-[4-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyrimidin-5-yl]acetate Chemical compound COC(=O)CC1=C(Cl)N=CN=C1NCC1=CC=C(OC)C=C1OC DWKBWEQGJORTQY-UHFFFAOYSA-N 0.000 description 1
- NIGZBZBAGCSDGV-UHFFFAOYSA-N methyl 2-[4-chloro-6-[(4-methoxyphenyl)methylamino]pyrimidin-5-yl]acetate Chemical compound COC(=O)CC1=C(Cl)N=CN=C1NCC1=CC=C(OC)C=C1 NIGZBZBAGCSDGV-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical group 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 108010067094 microcystin Proteins 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000008185 minitablet Substances 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QSRNOFDYCBMUHQ-UHFFFAOYSA-N n-(5-bromothiophen-2-yl)sulfonyl-2,4-dichlorobenzamide;sodium Chemical compound [Na].ClC1=CC(Cl)=CC=C1C(=O)NS(=O)(=O)C1=CC=C(Br)S1 QSRNOFDYCBMUHQ-UHFFFAOYSA-N 0.000 description 1
- IPFLRBKGUDQKOI-UHFFFAOYSA-N n-[2-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-ylimidazol-1-yl]ethyl]-n-methylpropan-2-amine Chemical compound CC(C)N(C)CCN1C=C(C=2C=C(C(F)=CC=2)C(F)(F)F)N=C1C1CCNCC1 IPFLRBKGUDQKOI-UHFFFAOYSA-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
- FTNFEHXDETWERN-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]-2,6-dimethyl-5-[(4-propan-2-yloxyphenyl)methyl]pyrimidin-4-amine Chemical compound C1=CC(OC(C)C)=CC=C1CC1=C(C)N=C(C)N=C1NP(=O)(N1CC1)N1CC1 FTNFEHXDETWERN-UHFFFAOYSA-N 0.000 description 1
- XHXVAJHZTIXQQD-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]-5-[(4-butoxyphenyl)methyl]-2,6-dimethylpyrimidin-4-amine Chemical compound C1=CC(OCCCC)=CC=C1CC1=C(C)N=C(C)N=C1NP(=O)(N1CC1)N1CC1 XHXVAJHZTIXQQD-UHFFFAOYSA-N 0.000 description 1
- ILAJAEJGLCKZMG-UHFFFAOYSA-N n-benzyl-2-chloro-n-methylethanamine;dihydrochloride Chemical compound Cl.Cl.ClCCN(C)CC1=CC=CC=C1 ILAJAEJGLCKZMG-UHFFFAOYSA-N 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229910000065 phosphene Inorganic materials 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- OHEDMAIVEXQCOZ-UHFFFAOYSA-N piperidine;dihydrochloride Chemical compound Cl.Cl.C1CCNCC1 OHEDMAIVEXQCOZ-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- ATLPLEZDTSBZQG-UHFFFAOYSA-N propan-2-ylphosphonic acid Chemical compound CC(C)P(O)(O)=O ATLPLEZDTSBZQG-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- DGIAHBRNEWBZAE-UHFFFAOYSA-N pyrimidine-4,5-dione Chemical compound O=C1C=NC=NC1=O DGIAHBRNEWBZAE-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028706 ribosome biogenesis Effects 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229940063683 taxotere Drugs 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
- 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
- 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 1
- VBTGHGZYWRPETH-UHFFFAOYSA-N tert-butyl 4-[4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(F)C(F)=CC=2)=CN1CCO VBTGHGZYWRPETH-UHFFFAOYSA-N 0.000 description 1
- UWJUDLBHRWOJBK-UHFFFAOYSA-N tert-butyl 4-[4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(Cl)C(F)=CC=2)=CN1CCO UWJUDLBHRWOJBK-UHFFFAOYSA-N 0.000 description 1
- BXYWLTTYUCUMJC-UHFFFAOYSA-N tert-butyl 4-[4-(3-chloro-4-fluorophenyl)-1-(2-methylsulfonyloxyethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(Cl)C(F)=CC=2)=CN1CCOS(C)(=O)=O BXYWLTTYUCUMJC-UHFFFAOYSA-N 0.000 description 1
- BQWIIWXJLRPGFE-UHFFFAOYSA-N tert-butyl 4-[4-(3-chloro-4-fluorophenyl)-1-(cyanomethyl)imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(Cl)C(F)=CC=2)=CN1CC#N BQWIIWXJLRPGFE-UHFFFAOYSA-N 0.000 description 1
- XZSSCEVZFOYYSI-GOSISDBHSA-N tert-butyl 4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-[(3r)-piperidin-3-yl]imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(C(F)=CC=2)C(F)(F)F)=CN1[C@H]1CNCCC1 XZSSCEVZFOYYSI-GOSISDBHSA-N 0.000 description 1
- 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 1
- 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 1
- ZTWUNSDSBMTLNL-UHFFFAOYSA-N tert-butyl 4-[5-(3-chloro-4-fluorophenyl)-1h-imidazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C=2C=C(Cl)C(F)=CC=2)=CN1 ZTWUNSDSBMTLNL-UHFFFAOYSA-N 0.000 description 1
- 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 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229940100411 torisel Drugs 0.000 description 1
- 238000004481 total suppression of sideband Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- 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
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Neurology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurosurgery (AREA)
- Child & Adolescent Psychology (AREA)
- Pulmonology (AREA)
- Emergency Medicine (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11327308P | 2008-11-11 | 2008-11-11 | |
| PCT/US2009/063020 WO2010056563A1 (en) | 2008-11-11 | 2009-11-03 | Akt and p70 s6 kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2011005000A true MX2011005000A (es) | 2011-05-25 |
Family
ID=41402451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2011005000A MX2011005000A (es) | 2008-11-11 | 2009-11-03 | Inhibidores de cinasa akt y p70 s6. |
Country Status (36)
| Country | Link |
|---|---|
| US (1) | US8148387B2 (OSRAM) |
| EP (1) | EP2358710B1 (OSRAM) |
| JP (1) | JP5432275B2 (OSRAM) |
| KR (1) | KR101334460B1 (OSRAM) |
| CN (1) | CN102216302B (OSRAM) |
| AR (1) | AR074072A1 (OSRAM) |
| AU (1) | AU2009314324B2 (OSRAM) |
| BR (1) | BRPI0921916A2 (OSRAM) |
| CA (1) | CA2743019C (OSRAM) |
| CO (1) | CO6382114A2 (OSRAM) |
| CR (1) | CR20110240A (OSRAM) |
| CY (1) | CY1113409T1 (OSRAM) |
| DK (1) | DK2358710T3 (OSRAM) |
| DO (1) | DOP2011000129A (OSRAM) |
| EA (1) | EA018947B1 (OSRAM) |
| EC (1) | ECSP11011048A (OSRAM) |
| ES (1) | ES2391704T3 (OSRAM) |
| HN (1) | HN2011001247A (OSRAM) |
| HR (1) | HRP20120738T1 (OSRAM) |
| IL (1) | IL211940A (OSRAM) |
| JO (1) | JO2822B1 (OSRAM) |
| MA (1) | MA32776B1 (OSRAM) |
| MX (1) | MX2011005000A (OSRAM) |
| MY (1) | MY161461A (OSRAM) |
| NZ (1) | NZ592062A (OSRAM) |
| PA (1) | PA8846901A1 (OSRAM) |
| PE (1) | PE20110807A1 (OSRAM) |
| PL (1) | PL2358710T3 (OSRAM) |
| PT (1) | PT2358710E (OSRAM) |
| RS (1) | RS52520B (OSRAM) |
| SI (1) | SI2358710T1 (OSRAM) |
| TN (1) | TN2011000207A1 (OSRAM) |
| TW (1) | TWI422587B (OSRAM) |
| UA (1) | UA100190C2 (OSRAM) |
| WO (1) | WO2010056563A1 (OSRAM) |
| ZA (1) | ZA201102549B (OSRAM) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20120106714A (ko) | 2009-07-02 | 2012-09-26 | 사노피 | 신규 (6-옥소-1,6-디히드로-피리미딘-2-일)아미드 유도체, 그의 제조법, 및 ａｋｔ(ｐｋｂ) 인산화 억제제로서의 그의 제약 용도 |
| MX2012004780A (es) * | 2009-10-23 | 2012-08-23 | Lilly Co Eli | Inhibidores de akt. |
| HUE026323T2 (en) | 2011-04-07 | 2016-05-30 | Bayer Ip Gmbh | Imidazopyridazines as akt kinase inhibitors |
| US8927572B2 (en) * | 2011-07-09 | 2015-01-06 | Xuanzhu Pharma Co., Ltd. | Crystal form I of salt of a dipeptidyl peptidase-IV inhibitor and preparation method and use thereof |
| WO2013040059A1 (en) | 2011-09-12 | 2013-03-21 | Merck Patent Gmbh | Novel imidazole amines as modulators of kinase activity |
| WO2013040044A1 (en) | 2011-09-12 | 2013-03-21 | Merck Patent Gmbh | Aminopyrimidine derivatives for use as modulators of kinase activity |
| AR093512A1 (es) | 2012-11-16 | 2015-06-10 | Merck Patent Gmbh | Derivados heterociclicos como moduladores de la actividad de cinasas |
| WO2014078634A1 (en) | 2012-11-16 | 2014-05-22 | Merck Patent Gmbh | Novel imidazol-piperidinyl derivatives as modulators of kinase activity |
| WO2014143612A1 (en) * | 2013-03-11 | 2014-09-18 | Merck Patent Gmbh | 6-[4-(1 h-imidazol-2-yl)piperidin-1 -yl]pyrimidin-4-amine derivatives as modulators of kinase activity |
| MX2016010268A (es) * | 2014-02-11 | 2016-10-13 | Merck Patent Gmbh | Pirimidinimidazolaminas como modulares de actividad de cinasa. |
| TW201718574A (zh) | 2015-08-12 | 2017-06-01 | 美國禮來大藥廠 | Ｃｇｒｐ受體拮抗劑 |
| WO2017200087A1 (ja) * | 2016-05-20 | 2017-11-23 | 大鵬薬品工業株式会社 | 新規５Ｈ－ピロロ［２，３－ｄ］ピリミジン－６（７Ｈ）－オン誘導体 |
| MX2022011188A (es) | 2020-03-17 | 2022-11-08 | Jiangsu Hengrui Pharmaceuticals Co Ltd | Derivado biciclico fusionado, metodo de preparacion y uso farmaceutico del mismo. |
| CN113444110B (zh) * | 2020-03-25 | 2023-05-12 | 江苏恒瑞医药股份有限公司 | 四氢吡咯并吡唑类衍生物、其制备方法及其在医药上的应用 |
| JP2024535857A (ja) | 2021-09-17 | 2024-10-02 | 江▲蘇▼恒瑞医▲薬▼股▲フン▼有限公司 | 縮合二環系誘導体の薬学的に許容される塩、結晶及びそれらの調製方法 |
| JPWO2024009977A1 (OSRAM) * | 2022-07-05 | 2024-01-11 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2005249380C1 (en) | 2004-04-23 | 2012-09-20 | Exelixis, Inc. | Kinase modulators and methods of use |
| 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 |
| WO2006071819A1 (en) | 2004-12-28 | 2006-07-06 | 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 |
| US7423043B2 (en) * | 2005-02-18 | 2008-09-09 | Lexicon Pharmaceuticals, Inc. | 4-Piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine compounds |
| US20090325924A1 (en) | 2005-06-30 | 2009-12-31 | Stuart Edward | GPCR Agonists |
| EP2037931A2 (en) | 2006-04-25 | 2009-03-25 | Astex Therapeutics Limited | Pharmaceutical combinations of pk inhibitors and other active agents |
| FI3719018T3 (fi) | 2006-04-25 | 2025-10-07 | Astex Therapeutics Ltd | Puriini- ja deatsapuriinijohdannaisia farmaseuttisina yhdisteinä |
| WO2008012635A2 (en) | 2006-07-26 | 2008-01-31 | Pfizer Products Inc. | Amine derivatives useful as anticancer agents |
| 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 |
-
2009
- 2009-10-28 AR ARP090104158A patent/AR074072A1/es unknown
- 2009-10-29 TW TW098136731A patent/TWI422587B/zh not_active IP Right Cessation
- 2009-10-29 JO JO2009400A patent/JO2822B1/en active
- 2009-10-29 PA PA20098846901A patent/PA8846901A1/es unknown
- 2009-11-03 EA EA201170680A patent/EA018947B1/ru not_active IP Right Cessation
- 2009-11-03 UA UAA201105367A patent/UA100190C2/ru unknown
- 2009-11-03 BR BRPI0921916A patent/BRPI0921916A2/pt not_active IP Right Cessation
- 2009-11-03 JP JP2011536383A patent/JP5432275B2/ja active Active
- 2009-11-03 NZ NZ592062A patent/NZ592062A/xx not_active IP Right Cessation
- 2009-11-03 CA CA2743019A patent/CA2743019C/en not_active Expired - Fee Related
- 2009-11-03 SI SI200930348T patent/SI2358710T1/sl unknown
- 2009-11-03 PT PT09744896T patent/PT2358710E/pt unknown
- 2009-11-03 PL PL09744896T patent/PL2358710T3/pl unknown
- 2009-11-03 MY MYPI2011002030A patent/MY161461A/en unknown
- 2009-11-03 HR HRP20120738AT patent/HRP20120738T1/hr unknown
- 2009-11-03 US US12/611,139 patent/US8148387B2/en active Active
- 2009-11-03 KR KR1020117010569A patent/KR101334460B1/ko not_active Expired - Fee Related
- 2009-11-03 ES ES09744896T patent/ES2391704T3/es active Active
- 2009-11-03 AU AU2009314324A patent/AU2009314324B2/en not_active Ceased
- 2009-11-03 DK DK09744896.3T patent/DK2358710T3/da active
- 2009-11-03 RS RS20120443A patent/RS52520B/sr unknown
- 2009-11-03 WO PCT/US2009/063020 patent/WO2010056563A1/en not_active Ceased
- 2009-11-03 EP EP09744896A patent/EP2358710B1/en active Active
- 2009-11-03 CN CN2009801449532A patent/CN102216302B/zh active Active
- 2009-11-03 PE PE2011001018A patent/PE20110807A1/es not_active Application Discontinuation
- 2009-11-03 MX MX2011005000A patent/MX2011005000A/es active IP Right Grant
-
2011
- 2011-03-24 IL IL211940A patent/IL211940A/en not_active IP Right Cessation
- 2011-04-06 ZA ZA2011/02549A patent/ZA201102549B/en unknown
- 2011-04-25 TN TN2011000207A patent/TN2011000207A1/fr unknown
- 2011-05-03 HN HN2011001247A patent/HN2011001247A/es unknown
- 2011-05-06 CR CR20110240A patent/CR20110240A/es unknown
- 2011-05-09 MA MA33822A patent/MA32776B1/fr unknown
- 2011-05-09 DO DO2011000129A patent/DOP2011000129A/es unknown
- 2011-05-11 EC EC2011011048A patent/ECSP11011048A/es unknown
- 2011-05-12 CO CO11058555A patent/CO6382114A2/es active IP Right Grant
-
2012
- 2012-10-05 CY CY20121100928T patent/CY1113409T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8148387B2 (en) | AKT and P70 S6 kinase inhibitors | |
| AU2017287762B2 (en) | Pyrazolopyrimidine derivatives as kinase inhibitor | |
| AU2008251692B2 (en) | P70 S6 kinase inhibitors | |
| AU2010310786B2 (en) | AKT inhibitors | |
| CA2880251C (en) | Novel heteroaryl and heterocycle compounds, composition and methods thereof | |
| JP2023509886A (ja) | 環式化合物およびその使用方法 | |
| HK1158203B (en) | Akt and p70 s6 kinase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG | Grant or registration |