CN113272304A - Akt抑制剂 - Google Patents
Akt抑制剂 Download PDFInfo
- Publication number
- CN113272304A CN113272304A CN202080005749.9A CN202080005749A CN113272304A CN 113272304 A CN113272304 A CN 113272304A CN 202080005749 A CN202080005749 A CN 202080005749A CN 113272304 A CN113272304 A CN 113272304A
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- CN
- China
- Prior art keywords
- methyl
- compound
- alkyl
- formula
- optionally substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000003197 protein kinase B inhibitor Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 246
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 claims abstract description 26
- 108091008611 Protein Kinase B Proteins 0.000 claims abstract description 20
- 230000001404 mediated effect Effects 0.000 claims abstract description 8
- -1 halo-C1-C3 alkoxy Chemical group 0.000 claims description 122
- 229910052757 nitrogen Inorganic materials 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 37
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- OWOJTYIGFIFRFV-BOFXEDATSA-N (5R)-4-[(3aS,6aS)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one Chemical compound C[C@@H]1CC(=O)NC2=C1C(=NC=N2)N3C[C@H]4CN(C[C@@H]4C3)C(=O)[C@H](CNC(C)C)C5=CC=C(C=C5)Cl OWOJTYIGFIFRFV-BOFXEDATSA-N 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims 6
- 238000002360 preparation method Methods 0.000 abstract description 19
- 229940126638 Akt inhibitor Drugs 0.000 abstract description 2
- 230000006806 disease prevention Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 239
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 162
- 238000006243 chemical reaction Methods 0.000 description 157
- 239000000243 solution Substances 0.000 description 150
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 141
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 102
- 239000007787 solid Substances 0.000 description 97
- 239000011541 reaction mixture Substances 0.000 description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 88
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 72
- 238000005160 1H NMR spectroscopy Methods 0.000 description 70
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- 229910001868 water Inorganic materials 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- 239000012074 organic phase Substances 0.000 description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 56
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
- 239000000047 product Substances 0.000 description 51
- 239000012043 crude product Substances 0.000 description 46
- 230000002829 reductive effect Effects 0.000 description 46
- 239000012071 phase Substances 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 239000002904 solvent Substances 0.000 description 40
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 37
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000013078 crystal Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000003208 petroleum Substances 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 31
- 238000004808 supercritical fluid chromatography Methods 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 29
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 125000006239 protecting group Chemical group 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 22
- 125000006242 amine protecting group Chemical group 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 21
- GQWRBNJRKSPGTF-CQSZACIVSA-N (2s)-2-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N(C(C)C)C[C@@H](C(O)=O)C1=CC=C(Cl)C=C1 GQWRBNJRKSPGTF-CQSZACIVSA-N 0.000 description 19
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 19
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 19
- 239000000758 substrate Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000000605 extraction Methods 0.000 description 17
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- 238000004440 column chromatography Methods 0.000 description 16
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 16
- 238000010839 reverse transcription Methods 0.000 description 16
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- 238000002474 experimental method Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
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- 239000012224 working solution Substances 0.000 description 11
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- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
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- 238000003786 synthesis reaction Methods 0.000 description 10
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 9
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- HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- HUHJIJQHHFHKQG-UHFFFAOYSA-N 2-tert-butylpiperazine-1-carboxylic acid Chemical compound CC(C)(C)C1CNCCN1C(O)=O HUHJIJQHHFHKQG-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- ZFDIRQKJPRINOQ-HWKANZROSA-N Ethyl crotonate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 description 5
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- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
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- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 5
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- OVPLZYJGTGDFNB-UHFFFAOYSA-N propan-2-yl carbamate Chemical compound CC(C)OC(N)=O OVPLZYJGTGDFNB-UHFFFAOYSA-N 0.000 description 5
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- 238000006467 substitution reaction Methods 0.000 description 5
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- 239000013641 positive control Substances 0.000 description 1
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- 238000002953 preparative HPLC Methods 0.000 description 1
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- 239000008213 purified water Substances 0.000 description 1
- OXSUQJLHQKSPNE-UHFFFAOYSA-N pyrano[2,3-d]triazole Chemical compound C1=COC2=NN=NC2=C1 OXSUQJLHQKSPNE-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 1
- USBQLUCOUDCOKL-LLVKDONJSA-N tert-butyl 4-[(5R)-5-methyl-7-oxo-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylate Chemical compound C[C@@H]1CC(=O)NC2=C1C(=NC=N2)N3CCN(CC3)C(=O)OC(C)(C)C USBQLUCOUDCOKL-LLVKDONJSA-N 0.000 description 1
- CYNDJHYFGQNZNQ-LLVKDONJSA-N tert-butyl 4-[(5R)-5-methyl-7-oxo-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-4-yl]piperidine-1-carboxylate Chemical compound C[C@@H]1CC(=O)NC2=NC=NC(=C12)C3CCN(CC3)C(=O)OC(C)(C)C CYNDJHYFGQNZNQ-LLVKDONJSA-N 0.000 description 1
- HNFTYGHQZXLBBV-UHFFFAOYSA-N tert-butyl 4-[6-amino-5-(1-hydroxyethyl)pyrimidin-4-yl]piperazine-1-carboxylate Chemical compound NC1=C(C(=NC=N1)N1CCN(CC1)C(=O)OC(C)(C)C)C(C)O HNFTYGHQZXLBBV-UHFFFAOYSA-N 0.000 description 1
- ZTNTYCJGYJIXNW-VOMCLLRMSA-N tert-butyl 5-[(5R)-5-methyl-7-oxo-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-4-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C2CC2N(CC1)C=1C2=C(N=CN1)NC(C[C@H]2C)=O ZTNTYCJGYJIXNW-VOMCLLRMSA-N 0.000 description 1
- GDXNFNLTRZQPET-UHFFFAOYSA-N tert-butyl N-[2-(4-chlorophenyl)-3-[4-(5-methyl-7-oxo-6,8-dihydropteridin-4-yl)piperazin-1-yl]-3-oxopropyl]-N-propan-2-ylcarbamate Chemical compound CC(C)N(CC(C1=CC=C(C=C1)Cl)C(=O)N2CCN(CC2)C3=NC=NC4=C3N(CC(=O)N4)C)C(=O)OC(C)(C)C GDXNFNLTRZQPET-UHFFFAOYSA-N 0.000 description 1
- NOAKRSCVGXYIPI-UHFFFAOYSA-N tert-butyl N-cyclopropyl-N-(methoxymethyl)carbamate Chemical compound CC(C)(C)OC(=O)N(COC)C1CC1 NOAKRSCVGXYIPI-UHFFFAOYSA-N 0.000 description 1
- OEQJOYQHIGIVTN-UHFFFAOYSA-N tert-butyl nonanoate Chemical compound CCCCCCCCC(=O)OC(C)(C)C OEQJOYQHIGIVTN-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了AKT抑制剂，具体地，涉及式I所示的化合物或其药学上可接受的盐。本发明还提供了其制备方法，以及用于预防和/或治疗AKT蛋白激酶介导的疾病的用途。
Description
PCT国内申请，说明书已公开。
Claims (16)
- PCT国内申请，权利要求书已公开。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410142331.2A CN117964620A (zh) | 2019-01-29 | 2020-01-22 | Akt抑制剂 |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910084801 | 2019-01-29 | ||
| CN2019100848013 | 2019-01-29 | ||
| PCT/CN2020/073798 WO2020156437A1 (zh) | 2019-01-29 | 2020-01-22 | Akt抑制剂 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410142331.2A Division CN117964620A (zh) | 2019-01-29 | 2020-01-22 | Akt抑制剂 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113272304A true CN113272304A (zh) | 2021-08-17 |
| CN113272304B CN113272304B (zh) | 2024-03-29 |
Family
ID=71841634
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080005749.9A Active CN113272304B (zh) | 2019-01-29 | 2020-01-22 | Akt抑制剂 |
| CN202410142331.2A Pending CN117964620A (zh) | 2019-01-29 | 2020-01-22 | Akt抑制剂 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410142331.2A Pending CN117964620A (zh) | 2019-01-29 | 2020-01-22 | Akt抑制剂 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20220144821A1 (zh) |
| EP (1) | EP3919491A4 (zh) |
| JP (1) | JP2022517866A (zh) |
| KR (1) | KR20210120054A (zh) |
| CN (2) | CN113272304B (zh) |
| AU (1) | AU2020214258A1 (zh) |
| CA (1) | CA3127884A1 (zh) |
| WO (1) | WO2020156437A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115836069A (zh) * | 2020-07-22 | 2023-03-21 | 南京正大天晴制药有限公司 | 一种二氢吡啶并[2,3-d]嘧啶酮衍生物的盐、其制备方法及用途 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021228223A1 (zh) * | 2020-05-15 | 2021-11-18 | 南京正大天晴制药有限公司 | 氘代akt激酶抑制剂 |
| WO2022017448A1 (zh) * | 2020-07-22 | 2022-01-27 | 南京正大天晴制药有限公司 | 一种二氢吡啶并[2,3-d]嘧啶酮衍生物的盐及晶型 |
| CN115916350A (zh) * | 2020-07-22 | 2023-04-04 | 南京正大天晴制药有限公司 | Akt抑制剂的单位剂量组合物 |
| WO2024146599A1 (zh) * | 2023-01-06 | 2024-07-11 | 南京正大天晴制药有限公司 | 一种二氢吡啶并[2,3-d]嘧啶酮的衍生物、其制备方法以及医药用途 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1882347A (zh) * | 2003-11-21 | 2006-12-20 | 阿雷生物药品公司 | Akt蛋白激酶抑制剂 |
| WO2009089462A1 (en) * | 2008-01-09 | 2009-07-16 | Array Biopharma Inc. | 5h-cyclopenta[d]pyrimidines as akt protein kinase inhibitors |
| CN101578273A (zh) * | 2006-07-06 | 2009-11-11 | 阵列生物制药公司 | 作为akt蛋白激酶抑制剂的羟基化和甲氧基化的环戊二烯并[d]嘧啶 |
| US20130065908A1 (en) * | 2009-12-07 | 2013-03-14 | Array Biopharma Inc. | Dihydrofuro pyrimidines as akt protein kinase inhibitors |
| CN105051043A (zh) * | 2012-11-16 | 2015-11-11 | 默克专利有限公司 | 用作激酶活性调节剂的新颖的杂环类衍生物 |
| CN109020957A (zh) * | 2017-06-12 | 2018-12-18 | 南京天印健华医药科技有限公司 | 作为mnk抑制剂的杂环化合物 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2049500B1 (en) | 2006-07-06 | 2011-09-07 | Array Biopharma, Inc. | Cyclopenta [d] pyrimidines as akt protein kinase inhibitors |
| WO2008006025A1 (en) | 2006-07-06 | 2008-01-10 | Array Biopharma Inc. | Dihydrofuro pyrimidines as akt protein kinase inhibitors |
| EP2491032B1 (en) * | 2009-10-23 | 2014-04-16 | Eli Lilly and Company | Akt inhibitors |
-
2020
- 2020-01-22 US US17/426,047 patent/US20220144821A1/en active Pending
- 2020-01-22 CN CN202080005749.9A patent/CN113272304B/zh active Active
- 2020-01-22 CA CA3127884A patent/CA3127884A1/en active Pending
- 2020-01-22 EP EP20748221.7A patent/EP3919491A4/en active Pending
- 2020-01-22 JP JP2021543533A patent/JP2022517866A/ja active Pending
- 2020-01-22 AU AU2020214258A patent/AU2020214258A1/en active Pending
- 2020-01-22 WO PCT/CN2020/073798 patent/WO2020156437A1/zh unknown
- 2020-01-22 KR KR1020217027161A patent/KR20210120054A/ko unknown
- 2020-01-22 CN CN202410142331.2A patent/CN117964620A/zh active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1882347A (zh) * | 2003-11-21 | 2006-12-20 | 阿雷生物药品公司 | Akt蛋白激酶抑制剂 |
| CN101578273A (zh) * | 2006-07-06 | 2009-11-11 | 阵列生物制药公司 | 作为akt蛋白激酶抑制剂的羟基化和甲氧基化的环戊二烯并[d]嘧啶 |
| WO2009089462A1 (en) * | 2008-01-09 | 2009-07-16 | Array Biopharma Inc. | 5h-cyclopenta[d]pyrimidines as akt protein kinase inhibitors |
| US20130065908A1 (en) * | 2009-12-07 | 2013-03-14 | Array Biopharma Inc. | Dihydrofuro pyrimidines as akt protein kinase inhibitors |
| CN105051043A (zh) * | 2012-11-16 | 2015-11-11 | 默克专利有限公司 | 用作激酶活性调节剂的新颖的杂环类衍生物 |
| CN109020957A (zh) * | 2017-06-12 | 2018-12-18 | 南京天印健华医药科技有限公司 | 作为mnk抑制剂的杂环化合物 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115836069A (zh) * | 2020-07-22 | 2023-03-21 | 南京正大天晴制药有限公司 | 一种二氢吡啶并[2,3-d]嘧啶酮衍生物的盐、其制备方法及用途 |
| CN115836069B (zh) * | 2020-07-22 | 2024-02-06 | 南京正大天晴制药有限公司 | 一种二氢吡啶并[2,3-d]嘧啶酮衍生物的盐、其制备方法及用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020156437A1 (zh) | 2020-08-06 |
| KR20210120054A (ko) | 2021-10-06 |
| EP3919491A1 (en) | 2021-12-08 |
| US20220144821A1 (en) | 2022-05-12 |
| EP3919491A4 (en) | 2022-10-19 |
| CN117964620A (zh) | 2024-05-03 |
| CA3127884A1 (en) | 2020-08-06 |
| JP2022517866A (ja) | 2022-03-10 |
| AU2020214258A1 (en) | 2021-09-16 |
| CN113272304B (zh) | 2024-03-29 |
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