CN104045654A - Cdk抑制剂 - Google Patents
Cdk抑制剂 Download PDFInfo
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- CN104045654A CN104045654A CN201410184794.1A CN201410184794A CN104045654A CN 104045654 A CN104045654 A CN 104045654A CN 201410184794 A CN201410184794 A CN 201410184794A CN 104045654 A CN104045654 A CN 104045654A
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- Prior art keywords
- alkylene
- compound
- independently
- alkyl
- groups
- Prior art date
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- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 262
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 108
- 125000000623 heterocyclic group Chemical group 0.000 claims description 108
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 59
- 125000002950 monocyclic group Chemical group 0.000 claims description 51
- 125000002619 bicyclic group Chemical group 0.000 claims description 46
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 40
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 37
- 125000004429 atom Chemical group 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 28
- 125000001188 haloalkyl group Chemical group 0.000 claims description 28
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 26
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 26
- 125000000304 alkynyl group Chemical group 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 12
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 120
- 239000000543 intermediate Substances 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- 238000005160 1H NMR spectroscopy Methods 0.000 description 101
- -1 methylene, ethylene, propylene Chemical group 0.000 description 54
- 238000000034 method Methods 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- 150000003840 hydrochlorides Chemical class 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 38
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 229940126142 compound 16 Drugs 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 26
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 19
- 235000019341 magnesium sulphate Nutrition 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical compound ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 229940126214 compound 3 Drugs 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- QDMPMBFLXOWHRY-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)pyridin-2-amine Chemical compound C1CN(C)CCN1C1=CC=C(N)N=C1 QDMPMBFLXOWHRY-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 238000010511 deprotection reaction Methods 0.000 description 11
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- XSBLMLFNMRLZDG-UHFFFAOYSA-N 2-nitro-5-(4-piperidin-1-ylpiperidin-1-yl)pyridine Chemical compound C1=NC([N+](=O)[O-])=CC=C1N1CCC(N2CCCCC2)CC1 XSBLMLFNMRLZDG-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- XHVJXFULOMYGJI-UHFFFAOYSA-N 2-chloro-7-[3-methyl-1-[(2-methylpropan-2-yl)oxycarbonylamino]butan-2-yl]pyrrolo[2,3-d]pyrimidine-6-carboxylic acid Chemical compound N1=C(Cl)N=C2N(C(CNC(=O)OC(C)(C)C)C(C)C)C(C(O)=O)=CC2=C1 XHVJXFULOMYGJI-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 108091007914 CDKs Proteins 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- NYYTUGICDWNNQC-UHFFFAOYSA-N tert-butyl n-[2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-3-methylbutyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(C(C)C)NC1=NC(Cl)=NC=C1Br NYYTUGICDWNNQC-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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 5
- VOVGSMNZLTVENJ-AWEZNQCLSA-N (2s)-2-n-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methylpentane-1,2-diamine Chemical compound CCOC(OCC)C#CC1=CN=C(Cl)N=C1N[C@H](CN)CC(C)C VOVGSMNZLTVENJ-AWEZNQCLSA-N 0.000 description 4
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 4
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- 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 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- PDUYATICFBMIMB-UHFFFAOYSA-N [2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-3-methylbutyl]carbamic acid Chemical compound OC(=O)NCC(C(C)C)NC1=NC(Cl)=NC=C1Br PDUYATICFBMIMB-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- UVLUIWTZYZPWGC-UHFFFAOYSA-N tert-butyl n-[2-[(5-bromo-2-chloropyrimidin-4-yl)amino]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCNC1=NC(Cl)=NC=C1Br UVLUIWTZYZPWGC-UHFFFAOYSA-N 0.000 description 3
- WFZSPMOWKRQQKD-UHFFFAOYSA-N tert-butyl n-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate Chemical compound N1=C(Cl)N=C2N(CCNC(=O)OC(C)(C)C)C(C(OCC)OCC)=CC2=C1 WFZSPMOWKRQQKD-UHFFFAOYSA-N 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- KCBBEHBEAPOBSC-UHFFFAOYSA-N tert-butyl n-(2-amino-2-methylpropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC(C)(C)N KCBBEHBEAPOBSC-UHFFFAOYSA-N 0.000 description 1
- YWAMFTBALAAREO-UHFFFAOYSA-N tert-butyl n-(2-amino-3-methylbutyl)carbamate Chemical compound CC(C)C(N)CNC(=O)OC(C)(C)C YWAMFTBALAAREO-UHFFFAOYSA-N 0.000 description 1
- AKVIZYGPJIWKOS-IUCAKERBSA-N tert-butyl n-[(1s,2s)-2-aminocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1N AKVIZYGPJIWKOS-IUCAKERBSA-N 0.000 description 1
- GKTZYOHYPBQYAX-QMMMGPOBSA-N tert-butyl n-[(2r)-1-amino-3-methylbutan-2-yl]carbamate Chemical compound CC(C)[C@H](CN)NC(=O)OC(C)(C)C GKTZYOHYPBQYAX-QMMMGPOBSA-N 0.000 description 1
- OOQRRYDVICNJGC-QMMMGPOBSA-N tert-butyl n-[(2r)-1-hydroxy-3-methylbutan-2-yl]carbamate Chemical compound CC(C)[C@H](CO)NC(=O)OC(C)(C)C OOQRRYDVICNJGC-QMMMGPOBSA-N 0.000 description 1
- YWAMFTBALAAREO-QMMMGPOBSA-N tert-butyl n-[(2r)-2-amino-3-methylbutyl]carbamate Chemical compound CC(C)[C@@H](N)CNC(=O)OC(C)(C)C YWAMFTBALAAREO-QMMMGPOBSA-N 0.000 description 1
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- OOQRRYDVICNJGC-MRVPVSSYSA-N tert-butyl n-[(2s)-1-hydroxy-3-methylbutan-2-yl]carbamate Chemical compound CC(C)[C@@H](CO)NC(=O)OC(C)(C)C OOQRRYDVICNJGC-MRVPVSSYSA-N 0.000 description 1
- FADBBKWBMKJEAF-SNVBAGLBSA-N tert-butyl n-[(2s)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-3,3-dimethylbutyl]carbamate Chemical compound CC(C)(C)OC(=O)NC[C@H](C(C)(C)C)NC1=NC(Cl)=NC=C1Br FADBBKWBMKJEAF-SNVBAGLBSA-N 0.000 description 1
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- YWAMFTBALAAREO-MRVPVSSYSA-N tert-butyl n-[(2s)-2-amino-3-methylbutyl]carbamate Chemical compound CC(C)[C@H](N)CNC(=O)OC(C)(C)C YWAMFTBALAAREO-MRVPVSSYSA-N 0.000 description 1
- BFCMNWXASVSVGJ-YGPZHTELSA-N tert-butyl n-[(2s)-2-amino-3-methylpentyl]carbamate Chemical compound CCC(C)[C@H](N)CNC(=O)OC(C)(C)C BFCMNWXASVSVGJ-YGPZHTELSA-N 0.000 description 1
- OMUFVQWMZAPPGI-VIFPVBQESA-N tert-butyl n-[(2s)-2-amino-4-methylpentyl]carbamate Chemical compound CC(C)C[C@H](N)CNC(=O)OC(C)(C)C OMUFVQWMZAPPGI-VIFPVBQESA-N 0.000 description 1
- OQDLNTMUQOBGON-UHFFFAOYSA-N tert-butyl n-[2-(2-chloro-6-formylpyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate Chemical compound N1=C(Cl)N=C2N(CCNC(=O)OC(C)(C)C)C(C=O)=CC2=C1 OQDLNTMUQOBGON-UHFFFAOYSA-N 0.000 description 1
- QUMNDJHVKVMMDZ-UHFFFAOYSA-N tert-butyl n-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methylpropyl]carbamate Chemical compound CCOC(OCC)C#CC1=CN=C(Cl)N=C1NC(C)(C)CNC(=O)OC(C)(C)C QUMNDJHVKVMMDZ-UHFFFAOYSA-N 0.000 description 1
- PBXSLSMTGHZLQB-UHFFFAOYSA-N tert-butyl n-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-4-methylpentyl]carbamate Chemical compound CCOC(OCC)C#CC1=CN=C(Cl)N=C1NC(CNC(=O)OC(C)(C)C)CC(C)C PBXSLSMTGHZLQB-UHFFFAOYSA-N 0.000 description 1
- PAJAZOMVSJXCNJ-UHFFFAOYSA-N tert-butyl n-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclohexyl]methyl]carbamate Chemical compound CCOC(OCC)C#CC1=CN=C(Cl)N=C1NC1(CNC(=O)OC(C)(C)C)CCCCC1 PAJAZOMVSJXCNJ-UHFFFAOYSA-N 0.000 description 1
- LYHIBHHOKUUNDF-UHFFFAOYSA-N tert-butyl n-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamate Chemical compound CCOC(OCC)C#CC1=CN=C(Cl)N=C1NC1(CNC(=O)OC(C)(C)C)CCCC1 LYHIBHHOKUUNDF-UHFFFAOYSA-N 0.000 description 1
- MXSNQMUVXLVDHI-UHFFFAOYSA-N tert-butyl n-butylcarbamate Chemical compound CCCCNC(=O)OC(C)(C)C MXSNQMUVXLVDHI-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- LWFUGGGWLUMXQZ-UHFFFAOYSA-N tetrazolo[1,5-b]pyridazine Chemical group C1=CC=NN2N=NN=C21 LWFUGGGWLUMXQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 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
- C07D487/12—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 three hetero rings
- C07D487/20—Spiro-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
- A61K31/499—Spiro-condensed pyrazines or piperazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
-
- 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
- C07D498/12—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 three hetero rings
- C07D498/14—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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| US61/406,498 | 2010-10-25 |
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| CN104045654A true CN104045654A (zh) | 2014-09-17 |
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| CN201410184792.2A Active CN103936745B (zh) | 2010-10-25 | 2011-10-25 | Cdk抑制剂 |
| CN201610323241.9A Active CN106008533B (zh) | 2010-10-25 | 2011-10-25 | Cdk抑制剂 |
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| CN201410184792.2A Active CN103936745B (zh) | 2010-10-25 | 2011-10-25 | Cdk抑制剂 |
| CN201610323241.9A Active CN106008533B (zh) | 2010-10-25 | 2011-10-25 | Cdk抑制剂 |
| CN201611022263.8A Pending CN106967074A (zh) | 2010-10-25 | 2011-10-25 | Cdk抑制剂 |
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| WO2006122150A1 (en) | 2005-05-10 | 2006-11-16 | Incyte Corporation | Modulators of indoleamine 2,3-dioxygenase and methods of using the same |
| MX2011000235A (es) | 2008-07-08 | 2011-02-23 | Incyte Corp | 1,2,5-oxadiazoles como inhibidores de indolamina 2,3-dioxigenasa. |
| WO2010132725A2 (en) | 2009-05-13 | 2010-11-18 | The University Of North Carolina At Chapel Hill | Cyclin dependent kinase inhibitors and methods of use |
| US8691830B2 (en) | 2010-10-25 | 2014-04-08 | G1 Therapeutics, Inc. | CDK inhibitors |
| CA2818046A1 (en) | 2010-11-17 | 2012-05-24 | The University Of North Carolina At Chapel Hill | Protection of renal tissues from ischemia through inhibition of the proliferative kinases cdk4 and cdk6 |
| WO2013148748A1 (en) | 2012-03-29 | 2013-10-03 | Francis Xavier Tavares | Lactam kinase inhibitors |
| CN104302620A (zh) * | 2012-04-26 | 2015-01-21 | 弗朗西斯·泽维尔·塔瓦雷斯 | 内酰胺的合成 |
| SI2861595T1 (sl) | 2012-06-13 | 2017-04-26 | Incyte Holdings Corporation | Substituirane triciklične spojine kot inhibitorji fgfr |
| CN107417691B (zh) * | 2013-03-15 | 2020-06-26 | G1治疗公司 | 高效的抗赘生剂和抗增生剂 |
| US9464092B2 (en) * | 2013-03-15 | 2016-10-11 | G1 Therapeutics, Inc. | Transient protection of normal cells during chemotherapy |
| WO2014144596A2 (en) * | 2013-03-15 | 2014-09-18 | G1 Therapeutics, Inc. | Transient protection of hematopoietic stem and progenitor cells against ionizing radiation |
| LT2986610T (lt) | 2013-04-19 | 2018-04-10 | Incyte Holdings Corporation | Bicikliniai heterociklai, kaip fgfr inhibitoriai |
| WO2015161288A1 (en) * | 2014-04-17 | 2015-10-22 | G1 Therapeutics, Inc. | Tricyclic lactams for use as anti-neoplastic and anti-proliferative agents |
| EP3191098A4 (en) | 2014-09-12 | 2018-04-25 | G1 Therapeutics, Inc. | Combinations and dosing regimes to treat rb-positive tumors |
| WO2016040848A1 (en) | 2014-09-12 | 2016-03-17 | G1 Therapeutics, Inc. | Treatment of rb-negative tumors using topoisomerase inhibitors in combination with cyclin dependent kinase 4/6 inhibitors |
| US20160220569A1 (en) * | 2015-02-03 | 2016-08-04 | G1 Therapeutics, Inc. | CDK4/6 Inhibitor Dosage Formulations For The Protection Of Hematopoietic Stem And Progenitor Cells During Chemotherapy |
| MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
| SG10201913036RA (en) | 2015-02-20 | 2020-02-27 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
| NZ749275A (en) | 2016-07-01 | 2023-06-30 | G1 Therapeutics Inc | Synthesis of n-(heteroaryl)-pyrrolo[2,3-d]pyrimidin-2-amines |
| WO2018005863A1 (en) * | 2016-07-01 | 2018-01-04 | G1 Therapeutics, Inc. | Pyrimidine-based compounds for the treatment of cancer |
| WO2018005860A1 (en) * | 2016-07-01 | 2018-01-04 | G1 Therapeutics, Inc. | Pyrimidine-based antiproliferative agents |
| WO2018005533A1 (en) | 2016-07-01 | 2018-01-04 | G1 Therapeutics, Inc. | Antiproliferative pyrimidine-based compounds |
| KR102466192B1 (ko) | 2016-08-23 | 2022-11-14 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 간세포성 암종의 치료를 위한 조합 요법 |
| SG11201902523UA (en) | 2016-10-20 | 2019-05-30 | Pfizer | Anti-proliferative agents for treating pah |
| AU2017359333B2 (en) | 2016-11-08 | 2024-03-21 | Dana-Farber Cancer Institute, Inc. | Compositions and methods of modulating anti-tumor immunity |
| JP6905069B2 (ja) * | 2016-11-11 | 2021-07-21 | 上海海雁醫藥科技有限公司 | ピリジルアミノ置換へテロ三環式化合物並びにその製造方法及び医薬用途 |
| KR20240024296A (ko) | 2016-12-05 | 2024-02-23 | 쥐원 쎄라퓨틱스, 인크. | 화학요법 레지멘 동안의 면역 반응의 보존 |
| MX2019008158A (es) | 2017-01-06 | 2019-12-09 | G1 Therapeutics Inc | Terapia de combinacion para el tratamiento del cancer. |
| US11395821B2 (en) | 2017-01-30 | 2022-07-26 | G1 Therapeutics, Inc. | Treatment of EGFR-driven cancer with fewer side effects |
| EP3585389A4 (en) | 2017-02-22 | 2020-12-23 | G1 Therapeutics, Inc. | EGFR-CAUSED CANCER TREATMENT WITH LESS SIDE EFFECTS |
| RU2764724C2 (ru) | 2017-03-16 | 2022-01-19 | ЭИСАЙ Р энд Д МЕНЕДЖМЕНТ КО., ЛТД. | Комбинированная терапия для лечения рака молочной железы |
| AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
| RU2019142591A (ru) | 2017-06-29 | 2021-07-29 | Г1 Терапьютикс, Инк. | Морфологические формы g1t38 и способы их получения |
| CN107383019B (zh) * | 2017-07-28 | 2019-10-15 | 江苏艾凡生物医药有限公司 | 吡唑并[4,3-h]喹唑啉类化合物及其用途 |
| CN109985241B (zh) * | 2017-12-29 | 2024-10-18 | 广州威溶特医药科技有限公司 | Cdk抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 |
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