JP6157680B2 - Cdk阻害剤 - Google Patents
Cdk阻害剤 Download PDFInfo
- Publication number
- JP6157680B2 JP6157680B2 JP2016082206A JP2016082206A JP6157680B2 JP 6157680 B2 JP6157680 B2 JP 6157680B2 JP 2016082206 A JP2016082206 A JP 2016082206A JP 2016082206 A JP2016082206 A JP 2016082206A JP 6157680 B2 JP6157680 B2 JP 6157680B2
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- Japan
- Prior art keywords
- compound
- formula
- amine
- pyrimidine
- pyrrolo
- Prior art date
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- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title description 6
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 129
- -1 heterocyclo Chemical group 0.000 claims description 77
- 125000002947 alkylene group Chemical group 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 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 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- GAPKLZRRWLERHL-UHFFFAOYSA-N 5-(4-propan-2-ylpiperazin-1-yl)pyridin-2-amine Chemical compound C1CN(C(C)C)CCN1C1=CC=C(N)N=C1 GAPKLZRRWLERHL-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 15
- 150000004982 aromatic amines Chemical class 0.000 claims 15
- 239000003960 organic solvent Substances 0.000 claims 3
- KBKYEKFQXHSSFA-UHFFFAOYSA-N 5-(4-morpholin-4-ylpiperidin-1-yl)pyridin-2-amine Chemical compound C1=NC(N)=CC=C1N1CCC(N2CCOCC2)CC1 KBKYEKFQXHSSFA-UHFFFAOYSA-N 0.000 claims 2
- VBBGHNGROGZGHG-UHFFFAOYSA-N 5-piperazin-1-ylpyridin-2-amine Chemical group C1=NC(N)=CC=C1N1CCNCC1 VBBGHNGROGZGHG-UHFFFAOYSA-N 0.000 claims 2
- PHNDZBFLOPIMSM-UHFFFAOYSA-N 4-morpholin-4-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCOCC1 PHNDZBFLOPIMSM-UHFFFAOYSA-N 0.000 claims 1
- HJSSTXGDOIYXFL-UHFFFAOYSA-N 5-(2,6-dimethylmorpholin-4-yl)pyridin-2-amine Chemical compound C1C(C)OC(C)CN1C1=CC=C(N)N=C1 HJSSTXGDOIYXFL-UHFFFAOYSA-N 0.000 claims 1
- UXPVYPKUBZTKIP-UHFFFAOYSA-N 5-(3,5-dimethylpiperazin-1-yl)pyridin-2-amine Chemical compound C1C(C)NC(C)CN1C1=CC=C(N)N=C1 UXPVYPKUBZTKIP-UHFFFAOYSA-N 0.000 claims 1
- AYYKYPIIMXENTG-UHFFFAOYSA-N 5-(4-piperidin-1-ylpiperidin-1-yl)pyridin-2-amine Chemical compound C1=NC(N)=CC=C1N1CCC(N2CCCCC2)CC1 AYYKYPIIMXENTG-UHFFFAOYSA-N 0.000 claims 1
- VGPKSPWYBWJRRT-UHFFFAOYSA-N 5-(4-thiomorpholin-4-ylpiperidin-1-yl)pyridin-2-amine Chemical compound C1=NC(N)=CC=C1N1CCC(N2CCSCC2)CC1 VGPKSPWYBWJRRT-UHFFFAOYSA-N 0.000 claims 1
- GLEGVQXZOJSYSA-UHFFFAOYSA-N 5-[4-(2-methylpropyl)piperazin-1-yl]pyridin-2-amine Chemical compound C1CN(CC(C)C)CCN1C1=CC=C(N)N=C1 GLEGVQXZOJSYSA-UHFFFAOYSA-N 0.000 claims 1
- ACYSKLGOADDKAI-UHFFFAOYSA-N 5-morpholin-4-ylpyridin-2-amine Chemical compound C1=NC(N)=CC=C1N1CCOCC1 ACYSKLGOADDKAI-UHFFFAOYSA-N 0.000 claims 1
- NEUQZUUDMLYGQM-UHFFFAOYSA-N 5-piperidin-1-ylpyridin-2-amine Chemical compound C1=NC(N)=CC=C1N1CCCCC1 NEUQZUUDMLYGQM-UHFFFAOYSA-N 0.000 claims 1
- INASTCGMVRITIL-UHFFFAOYSA-N 5-thiomorpholin-4-ylpyridin-2-amine Chemical compound C1=NC(N)=CC=C1N1CCSCC1 INASTCGMVRITIL-UHFFFAOYSA-N 0.000 claims 1
- IEUHTZVAUDMKQJ-UHFFFAOYSA-N 6-morpholin-4-ylpyridazin-3-amine Chemical compound N1=NC(N)=CC=C1N1CCOCC1 IEUHTZVAUDMKQJ-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 238000009835 boiling Methods 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 121
- 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 100
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000003786 synthesis reaction Methods 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 41
- 125000000623 heterocyclic group Chemical group 0.000 description 41
- 150000003840 hydrochlorides Chemical class 0.000 description 40
- 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
- 125000002950 monocyclic group Chemical group 0.000 description 36
- 125000002619 bicyclic group Chemical group 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 150000003254 radicals Chemical class 0.000 description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 19
- 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
- 238000005481 NMR spectroscopy Methods 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 229940126214 compound 3 Drugs 0.000 description 13
- SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical compound ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 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 12
- 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 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 11
- 0 C*(*)C(**(*)*C(*)Nc(nc1)nc2c1c(*)c(C1(C)*)[n]2*N(*)C1=O)=* Chemical compound C*(*)C(**(*)*C(*)Nc(nc1)nc2c1c(*)c(C1(C)*)[n]2*N(*)C1=O)=* 0.000 description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 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
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 238000003756 stirring Methods 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
- 108091007914 CDKs Proteins 0.000 description 7
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 125000004434 sulfur atom Chemical group 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
- 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 5
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
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- 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
- 102000004190 Enzymes Human genes 0.000 description 4
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- 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 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
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- 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
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- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- PEDGODRBOPTSAI-JHJMLUEUSA-N tert-butyl (4r)-5-(6-aminopyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C([C@@]1(CN2C(=O)OC(C)(C)C)[H])C2CN1C1=CC=C(N)N=C1 PEDGODRBOPTSAI-JHJMLUEUSA-N 0.000 description 1
- RKWHXYAMXGVBMO-JHJMLUEUSA-N tert-butyl (4r)-5-(6-nitropyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C([C@@]1(CN2C(=O)OC(C)(C)C)[H])C2CN1C1=CC=C([N+]([O-])=O)N=C1 RKWHXYAMXGVBMO-JHJMLUEUSA-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
- NIBVMIBRJSODHF-HOTGVXAUSA-N tert-butyl n-[(1s,2s)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]carbamate Chemical compound CCOC(OCC)C#CC1=CN=C(Cl)N=C1N[C@@H]1[C@@H](NC(=O)OC(C)(C)C)CCC1 NIBVMIBRJSODHF-HOTGVXAUSA-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
- GKTZYOHYPBQYAX-MRVPVSSYSA-N tert-butyl n-[(2s)-1-amino-3-methylbutan-2-yl]carbamate Chemical compound CC(C)[C@@H](CN)NC(=O)OC(C)(C)C GKTZYOHYPBQYAX-MRVPVSSYSA-N 0.000 description 1
- CLUUDOMFHPDBIR-LLVKDONJSA-N tert-butyl n-[(2s)-2-amino-2-phenylethyl]carbamate Chemical compound CC(C)(C)OC(=O)NC[C@@H](N)C1=CC=CC=C1 CLUUDOMFHPDBIR-LLVKDONJSA-N 0.000 description 1
- OTSWUUVDIYKZTD-MRVPVSSYSA-N tert-butyl n-[(2s)-2-amino-3,3-dimethylbutyl]carbamate Chemical compound CC(C)(C)OC(=O)NC[C@@H](N)C(C)(C)C OTSWUUVDIYKZTD-MRVPVSSYSA-N 0.000 description 1
- 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
- ZJUDNFSNXBZPTL-UHFFFAOYSA-N tert-butyl n-[2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methylpropyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC(C)(C)NC1=NC(Cl)=NC=C1Br ZJUDNFSNXBZPTL-UHFFFAOYSA-N 0.000 description 1
- 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 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
- 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 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
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 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
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- 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
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- Health & Medical Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- 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)
Description
本願は、あらゆる目的のためにその全体を参照により本明細書に援用する2010年10月25日付で提出された同時係属中の米国仮特許出願第61/406,498号に関連し、その利益を主張する。
本発明は、サイクリン依存性キナーゼ(「CDK」)を阻害するのに有用な化合物に関する。
Zは、−(CH2)x−(ここで、xは1、2、3、若しくは4である)又は−O−(CH2)z−(ここで、zは2、3、又は4である)であり;
各Xは、独立して、CH又はNであり;
各X’は、独立して、CH又はNであり;
X’’は、CH2、S、又はNHであり;
各R及びR8は、独立して、H、C1−C3アルキル、又はハロアルキルであり;
各R1は、独立して、アリール、アルキル、シクロアルキル、又はハロアルキルであり、前記アルキル、シクロアルキル、及びハロアルキル基のそれぞれは、鎖中に炭素の代わりにO又はN異種原子を含んでよく、隣接する環原子上又は同じ環原子上の2個のR1が、それらが結合している環原子と一緒に3〜8員環を形成してもよく;
yは、0、1、2、3、又は4であり;
R2は、−(アルキレン)m−ヘテロシクロ、−(アルキレン)m−ヘテロアリール、−(アルキレン)m−NR3R4、−(アルキレン)m−C(O)−NR3R4;−(アルキレン)m−C(O)−O−アルキル;−(アルキレン)m−O−R5、−(アルキレン)m−S(O)n−R5、又は−(アルキレン)m−S(O)n−NR3R4であり、これらはいずれも原子価的に可能な限りにおいて独立して1又は複数のRx基で置換されていてよく、同じ又は隣接する原子に結合している2個のRx基が一緒になって環を形成してよく、mは、0又は1であり、nは、0、1、又は2であり;
各R3及びR4は、独立して、
(i)水素又は
(ii)アルキル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル、又はヘテロアリールアルキルであって、これらはいずれも原子価的に可能な限りにおいて独立して1又は複数のRx基で置換されていてよく、同じ又は隣接する原子に結合している2個のRx基が一緒に環を形成してもよく;あるいは、R3及びR4は、それらが結合している窒素原子と一緒に、結合して、原子価的に可能な限りにおいて1又は複数のRx基で独立して置換されていてよいヘテロシクロ環を形成してよく、同じ又は隣接する原子に結合している2個のRx基が一緒に環を形成してもよく;
各R5及びR5*は、
(i)水素又は
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル、又はヘテロアリールアルキルであり、これらはいずれも原子価的に可能な限りにおいて独立して1又は複数のRx基で置換されていてよく;
各Rxは、独立して、ハロ、シアノ、ニトロ、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、ヘテロシクロアルキル、−(アルキレン)m−OR5、−(アルキレン)m−O−アルキレン−OR5、−(アルキレン)m−S(O)n−R5、−(アルキレン)m−NR3R4、−(アルキレン)m−CN、−(アルキレン)m−C(O)−R5、−(アルキレン)m−C(S)−R5、−(アルキレン)m−C(O)−OR5、−(アルキレン)m−O−C(O)−R5、−(アルキレン)m−C(S)−OR5、−(アルキレン)m−C(O)−(アルキレン)m−NR3R4、−(アルキレン)m−C(S)−NR3R4、−(アルキレン)m−N(R3)−C(O)−NR3R4、−(アルキレン)m−N(R3)−C(S)−NR3R4、−(アルキレン)m−N(R3)−C(O)−R5、−(アルキレン)m−N(R3)−C(S)−R5、−(アルキレン)m−O−C(O)−NR3R4、−(アルキレン)m−O−C(S)−NR3R4、−(アルキレン)m−SO2−NR3R4、−(アルキレン)m−N(R3)−SO2−R5、−(アルキレン)m−N(R3)−SO2−NR3R4、−(アルキレン)m−N(R3)−C(O)−OR5、−(アルキレン)m−N(R3)−C(S)−OR5、又は−(アルキレン)m−N(R3)−SO2−R5であり;前記アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、及びヘテロシクロアルキル基は、独立して、1又は複数の−(アルキレン)m−CN、−(アルキレン)m−OR5*、−(アルキレン)m−S(O)n−R5*、−(アルキレン)m−NR3*R4*、−(アルキレン)m−C(O)−R5*、−(アルキレン)m−C(=S)R5*、−(アルキレン)m−C(=O)OR5*、−(アルキレン)m−OC(=O)R5*、−(アルキレン)m−C(S)−OR5*、−(アルキレン)m−C(O)−NR3*R4*、−(アルキレン)m−C(S)−NR3*R4*、−(アルキレン)m−N(R
3*)−C(O)−NR3*R4*、−(アルキレン)m−N(R3*)−C(S)−NR3*R4*、−(アルキレン)m−N(R3*)−C(O)−R5*、−(アルキレン)m−N(R3*)−C(S)−R5*、−(アルキレン)m−O−C(O)−NR3*R4*、−(アルキレン)m−O−C(S)−NR3*R4*、−(アルキレン)m−SO2−NR3*R4*、−(アルキレン)m−N(R3*)−SO2−R5*、−(アルキレン)m−N(R3*)−SO2−NR3*R4*、−(アルキレン)m−N(R3*)−C(O)−OR5*、−(アルキレン)m−N(R3*)−C(S)−OR5*、又は−(アルキレン)m−N(R3*)−SO2−R5*で更に置換されていてよく、nは0、1、又は2であり、mは0又は1であり;
各R3*及びR4*は、独立して、
(i)水素又は
(ii)原子価的に可能な限りにおいて独立して1又は複数のRx基で置換されていてよいアルキル、アルケニル、アルキニル シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル、又はヘテロアリールアルキルであり;あるいは、R3*及びR4*は、それらが結合している窒素原子と一緒に、結合して、原子価的に可能な限りにおいて独立して1又は複数のRx基で置換されていてよいヘテロシクロ環を形成してよく;
R6は、H又は低級アルキルである}。
R2*は、結合、アルキレン、−(アルキレン)m−O−(アルキレン)m−、−(アルキレン)m−C(O)−(アルキレン)m−、−(アルキレン)m−S(O)2−(アルキレン)m−、または−(アルキレン)m−NH−(アルキレン)m−(ここで、各mは独立して0又は1である)であり;
Pは、4〜8員の単環又は二環式飽和ヘテロシクリル基であり;
各Rx1は、独立して、−(アルキレン)m−(C(O))m−(アルキレン)m−(N(RN))m−(アルキル)m(ここで、各mは独立して0又は1であるが、少なくとも1つのmは1である)、−(C(O))−O−アルキル、−(アルキレン)m−シクロアルキル(ここで、mは0又は1である)、−N(RN)−シクロアルキル、−C(O)−シクロアルキル、−(アルキレン)m−ヘテロシクリル(ここで、mは0又は1である)、又は−N(RN)−ヘテロシクリル、−C(O)−ヘテロシクリル、−S(O)2−(アルキレン)m(ここで、mは1又は2である)であり、
RNは、H、C1−C4アルキル、又はC1−C6ヘテロアルキルであり、 2個のRx1は、P上のそれらが結合している原子(同じ原子であってもよい)と一緒に環を形成してもよく;
tは、0、1又は2である]である。
R2*は、結合、アルキレン、−(アルキレン)m−O−(アルキレン)m−、−(アルキレン)m−C(O)−(アルキレン)m−、−(アルキレン)m−S(O)2−(アルキレン)m−、及び−(アルキレン)m−NH−(アルキレン)m−(ここで、各mは独立して0又は1である)であり;
Pは、4〜8員の単環又は二環式飽和ヘテロシクリル基であり;
P1は、4〜6員の単環式飽和ヘテロシクリル基であり;
各Rx2は、独立して、水素又はアルキルであり;
sは、0、1、又は2である]である。
特に断りのない限り、明細書及び特許請求の範囲を含む本願で使用される以下の用語の定義は以下に示す通りである。明細書及び特許請求の範囲中、単数形は、文脈で明確に単数でないことが示されていない限り、複数の参照対象を含む。標準的な化学用語の定義は、Carey and Sundberg (2007) Advanced Organic Chemistry 5th Ed. Vols. A and B, Springer Science+Business Media LLC, New Yorkを初めとする参照文献中に見つけることができる。本発明の実施には、特に断りのない限り、合成有機化学、質量分析法、クロマトグラフィーの分取及び分析方法、タンパク質化学、生化学、組換えDNA技術、並びに薬理学の従来の方法が用いられる。有機化学の従来の方法には、March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition, M.B. Smith and J. March, John Wiley & Sons, Inc., Hoboken, NJ, 2007に含まれているものが含まれる。
例としてはピペリジルメチル及びモルホリニルエチルが含まれる。
開示されている化合物は以下の一般的スキームに従って製造することができる。
tert−ブチルN−[2−[(5−ブロモ−2−クロロ−ピリミジン−4−イル)アミノ]エチル]カルバマート
(M + H)。
1H NMR (δ6-DMSO) 8.26 (s, 1H), 8.15 (1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H)。
分析データ(NMR及び質量分析)は中間体Aのものと一致していた。
分析データ(NMR及び質量分析)は中間体Aのものと一致していた。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.34 - 1.52 (m, 2 H) 1.78 (m, 2 H) 2.14 (m, 1 H) 2.43 (m, 4 H) 3.32 (d, J=12.30 Hz, 4 H) 3.47 - 3.59 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.11 (dd, J=8.93, 2.78 Hz, 1 H) 7.47 - 7.62 (m, 1 H)。LCMS (ESI) 263 (M + H)。
反応混合物をCELITE(商標)で濾過した後、有機層を真空下で濃縮し、tert−ブチルN−(2−アミノ−3−メチル−ブチル)カルバマート(3.8g)を得た。
7−[1−[(tert−ブトキシカルボニルアミノ)メチル]−2−メチル−プロピル]−2−クロロ−ピロロ[2,3−d]ピリミジン−6−カルボン酸(0.050g、0.00013モル)のDCM(1.5mL)溶液にDIC(32.7mg)及びDMAP(10mg)を加えた。内容物を2時間撹拌した。次いで、トリフルオロ酢酸(0.4mL)を加え、更に30分間撹拌を続けた。飽和NaHCO3を加えて過剰な酸を中和した後、酢酸エチルを加え、有機層を分離し、硫酸マグネシウムで乾燥させ、その後、真空下で濃縮した。ヘキサン/酢酸エチル(0〜100%)を用いてシリカゲル上で粗生成物のカラムクロマトグラフィーを行い、中間体1Aを得た。1H NMR (600 MHz, DMSO-d6) δ ppm 0.72 (d, J=6.73 Hz, 3 H) 0.97 (d, J=6.73 Hz, 3 H) 2.09 - 2.22 (m, 1 H) 3.57 (dd, J=13.18, 4.98 Hz, 1 H) 3.72 (dd, J=13.61, 4.25 Hz, 1 H) 4.53 (dd, J=8.05, 3.95 Hz, 1 H) 7.20 (s, 1 H) 8.34 (d, J=4.98 Hz, 1 H) 9.08 (s, 1 H)。LCMS (ESI) 265 (M + H)。
中間体1Aに記載したのと同様な合成順序で中間体1Gを合成した。1H NMR (600 MHz, DMSO-d6) δ ppm 3.58 - 3.69 (m, 1 H) 4.13 (dd, J=13.47, 4.39 Hz, 1 H) 6.07 (d, J=3.81 Hz, 1 H) 6.85 (d, J=7.32 Hz, 2 H) 7.19 - 7.31 (m, 3 H) 7.34 (s, 1 H) 8.27 (d, J=5.27 Hz, 1 H) 9.13 (s, 1 H)。LCMS (ESI) 299 (M + H)。
中間体1Aで記載したのと同様な合成順序で中間体1Hを合成した。LCMS (ESI) 265 (M + H)。
中間体1Aで記載したのと同様な合成順序で中間体1Jを合成した。1H NMR (600 MHz, DMSO-d6) δ ppm 1.73 (s, 6 H) 3.50 (d, J=2.93 Hz, 2 H) 7.25 (s, 1 H) 8.46 - 8.55 (m, 1 H) 9.07 (s, 1 H)。LCMS (ESI) 251 (M + H)。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.37 - 1.54 (m, 13 H) 1.75 (br. s., 4 H) 2.74 (br. s., 2 H) 3.78 - 3.84 (m, 2 H) 7.44 - 7.51 (m, 1 H) 8.23 (s, 1 H) 9.11 (s, 1 H)。LCMS (ESI) 409 (M + H)。
中間体1Aで記載したのと同様な合成順序で中間体1Kを合成した。1H NMR (600 MHz, DMSO-d6) δ ppm 1.28 (br. s., 2 H) 1.42 (br. s., 2 H) 1.70 (br. s., 4 H) 1.85 - 1.95 (m, 2 H) 2.69 (m, 2 H) 7.16 - 7.25 (m, 1 H) 8.41 (br. s., 1 H) 9.04 (s, 1 H)。LCMS 291 (M + H)。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.47 (s, 9 H) 1.74 (br. s., 2 H) 1.88 (br. s., 2 H) 2.04 (br. s., 2 H) 2.41 - 2.45 (m, 2 H) 4.06 (s, 2 H) 7.45 (s, 1 H) 9.11 (s, 1 H)。LCMS (ESI) 395 (M + H)。
中間体1Aで記載したのと同様な合成順序で中間体1Lを合成した。1H NMR (600 MHz, DMSO-d6) δ ppm 1.72 (br. s., 2 H) 1.86 - 1.93 (m, 2 H) 1.99 (d, J=3.81 Hz, 2 H) 2.40 (br. s., 2 H) 3.48 (d, J=2.34 Hz, 2 H) 7.22 (s, 1 H) 8.53 (br. s., 1 H) 9.05 (s, 1 H)。LCMS (ESI) 277 (M + H)。
中間体1Aで記載したのと同様な合成順序で中間体1Mを合成した。分析データはL−異性体に記載したものと一致した。
中間体1Aで記載したのと同様な合成順序で中間体1Nを合成した。1H NMR (600 MHz, DMSO-d6) δ ppm 1.48 - 1.60 (m, 1 H) 1.88 - 1.98 (m, 3 H) 1.99 - 2.08 (m, 1 H) 2.66 - 2.75 (m, 1 H) 3.63 - 3.74 (m, 1 H) 3.99 - 4.12 (m, 1 H) 7.21 (s, 1 H) 8.89 (s, 1 H) 9.04 (s, 1 H)。LCMS (ESI) 263 (M + H)。
(s, 1H), 4.30 (m, 2H), 3.64 (m, 2H), 3.36 (m, 4H), 3.25 (m, 4H)。LCMS (ESI) 465 (M + H)。
化合物5
化合物8
12チャンネルのCaliper LabChip機器を検出デバイスとして用いて、384ウェルマイクロプレート中でキナーゼ酵素反応を行った。ペプチドが酵素でリン酸化されると実効電荷が変化するので、電気泳動で生成物を基質から分離できる。基質と生成物が分離されると2つの蛍光ピークが観察される。基質ピーク及び生成物ピークの相対的蛍光強度の変化が、測定されるパラメーターであり、酵素活性を反映する。阻害剤存在下では、生成物と基質の割合が変化する。生成物のシグナルは減少し、一方、基質のシグナルは増加する。
一実施態様では、本発明の化合物を含んでなる医薬組成物が提供される。第1の態様では、医薬組成物は更に、1又は複数の薬学的に許容される賦形剤又はビヒクル、更に必要に応じて他の治療的及び/又は予防的成分を含んでなる。そのような賦形剤は当業者に公知である。本発明の化合物には、限定されるものではないが、遊離塩基等の塩基性化合物が含まれる。薬学的に許容される賦形剤及び塩の詳細な説明はRemington's Pharmaceutical Sciences、18th Edition(Easton、Pennsylvania:Mack Publishing Company, 1990)に見つけることができる。
経口用の錠剤及びカプセル剤は通常、1又は複数の、ラクトース、コーンスターチ等の一般的に用いられるキャリアを含む。典型的には、ステアリン酸マグネシウム等の滑沢剤も添加される。液体懸濁剤を用いる場合、活性薬剤を乳化剤及び懸濁化剤と一緒に用いてよい。所望であれば、香味剤、着色剤、及び/又は矯味剤も添加してよい。必要に応じて本明細書の経口製剤に含めるその他の構成要素としては、限定されるものではないが、保存剤、懸濁化剤、増粘剤等が含まれる。
Claims (23)
- 2’−クロロ−ラクタム−ピロロ[3,2−d]ピリミジンとヘテロアリールまたはアリールアミンとを反応させることを含む、2’−(ヘテロアリールまたはアリールアミン)−ラクタム−ピロロ[3,2−d]ピリミジンの製造方法であって、前記2’−(ヘテロアリールまたはアリールアミン)−ラクタム−ピロロ[3,2−d]ピリミジンが、式I、式IIまたは式III:
Zは、−(CH 2 ) x −(ここで、xは、1、2、3、もしくは4である)または−O−(CH 2 ) z −(ここで、zは、2、3、もしくは4である)であり;
各Xは、独立して、CHまたはNであり;
各X’は、独立して、CHまたはNであり;
X’’は、CH 2 、S、またはNHであり;
各RおよびR 8 は、独立して、H、C 1 −C 3 アルキル、またはハロアルキルであり;
各R 1 は、独立して、アリール、アルキル、シクロアルキル、またはハロアルキルであり、前記各アルキル、シクロアルキル、およびハロアルキル基は、鎖中に炭素の代わりにOまたはNヘテロ原子を含んでよく、隣接する環原子上または同じ環原子上の2個のR 1 が、それらが結合している環原子と一緒に3〜8員環を形成してもよく;
yは、0、1、2、3、または4であり;
R 2 は、−(アルキレン) m −ヘテロシクロ、−(アルキレン) m −ヘテロアリール、−(アルキレン) m −NR 3 R 4 、−(アルキレン) m −C(O)−NR 3 R 4 ;−(アルキレン) m −C(O)−O−アルキル;−(アルキレン) m −O−R 5 、−(アルキレン) m −S(O) n −R 5 、または−(アルキレン) m −S(O) n −NR 3 R 4 であり、いずれも原子価的に可能な限りにおいて独立して1または複数のR x 基で置換されていてよく、同じまたは隣接する原子に結合している2個のR x 基が一緒になって環を形成してよく、mは、0または1であり、nは、0、1、または2であり;
各R 3 およびR 4 は、独立して、
(i)水素または
(ii)アルキル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル、またはヘテロアリールアルキルであり、いずれも原子価的に可能な限りにおいて独立して1または複数のR x 基で置換されていてよく、同じまたは隣接する原子に結合している2個のR x 基が一緒に環を形成してもよく;あるいは、R 3 およびR 4 は、それらが結合している窒素原子と一緒に、原子価的に可能な限りにおいて独立して1または複数のR x 基で置換されていてよいヘテロシクロ環を形成してよく、同じまたは隣接する原子に結合している2個のR x 基が一緒に環を形成してもよく;
R 5 は、
(i)水素または
(ii)アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロ、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキル、アリールアルキル、又はヘテロアリールアルキルであり、いずれも独立して原子価的に可能な限りにおいて1又は複数のR x 基で置換されていてよく;
各R x は、独立して、ハロ、シアノ、ニトロ、オキソ、アルキル、ハロアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、ヘテロシクロ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、シクロアルキルアルキル、又はヘテロシクロアルキルであり、
nは、0、1、または2であり、
mは、0または1であり、
R 6 は、Hまたは低級アルキルである]
から選択される、方法。 - 前記反応が有機溶媒中で行われる、請求項6に記載の方法。
- 前記反応が少なくとも100℃の温度下で行われる、請求項7に記載の方法。
- 前記反応温度が、前記有機溶媒の還流温度以上である、請求項8に記載の方法。
- 前記有機溶媒の沸点が90℃よりも高い、請求項8に記載の方法。
- 2’−クロロ−ラクタム−ピロロ[3,2−d]ピリミジンが、請求項1に記載の化合物である、請求項6に記載の方法。
- ヘテロアリールまたはアリールアミンが、5−(ピペラジン−1−イル)ピリジン−2−アミン、5−(4−メチルピペラジン−1−イル)ピリジン−2−アミン、5−モルホリノピリジン−2−アミン、6−モルホリノピリダジン−3−アミン、4−モルホリノアニリン、5−(4−イソプロピルピペラジン−1−イル)ピリジン−2−アミン、5−(4−イソブチルピペラジン−1−イル)ピリジン−2−アミン、5−(2,6−ジメチルモルホリノ)ピリジン−2−アミン、5−(ピペリジン−1−イル)ピリジン−2−アミン、5−(4−モルホリノピペリジン−1−イル)ピリジン−2−アミン、5−([1,4’−ビピペリジン]−1’−イル)ピリジン−2−アミン、5−チオモルホリノピリジン−2−アミン、5−(3,5−ジメチルピペラジン−1−イル)ピリジン−2−アミン、5−(4−チオモルホリノピペリジン−1−イル)ピリジン−2−アミンまたは5−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−2−アミンである、請求項6に記載の方法。
- 2’−クロロ−ラクタム−ピロロ[3,2−d]ピリミジンが、分子内環化およびその後の脱保護により中間体から形成される、請求項6に記載の方法。
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Families Citing this family (103)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101212967A (zh) | 2005-05-10 | 2008-07-02 | 因塞特公司 | 吲哚胺2,3-双加氧酶调节剂及其用法 |
AU2009268739B2 (en) | 2008-07-08 | 2014-05-08 | Incyte Holdings Corporation | 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase |
CA2761896A1 (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 |
EP2640394A4 (en) | 2010-11-17 | 2015-02-25 | Univ North Carolina | PROTECTION OF RENAL TISSUES AGAINST ISCHEMIA THROUGH INHIBITION OF CDK4 AND CDK6 PROLIFERATIVE KINASES |
CA2868966C (en) | 2012-03-29 | 2021-01-26 | Francis Xavier Tavares | Lactam kinase inhibitors |
EP2841417A1 (en) * | 2012-04-26 | 2015-03-04 | Francis Xavier Tavares | Synthesis of lactams |
CN107383009B (zh) | 2012-06-13 | 2020-06-09 | 因塞特控股公司 | 作为fgfr抑制剂的取代的三环化合物 |
EP2967050A4 (en) * | 2013-03-15 | 2016-09-28 | G1 Therapeutics Inc | HIGH-ACTIVE ANTINEOPLASTIC AND ANTIPROLIFERATIVE AGENTS |
EP2968291A4 (en) * | 2013-03-15 | 2016-09-28 | G1 Therapeutics Inc | HSPC-PROOF TREATMENTS FOR RB-POSITIVE ABNORMAL CELLULAR PROLIFERATION |
US20140274896A1 (en) * | 2013-03-15 | 2014-09-18 | G1 Therapeutics, Inc. | Transient Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation |
CN105263931B (zh) | 2013-04-19 | 2019-01-25 | 因赛特公司 | 作为fgfr抑制剂的双环杂环 |
WO2015161288A1 (en) * | 2014-04-17 | 2015-10-22 | G1 Therapeutics, Inc. | Tricyclic lactams for use as anti-neoplastic and anti-proliferative agents |
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 |
WO2016040858A1 (en) * | 2014-09-12 | 2016-03-17 | G1 Therapeutics, Inc. | Combinations and dosing regimes to treat rb-positive tumors |
WO2016126889A1 (en) * | 2015-02-03 | 2016-08-11 | 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 |
EP3617205B1 (en) | 2015-02-20 | 2021-08-04 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
WO2018005533A1 (en) | 2016-07-01 | 2018-01-04 | G1 Therapeutics, Inc. | Antiproliferative pyrimidine-based compounds |
CN109789143A (zh) | 2016-07-01 | 2019-05-21 | G1治疗公司 | 基于嘧啶的抗增殖剂 |
WO2018005863A1 (en) * | 2016-07-01 | 2018-01-04 | G1 Therapeutics, Inc. | Pyrimidine-based compounds for the treatment of cancer |
JP7106462B2 (ja) | 2016-07-01 | 2022-07-26 | ジー1 セラピューティクス, インコーポレイテッド | N-(ヘテロアリール)-ピロロ[3,2-d]ピリミジン-2-アミンの合成 |
CA3034875C (en) | 2016-08-23 | 2024-05-28 | Eisai R&D Management Co., Ltd. | Combination therapies for the treatment of hepatocellular carcinoma |
CA3040815C (en) | 2016-10-20 | 2021-07-20 | Steven Martin Evans | Anti-proliferative agents for treating pah |
US11865176B2 (en) | 2016-11-08 | 2024-01-09 | Dana-Farber Cancer Institute, Inc. | Compositions and methods of modulating anti-tumor immunity |
EP3505519B1 (en) * | 2016-11-11 | 2022-01-05 | Shanghai Haiyan Pharmaceutical Technology Co., Ltd. | Pyridinamine-substituted heterotricyclo compounds, preparation thereof, and use in medicines |
EP3548030A4 (en) | 2016-12-05 | 2020-08-12 | G1 Therapeutics, Inc. | PRESERVATION OF THE IMMUNE RESPONSE IN CHEMOTHERAPIES |
BR112019013814A2 (pt) | 2017-01-06 | 2020-01-21 | G1 Therapeutics Inc | método para tratamento de câncer ou de um tumor em um indivíduo, composição farmacêutica, combinação, e, kit. |
US11395821B2 (en) | 2017-01-30 | 2022-07-26 | G1 Therapeutics, Inc. | Treatment of EGFR-driven cancer with fewer side effects |
WO2018156812A1 (en) | 2017-02-22 | 2018-08-30 | G1 Therapeutics, Inc. | Treatment of egfr-driven cancer with fewer side effects |
AU2018234903B2 (en) | 2017-03-16 | 2024-02-08 | Eisai R&D Management Co., Ltd. | Combination therapies for the treatment of breast cancer |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
WO2019006393A1 (en) | 2017-06-29 | 2019-01-03 | G1 Therapeutics, Inc. | MORPHIC FORMS OF GIT38 AND METHODS OF MAKING SAME |
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 |
CN109985241A (zh) * | 2017-12-29 | 2019-07-09 | 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 |
EP3738084A4 (en) | 2018-01-08 | 2021-11-17 | G1 Therapeutics, Inc. | G1T38 SUPERIOR DOSAGE RATES |
CN117903140A (zh) | 2018-02-27 | 2024-04-19 | 因赛特公司 | 作为a2a/a2b抑制剂的咪唑并嘧啶和三唑并嘧啶 |
US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
JP2021523118A (ja) | 2018-05-04 | 2021-09-02 | インサイト・コーポレイションIncyte Corporation | Fgfr阻害剤の塩 |
CA3100731A1 (en) | 2018-05-18 | 2019-11-21 | Incyte Corporation | Fused pyrimidine derivatives as a2a / a2b inhibitors |
TWI829716B (zh) | 2018-07-05 | 2024-01-21 | 美商英塞特公司 | 作為a2a/a2b 抑制劑之稠合吡嗪衍生物 |
EP3840756A4 (en) | 2018-08-24 | 2022-04-27 | G1 Therapeutics, Inc. | IMPROVED SYNTHESIS OF 1,4-DIAZASPIRO[5.5]UNDECAN-3-ONE |
EP3849537A4 (en) | 2018-09-10 | 2022-06-29 | Mirati Therapeutics, Inc. | Combination therapies |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
JP2022506829A (ja) * | 2018-11-09 | 2022-01-17 | ジー1、セラピューティクス、インコーポレイテッド | エリブリンと選択的cdk4/6阻害剤との組合せを使用する癌の処置のための治療レジメン |
TW202038957A (zh) | 2018-12-21 | 2020-11-01 | 日商第一三共股份有限公司 | 抗體-藥物結合物與激酶抑制劑之組合 |
CN111377924A (zh) * | 2018-12-29 | 2020-07-07 | 武汉光谷通用名药物研究院有限公司 | 新型cdk4抑制剂及其用途 |
CN111377935B (zh) * | 2018-12-29 | 2021-06-29 | 武汉光谷通用名药物研究院有限公司 | 选择性cdk4/6抑制剂及其应用 |
TWI829857B (zh) | 2019-01-29 | 2024-01-21 | 美商英塞特公司 | 作為a2a / a2b抑制劑之吡唑并吡啶及三唑并吡啶 |
WO2020168197A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors |
AU2020221293A1 (en) | 2019-02-15 | 2021-09-02 | Incyte Corporation | Cyclin-dependent kinase 2 biomarkers and uses thereof |
WO2020180959A1 (en) | 2019-03-05 | 2020-09-10 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
WO2020205560A1 (en) | 2019-03-29 | 2020-10-08 | Incyte Corporation | Sulfonylamide compounds as cdk2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
CA3148776A1 (en) | 2019-08-01 | 2021-02-04 | Incyte Corporation | A dosing regimen for an ido inhibitor |
TW202115024A (zh) | 2019-08-14 | 2021-04-16 | 美商英塞特公司 | 作為cdk2 抑制劑之咪唑基嘧啶基胺化合物 |
CA3157681A1 (en) | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
AU2020366006A1 (en) | 2019-10-14 | 2022-04-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
BR112022010664A2 (pt) | 2019-12-04 | 2022-08-16 | Incyte Corp | Derivados de um inibidor de fgfr |
EP4069696A1 (en) | 2019-12-04 | 2022-10-12 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
WO2021146424A1 (en) | 2020-01-15 | 2021-07-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
AU2021230385A1 (en) | 2020-03-06 | 2022-09-22 | Incyte Corporation | Combination therapy comprising AXL/MER and PD-1/PD-L1 inhibitors |
JP2021167301A (ja) | 2020-04-08 | 2021-10-21 | ファイザー・インク | Cdk2阻害剤に対する腫瘍適応を抑制するためのcdk4/6およびcdk2阻害剤による同時処置 |
JP2023522202A (ja) | 2020-04-16 | 2023-05-29 | インサイト・コーポレイション | 融合三環式kras阻害剤 |
US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
CN115698014A (zh) | 2020-05-19 | 2023-02-03 | G1治疗公司 | 用于治疗医学病症的细胞周期蛋白依赖性激酶抑制化合物 |
US10988479B1 (en) | 2020-06-15 | 2021-04-27 | G1 Therapeutics, Inc. | Morphic forms of trilaciclib and methods of manufacture thereof |
CN116157403A (zh) * | 2020-06-15 | 2023-05-23 | G1治疗公司 | 曲拉西利的形态及其制造方法 |
US11999752B2 (en) | 2020-08-28 | 2024-06-04 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of KRAS |
WO2022072783A1 (en) | 2020-10-02 | 2022-04-07 | Incyte Corporation | Bicyclic dione compounds as inhibitors of kras |
US20230374028A1 (en) * | 2020-10-08 | 2023-11-23 | Teva Pharmaceuticals International Gmbh | Solid state forms of trilaciclib and of trilaciclib salts |
WO2022155941A1 (en) | 2021-01-25 | 2022-07-28 | Qilu Regor Therapeutics Inc. | Cdk2 inhibitors |
WO2022206888A1 (en) | 2021-03-31 | 2022-10-06 | Qilu Regor Therapeutics Inc. | Cdk2 inhibitors and use thereof |
CA3215903A1 (en) | 2021-04-12 | 2022-10-20 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
JP2024522189A (ja) | 2021-06-09 | 2024-06-11 | インサイト・コーポレイション | Fgfr阻害剤としての三環式ヘテロ環 |
WO2022261159A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
US11981671B2 (en) | 2021-06-21 | 2024-05-14 | Incyte Corporation | Bicyclic pyrazolyl amines as CDK2 inhibitors |
CA3224674A1 (en) | 2021-07-07 | 2023-01-12 | Pei Gan | Tricyclic compounds as inhibitors of kras |
US20230114765A1 (en) | 2021-07-14 | 2023-04-13 | Incyte Corporation | Tricyclic compounds as inhibitors of kras |
IL310243A (en) | 2021-07-26 | 2024-03-01 | Celcuity Inc | 1-(4-{[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]CARBONYL}PHENYL)-3-[4-(4,6-DIMORHOLIN-4-YL-1,3,5-TRIAZIN-2-YL )PHENYL]urea (GEDATOLISIB) and its combinations for use in cancer treatment |
CN113788837B (zh) * | 2021-08-02 | 2022-08-26 | 深圳湾实验室坪山生物医药研发转化中心 | Trilaciclib的合成方法 |
CA3229855A1 (en) | 2021-08-31 | 2023-03-09 | Incyte Corporation | Naphthyridine compounds as inhibitors of kras |
US20230151005A1 (en) | 2021-09-21 | 2023-05-18 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of kras |
WO2023056421A1 (en) | 2021-10-01 | 2023-04-06 | Incyte Corporation | Pyrazoloquinoline kras inhibitors |
AU2022367432A1 (en) | 2021-10-14 | 2024-05-02 | Incyte Corporation | Quinoline compounds as inhibitors of kras |
AU2022389961A1 (en) | 2021-11-22 | 2024-06-06 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a kras inhibitor |
TW202329937A (zh) | 2021-12-03 | 2023-08-01 | 美商英塞特公司 | 雙環胺ck12抑制劑 |
US20230183251A1 (en) | 2021-12-10 | 2023-06-15 | Incyte Corporation | Bicyclic amines as cdk12 inhibitors |
US11976073B2 (en) | 2021-12-10 | 2024-05-07 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
US20230192722A1 (en) | 2021-12-22 | 2023-06-22 | Incyte Corporation | Salts and solid forms of an fgfr inhibitor and processes of preparing thereof |
WO2023168686A1 (en) | 2022-03-11 | 2023-09-14 | Qilu Regor Therapeutics Inc. | Substituted cyclopentanes as cdk2 inhibitors |
TW202341982A (zh) | 2021-12-24 | 2023-11-01 | 大陸商上海齊魯銳格醫藥研發有限公司 | Cdk2抑制劑及其用途 |
WO2023164255A1 (en) | 2022-02-28 | 2023-08-31 | Teva Pharmaceuticals International Gmbh | Crystalline forms of trilaciclib and trilaciclib salts |
TW202342023A (zh) | 2022-03-07 | 2023-11-01 | 美商英塞特公司 | Cdk2抑制劑之固體形式、鹽及製備方法 |
WO2023250430A1 (en) | 2022-06-22 | 2023-12-28 | Incyte Corporation | Bicyclic amine cdk12 inhibitors |
US20240101557A1 (en) | 2022-07-11 | 2024-03-28 | Incyte Corporation | Fused tricyclic compounds as inhibitors of kras g12v mutants |
CN115536663A (zh) * | 2022-10-11 | 2022-12-30 | 杭州科巢生物科技有限公司 | 一种曲拉西利中间体及其制备与应用 |
WO2024116069A1 (en) * | 2022-11-28 | 2024-06-06 | Assia Chemical Industries Ltd. | Novel trilaciclib intermediates, method of preparation and use thereof |
CN117069663B (zh) * | 2023-08-31 | 2023-12-26 | 四川维亚本苑生物科技有限公司 | 一种瑞博西尼中间体v的合成方法及瑞博西尼的合成方法 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06502147A (ja) * | 1990-10-09 | 1994-03-10 | ニューロゲン コーポレイション | 或る種のシクロアルキルおよびアザシクロアルキルピロロピリミジン;新規な種類のgaba脳リセプタリガンド |
GB9718913D0 (en) | 1997-09-05 | 1997-11-12 | Glaxo Group Ltd | Substituted oxindole derivatives |
ATE468339T1 (de) * | 2001-12-20 | 2010-06-15 | Osi Pharm Inc | Pyrrolopyrimidin a2b selektive antagonistische verbindungen, deren synthese und verwendung |
DK1470124T3 (da) | 2002-01-22 | 2006-04-18 | Warner Lambert Co | 2-(Pyridin-2-yl amino)-pyrido[2,3]pyrimidin-7-oner |
US20040127492A1 (en) * | 2002-02-19 | 2004-07-01 | Pharmacia Corporation | Cyclic pyrazoles for the inhibition of mitogen activated protein kinase-activated protein kinase-2 |
ATE433967T1 (de) | 2003-01-17 | 2009-07-15 | Warner Lambert Co | 2-aminopyridin-substituierteheterocyclen als inhibitoren der zellulären proliferation |
ES2436524T3 (es) * | 2003-05-22 | 2014-01-02 | Nerviano Medical Sciences S.R.L. | Derivados de pirazolo-quinazolina, procedimiento para su preparación y su uso como inhibidores de cinasas |
DE602004010419T2 (de) | 2003-10-23 | 2008-10-09 | F. Hoffmann-La Roche Ag | Triazaspiropiperidinderivate zur verwendung als glyt-1-inhibitoren bei der behandlung von neurologischen und neuropsychiatrischen erkrankungen |
GB0327380D0 (en) * | 2003-11-25 | 2003-12-31 | Cyclacel Ltd | Method |
ITMI20040874A1 (it) | 2004-04-30 | 2004-07-30 | Ist Naz Stud Cura Dei Tumori | Derivati indolici ed azaindolici con azione antitumorale |
EP1779848A1 (en) | 2005-10-28 | 2007-05-02 | Nikem Research S.R.L. | V-ATPase inhibitors for the treatment of inflammatory and autoimmune diseases |
JO3235B1 (ar) * | 2006-05-26 | 2018-03-08 | Astex Therapeutics Ltd | مركبات بيررولوبيريميدين و استعمالاتها |
SI2125822T1 (sl) * | 2006-12-21 | 2015-01-30 | Nerviano Medical Sciences S.R.L. | Substituirani pirazolo-kinazolinski derivati, postopek za njihovo pripravo in njihova uporaba kot inhibitorji kinaze |
MX2009013897A (es) | 2007-06-25 | 2010-03-30 | Neurogen Corp | Piperacinil oxoalquil tetrahidro-beta-carbolinas y analogos relacionados. |
BRPI0821209A2 (pt) * | 2007-12-19 | 2019-09-24 | Amgen Inc | composto, composição farmacêutica, métodos de tratar câncer, para reduzir o tamanho de tumor, para tratar distúrbios, e para reduzir metástase em um tumor. |
KR101353857B1 (ko) | 2008-08-22 | 2014-01-21 | 노파르티스 아게 | Cdk 억제제로서 피롤로피리미딘 화합물 |
JP2012504645A (ja) | 2008-10-01 | 2012-02-23 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | 健康な細胞に対する電離放射線の影響を低下させる又は防止するための医薬組成物 |
WO2010039997A2 (en) | 2008-10-01 | 2010-04-08 | The University Of North Carolina At Chapel Hill | Hematopoietic protection against chemotherapeutic compounds using selective cyclin-dependent kinase 4/6 inhibitors |
CA2761896A1 (en) | 2009-05-13 | 2010-11-18 | The University Of North Carolina At Chapel Hill | Cyclin dependent kinase inhibitors and methods of use |
WO2011103485A1 (en) | 2010-02-18 | 2011-08-25 | Medivation Technologies, Inc. | Fused tetracyclic pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives and methods of use |
CA2868966C (en) * | 2012-03-29 | 2021-01-26 | Francis Xavier Tavares | Lactam kinase inhibitors |
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