ES2548414T3 - Novedosos derivados de pirrolo pirimidina - Google Patents
Novedosos derivados de pirrolo pirimidina Download PDFInfo
- Publication number
- ES2548414T3 ES2548414T3 ES12761655.5T ES12761655T ES2548414T3 ES 2548414 T3 ES2548414 T3 ES 2548414T3 ES 12761655 T ES12761655 T ES 12761655T ES 2548414 T3 ES2548414 T3 ES 2548414T3
- Authority
- ES
- Spain
- Prior art keywords
- pyrrolo
- phenyl
- methyl
- pyrimidin
- fluoro
- 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.)
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 139
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 94
- 239000001257 hydrogen Substances 0.000 claims abstract description 93
- 229910052736 halogen Chemical group 0.000 claims abstract description 74
- 150000002367 halogens Chemical group 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 62
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 60
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 51
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 28
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 13
- 125000004429 atom Chemical group 0.000 claims abstract description 8
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 7
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims abstract description 4
- 150000003976 azacycloalkanes Chemical group 0.000 claims abstract description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical group O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims abstract 2
- -1 dimethylamide -3,6-dihydro-2H-pyridine-1-carboxylic acid Chemical compound 0.000 claims description 238
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 73
- 239000002253 acid Substances 0.000 claims description 66
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 63
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 56
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 49
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 201000010099 disease Diseases 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 24
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 24
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 21
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 230000001404 mediated effect Effects 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 14
- YWPMKTWUFVOFPL-UHFFFAOYSA-N 3,4-dihydro-2h-isoquinolin-1-one Chemical group C1=CC=C2C(=O)NCCC2=C1 YWPMKTWUFVOFPL-UHFFFAOYSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- DEDSPQBYYGKANF-UHFFFAOYSA-N 4-tert-butyl-n-[5-fluoro-3-[6-(4-hydroxycyclohexen-1-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]benzamide Chemical compound C1=C(F)C=C(C=2C=3C=C(NC=3N=CN=2)C=2CCC(O)CC=2)C(C)=C1NC(=O)C1=CC=C(C(C)(C)C)C=C1 DEDSPQBYYGKANF-UHFFFAOYSA-N 0.000 claims description 6
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 claims description 5
- UZQDYTBAPMZXKM-UHFFFAOYSA-N 4-cyclopropyl-n-[5-fluoro-2-methyl-3-[6-[1-(pyrrolidine-1-carbonyl)-3,6-dihydro-2h-pyridin-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide Chemical compound C1=C(F)C=C(C=2C=3C=C(NC=3N=CN=2)C=2CCN(CC=2)C(=O)N2CCCC2)C(C)=C1NC(=O)C(C=C1)=CC=C1C1CC1 UZQDYTBAPMZXKM-UHFFFAOYSA-N 0.000 claims description 4
- DVAUUEDPFRNAMP-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-(4-hydroxycyclohexen-1-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]benzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)NC1=CC=CC(C=2C=3C=C(NC=3N=CN=2)C=2CCC(O)CC=2)=C1CO DVAUUEDPFRNAMP-UHFFFAOYSA-N 0.000 claims description 4
- LOIGITGGOMQGLY-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-(4-hydroxycyclohexen-1-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]benzamide Chemical compound C1=CC=C(C=2C=3C=C(NC=3N=CN=2)C=2CCC(O)CC=2)C(C)=C1NC(=O)C1=CC=C(C(C)(C)C)C=C1 LOIGITGGOMQGLY-UHFFFAOYSA-N 0.000 claims description 4
- CELWNVZCXQHXSO-UHFFFAOYSA-N 4-tert-butyl-n-[5-fluoro-2-methyl-3-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide Chemical compound C1=C(F)C=C(C=2C=3C=C(NC=3N=CN=2)C=2CCNCC=2)C(C)=C1NC(=O)C1=CC=C(C(C)(C)C)C=C1 CELWNVZCXQHXSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 claims description 3
- YIRNNHURQFNQDX-UHFFFAOYSA-N 3,6-dihydro-2h-pyridine-1-carboxylic acid Chemical compound OC(=O)N1CCC=CC1 YIRNNHURQFNQDX-UHFFFAOYSA-N 0.000 claims description 3
- VRYZQIAOLUEBDN-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]benzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)NC1=CC=CC(C=2C=3C=C(NC=3N=CN=2)C=2CCC3(CC=2)OCCO3)=C1CO VRYZQIAOLUEBDN-UHFFFAOYSA-N 0.000 claims description 3
- VPKOYSJAJAWJEV-UHFFFAOYSA-N 5-fluoro-1,3-dihydroisoindole-2-carboxylic acid Chemical compound C1=C(F)C=C2CN(C(=O)O)CC2=C1 VPKOYSJAJAWJEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- PSLXNEVDCJSLEL-UHFFFAOYSA-N n-[3-[6-(3,6-dihydro-2h-pyran-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide Chemical compound C1=C(F)C=C(C=2C=3C=C(NC=3N=CN=2)C=2CCOCC=2)C(C)=C1NC(=O)C1=CC=C(C(C)(C)O)C=C1F PSLXNEVDCJSLEL-UHFFFAOYSA-N 0.000 claims description 3
- CTGDAVDRLMDGCN-UHFFFAOYSA-N n-[3-[6-(3,6-dihydro-2h-pyran-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-(dimethylamino)benzamide Chemical compound C1=CC(N(C)C)=CC=C1C(=O)NC1=CC(F)=CC(C=2C=3C=C(NC=3N=CN=2)C=2CCOCC=2)=C1C CTGDAVDRLMDGCN-UHFFFAOYSA-N 0.000 claims description 3
- IEYMWIJHVRBMOB-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]benzamide Chemical compound C1=CC=C(C=2C=3C=C(NC=3N=CN=2)C=2CCC3(CC=2)OCCO3)C(C)=C1NC(=O)C1=CC=C(C(C)(C)C)C=C1 IEYMWIJHVRBMOB-UHFFFAOYSA-N 0.000 claims description 2
- NECGVVPXSMRWLI-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-(3,6-dihydro-2h-pyran-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]benzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)NC1=CC=CC(C=2C=3C=C(NC=3N=CN=2)C=2CCOCC=2)=C1CO NECGVVPXSMRWLI-UHFFFAOYSA-N 0.000 claims description 2
- QYSLVNJERLKIKQ-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-[1-(dimethylsulfamoyl)-3,6-dihydro-2h-pyridin-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]benzamide Chemical compound C1N(S(=O)(=O)N(C)C)CCC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(NC(=O)C=3C=CC(=CC=3)C(C)(C)C)C=C(F)C=2)C)=C1 QYSLVNJERLKIKQ-UHFFFAOYSA-N 0.000 claims description 2
- LJSAWTQFYUQZFA-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-[4-(dimethylamino)cyclohexen-1-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]benzamide Chemical compound C1C(N(C)C)CCC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(NC(=O)C=3C=CC(=CC=3)C(C)(C)C)C=CC=2)CO)=C1 LJSAWTQFYUQZFA-UHFFFAOYSA-N 0.000 claims description 2
- MDFVNQDNQGGSDP-UHFFFAOYSA-N 4-tert-butyl-n-[3-[6-[4-(dimethylamino)cyclohexen-1-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]benzamide Chemical compound C1C(N(C)C)CCC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(NC(=O)C=3C=CC(=CC=3)C(C)(C)C)C=CC=2)C)=C1 MDFVNQDNQGGSDP-UHFFFAOYSA-N 0.000 claims description 2
- FEUPGDZLUUHGNR-UHFFFAOYSA-N 4-tert-butyl-n-[5-fluoro-2-methyl-3-[6-(1-methylsulfonyl-3,6-dihydro-2h-pyridin-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide Chemical compound C1=C(F)C=C(C=2C=3C=C(NC=3N=CN=2)C=2CCN(CC=2)S(C)(=O)=O)C(C)=C1NC(=O)C1=CC=C(C(C)(C)C)C=C1 FEUPGDZLUUHGNR-UHFFFAOYSA-N 0.000 claims description 2
- SCGWVZNPYKESGN-UHFFFAOYSA-N n-[5-fluoro-2-methyl-3-[6-[1-(pyrrolidine-1-carbonyl)-3,6-dihydro-2h-pyridin-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-4-(pentafluoro-$l^{6}-sulfanyl)benzamide Chemical compound C1=C(F)C=C(C=2C=3C=C(NC=3N=CN=2)C=2CCN(CC=2)C(=O)N2CCCC2)C(C)=C1NC(=O)C1=CC=C(S(F)(F)(F)(F)F)C=C1 SCGWVZNPYKESGN-UHFFFAOYSA-N 0.000 claims description 2
- UJVGRWVBHNSHNC-UHFFFAOYSA-N n-[5-fluoro-3-[6-[1-(2-hydroxyacetyl)-3,6-dihydro-2h-pyridin-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-4-(pentafluoro-$l^{6}-sulfanyl)benzamide Chemical compound C1=C(F)C=C(C=2C=3C=C(NC=3N=CN=2)C=2CCN(CC=2)C(=O)CO)C(C)=C1NC(=O)C1=CC=C(S(F)(F)(F)(F)F)C=C1 UJVGRWVBHNSHNC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 14
- KCKMAHVALNYTJA-UHFFFAOYSA-N 2-pyrimidin-4-ylbenzamide Chemical compound NC(=O)C1=CC=CC=C1C1=CC=NC=N1 KCKMAHVALNYTJA-UHFFFAOYSA-N 0.000 claims 1
- OFIHLJVSTBCYEM-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxy]azetidine Chemical compound CC(C)(C)OC1CNC1 OFIHLJVSTBCYEM-UHFFFAOYSA-N 0.000 claims 1
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 179
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 124
- 238000005160 1H NMR spectroscopy Methods 0.000 description 93
- 239000000203 mixture Substances 0.000 description 91
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 77
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- 239000000243 solution Substances 0.000 description 53
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 51
- 239000000543 intermediate Substances 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 238000000034 method Methods 0.000 description 37
- 239000007787 solid Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 31
- 238000003818 flash chromatography Methods 0.000 description 30
- 230000005764 inhibitory process Effects 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000012267 brine Substances 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 229940124597 therapeutic agent Drugs 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 17
- 239000000377 silicon dioxide Substances 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 229910052805 deuterium Inorganic materials 0.000 description 16
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- 125000001072 heteroaryl group Chemical group 0.000 description 8
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
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- 108091000080 Phosphotransferase Proteins 0.000 description 7
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- 239000008280 blood Substances 0.000 description 7
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- 125000000623 heterocyclic group Chemical group 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- 230000010933 acylation Effects 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- 208000026935 allergic disease Diseases 0.000 description 6
- 150000001502 aryl halides Chemical class 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- 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
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- 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
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US201161505560P | 2011-07-08 | ||
| PCT/IB2012/001699 WO2013008095A1 (en) | 2011-07-08 | 2012-07-07 | Novel pyrrolo pyrimidine derivatives |
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| CN103732596B (zh) | 2011-07-08 | 2016-06-01 | 诺华股份有限公司 | 吡咯并嘧啶衍生物 |
| WO2013157021A1 (en) | 2012-04-20 | 2013-10-24 | Advinus Therapeutics Limited | Bicyclic compounds, compositions and medicinal applications thereof |
| CA2869954C (en) * | 2012-04-20 | 2023-01-03 | Advinus Therapeutics Limited | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof in medical conditions related to modulation of bruton's tyrosine kinase activity |
| KR20150032340A (ko) | 2012-07-24 | 2015-03-25 | 파마시클릭스, 인코포레이티드 | 브루톤 티로신 키나제(btk)의 억제제에 대한 내성과 관련된 돌연변이 |
| SMT201700160T1 (it) | 2013-04-25 | 2017-05-08 | Beigene Ltd | Composti eterociclici fusi come inibitori di protein chinasi |
| ES2792183T3 (es) | 2013-09-13 | 2020-11-10 | Beigene Switzerland Gmbh | Anticuerpos anti-PD1 y su uso como productos terapéuticos y de diagnóstico |
| US9512084B2 (en) | 2013-11-29 | 2016-12-06 | Novartis Ag | Amino pyrimidine derivatives |
| US20150157634A1 (en) * | 2013-12-02 | 2015-06-11 | Pharmacyclics, Inc. | Methods of treating and preventing alloantibody driven chronic graft versus host disease |
| CN106604742B (zh) | 2014-07-03 | 2019-01-11 | 百济神州有限公司 | 抗pd-l1抗体及其作为治疗剂及诊断剂的用途 |
| UA125061C2 (uk) * | 2014-10-06 | 2022-01-05 | Мерк Патент Ґмбг | Сполуки гетероарилу як інгібітори ткб і їх застосування |
| HUE050706T2 (hu) * | 2014-10-24 | 2020-12-28 | Bristol Myers Squibb Co | Indol karboxamid vegyületek, amelyek hasznosak kináz inhibitorokként |
| WO2016079669A1 (en) * | 2014-11-19 | 2016-05-26 | Novartis Ag | Labeled amino pyrimidine derivatives |
| AR102871A1 (es) * | 2014-12-03 | 2017-03-29 | Pharmacyclics Llc | Métodos de tratamiento de fibrosis |
| EP3042903B1 (en) | 2015-01-06 | 2019-08-14 | Impetis Biosciences Ltd. | Substituted hetero-bicyclic compounds, compositions and medicinal applications thereof |
| EP3365340B1 (en) | 2015-10-19 | 2022-08-10 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| HUE060680T2 (hu) | 2015-11-19 | 2023-04-28 | Incyte Corp | Heterociklusos vegyületek mint immunmodulátorok |
| WO2017106634A1 (en) * | 2015-12-17 | 2017-06-22 | Incyte Corporation | N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators |
| EP3394033B1 (en) | 2015-12-22 | 2020-11-25 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| WO2017192961A1 (en) | 2016-05-06 | 2017-11-09 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| TW201808902A (zh) | 2016-05-26 | 2018-03-16 | 美商英塞特公司 | 作為免疫調節劑之雜環化合物 |
| MD3472167T2 (ro) | 2016-06-20 | 2023-02-28 | Incyte Corp | Compuși heterociclici ca imunomodulatori |
| CN109475536B (zh) | 2016-07-05 | 2022-05-27 | 百济神州有限公司 | 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合 |
| WO2018013789A1 (en) | 2016-07-14 | 2018-01-18 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| WO2018033853A2 (en) | 2016-08-16 | 2018-02-22 | Beigene, Ltd. | Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof |
| PT3500299T (pt) | 2016-08-19 | 2024-02-21 | Beigene Switzerland Gmbh | Combinação de zanubrutinib com um anticorpo anti-cd20 ou anti-pd-1 para utilização no tratamento do cancro |
| US20180057486A1 (en) | 2016-08-29 | 2018-03-01 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
| MA46285A (fr) | 2016-09-19 | 2019-07-31 | Mei Pharma Inc | Polythérapie |
| KR102686957B1 (ko) * | 2016-11-08 | 2024-07-22 | 주식회사 대웅제약 | 신규한 피롤로피리미딘 유도체 및 이를 포함하는 약학적 조성물 |
| PE20200005A1 (es) | 2016-12-22 | 2020-01-06 | Incyte Corp | Derivados de tetrahidro imidazo[4,5-c]piridina como inductores de internalizacion pd-l1 |
| EP3558973B1 (en) | 2016-12-22 | 2021-09-15 | Incyte Corporation | Pyridine derivatives as immunomodulators |
| EP3558989B1 (en) | 2016-12-22 | 2021-04-14 | Incyte Corporation | Triazolo[1,5-a]pyridine derivatives as immunomodulators |
| MA47123A (fr) | 2016-12-22 | 2021-03-17 | Incyte Corp | Dérivés de benzooxazole en tant qu'mmunomodulateurs |
| EP3558963B1 (en) | 2016-12-22 | 2022-03-23 | Incyte Corporation | Bicyclic heteroaromatic compounds as immunomodulators |
| CN110461847B (zh) | 2017-01-25 | 2022-06-07 | 百济神州有限公司 | (S)-7-(1-(丁-2-炔酰基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的结晶形式、其制备及用途 |
| WO2018145525A1 (zh) | 2017-02-08 | 2018-08-16 | 中国医药研究开发中心有限公司 | 吡咯并芳杂环类化合物及其制备方法和医药用途 |
| TW202515616A (zh) | 2017-06-26 | 2025-04-16 | 英屬開曼群島商百濟神州有限公司 | 抗pd-1抗體或其抗原結合片段在製備治療用於患有肝細胞癌(hcc)之藥物的用途 |
| CN110997677A (zh) | 2017-08-12 | 2020-04-10 | 百济神州有限公司 | 具有改进的双重选择性的Btk抑制剂 |
| WO2019108795A1 (en) | 2017-11-29 | 2019-06-06 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors |
| CN111936501B (zh) * | 2018-03-26 | 2023-09-22 | 诺华股份有限公司 | 布鲁顿酪氨酸激酶降解剂 |
| EP3774804A1 (en) * | 2018-03-26 | 2021-02-17 | Novartis AG | N-(3-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)benzamide derivatives |
| PL4212529T3 (pl) | 2018-03-30 | 2025-07-07 | Incyte Corporation | Związki heterocykliczne jako immunomodulatory |
| HRP20230306T1 (hr) | 2018-05-11 | 2023-05-12 | Incyte Corporation | Derivati tetrahidro-imidazo[4,5-c]piridina kao pd-l1 imunomodulatori |
| WO2020249001A1 (zh) | 2019-06-10 | 2020-12-17 | 百济神州瑞士有限责任公司 | 一种含有布鲁顿氏酪氨酸激酶抑制剂的口服固体片剂及其制备方法 |
| WO2021030162A1 (en) | 2019-08-09 | 2021-02-18 | Incyte Corporation | Salts of a pd-1/pd-l1 inhibitor |
| IL291471B2 (en) | 2019-09-30 | 2025-04-01 | Incyte Corp | Pyrimido[3,2–D]pyrimidine compounds as immunomodulators |
| CR20220237A (es) | 2019-11-11 | 2022-08-05 | Incyte Corp | Sales y formas cristalinas de un inhibidor de pd-1/pd-l1 |
| CN111704617B (zh) * | 2020-06-15 | 2022-08-23 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
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| AR124001A1 (es) | 2020-11-06 | 2023-02-01 | Incyte Corp | Proceso para fabricar un inhibidor pd-1 / pd-l1 y sales y formas cristalinas del mismo |
| WO2022099075A1 (en) | 2020-11-06 | 2022-05-12 | Incyte Corporation | Crystalline form of a pd-1/pd-l1 inhibitor |
| CN116782946A (zh) * | 2021-01-30 | 2023-09-19 | 百济神州有限公司 | 使用btk抑制剂治疗慢性活动性抗体介导的排斥的方法 |
| US20240216513A1 (en) | 2021-03-12 | 2024-07-04 | Novartis Ag | Fatty acid-bifunctional degrader conjugates and their methods of use |
| CN115073469B (zh) * | 2021-03-15 | 2023-12-22 | 药雅科技(上海)有限公司 | 吡咯并嘧啶类化合物作为激酶抑制剂的制备及其应用 |
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-
2012
- 2012-07-07 CN CN201280033935.9A patent/CN103732596B/zh not_active Expired - Fee Related
- 2012-07-07 CA CA2841111A patent/CA2841111A1/en not_active Abandoned
- 2012-07-07 MX MX2014000338A patent/MX2014000338A/es unknown
- 2012-07-07 BR BR112014000314A patent/BR112014000314A2/pt not_active IP Right Cessation
- 2012-07-07 WO PCT/IB2012/001699 patent/WO2013008095A1/en not_active Ceased
- 2012-07-07 EP EP12761655.5A patent/EP2729466B1/en not_active Not-in-force
- 2012-07-07 EA EA201490229A patent/EA201490229A1/ru unknown
- 2012-07-07 ES ES12761655.5T patent/ES2548414T3/es active Active
- 2012-07-07 AU AU2012282229A patent/AU2012282229B2/en not_active Expired - Fee Related
- 2012-07-07 US US14/130,536 patent/US9233111B2/en not_active Expired - Fee Related
- 2012-07-07 KR KR1020147002986A patent/KR20140058543A/ko not_active Withdrawn
- 2012-07-07 JP JP2014517980A patent/JP6145451B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US20140243306A1 (en) | 2014-08-28 |
| JP2014520793A (ja) | 2014-08-25 |
| JP6145451B2 (ja) | 2017-06-14 |
| AU2012282229B2 (en) | 2015-05-07 |
| MX2014000338A (es) | 2014-05-01 |
| AU2012282229A1 (en) | 2014-01-16 |
| EP2729466A1 (en) | 2014-05-14 |
| BR112014000314A2 (pt) | 2017-01-10 |
| EP2729466B1 (en) | 2015-08-19 |
| EA201490229A1 (ru) | 2014-05-30 |
| CA2841111A1 (en) | 2013-01-17 |
| WO2013008095A1 (en) | 2013-01-17 |
| KR20140058543A (ko) | 2014-05-14 |
| CN103732596B (zh) | 2016-06-01 |
| CN103732596A (zh) | 2014-04-16 |
| US9233111B2 (en) | 2016-01-12 |
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