KR102228034B1 - 치환된 피리미딘 화합물 및 syk 억제제로서의 이의 용도 - Google Patents
치환된 피리미딘 화합물 및 syk 억제제로서의 이의 용도 Download PDFInfo
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- KR102228034B1 KR102228034B1 KR1020167013308A KR20167013308A KR102228034B1 KR 102228034 B1 KR102228034 B1 KR 102228034B1 KR 1020167013308 A KR1020167013308 A KR 1020167013308A KR 20167013308 A KR20167013308 A KR 20167013308A KR 102228034 B1 KR102228034 B1 KR 102228034B1
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- South Korea
- Prior art keywords
- methyl
- compound
- ylamino
- indol
- cyclopropyl
- 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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- 239000003112 inhibitor Substances 0.000 title description 23
- 150000003230 pyrimidines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 221
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 79
- 201000010099 disease Diseases 0.000 claims abstract description 62
- 238000000034 method Methods 0.000 claims abstract description 61
- -1 amino, hydroxy Chemical group 0.000 claims description 59
- 125000003118 aryl group Chemical group 0.000 claims description 51
- 125000005843 halogen group Chemical group 0.000 claims description 41
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 41
- 210000004027 cell Anatomy 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- 125000001188 haloalkyl group Chemical group 0.000 claims description 21
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 208000035475 disorder Diseases 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 16
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 16
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 208000006673 asthma Diseases 0.000 claims description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims description 12
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 12
- 206010025323 Lymphomas Diseases 0.000 claims description 12
- 208000010668 atopic eczema Diseases 0.000 claims description 11
- 230000001684 chronic effect Effects 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 9
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 9
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 9
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 9
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 9
- 230000000172 allergic effect Effects 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000001448 anilines Chemical class 0.000 claims description 8
- 201000004624 Dermatitis Diseases 0.000 claims description 7
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 7
- 201000010105 allergic rhinitis Diseases 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 206010010741 Conjunctivitis Diseases 0.000 claims description 6
- 208000011231 Crohn disease Diseases 0.000 claims description 6
- 208000001132 Osteoporosis Diseases 0.000 claims description 6
- 241000721454 Pemphigus Species 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 230000036210 malignancy Effects 0.000 claims description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 5
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- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 208000024376 chronic urticaria Diseases 0.000 claims description 5
- 150000003278 haem Chemical class 0.000 claims description 5
- 238000007918 intramuscular administration Methods 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 239000003446 ligand Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 206010039083 rhinitis Diseases 0.000 claims description 5
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
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- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 206010047115 Vasculitis Diseases 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- NYENOWAOSWSSCL-KRWDZBQOSA-N (4S)-2-[[1-[2-[(3-chloro-1,2-dimethylindol-5-yl)amino]pyrimidin-4-yl]-3-methylpyrazol-4-yl]methyl]-1,2-oxazolidin-4-ol Chemical compound Cc1nn(cc1CN1C[C@H](O)CO1)-c1ccnc(Nc2ccc3n(C)c(C)c(Cl)c3c2)n1 NYENOWAOSWSSCL-KRWDZBQOSA-N 0.000 claims description 3
- XHZBYLHQKQHUCB-INIZCTEOSA-N (4S)-2-[[3-methyl-1-[2-[(1-methyl-3-methylsulfonylindazol-5-yl)amino]pyrimidin-4-yl]pyrazol-4-yl]methyl]-1,2-oxazolidin-4-ol Chemical compound Cc1nn(cc1CN1C[C@H](O)CO1)-c1ccnc(Nc2ccc3n(C)nc(c3c2)S(C)(=O)=O)n1 XHZBYLHQKQHUCB-INIZCTEOSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- BLFQYOOGPVKCNI-IBGZPJMESA-N 1-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]-2-methylpropan-1-one Chemical compound O[C@H]1CN(OC1)CC=1C(=NN(C1)C1=NC(=NC=C1)NC=1C=C2C(=CN(C2=CC1)C)C(C(C)C)=O)C BLFQYOOGPVKCNI-IBGZPJMESA-N 0.000 claims description 3
- UTFPDGMYJZGSMM-SFHVURJKSA-N 1-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]ethanone Chemical compound O[C@H]1CN(OC1)CC=1C(=NN(C1)C1=NC(=NC=C1)NC=1C=C2C(=CN(C2=CC1)C)C(C)=O)C UTFPDGMYJZGSMM-SFHVURJKSA-N 0.000 claims description 3
- LHMGCDLXAOCQAV-KRWDZBQOSA-N 2,2,2-trifluoro-1-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]-5-methylpyrimidin-2-yl]amino]-1-methylindol-3-yl]ethanone Chemical compound FC(C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=C(C(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)C)C)(F)F LHMGCDLXAOCQAV-KRWDZBQOSA-N 0.000 claims description 3
- SUGDFLIUHAHCQF-INIZCTEOSA-N 2,2,2-trifluoro-1-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]ethanone Chemical compound FC(C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)C)(F)F SUGDFLIUHAHCQF-INIZCTEOSA-N 0.000 claims description 3
- SEMOWYYGGGLRRG-HNNXBMFYSA-N 2,2,2-trifluoro-1-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1H-indol-3-yl]ethanone Chemical compound FC(C(=O)C1=CNC2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)(F)F SEMOWYYGGGLRRG-HNNXBMFYSA-N 0.000 claims description 3
- BIYFOBJTTQVRAK-MRXNPFEDSA-N 2,2-difluoro-1-[5-[[4-[4-[[(4R)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]ethanone Chemical compound FC(C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@@H](C1)O)C)C)F BIYFOBJTTQVRAK-MRXNPFEDSA-N 0.000 claims description 3
- BIYFOBJTTQVRAK-INIZCTEOSA-N 2,2-difluoro-1-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]ethanone Chemical compound FC(C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)C)F BIYFOBJTTQVRAK-INIZCTEOSA-N 0.000 claims description 3
- 201000010000 Agranulocytosis Diseases 0.000 claims description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 3
- 208000004332 Evans syndrome Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- 208000024869 Goodpasture syndrome Diseases 0.000 claims description 3
- 206010018687 Granulocytopenia Diseases 0.000 claims description 3
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 3
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 3
- 208000010159 IgA glomerulonephritis Diseases 0.000 claims description 3
- 206010021263 IgA nephropathy Diseases 0.000 claims description 3
- 206010052568 Urticaria chronic Diseases 0.000 claims description 3
- 206010047112 Vasculitides Diseases 0.000 claims description 3
- 230000036783 anaphylactic response Effects 0.000 claims description 3
- 208000003455 anaphylaxis Diseases 0.000 claims description 3
- 208000007502 anemia Diseases 0.000 claims description 3
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 3
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- IYIKRZHAOWGOJG-SFHVURJKSA-N cyclopropyl-[1-(2,2-difluoroethyl)-5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]pyrazol-1-yl]pyrimidin-2-yl]amino]indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=CC(=C1)CN1OC[C@H](C1)O)CC(F)F IYIKRZHAOWGOJG-SFHVURJKSA-N 0.000 claims description 3
- SBYVJMFCOAMQIQ-AIBWNMTMSA-N cyclopropyl-[1-(2-fluoroethyl)-5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-2,3-dihydroindol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)CCF SBYVJMFCOAMQIQ-AIBWNMTMSA-N 0.000 claims description 3
- OGZHYXKABPBMCC-FQEVSTJZSA-N cyclopropyl-[1-(2-fluoroethyl)-5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)CCF OGZHYXKABPBMCC-FQEVSTJZSA-N 0.000 claims description 3
- FUBSRPKXGDKVIE-NRFANRHFSA-N cyclopropyl-[1-ethyl-5-[[4-[3-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-4-methylpyrrol-1-yl]pyrimidin-2-yl]amino]indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1C=C(C(=C1)C)CN1OC[C@H](C1)O)CC FUBSRPKXGDKVIE-NRFANRHFSA-N 0.000 claims description 3
- IJTHACUZXNAFPR-UHFFFAOYSA-N cyclopropyl-[1-ethyl-5-[[4-[4-[(4-hydroxy-4-methyl-1,2-oxazolidin-2-yl)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]indol-3-yl]methanone Chemical compound CCn1cc(C(=O)C2CC2)c2cc(Nc3nccc(n3)-n3cc(CN4CC(C)(O)CO4)c(C)n3)ccc12 IJTHACUZXNAFPR-UHFFFAOYSA-N 0.000 claims description 3
- UHASCOWLSSMTES-NRFANRHFSA-N cyclopropyl-[1-ethyl-5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]-5-methylpyrimidin-2-yl]amino]indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=C(C(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)C)CC UHASCOWLSSMTES-NRFANRHFSA-N 0.000 claims description 3
- KCQSZKBRMVTRRJ-IBGZPJMESA-N cyclopropyl-[1-ethyl-5-[[5-fluoro-4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=C(C(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)F)CC KCQSZKBRMVTRRJ-IBGZPJMESA-N 0.000 claims description 3
- LIDCFKBKXOTSEC-NRFANRHFSA-N cyclopropyl-[5-[[4-[3-cyclopropyl-4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]pyrazol-1-yl]pyrimidin-2-yl]amino]-1-ethylindol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C1CC1)CC LIDCFKBKXOTSEC-NRFANRHFSA-N 0.000 claims description 3
- IBTPVKVXHQWXCK-UHFFFAOYSA-N cyclopropyl-[5-[[4-[4-[(4-hydroxy-4-methyl-1,2-oxazolidin-2-yl)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-(2,2,2-trifluoroethyl)indol-3-yl]methanone Chemical compound Cc1nn(cc1CN1CC(C)(O)CO1)-c1ccnc(Nc2ccc3n(CC(F)(F)F)cc(C(=O)C4CC4)c3c2)n1 IBTPVKVXHQWXCK-UHFFFAOYSA-N 0.000 claims description 3
- QLSIKNVCSGLJIF-UHFFFAOYSA-N cyclopropyl-[5-[[4-[4-[(4-hydroxy-4-methyl-1,2-oxazolidin-2-yl)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone Chemical compound Cc1nn(cc1CN1CC(C)(O)CO1)-c1ccnc(Nc2ccc3n(C)cc(C(=O)C4CC4)c3c2)n1 QLSIKNVCSGLJIF-UHFFFAOYSA-N 0.000 claims description 3
- LVECTQJBPIVAIR-IBGZPJMESA-N cyclopropyl-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-(2,2,2-trifluoroethyl)indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)CC(F)(F)F LVECTQJBPIVAIR-IBGZPJMESA-N 0.000 claims description 3
- HOFPWOAFILPHER-IBGZPJMESA-N cyclopropyl-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylsulfonylindol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)S(=O)(=O)C HOFPWOAFILPHER-IBGZPJMESA-N 0.000 claims description 3
- QFFPVRRLEUQNPK-NRFANRHFSA-N cyclopropyl-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-propan-2-ylindol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)C(C)C QFFPVRRLEUQNPK-NRFANRHFSA-N 0.000 claims description 3
- RNHQHTDFADEGJD-SFHVURJKSA-N cyclopropyl-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1H-indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CNC2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C RNHQHTDFADEGJD-SFHVURJKSA-N 0.000 claims description 3
- LGAANFVKOYQKJI-SFHVURJKSA-N cyclopropyl-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]pyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=CC(=C1)CN1OC[C@H](C1)O)C LGAANFVKOYQKJI-SFHVURJKSA-N 0.000 claims description 3
- YCZUBLQESBVOSH-IBGZPJMESA-N cyclopropyl-[5-[[4-[4-[[(4s)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-1-methylindol-3-yl]methanone Chemical compound CC1=NN(C=2N=C(NC=3C=C4C(C(=O)C5CC5)=CN(C)C4=CC=3)N=CC=2)C=C1CN1C[C@H](O)CO1 YCZUBLQESBVOSH-IBGZPJMESA-N 0.000 claims description 3
- MNHCFWZFYYYFED-IBGZPJMESA-N ethyl 3-acetyl-5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]indole-1-carboxylate Chemical compound C(C)(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=C(C(=C1)CN1OC[C@H](C1)O)C)C(=O)OCC MNHCFWZFYYYFED-IBGZPJMESA-N 0.000 claims description 3
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 3
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 231100000283 hepatitis Toxicity 0.000 claims description 3
- 210000004698 lymphocyte Anatomy 0.000 claims description 3
- 208000008585 mastocytosis Diseases 0.000 claims description 3
- 208000004235 neutropenia Diseases 0.000 claims description 3
- 238000011200 topical administration Methods 0.000 claims description 3
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 2
- 208000034189 Sclerosis Diseases 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 230000001363 autoimmune Effects 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 206010072757 chronic spontaneous urticaria Diseases 0.000 claims description 2
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 2
- YBDFABRBIIRYCZ-SFHVURJKSA-N cyclopropyl-[5-[[4-[4-[[(4S)-4-hydroxy-1,2-oxazolidin-2-yl]methyl]pyrazol-1-yl]pyrimidin-2-yl]amino]-1-(2,2,2-trifluoroethyl)indol-3-yl]methanone Chemical compound C1(CC1)C(=O)C1=CN(C2=CC=C(C=C12)NC1=NC=CC(=N1)N1N=CC(=C1)CN1OC[C@H](C1)O)CC(F)(F)F YBDFABRBIIRYCZ-SFHVURJKSA-N 0.000 claims description 2
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- 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
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
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| JP2022526713A (ja) | 2019-03-21 | 2022-05-26 | オンクセオ | がんの処置のための、キナーゼ阻害剤と組み合わせたＤｂａｉｔ分子 |
| KR20220098759A (ko) | 2019-11-08 | 2022-07-12 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | 키나제 억제제에 대해 내성을 획득한 암의 치료 방법 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| CN113248472B (zh) * | 2020-02-12 | 2022-06-28 | 中国药科大学 | 抗骨质疏松化合物及其衍生物，药物组合物、制备方法和应用 |
| KR20210152312A (ko) * | 2020-06-08 | 2021-12-15 | 주식회사 종근당 | 카나비노이드 수용체 (cb1 수용체) 길항제로서의 4-(4,5-디하이드로-1h-피라졸-1-닐)피리미딘 화합물 및 이를 포함하는 약제학적 조성물 |
| US20240285621A1 (en) * | 2020-09-23 | 2024-08-29 | Nerviano Medical Sciences S.R.L. | Pyrazolyl-pyrimidine derivatives as kinase inhibitors |
| AU2024259993A1 (en) * | 2023-04-24 | 2025-11-06 | Foshan Ionova Biotherapeutics Co., Inc. | Cdk2 inhibitors and methods of using same |
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| WO2013109882A1 (en) * | 2012-01-20 | 2013-07-25 | Genosco | Substituted pyrimidine compounds and their use as syk inhibitors |
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| US20030158195A1 (en) | 2001-12-21 | 2003-08-21 | Cywin Charles L. | 1,6 naphthyridines useful as inhibitors of SYK kinase |
| EP1558753A2 (en) | 2002-10-16 | 2005-08-03 | Millennium Pharmaceuticals, Inc. | Spleen tyrosine kinase catalytic domain: crystal structure and binding pockets thereof |
| SE0300119D0 (sv) * | 2003-01-17 | 2003-01-17 | Astrazeneca Ab | Novel compounds |
| SE0300120D0 (sv) * | 2003-01-17 | 2003-01-17 | Astrazeneca Ab | Novel compounds |
| PL378221A1 (pl) * | 2003-01-17 | 2006-03-20 | Astrazeneca Ab | Tienopirydazynony i ich zastosowanie w modulacji choroby autoimmunologicznej |
| EA200800664A1 (ru) | 2005-10-13 | 2009-02-27 | Глаксо Груп Лимитед | Производные пирролопиримидина в качестве ингибиторов syk |
| AU2008296479A1 (en) * | 2007-08-28 | 2009-03-12 | Dana Farber Cancer Institute | Amino substituted pyrimidine, pyrollopyridine and pyrazolopyrimidine derivatives useful as kinase inhibitors and in treating proliferative disorders and diseases associated with angiogenesis |
| WO2010015520A1 (de) | 2008-08-05 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Substituierte naphthyridine und ihre verwendung als arzneimittel |
| WO2010015518A2 (de) | 2008-08-05 | 2010-02-11 | Boehringer Ingelheim Interntional Gmbh | 4-dimethylamino-phenyl-substituierte naphthyridine und ihre verwendung als arzneimittel |
| KR20120125267A (ko) | 2010-01-29 | 2012-11-14 | 베링거 인겔하임 인터내셔날 게엠베하 | 치환된 나프티리딘 및 ｓｙｋ 키나제 억제제로서의 이의 용도 |
| GB201007203D0 (en) | 2010-04-29 | 2010-06-16 | Glaxo Group Ltd | Novel compounds |
| JP2013529204A (ja) | 2010-05-20 | 2013-07-18 | エフ．ホフマン−ラ ロシュ アーゲー | ピロロ［２，３−ｂ］ピラジン−７−カルボキサミド誘導体とＪＡＫ及びＳＹＫ及び阻害剤としてのそれらの使用 |
| WO2011156698A2 (en) * | 2010-06-11 | 2011-12-15 | Abbott Laboratories | NOVEL PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS |
| UY34484A (es) * | 2011-12-15 | 2013-07-31 | Bayer Ip Gmbh | Benzotienilo-pirrolotriazinas disustituidas y sus usos |
| JP6101341B2 (ja) * | 2012-03-22 | 2017-03-22 | オスコテック, インコーポレーテッドOscotec, Inc. | 置換ピリドピリミジン化合物およびｆｌｔ３阻害剤としてのこれらの使用 |
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| WO2013109882A1 (en) * | 2012-01-20 | 2013-07-25 | Genosco | Substituted pyrimidine compounds and their use as syk inhibitors |
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