HRP20000799A2 - Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation - Google Patents

Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation Download PDF

Info

Publication number: HRP20000799A2
Authority: HR; Croatia
Prior art keywords: pyrimido; phenylamino; pyrimidin; dihydro; methyl
Prior art date: 1998-05-26

Application number

HR20000799A

Other languages

English (en)

Croatian (hr)

Inventor

Ellen Myra Dobrusin

James Marino Hamby

James Bernard Kramer

Mel Conrad Schroeder

Howard Daniel Hollis Showalter

Peter Laurence Toogood

Susanne A Trumpp-Kallmeyer

Original Assignee

Warner Lambert Co

Priority date (The priority date 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 date listed.)

1998-05-26

Filing date

2000-11-20

Publication date

2001-06-30

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26775058&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=HRP20000799(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2000-11-20 Application filed by Warner Lambert Co filed Critical Warner Lambert Co

2001-06-30 Publication of HRP20000799A2 publication Critical patent/HRP20000799A2/hr

Links

-1 Bicyclic pyrimidines Chemical class 0.000 title claims description 106
239000003112 inhibitor Substances 0.000 title description 11
230000004663 cell proliferation Effects 0.000 title description 5
150000001875 compounds Chemical class 0.000 claims description 141
125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 58
238000000034 method Methods 0.000 claims description 57
HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims description 52
125000000217 alkyl group Chemical group 0.000 claims description 41
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
229910052757 nitrogen Inorganic materials 0.000 claims description 38
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
150000003839 salts Chemical class 0.000 claims description 28
125000000753 cycloalkyl group Chemical group 0.000 claims description 25
229910052736 halogen Inorganic materials 0.000 claims description 23
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 23
229910052760 oxygen Inorganic materials 0.000 claims description 23
150000002367 halogens Chemical class 0.000 claims description 22
125000001072 heteroaryl group Chemical group 0.000 claims description 22
101100295741 Gallus gallus COR4 gene Proteins 0.000 claims description 21
206010028980 Neoplasm Diseases 0.000 claims description 21
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
125000003545 alkoxy group Chemical group 0.000 claims description 20
RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 19
150000002466 imines Chemical group 0.000 claims description 18
229910052717 sulfur Inorganic materials 0.000 claims description 18
102000003903 Cyclin-dependent kinases Human genes 0.000 claims description 17
108090000266 Cyclin-dependent kinases Proteins 0.000 claims description 17
230000002401 inhibitory effect Effects 0.000 claims description 17
102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 16
108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 16
108091000080 Phosphotransferase Proteins 0.000 claims description 15
102000020233 phosphotransferase Human genes 0.000 claims description 15
VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 15
150000003573 thiols Chemical class 0.000 claims description 15
125000000547 substituted alkyl group Chemical group 0.000 claims description 14
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical class [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
201000011510 cancer Diseases 0.000 claims description 13
239000001301 oxygen Chemical class 0.000 claims description 13
230000002062 proliferating effect Effects 0.000 claims description 13
201000010099 disease Diseases 0.000 claims description 12
125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 12
239000001257 hydrogen Substances 0.000 claims description 12
229910052739 hydrogen Inorganic materials 0.000 claims description 12
125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 12
108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 11
102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 11
229940126864 fibroblast growth factor Drugs 0.000 claims description 11
125000005842 heteroatom Chemical group 0.000 claims description 11
125000004076 pyridyl group Chemical group 0.000 claims description 11
LPUCHTNHUHOTRY-UHFFFAOYSA-N 1-(3-bicyclo[2.2.1]heptanyl)ethanamine Chemical compound C1CC2C(C(N)C)CC1C2 LPUCHTNHUHOTRY-UHFFFAOYSA-N 0.000 claims description 10
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 10
125000003342 alkenyl group Chemical group 0.000 claims description 10
125000000304 alkynyl group Chemical group 0.000 claims description 10
230000033115 angiogenesis Effects 0.000 claims description 10
125000004432 carbon atom Chemical group C* 0.000 claims description 10
101150073031 cdk2 gene Proteins 0.000 claims description 10
230000035755 proliferation Effects 0.000 claims description 10
208000037803 restenosis Diseases 0.000 claims description 10
201000001320 Atherosclerosis Diseases 0.000 claims description 9
101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 claims description 9
108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 9
239000004202 carbamide Substances 0.000 claims description 9
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
208000035475 disorder Diseases 0.000 claims description 9
239000003102 growth factor Substances 0.000 claims description 9
150000002829 nitrogen Chemical class 0.000 claims description 9
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 8
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
125000000623 heterocyclic group Chemical group 0.000 claims description 8
150000002825 nitriles Chemical class 0.000 claims description 8
239000011593 sulfur Chemical class 0.000 claims description 8
125000004001 thioalkyl group Chemical group 0.000 claims description 8
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 7
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
241000124008 Mammalia Species 0.000 claims description 7
201000004681 Psoriasis Diseases 0.000 claims description 7
230000001404 mediated effect Effects 0.000 claims description 7
210000002464 muscle smooth vascular Anatomy 0.000 claims description 7
150000002923 oximes Chemical class 0.000 claims description 7
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 7
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 6
JPOJBQLUJAIHHL-UHFFFAOYSA-N 1h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=CN=C2NC(=O)N=CC2=C1 JPOJBQLUJAIHHL-UHFFFAOYSA-N 0.000 claims description 6
150000002431 hydrogen Chemical class 0.000 claims description 6
102000037979 non-receptor tyrosine kinases Human genes 0.000 claims description 6
108091008046 non-receptor tyrosine kinases Proteins 0.000 claims description 6
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
239000003085 diluting agent Substances 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical class ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 5
CKEBVRPXMIKWIP-UHFFFAOYSA-N 8-methyl-2-(4-pyrazol-1-ylanilino)-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound N1=C2N(C)C(=O)NCC2=CN=C1NC(C=C1)=CC=C1N1C=CC=N1 CKEBVRPXMIKWIP-UHFFFAOYSA-N 0.000 claims description 4
FXCWWKGXYURZGF-UHFFFAOYSA-N 8-methyl-2-[4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C(CNC(=O)N2C)C2=N1 FXCWWKGXYURZGF-UHFFFAOYSA-N 0.000 claims description 4
102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 4
108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 4
230000003993 interaction Effects 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
239000000546 pharmaceutical excipient Substances 0.000 claims description 4
NFKADCJUKLTGRB-UHFFFAOYSA-N 1-propan-2-yl-7-(4-pyrazol-1-ylanilino)pyrimido[4,5-d]pyrimidin-2-one Chemical compound N=1C=C2C=NC(=O)N(C(C)C)C2=NC=1NC(C=C1)=CC=C1N1C=CC=N1 NFKADCJUKLTGRB-UHFFFAOYSA-N 0.000 claims description 3
AKJJXTNCIMJSTI-UHFFFAOYSA-N 7-[4-(4-methylpiperazin-1-yl)anilino]-1-propan-2-ylpyrimido[4,5-d]pyrimidin-2-one Chemical compound N=1C=C2C=NC(=O)N(C(C)C)C2=NC=1NC(C=C1)=CC=C1N1CCN(C)CC1 AKJJXTNCIMJSTI-UHFFFAOYSA-N 0.000 claims description 3
LSQGLPJPPZIBTL-UHFFFAOYSA-N 7-[4-(diethylamino)butylamino]-3-(3,5-dimethoxyphenyl)-1-ethyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound O=C1N(CC)C2=NC(NCCCCN(CC)CC)=NC=C2CN1C1=CC(OC)=CC(OC)=C1 LSQGLPJPPZIBTL-UHFFFAOYSA-N 0.000 claims description 3
KQWHLVPKNZXXEV-UHFFFAOYSA-N 7-[4-[4-(dimethylamino)piperidin-1-yl]anilino]-1-propan-2-ylpyrimido[4,5-d]pyrimidin-2-one Chemical compound N=1C=C2C=NC(=O)N(C(C)C)C2=NC=1NC(C=C1)=CC=C1N1CCC(N(C)C)CC1 KQWHLVPKNZXXEV-UHFFFAOYSA-N 0.000 claims description 3
SRCVYIHSYUUCQT-UHFFFAOYSA-N 8-(3-bicyclo[2.2.1]heptanyl)-2-[4-(4-methylpiperazin-1-yl)anilino]-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C(CNC(=O)N2C3C4CCC(C4)C3)C2=N1 SRCVYIHSYUUCQT-UHFFFAOYSA-N 0.000 claims description 3
QQOUBGFAMSXQJP-UHFFFAOYSA-N 8-propan-2-yl-2-(4-pyrazol-1-ylanilino)-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound N1=C2N(C(C)C)C(=O)NCC2=CN=C1NC(C=C1)=CC=C1N1C=CC=N1 QQOUBGFAMSXQJP-UHFFFAOYSA-N 0.000 claims description 3
206010039491 Sarcoma Diseases 0.000 claims description 3
206010057469 Vascular stenosis Diseases 0.000 claims description 3
230000002980 postoperative effect Effects 0.000 claims description 3
OWTGPKDIDKXNHZ-UHFFFAOYSA-N 1-(3-bicyclo[2.2.1]heptanyl)-7-(4-pyrazol-1-ylanilino)pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C3C4CCC(C4)C3)C(=O)N=CC2=CN=C1NC(C=C1)=CC=C1N1C=CC=N1 OWTGPKDIDKXNHZ-UHFFFAOYSA-N 0.000 claims description 2
CXCVAMWLZIFURV-UHFFFAOYSA-N 1-(3-bicyclo[2.2.1]heptanyl)-7-[4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]anilino]pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C3C4CCC(C4)C3)C(=O)N=CC2=CN=C1NC(C=C1)=CC=C1N(CC1)CCC1CCCN1CCOCC1 CXCVAMWLZIFURV-UHFFFAOYSA-N 0.000 claims description 2
WVONWGTWBWLAOJ-UHFFFAOYSA-N 1-(3-bicyclo[2.2.1]heptanyl)-7-[4-[4-(dimethylamino)piperidin-1-yl]anilino]pyrimido[4,5-d]pyrimidin-2-one Chemical compound C1CC(N(C)C)CCN1C(C=C1)=CC=C1NC1=NC=C(C=NC(=O)N2C3C4CCC(C4)C3)C2=N1 WVONWGTWBWLAOJ-UHFFFAOYSA-N 0.000 claims description 2
WALFZDZPONVUIH-UHFFFAOYSA-N 1-(3-hydroxypropyl)-7-[4-(4-methylpiperazin-1-yl)anilino]pyrido[4,3-d]pyrimidin-2-one Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC(N=C1)=CC2=C1C=NC(=O)N2CCCO WALFZDZPONVUIH-UHFFFAOYSA-N 0.000 claims description 2
FOTIWFNYARKEJV-UHFFFAOYSA-N 1-[2-[4-(4-acetylpiperazin-1-yl)anilino]-5,8-dihydropyrimido[4,5-d]pyrimidin-7-yl]-3-propan-2-ylurea Chemical compound N=1C=C2CNC(NC(=O)NC(C)C)=NC2=NC=1NC(C=C1)=CC=C1N1CCN(C(C)=O)CC1 FOTIWFNYARKEJV-UHFFFAOYSA-N 0.000 claims description 2
JMNNHVDOWHBZGS-UHFFFAOYSA-N 1-[3-(2-chloro-3,5-dimethoxyphenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-4h-pyrimido[4,5-d]pyrimidin-2-yl]-3-ethylurea Chemical compound N=1C=C2CN(C=3C(=C(OC)C=C(OC)C=3)Cl)C(NC(=O)NCC)=NC2=NC=1NC1=CC=C(OCCN(CC)CC)C=C1 JMNNHVDOWHBZGS-UHFFFAOYSA-N 0.000 claims description 2
JMZBFDDWDQKWEU-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-7-[4-(4-methylpiperazin-1-yl)anilino]pyrido[4,3-d]pyrimidin-2-one Chemical compound N=1C=C2C=NC(=O)N(CCCN(C)C)C2=CC=1NC(C=C1)=CC=C1N1CCN(C)CC1 JMZBFDDWDQKWEU-UHFFFAOYSA-N 0.000 claims description 2
FAKVFHGYAUSYSU-UHFFFAOYSA-N 1-[7-(4-piperazin-1-ylanilino)pyrimido[4,5-d]pyrimidin-2-yl]-3-propan-2-ylurea Chemical compound N=1C2=NC(NC(=O)NC(C)C)=NC=C2C=NC=1NC(C=C1)=CC=C1N1CCNCC1 FAKVFHGYAUSYSU-UHFFFAOYSA-N 0.000 claims description 2
SEGPMNJSRKJLRF-UHFFFAOYSA-N 1-cyclopentyl-7-(4-fluoro-3-methylanilino)pyrimido[4,5-d]pyrimidin-2-one Chemical compound C1=C(F)C(C)=CC(NC=2N=C3N(C4CCCC4)C(=O)N=CC3=CN=2)=C1 SEGPMNJSRKJLRF-UHFFFAOYSA-N 0.000 claims description 2
LYPJMMVRHFYBED-UHFFFAOYSA-N 1-cyclopentyl-7-(4-methylsulfonylanilino)pyrimido[4,5-d]pyrimidin-2-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1NC1=NC=C(C=NC(=O)N2C3CCCC3)C2=N1 LYPJMMVRHFYBED-UHFFFAOYSA-N 0.000 claims description 2
CMPAWLHWVNKEHO-UHFFFAOYSA-N 1-cyclopentyl-7-(pyridin-4-ylamino)pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C3CCCC3)C(=O)N=CC2=CN=C1NC1=CC=NC=C1 CMPAWLHWVNKEHO-UHFFFAOYSA-N 0.000 claims description 2
MAFLMDDLVBFCJM-UHFFFAOYSA-N 1-cyclopentyl-7-[4-[4-(3-morpholin-4-ylpropyl)piperidin-1-yl]anilino]pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C3CCCC3)C(=O)N=CC2=CN=C1NC(C=C1)=CC=C1N(CC1)CCC1CCCN1CCOCC1 MAFLMDDLVBFCJM-UHFFFAOYSA-N 0.000 claims description 2
CYLYLWLMVRIMFM-UHFFFAOYSA-N 1-hexa-2,4-dienyl-7-[4-(4-methylpiperazin-1-yl)anilino]-3,4-dihydropyrido[4,3-d]pyrimidin-2-one Chemical compound C1=C2N(CC=CC=CC)C(=O)NCC2=CN=C1NC(C=C1)=CC=C1N1CCN(C)CC1 CYLYLWLMVRIMFM-UHFFFAOYSA-N 0.000 claims description 2
MXEAYMDSLOTGOA-UHFFFAOYSA-N 1-hexa-2,4-dienyl-7-[4-(4-methylpiperazin-1-yl)anilino]pyrido[4,3-d]pyrimidin-2-one Chemical compound N=1C=C2C=NC(=O)N(CC=CC=CC)C2=CC=1NC(C=C1)=CC=C1N1CCN(C)CC1 MXEAYMDSLOTGOA-UHFFFAOYSA-N 0.000 claims description 2
WGFUGBMZQCPOMB-UHFFFAOYSA-N 1-methyl-7-(4-pyrazol-1-ylanilino)pyrimido[4,5-d]pyrimidin-2-one Chemical compound N=1C=C2C=NC(=O)N(C)C2=NC=1NC(C=C1)=CC=C1N1C=CC=N1 WGFUGBMZQCPOMB-UHFFFAOYSA-N 0.000 claims description 2
FAIRRWVQRAQPBG-UHFFFAOYSA-N 1-tert-butyl-3-[3-(2-chloro-3,5-dimethoxyphenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-4h-pyrimido[4,5-d]pyrimidin-2-yl]urea Chemical compound C1=CC(OCCN(CC)CC)=CC=C1NC1=NC=C(CN(C(NC(=O)NC(C)(C)C)=N2)C=3C(=C(OC)C=C(OC)C=3)Cl)C2=N1 FAIRRWVQRAQPBG-UHFFFAOYSA-N 0.000 claims description 2
VPNHAJYZVQXPDL-UHFFFAOYSA-N 2-[4-(2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[3,4-c]pyrrol-5-yl)anilino]-8-cyclopentyl-8h-pyrido[4,3-d]pyrimidin-7-one Chemical compound O=C1N=CC2=CN=C(NC=3C=CC(=CC=3)N3CC4CNCC4C3)N=C2C1C1CCCC1 VPNHAJYZVQXPDL-UHFFFAOYSA-N 0.000 claims description 2
UFSSFDMEEMIJIW-UHFFFAOYSA-N 2-[4-(3-aminopyrrolidin-1-yl)anilino]-8-propan-2-yl-8h-pyrido[4,3-d]pyrimidin-7-one Chemical compound N1=C2C(C(C)C)C(=O)N=CC2=CN=C1NC(C=C1)=CC=C1N1CCC(N)C1 UFSSFDMEEMIJIW-UHFFFAOYSA-N 0.000 claims description 2
KQVTUIKOGACPKS-UHFFFAOYSA-N 2-[4-(4-acetylpiperazin-1-yl)anilino]-8-cyclopentyl-8h-pyrido[4,3-d]pyrimidin-7-one Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1NC1=NC=C(C=NC(=O)C2C3CCCC3)C2=N1 KQVTUIKOGACPKS-UHFFFAOYSA-N 0.000 claims description 2
SLSXXMZCLRYNCE-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)anilino]-8-propan-2-ylpyrimido[4,5-d]pyrimidine-5,7-dione Chemical compound N=1C=C2C(=O)NC(=O)N(C(C)C)C2=NC=1NC(C=C1)=CC=C1N1CCN(C)CC1 SLSXXMZCLRYNCE-UHFFFAOYSA-N 0.000 claims description 2
CCECTNAHAIMUMV-UHFFFAOYSA-N 2-[4-[2-(diethylamino)ethoxy]anilino]-6-(3,5-dimethoxyphenyl)-5,8-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound C1=CC(OCCN(CC)CC)=CC=C1NC1=NC=C(CN(C(=O)N2)C=3C=C(OC)C=C(OC)C=3)C2=N1 CCECTNAHAIMUMV-UHFFFAOYSA-N 0.000 claims description 2
DKTBRRPWLIMTOU-UHFFFAOYSA-N 2-[4-[2-(diethylamino)ethoxy]anilino]-8-propan-2-ylpyrimido[4,5-d]pyrimidine-5,7-dione Chemical compound C1=CC(OCCN(CC)CC)=CC=C1NC1=NC=C2C(=O)NC(=O)N(C(C)C)C2=N1 DKTBRRPWLIMTOU-UHFFFAOYSA-N 0.000 claims description 2
NNXCBTRERGAZEA-UHFFFAOYSA-N 3-(2,6-dichloro-3-hydroxyphenyl)-7-[3-(hydroxymethyl)anilino]-1-methyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=C2N(C)C(=O)N(C=3C(=C(O)C=CC=3Cl)Cl)CC2=CN=C1NC1=CC=CC(CO)=C1 NNXCBTRERGAZEA-UHFFFAOYSA-N 0.000 claims description 2
ZMJAWSDJCUMJJN-UHFFFAOYSA-N 3-(2,6-dichloro-3-hydroxyphenyl)-7-[4-[2-(ethylamino)ethoxy]anilino]-1-methyl-4h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound C1=CC(OCCNCC)=CC=C1NC1=NC=C(CN(C(=O)N2C)C=3C(=C(O)C=CC=3Cl)Cl)C2=N1 ZMJAWSDJCUMJJN-UHFFFAOYSA-N 0.000 claims description 2
DDHHWHJBJCYDFY-UHFFFAOYSA-N 3-(3,5-dimethoxyphenyl)-1-ethyl-7-(pyridin-4-ylamino)-4h-pyrido[4,3-d]pyrimidin-2-one Chemical compound C1=C2N(CC)C(=O)N(C=3C=C(OC)C=C(OC)C=3)CC2=CN=C1NC1=CC=NC=C1 DDHHWHJBJCYDFY-UHFFFAOYSA-N 0.000 claims description 2
BKHNPXOUNMTMCY-UHFFFAOYSA-N 3-[[3-(2,6-dichlorophenyl)-1-methyl-2-oxo-4h-pyrimido[4,5-d]pyrimidin-7-yl]amino]benzoic acid Chemical compound N1=C2N(C)C(=O)N(C=3C(=CC=CC=3Cl)Cl)CC2=CN=C1NC1=CC=CC(C(O)=O)=C1 BKHNPXOUNMTMCY-UHFFFAOYSA-N 0.000 claims description 2
ZGVAHFAZEXHQBU-UHFFFAOYSA-N 3-methyl-n-[2-[4-(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)anilino]-5,8-dihydropyrimido[4,5-d]pyrimidin-7-yl]butanamide Chemical compound N=1C=C2CNC(NC(=O)CC(C)C)=NC2=NC=1NC(C=C1)=CC=C1N1CC2CN(C)CC2C1 ZGVAHFAZEXHQBU-UHFFFAOYSA-N 0.000 claims description 2
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FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
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XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 description 1
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150000003384 small molecules Chemical class 0.000 description 1
239000004299 sodium benzoate Substances 0.000 description 1
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TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical class OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 1
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150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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
- C07D487/02—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 two hetero rings
- C07D487/04—Ortho-condensed systems

HR20000799A 1998-05-26 2000-11-20 Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation HRP20000799A2 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US8670898P	1998-05-26	1998-05-26
US12615899P	1999-03-25	1999-03-25
PCT/US1999/010187 WO1999061444A2 (en)	1998-05-26	1999-05-10	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation

Publications (1)

Publication Number	Publication Date
HRP20000799A2 true HRP20000799A2 (en)	2001-06-30

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ID=26775058

Family Applications (1)

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HR20000799A HRP20000799A2 (en)	1998-05-26	2000-11-20	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation

Country Status (29)

Country	Link
US (1)	US7501425B1 (zh)
EP (1)	EP1080092B1 (zh)
JP (1)	JP2002516327A (zh)
KR (1)	KR20010043829A (zh)
CN (1)	CN1138778C (zh)
AP (1)	AP2000001964A0 (zh)
AT (1)	ATE402177T1 (zh)
AU (1)	AU763839B2 (zh)
BG (1)	BG104960A (zh)
BR (1)	BR9911590A (zh)
CA (1)	CA2329703C (zh)
DE (1)	DE69939168D1 (zh)
EA (1)	EA003640B1 (zh)
EE (1)	EE200000706A (zh)
ES (1)	ES2310039T3 (zh)
GE (1)	GEP20033093B (zh)
HK (1)	HK1039483A1 (zh)
HR (1)	HRP20000799A2 (zh)
HU (1)	HUP0102514A3 (zh)
ID (1)	ID27589A (zh)
IL (1)	IL139599A0 (zh)
IS (1)	IS5687A (zh)
NO (1)	NO20005928L (zh)
NZ (1)	NZ508268A (zh)
PL (1)	PL344248A1 (zh)
SK (1)	SK17532000A3 (zh)
TR (1)	TR200003429T2 (zh)
WO (1)	WO1999061444A2 (zh)
YU (1)	YU73300A (zh)

Families Citing this family (101)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ID27589A (id)	1998-05-26	2001-04-12	Warner Lambert Comapny	Pirimidina bisiklik dan dihidropirimidina bisiklik 3,4 sebagai penghambat proliferasi selular
WO2000024744A1 (en) *	1998-10-23	2000-05-04	F. Hoffmann-La Roche Ag	Bicyclic nitrogen heterocycles
CN1156477C (zh) *	1999-10-21	2004-07-07	霍夫曼-拉罗奇有限公司	作为p38蛋白激酶的抑制剂的烷基氨基-取代的双环氮杂环类化合物
ATE353329T1 (de)	1999-10-21	2007-02-15	Hoffmann La Roche	Heteroalkylamino-substituierte bicyclische stickstoffheterocyclen
EE200200412A (et) *	2000-01-24	2003-10-15	Warner-Lambert Company	3-aminokinasoliin-2,4-dioon kui antibakteriaalne agens
AP2002002586A0 (en) *	2000-01-25	2002-09-30	Warner Lambert Co	Pyrido[2,3-d] pyrimidine-2,7-diamine kinase inhibitors.
US7053070B2 (en)	2000-01-25	2006-05-30	Warner-Lambert Company	Pyrido[2,3-d]pyrimidine-2,7-diamine kinase inhibitors
MY141144A (en) *	2000-03-02	2010-03-15	Smithkline Beecham Corp	1, 5-disubstituted-3,4-dihydro-1h-pyrimido 4,5-dipyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
US7235551B2 (en) *	2000-03-02	2007-06-26	Smithkline Beecham Corporation	1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
IL151480A0 (en) *	2000-03-06	2003-04-10	Warner Lambert Co	5-alkylpyrido[2,3-d] pyrimidines tyrosine kinase inhibitors
US6506749B2 (en)	2000-08-31	2003-01-14	Syntex (U.S.A.) Llc	7-oxo-pyridopyrimidines (I)
AU9378401A (en) *	2000-08-31	2002-03-13	Hoffmann La Roche	7-oxo pyridopyrimidines as inhibitors of a cellular proliferation
CZ20031125A3 (cs)	2000-10-23	2003-10-15	Smithkline Beecham Corporation	Nové sloučeniny
GB0029015D0 (en)	2000-11-28	2001-01-10	Univ London	Medical device
JP2004521118A (ja)	2001-01-19	2004-07-15	スミスクライン・ビーチャム・コーポレイション	新規化合物およびその使用
HU229604B1 (en)	2001-02-12	2014-02-28	Hoffmann La Roche	6-substituted pyrido-pyrimidines, process for their preparation and pharmaceutical compositions containing them
US7105667B2 (en)	2001-05-01	2006-09-12	Bristol-Myers Squibb Co.	Fused heterocyclic compounds and use thereof
MXPA03010799A (es)	2001-05-30	2005-07-25	Warner Lambert Co	Agentes antibacterianos.
ATE314370T1 (de) *	2002-01-22	2006-01-15	Warner Lambert Co	2-(pyridin-2-ylamino)-pyrido(2,3-d)pyrimidin-7- one
US7176310B1 (en)	2002-04-09	2007-02-13	Ucb Sa	Pyrimidinecarboxamide derivatives and their use as anti-inflammatory agents
PL373339A1 (en)	2002-04-19	2005-08-22	Smithkline Beecham Corporation	Novel compounds
US7196090B2 (en) *	2002-07-25	2007-03-27	Warner-Lambert Company	Kinase inhibitors
DE60316581T2 (de)	2002-08-06	2008-07-03	F. Hoffmann-La Roche Ag	6-alkoxypyridopyrimidine als inhibitoren der p-38-map-kinase
US7084270B2 (en) *	2002-08-14	2006-08-01	Hoffman-La Roche Inc.	Pyrimido compounds having antiproliferative activity
TW200413381A (en) *	2002-11-04	2004-08-01	Hoffmann La Roche	Novel amino-substituted dihydropyrimido [4,5-d]pyrimidinone derivatives, their manufacture and use as pharmaceutical agents
US7112676B2 (en) *	2002-11-04	2006-09-26	Hoffmann-La Roche Inc.	Pyrimido compounds having antiproliferative activity
JP2006516561A (ja) *	2003-01-17	2006-07-06	ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー	細胞増殖の阻害剤としての２−アミノピリジン置換ヘテロ環類
EP1615928A1 (en)	2003-04-10	2006-01-18	F.Hoffmann-La Roche Ag	Pyrimido compounds
DE10325133A1 (de) *	2003-06-04	2004-12-23	Bayer Cropscience Ag	Triazolopyrimidine
MXPA06001098A (es)	2003-07-29	2006-04-24	Irm Llc	Compuestos y composiciones utiles como inhibidores de proteina cinasa.
DK1685131T3 (da)	2003-11-13	2007-07-09	Hoffmann La Roche	Hydroxyalkylsubstituerede pyrido-7-pyrimidin-7-oner
EP1763514A2 (en) *	2004-05-18	2007-03-21	Rigel Pharmaceuticals, Inc.	Cycloalkyl substituted pyrimidinediamine compounds and their uses
RU2007111758A (ru)	2004-08-31	2008-10-10	Ф.Хоффманн-Ля Рош Аг (Ch)	Аминопроизводные 7- амино-3-фенилдигидропиримидо [4,5-d] пиримидинонов, их получение и применение в качестве ингибиторов протеинкиназ
CA2576818A1 (en)	2004-08-31	2006-03-09	F. Hoffmann-La Roche Ag	Amide derivatives of 3-phenyl dihydropyrimido[4,5-d]pyrimidinones, their manufacture and use as pharmaceutical agents
WO2006065703A1 (en)	2004-12-13	2006-06-22	Sunesis Pharmaceuticals, Inc.	Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors
US7479558B2 (en)	2005-03-25	2009-01-20	Glaxo Group Limited	Process for preparing pyrido[2,3-d]pyrimidin-7-one and 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives
EP1868612A4 (en)	2005-03-25	2010-03-24	Glaxo Group Ltd	NOVEL CONNECTIONS
PE20100737A1 (es)	2005-03-25	2010-11-27	Glaxo Group Ltd	Nuevos compuestos
PE20100741A1 (es)	2005-03-25	2010-11-25	Glaxo Group Ltd	COMPUESTOS DERIVADOS DE 3,4-DIHIDROPIRIMIDO[4,5-d]PIRIMIDIN-2(1H)-ONA COMO INHIBIDORES DE QUINASA p38
CN101374840B (zh)	2006-01-31	2011-09-28	霍夫曼-拉罗奇有限公司	7h-吡啶并[3,4-d]嘧啶-8-酮、它们的制备及作为蛋白激酶抑制剂的应用
PL2168966T3 (pl) *	2007-06-15	2017-06-30	Msd K.K.	Pochodna bicykloaniliny
BRPI0906598A2 (pt)	2008-02-01	2015-07-07	Takeda Pharmaceutical	Oxim derivattivos como inibidores hsp90
EP2376494A4 (en) *	2008-12-12	2012-07-11	Msd Kk	DIHYDROPYRIMIDOPIRYMIDINE DERIVATIVES
EP2376493B1 (en)	2008-12-12	2016-10-05	Msd K.K.	Dihydropyrimidopyrimidine derivative
WO2010080712A2 (en) *	2009-01-06	2010-07-15	Dana Farber Cancer Institute	Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders
AU2010218781A1 (en) *	2009-02-25	2011-07-28	Msd K.K.	Pyrimidopyrimidoindazole derivative
SA111320200B1 (ar) *	2010-02-17	2014-02-16	ديبيوفارم اس ايه	مركبات ثنائية الحلقة واستخداماتها كمثبطات c-src/jak مزدوجة
CA2807498C (en) *	2010-08-05	2017-02-07	Temple University-Of The Commonwealth System Of Higher Education	2-substituted-8-alkyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitriles and uses thereof
US8754114B2 (en)	2010-12-22	2014-06-17	Incyte Corporation	Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
TWI548621B (zh)	2011-04-22	2016-09-11	標誌製藥公司	經取代之二胺基甲醯胺及二胺基甲腈嘧啶、其組合物、及以該等治療之方法
SI2766346T1 (sl)	2011-10-14	2017-05-31	Bristol-Myers Squibb Company	Substituirane tetrahidroizokinolinske spojine kot faktor xia inhibitorji
ES2579832T3 (es)	2011-10-14	2016-08-17	Bristol-Myers Squibb Company	Compuestos de tetrahidroisoquinolina sustituida como inhibidores del factor XIa
WO2013055984A1 (en)	2011-10-14	2013-04-18	Bristol-Myers Squibb Company	Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
ME03300B (me) *	2012-06-13	2019-07-20	Incyte Holdings Corp	Supsтituisana triciklična jedinjenja као inhibiтori fgfr
DK2872491T3 (da) *	2012-07-11	2021-08-09	Blueprint Medicines Corp	Inhibitorer af fibroblastvækstfaktorreceptoren
WO2014026125A1 (en)	2012-08-10	2014-02-13	Incyte Corporation	Pyrazine derivatives as fgfr inhibitors
WO2014059214A1 (en)	2012-10-12	2014-04-17	Bristol-Myers Squibb Company	Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors
US9315519B2 (en)	2012-10-12	2016-04-19	Bristol-Myers Squibb Company	Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
SI2906551T1 (en)	2012-10-12	2018-05-31	Bristol-Myers Squibb Company	CRYSTALINOUS FORMATS OF XIA FACTOR INHIBITOR
US9266892B2 (en)	2012-12-19	2016-02-23	Incyte Holdings Corporation	Fused pyrazoles as FGFR inhibitors
US9321786B2 (en)	2013-03-15	2016-04-26	Celgene Avilomics Research, Inc.	Heteroaryl compounds and uses thereof
EP3943087A1 (en)	2013-03-15	2022-01-26	Celgene CAR LLC	Heteroaryl compounds and uses thereof
CN111793068A (zh)	2013-03-15	2020-10-20	西建卡尔有限责任公司	杂芳基化合物和其用途
WO2014160668A1 (en)	2013-03-25	2014-10-02	Bristol-Myers Squibb Company	Tetrahydroisoquinolines containing substituted azoles as factor xia inhibitors
DK2986610T5 (en) *	2013-04-19	2018-12-10	Incyte Holdings Corp	BICYCLIC HETEROCYCLES AS FGFR INHIBITORS
US9783504B2 (en)	2013-07-09	2017-10-10	Dana-Farber Cancer Institute, Inc.	Kinase inhibitors for the treatment of disease
TWI597268B (zh)	2013-10-18	2017-09-01	衛材Ｒ＆Ｄ企管股份有限公司	纖維母細胞受體４（ｆｇｆｒ４）抑制劑
JP6458023B2 (ja)	2013-10-25	2019-01-23	ブループリントメディシンズコーポレイション	繊維芽細胞成長因子受容体の阻害剤
MX2016007898A (es)	2013-12-20	2016-10-07	Signal Pharm Llc	Compuestos diaminopirimidilo sustituidos, las composiciones de estos y los metodos de tratamiento con estos.
JP6464176B2 (ja)	2014-01-31	2019-02-06	ブリストル−マイヤーズスクイブカンパニーＢｒｉｓｔｏｌ−ＭｙｅｒｓＳｑｕｉｂｂＣｏｍｐａｎｙ	芳香族ｐ２’基を有する第ｘｉａ因子阻害剤としてのマクロ環
NO2760821T3 (zh)	2014-01-31	2018-03-10
CN103880861B (zh) *	2014-02-21	2016-02-03	温州医科大学	一种作用于FGF受体的4,6-二甲基-噁唑并[5,4-d]嘧啶-5,7（4H,6H）-二酮衍生物
JP6526796B2 (ja)	2014-09-04	2019-06-05	ブリストル−マイヤーズスクイブカンパニーＢｒｉｓｔｏｌ−ＭｙｅｒｓＳｑｕｉｂｂＣｏｍｐａｎｙ	Ｆｘｉａ阻害剤であるジアミドマクロ環
US9453018B2 (en)	2014-10-01	2016-09-27	Bristol-Myers Squibb Company	Pyrimidinones as factor XIa inhibitors
US10851105B2 (en)	2014-10-22	2020-12-01	Incyte Corporation	Bicyclic heterocycles as FGFR4 inhibitors
WO2016134294A1 (en)	2015-02-20	2016-08-25	Incyte Corporation	Bicyclic heterocycles as fgfr4 inhibitors
EA038045B1 (ru)	2015-02-20	2021-06-28	Инсайт Корпорейшн	Бициклические гетероциклы в качестве ингибиторов fgfr
MA41551A (fr)	2015-02-20	2017-12-26	Incyte Corp	Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
ES2864712T3 (es)	2015-04-14	2021-10-14	Eisai R&D Man Co Ltd	Compuesto inhibidor de FGFR4 cristalino y usos del mismo
WO2017196854A1 (en)	2016-05-10	2017-11-16	Eisai R&D Management Co., Ltd.	Drug combinations for reducing cell viability and/or cell proliferation
CN107459519A (zh) *	2016-06-06	2017-12-12	上海艾力斯医药科技有限公司	稠合嘧啶哌啶环衍生物及其制备方法和应用
KR20190075043A (ko) *	2016-07-05	2019-06-28	더 브로드 인스티튜트, 인코퍼레이티드	비시클릭 우레아 키나제 억제제 및 그의 용도
TWI808958B (zh)	2017-01-25	2023-07-21	美商特普醫葯公司	涉及二芳基巨環化合物之組合療法
RU2019129727A (ru)	2017-02-28	2021-03-30	Зэ Дженерал Хоспитал Корпорэйшн	Применения пиримидопиримидинонов в качестве ингибиторов sik
AR111960A1 (es)	2017-05-26	2019-09-04	Incyte Corp	Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
US11466004B2 (en)	2018-05-04	2022-10-11	Incyte Corporation	Solid forms of an FGFR inhibitor and processes for preparing the same
EA202092649A1 (ru)	2018-05-04	2021-06-21	Инсайт Корпорейшн	Соли ингибитора fgfr
US11628162B2 (en)	2019-03-08	2023-04-18	Incyte Corporation	Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en)	2019-07-09	2023-02-28	Incyte Corporation	Bicyclic heterocycles as FGFR inhibitors
IL291901A (en)	2019-10-14	2022-06-01	Incyte Corp	Bicyclyl heterocycles as fgr suppressors
WO2021076728A1 (en)	2019-10-16	2021-04-22	Incyte Corporation	Bicyclic heterocycles as fgfr inhibitors
WO2021113479A1 (en)	2019-12-04	2021-06-10	Incyte Corporation	Tricyclic heterocycles as fgfr inhibitors
KR20220131900A (ko)	2019-12-04	2022-09-29	인사이트 코포레이션	Fgfr 억제제의 유도체
US11691971B2 (en)	2020-06-19	2023-07-04	Incyte Corporation	Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en)	2020-06-19	2023-09-12	Incyte Corporation	Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
WO2022006456A1 (en)	2020-07-02	2022-01-06	Incyte Corporation	Tricyclic pyridone compounds as jak2 v617f inhibitors
MX2023000056A (es)	2020-07-02	2023-04-12	Incyte Corp	Compuestos tricíclicos de urea como inhibidores de la variante v617f de la cinasa de janus 2 (jak2 v617f).
US11661422B2 (en)	2020-08-27	2023-05-30	Incyte Corporation	Tricyclic urea compounds as JAK2 V617F inhibitors
WO2022140231A1 (en)	2020-12-21	2022-06-30	Incyte Corporation	Deazaguaine compounds as jak2 v617f inhibitors
TW202302589A (zh)	2021-02-25	2023-01-16	美商英塞特公司	作為ｊａｋ２ｖ６１７ｆ抑制劑之螺環內醯胺
AR126102A1 (es)	2021-06-09	2023-09-13	Incyte Corp	Heterociclos tricíclicos como inhibidores de fgfr

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US2949466A (en)	1958-03-04	1960-08-16	Parke Davis & Co	Pyrimidine compounds and means of producing the same
NL6704601A (zh)	1966-04-06	1967-10-09
US3912723A (en)	1971-03-29	1975-10-14	Pfizer	2-Phenyl-as-triazine-3,5(2H,4H)diones
CA1132137A (en) *	1979-06-14	1982-09-21	David S. Duch	Alkoxybenzylpyridopyrimidines, methods for their preparation, formulations thereof and their use in medicine
US4425346A (en)	1980-08-01	1984-01-10	Smith And Nephew Associated Companies Limited	Pharmaceutical compositions
JPS60226882A (ja)	1984-04-24	1985-11-12	Nippon Zoki Pharmaceut Co Ltd	新規ピリミドピリミジン誘導体
EP0278686A1 (en) *	1987-02-07	1988-08-17	The Wellcome Foundation Limited	Pyridopyrimidines methods for their preparation and pharmaceutical formulations thereof
DK0584222T3 (da) *	1991-05-10	1998-02-23	Rhone Poulenc Rorer Int	Bis-mono- og bicycliske aryl- og heteroarylforbindelser, som inhiberer EGF- og/eller PDGF-receptor-tyrosinkinase
US5679683A (en) *	1994-01-25	1997-10-21	Warner-Lambert Company	Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
IL112249A (en)	1994-01-25	2001-11-25	Warner Lambert Co	Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
JP2002515008A (ja)	1994-10-27	2002-05-21	メルクエンドカンパニーインコーポレーテッド	ムスカリン・アンタゴニスト
EP0790997B1 (en) *	1994-11-14	2000-03-22	Warner-Lambert Company	6-ARYL PYRIDO[2,3-d]PYRIMIDINES AND NAPHTHYRIDINES FOR INHIBITING PROTEIN TYROSINE KINASE MEDIATED CELLULAR PROLIFERATION
IL117923A (en) *	1995-05-03	2000-06-01	Warner Lambert Co	Anti-cancer pharmaceutical compositions containing polysubstituted pyrido¬2,3-d¾pyrimidine derivatives and certain such novel compounds
DE69710712T3 (de)	1996-04-12	2010-12-23	Warner-Lambert Co. Llc	Umkehrbare inhibitoren von tyrosin kinasen
JP2001509805A (ja) *	1997-02-05	2001-07-24	ワーナー−ランバート・コンパニー	細胞増殖阻害剤としてのピリド〔２，３−ｄ〕ピリミジンおよび４−アミノピリミジン
ZA986732B (en) *	1997-07-29	1999-02-02	Warner Lambert Co	Irreversible inhibitiors of tyrosine kinases
ATE286053T1 (de) *	1997-08-20	2005-01-15	Warner Lambert Co	Naphthyridinone zur hemmung der durch protein- tyrosin-kinase und zellzyklus kinase hervorgerufenen zellvermehrung
JP4038624B2 (ja)	1997-11-29	2008-01-30	日本農薬株式会社	縮合複素環誘導体及びその中間体並びに有害生物防除剤
ID27589A (id)	1998-05-26	2001-04-12	Warner Lambert Comapny	Pirimidina bisiklik dan dihidropirimidina bisiklik 3,4 sebagai penghambat proliferasi selular
WO2000024744A1 (en) *	1998-10-23	2000-05-04	F. Hoffmann-La Roche Ag	Bicyclic nitrogen heterocycles
ATE353329T1 (de)	1999-10-21	2007-02-15	Hoffmann La Roche	Heteroalkylamino-substituierte bicyclische stickstoffheterocyclen
CN1156477C (zh)	1999-10-21	2004-07-07	霍夫曼-拉罗奇有限公司	作为p38蛋白激酶的抑制剂的烷基氨基-取代的双环氮杂环类化合物
MY141144A (en)	2000-03-02	2010-03-15	Smithkline Beecham Corp	1, 5-disubstituted-3,4-dihydro-1h-pyrimido 4,5-dipyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases

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YU73300A (sh)	2003-08-29
EA003640B1 (ru)	2003-08-28
ID27589A (id)	2001-04-12
CN1138778C (zh)	2004-02-18
HK1039483A1 (en)	2002-04-26
PL344248A1 (en)	2001-10-22
JP2002516327A (ja)	2002-06-04
ES2310039T3 (es)	2008-12-16
KR20010043829A (ko)	2001-05-25
TR200003429T2 (tr)	2001-07-23
EP1080092A2 (en)	2001-03-07
NZ508268A (en)	2004-02-27
ATE402177T1 (de)	2008-08-15
BG104960A (en)	2001-10-31
AP2000001964A0 (en)	2000-12-31
AU763839B2 (en)	2003-07-31
CN1302301A (zh)	2001-07-04
GEP20033093B (en)	2003-10-27
WO1999061444A3 (en)	2000-02-03
EE200000706A (et)	2002-06-17
DE69939168D1 (de)	2008-09-04
US7501425B1 (en)	2009-03-10
SK17532000A3 (sk)	2002-08-06
WO1999061444A2 (en)	1999-12-02
IS5687A (is)	2000-10-27
EA200001171A1 (ru)	2001-06-25
EP1080092B1 (en)	2008-07-23
IL139599A0 (en)	2002-02-10
NO20005928D0 (no)	2000-11-23
HUP0102514A2 (hu)	2001-11-28
BR9911590A (pt)	2001-02-13
CA2329703C (en)	2005-12-20
CA2329703A1 (en)	1999-12-02
HUP0102514A3 (en)	2002-03-28
AU4073499A (en)	1999-12-13
NO20005928L (no)	2000-11-23

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Publication	Publication Date	Title
HRP20000799A2 (en)	2001-06-30	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
EP0964864B1 (en)	2008-04-09	Pyrido 2,3-d pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation
US20040044012A1 (en)	2004-03-04	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
US5945422A (en)	1999-08-31	N-oxides of amino containing pyrido 2,3-D! pyrimidines
ES2274526T3 (es)	2007-05-16	Pirido(2,3-d)pirimidinas para inhibir la proliferacion celular mediada por tirosinaquinasa.
KR100421156B1 (ko)	2004-04-27	단백질티로신키나제매개세포증식을억제하기위한피리도[2,3-d]피리미딘
US20070049600A1 (en)	2007-03-01	Pteridinones as kinase inhibitors
CZ286160B6 (cs)	2000-01-12	6-Arylpyrido[2,3-d]pyrimidiny a naftyridiny a farmaceutické prostředky na jejich bázi
El-Zahar et al.	2011	Synthesis, antitumor activity and molecular docking study of novel benzofuran-2-yl pyrazole pyrimidine derivatives
KR20020070520A (ko)	2002-09-09	신경퇴행성 질병의 치료를 위한 피리도피리미디논 유도체
Abd El-Salam et al.	2012	Synthesis, Structural Characterization of Some Pyrazolo [3, 4-d] pyrimidine Derivatives as Anti-inflammatory Agents
EP1801112A1 (en)	2007-06-27	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
CZ20004246A3 (cs)	2001-04-11	Bicyklické pyrimidiny a bicyklické 3,4- dihydropyrimidiny jako inhibitory buněčné proliferace
MXPA00010738A (en)	2001-09-07	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
OA11554A (en)	2004-06-03	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation.
ZA200006536B (en)	2002-02-11	Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation.
CN116731038A (zh)	2023-09-12	含氮杂环化合物及其制备方法和应用
CA2199964A1 (en)	1996-05-23	6-aryl pyrido[2,3-d]pyrimidines and naphthyridines for inhibiting protein tyrosine kinase mediated cellular proliferation