KR20100031639A - 증식성 질환의 치료용 삼중 치환된 피리미딘 유도체 - Google Patents
증식성 질환의 치료용 삼중 치환된 피리미딘 유도체 Download PDFInfo
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- KR20100031639A KR20100031639A KR1020107002969A KR20107002969A KR20100031639A KR 20100031639 A KR20100031639 A KR 20100031639A KR 1020107002969 A KR1020107002969 A KR 1020107002969A KR 20107002969 A KR20107002969 A KR 20107002969A KR 20100031639 A KR20100031639 A KR 20100031639A
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- South Korea
- Prior art keywords
- alkyl
- alkoxy
- amino
- bis
- phenyl
- 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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- 238000011282 treatment Methods 0.000 title claims abstract description 28
- 201000010099 disease Diseases 0.000 title claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 27
- 230000002062 proliferating effect Effects 0.000 title claims description 13
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 2
- 150000003230 pyrimidines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 2064
- -1 nitro, hydroxy Chemical group 0.000 claims description 784
- 125000003545 alkoxy group Chemical group 0.000 claims description 522
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 242
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 236
- 125000005843 halogen group Chemical group 0.000 claims description 223
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 210
- 125000001424 substituent group Chemical group 0.000 claims description 197
- 125000000623 heterocyclic group Chemical group 0.000 claims description 173
- 229910052739 hydrogen Inorganic materials 0.000 claims description 158
- 239000001257 hydrogen Substances 0.000 claims description 158
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 125
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 124
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 123
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 122
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 113
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 109
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 101
- 125000001589 carboacyl group Chemical group 0.000 claims description 100
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 89
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 89
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 83
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 76
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 75
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 73
- 229910052799 carbon Inorganic materials 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- 229910052717 sulfur Inorganic materials 0.000 claims description 54
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 53
- 229910052757 nitrogen Inorganic materials 0.000 claims description 53
- 229910052760 oxygen Inorganic materials 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 50
- 150000002431 hydrogen Chemical class 0.000 claims description 49
- 125000004429 atom Chemical group 0.000 claims description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 43
- 206010028980 Neoplasm Diseases 0.000 claims description 42
- 125000004432 carbon atom Chemical group C* 0.000 claims description 41
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 39
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 39
- 229910052727 yttrium Inorganic materials 0.000 claims description 38
- 125000002837 carbocyclic group Chemical group 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 30
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 25
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 25
- 125000005647 linker group Chemical group 0.000 claims description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 21
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 21
- 125000004043 oxo group Chemical group O=* 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 20
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 19
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 18
- 125000001544 thienyl group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 17
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 16
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 16
- 125000000335 thiazolyl group Chemical group 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 13
- 241001465754 Metazoa Species 0.000 claims description 13
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 13
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 9
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 9
- 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 claims description 8
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 8
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 7
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 7
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 6
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 6
- 230000001028 anti-proliverative effect Effects 0.000 claims description 5
- 208000026278 immune system disease Diseases 0.000 claims description 5
- 230000000414 obstructive effect Effects 0.000 claims description 5
- 125000005936 piperidyl group Chemical group 0.000 claims description 5
- 208000023504 respiratory system disease Diseases 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 4
- 125000004463 2,4-dimethyl-thiazol-5-yl group Chemical group CC=1SC(=C(N1)C)* 0.000 claims description 4
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 claims description 4
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 8
- 239000004202 carbamide Substances 0.000 claims 4
- 241000282412 Homo Species 0.000 claims 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 2
- DYBRCIRRFKVZDL-UHFFFAOYSA-N [S]C1=NC=CS1 Chemical compound [S]C1=NC=CS1 DYBRCIRRFKVZDL-UHFFFAOYSA-N 0.000 claims 2
- HIEHQJOVJDWRSX-FQEVSTJZSA-N 1-(2-fluoroethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-[1-(2-methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C=2C(=CC=CC=2)C)=NC(C=2C=CC(NC(=O)NCCF)=CC=2)=N1 HIEHQJOVJDWRSX-FQEVSTJZSA-N 0.000 claims 1
- JGBNGNTWBQKUHG-KRWDZBQOSA-N 1-(2-fluoroethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C=2SC=C(C)N=2)=NC(C=2C=CC(NC(=O)NCCF)=CC=2)=N1 JGBNGNTWBQKUHG-KRWDZBQOSA-N 0.000 claims 1
- PHWFBNWMJNYDGW-HNNXBMFYSA-N 1-(2-hydroxyethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(C)(=O)=O)=NC(C=2C=CC(NC(=S)NCCO)=CC=2)=N1 PHWFBNWMJNYDGW-HNNXBMFYSA-N 0.000 claims 1
- SDARAZUEIRWPTB-SFHVURJKSA-N 1-(2-hydroxyethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-(1-pyridin-2-ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C=2N=CC=CC=2)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 SDARAZUEIRWPTB-SFHVURJKSA-N 0.000 claims 1
- GWHGRDMKYYLJQZ-SFHVURJKSA-N 1-(2-hydroxyethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-(1-pyridin-4-ylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]thiourea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C=2C=CN=CC=2)=NC(C=2C=CC(NC(=S)NCCO)=CC=2)=N1 GWHGRDMKYYLJQZ-SFHVURJKSA-N 0.000 claims 1
- TVSLEPMCGNSXKE-FQEVSTJZSA-N 1-(2-hydroxyethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-[1-(2-methylphenyl)sulfonylcyclopropyl]pyrimidin-2-yl]phenyl]urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C=2C(=CC=CC=2)C)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 TVSLEPMCGNSXKE-FQEVSTJZSA-N 0.000 claims 1
- QZAUFLOIQNLBCO-SFHVURJKSA-N 1-(2-hydroxyethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]cyclobutyl]pyrimidin-2-yl]phenyl]urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CCC2)S(=O)(=O)C=2SC=C(C)N=2)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 QZAUFLOIQNLBCO-SFHVURJKSA-N 0.000 claims 1
- RWHWLGUIESKCSW-KRWDZBQOSA-N 1-(2-hydroxyethyl)-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-[1-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]cyclopropyl]pyrimidin-2-yl]phenyl]urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C=2SC=C(C)N=2)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 RWHWLGUIESKCSW-KRWDZBQOSA-N 0.000 claims 1
- ZEIPTVRCOPZNMB-ROUUACIJSA-N 1-[(2s)-1-hydroxypropan-2-yl]-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-6-[1-(1,3-thiazol-2-ylsulfonyl)cyclobutyl]pyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)N[C@H](CO)C)=CC=C1C1=NC(N2[C@H](COCC2)C)=CC(C2(CCC2)S(=O)(=O)C=2SC=CN=2)=N1 ZEIPTVRCOPZNMB-ROUUACIJSA-N 0.000 claims 1
- IZOIHVJEIVFFJZ-KRWDZBQOSA-N 1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3s)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CCC2)S(=O)(=O)C2CC2)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 IZOIHVJEIVFFJZ-KRWDZBQOSA-N 0.000 claims 1
- WGDGAMUOADKOIM-ROUUACIJSA-N 1-[4-[4-(1-cyclopropylsulfonylcyclobutyl)-6-[(3s)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-[(2s)-1-hydroxypropan-2-yl]urea Chemical compound C1=CC(NC(=O)N[C@H](CO)C)=CC=C1C1=NC(N2[C@H](COCC2)C)=CC(C2(CCC2)S(=O)(=O)C2CC2)=N1 WGDGAMUOADKOIM-ROUUACIJSA-N 0.000 claims 1
- JWGVUDPAMQEIJU-INIZCTEOSA-N 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3s)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)thiourea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C2CC2)=NC(C=2C=CC(NC(=S)NCCO)=CC=2)=N1 JWGVUDPAMQEIJU-INIZCTEOSA-N 0.000 claims 1
- IUFFUJSXZMPACZ-INIZCTEOSA-N 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3s)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C2CC2)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 IUFFUJSXZMPACZ-INIZCTEOSA-N 0.000 claims 1
- KCXPUAAWQBOQAV-IRXDYDNUSA-N 1-[4-[4-(1-cyclopropylsulfonylcyclopropyl)-6-[(3s,5s)-3,5-dimethylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea Chemical compound C[C@H]1COC[C@H](C)N1C1=CC(C2(CC2)S(=O)(=O)C2CC2)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 KCXPUAAWQBOQAV-IRXDYDNUSA-N 0.000 claims 1
- SKEKHHDRURKHGL-KRWDZBQOSA-N 1-[4-[4-(1-ethylsulfonylcyclobutyl)-6-[(3s)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)thiourea Chemical compound C=1C(N2[C@H](COCC2)C)=NC(C=2C=CC(NC(=S)NCCO)=CC=2)=NC=1C1(S(=O)(=O)CC)CCC1 SKEKHHDRURKHGL-KRWDZBQOSA-N 0.000 claims 1
- JIVMEOCATHYZDN-HNNXBMFYSA-N 1-[4-[4-(1-ethylsulfonylcyclopropyl)-6-[(3s)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methylurea Chemical compound C=1C(N2[C@H](COCC2)C)=NC(C=2C=CC(NC(=O)NC)=CC=2)=NC=1C1(S(=O)(=O)CC)CC1 JIVMEOCATHYZDN-HNNXBMFYSA-N 0.000 claims 1
- GMGAAJUMFDRDDP-SFHVURJKSA-N 1-[4-[4-[(3s)-3-ethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea Chemical compound CC[C@H]1COCCN1C1=CC(C2(CC2)S(C)(=O)=O)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 GMGAAJUMFDRDDP-SFHVURJKSA-N 0.000 claims 1
- DISAHEAVJOYDCP-HOTGVXAUSA-N 1-[4-[4-[(3s,5s)-3,5-dimethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-3-(2-fluoroethyl)urea Chemical compound C[C@H]1COC[C@H](C)N1C1=CC(C2(CC2)S(C)(=O)=O)=NC(C=2C=CC(NC(=O)NCCF)=CC=2)=N1 DISAHEAVJOYDCP-HOTGVXAUSA-N 0.000 claims 1
- JNYGNLVZELHTJV-HOTGVXAUSA-N 1-[4-[4-[(3s,5s)-3,5-dimethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea Chemical compound C[C@H]1COC[C@H](C)N1C1=CC(C2(CC2)S(C)(=O)=O)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 JNYGNLVZELHTJV-HOTGVXAUSA-N 0.000 claims 1
- DYHHRFXAFJVSNH-HOTGVXAUSA-N 1-[4-[4-[(3s,5s)-3,5-dimethylmorpholin-4-yl]-6-(1-methylsulfonylcyclopropyl)pyrimidin-2-yl]phenyl]-3-ethylurea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C1=NC(N2[C@H](COC[C@@H]2C)C)=CC(C2(CC2)S(C)(=O)=O)=N1 DYHHRFXAFJVSNH-HOTGVXAUSA-N 0.000 claims 1
- DPZWLHXUFZVCQC-KRWDZBQOSA-N 1-[4-[4-[1-(2,4-difluorophenyl)sulfonylcyclopropyl]-6-[(3s)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-(2-hydroxyethyl)urea Chemical compound C[C@H]1COCCN1C1=CC(C2(CC2)S(=O)(=O)C=2C(=CC(F)=CC=2)F)=NC(C=2C=CC(NC(=O)NCCO)=CC=2)=N1 DPZWLHXUFZVCQC-KRWDZBQOSA-N 0.000 claims 1
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Classifications
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- A61P37/00—Drugs for immunological or allergic disorders
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| US60/948,566 | 2007-07-09 | ||
| US3029708P | 2008-02-21 | 2008-02-21 | |
| US61/030,297 | 2008-02-21 |
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| KR20100031639A true KR20100031639A (ko) | 2010-03-23 |
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| EP (1) | EP2074118A2 (enExample) |
| JP (1) | JP2010533158A (enExample) |
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| BR (1) | BRPI0814818A2 (enExample) |
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| NI (1) | NI201000004A (enExample) |
| PE (1) | PE20090773A1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2307400B1 (en) | 2008-05-30 | 2014-04-23 | Amgen, Inc | Inhibitors of pi3 kinase |
| TWI378933B (en) | 2008-10-14 | 2012-12-11 | Daiichi Sankyo Co Ltd | Morpholinopurine derivatives |
| TW201028410A (en) | 2008-12-22 | 2010-08-01 | Astrazeneca Ab | Chemical compounds 610 |
| EP2406258B1 (en) | 2009-03-13 | 2014-12-03 | Cellzome Limited | PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
| UY32582A (es) | 2009-04-28 | 2010-11-30 | Amgen Inc | Inhibidores de fosfoinositida 3 cinasa y/u objetivo mamífero |
| US8946204B2 (en) | 2009-05-07 | 2015-02-03 | Gruenenthal Gmbh | Substituted phenylureas and phenylamides as vanilloid receptor ligands |
| CN106243037A (zh) * | 2009-05-07 | 2016-12-21 | 格吕伦塔尔有限公司 | 作为香草类化合物受体之配体的取代的苯基脲及苯基酰胺 |
| MA33501B1 (fr) | 2009-07-02 | 2012-08-01 | Sanofi Sa | Nouveaux derives de (6-oxo-1,6-dihydro-pyrimidin-2-yl)-amide, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb) |
| EP2448932B1 (fr) | 2009-07-02 | 2014-03-05 | Sanofi | Nouveaux derives de 6-morpholin-4-yl-pyrimidin-4-(3h)-one, leur preparation pharmaceutique comme inhibiteurs de phosphorylation d'akt(pkb) |
| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| EP2762142A1 (en) | 2009-10-30 | 2014-08-06 | ARIAD Pharmaceuticals, Inc. | Compositions for treating cancer |
| PH12012501581A1 (en) | 2010-02-03 | 2012-10-22 | Signal Pharm Llc | Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors |
| EP2542536B1 (en) | 2010-03-04 | 2015-01-21 | Cellzome Limited | Morpholino substituted urea derivatives as mtor inhibitors |
| KR20130114122A (ko) * | 2010-09-03 | 2013-10-16 | 피라말 엔터프라이지즈 리미티드 | Dgat1 억제제로서 헤테로사이클릭 화합물 |
| WO2012058671A1 (en) | 2010-10-31 | 2012-05-03 | Endo Pharmaceuticals Inc. | Substituted quinazoline and pyrido-pyrimidine derivatives |
| SI2658844T1 (sl) | 2010-12-28 | 2017-02-28 | Sanofi | Novi derivati pirimidina, njihova priprava in njihova farmacevtska uporaba kot inhibitorje AKT(PKB) fosforilacije |
| US20140163023A1 (en) | 2011-04-04 | 2014-06-12 | Cellzome Limited | Dihydropyrrolo pyrimidine derivatives as mtor inhibitors |
| HK1199068A1 (en) | 2011-08-03 | 2015-06-19 | 西格诺药品有限公司 | Identification of gene expression profile as a predictive biomarker for lkb1 status |
| EP2758379B1 (en) | 2011-09-21 | 2016-10-19 | Cellzome Limited | Urea and carbamate derivatives of 2-morpholino-1,3,5-triazine as mTOR inhibitors for the treatment of immunological or proliferative diseases |
| EP2771337B1 (en) | 2011-09-27 | 2017-08-02 | Novartis AG | 3-(pyrimidin-4-yl)-oxazolidin-2-ones as inhibitors of mutant idh |
| AU2012320465B2 (en) | 2011-10-07 | 2016-03-03 | Cellzome Limited | Morpholino substituted bicyclic pyrimidine urea or carbamate derivatives as mTOR inhibitors |
| UY34632A (es) | 2012-02-24 | 2013-05-31 | Novartis Ag | Compuestos de oxazolidin- 2- ona y usos de los mismos |
| KR20160027219A (ko) | 2012-05-23 | 2016-03-09 | 에프. 호프만-라 로슈 아게 | 내배엽 및 간세포를 수득하고 사용하는 조성물 및 방법 |
| AU2013203714B2 (en) | 2012-10-18 | 2015-12-03 | Signal Pharmaceuticals, Llc | Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity |
| US9296733B2 (en) | 2012-11-12 | 2016-03-29 | Novartis Ag | Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases |
| WO2014141104A1 (en) | 2013-03-14 | 2014-09-18 | Novartis Ag | 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant idh |
| BR112015026257B1 (pt) | 2013-04-17 | 2022-12-20 | Signal Pharmaceuticals, Llc | Uso de um composto dihidropirazino-pirazina e enzalutamida, composição farmacêutica que os compreende, e kit |
| JP6382945B2 (ja) | 2013-04-17 | 2018-08-29 | シグナル ファーマシューティカルズ，エルエルシー | ジヒドロピラジノ−ピラジンによる癌治療 |
| EP2986321A1 (en) | 2013-04-17 | 2016-02-24 | Signal Pharmaceuticals, LLC | Combination therapy comprising a tor kinase inhibitor and a cytidine analog for treating cancer |
| MX393164B (es) | 2013-04-17 | 2025-03-21 | Signal Pharm Llc | Formulaciones farmacéuticas, proceso, formas sólidas y métodos de uso relacionados con 1-etil-7-(2-metil-6-(1h-1,2,4-triazol-3-ii)piridin-3-ii)-3,4-dihidropirazino[2,3-b]pirazin-2(1h)-ona. |
| CN105339008A (zh) | 2013-04-17 | 2016-02-17 | 西格诺药品有限公司 | 用于治疗癌症的包括tor激酶抑制剂和n-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯基氨基)嘧啶-4-基氨基)苯基)丙烯酰胺的组合疗法 |
| HK1221150A1 (zh) | 2013-04-17 | 2017-05-26 | 西格诺药品有限公司 | 用二氢吡嗪并-吡嗪类对癌症的治疗 |
| MX368286B (es) | 2013-04-17 | 2019-09-27 | Signal Pharm Llc | Terapia de combinacion que comprende un inhibidor de tor cinasa y un compuesto de quinazolinona 5-sustituida para tratar cancer. |
| NZ629486A (en) | 2013-05-29 | 2017-11-24 | Signal Pharm Llc | Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1h)-one, a solid form thereof and methods of their use |
| EP3131551A4 (en) | 2014-04-16 | 2017-09-20 | Signal Pharmaceuticals, LLC | SOLID FORMS COMPRISING 1-ETHYL-7-(2-METHYL-6-(1H-1,2,4-TRIAZOL-3-YL) PYRIDIN-3-YL)-3,4-DIHYDROPYRAZINO(2,3-b)PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF |
| NZ714742A (en) | 2014-04-16 | 2017-04-28 | Signal Pharm Llc | Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use |
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- 2008-07-08 KR KR1020107002969A patent/KR20100031639A/ko not_active Withdrawn
- 2008-07-08 BR BRPI0814818A patent/BRPI0814818A2/pt not_active IP Right Cessation
- 2008-07-08 AR ARP080102944A patent/AR067478A1/es unknown
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| AU2008273889B2 (en) | 2012-03-08 |
| AR067478A1 (es) | 2009-10-14 |
| EP2074118A2 (en) | 2009-07-01 |
| CL2008002006A1 (es) | 2009-06-26 |
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| UY31215A1 (es) | 2009-03-02 |
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