RU2459821C2 - Модуляторы киназы, ассоциированной с рецептором интерлейкина-1 - Google Patents
Модуляторы киназы, ассоциированной с рецептором интерлейкина-1 Download PDFInfo
- Publication number
- RU2459821C2 RU2459821C2 RU2009112598/04A RU2009112598A RU2459821C2 RU 2459821 C2 RU2459821 C2 RU 2459821C2 RU 2009112598/04 A RU2009112598/04 A RU 2009112598/04A RU 2009112598 A RU2009112598 A RU 2009112598A RU 2459821 C2 RU2459821 C2 RU 2459821C2
- Authority
- RU
- Russia
- Prior art keywords
- benzo
- alkyl
- indazol
- radical
- ylamino
- Prior art date
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- 102000006940 Interleukin-1 Receptor-Associated Kinases Human genes 0.000 title 1
- 108010072621 Interleukin-1 Receptor-Associated Kinases Proteins 0.000 title 1
- -1 amino, methoxy Chemical group 0.000 claims abstract description 197
- 150000001875 compounds Chemical class 0.000 claims abstract description 153
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 78
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 48
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 29
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 25
- 150000002367 halogens Chemical class 0.000 claims abstract description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims abstract 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract 5
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 206010040047 Sepsis Diseases 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 206010052779 Transplant rejections Diseases 0.000 claims description 6
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 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 5
- RSFJUAJAYHSBHD-UHFFFAOYSA-N 1-cyclohexyl-n-[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]-5-(morpholin-4-ylmethyl)benzimidazol-2-amine Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CN5CCOCC5)C=C4N=3)C3CCCCC3)C2=C1 RSFJUAJAYHSBHD-UHFFFAOYSA-N 0.000 claims description 4
- FETDUDQELDASEU-UHFFFAOYSA-N 3-[2-[[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]amino]benzimidazol-1-yl]propan-1-ol Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=CC=C4N=3)CCCO)C2=C1 FETDUDQELDASEU-UHFFFAOYSA-N 0.000 claims description 4
- XNNSMLBQCJOFTI-UHFFFAOYSA-N 4-[5-(hydroxymethyl)-2-[[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]amino]benzimidazol-1-yl]cyclohexan-1-ol Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CO)C=C4N=3)C3CCC(O)CC3)C2=C1 XNNSMLBQCJOFTI-UHFFFAOYSA-N 0.000 claims description 4
- RCDOOVVHRGUAKF-UHFFFAOYSA-N [1-cyclohexyl-2-[[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]amino]benzimidazol-5-yl]methanol Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CO)C=C4N=3)C3CCCCC3)C2=C1 RCDOOVVHRGUAKF-UHFFFAOYSA-N 0.000 claims description 4
- PGSYKHBFXWTSGP-UHFFFAOYSA-N [2-[[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]amino]-1-phenylbenzimidazol-5-yl]methanol Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CO)C=C4N=3)C=3C=CC=CC=3)C2=C1 PGSYKHBFXWTSGP-UHFFFAOYSA-N 0.000 claims description 4
- MYSIISRDNSWBDA-UHFFFAOYSA-N ethyl 1-(4-hydroxycyclohexyl)-2-[[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]amino]benzimidazole-5-carboxylate Chemical compound N=1NC2=CC=C(C=3C(=CC=NC=3)OC)C=C2C=1NC1=NC2=CC(C(=O)OCC)=CC=C2N1C1CCC(O)CC1 MYSIISRDNSWBDA-UHFFFAOYSA-N 0.000 claims description 4
- CFSUYKKSSWNBCA-UHFFFAOYSA-N n-cyclopentyl-1-(4-hydroxycyclohexyl)-2-[[5-(2-methoxyphenyl)-1h-indazol-3-yl]amino]benzimidazole-5-carboxamide Chemical compound COC1=CC=CC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(C=C4N=3)C(=O)NC3CCCC3)C3CCC(O)CC3)C2=C1 CFSUYKKSSWNBCA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- VTJFVOQGGHESGO-UHFFFAOYSA-N 1-cyclohexyl-n-[5-(4-methoxypyridin-3-yl)-1h-indazol-3-yl]-5-(piperidin-1-ylmethyl)benzimidazol-2-amine Chemical compound COC1=CC=NC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(CN5CCCCC5)C=C4N=3)C3CCCCC3)C2=C1 VTJFVOQGGHESGO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
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- 208000006011 Stroke Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- VDRMHRQQXLXAAC-UHFFFAOYSA-N [1-(4-hydroxycyclohexyl)-2-[[5-(2-methoxyphenyl)-1h-indazol-3-yl]amino]benzimidazol-5-yl]-pyrrolidin-1-ylmethanone Chemical compound COC1=CC=CC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(C=C4N=3)C(=O)N3CCCC3)C3CCC(O)CC3)C2=C1 VDRMHRQQXLXAAC-UHFFFAOYSA-N 0.000 claims description 3
- 230000001771 impaired effect Effects 0.000 claims description 3
- 206010028417 myasthenia gravis Diseases 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- AXZVEOQAICRWJY-UHFFFAOYSA-N 1-(4-hydroxycyclohexyl)-2-[[5-(2-methoxyphenyl)-1h-indazol-3-yl]amino]-n-(3-methylbutyl)benzimidazole-5-carboxamide Chemical compound COC1=CC=CC=C1C1=CC=C(NN=C2NC=3N(C4=CC=C(C=C4N=3)C(=O)NCCC(C)C)C3CCC(O)CC3)C2=C1 AXZVEOQAICRWJY-UHFFFAOYSA-N 0.000 claims description 2
- QZMAOGLWCNTFCG-UHFFFAOYSA-N 1-(4-hydroxycyclohexyl)-n-(3-methylbutyl)-2-[[5-[2-(trifluoromethoxy)phenyl]-1h-indazol-3-yl]amino]benzimidazole-5-carboxamide Chemical compound N=1NC2=CC=C(C=3C(=CC=CC=3)OC(F)(F)F)C=C2C=1NC1=NC2=CC(C(=O)NCCC(C)C)=CC=C2N1C1CCC(O)CC1 QZMAOGLWCNTFCG-UHFFFAOYSA-N 0.000 claims description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 2
- JIDRQSULGLZGQN-UHFFFAOYSA-N 3-[2-[(5-bromo-1h-indazol-3-yl)amino]benzimidazol-1-yl]propan-1-ol Chemical compound C1=CC=C2N(CCCO)C(NC=3C4=CC(Br)=CC=C4NN=3)=NC2=C1 JIDRQSULGLZGQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- OYBSTTITNAOGPL-UHFFFAOYSA-N n-cyclopentyl-1-(4-hydroxycyclohexyl)-2-[[5-[2-(trifluoromethoxy)phenyl]-1h-indazol-3-yl]amino]benzimidazole-5-carboxamide Chemical compound C1CC(O)CCC1N1C2=CC=C(C(=O)NC3CCCC3)C=C2N=C1NC1=NNC2=CC=C(C=3C(=CC=CC=3)OC(F)(F)F)C=C12 OYBSTTITNAOGPL-UHFFFAOYSA-N 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 10
- 108010093036 interleukin receptors Proteins 0.000 abstract description 2
- 102000002467 interleukin receptors Human genes 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 2
- 150000003254 radicals Chemical class 0.000 description 130
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 119
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- 239000000203 mixture Substances 0.000 description 107
- 125000003118 aryl group Chemical group 0.000 description 67
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 55
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 39
- 235000019439 ethyl acetate Nutrition 0.000 description 38
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 125000001931 aliphatic group Chemical group 0.000 description 35
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 33
- 238000000034 method Methods 0.000 description 33
- 102100036342 Interleukin-1 receptor-associated kinase 1 Human genes 0.000 description 31
- 125000003368 amide group Chemical group 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 101710199015 Interleukin-1 receptor-associated kinase 1 Proteins 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 26
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 229920000642 polymer Polymers 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- 239000003814 drug Substances 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 229940124597 therapeutic agent Drugs 0.000 description 18
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 125000000304 alkynyl group Chemical group 0.000 description 15
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- 235000011152 sodium sulphate Nutrition 0.000 description 15
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- 235000019341 magnesium sulphate Nutrition 0.000 description 14
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 125000002252 acyl group Chemical group 0.000 description 13
- 125000003435 aroyl group Chemical group 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
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- 239000001257 hydrogen Substances 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 13
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- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 12
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 12
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 11
- 125000004104 aryloxy group Chemical group 0.000 description 11
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- 125000001188 haloalkyl group Chemical group 0.000 description 11
- 125000005553 heteroaryloxy group Chemical group 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 125000004043 oxo group Chemical group O=* 0.000 description 11
- 238000002953 preparative HPLC Methods 0.000 description 11
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 11
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- 239000013543 active substance Substances 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
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- KZCIYZXJEMGNJQ-UHFFFAOYSA-N 2-[(5-bromo-3-iodoindazol-1-yl)methoxy]ethyl-trimethylsilane Chemical compound BrC1=CC=C2N(COCC[Si](C)(C)C)N=C(I)C2=C1 KZCIYZXJEMGNJQ-UHFFFAOYSA-N 0.000 description 8
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- 238000001514 detection method Methods 0.000 description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- 125000004448 alkyl carbonyl group Chemical group 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
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- 238000004587 chromatography analysis Methods 0.000 description 6
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- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 6
- 125000002541 furyl group Chemical group 0.000 description 6
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- 238000010992 reflux Methods 0.000 description 6
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84280106P | 2006-09-07 | 2006-09-07 | |
| US60/842,801 | 2006-09-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2009112598A RU2009112598A (ru) | 2010-10-20 |
| RU2459821C2 true RU2459821C2 (ru) | 2012-08-27 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2009112598/04A RU2459821C2 (ru) | 2006-09-07 | 2007-09-07 | Модуляторы киназы, ассоциированной с рецептором интерлейкина-1 |
Country Status (15)
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| AU (1) | AU2007292929A1 (enExample) |
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| CA (1) | CA2663100A1 (enExample) |
| IL (1) | IL197274A0 (enExample) |
| MX (1) | MX2009002377A (enExample) |
| NO (1) | NO20091326L (enExample) |
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| RU (1) | RU2459821C2 (enExample) |
| WO (1) | WO2008030584A2 (enExample) |
| ZA (1) | ZA200901529B (enExample) |
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| RU2666899C2 (ru) * | 2013-02-07 | 2018-09-13 | Мерк Патент Гмбх | Производные пиридазинон-амидов |
Families Citing this family (37)
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| EP2746259A1 (en) | 2012-12-21 | 2014-06-25 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds |
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| US20160166576A1 (en) | 2013-07-11 | 2016-06-16 | Merck Sharp & Dohme Corp. | Substituted amidopyrazole inhibitors of interleukin receptor-associated kinases (irak-4) |
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| HRP20181795T1 (hr) * | 2014-01-13 | 2019-01-25 | Aurigene Discovery Technologies Limited | Biciklički heterociklilni derivati kao inhibitori irak4 |
| EP3157521A4 (en) * | 2014-06-20 | 2018-02-14 | Aurigene Discovery Technologies Limited | Substituted indazole compounds as irak4 inhibitors |
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| TW201702218A (zh) | 2014-12-12 | 2017-01-16 | 美國杰克森實驗室 | 關於治療癌症、自體免疫疾病及神經退化性疾病之組合物及方法 |
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| UY36660A (es) | 2015-04-30 | 2016-11-30 | Bayer Pharma AG | Combinaciones de inhibidores de irak4 |
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| US10435396B2 (en) | 2016-03-03 | 2019-10-08 | Bayer Pharma Aktiegesellschaft | 2-substituted indazoles, methods for producing same, pharmaceutical preparations that contain same, and use of same to produce drugs |
| EP3219329A1 (en) | 2016-03-17 | 2017-09-20 | Bayer Pharma Aktiengesellschaft | Combinations of copanlisib |
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| PT3448849T (pt) | 2016-04-29 | 2020-06-30 | Bayer Pharma AG | Síntese de indazóis |
| AU2017272505B9 (en) | 2016-06-01 | 2021-10-28 | Bayer Pharma Aktiengesellschaft | Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals |
| CN106222183B (zh) * | 2016-07-25 | 2019-11-08 | 南通大学 | 靶向人irak1基因的小干扰rna及其应用 |
| JOP20180011A1 (ar) | 2017-02-16 | 2019-01-30 | Gilead Sciences Inc | مشتقات بيرولو [1، 2-b]بيريدازين |
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| EP3704108B1 (en) | 2017-10-31 | 2024-04-24 | Curis, Inc. | Irak4 inhibitor in combination with a bcl-2 inhibitor for use in treating cancer |
| WO2019111218A1 (en) | 2017-12-08 | 2019-06-13 | Cadila Healthcare Limited | Novel heterocyclic compounds as irak4 inhibitors |
| TWI842978B (zh) | 2018-07-13 | 2024-05-21 | 美商基利科學股份有限公司 | 衍生物 |
| WO2020097398A1 (en) | 2018-11-07 | 2020-05-14 | Dana-Farber Cancer Institute, Inc. | Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof |
| WO2020263967A1 (en) * | 2019-06-27 | 2020-12-30 | Biogen Ma Inc. | 2h-indazole derivatives and their use in the treatment of disease |
| CA3181537A1 (en) | 2020-05-06 | 2021-11-11 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| WO2022140527A1 (en) | 2020-12-23 | 2022-06-30 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| KR20240004476A (ko) | 2021-04-08 | 2024-01-11 | 쿠리스 인코퍼레이션 | 암 치료를 위한 병용 요법 |
| CN115710253B (zh) * | 2021-08-23 | 2024-07-02 | 上海交通大学 | 一类含有氨基苯并咪唑类衍生物及其制备和用途 |
| CA3234638A1 (en) | 2021-11-09 | 2023-05-19 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| TW202325289A (zh) | 2021-11-09 | 2023-07-01 | 美商雅捷可斯治療公司 | Ｊａｋ２抑制劑之形式及組合物 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2176642C2 (ru) * | 1996-11-15 | 2001-12-10 | Дарвин Дискавери Лимитед | Бициклические карбоксамиды и их фармацевтически приемлемые соли и фармацевтическая композиция на их основе |
| RU2261248C2 (ru) * | 1999-06-23 | 2005-09-27 | Авентис Фарма Дойчланд Гмбх | Замещенные бензимидазолы и лекарственное средство на их основе |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8716111D0 (en) * | 1987-07-08 | 1987-08-12 | Unilever Plc | Edible plastic dispersion |
| JP2001518094A (ja) * | 1997-03-31 | 2001-10-09 | デュポン ファーマシューティカルズ カンパニー | Ｈｉｖプロテアーゼ阻害剤として有用なインダゾール−環式尿素 |
| ATE511840T1 (de) * | 2001-10-09 | 2011-06-15 | Amgen Inc | Imidazolderivate als entzündungshemmende mittel |
| JP4628678B2 (ja) | 2002-03-29 | 2011-02-09 | ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド | 置換ベンズアゾールおよびＲａｆキナーゼ阻害剤としてのそれらの使用 |
-
2007
- 2007-09-07 EP EP07837920A patent/EP2061786A2/en not_active Withdrawn
- 2007-09-07 MX MX2009002377A patent/MX2009002377A/es not_active Application Discontinuation
- 2007-09-07 RU RU2009112598/04A patent/RU2459821C2/ru not_active IP Right Cessation
- 2007-09-07 BR BRPI0716549-8A2A patent/BRPI0716549A2/pt not_active IP Right Cessation
- 2007-09-07 AU AU2007292929A patent/AU2007292929A1/en not_active Abandoned
- 2007-09-07 CN CN200780041379A patent/CN101616910A/zh active Pending
- 2007-09-07 KR KR1020097006123A patent/KR20090049076A/ko not_active Ceased
- 2007-09-07 JP JP2009527438A patent/JP2010502717A/ja active Pending
- 2007-09-07 US US12/440,163 patent/US8293923B2/en not_active Expired - Fee Related
- 2007-09-07 CA CA002663100A patent/CA2663100A1/en not_active Abandoned
- 2007-09-07 NZ NZ575410A patent/NZ575410A/en not_active IP Right Cessation
- 2007-09-07 WO PCT/US2007/019588 patent/WO2008030584A2/en not_active Ceased
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2009
- 2009-02-26 IL IL197274A patent/IL197274A0/en unknown
- 2009-03-03 ZA ZA200901529A patent/ZA200901529B/xx unknown
- 2009-04-01 NO NO20091326A patent/NO20091326L/no not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2176642C2 (ru) * | 1996-11-15 | 2001-12-10 | Дарвин Дискавери Лимитед | Бициклические карбоксамиды и их фармацевтически приемлемые соли и фармацевтическая композиция на их основе |
| RU2261248C2 (ru) * | 1999-06-23 | 2005-09-27 | Авентис Фарма Дойчланд Гмбх | Замещенные бензимидазолы и лекарственное средство на их основе |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2660435C2 (ru) * | 2013-02-07 | 2018-07-06 | Мерк Патент Гмбх | Макроциклические производные пиридазинона |
| RU2666899C2 (ru) * | 2013-02-07 | 2018-09-13 | Мерк Патент Гмбх | Производные пиридазинон-амидов |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2663100A1 (en) | 2008-03-13 |
| EP2061786A2 (en) | 2009-05-27 |
| BRPI0716549A2 (pt) | 2013-09-24 |
| CN101616910A (zh) | 2009-12-30 |
| US8293923B2 (en) | 2012-10-23 |
| ZA200901529B (en) | 2009-11-25 |
| NO20091326L (no) | 2009-04-01 |
| JP2010502717A (ja) | 2010-01-28 |
| WO2008030584A2 (en) | 2008-03-13 |
| MX2009002377A (es) | 2009-03-13 |
| IL197274A0 (en) | 2009-12-24 |
| AU2007292929A1 (en) | 2008-03-13 |
| RU2009112598A (ru) | 2010-10-20 |
| NZ575410A (en) | 2012-03-30 |
| KR20090049076A (ko) | 2009-05-15 |
| US20110152260A1 (en) | 2011-06-23 |
| WO2008030584A3 (en) | 2008-07-17 |
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