ES2342976T3 - Compuestos triciclicos basados en 1,6-dihidro-1,3,5,6-tetraaza-as-indaceno y composiciones farmaceuticas que comprenden los mismos como inhibidores de la actividad de encima ikk. - Google Patents
Compuestos triciclicos basados en 1,6-dihidro-1,3,5,6-tetraaza-as-indaceno y composiciones farmaceuticas que comprenden los mismos como inhibidores de la actividad de encima ikk. Download PDFInfo
- Publication number
- ES2342976T3 ES2342976T3 ES06759417T ES06759417T ES2342976T3 ES 2342976 T3 ES2342976 T3 ES 2342976T3 ES 06759417 T ES06759417 T ES 06759417T ES 06759417 T ES06759417 T ES 06759417T ES 2342976 T3 ES2342976 T3 ES 2342976T3
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- Prior art keywords
- alkyl
- heteroaryl
- aryl
- cycloalkyl
- heterocycle
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 150
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 230000000694 effects Effects 0.000 title description 10
- 239000003112 inhibitor Substances 0.000 title description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 894
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 323
- 125000003118 aryl group Chemical group 0.000 claims abstract description 313
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 300
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 290
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 219
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 143
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 137
- 239000001257 hydrogen Substances 0.000 claims abstract description 130
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 86
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 85
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 77
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 61
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 49
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 125000001424 substituent group Chemical group 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 28
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 28
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 25
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 15
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 12
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 4
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 26
- -1 prop-2-enyl Chemical group 0.000 claims description 79
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 56
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 238000011282 treatment Methods 0.000 claims description 28
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 125000004429 atom Chemical group 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000002393 azetidinyl group Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 239000001301 oxygen Chemical group 0.000 claims description 5
- 229910052717 sulfur Chemical group 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims 1
- 230000000414 obstructive effect Effects 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
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- 125000005330 8 membered heterocyclic group Chemical group 0.000 abstract description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 abstract 1
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 abstract 1
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 abstract 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 400
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 209
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 203
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 195
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 162
- 239000011541 reaction mixture Substances 0.000 description 121
- 239000000203 mixture Substances 0.000 description 119
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 111
- 239000002904 solvent Substances 0.000 description 103
- 239000000243 solution Substances 0.000 description 95
- 230000002829 reductive effect Effects 0.000 description 89
- 238000006243 chemical reaction Methods 0.000 description 82
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 81
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 77
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 76
- 238000004128 high performance liquid chromatography Methods 0.000 description 75
- 239000007787 solid Substances 0.000 description 75
- 235000019439 ethyl acetate Nutrition 0.000 description 70
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 230000014759 maintenance of location Effects 0.000 description 53
- 239000000047 product Substances 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- 238000005481 NMR spectroscopy Methods 0.000 description 44
- 239000000741 silica gel Substances 0.000 description 44
- 229910002027 silica gel Inorganic materials 0.000 description 44
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 39
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 35
- 239000002253 acid Chemical group 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- 229960005419 nitrogen Drugs 0.000 description 26
- 229940086542 triethylamine Drugs 0.000 description 26
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 25
- 238000000034 method Methods 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 22
- 238000001023 centrifugal evaporation Methods 0.000 description 20
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 19
- 238000001914 filtration Methods 0.000 description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- 238000004587 chromatography analysis Methods 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 150000001412 amines Chemical group 0.000 description 16
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 16
- 230000002757 inflammatory effect Effects 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 13
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
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- 239000003814 drug Substances 0.000 description 12
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- 230000015572 biosynthetic process Effects 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 238000004296 chiral HPLC Methods 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 10
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
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- 108090000623 proteins and genes Proteins 0.000 description 8
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
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- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
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- 150000004702 methyl esters Chemical class 0.000 description 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 6
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
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- 125000000547 substituted alkyl group Chemical group 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 229940022663 acetate Drugs 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
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- 239000011630 iodine Substances 0.000 description 5
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- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
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- 239000011734 sodium Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
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- YHNJGSISJOHCON-UHFFFAOYSA-N n-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-cyclopropanecarboxamide Chemical compound C=1C=2C=3N(C)C=NC=3C(NC)=NC=2NC=1C(N=1)=CC=CC=1CNC(=O)C1CC1 YHNJGSISJOHCON-UHFFFAOYSA-N 0.000 description 1
- YHIVWGVBZFVPTQ-UHFFFAOYSA-N n-methyl-3,5-dinitropyridin-4-amine Chemical compound CNC1=C([N+]([O-])=O)C=NC=C1[N+]([O-])=O YHIVWGVBZFVPTQ-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 150000002814 niacins Chemical class 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000003566 oxetanyl group Chemical group 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- UVBXZOISXNZBLY-UHFFFAOYSA-L palladium(2+);triphenylphosphane;diacetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UVBXZOISXNZBLY-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
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- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
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- APXBXAJWVZTKSE-UHFFFAOYSA-N pyridine-2,3,4-triamine Chemical compound NC1=CC=NC(N)=C1N APXBXAJWVZTKSE-UHFFFAOYSA-N 0.000 description 1
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- 238000010791 quenching Methods 0.000 description 1
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- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
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- 241000894007 species Species 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000000758 substrate Substances 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- SSDAUMHJIKPITN-UHFFFAOYSA-N tert-butyl 3-ethynylbenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC(C#C)=C1 SSDAUMHJIKPITN-UHFFFAOYSA-N 0.000 description 1
- RCYWPTPMHDFYLP-UHFFFAOYSA-N tert-butyl N-[1-[3-[3-methyl-7-(methylamino)-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-11-yl]phenyl]ethyl]carbamate Chemical compound C=1C=2C=3N(C)C=NC=3C(NC)=NC=2NC=1C1=CC=CC(C(C)NC(=O)OC(C)(C)C)=C1 RCYWPTPMHDFYLP-UHFFFAOYSA-N 0.000 description 1
- VYAYKLGRGQXJQW-UHFFFAOYSA-N tert-butyl N-[11-(3-cyanophenyl)-3-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-7-yl]-N-methylcarbamate Chemical compound C=1C=2C=3N(C)C=NC=3C(N(C(=O)OC(C)(C)C)C)=NC=2NC=1C1=CC=CC(C#N)=C1 VYAYKLGRGQXJQW-UHFFFAOYSA-N 0.000 description 1
- GSKDDHFLESEVJL-UHFFFAOYSA-N tert-butyl N-[11-(4-cyanophenyl)-3-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-7-yl]-N-methylcarbamate Chemical compound C=1C2=C3N(C)C=NC3=C(N(C(=O)OC(C)(C)C)C)NC2=NC=1C1=CC=C(C#N)C=C1 GSKDDHFLESEVJL-UHFFFAOYSA-N 0.000 description 1
- LGFMCWOTFKNREX-UHFFFAOYSA-N tert-butyl N-[11-[3-[(2,2-dimethylpropanoylamino)methyl]phenyl]-3-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-7-yl]-N-methylcarbamate Chemical compound C=1C2=C3N(C)C=NC3=C(N(C(=O)OC(C)(C)C)C)NC2=NC=1C1=CC=CC(CNC(=O)C(C)(C)C)=C1 LGFMCWOTFKNREX-UHFFFAOYSA-N 0.000 description 1
- OGQMCAIAAWDWNU-UHFFFAOYSA-N tert-butyl n-(6-chloro-1-methylimidazo[4,5-c]pyridin-4-yl)-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)C1=NC(Cl)=CC2=C1N=CN2C OGQMCAIAAWDWNU-UHFFFAOYSA-N 0.000 description 1
- SBCLSTWHYCWVLP-UHFFFAOYSA-N tert-butyl n-methyl-n-[(2-methylpropan-2-yl)oxycarbonylcarbamothioyl]carbamate Chemical compound CC(C)(C)OC(=O)N(C)C(S)=NC(=O)OC(C)(C)C SBCLSTWHYCWVLP-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- JUDXOKKZTISQDJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 JUDXOKKZTISQDJ-UHFFFAOYSA-N 0.000 description 1
- WIOADUFWOUUQCV-UHFFFAOYSA-N triphenylphosphanium dichloride Chemical compound [Cl-].[Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 WIOADUFWOUUQCV-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Pulmonology (AREA)
- Rheumatology (AREA)
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- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US430215 | 1989-11-01 | ||
| US67969205P | 2005-05-10 | 2005-05-10 | |
| US679692P | 2005-05-10 | ||
| US11/430,215 US7737279B2 (en) | 2005-05-10 | 2006-05-08 | 1,6-dihydro-1,3,5,6-tetraaza-as-indacene based tricyclic compounds and pharmaceutical compositions comprising same |
Publications (1)
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| ES2342976T3 true ES2342976T3 (es) | 2010-07-20 |
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| ES06759417T Active ES2342976T3 (es) | 2005-05-10 | 2006-05-09 | Compuestos triciclicos basados en 1,6-dihidro-1,3,5,6-tetraaza-as-indaceno y composiciones farmaceuticas que comprenden los mismos como inhibidores de la actividad de encima ikk. |
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| EP (1) | EP1888584B1 (enExample) |
| JP (1) | JP5047164B2 (enExample) |
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| AT (1) | ATE465162T1 (enExample) |
| CY (1) | CY1110419T1 (enExample) |
| DE (1) | DE602006013816D1 (enExample) |
| DK (1) | DK1888584T3 (enExample) |
| ES (1) | ES2342976T3 (enExample) |
| PE (1) | PE20061424A1 (enExample) |
| PL (1) | PL1888584T3 (enExample) |
| PT (1) | PT1888584E (enExample) |
| SI (1) | SI1888584T1 (enExample) |
| TW (1) | TW200718422A (enExample) |
| WO (1) | WO2006122137A1 (enExample) |
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| US7737279B2 (en) * | 2005-05-10 | 2010-06-15 | Bristol-Myers Squibb Company | 1,6-dihydro-1,3,5,6-tetraaza-as-indacene based tricyclic compounds and pharmaceutical compositions comprising same |
| UY31881A (es) | 2008-06-10 | 2010-01-29 | Abbott Lab | Derivados sustituidos de imidazo[1,5-a]pirrolo[2,3-e]pirazinas e imidazo[1,2-a]pirrolo[2,3-e]pirazinas, sus sales, prodrogas, metabolitos biológicalmente activos, estereoisómeros e isómeros farmacéuticamente aceptables. |
| AU2010289497B2 (en) | 2009-09-03 | 2016-04-14 | Bristol-Myers Squibb Company | JAK2 inhibitors and their use for the treatment of myeloproliferative diseases and cancer |
| CA2991896A1 (en) * | 2009-12-01 | 2011-06-09 | Abbvie Inc. | Novel tricyclic compounds as protein kinase inhibitors |
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| JP2008540547A (ja) | 2008-11-20 |
| JP5047164B2 (ja) | 2012-10-10 |
| DE602006013816D1 (de) | 2010-06-02 |
| PT1888584E (pt) | 2010-06-22 |
| US20060270654A1 (en) | 2006-11-30 |
| US8268855B2 (en) | 2012-09-18 |
| WO2006122137A1 (en) | 2006-11-16 |
| PL1888584T3 (pl) | 2010-09-30 |
| US7737279B2 (en) | 2010-06-15 |
| US20100210629A1 (en) | 2010-08-19 |
| EP1888584A1 (en) | 2008-02-20 |
| SI1888584T1 (sl) | 2010-07-30 |
| TW200718422A (en) | 2007-05-16 |
| EP1888584B1 (en) | 2010-04-21 |
| ATE465162T1 (de) | 2010-05-15 |
| PE20061424A1 (es) | 2006-12-17 |
| DK1888584T3 (da) | 2010-08-09 |
| AR053725A1 (es) | 2007-05-16 |
| CY1110419T1 (el) | 2015-04-29 |
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