JP4604086B2 - Ｒａｆモジュレーターおよびその使用方法 - Google Patents
Ｒａｆモジュレーターおよびその使用方法 Download PDFInfo
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- JP4604086B2 JP4604086B2 JP2007511366A JP2007511366A JP4604086B2 JP 4604086 B2 JP4604086 B2 JP 4604086B2 JP 2007511366 A JP2007511366 A JP 2007511366A JP 2007511366 A JP2007511366 A JP 2007511366A JP 4604086 B2 JP4604086 B2 JP 4604086B2
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- JP
- Japan
- Prior art keywords
- optionally substituted
- alkyl
- hydroxy
- dihydro
- oxo
- 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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- 238000000034 method Methods 0.000 title description 44
- -1 amino, amidino Chemical group 0.000 claims description 476
- 150000001875 compounds Chemical class 0.000 claims description 248
- 125000000217 alkyl group Chemical group 0.000 claims description 172
- 239000000203 mixture Substances 0.000 claims description 131
- 125000000623 heterocyclic group Chemical group 0.000 claims description 103
- 230000000694 effects Effects 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 51
- 125000003107 substituted aryl group Chemical group 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- 201000010099 disease Diseases 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 108010077182 raf Kinases Proteins 0.000 claims description 15
- 102000009929 raf Kinases Human genes 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 230000001413 cellular effect Effects 0.000 claims description 10
- 229910052698 phosphorus Inorganic materials 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000005418 aryl aryl group Chemical group 0.000 claims description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 230000002159 abnormal effect Effects 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 150000003857 carboxamides Chemical class 0.000 claims description 3
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 208000002780 macular degeneration Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 150000003456 sulfonamides Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 405
- 238000005481 NMR spectroscopy Methods 0.000 description 389
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 367
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 288
- 239000000243 solution Substances 0.000 description 187
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 119
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 98
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 84
- 239000012267 brine Substances 0.000 description 77
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 77
- 239000011541 reaction mixture Substances 0.000 description 74
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 71
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 68
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
- 239000007787 solid Substances 0.000 description 61
- 230000002829 reductive effect Effects 0.000 description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 239000012044 organic layer Substances 0.000 description 53
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 51
- 239000003795 chemical substances by application Substances 0.000 description 51
- 229910052938 sodium sulfate Inorganic materials 0.000 description 50
- 235000011152 sodium sulphate Nutrition 0.000 description 50
- 238000001914 filtration Methods 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 108091000080 Phosphotransferase Proteins 0.000 description 40
- 102000020233 phosphotransferase Human genes 0.000 description 40
- 239000000047 product Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 38
- 229910002027 silica gel Inorganic materials 0.000 description 38
- 125000004122 cyclic group Chemical group 0.000 description 34
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- 230000027455 binding Effects 0.000 description 29
- 239000003153 chemical reaction reagent Substances 0.000 description 29
- 239000000706 filtrate Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000010410 layer Substances 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 23
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 229960000583 acetic acid Drugs 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 239000003814 drug Substances 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 229940002612 prodrug Drugs 0.000 description 19
- 239000000651 prodrug Substances 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 19
- 108090000623 proteins and genes Proteins 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- 102000001253 Protein Kinase Human genes 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000010189 synthetic method Methods 0.000 description 17
- 201000011510 cancer Diseases 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 239000000460 chlorine Chemical group 0.000 description 16
- 108060006633 protein kinase Proteins 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 16
- 108020003175 receptors Proteins 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 238000004007 reversed phase HPLC Methods 0.000 description 12
- RITAQDHCJBLSSL-UHFFFAOYSA-N 2-(4-chloro-3-nitrobenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 RITAQDHCJBLSSL-UHFFFAOYSA-N 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 11
- 235000015165 citric acid Nutrition 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 108020001756 ligand binding domains Proteins 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 239000002002 slurry Substances 0.000 description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
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- 239000012071 phase Substances 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
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- 238000003756 stirring Methods 0.000 description 9
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- 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 9
- CQABEJNSGNJNEG-UHFFFAOYSA-N 2-benzyl-3-(3,4-diaminophenyl)-3-hydroxyisoindol-1-one Chemical compound C1=C(N)C(N)=CC=C1C1(O)C2=CC=CC=C2C(=O)N1CC1=CC=CC=C1 CQABEJNSGNJNEG-UHFFFAOYSA-N 0.000 description 8
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- 125000002947 alkylene group Chemical group 0.000 description 8
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- 230000015572 biosynthetic process Effects 0.000 description 8
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- 125000003003 spiro group Chemical group 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 7
- 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 7
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
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- UGOMNIBRMAXPJB-UHFFFAOYSA-N 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxyisoindol-1-one Chemical compound C1=C(N)C(N)=CC=C1C1(O)C2=CC=CC=C2C(=O)N1C1=CC=CC(Cl)=C1F UGOMNIBRMAXPJB-UHFFFAOYSA-N 0.000 description 5
- NYGUWSCZBSDNCA-UHFFFAOYSA-N 2-(4-amino-3-nitrobenzoyl)benzoic acid Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1C(=O)C1=CC=CC=C1C(O)=O NYGUWSCZBSDNCA-UHFFFAOYSA-N 0.000 description 5
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- 239000002253 acid Substances 0.000 description 5
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Classifications
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
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- 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
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Landscapes
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- Health & Medical Sciences (AREA)
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| US56900904P | 2004-05-07 | 2004-05-07 | |
| PCT/US2005/010187 WO2005112932A2 (en) | 2004-05-07 | 2005-03-25 | Raf modulators and methods of use |
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| JP2009235794A Division JP2010006840A (ja) | 2004-05-07 | 2009-10-09 | Ｒａｆモジュレーターおよびその使用方法 |
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| JP2009235794A Withdrawn JP2010006840A (ja) | 2004-05-07 | 2009-10-09 | Ｒａｆモジュレーターおよびその使用方法 |
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| EP (1) | EP1751124A4 (enExample) |
| JP (2) | JP4604086B2 (enExample) |
| AU (1) | AU2005244736B2 (enExample) |
| CA (1) | CA2565200C (enExample) |
| WO (1) | WO2005112932A2 (enExample) |
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| GB0419481D0 (en) * | 2004-09-02 | 2004-10-06 | Cancer Rec Tech Ltd | Isoindolin-1-one derivatives |
| RU2452469C2 (ru) * | 2006-07-21 | 2012-06-10 | Новартис Аг | Составы бензимидазолилпиридилэфиров |
| PE20090370A1 (es) | 2007-06-05 | 2009-04-30 | Takeda Pharmaceutical | Derivados de heterociclo fusionado como inhibidores de quinasa |
| WO2009017838A2 (en) * | 2007-08-01 | 2009-02-05 | Exelixis, Inc. | Combinations of jak-2 inhibitors and other agents |
| WO2009025358A1 (ja) | 2007-08-23 | 2009-02-26 | Takeda Pharmaceutical Company Limited | 複素環化合物およびその用途 |
| JP5350247B2 (ja) | 2007-08-29 | 2013-11-27 | 武田薬品工業株式会社 | 複素環化合物およびその用途 |
| JP5579619B2 (ja) | 2008-12-01 | 2014-08-27 | 武田薬品工業株式会社 | 複素環化合物およびその用途 |
| JO3101B1 (ar) | 2008-12-02 | 2017-09-20 | Takeda Pharmaceuticals Co | مشتقات بنزوثيازول كعوامل مضادة للسرطان |
| WO2010093808A1 (en) * | 2009-02-11 | 2010-08-19 | Reaction Biology Corp. | Selective kinase inhibitors |
| US20100222381A1 (en) | 2009-02-27 | 2010-09-02 | Hariprasad Vankayalapati | Cyclopentathiophene/cyclohexathiophene DNA methyltransferase inhibitors |
| AR082453A1 (es) | 2010-04-21 | 2012-12-12 | Novartis Ag | Compuestos de furopiridina, composiciones farmaceuticas que los contienen y usos de los mismos |
| PT2624696T (pt) | 2010-10-06 | 2017-03-21 | Glaxosmithkline Llc | Derivados de benzimidazole como inibidores da cinase pi3 |
| US9408885B2 (en) | 2011-12-01 | 2016-08-09 | Vib Vzw | Combinations of therapeutic agents for treating melanoma |
| JP5965499B2 (ja) * | 2012-12-25 | 2016-08-03 | 日本曹達株式会社 | ハロゲン化アニリンおよびその製造方法 |
| EP2842614A1 (en) * | 2013-08-30 | 2015-03-04 | Biotage AB | Sample preparation method for analysis of acrylamide |
| BR112016011024B1 (pt) | 2013-11-18 | 2020-09-01 | Forma Therapeutics, Inc | Composto, composição farmacêutica, e, usos dos mesmos |
| WO2015074081A1 (en) | 2013-11-18 | 2015-05-21 | Bair Kenneth W | Benzopiperazine compositions as bet bromodomain inhibitors |
| EP3134443B1 (en) * | 2014-04-23 | 2019-10-30 | Sun Chemical Corporation | Led photoinitiators |
| US10562886B2 (en) | 2015-05-21 | 2020-02-18 | The Regents Of The University Of California | Anti-cancer compounds |
| WO2017091681A1 (en) | 2015-11-24 | 2017-06-01 | Aclaris Therapeutics, Inc. | Selective kinase inhibitors |
| EP3889139B1 (en) | 2015-11-30 | 2025-03-19 | The Children's Medical Center Corporation | Compounds for treating proliferative diseases |
| US11072600B2 (en) | 2016-06-24 | 2021-07-27 | The Regents Of The University Of California | Phthalazine derivatives as inhibitors of PARP1, PARP2, and/or tubulin useful for the treatment of cancer |
| EP3579872A1 (en) | 2017-02-10 | 2019-12-18 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the mapk pathway |
| CA3086765A1 (en) | 2017-12-28 | 2019-07-04 | Tract Pharmaceuticals, Inc. | Stem cell culture systems for columnar epithelial stem cells, and uses related thereto |
| HUE066783T2 (hu) | 2018-04-18 | 2024-09-28 | Constellation Pharmaceuticals Inc | Metil módosító enzimek modulátorai, ezek készítményei és alkalmazásuk |
| WO2019226491A1 (en) | 2018-05-21 | 2019-11-28 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| RS65335B1 (sr) | 2018-10-05 | 2024-04-30 | Annapurna Bio Inc | Jedinjenja i kompozicije za lečenje stanja povezanih sa aktivnošću receptora apj |
| EP3876939A4 (en) | 2018-11-07 | 2022-08-10 | Dana-Farber Cancer Institute, Inc. | Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof |
| PH12022552056A1 (en) | 2020-02-07 | 2024-02-12 | Gasherbrum Bio Inc | Heterocyclic glp-1 agonists |
| BR112022022409A2 (pt) | 2020-05-06 | 2023-02-07 | Ajax Therapeutics Inc | 6-heteroarilóxi benzimidazóis e azabenzimidazóis como inibidores de jak2 |
| WO2021257863A1 (en) | 2020-06-19 | 2021-12-23 | Incyte Corporation | Pyrrolotriazine compounds as jak2 v617f inhibitors |
| US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
| IL299612A (en) | 2020-07-02 | 2023-03-01 | Incyte Corp | Tricyclic urea compounds as JAK2 V617F inhibitors |
| US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
| 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 |
| EP4267574B1 (en) | 2020-12-23 | 2025-04-23 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors |
| US11958861B2 (en) | 2021-02-25 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
| CN113045479B (zh) * | 2021-03-29 | 2022-05-24 | 南京工业大学 | 一种可见光促进3-羟基异吲哚-1-酮类化合物的合成方法 |
| US11970494B2 (en) | 2021-11-09 | 2024-04-30 | Ajax Therapeutics, Inc. | 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors |
| WO2023086320A1 (en) | 2021-11-09 | 2023-05-19 | Ajax Therapeutics, Inc. | Forms and compositions of inhibitors of jak2 |
| EP4493558A1 (en) | 2022-03-17 | 2025-01-22 | Incyte Corporation | Tricyclic urea compounds as jak2 v617f inhibitors |
| CN120957993A (zh) | 2023-02-16 | 2025-11-14 | 加舒布鲁姆生物公司 | 杂环glp-1激动剂 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1534862A4 (en) * | 2002-08-07 | 2007-10-10 | Exelixis Inc | RABGGT MODULATORS AND METHODS OF USE THEREOF |
| WO2004103974A1 (ja) * | 2003-05-23 | 2004-12-02 | Japan Tobacco Inc. | 置換２－オキソキノリン化合物およびその医薬用途 |
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2005
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- 2005-03-25 JP JP2007511366A patent/JP4604086B2/ja not_active Expired - Fee Related
- 2005-03-25 AU AU2005244736A patent/AU2005244736B2/en not_active Ceased
- 2005-03-25 EP EP05731363A patent/EP1751124A4/en not_active Withdrawn
- 2005-03-25 US US11/568,789 patent/US7846959B2/en active Active
- 2005-03-25 WO PCT/US2005/010187 patent/WO2005112932A2/en not_active Ceased
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2010
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1751124A2 (en) | 2007-02-14 |
| JP2007536224A (ja) | 2007-12-13 |
| JP2010006840A (ja) | 2010-01-14 |
| CA2565200A1 (en) | 2005-12-01 |
| US7846959B2 (en) | 2010-12-07 |
| WO2005112932A2 (en) | 2005-12-01 |
| US8697737B2 (en) | 2014-04-15 |
| CA2565200C (en) | 2013-12-24 |
| US20080009488A1 (en) | 2008-01-10 |
| EP1751124A4 (en) | 2010-04-14 |
| AU2005244736B2 (en) | 2012-06-28 |
| WO2005112932A3 (en) | 2006-11-23 |
| AU2005244736A1 (en) | 2005-12-01 |
| US20110071145A1 (en) | 2011-03-24 |
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