ES2313283T3 - Derivados de heteroarilo condensados para usar inhibidores de quinasa p38`. - Google Patents
Derivados de heteroarilo condensados para usar inhibidores de quinasa p38`. Download PDFInfo
- Publication number
- ES2313283T3 ES2313283T3 ES05702022T ES05702022T ES2313283T3 ES 2313283 T3 ES2313283 T3 ES 2313283T3 ES 05702022 T ES05702022 T ES 05702022T ES 05702022 T ES05702022 T ES 05702022T ES 2313283 T3 ES2313283 T3 ES 2313283T3
- Authority
- ES
- Spain
- Prior art keywords
- fluoro
- indazol
- methyl
- baselineskip
- compound
- 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.)
- Expired - Lifetime
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- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 338
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 230000000694 effects Effects 0.000 claims abstract description 22
- 230000001404 mediated effect Effects 0.000 claims abstract description 18
- 102000004127 Cytokines Human genes 0.000 claims abstract description 14
- 108090000695 Cytokines Proteins 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 97
- -1 -CONHR 13 Chemical group 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 125000001072 heteroaryl group Chemical group 0.000 claims description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 125000005842 heteroatom Chemical group 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical group FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 14
- 239000003085 diluting agent Substances 0.000 claims description 14
- 239000011737 fluorine Chemical group 0.000 claims description 14
- 229910052731 fluorine Chemical group 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000011593 sulfur Substances 0.000 claims description 12
- 108091000080 Phosphotransferase Proteins 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 11
- 239000000460 chlorine Chemical group 0.000 claims description 11
- 102000020233 phosphotransferase Human genes 0.000 claims description 11
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052801 chlorine Chemical group 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 230000007170 pathology Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 150000002429 hydrazines Chemical class 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- NDSAZMGBKQEREV-UHFFFAOYSA-N 3-fluoro-5-[3-(4-fluorophenyl)-1h-indazol-6-yl]-4-methyl-n-(2-methylpyrazol-3-yl)benzamide Chemical compound CC1=C(F)C=C(C(=O)NC=2N(N=CC=2)C)C=C1C(C=C1NN=2)=CC=C1C=2C1=CC=C(F)C=C1 NDSAZMGBKQEREV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- XXKHSBRGJGQQJN-UHFFFAOYSA-N n-(2,4-dimethylpyrazol-3-yl)-3-[3-(4-fluorophenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound C1=NN(C)C(NC(=O)C=2C=C(C(C)=CC=2)C=2C=C3NN=C(C3=CC=2)C=2C=CC(F)=CC=2)=C1C XXKHSBRGJGQQJN-UHFFFAOYSA-N 0.000 claims description 3
- QXTNFKQMOZXGAJ-UHFFFAOYSA-N n-(2,4-dimethylpyrazol-3-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound C1=NN(C)C(NC(=O)C=2C=C(C(C)=C(F)C=2)C=2C=C3NN=C(C3=CC=2)C=2C=CC(F)=CC=2)=C1C QXTNFKQMOZXGAJ-UHFFFAOYSA-N 0.000 claims description 3
- IAHWGNBUSRCASO-UHFFFAOYSA-N n-(2-ethylpyrazol-3-yl)-3-fluoro-5-[3-(4-fluorophenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound CCN1N=CC=C1NC(=O)C1=CC(F)=C(C)C(C=2C=C3NN=C(C3=CC=2)C=2C=CC(F)=CC=2)=C1 IAHWGNBUSRCASO-UHFFFAOYSA-N 0.000 claims description 3
- UVOQFNITQPYYOI-UHFFFAOYSA-N n-cyclopropyl-3-[1-[4-(2,3-dihydroxypropylamino)phenyl]indazol-5-yl]-5-fluoro-4-methylbenzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1C=N2)=CC=C1N2C1=CC=C(NCC(O)CO)C=C1 UVOQFNITQPYYOI-UHFFFAOYSA-N 0.000 claims description 3
- JWLBNZMPMCOTIL-UHFFFAOYSA-N n-cyclopropyl-3-[1-[4-[2-(dimethylamino)ethylamino]phenyl]indazol-5-yl]-5-fluoro-4-methylbenzamide Chemical compound C1=CC(NCCN(C)C)=CC=C1N1C2=CC=C(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)C=C2C=N1 JWLBNZMPMCOTIL-UHFFFAOYSA-N 0.000 claims description 3
- BGMAADGYDIEDFZ-UHFFFAOYSA-N n-cyclopropyl-3-[3-(4-fluorophenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1C(C=C1NN=2)=CC=C1C=2C1=CC=C(F)C=C1 BGMAADGYDIEDFZ-UHFFFAOYSA-N 0.000 claims description 3
- GQBCGYCOKDKXLT-UHFFFAOYSA-N n-cyclopropyl-3-[3-(4-methoxyphenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound C1=CC(OC)=CC=C1C1=NNC2=CC(C=3C(=CC=C(C=3)C(=O)NC3CC3)C)=CC=C12 GQBCGYCOKDKXLT-UHFFFAOYSA-N 0.000 claims description 3
- YDTSBAIFSIHQBL-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-(1-phenylindazol-5-yl)benzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1C=N2)=CC=C1N2C1=CC=CC=C1 YDTSBAIFSIHQBL-UHFFFAOYSA-N 0.000 claims description 3
- XAFMUBMMTNHFMW-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[1-(4-methylsulfonylphenyl)indazol-5-yl]benzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1C=N2)=CC=C1N2C1=CC=C(S(C)(=O)=O)C=C1 XAFMUBMMTNHFMW-UHFFFAOYSA-N 0.000 claims description 3
- HTIATUHGLIHMDC-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[1-[(1-oxidopyridin-1-ium-2-yl)methyl]indazol-5-yl]benzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1C=N2)=CC=C1N2CC1=CC=CC=[N+]1[O-] HTIATUHGLIHMDC-UHFFFAOYSA-N 0.000 claims description 3
- CYKMFIZQLQHACP-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[1-[4-[2-(methylamino)-2-oxoethyl]phenyl]indazol-5-yl]benzamide Chemical compound C1=CC(CC(=O)NC)=CC=C1N1C2=CC=C(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)C=C2C=N1 CYKMFIZQLQHACP-UHFFFAOYSA-N 0.000 claims description 3
- GEURZXJNLFHMMI-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-5-[1-(4-fluoro-2-methylphenyl)indazol-5-yl]-4-methylbenzamide Chemical compound CC1=CC(F)=CC=C1N1C2=CC=C(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)C=C2C=N1 GEURZXJNLFHMMI-UHFFFAOYSA-N 0.000 claims description 3
- OYTNAQPOJGJNTO-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-5-[1-(4-fluorophenyl)indazol-5-yl]-4-methylbenzamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C(C=C1C=N2)=CC=C1N2C1=CC=C(F)C=C1 OYTNAQPOJGJNTO-UHFFFAOYSA-N 0.000 claims description 3
- QXXQWHJTTDKUMU-UHFFFAOYSA-N n-ethyl-3-[3-(4-methoxyphenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound CCNC(=O)C1=CC=C(C)C(C=2C=C3NN=C(C3=CC=2)C=2C=CC(OC)=CC=2)=C1 QXXQWHJTTDKUMU-UHFFFAOYSA-N 0.000 claims description 3
- ICUDUXKKHGONMS-UHFFFAOYSA-N n-ethyl-3-fluoro-5-[3-(4-fluoro-2-methoxyphenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound CCNC(=O)C1=CC(F)=C(C)C(C=2C=C3NN=C(C3=CC=2)C=2C(=CC(F)=CC=2)OC)=C1 ICUDUXKKHGONMS-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- DVFVWYWKPJGSHJ-UHFFFAOYSA-N n-ethyl-3-[3-(4-fluorophenyl)-1h-indazol-6-yl]-4-methylbenzamide Chemical compound CCNC(=O)C1=CC=C(C)C(C=2C=C3NN=C(C3=CC=2)C=2C=CC(F)=CC=2)=C1 DVFVWYWKPJGSHJ-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 270
- 239000000543 intermediate Substances 0.000 description 190
- 239000000203 mixture Substances 0.000 description 172
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 147
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 141
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 122
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 119
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 102
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 85
- 239000002904 solvent Substances 0.000 description 82
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000000377 silicon dioxide Substances 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
- 239000000243 solution Substances 0.000 description 64
- 239000002253 acid Substances 0.000 description 60
- 239000007787 solid Substances 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 58
- 235000017557 sodium bicarbonate Nutrition 0.000 description 58
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 229960004592 isopropanol Drugs 0.000 description 47
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 42
- 150000003839 salts Chemical class 0.000 description 39
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 38
- 230000002209 hydrophobic effect Effects 0.000 description 36
- 238000002953 preparative HPLC Methods 0.000 description 29
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- 238000004587 chromatography analysis Methods 0.000 description 24
- 239000003981 vehicle Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000003446 ligand Substances 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 19
- 238000010992 reflux Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- 238000009472 formulation Methods 0.000 description 16
- 239000012453 solvate Substances 0.000 description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 241000282414 Homo sapiens Species 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 12
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 12
- 239000002480 mineral oil Substances 0.000 description 12
- 235000010446 mineral oil Nutrition 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- GIWCBSLJBLIGKK-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-5-(1h-indazol-5-yl)-4-methylbenzamide Chemical compound C1=C(C=2C=C3C=NNC3=CC=2)C(C)=C(F)C=C1C(=O)NC1CC1 GIWCBSLJBLIGKK-UHFFFAOYSA-N 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 9
- UTQNRIPCXSLLAZ-UHFFFAOYSA-N 6-bromo-3-(4-fluorophenyl)-1h-indazole Chemical compound C1=CC(F)=CC=C1C1=NNC2=CC(Br)=CC=C12 UTQNRIPCXSLLAZ-UHFFFAOYSA-N 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 description 9
- 230000001684 chronic effect Effects 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 235000019698 starch Nutrition 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- 239000006071 cream Substances 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- OWIUPIRUAQMTTK-UHFFFAOYSA-M n-aminocarbamate Chemical compound NNC([O-])=O OWIUPIRUAQMTTK-UHFFFAOYSA-M 0.000 description 8
- UBSOWCULIXVZGE-UHFFFAOYSA-N n-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide Chemical compound CCNC(=O)C1=CC=C(C)C(B2OC(C)(C)C(C)(C)O2)=C1 UBSOWCULIXVZGE-UHFFFAOYSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
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Classifications
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- 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
- C07D413/12—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 linked by a chain containing hetero atoms as chain links
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- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
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| CA2655999A1 (en) * | 2006-06-28 | 2008-01-03 | Aska Pharmaceutical Co., Ltd. | Treating agent of inflammatory bowel disease |
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| EP2547686B1 (en) | 2010-03-15 | 2014-01-22 | Amgen Inc. | Amino-dihydrooxazine and amino-dihydrothiazine spiro compounds as beta-secretase modulators and their medical use |
| US8883782B2 (en) | 2010-03-15 | 2014-11-11 | Amgen Inc. | Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use |
| WO2011120153A1 (en) | 2010-04-01 | 2011-10-06 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
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| EP2643325A1 (en) | 2010-11-23 | 2013-10-02 | Amgen Inc. | Spiro-amino-imidazolone and spiro-amino-dihydro-pyrimidinone compounds as beta-secretase modulators and methods of use |
| EP2673279A1 (en) | 2011-02-07 | 2013-12-18 | Amgen Inc. | 5-amino-oxazepine and 5-amino-thiazepane compounds as beta-secretase antagonists and methods of use |
| EP2675810A1 (en) | 2011-02-15 | 2013-12-25 | Amgen Inc. | Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use |
| JP2014526560A (ja) | 2011-09-21 | 2014-10-06 | アムジエン・インコーポレーテツド | β‐セクレターゼ調節因子としてのアミノオキサジン化合物およびアミノジヒドロチアジン化合物および使用方法 |
| US9725469B2 (en) | 2012-11-15 | 2017-08-08 | Amgen, Inc. | Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use |
| CN105017256A (zh) | 2014-04-29 | 2015-11-04 | 浙江导明医药科技有限公司 | 多氟化合物作为布鲁顿酪氨酸激酶抑制剂 |
| US9717745B2 (en) | 2015-03-19 | 2017-08-01 | Zhejiang DTRM Biopharma Co. Ltd. | Pharmaceutical compositions and their use for treatment of cancer and autoimmune diseases |
| US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| PT3691620T (pt) | 2017-10-05 | 2022-10-06 | Fulcrum Therapeutics Inc | Os inibidores da quinase p38 reduzem a expressão de dux4 e genes a jusante para o tratamento de fshd |
| TW201922256A (zh) | 2017-10-27 | 2019-06-16 | 中國大陸商浙江導明醫藥科技有限公司 | 治療淋巴樣惡性疾病之方法 |
| WO2021038419A1 (en) * | 2019-08-23 | 2021-03-04 | Insilico Medicine Ip Limited | Kinase inhibitors and methods of synthesis and treatment |
| US12293809B2 (en) | 2019-08-23 | 2025-05-06 | Insilico Medicine Ip Limited | Workflow for generating compounds with biological activity against a specific biological target |
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-
2004
- 2004-01-30 GB GBGB0402143.2A patent/GB0402143D0/en not_active Ceased
-
2005
- 2005-01-27 JP JP2006550294A patent/JP2007519692A/ja active Pending
- 2005-01-27 DE DE602005009318T patent/DE602005009318D1/de not_active Expired - Lifetime
- 2005-01-27 EP EP05702022A patent/EP1708996B1/en not_active Expired - Lifetime
- 2005-01-27 WO PCT/GB2005/000265 patent/WO2005073189A1/en not_active Ceased
- 2005-01-27 US US10/587,790 patent/US20090023725A1/en not_active Abandoned
- 2005-01-27 ES ES05702022T patent/ES2313283T3/es not_active Expired - Lifetime
- 2005-01-27 AT AT05702022T patent/ATE406351T1/de not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| US20090023725A1 (en) | 2009-01-22 |
| ATE406351T1 (de) | 2008-09-15 |
| JP2007519692A (ja) | 2007-07-19 |
| EP1708996A1 (en) | 2006-10-11 |
| DE602005009318D1 (de) | 2008-10-09 |
| EP1708996B1 (en) | 2008-08-27 |
| WO2005073189A1 (en) | 2005-08-11 |
| GB0402143D0 (en) | 2004-03-03 |
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