JP2010522765A - 受容体チロシンキナーゼとしてのイミダゾ［１，２−ａ］ピリジン化合物 - Google Patents

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Publication number

JP2010522765A

JP2010522765A JP2010501214A JP2010501214A JP2010522765A JP 2010522765 A JP2010522765 A JP 2010522765A JP 2010501214 A JP2010501214 A JP 2010501214A JP 2010501214 A JP2010501214 A JP 2010501214A JP 2010522765 A JP2010522765 A JP 2010522765A

Authority

JP

Japan

Prior art keywords

alkyl

mmol

formula

compound

imidazo

Prior art date

2007-03-28

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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• 108091008598 receptor tyrosine kinases Proteins 0.000 title claims abstract description 17
• 102000027426 receptor tyrosine kinases Human genes 0.000 title claims abstract description 17
• 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 165
• -1 imidazopyridine compound Chemical class 0.000 claims abstract description 92
• 230000001404 mediated effect Effects 0.000 claims abstract description 14
• 125000000217 alkyl group Chemical group 0.000 claims description 238
• 238000002360 preparation method Methods 0.000 claims description 149
• 238000000034 method Methods 0.000 claims description 54
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 49
• 229910052739 hydrogen Inorganic materials 0.000 claims description 48
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims description 29
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
• 229910052731 fluorine Inorganic materials 0.000 claims description 27
• 150000003839 salts Chemical class 0.000 claims description 26
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
• 239000001257 hydrogen Substances 0.000 claims description 15
• 125000004429 atom Chemical group 0.000 claims description 14
• 229910052801 chlorine Inorganic materials 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 229910052757 nitrogen Inorganic materials 0.000 claims description 13
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 12
• 125000003118 aryl group Chemical group 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 201000011510 cancer Diseases 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 229910052763 palladium Inorganic materials 0.000 claims description 9
• 241000124008 Mammalia Species 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
• 208000024891 symptom Diseases 0.000 claims description 8
• 206010016654 Fibrosis Diseases 0.000 claims description 7
• 239000003054 catalyst Substances 0.000 claims description 7
• 239000003153 chemical reaction reagent Substances 0.000 claims description 7
• 230000004761 fibrosis Effects 0.000 claims description 7
• 239000003446 ligand Substances 0.000 claims description 7
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
• 125000002971 oxazolyl group Chemical group 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
• 239000003638 chemical reducing agent Substances 0.000 claims description 5
• 230000008878 coupling Effects 0.000 claims description 5
• 238000010168 coupling process Methods 0.000 claims description 5
• 238000005859 coupling reaction Methods 0.000 claims description 5
• 150000002431 hydrogen Chemical class 0.000 claims description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 3
• 230000001335 demethylating effect Effects 0.000 claims description 2
• 125000006239 protecting group Chemical group 0.000 claims description 2
• 125000005330 8 membered heterocyclic group Chemical group 0.000 claims 1
• 239000003112 inhibitor Substances 0.000 abstract description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
• 101001001642 Xenopus laevis Serine/threonine-protein kinase pim-3 Proteins 0.000 abstract description 13
• 201000010099 disease Diseases 0.000 abstract description 11
• 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 abstract description 10
• 102000027495 nuclear receptors type III Human genes 0.000 abstract description 7
• 108091008732 nuclear receptors type III Proteins 0.000 abstract description 7
• 102000005962 receptors Human genes 0.000 abstract description 3
• 108020003175 receptors Proteins 0.000 abstract description 3
• 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 abstract 1
• OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 abstract 1
• 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 abstract 1
• 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 abstract 1
• OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 288
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 243
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 240
• 238000006243 chemical reaction Methods 0.000 description 208
• 239000000203 mixture Substances 0.000 description 120
• 239000007787 solid Substances 0.000 description 115
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
• 201000006417 multiple sclerosis Diseases 0.000 description 97
• 235000019439 ethyl acetate Nutrition 0.000 description 95
• 239000000047 product Substances 0.000 description 88
• 239000000243 solution Substances 0.000 description 85
• 239000011541 reaction mixture Substances 0.000 description 72
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
• 239000011734 sodium Substances 0.000 description 57
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 49
• 239000010410 layer Substances 0.000 description 43
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 40
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 39
• 238000010992 reflux Methods 0.000 description 38
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 32
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 32
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
• 229920006395 saturated elastomer Polymers 0.000 description 28
• 239000003921 oil Substances 0.000 description 27
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
• 238000003818 flash chromatography Methods 0.000 description 21
• 239000012074 organic phase Substances 0.000 description 21
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
• 229910052786 argon Inorganic materials 0.000 description 20
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• 238000010898 silica gel chromatography Methods 0.000 description 16
• HBBYDTFNQNAFJA-UHFFFAOYSA-N 4-(2-methoxyethoxy)pyridin-2-amine Chemical compound COCCOC1=CC=NC(N)=C1 HBBYDTFNQNAFJA-UHFFFAOYSA-N 0.000 description 15
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 15
• 210000004027 cell Anatomy 0.000 description 15
• SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 13
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 12
• 239000008346 aqueous phase Substances 0.000 description 12
• 239000008367 deionised water Substances 0.000 description 12
• 229910021641 deionized water Inorganic materials 0.000 description 12
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 12
• 229910002027 silica gel Inorganic materials 0.000 description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
• CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 12
• 208000031261 Acute myeloid leukaemia Diseases 0.000 description 11
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
• 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• 229910052794 bromium Inorganic materials 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 239000000843 powder Substances 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• MTDOAXRREVUUAU-UHFFFAOYSA-N 2-chloro-4-(2-methoxyethoxy)pyridine Chemical compound COCCOC1=CC=NC(Cl)=C1 MTDOAXRREVUUAU-UHFFFAOYSA-N 0.000 description 9
• NWPHMULLPITJJY-UHFFFAOYSA-N 8-bromo-5-fluoroquinoline-2-carboxylic acid Chemical compound FC1=CC=C(Br)C2=NC(C(=O)O)=CC=C21 NWPHMULLPITJJY-UHFFFAOYSA-N 0.000 description 9
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 9
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
• SGDSAOOGSGZQQW-UHFFFAOYSA-N benzyl n-(4-methylpiperidin-4-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1(C)CCNCC1 SGDSAOOGSGZQQW-UHFFFAOYSA-N 0.000 description 9
• 238000001816 cooling Methods 0.000 description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
• 238000000605 extraction Methods 0.000 description 9
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• CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 9
• CLFPSUQMEIZXHS-UHFFFAOYSA-N 8-bromo-6-fluoroquinoline-2-carboxylic acid Chemical compound C1=C(F)C=C(Br)C2=NC(C(=O)O)=CC=C21 CLFPSUQMEIZXHS-UHFFFAOYSA-N 0.000 description 8
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
• WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 8
• 239000011521 glass Substances 0.000 description 8
• 229910052740 iodine Inorganic materials 0.000 description 8
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 8
• 239000012452 mother liquor Substances 0.000 description 8
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
• 235000017557 sodium bicarbonate Nutrition 0.000 description 8
• 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 8
• UDVPQRRWUGKGQY-XQHVRGAUSA-N (e)-but-2-enal Chemical compound C\C=C\C=O.C\C=C\C=O UDVPQRRWUGKGQY-XQHVRGAUSA-N 0.000 description 7
• KDBADDXDBJFAAO-UHFFFAOYSA-N 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine Chemical compound C1=C(OCCOC)C=CN2C=CN=C21 KDBADDXDBJFAAO-UHFFFAOYSA-N 0.000 description 7
• MJWZFQJNGFPWGE-UHFFFAOYSA-N 8-bromo-5-fluoroquinoline-2-carbaldehyde Chemical compound O=CC1=CC=C2C(F)=CC=C(Br)C2=N1 MJWZFQJNGFPWGE-UHFFFAOYSA-N 0.000 description 7
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
• 238000004587 chromatography analysis Methods 0.000 description 7
• 239000012043 crude product Substances 0.000 description 7
• UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 7
• 239000000463 material Substances 0.000 description 7
• 229910001961 silver nitrate Inorganic materials 0.000 description 7
• 239000002904 solvent Substances 0.000 description 7
• 238000001665 trituration Methods 0.000 description 7
• XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 6
• OKBNEDPOUYRYNP-UHFFFAOYSA-N 4-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C)(C(O)=O)CC1 OKBNEDPOUYRYNP-UHFFFAOYSA-N 0.000 description 6
• WNCMKCYNUDBQQO-UHFFFAOYSA-N 8-bromo-2-(dibromomethyl)-5-fluoroquinoline Chemical compound BrC(Br)C1=CC=C2C(F)=CC=C(Br)C2=N1 WNCMKCYNUDBQQO-UHFFFAOYSA-N 0.000 description 6
• LRBSJYHYOPQSOG-UHFFFAOYSA-N 8-bromo-2-(dibromomethyl)-6-fluoroquinoline Chemical compound N1=C(C(Br)Br)C=CC2=CC(F)=CC(Br)=C21 LRBSJYHYOPQSOG-UHFFFAOYSA-N 0.000 description 6
• ZCACBJCEFFPJFB-UHFFFAOYSA-N 8-bromo-5-fluoro-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound FC1=CC=C(Br)C2=NC(C=3N4C=CC(=CC4=NC=3)OCCOC)=CC=C21 ZCACBJCEFFPJFB-UHFFFAOYSA-N 0.000 description 6
• SKYJNBNYCRKOPC-UHFFFAOYSA-N 8-bromo-5-fluoro-2-methylquinoline Chemical compound FC1=CC=C(Br)C2=NC(C)=CC=C21 SKYJNBNYCRKOPC-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
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• 238000003556 assay Methods 0.000 description 6
• ZTWNQHNXEOMECF-UHFFFAOYSA-N ethyl 8-bromo-6-fluoroquinoline-2-carboxylate Chemical compound C1=C(F)C=C(Br)C2=NC(C(=O)OCC)=CC=C21 ZTWNQHNXEOMECF-UHFFFAOYSA-N 0.000 description 6
• 239000000284 extract Substances 0.000 description 6
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• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
• 239000002002 slurry Substances 0.000 description 6
• 238000000638 solvent extraction Methods 0.000 description 6
• 238000010792 warming Methods 0.000 description 6
• LIEPVGBDUYKPLC-UHFFFAOYSA-N 2-chloro-4-nitropyridine Chemical compound [O-][N+](=O)C1=CC=NC(Cl)=C1 LIEPVGBDUYKPLC-UHFFFAOYSA-N 0.000 description 5
• JEDALECUOKHQDK-UHFFFAOYSA-M 4-ethyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylate Chemical compound CCC1(C([O-])=O)CCN(C(=O)OC(C)(C)C)CC1 JEDALECUOKHQDK-UHFFFAOYSA-M 0.000 description 5
• JEHWQJWDPOQIMX-UHFFFAOYSA-N 8-bromo-5-fluoro-2-(2-methoxyethenyl)quinoline Chemical compound FC1=CC=C(Br)C2=NC(C=COC)=CC=C21 JEHWQJWDPOQIMX-UHFFFAOYSA-N 0.000 description 5
• HYNGTUOHHRSCMG-UHFFFAOYSA-N 8-bromo-6-fluoro-2-(2-methoxyethenyl)quinoline Chemical compound C1=C(F)C=C(Br)C2=NC(C=COC)=CC=C21 HYNGTUOHHRSCMG-UHFFFAOYSA-N 0.000 description 5
• XGQUPMSDMCTRLT-UHFFFAOYSA-N 8-bromo-6-fluoro-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound C1=C(F)C=C(Br)C2=NC(C=3N4C=CC(=CC4=NC=3)OCCOC)=CC=C21 XGQUPMSDMCTRLT-UHFFFAOYSA-N 0.000 description 5
• IWVKLZLPGJIBHU-UHFFFAOYSA-N 8-bromo-6-fluoroquinoline-2-carbaldehyde Chemical compound N1=C(C=O)C=CC2=CC(F)=CC(Br)=C21 IWVKLZLPGJIBHU-UHFFFAOYSA-N 0.000 description 5
• 201000003793 Myelodysplastic syndrome Diseases 0.000 description 5
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 5
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 5
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
• 239000002585 base Substances 0.000 description 5
• DWPWWTIOOLQURY-NEPJUHHUSA-N benzyl n-[(3r,4s)-3-fluoropiperidin-4-yl]carbamate Chemical compound F[C@@H]1CNCC[C@@H]1NC(=O)OCC1=CC=CC=C1 DWPWWTIOOLQURY-NEPJUHHUSA-N 0.000 description 5
• 239000003814 drug Substances 0.000 description 5
• XAHXFLGTAKROPJ-UHFFFAOYSA-N ethyl 8-bromo-5-fluoroquinoline-2-carboxylate Chemical compound FC1=CC=C(Br)C2=NC(C(=O)OCC)=CC=C21 XAHXFLGTAKROPJ-UHFFFAOYSA-N 0.000 description 5
• SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 5
• 230000035772 mutation Effects 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• YUWOECMFUBVGSE-UHFFFAOYSA-N quinolin-8-yl trifluoromethanesulfonate Chemical compound C1=CN=C2C(OS(=O)(=O)C(F)(F)F)=CC=CC2=C1 YUWOECMFUBVGSE-UHFFFAOYSA-N 0.000 description 5
• 239000012279 sodium borohydride Substances 0.000 description 5
• 229910000033 sodium borohydride Inorganic materials 0.000 description 5
• 238000003756 stirring Methods 0.000 description 5
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