AU2012254082B2 - Triazolopyridine compounds as PIM kinase inhibitors - Google Patents

Info

Publication number

AU2012254082B2

AU2012254082B2 AU2012254082A AU2012254082A AU2012254082B2 AU 2012254082 B2 AU2012254082 B2 AU 2012254082B2 AU 2012254082 A AU2012254082 A AU 2012254082A AU 2012254082 A AU2012254082 A AU 2012254082A AU 2012254082 B2 AU2012254082 B2 AU 2012254082B2

Authority

AU

Australia

Prior art keywords

triazolo

pyridin

pyrrolidin

amine

trifluoro

Prior art date

2011-02-25

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.)

Ceased

Links

• Espacenet
• Global Dossier
• Discuss

• 101000595531 Homo sapiens Serine/threonine-protein kinase pim-1 Proteins 0.000 title description 6
• 102100036077 Serine/threonine-protein kinase pim-1 Human genes 0.000 title description 6
• 150000008523 triazolopyridines Chemical class 0.000 title description 3
• 229940043355 kinase inhibitor Drugs 0.000 title description 2
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 247
• 125000000217 alkyl group Chemical group 0.000 claims description 361
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 304
• -1 tetrahydropyranyloxy Chemical group 0.000 claims description 274
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 271
• 125000003545 alkoxy group Chemical group 0.000 claims description 248
• 238000002360 preparation method Methods 0.000 claims description 203
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 195
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 182
• NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 claims description 182
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 125
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 106
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 92
• 239000000203 mixture Substances 0.000 claims description 88
• 238000006243 chemical reaction Methods 0.000 claims description 80
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 60
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 60
• 238000000034 method Methods 0.000 claims description 58
• 125000001153 fluoro group Chemical group F* 0.000 claims description 57
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 50
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
• 229910052736 halogen Inorganic materials 0.000 claims description 43
• 150000002367 halogens Chemical class 0.000 claims description 43
• 229910052739 hydrogen Inorganic materials 0.000 claims description 43
• 150000003839 salts Chemical class 0.000 claims description 39
• 101001001642 Xenopus laevis Serine/threonine-protein kinase pim-3 Proteins 0.000 claims description 37
• 206010028980 Neoplasm Diseases 0.000 claims description 36
• 239000002585 base Substances 0.000 claims description 35
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
• PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 34
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 34
• 238000011282 treatment Methods 0.000 claims description 33
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 32
• 239000003153 chemical reaction reagent Substances 0.000 claims description 30
• 208000023275 Autoimmune disease Diseases 0.000 claims description 29
• 229910052731 fluorine Inorganic materials 0.000 claims description 29
• 125000004429 atom Chemical group 0.000 claims description 28
• 201000006417 multiple sclerosis Diseases 0.000 claims description 26
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 23
• 101100297651 Mus musculus Pim2 gene Proteins 0.000 claims description 23
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
• 125000004432 carbon atom Chemical group C* 0.000 claims description 22
• 101100297652 Coturnix japonica PIM3 gene Proteins 0.000 claims description 21
• JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 claims description 21
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
• 201000011510 cancer Diseases 0.000 claims description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 20
• 241000124008 Mammalia Species 0.000 claims description 18
• 230000008878 coupling Effects 0.000 claims description 17
• 238000010168 coupling process Methods 0.000 claims description 17
• 238000005859 coupling reaction Methods 0.000 claims description 17
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 16
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 16
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 208000027866 inflammatory disease Diseases 0.000 claims description 16
• 230000001404 mediated effect Effects 0.000 claims description 16
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
• 206010025135 lupus erythematosus Diseases 0.000 claims description 13
• 229910052740 iodine Inorganic materials 0.000 claims description 12
• NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 claims description 11
• 230000002757 inflammatory effect Effects 0.000 claims description 11
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
• 125000006239 protecting group Chemical group 0.000 claims description 11
• 125000004414 alkyl thio group Chemical group 0.000 claims description 10
• 239000003054 catalyst Substances 0.000 claims description 10
• WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 9
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 9
• 239000003638 chemical reducing agent Substances 0.000 claims description 9
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
• 239000012453 solvate Substances 0.000 claims description 9
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 8
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
• 125000006242 amine protecting group Chemical group 0.000 claims description 8
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical group F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 8
• 125000000623 heterocyclic group Chemical group 0.000 claims description 8
• JCZPOYAMKJFOLA-ZXZARUISSA-N (3s,4r)-pyrrolidine-3,4-diol Chemical compound O[C@H]1CNC[C@H]1O JCZPOYAMKJFOLA-ZXZARUISSA-N 0.000 claims 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 claims description 7
• 229910003827 NRaRb Inorganic materials 0.000 claims description 7
• 125000005647 linker group Chemical group 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 6
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
• 125000005842 heteroatom Chemical group 0.000 claims description 6
• 229910052702 rhenium Inorganic materials 0.000 claims description 6
• 108091000080 Phosphotransferase Proteins 0.000 claims description 5
• 229940047889 isobutyramide Drugs 0.000 claims description 5
• 125000003566 oxetanyl group Chemical group 0.000 claims description 5
• 102000020233 phosphotransferase Human genes 0.000 claims description 5
• MMCIXNVRVDTQSG-UHFFFAOYSA-N quinoline-7-carboxamide Chemical compound C1=CC=NC2=CC(C(=O)N)=CC=C21 MMCIXNVRVDTQSG-UHFFFAOYSA-N 0.000 claims description 5
• 125000001424 substituent group Chemical group 0.000 claims description 5
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 239000011630 iodine Substances 0.000 claims description 4
• 229910052763 palladium Inorganic materials 0.000 claims description 4
• 230000008569 process Effects 0.000 claims description 4
• 239000002841 Lewis acid Substances 0.000 claims description 3
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
• 150000007517 lewis acids Chemical class 0.000 claims description 3
• 239000003446 ligand Substances 0.000 claims description 3
• 229910052751 metal Inorganic materials 0.000 claims description 3
• 239000002184 metal Substances 0.000 claims description 3
• 125000000962 organic group Chemical group 0.000 claims description 3
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
• 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 claims description 2
• 150000008065 acid anhydrides Chemical class 0.000 claims description 2
• WXXVQWSDMOAHHV-UHFFFAOYSA-N quinoline-7-carboxylic acid Chemical compound C1=CC=NC2=CC(C(=O)O)=CC=C21 WXXVQWSDMOAHHV-UHFFFAOYSA-N 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 23
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 8
• OFUCQLPMKBNFQH-OWJIYDKWSA-N 3-methyl-1-[(1s)-2,2,2-trifluoro-1-[3-(8-propan-2-yloxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-ol Chemical compound N1([C@@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)OC(C)C)C(F)(F)F)CCC(C)(O)C1 OFUCQLPMKBNFQH-OWJIYDKWSA-N 0.000 claims 2
• SNKYLLGDJMEMCT-UHFFFAOYSA-N cyclopentanol;dihydrochloride Chemical compound Cl.Cl.OC1CCCC1 SNKYLLGDJMEMCT-UHFFFAOYSA-N 0.000 claims 2
• MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims 2
• WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 claims 2
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
• XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 claims 2
• MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims 2
• CIIFKVFOVFJZDM-UHFFFAOYSA-N quinoline-8-carbonitrile Chemical compound C1=CN=C2C(C#N)=CC=CC2=C1 CIIFKVFOVFJZDM-UHFFFAOYSA-N 0.000 claims 2
• WGOTYEXMECPWDT-FKSKYRLFSA-N (3r)-1-[1-[3-[8-(cyclopropylmethoxy)quinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine Chemical compound C1[C@H](N)CCN1C(C(F)(F)F)C1=CN2C(C=3N=C4C(OCC5CC5)=CC=CC4=CC=3)=NN=C2C=C1 WGOTYEXMECPWDT-FKSKYRLFSA-N 0.000 claims 1
• IITUWPPECMPNGH-RNODOKPDSA-N (3s)-1-[(1r)-1-[3-(6,8-difluoro-7-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine Chemical compound N1([C@H](C=2C=CC3=NN=C(N3C=2)C=2C=CC3=CC(F)=C(C(=C3N=2)F)OC)C(F)(F)F)CC[C@H](N)C1 IITUWPPECMPNGH-RNODOKPDSA-N 0.000 claims 1
• SUZJDGBUULMCJU-MHECFPHRSA-N (3s)-1-[(1r)-1-[3-[8-(1,3-dimethoxypropan-2-yloxy)quinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine Chemical compound N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)OC(COC)COC)C(F)(F)F)CC[C@H](N)C1 SUZJDGBUULMCJU-MHECFPHRSA-N 0.000 claims 1
• AZNPEIIHHTWGRR-XQZUBTRRSA-N 2-[6-[(1r)-1-(1,7-diazaspiro[4.4]nonan-7-yl)-2,2,2-trifluoroethyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-7-ethoxyquinoline Chemical compound C1N([C@H](C=2C=CC3=NN=C(N3C=2)C=2C=CC3=CC=C(C=C3N=2)OCC)C(F)(F)F)CCC21CCCN2 AZNPEIIHHTWGRR-XQZUBTRRSA-N 0.000 claims 1
• MJGSLNIPTRPYJV-UHFFFAOYSA-N Ethyl 2-ethylbutanoate Chemical compound CCOC(=O)C(CC)CC MJGSLNIPTRPYJV-UHFFFAOYSA-N 0.000 claims 1
• YKDCATRNPVJHMY-UHFFFAOYSA-N ethyl 2,2-dimethylbutanoate Chemical compound CCOC(=O)C(C)(C)CC YKDCATRNPVJHMY-UHFFFAOYSA-N 0.000 claims 1
• HHEIMYAXCOIQCJ-UHFFFAOYSA-N ethyl 2,2-dimethylpropanoate Chemical compound CCOC(=O)C(C)(C)C HHEIMYAXCOIQCJ-UHFFFAOYSA-N 0.000 claims 1
• BQIVJVAZDJHDJF-UHFFFAOYSA-N ethyl 2-amino-3-methylbutanoate Chemical compound CCOC(=O)C(N)C(C)C BQIVJVAZDJHDJF-UHFFFAOYSA-N 0.000 claims 1
• LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims 1
• OZMHIFNNCZPJFS-UHFFFAOYSA-N quinoline-7-carbonitrile Chemical compound C1=CC=NC2=CC(C#N)=CC=C21 OZMHIFNNCZPJFS-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 265
• 239000007787 solid Substances 0.000 description 135
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 131
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 126
• 239000000243 solution Substances 0.000 description 126
• 229910001868 water Inorganic materials 0.000 description 125
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 112
• 235000019439 ethyl acetate Nutrition 0.000 description 100
• 239000012267 brine Substances 0.000 description 57
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 57
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 53
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 51
• 239000012044 organic layer Substances 0.000 description 51
• 239000011541 reaction mixture Substances 0.000 description 50
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 49
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
• 238000010992 reflux Methods 0.000 description 44
• WXFAZCYUMXZXBA-UHFFFAOYSA-N 8-methoxyquinoline-2-carbaldehyde Chemical compound C1=C(C=O)N=C2C(OC)=CC=CC2=C1 WXFAZCYUMXZXBA-UHFFFAOYSA-N 0.000 description 42
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 42
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
• 229910052938 sodium sulfate Inorganic materials 0.000 description 42
• 235000011152 sodium sulphate Nutrition 0.000 description 42
• 238000001816 cooling Methods 0.000 description 41
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• 201000010099 disease Diseases 0.000 description 39
• 239000002904 solvent Substances 0.000 description 39
• 210000004027 cell Anatomy 0.000 description 36
• 239000000741 silica gel Substances 0.000 description 36
• 229910002027 silica gel Inorganic materials 0.000 description 36
• 238000003818 flash chromatography Methods 0.000 description 34
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 27
• 210000001744 T-lymphocyte Anatomy 0.000 description 27
• 238000003556 assay Methods 0.000 description 26
• 239000000706 filtrate Substances 0.000 description 26
• JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 26
• 238000001914 filtration Methods 0.000 description 25
• 239000010410 layer Substances 0.000 description 25
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 25
• 239000003921 oil Substances 0.000 description 23
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
• 239000001257 hydrogen Substances 0.000 description 19
• 241000699670 Mus sp. Species 0.000 description 18
• ZPVSAUSAHRIAQM-UHFFFAOYSA-N 8-ethyl-2-methylquinoline Chemical compound C1=C(C)N=C2C(CC)=CC=CC2=C1 ZPVSAUSAHRIAQM-UHFFFAOYSA-N 0.000 description 17
• 229910000027 potassium carbonate Inorganic materials 0.000 description 17
• MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 16
• 238000004440 column chromatography Methods 0.000 description 15
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
• ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 14
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 14
• 239000012074 organic phase Substances 0.000 description 14
• 102000004127 Cytokines Human genes 0.000 description 13
• 108090000695 Cytokines Proteins 0.000 description 13
• 229910052801 chlorine Inorganic materials 0.000 description 13
• 239000003112 inhibitor Substances 0.000 description 13
• 238000000746 purification Methods 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
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