JP6039585B2 - Ｐｉｍキナーゼ阻害剤としてのトリアゾロピリジン化合物 - Google Patents

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Publication number

JP6039585B2

JP6039585B2 JP2013555610A JP2013555610A JP6039585B2 JP 6039585 B2 JP6039585 B2 JP 6039585B2 JP 2013555610 A JP2013555610 A JP 2013555610A JP 2013555610 A JP2013555610 A JP 2013555610A JP 6039585 B2 JP6039585 B2 JP 6039585B2

Authority

JP

Japan

Prior art keywords

alkyl

alkoxy

formula

methyl

pharmaceutically acceptable

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.)

Expired - Fee Related

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• 101000595531 Homo sapiens Serine/threonine-protein kinase pim-1 Proteins 0.000 title description 11
• 102100036077 Serine/threonine-protein kinase pim-1 Human genes 0.000 title description 11
• 229940043355 kinase inhibitor Drugs 0.000 title description 3
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
• 150000008523 triazolopyridines Chemical class 0.000 title description 2
• 125000000217 alkyl group Chemical group 0.000 claims description 469
• -1 tetrahydropyranyloxy Chemical group 0.000 claims description 395
• 125000003545 alkoxy group Chemical group 0.000 claims description 312
• 150000001875 compounds Chemical class 0.000 claims description 285
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 106
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 99
• 239000000203 mixture Substances 0.000 claims description 97
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 85
• 150000003839 salts Chemical class 0.000 claims description 82
• 125000001153 fluoro group Chemical group F* 0.000 claims description 76
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 76
• 238000006243 chemical reaction Methods 0.000 claims description 75
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 73
• 229910052739 hydrogen Inorganic materials 0.000 claims description 64
• 229910052736 halogen Inorganic materials 0.000 claims description 61
• 150000002367 halogens Chemical class 0.000 claims description 61
• 238000000034 method Methods 0.000 claims description 59
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 49
• PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 46
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 45
• 239000012453 solvate Substances 0.000 claims description 44
• 239000002585 base Substances 0.000 claims description 43
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 41
• 201000006417 multiple sclerosis Diseases 0.000 claims description 40
• 125000004429 atom Chemical group 0.000 claims description 38
• 201000010099 disease Diseases 0.000 claims description 38
• 239000003153 chemical reaction reagent Substances 0.000 claims description 36
• 239000002904 solvent Substances 0.000 claims description 36
• 206010028980 Neoplasm Diseases 0.000 claims description 35
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
• 101001001642 Xenopus laevis Serine/threonine-protein kinase pim-3 Proteins 0.000 claims description 34
• 229910052731 fluorine Inorganic materials 0.000 claims description 32
• 208000023275 Autoimmune disease Diseases 0.000 claims description 31
• 125000004432 carbon atom Chemical group C* 0.000 claims description 27
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
• 101100297651 Mus musculus Pim2 gene Proteins 0.000 claims description 25
• 201000011510 cancer Diseases 0.000 claims description 25
• 101100297652 Coturnix japonica PIM3 gene Proteins 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 23
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
• 125000000623 heterocyclic group Chemical group 0.000 claims description 21
• 241000124008 Mammalia Species 0.000 claims description 19
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
• 208000027866 inflammatory disease Diseases 0.000 claims description 18
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 17
• 229910052799 carbon Inorganic materials 0.000 claims description 17
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
• 230000008878 coupling Effects 0.000 claims description 15
• 238000010168 coupling process Methods 0.000 claims description 15
• 238000005859 coupling reaction Methods 0.000 claims description 15
• 206010025135 lupus erythematosus Diseases 0.000 claims description 14
• 125000004414 alkyl thio group Chemical group 0.000 claims description 13
• 239000003054 catalyst Substances 0.000 claims description 13
• 230000001404 mediated effect Effects 0.000 claims description 13
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
• 125000006239 protecting group Chemical group 0.000 claims description 12
• 239000003638 chemical reducing agent Substances 0.000 claims description 11
• 208000035475 disorder Diseases 0.000 claims description 11
• 125000005647 linker group Chemical group 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
• 125000006242 amine protecting group Chemical group 0.000 claims description 9
• 108091000080 Phosphotransferase Proteins 0.000 claims description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
• 102000020233 phosphotransferase Human genes 0.000 claims description 8
• 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
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 229910052763 palladium Inorganic materials 0.000 claims description 7
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
• PBVFROWIWWGIFK-UHFFFAOYSA-N fluoromethyl-(2-hydroxyethyl)-dimethylazanium Chemical compound FC[N+](C)(C)CCO PBVFROWIWWGIFK-UHFFFAOYSA-N 0.000 claims description 6
• 229910052740 iodine Inorganic materials 0.000 claims description 6
• 125000003566 oxetanyl group Chemical group 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
• 125000002252 acyl group Chemical group 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 239000011630 iodine Substances 0.000 claims description 5
• 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims description 4
• 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 4
• 239000002841 Lewis acid Substances 0.000 claims description 4
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
• 150000007517 lewis acids Chemical class 0.000 claims description 4
• 239000003446 ligand Substances 0.000 claims description 4
• 229910052751 metal Inorganic materials 0.000 claims description 4
• 239000002184 metal Substances 0.000 claims description 4
• 150000008065 acid anhydrides Chemical class 0.000 claims description 3
• 125000003158 alcohol group Chemical group 0.000 claims description 2
• 125000003277 amino group Chemical group 0.000 claims description 2
• KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 2
• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 281
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 201
• 238000002360 preparation method Methods 0.000 description 185
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 144
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 125
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
• 239000007787 solid Substances 0.000 description 114
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 107
• 235000019439 ethyl acetate Nutrition 0.000 description 93
• 239000000243 solution Substances 0.000 description 92
• KFTZCNLLRKFMQH-UHFFFAOYSA-N pyrrolidin-3-ylcarbamic acid Chemical compound OC(=O)NC1CCNC1 KFTZCNLLRKFMQH-UHFFFAOYSA-N 0.000 description 62
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
• 239000012267 brine Substances 0.000 description 51
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 51
• 239000012044 organic layer Substances 0.000 description 49
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
• 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 40
• 239000011541 reaction mixture Substances 0.000 description 40
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 39
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
• 238000010992 reflux Methods 0.000 description 39
• 229910052938 sodium sulfate Inorganic materials 0.000 description 39
• 235000011152 sodium sulphate Nutrition 0.000 description 39
• LLPIYFGPNMWSOG-BWDMCYIDSA-N tert-butyl n-[(3s)-1-[1-[3-(7-cyclopropylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)CCN1C(C(F)(F)F)C1=CN2C(C=3N=C4C=C(C=CC4=CC=3)C3CC3)=NN=C2C=C1 LLPIYFGPNMWSOG-BWDMCYIDSA-N 0.000 description 39
• 238000001816 cooling Methods 0.000 description 38
• 210000004027 cell Anatomy 0.000 description 37
• 238000003818 flash chromatography Methods 0.000 description 36
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 36
• 239000000741 silica gel Substances 0.000 description 34
• 229910002027 silica gel Inorganic materials 0.000 description 34
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
• FIXCILPMNWOOPP-HXBUSHRASA-N tert-butyl n-[(3s)-1-[1-[3-(7-bromoquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)CCN1C(C(F)(F)F)C1=CN2C(C=3N=C4C=C(Br)C=CC4=CC=3)=NN=C2C=C1 FIXCILPMNWOOPP-HXBUSHRASA-N 0.000 description 28
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
• 210000001744 T-lymphocyte Anatomy 0.000 description 26
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
• 238000001914 filtration Methods 0.000 description 25
• 239000003921 oil Substances 0.000 description 25
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
• 238000003556 assay Methods 0.000 description 24
• 239000010410 layer Substances 0.000 description 24
• SOGQXABASMLRNX-WCQYABFASA-N tert-butyl n-[(3s)-1-[(1r)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl]pyrrolidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)CCN1[C@@H](C(F)(F)F)C1=CC=C(NN)N=C1 SOGQXABASMLRNX-WCQYABFASA-N 0.000 description 23
• ZPVSAUSAHRIAQM-UHFFFAOYSA-N 8-ethyl-2-methylquinoline Chemical compound C1=C(C)N=C2C(CC)=CC=CC2=C1 ZPVSAUSAHRIAQM-UHFFFAOYSA-N 0.000 description 22
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 21
• 239000000706 filtrate Substances 0.000 description 21
• 239000001257 hydrogen Substances 0.000 description 20
• JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 20
• 241000699670 Mus sp. Species 0.000 description 19
• WIEJVMZWPIUWHO-QMMMGPOBSA-N tert-butyl n-[[(3s)-pyrrolidin-3-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NC[C@H]1CCNC1 WIEJVMZWPIUWHO-QMMMGPOBSA-N 0.000 description 19
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 17
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 17
• MLPVBIWIRCKMJV-UHFFFAOYSA-N 2-ethylaniline Chemical compound CCC1=CC=CC=C1N MLPVBIWIRCKMJV-UHFFFAOYSA-N 0.000 description 16
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
• NJPNCMOUEXEGBL-UHFFFAOYSA-N pyrrolidin-1-ium-3-ylazanium;dichloride Chemical compound Cl.Cl.NC1CCNC1 NJPNCMOUEXEGBL-UHFFFAOYSA-N 0.000 description 16
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 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
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
• 229910052801 chlorine Inorganic materials 0.000 description 13
• 239000003112 inhibitor Substances 0.000 description 13
• DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 13
• KUPHUIFUXRACHJ-UHFFFAOYSA-N 8-propan-2-yloxyquinoline-2-carbaldehyde Chemical compound C1=C(C=O)N=C2C(OC(C)C)=CC=CC2=C1 KUPHUIFUXRACHJ-UHFFFAOYSA-N 0.000 description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
• 150000001299 aldehydes Chemical class 0.000 description 12
• 238000004440 column chromatography Methods 0.000 description 12
• 208000037765 diseases and disorders Diseases 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 12
• 239000000047 product Substances 0.000 description 12
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 12
• 238000002965 ELISA Methods 0.000 description 11
• 210000003719 b-lymphocyte Anatomy 0.000 description 11
• FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 11
• 238000000926 separation method Methods 0.000 description 11
• 239000000725 suspension Substances 0.000 description 11
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 10
• JSTPXQLNMGIGGW-UHFFFAOYSA-N 8-(cyclopropylmethoxy)quinoline-2-carbaldehyde Chemical compound C12=NC(C=O)=CC=C2C=CC=C1OCC1CC1 JSTPXQLNMGIGGW-UHFFFAOYSA-N 0.000 description 10
• 230000000694 effects Effects 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• 229910002091 carbon monoxide Inorganic materials 0.000 description 9
• 201000002491 encephalomyelitis Diseases 0.000 description 9
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 9
• SOGQXABASMLRNX-AMGKYWFPSA-N tert-butyl n-[(3s)-1-[2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl]pyrrolidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)CCN1C(C(F)(F)F)C1=CC=C(NN)N=C1 SOGQXABASMLRNX-AMGKYWFPSA-N 0.000 description 9
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
• 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 8
• 229910052794 bromium Inorganic materials 0.000 description 8
• 210000002865 immune cell Anatomy 0.000 description 8
• 229910052760 oxygen Inorganic materials 0.000 description 8
• DIQWSFWWYVRXRO-JTQLQIEISA-N tert-butyl n-[(3s)-3-methylpyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@]1(C)CCNC1 DIQWSFWWYVRXRO-JTQLQIEISA-N 0.000 description 8
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 7
• BDLLDGUBELPPAD-UHFFFAOYSA-N 8-cyclopropylquinoline-2-carbaldehyde Chemical compound C12=NC(C=O)=CC=C2C=CC=C1C1CC1 BDLLDGUBELPPAD-UHFFFAOYSA-N 0.000 description 7
• 230000002159 abnormal effect Effects 0.000 description 7
• 239000008346 aqueous phase Substances 0.000 description 7
• APIRFPUAFXNWNX-UHFFFAOYSA-N benzyl 3-methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrolidine-1-carboxylate Chemical compound C1C(NC(=O)OC(C)(C)C)(C)CCN1C(=O)OCC1=CC=CC=C1 APIRFPUAFXNWNX-UHFFFAOYSA-N 0.000 description 7
• 238000004296 chiral HPLC Methods 0.000 description 7
• 230000016396 cytokine production Effects 0.000 description 7
• 238000010790 dilution Methods 0.000 description 7
• 239000012895 dilution Substances 0.000 description 7
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
• 238000003756 stirring Methods 0.000 description 7
• 150000003512 tertiary amines Chemical class 0.000 description 7
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
• SDNPYGIJRJTTRV-UHFFFAOYSA-N 6-fluoro-7-methoxy-2-methylquinoline Chemical compound CC1=CC=C2C=C(F)C(OC)=CC2=N1 SDNPYGIJRJTTRV-UHFFFAOYSA-N 0.000 description 6
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
• 201000004681 Psoriasis Diseases 0.000 description 6
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• ZMVPQYODGWGINJ-UHFFFAOYSA-N (2-methylquinolin-8-yl) cyclopropanecarboxylate Chemical compound C1(CC1)C(=O)OC=1C=CC=C2C=CC(=NC=12)C ZMVPQYODGWGINJ-UHFFFAOYSA-N 0.000 description 1
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• PJGARSCJQJYTIN-CKQAZREJSA-N (3S)-1-[1-[3-[8-[(2R)-1-methoxypropan-2-yl]oxyquinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine trihydrochloride Chemical compound Cl.Cl.Cl.N1=C2C(O[C@H](C)COC)=CC=CC2=CC=C1C(N1C=2)=NN=C1C=CC=2C(C)N1CC[C@H](N)C1 PJGARSCJQJYTIN-CKQAZREJSA-N 0.000 description 1
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• PWHSBZOADLZSJA-NBLKBULHSA-N (3S)-1-[2,2,2-trifluoro-1-[3-[7-(1-methylpyrazol-4-yl)quinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine trihydrochloride Chemical compound Cl.Cl.Cl.C1=NN(C)C=C1C1=CC=C(C=CC(=N2)C=3N4C=C(C=CC4=NN=3)C(N3C[C@@H](N)CC3)C(F)(F)F)C2=C1 PWHSBZOADLZSJA-NBLKBULHSA-N 0.000 description 1
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• WGOTYEXMECPWDT-WZONZLPQSA-N (3r)-1-[(1r)-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)CCN1[C@@H](C(F)(F)F)C1=CN2C(C=3N=C4C(OCC5CC5)=CC=CC4=CC=3)=NN=C2C=C1 WGOTYEXMECPWDT-WZONZLPQSA-N 0.000 description 1
• WGOTYEXMECPWDT-JPYJTQIMSA-N (3r)-1-[(1s)-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)CCN1[C@H](C(F)(F)F)C1=CN2C(C=3N=C4C(OCC5CC5)=CC=CC4=CC=3)=NN=C2C=C1 WGOTYEXMECPWDT-JPYJTQIMSA-N 0.000 description 1
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• TWFZSUDMJSCESP-PRMRSNQMSA-N (3r)-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-amine;dihydrochloride Chemical compound Cl.Cl.N1([C@@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)OC(C)C)C(F)(F)F)CC[C@@](C)(N)C1 TWFZSUDMJSCESP-PRMRSNQMSA-N 0.000 description 1
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• ARMRSXRDMFQIRO-GOMYIDBISA-N (3r,4r)-4-amino-1-[(1r)-1-[3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-ol;dihydrochloride Chemical compound Cl.Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)C(C)(C)C)C(F)(F)F)C[C@@H](N)[C@H](O)C1 ARMRSXRDMFQIRO-GOMYIDBISA-N 0.000 description 1
• LKSLHKFZIFAQDY-NLKWXFQQSA-N (3s)-1-[(1r)-1-[3-(7-cyclopropyl-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC(=C(C3=N2)OC)C2CC2)C(F)(F)F)CC[C@H](N)C1 LKSLHKFZIFAQDY-NLKWXFQQSA-N 0.000 description 1
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• KEEDCLNGUXMZSY-QWABXWKJSA-N (3s)-1-[(1r)-1-[3-(7-ethoxy-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine;hydrochloride Chemical compound Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C=2N=C3C=C(C(=CC3=CC=2)F)OCC)C(F)(F)F)CC[C@H](N)C1 KEEDCLNGUXMZSY-QWABXWKJSA-N 0.000 description 1
• PXQGEVOWHFTWTC-JEKHSYBRSA-N (3s)-1-[(1r)-1-[3-(8-cyclopropyl-7-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1[C@@H](N)CCN1[C@@H](C(F)(F)F)C1=CN2C(C=3N=C4C(C5CC5)=C(F)C=CC4=CC=3)=NN=C2C=C1 PXQGEVOWHFTWTC-JEKHSYBRSA-N 0.000 description 1
• QNUOIPWMUNIDEF-SYTOWBIOSA-N (3s)-1-[(1r)-1-[3-(8-cyclopropylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]-3-methylpyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1[C@@](C)(N)CCN1[C@@H](C(F)(F)F)C1=CN2C(C=3N=C4C(C5CC5)=CC=CC4=CC=3)=NN=C2C=C1 QNUOIPWMUNIDEF-SYTOWBIOSA-N 0.000 description 1
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• UFUWTTWDJCBGIS-UBECOWFTSA-N (3s)-1-[(1r)-1-[3-[8-(cyclopropylmethoxy)quinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]-n-methylpyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1[C@@H](NC)CCN1[C@@H](C(F)(F)F)C1=CN2C(C=3N=C4C(OCC5CC5)=CC=CC4=CC=3)=NN=C2C=C1 UFUWTTWDJCBGIS-UBECOWFTSA-N 0.000 description 1
• OLNLEECDEBSKPL-LOQMHBAWSA-N (3s)-1-[(1r)-1-[3-[8-(cyclopropylmethoxy)quinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1[C@@H](N)CCN1[C@@H](C(F)(F)F)C1=CN2C(C=3N=C4C(OCC5CC5)=CC=CC4=CC=3)=NN=C2C=C1 OLNLEECDEBSKPL-LOQMHBAWSA-N 0.000 description 1
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• WPMRAXFRWKOOEY-JXVZSMLKSA-N (3s)-1-[(1r)-2,2,2-trifluoro-1-[3-(6-fluoro-7-propan-2-yloxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;hydrochloride Chemical compound Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C=2N=C3C=C(C(=CC3=CC=2)F)OC(C)C)C(F)(F)F)CC[C@H](N)C1 WPMRAXFRWKOOEY-JXVZSMLKSA-N 0.000 description 1
• KMNWDEFAKUMNER-ICCPGPOKSA-N (3s)-1-[(1r)-2,2,2-trifluoro-1-[3-(6-fluoro-8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;hydrochloride Chemical compound Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=C(F)C=C(C3=N2)OC)C(F)(F)F)CC[C@H](N)C1 KMNWDEFAKUMNER-ICCPGPOKSA-N 0.000 description 1
• DVEHXWJVIVREAX-OTCZLQCGSA-N (3s)-1-[(1r)-2,2,2-trifluoro-1-[3-(6-fluoro-8-propan-2-yloxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;hydrochloride Chemical compound Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=C(F)C=C(C3=N2)OC(C)C)C(F)(F)F)CC[C@H](N)C1 DVEHXWJVIVREAX-OTCZLQCGSA-N 0.000 description 1
• JWOXYSOEZPWHDX-NFJCIPKMSA-N (3s)-1-[(1r)-2,2,2-trifluoro-1-[3-(6-methyl-8-propan-2-yloxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;hydrochloride Chemical compound Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=C(C)C=C(C3=N2)OC(C)C)C(F)(F)F)CC[C@H](N)C1 JWOXYSOEZPWHDX-NFJCIPKMSA-N 0.000 description 1
• FJWISOKSOGCQAI-JXVZSMLKSA-N (3s)-1-[(1r)-2,2,2-trifluoro-1-[3-(7-fluoro-8-propan-2-yloxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;hydrochloride Chemical compound Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC(F)=C(C3=N2)OC(C)C)C(F)(F)F)CC[C@H](N)C1 FJWISOKSOGCQAI-JXVZSMLKSA-N 0.000 description 1
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• WMOLZLPYGGGXDK-SWSMCDPZSA-N (3s)-1-[(1r)-2,2,2-trifluoro-1-[3-(7-methoxy-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;hydrochloride Chemical compound Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C=2C=CC3=CC=C(C(=C3N=2)C)OC)C(F)(F)F)CC[C@H](N)C1 WMOLZLPYGGGXDK-SWSMCDPZSA-N 0.000 description 1
• JJSCGBPRTZQEJE-HVDCVHHPSA-N (3s)-1-[(1r)-2,2,2-trifluoro-1-[3-(7-propan-2-yloxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C=2C=CC3=CC=C(C=C3N=2)OC(C)C)C(F)(F)F)CC[C@H](N)C1 JJSCGBPRTZQEJE-HVDCVHHPSA-N 0.000 description 1
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• UWWIJQMBAXJUQK-AVRDEDQJSA-N (3s)-1-[(1s)-1-[3-(7-cyclopropylquinolin-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)CCN1[C@H](C(F)(F)F)C1=CN2C(C=3N=C4C=C(C=CC4=CC=3)C3CC3)=NN=C2C=C1 UWWIJQMBAXJUQK-AVRDEDQJSA-N 0.000 description 1
• OLNLEECDEBSKPL-IOGPUEAOSA-N (3s)-1-[(1s)-1-[3-[8-(cyclopropylmethoxy)quinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]pyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1[C@@H](N)CCN1[C@H](C(F)(F)F)C1=CN2C(C=3N=C4C(OCC5CC5)=CC=CC4=CC=3)=NN=C2C=C1 OLNLEECDEBSKPL-IOGPUEAOSA-N 0.000 description 1
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• NFIDFKPAROZDNZ-XPYPCIIASA-N (3s)-1-[(1s)-2,2,2-trifluoro-1-[3-(8-methoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]ethyl]pyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.N1([C@@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)OC)C(F)(F)F)CC[C@H](N)C1 NFIDFKPAROZDNZ-XPYPCIIASA-N 0.000 description 1
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• FQQGYYUVDXLAAB-VJAPEELYSA-N (3s)-1-[1-[3-[8-(cyclopropylmethoxy)quinolin-2-yl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-2,2,2-trifluoroethyl]-n-propan-2-ylpyrrolidin-3-amine;dihydrochloride Chemical compound Cl.Cl.C1[C@@H](NC(C)C)CCN1C(C(F)(F)F)C1=CN2C(C=3N=C4C(OCC5CC5)=CC=CC4=CC=3)=NN=C2C=C1 FQQGYYUVDXLAAB-VJAPEELYSA-N 0.000 description 1
• WGOTYEXMECPWDT-XNUZUHMRSA-N (3s)-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-XNUZUHMRSA-N 0.000 description 1
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• TWFZSUDMJSCESP-SYTOWBIOSA-N (3s)-3-methyl-1-[(1r)-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-amine;dihydrochloride Chemical compound Cl.Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)OC(C)C)C(F)(F)F)CC[C@](C)(N)C1 TWFZSUDMJSCESP-SYTOWBIOSA-N 0.000 description 1
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• XHFSGAMVELLKDK-UBECOWFTSA-N (3s)-n-(2-fluoroethyl)-1-[(1r)-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-amine;dihydrochloride Chemical compound Cl.Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)OC(C)C)C(F)(F)F)CC[C@H](NCCF)C1 XHFSGAMVELLKDK-UBECOWFTSA-N 0.000 description 1
• IEUCMHOAPCWMHF-LOQMHBAWSA-N (3s)-n-methyl-1-[(1r)-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-amine;dihydrochloride Chemical compound Cl.Cl.C1[C@@H](NC)CCN1[C@@H](C(F)(F)F)C1=CN2C(C=3N=C4C(OC(C)C)=CC=CC4=CC=3)=NN=C2C=C1 IEUCMHOAPCWMHF-LOQMHBAWSA-N 0.000 description 1
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• KLVJEGGMJOKBLS-YCRPNKLZSA-N 2-[2-[6-[(1r)-1-[(3s)-3-aminopyrrolidin-1-yl]-2,2,2-trifluoroethyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl]-6-fluoroquinolin-7-yl]oxyethanol Chemical compound C1[C@@H](N)CCN1[C@@H](C(F)(F)F)C1=CN2C(C=3N=C4C=C(OCCO)C(F)=CC4=CC=3)=NN=C2C=C1 KLVJEGGMJOKBLS-YCRPNKLZSA-N 0.000 description 1
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• WSNCLHVLCYTXAB-HVDCVHHPSA-N 2-[2-[6-[(1r)-1-[(3s)-3-aminopyrrolidin-1-yl]-2,2,2-trifluoroethyl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl]quinolin-8-yl]-2-methylpropanenitrile;dihydrochloride Chemical compound Cl.Cl.N1([C@H](C=2C=CC3=NN=C(N3C=2)C2=CC=C3C=CC=C(C3=N2)C(C)(C#N)C)C(F)(F)F)CC[C@H](N)C1 WSNCLHVLCYTXAB-HVDCVHHPSA-N 0.000 description 1
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