RU2630694C2 - Азотсодержащее спироциклическое соединение и его применение в медицине - Google Patents

Info

Publication number

RU2630694C2

RU2630694C2 RU2012106344A RU2012106344A RU2630694C2 RU 2630694 C2 RU2630694 C2 RU 2630694C2 RU 2012106344 A RU2012106344 A RU 2012106344A RU 2012106344 A RU2012106344 A RU 2012106344A RU 2630694 C2 RU2630694 C2 RU 2630694C2

Authority

RU

Russia

Prior art keywords

pharmaceutically acceptable

acceptable salt

compound according

compound

mixture

Prior art date

2009-07-31

Links

• Espacenet
• Global Dossier
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims abstract description 392
• 239000003814 drug Substances 0.000 title claims abstract description 17
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title description 5
• 239000000126 substance Substances 0.000 claims abstract description 152
• 229920006395 saturated elastomer Polymers 0.000 claims abstract description 88
• 238000011282 treatment Methods 0.000 claims abstract description 27
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
• 230000002265 prevention Effects 0.000 claims abstract description 18
• 206010052779 Transplant rejections Diseases 0.000 claims abstract description 16
• 238000002054 transplantation Methods 0.000 claims abstract description 16
• 208000026935 allergic disease Diseases 0.000 claims abstract description 15
• 201000010099 disease Diseases 0.000 claims abstract description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
• 125000005843 halogen group Chemical group 0.000 claims abstract description 15
• 210000000056 organ Anatomy 0.000 claims abstract description 15
• 125000001424 substituent group Chemical group 0.000 claims abstract description 15
• 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 14
• 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims abstract description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 14
• 201000004681 Psoriasis Diseases 0.000 claims abstract description 13
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract description 6
• 206010012438 Dermatitis atopic Diseases 0.000 claims abstract description 6
• 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 6
• 206010013774 Dry eye Diseases 0.000 claims abstract description 6
• 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 6
• 230000000694 effects Effects 0.000 claims abstract description 6
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims abstract description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 4
• 125000004429 atom Chemical group 0.000 claims abstract description 4
• 150000003839 salts Chemical class 0.000 claims description 129
• 238000000034 method Methods 0.000 claims description 45
• 125000000217 alkyl group Chemical group 0.000 claims description 27
• 239000003795 chemical substances by application Substances 0.000 claims description 26
• 238000004519 manufacturing process Methods 0.000 claims description 26
• 230000002401 inhibitory effect Effects 0.000 claims description 24
• 239000008194 pharmaceutical composition Substances 0.000 claims description 19
• 102000015617 Janus Kinases Human genes 0.000 claims description 18
• 108010024121 Janus Kinases Proteins 0.000 claims description 18
• 108091000080 Phosphotransferase Proteins 0.000 claims description 16
• 102000020233 phosphotransferase Human genes 0.000 claims description 16
• 208000024908 graft versus host disease Diseases 0.000 claims description 13
• 230000000069 prophylactic effect Effects 0.000 claims description 13
• 230000001225 therapeutic effect Effects 0.000 claims description 12
• 241000124008 Mammalia Species 0.000 claims description 11
• 229940122245 Janus kinase inhibitor Drugs 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 108010019437 Janus Kinase 2 Proteins 0.000 claims description 7
• 229910052731 fluorine Chemical group 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 5
• 108010019421 Janus Kinase 3 Proteins 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
• 230000001363 autoimmune Effects 0.000 claims description 5
• 238000011321 prophylaxis Methods 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 4
• 239000003112 inhibitor Substances 0.000 claims description 4
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
• 208000009329 Graft vs Host Disease Diseases 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 239000001257 hydrogen Substances 0.000 claims description 2
• 229910052739 hydrogen Inorganic materials 0.000 claims description 2
• 102000006503 Janus Kinase 2 Human genes 0.000 claims 3
• 102000006500 Janus Kinase 3 Human genes 0.000 claims 2
• 102000008986 Janus Human genes 0.000 claims 1
• 108050000950 Janus Proteins 0.000 claims 1
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract description 3
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 375
• 239000000203 mixture Substances 0.000 description 286
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 208
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 192
• 238000005160 1H NMR spectroscopy Methods 0.000 description 184
• -1 nitrogen-containing alcohol cyclic compounds Chemical class 0.000 description 140
• 239000000243 solution Substances 0.000 description 139
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 122
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 120
• 230000002829 reductive effect Effects 0.000 description 120
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 104
• 239000002904 solvent Substances 0.000 description 95
• 239000012044 organic layer Substances 0.000 description 90
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 73
• 238000006243 chemical reaction Methods 0.000 description 72
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
• 239000007864 aqueous solution Substances 0.000 description 64
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
• 239000011780 sodium chloride Substances 0.000 description 61
• 239000011541 reaction mixture Substances 0.000 description 58
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
• 239000003480 eluent Substances 0.000 description 53
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 52
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
• 238000010898 silica gel chromatography Methods 0.000 description 51
• 239000012453 solvate Substances 0.000 description 48
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 42
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• 239000010410 layer Substances 0.000 description 36
• 230000014759 maintenance of location Effects 0.000 description 35
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
• 239000007787 solid Substances 0.000 description 34
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
• 239000000706 filtrate Substances 0.000 description 30
• 239000002585 base Substances 0.000 description 29
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
• 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 24
• 230000035484 reaction time Effects 0.000 description 24
• 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 23
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
• 235000017557 sodium bicarbonate Nutrition 0.000 description 23
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
• JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 22
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
• 229910000343 potassium bisulfate Inorganic materials 0.000 description 22
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 21
• 125000006239 protecting group Chemical group 0.000 description 21
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
• 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 19
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
• 230000014509 gene expression Effects 0.000 description 18
• 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 17
• 238000010511 deprotection reaction Methods 0.000 description 17
• JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 17
• 229940011051 isopropyl acetate Drugs 0.000 description 17
• GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 17
• 239000000725 suspension Substances 0.000 description 17
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
• 239000013543 active substance Substances 0.000 description 16
• 150000001412 amines Chemical class 0.000 description 16
• 230000005764 inhibitory process Effects 0.000 description 16
• 229910000027 potassium carbonate Inorganic materials 0.000 description 16
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 15
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
• 239000003153 chemical reaction reagent Substances 0.000 description 15
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
• 239000000872 buffer Substances 0.000 description 13
• 229910052799 carbon Inorganic materials 0.000 description 13
• CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 12
• 239000012046 mixed solvent Substances 0.000 description 12
• 238000002360 preparation method Methods 0.000 description 12
• 238000012360 testing method Methods 0.000 description 12
• ZSAYVPCIKVBDRI-UHFFFAOYSA-N benzyl decanoate Chemical compound CCCCCCCCCC(=O)OCC1=CC=CC=C1 ZSAYVPCIKVBDRI-UHFFFAOYSA-N 0.000 description 11
• 239000013078 crystal Substances 0.000 description 11
• WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
• HWYNYLXTVJYPOW-UHFFFAOYSA-N piperidine-1,3-dicarboxylic acid Chemical compound OC(=O)C1CCCN(C(O)=O)C1 HWYNYLXTVJYPOW-UHFFFAOYSA-N 0.000 description 11
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
• KPQPHSJNRLPASK-UHFFFAOYSA-N 3-but-3-en-2-yl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound C=CC(C)C1(C(O)=O)CCCN(C(=O)OC(C)(C)C)C1 KPQPHSJNRLPASK-UHFFFAOYSA-N 0.000 description 10
• 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 10
• 238000007254 oxidation reaction Methods 0.000 description 10
• IJXJGQCXFSSHNL-MRVPVSSYSA-N (2s)-2-amino-2-phenylethanol Chemical compound OC[C@@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-MRVPVSSYSA-N 0.000 description 9
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• 238000004128 high performance liquid chromatography Methods 0.000 description 9
• 238000010992 reflux Methods 0.000 description 9
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
• 102000042838 JAK family Human genes 0.000 description 8
• 108091082332 JAK family Proteins 0.000 description 8
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 8
• 238000007363 ring formation reaction Methods 0.000 description 8
• 238000003786 synthesis reaction Methods 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
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 8
• STVVMTBJNDTZBF-SECBINFHSA-N (2r)-2-amino-3-phenylpropan-1-ol Chemical compound OC[C@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-SECBINFHSA-N 0.000 description 7
• DDWZYWSLHBDVGR-UHFFFAOYSA-N 3-(3,5-dimethylpyrazol-1-yl)-3-oxopropanenitrile Chemical compound CC=1C=C(C)N(C(=O)CC#N)N=1 DDWZYWSLHBDVGR-UHFFFAOYSA-N 0.000 description 7
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
• 150000001408 amides Chemical class 0.000 description 7
• 235000019270 ammonium chloride Nutrition 0.000 description 7
• 235000019445 benzyl alcohol Nutrition 0.000 description 7
• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 7
• 150000008282 halocarbons Chemical class 0.000 description 7
• 150000002430 hydrocarbons Chemical group 0.000 description 7
• 230000003647 oxidation Effects 0.000 description 7
• 239000000047 product Substances 0.000 description 7
• 230000008707 rearrangement Effects 0.000 description 7
• 238000006722 reduction reaction Methods 0.000 description 7
• NGUVGNXCCFAHHI-UHFFFAOYSA-N 3-(1,1-difluoroprop-2-enyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC(C(F)(F)C=C)(C(O)=O)C1 NGUVGNXCCFAHHI-UHFFFAOYSA-N 0.000 description 6
• BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 description 6
• 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
• 229940123241 Janus kinase 3 inhibitor Drugs 0.000 description 6
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• 239000002253 acid Substances 0.000 description 6
• 239000004480 active ingredient Substances 0.000 description 6
• 125000003277 amino group Chemical group 0.000 description 6
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
• 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
• 229950008138 carmellose Drugs 0.000 description 6
• 235000015165 citric acid Nutrition 0.000 description 6
• 238000005658 halogenation reaction Methods 0.000 description 6
• 239000000741 silica gel Substances 0.000 description 6
• 229910002027 silica gel Inorganic materials 0.000 description 6
• 239000012279 sodium borohydride Substances 0.000 description 6
• 229910000033 sodium borohydride Inorganic materials 0.000 description 6
• OEQJOYQHIGIVTN-UHFFFAOYSA-N tert-butyl nonanoate Chemical compound CCCCCCCCC(=O)OC(C)(C)C OEQJOYQHIGIVTN-UHFFFAOYSA-N 0.000 description 6
• IJXJGQCXFSSHNL-QMMMGPOBSA-N (R)-(-)-2-Phenylglycinol Chemical compound OC[C@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-QMMMGPOBSA-N 0.000 description 5
• LXWOTQPRJHDZSM-UHFFFAOYSA-N 3-(1,1-difluoroprop-2-enyl)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(F)(F)C=C)(C(O)=O)C1 LXWOTQPRJHDZSM-UHFFFAOYSA-N 0.000 description 5
• 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 5
• 238000005481 NMR spectroscopy Methods 0.000 description 5
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 5
• 229940125904 compound 1 Drugs 0.000 description 5
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 5
• 238000001514 detection method Methods 0.000 description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
• 125000000524 functional group Chemical group 0.000 description 5
• UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
• 150000007530 organic bases Chemical class 0.000 description 5
• NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 5
• 239000000651 prodrug Substances 0.000 description 5
• 229940002612 prodrug Drugs 0.000 description 5
• 230000009467 reduction Effects 0.000 description 5
• YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
• RTCUCQWIICFPOD-SECBINFHSA-N (1r)-1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C([C@H](N)C)=CC=CC2=C1 RTCUCQWIICFPOD-SECBINFHSA-N 0.000 description 4
• NXILIHONWRXHFA-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC(C(O)=O)C1 NXILIHONWRXHFA-UHFFFAOYSA-N 0.000 description 4
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
• MJIOLXSCSZFEQE-UHFFFAOYSA-N 2-propyloctanedioic acid Chemical compound CCCC(C(O)=O)CCCCCC(O)=O MJIOLXSCSZFEQE-UHFFFAOYSA-N 0.000 description 4
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
• 239000004215 Carbon black (E152) Substances 0.000 description 4
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
• 102000004190 Enzymes Human genes 0.000 description 4
• 108090000790 Enzymes Proteins 0.000 description 4
• 208000032027 Essential Thrombocythemia Diseases 0.000 description 4
• 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
• STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 4
• TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
• 208000008601 Polycythemia Diseases 0.000 description 4
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
• VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 4
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 4
• UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 4
• 229940098773 bovine serum albumin Drugs 0.000 description 4
• 229910052801 chlorine Inorganic materials 0.000 description 4
• 125000001309 chloro group Chemical group Cl* 0.000 description 4
• LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 4
• 229940079593 drug Drugs 0.000 description 4
• 150000002148 esters Chemical class 0.000 description 4
• 238000007429 general method Methods 0.000 description 4
• 210000003958 hematopoietic stem cell Anatomy 0.000 description 4
• 238000006197 hydroboration reaction Methods 0.000 description 4
• 229930195733 hydrocarbon Natural products 0.000 description 4
• 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
• 239000012280 lithium aluminium hydride Substances 0.000 description 4
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
• 235000019359 magnesium stearate Nutrition 0.000 description 4
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
• 206010028537 myelofibrosis Diseases 0.000 description 4
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 4
• NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
• 208000003476 primary myelofibrosis Diseases 0.000 description 4
• 108090000623 proteins and genes Proteins 0.000 description 4
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 4
• 229960001404 quinidine Drugs 0.000 description 4
• 229910000029 sodium carbonate Inorganic materials 0.000 description 4
• 235000017550 sodium carbonate Nutrition 0.000 description 4
• 239000012312 sodium hydride Substances 0.000 description 4
• 229910000104 sodium hydride Inorganic materials 0.000 description 4
• BEQGLZWFHGTCMB-UHFFFAOYSA-N tert-butyl undecanoate Chemical compound CCCCCCCCCCC(=O)OC(C)(C)C BEQGLZWFHGTCMB-UHFFFAOYSA-N 0.000 description 4
• 238000004809 thin layer chromatography Methods 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
• STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
• DIBJMIAIIUIGLC-UHFFFAOYSA-N 2-[benzyl(2-chloropropyl)amino]acetic acid Chemical compound CC(Cl)CN(CC(O)=O)Cc1ccccc1 DIBJMIAIIUIGLC-UHFFFAOYSA-N 0.000 description 3
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
• QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
• 229940121730 Janus kinase 2 inhibitor Drugs 0.000 description 3
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
• WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
• 229920002472 Starch Polymers 0.000 description 3
• DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
• 239000000654 additive Substances 0.000 description 3
• 238000007112 amidation reaction Methods 0.000 description 3
• 125000006242 amine protecting group Chemical group 0.000 description 3
• 235000001014 amino acid Nutrition 0.000 description 3
• 208000006673 asthma Diseases 0.000 description 3
• 239000003054 catalyst Substances 0.000 description 3
• 229920002678 cellulose Polymers 0.000 description 3
• 239000001913 cellulose Substances 0.000 description 3
• 235000010980 cellulose Nutrition 0.000 description 3
• 239000003638 chemical reducing agent Substances 0.000 description 3
• 229940125782 compound 2 Drugs 0.000 description 3
• 229940126214 compound 3 Drugs 0.000 description 3
• 229940125878 compound 36 Drugs 0.000 description 3
• 229940125898 compound 5 Drugs 0.000 description 3
• 238000001816 cooling Methods 0.000 description 3
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
• 230000026030 halogenation Effects 0.000 description 3
• 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
• 150000007529 inorganic bases Chemical class 0.000 description 3
• 229910052740 iodine Inorganic materials 0.000 description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
• 239000008101 lactose Substances 0.000 description 3
• 235000010355 mannitol Nutrition 0.000 description 3
• 150000007522 mineralic acids Chemical class 0.000 description 3
• 230000004048 modification Effects 0.000 description 3
• 238000012986 modification Methods 0.000 description 3
• 150000004682 monohydrates Chemical class 0.000 description 3
• 230000003287 optical effect Effects 0.000 description 3
• 150000007524 organic acids Chemical class 0.000 description 3
• FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
• 238000000746 purification Methods 0.000 description 3
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
• ADPQWEGXWVSSKZ-UHFFFAOYSA-N pyrrolidine-1,3-dicarboxylic acid Chemical compound OC(=O)C1CCN(C(O)=O)C1 ADPQWEGXWVSSKZ-UHFFFAOYSA-N 0.000 description 3
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
• 235000019345 sodium thiosulphate Nutrition 0.000 description 3
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
• 239000008107 starch Substances 0.000 description 3
• 235000019698 starch Nutrition 0.000 description 3
• PFNBEWOGFKQFNL-UHFFFAOYSA-N tert-butyl 3-amino-3-(1-hydroxypropan-2-yl)piperidine-1-carboxylate Chemical compound OCC(C)C1(N)CCCN(C(=O)OC(C)(C)C)C1 PFNBEWOGFKQFNL-UHFFFAOYSA-N 0.000 description 3
• YYYIDTGDLPDJQB-UHFFFAOYSA-N tert-butyl 3-but-3-en-2-yl-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylate Chemical compound C=1C=CC=CC=1COC(=O)NC1(C(C=C)C)CCCN(C(=O)OC(C)(C)C)C1 YYYIDTGDLPDJQB-UHFFFAOYSA-N 0.000 description 3
• RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 3
• ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
• RTCUCQWIICFPOD-VIFPVBQESA-N (1s)-1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C([C@@H](N)C)=CC=CC2=C1 RTCUCQWIICFPOD-VIFPVBQESA-N 0.000 description 2
• VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
• 125000006017 1-propenyl group Chemical group 0.000 description 2
• 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 2
• DVFUHLHQALFXCF-UHFFFAOYSA-N 2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound OCCCC1(C(O)=O)CCCN1C(O)=O DVFUHLHQALFXCF-UHFFFAOYSA-N 0.000 description 2
• XSYZALCRAJQHTQ-UHFFFAOYSA-N 2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)N1CCCC1(CCC=O)C(O)=O XSYZALCRAJQHTQ-UHFFFAOYSA-N 0.000 description 2
• PJXWCRXOPLGFLX-UHFFFAOYSA-N 2-(benzylamino)propan-1-ol Chemical compound OCC(C)NCC1=CC=CC=C1 PJXWCRXOPLGFLX-UHFFFAOYSA-N 0.000 description 2
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
• RXALDHKJANPFGN-UHFFFAOYSA-N 2-[3-(benzylamino)propyl]pyrrolidine-1,2-dicarboxylic acid Chemical compound C(C1=CC=CC=C1)NCCCC1(N(CCC1)C(=O)O)C(=O)O RXALDHKJANPFGN-UHFFFAOYSA-N 0.000 description 2
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
• WUDDSDIHJHPJRP-UHFFFAOYSA-N 2-ethyloctanedioic acid Chemical compound CCC(C(O)=O)CCCCCC(O)=O WUDDSDIHJHPJRP-UHFFFAOYSA-N 0.000 description 2
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
• DPPAXEFZICTNSJ-UHFFFAOYSA-N 3-(1-hydroxypropan-2-yl)-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC(=O)NC1(CN(CCC1)C(=O)O)C(CO)C DPPAXEFZICTNSJ-UHFFFAOYSA-N 0.000 description 2
• GWQBXRYSVSZLSL-UHFFFAOYSA-N 3-(trichloromethyl)-5,6,7,7a-tetrahydro-3h-pyrrolo[1,2-c][1,3]oxazol-1-one Chemical compound C1CCN2C(C(Cl)(Cl)Cl)OC(=O)C21 GWQBXRYSVSZLSL-UHFFFAOYSA-N 0.000 description 2
• GDDNTTHUKVNJRA-UHFFFAOYSA-N 3-bromo-3,3-difluoroprop-1-ene Chemical compound FC(F)(Br)C=C GDDNTTHUKVNJRA-UHFFFAOYSA-N 0.000 description 2
• YZAJNACTNXAHDE-UHFFFAOYSA-N 7a-prop-2-enyl-3-(trichloromethyl)-3,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazol-1-one Chemical compound C1CCN2C(C(Cl)(Cl)Cl)OC(=O)C21CC=C YZAJNACTNXAHDE-UHFFFAOYSA-N 0.000 description 2
• FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 2
• 229920000936 Agarose Polymers 0.000 description 2
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
• 241000282693 Cercopithecidae Species 0.000 description 2
• 206010009900 Colitis ulcerative Diseases 0.000 description 2
• 229920002261 Corn starch Polymers 0.000 description 2
• 208000011231 Crohn disease Diseases 0.000 description 2
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
• FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
• RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
• 239000004375 Dextrin Substances 0.000 description 2
• 229920001353 Dextrin Polymers 0.000 description 2
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
• 208000003456 Juvenile Arthritis Diseases 0.000 description 2
• 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 2
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
• 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
• 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
• 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
• 108010090804 Streptavidin Proteins 0.000 description 2
• 229930006000 Sucrose Natural products 0.000 description 2
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
• 210000001744 T-lymphocyte Anatomy 0.000 description 2
• GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
• 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 2
• 201000006704 Ulcerative Colitis Diseases 0.000 description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
• 230000000996 additive effect Effects 0.000 description 2
• 239000005456 alcohol based solvent Substances 0.000 description 2
• 150000001336 alkenes Chemical group 0.000 description 2
• BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
• 150000001413 amino acids Chemical class 0.000 description 2
• 238000004458 analytical method Methods 0.000 description 2
• 239000003963 antioxidant agent Substances 0.000 description 2
• 235000006708 antioxidants Nutrition 0.000 description 2
• 125000003118 aryl group Chemical group 0.000 description 2
• 235000010323 ascorbic acid Nutrition 0.000 description 2
• 239000011668 ascorbic acid Substances 0.000 description 2
• 229960005070 ascorbic acid Drugs 0.000 description 2
• 238000010533 azeotropic distillation Methods 0.000 description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
• FBJKBSNWVMNAMI-UHFFFAOYSA-N benzyl 3,3-difluoro-1,8-diazaspiro[3.5]nonane-1-carboxylate hydrochloride Chemical compound Cl.FC1(F)CN(C(=O)OCc2ccccc2)C11CCCNC1 FBJKBSNWVMNAMI-UHFFFAOYSA-N 0.000 description 2
• SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
• 239000011230 binding agent Substances 0.000 description 2
• 230000033228 biological regulation Effects 0.000 description 2
• 229960002685 biotin Drugs 0.000 description 2
• 235000020958 biotin Nutrition 0.000 description 2
• 239000011616 biotin Substances 0.000 description 2
• 238000009835 boiling Methods 0.000 description 2
• 239000007853 buffer solution Substances 0.000 description 2
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
• 239000002775 capsule Substances 0.000 description 2
• 239000004202 carbamide Substances 0.000 description 2
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
• 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
• 210000004027 cell Anatomy 0.000 description 2
• 230000004663 cell proliferation Effects 0.000 description 2
• OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
• 239000003086 colorant Substances 0.000 description 2
• 238000007796 conventional method Methods 0.000 description 2
• 239000008120 corn starch Substances 0.000 description 2
• 238000002425 crystallisation Methods 0.000 description 2
• 230000008025 crystallization Effects 0.000 description 2
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
• JDPQWHLMBJZURR-UHFFFAOYSA-N decan-5-one Chemical compound CCCCCC(=O)CCCC JDPQWHLMBJZURR-UHFFFAOYSA-N 0.000 description 2
• GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
• 235000019425 dextrin Nutrition 0.000 description 2
• AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 2
• 239000007884 disintegrant Substances 0.000 description 2
• NKCASRREJZGRDY-UHFFFAOYSA-N ditert-butyl 2-[2-(benzylamino)ethyl]-3-methylazetidine-1,2-dicarboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)C1(C(=O)OC(C)(C)C)CCNCC1=CC=CC=C1 NKCASRREJZGRDY-UHFFFAOYSA-N 0.000 description 2
• DBHQVROMVVEUKC-UHFFFAOYSA-N ditert-butyl 3-methylazetidine-1,2-dicarboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)C1C(=O)OC(C)(C)C DBHQVROMVVEUKC-UHFFFAOYSA-N 0.000 description 2
• 239000002552 dosage form Substances 0.000 description 2
• 238000010828 elution Methods 0.000 description 2
• 125000004185 ester group Chemical group 0.000 description 2
• HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 2
• 235000003599 food sweetener Nutrition 0.000 description 2
• 102000037865 fusion proteins Human genes 0.000 description 2
• 108020001507 fusion proteins Proteins 0.000 description 2
• 239000008187 granular material Substances 0.000 description 2
• 125000005842 heteroatom Chemical group 0.000 description 2
• GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
• 102000049921 human JAK2 Human genes 0.000 description 2
• 102000049912 human JAK3 Human genes 0.000 description 2
• 238000005984 hydrogenation reaction Methods 0.000 description 2
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
• 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
• 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 2
• 239000005453 ketone based solvent Substances 0.000 description 2
• JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
• 239000007788 liquid Substances 0.000 description 2
• 239000000314 lubricant Substances 0.000 description 2
• 206010025135 lupus erythematosus Diseases 0.000 description 2
• 229910001629 magnesium chloride Inorganic materials 0.000 description 2
• 238000005259 measurement Methods 0.000 description 2
• 230000001404 mediated effect Effects 0.000 description 2
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
• 239000008108 microcrystalline cellulose Substances 0.000 description 2
• 229940016286 microcrystalline cellulose Drugs 0.000 description 2
• 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
• 239000002480 mineral oil Substances 0.000 description 2
• 235000010446 mineral oil Nutrition 0.000 description 2
• 238000002156 mixing Methods 0.000 description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
• 201000006417 multiple sclerosis Diseases 0.000 description 2
• 206010028417 myasthenia gravis Diseases 0.000 description 2
• YWXLSHOWXZUMSR-UHFFFAOYSA-N octan-4-one Chemical compound CCCCC(=O)CCC YWXLSHOWXZUMSR-UHFFFAOYSA-N 0.000 description 2
• KIMVTSGNCBGHES-UHFFFAOYSA-N octane;dihydrochloride Chemical compound Cl.Cl.CCCCCCCC KIMVTSGNCBGHES-UHFFFAOYSA-N 0.000 description 2
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
• 125000004430 oxygen atom Chemical group O* 0.000 description 2
• QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
• 239000000546 pharmaceutical excipient Substances 0.000 description 2
• WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
• 239000011698 potassium fluoride Substances 0.000 description 2
• 235000003270 potassium fluoride Nutrition 0.000 description 2
• 229940069328 povidone Drugs 0.000 description 2
• 239000002243 precursor Substances 0.000 description 2
• 239000003755 preservative agent Substances 0.000 description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
• 230000008569 process Effects 0.000 description 2
• 238000012545 processing Methods 0.000 description 2
• 102000004169 proteins and genes Human genes 0.000 description 2
• 102000005962 receptors Human genes 0.000 description 2
• 108020003175 receptors Proteins 0.000 description 2
• 238000011084 recovery Methods 0.000 description 2
• 238000001953 recrystallisation Methods 0.000 description 2
• 206010039083 rhinitis Diseases 0.000 description 2
• 230000019491 signal transduction Effects 0.000 description 2
• 239000002002 slurry Substances 0.000 description 2
• 239000011734 sodium Substances 0.000 description 2
• 229910052708 sodium Inorganic materials 0.000 description 2
• 239000001509 sodium citrate Substances 0.000 description 2
• NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
• CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 2
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
• 238000003797 solvolysis reaction Methods 0.000 description 2
• 229960002920 sorbitol Drugs 0.000 description 2
• 238000010561 standard procedure Methods 0.000 description 2
• 239000000758 substrate Substances 0.000 description 2
• 239000005720 sucrose Substances 0.000 description 2
• 229910052717 sulfur Inorganic materials 0.000 description 2
• 125000004434 sulfur atom Chemical group 0.000 description 2
• 230000001629 suppression Effects 0.000 description 2
• 239000000375 suspending agent Substances 0.000 description 2
• 239000003765 sweetening agent Substances 0.000 description 2
• 230000009885 systemic effect Effects 0.000 description 2
• ROVTUJRZGCDHDL-UHFFFAOYSA-N tert-butyl 2-ethylheptanoate Chemical compound CCCCCC(CC)C(=O)OC(C)(C)C ROVTUJRZGCDHDL-UHFFFAOYSA-N 0.000 description 2
• UGIJIQIALDVXGI-UHFFFAOYSA-N tert-butyl 3-(1,1-difluoro-2-hydroxyethyl)-3-(phenylmethoxycarbonylamino)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1(C(F)(F)CO)NC(=O)OCC1=CC=CC=C1 UGIJIQIALDVXGI-UHFFFAOYSA-N 0.000 description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
• UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
• ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
• 229920002554 vinyl polymer Polymers 0.000 description 2
• 229910000166 zirconium phosphate Inorganic materials 0.000 description 2
• SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
• ICPWFHKNYYRBSZ-GSVOUGTGSA-N (2r)-2-methoxypropanoic acid Chemical compound CO[C@H](C)C(O)=O ICPWFHKNYYRBSZ-GSVOUGTGSA-N 0.000 description 1
• LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
• UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
• NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
• XTHUGLFFHZPVGL-XQHVRGAUSA-N (E)-but-2-en-1-ol Chemical compound C(\C=C\C)O.C(\C=C\C)O XTHUGLFFHZPVGL-XQHVRGAUSA-N 0.000 description 1
• BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 description 1
• BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
• UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
• CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 1
• FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
• ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 description 1
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
• DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 1
• HRMRQBJUFWFQLX-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-3-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)C1 HRMRQBJUFWFQLX-UHFFFAOYSA-N 0.000 description 1
• WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
• OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
• DVPHFCAEZWKFDG-UHFFFAOYSA-N 1-amino-2-phenylethanol Chemical compound NC(O)CC1=CC=CC=C1 DVPHFCAEZWKFDG-UHFFFAOYSA-N 0.000 description 1
• LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
• 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
• 125000006025 1-methyl-1-butenyl group Chemical group 0.000 description 1
• 125000006019 1-methyl-1-propenyl group Chemical group 0.000 description 1
• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
• MWAGUKZCDDRDCS-UHFFFAOYSA-N 1-nitro-4-(4-nitrophenoxy)benzene Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=C([N+]([O-])=O)C=C1 MWAGUKZCDDRDCS-UHFFFAOYSA-N 0.000 description 1
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
• OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
• 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 1
• LHTUMNQHOQYDLN-UHFFFAOYSA-N 2-[3-(benzylamino)propyl]pyrrolidine-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)NCCCC1(NCCC1)C(=O)O LHTUMNQHOQYDLN-UHFFFAOYSA-N 0.000 description 1
• HTUUBIAULRBCEZ-UHFFFAOYSA-N 2-[benzyl(1-chloropropan-2-yl)amino]acetic acid Chemical compound C(C1=CC=CC=C1)N(C(CCl)C)CC(=O)O HTUUBIAULRBCEZ-UHFFFAOYSA-N 0.000 description 1
• DPIUMKNCLRFTRA-UHFFFAOYSA-N 2-[benzyl(1-hydroxypropan-2-yl)amino]acetic acid Chemical compound C(C1=CC=CC=C1)N(C(CO)C)CC(=O)O DPIUMKNCLRFTRA-UHFFFAOYSA-N 0.000 description 1
• 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
• 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
• 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
• JSBBMMHTNIUVTC-UHFFFAOYSA-N 2-hydroxyethanone Chemical group OC[C]=O JSBBMMHTNIUVTC-UHFFFAOYSA-N 0.000 description 1
• 125000006026 2-methyl-1-butenyl group Chemical group 0.000 description 1
• 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
• HGFMUEUHURMNPE-UHFFFAOYSA-N 3,3-difluoro-1,8-diazaspiro[3.5]nonane-1,8-dicarboxylic acid Chemical compound FC1(CN(C11CN(CCC1)C(=O)O)C(=O)O)F HGFMUEUHURMNPE-UHFFFAOYSA-N 0.000 description 1
• PDKOYUKKMKOSDK-UHFFFAOYSA-N 3,3-difluoro-8-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,8-diazaspiro[3.5]nonane-1-carboxylic acid Chemical compound FC1(CN(C11CN(CCC1)C=1C2=C(N=CN=1)NC=C2)C(=O)O)F PDKOYUKKMKOSDK-UHFFFAOYSA-N 0.000 description 1
• WBEOLGLACADALX-UHFFFAOYSA-N 3-(1,1-difluoro-2-hydroxyethyl)-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC(=O)NC1(CN(CCC1)C(=O)O)C(CO)(F)F WBEOLGLACADALX-UHFFFAOYSA-N 0.000 description 1
• YQBRTZIEBMLJQJ-UHFFFAOYSA-N 3-(1,1-difluoro-2-methylsulfonyloxyethyl)-3-(phenylmethoxycarbonylamino)pyrrolidine-1-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC(=O)NC1(CN(CC1)C(=O)O)C(COS(=O)(=O)C)(F)F YQBRTZIEBMLJQJ-UHFFFAOYSA-N 0.000 description 1
• SXURUEMOPUUEFC-UHFFFAOYSA-N 3-(2-hydroxyethyl)-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC(=O)NC1(CN(CCC1)C(=O)O)CCO SXURUEMOPUUEFC-UHFFFAOYSA-N 0.000 description 1
• VUHWQBJVFDDFAF-UHFFFAOYSA-N 3-[3,3-difluoro-8-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1,8-diazaspiro[3.5]nonan-1-yl]-3-oxopropanenitrile Chemical compound FC1(F)CN(C(=O)CC#N)C11CN(C=2C=3C=CNC=3N=CN=2)CCC1 VUHWQBJVFDDFAF-UHFFFAOYSA-N 0.000 description 1
• WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 1
• SHBHYINHXNTBRP-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(2-methylsulfonylethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCCS(=O)(=O)C)C=CC=1 SHBHYINHXNTBRP-UHFFFAOYSA-N 0.000 description 1
• KQWKPEXFPAKREG-UHFFFAOYSA-N 3-amino-3-(1-hydroxypropan-2-yl)piperidine-1-carboxylic acid Chemical compound NC1(CN(CCC1)C(=O)O)C(CO)C KQWKPEXFPAKREG-UHFFFAOYSA-N 0.000 description 1
• CFVNCDVPLHXULP-UHFFFAOYSA-N 3-amino-3-(2-hydroxyethyl)piperidine-1-carboxylic acid Chemical compound NC1(CN(CCC1)C(=O)O)CCO CFVNCDVPLHXULP-UHFFFAOYSA-N 0.000 description 1
• BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
• 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
• 125000006027 3-methyl-1-butenyl group Chemical group 0.000 description 1
• HPMCGAHRSKNESN-UHFFFAOYSA-N 3-methyl-2-(2-oxoethyl)azetidine-1,2-dicarboxylic acid Chemical compound CC1C(N(C1)C(=O)O)(C(=O)O)CC=O HPMCGAHRSKNESN-UHFFFAOYSA-N 0.000 description 1
• CMBIWMXWKCJNAR-UHFFFAOYSA-N 3-methyl-2-(3-methylbut-2-enyl)azetidine-1,2-dicarboxylic acid Chemical compound CC1C(N(C1)C(=O)O)(C(=O)O)CC=C(C)C CMBIWMXWKCJNAR-UHFFFAOYSA-N 0.000 description 1
• WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
• BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
• TUPDYYUPEZPPGP-UHFFFAOYSA-N 4-(3,3-difluoro-1,8-diazaspiro[3.5]nonan-8-yl)-7h-pyrrolo[2,3-d]pyrimidine Chemical compound FC1(F)CNC11CN(C=2C=3C=CNC=3N=CN=2)CCC1 TUPDYYUPEZPPGP-UHFFFAOYSA-N 0.000 description 1
• KYWCWBXGRWWINE-UHFFFAOYSA-N 4-methoxy-N1,N3-bis(3-pyridinylmethyl)benzene-1,3-dicarboxamide Chemical compound COC1=CC=C(C(=O)NCC=2C=NC=CC=2)C=C1C(=O)NCC1=CC=CN=C1 KYWCWBXGRWWINE-UHFFFAOYSA-N 0.000 description 1
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
• 244000215068 Acacia senegal Species 0.000 description 1
• NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
• 239000004475 Arginine Substances 0.000 description 1
• 108010011485 Aspartame Proteins 0.000 description 1
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
• 239000005711 Benzoic acid Substances 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• 125000006414 CCl Chemical group ClC* 0.000 description 1
• 241000282472 Canis lupus familiaris Species 0.000 description 1
• 241000700198 Cavia Species 0.000 description 1
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
• 229940126639 Compound 33 Drugs 0.000 description 1
• 241000699800 Cricetinae Species 0.000 description 1
• 229920002785 Croscarmellose sodium Polymers 0.000 description 1
• 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
• ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
• RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
• 229930182820 D-proline Natural products 0.000 description 1
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
• XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
• 241000283086 Equidae Species 0.000 description 1
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
• PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
• RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• 230000005526 G1 to G0 transition Effects 0.000 description 1
• 108010010803 Gelatin Proteins 0.000 description 1
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
• WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
• BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
• 229920000084 Gum arabic Polymers 0.000 description 1
• 241000282412 Homo Species 0.000 description 1
• 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
• 206010062016 Immunosuppression Diseases 0.000 description 1
• 102000003812 Interleukin-15 Human genes 0.000 description 1
• 108090000172 Interleukin-15 Proteins 0.000 description 1
• 108010002350 Interleukin-2 Proteins 0.000 description 1
• 102000000588 Interleukin-2 Human genes 0.000 description 1
• 102100030703 Interleukin-22 Human genes 0.000 description 1
• 102000004388 Interleukin-4 Human genes 0.000 description 1
• 108090000978 Interleukin-4 Proteins 0.000 description 1
• 102100021592 Interleukin-7 Human genes 0.000 description 1
• 108010002586 Interleukin-7 Proteins 0.000 description 1
• 108010002335 Interleukin-9 Proteins 0.000 description 1
• 102000000585 Interleukin-9 Human genes 0.000 description 1
• 108010000837 Janus Kinase 1 Proteins 0.000 description 1
• 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 1
• 206010072206 Janus kinase 2 mutation Diseases 0.000 description 1
• VHJLVAABSRFDPM-IMJSIDKUSA-N L-1,4-dithiothreitol Chemical compound SC[C@H](O)[C@@H](O)CS VHJLVAABSRFDPM-IMJSIDKUSA-N 0.000 description 1
• ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
• CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
• WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
• 239000004472 Lysine Substances 0.000 description 1
• 241001465754 Metazoa Species 0.000 description 1
• NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
• UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
• 241000699666 Mus <mouse, genus> Species 0.000 description 1
• 241000699670 Mus sp. Species 0.000 description 1
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
• 208000033833 Myelomonocytic Chronic Leukemia Diseases 0.000 description 1
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
• LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
• 208000033755 Neutrophilic Chronic Leukemia Diseases 0.000 description 1
• GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
• 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
• 241000283973 Oryctolagus cuniculus Species 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
• OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
• 102000001253 Protein Kinase Human genes 0.000 description 1
• 241000700159 Rattus Species 0.000 description 1
• PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
• 239000004288 Sodium dehydroacetate Substances 0.000 description 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
• 241000282887 Suidae Species 0.000 description 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
• 201000008736 Systemic mastocytosis Diseases 0.000 description 1
• 108010010057 TYK2 Kinase Proteins 0.000 description 1
• FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
• ALHZEIINTQJLOT-VKHMYHEASA-N [(2s)-1-chloro-1-oxopropan-2-yl] acetate Chemical compound ClC(=O)[C@H](C)OC(C)=O ALHZEIINTQJLOT-VKHMYHEASA-N 0.000 description 1
• SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
• 238000010521 absorption reaction Methods 0.000 description 1
• 235000010489 acacia gum Nutrition 0.000 description 1
• 239000000205 acacia gum Substances 0.000 description 1
• 235000011054 acetic acid Nutrition 0.000 description 1
• KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
• 150000008065 acid anhydrides Chemical class 0.000 description 1
• 230000002378 acidificating effect Effects 0.000 description 1
• 125000002252 acyl group Chemical group 0.000 description 1
• 208000037883 airway inflammation Diseases 0.000 description 1
• 125000001980 alanyl group Chemical group 0.000 description 1
• 230000001476 alcoholic effect Effects 0.000 description 1
• 239000003513 alkali Substances 0.000 description 1
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
• 150000003973 alkyl amines Chemical class 0.000 description 1
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
• 125000002947 alkylene group Chemical group 0.000 description 1
• OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
• IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
• 125000005336 allyloxy group Chemical group 0.000 description 1
• BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
• WLDHEUZGFKACJH-UHFFFAOYSA-K amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1N=NC1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-UHFFFAOYSA-K 0.000 description 1
• 230000009435 amidation Effects 0.000 description 1
• 125000003368 amide group Chemical group 0.000 description 1
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
• 150000003863 ammonium salts Chemical class 0.000 description 1
• 230000003078 antioxidant effect Effects 0.000 description 1
• ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
• 235000009697 arginine Nutrition 0.000 description 1
• 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
• 239000000605 aspartame Substances 0.000 description 1
• IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
• 235000010357 aspartame Nutrition 0.000 description 1
• 229960003438 aspartame Drugs 0.000 description 1
• 235000003704 aspartic acid Nutrition 0.000 description 1
• 125000002393 azetidinyl group Chemical group 0.000 description 1
• 125000004069 aziridinyl group Chemical group 0.000 description 1
• 210000003719 b-lymphocyte Anatomy 0.000 description 1
• 125000003910 behenoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 230000009286 beneficial effect Effects 0.000 description 1
• 229960000686 benzalkonium chloride Drugs 0.000 description 1
• JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
• 235000010233 benzoic acid Nutrition 0.000 description 1
• 229960004365 benzoic acid Drugs 0.000 description 1
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
• LBIADNPMIFPXBK-UHFFFAOYSA-N benzyl 3,3-difluoro-8-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1,8-diazaspiro[3.5]nonane-1-carboxylate Chemical compound C1CCN(C=2C=3C=CNC=3N=CN=2)CC11C(F)(F)CN1C(=O)OCC1=CC=CC=C1 LBIADNPMIFPXBK-UHFFFAOYSA-N 0.000 description 1
• 229960002903 benzyl benzoate Drugs 0.000 description 1
• CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
• OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
• 235000013734 beta-carotene Nutrition 0.000 description 1
• 239000011648 beta-carotene Substances 0.000 description 1
• TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
• 229960002747 betacarotene Drugs 0.000 description 1
• XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
• 230000000903 blocking effect Effects 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
• NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical compound [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 description 1
• KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
• 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
• 229910000024 caesium carbonate Inorganic materials 0.000 description 1
• 159000000007 calcium salts Chemical class 0.000 description 1
• CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
• 239000008116 calcium stearate Substances 0.000 description 1
• 235000013539 calcium stearate Nutrition 0.000 description 1
• OYPRJOBELJOOCE-RNFDNDRNSA-N calcium-44 Chemical compound [44Ca] OYPRJOBELJOOCE-RNFDNDRNSA-N 0.000 description 1
• 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 1
• 229960004926 chlorobutanol Drugs 0.000 description 1
• SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
• 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 1
• 201000010903 chronic neutrophilic leukemia Diseases 0.000 description 1
• 238000003776 cleavage reaction Methods 0.000 description 1
• 239000003245 coal Substances 0.000 description 1
• 239000002131 composite material Substances 0.000 description 1
• 229940126543 compound 14 Drugs 0.000 description 1
• 229940125810 compound 20 Drugs 0.000 description 1
• 229940125936 compound 42 Drugs 0.000 description 1
• 235000005687 corn oil Nutrition 0.000 description 1
• 239000002285 corn oil Substances 0.000 description 1
• 229960001681 croscarmellose sodium Drugs 0.000 description 1
• 229960000913 crospovidone Drugs 0.000 description 1
• 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
• 239000012043 crude product Substances 0.000 description 1
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
• 238000000354 decomposition reaction Methods 0.000 description 1
• 230000007547 defect Effects 0.000 description 1
• 150000005690 diesters Chemical class 0.000 description 1
• ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
• 150000004683 dihydrates Chemical class 0.000 description 1
• 229940043279 diisopropylamine Drugs 0.000 description 1
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
• 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
• BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
• 229910000397 disodium phosphate Inorganic materials 0.000 description 1
• 235000019800 disodium phosphate Nutrition 0.000 description 1
• RAGZEDHHTPQLAI-UHFFFAOYSA-L disodium;2',4',5',7'-tetraiodo-3-oxospiro[2-benzofuran-1,9'-xanthene]-3',6'-diolate Chemical compound [Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(I)=C([O-])C(I)=C1OC1=C(I)C([O-])=C(I)C=C21 RAGZEDHHTPQLAI-UHFFFAOYSA-L 0.000 description 1
• 238000004821 distillation Methods 0.000 description 1
• DXJOICJBPIWBKF-UHFFFAOYSA-N ditert-butyl 3-methyl-2-(3-methylbut-2-enyl)azetidine-1,2-dicarboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)C1(CC=C(C)C)C(=O)OC(C)(C)C DXJOICJBPIWBKF-UHFFFAOYSA-N 0.000 description 1
• VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 239000003759 ester based solvent Substances 0.000 description 1
• BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
• 239000004210 ether based solvent Substances 0.000 description 1
• 150000002170 ethers Chemical class 0.000 description 1
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
• WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
• 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
• 238000002474 experimental method Methods 0.000 description 1
• 239000000576 food coloring agent Substances 0.000 description 1
• 239000001530 fumaric acid Substances 0.000 description 1
• 235000011087 fumaric acid Nutrition 0.000 description 1
• 239000008273 gelatin Substances 0.000 description 1
• 229920000159 gelatin Polymers 0.000 description 1
• 239000007903 gelatin capsule Substances 0.000 description 1
• 235000019322 gelatine Nutrition 0.000 description 1
• 235000011852 gelatine desserts Nutrition 0.000 description 1
• 239000000174 gluconic acid Substances 0.000 description 1
• 235000012208 gluconic acid Nutrition 0.000 description 1
• 229950006191 gluconic acid Drugs 0.000 description 1
• 239000008103 glucose Substances 0.000 description 1
• 239000004220 glutamic acid Substances 0.000 description 1
• 235000013922 glutamic acid Nutrition 0.000 description 1
• 229940075507 glyceryl monostearate Drugs 0.000 description 1
• JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
• 229940093915 gynecological organic acid Drugs 0.000 description 1
• 125000006038 hexenyl group Chemical group 0.000 description 1
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 0.000 description 1
• 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
• 230000005965 immune activity Effects 0.000 description 1
• 230000001506 immunosuppresive effect Effects 0.000 description 1
• 238000001727 in vivo Methods 0.000 description 1
• 230000003993 interaction Effects 0.000 description 1
• 108010074108 interleukin-21 Proteins 0.000 description 1
• GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
• 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
• FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
• 239000012948 isocyanate Substances 0.000 description 1
• 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
• 238000002955 isolation Methods 0.000 description 1
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000005932 isopentyloxycarbonyl group Chemical group 0.000 description 1
• 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
• OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
• 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
• 125000003971 isoxazolinyl group Chemical group 0.000 description 1
• 150000002576 ketones Chemical class 0.000 description 1
• 210000003734 kidney Anatomy 0.000 description 1
• 239000004310 lactic acid Substances 0.000 description 1
• 235000014655 lactic acid Nutrition 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• 235000018977 lysine Nutrition 0.000 description 1
• 229960003511 macrogol Drugs 0.000 description 1
• 159000000003 magnesium salts Chemical class 0.000 description 1
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
• 239000011976 maleic acid Substances 0.000 description 1
• 239000001630 malic acid Substances 0.000 description 1
• 235000011090 malic acid Nutrition 0.000 description 1
• 230000035800 maturation Effects 0.000 description 1
• 125000005905 mesyloxy group Chemical group 0.000 description 1
• 229940098779 methanesulfonic acid Drugs 0.000 description 1
• NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
• ZPOATZIYXILXRK-UHFFFAOYSA-N methyl 2-[3-(benzylamino)propyl]pyrrolidine-2-carboxylate Chemical compound C=1C=CC=CC=1CNCCCC1(C(=O)OC)CCCN1 ZPOATZIYXILXRK-UHFFFAOYSA-N 0.000 description 1
• 229920000609 methyl cellulose Polymers 0.000 description 1
• 125000004492 methyl ester group Chemical group 0.000 description 1
• 150000004702 methyl esters Chemical class 0.000 description 1
• 239000001923 methylcellulose Substances 0.000 description 1
• 235000010981 methylcellulose Nutrition 0.000 description 1
• 229960002900 methylcellulose Drugs 0.000 description 1
• 239000011259 mixed solution Substances 0.000 description 1
• 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
• 125000002950 monocyclic group Chemical group 0.000 description 1
• 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
• 125000002757 morpholinyl group Chemical group 0.000 description 1
• 230000035772 mutation Effects 0.000 description 1
• 229940037525 nasal preparations Drugs 0.000 description 1
• 210000000822 natural killer cell Anatomy 0.000 description 1
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 125000005933 neopentyloxycarbonyl group Chemical group 0.000 description 1
• 229910017604 nitric acid Inorganic materials 0.000 description 1
• 231100000252 nontoxic Toxicity 0.000 description 1
• 230000003000 nontoxic effect Effects 0.000 description 1
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
• 239000004006 olive oil Substances 0.000 description 1
• 235000008390 olive oil Nutrition 0.000 description 1
• 235000005985 organic acids Nutrition 0.000 description 1
• 239000003960 organic solvent Substances 0.000 description 1
• 235000006408 oxalic acid Nutrition 0.000 description 1
• 125000000160 oxazolidinyl group Chemical group 0.000 description 1
• 125000005968 oxazolinyl group Chemical group 0.000 description 1
• 125000003566 oxetanyl group Chemical group 0.000 description 1
• 238000007248 oxidative elimination reaction Methods 0.000 description 1
• 125000000466 oxiranyl group Chemical group 0.000 description 1
• 229910052763 palladium Inorganic materials 0.000 description 1
• 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 230000001575 pathological effect Effects 0.000 description 1
• 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
• 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
• 125000005633 phthalidyl group Chemical group 0.000 description 1
• 125000004193 piperazinyl group Chemical group 0.000 description 1
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 125000003386 piperidinyl group Chemical group 0.000 description 1
• 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
• 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
• 239000011591 potassium Substances 0.000 description 1
• 229910052700 potassium Inorganic materials 0.000 description 1
• XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
• 235000011181 potassium carbonates Nutrition 0.000 description 1
• 229910000160 potassium phosphate Inorganic materials 0.000 description 1
• 235000011009 potassium phosphates Nutrition 0.000 description 1
• 239000000843 powder Substances 0.000 description 1
• 238000002953 preparative HPLC Methods 0.000 description 1
• 230000002335 preservative effect Effects 0.000 description 1
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
• 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
• 229960004063 propylene glycol Drugs 0.000 description 1
• 235000013772 propylene glycol Nutrition 0.000 description 1
• 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
• 108060006633 protein kinase Proteins 0.000 description 1
• 235000018102 proteins Nutrition 0.000 description 1
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
• 230000002685 pulmonary effect Effects 0.000 description 1
• 239000008213 purified water Substances 0.000 description 1
• 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
• 125000002755 pyrazolinyl group Chemical group 0.000 description 1
• NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
• 238000006268 reductive amination reaction Methods 0.000 description 1
• 230000001105 regulatory effect Effects 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 230000000717 retained effect Effects 0.000 description 1
• 229930195734 saturated hydrocarbon Natural products 0.000 description 1
• 230000007017 scission Effects 0.000 description 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
• 239000000932 sedative agent Substances 0.000 description 1
• 230000001624 sedative effect Effects 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 239000008159 sesame oil Substances 0.000 description 1
• 235000011803 sesame oil Nutrition 0.000 description 1
• 208000002491 severe combined immunodeficiency Diseases 0.000 description 1
• RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• 229940083542 sodium Drugs 0.000 description 1
• 235000015424 sodium Nutrition 0.000 description 1
• 239000001632 sodium acetate Substances 0.000 description 1
• 235000017281 sodium acetate Nutrition 0.000 description 1
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
• WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
• 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
• 235000011083 sodium citrates Nutrition 0.000 description 1
• 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
• 229940079839 sodium dehydroacetate Drugs 0.000 description 1
• 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
• 159000000000 sodium salts Chemical class 0.000 description 1
• 235000010265 sodium sulphite Nutrition 0.000 description 1
• DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
• ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 1
• NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
• 239000011877 solvent mixture Substances 0.000 description 1
• 239000004334 sorbic acid Substances 0.000 description 1
• 235000010199 sorbic acid Nutrition 0.000 description 1
• 229940075582 sorbic acid Drugs 0.000 description 1
• 230000003595 spectral effect Effects 0.000 description 1
• 125000003003 spiro group Chemical group 0.000 description 1
• 239000007858 starting material Substances 0.000 description 1
• 238000006467 substitution reaction Methods 0.000 description 1
• UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
• DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
• 239000000829 suppository Substances 0.000 description 1
• 235000020357 syrup Nutrition 0.000 description 1
• 239000006188 syrup Substances 0.000 description 1
• 239000003826 tablet Substances 0.000 description 1
• 239000000454 talc Substances 0.000 description 1
• 229910052623 talc Inorganic materials 0.000 description 1
• 235000012222 talc Nutrition 0.000 description 1
• 239000011975 tartaric acid Substances 0.000 description 1
• 235000002906 tartaric acid Nutrition 0.000 description 1
• AAHDLRDOCKVUDL-UHFFFAOYSA-N tert-butyl 1-benzyl-3-methylazetidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1C(C)CN1CC1=CC=CC=C1 AAHDLRDOCKVUDL-UHFFFAOYSA-N 0.000 description 1
• FFYXWYIFHDEHEK-UHFFFAOYSA-N tert-butyl 2-[benzyl(1-chloropropan-2-yl)amino]acetate Chemical compound CC(C)(C)OC(=O)CN(C(CCl)C)CC1=CC=CC=C1 FFYXWYIFHDEHEK-UHFFFAOYSA-N 0.000 description 1
• TXUASIWBVUPKRO-UHFFFAOYSA-N tert-butyl 2-[benzyl(1-hydroxypropan-2-yl)amino]acetate Chemical compound CC(C)(C)OC(=O)CN(C(CO)C)CC1=CC=CC=C1 TXUASIWBVUPKRO-UHFFFAOYSA-N 0.000 description 1
• RKJKISQHLDRUJF-UHFFFAOYSA-N tert-butyl 3-(1,1-difluoro-2-hydroxyethyl)-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1(C(F)(F)CO)NC(=O)OCC1=CC=CC=C1 RKJKISQHLDRUJF-UHFFFAOYSA-N 0.000 description 1
• JCXPZKKHPWTHMT-UHFFFAOYSA-N tert-butyl 3-(1,1-difluoro-2-methylsulfonyloxyethyl)-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1(C(F)(F)COS(C)(=O)=O)NC(=O)OCC1=CC=CC=C1 JCXPZKKHPWTHMT-UHFFFAOYSA-N 0.000 description 1
• IAICXCUCYWQORU-UHFFFAOYSA-N tert-butyl 3-(1,1-difluoro-2-methylsulfonyloxyethyl)-3-(phenylmethoxycarbonylamino)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1(C(F)(F)COS(C)(=O)=O)NC(=O)OCC1=CC=CC=C1 IAICXCUCYWQORU-UHFFFAOYSA-N 0.000 description 1
• HCISWMHRVAIWKK-UHFFFAOYSA-N tert-butyl 3-(1-hydroxypropan-2-yl)-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylate Chemical compound C=1C=CC=CC=1COC(=O)NC1(C(CO)C)CCCN(C(=O)OC(C)(C)C)C1 HCISWMHRVAIWKK-UHFFFAOYSA-N 0.000 description 1
• UVTYUXHRXLENCQ-UHFFFAOYSA-N tert-butyl 3-(2-hydroxyethyl)-3-(phenylmethoxycarbonylamino)piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC1(CCO)NC(=O)OCC1=CC=CC=C1 UVTYUXHRXLENCQ-UHFFFAOYSA-N 0.000 description 1
• ZMXUNTOQZJRDNS-UHFFFAOYSA-N tert-butyl 3-amino-3-(2-hydroxyethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(N)(CCO)C1 ZMXUNTOQZJRDNS-UHFFFAOYSA-N 0.000 description 1
• MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
• LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 1
• QIQCZROILFZKAT-UHFFFAOYSA-N tetracarbon dioxide Chemical group O=C=C=C=C=O QIQCZROILFZKAT-UHFFFAOYSA-N 0.000 description 1
• 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
• 229940124597 therapeutic agent Drugs 0.000 description 1
• 125000001984 thiazolidinyl group Chemical group 0.000 description 1
• 125000001166 thiolanyl group Chemical group 0.000 description 1
• 150000003573 thiols Chemical class 0.000 description 1
• 125000005505 thiomorpholino group Chemical group 0.000 description 1
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
• 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
• 230000009466 transformation Effects 0.000 description 1
• HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
• UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
• 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• 239000008096 xylene Substances 0.000 description 1
• OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1