CN112638902A - 用于制备jak抑制剂的方法及其中间体 - Google Patents
用于制备jak抑制剂的方法及其中间体 Download PDFInfo
- Publication number
- CN112638902A CN112638902A CN201980057683.5A CN201980057683A CN112638902A CN 112638902 A CN112638902 A CN 112638902A CN 201980057683 A CN201980057683 A CN 201980057683A CN 112638902 A CN112638902 A CN 112638902A
- Authority
- CN
- China
- Prior art keywords
- compound
- group
- salt
- formula
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 33
- 239000000543 intermediate Substances 0.000 title description 7
- 229940122245 Janus kinase inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 141
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 56
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 51
- 125000006239 protecting group Chemical group 0.000 claims description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- 125000002252 acyl group Chemical group 0.000 claims description 21
- 125000005002 aryl methyl group Chemical group 0.000 claims description 20
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 17
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 16
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 16
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- DWOZNANUEDYIOF-UHFFFAOYSA-L 4-ditert-butylphosphanyl-n,n-dimethylaniline;dichloropalladium Chemical compound Cl[Pd]Cl.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 DWOZNANUEDYIOF-UHFFFAOYSA-L 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims description 5
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 claims description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims description 4
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical compound OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 20
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 239000011541 reaction mixture Substances 0.000 description 79
- 239000000243 solution Substances 0.000 description 64
- -1 di-tert-butylphosphino Chemical group 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- 239000012043 crude product Substances 0.000 description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- 238000012544 monitoring process Methods 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000002156 mixing Methods 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- 102000042838 JAK family Human genes 0.000 description 16
- 108091082332 JAK family Proteins 0.000 description 16
- 210000004072 lung Anatomy 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 238000003556 assay Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 239000002002 slurry Substances 0.000 description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
- 239000007821 HATU Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000006227 byproduct Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 102100031294 Thymic stromal lymphopoietin Human genes 0.000 description 10
- 229940011051 isopropyl acetate Drugs 0.000 description 10
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 108010029307 thymic stromal lymphopoietin Proteins 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 7
- UYTYMXGFSHEMGK-XCUBXKJBSA-N Cl.Cl.C[C@@H]1CN(CCN1)CCO Chemical compound Cl.Cl.C[C@@H]1CN(CCN1)CCO UYTYMXGFSHEMGK-XCUBXKJBSA-N 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 6
- PGMBVOVVYOIMBB-UHFFFAOYSA-N 1-ethyl-3-phenylmethoxybenzene Chemical compound CCC1=CC=CC(OCC=2C=CC=CC=2)=C1 PGMBVOVVYOIMBB-UHFFFAOYSA-N 0.000 description 5
- PCFIABOQFAFDAU-UHFFFAOYSA-N 4-bromo-2-fluorobenzoyl chloride Chemical compound FC1=CC(Br)=CC=C1C(Cl)=O PCFIABOQFAFDAU-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- ZDRJMZMVJTUQHH-UHFFFAOYSA-N borane;potassium Chemical compound B.[K] ZDRJMZMVJTUQHH-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 5
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- CCGHCCTXMYYHQC-NSHDSACASA-N (6S)-3,5-bis[(2-methylpropan-2-yl)oxycarbonyl]-6,7-dihydro-4H-imidazo[4,5-c]pyridine-6-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1C=NC2=C1CN([C@@H](C2)C(=O)O)C(=O)OC(C)(C)C CCGHCCTXMYYHQC-NSHDSACASA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- BIIDVVFATFVXTC-UHFFFAOYSA-N 1-bromo-2-ethyl-4-phenylmethoxybenzene Chemical compound C1=C(Br)C(CC)=CC(OCC=2C=CC=CC=2)=C1 BIIDVVFATFVXTC-UHFFFAOYSA-N 0.000 description 4
- UFMHRNIBPKQDJY-SFHVURJKSA-N 6-O-benzyl 3-O,5-O-ditert-butyl (6S)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-3,5,6-tricarboxylate Chemical compound N1=CN(C=2CN([C@@H](CC=21)C(=O)OCC1=CC=CC=C1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C UFMHRNIBPKQDJY-SFHVURJKSA-N 0.000 description 4
- SFACXNFWAROQKE-MHZLTWQESA-N 6-O-benzyl 5-O-tert-butyl (6S)-3-benzyl-2-(4-bromo-2-fluorobenzoyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-5,6-dicarboxylate Chemical compound C(C1=CC=CC=C1)N1C(=NC2=C1CN([C@@H](C2)C(=O)OCC1=CC=CC=C1)C(=O)OC(C)(C)C)C(C1=C(C=C(C=C1)Br)F)=O SFACXNFWAROQKE-MHZLTWQESA-N 0.000 description 4
- BLMQUENFEUQJRY-FERBBOLQSA-N Cl.C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN[C@@H](C2)C(=O)O)N1 Chemical compound Cl.C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN[C@@H](C2)C(=O)O)N1 BLMQUENFEUQJRY-FERBBOLQSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- IJWPDVGZOCCGRA-JEDNCBNOSA-N hydron;(6s)-4,5,6,7-tetrahydro-3h-imidazo[4,5-c]pyridine-6-carboxylic acid;chloride Chemical compound Cl.C1N[C@H](C(=O)O)CC2=C1NC=N2 IJWPDVGZOCCGRA-JEDNCBNOSA-N 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- DHXXDTCOJUYKOQ-UHFFFAOYSA-N n,n-dimethylazetidin-3-amine;dihydrochloride Chemical compound Cl.Cl.CN(C)C1CNC1 DHXXDTCOJUYKOQ-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 3
- SVPDDTOIPKRVQR-UHFFFAOYSA-N 2-(2-ethyl-4-phenylmethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C(C1=CC=CC=C1)OC1=CC(=C(C=C1)B1OC(C(O1)(C)C)(C)C)CC SVPDDTOIPKRVQR-UHFFFAOYSA-N 0.000 description 3
- HMNKTRSOROOSPP-UHFFFAOYSA-N 3-Ethylphenol Chemical compound CCC1=CC=CC(O)=C1 HMNKTRSOROOSPP-UHFFFAOYSA-N 0.000 description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 3
- JZCWMNFSPRPADO-UFUJWDBKSA-N Cl.C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1)N(C(=N2)C2=NNC1=CC(=CC=C21)C2=C(C=C(C=C2)OCC2=CC=CC=C2)CC)CC2=CC=CC=C2 Chemical compound Cl.C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1)N(C(=N2)C2=NNC1=CC(=CC=C21)C2=C(C=C(C=C2)OCC2=CC=CC=C2)CC)CC2=CC=CC=C2 JZCWMNFSPRPADO-UFUJWDBKSA-N 0.000 description 3
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 102000001712 STAT5 Transcription Factor Human genes 0.000 description 3
- 108010029477 STAT5 Transcription Factor Proteins 0.000 description 3
- 108010011005 STAT6 Transcription Factor Proteins 0.000 description 3
- 102100023980 Signal transducer and activator of transcription 6 Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001768 cations Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- VBEKMNXJHBOWCT-SNVBAGLBSA-N tert-butyl (2r)-4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(CCO)CCN1C(=O)OC(C)(C)C VBEKMNXJHBOWCT-SNVBAGLBSA-N 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- XFTHQJCNBIZOBX-FQEVSTJZSA-N (6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-methyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid Chemical compound C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)O)C)N1 XFTHQJCNBIZOBX-FQEVSTJZSA-N 0.000 description 2
- NDXQRNJVDGDWPC-QFIPXVFZSA-N (6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propan-2-yl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid Chemical compound C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)O)C(C)C)N1 NDXQRNJVDGDWPC-QFIPXVFZSA-N 0.000 description 2
- FYXITXIYHLHKMS-QFIPXVFZSA-N (6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid Chemical compound C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)O)CCC)N1 FYXITXIYHLHKMS-QFIPXVFZSA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 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
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-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
- ZQQSRVPOAHYHEL-UHFFFAOYSA-N 4-bromo-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1F ZQQSRVPOAHYHEL-UHFFFAOYSA-N 0.000 description 2
- MZFPAWGWFDGCHP-UHFFFAOYSA-N 5-diphenylphosphanylpentyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 MZFPAWGWFDGCHP-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 238000012815 AlphaLISA Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DHARWGXELNZZHG-DEOSSOPVSA-N C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)N(C(=N2)C2=NNC1=CC(=CC=C21)Br)CC2=CC=CC=C2 Chemical compound C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)N(C(=N2)C2=NNC1=CC(=CC=C21)Br)CC2=CC=CC=C2 DHARWGXELNZZHG-DEOSSOPVSA-N 0.000 description 2
- MSZFGERFKMEWQR-IBGZPJMESA-N C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)N(C=N2)CC2=CC=CC=C2 Chemical compound C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)N(C=N2)CC2=CC=CC=C2 MSZFGERFKMEWQR-IBGZPJMESA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-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
- 238000002965 ELISA Methods 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 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
- 239000007995 HEPES buffer Substances 0.000 description 2
- 101000978362 Homo sapiens C-C motif chemokine 17 Proteins 0.000 description 2
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- SYBBGGQKRZUDAX-UHFFFAOYSA-N N1=CC=CC(=C1C(=O)OCC1=CC=CC=C1)C(=O)OC(C)(C)C Chemical compound N1=CC=CC(=C1C(=O)OCC1=CC=CC=C1)C(=O)OC(C)(C)C SYBBGGQKRZUDAX-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000012911 assay medium Substances 0.000 description 2
- 238000013096 assay test 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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- 102000044064 human CCL17 Human genes 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 238000010926 purge Methods 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
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 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 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 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 2
- KQAJQVQIWBQIFM-VKGTZQKMSA-N tert-butyl (3S)-4-[(6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-methyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carbonyl]-3-methylpiperazine-1-carboxylate Chemical compound C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)N2[C@H](CN(CC2)C(=O)OC(C)(C)C)C)C)N1 KQAJQVQIWBQIFM-VKGTZQKMSA-N 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-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
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- AVAWMINJNRAQFS-LURJTMIESA-N (3s)-n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)[C@H]1CCNC1 AVAWMINJNRAQFS-LURJTMIESA-N 0.000 description 1
- JIJUVMQGKMEJAS-NRFANRHFSA-N (6S)-5-ethyl-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-6-carboxylic acid Chemical compound C(C)N1CC2=C(C[C@H]1C(=O)O)N=C(N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C=C1)O)CC JIJUVMQGKMEJAS-NRFANRHFSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-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
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-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
- WLUAJCSMROZCDP-UHFFFAOYSA-N 2-methyl-2,5-diazabicyclo[2.2.1]heptane;dihydrobromide Chemical compound Br.Br.C1C2N(C)CC1NC2 WLUAJCSMROZCDP-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- ASZZHBXPMOVHCU-UHFFFAOYSA-N 3,9-diazaspiro[5.5]undecane-2,4-dione Chemical compound C1C(=O)NC(=O)CC11CCNCC1 ASZZHBXPMOVHCU-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
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- FULGHTIHNXKJCZ-NRFANRHFSA-N C(C)C1=C(C=C(C(=C1)O)F)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)O)C(C)C)N1 Chemical compound C(C)C1=C(C=C(C(=C1)O)F)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)O)C(C)C)N1 FULGHTIHNXKJCZ-NRFANRHFSA-N 0.000 description 1
- YQBKCXNKLJQMBN-KDXMTYKHSA-N C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)N(C(=N2)C2=NNC1=CC(=CC=C21)C2=C(C=C(C=C2)OCC2=CC=CC=C2)CC)CC2=CC=CC=C2 Chemical compound C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)N(C(=N2)C2=NNC1=CC(=CC=C21)C2=C(C=C(C=C2)OCC2=CC=CC=C2)CC)CC2=CC=CC=C2 YQBKCXNKLJQMBN-KDXMTYKHSA-N 0.000 description 1
- OWJSJKLKHDZWJJ-ZDUSSCGKSA-N C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)NC=N2 Chemical compound C(C1=CC=CC=C1)OC(=O)[C@@H]1CC2=C(CN1C(=O)O)NC=N2 OWJSJKLKHDZWJJ-ZDUSSCGKSA-N 0.000 description 1
- GMBXCXWBMHAZCF-UHFFFAOYSA-N C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC2=C1C1=C(CO2)C=CC=C1 Chemical compound C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC2=C1C1=C(CO2)C=CC=C1 GMBXCXWBMHAZCF-UHFFFAOYSA-N 0.000 description 1
- RYACCWZJZAKABF-ATJOBZSNSA-N CCc1cc(O)c(F)cc1C1CCC2C(C1)NNC2c1nc2C[C@H](N(Cc2[nH]1)C(C)C)C(=O)N1CC(C1)N(C)C Chemical compound CCc1cc(O)c(F)cc1C1CCC2C(C1)NNC2c1nc2C[C@H](N(Cc2[nH]1)C(C)C)C(=O)N1CC(C1)N(C)C RYACCWZJZAKABF-ATJOBZSNSA-N 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 102100038497 Cytokine receptor-like factor 2 Human genes 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
- 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
- 108010016626 Dipeptides Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 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 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-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
- 229910004039 HBF4 Inorganic materials 0.000 description 1
- 101000956427 Homo sapiens Cytokine receptor-like factor 2 Proteins 0.000 description 1
- 101000617830 Homo sapiens Sterol O-acyltransferase 1 Proteins 0.000 description 1
- 101000845170 Homo sapiens Thymic stromal lymphopoietin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 108010024121 Janus Kinases Proteins 0.000 description 1
- 102000015617 Janus Kinases Human genes 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
- 241000124008 Mammalia Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 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
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100021993 Sterol O-acyltransferase 1 Human genes 0.000 description 1
- 101000697584 Streptomyces lavendulae Streptothricin acetyltransferase Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000000887 Transcription factor STAT Human genes 0.000 description 1
- 108050007918 Transcription factor STAT Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- UWZLUJZCOIATJC-NDEPHWFRSA-N [(6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propan-2-yl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]-(4-methyl-1,4-diazepan-1-yl)methanone Chemical compound C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)N2CCN(CCC2)C)C(C)C)N1 UWZLUJZCOIATJC-NDEPHWFRSA-N 0.000 description 1
- FTQBYQRDFCFCFN-NDEPHWFRSA-N [(6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]-[4-(2-hydroxyethyl)piperazin-1-yl]methanone Chemical compound C(C)C1=C(C=CC(=C1)O)C1=CC=C2C(=NNC2=C1)C1=NC2=C(CN([C@@H](C2)C(=O)N2CCN(CC2)CCO)CCC)N1 FTQBYQRDFCFCFN-NDEPHWFRSA-N 0.000 description 1
- KAVVKRQBEAWLIE-MHZLTWQESA-N [3-(dimethylamino)-3-methylazetidin-1-yl]-[(6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propan-2-yl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]methanone Chemical compound CN(C1(CN(C1)C(=O)[C@@H]1CC2=C(CN1C(C)C)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C=C1)O)CC)C)C KAVVKRQBEAWLIE-MHZLTWQESA-N 0.000 description 1
- LXCJYFUAMDZSGA-MHZLTWQESA-N [3-(dimethylamino)-3-methylazetidin-1-yl]-[(6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]methanone Chemical compound CN(C1(CN(C1)C(=O)[C@@H]1CC2=C(CN1CCC)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C=C1)O)CC)C)C LXCJYFUAMDZSGA-MHZLTWQESA-N 0.000 description 1
- RINWDSCUVKTALQ-SANMLTNESA-N [3-(dimethylamino)-3-methylazetidin-1-yl]-[(6S)-5-ethyl-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]methanone Chemical compound CN(C1(CN(C1)C(=O)[C@@H]1CC2=C(CN1CC)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C=C1)O)CC)C)C RINWDSCUVKTALQ-SANMLTNESA-N 0.000 description 1
- VQIIUJSNIKEMCK-MHZLTWQESA-N [3-(dimethylamino)azetidin-1-yl]-[(6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propan-2-yl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]methanone Chemical compound CN(C1CN(C1)C(=O)[C@@H]1CC2=C(CN1C(C)C)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C=C1)O)CC)C VQIIUJSNIKEMCK-MHZLTWQESA-N 0.000 description 1
- IOVFFTMQWCOHDE-MHZLTWQESA-N [3-(dimethylamino)azetidin-1-yl]-[(6S)-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-5-propyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]methanone Chemical compound CN(C1CN(C1)C(=O)[C@@H]1CC2=C(CN1CCC)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C=C1)O)CC)C IOVFFTMQWCOHDE-MHZLTWQESA-N 0.000 description 1
- YAHQISLGSOFLRU-SANMLTNESA-N [3-(dimethylamino)azetidin-1-yl]-[(6S)-5-ethyl-2-[6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-6-yl]methanone Chemical compound CN(C1CN(C1)C(=O)[C@@H]1CC2=C(CN1CC)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C=C1)O)CC)C YAHQISLGSOFLRU-SANMLTNESA-N 0.000 description 1
- COERJHDMQUPDCV-UHFFFAOYSA-N [K].FB(F)F Chemical compound [K].FB(F)F COERJHDMQUPDCV-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 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
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- PDDVWFQPIXIRGN-WBCKFURZSA-N benzyl (6S)-1-benzyl-2-[6-(2-ethyl-5-fluoro-4-phenylmethoxyphenyl)-1H-indazol-3-yl]-5-propan-2-yl-6,7-dihydro-4H-imidazo[4,5-c]pyridine-6-carboxylate Chemical compound C(C1=CC=CC=C1)N1C(=NC=2CN([C@@H](CC=21)C(=O)OCC1=CC=CC=C1)C(C)C)C1=NNC2=CC(=CC=C12)C1=C(C=C(C(=C1)F)OCC1=CC=CC=C1)CC PDDVWFQPIXIRGN-WBCKFURZSA-N 0.000 description 1
- PNEBXWLVOMLIPS-UHFFFAOYSA-N benzyl pyridine-2-carboxylate Chemical compound C=1C=CC=NC=1C(=O)OCC1=CC=CC=C1 PNEBXWLVOMLIPS-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N beta-hydroxyethanesulfonic acid Natural products OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 210000000424 bronchial epithelial cell Anatomy 0.000 description 1
- 230000005587 bubbling Effects 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
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000013000 chemical inhibitor Substances 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 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
- 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 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
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- NMUZMGPHYASFRU-UHFFFAOYSA-N formaldehyde;dihydrochloride Chemical compound Cl.Cl.O=C NMUZMGPHYASFRU-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 229960005219 gentisic acid Drugs 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
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 102000045535 human TSLP Human genes 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960002725 isoflurane Drugs 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
- 238000000021 kinase assay Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 210000002540 macrophage Anatomy 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
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MHJUNMARMFAUBI-UHFFFAOYSA-N n-phenyliminobenzamide Chemical compound C=1C=CC=CC=1C(=O)N=NC1=CC=CC=C1 MHJUNMARMFAUBI-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- FITZJYAVATZPMJ-UHFFFAOYSA-N naphthalene-2,6-disulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=CC2=CC(S(=O)(=O)O)=CC=C21 FITZJYAVATZPMJ-UHFFFAOYSA-N 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940074355 nitric acid Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000004647 pro-inflammatory pathway Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000004879 pulmonary tissue Anatomy 0.000 description 1
- CGNOCXFIMTXTGY-UHFFFAOYSA-N pyridine-2-carboxylic acid;dihydrochloride Chemical compound Cl.Cl.OC(=O)C1=CC=CC=N1 CGNOCXFIMTXTGY-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- 238000013207 serial dilution Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DATRVIMZZZVHMP-MRVPVSSYSA-N tert-butyl (2r)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-MRVPVSSYSA-N 0.000 description 1
- FMLPQHJYUZTHQS-QMMMGPOBSA-N tert-butyl (3s)-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-QMMMGPOBSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明涉及一种制备化合物的方法,所述化合物可用作用于制备对JAK具有抑制活性的药剂的中间体。
Description
技术领域
本发明涉及一种制备化合物的方法,所述化合物可用作用于制备药剂的中间体。特定来说,本发明涉及制备JAK抑制剂的中间体。
背景技术
JAK家族包括四个成员,JAK1、JAK2、JAK3和酪氨酸激酶2(TYK2)。细胞因子与JAK依赖性细胞因子受体的结合诱导受体二聚合,其导致JAK激酶上的酪氨酸残基的磷酸化,从而实现JAK活化。经磷酸化的JAK又结合各种STAT蛋白并将其磷酸化,所述蛋白质二聚合、在细胞核中内部化及直接调节基因转录,尤其导致与发炎性疾病相关联的下游效应。JAK通常与呈均二聚体或异二聚体对的细胞因子受体相关联。JAK家族的四个成员中的每一个牵涉与发炎相关联的细胞因子中的至少一个的信号传导。因此,具有针对JAK家族的所有成员的泛活性的化学抑制剂可调节宽范围的促发炎路径,所述路径有助于肺发炎性疾病,如严重哮喘、COPD和慢性肺同种异体移植功能障碍(CLAD)。因此期望具有用于制备特异性JAK抑制剂的有效方法。
发明内容
本发明涉及一种制备化合物的方法,所述化合物可用作用于制备具有对JAK的抑制活性的药剂的中间体。
因此,在一方面中,本发明提供一种制备式J-15化合物或其盐的方法:
其中
X是选自由Br、I和Cl组成的群组;
PG1为羧酸保护基;
PG2为氨基保护基;且
PG3为氨基保护基;
所述方法包括:
(a)使式J-14化合物:
或其盐与肼反应以得到所述式J-15化合物及
(b)任选地形成化合物J-15的盐。
在另一方面中,本发明提供式J-14化合物:
或其盐,其中
X是选自由Br、I和Cl组成的群组;
PG1为羧酸保护基;
PG2为氨基保护基;且
PG3为氨基保护基。
在另一方面中,本发明提供式J-15化合物:
或其盐,
其中
X是选自由Br、I和Cl组成的群组;
PG1为羧酸保护基;
PG2为氨基保护基;且
PG3为氨基保护基。
在另一方面中,本发明提供一种制备式J-16化合物或其盐的方法:
其中
PG1为羧酸保护基;
PG2为氨基保护基;
PG3为氨基保护基;
PG4为羟基保护基;且
R为H或F;
所述方法包括:
(a)在碱的存在下使式J-13化合物:
其中X是选自由Br、I和Cl组成的群组;且Y为离去基团;与式J-11化合物反应:
以得到式J-14化合物:
及任选地形成化合物J-14的盐;
(b)使所述式J-14化合物或其盐与肼反应以得到式J-15化合物:
及任选地形成化合物J-15的盐;
(c)在碱、钯催化剂和膦配位体的存在下使所述式J-15化合物或其盐与式J-5、J-6或J-7化合物反应:
其中Ra和Rb各自独立地选自C1-8烷基,其中Ra和Rb可任选地连接以形成4到8元环;以得到所述式J-16化合物,及任选地形成化合物J-16的盐。
具体实施方式
在一方面中,本发明提供一种制备式J-15化合物或其盐的方法:
其中
X是选自由Br、I和Cl组成的群组;
PG1为羧酸保护基;
PG2为氨基保护基;且
PG3为氨基保护基;
所述方法包括:
(a)使式J-14化合物:
或其盐与肼反应以得到所述式J-15化合物及
(b)任选地形成化合物J-15的盐。
在一些方面中,在约60℃下进行所述与肼的反应。在一些方面中,在60℃±20℃下进行所述与肼的反应。
在一些方面中,X是选自由Br、I和Cl组成的群组;PG1为烷基或苄基,其中所述苄基任选地经取代;PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;且PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组。
在一些方面中,X为Br。在一些方面中,X为Br,PG1为苄基,PG2为叔丁氧羰基且PG3为苄基。
在一些方面中,通过以下制备化合物J-14或其盐:
(a)在碱的存在下使式J-13化合物:
其中Y为离去基团,与式J-11化合物反应:
以得到J-14,及
(b)任选地形成化合物J-14的盐。
在一些方面中,Y为Cl。
在另一方面中,本发明提供式J-14化合物:
或其盐,其中
X是选自由Br、I和Cl组成的群组;
PG1为羧酸保护基;
PG2为氨基保护基;且
PG3为氨基保护基。
在一些方面中,X是选自由Br、I和Cl组成的群组;PG1为烷基或苄基,其中所述苄基任选地经取代;PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;且PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组。
在另一方面中,本发明提供式I-14化合物:
或其盐。
在另一方面中,本发明提供式J-15化合物:
或其盐,
其中
X是选自由Br、I和Cl组成的群组;
PG1为羧酸保护基;
PG2为氨基保护基;且
PG3为氨基保护基。
在一些方面中,X是选自由Br、I和Cl组成的群组;PG1为烷基或苄基,其中所述苄基任选地经取代;PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;且PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组。
在另一方面中,本发明提供式I-15化合物:
或其盐。
在另一方面中,本发明提供一种制备式J-16化合物或其盐的方法:
其中
PG1为羧酸保护基;
PG2为氨基保护基;
PG3为氨基保护基;
PG4为羟基保护基;且
R为H或F;
所述方法包括:
(a)在碱的存在下使式J-13化合物:
其中X是选自由Br、I和Cl组成的群组;且Y为离去基团;与式J-11化合物反应:
以得到式J-14化合物:
及任选地形成化合物J-14的盐;
(b)使所述式J-14化合物或其盐与肼反应以得到式J-15化合物:
及任选地形成化合物J-15的盐;
(c)在碱、钯催化剂及膦配位体的存在下使所述式J-15化合物或其盐与式J-5、J-6或J-7化合物反应:
其中Ra和Rb各自独立地选自C1-8烷基,其中Ra和Rb可任选地连接以形成4到8元环;以得到所述式J-16化合物,及任选地形成化合物J-16的盐。
在一些方面中,在二硼试剂的存在下进行步骤(c)。在一些方面中,在四羟基二硼或二硼酸酯的存在下进行步骤(c)。在一些实施例中,所述催化剂为双(频哪醇基)二硼与氟化钾氢氟化物的反应产物。在一些实施例中,通过含在丙-2-醇中的双(频哪醇基)二硼与含在水中的氟化钾氢氟化物反应接着过滤及干燥所获得的固体来获得所述催化剂。
在一些方面中,在60℃±20℃下进行步骤(b)中的所述与肼的反应。
在一些方面中,X是选自由Br、I和Cl组成的群组;PG1为烷基或苄基,其中所述苄基任选地经取代;PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;PG4是选自由硅基、酰基和芳基甲基组成的群组。在一些方面中,X为Br。在一些方面中,X为Br,PG1为苄基,PG2为叔丁氧羰基,PG3为苄基且PG4为苄基。
在一些方面中,Y为Cl。
在一些方面中,所述步骤(c)的钯催化剂和膦配位体为双(二叔丁基(4-二甲氨基苯基)膦)二氯钯(II)。
在本方法中,在碱的存在下使化合物J-13:
与式J-11化合物反应:
以得到式J-14化合物:
通常,在溶剂(如乙腈)中,在过量(例如3到7当量)碱(如三甲胺)的存在下进行所述反应。通常使用1到2当量的J-13。
在本方法中,使化合物J-14或其盐与肼反应以得到式J-15化合物:
通常,在溶剂(如THF)中进行所述反应及使用过量肼,例如介于2与10当量之间。将所述反应在约60℃下加热直到完成,通常介于0.5与6小时之间。
在本方法中,在碱、钯催化剂和膦配位体的存在下使化合物J-15或其盐与式J-5、J-6或J-7化合物反应:
以得到式J-16化合物:
通常通过在催化量的钯催化剂和膦配位体(在约0.005当量与约0.1当量之间)和约2与约6当量之间的碱的存在下使J-16与约1当量与约1.5当量之间的J-5、J-6或J-7接触来进行所述反应。在额外催化剂的存在下进行所述反应增加产物J-16的产率。所述额外催化剂可为二硼试剂。所述额外催化剂可为四羟基二硼、二硼酸酯或双(频哪醇基)二硼与氟化钾氢氟化物的反应产物,如制备4中所述。
适合的钯催化剂包括双(二-叔丁基(4-二甲氨基苯基)膦)二氯钯(II)、三(二亚苄基丙酮)二钯(0)(Pd2dba3)、乙酸钯(II)(Pd(OAc)2)、二氯(1,1’-双(二苯基膦基)-二茂铁)二钯(II)(Pd(dppf)Cl2)、二氯双(三苯基膦)-钯(II)(Pd(PPh3)2Cl2)等,其中在括号内提供常见缩略语。可用于本反应的膦配位体包括三环己基膦(PCy3)、四氟硼酸三环己基膦(PCy3HBF4)、1,1'-双(二苯基膦基)-二茂铁(dppf)、1,1'-双(二-叔丁基膦基)二茂铁、三(2-呋喃基)膦、1,3-双(二苯基膦基)丙烷(dppp)、1,5-双(二苯基膦基)戊烷(dpppe)、三-叔丁基膦(P(t-Bu)3)和9,9-二甲基-4,5-双(二苯基膦基)二苯并哌喃(Xantphos)。
用于偶合反应的典型碱包括氟化钾、碳酸铯和氟化铯。或者,碳酸钠、碳酸钾、乙酸钠、叔丁醇钾、1,8-二氮杂二环[5.4.0]十一-7-烯(DBU)或1,4-二氮杂二环[2.2.2]辛烷(DABCO)可用于所述碱。通常在惰性稀释剂(如四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷酮)中进行所述反应。适合的混合溶剂体系包括四氢呋喃和水、四氢呋喃和N,N-二甲基甲酰胺、四氢呋喃和N-甲基吡咯烷酮、丙酮和水、乙醇和水、和异丙醇和水。通常在约40℃与约120℃之间的温度下进行所述反应持续约1小时到约20小时或直到反应基本上完成。通过常规程序单离(isolate)呈固体的产物J-16。
定义
当描述本发明(包括其各种方面和实施例)时,除非另有指定,否则下列术语具有下列含义。
术语“烷基”意指单价饱和烃基,其可为直链或支链或其组合。除非另有指定,否则此类烷基通常含有1到10个碳原子。举例而言,代表性烷基包括甲基(Me)、乙基(Et)、正丙基(n-Pr)或(nPr)、异丙基(i-Pr)或(iPr)、正丁基(n-Bu)或(nBu)、仲丁基、异丁基、叔丁基(t-Bu)或(tBu)、正戊基、正己基、2,2-二甲基丙基、2-甲基丁基、3-甲基丁基、2-乙基丁基、2,2-二甲基戊基、2-丙基戊基等。
当打算将碳原子的特定数目用于特定术语时,在所述术语之前显示所述碳原子的数目。例如,术语“C1-3烷基”意指具有1到3个碳原子的烷基,其中所述碳原子呈任何化学上可接受的构型,包括直链或支链构型。
术语“环烷基”意指单价饱和碳环基,其可为单环或多环。除非另有指定,否则此类环烷基通常含有3到10个碳原子。举例而言,代表性环烷基包括环丙基(cPr)、环丁基(cBu)、环戊基、环己基、环庚基、环辛基、金刚烷基等。
术语“环丙基(cpropyl)”意指环丙基(cyclopropyl)。
术语“杂环基”、“杂环(heterocycle/heterocyclic/heterocyclic ring)”意指具有3到10个总环原子的单价饱和或部分不饱和环状非芳族基,其中所述环含有2到9个碳环原子及1到4个选自氮、氧和硫的环杂原子。杂环基可为单环或多环(即,稠合或桥接)。举例而言,代表性杂环基包括吡咯烷基、哌啶基、哌嗪基、咪唑烷基、吗啉基、硫代吗啉基、吲哚啉-3-基、2-咪唑啉基、四氢哌喃基、1,2,3,4-四氢异喹啉-2-基、奎宁环基、7-氮杂降莰烷基(7-azanorbornanyl)、降莨菪碱基(nortropanyl)等,其中连接点是在任何可供使用的碳或氮环原子上。在上下文使杂环基的连接点明显的情况下,或者可将此类基团称作非价物种,即,吡咯烷、哌啶、哌嗪、咪唑、四氢哌喃等。
术语“卤基”意指氟、氯、溴或碘。
术语“治疗上有效量”意指当对需要治疗的患者给予时足以实现治疗的量。
术语“治疗(treating/treatment)”意指预防、改善或抑制患者(特定来说人类)的正在治疗的医学病状、疾病或病症(例如,呼吸疾病);或减轻所述医学病状、疾病或病症的症状。
术语“药学上可接受的盐”意指用于对患者或哺乳动物(如人类)给予可接受的盐(例如,针对给定剂量方案具有可接受的哺乳动物安全性的盐)。代表性药学上可接受的盐包括以下的盐:乙酸、抗坏血酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、乙二磺酸(edisylic)、富马酸、龙胆酸、葡糖酸、葡萄糖醛酸、谷氨酸、马尿酸、氢溴酸、氢氯酸、羟基乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、萘磺酸、萘-1,5-二磺酸、萘-2,6-二磺酸、烟碱酸、硝酸、乳清酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸和辛那酸(xinafoic acid)等。
术语“其盐”意指当酸的氢经阳离子(如金属阳离子或有机阳离子等)置换时形成的化合物。例如,阳离子可为化合物的质子化形式,即,一或多个氨基已通过酸质子化的形式。通常,所述盐为药学上可接受的盐,虽然此对于不打算对患者给予的中间体化合物的盐是不必需。
术语“氨基保护基”意指适用于防止氨基氮处的非所需反应的保护基。代表性氨基保护基包括(但不限于)甲酰基;酰基,例如烷酰基,如乙酰基和三氟乙酰基;烷氧羰基,如叔丁氧羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)、9-芴基甲氧羰基(Fmoc)、对硝基苄氧羰基(PNZ)、2,4-二氯苄氧羰基和5-苯并异噁唑基甲氧羰基;芳基甲基,如苄基(Bn)、4-甲氧基苄基、三苯甲基(Tr)和1,1-二-(4’-甲氧基苯基)甲基;硅基,如三甲基硅基(TMS)、叔丁基二甲基硅基(TBDMS)、[2-(三甲基硅基)乙氧基]甲基(SEM);等。
术语“羧酸保护基”意指适用于防止在羧酸处的非所需反应的保护基。代表性羧酸保护基包括(但不限于)酯,如甲基、乙基、叔丁基、苄基(Bn)、对甲氧基苄基(PMB)、9-芴基甲基(Fm)、三甲基硅基(TMS)、叔丁基二甲基硅基(TBS、TBDMS)、二苯基甲基(二苯甲基,DPM)等。
术语“羟基保护基”意指适用于防止羟基处的非所需反应的保护基。代表性羟基保护基包括(但不限于)硅基,包括三(C1-6烷基)硅基,如三甲基硅基(TMS)、三乙基硅基(TES)、叔丁基二甲基硅基(TBS)等;酯(酰基),包括C1-6烷酰基,如甲酰基、乙酰基等;芳基甲基,如苄基(Bn)、对甲氧基苄基(PMB)、9-芴基甲基(Fm)、二苯基甲基(二苯甲基,DPM)等。
许多保护基及其引入及去除述于格林(T.W.Greene)与伍兹(P.G.M.Wuts),有机合成中的保护基(Protecting Groups in Organic Synthesis),第三版,威利(Wiley),纽约(New York)中。
实例
提供下列合成实例以说明本发明,且不以任何方式解释为限制本发明的范围。在以下实例中,除非另有指定,否则下列缩写具有下列含义。以下未定义的缩写具有其一般接受的含义。
ACN=乙腈
DMF=N,N-二甲基甲酰胺
EtOAc=乙酸乙酯
EtOH=乙醇
NaHMDS=双(三甲基硅基)氨基钠
MeTHF=2-甲基四氢呋喃
MTBE=叔丁基甲基醚
psi=磅/平方英寸
Rt=滞留时间
试剂和溶剂是购自商业供货商(奥德里奇(Aldrich)、施特雷姆化学品有限公司(Strem Chemicals,Inc.)等)且无需进一步纯化即可使用。通过分析型高效液相色谱法和质谱法监测反应混合物的进程。使用下述方案通过HPLC分析测定产物的内/外(Endo/exo)比率。如各反应中特定叙述处理反应混合物;其通常通过萃取及其它纯化方法(如温度依赖性及溶剂依赖性结晶,和沉淀)纯化。反应产物的表征常规通过质谱法和1H-NMR光谱法进行。针对NMR测量,将样品溶解在氘化溶剂(DMSO-d6或CDCl3)中,及使用瓦里安杰米2000(Varian Gemini 2000)仪器(400MHz)在标准观察条件下获取1H-NMR光谱。使用安捷伦(Agilent)(加利福尼亚州帕罗奥图(Palo Alto,CA))型号1100LC/MSD仪器进行化合物的质谱识别。
一般HPLC条件
柱:佐尔巴克(Zorbax)SB-Aq,5μm.4.6x250mm
柱温度:40℃
流率:1.0mL/min
流动相:A=水/ACN(98:2)+0.1%TFA
B=水/ACN(10:90)+0.1%TFA,
注射体积:10μL
检测器波长:214nm
HPLC方法1
将粗制化合物以约1mg/mL溶解在水/ACN(50:50)中及使用下列梯度历时20分钟(时间(分钟)/%B)分析:0/10、2.5/20、9/75、15/90、17/90、18/10、20/10。
HPLC方法2
将化合物以约1mg/mL溶解在水/ACN(90:10)中及使用下列梯度历时30分钟(时间(分钟)/%B)分析:0/10、13/10、23/65、28/90、29/90、30/10。
HPLC方法3
将化合物以约1mg/mL溶解在水/ACN(90:10)中及使用下列梯度历时55分钟(时间(分钟)/%B)分析:0/10、10/20、46/75、47/90、50/10、55/10。
制备1:4-(苄氧基)-2-乙基苯基)三氟-λ4-硼烷钾盐I-5
(a)1-(苄氧基)-3-乙基苯(I-2)
在室温下,向经搅拌的含在ACN(250mL,10体积)中的3-乙基苯酚(I-1)(25.0g,204.0mmol)的溶液中添加碳酸钾(42.0g,306mmol)。将所得反应物料在室温下搅拌15分钟,接着以逐滴方式添加苄基溴(24.0mL,204mmol)。将所得反应混合物在室温下搅拌6小时。在完成反应(TLC监测)后,将所得反应物料倒入水(1.0L)中,接着将化合物用EtOAc(2x2L)萃取。将合并的有机物用冷水、盐水溶液洗涤及经硫酸钠干燥、过滤及在减压下蒸发。然后通过柱色谱法在硅胶上(100到200M)通过使用洗脱剂2%EtOAc/己烷纯化粗产物,以得到呈浅黄色油状化合物的所需产物(I-2)(35.0g,81%)。1H NMR(400MHz,氯仿-d)δ7.46-7.44(m,2H),7.39(t,J=7.6Hz,2H),7.34-7.31(m,1H),7.21(t,J=7.6Hz),6.86-6.80(m,3H),5.07(s,2H),2.64(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H)。
(b)4-(苄氧基)-1-溴-2-乙基苯(I-3)
将N-溴琥珀酰亚胺(32.0g,181mmol)分数份添加到1-(苄氧基)-3-乙基苯(I-2)(35.0g,164mmol)在ACN(525mL,15体积)中的冰冷搅拌溶液中历时15分钟的时间。将所得反应混合物在室温搅拌1小时。在完成反应(TLC监测)后,将所得反应物料倒入冰冷水(1.50L)中,接着将化合物用EtOAc(2x1L)萃取。将合并的有机物用水洗涤及经硫酸钠干燥、过滤及在减压下蒸发以获得粗产物。将正己烷(250mL)添加到粗物质中,产生浆液,接着通过烧结漏斗过滤。将母液在减压下蒸发以获得呈浅黄色油状化合物的所需产物I-3(42.0g,87%)。1H NMR(400MHz,氯仿-d)δ7.52-7.29(m,7H),6.88(s,1H),6.68(d,J=6.0Hz,1H),5.04(s,2H),2.69(q,J=7.6Hz,2H),1.20(t,J=7.5Hz,3H)。
(c)2-(4-(苄氧基)-2-乙基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼戊环(dioxaborolane)(I-4)
将4-(苄氧基)-1-溴-2-乙基苯(I-3)(42.0g,144mmol)、双(频哪醇基)二硼(44.0g,173mmol)和乙酸钾(28g,288mmol)在二噁烷(440mL)中的搅拌溶液通过N2(g)吹洗15分钟脱气,接着添加PdCl2(dppf).DCM复合物(11.0g,15mmol)。将所得反应混合物加热到80℃持续16小时。在完成反应(TLC监测)后,将反应物料通过硅藻土床过滤及将母液在减压下蒸发,以获得粗产物。通过柱色谱法在硅胶上(100到200M)通过使用洗脱剂1%EtOAc/己烷纯化粗制残余物,以得到呈浅黄色油状化合物的所需产物(I-4)(32.0g,66%)。1H NMR(400MHz,氯仿-d)δ7.74(d,J=8.4Hz,1H),7.45-7.36(m,5H),6.84-6.78(m,2H),5.08(s,2H),2.91(q,J=7.6Hz),1.33(s,12H),1.19(t,J=7.6Hz,3H)。
(d)(4-(苄氧基)-2-乙基苯基)三氟-λ4-硼烷钾盐(I-5)
向经搅拌的含在丙酮:甲醇(200mL,1:1比率,10体积)中的化合物2-(4-(苄氧基)-2-乙基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼戊环(I-4)(20g,59.0mmol)的溶液中添加3M氟化氢钾的溶液(23.0g,295mmol,溶解在98.0mL水中)。将所得反应混合物在室温下搅拌16小时。在完成反应(TLC监测)后,将所得反应物料在减压下蒸发。将因此获得的固体溶于水(100mL)中及在室温下搅拌30分钟。将所得反应物料通过烧结漏斗过滤,用正己烷洗涤及在减压下干燥,以得到呈白色固体的所需产物(I-5)(14.0g,74%)。1H NMR(400MHz,氯仿-d)δ7.43(d,J=7.2Hz,2H),7.37(t,J=7.5Hz,2H),7.30(t,J=7.1Hz,1H),7.22(d,J=8.0Hz),6.58(s,1H),6.53(d,J=7.9Hz,1H),5.00(s,2H),2.65(q,J=7.5Hz,2H),1.07(t,J=7.4Hz,3H)。
制备2:(S)-3-苄基-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-11)
(a)(S)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸盐酸盐(I-7)
以逐滴方式向冰冷经搅拌的含在水(40L,8体积)中的L-组氨酸(I-6)(5.0kg,32.14mol)的悬浮液中添加浓盐酸(3.93L,33.75mol),接着添加甲醛(5.50L,67.5mol,37%水溶液)。将所得溶液在相同温度下搅拌30分钟及然后在80℃下加热8小时。通过LCMS监测反应进程。在减压下去除水以获得粗产物,及将所得粗制物在甲苯(20L)中搅拌2小时。在减压下去除有机物以去除过量水及将化合物共沸干燥。然后将所得物质溶于乙醚(20L)中及搅拌2小时。然后将固体物质过滤及空气干燥,以获得呈灰白色固体的所需产物(I-7)(6.50Kg,85%)。1H NMR(400MHz,D2O)δ8.69(s,1H),4.56(d,J=15.4Hz,1H),4.42(d,J=15.5Hz,1H),4.20(dd,J=5.5,5.2Hz,1H),3.42(dd,J=5.0,17.0Hz,1H),3.11(dd,J=10.2,16.8Hz,1H)。
(b)(S)-3,5-双(叔丁氧羰基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸(I-8)
向冰冷经搅拌的含在1,4-二噁烷(48L,8体积)和水(48L,8体积)中的(S)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸二盐酸盐(I-7)(6.10Kg,25.40mol)的溶液中逐滴添加三乙胺(12.36L,89mol),接着历时30分钟的时间添加二碳酸二叔丁酯(18.07L,78.74mol,溶解在5L 1,4-二噁烷中)。将所得反应混合物在室温下搅拌16小时。在完成反应(TLC和LCMS监测)后,将微黄色反应混合物用水(10L)稀释及用乙醚(2x10L)和EtOAc(2x7.50L)连续洗涤。丢弃有机相。将水层冷却及用6N HCl溶液调到pH约3;将水相用EtOAc(3x10L)萃取。将合并的有机物用盐水溶液洗涤,经硫酸钠干燥,及在减压下浓缩。将油性残余物从30%EtOAc:己烷结晶,以得到呈灰白色固体的所需产物(I-8)(5.1Kg,55%)。(m/z):[M+H]+针对C17H25N3O6计算值368.18,实测值368.21。
(c)(S)-6,7-二氢-3H-咪唑并[4,5-c]吡啶-3,5,6(4H)-三甲酸6-苄酯3,5-二-叔丁酯(I-9)
向含在DCM(51L,10体积)中的(S)-3,5-双(叔丁氧羰基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸(I-8)(5.1Kg,13.88mol)的冰冷溶液中依序添加饱和碳酸氢钠水溶液(41.0L,8体积)、四丁基碘化铵(5.13Kg,13.88mol)和苄基溴(2.47L,20.82mol)。将所得反应混合物在室温下搅拌16小时。在完成反应(TLC及LCMS监测)后,分离两相溶液。将水层用DCM(3x10L)萃取。将合并的有机物用盐水溶液洗涤,经硫酸钠干燥,过滤及在减压下浓缩,以获得粗产物,通过柱色谱法通过硅胶(100到200M)通过使用洗脱剂40%EtOAc/己烷纯化所述粗产物,以得到呈黏性油的所需产物(I-9)(4.50Kg,72%)。(m/z):[M+H]+针对C24H31N3O6计算值458.22,实测值458.60。
(d)(S)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-10)
向含在IPA(45L,10体积)中的(S)-6,7-二氢-3H-咪唑并[4,5-c]吡啶-3,5,6(4H)-三甲酸6-苄酯3,5-二-叔丁酯(I-9)(4.50Kg,9.84mol)的冰冷溶液中逐滴添加氢氧化铵(36L,8体积)。将所得反应混合物进一步在室温下再搅拌16小时。在完成反应(TLC及LCMS监测)后,将所得混合物用水(25L)稀释,接着用EtOAc(3x20L)萃取。将合并的有机物用盐水溶液洗涤,经硫酸钠干燥,过滤及在减压下浓缩,以得到粗产物,通过柱色谱法通过硅胶(100到200M)通过使用洗脱剂2%MeOH/DCM纯化所述粗产物,以得到呈稠黏性油的所需产物(I-10)(2.70Kg,77%)。(m/z):[M+H]+针对C19H23N3O4计算值358.17,实测值358.33。
(e)(S)-3-苄基-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-11)
向含在DCM(32.4L,12体积)中的(S)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-10)(2.70kg,7.55mol)的冰冷溶液中添加1N氢氧化钠水溶液(24.3L,9体积),接着依序添加四丁基碘化铵(2.80Kg,7.55mol)和苄基溴(0.99L,8.31mol)。将所得反应混合物在室温下搅拌2小时。在完成反应(TLC及LCMS监测)后,分离两相溶液。将水层用DCM(3x10L)萃取。将合并的有机物用盐水溶液洗涤,经硫酸钠干燥,过滤及在减压下浓缩,以得到粗产物,通过柱色谱法在硅胶(100到200M)上通过使用洗脱剂40%EtOAc/己烷纯化所述粗产物,以获得呈黏性油的所需产物(I-11)(1.70Kg,63%)。(m/z):[M+H]+针对C26H29N3O4计算值448.22,实测值448.20。
制备3:(S)-3-苄基-2-(6-溴-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-15)
(a)4-溴-2-氟苯甲酰氯(I-13)
以逐滴方式向冰冷经搅拌的含在DCM(12.5L,15体积)中的4-溴-2-氟苯甲酸(I-12)(1.25Kg,5.71mol)的溶液中添加草酰氯(0.98L,11.42mol)。将所得反应混合物在相同温度下搅拌10分钟。然后以逐滴方式将DMF(150mL)添加到反应混合物中。允许将所得反应物料升温到室温并搅拌2小时。在完成反应(通过TLC监测)后,在减压下在氮气氛围下去除过量草酰氯,以获得粗产物(I-13)(1.08Kg,80%),所述粗产物无需进一步纯化即可用于下个步骤。
(b)(S)-3-苄基-2-(4-溴-2-氟苯甲酰基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-14)
在室温下,向经搅拌的含在ACN(13.6L,8体积)中的(S)-3-苄基-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-11)(1.70Kg,3.80mol)的溶液中添加三乙胺(2.11L,15.2mol),接着添加4-溴-2-氟苯甲酰氯(I-13)(1.08Kg,4.56mol含在3.4L ACN中,2体积)。在完成添加后,所得反应混合物颜色从浅黄色变成棕色。将所得反应混合物在相同温度下搅拌30分钟,及通过TLC监测反应进程。将所得反应混合物用冰冷水(10L)淬灭,接着用EtOAc(3x5L)萃取及将合并的有机物用盐水溶液洗涤。将有机物经硫酸钠干燥,过滤及在减压下浓缩得到粗产物,通过柱色谱法在硅胶(100到200M)上通过使用洗脱剂20%EtOAc/己烷纯化所述粗产物,以获得所需产物(I-14)(1.74Kg,71%)。(m/z):[M+H]+针对C33H31BrFN3O5计算值648.14,实测值648.20。
(c)(S)-3-苄基-2-(6-溴-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-15)
在室温下,向经搅拌的含在THF(26.0L,15体积)中的(S)-3-苄基-2-(4-溴-2-氟苯甲酰基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-14)(1.74Kg,2.68mol)的溶液中添加水合肼(0.705L,13.4mol)。将所得反应混合物在60℃下加热3小时。在完成反应(TLC监测)后,将所得反应物料倒入冰冷水(10L)中,接着将化合物用EtOAc(3x10L)萃取。将合并的有机物用盐水洗涤及经硫酸钠干燥,过滤及在减压下蒸发以得到粗产物,通过柱色谱法在硅胶(100到200M)上通过使用洗脱剂20%EtOAc/己烷纯化所述粗产物,以获得呈灰白色固体的所需产物(I-15)(1.12Kg,65%)。(m/z):[M+H]+针对C33H32BrN5O4计算值642.16,实测值642.21。
制备4:(S)-3-苄基-2-(6-(4-(苄氧基)-2-乙基苯基)-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-16)
将双(频哪醇基)二硼(250g,984mmol)连同丙-2-醇(1882mL,2.46E+04mmol)放入先前使用氟化物化学品蚀刻的5L 3颈单壁烧瓶中及将混合物搅拌直到完全溶解。溶解是吸热(-4℃)。在先前使用氟化物化学品蚀刻的4L爱伦美氏(Erlenmeyer)瓶中,将氟化钾氢氟化物(538g,6891mmol)溶解在水(2306mL,1.28E+05mmol)中以形成3M溶液。溶解是吸热(-12℃)。然后将溶液过滤以从KHF2去除少量不可溶物质。一旦两种溶液完全溶解,将爱伦美氏瓶的内容物历时15分钟逐份放入单壁烧瓶中。观察到适度放热(+10℃)。在添加期间溶液变成稠且半透明半不透明灰色浆液及增加搅拌以保持内容物充分混合。将混合物搅拌1.5小时,及然后通过粗玻璃熔结漏斗(4L,先前经蚀刻)过滤。过滤需要30到45分钟完成。丢弃澄清两相滤液。将白色固体在过滤器上干燥10分钟(观察到滤饼开裂)。将固体转移回清洁的5L 3颈单壁烧瓶中及用水(1330mL,7.38E+04mmol)再浆化。将浆液搅拌2小时,之后其形成澄清均匀水凝胶。将溶液再搅拌1小时,届时将固体/凝胶使用4L粗玻璃漏斗(先前经蚀刻)过滤掉。允许将固体在过滤器上干燥30分钟。将固体转移回清洁的5L 3颈单壁烧瓶中及在丙酮(1084mL,1.48E+04mmol)中再浆化。将白色/灰色浆液搅拌1小时及然后在4L粗玻璃漏斗(先前经蚀刻)上过滤。过滤需要20分钟完成,及然后在漏斗上再干燥1小时。在此期间,偶尔搅动固体以确保均匀干燥。浅白色粉末在干燥后保留在过滤器上。将固体在55℃下在真空下随着缓慢氮气排放干燥20小时,以得到疏松白色固体(收集200.3g)。
向经搅拌的含在2-甲基四氢呋喃(100mL,10体积)中的(S)-3-苄基-2-(6-溴-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-15)(10.0g,16.0mmol)的溶液中添加(4-(苄氧基)-2-乙基苯基)三氟-λ4-硼烷钾盐(I-5)(8.0g,20mmol)和以上获得的疏松白色固体(0.20g)。将所得反应混合物用氮气脱气30分钟。向此溶液中添加经制备的碳酸铯水溶液(20.0g,62.0mmol含在60mL水中,6体积)。将所得反应混合物进一步脱气15分钟,接着添加双(二-叔丁基(4-二甲氨基苯基)膦)二氯钯(II)(0.66g,0.93mmol),及将反应混合物在真空下排空及通过氮气冲洗。将所得反应混合物在110℃下加热20小时。在完成反应(TLC及LCMS监测)后,将所得反应混合物冷却到室温及通过硅藻土床过滤,然后进一步用EtOAc(3x0.5L)洗涤。将合并的有机物用1N氢氧化钠溶液(3x0.5L)洗涤。然后将合并的有机物用盐水洗涤及经硫酸钠干燥,过滤及在减压下蒸发以得到粗产物,通过柱色谱法在硅胶(100到200M)上通过使用洗脱剂20%EtOAc/己烷纯化所述粗产物,以获得呈浅黄色固体的所需产物(I-16)(作为N-苄基区域异构体的混合物)(8.0g,66%)。(m/z):[M+H]+针对C48H47N5O5计算值774.36,实测值774.59。
制备5:(S)-2-(6-(2-乙基-4-羟基苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸盐酸盐(I-18)
(a)(S)-3-苄基-2-(6-(4-(苄氧基)-2-乙基苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸苄酯盐酸盐(I-17)
将(S)-3-苄基-2-(6-(4-(苄氧基)-2-乙基苯基)-1H-吲唑-3-基)-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(I-16)(1.0g,1.292mmol)溶解在二噁烷(8mL)和水(1.5mL)中,然后添加4M氯化氢二噁烷溶液(7mL,28.0mmol)及将反应混合物在室温下搅拌3小时(通过LCMS监测反应进程)。然后将反应混合物冷冻及冻干,及将粗产物(I-17)直接用于下个反应(假设定量产率)。(m/z):[M+H]+针对C43H39N5O3计算值674.31,实测值674.3。
(b)(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸盐酸盐(I-18)
在50℃下,将(S)-3-苄基-2-(6-(4-(苄氧基)-2-乙基苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸苄酯盐酸盐(I-17)(0.918g,1.292mmol)溶解在2-丙醇(15mL)、5M氯化氢水溶液(0.258mL,1.292mmol)和水(0.25mL)中,然后添加10重量%碳载钯,50%水(0.138g,0.065mmol)。然后将反应烧瓶用氮气吹洗,附接氢气球,及将反应混合物在50℃下搅拌4天,其中视需要补充氢气球(通过LCMS监测反应进程)。然后通过过滤去除所有固体及将所得溶液浓缩。将残余物溶解在1:1ACN/水中,冷冻及冻干。所得粉末(I-18)无需进一步纯化即可使用(假设定量产率)。(m/z):[M+H]+针对C22H21N5O3计算值404.17,实测值404.2。
制备6:(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸(I-19)
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸HCl盐(I-18)(0.25g,0.568mmol)悬浮在DMF(2.5mL)和丙酮(2.5mL)中,然后添加乙酸(0.098mL,1.705mmol)和氰基硼氢化钠(0.179g,2.84mmol)及将反应混合物在室温下搅拌24小时(通过LCMS监测反应进程)。将反应混合物浓缩,然后通过逆相色谱法(5到70%ACN/水梯度,50g C18aq柱)纯化粗产物,以得到标题化合物的TFA盐(149mg,47%产率)。(m/z):[M+H]+针对C25H27N5O3计算值446.21,实测值446.3。
制备7:(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸(I-20)
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸HCl盐(I-18)(0.160g,0.364mmol)和丙醛(0.039mL,0.546mmol)溶解在甲醇(3.0mL)中,然后添加氰基硼氢化钠(0.069g,1.091mmol)及将反应混合物在室温下搅拌24小时(通过LCMS监测反应进程)。将反应混合物浓缩及通过逆相色谱法(5到70%ACN/水梯度,50g C18柱)纯化粗产物,以得到标题化合物的TFA盐(78mg,38%产率)。(m/z):[M+H]+针对C25H27N5O3计算值446.21,实测值446.3。
制备8:(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸(I-21)
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸HCl盐(I-18)(0.160g,0.364mmol)和37重量%甲醛水溶液(0.032mL,0.436mmol)溶解在甲醇(3.0mL)中,然后添加氰基硼氢化钠(0.069g,1.091mmol)及将反应混合物在室温下搅拌4小时(通过LCMS监测反应进程)。添加硼氢化钠(14mg,0.364mmol)以淬灭任何过量甲醛,然后将反应混合物浓缩。通过逆相色谱法(5到70%ACN/水梯度,50gC18柱)纯化粗产物,以得到标题化合物的TFA盐(110mg,57%产率)。(m/z):[M+H]+针对C23H23N5O3计算值418.18,实测值418.2。
制备9:(R)-2-(3-甲基哌嗪-1-基)乙-1-醇二盐酸盐(I-24)
(a)(R)-4-(2-羟乙基)-2-甲基哌嗪-1-甲酸叔丁酯(I-23)
将(R)-1-boc-2-甲基哌嗪(0.2g,0.999mmol)、DIPEA(0.698mL,3.99mmol)和2-溴乙醇(0.085mL,1.198mmol)溶解在DMF(5mL)中及将反应混合物在60℃下搅拌16小时(通过LCMS监测反应进程)。将反应混合物浓缩,然后将10mL乙醚添加到残余物。将溶液音波处理直到残余物凝胶消失及固体形成。然后将醚溶液从固体倾析除掉。然后将固体直接用于下个反应中(假设定量产率)。(m/z):[M+H]+针对C12H24N2O3计算值245.18,实测值245.4。
(b)(R)-2-(3-甲基哌嗪-1-基)乙-1-醇二盐酸盐(I-24)
将(R)-4-(2-羟乙基)-2-甲基哌嗪-1-甲酸叔丁酯(0.244g,0.999mmol)溶解在二噁烷(3.0mL)和水(0.5mL)中,然后添加4M氯化氢二噁烷溶液(2.0mL,65.8mmol)及将反应混合物在室温下搅拌3小时(通过LCMS监测反应进程)。将反应混合物冷冻及冻干,及无需纯化即可使用所得产物(假设定量产率)。(m/z):[M+H]+针对C7H16N2O计算值145.13,实测值145.4。
实例1:(S)-(2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)(4-(2-羟乙基)哌嗪-1-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(I-20)(40mg,0.071mmol)、n-(2-羟乙基)哌嗪(0.018mL,0.143mmol)和DIPEA(0.025mL,0.143mmol)溶解在DMF(1.5mL)中,然后添加HATU(40.8mg,0.107mmol)及将反应混合物在室温下搅拌3小时(通过LCMS监测反应进程)。添加肼(0.011mL,0.357mmol)以裂解非所需副产物,然后将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到70%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(31mg,56%产率)。(m/z):[M+H]+针对C31H39N7O3计算值558.31,实测值558.3。1HNMR(400MHz,DMSO-d6)δ13.10(s,1H),12.27(d,J=48.92Hz,1H),9.40(s,1H),8.28(t,J=8.10Hz,1H),7.30(s,1H),7.04(m,2H),6.71(d,J=2.46Hz,1H),6.64(dd,J=2.50,8.23Hz,1H),4.44(t,J=5.31Hz,1H),4.11(q,J=5.26,2H),3.96(m,1H),3.86-3.52(m,6H),3.49(q,J=6.01Hz,2H),2.95(m,2H),2.48(q,J=7.48Hz,2H),2.42-2.21(m,4H),2.37(t,J=6.20Hz,2H),1.42(m,2H),1.00(t,J=7.52Hz,3H),0.81(m,3H)。
实例2:((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)((1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(I-20)(40mg,0.071mmol)、(1S,4S)-5-甲基-2,5-二氮杂双环[2.2.1]庚烷二氢溴化物(29.4mg,0.107mmol)和DIPEA(0.062mL,0.357mmol)溶解在DMF(1.5mL)中,然后添加HATU(40.8mg,0.107mmol)及将反应混合物在室温下搅拌3小时(通过LCMS监测反应进程)。添加肼(0.011mL,0.357mmol)以裂解非所需副产物,然后将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到70%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(32mg,59%产率)。(m/z):[M+H]+针对C31H37N7O2计算值540.30,实测值540.3。
实例3:((S)-2,4-二甲基哌嗪-1-基)((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮3
(a)(S)-4-((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-羰基)-3-甲基哌嗪-1-甲酸叔丁酯(I-25)
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(I-21)(55mg,0.103mmol)、(s)-4-n-boc-2-甲基哌嗪(41.5mg,0.207mmol)和DIPEA(0.036mL,0.207mmol)溶解在DMF(1.5mL)中,然后添加HATU(59.0mg,0.155mmol)并将反应混合物在室温下搅拌16小时(通过LCMS监测反应进程)。添加肼(0.016mL,0.517mmol)以裂解非所需副产物,然后将反应混合物在室温下搅拌10分钟。然后将反应混合物浓缩并通过反相色谱法(5到70%ACN/水梯度,50g C18柱)纯化粗产物,以得到标题化合物的TFA盐(54mg,72%产率)。(m/z):C33H41N7O4的[M+H]+计算值600.33,实测值600.3。
(b)((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)((S)-2-甲基哌嗪-1-基)甲酮(I-26)
将(S)-4-((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-羰基)-3-甲基哌嗪-1-甲酸叔丁酯TFA盐(I-25)(0.126g,0.177mmol)溶解在二噁烷(1.5mL)和水(0.3mL)中,然后添加4M氯化氢的二噁烷溶液(1.5mL,6.00mmol)并将反应混合物在室温搅拌2小时(通过LCMS监测反应进程)。将反应混合物冷冻及冻干,且将所得粉末直接用于下个反应(假设定量产率)。(m/z):C28H33N7O2的[M+H]+计算值500.27,实测值500.3。
(c)((S)-2,4-二甲基哌嗪-1-基)((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)((S)-2-甲基哌嗪-1-基)甲酮二盐酸盐(0.101g,0.176mmol)和37重量%甲醛的水溶液(0.016mL,0.212mmol)溶解在甲醇(3.0mL)中,然后添加氰基硼氢化钠(0.055g,0.882mmol)并将反应混合物在室温搅拌16小时(通过LCMS监测反应进程)。添加硼氢化钠(7mg,0.176mmol)以淬灭任何剩余甲醛。将反应混合物浓缩,然后通过制备型HPLC(5到60%ACN/水梯度,C18柱)纯化粗产物,得到标题化合物的TFA盐(28mg,21%产率)。(m/z):C29H35N7O2的[M+H]+计算值514.29,实测值514.3。
实例4:(S)-(2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(I-19)(50mg,0.089mmol)、1-甲基高哌嗪(0.022mL,0.179mmol)和DIPEA(0.031mL,0.179mmol)溶解在DMF(1.5mL)中,然后添加HATU(51.0mg,0.134mmol),及将反应混合物在室温搅拌3小时(通过LCMS监测反应进程)。添加肼(0.014mL,0.447mmol)以裂解非所需副产物,及将溶液在室温搅拌10分钟。然后将反应混合物浓缩,及通过制备型HPLC(2到70%ACN/水梯度,C18柱)纯化粗产物,得到标题化合物的TFA盐(29mg,42%产率)。(m/z):[M+H]+针对C31H39N7O2计算值542.32,实测值542.3。1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),12.21(d,J=29.9Hz,1H),9.40(s,1H),8.27(d,J=8.33Hz,1H),7.30(s,1H),7.04(t,J=8.05,2H),6.71(d,J=2.53Hz,1H),6.64(dd,J=2.54,8.23Hz,1H),4.11(m,3H),3.91-3.52(m,6H),2.97(m,1H),2.91-2.53(m,4H),2.49(q,J=7.46,2H),2.23(d,J=13.9Hz,3H),1.76(m,2H),1.0(m,9H)。
实例5:((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)((R)-4-(2-羟乙基)-2-甲基哌嗪-1-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(I-21)(55mg,0.103mmol)、(R)-2-(3-甲基哌嗪-1-基)乙-1-醇二盐酸盐(I-24)(33.7mg,0.155mmol)和DIPEA(0.090mL,0.517mmol)溶解在DMF(1.5mL)中,然后添加HATU(59.0mg,0.155mmol)及将反应混合物在室温下搅拌16小时(通过LCMS监测反应进程)。添加肼(0.016mL,0.517mmol)以裂解非所需副产物,然后将反应混合物在室温下搅拌10分钟。然后将反应混合物浓缩,及通过制备型HPLC(5到70%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(22mg,28%产率)。(m/z):[M+H]+针对C30H37N7O3计算值544.30,实测值544.3。
实例6:((S)-3-(二甲氨基)吡咯烷-1-基)((S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(I-19)(50mg,0.089mmol)、(S)-(-)-3-(二甲氨基)吡咯烷(0.023mL,0.179mmol)和DIPEA(0.031mL,0.179mmol)溶解在DMF(1.5ml)中,然后添加HATU(51.0mg,0.134mmol)及将反应混合物在室温下搅拌3小时(通过LCMS监测反应进程)。添加肼(0.014mL,0.447mmol)以裂解非所需副产物,及将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到70%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(37mg,53%产率)。(m/z):[M+H]+针对C31H39N7O2计算值542.32,实测值542.3。
实例7:(S)-(3-(二甲氨基)氮杂环丁烷-1-基)(2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(I-19)(50mg,0.089mmol)、3-(二甲氨基)氮杂环丁烷二盐酸盐(23.20mg,0.134mmol)和DIPEA(0.078mL,0.447mmol)溶解在DMF(1.5mL)中,然后添加HATU(51.0mg,0.134mmol)及将反应混合物在室温下搅拌3小时(通过LCMS监测反应进程)。添加肼(0.014mL,0.447mmol)以裂解非所需副产物,及将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到70%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(25mg,37%产率)。(m/z):[M+H]+针对C30H37N7O2计算值528.30,实测值528.3。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.40(s,1H),8.27(d,J=8.31,1H),7.30(s,1H),7.04(m,2H),6.71(d,J=2.54,1H),6.64(dd,J=2.53,8.26,1H),4.26(m,1H),4.06(m,2H),3.82(m,2H),3.64(m,2H),3.03(m,2H),2.74(m,2H),2.47(q,J=7.56,2H),2.07(d,J=3.69,6H),1.07(m,6H),1.00(t,J=7.50,3H)。
制备10:(S)-1-苄基-2-(6-(4-(苄氧基)-2-乙基-5-氟苯基)-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)
向经搅拌的含在2-甲基四氢呋喃(11.2L,10体积)中的(S)-1-苄基-2-(6-溴-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(1.12Kg,1.74mol)的溶液中添加((4-(苄氧基)-2-乙基-5-氟苯基)三氟硼烷钾盐)(0.702Kg,2.1mol)及在制备4中单离的疏松白色固体(0.223Kg,1.04mol)。将所得反应混合物通过滴管入口用氮气再脱气30分钟。向此溶液中添加经制备的Cs2CO3的水溶液(2.27Kg,6.96mol含在7.30L H2O中,6体积)。将所得反应混合物进一步脱气历时接下来15分钟。将Pd(amphos)(0.74Kg,1.04mol)添加到所得反应混合物中及将反应混合物在真空下排空及用氮气冲洗。将所得反应混合物加热到90℃持续20小时。在完成反应后,将所得反应混合物冷却到室温及通过硅藻土床过滤,及用乙酸乙酯(3x7.5L)洗涤。将合并的有机物用1N NaOH溶液(3x3L)洗涤。将合并的有机物用盐水洗涤及经Na2SO4干燥,过滤及在减压下蒸发以得到粗物质,将所述粗物质使用柱色谱法在硅胶(100到200M)上通过使用洗脱剂20%乙酸乙酯/己烷纯化,以获得作为区域异构体的混合物的呈灰白色固体的标题产物(1.10Kg,80%)。(m/z):[M+H]+针对C48H46FN5O5计算值792.92,实测值792.34。
制备11:(S)-1-苄基-2-(6-(4-(苄氧基)-2-乙基-5-氟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-6-甲酸苄酯2苯磺酸
在氮气下,向含在2-甲基四氢呋喃(10,050mL)和乙酸异丙酯(4,321.5mL)中的(S)-1-苄基-2-(6-(4-(苄氧基)-2-乙基-5-氟苯基)-1H-吲唑-3-基)-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5,6-二甲酸6-苄酯5-(叔丁酯)(1,005g,1269mmol)的溶液中添加苯磺酸(703g,4,442mmol)。将所得反应混合物在50℃下搅拌历时15小时。向完成的反应中添加乙酸异丙酯(5,728.5mL)。将浆液冷却到20℃及保持1小时。然后将稠化的浆液在氮气压力下过滤。然后将滤饼用乙酸异丙酯(5,000mL)冲洗及在氮气压力下在25℃下干燥历时2小时,接着在60℃下在高真空下使用氮气排放进一步干燥历时16小时,以得到呈灰白色自由流动固体的标题化合物(1,210g,95%产率)。(m/z):[M+H]+针对C43H38FN5O3计算值692.81,实测值692.88。
制备12:(S)-1-苄基-2-(6-(4-(苄氧基)-2-乙基-5-氟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-6-甲酸苄酯
向含在丙酮(12.0L)中的分子筛(1.21Kg)的悬浮液中添加(S)-1-苄基-2-(6-(4-(苄氧基)-2-乙基-5-氟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-6-甲酸苄酯2苯磺酸(1.20Kg,1,190mmol)和乙酸(26mL,446mmol)。允许将悬浮液在25℃下搅拌历时30分钟以得到不均匀灰白色到黄色不均匀混合物。向反应混合物中添加三乙酰氧基硼氢化钠(492g,2,321mmol)及在25℃下搅拌历时1小时。将反应混合物通过硅藻土过滤及将滤饼用2-甲基四氢呋喃(500mL)洗涤。将滤液用2-甲基四氢呋喃(8.0L)稀释及通过蒸馏将溶剂交换为丙酮。为了洗涤溶液,添加饱和碳酸氢钠(3,025mL)及将混合物搅拌1小时,停止搅拌,历时15分钟分离各层,丢弃水层(pH=7.5)及重复洗涤,此次在层分离之前允许2小时搅拌时间。将有机层蒸馏降到2.0L,添加乙酸异丙酯(8.0L)及通过蒸馏将溶剂交换为2-甲基四氢呋喃以得到浆液。将浆液在20℃下搅拌历时1小时,然后在氮气压力下过滤以得到呈灰白色固体的标题化合物(795g,91%产率)。(m/z):[M+H]+针对C46H44FN5O3计算值734.89,实测值734.96。
制备13:(S)-2-(6-(2-乙基-5-氟-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸2HCl盐
在50℃下,向经脱气的经搅拌的(S)-1-苄基-2-(6-(4-(苄氧基)-2-乙基-5-氟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-6-甲酸苄酯(760g,1,036mmol)、丙-2-醇(3,800mL)和1M氯化氢(aq)(2589mL,2,589mmol)的均匀溶液中添加10重量%Pd/C,50重量%H2O(76g,35.7mmol),接着立即通过反应混合物氢气鼓泡历时4小时。将反应混合物通过硅藻土(200克)垫过滤。向澄清暗黄色滤液中添加斯美兹硫醇(SiliaMetS Thiol)(76g,呈白色固体)及在50℃下搅拌历时1小时以清除剩余钯。将斯美兹硫醇通过0.2微米过滤器过滤掉以得到浅黄色均匀滤液,此时斯美兹硫醇是亮橙色。向所述滤液中添加乙酸异丙酯(7,600mL)及将其在旋转蒸发仪上浓缩到约3.0升。向呈浑浊悬浮液的浓缩溶液中添加乙酸异丙酯(7,600mL),接着浓缩到约3.0升。然后向呈稠浆液的浓缩物中添加乙酸异丙酯(7,600mL),此时浆液是自由流动且可过滤。将浆液过滤及将滤饼用乙酸异丙酯(3,000mL)冲洗,在高真空下干燥历时1小时,然后在高真空下使用氮气排放在50℃下进一步干燥历时18小时以得到标题化合物(472g,81%产率)。(m/z):[M+H]+针对C25H26FN5O3计算值464.51,实测值464.58。
实例8:(S)-(3-(二甲氨基)氮杂环丁烷-1-基)(2-(6-(2-乙基-5-氟-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
向冷却到-20℃的经搅拌的含在N,N-二甲基乙酰胺(2,436mL)中的(S)-2-(6-(2-乙基-5-氟-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸2HCl盐(470g,876mmol)和N,N-二甲基氮杂环丁烷-3-胺2HCl盐(197g,1,139mmol)的溶液中历时不少于15分钟添加DIPEA(413mL,2,366mmol)(放热添加造成批次温度上升到-9.1℃)。将批次冷却回到-15℃及添加HCTU(453g,1095mmol)。将混合物历时1小时升温到20℃及再保持1小时。向完成的反应混合物中添加乙酸异丙酯(5.0L)和1M HCl(2.0L)及将混合物搅拌历时15分钟,分离各层以将杂质萃取到乙酸异丙酯层中。将含有产物的水层用乙酸异丙酯(各5.0L)再萃取3次。在第4次萃取后,将水层添加到2-甲基四氢呋喃接着饱和碳酸氢钠溶液(约2.2L,以调整pH=8)中,搅拌15分钟,分离各层,及丢弃水层。将有机层溶剂交换成乙腈及在2.35L的最终体积下搅拌,此时产物呈非晶型可过滤固体沉淀出溶液。然后将浆液在氮气压力下过滤以得到345克粗产物。将粗产物(345g)溶解在甲醇(1.035L)中,保持在55℃下搅拌历时15小时以使产物从溶液结晶出来。将浆液冷却到10℃及保持在所述温度下,搅拌历时2小时。将稠浆液在氮气压力下历时2小时在20℃下过滤,接着在高真空下使用氮气排放在65℃下进一步干燥历时18小时以得到呈灰白色到白色自由流动固体的标题化合物(253g,53%产率)。(m/z):[M+H]+针对C30H36FN7O2计算值546.66,实测值546.73。
制备14:(S)-5-乙基-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸HCl盐(0.100g,0.227mmol)(I-18)和乙醛(0.019mL,0.341mmol)溶解在甲醇(3.0mL)中,然后添加氰基硼氢化钠(0.057g,0.909mmol)及将反应混合物在室温下搅拌16小时(通过LCMS监测反应进程)。添加硼氢化钠(9mg,0.227mmol)以淬灭任何剩余乙醛,然后将反应混合物浓缩。然后通过逆相色谱法(5到70%ACN/水梯度,40g C18柱)纯化粗产物,以得到标题化合物的TFA盐(62mg,50%产率)。(m/z):[M+H]+针对C24H25N5O3计算值432.20,实测值432.1。
实例9:(S)-(3-(二甲氨基)氮杂环丁烷-1-基)(5-乙基-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将(S)-5-乙基-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(30mg,0.055mmol)、3-(二甲氨基)氮杂环丁烷二盐酸盐(14.28mg,0.082mmol)和DIPEA(0.048mL,0.275mmol)溶解在DMF(1.50mL)中,然后添加HATU(31.4mg,0.082mmol)及将反应混合物在室温下搅拌1小时(通过LCMS监测反应进程)。添加肼(5.18μl,0.165mmol)以裂解非所需副产物,然后将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到60%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(25mg,63%产率)。(m/z):[M+H]+针对C29H35N7O2计算值514.29,实测值514.2。
实例10:(S)-(3-(二甲氨基)-3-甲基氮杂环丁烷-1-基)(5-乙基-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将(S)-5-乙基-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(30mg,0.055mmol)、N,N,3-三甲基氮杂环丁烷-3-胺盐酸盐(12.43mg,0.082mmol)和DIPEA(0.048mL,0.275mmol)溶解在DMF(1.50mL)中,然后添加HATU(31.4mg,0.082mmol)及将反应混合物在室温下搅拌1小时(通过LCMS监测反应进程)。添加肼(5.18μl,0.165mmol)以裂解非所需副产物,然后将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到60%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(25mg,62%产率)。(m/z):[M+H]+针对C30H37N7O2计算值528.30,实测值528.2。
实例11:(S)-(3-(二甲氨基)-3-甲基氮杂环丁烷-1-基)(2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-异丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸(40mg,0.090mmol)(I-19)、N,N,3-三甲基氮杂环丁烷-3-胺盐酸盐(20.29mg,0.135mmol)和DIPEA(0.047mL,0.269mmol)溶解在DMF(1.50mL)中,然后添加HATU(51.2mg,0.135mmol)及将反应混合物在室温搅拌16小时(通过LCMS监测反应进程)。添加肼(8.45μl,0.269mmol)以裂解非所需副产物,然后将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到60%ACN/水梯度,C18柱)纯化粗产物,得到标题化合物的TFA盐(26mg,38%产率)。(m/z):[M+H]+针对C31H39N7O2计算值542.32,实测值542.2。
实例12:(S)-(3-(二甲氨基)氮杂环丁烷-1-基)(2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(30mg,0.054mmol)(I-20)、3-(二甲氨基)氮杂环丁烷二盐酸盐(13.92mg,0.080mmol)和DIPEA(0.047mL,0.268mmol)溶解在DMF(1.50mL)中,然后添加HATU(30.6mg,0.080mmol)及将反应混合物在室温下搅拌1小时(通过LCMS监测反应进程)。添加肼(5.05μl,0.161mmol)以裂解非所需副产物,然后将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到60%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(26mg,63%产率)。(m/z):[M+H]+针对C30H37N7O2计算值528.30,实测值528.2。
实例13:(S)-(3-(二甲氨基)-3-甲基氮杂环丁烷-1-基)(2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-基)甲酮
将(S)-2-(6-(2-乙基-4-羟苯基)-1H-吲唑-3-基)-5-丙基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-6-甲酸TFA盐(30mg,0.054mmol)(I-20)、N,N,3-三甲基氮杂环丁烷-3-胺盐酸盐(12.12mg,0.080mmol)和DIPEA(0.047mL,0.268mmol)溶解在DMF(1.50mL)中,然后添加HATU(30.6mg,0.080mmol)及将反应混合物在室温下搅拌1小时(通过LCMS监测反应进程)。添加肼(5.05μl,0.161mmol)以裂解非所需副产物,然后将溶液在室温下搅拌10分钟。然后将反应混合物浓缩及通过制备型HPLC(5到60%ACN/水梯度,C18柱)纯化粗产物,以得到标题化合物的TFA盐(18mg,44%产率)。(m/z):[M+H]+针对C31H39N7O2计算值542.32,实测值542.2。
生物检定
已在下列生物检定中的一或多个中表征本发明的化合物。
检定1:生物化学JAK激酶检定
在常见激酶反应缓冲液(50mM HEPES,pH 7.5,0.01%Brij-35,10mM MgCl2和1mMEGTA)中进行一组四种蓝赛琳(LanthaScreen)JAK生物化学检定(JAK1、2、3和Tyk2)。重组GST标记的JAK酶和GFP标记的STAT1肽底物是获自生命科技公司(Life Technologies)。
将经连续稀释的化合物在白色384孔微量培养板(康宁(Corning))中在环境温度下与四种JAK酶中的每一个和底物一起预培育1小时。随后以10μL总体积(含有1%DMSO)添加ATP以启动激酶反应。JAK1、2、3和Tyk2的最终酶浓度分别为4.2nM、0.1nM、1nM和0.25nM;使用的对应Km ATP浓度为25μM、3μM、1.6μM和10μM;同时针对所有四种检定的底物浓度为200nM。允许在环境温度下继续进行激酶反应1小时,之后添加10μL含在TR-FRET稀释缓冲液(生命科技公司)中的EDTA(10mM最终浓度)和Tb-抗pSTAT1(pTyr701)抗体(生命科技公司,2nM最终浓度)的制备物。允许将板在环境温度下培育1小时,之后在远景(EnVision)读取器(珀金埃尔默(Perkin Elmer))上读取。记录及使用发射比率信号(520nm/495nm)以根据DMSO及背景对照计算抑制%值。
针对剂量反应分析,将抑制%数据对化合物浓度作图,及使用普利姆(Prism)软件(格帕软件(GraphPad Software))从4-参数稳健拟合模型测定IC50值。将结果表示为pIC50(IC50的负对数)及随后使用陈-普鲁夫(Cheng-Prusoff)方程式转化成pKi(解离常数Ki的负对数)。
在四个JAK检定中的每一个中具有较低Ki值或较高pKi值的测试化合物显示JAK活性的更大抑制。
检定2:经IL-2刺激的pSTAT5在Tall-1 T细胞中的抑制
在Tall-1人类T细胞系(DSMZ)中使用阿法利萨(AlphaLisa)测量测试化合物抑制经介白素-2(IL-2)刺激的STAT5磷酸化的效力。因为IL-2通过JAK1/3信号传导,此检定提供JAK1/3细胞效力的量度。
经由阿法利萨神火安加(AlphaLISA SureFire Ultra)pSTAT5(Tyr694/699)试剂盒(珀金埃尔默)测量经磷酸化的STAT5。
将来自Tall-1细胞系的人类T细胞在37℃,5%CO2加湿培育箱中在补充有15%热灭活胎牛血清(FBS,生命科技公司)、2mM谷丙氨酸二肽(Glutamax)(生命科技公司)、25mMHEPES(生命科技公司)和1X盘尼西林(Pen)/链霉素(Strep)(生命科技公司)的RPMI(生命科技公司)中培育。将化合物在DMSO中连续稀释及以声学方式分配到空孔。分配(4μL/孔)检定培养基(补充有10%FBS(ATCC)的无酚红DMEM(生命科技公司))及将板在900rpm下振荡10分钟。将细胞在检定培养基(4μL/孔)中以45,000个细胞/孔接种,及在37℃,5%CO2下培育1小时,接着添加含在预加温检定培养基(4μL)中的IL-2(R&D体系(R&D Systems);最终浓度300ng/mL)持续30分钟。在细胞因子刺激后,将细胞用含有1x磷酸酶抑制剂混合片(PhosStop)和完全锭剂(罗氏(Roche))的6μl 3x阿法利萨裂解缓冲液(珀金埃尔默)裂解。将裂解物在室温(RT)下在900rpm下振荡10分钟。经由pSTAT5阿法利萨试剂盒(珀金埃尔默)测量经磷酸化的STAT5。在经绿光滤波<100lux光下将新鲜制备的受体珠混合物分配到裂解物(5μL)。将板在900rpm下振荡2分钟,短暂旋转下来,及在RT下在暗处培育2小时。在经绿光滤波<100lux光下分配供体珠(5μL)。将板在900rpm下振荡2分钟,短暂旋转下来,及在RT下在暗处培育过夜。使用远景板读取器(珀金埃尔默)在经绿光滤波<100lux光下使用在689nm处的激发及在570nm处的发射测量发光。
为测定测试化合物对IL-2反应的抑制效力,在人类T细胞系中测量结合到pSTAT5的珠的平均发射强度。从分析信号强度对化合物浓度的抑制曲线来测定IC50值。将数据表示为pIC50(负十进制对数IC50)值(平均值±标准偏差)。
体外检定结果
在上述四种JAK酶检定(JAK1、JAK2、JAK3和Tyk2)和BEAS-2B细胞效力检定中测试本发明的化合物。
表1
检定3:肺组织中的IL-13诱导的pSTAT6诱导的鼠科(小鼠)模型
IL-13为哮喘的病理生理学基础的重要细胞因子(酷兹(Kudlacz)等人,欧洲药理学杂志(Eur.J.Pharmacol),2008,582,154-161)。IL-13结合到加纳斯(Janus)激酶家族(JAK)的细胞表面受体活化成员,其然后将STAT6磷酸化及随后活化另外转录路径。在所述模型中,将一剂量的IL-13局部递送到小鼠的肺以诱导STAT6的磷酸化(pSTAT6),然后测量其作为终点。
在所述检定中使用来自哈兰(Harlan)的成年Balb/c小鼠。在研究当天,将动物用异氟醚轻微麻醉及经由口吸入给予媒剂或测试化合物(1mg/mL,历时若干次呼吸50μL总体积)。在给药后将动物以侧卧放置及在返回其家笼之前监测从麻醉完全恢复。四小时后,将动物再次短暂麻醉及经由口吸入用媒剂或IL-13(0.03μg总递送剂量,50μL总体积)刺激,之后监测从麻醉恢复并返回其家笼。在媒剂或IL-13给予1小时后,收集全血和肺用于在肺匀浆中使用珀金埃尔默阿法利萨(Perkin Elmer AlphaLISA)神火(SureFire)安加(Ultra)TMHV p-STAT6(Tyr641)检定试剂盒的pSTAT6检测及用于在肺和血浆二者中的总药物浓度分析二者。将血液样品在约12,000rpm下在4℃下离心(艾本德(Eppendorf)离心机,5804R)4分钟以收集血浆。将肺在DPBS(杜贝克氏(Dulbecco’s)磷酸盐缓冲盐水)中冲洗,垫干,急速冷冻,称量及在0.1%甲酸/HPLC水中以1:3稀释均质化。针对于测试矩阵中构造成标准曲线的分析标准通过LC-MS分析测定测试化合物的血浆和肺含量。在5小时时以肺浓度(单位ng/g)与血浆浓度(单位ng/mL)的比率测定肺与血浆比率。
模型的活性通过在5小时时存在于经处理动物的肺中的pSTAT6的含量相较于经媒剂处理的经IL-13刺激的对照动物减少来证实。在任何给定实验中经媒剂处理的经IL-13刺激的对照动物与经媒剂处理的经媒剂刺激的对照动物之间的差异分别指示0%和100%抑制效应。检定中所测试的化合物展示在IL-13刺激后5小时时STAT6磷酸化的抑制,如下所记载。
表2:观察到的pSTAT6抑制及血浆/肺暴露
观察到小鼠肺中所测试的化合物的显著浓度证实,观察到的IL-13诱导的pSTAT6诱导的抑制为测试化合物活性的结果。在5小时时肺与血浆比率显示,化合物1到6展示与小鼠血浆中暴露相比,于小鼠肺中显著更多的暴露。
检定4:在人类外周血单核细胞中的TSLP激发的TARC释放的抑制
胸腺基质淋巴细胞生成素(TSLP)及胸腺及活化调节细胞因子(TARC)在哮喘气道中过度表现,且与疾病严重度相关。在肺中,TSLP可通过支气管上皮细胞对过敏原及病毒感染反应而释放。TSLP通过在宽范围组织及细胞类型(包括上皮细胞、内皮细胞、嗜中性粒细胞、巨噬细胞和肥大细胞)中发现的IL-7Rα/TSLPR异二聚体信号传导。TSLP与其受体的结合诱导活化JAK1和JAK2以将各种转录因子(包括STAT3和STAT5)磷酸化的构象改变。在免疫细胞中,此触发一连串细胞内事件,所述事件导致细胞增殖、抗细胞凋亡、树突状细胞迁移和Th2细胞因子及趋化因子的产生。在外周血单核细胞(PBMC)中,TSLP具有通过活化髓样树突状细胞以吸引和刺激T细胞(通过化学引诱物TARC介导的过程)的促发炎效应。
在此检定中,显示TSLP刺激诱导TARC从PBMC释放,及此反应在用化合物处理后以剂量依赖性方式减弱。针对TARC释放的抑制测量测试化合物的效力。
将来自3到5名供体的PBMC等分试样(先前从全血单离及以等分试样在-80℃下冷冻)在37℃下解冻及逐滴添加到在50mL法康(Falcon)管中的40mL经预加温无菌过滤的完全RPMI培养基中。将细胞沉淀集结(pellet)及以2.24×106个细胞/mL再悬浮在完全培养基中。将细胞在经组织培养物处理的96孔平底微量培养板中以85μL(190,000个细胞)/孔接种。允许将细胞在37℃与5%CO2下静置1小时。
接收化合物作为10mM含在DMSO中的储备溶液。进行3.7倍连续稀释以在300X最终检定测试浓度下产生含在DMSO中的测试化合物的9个浓度。在完全培养基中进行150倍中间稀释以产生2X最终检定测试浓度的化合物与0.2%DMSO。在1小时静置时间后,针对33.33μM到0.95μM的最终检定浓度范围将95μL 2X化合物添加到PBMC的各孔。将95μL含0.2%DMSO的完全培养基添加到未经处理的对照孔中。在刺激之前在37℃与5%CO2下将细胞用化合物预处理1小时。
将重组人类TSLP蛋白在含有0.1%BSA的无菌DPBS中以10μg/mL复水并以等分试样储存在-20℃下。在紧接使用之前,将等分试样解冻及在完全培养基中以20X最终检定浓度制备。针对10ng/mL的最终检定浓度,将10μL 20X TSLP添加到PBMC的各孔。将10μL完全培养基添加到未经刺激的对照孔。在37℃与5%CO2下在化合物的存在下将细胞刺激48小时。
在刺激后,收获细胞培养物上清液及根据制造商的说明,使用人类CCL17/TARC匡提金(Quantikine)ELISA试剂盒(R&D体系#DDN00),通过酶联免疫吸附检定(ELISA)检测TARC含量。
针对剂量反应分析,将log[测试化合物(M)]对各供体的反应%值作图,及使用非线性回归分析使用格帕普利姆(GraphPad Prism)软件使用具有可变斜率的4-参数s形剂量反应算法测定IC50值。将数据表示为从个别供体的pIC50值计算的平均pIC50(负十进制对数IC50)值并舍入到一个小数位。表3中概述抑制的效力值。
表3:测试化合物抑制在人类外周血单核细胞中的TSLP激发的TARC释放的效力(pIC50)值
虽然已参考其特定实施例描述本发明,但是所属领域的技术人员应了解,可在不背离本发明的真正精神和范围下作出各种改变和取代等效物。此外,可作出许多修改以使特定情况、材料、物质的组成、工艺、工艺步骤或多个步骤适应本发明的目标、精神和范围。打算所有此类修改是在其所附的权利要求书的范围内。此外,上文中所引用的所有公开案、专利和专利文档的全文以引用的方式并入本文中,并入程度如同以引用的方式个别并入一般。
Claims (21)
2.根据权利要求1所述的方法,其中与肼的所述反应是在60℃±20℃进行。
3.根据权利要求1或2所述的方法,其中
X是选自由Br、I和Cl组成的群组;
PG1为烷基或苄基,其中所述苄基任选地经取代;
PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;且
PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组。
4.根据权利要求1或2所述的方法,其中X为Br,PG1为苄基,PG2为叔丁氧羰基且PG3为苄基。
6.根据权利要求5所述的方法,其中Y为Cl。
8.根据权利要求7所述的化合物或其盐,其中
X是选自由Br、I和Cl组成的群组;
PG1为烷基或苄基,其中所述苄基任选地经取代;
PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;且
PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组。
11.根据权利要求10所述的化合物或其盐,其中
X是选自由Br、I和Cl组成的群组;
PG1为烷基或苄基,其中所述苄基任选地经取代;
PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;且
PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组。
13.一种制备式J-16化合物或其盐的方法,
其中
PG1为羧酸保护基;
PG2为氨基保护基;
PG3为氨基保护基;
PG4为羟基保护基;且
R为H或F;
所述方法包括:
(a)使式J-13化合物:
其中X是选自由Br、I和Cl组成的群组;且Y为离去基团;与式J-11化合物在碱存在下反应:
得到式J-14化合物:
及任选地形成化合物J-14的盐;
(b)使所述式J-14化合物或其盐与肼反应,得到式J-15化合物:
及任选地形成化合物J-15的盐;
(c)使所述式J-15化合物或其盐与式J-5、J-6或J-7化合物在碱、钯催化剂和膦配位体存在下反应:
其中Ra和Rb各自独立地选自C1-8烷基,其中Ra和Rb可能任选地连接形成4到8元环;得到所述式J-16化合物,及任选地形成化合物J-16的盐。
14.根据权利要求13所述的方法,其中步骤(c)是在二硼试剂或催化剂存在下进行。
15.根据权利要求14所述的方法,其中步骤(c)是在四羟基二硼、二硼酸酯或双(频哪醇基)二硼与氟化钾氢氟化物的反应产物存在下进行。
16.根据权利要求13到15中任一权利要求所述的方法,其中步骤(b)中与肼的所述反应是在60℃±20℃进行。
17.根据权利要求13到16中任一权利要求所述的方法,其中
X是选自由Br、I和Cl组成的群组;
PG1为烷基或苄基,其中所述苄基任选地经取代;
PG2是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;
PG3是选自由酰基、烷氧羰基、芳基甲基和硅基组成的群组;
PG4是选自由硅基、酰基和芳基甲基组成的群组。
18.根据权利要求13到16中任一权利要求所述的方法,其中X为Br,PG1为苄基,PG2为叔丁氧羰基,PG3为苄基,且PG4为苄基。
19.根据权利要求13到18中任一权利要求所述的方法,其中Y为Cl。
20.根据权利要求13到19中任一权利要求所述的方法,其中步骤(c)的所述钯催化剂和膦配位体为双(二叔丁基(4-二甲氨基苯基)膦)二氯钯(II)。
21.根据权利要求13到20中任一权利要求所述的方法,其中在步骤(c)中使用式J-5化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862726600P | 2018-09-04 | 2018-09-04 | |
US62/726,600 | 2018-09-04 | ||
PCT/US2019/049338 WO2020051135A1 (en) | 2018-09-04 | 2019-09-03 | Process for preparing jak inhibitors and intermediates thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112638902A true CN112638902A (zh) | 2021-04-09 |
Family
ID=67957449
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980057683.5A Pending CN112638902A (zh) | 2018-09-04 | 2019-09-03 | 用于制备jak抑制剂的方法及其中间体 |
Country Status (15)
Country | Link |
---|---|
US (1) | US10844057B2 (zh) |
EP (1) | EP3837253B1 (zh) |
JP (1) | JP2021535176A (zh) |
KR (1) | KR20210056382A (zh) |
CN (1) | CN112638902A (zh) |
AR (1) | AR116116A1 (zh) |
AU (1) | AU2019335199A1 (zh) |
BR (1) | BR112021004087A2 (zh) |
CA (1) | CA3108848A1 (zh) |
IL (1) | IL281152B2 (zh) |
MX (1) | MX2021002273A (zh) |
PH (1) | PH12021550388A1 (zh) |
SG (1) | SG11202101785UA (zh) |
TW (1) | TWI808250B (zh) |
WO (1) | WO2020051135A1 (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180073687A (ko) | 2015-11-03 | 2018-07-02 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | 호흡기 질환의 치료를 위한 jak 키나제 저해제 화합물 |
EA037748B1 (ru) | 2017-03-09 | 2021-05-18 | ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи, ЭлЭлСи | Конденсированные имидазо-пиперидиновые ингибиторы jak |
SG11202101751XA (en) | 2018-09-04 | 2021-03-30 | Theravance Biopharma R&D Ip Llc | 5 to 7 membered heterocyclic amides as jak inhibitors |
KR20210056381A (ko) | 2018-09-04 | 2021-05-18 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | Jak 억제제로서 디메틸 아미노 아제티딘 아마이드 |
TW202144343A (zh) | 2020-03-02 | 2021-12-01 | 美商施萬生物製藥研發 Ip有限責任公司 | Jak抑制劑化合物之結晶水合物 |
WO2021226637A1 (en) * | 2020-05-08 | 2021-11-11 | Theravance Biopharma R&D Ip, Llc | Method of treating a patient infected with a coronavirus with nezulcitinib |
WO2022081872A1 (en) * | 2020-10-16 | 2022-04-21 | Gb008, Inc. | Janus kinase inhibitors |
US20230021647A1 (en) | 2021-06-21 | 2023-01-26 | Theravance Biopharma R&D Ip, Llc | Method of treating a patient infected with a coronavirus and having a baseline level of crp below 150 mg/l |
WO2023215478A1 (en) | 2022-05-05 | 2023-11-09 | Theravance Biopharma R&D Ip, Llc | Nezulcitinib for delivery by nebulized oral inhalation |
WO2023230236A1 (en) * | 2022-05-26 | 2023-11-30 | Theravance Biopharma R&D Ip, Llc | Process for preparing jak inhibitors and intermediates thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102348693A (zh) * | 2009-01-15 | 2012-02-08 | 因西特公司 | 制备jak抑制剂及相关中间化合物的方法 |
CN103717599A (zh) * | 2011-07-27 | 2014-04-09 | 辉瑞有限公司 | 吲唑 |
CN104024256A (zh) * | 2011-09-07 | 2014-09-03 | 因塞特公司 | 用于制备jak抑制剂的方法和中间体 |
CN105189509A (zh) * | 2013-03-06 | 2015-12-23 | 因赛特公司 | 用于制备jak抑制剂的方法及中间体 |
WO2017079205A1 (en) * | 2015-11-03 | 2017-05-11 | Theravance Biopharma R&D Ip, Llc | Jak kinase inhibitor compounds for treatment of respiratory disease |
WO2017077283A1 (en) * | 2015-11-03 | 2017-05-11 | Topivert Pharma Limited | 4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors |
WO2017077288A1 (en) * | 2015-11-03 | 2017-05-11 | Topivert Pharma Limited | 4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4812462A (en) * | 1986-04-01 | 1989-03-14 | Warner-Lambert Company | 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity |
TWI262914B (en) | 1999-07-02 | 2006-10-01 | Agouron Pharma | Compounds and pharmaceutical compositions for inhibiting protein kinases |
EP1648455A4 (en) | 2003-07-23 | 2009-03-04 | Exelixis Inc | MODULATORS OF ALK PROTEIN (ANAPLASTIC LYMPHOMA KINASE) AND METHODS OF USE |
US20050090529A1 (en) | 2003-07-31 | 2005-04-28 | Pfizer Inc | 3,5 Disubstituted indazole compounds with nitrogen-bearing 5-membered heterocycles, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation |
US7884109B2 (en) | 2005-04-05 | 2011-02-08 | Wyeth Llc | Purine and imidazopyridine derivatives for immunosuppression |
US8648069B2 (en) | 2007-06-08 | 2014-02-11 | Abbvie Inc. | 5-substituted indazoles as kinase inhibitors |
JP2010111624A (ja) | 2008-11-06 | 2010-05-20 | Shionogi & Co Ltd | Ttk阻害作用を有するインダゾール誘導体 |
EP2414340A1 (en) | 2009-04-03 | 2012-02-08 | Dainippon Sumitomo Pharma Co., Ltd. | Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof |
EP2464231A4 (en) * | 2009-08-10 | 2013-02-06 | Samumed Llc | INDAZOLE AS WNT / B-CATENINE SIGNALING PATHWASHER AND THERAPEUTIC APPLICATIONS THEREOF |
PL3001903T3 (pl) | 2009-12-21 | 2018-03-30 | Samumed, Llc | 1H-pirazolo[3,4-b]pirydyny i ich zastosowania terapeutyczne |
EP3318565B1 (en) | 2013-12-05 | 2021-04-14 | Pfizer Inc. | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides |
TN2016000503A1 (en) | 2014-05-14 | 2018-04-04 | Pfizer | Pyrazolopyridines and pyrazolopyrimidines |
WO2016026078A1 (en) | 2014-08-19 | 2016-02-25 | Changzhou Jiekai Pharmatech Co., Ltd. | Heterocyclic compounds as erk inhibitors |
KR101663277B1 (ko) | 2015-03-30 | 2016-10-06 | 주식회사 녹십자 | TNIK, IKKε 및 TBK1 억제제로서의 피라졸계 유도체 및 이를 포함하는 약학적 조성물 |
EA037748B1 (ru) | 2017-03-09 | 2021-05-18 | ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи, ЭлЭлСи | Конденсированные имидазо-пиперидиновые ингибиторы jak |
AR111495A1 (es) | 2017-05-01 | 2019-07-17 | Theravance Biopharma R&D Ip Llc | Compuestos de imidazo-piperidina fusionada como inhibidores de jak |
CA3059785A1 (en) | 2017-05-01 | 2018-11-08 | Theravance Biopharma R&D Ip, Llc | Methods of treatment using a jak inhibitor compound |
EP3619208B1 (en) | 2017-05-01 | 2023-06-07 | Theravance Biopharma R&D IP, LLC | Crystalline forms of a jak inhibitor compound |
SG11202101751XA (en) | 2018-09-04 | 2021-03-30 | Theravance Biopharma R&D Ip Llc | 5 to 7 membered heterocyclic amides as jak inhibitors |
KR20210056381A (ko) | 2018-09-04 | 2021-05-18 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | Jak 억제제로서 디메틸 아미노 아제티딘 아마이드 |
JP2022506111A (ja) | 2018-10-29 | 2022-01-17 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | Jak阻害剤としての2-アザビシクロヘキサン化合物 |
PE20212069A1 (es) | 2019-02-25 | 2021-10-26 | Henan Medinno Pharmaceutical Tech Co Ltd | Compuesto inhibidor de jak y uso del mismo |
-
2019
- 2019-09-03 TW TW108131709A patent/TWI808250B/zh active
- 2019-09-03 KR KR1020217009940A patent/KR20210056382A/ko active Search and Examination
- 2019-09-03 US US16/559,091 patent/US10844057B2/en active Active
- 2019-09-03 MX MX2021002273A patent/MX2021002273A/es unknown
- 2019-09-03 AR ARP190102521A patent/AR116116A1/es unknown
- 2019-09-03 CN CN201980057683.5A patent/CN112638902A/zh active Pending
- 2019-09-03 JP JP2021512248A patent/JP2021535176A/ja not_active Ceased
- 2019-09-03 CA CA3108848A patent/CA3108848A1/en active Pending
- 2019-09-03 EP EP19769346.8A patent/EP3837253B1/en active Active
- 2019-09-03 SG SG11202101785UA patent/SG11202101785UA/en unknown
- 2019-09-03 AU AU2019335199A patent/AU2019335199A1/en not_active Abandoned
- 2019-09-03 BR BR112021004087-0A patent/BR112021004087A2/pt unknown
- 2019-09-03 IL IL281152A patent/IL281152B2/en unknown
- 2019-09-03 WO PCT/US2019/049338 patent/WO2020051135A1/en active Application Filing
-
2021
- 2021-02-24 PH PH12021550388A patent/PH12021550388A1/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102348693A (zh) * | 2009-01-15 | 2012-02-08 | 因西特公司 | 制备jak抑制剂及相关中间化合物的方法 |
CN103717599A (zh) * | 2011-07-27 | 2014-04-09 | 辉瑞有限公司 | 吲唑 |
CN104024256A (zh) * | 2011-09-07 | 2014-09-03 | 因塞特公司 | 用于制备jak抑制剂的方法和中间体 |
CN105189509A (zh) * | 2013-03-06 | 2015-12-23 | 因赛特公司 | 用于制备jak抑制剂的方法及中间体 |
WO2017079205A1 (en) * | 2015-11-03 | 2017-05-11 | Theravance Biopharma R&D Ip, Llc | Jak kinase inhibitor compounds for treatment of respiratory disease |
WO2017077283A1 (en) * | 2015-11-03 | 2017-05-11 | Topivert Pharma Limited | 4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors |
WO2017077288A1 (en) * | 2015-11-03 | 2017-05-11 | Topivert Pharma Limited | 4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP3837253B1 (en) | 2023-06-07 |
KR20210056382A (ko) | 2021-05-18 |
IL281152B2 (en) | 2023-12-01 |
TWI808250B (zh) | 2023-07-11 |
EP3837253C0 (en) | 2023-06-07 |
SG11202101785UA (en) | 2021-03-30 |
EP3837253A1 (en) | 2021-06-23 |
CA3108848A1 (en) | 2020-03-12 |
TW202024074A (zh) | 2020-07-01 |
PH12021550388A1 (en) | 2021-11-08 |
JP2021535176A (ja) | 2021-12-16 |
AU2019335199A1 (en) | 2021-03-11 |
US20200071324A1 (en) | 2020-03-05 |
US10844057B2 (en) | 2020-11-24 |
AR116116A1 (es) | 2021-03-31 |
IL281152A (en) | 2021-04-29 |
IL281152B1 (en) | 2023-08-01 |
BR112021004087A2 (pt) | 2021-05-25 |
MX2021002273A (es) | 2021-05-27 |
WO2020051135A1 (en) | 2020-03-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112638902A (zh) | 用于制备jak抑制剂的方法及其中间体 | |
JP6800969B2 (ja) | 呼吸器疾患の処置のためのjakキナーゼ阻害剤化合物 | |
JP6273075B1 (ja) | 新規縮合ピリミジン化合物又はその塩 | |
US11046681B2 (en) | Substituted piperidines for the treatment of cancer | |
AU2011229267B2 (en) | Inhibitors of Semicarabazide - sensitive amine oxidase | |
US7704989B2 (en) | Derivatives of imidazo[1,2-a]pyridine-2-carboxamides, preparation method thereof and use of same in therapeutics | |
US7087626B2 (en) | Pyrrole derivatives as pharmaceutical agents | |
CA2933480A1 (en) | Inhibitors of lysine specific demethylase-1 | |
US7786114B2 (en) | Bis-azaindole derivatives, preparation and pharmaceutical use thereof as kinase inhibitors | |
WO2013118817A1 (ja) | キノリルピロロピリミジン化合物又はその塩 | |
TW201141869A (en) | Pyrazolopyrimidine compounds and their use as PDE10 inhibitors | |
US20200399268A1 (en) | Pharmaceutical 6,5 Heterobicyclic Ring Derivatives | |
EP0994878B1 (en) | Quinolone carboxylic acid derivatives | |
RU2786361C2 (ru) | Способ получения ингибиторов jak и их промежуточных соединений | |
JP4100865B2 (ja) | 三環式縮合異項環化合物、その製造法およびその医薬 | |
US20230373960A1 (en) | Indoline compounds and derivatives as egfr inhibitors | |
TW202241413A (zh) | 吡唑並喹唑啉類化合物、其製備方法及用途 | |
CN117098765A (zh) | 作为詹纳斯激酶抑制剂的杂环衍生物 | |
TW201002713A (en) | Pyrrolo[2,3-d]pyrimidin-2-yl-amine derivatives as PKC-theta inhibitors | |
EP3597642A1 (en) | Pharmaceutical 6,5 heterobicyclic ring derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |