CN115038705A - 7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺化合物 - Google Patents
7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺化合物 Download PDFInfo
- Publication number
- CN115038705A CN115038705A CN202180014348.4A CN202180014348A CN115038705A CN 115038705 A CN115038705 A CN 115038705A CN 202180014348 A CN202180014348 A CN 202180014348A CN 115038705 A CN115038705 A CN 115038705A
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- mmol
- methyl
- 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
- VFCWVVGVAMCILW-UHFFFAOYSA-N 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical class CNC1=CC=NC=2N1N=CC=2C(=O)N VFCWVVGVAMCILW-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 123
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 11
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims abstract description 9
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 description 41
- 239000007787 solid Substances 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 23
- -1 (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate Chemical compound 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 201000006417 multiple sclerosis Diseases 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 9
- 102000013264 Interleukin-23 Human genes 0.000 description 9
- 108010065637 Interleukin-23 Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000700 radioactive tracer Substances 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000012815 AlphaLISA Methods 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VZDMTWJWRRUJED-SCSAIBSYSA-N (3r)-3-amino-1-methylpyrrolidin-2-one Chemical compound CN1CC[C@@H](N)C1=O VZDMTWJWRRUJED-SCSAIBSYSA-N 0.000 description 3
- 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 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- 208000011231 Crohn disease Diseases 0.000 description 3
- 206010012438 Dermatitis atopic Diseases 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 description 3
- 208000004631 alopecia areata Diseases 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 3
- MAJFINHRLBJIQL-UHFFFAOYSA-N benzyl n-(2-oxo-1h-pyridin-3-yl)carbamate Chemical compound OC1=NC=CC=C1NC(=O)OCC1=CC=CC=C1 MAJFINHRLBJIQL-UHFFFAOYSA-N 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- CSOYDALHEQEMAK-UHFFFAOYSA-N 2h-pyrimidine-1-carboxylic acid Chemical compound OC(=O)N1CN=CC=C1 CSOYDALHEQEMAK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000042838 JAK family Human genes 0.000 description 2
- 108091082332 JAK family Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- WBMQPJCQLMJMDU-UHFFFAOYSA-N NC=1C(N(C=CC=1)C1=NC=C(C=C1)C)=O Chemical compound NC=1C(N(C=CC=1)C1=NC=C(C=C1)C)=O WBMQPJCQLMJMDU-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 102000004495 STAT3 Transcription Factor Human genes 0.000 description 2
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108010010057 TYK2 Kinase Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- YPXGHKWOJXQLQU-UHFFFAOYSA-N ethyl 5-amino-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1N YPXGHKWOJXQLQU-UHFFFAOYSA-N 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- VLYLVPWRADZEDL-UHFFFAOYSA-N methylsulfanylmethane;hydroiodide Chemical compound [I-].C[SH+]C VLYLVPWRADZEDL-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- PENAXHPKEVTBLF-UHFFFAOYSA-L palladium(2+);prop-1-ene;dichloride Chemical compound [Pd+]Cl.[Pd+]Cl.[CH2-]C=C.[CH2-]C=C PENAXHPKEVTBLF-UHFFFAOYSA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 2
- IMUSLIHRIYOHEV-SSDOTTSWSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-methylsulfanylbutanoic acid Chemical compound CSCC[C@H](C(O)=O)NC(=O)OC(C)(C)C IMUSLIHRIYOHEV-SSDOTTSWSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 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
- YWNJQQNBJQUKME-UHFFFAOYSA-N 2-bromo-5-methylpyridine Chemical compound CC1=CC=C(Br)N=C1 YWNJQQNBJQUKME-UHFFFAOYSA-N 0.000 description 1
- SOHDPICLICFSOP-UHFFFAOYSA-N 2-bromo-6-methylpyridine Chemical compound CC1=CC=CC(Br)=N1 SOHDPICLICFSOP-UHFFFAOYSA-N 0.000 description 1
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- FIAZRZSVFOMYSD-UHFFFAOYSA-N 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline Chemical compound COC1=C(N)C=CC=C1C1=NN(C)C=N1 FIAZRZSVFOMYSD-UHFFFAOYSA-N 0.000 description 1
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 description 1
- FDMIXMPVERSCTG-UHFFFAOYSA-N 3-amino-1-(6-methylpyridin-2-yl)pyridin-2-one Chemical compound CC1=NC(=CC=C1)N1C=CC=C(N)C1=O FDMIXMPVERSCTG-UHFFFAOYSA-N 0.000 description 1
- VWNKDWVUOHDCRR-UHFFFAOYSA-N 3-amino-1-pyridin-2-ylpiperidin-2-one Chemical compound O=C1C(N)CCCN1C1=CC=CC=N1 VWNKDWVUOHDCRR-UHFFFAOYSA-N 0.000 description 1
- WNOJGCODYVEOMJ-UHFFFAOYSA-N 3-amino-1-pyridin-2-ylpyridin-2-one Chemical compound NC=1C(N(C=CC1)C1=NC=CC=C1)=O WNOJGCODYVEOMJ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- BFMBHQZQBXFKTK-UHFFFAOYSA-N 5-chloro-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound ClC1=NC=2N(C(=C1)NC)N=CC=2C(=O)O BFMBHQZQBXFKTK-UHFFFAOYSA-N 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- RLIVNOMWYWMZRB-UHFFFAOYSA-N CC1=CC=CC(=N1)N1C(C(=CC=C1)NC(OCC1=CC=CC=C1)=O)=O Chemical compound CC1=CC=CC(=N1)N1C(C(=CC=C1)NC(OCC1=CC=CC=C1)=O)=O RLIVNOMWYWMZRB-UHFFFAOYSA-N 0.000 description 1
- WIDWIMDVSZVNOD-UHFFFAOYSA-N CCOC(=O)c1cnn2c(NC)cc(Cl)nc12 Chemical compound CCOC(=O)c1cnn2c(NC)cc(Cl)nc12 WIDWIMDVSZVNOD-UHFFFAOYSA-N 0.000 description 1
- NGNFQUFVSBEAHW-UHFFFAOYSA-N CNC1=CC(=NC=2N1N=CC=2C(=O)O)NC=1C(N(C=CC=1)C1=NC(=CC=C1)C)=O Chemical compound CNC1=CC(=NC=2N1N=CC=2C(=O)O)NC=1C(N(C=CC=1)C1=NC(=CC=C1)C)=O NGNFQUFVSBEAHW-UHFFFAOYSA-N 0.000 description 1
- RDCOYXVXPNOUPU-UHFFFAOYSA-N CNC1=CC(=NC=2N1N=CC=2C(=O)OCC)NC=1C(N(C=CC=1)C1=NC(=CC=C1)C)=O Chemical compound CNC1=CC(=NC=2N1N=CC=2C(=O)OCC)NC=1C(N(C=CC=1)C1=NC(=CC=C1)C)=O RDCOYXVXPNOUPU-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102100036672 Interleukin-23 receptor Human genes 0.000 description 1
- 101710195550 Interleukin-23 receptor Proteins 0.000 description 1
- 102000008986 Janus Human genes 0.000 description 1
- 108050000950 Janus Proteins 0.000 description 1
- 108010024121 Janus Kinases Proteins 0.000 description 1
- 102000015617 Janus Kinases Human genes 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 101000666920 Streptomyces hygroscopicus subsp. limoneus Validoxylamine A 7'-phosphate phosphatase Proteins 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 1
- 229960001164 apremilast Drugs 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- RZIWIDALPGIKTH-UHFFFAOYSA-N benzyl N-(2-oxo-1-pyridin-2-ylpyridin-3-yl)carbamate Chemical compound O=C(NC1=CC=CN(C1=O)C1=NC=CC=C1)OCC1=CC=CC=C1 RZIWIDALPGIKTH-UHFFFAOYSA-N 0.000 description 1
- BIQKBSKEBGXBST-UHFFFAOYSA-N benzyl N-[1-(5-methylpyridin-2-yl)-2-oxopyridin-3-yl]carbamate Chemical compound CC1=CC=C(N=C1)N1C=CC=C(NC(=O)OCC2=CC=CC=C2)C1=O BIQKBSKEBGXBST-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 150000005752 bromopyridines Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- REWLCYPYZCHYSS-UHFFFAOYSA-N ditert-butyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C(C)(C)C)C(C)(C)C REWLCYPYZCHYSS-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XHUWDDXMORFULQ-UHFFFAOYSA-N ethyl 2h-pyrimidine-1-carboxylate Chemical compound CCOC(=O)N1CN=CC=C1 XHUWDDXMORFULQ-UHFFFAOYSA-N 0.000 description 1
- JDTUBXNZVFYLQV-UHFFFAOYSA-N ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound ClC1=CC(Cl)=NC2=C(C(=O)OCC)C=NN21 JDTUBXNZVFYLQV-UHFFFAOYSA-N 0.000 description 1
- WXJHHRMJGBPYEG-UHFFFAOYSA-N ethyl 5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylate Chemical compound CCOC(=O)C1=NN=C(SC)N=C1Cl WXJHHRMJGBPYEG-UHFFFAOYSA-N 0.000 description 1
- QSZVAHIUOTZVIZ-UHFFFAOYSA-N ethyl 7-hydroxy-5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)c1cnn2c(O)cc(=O)[nH]c12 QSZVAHIUOTZVIZ-UHFFFAOYSA-N 0.000 description 1
- JEMAMNBFHPIPCR-UHFFFAOYSA-N ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound C1=CC=NC2=C(C(=O)OCC)C=NN21 JEMAMNBFHPIPCR-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
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 102000055277 human IL2 Human genes 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940124829 interleukin-23 Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- TVJWTRPGFVNAJI-UHFFFAOYSA-N tert-butyl 4-(4-aminopyrazol-1-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1N=CC(N)=C1 TVJWTRPGFVNAJI-UHFFFAOYSA-N 0.000 description 1
- FYOUTJSPFQTMTQ-MRVPVSSYSA-N tert-butyl n-[(2r)-1-(methylamino)-4-methylsulfanyl-1-oxobutan-2-yl]carbamate Chemical compound CSCC[C@H](C(=O)NC)NC(=O)OC(C)(C)C FYOUTJSPFQTMTQ-MRVPVSSYSA-N 0.000 description 1
- AQTGZJWIZODIFY-SSDOTTSWSA-N tert-butyl n-[(3r)-1-methyl-2-oxopyrrolidin-3-yl]carbamate Chemical compound CN1CC[C@@H](NC(=O)OC(C)(C)C)C1=O AQTGZJWIZODIFY-SSDOTTSWSA-N 0.000 description 1
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供了式I的化合物,其中R是(II)、(III)或(IV)、或其可药用盐,其可用于治疗牛皮癣、系统性红斑狼疮或1型糖尿病
Description
本发明涉及与TYK2的假激酶结构域(JH2)结合并抑制某些细胞因子信号传导,特别是IL-23和IFNα信号传导的新型化合物,涉及包含该化合物的药物组合物,涉及使用该化合物治疗某些自身免疫性疾病的方法,并涉及可用于合成该化合物的中间体和方法。
牛皮癣和其它自身免疫性疾病(如糖尿病)据信通过某些促炎细胞因子的TYK2信号传导来介导(参见例如J.S.Tokarski等人, J. Biol. Chem., 第290卷(17), 第11061-11074页(2015);和L.Marroqui等人, Diabetes, 第64卷, 第3808-3817 页(2015))。牛皮癣是一种慢性皮肤病,估计影响大约2%的普通人群。牛皮癣的治疗选择包括例如局部治疗,如皮质类固醇,光线疗法,如紫外B(UVB)光,和全身治疗,如甲氨喋呤和阿普斯特。不幸的是,此类药剂并不总是提供有效的治疗,并可能与各种不良副作用相关。
US 2019/0031664 A1公开了可用于通过抑制TYK2治疗各种炎性和自身免疫性病症的某些取代的吡唑并[1,5-a]嘧啶。美国专利号7,557,110公开了作为激酶抑制剂的某些吡唑并[1,5-a]嘧啶衍生物,其可用于治疗激酶介导的病症,如炎性疾病和自身免疫性疾病。
需要自身免疫性疾病,如牛皮癣、系统性红斑狼疮(SLE)和糖尿病的替代治疗。特别地,需要与TYK2 JH2结构域结合的化合物。此外,需要与TYK2 JH2结构域结合并抑制IL-23和IFNα信号转导的化合物。
因此,在一个实施方案中,本发明提供了式I的化合物:
其中R是:
或其可药用盐。
在一个特定实施方案中,该化合物具有式Ia:
或其可药用盐。
在一个特定实施方案中,该化合物具有式Ib:
或其可药用盐。
在一实施方案中,R是:
或其可药用盐。
在一实施方案中,R是:
或其可药用盐。
在一实施方案中,R是:
或其可药用盐。
在一实施方案中,该化合物是:
或其可药用盐。
在一实施方案中,该化合物是:
或其可药用盐。
在一实施方案中,该化合物是:
或其可药用盐。
在一实施方案中,本发明还提供了在需要此类治疗的患者中治疗牛皮癣的方法,包括向患者施用有效量的式I的化合物或其可药用盐。在一实施方案中,本发明进一步提供了在需要此类治疗的患者中治疗SLE的方法,包括向患者施用有效量的式I的化合物或其可药用盐。在一实施方案中,本发明进一步提供了在需要此类治疗的患者中治疗选自炎性肠病、溃疡性结肠炎、克罗恩病、牛皮癣性关节炎、类风湿性关节炎(RA)、斑秃、特应性皮炎、中轴型脊柱关节炎、多发性硬化(MS)、1型糖尿病、2型糖尿病和成人隐匿性自身免疫性糖尿病(LADA)的疾病的方法,包括向患者施用有效量的式I的化合物或其可药用盐。
在一实施方案中,本发明进一步提供了用于治疗的式I的化合物或其可药用盐。在一实施方案中,本发明提供了用于治疗牛皮癣的式I的化合物或其可药用盐。在一实施方案中,本发明提供了用于治疗SLE的式I的化合物或其可药用盐。在一实施方案中,本发明还提供了用于治疗选自炎性肠病、溃疡性结肠炎、克罗恩病、牛皮癣性关节炎、RA、斑秃、特应性皮炎、中轴型脊柱关节炎、MS、1型糖尿病、2型糖尿病和LADA的疾病的式I的化合物或其可药用盐。
在一实施方案中,本发明还提供了式I的化合物或其可药用盐用于制备治疗牛皮癣的药物的用途。在一实施方案中,本发明提供了式I的化合物或其可药用盐用于制备治疗SLE的药物的用途。在一实施方案中,本发明还提供了式I的化合物或其可药用盐用于制备治疗选自炎性肠病、溃疡性结肠炎、克罗恩病、牛皮癣性关节炎、RA、斑秃、特应性皮炎、中轴型脊柱关节炎、MS、1型糖尿病、2型糖尿病和LADA的疾病的药物的用途。
在一实施方案中,本发明进一步提供了药物组合物,其包含式I的化合物或其可药用盐与一种或多种可药用载体、稀释剂或赋形剂。在一实施方案中,本发明进一步提供了制备药物组合物的方法,包括将式I的化合物或其可药用盐与一种或多种可药用载体、稀释剂或赋形剂混合。在一实施方案中,本发明还涵盖了用于合成式I的化合物的新型中间体和方法。
本文中所用的术语“治疗”包括限制、减缓、停止或逆转现有症状或病症的进展或严重程度。
本文中所用的术语“患者”是指哺乳动物,特别是人类。
本文中所用的术语“有效量”是指本发明的化合物或其可药用盐的量或剂量,其在单剂或多剂施用于患者时在接受诊断或治疗的患者中提供所需效果。
有效量可以由本领域技术人员通过使用已知技术并通过观察在类似情况下获得的结果来确定。在对患者确定有效量时,主治诊断师会考虑许多因素,包括但不限于:患者的物种;其大小、年龄和一般健康状况;涉及的具体疾病或病症;疾病或病症的牵涉程度或严重性;个体患者的反应;施用的特定化合物;施用方式;施用的制剂的生物利用度特性;所选择的剂量方案;同时使用药物;和其它相关情况。
本发明的化合物被配置为药物组合物,所述药物组合物通过使该化合物具有生物可利用性的任何途径施用。最优选地,此类组合物用于口服施用。此类药物组合物及其制备方法在本领域中是公知的(参见例如Remington: The Science and Practice ofPharmacy, L.V. Allen, 著, 第22版, Pharmaceutical Press, 2012)。
式I的化合物或其可药用盐特别可用于本发明的治疗方法,其所有构型(包括对映异构体)及其混合物(包括外消旋体)均设想在本发明的范围内。要理解的是,这些构型适用于本发明的治疗方法和化合物。
在下文制备例中描述的某些中间体可含有一个或多个氮保护基团。要理解的是,保护基团可以如本领域技术人员理解的那样根据特定反应条件和要进行的特定转化而不同。保护和脱保护条件是技术人员公知的,并描述在文献中(参见例如“Greene’s Protective Groups in Organic Synthesis”, 第四版, Peter G.M. Wuts和Theodora W.Greene, John Wiley and Sons, Inc. 2007)。
单个异构体(包括对映异构体)可由本领域普通技术人员在本发明的化合物的合成中的任何方便的点通过诸如选择性结晶技术或手性色谱法来分离或拆分y(参见例如J.Jacques等人, “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons,Inc., 1981及E.L. Eliel和S.H. Wilen, “Stereochemistry of Organic Compounds”,Wiley-Interscience, 1994)。
本发明的化合物的可药用盐可以例如通过本发明的化合物的适当的游离碱、适当的可药用酸在合适的溶剂(如二乙醚)中在本领域中公知的标准条件下的反应来形成。此外,此类可药用盐的形成可以在氮保护基团的脱保护下同时发生。参见例如Gould, P.L.,“Salt selection for basic drugs,” International Journal of Pharmaceutics, 33:201-217 (1986);Bastin, R.J.等人, “Salt Selection and Optimization Proceduresfor Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427-435 (2000);和Berge, S.M.等人, “Pharmaceutical Salts,”Journal of Pharmaceutical Sciences, 66: 1-19, (1977)。
某些缩写定义如下:“BINAP”是指(±)-2,2′-双(二苯基膦)-1,1′-联二萘;“BOP”是指(苯并三唑-1-基氧基)三(二甲氨基)六氟磷酸鏻;“BrettPhos”是指二环己基[3,6-二甲氧基-2',4',6'-三(1-甲基乙基)[1,1'-联苯]-2-基]膦;“DCM”是指二氯甲烷;“DEM”是指丙二酸二乙酯;“DIEA”是指N,N-二异丙基乙胺;“DMEM”是指杜皮克氏改良爱哥尔氏培养基;“DMF”是指N,N-二甲基甲酰胺;“DMSO”是指二甲亚砜;“EtOAc”是指乙酸乙酯;“EtOH”是指乙醇和乙基醇;“FBS”是指胎牛血清;“HATU”是指1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓 3-氧化六氟磷酸盐;“HEPES”是指4-(2-羟乙基)-1-哌嗪乙磺酸;“HPLC”是指高效液相色谱法;“IFNα”是指α-干扰素;“IL-2”是指白介素2;“IL-23”是指白介素23;“JAK”是指两面神激酶;“LiHMDS”是指六甲基二硅基氨基锂;“MeI”是指甲基碘;“MeNH2”是指甲胺;“MeOH”是指甲醇和甲基醇;“MTBE”是指甲基叔丁基醚;“NaOEt”是指乙醇钠;“Pd-175 [tBuBrettPhos Pd(allyl)]OTf”是指烯丙基(2-二叔丁基膦基-3,6-二甲氧基-2’,4’,6’-三异丙基-1,1’-联苯)钯(II)三氟甲磺酸盐;“RPM”是指每分钟转数;“RPMI”是指Roswell Park Memorial Institute;“TEA”是指三乙胺;“THF”是指四氢呋喃;“TYK2”是指酪氨酸激酶2;“UVB”是指紫外线B;且“STAT”是指转录蛋白的信号转导子和激活子。
本发明的化合物或其可药用盐可以通过本领域普通技术人员已知的多种程序来制备,其中一些在下面的方案、制备例和实施例中进行了说明。以下方案中每个步骤的产物可以通过本领域中公知的常规方法来回收,包括萃取、蒸发、沉淀、色谱法、过滤、研磨和结晶。在下面的方案中,除非另行说明,所有取代基如前所定义。试剂和原材料对本领域普通技术人员而言容易获得。在不限制本发明范围的情况下,提供以下方案、制备例和实施例以进一步说明本发明。
方案1
在方案1步骤A中,化合物(2)的形成显示为使用合适的有机碱如DIEA和合适的偶联剂如HATU在溶剂如DMF中在0-22℃下在化合物(1)与MeNH2之间在本领域中公知的条件下的酰胺偶联。
在步骤B中,将MeI添加到化合物(2)中以形成二甲基碘化锍盐,随后用合适的碱如LiHMDS在合适的溶剂如THF中在0-22℃下处理以获得环化的化合物(3)。
在步骤C中,化合物(3)在标准条件下使用合适的酸如4-甲基苯磺酸在合适的溶剂如乙腈中在大约55℃下脱保护,随后添加溶剂如MTBE以沉淀化合物(4)。
方案2
在方案2步骤A中,使用CuI与合适的碱如碳酸钾在合适的溶剂如DMF和1,4-二氧杂环己烷中在化合物(5)和取代的溴吡啶之间进行Buchwald偶联以获得化合物(6)。在一些情况下,也可将N',N'-二甲基乙烷-1,2-二胺添加到该反应混合物中。
步骤B描绘了使用合适的催化剂如10% Pd/C或20% Pd(OH)2/C在溶剂如EtOH或MeOH中在加压氢气氛中通过氢化将化合物(6)脱保护以获得化合物(7)。
方案3
方案3步骤A描绘了将DEM加成到化合物(8)上并随后使用合适的碱如NaOEt或叔丁醇钾在大约80℃下在溶剂如EtOH中环化成化合物(9)。
在步骤B中,化合物(9)的7-羟基和5-氧代基团可使用合适的氯源如POCl3和合适的有机碱如吡啶在大约50-100℃下在合适的溶剂如乙腈中氯化以获得化合物(10)。
在步骤C中,化合物(10)的7-氯基团上的选择性亲核芳族取代可以在本领域中公知的条件下使用适当的亲核试剂如MeNH2在合适的溶剂如THF中在环境温度下进行以获得化合物(11)。
在步骤D中,可以使用合适的催化剂和配体体系如Pd-175 [tBuBrettPhos Pd(allyl)]OTf与合适的碱如乙酸钾在适当的溶剂如2-甲基-2-丁醇中在100℃下加热的情况下对化合物(11)与化合物(7)来进行Buchwald偶联以形成化合物(12)。
化合物(12)可用合适的碱如LiOH水溶液在合适的溶剂体系如EtOH和THF在回流下处理以通过步骤E中所示的酯的碱性水解来获得化合物(13)。
步骤F描绘了在本领域中公知的条件下使用合适的有机碱如DIEA和合适的偶联剂如BOP在溶剂如DMF中在化合物(13)与化合物(4)之间进行酰胺偶联以形成式Ia的化合物。
方案4
方案4步骤A描绘了化合物(11)用合适的碱如NaOH水溶液在溶剂如1,4-二氧杂环已烷中在50℃下碱性水解以获得化合物(14)。
步骤B显示了使用方案3步骤F中一般描述的条件在化合物(14)和(15)之间进行酰胺偶联以获得化合物(16)。
在步骤C中,可以使用合适的催化剂和配体体系如Pd-175 [tBuBrettPhos Pd(allyl)]Otf或烯丙基氯化钯(II)二聚体和BINAP与合适的碱如乙酸钾在适当的溶剂体积如1,4-二氧杂环已烷和2-甲基-2-丁醇中在120-140℃下加热的情况下在化合物(16)与(7)之间进行Buchwald偶联以获得式Ia的化合物。
制备例1
N-[(1R)-1-(甲基氨基甲酰基)-3-甲基硫烷基-丙基]氨基甲酸叔丁酯
方案1步骤A:将(叔丁氧基羰基)-D-蛋氨酸(400克,1.6摩尔)、甲胺盐酸盐(162.47克,2.4摩尔)和DIEA(700毫升,4.01摩尔)在DMF(4升)中的溶液冷却至0℃并加入HATU(732.1克,1.92摩尔)。将该反应升温至环境温度。搅拌2小时后,将溶剂蒸发。随后加入水(10升)并用DCM(2×3升)萃取水溶液。将有机层合并,用饱和碳酸氢钠水溶液(3升)洗涤,在硫酸钠上干燥,并真空浓缩。所得残余物通过用己烷中的EtOAc洗脱的硅胶色谱法提纯以获得作为白色固体的标题化合物(368克,87%)。ES/MS m/z 263 (M+H).
制备例2
N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]氨基甲酸叔丁酯
方案1步骤B:N-[(1R)-1-(甲基氨基甲酰基)-3-甲基硫烷基-丙基]氨基甲酸叔丁酯(368克,1.40摩尔)和MeI(3.68升,59.11摩尔)的混合物在环境温度下搅拌18小时。随后该混合物真空浓缩。将一部分所得粗二甲基碘化锍盐(210克,0.52摩尔)溶解在THF(4.7升)中,在氮气氛下冷却至0℃,并逐滴加入LiHMDS(THF中的1.00M溶液,1.16升,1.16摩尔)。该反应混合物随后升温至环境温度。在4小时后,加入水(2.4升)并将溶剂浓缩至一半体积。该混合物用DCM(2×3升)萃取。将有机物合并并真空浓缩。残余物通过用DCM 中的MeOH洗脱的硅胶色谱法提纯以获得作为白色固体的标题化合物 (50 g). ES/MS m/z 215 (M+H). 手性HPLC:Rt (保留时间) = 9.13分钟;LC柱: ChiralPAc IA OD 4.6×250 mm 5 µm; 等度:0.1%二乙胺/己烷/乙醇(85/15); 柱温: 25℃; 流速: 1.0 mL/min。
旋光度:[α]D 20 = +53 ° (C=0.5, MeOH).
制备例3
(3R)-3-氨基-1-甲基-吡咯烷-2-酮;4-甲基苯磺酸
方案1步骤C:N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]氨基甲酸叔丁酯(46克,214.69毫摩尔)和4-甲基苯磺酸(74.5克,433毫摩尔)在乙腈(500毫升)中的混合物在55℃下加热并搅拌4小时。随后加入MTBE(1升),将混合物冷却至22℃。过滤收集所得固体,用附加的MTBE洗涤,并真空干燥至恒重以获得作为白色固体的标题化合物(60克,95%)。ES/MSm/z 115 (M+H).
旋光度:[α]D 20 = +31.3 ° (C=0.5, MeOH).
制备例4
N-[1-(5-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基甲酸苄酯
方案2步骤A:向高压容器中装入N-(2-氧代-1H-吡啶-3-基)氨基甲酸苄酯(6克,24毫摩尔)、碘化亚铜(0.9克,5毫摩尔)、2-溴-5-甲基吡啶(3.75克,21.4毫摩尔)、碳酸钾(7克,51毫摩尔)、1,4-二氧杂环已烷(130毫升)和DMF(0.5毫升)。反应在110℃下加热4小时。将该混合物冷却至环境温度,经硅藻土过滤,并用1,4-二氧杂环已烷洗涤。将滤液真空浓缩以获得深棕色油。所得残余物通过用0-60% EtOAc/己烷洗脱的硅胶快速色谱法经25分钟提纯以获得作为淡白色固体的标题化合物(5克,62%)。ES/MS m/z 336 (M+H).
制备例5
N-[2-氧代-1-(2-吡啶基)-3-吡啶基]氨基甲酸苄酯
方案2步骤A:向高压容器中装入N-(2-氧代-1H-吡啶-3-基)氨基甲酸苄酯(10.10克,41.36毫摩尔)、碘化亚铜(1.6克,8.6毫摩尔)、2-溴吡啶(5.2毫升,54毫摩尔)、碳酸钾(11.8克,86毫摩尔)、1,4-二氧杂环已烷(200毫升)和N',N'-二甲基乙烷-1,2-二胺(2毫升,17.4毫摩尔)。该反应在115℃下加热18小时。将该混合物冷却至环境温度并经硅藻土过滤。将滤液真空浓缩以获得棕色油。所得残余物通过用0-60% EtOAc/己烷洗脱的硅胶快速色谱法经30分钟提纯以获得作为白色固体的标题化合物(10.14克,76%)。ES/MS m/z 322.0 (M+H).
制备例6
N-[1-(6-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基甲酸苄酯
方案2步骤A:向高压容器中装入N-(2-氧代-1H-吡啶-3-基)氨基甲酸苄酯(9.8克,40毫摩尔)、碘化亚铜(1.9克,10毫摩尔)、2-溴-6-甲基吡啶(5.9毫升,51毫摩尔)、碳酸钾(11克,80毫摩尔)、N',N'-二甲基乙烷-1,2-二胺(2毫升)和1,4-二氧杂环已烷(190毫升)。该反应在115℃下加热5小时。将该混合物冷却至环境温度并经硅藻土过滤。将滤液真空浓缩以获得棕色油。所得残余物通过用0-50% EtOAc/己烷洗脱的硅胶快速色谱法经30分钟提纯以获得作为白色固体的标题化合物(7.77克,58%)。ES/MS m/z 336.0 (M+H).
制备例7
3-氨基-1-(5-甲基-2-吡啶基)吡啶-2-酮
方案2步骤B:用氮气吹扫帕尔摇动器并装入10% Pd/C(1.27克,1.19毫摩尔)。用氮气吹扫该帕尔摇动器并随后装入MeOH(25毫升)与溶解在MeOH(25毫升)和EtOAc(10毫升)中的N-[1-(5-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基甲酸苄酯(5.0克,15毫摩尔)。将该帕尔摇动器密封,用氮气吹扫,随后用氢气吹扫,并加压至138 kPa。该混合物在30℃下搅拌20分钟。将该反应混合物过滤,溶剂真空浓缩以获得作为黄色固体的标题化合物(2.7克,90%)。ES/MS m/z 202 (M+H).
制备例8
3-氨基-1-(2-吡啶基)哌啶-2-酮
方案2步骤B:用氮气吹扫帕尔摇动器并装入20% Pd(OH)2/C (5.7克,41毫摩尔)。用氮气吹扫该帕尔摇动器并随后装入EtOH(200毫升)和溶解在EtOH(200毫升)中的N-[2-氧代-1-(2-吡啶基)-3-吡啶基]氨基甲酸苄酯(9.2克,29毫摩尔)。将该帕尔摇动器密封,用氮气吹扫,随后用氢气吹扫,并加压至48 kPa。该混合物在环境温度下搅拌50分钟。将该反应混合物过滤,溶剂真空浓缩以获得作为黄色固体的标题化合物(5.3克,99%)。ES/MS m/z188.0 (M+H).
制备例9
3-氨基-1-(6-甲基-2-吡啶基)吡啶-2-酮
方案2步骤B:向用氮气吹扫的帕尔摇动器中装入20% Pd(OH)2/C(7.7克,55毫摩尔)。用氮气吹扫该帕尔摇动器并随后装入EtOH(200毫升)和溶解在EtOH(200毫升)中的N-[1-(6-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基甲酸苄酯(7.77克,23毫摩尔)。将该帕尔摇动器密封,用氮气吹扫,随后用氢气吹扫,并加压至62 kPa。该混合物在环境温度下搅拌55分钟。将该反应混合物过滤,溶剂真空浓缩成粘稠的油。该粗材料悬浮在DCM(40毫升)中并在搅拌的情况下加入己烷,直到形成沉淀物。将该混合物过滤并空气干燥以获得作为棕褐色固体的标题化合物(3.0克,51%)。ES/MS m/z 202.0 (M+H).
制备例10
7-羟基-5-氧代-4H-吡唑并[1,5-a]嘧啶-3-甲酸乙酯
方案3步骤A:将5-氨基-1H-吡唑-4-甲酸乙酯(12.5克,80.6毫摩尔)和DEM(18.5毫升,121毫摩尔)溶解在EtOH(90毫升)中。向该混合物中加入NaOEt(在EtOH中21质量%,45.1毫升,121毫摩尔),该反应在90℃下搅拌24小时。此后,将该反应冷却至环境温度。随后用5NHCl水溶液使该混合物呈酸性,将所得沉淀物过滤以获得作为白色固体的标题化合物(11.7克,65.1%)。ES/MS m/z 224 (M+H).
替代制备例10
方案3步骤A:在25℃下在氮气下向5-氨基-1H-吡唑-4-甲酸乙酯(400克,2.58摩尔)和DEM(584毫升,3.87摩尔)在EtOH(6.00升)中的溶液中加入叔丁醇钾(578克,5.16摩尔)。该溶液在80℃下搅拌12小时并随后将该反应冷却至22℃。该反应混合物用0.1N HCl(2升)稀释并用5N HCl将pH调节为3。将该混合物过滤,滤饼用水(800毫升)洗涤。固体真空干燥至恒重以获得作为灰白色固体的标题化合物(460克,81%)。ES/MS m/z 224 (M+H).
制备例11
5,7-二氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯
方案3步骤B:将7-羟基-5-氧代-4H-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(11.7克,52.4毫摩尔)悬浮在乙腈(50毫升)中并用氮气吹扫5分钟。在50℃下向该混合物中加入POCl3(14.8毫升,157毫摩尔),随后加入吡啶(4.28毫升,52.4毫摩尔),该反应随后在100℃下搅拌5小时。此后,将该反应冷却至环境温度并倾入冰/水混合物中。该混合物用碳酸氢钠饱和水溶液中和,将所得沉淀物过滤以获得作为白色固体的标题化合物(13克,95.3%)。ES/MS m/z (35Cl/37Cl) 260/262 [M+H]+.
替代制备例11
方案3步骤B:在50℃下在氮气下向7-羟基-5-氧代-4H-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(400克,1.79摩尔)在乙腈(2升)中的悬浮液中逐滴加入POCl3(416毫升,4.48摩尔)和吡啶(217毫升,2.69摩尔)。该反应在80℃下搅拌12小时。该反应混合物真空浓缩,将残余物倾入水(2升)中。将该反应混合物过滤,固体用水(800毫升)洗涤。该固体真空干燥至恒重以获得作为橙色固体的标题化合物(360克,66%)。ES/MS m/z (35Cl/37Cl) 260/262 [M+H]+.
制备例12
5-氯-7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯
方案3步骤C:将5,7-二氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(50.0克,192毫摩尔)添加到THF(250毫升)中,溶液冷却至10℃。随后加入MeNH2的溶液(33 % w/w在EtOH中)(79毫升,634毫摩尔),保持温度低于20℃。搅拌该反应混合物并升温至22℃,搅拌4小时。随后加入水(300毫升),该混合物搅拌附加的1小时。
过滤收集所得固体并用THF/水混合物(2:3)(100毫升)和水(400毫升)洗涤。该固体随后真空干燥(10 mbar/50℃)至恒重以获得作为淡棕色固体的标题化合物(49.5克,90%)。ES/MS m/z (35Cl/37Cl) 255/257 [M+H]+.
制备例13
5-氯-7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酸
方案4步骤A:将1N NaOH (50毫升,50毫摩尔)添加到在1,4-二氧杂环已烷(50毫升)中的5-氯-7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(9.05克,35.5毫摩尔)中并将该混合物升温至50℃。在16小时后,将该混合物冷却至环境温度并通过添加1N HCl将pH调节至~3。收集所得固体并真空干燥以获得作为浅棕褐色固体的标题化合物(8.0克,>99%)。ES/MS m/z (35Cl/37Cl) 227/229 [M+H]+.
制备例14
5-氯-7-(甲氨基)-N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]吡唑并[1,5-a]嘧啶-3-甲酰胺
方案4步骤B:向5-氯-7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酸(4.3克,19毫摩尔)和(R)-3-氨基-1-甲基-吡咯烷-2-酮(2.4克,21毫摩尔)在DMF(95毫升)中的混合物中加入DIEA(14毫升,80毫摩尔)和BOP(11克,24毫摩尔)。该混合物在环境温度下搅拌2小时并随后用水骤冷,形成灰白色固体。将所得固体过滤并在环境温度下真空干燥以获得作为灰白色固体的标题化合物(5克,82%)。ES/MS m/z 323 (M+H).
制备例15
7-(甲氨基)-5-[[1-(6-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基]吡唑并[1,5-a]嘧啶-3-甲酸乙酯
方案3步骤D:向圆底烧瓶中装入5-氯-7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(2克,7.8毫摩尔)、乙酸钾(2.2克,15.7毫摩尔)和2-甲基丁-2-醇(25毫升)。该烧瓶用氮气冲洗5分钟。加入Pd-175 [tBuBrettPhos Pd(allyl)]Otf(184毫克,0.24毫摩尔)和乙酸(0.045毫升,0.79毫摩尔)。该混合物在100℃下加热18小时。随后将该混合物冷却至环境温度并用DCM/水(30毫升)稀释。将该混合物过滤并在环境温度下真空干燥以获得标题化合物(2.4克,73%)。ES/MS m/z 420.0 (M+H).
制备例16
7-(甲氨基)-5-[[1-(6-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基]吡唑并[1,5-a]嘧啶-3-甲酸
方案3步骤E:向圆底烧瓶中装入7-(甲氨基)-5-[[1-(6-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基]吡唑并[1,5-a]嘧啶-3-甲酸乙酯(2.4克,5.7毫摩尔)、EtOH(20毫升)和溶解在水(12毫升)中的氢氧化锂(0.34克,4.1毫摩尔)。该混合物在氮气下加热至回流18小时,随后冷却至环境温度。通过添加1N HCl将pH调节至~2。搅拌30分钟后,将所得固体过滤,用冰冷的水洗涤(20毫升)并在环境温度下真空干燥以获得标题化合物(1.6克,71%)。ES/MSm/z 392.0 (M+H).
制备例17
制备用于TYK2-JH2示踪剂结合测定的示踪剂
(2E)-2-[(2E,4E)-5-[3-[6-[4-[4-[[5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-6-(甲基氨基甲酰基)-1,2,4-三嗪-3-基]氨基]吡唑-1-基]-1-哌啶基]-6-氧代-己基]-3-甲基-5-磺酸根合-1-(3-磺酸根合丙基)吲哚-1-鎓-2-基]戊-2,4-二烯叉基]-3,3-二甲基-1-(3-磺酸根合丙基)二氢吲哚-5-磺酸盐;三乙基铵
将2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺(5.95克,29.1毫摩尔)添加到NMP(20毫升)中的5-氯-3-甲基硫烷基-1,2,4-三嗪-6-甲酸乙酯(6.8克,29.0毫摩尔)中并在环境温度下搅拌。在90分钟后,加入二乙醚(100毫升),该混合物搅拌15分钟。将所得固体过滤并用二乙醚洗涤。固体在DCM和碳酸氢钠饱和水溶液之间分配。有机层用氯化钠饱和水溶液进一步洗涤,在硫酸钠上干燥,过滤并蒸发以获得作为淡黄色固体的5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-3-甲基硫烷基-1,2,4-三嗪-6-甲酸乙酯(10.12克,82%)。ES/MS m/z 402.2 (M+H).
5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-3-甲基硫烷基-1,2,4-三嗪-6-甲酸乙酯(10.12克,23.7毫摩尔)在环境温度下在THF中的2M MeNH2中(75毫升,150毫摩尔)搅拌4小时。加入二乙醚(100毫升)并将该混合物搅拌15分钟。收集所得固体,用二乙醚(50毫升)洗涤并真空干燥以获得作为浅黄色固体的5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-N-甲基-3-甲基硫烷基-1,2,4-三嗪-6-甲酰胺(8.03克,78%)。ES/MS m/z387.0 (M+H).
在0℃下将间氯过氧苯甲酸(703毫克,3.14毫摩尔)添加到5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-N-甲基-3-甲基硫烷基-1,2,4-三嗪-6-甲酰胺(500毫克,1.26毫摩尔)在DMF(12.5毫升)中的悬浮液中并令其升温至环境温度。在30分钟后,加入4-(4-氨基吡唑-1-基)哌啶-1-甲酸叔丁酯(520毫克,1.89毫摩尔),该混合物在环境温度下搅拌。24小时后,该混合物在DCM与碳酸氢钠饱和水溶液之间分配。有机层在硫酸镁上干燥,过滤并蒸发。所得固体用二乙醚研磨数次并真空干燥以获得作为86%纯的黄色固体的4-[4-[[5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-6-(甲基氨基甲酰基)-1,2,4-三嗪-3-基]氨基]吡唑-1-基]哌啶-1-甲酸叔丁酯(720毫克,81%)。ES/MS m/z 605.2 (M+H).
向4-[4-[[5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-6-(甲基氨基甲酰基)-1,2,4-三嗪-3-基]氨基]吡唑-1-基]哌啶-1-甲酸叔丁酯(720毫克,1.0毫摩尔)在MeOH(5毫升)中的悬浮液中加入二氧杂环已烷中的4N HCl(2.5毫升,10毫摩尔)并在环境温度下搅拌。72小时后,蒸发该混合物。所得材料在DCM(100毫升)与水(20毫升)之间分配。通过添加1N NaOH将水层的pH调节至>8并用3:1氯仿/异丙醇萃取。将有机层合并,在硫酸镁上干燥,过滤并蒸发。所得固体用二乙醚研磨并随后真空干燥以获得作为86%纯的黄色固体的5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-N-甲基-3-[[1-(4-哌啶基)吡唑-4-基]氨基]-1,2,4-三嗪-6-甲酰胺(585毫克,97%)。ES/MS m/z 505.0 (M+H).
将(2E)-2-[(2E,4E)-5-[3-[6-(2,5-二氧代吡咯烷-1-基)氧基-6-氧代-己基]-3-甲基-5-磺酸根合-1-(3-磺酸根合丙基)吲哚-1-鎓-2-基]戊-2,4-二烯叉基]-3,3-二甲基-1-(3-磺酸根合丙基)二氢吲哚-5-磺酸三乙基铵(10毫克,0.008毫摩尔)在DMSO(1毫升)中的溶液添加到5-[2-甲氧基-3-(1-甲基-1,2,4-三唑-3-基)苯胺基]-N-甲基-3-[[1-(4-哌啶基)吡唑-4-基]氨基]-1,2,4-三嗪-6-甲酰胺(4.5毫克,0.008毫摩尔)和TEA(0.002毫升,0.014毫摩尔)在DMSO(1毫升)中的溶液中。反应小瓶包裹在铝箔中以避光,并在环境温度下搅拌整夜。所得残余物通过用水中0至20%乙腈洗脱的制备型HPLC(Kinetix EVO C18 30 mm×100 mm, 5μm)提纯以获得作为亮蓝色固体的标题化合物(8.5毫克,65%)。ES/MS m/z673.4 (M+H).
实施例1
7-(甲氨基)-N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]-5-[[1-(5-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基]吡唑并[1,5-a]嘧啶-3-甲酰胺
方案4步骤C:向微波容器中装入5-氯-7-(甲氨基)-N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]吡唑并[1,5-a]嘧啶-3-甲酰胺(76毫克,0.23毫摩尔)、3-氨基-1-(5-甲基-2-吡啶基)吡啶-2-酮(72毫克,0.359毫摩尔)、乙酸钾(48毫克,0.47毫摩尔)、2-甲基丁-2-醇(0.8毫升)和1,4-二氧杂环已烷(0.8毫升)。该烧瓶用氮气冲洗5分钟。加入BINAP(59毫克,0.093毫摩尔)和烯丙基氯化钯(II)二聚体(16.7毫克,0.0447毫摩尔)。该容器在微波中在120℃下加热。20分钟后,将该混合物冷却至环境温度并经硅藻土过滤。所得残余物经由反相色谱法提纯以获得标题化合物(87毫克,75%)。ES/MS m/z 488.2 (M+H).
实施例2
7-(甲氨基)-N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]-5-[[1-(6-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基]吡唑并[1,5-a]嘧啶-3-甲酰胺
方案3步骤F:向7-(甲氨基)-5-[[1-(6-甲基-2-吡啶基)-2-氧代-3-吡啶基]氨基]吡唑并[1,5-a]嘧啶-3-甲酸(1.2克,3.1毫摩尔)和(3R)-3-氨基-1-甲基-吡咯烷-2-酮;4-甲基苯磺酸(0.9克,3毫摩尔)在DMF(15毫升)中的混合物中加入DIEA(2.1毫升,12毫摩尔)和BOP(1.8克,3.9毫摩尔)。在环境温度下搅拌1小时后,将该反应混合物添加到水(240毫升)中并将pH调节至~6-7。搅拌30分钟后,将所得固体过滤,用冰冷的水(20毫升)洗涤,并在环境温度下真空干燥。所得残余物经由反相色谱法提纯并由MeOH重结晶以获得标题化合物(446毫克,30%)。ES/MS m/z 488.2 (M+H).
实施例3
7-(甲氨基)-N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]-5-[[2-氧代-1-(2-吡啶基)-3-吡啶基]氨基]吡唑并[1,5-a]嘧啶-3-甲酰胺
方案4步骤C:向微波容器中装入5-氯-7-(甲氨基)-N-[(3R)-1-甲基-2-氧代-吡咯烷-3-基]吡唑并[1,5-a]嘧啶-3-甲酰胺(0.302克,0.935毫摩尔)、3-氨基-1-(2-吡啶基)吡啶-2-酮(0.21克,1.1毫摩尔)、乙酸钾(281毫克,2.7毫摩尔)、2-甲基丁-2-醇(7.5毫升)和1,4-二氧杂环已烷(7.5毫升)。该烧瓶用氮气冲洗5分钟。加入Pd-175 [tBuBrettPhos Pd(allyl)]Otf(30毫克,0.038毫摩尔)。该容器在微波中在140℃下加热。40分钟后,将该混合物冷却至环境温度并经硅藻土过滤。所得残余物经由反相色谱法提纯以获得标题化合物(265毫克,60%)。ES/MS (m/z): 474.2 (M+H).
TYK2-JH2示踪剂结合测定
具有N端His6标签的人JAK(细胞质酪氨酸激酶的两面神家族)家族酪氨酸激酶2(TYK2)(Genbank NP_003322)的假激酶结构域(JH2)在杆状病毒中表达并通过HisPur Ni-NTA亲和力和Superdex 200尺寸排阻色谱法纯化。制备例17中制备的化合物,其是AlexaFluor 647染料(Thermo Fisher Scientific)与合适的TYK2 JH2结合剂的缀合物,在本文中被称为“示踪剂”。在100% DMSO中制备化合物(实施例1、2和3)的3倍、10点连续稀释,并使用声学液体处理将50 nL/孔转移到Proxiplate-384F白板(PerkinElmer 6008280)中。用于确定百分比抑制的对照孔含有100% DMSO(50 nL)和含有示踪剂(2.00 nM最终浓度)(最低,低FRET)或稀释的TYK2-JH2酶(0.200 nM最终浓度)与示踪剂(2.00 nM最终浓度)(最大,高FRET)的测定缓冲液。
将5.0 µL在测定缓冲液 (50 mM HEPES pH 7.5,10 mM氯化镁,1 mM乙二醇-双(β-氨基乙基醚)-N,N,N′,N′-四乙酸,0.01% Brij-35和Milli-Q)水中的His标记的TYK2-JH2(0.402 nM)和LanthaScreen Eu-anti-HIS Ab(4.02 nM, LifeTech, PV5597)添加到含有50 nL稀释化合物的Proxiplate-384板和对照孔中。将5.0 µL的测定缓冲液中的示踪剂(2.00 nM最终浓度)添加到该板中并令其在环境温度下平衡30分钟。30分钟后,该板在PerkinElmer Envision上使用以下设置进行计数:激发(340 nm),示踪剂发射(665 nm)和LanthaScreen Eu-anti-His抗体发射(615 nm)。确定示踪剂发射(665 nm)对LanthaScreenEu-anti-His抗体发射(615 nm)的比。使用最大和最小对照孔计算每个抑制剂浓度下的百分比抑制率,并拟合至GeneData Screener®中的四参数非线性逻辑方程以获得受试化合物的IC50。表1中描述的数据表明实施例1-3的化合物在体外与TYK2-JH2假激酶结构域结合。
表1:对实施例1-3提供的IC50值
化合物 | TYK2-JH2结合(nM) |
实施例1 | <0.254 (n=4) |
实施例2 | <0.254 (n=1) |
实施例3 | <0.254 (n=3) |
在TF1细胞中抑制通过pSTAT1的IFNα信号传导
TF1细胞(ATCC, CL-2003)在补充有10%透析FBS、0.1 mg/mL氨苄青霉素和2 ng/mL粒细胞巨噬细胞集落刺激因子的RPMI 1640(GIBCO)中生长。将TF1细胞(每孔100 K个)接种在无血清DMEM中的96孔聚-D-赖氨酸涂布的板中并在37℃下在5% CO2下温育整夜。将实施例1在DMSO中连续稀释,添加到细胞中,并在37℃下温育1小时。随后37℃下用10 ng/mL IFNα2刺激细胞20分钟。除去培养基后,将细胞在含有 Halt 蛋白酶和磷酸酶抑制剂混合物的缓冲液(Thermo Scientific #78441)中在环境温度下裂解30分钟。根据供应商推荐的方案,使用 AlphaLISA SureFire Ultra p-Stat1 (Tyr701)测定试剂盒(Perkin Elmer #ALSU-PST1-A50K)将p-Stat1(Tyr701)的量量化为615 nm处的光发射。计算每个抑制剂浓度下的百分比抑制,并使用Genedata Screener®拟合至四参数非线性逻辑方程以获得表示为具有平均值标准误差(SEM)的几何平均值的受试化合物的IC50。表2中描述的数据表明实施例1-3的化合物是TF1细胞中通过pSTAT1的IFNα信号传导的抑制剂。
表2:对实施例1-3提供的IC50值
化合物 | IFNα inh (µM) |
实施例1 | 0.112 (±0.055 µM, n=4) |
实施例2 | 0.206 (±0.065 µM, n=3) |
实施例3 | 0.106 (±0.070 µM, n=3) |
IL23 pSTAT3 AlphaLISA测定
表达内源性IL23受体的IL2依赖性Kit225细胞(University of Texas MDAnderson Cancer Center)用连接至荧火虫荧光素酶的Lenti STAT3 Reporter(SABiosciences CLS-6028L)稳定转导。这些细胞用于通过使用AlphaLISA技术(TGRBiosciences ALSU-TST3-A50K)在IL2的存在下由IL23诱导后量化由STAT3磷酰化导致的基因表达来监控TYK2活性。该细胞在补充有10% FBS(Invitrogen 10082)、1X Pen/Strep(Gibco 15140-122)、200 ng/ml Puromycin(Sigma P9620)和新鲜的10 ng/ml重组人IL2(R&D Systems 202-IL-50)的RPMI 1640(Gibco 22400)中生长。
对于测定准备,将细胞以300,000个细胞/孔分配到DMEM(Sigma D5796)中的Biocoat黑色聚-D-赖氨酸涂布的透明底384孔板(Becton Dickinson Bio-Coat 35-4640)中并在37℃下温育整夜。溶解在DMSO中的化合物连续稀释1:3以产生10点浓度响应曲线(最终DMSO = 0.1%)。细胞在37℃下用实施例1预温育1小时,随后用IL23(25 ng/mL最终)刺激30分钟。在以2000 rpm离心10分钟后,细胞团块用1:1裂解缓冲液(TGR Biosciences)和Halt Protease & Phosphatase混合抑制剂(Thermo Scientific 1861281)的混合物裂解30分钟。根据供应商推荐的方案进行AlphaLISA反应,并使用Envision读板仪(PerkinElmer)测量荧光素酶水平。使用四参数非线性逻辑方程(GeneData Screener 13.0.5)计算相对IC50以获得表示为具有平均值标准误差(SEM)的几何平均值的受试化合物的IC50。表3中描述的数据表明实施例1-3的化合物在基于细胞的测定中是IL-23信号传导的抑制剂。
表3:对实施例1-3提供的IC50值
化合物 | IL-23 inh (µM) |
实施例1 | 0.065 (±0.011 µM, n=4) |
实施例2 | 0.101 (±0.0005 µM, n=2) |
实施例3 | 0.101 (±0.022 µM, n=3) |
Claims (22)
12.在患者中治疗牛皮癣的方法,包括对需要此类治疗的患者施用有效量的如权利要求1至11任一项所述的化合物或其可药用盐。
13.在患者中治疗系统性红斑狼疮的方法,包括对需要此类治疗的患者施用有效量的如权利要求1至11任一项所述的化合物或其可药用盐。
14.在患者中治疗1型糖尿病的方法,包括对需要此类治疗的患者施用有效量的如权利要求1至11任一项所述的化合物或其可药用盐。
15.如权利要求1至11任一项所述的化合物或其可药用盐,其用于治疗。
16.如权利要求1至11任一项所述的化合物或其可药用盐,其用于治疗牛皮癣。
17.如权利要求1至11任一项所述的化合物或其可药用盐,其用于治疗系统性红斑狼疮。
18.如权利要求1至11任一项所述的化合物或其可药用盐,其用于治疗1型糖尿病。
19.如权利要求1至11任一项所述的化合物或其可药用盐用于制备治疗牛皮癣的药物的用途。
20.如权利要求1至11任一项所述的化合物或其可药用盐用于制备治疗系统性红斑狼疮的药物的用途。
21.如权利要求1至11任一项所述的化合物或其可药用盐用于制备治疗1型糖尿病的药物的用途。
22.药物组合物,包含权利要求1至11任一项所述的化合物或其可药用盐,以及一种或多种可药用载体、稀释剂或赋形剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062975257P | 2020-02-12 | 2020-02-12 | |
US62/975257 | 2020-02-12 | ||
PCT/US2021/016737 WO2021162942A1 (en) | 2020-02-12 | 2021-02-05 | 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115038705A true CN115038705A (zh) | 2022-09-09 |
Family
ID=74845061
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180014348.4A Pending CN115038705A (zh) | 2020-02-12 | 2021-02-05 | 7-(甲氨基)吡唑并[1,5-a]嘧啶-3-甲酰胺化合物 |
Country Status (13)
Country | Link |
---|---|
US (1) | US11634423B2 (zh) |
EP (1) | EP4103565B1 (zh) |
JP (1) | JP7408826B2 (zh) |
KR (1) | KR20220140789A (zh) |
CN (1) | CN115038705A (zh) |
AR (1) | AR121251A1 (zh) |
AU (1) | AU2021219634B2 (zh) |
BR (1) | BR112022015235A2 (zh) |
CA (1) | CA3167301A1 (zh) |
IL (1) | IL295380A (zh) |
MX (1) | MX2022009884A (zh) |
TW (1) | TWI810520B (zh) |
WO (1) | WO2021162942A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3849981B1 (en) * | 2018-09-10 | 2023-02-01 | Eli Lilly and Company | Pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives useful in the treatment of psoriasis and systemic lupus erythematosus |
CN117043164A (zh) * | 2021-01-19 | 2023-11-10 | 安锐生物医药科技(广州)有限公司 | 咪唑并哒嗪或吡唑并嘧啶化合物和组合物 |
WO2023169336A1 (zh) * | 2022-03-09 | 2023-09-14 | 成都科岭源医药技术有限公司 | 一种哒嗪类化合物及其制备方法及用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019023468A1 (en) * | 2017-07-28 | 2019-01-31 | Nimbus Lakshmi, Inc. | TYK2 INHIBITORS AND USES THEREOF |
WO2020055636A1 (en) * | 2018-09-10 | 2020-03-19 | Eli Lilly And Company | Pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives useful in the treatment of psoriasis and systemic lupus erythematosus |
WO2020123225A1 (en) * | 2018-12-10 | 2020-06-18 | Eli Lilly And Company | 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10223917A1 (de) | 2002-05-29 | 2003-12-11 | Bayer Cropscience Ag | Pyrazolopyrimidine |
US7119200B2 (en) | 2002-09-04 | 2006-10-10 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
CA2497544C (en) | 2002-09-04 | 2010-11-02 | Schering Corporation | Pyrazolo[1,5-a]pyrimidines compounds as cyclin dependent kinase inhibitors |
KR101088922B1 (ko) | 2002-09-04 | 2011-12-01 | 파마코페이아, 엘엘씨. | 사이클린 의존성 키나제 억제제로서의 피라졸로피리미딘 |
CA2516824A1 (en) | 2003-02-28 | 2004-09-10 | Teijin Pharma Limited | Pyrazolo[1,5-a]pyrimidine derivatives |
US7645762B2 (en) | 2005-10-06 | 2010-01-12 | Schering Corporation | Substituted pyrazolo[1,5-a] pyrimidines as protein kinase inhibitors |
AR061793A1 (es) | 2006-07-05 | 2008-09-24 | Mitsubishi Tanabe Pharma Corp | Compuesto de pirazolo[1,5-a] pirimidina y composicion farmaceutica |
PE20131197A1 (es) | 2008-10-31 | 2013-11-06 | Genentech Inc | Compuestos de pirazolopirimidina como inhibidores de jak y composiciones farmaceuticas que los contienen |
DK2649075T3 (en) | 2010-12-08 | 2018-07-30 | Us Health | SUBSTITUTED PYRAZOLOPYRIMIDINES AS GLUCOCEREBROSIDASE ACTIVATORS |
US10273237B2 (en) | 2013-12-10 | 2019-04-30 | Bristol-Myers Squibb Company | Imidazopyridazine compounds useful as modulators of IL-12, IL-23 and/or IFN-α responses |
KR20180081584A (ko) | 2015-11-18 | 2018-07-16 | 브리스톨-마이어스 스큅 컴퍼니 | Il-12, il-23 및/또는 ifn 알파 반응의 조정제로서 유용한 이미다조피리다진 화합물 |
CN110036015B (zh) | 2016-10-07 | 2022-07-19 | 百时美施贵宝公司 | 可用作IL-12、IL-23和/或IFNα应答的调节剂的咪唑并哒嗪化合物 |
CN110191887B (zh) | 2016-11-17 | 2022-02-18 | 百时美施贵宝公司 | IL-12、IL-23和/或IFN-α的咪唑并哒嗪调节剂 |
AU2019360941A1 (en) | 2018-10-15 | 2021-04-29 | Takeda Pharmaceutical Company Limited | TYK2 inhibitors and uses thereof |
-
2021
- 2021-02-02 AR ARP210100270A patent/AR121251A1/es unknown
- 2021-02-02 TW TW110103764A patent/TWI810520B/zh active
- 2021-02-05 IL IL295380A patent/IL295380A/en unknown
- 2021-02-05 WO PCT/US2021/016737 patent/WO2021162942A1/en active Application Filing
- 2021-02-05 KR KR1020227031303A patent/KR20220140789A/ko unknown
- 2021-02-05 EP EP21709238.6A patent/EP4103565B1/en active Active
- 2021-02-05 AU AU2021219634A patent/AU2021219634B2/en active Active
- 2021-02-05 BR BR112022015235A patent/BR112022015235A2/pt unknown
- 2021-02-05 JP JP2022548684A patent/JP7408826B2/ja active Active
- 2021-02-05 CN CN202180014348.4A patent/CN115038705A/zh active Pending
- 2021-02-05 US US17/168,399 patent/US11634423B2/en active Active
- 2021-02-05 MX MX2022009884A patent/MX2022009884A/es unknown
- 2021-02-05 CA CA3167301A patent/CA3167301A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019023468A1 (en) * | 2017-07-28 | 2019-01-31 | Nimbus Lakshmi, Inc. | TYK2 INHIBITORS AND USES THEREOF |
WO2020055636A1 (en) * | 2018-09-10 | 2020-03-19 | Eli Lilly And Company | Pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives useful in the treatment of psoriasis and systemic lupus erythematosus |
WO2020123225A1 (en) * | 2018-12-10 | 2020-06-18 | Eli Lilly And Company | 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives |
Also Published As
Publication number | Publication date |
---|---|
TWI810520B (zh) | 2023-08-01 |
TW202144355A (zh) | 2021-12-01 |
US20210253581A1 (en) | 2021-08-19 |
US11634423B2 (en) | 2023-04-25 |
WO2021162942A1 (en) | 2021-08-19 |
EP4103565B1 (en) | 2024-05-01 |
JP2023515774A (ja) | 2023-04-14 |
BR112022015235A2 (pt) | 2022-09-20 |
JP7408826B2 (ja) | 2024-01-05 |
KR20220140789A (ko) | 2022-10-18 |
IL295380A (en) | 2022-10-01 |
AR121251A1 (es) | 2022-05-04 |
AU2021219634A1 (en) | 2022-09-01 |
EP4103565A1 (en) | 2022-12-21 |
AU2021219634B2 (en) | 2024-01-25 |
CA3167301A1 (en) | 2021-08-19 |
MX2022009884A (es) | 2022-08-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2021219634B2 (en) | 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds | |
EP3894412B1 (en) | 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives | |
EP3849981B1 (en) | Pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives useful in the treatment of psoriasis and systemic lupus erythematosus | |
EA019723B1 (ru) | ИНГИБИТОРЫ cMET | |
TW201113285A (en) | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors | |
JP2022506111A (ja) | Jak阻害剤としての2-アザビシクロヘキサン化合物 | |
KR20230004612A (ko) | 염증성 질병의 치료를 위한 치환된 피리딘 | |
WO2019011228A1 (zh) | 咪唑并[1,2-b]嘧啶并[4,5-d]哒嗪-5(6H)-酮类化合物及其应用 | |
US20190292179A1 (en) | TGF Beta RECEPTOR ANTAGONISTS | |
EP4103279B1 (en) | Substituted 7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide derivatives | |
EA046473B1 (ru) | СОЕДИНЕНИЯ 7-(МЕТИЛАМИНО)ПИРАЗОЛО[1,5-a]ПИРИМИДИН-3-КАРБОКСАМИДА |
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 |