CN112159394B - 一种作为jak激酶抑制剂的小分子化合物及其用途 - Google Patents
一种作为jak激酶抑制剂的小分子化合物及其用途 Download PDFInfo
- Publication number
- CN112159394B CN112159394B CN202011072699.4A CN202011072699A CN112159394B CN 112159394 B CN112159394 B CN 112159394B CN 202011072699 A CN202011072699 A CN 202011072699A CN 112159394 B CN112159394 B CN 112159394B
- Authority
- CN
- China
- Prior art keywords
- compound
- small molecule
- molecule compound
- reaction
- lcms
- 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.)
- Active
Links
- -1 Small molecule compound Chemical class 0.000 title claims abstract description 29
- 102000042838 JAK family Human genes 0.000 title claims abstract description 25
- 108091082332 JAK family Proteins 0.000 title claims abstract description 25
- 229940043355 kinase inhibitor Drugs 0.000 title description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 201000004624 Dermatitis Diseases 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 208000023275 Autoimmune disease Diseases 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 208000010668 atopic eczema Diseases 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 206010047642 Vitiligo Diseases 0.000 claims description 6
- 208000004631 alopecia areata Diseases 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 230000008506 pathogenesis Effects 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 241000896563 Glossus Species 0.000 claims description 3
- 206010024434 Lichen sclerosus Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 206010047115 Vasculitis Diseases 0.000 claims description 3
- 206010000496 acne Diseases 0.000 claims description 3
- 201000001981 dermatomyositis Diseases 0.000 claims description 3
- 208000002557 hidradenitis Diseases 0.000 claims description 3
- 201000007162 hidradenitis suppurativa Diseases 0.000 claims description 3
- 201000011486 lichen planus Diseases 0.000 claims description 3
- 206010033675 panniculitis Diseases 0.000 claims description 3
- 230000008482 dysregulation Effects 0.000 claims description 2
- 230000011664 signaling Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000036039 immunity Effects 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 18
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 abstract description 14
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 abstract description 14
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract description 14
- 239000003112 inhibitor Substances 0.000 abstract description 14
- 125000003118 aryl group Chemical group 0.000 abstract description 11
- 229940125436 dual inhibitor Drugs 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- 239000012453 solvate Substances 0.000 abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000002360 preparation method Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 238000001514 detection method Methods 0.000 description 19
- 230000000694 effects Effects 0.000 description 17
- 239000004973 liquid crystal related substance Substances 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- 238000001035 drying Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 8
- 108091000080 Phosphotransferase Proteins 0.000 description 8
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 8
- 102000020233 phosphotransferase Human genes 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 7
- 208000027866 inflammatory disease Diseases 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000011535 reaction buffer Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 3
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 3
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 3
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 3
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 3
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 3
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229940126650 Compound 3f Drugs 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108010024121 Janus Kinases Proteins 0.000 description 3
- 102000015617 Janus Kinases Human genes 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229940123371 Tyrosine kinase 2 inhibitor Drugs 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000011285 therapeutic regimen Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 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
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 1
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 1
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 1
- FRIVSOMHKNBSIK-NQLNTKRDSA-N (9Z,12Z)-3-methyl-5-nitrooctadeca-9,12-dienoic acid Chemical compound CC(CC(=O)O)CC(CCC\C=C/C\C=C/CCCCC)[N+](=O)[O-] FRIVSOMHKNBSIK-NQLNTKRDSA-N 0.000 description 1
- ZIWUSRIDVYWFOH-MURFETPASA-N (9Z,12Z)-N,3-dimethyl-5-nitrooctadeca-9,12-dienamide Chemical compound CNC(CC(CC(CCC\C=C/C\C=C/CCCCC)[N+](=O)[O-])C)=O ZIWUSRIDVYWFOH-MURFETPASA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- 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 1
- BFFMUNPKUZVJBT-UHFFFAOYSA-N 2-[3-[4-(2-chloropyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile Chemical compound ClC1=NC=CC(C2=CN(N=C2)C2(CC#N)CNC2)=N1 BFFMUNPKUZVJBT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- FEOJGOCPLBYATN-NRFANRHFSA-N C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC1=CC(=C(C(=O)NCC)C=C1)C Chemical compound C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC1=CC(=C(C(=O)NCC)C=C1)C FEOJGOCPLBYATN-NRFANRHFSA-N 0.000 description 1
- XBLHTINWTZVARA-FQEVSTJZSA-N C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC1=CC=C(C(=O)NCC)C=C1 Chemical compound C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC1=CC=C(C(=O)NCC)C=C1 XBLHTINWTZVARA-FQEVSTJZSA-N 0.000 description 1
- UYKSYNBDOUCANP-KRWDZBQOSA-N C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)N)C Chemical compound C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)N)C UYKSYNBDOUCANP-KRWDZBQOSA-N 0.000 description 1
- GOURSMXGANLBLJ-SFHVURJKSA-N C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)NC)C Chemical compound C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1C=C(C=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)NC)C GOURSMXGANLBLJ-SFHVURJKSA-N 0.000 description 1
- LNFHZXXASVJVTC-IBGZPJMESA-N C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1N=CC(=C1)C1=NC(=NC=C1)NC1=CC=C(C(=O)NCC)C=C1 Chemical compound C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1N=CC(=C1)C1=NC(=NC=C1)NC1=CC=C(C(=O)NCC)C=C1 LNFHZXXASVJVTC-IBGZPJMESA-N 0.000 description 1
- UNTUICULBUYJEM-INIZCTEOSA-N C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1N=CC(=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)N)C Chemical compound C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1N=CC(=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)N)C UNTUICULBUYJEM-INIZCTEOSA-N 0.000 description 1
- XDHMCWYMAGQEKB-KRWDZBQOSA-N C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1N=CC(=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)NC)C Chemical compound C(#N)CC1(CN(C1)C(=O)[C@H]1C(C1)(F)F)N1N=CC(=C1)C1=NC(=NC=C1)NC=1C=C(C(=NC1)C(=O)NC)C XDHMCWYMAGQEKB-KRWDZBQOSA-N 0.000 description 1
- YWTVYXORDOAXNY-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC(C1)(CC#N)N1C=C(C=C1)C1=NC(=NC=C1)Cl Chemical compound C(C)(C)(C)OC(=O)N1CC(C1)(CC#N)N1C=C(C=C1)C1=NC(=NC=C1)Cl YWTVYXORDOAXNY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- MCBYNMVIXONDJR-UHFFFAOYSA-N ClC1=NC=CC(=N1)C1=CN(C=C1)C1(CNC1)CC#N Chemical compound ClC1=NC=CC(=N1)C1=CN(C=C1)C1(CNC1)CC#N MCBYNMVIXONDJR-UHFFFAOYSA-N 0.000 description 1
- MFUVUXZMMYPEOY-NSHDSACASA-N ClC1=NC=CC(=N1)C=1C=NN(C1)C1(CN(C1)C(=O)[C@H]1C(C1)(F)F)CC#N Chemical compound ClC1=NC=CC(=N1)C=1C=NN(C1)C1(CN(C1)C(=O)[C@H]1C(C1)(F)F)CC#N MFUVUXZMMYPEOY-NSHDSACASA-N 0.000 description 1
- LPXAKKHBJYDQPV-UHFFFAOYSA-N Clc1nccc(n1)-c1cc[nH]c1 Chemical compound Clc1nccc(n1)-c1cc[nH]c1 LPXAKKHBJYDQPV-UHFFFAOYSA-N 0.000 description 1
- 229940125761 Compound 6g Drugs 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- VAEGPAMOKBZMTM-CVMIBEPCSA-N FC1([C@@H](C1)C(=O)N1CC(C1)(N1C=C(C=C1)C1=NC(=NC=C1)NC=1C=NC(=CC1)C(CO)C)CC#N)F Chemical compound FC1([C@@H](C1)C(=O)N1CC(C1)(N1C=C(C=C1)C1=NC(=NC=C1)NC=1C=NC(=CC1)C(CO)C)CC#N)F VAEGPAMOKBZMTM-CVMIBEPCSA-N 0.000 description 1
- HSWVJQBEXRKOBZ-QGZVFWFLSA-N FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F HSWVJQBEXRKOBZ-QGZVFWFLSA-N 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- HYDUBJXQIUNNEN-UHFFFAOYSA-N NC=1C=C(C(=NC=1)C(=O)NC)C Chemical compound NC=1C=C(C(=NC=1)C(=O)NC)C HYDUBJXQIUNNEN-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 210000000662 T-lymphocyte subset Anatomy 0.000 description 1
- 108010010057 TYK2 Kinase Proteins 0.000 description 1
- 102000015774 TYK2 Kinase Human genes 0.000 description 1
- 210000000447 Th1 cell Anatomy 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000004347 all-trans-retinol derivatives Chemical class 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy 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
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- BPERZHAZUJAZJI-UTJQPWESSA-N ethyl (9Z,12Z)-3-methyl-5-nitrooctadeca-9,12-dienoate Chemical compound CC(CC(=O)OCC)CC(CCC\C=C/C\C=C/CCCCC)[N+](=O)[O-] BPERZHAZUJAZJI-UTJQPWESSA-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
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 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
- 230000009054 pathological process Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- KZNCBQULUUIOLT-UHFFFAOYSA-N tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1(CC#N)N1N=CC(B2OC(C)(C)C(C)(C)O2)=C1 KZNCBQULUUIOLT-UHFFFAOYSA-N 0.000 description 1
- KDAVZPFGPGERJF-UHFFFAOYSA-N tert-butyl 3-[4-(2-chloropyrimidin-4-yl)pyrazol-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1(CC#N)N1N=CC(C=2N=C(Cl)N=CC=2)=C1 KDAVZPFGPGERJF-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明提供了一种小分子化合物,所述小分子化合物为由下式表示的化合物,或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、以及药学上可接受的盐或前药,其中R1至R5各自独立地选自C或N;并且其中R选自环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基。本发明的小分子化合物能够抑制JAK激酶,更特别是作为JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂。
Description
技术领域
本发明属于小分子化合物领域,具体地,涉及一种能够用于预防或治疗缓解自身免疫性疾病如风湿性关节炎、溃疡性结肠炎和系统性红斑狼疮等,或相关的炎症性皮肤病如银屑病、湿疹、白癜风和斑秃等的小分子化合物。
背景技术
JAK(Janus激酶,Janus Kinase)是细胞内非受体性酪氨酸蛋白激酶的一个家族,包括JAK1、JAK2、JAK3和Tyk2四个成员。JAK-STAT(转录蛋白的信号转导和激活剂,SignalTransducer and Activator of Transcription proteins)信号传导通路是炎症性细胞因子和受体相结合之后激发的信号在细胞内传导的主要通路。许多证据表明,JAK-STAT信号传导通路在很多疾病的发病机理中起到不可或缺的驱动作用,特别是自身免疫性疾病如风湿性关节炎、红斑狼疮、炎症性肠病、多发性硬化、干燥综合征、银屑病、斑秃和白癜风等;过敏性疾病如哮喘、过敏性鼻炎、过敏性结膜炎、特应性皮炎和湿疹等等。因此,利用高效的小分子对JAK激酶活性,特别是JAK1、TYK2激酶活性进行抑制可以阻断参与炎症反应的细胞因子介导的信号通路,从而控制炎症,有效治疗自身免疫性疾病和/或过敏性炎症性疾病。
不同炎症性疾病发病过程中T细胞会根据不同的炎症诱发因素如病毒或细菌感染而向不同的方向分化,形成Th1,Th2,Th17等T细胞亚群,这些T细胞相应地产生不同的细胞因子,如与病毒感染引起的急性炎症相关的Th1细胞产生IFNγ,IL-2;与过敏有关的Th2细胞产生IL-4,IL-5,IL-13;与自身免疫有关的Th17细胞产生IL-17,IL-12,IL-21,IL-22,IL-23;这些细胞因子和细胞表面的受体结合后,通过细胞内的JAK传递炎症信号,驱动疾病的病理过程。更重要的是,很多病因不清楚的炎症性疾病发表机理复杂,在不同的阶段甚至同一阶段会涉及多种T细胞亚群,也就是会涉及多个JAK通路,这就对开发针对JAK的炎症性疾病治疗药物提出了新的要求。
虽然有研究报道JAK1抑制剂对Th2类过敏性炎症有特异性抑制,同时有效抑制JAK1和/或TYK2抑制剂的研究鲜有报道,尤其我们认为JAK1/Tyk2双抑制剂和Tyk2抑制剂在临床上有更广泛的前途,尤其发病机制涉及到自身免疫异常的炎症性疾病。此外,更多的炎症性疾病尤其是炎症性皮肤病的发病机理可能涉及多个JAK,因此开发强效JAK1和Tyk2的单抑制剂或双抑制剂具有重要意义,尤其用于皮肤病的外用治疗,强效抑制剂在带来很好的疗效的同时又能避免系统用药造成的副作用,但是这将同时需要很强的抑制活性才能实现。
发明内容
本发明的目的旨在获得高效的JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂,为不同的炎症性疾病提供有针对性的靶向治疗,例如JAK1/Tyk2双抑制剂可能适合于SLE、白癜风、IBD和湿疹等疾病,Tyk2特异性抑制剂可能更适合于治疗类风湿性关节炎、银屑病和斑秃等,同时克服由于抑制JAK2带来的造血抑制和凝血异常。另外,选择适合用于外用给药途径如针对炎症性皮肤病外用与疾病病因和症状表现相关联的不同性质的JAK家族成员抑制剂对疾病进行干预和症状控制,能够获得好的治疗效应。
为了实现上述目的,在一方面,本发明提供了一种小分子化合物,所述小分子化合物为由如下所示的式I表示的化合物,或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、以及药学上可接受的盐或前药:
[式I]
其中,R1至R5各自独立地选自C或N;并且
其中,R选自环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基。
在一个实施方式中,R1至R5中的至多两个为N。
在另一个实施方式中,R具有如下所示的式II表示的结构:
[式II]
其中,R6选自C或N;
其中,R7选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R8选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在另一个实施方式中,R7和R8各自独立地选自氢、烷基或环烷基。
在另一个实施方式中,R具有如下所示的式III表示的结构:
[式III]
其中,R9选自C或N;
其中,R10选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R11选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在另一个实施方式中,R10和R11各自独立地选自氢、烷基或环烷基。
在另一个实施方式中,所述烷基为甲基、乙基、丙基或异丙基,所述环烷基为环丙基、环丁基或环丙基甲基。
在另一方面,本发明还提供了如上所述的小分子化合物在抑制JAK激酶中的用途。
在另一方面,本发明还提供了如上所述的小分子化合物在制备用于预防或治疗JAK相关的自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药物中的用途。
在一个实施方式中,所述自身免疫性疾病选自类风湿性关节炎、强直性脊柱炎、溃疡性结肠炎、克罗恩病、系统性红斑狼疮、皮肌炎、多发性硬化、I型糖尿病、干燥综合症和血管炎中的至少一种。
在另一个实施方式中,所述与免疫有关的炎症性皮肤疾病选自特应性皮炎、湿疹、斑秃、银屑病、白癜风、扁平苔藓、光泽苔藓、硬化萎缩性苔藓、脂膜炎、痤疮和化脓性汗腺炎中的至少一种。
本发明的作用和效果:
本发明根据JAK激酶的蛋白结构,特别是Tyk2的蛋白结构,进行了小分子化合物有目的的合理设计,合成的化合物首先进行JAK的激酶生化活性检测,根据IC50建立SAR(structure-activity relationship),对IC50在200nM以下的强效抑制剂再进行细胞学的测试,并确定化合物的选择性。参见具体活性实验数据可以发现,本发明涉及的化合物具有良好的JAK激酶活性和细胞生物学活性的抑制能力。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不用于限制本发明。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
在详细描述本发明前,应了解,在此使用的术语只在于描述特定的实施方式,而不希望限制本发明的范围,本发明的范围仅由所附权利要求书限定。为了更完全地了解在此描述的本发明,采用以下术语,它们的定义如下所示。除非另外定义,在此使用的所有技术和科学术语具有与本发明所属领域的普通技术人员所理解的相同的含义。
在一方面,本发明提供了一种小分子化合物,所述小分子化合物为由如下所示的式I表示的化合物,或其立体异构体、几何异构体、互变异构体、水合物、溶剂化物、以及药学上可接受的盐或前药:
[式I]
其中,R1至R4各自独立地选自C或N;并且
其中,R选自环烷基、取代的环烷基、杂环烷基、取代的杂环烷基、芳基、取代的芳基、杂芳基或取代的杂芳基。
也就是说,R1、R2、R3、R4和R5可以各自独立地选自C或N。在一个优选的实施方式中,R1至R5中的至多三个(即0、1、2或3个)可以为N。在一个优选的实施方式中,R1至R5中的至多两个(即0、1或2个)可以为N。在另一个优选的实施方式中,R1至R5中的至多一个(即0或1个)可以为N。
根据本发明,在一个优选的实施方式中,R可以具有如下所示的式II表示的结构:
[式II]
其中,R6可以选自C或N;
其中,R7选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R8选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在一个更优选的实施方式中,R7和R8可以各自独立地选自氢、烷基或环烷基,进一步,所述烷基可以为甲基、乙基、丙基或异丙基,所述环烷基为环丙基、环丁基或环丙基甲基。
例如,在一个具体的实施方式中,R6为N,R7为甲基,且R8为甲基。在这种情况下,R可以具有如下所示的结构:。
例如,在一个具体的实施方式中,R6为C,R7为甲基,且R8为乙基。在这种情况下,R可以具有如下所示的结构:。
例如,在一个具体的实施方式中,R6为N,R7为甲基,且R8为氢。在这种情况下,R可以具有如下所示的结构:。
根据本发明,在另一个优选的实施方式中,R可以具有如下所示的式III表示的结构:
[式III]
其中,R9可以选自C或N;
其中,R10选自氢、卤素、烷基、氨基、酰胺基、环烷基、杂环烷基、芳基或杂芳基;并且
R11选自氢、烷基、环烷基、杂环烷基、芳基或杂芳基。
在一个更优选的实施方式中,R10和R11可以各自独立地选自氢、烷基或环烷基,进一步,所述烷基可以为甲基、乙基、丙基或异丙基,所述环烷基为环丙基、环丁基或环丙基甲基。
如本文所用,术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质,并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。在本发明中,“药学上可接受的盐”可以包括无机盐和有机盐,其中,所述有机盐可以包括但不限于铵、锂、钠、钾、铯、钙、镁、铜、铝、锌、钡或季铵盐,并且所述无机盐可以包括但不限于精氨酸、叔丁胺、二甲胺、二乙醇胺、乙醇胺、乙二胺、咪唑、赖氨酸、甲胺、吡啶、吡啶甲酸酯、哌嗪、三乙胺、三乙醇胺、三甲胺或脲盐。
在另一方面,本发明提供了上述小分子化合物在抑制JAK激酶中的用途,特别是作为JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂。
在另一方面,本发明还提供了上述小分子化合物在制备用于预防或治疗自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药物中的用途。研究表明,这些疾病的发病机理均与JAK信号传导的失调相关。
如本文所用,术语“治疗”是指根据治疗性方案的治疗性试剂的任何施用,所述治疗性方案达到所需效果,即部分或完全减轻、改善、缓解、抑制、延迟发作、降低严重程度和/或降低特定疾病、障碍和/或病症的一种或多种症状或特征的发生率;在一些实施方式中,根据治疗性方案的治疗性试剂的施用与所需效果的实现相关。这种治疗可以针对没有表现出相关疾病、障碍和/或病症的受试者和/或针对仅表现出疾病、障碍和/或病症的早期迹象的受试者。替代地或另外地,这种治疗可以针对表现出相关疾病、障碍和/或病症的一种或多种所确定迹象的受试者。在一些实施方式中,治疗可以针对已被诊断患有相关疾病、障碍和/或病症的受试者。在一些实施方式中,治疗可以针对已知具有一种或多种易感因素的受试者,所述易感因素在统计学上与相关疾病、障碍和/或病症发展的风险增加相关。
根据本发明,上述用途中制得的药物可以包含有效量的本发明的小分子化合物,以及药学上可接受的赋形剂、载体或稀释剂。
如本文所用,术语“有效量”、“治疗有效量”或“药学有效量”是指对于治疗的受试者以适用于任何药物治疗的合理受益/风险比赋予治疗效果的治疗性试剂的量。这样的治疗效果可以是客观的(即可以通过某种测试或标记测量)或主观的(即受试者给出指示或感觉到效果)。在一些实施方式中,“治疗有效量”是指诸如通过改善与疾病有关的症状、预防或延迟疾病发作和/或还减轻疾病症状的严重性或频率来有效治疗、改善或预防(例如延迟发作)相关疾病或病症和/或表现出可检测的治疗或预防效果的治疗性试剂或组合物的量。
本领域的技术人员将认识到,待施用的所述小分子化合物的治疗有效量将根据以下各项而变化:受试者和疾病的性质和严重程度、受试者的身体状况、治疗方案(例如是否使用第二治疗剂)、以及所选择的施用途径;合适的剂量可以由本领域的技术人员容易地确定。另外,该药物的个体剂量的最佳数量和间隔将通过所治疗的病状的性质和程度、施用的形式、途径和位置、以及所治疗的特定受试者的年龄和病状确定,并且医师将最终确定待施用的合适剂量。此剂量可以视需要重复多次。如果出现副作用,则可以根据正常临床实践改变或减少剂量的量和/或频率。
在本发明中,“药学上可接受的赋形剂、载体或稀释剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂等。
根据本发明,进一步地,上述用途中制得的药物除了可以包含本发明的小分子化合物作为有效成分之外,还可以包含其他可用于预防或治疗自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药剂作为另一种有效成分。所述药剂的实例包括但不限于维生素D衍生物、维生素A衍生物、糖皮质激素、钙调神经磷酸酶抑制剂或非甾体类抗炎药等。当该药物包含多种有效成分时,各有效成分可以根据医师的判断同时、依次或分开施用。
另外,本发明的小分子化合物可以通过多种途径施用于患者,这些途径诸如口服、透皮、皮下、鼻内、静脉内、肌内、鞘内、区域或局部(例如粘膜)。在任何给定情况下最适合的施用途径将取决于受试者和疾病的性质和严重程度、以及受试者的身体状况等。在一个实施方式中,本发明的小分子化合物可以经静脉内施用。在另一个实施方式中,本发明的小分子化合物可以口服施用。相应地,根据不同的施用方式,本发明的药物可以制备为不同的剂型。例如,在一个实施方式中,所述药物可以制备为片剂、胶囊剂、丸剂、颗粒剂、雾化剂、喷雾剂或注射剂。
经发明人研究发现,本发明的小分子化合物或其制得的药物在用于预防或治疗JAK相关的自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病能够发挥优异的效果。具体地,所述自身免疫性疾病可以包括但不限于类风湿性关节炎、强直性脊柱炎、溃疡性结肠炎、克罗恩病、系统性红斑狼疮、皮肌炎、多发性硬化、I型糖尿病、干燥综合症和血管炎等;而所述与免疫有关的炎症性皮肤疾病可以包括但不限于特应性皮炎、湿疹、斑秃、银屑病或白癜风、扁平苔藓、光泽苔藓、硬化萎缩性苔藓、脂膜炎、痤疮和化脓性汗腺炎等。
以下,将通过实施例对本发明的特定小分子化合物的效果进行详细描述。
实施例
实施例1合成化合物1的一般方法(TDM-180973)
步骤1:化合物1c(2-氯-4-(1H-吡咯-3-基)嘧啶)的制备
向250mL三口烧瓶中加入化合物1a(2g,13.43mmol),化合物1b(4.69g,13.43mmol),四(三苯基膦)钯(940mg,1.08mmol),碳酸钾(3.7g,26.85mmol),二氧六环(120mL)和水(120ml)。反应液氮气置换数次,升温至80℃反应45分钟,LCMS[M+H]+=180,检测反应完全。后处理:反应液浓缩拉干,得到的粗品过柱,[洗脱剂:(EA/PE)=0-30%]得到黄色固体目标化合物(化合物1c,1.13g,收率46.86%),LCMS[M+1]+=180。
步骤2:化合物1e(3-(3-(2-氯嘧啶-4-基)-1H-吡咯-1-基)-3-(氰基甲基)氮杂环丁烷-1-羧酸叔丁酯)的制备
向化合物1c(1.23g,6.88mmol)的乙腈(100ml)溶液钟加入化合物1d(1.47g,7.56mmol),1,8-二氮杂二环十一碳-7-烯(710mg,4.68mmol),反应液升温至70℃搅拌2小时。LCMS[M+H]+=374,检测反应完全。后处理:反应液浓缩拉干,得到的粗品过柱,[洗脱剂:(EA/PE)=0-30%]得到黄色固体目标化合物(化合物1e,2.085g,收率81.09%),LCMS[M+H]+=374。
步骤3:化合物1f(2-(3-(3-(2-氯嘧啶-4-基)-1H-吡咯-1-基)氮杂环丁烷-3-基)乙腈)的制备
向化合物1e(1.6g,4.3mmol)的二氯甲烷(128ml)溶液中加入三氟乙酸(25.6ml),反应液室温搅拌一小时。LCMS[M+H]+=274,检测反应完全。后处理:反应液在冰浴下用三乙胺中和,浓缩拉干,得到的粗品过柱,[洗脱剂:(D/M=10/1):DCM=0-50%]得到黄色固体目标化合物(化合物1f,950mg,收率89.7%),LCMS[M+H]+=274。
步骤4:化合物1h((S)-2-(3-(3-(2-氯嘧啶-4-基)-1H-吡咯-1-基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁-3-基))的制备
向化合物1f(1g,3.65mmol)的N,N-二甲基甲酰胺(100ml)溶液中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.78g,7.3mmol),N,N-二异丙基乙胺(5g,7.3mmol)和化合物1g(450mg,3.65mmol)。反应液室温搅拌1小时,LCMS[M+H]+=378,检测反应完全。后处理:反应液浓缩拉干,得到的粗品过柱,[洗脱剂:(EA/PE)=0-50%]得到黄色固体目标化合物(化合物1h,1120mg,收率81.16%),LCMS[M+H]+=378。
步骤5:化合物1((S)-4-((4-(1-(3-(氰基甲基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-N-乙基苯甲酰胺)的制备
向化合物1h(120mg,0.317mmol)的正丁醇(20ml)溶液中加入化合物1i(104mg,0.64mmol)和一水合对甲苯磺酸(120.8mg,0.64mmol)。反应液升温至110℃搅拌2小时,LCMS[M+H]+=506,检测反应完全。后处理:反应液浓缩拉干,制备得到类白色固体目标化合物(化合物1,29mg,收率18.1%),LCMS[M+H]+=506.2。
1H NMR(400MHz,DMSO)δ9.71(s,1H),8.41(d,J=5.3Hz,1H),8.25(t,J=5.5Hz,1H),7.95–7.86(m,3H),7.79(d,J=8.8Hz,2H),7.25–7.10(m,2H),6.84(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=52.1,41.5,9.6Hz,2H),4.48–4.19(m,2H),3.60(s,2H),3.30–3.22(m,2H),2.79(dq,J=13.2,8.8Hz,1H),2.00–1.84(m,2H),1.12(t,J=7.2Hz,3H)。
实施例2合成化合物2的一般方法(TDM-180975)
步骤1:化合物2b(3-甲基-5-硝基吡啶甲基酰胺)的制备
将化合物2a(3g,18.4mmol)和浓硫酸(18ml)的混合溶液升温至80℃搅拌25分钟。LCMS[M+H]+=182,检测反应完全。后处理:将反应液冷却至室温,倒入冰水(100ml)中,随后用碳酸钠调PH至中性,混合液用乙酸乙酯(3*100ml)萃取三次,合并有机相,饱和食盐水洗,无水硫酸钠干燥,抽滤,浓缩拉干得到黄色目标化合物(化合物2b,3.33g,收率94.2%),LCMS[M+1]+=182。
步骤2:化合物2c(5-氨基-3-甲基吡啶甲基酰胺)的制备
在氮气保护下向化合物2b(3.14g,17.33mmol)的甲醇(150ml)溶液中加入钯碳(10%,300mg),用氢气在真空下置换数次,反应液在氢气球下室温搅拌2小时。LCMS[M+H]+=152,检测反应完全。后处理:将反应液过滤除去钯碳,滤液浓缩拉干,得到的粗品再重结晶得到白色固体目标化合物(化合物2c,2.3g,收率87.8%),LCMS[M+1]+=152。
步骤3:化合物2((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-3-甲基吡啶啉酰胺)的制备
向化合物2d(150mg,0.397mmol)的正丁醇(15ml)溶液中加入化合物2c(120mg,0.79mmol)和一水合对甲苯磺酸(151mg,0.79mmol)。反应液升温至110℃搅拌7小时,LCMS[M+H]+=493,检测反应完全。后处理:反应液浓缩拉干,残留物加水和乙酸乙酯(3*30ml)萃取,合并有机相,并用饱和食盐水洗,无水硫酸钠干燥,抽滤,拉干,粗品制备得到类白色固体目标化合物(化合物2,7.9mg,收率4.04%),LCMS[M+H]+=493.2。
1H NMR(400MHz,DMSO)δ9.89(s,1H),8.80(s,1H),8.44(d,J=5.3Hz,1H),8.32(s,1H),7.89(d,J=21.0Hz,2H),7.26–7.15(m,3H),6.84(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=53.5,41.8,9.6Hz,2H),4.46–4.24(m,2H),3.58(d,J=16.7Hz,2H),2.78(dt,J=11.7,8.9Hz,1H),2.61(s,3H),2.00–1.84(m,2H)。
实施例3合成化合物3的一般方法(TDM-180976)
步骤1:化合物3b(3-甲基-5-硝基亚油酸乙酯)的制备
将浓硫酸(40ml)缓慢加入至0℃下的乙醇(160ml)溶液中,随后向反应液中分批加入化合物3a(4g,24.5mmol),并将反应液升温至回流搅拌72小时。LCMS[M+H]+=211,检测反应完全。后处理:将反应液冷却至室温并倒入水(50ml)中,用乙酸乙酯(3*50mL)萃取三次,合并有机相,并用饱和食盐水洗,无水硫酸钠干燥,抽滤,浓缩拉干得到黄色目标化合物(化合物3b,3.73g,收率72.56%),LCMS[M+1]+=211。
步骤2:化合物3c(3-甲基-5-硝基亚油酸)的制备
向化合物3b(4.2g,20.03mmol)的四氢呋喃(200ml)溶液中加入1N的氢氧化钠(120ml,120.16mmol)溶液,反应液室温搅拌1小时,LCMS[M+H]+=183,检测反应完全。后处理:将反应液缓慢倒入冰水(30ml)中,水相用二氯甲烷(2*15mL)萃取两次,水相用1N稀盐酸调至pH=5-6,然后用乙酸乙酯(3*15mL)萃取三次,合并有机相,并用饱和食盐水洗,无水硫酸钠干燥,抽滤,浓缩拉干,粗品重结晶得到黄色固体目标化合物(化合物3c,3.0g,收率82.19%),LCMS[M+1]+=183。
步骤3:化合物3e(N,3-二甲基-5-硝基亚油酰胺)的制备
向化合物3c(3.0g,16.48mmol)的N,N-二甲基甲酰胺(100ml)溶液中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(10.03g,26.37mmol),N,N-二异丙基乙胺(7.5g,57.68mmol)和化合物3d(2.26g,32.96mmol)。反应液室温搅拌1小时,LCMS[M+H]+=196,检测反应完全。后处理:反应液浓缩拉干,得到的粗品过柱,[洗脱剂:(EA/PE)=0-30%],粗品再重结晶得到黄色固体目标化合物(化合物3e,3.0g,收率93.75%),LCMS[M+1]+=196。
步骤4:化合物3f(5-氨基-N,3-二甲基吡啶甲酰胺)的制备
在氮气保护下向化合物3e(3.5g,17.9mmol)的甲醇(200ml)溶液中加入钯碳(10%,350mg),用氢气在真空下置换数次,反应液在氢气球下室温搅拌2小时。LCMS[M+H]+=166,检测反应完全。后处理:将反应液过滤除去钯碳,滤液浓缩拉干,得到的粗品过柱,[洗脱剂:(D/M=10/1):DCM=0-10%],再重结晶得到黄色固体目标化合物(化合物3f,1.8g,收率60.87%),LCMS[M+1]+=166。
步骤5:化合物3((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-N,3-二甲基吡啶甲酸酰胺)的制备
向化合物3g(150mg,0.40mmol)的正丁醇(35ml)溶液中加入化合物3f(131.2mg,0.79mmol)和一水合对甲苯磺酸(151.03mg,0.79mmol)。反应液升温至110℃搅拌7小时,LCMS[M+H]+=507,检测反应完全。后处理:反应液浓缩拉干,残留物加水和乙酸乙酯(3*30ml)萃取,合并有机相,并用饱和食盐水洗,无水硫酸钠干燥,抽滤,拉干,粗品制备得到类白色固体目标化合物(化合物3,6.8mg,收率3.38%),LCMS[M+1]+=507.2。
1H NMR(400MHz,DMSO)δ9.88(s,1H),8.82(d,J=2.3Hz,1H),8.45(dd,J=8.9,4.8Hz,2H),8.30(s,1H),7.91(s,1H),7.32–7.10(m,2H),6.83(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=53.5,41.7,9.6Hz,2H),4.48–4.19(m,2H),3.60(s,2H),2.82–2.70(m,4H),2.61(s,3H),1.97–1.85(m,2H)。
实施例4合成化合物4的一般方法(TDM-180978)
步骤1:化合物4((S)-4-((4-(1-(3-(氰基甲基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁烷-3-基)-1H-吡咯-3-基)嘧啶-2-基)氨基)-N-乙基-2-甲基苯甲酰胺)的制备
以相似的方法制备得到化合物4(类白色固体,16.8mg,收率4.3%)。
1H NMR(400MHz,DMSO)δ9.52(s,1H),8.38(d,J=5.2Hz,1H),8.05(t,J=5.6Hz,1H),7.87(t,J=1.8Hz,1H),7.74(d,J=2.5Hz,1H),7.69(d,J=8.5Hz,1H),7.29(d,J=8.4Hz,1H),7.23–7.14(m,1H),7.10(dd,J=5.2,3.8Hz,1H),6.83(dd,J=2.9,1.6Hz,1H),4.71(ddd,J=53.1,42.0,9.6Hz,2H),4.48–4.19(m,2H),3.60(s,2H),3.26–3.17(m,2H),2.79(dd,J=12.3,9.6Hz,1H),2.34(d,J=13.1Hz,3H),1.93(dd,J=17.3,9.3Hz,2H),1.11(t,J=7.2Hz,3H)。LCMS[M+H]+=520.2。
实施例5合成化合物5的一般方法(TDM-180996)
步骤1:化合物5(2-(1-((S)-2,2-二氟环丙烷-1-羰基)-3-(3-(2-((6-(1-羟基丙烷-2-基)吡啶-3-基)氨基)嘧啶-4-基)-1H-吡咯-1-基)氮杂环丁烷-3-基)乙腈)的制备
以相似的方法制备得到化合物5(类白色固体,19.2mg,收率7.35%)。
1H NMR(401MHz,DMSO)δ9.50(s,1H),8.81(d,J=2.5Hz,1H),8.36(d,J=5.3Hz,1H),8.21(d,J=8.5Hz,1H),8.15(s,1H),7.87(s,1H),7.17(dd,J=8.3,5.6Hz,2H),7.10(dd,J=5.2,4.0Hz,1H),6.81(dd,J=2.8,1.6Hz,1H),4.75(dt,J=18.0,9.6Hz,2H),4.58(d,J=9.5Hz,1H),4.42(dd,J=10.6,5.9Hz,1H),4.36–4.21(m,1H),3.68–3.57(m,3H),3.48(dd,J=10.2,7.0Hz,1H),2.90(dd,J=13.7,6.9Hz,1H),2.83–2.72(m,1H),1.99–1.81(m,2H),1.19(d,J=6.9Hz,3H)。LCMS[M+H]+=494.2。
实施例6合成化合物6的一般方法(TDM-180982)
步骤1:化合物6c(3-(氰基甲基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑-1-基)氮杂环丁-1-甲酸叔丁基酯)的制备
在室温下,向化合物6a(2g,10.3mmol)的乙腈(40mL)混合物中加入化合物6b(2g,10.3mmol)和1,8-二氮杂二环十一碳-7-烯(1mL,10.3mmol),将混合物加热至70℃,搅拌过夜。反应结束减压浓缩混合物,残余物通过硅胶色谱法纯化(石油醚/乙酸乙酯=0%-50%),得到白色固体目标化合物(化合物6c,2.42g,收率60.5%)。LCMS[M-C4H9]+=333.2。
步骤2:化合物6e(3-(4-(2-氯嘧啶-4-基)-1H-吡唑-1-基)-3-(氰甲基)氮杂环丁烷-1-羧酸叔丁酯)的制备
向化合物6d(2.13g,5.486mmol),化合物6c(1.31g,8.777mmol),碳酸钠(1.16g,10.972mmol)和1,1'-双二苯基膦二茂铁二氯化钯(401mg,0.549mmol)的混合物中加入二氧六环(120ml)和水(20ml),用氮气置换几次,然后加热到80℃并搅拌1小时。将混合物在减压下浓缩,残余物通过硅胶色谱法纯化(石油醚/乙酸乙酯=0%-42%),得到淡黄色固体目标化合物(化合物6e,1.67g,收率81.2%)。LCMS[M+H]+=375。
步骤3:化合物6f(2-(3-(4-(2-氯嘧啶-4-基)-1H-吡唑-1-基)氮杂环丁-3-基)乙腈)的制备
向化合物6e(1.4g,3.735mmol)的二氯甲烷(80ml)溶液中滴加三氟乙酸(16ml),将混合物在室温搅拌1小时。反应结束向混合物中加入水并用氢氧化钠水溶液中和,然后用二氯甲烷(80ml*3)萃取,合并有机层,用盐水(100ml)洗涤,用硫酸钠干燥,将滤液减压浓缩,残余物通过硅胶色谱法纯化(二氯甲烷/含10%甲醇的二氯甲烷溶液=0%-100%),得到白色固体目标化合物(化合物6f,571.1mg,收率55.7%)。LCMS[M+H]+=275。
步骤4:化合物6h((S)-2-(3-(4-(2-氯嘧啶-4-基)-1H-吡唑-1-基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁-3-基)乙腈)的制备
向化合物6g(293.3mg,2.403mmol)的N,N-二甲基甲酰胺(30ml)溶液加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(913.7mg,2.403mmol)和N,N-二异丙基乙胺(776.2mg,3.003mmol),将混合物搅拌5分钟,然后加入化合物6f(550mg,2.002mmol),将混合物在室温搅拌1小时。反应结束向混合物中加入水并用乙酸乙酯(50ml*3)萃取,合并有机层,用水(50mL*3)和饱和盐水(50ml)洗涤,用硫酸钠干燥,将滤液减压浓缩,将残余物用硅胶色谱纯化(石油醚/乙酸乙酯=0%-50%),得到白色固体目标化合物(化合物6h,566mg,收率74.6%)。LCMS[M+H]+=379。
步骤5:化合物6((S)-4-((4-(1-(3-(氰基甲基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-N-乙基苯甲酰胺)的制备
向化合物6h(50mg,0.132mmol)的正丁醇(5ml)溶液加入化合物6i(43.4mg,0.264mmol)和对甲苯磺酸一水合物(50.2mg,0.264mmol)。将所得混合物加热至110℃并搅拌3小时。将混合物在减压下浓缩,残余物通过制备型HPLC(甲酸)纯化,以得到白色固体目标化合物TDM-180982(化合物6,11.4mg,收率17.1%)。LCMS[M+H]+=507.2。
1H NMR(400MHz,DMSO)δ9.85(s,1H),8.86(d,J=4.6Hz,1H),8.51(d,J=5.2Hz,1H),8.32(s,1H),8.27(t,J=5.5Hz,1H),7.90(d,J=8.8Hz,2H),7.81(d,J=8.8Hz,2H),7.23(dd,J=5.2,1.4Hz,1H),4.86(dd,J=35.3,9.6Hz,1H),4.67(dd,J=41.8,9.6Hz,1H),4.51(t,J=9.9Hz,1H),4.31(t,J=10.2Hz,1H),3.72(d,J=2.8Hz,2H),3.30–3.23(m,2H),2.90–2.74(m,1H),1.92(qd,J=11.0,7.4Hz,2H),1.12(t,J=7.2Hz,3H)。
实施例7合成化合物7的一般方法(TDM-180983)
步骤1:化合物7((S)-5-((4-(4-(4-(2,2-二氟环丙烷-1-羧酰胺基)苯基)嘧啶-2-基)氨基)-N,3-二甲基吡啶啉酰胺)的制备
以相似的方法制备得到化合物7(白色固体,12.7mg,收率14.5%)。
1H NMR(400MHz,DMSO)δ9.66(s,1H),8.84(d,J=4.2Hz,1H),8.49(d,J=5.2Hz,1H),8.30(s,1H),8.06(t,J=5.6Hz,1H),7.73–7.65(m,2H),7.34–7.27(m,1H),7.19(dd,J=5.1,1.9Hz,1H),4.84(dd,J=34.2,9.6Hz,1H),4.66(dd,J=42.4,9.5Hz,1H),4.49(t,J=10.3Hz,1H),4.30(t,J=10.2Hz,1H),3.72(d,J=1.8Hz,2H),3.27–3.16(m,2H),2.82(ddd,J=19.2,12.0,9.0Hz,1H),2.36(s,3H),2.00–1.85(m,2H),1.11(t,J=7.2Hz,3H)。LCMS[M+H]+=521.1。
实施例8合成化合物8的一般方法(TDM-180985)
步骤1:化合物8((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-N,3-二甲基吡啶甲酸酰胺)的制备
向化合物8a(80mg,0.258mmol)的正丁醇(8mL)溶液中加入化合物8b(85mg,0.517mmol)和对甲苯磺酸一水合物(98mg,0.517mmol)。将所得混合物加热至115℃并搅拌过夜。反应结束将混合物冷却至室温,加水,然后用乙酸乙酯(30ml*3)萃取,合并有机层,用饱和盐水(50ml)洗涤,用硫酸钠干燥,将滤液减压浓缩,残余物通过制备型HPLC(甲酸)纯化,得到类白色固体目标化合物TDM-180985(化合物8,10.2mg,收率6.2%)。LCMS[M+H]+=508.2。
1H NMR(400MHz,DMSO)δ10.01(s,1H),8.88(d,J=4.5Hz,1H),8.81(d,J=2.3Hz,1H),8.55(d,J=5.2Hz,1H),8.46(d,J=4.8Hz,1H),8.30(s,1H),8.27(d,J=2.1Hz,1H),7.28(dd,J=5.2,1.9Hz,1H),4.85(dd,J=33.3,9.6Hz,1H),4.67(dd,J=42.3,9.6Hz,1H),4.49(t,J=10.4Hz,1H),4.31(t,J=10.3Hz,1H),3.72(s,2H),2.89–2.74(m,4H),2.61(s,3H),2.01–1.84(m,2H)。
实施例9合成化合物9的一般方法(TDM-180986)
步骤1:化合物9((S)-5-((4-(1-(3-(氰基甲基)-1-(2,2-二氟环丙烷-1-羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)嘧啶-2-基)氨基)-3-甲基吡啶啉酰胺)的制备
以相似的方法制备得到化合物9(类白色固体,10.7mg,收率8.4%)。
1H NMR(400MHz,DMSO)δ10.03(s,1H),8.88(d,J=4.4Hz,1H),8.80(d,J=2.0Hz,1H),8.55(d,J=5.2Hz,1H),8.29(d,J=11.4Hz,2H),7.87(s,1H),7.38–7.16(m,2H),4.85(dd,J=33.3,9.6Hz,1H),4.67(dd,J=42.5,9.6Hz,1H),4.49(t,J=10.4Hz,1H),4.31(t,J=10.2Hz,1H),3.72(s,2H),2.90–2.75(m,1H),2.61(s,3H),1.94(d,J=8.0Hz,2H)。LCMS[M+H]+=494.3。
实施例10合成化合物10的一般方法(TDM-180990)
步骤1:化合物10(2-(1-((S)-2,2-二氟环丙烷-1-羰基)-3-(4-(2-(((6-(1-羟基丙烷-2-基)吡啶-3-基)氨基)嘧啶-4-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙腈)的制备
向化合物10a(190mg,0.502mmol),化合物10b(153mg,1.003mmol),醋酸钯(11.4mg,0.050mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(58.1mg,0.1mmol)和碳酸铯(461mg,1.506mmol)的混合物中加入二氧六环(40mL),将混合物用氩气置换几次,将混合物加热至100℃并搅拌1小时。反应结束向反应物中加入水(60mL),并用乙酸乙酯(60mL*3)萃取,合并有机层,然后用水(100mL)和饱和盐水(100mL*2)洗涤,用硫酸钠干燥,将滤液减压浓缩,残余物通过硅胶色谱法(石油醚/乙酸乙酯=0%-70%)和制备型HPLC(甲酸)纯化,得到白色固体目标化合物TDM-180990(化合物10,76.6mg,收率30.9%)。LCMS[M+H]+=495.2。
1H NMR(400MHz,DMSO)δ9.65(s,1H),8.85(d,J=4.3Hz,1H),8.79(s,1H),8.47(d,J=5.2Hz,1H),8.29(s,1H),8.21(dt,J=8.5,2.9Hz,1H),8.17(s,1H),7.19(dd,J=10.2,5.1Hz,2H),4.85(dd,J=33.3,9.6Hz,1H),4.66(dd,J=42.4,9.6Hz,2H),4.50(t,J=11.0Hz,1H),4.30(t,J=10.2Hz,1H),3.71(d,J=2.8Hz,2H),3.63(dd,J=10.2,6.6Hz,1H),3.49(dd,J=10.2,7.0Hz,1H),2.90(dt,J=12.7,6.4Hz,1H),2.81(ddd,J=13.2,10.4,6.2Hz,1H),2.00–1.86(m,2H),1.20(d,J=6.9Hz,3H)。
测试例1JAK激酶小分子抑制剂的酶活性抑制检测
实验方案
1、试剂准备
激酶反应缓冲液:配置激酶反应缓冲液,组分如下:50mM HEPES,pH 7.5,1mMEGTA,10mM MgCl2,2mM DTT,0.01%Tween20。1X检测缓冲液:配置检测缓冲液,去离子水9:1稀释10X检测缓冲液至1X。4X激酶溶液:激酶反应缓冲液稀释JAK激酶至4X终浓度(JAK1:80nM,JAK2/JAK3/Tyk2:4nM)。4X底物溶液:激酶反应缓冲液稀释ULightTM-JAK(Tyr1023)底物至200nM(终浓度:50nM)。4XATP溶液:激酶反应缓冲液稀释ATP至4X终浓度(JAK1:160μM,JAK2/JAK3/Tyk2:40μM)。4X测试化合物溶液:DMSO溶解测试用化合物至10mM储存液,3倍梯度稀释配置成所需浓度,每个化合物设置10个浓度点,测试化合物终浓度范围为:10μM-0.5nM。4X酶反应终止液:1X检测缓冲液溶解EDTA至40mM(EDTA终浓度:10mM)。4X检测抗体溶液:1X检测缓冲液稀释Eu标记检测抗体(抗磷酸酪氨酸(PT66))至8nM(抗体终浓度:2nM)。
2、实验过程
向384微孔板中依次加入2.5μL的4X激酶溶液和2.5μL已经稀释好的不同浓度的4X测试化合物溶液,每个浓度设置2个复孔,同时设置酶溶液空白对照组和阴性对照组(DMSO组)。震荡384多孔板,混匀酶和化合物,1000转,离心1分钟,在室温下孵育60分钟。向384多孔板中加入2.5μL,4X底物溶液,1000转离心1分钟。向384多孔板中加入2.5μL,4XATP溶液,1000转离心1分钟,起始酶反应。JAK1室温反应2小时,JAK2/JAK3/Tyk2室温反应1小时。JAK1反应的各组分终浓度分别为:JAK1:20nM,底物:50nM,ATP:40uM,测试化合物终浓度范围为:10μM-0.5nM。JAK2/JAK3/Tyk2反应的各组分终浓度分别为:JAK2:1nM,底物:50nM,ATP:10μM,测试化合物终浓度范围为:10μM-0.5nM。酶反应结束后,向384多孔板每孔中加入5μL,4X酶反应终止液,1000转,离心1分钟,在室温下孵育5分钟。向384多孔板每孔中加入5μL,4X检测抗体溶液,(检测抗体终浓度为2nM),1000转,离心1分钟,室温条件下孵育1小时。抗体孵育结束后,在Envision读板仪上测定各孔的信号值
3、数据分析
以酶溶液空白对照组为100%抑制率和阴性对照组(DMSO组)为0%抑制率,计算检测各个浓度对应的百分比抑制率。在GraphPad Prism软件中对检测化合物的浓度对数值和相对应的百分比抑制率进行非线性回归分析,得到检测化合物的半数抑制浓度(IC50),针对实施例1-10的化合物所测得的实验结果列在下表1中。
表1
编号 | Tyk2/μM | JAK1/μM | JAK2/μM | JAK3/μM |
TDM-180973 | 0.007 | 0.003 | 0.009 | 0.443 |
TDM-180975 | 0.008 | 0.012 | 0.007 | 0.674 |
TDM-180976 | 0.009 | 0.009 | 0.013 | 0.599 |
TDM-180978 | 0.011 | 0.007 | 0.012 | 0.280 |
TDM-180996 | 0.039 | 0.055 | 0.038 | 0.843 |
TDM-180982 | 0.019 | 0.018 | 0.022 | 1.296 |
TDM-180983 | 0.017 | 0.045 | 0.027 | 0.791 |
TDM-180985 | 0.021 | 0.054 | 0.064 | 2.368 |
TDM-180986 | 0.056 | 0.125 | 0.052 | 3.056 |
TDM-180990 | 0.112 | 0.224 | - | - |
从上表1的结果可以看出,本申请的化合物的酶活性数据优异,以上具体化合物测得的半数抑制浓度较低,特别是针对Tyk2、JAK1和JAK2时基本上达到0.01-0.1μM左右,尤其是化合物TDM-180973、TDM-180975、TDM-180976和TDM-180978,其半数抑制浓度均在0.01μM左右。因此,通过以上实验已经证明了本申请的小分子化合物是一类针对JAK家族靶向性强、酶活性优异的化合物,能够作为JAK1/Tyk2双抑制剂和Tyk2特异性抑制剂。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (6)
2.根据权利要求1所述的小分子化合物,其特征在于,R7和R8各自独立地选自氢、甲基、乙基、丙基、异丙基、环丙基、环丁基或环丙基甲基。
3.根据权利要求1-2中任一项所述的小分子化合物在制备用于抑制JAK激酶的药物中的用途。
4.根据权利要求1-2中任一项所述的小分子化合物在制备用于预防或治疗自身免疫性疾病、以及与免疫有关的炎症性皮肤疾病的药物中的用途,其中,这些疾病的发病机理均与JAK信号传导的失调相关。
5.根据权利要求4所述的用途,其中,所述自身免疫性疾病选自类风湿性关节炎、强直性脊柱炎、溃疡性结肠炎、克罗恩病、系统性红斑狼疮、皮肌炎、多发性硬化、I型糖尿病、干燥综合症和血管炎中的至少一种。
6.根据权利要求4所述的用途,其中,所述与免疫有关的炎症性皮肤疾病选自特应性皮炎、湿疹、斑秃、银屑病、白癜风、扁平苔藓、光泽苔藓、硬化萎缩性苔藓、脂膜炎、痤疮和化脓性汗腺炎中的至少一种。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011072699.4A CN112159394B (zh) | 2020-10-09 | 2020-10-09 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
JP2023521674A JP2023545784A (ja) | 2020-10-09 | 2021-09-24 | Jakキナーゼ阻害剤としての小分子化合物及びその用途 |
PCT/CN2021/120120 WO2022073425A1 (zh) | 2020-10-09 | 2021-09-24 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
EP21876943.8A EP4219480A1 (en) | 2020-10-09 | 2021-09-24 | Small molecule compound serving as jak kinase inhibitor, and use thereof |
US18/030,962 US20230406842A1 (en) | 2020-10-09 | 2021-09-24 | Small molecule compound serving as jak kinase inhibitor, and use thereof |
KR1020237015633A KR20240004212A (ko) | 2020-10-09 | 2021-09-24 | Jak 키나아제 억제제인 저분자 화합물 및 이의 용도 |
TW110137631A TWI780943B (zh) | 2020-10-09 | 2021-10-08 | 作為jak激酶抑制劑的小分子化合物及其應用之用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011072699.4A CN112159394B (zh) | 2020-10-09 | 2020-10-09 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112159394A CN112159394A (zh) | 2021-01-01 |
CN112159394B true CN112159394B (zh) | 2021-10-22 |
Family
ID=73866371
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011072699.4A Active CN112159394B (zh) | 2020-10-09 | 2020-10-09 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20230406842A1 (zh) |
EP (1) | EP4219480A1 (zh) |
JP (1) | JP2023545784A (zh) |
KR (1) | KR20240004212A (zh) |
CN (1) | CN112159394B (zh) |
TW (1) | TWI780943B (zh) |
WO (1) | WO2022073425A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112159394B (zh) * | 2020-10-09 | 2021-10-22 | 嘉兴特科罗生物科技有限公司 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
WO2023076161A1 (en) | 2021-10-25 | 2023-05-04 | Kymera Therapeutics, Inc. | Tyk2 degraders and uses thereof |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ME02763B (me) * | 2013-05-17 | 2018-01-20 | Incyte Corp | Derivati bipirazola kao inhibitori jak |
JP7034942B2 (ja) * | 2016-05-05 | 2022-03-14 | エフ.ホフマン-ラ ロシュ アーゲー | ピラゾール誘導体、その組成物及び治療的使用 |
CN113508114B (zh) * | 2019-02-27 | 2024-03-26 | 四川科伦博泰生物医药股份有限公司 | 以氮杂环丁烷衍生物为活性成分的口服药物组合物、其制备方法及用途 |
CN110862380A (zh) * | 2019-10-24 | 2020-03-06 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
CN110862376A (zh) * | 2019-10-24 | 2020-03-06 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
CN110734428A (zh) * | 2019-10-24 | 2020-01-31 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
CN111704617B (zh) * | 2020-06-15 | 2022-08-23 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
CN112159394B (zh) * | 2020-10-09 | 2021-10-22 | 嘉兴特科罗生物科技有限公司 | 一种作为jak激酶抑制剂的小分子化合物及其用途 |
-
2020
- 2020-10-09 CN CN202011072699.4A patent/CN112159394B/zh active Active
-
2021
- 2021-09-24 JP JP2023521674A patent/JP2023545784A/ja active Pending
- 2021-09-24 WO PCT/CN2021/120120 patent/WO2022073425A1/zh unknown
- 2021-09-24 US US18/030,962 patent/US20230406842A1/en active Pending
- 2021-09-24 EP EP21876943.8A patent/EP4219480A1/en active Pending
- 2021-09-24 KR KR1020237015633A patent/KR20240004212A/ko active Search and Examination
- 2021-10-08 TW TW110137631A patent/TWI780943B/zh active
Also Published As
Publication number | Publication date |
---|---|
EP4219480A1 (en) | 2023-08-02 |
TW202214599A (zh) | 2022-04-16 |
KR20240004212A (ko) | 2024-01-11 |
US20230406842A1 (en) | 2023-12-21 |
JP2023545784A (ja) | 2023-10-31 |
TWI780943B (zh) | 2022-10-11 |
CN112159394A (zh) | 2021-01-01 |
WO2022073425A1 (zh) | 2022-04-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112142675B (zh) | 一种作为jak激酶抑制剂的小分子化合物及其用途 | |
EP3409673B1 (en) | Pyrrolopyrimidine five-membered azacyclic derivative and application thereof | |
RU2753520C2 (ru) | Производные n-(замещенный фенил)-сульфонамида в качестве ингибиторов киназы | |
EP3023101A1 (en) | Therapeutic agent for fgfr inhibitor-resistant cancer | |
CN112159394B (zh) | 一种作为jak激酶抑制剂的小分子化合物及其用途 | |
TW200424206A (en) | Salts of tricyclic inhibitors of poly(ADP-ribose) polymerases | |
TWI779840B (zh) | 作為jak激酶抑制劑的藥物化合物 | |
EP2933248B1 (en) | Novel renin inhibitor | |
TWI790024B (zh) | 三氮唑並吡嗪類化合物及其用途 | |
KR20200041954A (ko) | 화합물, 이의 약제학적 조성물, 및 이의 용도 및 응용 | |
CN112028877B (zh) | 烷氧吡啶酮化合物及其制备方法和用途 | |
CN112300173B (zh) | 一类含氮多环类化合物、制备方法和用途 | |
TW202039503A (zh) | 苯并噻二嗪衍生物及包含該衍生物之用以治療腺苷媒介疾病的組合物 | |
CN113549065B (zh) | 作为JAK抑制剂的吡咯并[2,3-b]吡啶衍生物 | |
EP3632912A1 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
CN109134431B (zh) | 作为囊性纤维化跨膜传导调节因子抑制剂的氨基咪唑偶联吡啶酮衍生物 | |
TWI692476B (zh) | 環丁基-咪唑啶酮化合物 | |
EP3854401A1 (en) | Cdc7-inhibiting purine derivatives and their use for the treatment of neurological conditions | |
CN116947764A (zh) | 一种嘧啶胺类nuak抑制剂及其制备方法和用途 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |