CN116283955A - 一种靶向降解hdac7的化合物及其制备方法和应用 - Google Patents
一种靶向降解hdac7的化合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN116283955A CN116283955A CN202310269772.4A CN202310269772A CN116283955A CN 116283955 A CN116283955 A CN 116283955A CN 202310269772 A CN202310269772 A CN 202310269772A CN 116283955 A CN116283955 A CN 116283955A
- Authority
- CN
- China
- Prior art keywords
- mmol
- compound
- group
- pharmaceutically acceptable
- esi
- 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
- 150000001875 compounds Chemical class 0.000 title claims abstract description 131
- 101001032113 Homo sapiens Histone deacetylase 7 Proteins 0.000 title claims description 28
- 102100038719 Histone deacetylase 7 Human genes 0.000 title claims 2
- 230000015556 catabolic process Effects 0.000 title description 21
- 238000006731 degradation reaction Methods 0.000 title description 21
- 238000002360 preparation method Methods 0.000 title description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 230000003287 optical effect Effects 0.000 claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 3
- 230000002159 abnormal effect Effects 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229940049920 malate Drugs 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 208000030159 metabolic disease Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 208000016097 disease of metabolism Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 37
- 210000002540 macrophage Anatomy 0.000 abstract description 18
- 108090001005 Interleukin-6 Proteins 0.000 abstract description 17
- 230000028327 secretion Effects 0.000 abstract description 11
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 9
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 230000002757 inflammatory effect Effects 0.000 abstract description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 274
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- 238000006243 chemical reaction Methods 0.000 description 96
- 230000015572 biosynthetic process Effects 0.000 description 89
- 238000003786 synthesis reaction Methods 0.000 description 89
- 239000000243 solution Substances 0.000 description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- -1 (1- (2- (1- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) propyl) -1H-1,2, 3-triazol-4-yl) ethyl) -4- (4-phenylthiazol-2-yl) piperidin-4-yl) methyl Chemical group 0.000 description 69
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 62
- 238000000034 method Methods 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- 210000004027 cell Anatomy 0.000 description 40
- 239000012043 crude product Substances 0.000 description 40
- 238000010898 silica gel chromatography Methods 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 239000012074 organic phase Substances 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- 239000002994 raw material Substances 0.000 description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- 239000007858 starting material Substances 0.000 description 31
- 102100038720 Histone deacetylase 9 Human genes 0.000 description 27
- 102000003964 Histone deacetylase Human genes 0.000 description 25
- 108090000353 Histone deacetylase Proteins 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 102000004889 Interleukin-6 Human genes 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 229940088598 enzyme Drugs 0.000 description 15
- 238000012544 monitoring process Methods 0.000 description 15
- 102000004190 Enzymes Human genes 0.000 description 14
- 108090000790 Enzymes Proteins 0.000 description 14
- HORXBWNTEDOVKN-UHFFFAOYSA-N n-[[4-(4-phenyl-1,3-thiazol-2-yl)oxan-4-yl]methyl]-3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide Chemical compound O1C(C(F)(F)F)=NC(C=2C=C(C=CC=2)C(=O)NCC2(CCOCC2)C=2SC=C(N=2)C=2C=CC=CC=2)=N1 HORXBWNTEDOVKN-UHFFFAOYSA-N 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- 238000001308 synthesis method Methods 0.000 description 14
- 239000000499 gel Substances 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 238000012546 transfer Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 102100040247 Tumor necrosis factor Human genes 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 7
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 229940125898 compound 5 Drugs 0.000 description 7
- 238000001962 electrophoresis Methods 0.000 description 7
- 239000003292 glue Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 230000002194 synthesizing effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000002033 PVDF binder Substances 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 5
- 229960003957 dexamethasone Drugs 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 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
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 239000006180 TBST buffer Substances 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000593 degrading effect Effects 0.000 description 4
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-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
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 3
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000006196 deacetylation Effects 0.000 description 3
- 238000003381 deacetylation reaction Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- KOZPJFOZJXZMSJ-UHFFFAOYSA-N pyrrolidine-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC(=O)C1CCCN1 KOZPJFOZJXZMSJ-UHFFFAOYSA-N 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- 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 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 2
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 2
- BHPYMZQTCPRLNR-UHFFFAOYSA-N 2-cyanoethanethioamide Chemical compound NC(=S)CC#N BHPYMZQTCPRLNR-UHFFFAOYSA-N 0.000 description 2
- CHZPJUSFUDUEMZ-UHFFFAOYSA-N 3-acetylbenzoic acid Chemical compound CC(=O)C1=CC=CC(C(O)=O)=C1 CHZPJUSFUDUEMZ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- WNXNUPJZWYOKMW-UHFFFAOYSA-N 5-bromopentanoic acid Chemical compound OC(=O)CCCCBr WNXNUPJZWYOKMW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000003893 Histone acetyltransferases Human genes 0.000 description 2
- 108090000246 Histone acetyltransferases Proteins 0.000 description 2
- 102000006947 Histones Human genes 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102000009572 RNA Polymerase II Human genes 0.000 description 2
- 108010009460 RNA Polymerase II Proteins 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 229940125878 compound 36 Drugs 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 229940125936 compound 42 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 229940127271 compound 49 Drugs 0.000 description 2
- 229940126545 compound 53 Drugs 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 238000006481 deamination reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- GHLKSLMMWAKNBM-UHFFFAOYSA-N dodecane-1,12-diol Chemical compound OCCCCCCCCCCCCO GHLKSLMMWAKNBM-UHFFFAOYSA-N 0.000 description 2
- 230000002729 effect on secretion Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- GOQJMMHTSOQIEI-UHFFFAOYSA-N hex-5-yn-1-ol Chemical group OCCCCC#C GOQJMMHTSOQIEI-UHFFFAOYSA-N 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- CSKSDAVTCKIENY-UHFFFAOYSA-N hydron;pyrrolidine-2-carboxamide;chloride Chemical compound Cl.NC(=O)C1CCCN1 CSKSDAVTCKIENY-UHFFFAOYSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- CNHXWWFZXWRQAK-RGMNGODLSA-N tert-butyl n-[(2s)-1-aminopropan-2-yl]carbamate;hydrochloride Chemical compound Cl.NC[C@H](C)NC(=O)OC(C)(C)C CNHXWWFZXWRQAK-RGMNGODLSA-N 0.000 description 2
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 2
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- NKAOIAGCQMMQLM-ILXRZTDVSA-N (2s)-2-[[(2s,3r)-3-amino-2-hydroxy-4-phenylbutyl]amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC[C@H](O)[C@H](N)CC1=CC=CC=C1 NKAOIAGCQMMQLM-ILXRZTDVSA-N 0.000 description 1
- VLHQXRIIQSTJCQ-LURJTMIESA-N (2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C VLHQXRIIQSTJCQ-LURJTMIESA-N 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- PTZNCCIULVXFIJ-UHFFFAOYSA-N 1-o-tert-butyl 4-o-methyl piperidine-1,4-dicarboxylate Chemical compound COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 PTZNCCIULVXFIJ-UHFFFAOYSA-N 0.000 description 1
- GWTBCUWZAVMAQV-UHFFFAOYSA-N 2,2,2-trifluoro-1-methoxyethanol Chemical compound COC(O)C(F)(F)F GWTBCUWZAVMAQV-UHFFFAOYSA-N 0.000 description 1
- ODUZJBKKYBQIBX-UHFFFAOYSA-N 2,6-difluoroaniline Chemical compound NC1=C(F)C=CC=C1F ODUZJBKKYBQIBX-UHFFFAOYSA-N 0.000 description 1
- LZIPBJBQQPZLOR-UHFFFAOYSA-N 2-(4-methylphenyl)sulfonyloxyethyl 4-methylbenzenesulfonate Chemical group C1=CC(C)=CC=C1S(=O)(=O)OCCOS(=O)(=O)C1=CC=C(C)C=C1 LZIPBJBQQPZLOR-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- JVGNPGXHRHJTFJ-UHFFFAOYSA-N 2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCCOCCNC(=O)OC(C)(C)C)C=C1 JVGNPGXHRHJTFJ-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 description 1
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 description 1
- FMSLIZMDBRKBQO-UHFFFAOYSA-N 2-prop-2-enoxyethyl 4-methylbenzenesulfonate Chemical group CC1=CC=C(S(=O)(=O)OCCOCC=C)C=C1 FMSLIZMDBRKBQO-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RYSICGXZRVMXDP-UHFFFAOYSA-N 3-bromopiperidine-2,6-dione Chemical compound BrC1CCC(=O)NC1=O RYSICGXZRVMXDP-UHFFFAOYSA-N 0.000 description 1
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 description 1
- GYLKKXHEIIFTJH-UHFFFAOYSA-N 3-cyanobenzoic acid Chemical compound OC(=O)C1=CC=CC(C#N)=C1 GYLKKXHEIIFTJH-UHFFFAOYSA-N 0.000 description 1
- WMZNGTSLFSJHMZ-UHFFFAOYSA-N 3-methoxycarbonylbenzoic acid Chemical compound COC(=O)C1=CC=CC(C(O)=O)=C1 WMZNGTSLFSJHMZ-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical group BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 1
- WJVQJXVMLRGNGA-UHFFFAOYSA-N 5-bromopentan-1-ol Chemical compound OCCCCCBr WJVQJXVMLRGNGA-UHFFFAOYSA-N 0.000 description 1
- RIMXEJYJXDBLIE-UHFFFAOYSA-N 6-bromohex-1-ene Chemical group BrCCCCC=C RIMXEJYJXDBLIE-UHFFFAOYSA-N 0.000 description 1
- GNYDYUQVALBGGZ-UHFFFAOYSA-N 7-bromohept-1-ene Chemical group BrCCCCCC=C GNYDYUQVALBGGZ-UHFFFAOYSA-N 0.000 description 1
- JLPQXFFMVVPIRW-UHFFFAOYSA-N 7-bromoheptanoic acid Chemical compound OC(=O)CCCCCCBr JLPQXFFMVVPIRW-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 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
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 101150077068 Hdac5 gene Proteins 0.000 description 1
- 102100021453 Histone deacetylase 5 Human genes 0.000 description 1
- 101000899255 Homo sapiens Histone deacetylase 5 Proteins 0.000 description 1
- 101001032092 Homo sapiens Histone deacetylase 9 Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- NHWZQIYTQZEOSJ-UHFFFAOYSA-N carbonic acid;phosphoric acid Chemical compound OC(O)=O.OP(O)(O)=O NHWZQIYTQZEOSJ-UHFFFAOYSA-N 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 210000001726 chromosome structure Anatomy 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- XSYZCZPCBXYQTE-UHFFFAOYSA-N cyclodecylcyclodecane Chemical compound C1CCCCCCCCC1C1CCCCCCCCC1 XSYZCZPCBXYQTE-UHFFFAOYSA-N 0.000 description 1
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000010595 endothelial cell migration Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- OCVXZQOKBHXGRU-UHFFFAOYSA-N iodine(1+) Chemical group [I+] OCVXZQOKBHXGRU-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000012886 linear function Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- ATCNYMVVGBLQMQ-UHFFFAOYSA-N oct-7-yn-1-ol Chemical group OCCCCCCC#C ATCNYMVVGBLQMQ-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000004072 osteoblast differentiation Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical group BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012474 protein marker Substances 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000013215 result calculation Methods 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- FQZLNQAUUMSUHT-UHFFFAOYSA-N tert-butyl n,n-bis(2-chloroethyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CCCl)CCCl FQZLNQAUUMSUHT-UHFFFAOYSA-N 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种式(Ⅰ)所示化合物、其光学异构体及其药学上可接受的盐。本发明得到的化合物对巨噬细胞中炎性因子IL‑6和TNF‑α的分泌具有较好的抑制作用。
Description
技术领域
本发明属于药物领域,具体涉及一种靶向降解HDAC7的化合物及其制备方法和应用。
背景技术
组蛋白去乙酰化酶(HDAC)是表观遗传因子的重要组成部分,与组蛋白乙酰转移酶(HAT)共同调控组蛋白的乙酰化和去乙酰化动态平衡,在基因转录调控过程中发挥关键作用。当组蛋白表面赖氨酸残基的正电荷发生乙酰化时,紧密的染色体会变得松散,与RNA聚合酶II结合,促进基因表达。HDAC的作用是恢复组蛋白表面赖氨酸侧链上的正电荷,使染色体结构重新变得紧密,进而使RNA聚合酶II难以结合,基因表达受到抑制。
与其他的I类和IV类HDAC类似,IIa类HDAC是锌依赖的水解酶,但与核定位的I类HDAC不同,由于IIa类HDAC在N端有一个独特的适配域,可以响应某些信号通路在细胞核和细胞质之间穿梭,可能具有除了去乙酰化之外的其他生物学功能。此外,由于其酶活中心的酪氨酸催化残基被组氨酸取代,导致其去乙酰化活性极低,生物学底物不明确,可能是具有非催化活性的假酶。IIa类HDAC包括HDAC4、5、7和9,参与各种生理病理过程。研究表明,HDAC4主要与其他蛋白质结合形成转录抑制因子复合物,例如在凋亡细胞中,HDAC4作用于凋亡相关因子,促进细胞凋亡;HDAC5在骨骼肌、成骨细胞分化以及血管生成过程中发挥着调节功能,例如HDAC5基因的缺失会导致相应的心肌肥厚;HDAC7则参与到细胞生长、分化和凋亡,血管生成,内皮细胞迁移等过程,与自身免疫性疾病密切相关;HDAC9主要在脂肪细胞分化、心肌发育以及免疫和代谢过程中发挥着关键作用。总的来说,IIa类HDAC与人类多种疾病的发生发展密切相关,其表达量的增高会影响肿瘤、神经退行性疾病、炎症以及代谢异常等疾病相关过程,研究表明抑制IIa类HDAC可有效遏制黑色素瘤细胞、乳腺癌细胞的增殖,也会影响到巨噬细胞的分化。
基于IIa类HDAC在许多生物学过程中扮演重要角色,开发小分子抑制剂干预其功能对于相关疾病的治疗具有重要意义。但是研究发现,敲除HDAC4和5基因后会导致心肌肥大,而目前IIa类HDAC的小分子抑制剂TMP269无法实现对各亚型(HDAC4、5、9)的选择性干预,存在着相应的心脏毒性问题,因此开发特异性抑制HDAC7或9的治疗策略是亟需解决的问题。此外,我们研究发现,沉默HDAC7和9能够抑制巨噬细胞中炎性因子IL-6和TNF-α的分泌,而抑制剂TMP269没有该效应,这提示我们抑制HDAC7或9的抗炎活性可能不依赖于其酶活功能。基于HDAC7和9在炎性反应中的潜在作用,我们认为针对其开发特异性干预分子有望成为治疗炎性疾病的有效治疗手段。
靶向蛋白降解技术通过诱导形成新的蛋白-蛋白相互作用面,有望实现对HDAC7和9的特异性干预,此外由于降解剂分子清除了蛋白本身,可以同时抑制其酶活和非酶活的全部功能。因此,我们利用IIa类HDAC抑制剂TMP269为靶头,设计并合成了一系列的降解剂,发现活性分子能够显著降解巨噬细胞中的HDAC7蛋白,而对其他IIa类HDAC蛋白(HDAC4,5和9)的表达没有显著影响,并且有降解活性的分子可显著抑制巨噬细胞中炎性因子IL-6和TNF-α的分泌,在自身免疫性疾病和炎症反应中表现出巨大的治疗潜力。目前对于HDCA7降解剂的降解活性有待提高,相关药理机制仍需要探索。
发明内容
本发明的目的是提供一种靶向降解HDAC7的化合物、其光学异构体及其药学上可接受的盐,对巨噬细胞中炎性因子IL-6和TNF-α的分泌具有较好的抑制作用。
为实现上述目的,本发明提供了式(Ⅰ)所示化合物、其光学异构体及其药学上可接受的盐:
其中,
X、Y各自独立地选自N、CH;
n选自0、1、2;
R2选自H、C1-3烷基;
R3选自CH3、CF3;
R4和R6各自独立地选自H、CN;
R5和R7各自独立地选自H、C1-6烷基、C3-6环烷基,其中C1-6烷基和C3-6环烷基可被1个或多个卤素取代;
X2、X3和X4不全选自键;
y选自0-10的整数,z选自1-5的整数,p选自1-3的整数;
作为优选,R3选自三氟甲基;R4选自H、R5选自三氟甲基;
在本发明的一些方案中,所述的化合物中,R2选自H、甲基。
在本发明的一些方案中,所述化合物具有式(Ⅱ)所示化合物、其光学异构体及其药学上可接受的盐:
所述化合物结构如下式所示:
或者
作为优选,z为3、4、5;在一些实施方案中,z为4。作为优选,y为5、6;在一些实施方案中,y为5。在本发明的一些方案中,所述化合物是:
作为优选,所述药学上可接受的盐为所述化合物的如下盐:盐酸盐、三氟乙酸盐、甲磺酸盐、苹果酸盐、枸橼酸盐、甲苯磺酸盐、L-酒石酸盐、D-酒石酸盐。
作为优选,所述药学上可接受的盐为:
名称如下:
N-((1-(2-(1-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氧基)丙基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(1)
N-((1-(4-(1-(4-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氧基)丁基)-1H-1,2,3-三唑-4-基)丁基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(2)
N-((1-(4-(1-(7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氧基)庚基)-1H-1,2,3-三唑-4-基)丁基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(3)
N-((1-((1-(7-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氧基)庚基)-1H-1,2,3-三唑-4-基)甲基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(4)
N-((1-(2-(1-(6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(5)
N-((1-(6-(1-(3-((2-(2,6-二氧哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丙基)-1H-1,2,3-三唑-4-基)己基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(6)
N-((1-(2-(1-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙氧基)丙基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(7)
N-((1-(2-(1-(6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(8)
N-((1-(2-(1-(6-((2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(9)
N-((1-(2-(1-(7-(4-(4-((2,6-二氧代哌啶-3-基)氨基)苯基)哌啶-1-基)-7-氧代庚基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(10)
N-((2R)-1-(苄基(2-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)氨基)丙-2-基)-4-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(11)
N-((1-(2-(1-(6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-甲基-1,2,4-恶二唑-3-基)苯甲酰胺(12)
N1-((1-(2-(1-(6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-N3-羟基间苯二甲酰胺(13)
N-((1-(2-(1-(6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(2-氧代-1,3-二氧环戊烯-4-基)苯甲酰胺(14)
(E)-N-((1-(2-(1-(6-((2-(2,6-二氧哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(4,4,4-三氟丁-2-烯酰基)苯甲酰胺(15)
N-(6-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)-2-(4-苯基噻唑-2-基)己基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(16)
N-((2-(2-(2-(1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)丙基)-1H-1,2,3-三唑-4-基)乙氧基)乙基)-4-(4-苯基噻唑-2-基)四氢-2H-吡喃-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(17)
N-((1-(12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)十二烷基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(18)
N-((1-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)乙氧基)乙氧基)乙氧基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(19)
N-((1-(2-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)苯氧基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(20)
N-((1-(1-(4-(4-((2,6-二氧代哌啶-3-基)氨基)苯基)哌啶-1-基)-2-氧代-6,9,12-三氧杂-3-氮杂十四-酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(21)
(E)-N-(2-(1-(2-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)乙基)-3-(4,4,4-三氟丁-2-烯酰基)苯甲酰胺(22)
N-((3R,4S)-1-(2-(1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氧基)己基)-1H-1,2,3-三唑-4-基)乙基)-3-(4-苯基噻唑-2-基)哌啶-4-基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(23)
N-((1-(2-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-5-氧代戊基)哌嗪-1-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(24)
N-((1-(5-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3-氧代丙基)哌嗪-1-基)戊基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(25)
N-((1-(2-(4-(2-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基-3-氧丙基)哌嗪-1-基)乙基)哌嗪-1-基)乙基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(26)
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-((S)-1-(4-(4)-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(27)
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(28)
(2S,4R)-1-((S)-3,3-二甲基-2-(2-(2-(2-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)乙氧基)乙氧基)乙酰氨基)丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(29)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(30)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-20-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15,18-五氧杂-3-氮杂二十烷基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(31)
N-((1-(((2S,3R)-3-氨基-2-羟基-4-苯基丁酰基)-L-缬氨酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(32)
N-((1-(4-((S)-2-((2S,3R)-3-氨基-2-羟基-4-苯基丁酰氨基)-3-甲基丁酰氨基)丁酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(33)
N-((1-(6-((S)-2-((2S,3R)-3-氨基-2-羟基-4-苯基丁酰氨基)-3-甲基丁酰氨基)己酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(34)
N-((1-(8-((S)-2-((2S,3R)-3-氨基-2-羟基-4-苯基丁酰氨基)-3-甲基丁酰氨基)辛酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(35)
N-((1-(11-((S)-2-((2S,3R)-3-氨基-2-羟基-4-苯基丁酰氨基)-3-甲基丁酰氨基)十一酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(36)
N-((1-(2-(2-((S)-2-((2S,3R)-3-氨基-2-羟基-4-苯基丁酰氨基)-3-甲基丁酰氨基)乙氧基)乙酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(37)
N-((1-((11S,14S,15R)-15-氨基-14-羟基-11-异丙基-10,13-二氧杂-16-苯基-3,6-二氧杂-9,12-二氮杂十六酰)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(38)
N-((1-((14S,17S,18R)-18-氨基-17-羟基-14-异丙基-13,16-二氧杂-19-苯基-3,6,9-三氧杂-12,15-二氮酮癸酰)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(39)
N-((1-((17S,20S,21R)-21-氨基-20-羟基-17-异丙基-16,19-二氧杂-22-苯基-3,6,9,12-四氧杂-15,18-二氮杂二十烷酰基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(40)
N-((1-(6-((S)-2-((2S,3R)-3-氨基-2-羟基-4-苯基丁酰氨基)-3-甲基丁酰氨基)己基)-4-(4-苯基噻唑-2-基)哌啶-4-基)甲基)-3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰胺(41)
(2S,4S)-N-(2,6-二氟苯基)-1-((R)-3,3-二甲基-2-((R)-2-(甲基氨基)丙酰胺基)丁酰基)-4-(6-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)己酰氨基)吡咯烷-2-甲酰胺(42)
(2S,4S)-N-(2,6-二氟苯基)-1-((R)-3,3-二甲基-2-((R)-2-(甲基氨基)丙酰胺基)丁酰基)-4-(8-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)辛酰氨基)吡咯烷-2-甲酰胺(43)
(2S,4S)-N-(2,6-二氟苯基)-1-((R)-3,3-二甲基-2-((R)-2-(甲基氨基)丙酰胺基)丁酰基)-4-(2-(2-(2-(4-(4-苯基噻唑-2-基))-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)乙氧基)乙氧基)乙酰氨基)吡咯烷-2-甲酰胺(44)
(2S,4S)-N-(2,6-二氟苯基)-1-((R)-3,3-二甲基-2-((R)-2-(甲基氨基)丙酰胺基)丁酰基)-4-(2-(2-(2-(2-(4-(4-苯基噻唑-2-基))-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)乙氧基)乙氧基)乙氧基)乙酰氨基)吡咯烷-2-甲酰胺(45)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺盐酸盐(46)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺三氟乙酸盐(47)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺甲磺酸盐(48)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(±)-苹果酸盐(49)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺枸橼酸盐(50)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺对甲苯磺酸盐(51)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺L-酒石酸盐(52)
(2S,4R)-1-((S)-2-(叔丁基)-4-氧代-17-(4-(4-苯基噻唑-2-基)-4-((3-(5-(三氟甲基)-1,2,4-恶二唑-3-基)苯甲酰氨基)甲基)哌啶-1-基)-6,9,12,15-四氧杂-3-氮杂十七酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺D-酒石酸盐(53)。
在本发明的一些方案中,提供一种药物组合物,其中,所述的药物组合物含有治疗有效量的上述任意一项所述化合物或其药学上可药用盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
在本发明的一些方案中,提供以上任意一项所述化合物或其可药用盐或药物组合物在制备预防和/或治疗HDAC7异常性疾病药物中的应用。
在本发明的一些方案中,提供以上任意一项所述化合物或其可药用盐或药物组合物在预防和/或治疗HDAC7异常性疾病中的应用。
在本发明的一些方案中,以上任一项所述化合物或其可药用盐或药物组合物的用途,所述疾病选自代谢性疾病、炎症性疾病、自身免疫性疾病。
在本发明的一些方案中,以上任一项所述化合物或其可药用盐或药物组合物的用途,所述炎症性疾病包括类风湿关节炎、多发性硬化症、骨质疏松症、骨关节炎、炎症性肠道病等。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
应该理解,本文中所述的取代和取代的组合,无论是否明确地说明,是指符合该被取代成员的化合价的取代。例如,应用于碳成员的取代是指C的四价;当应用于氮成员时,其是指N的三价;在通常表示带有正电荷时,其是指氮成员的四键。化合价允许的选项为本领域技术的一部分。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸-氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡萄糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
术语“异构体”是指本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
除非另有说明,“(D)”或者“(+)”表示右旋,“(L)”或者“(-)”表示左旋,“(DL)”或者“(士)”表示外消旋。
除非另有说明,用楔形实线键和楔形虚线键/>表示一个立体中心的绝对构型,用直形实线键/>和直形虚线键/>表示立体中心的相对构型,用波浪线/>表示楔形实线键/>或楔形虚线键/>或用波浪线/>表示直形实线键/>和直形虚线键/>
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当其中一个变量选自键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表键时表示该结构实际上是A-Z。
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时,这种取代基可以通过其任何原子相键合,例如,苯基作为取代基可以通过苯环上任意一个碳原子连接到被取代的基团上;取代基画一个键连接到中心的环上形成的环体系(如所示)代表取代基在该环体系上所有可取代的位置择一取代。
除非另有规定,术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3),可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me),乙基(Et),丙基(如,n-丙基和异丙基),丁基(如,n-丁基,异丁基,s-丁基,t-丁基),戊基(如,n-戊基,异戊基,新戊基)等。
除非另有规定,环烷基包括任何稳定的环状或多环烃基,任何碳原子都是饱和的,可以是单取代或多取代的,可以是一价、二价或者多价。这些环烷基的实例包括,但不限于,环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定,术语“卤素”本身或作为另一取代基的一部分表示氟(F)、氯(Cl)、溴(Br)或碘(I)原子。
除非另有规定,数字范围表示包含范围两端数字在内的所有整数。除非另有规定,0-10的整数表示0、1、2、3、4、5、6、7、8、9、10;1-5的整数表示1、2、3、4、5;1-3的整数表示1、2、3;C1-3烷基表示C1、C2、C3烷基;C1-6烷基表示C1、C2、C3、C4、C5、C6烷基;C3-6环烷基表示C3、C4、C5、C6环烷基,以此类推。
本发明中,当所列举的基团为二价(例如L1、L2、X1、X2、X3、X4、X5)且没有指明两个连接键连接至化合物的具体位置时,这种二价基团的两个连接键在化合物中的连接位置可以互换,例如,X3选自可以是炔基的C与X2连接,也可以是哌啶环上的N与X2连接。
本发明提供的化合物对巨噬细胞中炎性因子IL-6和TNF-α的分泌具有较好的抑制作用。
附图说明
图1为筛选化合物的链长,并确定最有效的linker链长。
图2为探究三氮唑距靶头位置对降解活性的影响。
图3为围绕化合物5进行改造,并与化合物5对比降解活性。
图4为围绕化合物5进行改造,并与化合物5对比降解活性。
图5为筛选以VHL为E3泛素连接酶配体的化合物降解活性。
图6为在巨噬细胞上验证化合物5、30对HDAC7蛋白的降解效果。
图7为考察TMP269(HDAC7抑制剂)、化合物5、30对巨噬细胞分泌的TNF-α水平的影响。
图8为考察TMP269(HDAC7抑制剂)、化合物5、30对巨噬细胞分泌的IL-6水平的影响。
图9为考察TMP269(HDAC7抑制剂)、化合物30和地塞米松在实验动物体内对LPS诱导所分泌的TNF-α水平的影响。
图10为考察TMP269(HDAC7抑制剂)、化合物30和地塞米松在实验动物体内对LPS诱导所分泌的IL-6水平的影响。
具体实施方式
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例中,未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件,或按照仪器制造商所建议的条件操作。
实施例1.中间体1a的合成
步骤一:在250mL圆底烧瓶中,将3-氰基苯甲酸1a-1(5g,34mmol)用100mL的乙醇溶解,加入8-羟基喹啉(24.65mg,0.17mmol)搅拌溶解,将盐酸羟胺(4.76g,68mmol)溶于20mL水中加入上述溶液中,再将碳酸钠(5.8g,54.4mmol)溶于20mL水中缓慢加入反应液中,将反应体系置于90℃回流充分搅拌反应4h。反应完毕后冷却至室温,减压浓缩,将反应液倒入20mL水中,用1N盐酸溶液调节pH值约为3,析出白色固体后,抽滤,滤饼水洗3次后再用丙酮洗涤3次,将所得粗产品干燥,得5.13g白色固体即中间体1a-2,收率84%。ESI(M+H)+=181。
步骤二:将中间体1a-2(5.13g,28.3mmol)溶于50mL无水吡啶中,冷却至0℃后,逐滴加入三氟乙酸酐(11.8mL,85mmol),缓慢升至室温后加热至50℃继续反应3h。将反应液冷却至室温后,倒入50mL冰水中,用1.5N盐酸溶液调节pH值约为4,再用乙酸乙酯萃取3次,合并有机层,用饱和氯化钠溶液洗2次后,无水硫酸钠干燥,减压浓缩,所得粗产品通过硅胶柱层析纯化得2.12g白色固体(中间体1a),收率29%,ESI(M-H)-=257。
实施例2.中间体1b的合成
步骤一:将2-溴苯乙酮1b-1(5g,25.13mmol)和2-氰基硫代乙酰胺(2.5g,25.13mmol)溶解于50mL乙醇中,将反应体系升至80℃后充分搅拌反应4h。反应完毕后将反应液冷却至室温,用氨水调节pH值大于7,乙酸乙酯萃取2次,水洗,饱和氯化钠洗涤后无水硫酸钠干燥,浓缩,所得粗产品用硅胶柱层析纯化得3.9g橙黄色固体(中间体1b-2),收率78%。ESI(M+H)+=201。
步骤二:在氮气保护下,将中间体1b-2(3.9g,19.5mmol)溶于10mL无水N,N-二甲基甲酰胺(DMF)中,在冰浴下分批加入氢化钠(2.4g,100mmol),活化30min后,滴加N,N-双(2-氯乙基)氨基甲酸叔丁酯(4.21mL,20mmol)的DMF溶液(5mL),升高温度至80℃反应3h。冰浴下加水淬灭反应体系,加入50mL乙酸乙酯萃取,有机相水洗1次后再用饱和氯化钠洗涤,无水硫酸钠干燥,浓缩,所得粗产品用硅胶柱层析纯化得3.29g黄色液体(中间体1b-3),收率46%。ESI((M-tBu)+H)+=314。
步骤三:在氮气保护下,氢化铝锂(1.32g,34.8mmol)溶于30mL无水四氢呋喃(THF)中,将中间体1b-3(3.29g,8.7mmol)溶解于10mL无水THF后在冰浴下加入上述混悬液中,升至室温反应1h。TLC监测反应完成后,冰浴下依次加入1.32mL H2O,1.32mL 15%NaOH溶液和3.96mL H2O淬灭,充分搅拌10min后,过硅藻土,滤液用乙酸乙酯萃取3次,无水硫酸钠干燥,减压浓缩,得2.13g粗产品(中间体1b),无需进一步纯化,直接投下一步。ESI(M+H)+=374。
实施例3.中间体1d的合成
步骤一:将中间体1a(1.2g,4.62mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI·HCl)(887mg,4.62mmol)及1-羟基苯并三唑一水合物(HOBt)(771mg,5.04mmol)溶于无水二氯甲烷中(10mL),冰浴条件下滴加N,N-二异丙基乙胺(DIPEA)(2.2mL,12.6mmol),搅拌10min后,缓慢加入中间体1b(1.56g,4.2mmol)的二氯甲烷溶液(5mL),室温搅拌过夜。反应完成后,倒入20mL水中,用二氯甲烷萃取反应液3次,合并有机相,用饱和氯化钠洗2次,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得1.84g白色固体(中间体1c),收率71%。1H-NMR(400MHz,DMSO-d6)δ8.79(t,J=6.4Hz,1H),8.43(s,1H),8.18(d,J=7.8Hz,1H),8.08(s,1H),8.05(d,J=7.7Hz,1H),7.93(d,J=7.3Hz,2H),7.68(t,J=7.8Hz,1H),7.38(t,J=7.6Hz,2H),7.29(t,J=7.3Hz,1H),3.83(d,J=13.5Hz,2H),3.56(d,J=6.3Hz,2H),2.94(s,2H),2.26(d,J=14.2Hz,2H),1.92–1.80(m,2H),1.37(s,9H)。ESI(M+H)+=614。
步骤二:中间体1c(1.84g,3mmol)溶解于2mL二氯甲烷中,加入2mol/L的氯化氢-乙酸乙酯溶液(15mL,30mmol),室温反应2h后旋干,得1.73g白色固体,即中间体1d。ESI(M+H)+=514。
实施例4.中间体1A的合成
步骤一:在0℃下,将原料1A-1 3-丁炔-1-醇(2g,28.6mmol)溶解于20mL二氯甲烷中,加入三乙胺(12mL,85.8mmol)和4-二甲氨基吡啶(349mg,2.86mmol),最后缓慢滴加对甲苯磺酰氯(6.6g,34.3mmol)的二氯甲烷溶液,升至室温反应2h。TLC监测原料1A-1完全反应后,向反应液中倒入60mL水,用二氯甲烷萃取3次后,有机相合并减压浓缩,通过柱色谱分离纯化得5.2g黄色液体(中间体1A-2),产率81%。1H-NMR(400MHz,DMSO-d6)δ7.80(d,J=8.4Hz,2H),7.49(d,J=7.9Hz,2H),4.04(t,J=6.2Hz,2H),2.88(t,J=2.7Hz,1H),2.52(td,J=6.2,2.7Hz,2H),2.42(s,3H)。ESI(M+H)+=225。
步骤二:在氮气保护下,将中间体1d(100mg,0.195mmol)溶于1mL的无水DMF溶液中,缓慢加入碳酸钾(80.7mg,0.585mmol),加热至40℃活化10min,向反应体系中滴加中间体1A-2的DMF溶液(1mL),40℃搅拌过夜。将反应液倒入10mL水中,乙酸乙酯萃取3次,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得67.5mg黄色液体(中间体1A),产率61%。1H-NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.44(s,1H),8.19(d,J=7.7Hz,1H),8.08(s,2H),7.93(d,J=7.6Hz,2H),7.81–7.60(m,1H),7.44–7.36(m,2H),7.35–7.27(m,1H),3.54(s,2H),3.03–2.63(m,4H),2.43–2.16(m,5H),2.26–1.91(m,4H)。ESI(M+H)+=566。
实施例5.中间体1B的合成
步骤一:将原料1B-a1邻碘苯甲酸(8g,32.2mmol)和高碘酸钠(7.24g,33.8mmol)溶于30%的冰醋酸水溶液(50mL)中,升高温度至120℃避光回流反应4h,加入150mL冰水淬灭反应体系,并在冰浴下继续搅拌1小时,使产物充分析出。避光条件下过滤,滤饼依次用冰水和丙酮洗涤,干燥后得7.63g白色粉末状固体(中间体1B-a),收率90%。1H-NMR(400MHz,DMSO-d6)δ8.05(s,1H),8.01(d,J=7.5Hz,1H),7.95(d,J=7.5Hz,1H),7.84(d,J=8.0Hz,1H),7.70(t,J=7.3Hz,1H)。
步骤二:在氮气保护下,将原料1B-1(2.2g,8.0mmol)溶于20mL无水DMF中,缓慢加入碳酸钠(5.1g,48mmol),加热至100℃活化15min,向反应体系中滴加3-溴丙烯的DMF溶液(10mL),保持在100℃继续搅拌反应过夜。加入50mL乙酸乙酯稀释反应液,用150mL水洗涤有机相3次,饱和氯化钠溶液洗涤2次,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得1.3g白色固体(中间体1B-2),产率53%。ESI(M+H)+=315。
步骤三:将中间体1B-2(314mg,1.0mmol)溶于0.2mL的二氯甲烷中,加入氧化剂1B-a(158mg,0.6mmol)搅拌均匀,缓慢滴加叠氮基三甲基硅烷(0.29mL,2.2mmol)和去离子水(0.036mL,2.0mmol),室温下避光反应过夜。TLC监测反应完成后,加入二氯甲烷和饱和碳酸氢钠溶液萃取,水相再用二氯甲烷萃取2次,合并有机相,减压浓缩,通过硅胶柱层析纯化得186mg白色固体(中间体1B),产率52%。1H-NMR(400MHz,DMSO-d6)δ11.08(s,1H),7.78(dd,J=8.5,7.3Hz,1H),7.49(d,J=8.6Hz,1H),7.43(d,J=7.2Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.24(t,J=6.1Hz,2H),3.53(t,J=6.7Hz,2H),3.03–2.75(m,1H),2.62–2.47(m,2H),2.06–1.93(m,3H)。ESI(M+NH4)+=375。
实施例6.目标化合物1的合成
将中间体1A(60mg,0.106mmol)溶于3mL叔丁醇和1.5mL二氯甲烷中,加入中间体1B(45.5mg,0.127mmol)和抗坏血酸钠(21mg,0.106mmol),充分搅拌,将五水硫酸铜(15.9mg,0.064mmol)溶于1.5mL水中后滴加至上述反应体系中,室温搅拌反应2h。反应完毕后,加入10mL水和5mL二氯甲烷萃取,水相再用二氯甲烷萃取2次,合并有机相,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得50mg白色固体(目标化合物1),产率51%。1H-NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.76(t,J=6.4Hz,1H),8.44(s,1H),8.18(d,J=7.8Hz,1H),8.06(d,J=6.3Hz,2H),7.92(d,J=7.1Hz,2H),7.88(s,1H),7.79(dd,J=8.5,7.2Hz,1H),7.68(t,J=7.8Hz,1H),7.46(dd,J=7.9,5.8Hz,2H),7.38(t,J=7.6Hz,2H),7.28(t,J=7.4Hz,1H),5.10(dd,J=12.9,5.4Hz,1H),4.52(t,J=6.8Hz,2H),4.16(t,J=6.0Hz,2H),3.55(d,J=6.3Hz,2H),2.96–2.83(m,3H),2.81–2.72(m,2H),2.63–2.50(m,4H),2.37–2.14(m,6H),2.06–1.93(m,3H)。ESI(M+H)+=923。
实施例7.目标化合物2的合成
参考实施例4和实施例5的方法合成中间体2A(3-丁炔-1-醇替换为5-己炔-1-醇)和2B(3-溴丙烯替换成4-溴-1-丁烯)。参考实施例6目标化合物的合成方法,用中间体2A(60mg,0.106mmol)代替中间体1A,中间体2B(44.5mg,0.127mmol)代替中间体1B,得48.7mg目标化合物2,收率51%。1H-NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.79(s,1H),8.44(s,1H),8.18(d,J=7.9Hz,1H),8.06(d,J=7.3Hz,2H),7.92(d,J=7.3Hz,2H),7.85(s,1H),7.83–7.77(m,1H),7.68(t,J=7.8Hz,1H),7.46(dd,J=14.3,7.9Hz,2H),7.38(t,J=7.6Hz,2H),7.29(t,J=7.3Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.41(t,J=6.9Hz,2H),4.21(t,J=6.2Hz,2H),3.54(s,2H),2.96–2.81(m,2H),2.65–2.54(m,5H),2.45–2.23(m,3H),2.09–1.94(m,5H),1.81–1.66(m,3H),1.64–1.47(m,5H),1.41–1.27(m,1H)。ESI(M+H)+=965。
实施例8.目标化合物3的合成
参考实施例5的方法合成中间体3B(3-溴丙烯替换为7-溴-1-庚烯)。参考实施例6目标化合物的合成方法,用中间体2A(60mg,0.106mmol)代替中间体1A,中间体3B(44mg,0.106mmol)代替中间体1B,得36mg目标化合物3,收率34%。1H-NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.81(t,J=6.4Hz,1H),8.44(s,1H),8.18(d,J=7.8Hz,1H),8.10–8.04(m,2H),7.92(d,J=7.0Hz,2H),7.82(s,1H),7.78(dd,J=8.5,7.3Hz,1H),7.68(t,J=7.8Hz,1H),7.47(d,J=8.6Hz,1H),7.44–7.35(m,3H),7.29(t,J=7.3Hz,1H),5.08(dd,J=12.8,5.4Hz,1H),4.27(t,J=7.0Hz,2H),4.16(t,J=6.4Hz,2H),3.55(d,J=6.3Hz,2H),3.07–2.98(m,2H),2.94–2.81(m,1H),2.68–2.52(m,4H),2.37(d,J=13.3Hz,2H),2.16–1.97(m,3H),1.83–1.67(m,4H),1.60–1.49(m,4H),1.45–1.31(m,4H),1.26–1.19(m,6H)。ESI(M+H)+=1007。
实施例9.目标化合物4的合成
参考实施例4的方法合成中间体3A(中间体1A-2替换为3-溴丙炔)。参考实施例6目标化合物的合成方法,用中间体3A(50mg,0.091mmol)代替中间体1A,中间体3B(35mg,0.091mmol)代替中间体1B为原料,得44mg目标化合物4,收率50%。1H-NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.75(t,1H),8.43(t,J=1.8Hz,1H),8.17(d,J=7.6Hz,1H),8.05(d,J=6.4Hz,2H),7.96(s,1H),7.91(d,J=7.0Hz,2H),7.78(dd,J=8.5,7.2Hz,1H),7.67(t,J=7.8Hz,1H),7.48(d,J=8.5Hz,1H),7.42(d,J=7.2Hz,1H),7.37(t,J=7.5Hz,2H),7.28(t,J=7.3Hz,1H),5.12–5.05(m,1H),4.29(t,J=6.9Hz,2H),4.16(t,J=6.3Hz,2H),3.64–3.43(m,4H),2.94–2.68(m,3H),2.63–2.50(m,3H),2.30(d,J=13.6Hz,2H),2.21–2.12(m,1H),2.05–1.94(m,3H),1.80–1.68(m,4H),1.46–1.26(m,6H)。ESI(M+H)+=965。
实施例10.目标化合物5的合成
参考实施例5的方法合成4B(3-溴丙烯替换为6-溴-1-己烯)。参考实施例6目标化合物的合成方法,以中间体1A(100mg,0.177mmol)为原料,中间体4B(77.7mg,0.195mmol)代替中间体1B,得55.8mg目标化合物5,收率33%。1H-NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.74(t,J=6.4Hz,1H),8.43(s,1H),8.18(d,J=7.8Hz,1H),8.04(s,2H),7.92(d,J=7.0Hz,2H),7.82(s,1H),7.77(dd,J=8.5,7.3Hz,1H),7.68(t,J=7.8Hz,1H),7.47(d,J=8.6Hz,1H),7.44–7.34(m,3H),7.31–7.26(m,1H),5.07(dd,J=12.9,5.4Hz,1H),4.27(t,J=7.0Hz,2H),4.15(t,J=6.3Hz,2H),3.55(d,J=5.9Hz,2H),2.96–2.79(m,3H),2.78–2.71(m,2H),2.64–2.51(m,2H),2.48–2.44(m,1H),2.31(d,J=12.2Hz,2H),2.24–2.07(m,2H),2.07–1.92(m,3H),1.86–1.74(m,2H),1.75–1.66(m,2H),1.56–1.38(m,2H),1.35–1.19(m,3H)。ESI(M+H)+=965。
实施例11.目标化合物6的合成
参考实施例4的方法合成中间体4A(3-丁炔-1-醇替换为7-辛炔-1-醇)。参考实施例6目标化合物的合成方法,用中间体4A(60mg,0.097mmol)代替中间体1A,中间体1B(42mg,0.116mmol)为原料,得35mg目标化合物6,收率37%。1H-NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.82(s,1H),8.44(t,J=1.7Hz,1H),8.19(d,1H),8.07(d,J=6.5Hz,2H),7.93(d,2H),7.86(s,1H),7.80(t,J=8.5,7.2Hz,1H),7.68(t,J=7.7Hz,1H),7.47(t,J=7.9,5.7Hz,2H),7.38(t,2H),7.30(t,1H),5.10(dd,J=12.9,5.4Hz,1H),4.52(t,J=6.8Hz,2H),4.18(t,J=6.0,5.3Hz,2H),3.61–3.51(m,2H),3.16–2.94(m,2H),2.97–2.83(m,2H),2.64–2.51(m,6H),2.45–2.26(m,6H),2.22–2.00(m,4H),1.60–1.38(m,6H)。ESI(M+H)+=979。
实施例12.目标化合物7的合成
参考实施例5的方法合成中间体5B(3-溴丙烯替换为2-(烯丙氧基)乙基4-甲基苯磺酸盐)。参考实施例6目标化合物的合成方法,以中间体1A(50mg,0.088mmol)为原料,中间体5B(37.3mg,0.093mmol)代替中间体1B,得32mg目标化合物7,收率38%。1H-NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.76(t,J=6.2Hz,1H),8.43(s,1H),8.18(d,J=8.0Hz,1H),8.06(d,J=5.3Hz,2H),7.92(d,J=7.1Hz,2H),7.82–7.76(m,2H),7.68(t,J=7.8Hz,1H),7.51(d,J=8.6Hz,1H),7.44(d,J=7.3Hz,1H),7.37(t,J=7.5Hz,2H),7.28(t,J=7.3Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.36–4.31(m,4H),3.75–3.72(m,2H),3.54(d,J=6.3Hz,2H),3.43(t,J=6.0Hz,3H),2.92–2.80(m,3H),2.76–2.70(m,2H),2.62–2.53(m,2H),2.32(d,J=12.7Hz,2H),2.26–2.09(m,2H),2.07–1.93(m,6H)。ESI(M+H)+=967。
实施例13.目标化合物8的合成
参考实施例5的方法合成中间体6B。参考实施例6目标化合物的合成方法,以中间体1A(34mg,0.067mmol)为原料,中间体6B(50mg,0.08mmol)代替中间体1B,得37mg目标化合物8,收率57%。1H-NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.78(t,1H),8.44(t,1H),8.18(d,J=7.8Hz,1H),8.07(d,J=6.4Hz,2H),7.93(d,J=7.0Hz,2H),7.85(s,1H),7.81(d,J=8.3Hz,1H),7.68(t,J=7.8Hz,1H),7.40–7.35(m,3H),7.32–7.26(m,2H),5.12(dd,J=12.9,5.4Hz,1H),4.28(t,J=6.9Hz,2H),4.12(t,J=6.4Hz,2H),3.56(d,J=5.9Hz,2H),3.02–2.74(m,5H),2.62–2.54(m,2H),2.38–2.31(m,2H),2.13–1.93(m,4H),1.81–1.68(m,4H),1.48–1.37(m,3H),1.30–1.24(m,4H)。ESI(M+H)+=965。
实施例14.目标化合物9的合成
参考实施例5的方法合成中间体7B。参考实施例6目标化合物的合成方法,以中间体1A(50mg,0.088mmol)为原料,中间体7B(37.3mg,0.093mmol)代替中间体1B,得30mg目标化合物9,收率36%。1H-NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.87(s,1H),8.44(s,1H),8.18(d,J=7.8,1.5Hz,1H),8.10(s,2H),7.93(d,2H),7.88(s,1H),7.68(t,J=7.8Hz,1H),7.38(t,J=7.5Hz,2H),7.33–7.22(m,2H),6.91(d,J=7.4Hz,1H),6.70(d,J=8.0Hz,1H),5.57(t,J=5.5Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.32–4.09(m,4H),3.63–3.28(m,10H),3.10–3.05(m,2H),3.02–2.80(m,4H),2.67–2.57(m,2H),2.43–2.24(m,3H),2.05–1.99(m,1H),1.82–1.72(m,2H),1.58–1.49(m,2H),1.39–1.32(m,2H)。ESI(M+H)+=950。
实施例15.目标化合物10的合成
步骤一:将原料8B-1(867mg,3.14mmol)溶解于13mL的无水DMF,室温下加入DIPEA(1.64mL,9.42mmol)和3-溴哌啶-2,6-二酮(500mg,2.62mmol),升温至60℃继续反应9h。TLC监测反应完成后,向反应液中加入50mL乙酸乙酯稀释反应液,用100mL水洗涤有机相3次,饱和氯化钠洗涤2次,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得254mg白色固体(中间体8B-2),产率25%。1H-NMR(400MHz,Chloroform-d)δ8.11(s,1H),7.06(d,J=8.5Hz,2H),6.64(d,J=8.5Hz,2H),4.68(d,J=3.6Hz,1H),4.39–4.13(m,2H),4.05(dt,J=12.4,4.2Hz,1H),3.01–2.69(m,4H),2.63–2.49(m,2H),1.90(qd,J=13.3,4.7Hz,1H),1.82–1.72(m,2H),1.62–1.49(m,2H),1.48(s,9H)。ESI((M-tBu)+H)+=332。参考实施例3步骤二的合成方法,将中间体1c换成中间体8B-2(254mg,0.656mmol),得225mg灰色固体(中间体8B-3)。ESI(M+H)+=288。
步骤二:将原料7-溴庚酸(500mg,2.4mmol)溶于无水DMF中(5mL),缓慢加入叠氮化钠(219mg,3.36mmol),升温至80℃搅拌过夜。反应完成后,缓慢加入20mL水中,用乙酸乙酯萃取反应液3次,合并有机相,用饱和氯化钠洗2次,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得309mg无色液体(中间体8B-5),收率75%。ESI(M-H)-=170。
步骤三:将中间体8B-5(90mg,0.523mmol)、EDCI(97mg,0.628mmol)及HOBt(104mg,0.68mmol)溶于无水DMF中(2mL),冰浴条件下滴加DIPEA(0.55mL,3.14mmol),搅拌10min后,缓慢加入中间体8B-3(150mg,0.523mmol)的DMF溶液(1mL),室温搅拌过夜。反应完成后,倒入10mL水中,用乙酸乙酯萃取反应液3次,合并有机相,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得130mg中间体8B,收率56%。ESI(M+H)+=441。
步骤四:参考实施例6目标化合物的合成方法,以中间体1A(44mg,0.078mmol)为原料,中间体8B(34mg,0.078mmol)代替中间体1B,得33mg目标化合物10,收率42%。1H-NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.80(s,1H),8.45(t,J=1.8Hz,1H),8.19(d,J=7.8,1.4Hz,1H),8.07(d,J=6.7Hz,2H),7.93(d,2H),7.85(s,1H),7.68(t,J=7.8Hz,1H),7.38(dd,J=8.3,6.8Hz,2H),7.29(t,1H),6.93(d,2H),6.60(d,J=8.6Hz,2H),5.68(d,J=7.5Hz,1H),4.50(d,J=12.7Hz,1H),4.26(t,J=6.7Hz,3H),3.90(d,J=13.2Hz,1H),3.56(d,J=4.7Hz,2H),3.01(t,J=12.0Hz,2H),2.87–2.67(m,4H),2.62–2.51(m,5H),2.35(d,J=12.5Hz,2H),2.27(t,J=7.4Hz,2H),2.16–1.92(m,4H),1.93–1.55(m,6H),1.51–1.26(m,8H)。ESI(M+H)+=1006。
实施例16.目标化合物11的合成
步骤一:将3A分子筛(600mg)和原料(S)-2-N-Boc-1,2-丙二胺盐酸盐(5A-1)(500mg,2.87mmol)加入50mL的圆底烧瓶中,抽真空后充入氮气,加入无水乙醚搅拌10min,加入苯甲醛5A-2(292μL,2.87mmol),室温下充分搅拌反应18h。反应完毕后过滤,滤饼用乙醚洗涤3次,合成滤液,减压浓缩,得737mg粗产品,无需进一步纯化,直接投下一步。将上述粗产品(737mg,2.81mmol)溶于10mL无水乙醇中,将反应体系温度降至0℃,分批缓慢加入硼氢化钠(160mg,4.21mmol),保持在0℃下反应3h。TLC监测原料反应完成后,减压浓缩,加入10mL甲醇溶解,过滤,滤液减压浓缩,所得粗产品用硅胶柱层析纯化得420mg中间体5A-3,收率55%(两步)。ESI(M+H)+=265。
步骤二:在氮气保护下,将中间体1A-2(596mg,2.66mmol)溶于5mL无水乙腈中,依次加入K2CO3(611mg,4.43mmol),KI(123mg,0.74mmol)和中间体5A-3(390mg,1.48mmol),升温至85℃回流搅拌反应过夜。减压浓缩,加入5mL二氯甲烷溶解,过滤,滤液旋干后用硅胶柱层析纯化。将所得产品(379mg,1.2mmol)用1mL二氯甲烷溶解,加入2mol/L的氯化氢-乙酸乙酯溶液(6mL,12mmol),室温反应2h后旋干,得270mg中间体5A-4,收率84%(两步)。ESI(M+H)+=217。
步骤三:参考实施例3中间体1c的合成方法,以中间体1a(220mg,0.85mmol)为原料,中间体5A-4(270mg,0.85mmol)代替中间体1b,得260mg中间体5A,收率67%。ESI(M+H)+=457。
步骤四:参考实施例6目标化合物的合成方法,以中间体5A-4(40mg,0.088mmol)代替中间体1A,中间体4B(35mg,0.088mmol)代替中间体1B,得25mg目标化合物11,收率33%。1H-NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.38(d,J=8.2Hz,1H),8.15(d,J=8.5Hz,2H),8.04(d,J=8.5Hz,2H),7.80(dd,1H),7.73(s,1H),7.48(d,J=8.5Hz,1H),7.43(d,J=7.2Hz,1H),7.38–7.33(m,1H),7.26–7.21(m,4H),5.07(dd,J=12.9,5.3Hz,1H),4.29–4.24(m,1H),4.22(t,2H),4.16(t,J=6.4Hz,2H),3.71–3.59(m,2H),2.92–2.59(m,8H),2.03–1.99(m,1H),1.74–1.63(m,5H),1.53–1.42(m,4H),1.10(d,J=6.6Hz,3H)。ESI(M+H)+=856。
实施例17.目标化合物12的合成
步骤一:参考实施例1中间体1a的合成方法得到中间体6A-1(三氟乙酸酐替换为乙酸酐)。参考实施例3中间体1d的合成方法,以中间体6A-1(100mg,0.85mmol)代替中间体1a,中间体1b(317mg,0.85mmol)为原料,得260mg中间体6A-2,收率67%(两步)。ESI(M+H)+=460。
步骤二:参考实施例4的方法(中间体1d替换为中间体6A-2)合成中间体6A。参考实施例6目标化合物的合成方法,以中间体6A(34mg,0.073mmol)代替中间体1A,中间体4B(35mg,0.088mmol)代替中间体1B,得26mg目标化合物12,收率39%。ESI(M+H)+=911。
实施例18.目标化合物13的合成
步骤一:参考实施例3合成中间体1d的具体实验步骤,以间苯二甲酸单甲酯7A-1(263mg,1.46mmol)代替中间体1a,中间体1b(545mg,1.46mmol)为原料,得586mg中间体7A-2,产率92%(两步)。ESI(M+H)+=436。
步骤二:参考实施例4步骤二合成方法,以中间体7A-2(586mg,1.35mmol)代替中间体1d,得426mg中间体7A-3,收率65%。ESI(M+H)+=488。
步骤三:在50mL圆底烧瓶中加入盐酸羟胺(1.2g,17.5mmol),用5mL甲醇溶解,将氢氧化钾(1.0g,18.4mmol)溶解于5mL甲醇中并在冰浴下加入上述反应体系,充分搅拌30min后过滤,向滤液中加入中间体7A-3(426mg,0.9mmol)搅拌均匀,将反应体系升至55℃充分反应1h。减压浓缩,用1N盐酸溶液调节pH值小于4,乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得125mg中间体7A,收率29%。ESI(M+H)+=489。
步骤四:参考实施例6目标化合物的合成方法,以中间体7A(80mg,0.163mmol)代替中间体1A,中间体4B(69mg,0.172mmol)代替中间体1B为原料,得50mg目标化合物13,收率35%。1H-NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.56(t,J=6.3Hz,1H),8.22(s,1H),8.19(t,J=1.8Hz,1H),8.04(s,1H),7.94(d,J=7.0Hz,2H),7.89(d,J=7.8Hz,1H),7.85(d,J=8.0Hz,1H),7.82(s,1H),7.78(dd,J=8.5,7.3Hz,1H),7.52–7.46(m,2H),7.41(t,J=7.4Hz,3H),7.31(t,J=7.3Hz,1H),5.07(dd,J=12.8,5.4Hz,1H),4.27(t,J=7.0Hz,2H),4.16(t,J=6.3Hz,2H),3.76–3.60(m,2H),3.52(d,J=6.3Hz,2H),2.93–2.80(m,3H),2.74(t,J=7.7Hz,2H),2.62–2.51(m,2H),2.49–2.44(m,1H),2.30(d,J=12.8Hz,2H),2.16(t,J=10.5Hz,2H),2.06–1.91(m,3H),1.85–1.64(m,4H),1.50–1.40(m,2H),1.34–1.19(m,2H)。ESI(M+H)+=888。
实施例19.目标化合物14的合成
将化合物13(10mg,11.3μmol)溶于700μL二氯甲烷中,加入N,N'-羰基二咪唑(2.7mg,16.9μmol),室温下搅拌反应2h。减压浓缩,所得粗产品用硅胶柱层析纯化得3.5mg目标化合物14,收率34%。ESI(M+H)+=913。
实施例20.目标化合物15的合成
步骤一:在氮气保护下,将三氟乙醛甲基半缩醛(317mg,2.44mmol)溶解于5mL无水THF中,在室温下滴加四氢吡咯(141μL,1.71mmol),充分搅拌30min,加入原料3-乙酰基苯甲酸(9A-1)(400mg,2.44mmol),升高温度至80℃回流反应过夜。反应完毕后,加入10mL乙酸乙酯稀释反应液,用饱和碳酸氢钠溶液萃取有机相3次,水相用1N盐酸溶液调节pH值约为1,再用乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得419mg白色固体(中间体9A-2),产率66%。ESI(M+H)+=263。参考实施例3中间体1d的合成方法,用中间体9A-2代替中间体1a,以中间体1b为原料,得中间体9A-3,收率80%(两步)。ESI(M+H)+=518。
步骤二:参考实施例4的方法合成中间体9A。参考实施例6目标化合物的合成方法,以中间体4B为原料,得中间体9A-4,收率32%。ESI(M+H)+=969。将中间体9A-4(35mg,0.0368mmol)溶于2mL甲苯中,加入对甲苯磺酸一水合物(4.9mg,0.0257mmol)和硫酸镁(40.9mg,0.341mmol),加热至120℃回流反应24h。冷却至室温后过滤,滤液减压浓缩后用硅胶柱层析纯化得目标化合物15。ESI(M+H)+=951。
实施例21.目标化合物16的合成
参考实施例2合成中间体1b的具体实验操作步骤,得到中间体10A-2后,参考实施例3中间体1c的合成方法(以中间体10A-2和中间体1a为原料)得到中间体10A。参考实施例6目标化合物的合成方法,以中间体10A(30mg,0.057mmol)代替中间体1A,中间体4B(25.1mg,0.063mmol)为原料,得21.9mg目标化合物16,收率42%。1H-NMR(400MHz,Chloroform-d)δ8.51(s,2H),8.20(d,J=7.8Hz,1H),8.01(d,J=8.0Hz,1H),7.90–7.80(m,3H),7.65(t,1H),7.58–7.51(m,1H),7.45–7.40(m,2H),7.38–7.28(m,4H),7.17(d,J=8.6Hz,1H),4.93(dd,J=12.2,5.2Hz,1H),4.30(t,2H),4.13(td,J=7.2,6.8,2.4Hz,2H),3.98–3.77(m,2H),3.52–3.31(m,1H),2.99–2.77(m,2H),2.76–2.67(m,3H),2.01–1.79(m,7H),1.77–1.67(m,2H),1.61–1.44(m,6H)。ESI(M+H)+=924。
实施例22.目标化合物17的合成
步骤一:在氮气保护下,将中间体1b-2(5g,25mmol)溶于50mL无水THF中,冷却至0℃后分批加入氢化钠(3g,75mmol),保持在0℃下活化20min,将(2-溴乙氧基)-叔丁基二甲基硅烷(12g,50mmol)溶于15mL无水THF后加入上述反应体系中,升至室温继续反应3h。加入100mL饱和氯化钠溶液淬灭反应,乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,减压浓缩,将所得粗产品用硅胶柱层析纯化。将纯化所得中间体(2g,3.876mmol)溶于3.8mL四氢呋喃中,加入乙酸(11.5mL,201.6mmol)和3.84mL水,室温下搅拌反应过夜。加入饱和碳酸氢钠溶液中和乙酸,用乙酸乙酯萃取水相3次,合并有机相,减压浓缩,得830mg中间体11A-1。ESI(M+H)+=289。
步骤二:将中间体11A-1(4.4g,15.28mmol)溶于75mL乙腈中,依次加入三氟甲磺酸亚铜CuOTf(162mg,0.764mmol),2,2'-联吡啶BPy(120mg,0.764mmol),2,2,6,6-四甲基哌啶氧化物TEMPO(119mg,0.764mmol)和N-甲基咪唑NMI(171mg,1.53mmol),室温下通大气搅拌反应过夜。TLC监测反应完成后,加水稀释,二氯甲烷萃取3次,合并有机相,减压浓缩,将所得粗产品用硅胶柱层析纯化得510mg中间体11A-2,收率12%。ESI(M+H)+=287。
步骤三:将中间体11A-2(510mg,1.78mmol)溶于4mL甲苯中,加入磷酰基乙酸三乙酯(519mg,2.32mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯DBU(299mg,1.96mmol),加热至80℃反应过夜。反应完成后,向反应液中加入10mL水稀释,二氯甲烷萃取3次,合并有机相,减压浓缩,将所得粗产品用硅胶柱层析纯化得279mg中间体11A-3,收率44%。ESI(M+H)+=357。
步骤四:参考实施例2步骤三具体实验方法,以中间体11A-3(279mg,0.78mmol)代替中间体1b-3,得188mg还原产物。将该中间体(188mg,0.59mmol)溶于2mL二氯甲烷中,在0℃下加入二碳酸二叔丁酯(141.5mg,0.65mmol)和三乙胺(98μL,0.708mmol),升至室温反应3h。加入10mL二氯甲烷和20mL水萃取,水相再用二氯甲烷萃取2次,合并有机相,无水硫酸钠干燥,减压浓缩,用硅胶柱层析纯化得106mg中间体11A-4,收率32%(两步)。ESI(M+H)+=419。
步骤五:参考实施例4中间体1A-2合成方法,以中间体11A-4(106mg,0.254mmol)代替原料1A-1,得119mg中间体11A-5,收率82%。ESI(M+H)+=573。
步骤六:在氮气保护下,将原料3-丁炔-1-醇(25mg,0.358mmol)溶于1mL无水N,N-二甲基甲酰胺(DMF)中,在冰浴下分批加入氢化钠(16mg,0.403mmol),活化30min后,滴加中间体11A-5(119mg,0.208mmol)的DMF溶液(1mL),升至室温反应3h。冰浴下加水淬灭反应体系,加入10mL乙酸乙酯萃取,有机相水洗1次后再用饱和氯化钠洗涤,无水硫酸钠干燥,浓缩,所得粗产品用硅胶柱层析纯化。然后按实施例3步骤二方法脱氨基保护得47mg中间体11A-6,收率61%(两步)。ESI(M+H)+=371。
步骤七:参考实施例3步骤一实验方法,以中间体1a(33mg,0.127mmol)为原料,中间体11A-6(47mg,0.127mmol)代替中间体1b,得25mg中间体11A,收率32%。参考实施例6目标化合物的合成方法,以中间体11A(25mg,0.041mmol)代替中间体1A,中间体1B(16mg,0.043mmol)为原料,得18mg目标化合物17,收率45%。1H-NMR(400MHz,Chloroform-d)δ8.67(d,J=59.3Hz,1H),8.48(d,J=1.9Hz,1H),8.21–8.03(m,2H),7.97(d,1H),7.87(d,J=7.2,1.7Hz,2H),7.78–7.69(m,1H),7.59(t,J=7.8Hz,1H),7.54–7.49(m,1H),7.46(d,J=1.6Hz,1H),7.40–7.30(m,4H),7.14–7.09(m,1H),4.91(dd,1H),4.74–4.60(m,2H),4.27–3.86(m,7H),3.78–3.40(m,4H),3.08–2.94(m,2H),2.89–2.57(m,3H),2.56–2.41(m,2H),2.07–1.98(m,3H),1.78–1.55(m,4H)。ESI(M+H)+=968。
实施例23.目标化合物18的合成
步骤一:参考文献合成方法(文献出处:https://doi.org/10.1002/ejoc.201501522),由原料12A-1(1,12-十二烷二醇)制得中间体12A-2,在氮气保护下,将原料1B-1(250mg,0.91mmol)和中间体12A-2(349mg,1.0mmol)溶于3mL无水DMF中,缓慢加入碳酸氢钠(153mg,1.82mmol)和碘化钾(151mg,0.91mmol),将反应体系加热至70℃反应24h。加入10mL乙酸乙酯稀释反应液,用饱和碳酸氢钠溶液洗涤有机相3次,饱和氯化钠洗涤2次,无水硫酸钠干燥,减压浓缩,得粗产品329mg黄绿色固体(中间体12A-3)。无需进一步纯化,直接投下一步。ESI(M+H)+=459。
步骤二:参考实施例4步骤一的合成方法,以中间体12A-3(329mg,0.72mmol)代替原料1A-1,得147mg中间体12A-4,收率26%(两步)。ESI(M+H)+=613。
步骤三:在氮气保护下,将原料1d(60mg,0.109mmol)溶于1mL无水DMF中,加入DIPEA(95μL,0.545mmol)和KI(21.7mg,0.131mmol),随后滴加中间体12A-4(80mg,0.131mmol)的无水DMF(1mL)溶液,保持室温搅拌反应过夜。向反应体系中加入10mL水,用乙酸乙酯萃取有机相3次,合并有机相,无水硫酸钠干燥,减压浓缩,得粗产品29mg黄色固体(目标化合物18),产率28%。1H-NMR(400MHz,Chloroform-d)δ8.51(t,J=1.8Hz,1H),8.21(dt,J=7.8,1.4Hz,1H),7.99(dt,J=7.8,1.5Hz,1H),7.90–7.83(m,2H),7.65(dd,J=8.5,7.3Hz,1H),7.54(t,J=7.8Hz,1H),7.48(s,1H),7.43(d,J=7.3Hz,1H),7.38–7.25(m,3H),7.20(d,J=8.5Hz,1H),4.94(dd,J=12.4,5.1Hz,1H),4.16(t,J=6.4Hz,2H),3.86(d,J=5.6Hz,2H),2.92–2.64(m,7H),2.50–2.28(m,4H),2.15–2.06(m,3H),1.86(dt,J=14.6,6.7Hz,2H),1.55–1.45(m,4H),1.44–1.22(m,14H)。ESI(M+H)+=954。
实施例24.目标化合物19的合成
参考实施例23目标化合物合成方法,以原料2,2'-(氧基双(乙烷-2,1-二基))双(氧基)双(1-乙醇)(13A-1)代替原料12A-1,具体实验步骤同实施例23,得14.4mg目标化合物19。1H-NMR(400MHz,Chloroform-d)δ8.50(t,J=1.8Hz,1H),8.20(d,J=7.8Hz,1H),8.01(d,J=7.9Hz,1H),7.85(d,J=6.8Hz,2H),7.65(t,1H),7.54(t,J=7.8Hz,1H),7.49(s,1H),7.44(d,J=7.3Hz,1H),7.40–7.29(m,3H),7.24(d,J=8.3Hz,1H),4.94(dd,J=12.0,5.4Hz,1H),4.32(t,J=5.1Hz,2H),3.92(t,J=4.6Hz,2H),3.90–3.86(m,2H),3.83–3.74(m,4H),3.72–3.50(m,6H),3.28–3.01(m,2H),2.98–2.68(m,6H),2.63–2.44(m,2H),2.38–2.22(m,3H),2.19–2.08(m,1H)。ESI(M+H)+=946。
实施例25.目标化合物20的合成
步骤一:在氮气保护下,将原料4-苄氧基苯酚14A-1(1.35g,6.74mmol)溶于5mL无水DMF中,加入K2CO3(2.48g,18.39mmol)活化10min后,滴加原料2-(2-((叔丁氧基羰基)氨基)乙氧基)乙基4-甲基苯磺酸酯14A-2(2.2g,6.13mmol)的DMF溶液(5mL),升温至70℃搅拌反应过夜。TLC监测反应完成后,向反应体系中加入30mL水,乙酸乙酯萃取3次,合并有机相,饱和氯化钠溶液洗涤2次,无水硫酸钠干燥,减压浓缩,将所得粗产品用硅胶柱层析纯化得1.12g中间体14A-3,收率47%。ESI(M+H)+=388。
步骤二:在氮气保护下,将所得中间体14A-3(1.12g,2.89mmol)溶于10mL甲醇中,加入10%钯碳(207mg)后置换氢气,将反应体系升至50℃充分搅拌。TLC监测反应完成后,过滤,滤液减压浓缩,得中间体14A-4,无需进一步纯化,直接投下一步。
步骤三:参考本实施例步骤一合成方法,以中间体14A-4(740mg,2.49mmol)代替14A-1,原料二对甲苯磺酸乙二醇酯(1.0g,2.72mmol)代替14A-2,得366mg中间体14A-5,收率30%。ESI((M-tBu)+H)+=440。
步骤四:参考本实施例步骤一合成方法,以中间体1d(110mg,0.214mmol)代替14A-1,中间体14A-5(127mg,0.257mmol)代替14A-2,将所得粗产品用硅胶柱层析纯化后,加入2mol/L的氯化氢-乙酸乙酯溶液脱Boc保护得115mg中间体14A-6。收率73%。ESI(M+H)+=737。
步骤五:在氮气保护下,将中间体14A-6(60mg,0.081mmol)溶于1mL无水二氯亚砜中,加入DIPEA(85μL,0.488mmol)活化10min后,滴加原料2-(2,6-二氧杂环哌啶-3-基)-4-氟异吲哚啉-1,3-二酮14B(25mg,0.081mmol)的二氯亚砜溶液(1mL),升温至110℃搅拌反应过夜。TLC监测反应完成后,向反应体系中加入10mL水,乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,减压浓缩,将所得粗产品用硅胶柱层析纯化得26mg目标化合物20,收率32%。1H-NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.77(t,J=6.4Hz,1H),8.43(t,J=1.8Hz,1H),8.18(d,J=7.8Hz,1H),8.06(d,J=4.6Hz,2H),7.92(d,J=7.0Hz,2H),7.69–7.66(m,2H),7.56(dd,J=8.6,7.1Hz,1H),7.37(t,J=7.8Hz,2H),7.29(t,J=7.3Hz,1H),7.14(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.82–6.80(m,4H),5.05(dd,J=12.7,5.4Hz,1H),4.01–3.95(m,4H),3.75–3.73(m,2H),3.67(t,J=5.4Hz,2H),3.54(d,J=6.3Hz,2H),3.49–3.47(m,2H),2.92–2.84(m,3H),2.62–2.58(m,2H),2.34–2.29(m,2H),2.26–2.17(m,2H),2.03–1.94(m,4H),1.64–1.60(m,1H)。ESI(M+H)+=993。
实施例26.目标化合物21的合成
步骤一:将原料8B-3(50mg,0.174mmol)溶解于1mL的无水DMF,加入DIPEA(90.8μL,0.522mmol)和溴乙酸叔丁酯(26.4μL,0.183mmol),室温下继续搅拌反应过夜。TLC监测反应完成后,向反应液中加入10mL水,用乙酸乙酯萃取有机相3次,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得42.4mg白色固体,产率61%。ESI(M+H)+=402。将该中间体溶解于0.24mL二氯甲烷中,缓慢加入三氟乙酸(81.2μL,1.06mmol),室温反应4h,TLC监测原料反应完全后旋干,得中间体9B-1。ESI(M+H)+=346。
步骤二:参考实施例3中间体1d的合成方法,以中间体15A-1(53mg,0.172mmol)代替中间体1a,中间体1d(70mg,0.136mmol)代替中间体1b,得51.6mg中间体15A-2,收率54%(两步)。ESI(M+H)+=703。
步骤三:将中间体9B-1(36.4mg,0.106mmol)、EDCI(15.5mg,0.081mmol)及HOBt(13.5mg,0.088mmol)溶于无水DMF中(0.5mL),冰浴条件下滴加DIPEA(0.1mL,0.588mmol),搅拌10min后,缓慢加入中间体15A-2(51.6mg,0.074mmol)的DMF溶液(0.5mL),室温搅拌过夜。反应完成后,倒入10mL水中,用乙酸乙酯萃取反应液3次,合并有机相,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得目标化合物21。1H-NMR(400MHz,Chloroform-d)δ8.48(t,J=1.7Hz,1H),8.26–8.16(m,2H),7.99(dt,J=7.9,1.5Hz,1H),7.90–7.84(m,2H),7.61–7.50(m,3H),7.40–7.28(m,3H),7.07(d,J=8.5Hz,2H),6.64(d,J=8.2Hz,2H),4.88–4.56(m,1H),4.20(s,2H),4.15–4.04(m,1H),3.99(dd,J=13.5,6.8Hz,1H),3.95–3.85(m,1H),3.80–3.54(m,14H),3.52–3.38(m,3H),3.29–2.95(m,2H),2.91–2.68(m,2H),2.62–2.17(m,6H),2.13–1.71(m,9H)。ESI(M+H)+=1030。
实施例27.目标化合物22的合成
步骤一:将二异丙基氨基锂(7.75mL,15.5mmol)溶于10mL无水四氢呋喃中,降低温度至-78℃,加入原料16A-1 1-叔丁氧羰基-4-哌啶甲酸甲酯(2.5g,10.3mmol)的无水THF溶液(10mL),充分搅拌30min,随后滴加溴乙腈(2.47g,20.6mmol)的无水THF溶液(10mL),缓慢升高温度至室温继续反应5h。TLC监测反应完成后,减压浓缩,加入50mL乙酸乙酯稀释后用1N盐酸溶液萃取,水相再用乙酸乙酯萃取2次,合并有机相,旋干,所得粗产品用硅胶柱层析纯化得1.25g中间体16A-2,收率43%。ESI(M+H)+=283。
步骤二:将中间体16A-2(1.25g,4.42mmol)溶于15mL氨水溶液中,室温搅拌反应过夜。减压浓缩,得850mg中间体16A-3,产率72%。ESI(M+H)+=268。
步骤三:将中间体16A-3(850mg,3.18mmol)溶于10mL无水THF,加入劳森试剂(1.29g,3.18mmol),回流搅拌反应6h。减压浓缩,加入10mL乙酸乙酯和20mL水萃取,水相再用乙酸乙酯萃取2次,合并有机相,用饱和碳酸氢钠溶液洗涤2次,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得504mg中间体16A-4,收率56%。ESI(M+H)+=284。
步骤四:参考实施例2步骤一实验方法,以中间体16A-4(504mg,1.78mmol)代替原料2-氰基硫代乙酰胺,得498mg中间体16A-5,收率73%。ESI(M+H)+=384。参考实施例2步骤三具体实验方法,以中间体16A-5(498mg,1.3mmol)代替中间体1b-3,得265mg中间体16A-6,收率53%。参考实施例3方法(中间体9A-2代替中间体1a;中间体16A-6代替中间体1b)得312mg中间体16A-7,收率86%(两步)。参考实施例4的方法(中间体16A-7代替中间体1d)合成中间体16A,参考实施例6目标化合物的合成方法,以中间体4B和中间体16A为原料,得中间体16A-8,收率36%。ESI(M+H)+=983。参考实施例20目标化合物15的合成方法,以中间体16A-8代替中间体9A-4,得目标化合物22。ESI(M+H)+=965。
实施例28.目标化合物23的合成
步骤一:将原料17A-1(R)-(+)-1-苯基乙胺(2.47g,20mmol)溶于10mL甲醇和10mL四氢呋喃中,加入乙酸(1.14mL,20mmol)和N-Boc-4-哌啶酮-3-甲酸甲酯(5g,19.4mmol),加热回流反应3h。加入50mL乙酸乙酯稀释,饱和氢氧化钠溶液萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得6.2g中间体17A-2,收率89%。ESI(M+H)+=361。
步骤二:将硼氢化钠(630mg,16.7mmol)溶于45mL无水THF中,在0℃下缓慢滴加三氟乙酸(3.71mL,49.8mmol),降低温度至-45℃,加入中间体17A-2(3g,8.3mmol)的乙腈溶液(16mL),继续搅拌反应1h。TLC监测反应完成后,在冰浴下加入25%的氯化铵溶液淬灭,乙酸乙酯萃取3次,水洗1次,饱和氯化钠溶液洗涤1次,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得2.6g中间体17A-3,收率87%。ESI(M+H)+=363。
步骤三:参考实施例25步骤二实验方法,以中间体17A-3(2.6g,7.2mmol)代替中间体14A-3,得1.65g中间体17A-4,产率89%。ESI(M+H)+=259。参考实施例27步骤二和步骤三方法得到中间体17A-6,参考实施例2步骤一实验方法得中间体17A-7,参考实施例3方法得中间体17A-8,参考实施例4的方法合成中间体17A,参考实施例6目标化合物的合成方法,以中间体4B为原料,得目标化合物23。ESI(M+H)+=951。
实施例29.目标化合物24的合成
步骤一:将中间体1d(150mg,0.273mmol)溶于2mL无水1,4-二氧六环中,加入三乙胺(189μL,1.365mmol),随后加入2-溴乙醇(47mg,0.382mmol)的二氧六环溶液(0.5mL),加热回流反应过夜。TLC监测反应完成后,减压浓缩,加入10mL乙酸乙酯和20mL水萃取,水相再用乙酸乙酯萃取2次,合并有机相,无水硫酸钠干燥,减压浓缩,将所得粗产品用硅胶柱层析纯化得63mg中间体18A-1,收率41%。ESI(M+H)+=558。参考实施例4步骤一方法,得中间体18A-2。ESI(M+H)+=712。
步骤二:将原料5-溴戊酸(600mg,3.33mmol)溶于4mL无水二氯甲烷中,冰浴下滴加草酰氯(0.56mL,6.66mmol)和无水DMF(1drop),升至室温反应2h。减压浓缩,滴加至原料10B-1泊马度胺(455mg,1.67mmol)的无水四氢呋喃溶液(15mL)中,加热回流反应4h。旋干,加入4mL乙酸乙酯充分溶解后再加入16mL石油醚,析出白色固体后过滤,将所得固体干燥即为中间体10B-2,产率96%。ESI(M+H)+=436。
步骤三:在氮气保护下,将原料1-叔丁氧羰基哌嗪(74.4mg,0.4mmol)溶于5mL无水DMF中,依次加入DIPEA(348μL,2.0mmol)和碘化钾(132.8mg,0.8mmol),活化5min后加入中间体10B-2(350mg,0.8mmol),室温下搅拌反应过夜。加入10mL乙酸乙酯稀释反应液,用饱和碳酸氢钠溶液洗涤有机相3次,饱和氯化钠洗涤2次,无水硫酸钠干燥,减压浓缩,将所得粗产品用硅胶柱层析纯化,参考实施例3步骤二方法得167mg中间体10B-3,收率77%(两步)。ESI(M+H)+=442。
步骤四:参考本实施例步骤三方法,以中间体10B-3(30mg,0.068mmol)代替1-叔丁氧羰基哌嗪,中间体18A-2(40mg,0.057mmol)代替中间体10B-2,得12.8mg目标化合物24,产率23%。ESI(M+H)+=981。
实施例30.目标化合物25的合成
参考实施例29目标化合物合成方法,以5-溴戊醇代替2-溴乙醇,3-溴丙酸代替5-溴戊酸,得目标化合物25。ESI(M+H)+=995。
实施例31.目标化合物26的合成
参考实施例29步骤一合成方法,得到4-(2-(对苯磺酰基)乙基)哌嗪-1-羧酸叔丁酯;根据实施例29步骤三得到中间体26-1;根据实施例29步骤四得到目标化合物26。ESI(M+H)+=1065。
实施例32.目标化合物27的合成
步骤一:在氮气保护下,将中间体1d(150mg,0.292mmol)溶于1mL无水DMF中,加入K2CO3(121mg,0.877mmol)活化10min后,滴加原料19A-1(193mg,0.585mmol)的DMF溶液(1mL),升温至60℃搅拌反应过夜。TLC监测反应完成后,向反应体系中加入10mL水,用乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,减压浓缩,将所得粗产品用硅胶柱层析纯化得137mg中间体,收率70%。ESI(M+H)+=672。将所得中间体(137mg,0.204mmol)用0.15mL二氯甲烷溶解,缓慢加入三氟乙酸(152μL,2.04mmol),室温反应4h,TLC监测原料反应完全后旋干,得中间体19A-2。ESI(M+H)+=616。
步骤二:将中间体19A-2(125mg,0.203mmol)、EDCI(38mg,0.244mmol)和HOBt(44mg,0.285mmol)溶于1mL无水DMF中,冰浴条件下滴加DIPEA(353μL,2.033mmol),搅拌10min后,缓慢加入中间体10B(90mg,0.203mmol)的DMF溶液(0.5mL),室温搅拌过夜。反应完成后,倒入10mL水中,用乙酸乙酯萃取反应液3次,合并有机相,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得36mg目标化合物27,收率17%。1H-NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.81(s,1H),8.47–8.40(m,2H),8.19(d,J=7.8Hz,1H),8.07(d,J=7.9Hz,2H),7.93(d,J=7.1Hz,2H),7.74–7.65(m,2H),7.44–7.40(m,3H),7.39–7.33(m,3H),7.29(t,J=7.3Hz,1H),5.15(s,1H),4.96–4.84(m,1H),4.54(d,J=9.6Hz,1H),4.44(t,J=8.3Hz,1H),4.28(s,1H),4.18–4.08(m,1H),3.97(s,2H),3.67–3.53(m,6H),2.45(s,3H),2.42–2.30(m,2H),2.25–1.97(m,4H),1.83–1.73(m,1H),1.68–1.59(m,1H),1.51–1.43(m,2H),1.39–1.33(m,4H),0.93(s,9H)。ESI(M+H)+=1042。
实施例33.目标化合物28的合成
参考实施例32目标化合物的合成方法,用20A-1代替19A-1,得目标化合物28。1H-NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.90(s,1H),8.50–8.44(m,2H),8.19(d,J=7.8Hz,1H),8.15–8.09(m,2H),7.94(d,J=7.0Hz,2H),7.69(t,J=7.8Hz,1H),7.42–7.30(m,8H),4.91–4.86(m,1H),4.54(d,J=9.6Hz,1H),4.43(t,J=8.3Hz,1H),4.28(s,1H),3.95(s,2H),3.78–3.72(m,2H),3.63–3.53(m,9H),3.26–3.10(m,2H),2.98–2.74(m,2H),2.44(s,3H),2.37–2.29(m,2H),2.10–2.03(m,1H),1.79–1.72(m,1H),1.48–1.38(m,1H),1.35(d,J=7.0Hz,3H),1.30–1.21(m,3H),0.91(s,9H)。ESI(M+H)+=1086。
实施例34.目标化合物29的合成
参考实施例32目标化合物的合成方法,用21A-1代替19A-1,得目标化合物29。1H-NMR(400MHz,DMSO-d6)δ8.96(s,2H),8.48(d,J=7.8Hz,2H),8.27–8.06(m,3H),7.95(d,J=7.5Hz,2H),7.70(t,J=7.7Hz,1H),7.50–7.28(m,8H),4.96–4.83(m,1H),4.54(d,J=9.4Hz,1H),4.44(t,J=8.1Hz,1H),4.30(s,1H),3.96(s,2H),3.81–3.71(m,2H),3.65–3.49(m,13H),3.27–3.14(m,2H),3.09–2.80(m,2H),2.45(s,3H),2.40–2.28(m,2H),2.12–2.01(m,1H),1.82–1.71(m,1H),1.50–1.24(m,7H),0.93(s,9H)。ESI(M+H)+=1130。
实施例35.目标化合物30的合成
参考实施例32目标化合物的合成方法,用22A-1代替19A-1,得目标化合物30。1H-NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.77(t,J=6.5Hz,1H),8.53–8.41(m,2H),8.30(s,1H),8.18(d,J=7.7Hz,1H),8.06(d,J=10.1Hz,2H),7.92(d,J=7.6Hz,2H),7.67(t,J=7.8Hz,1H),7.45–7.34(m,6H),7.29(t,J=7.3Hz,1H),4.90(t,J=7.2Hz,1H),4.54(d,J=9.6Hz,1H),4.45(t,J=8.2Hz,1H),4.28(s,1H),3.95(s,2H),3.67–3.43(m,18H),2.84(d,J=11.2Hz,2H),2.45(s,5H),2.35–2.15(m,4H),2.11–1.94(m,3H),1.83–1.72(m,1H),1.52–1.20(m,4H),0.93(s,9H)。ESI(M+H)+=1174。
实施例36.目标化合物31的合成
参考实施例32目标化合物的合成方法,用23A-1代替19A-1,得目标化合物31。1H-NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.85(s,1H),8.50–8.42(m,2H),8.20(d,J=7.8Hz,1H),8.14–8.06(m,2H),7.94(d,J=6.9Hz,2H),7.69(t,J=7.8Hz,1H),7.44–7.28(m,8H),4.94–4.86(m,1H),4.54(d,J=9.5Hz,1H),4.44(t,J=8.1Hz,1H),4.28(s,1H),4.00–3.94(m,4H),3.61–3.48(m,21H),2.45(s,3H),2.43–2.32(m,2H),2.24–2.09(m,2H),2.08–2.03(m,1H),1.81–1.73(m,1H),1.59–1.45(m,4H),1.37(d,J=7.1Hz,3H),1.33–1.29(m,2H),0.93(s,9H)。ESI(M+H)+=1218。
实施例37.目标化合物32的合成
步骤一:将原料(S)-2-((2S,3R)-3-氨基-2-羟基-4-苯丁胺基)-4-甲基戊酸11B-1(150mg,0.487mmol)和碳酸钾(80.1mg,0.584mmol)溶于6.6mL中,在0℃下加入二碳酸二叔丁酯(134μL,0.584mmol)的四氢呋喃/水(1:1)溶液(1.65mL),将反应体系升至室温反应7h。加入10mL乙酸乙酯和20mL水萃取,水相再用乙酸乙酯萃取2次,合并有机相,无水硫酸钠干燥,减压浓缩,得175mg白色固体,即中间体11B,收率88%。无需进一步纯化,直接投下一步。ESI(M+H)+=409。
步骤二:将原料N-Boc-甘氨酸24A-1(18.8mg,0.107mmol)、EDCI(20.6mg,0.107mmol)和HOBt(17.9mg,0.117mmol)溶于0.5mL无水DMF中,冰浴条件下滴加DIPEA(136μL,0.78mmol),搅拌10min后,缓慢加入中间体1d(50mg,0.098mmol)的DMF溶液(0.5mL),室温搅拌过夜。反应完成后,倒入10mL水中,用乙酸乙酯萃取反应液3次,合并有机相,无水硫酸钠干燥,旋干,所得粗产品用硅胶柱层析纯化得66.6mg白色固体。加入2mol/L的氯化氢-乙酸乙酯溶液(0.5mL,1.0mmol),室温反应2h后旋干,得47.9mg中间体24A-2,收率86%(两步)。ESI(M+H)+=571。
步骤三:参考本实施例步骤二实验方法,以中间体11B(37.7mg,0.092mmol)代替24A-1,中间体24A-2(47.9mg,0.084mmol)代替中间体1d,得目标化合物32,收率50%(两步)。1H-NMR(400MHz,DMSO-d6)δ8.82(t,J=6.4Hz,1H),8.43(s,1H),8.19(d,J=7.8Hz,1H),8.16–8.04(m,4H),8.00(d,J=5.4Hz,2H),7.93(d,J=7.2Hz,2H),7.68(t,J=7.8Hz,1H),7.38(t,J=7.6Hz,2H),7.34–7.21(m,4H),4.34(q,J=7.8Hz,1H),4.13(d,J=13.3Hz,1H),4.06–3.97(m,2H),3.93(t,J=4.4Hz,1H),3.84-3.76(m,4H),3.58(d,J=6.6Hz,3H),3.16(t,J=10.8Hz,1H),3.04–2.81(m,3H),2.46–2.20(m,2H),2.05–1.77(m,2H),1.69–1.59(m,1H),1.56–1.47(m,2H),0.87(t,6H)。ESI(M+H)+=861。
实施例38.目标化合物33的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料25A-1代替24A-1,得目标化合物33。1H-NMR(400MHz,DMSO-d6)δ8.80(t,J=6.1Hz,1H),8.43(s,1H),8.18(d,J=7.6Hz,1H),8.14–8.08(m,2H),8.06(d,J=7.7Hz,1H),7.98–7.91(m,3H),7.68(t,J=7.7Hz,1H),7.38(t,J=7.5Hz,2H),7.33–7.26(m,6H),4.26–4.11(m,2H),3.95(d,J=3.1Hz,1H),3.78(d,J=13.3Hz,1H),3.60–3.56(m,3H),3.54–3.45(m,2H),3.14–3.00(m,4H),2.93–2.78(m,3H),2.29(q,J=15.3,13.1Hz,4H),1.93–1.80(m,2H),1.63–1.54(m,3H),1.52–1.43(m,2H),0.85(t,J=9.7,6.3Hz,6H)。ESI(M+H)+=889。
实施例39.目标化合物34的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料26A-1代替24A-1,得目标化合物34。1H-NMR(400MHz,DMSO-d6)δ8.81(t,J=6.4Hz,1H),8.43(s,1H),8.18(d,J=7.7Hz,1H),8.10–8.04(m,3H),8.02–7.97(m,3H),7.93(d,J=7.5Hz,2H),7.68(t,J=7.8Hz,1H),7.38(t,J=7.5Hz,2H),7.34–7.27(m,4H),4.27–4.14(m,2H),3.99(d,J=3.5Hz,1H),3.81(d,J=10.8Hz,1H),3.14(t,J=10.6Hz,1H),3.02–2.81(m,6H),2.36–2.23(m,5H),1.93–1.80(m,2H),1.55–1.16(m,13H),0.86(t,6H)。ESI(M+H)+=917。
实施例40.目标化合物35的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料27A-1代替24A-1,得目标化合物35。1H-NMR(400MHz,DMSO-d6)δ8.81(t,J=6.2Hz,1H),8.43(s,1H),8.18(d,J=7.8Hz,1H),8.09–7.98(m,6H),7.93(d,J=7.1Hz,2H),7.68(t,J=7.8Hz,1H),7.38(t,J=7.5Hz,2H),7.34–7.28(m,4H),4.26–4.15(m,2H),4.00(d,J=3.3Hz,1H),3.83(d,J=13.4Hz,1H),3.59–3.48(m,11H),3.19–2.79(m,8H),2.37–2.23(m,4H),1.91–1.77(m,2H),1.61–1.41(m,6H),0.86(t,J=9.5,6.4Hz,6H)。ESI(M+H)+=945。
实施例41.目标化合物36的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料28A-1代替24A-1,得目标化合物36。ESI(M+H)+=987。
实施例42.目标化合物37的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料29A-1代替24A-1,得目标化合物37。ESI(M+H)+=905。
实施例43.目标化合物38的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料30A-1代替24A-1,得目标化合物38。ESI(M+H)+=949。
实施例44.目标化合物39的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料31A-1代替24A-1,得目标化合物39。ESI(M+H)+=993。
实施例45.目标化合物40的合成
参考实施例37目标化合物合成方法,以中间体1d为原料,原料32A-1代替24A-1,得目标化合物40。ESI(M+H)+=1037。
实施例46.目标化合物41的合成
参考实施例32步骤一中间体19A-2的合成方法,以中间体1d为原料,原料32A-1代替19A-1,得中间体32A-2,再根据实施例37步骤三目标化合物的合成方法,得目标化合物41。1H-NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.17–8.06(m,3H),7.96(d,J=7.7Hz,3H),7.90(d,J=7.6Hz,2H),7.66(t,J=7.7Hz,1H),7.38–7.21(m,7H),6.65(d,J=5.8Hz,1H),4.24–4.15(m,1H),3.99–3.91(m,1H),3.56–3.36(m,9H),3.11–2.62(m,7H),2.39–2.28(m,2H),1.72–1.07(m,12H),1.01(t,J=7.0Hz,1H),0.82(t,J=7.8Hz,6H)。ESI(M+H)+=903。
实施例47.目标化合物42的合成
步骤一:将原料12B-1L-叔亮氨酸甲酯盐酸盐(4.45g,24.6mmol)溶于42mL二氯甲烷中,加入原料12B-2Boc-N-甲基-L-丙氨酸(5g,24.6mmol)搅拌均匀,冰浴下依次加入N-甲基吗啉(5.4mL,49.2mmol),EDCI(5.67g,29.5mmol)和HOBt(4.52g,29.5mmol),升温至室温搅拌反应过夜。将反应液倒入50mL饱和碳酸氢钠溶液中萃取,有机相用1N盐酸溶液洗涤,再用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,所得粗产品用硅胶柱层析纯化得3.28g淡黄色液体,收率40%。将所得中间体(3.28g,9.9mmol)溶于24mL四氢呋喃和3mL甲醇中,加入氢氧化锂(548mg,22.8mmol)的水溶液(3mL),室温搅拌反应过夜,用1N盐酸溶液调节pH约为3,乙酸乙酯萃取3次,合并有机相,旋干,得2.9g中间体12B-3,收率92%。ESI(M+H)+=317。
步骤二:参考实施例4步骤一中间体1A-2的合成方法,以原料12B-4N-Boc-反式-4-羟基-L-脯氨酸甲酯(8g,32.6mmol)代替中间体1A-1,得9.6g黄色液体,收率74%。按照本实施例步骤一中间体12B-3合成方法,将上述所得中间体(9.6g,24mmol)碱性水解得中间体12B-5(8.92g,收率97%)。ESI(M+H)+=386。
步骤三:将中间体12B-5(8.92g,23.17mmol)和原料2,6-二氟苯胺(2.62mL,24.33mmol)溶于100mL二氯甲烷中,加入N,N'-二环己基碳酰亚胺(5g,24.33mmol),室温反应过夜。过滤,滤液旋干后用硅胶柱层析纯化得9.84g白色固体,收率86%。参考实施例3步骤二方法,将该白色固体脱去氨基保护得7.54g中间体12B-6,ESI(M+H)+=397。
步骤四:参考实施例3步骤一具体实验方法,以中间体12B-3(2.9g,9.18mmol)代替中间体1a,中间体12B-6(4.36g,11.01mmol)代替中间体1b,得2.9g中间体12B-7,收率46%。ESI(M+H)+=695。
步骤五:将中间体12B-7(2.9g,4.18mmol)溶于30mL无水DMF中,加入叠氮化钠(353mg,5.43mmol),升高温度至80℃反应过夜。冷却至室温,倒入100mL冰水中,用甲基叔丁基醚萃取3次,合并有机相,减压浓缩,得2.17g中间体12B-8,收率92%。无需进一步纯化,直接投下一步。ESI(M+H)+=566。
步骤六:在氮气保护下,将所得中间体12B-8(2.17g,3.84mmol)溶于25mL甲醇中,加入10%钯碳(217mg)后置换氢气,室温下充分均匀搅拌。TLC监测反应完成后,过滤,滤液减压浓缩,用硅胶柱层析纯化得1.5g白色固体(中间体12B),收率72%。ESI(M+H)+=540。
步骤七:参考实施例32目标化合物的合成方法,用33A-1代替19A-1,得目标化合物42。1H-NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.74(t,J=6.4Hz,1H),8.43(s,1H),8.18(d,J=6.4Hz,1H),8.04(d,J=6.7Hz,3H),7.92(d,J=7.1Hz,2H),7.85(d,J=9.3Hz,1H),7.67(t,J=7.8Hz,1H),7.39–7.26(m,4H),7.14(t,J=8.1Hz,2H),4.56–4.50(m,1H),4.44(d,J=9.3Hz,1H),4.36–4.25(m,1H),4.15–4.05(m,1H),3.53(d,J=6.4Hz,2H),3.23(t,J=9.3Hz,1H),3.01–2.91(m,1H),2.78–2.66(m,2H),2.33–2.26(m,2H),2.19–2.12(m,5H),2.07–1.99(m,4H),1.98–1.88(m,3H),1.82–1.73(m,1H),1.51–1.43(m,2H),1.39–1.33(m,2H),1.23–1.21(m,2H),1.11(d,J=6.9Hz,3H),0.91(s,9H)。ESI(M+H)+=1049。
实施例48.目标化合物43的合成
参考实施例32目标化合物的合成方法,用34A-1代替19A-1,得目标化合物43。1H-NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.73(t,J=6.4Hz,1H),8.43(s,1H),8.17(d,J=7.7Hz,1H),8.04(d,J=11.2Hz,3H),7.91(d,J=7.7Hz,2H),7.86(d,J=9.4Hz,1H),7.67(t,J=7.8Hz,1H),7.38–7.26(m,4H),7.13(t,J=8.1Hz,2H),4.54(t,J=8.6Hz,1H),4.44(d,J=9.3Hz,1H),4.36–4.27(m,1H),4.15–4.06(m,1H),3.53(d,J=6.0Hz,2H),3.24(t,J=9.3Hz,1H),3.00–2.93(m,1H),2.75–2.69(m,2H),2.29(d,J=12.5Hz,2H),2.18–2.12(m,5H),2.07–1.91(m,7H),1.83–1.74(m,1H),1.49–1.43(m,2H),1.38–1.33(m,2H),1.23–1.19(m,6H),1.11(d,J=6.8Hz,3H),0.92(s,9H).ESI(M+H)+=1077。
实施例49.目标化合物44的合成
参考实施例3中间体1d的合成方法,以中间体20A-2代替中间体1a,中间体12B代替中间体1b,得目标化合物44。1H-NMR(400MHz,DMSO-d6)δ10.09(s,1H),9.72(s,1H),9.05–8.99(m,1H),8.66(d,J=7.6Hz,1H),8.45(s,1H),8.23–8.14(m,4H),7.94(d,J=7.1Hz,2H),7.70(t,J=7.9Hz,1H),7.39–7.30(m,4H),7.13(t,J=8.1Hz,2H),4.61–4.58(m,1H),4.43–4.41(m,1H),4.15–4.10(m,1H),4.09–4.05(m,1H),4.00–3.92(m,2H),3.87–3.84(m,2H),3.75(t,J=4.7Hz,1H),3.62–3.53(m,4H),3.48–3.36(m,3H),3.18–3.14(m,2H),2.95–2.86(m,2H),2.46–2.39(m,5H),1.36(d,J=6.8Hz,3H),1.34–1.19(m,6H),0.97(s,9H).ESI(M+H)+=1081。
实施例50.目标化合物45的合成
参考实施例3中间体1d的合成方法,以中间体21A-2代替中间体1a,中间体12B代替中间体1b,得目标化合物45。1H-NMR(400MHz,DMSO-d6)δ10.09(s,1H),9.70(s,1H),9.02(t,J=6.3Hz,1H),8.66(d,J=7.8Hz,1H),8.44(s,1H),8.21–8.14(m,4H),7.93(d,J=8.5Hz,2H),7.69(t,J=7.8Hz,1H),7.40–7.29(m,4H),7.13(t,J=8.2Hz,2H),4.64–4.61(m,2H),4.45–4.38(m,2H),4.08–3.96(m,2H),3.89–3.86(m,2H),3.76(t,J=5.0Hz,1H),3.57–3.45(m,11H),3.22–3.12(m,2H),2.95–2.85(m,2H),2.46–2.38(m,5H),1.35(d,J=6.8Hz,3H),1.32–1.18(m,6H),0.97(s,9H)。ESI(M+H)+=1125。
实施例51.目标化合物46的合成
将化合物30(10mg,8.5μmol)溶解于2mol/L的氯化氢-乙酸乙酯溶液(4.3μL,8.5μmol),室温下搅拌反应过夜,有白色固体析出,离心得9.8mg白色固体,即目标化合物46,产率95%,ESI(M+H)+=1174。
实施例52.目标化合物47的合成
将化合物30(10mg,8.5μmol)和三氟乙酸(1mg,8.5μmol)溶解于650μL的无水乙醇中,室温下搅拌反应过夜,有白色固体析出,离心得10.3mg白色固体,即目标化合物47,产率94%,ESI(M+H)+=1174。
实施例53.目标化合物48的合成
参考实施例52的实验步骤,将三氟乙酸替换成甲磺酸,得目标化合物48,ESI(M+H)+=1174。
实施例54.目标化合物49的合成
参考实施例52的实验步骤,将三氟乙酸替换成(±)-苹果酸,得目标化合物49,ESI(M+H)+=1174。
实施例55.目标化合物50的合成
参考实施例52的实验步骤,将三氟乙酸替换成枸橼酸,得目标化合物50,ESI(M+H)+=1174。
实施例56.目标化合物51的合成
参考实施例52的实验步骤,将三氟乙酸替换成对甲苯磺酸,得目标化合物51,ESI(M+H)+=1174。
实施例57.目标化合物52的合成
参考实施例52的实验步骤,将三氟乙酸替换成L-酒石酸,得目标化合物52,ESI(M+H)+=1174。
实施例58.目标化合物53的合成
参考实施例52的实验步骤,将三氟乙酸替换成D-酒石酸,得目标化合物53,ESI(M+H)+=1174。
实施例59.生物活性评价
一、HDAC7酶活检测
仪器:酶标仪TECAN SPARK(TECAN,Switzerland)
材料:HDAC7蛋白,纯化于SF9细胞;底物Ac-Leu-Lys(TFAc)-AMC
样本处理:化合物用DMSO溶解,低温保存,梯度稀释,且DMSO在最终体系中的浓度控制在不影响酶活检测的范围以内。实验采用的阳性化合物为TMP269。
测定方法:100nM的HDAC7蛋白和50μM的底物溶解于激酶反应缓冲液(500mM NaCl,50mM Tris,pH 8.0)。分别将0.3μM,3μM的化合物加入反应体系(100μL)中,同时设置不加药组,阳性化合物(TMP269,0.3μM)和空白对照组,每个样品每个浓度设2个复孔。充分溶解后,将体系转移到96孔板,再加入100μL 10mg/ml的trypsin,37℃孵育。通过酶标仪检测荧光值(吸收光460nm,激发光390nm),以指征AMC的释放。通过样品读数计算样品酶活抑制率,计算公式为:(RFU不加药-RFU化合物)/RFU不加药×100%。
表1化合物对HDAC7酶活的抑制率
实验结果:本发明化合物对HDAC7的酶活有适中的抑制效果。
二、蛋白质免疫印迹(Western blot)检测化合物对HDAC7的降解效果
以TMP269化合物为阴性对照,采用蛋白质免疫印迹法(Western blot)测定化合物对HEK293细胞上HDAC7蛋白的降解情况,并选取其中降解效果最佳的两个化合物验证其在RAW264.7(小鼠单核巨噬细胞)细胞上降解HDAC7蛋白的能力。
实验材料:
细胞株:HEK293细胞,小鼠单核巨噬细胞(RAW264.7)
培养基:DMEM
HEK293:DMEM+10% Hyclone血清
RAW264.7:DMEM+10% Gibco血清
药物配制方法:将化合物溶于DMSO中制成50mM的储备液,并按一定比例稀释得到相应浓度。
1.HEK293细胞体外培养及给药
(1)HEK293细胞体外培养:
将所选取的HEK293于含5% CO2的37℃恒温培养箱培养,培养条件为DMEM+10%Hyclone血清,待细胞密度长到70~90%时传代,用于以后实验所需。
(2)细胞种板:消化细胞并把细胞悬液加入1.5mL Eppendorf管中,1,000rpm离心5min,用2mL培液重悬细胞并计数,将细胞悬液种于24孔板中,每孔20万细胞,放置8-12h待细胞全部贴壁。
(3)细胞给药:用DMEM+10%Hyclone血清稀释储备液为50mM的化合物,使其终浓度分别为1μM,5μM,于37℃、含5% CO2细胞培养箱中孵育24h,以DMSO组为空白对照。
2.RAW264.7细胞体外培养及给药
(1)RAW264.7细胞体外培养:
将所选取的RAW264.7细胞于含5% CO2的37℃恒温培养箱培养,培养条件为DMEM+10% Gibco血清,待细胞密度长到70~90%时传代(RAW264.7细胞需要刮刀轻轻刮下来,不能用胰酶消化),用于以后实验所需。
(2)细胞种板:消化细胞并将细胞悬液加入1.5mL Eppendorf管中,1,000rpm离心5min,用2mL培液重悬细胞并计数,将细胞悬液种于24孔板中,每孔20万细胞,放置8-12h待细胞全部贴壁。
(3)细胞给药:用DMEM+10%Hyclone血清稀释储备液为50mM的化合物,使其终浓度分别为1μM,5μM,于37℃、含5% CO2细胞培养箱中孵育24h,以DMSO组为空白对照。
3.细胞裂解
作用时间终点时将细胞收下,用PBS洗一遍;根据细胞量加入相应体积4% SDS裂解细胞,超声至细胞不再粘稠;12,000rpm室温离心30min;取上清转移至新的EP管进行蛋白定量。
4.蛋白定量
取2mg/mL BSA标准品倍半稀释成标准曲线所用浓度,依次为2mg/mL,1mg/mL,0.5mg/mL,0.25mg/mL,0.0625mg/mL;按每个样本需200μL BCA定量试剂盒中的A液和4μL B液计算,取相应体积的A液和B液(体积比为50:1)混匀;取10μL不同浓度的BSA及样本分别加入96孔板中,然后加入200μL混匀的A液和B液,轻轻拍匀后置于37℃避光反应30min;反映结束后,于562nm处测定吸光度值,利用标准曲线计算样本蛋白浓度。
5.Western Blot
(1)蛋白样本制备
取20μg蛋白根据体积加入一定量的6×Loading Buffer使其终浓度为1×LoadingBuffer;95℃加热变性10min,待冷却后离心混匀进行Western Blot实验,剩余样本冻存在-80℃。
(2)制胶
a.分离胶:根据目标蛋白分子量选择要制备的分离胶浓度,先搭制胶夹:将厚薄两块玻璃夹紧并保持地面平整;依次添加分离胶试剂到离心管中,涡旋混匀;混匀后将分离胶加至两块玻璃之间,再加入适量的异丙醇在胶面的上层,等待凝固。
b.浓缩胶:弃去分离胶上层异丙醇并用三蒸水洗净遗留的残液,配制浓缩胶并涡旋混匀,混匀后将浓缩胶加至两块玻璃之间,插入制胶梳子,等待凝固。
(3)电泳
a.准备:将制备好的胶架安装到电泳槽并放入电泳仪,把稀释好的1×Tricine缓冲液加入中间的电泳槽,并在外槽中加入1×Running缓冲液,静置数分钟。
b.上样:将样本涡旋混匀,吸取一定量的样本(5-10μL)上样,上样结束之后,打开电泳仪,先调恒压模式,电压70V电泳10min,并确认电流正常,待样本进入分离胶后,将电压调为130V,等样本跑到合适位置,停止电泳。
(4)转膜及封闭
a.转膜:在转膜夹中依次加海绵,厚滤纸,薄滤纸;取胶:用剥胶铲除去边缘的浓缩胶块,并将分离胶小心取下,置于滤纸中央;贴膜:将提前用甲醇活化好的PVDF膜从一侧贴到胶上,并赶出气泡;再依次加薄滤纸,厚滤纸,海绵并将转膜夹夹好,依次组装好转膜夹。在转膜槽内加入适量的转膜液,转膜槽外层加入适量的水并放入冰袋,使转膜槽处于冰水中防止转膜过程中放出大量的热量影响转膜效果。
b.封闭:转膜结束后,打开转膜夹,去除胶和PVDF膜(若转膜成功可以看到蛋白Marker已经全部转移到PVDF膜上),随后根据目标蛋白分子量剪开PVDF膜,并将膜置于5%脱脂牛奶,室温封闭60min。
(5)孵育抗体
a.孵育一抗:封闭结束后,弃去牛奶并用TBST清洗3次PVDF膜(15min,5min,5min),再加入适量的一抗(一般按一抗:抗体稀释液=1:1000稀释),置于4℃摇床孵育过夜。
b.孵育二抗:回收一抗,并用TBST清洗3次(15min,5min,5min),并加入二抗(一般按二抗:5%脱脂牛奶=1:5000配制),于水平摇床室温孵育60min。
(6)曝光
a.洗膜:弃去二抗,并用TBST清洗3次(15min,5min,5min),
b.曝光:准备ECL发光液:A液:B液=1:1。先用滤纸吸干条带上残留的TBST,并用镊子把条带夹取到曝光板上,在条带上滴加ECL显色液使条带覆盖,静止1min左右。将曝光板放入AI800曝光机内,选择合适的时间进行曝光。
其中降解率计算方法为:通过Image J软件对曝光结果进行定量分析,即先通过Image J软件对曝光条带进行灰度值的计算,再把目的蛋白的灰度值除以内参蛋白的灰度值,进行归一化处理,计算公式为R样本=A目的蛋白/A内参蛋白×100%(A为灰度值,R为降解率)。
表2化合物在HEK293细胞上降解HDAC7结果
实验结果:表2以及附图1~5表明的结果表明,本发明化合物在HEK293细胞上对HDAC7具有一定的降解效果,且化合物5和化合物30降解HDAC7的效果最佳。
表3化合物在RAW264.7细胞上降解HDAC7结果
实验结果:表3和附图6的结果表明,在HEK293细胞上对HDAC7降解活性最优的化合物5、30在RAW264.7细胞上也表现出显著降解HDAC7蛋白的效果。
三、酶联免疫吸附法(ELISA)检测巨噬细胞分泌的细胞因子
选用酶标仪TECAN SPARK(TECAN,Switzerland)来检测化合物对巨噬细胞分泌的细胞因子IL-6和TNF-α影响。
酶联免疫吸附法ELISA采用的是抗原或抗体的固相化反应原理:结合在固相载体表面的抗原或抗体持有免疫学活性,酶标记的抗原或抗体既保留其免疫学活性,又保留酶的活性。在测定时,受检样本与固相载体表面的抗原或抗体起反应。用洗涤的方法使固相载体上形成的抗原抗体复合物与液体中的其他物质分开,再加入酶标记的抗原或抗体,使其通过反应而结合在固相载体上(固相上的酶量与标本中受检物质的量呈一定的比例),最后加入酶反应的底物后,底物被酶催化成为有色产物,产物的量与标本中受检物质的量直接相关,故可根据呈色的深浅进行定性或定量分析。
实验材料:
细胞株:小鼠单核巨噬细胞(RAW264.7)
培养基:DMEM
RAW264.7:DMEM+10% Gibco血清
药物配制方法:将化合物溶于DMSO中制成50mM的储备液,并按一定比例稀释得到相应浓度。
1.RAW264.7细胞给药及样本收集
用DMEM+10%Hyclone血清稀释储备液为50mM的化合物,使其终浓度为5μM,于37℃、含5% CO2细胞培养箱中孵育12h,以DMSO组为空白对照。然后每孔给10ng/mL LPS继续作用24h。实验终点时收取细胞上清作为实验样本。
2.酶联免疫吸附法(ELISA)检测巨噬细胞分泌的细胞因子
(1)按照所需孵育体积将10×counting buffer稀释至1×(稀释液为去离子水),并配制1×Cap Ab(稀释液为1×counting buffer),再加入100μL/孔的1×CapAb,并在4℃孵育过夜。
(2)弃去一抗,并用100μL/孔PBST清洗三次,每次2min,甩干。
加入1×封闭液,200μL/孔(稀释液为去离子水),室温孵育1h。
(3)弃去封闭液,并用100μL/孔PBST清洗三次每次2min,甩干。
(4)配置标曲,于4℃冰箱静止20min,加入对应的样本100μL/孔(样本稀释液为1×封闭液),每个样品设置2个平行孔,并在室温放置2h(或4℃孵育过夜)。
(5)弃去样本,并用100μL/孔PBST清洗三次,每次2min,甩干。
(6)加入100μL/孔的1×Det Ab(样本稀释液为1×封闭液),并在室温孵育1h。
(7)弃去二抗,并用100μL/孔PBST清洗四次,每次2min,甩干。
(8)加入100μL/孔的Streptavidin-HRP(稀释液为1×封闭液),并在室温孵育0.5h。
(9)弃去HRP,并用100μL/孔双蒸水清洗20次,甩干。
(10)加入80μL/孔TMB(mouse),并孵育15min。
(11)加入80μL/孔1M H2SO4终止反应。
(12)擦净板底,酶标仪检测吸光值(450nm;Reference:570nm)
通过吸光值来计算对应细胞因子浓度,进而可与对照组对比相应的细胞因子变化情况。
结果计算:根据标准品OD值与浓度绘制标准曲线,并得到标准曲线公式(关于OD值与浓度的一次函数),根据标准曲线公式计算出样本浓度(C给药组),并计算出给药组相对空白组的分泌表达量情况:C给药组/C空白组。
表4化合物对巨噬细胞TNF-α和IL-6分泌水平的影响
化合物编号 | TNF-α相对分泌水平 | IL-6相对分泌水平 |
空白给药组 | 1.00 | 1.00 |
5 | 0.56 | 0.42 |
30 | 0.50 | 0.34 |
TMP269 | 0.88 | 1.00 |
实验结果:表4结果表明,本发明化合物能够显著降低巨噬细胞分泌TNF-α(见附图7)和IL-6水平(见附图8),对相关炎症性疾病具有潜在治疗效果,HDAC7抑制剂TMP269对TNF-α和IL-6水平影响较小(见附图7和8)。
四、靶向降解HDAC7的化合物抗炎作用的动物实验
实验对象:
ICR小鼠,6-8周,雄性
实验方法:
1.化合物提前6h给药,尾静脉给药;地塞米松灌胃给药;
2.LPS诱导炎症,10mg/kg,腹腔注射;
3. 6h后小鼠摘眼球取血,室温静置4-6h至血液分层,离心4000rpm,30min,取上清(100—300μL);
给药组别:
注:第1组为空白组,第2组为LPS诱导组,第3组为地塞米松阳性对照组;第4组为采用化合物30的组;第5组为TMP269对照组。
检测指标:
血清细胞因子:检测血清中TNF-α、IL-6含量。
(ELISA实验-操作步骤同上,结果计算方法同上)
表5化合物在小鼠体内对TNF-α和IL-6分泌水平的影响
化合物编号 | TNF-α相对分泌水平 | IL-6相对分泌水平 |
空白组 | 0.05 | 0.03 |
LPS诱导组 | 1 | 1 |
阳性对照组 | 0.06 | 0.08 |
TMP269 | 0.35 | 0.38 |
30 | 0.07 | 0.03 |
实验结果:本发明化合物在小鼠体内能够显著降低LPS诱导所分泌的TNF-α、IL-6水平,其效果与临床抗炎药物地塞米松相当,因此对相关炎症性疾病具有较好的治疗效果,HDAC7抑制剂TMP269对TNF-α和IL-6水平影响较小(附图9和附图10)。
Claims (15)
10.根据权利要求1~9任一所述化合物、其光学异构体及其药学上可接受的盐,其中,所述药学上可接受的盐为所述化合物的如下盐:盐酸盐、三氟乙酸盐、甲磺酸盐、苹果酸盐、枸橼酸盐、甲苯磺酸盐、L-酒石酸盐、D-酒石酸盐。
12.一种药物组合物,其中,所述的药物组合物含有治疗有效量的如权利要求1-11任意一项所述化合物或其药学上可药用盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
13.根据权利要求1-11任意一项所述化合物或其可药用盐或根据权利要求10所述的药物组合物在制备预防和/或治疗HDAC7异常性疾病的药物中的应用。
14.根据权利要求113所述的应用,其中,所述疾病选自代谢性疾病、炎症性疾病、自身免疫性疾病。
15.根据权利要求14所述的应用,其中,所述炎症性疾病包括类风湿关节炎,多发性硬化症,骨质疏松症,骨关节炎,炎症性肠道病中的一种或多种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310269772.4A CN116283955A (zh) | 2023-03-14 | 2023-03-14 | 一种靶向降解hdac7的化合物及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310269772.4A CN116283955A (zh) | 2023-03-14 | 2023-03-14 | 一种靶向降解hdac7的化合物及其制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116283955A true CN116283955A (zh) | 2023-06-23 |
Family
ID=86823707
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310269772.4A Pending CN116283955A (zh) | 2023-03-14 | 2023-03-14 | 一种靶向降解hdac7的化合物及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116283955A (zh) |
-
2023
- 2023-03-14 CN CN202310269772.4A patent/CN116283955A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6611799B2 (ja) | 新規化合物 | |
CA2944198C (en) | Hydroxyindole carboxylic acid based inhibitors for oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (shp2) | |
JP5408434B2 (ja) | アミド化合物 | |
CN112341451B (zh) | 一种免疫调节剂 | |
EA020874B1 (ru) | АНТАГОНИСТЫ C5aR | |
US11111239B2 (en) | Solid forms of(Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl) benzoic acid | |
JP2017528503A (ja) | 新規化合物αvβ6インテグリンアンタゴニスト | |
JP2010279372A (ja) | Pth産生に対する被験物質の作用をアッセイする方法 | |
CN101641325A (zh) | 鸟氨酸衍生物 | |
JPWO2016039408A1 (ja) | 複素環化合物 | |
WO2021052501A1 (zh) | 杂环酰胺类化合物、其可药用的盐及其制备方法和用途 | |
RU2541475C2 (ru) | 5-(3,4-дихлорфенил)-n-(2-гидроксициклогексил)-6-(2,2,2-трифторэтокси)никотинамид и его соли в качестве средств, повышающих концентрацию лвп холестерина | |
TWI821169B (zh) | 免疫蛋白酶體抑制劑 | |
TW202241404A (zh) | 呋喃稠環取代的戊二醯亞胺類化合物 | |
CN112225731B (zh) | FAPα特异性识别的具有肿瘤诊断治疗功能的亚甲蓝衍生物及其制备方法和应用 | |
WO2021160012A1 (zh) | 一种特异性降解tau蛋白的小分子化合物及其用途 | |
CN117580831A (zh) | Grk2抑制剂及其用途 | |
CN116283955A (zh) | 一种靶向降解hdac7的化合物及其制备方法和应用 | |
CN114292270B (zh) | 一种btk抑制剂及其制备方法与应用 | |
UA125327C2 (uk) | Кристалічні форми (1-піримідин-2-іл-циклопропіл)аміду (3s,4s)-1-циклопропілметил-4-{[5-(2,4-дифторфеніл)ізоксазол-3-карбоніл]аміно}піперидин-3-карбонової кислоти | |
CN113979999A (zh) | 靶向泛素化降解bcr-abl激酶的化合物及其制备方法、组合物和用途 | |
BR112014004267B1 (pt) | Derivado de ácido pirrolidina-3-ilacético | |
WO2019189766A1 (ja) | 新規ビアリールアミド誘導体 | |
CN115160204B (zh) | 一种成纤维细胞活化蛋白抑制剂及其制备方法和应用 | |
CN114751927B (zh) | 一种硼酸化合物、制备方法及用途 |
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 |