WO2020103939A1 - Composé à cycle triazolo, son procédé de préparation, intermédiaires de celui-ci et utilisation associée - Google Patents
Composé à cycle triazolo, son procédé de préparation, intermédiaires de celui-ci et utilisation associéeInfo
- Publication number
- WO2020103939A1 WO2020103939A1 PCT/CN2019/120284 CN2019120284W WO2020103939A1 WO 2020103939 A1 WO2020103939 A1 WO 2020103939A1 CN 2019120284 W CN2019120284 W CN 2019120284W WO 2020103939 A1 WO2020103939 A1 WO 2020103939A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- substituted
- unsubstituted
- alkylene
- heteroalkylene
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 308
- 238000002360 preparation method Methods 0.000 title abstract description 134
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 34
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 32
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 32
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 189
- 125000004429 atom Chemical group 0.000 claims description 154
- -1 substituted Chemical class 0.000 claims description 144
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 115
- 125000005549 heteroarylene group Chemical group 0.000 claims description 93
- 125000001072 heteroaryl group Chemical group 0.000 claims description 58
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 58
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 51
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 49
- 125000002947 alkylene group Chemical group 0.000 claims description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 33
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 32
- 239000005977 Ethylene Substances 0.000 claims description 32
- 125000000732 arylene group Chemical group 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 229940002612 prodrug Drugs 0.000 claims description 27
- 239000000651 prodrug Substances 0.000 claims description 27
- 230000000155 isotopic effect Effects 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 239000002207 metabolite Substances 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- 125000004450 alkenylene group Chemical group 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 125000004419 alkynylene group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 13
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 10
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000006589 (C3-C10) heterocycloalkylene group Chemical group 0.000 claims description 8
- 102000007471 Adenosine A2A receptor Human genes 0.000 claims description 8
- 108010085277 Adenosine A2A receptor Proteins 0.000 claims description 8
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 4
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 4
- 108010033040 Histones Proteins 0.000 claims description 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000004406 C3-C8 cycloalkylene group Chemical group 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 230000006196 deacetylation Effects 0.000 claims 1
- 238000003381 deacetylation reaction Methods 0.000 claims 1
- 101150051188 Adora2a gene Proteins 0.000 abstract description 26
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 230000003042 antagnostic effect Effects 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 description 128
- 238000005481 NMR spectroscopy Methods 0.000 description 72
- 239000007787 solid Substances 0.000 description 70
- 239000002994 raw material Substances 0.000 description 51
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 49
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 49
- 239000003153 chemical reaction reagent Substances 0.000 description 46
- 239000000243 solution Substances 0.000 description 46
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 37
- DRECSUVFISSLIO-UHFFFAOYSA-N 5-(furan-2-yl)-1h-1,2,4-triazole Chemical compound C1=COC(C=2NN=CN=2)=C1 DRECSUVFISSLIO-UHFFFAOYSA-N 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 0 C[n]1nc2nc(N(*)*)[n]3nc(*)nc3c2c1 Chemical compound C[n]1nc2nc(N(*)*)[n]3nc(*)nc3c2c1 0.000 description 22
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- ZDRXSQHVFIHVNW-UHFFFAOYSA-N Nc1ncn(n1)-c1ccco1 Chemical compound Nc1ncn(n1)-c1ccco1 ZDRXSQHVFIHVNW-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 11
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 11
- 239000000872 buffer Substances 0.000 description 11
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 10
- 208000018737 Parkinson disease Diseases 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 229960005305 adenosine Drugs 0.000 description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- AQBJGAUQEJFPKZ-UHFFFAOYSA-N methyl 4-(aminomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CN)C=C1 AQBJGAUQEJFPKZ-UHFFFAOYSA-N 0.000 description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000007821 HATU Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- HNNUQHJWFIPTLJ-UHFFFAOYSA-N methyl 4-(2-bromoethyl)benzoate Chemical compound COC(=O)C1=CC=C(CCBr)C=C1 HNNUQHJWFIPTLJ-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- VMFLDSVGJFWXAL-UHFFFAOYSA-N 2-ethyl-n-hydroxybenzamide Chemical compound CCC1=CC=CC=C1C(=O)NO VMFLDSVGJFWXAL-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 5
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 5
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 5
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 5
- 208000023105 Huntington disease Diseases 0.000 description 5
- 101100348848 Mus musculus Notch4 gene Proteins 0.000 description 5
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 5
- XNBRWUQWSKXMPW-UHFFFAOYSA-N Tozadenant Chemical compound C1=2SC(NC(=O)N3CCC(C)(O)CC3)=NC=2C(OC)=CC=C1N1CCOCC1 XNBRWUQWSKXMPW-UHFFFAOYSA-N 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 229940044551 receptor antagonist Drugs 0.000 description 5
- 239000002464 receptor antagonist Substances 0.000 description 5
- 238000012552 review Methods 0.000 description 5
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 5
- FELBQUPQCJZQQX-UHFFFAOYSA-N tert-butyl n-(2-amino-5-fluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(F)=CC=C1N FELBQUPQCJZQQX-UHFFFAOYSA-N 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- AYKYOOPFBCOXSL-UHFFFAOYSA-N (4-hydroxyphenyl)acetonitrile Chemical compound OC1=CC=C(CC#N)C=C1 AYKYOOPFBCOXSL-UHFFFAOYSA-N 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 102000008016 Eukaryotic Initiation Factor-3 Human genes 0.000 description 4
- 108010089790 Eukaryotic Initiation Factor-3 Proteins 0.000 description 4
- 101100317378 Mus musculus Wnt3 gene Proteins 0.000 description 4
- 208000012902 Nervous system disease Diseases 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- QAWFLJGZSZIZHO-UHFFFAOYSA-N methyl 4-bromobutanoate Chemical compound COC(=O)CCCBr QAWFLJGZSZIZHO-UHFFFAOYSA-N 0.000 description 4
- TZJVWRXHKAXSEA-UHFFFAOYSA-N methyl 6-aminohexanoate Chemical compound COC(=O)CCCCCN TZJVWRXHKAXSEA-UHFFFAOYSA-N 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- HQSBCDPYXDGTCL-UHFFFAOYSA-N 3-[(4-amino-3-methylphenyl)methyl]-7-(furan-2-yl)triazolo[4,5-d]pyrimidin-5-amine Chemical compound C1=C(N)C(C)=CC(CN2C3=NC(N)=NC(=C3N=N2)C=2OC=CC=2)=C1 HQSBCDPYXDGTCL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229940123702 Adenosine A2a receptor antagonist Drugs 0.000 description 3
- 102000009346 Adenosine receptors Human genes 0.000 description 3
- 108050000203 Adenosine receptors Proteins 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 3
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 3
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 3
- UTLPKQYUXOEJIL-UHFFFAOYSA-N LSM-3822 Chemical compound N1=CC=2C3=NC(C=4OC=CC=4)=NN3C(N)=NC=2N1CCC1=CC=CC=C1 UTLPKQYUXOEJIL-UHFFFAOYSA-N 0.000 description 3
- 101100446506 Mus musculus Fgf3 gene Proteins 0.000 description 3
- 208000025966 Neurological disease Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 239000002467 adenosine A2a receptor antagonist Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003412 degenerative effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229960004502 levodopa Drugs 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- GXDUKCCHZFWPRF-UHFFFAOYSA-N methyl 4-[2-(methylamino)ethoxy]benzoate Chemical compound CNCCOC1=CC=C(C(=O)OC)C=C1 GXDUKCCHZFWPRF-UHFFFAOYSA-N 0.000 description 3
- QKKXVGNAZNFIKI-UHFFFAOYSA-N methyl 4-[3-(methylamino)propyl]benzoate Chemical compound CNCCCC1=CC=C(C(=O)OC)C=C1 QKKXVGNAZNFIKI-UHFFFAOYSA-N 0.000 description 3
- RBOHZKFJKGYRPA-UHFFFAOYSA-N methyl 4-piperidin-4-ylbenzoate;hydrochloride Chemical compound Cl.C1=CC(C(=O)OC)=CC=C1C1CCNCC1 RBOHZKFJKGYRPA-UHFFFAOYSA-N 0.000 description 3
- 229940095102 methyl benzoate Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 3
- 229960005184 panobinostat Drugs 0.000 description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-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
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 2
- KOVPXZDUVJGGFU-UHFFFAOYSA-N 8-methoxy-8-oxooctanoic acid Chemical compound COC(=O)CCCCCCC(O)=O KOVPXZDUVJGGFU-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- ALBYIUDWACNRRB-UHFFFAOYSA-N CCCCCC(N)=O Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 description 2
- LTHCSWBWNVGEFE-UHFFFAOYSA-N CCCCCCCC(N)=O Chemical compound CCCCCCCC(N)=O LTHCSWBWNVGEFE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108010077544 Chromatin Proteins 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 2
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 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
- 102100039999 Histone deacetylase 2 Human genes 0.000 description 2
- 102000006947 Histones Human genes 0.000 description 2
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 108010064862 Nicotinamide phosphoribosyltransferase Proteins 0.000 description 2
- 102000015532 Nicotinamide phosphoribosyltransferase Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000011990 Sirtuin Human genes 0.000 description 2
- 108050002485 Sirtuin Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 229940125644 antibody drug Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 210000003483 chromatin Anatomy 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 230000006197 histone deacetylation Effects 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- IQVRBWUUXZMOPW-PKNBQFBNSA-N istradefylline Chemical compound CN1C=2C(=O)N(CC)C(=O)N(CC)C=2N=C1\C=C\C1=CC=C(OC)C(OC)=C1 IQVRBWUUXZMOPW-PKNBQFBNSA-N 0.000 description 2
- 229950009028 istradefylline Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 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 2
- 230000007246 mechanism Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- XGBXOGQDEAGJKO-UHFFFAOYSA-N methyl 4-(2-aminoethyl)benzoate Chemical compound COC(=O)C1=CC=C(CCN)C=C1 XGBXOGQDEAGJKO-UHFFFAOYSA-N 0.000 description 2
- POJGCTWJHFRKNS-UHFFFAOYSA-N methyl 4-(3-aminopropyl)benzoate Chemical compound COC(=O)C1=CC=C(CCCN)C=C1 POJGCTWJHFRKNS-UHFFFAOYSA-N 0.000 description 2
- RAVVJKCSZXAIQP-UHFFFAOYSA-N methyl 5-bromopentanoate Chemical compound COC(=O)CCCCBr RAVVJKCSZXAIQP-UHFFFAOYSA-N 0.000 description 2
- HDXZVYVAPXHPIE-UHFFFAOYSA-N methyl 8-[4-(2-hydroxyethyl)anilino]-8-oxooctanoate Chemical compound OCCC1=CC=C(C=C1)NC(CCCCCCC(=O)OC)=O HDXZVYVAPXHPIE-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 2
- 229960003452 romidepsin Drugs 0.000 description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 2
- 108010091666 romidepsin Proteins 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 102000013498 tau Proteins Human genes 0.000 description 2
- 108010026424 tau Proteins Proteins 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 229950003008 vipadenant Drugs 0.000 description 2
- PMJHHCWVYXUKFD-SNAWJCMRSA-N (E)-1,3-pentadiene Chemical group C\C=C\C=C PMJHHCWVYXUKFD-SNAWJCMRSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- 125000005838 1,3-cyclopentylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:2])C([H])([H])C1([H])[*:1] 0.000 description 1
- 125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 description 1
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical compound NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 1
- QXHDYMUPPXAMPQ-UHFFFAOYSA-N 2-(4-aminophenyl)ethanol Chemical compound NC1=CC=C(CCO)C=C1 QXHDYMUPPXAMPQ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- ZTTWQKYKGNLCCA-UHFFFAOYSA-N 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine Chemical compound N1C2=CC=CC=C2N=C(N)C2=C1SC(C)=C2 ZTTWQKYKGNLCCA-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- MAUCONCHVWBMHK-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide Chemical compound O1C2=CC=CC=C2C(CN(C)C)=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 MAUCONCHVWBMHK-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PWTBZOIUWZOPFT-UHFFFAOYSA-N 4-[2-[[7-amino-2-(2-furanyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl]amino]ethyl]phenol Chemical compound N=1C2=NC(C=3OC=CC=3)=NN2C(N)=NC=1NCCC1=CC=C(O)C=C1 PWTBZOIUWZOPFT-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- KWEWNOOZQVJONF-UHFFFAOYSA-N 4-fluorobenzene-1,2-diamine Chemical group NC1=CC=C(F)C=C1N KWEWNOOZQVJONF-UHFFFAOYSA-N 0.000 description 1
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- NCWQLHHDGDXIJN-UHFFFAOYSA-N 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine Chemical compound ClC1=NC(C)=CC(C=2C(=NC(N)=NN=2)C=2C=CC(F)=CC=2)=C1 NCWQLHHDGDXIJN-UHFFFAOYSA-N 0.000 description 1
- KURQKNMKCGYWRJ-HNNXBMFYSA-N 7-(5-methylfuran-2-yl)-3-[[6-[[(3s)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine Chemical compound O1C(C)=CC=C1C1=NC(N)=NC2=C1N=NN2CC1=CC=CC(CO[C@@H]2COCC2)=N1 KURQKNMKCGYWRJ-HNNXBMFYSA-N 0.000 description 1
- MSJODEOZODDVGW-UHFFFAOYSA-N 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine Chemical compound N=1N2C(N)=NC3=CC=C(Cl)C=C3C2=NC=1C1=CC=CO1 MSJODEOZODDVGW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- VSKJCTSEACBXRC-UHFFFAOYSA-N CC(NCc1ccc(C)cc1)=O Chemical compound CC(NCc1ccc(C)cc1)=O VSKJCTSEACBXRC-UHFFFAOYSA-N 0.000 description 1
- AEDIXYWIVPYNBI-UHFFFAOYSA-N CCCCCCC(N)=O Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 description 1
- DWWMMANVIWQXLM-UHFFFAOYSA-N CCCCCCCCC(NC)=O Chemical compound CCCCCCCCC(NC)=O DWWMMANVIWQXLM-UHFFFAOYSA-N 0.000 description 1
- VJLADWISUTXPCJ-UHFFFAOYSA-N CN(CCCc(cc1)ccc1C(O)=O)c1cc2nc(-c3ccc[o]3)n[n]2c(N)n1 Chemical compound CN(CCCc(cc1)ccc1C(O)=O)c1cc2nc(-c3ccc[o]3)n[n]2c(N)n1 VJLADWISUTXPCJ-UHFFFAOYSA-N 0.000 description 1
- GTDABFSZFWNDDN-UHFFFAOYSA-N COC(CCCCCCC(Nc1ccc(CC#N)cc1)=O)=O Chemical compound COC(CCCCCCC(Nc1ccc(CC#N)cc1)=O)=O GTDABFSZFWNDDN-UHFFFAOYSA-N 0.000 description 1
- VNGYYFDZNLVBRV-UHFFFAOYSA-N COC(c1ccc(CCNc2c(C=N)c3nc(-c4ccc[o]4)n[n]3c(N)n2)cc1)=O Chemical compound COC(c1ccc(CCNc2c(C=N)c3nc(-c4ccc[o]4)n[n]3c(N)n2)cc1)=O VNGYYFDZNLVBRV-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- SVZDFSGJYZIBKO-UHFFFAOYSA-N Cc1ccc(-c2n[n]3c(N)nc(NCCc(cc4)ccc4C(O)=O)nc3n2)[o]1 Chemical compound Cc1ccc(-c2n[n]3c(N)nc(NCCc(cc4)ccc4C(O)=O)nc3n2)[o]1 SVZDFSGJYZIBKO-UHFFFAOYSA-N 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 108010025461 Cyclin-Dependent Kinase 9 Proteins 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101710113864 Heat shock protein 90 Proteins 0.000 description 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000015021 Meningeal Neoplasms Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- YALNUENQHAQXEA-UHFFFAOYSA-N N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester Chemical compound C1=CC2=CC(CN(CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(=O)NO)C=C1 YALNUENQHAQXEA-UHFFFAOYSA-N 0.000 description 1
- 150000007945 N-acyl ureas Chemical class 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- SNHLRGKQUJCRFB-UHFFFAOYSA-N Nc1nc(N(C2)CC2C(NCc(cc2)ccc2C(O)=O)=O)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(N(C2)CC2C(NCc(cc2)ccc2C(O)=O)=O)nc2nc(-c3ccc[o]3)n[n]12 SNHLRGKQUJCRFB-UHFFFAOYSA-N 0.000 description 1
- JEHOBGDVMGAKRW-UHFFFAOYSA-N Nc1nc(N(CC2)CCC2C(NCc(cc2)ccc2C(O)=O)=O)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(N(CC2)CCC2C(NCc(cc2)ccc2C(O)=O)=O)nc2nc(-c3ccc[o]3)n[n]12 JEHOBGDVMGAKRW-UHFFFAOYSA-N 0.000 description 1
- MXEAUKGETSVPQM-QLPKVWCKSA-N Nc1nc(N(C[C@H]23)C[C@@H]2[C@H]3NCCc(cc2)ccc2C(O)=O)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(N(C[C@H]23)C[C@@H]2[C@H]3NCCc(cc2)ccc2C(O)=O)nc2nc(-c3ccc[o]3)n[n]12 MXEAUKGETSVPQM-QLPKVWCKSA-N 0.000 description 1
- MOXDCULLUJQMIG-UHFFFAOYSA-N Nc1nc(N2C(C3)CN(CCc(cc4)ccc4C(O)=O)C3C2)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(N2C(C3)CN(CCc(cc4)ccc4C(O)=O)C3C2)nc2nc(-c3ccc[o]3)n[n]12 MOXDCULLUJQMIG-UHFFFAOYSA-N 0.000 description 1
- YCZQEOMYFPGTBV-UHFFFAOYSA-N Nc1nc(N2CCN(CCc(cc3)ccc3C(O)=O)CC2)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(N2CCN(CCc(cc3)ccc3C(O)=O)CC2)nc2nc(-c3ccc[o]3)n[n]12 YCZQEOMYFPGTBV-UHFFFAOYSA-N 0.000 description 1
- AKMBHQVSQWBYHV-UHFFFAOYSA-N Nc1nc(NCCN(CC2)CCC2c(cc2)ccc2C(O)=O)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(NCCN(CC2)CCC2c(cc2)ccc2C(O)=O)nc2nc(-c3ccc[o]3)n[n]12 AKMBHQVSQWBYHV-UHFFFAOYSA-N 0.000 description 1
- XJNIMAIERWLTEG-UHFFFAOYSA-N Nc1nc(NCCN(CC2)CCN2c(nc2)ncc2C(O)=O)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(NCCN(CC2)CCN2c(nc2)ncc2C(O)=O)nc2nc(-c3ccc[o]3)n[n]12 XJNIMAIERWLTEG-UHFFFAOYSA-N 0.000 description 1
- APJMVONNKSRDJS-UHFFFAOYSA-N Nc1nc(NCCc(cc2)ccc2C(O)=O)cc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(NCCc(cc2)ccc2C(O)=O)cc2nc(-c3ccc[o]3)n[n]12 APJMVONNKSRDJS-UHFFFAOYSA-N 0.000 description 1
- IJLLNIVVGITBCO-UHFFFAOYSA-N Nc1nc(NCCc(cc2)ccc2C(O)=O)nc2nc(-c3ccccc3)n[n]12 Chemical compound Nc1nc(NCCc(cc2)ccc2C(O)=O)nc2nc(-c3ccccc3)n[n]12 IJLLNIVVGITBCO-UHFFFAOYSA-N 0.000 description 1
- ZWXLWDCEWHLMNV-UHFFFAOYSA-N Nc1nc(NCCc(cc2)ccc2NC(CCCCCCC(NO)=O)=O)nc2nc(-c3ccc[o]3)n[n]12 Chemical compound Nc1nc(NCCc(cc2)ccc2NC(CCCCCCC(NO)=O)=O)nc2nc(-c3ccc[o]3)n[n]12 ZWXLWDCEWHLMNV-UHFFFAOYSA-N 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 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
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 1
- 229950008805 abexinostat Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960001171 acetohydroxamic acid Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229940124533 adjunct drug Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- GNTFBMAGLFYMMZ-UHFFFAOYSA-N bicyclo[3.2.2]nonane Chemical compound C1CC2CCC1CCC2 GNTFBMAGLFYMMZ-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 125000004369 butenyl group Chemical group C(=CCC)* 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
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 210000003520 dendritic spine Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229950005837 entinostat Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229950010415 givinostat Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- LZMKLGSLUKISQE-UHFFFAOYSA-N hydroxylamine;methanol Chemical compound OC.ON LZMKLGSLUKISQE-UHFFFAOYSA-N 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940045996 isethionic acid Drugs 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
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000022006 malignant tumor of meninges Diseases 0.000 description 1
- 208000016847 malignant urinary system neoplasm Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- PUEZJQKDZBXXMM-UHFFFAOYSA-N methyl 1,2,3,4-tetrahydroisoquinoline-7-carboxylate;hydrochloride Chemical group Cl.C1CNCC2=CC(C(=O)OC)=CC=C21 PUEZJQKDZBXXMM-UHFFFAOYSA-N 0.000 description 1
- UCJNRYHJEDJKAI-UHFFFAOYSA-N methyl 2,3-dihydro-1h-isoindole-5-carboxylate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=C2CNCC2=C1 UCJNRYHJEDJKAI-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical group COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- SMRYWTZXDXXQKC-UHFFFAOYSA-N methyl 4-(2-aminoethoxy)benzoate Chemical compound COC(=O)C1=CC=C(OCCN)C=C1 SMRYWTZXDXXQKC-UHFFFAOYSA-N 0.000 description 1
- RVBJPYYTGUCVFR-UHFFFAOYSA-N methyl 4-(2-bromoethoxy)benzoate Chemical compound COC(=O)C1=CC=C(OCCBr)C=C1 RVBJPYYTGUCVFR-UHFFFAOYSA-N 0.000 description 1
- VMHPVAWXMHRICK-UHFFFAOYSA-N methyl 4-(3-bromopropyl)benzoate Chemical compound COC(=O)C1=CC=C(CCCBr)C=C1 VMHPVAWXMHRICK-UHFFFAOYSA-N 0.000 description 1
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- GVAVCUOTPGIFOJ-UHFFFAOYSA-N methyl 4-[2-(methylamino)ethyl]benzoate Chemical compound CNCCC1=CC=C(C(=O)OC)C=C1 GVAVCUOTPGIFOJ-UHFFFAOYSA-N 0.000 description 1
- DOLFAXMOGLCGEU-UHFFFAOYSA-N methyl 4-[4-(2-aminoethyl)phenoxy]butanoate Chemical compound COC(=O)CCCOC1=CC=C(CCN)C=C1 DOLFAXMOGLCGEU-UHFFFAOYSA-N 0.000 description 1
- BBPFPEWQAUGCQF-UHFFFAOYSA-N methyl 4-[4-(cyanomethyl)phenoxy]butanoate Chemical compound COC(=O)CCCOC1=CC=C(CC#N)C=C1 BBPFPEWQAUGCQF-UHFFFAOYSA-N 0.000 description 1
- RWJHKHNOEJDAJR-UHFFFAOYSA-N methyl 6-[4-(2-bromoethyl)phenoxy]hexanoate Chemical compound COC(=O)CCCCCOC1=CC=C(C=C1)CCBr RWJHKHNOEJDAJR-UHFFFAOYSA-N 0.000 description 1
- OPEBUIGLHBGXJC-UHFFFAOYSA-N methyl 6-[4-(2-hydroxyethyl)phenoxy]hexanoate Chemical compound COC(=O)CCCCCOC1=CC=C(C=C1)CCO OPEBUIGLHBGXJC-UHFFFAOYSA-N 0.000 description 1
- KYLVAMSNNZMHSX-UHFFFAOYSA-N methyl 6-bromohexanoate Chemical compound COC(=O)CCCCCBr KYLVAMSNNZMHSX-UHFFFAOYSA-N 0.000 description 1
- AZRQWZVPEAHOOA-UHFFFAOYSA-N methyl 7-aminoheptanoate Chemical compound COC(=O)CCCCCCN AZRQWZVPEAHOOA-UHFFFAOYSA-N 0.000 description 1
- SIJNJSDAJMWFFQ-UHFFFAOYSA-N methyl 8-[4-(2-aminoethyl)anilino]-8-oxooctanoate Chemical compound COC(=O)CCCCCCC(=O)NC1=CC=C(C=C1)CCN SIJNJSDAJMWFFQ-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 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
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 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
- 230000008271 nervous system development Effects 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 108010028584 nucleotidase Proteins 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- PMJHHCWVYXUKFD-UHFFFAOYSA-N piperylene Natural products CC=CC=C PMJHHCWVYXUKFD-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- DTYWJKSSUANMHD-UHFFFAOYSA-N preladenant Chemical compound C1=CC(OCCOC)=CC=C1N1CCN(CCN2C3=C(C4=NC(=NN4C(N)=N3)C=3OC=CC=3)C=N2)CC1 DTYWJKSSUANMHD-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 230000001696 purinergic effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 210000003370 receptor cell Anatomy 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 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
- 210000002966 serum Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ATFXVNUWQOXRRU-UHFFFAOYSA-N taminadenant Chemical compound BrC=1C(N)=NC(N2N=CC=C2)=NC=1N1C=CC=N1 ATFXVNUWQOXRRU-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940066453 tecentriq Drugs 0.000 description 1
- HGRPNDFQSJGNND-UHFFFAOYSA-N tert-butyl 4-[2-(4-methoxycarbonylphenyl)ethyl]piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CC1)CCC2=CC=C(C=C2)C(=O)OC HGRPNDFQSJGNND-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950000564 tozadenant Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 201000004435 urinary system cancer Diseases 0.000 description 1
- 238000007631 vascular surgery Methods 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
Definitions
- the invention relates to a triazolo ring compound, its preparation method, intermediate and application.
- Adenosine is an endogenous purine nucleoside substance, which mainly exerts its physiological regulation function by combining with adenosine receptors (AR) on the cell membrane.
- Adenosine receptors belong to G protein-coupled receptors (GPCR, or seven transmembrane receptors, 7TMR), and are divided into 4 subtypes: A1, A2A, A2B, and A3.
- A2A receptors are located in the central nervous system and the periphery There are widely distributed.
- A2A receptors are distributed at a high density in the central nervous system and are closely related to the pathogenesis of various degenerative central nervous system diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease (Gomes) ., Biochimica Biophysica Acta, 2011, 1808, 1380-1399).
- Parkinson's disease the A2A receptor is highly expressed in the nigrostriatal and can co-localize with the dopamine D2 receptor and form a heterodimer.
- the A2A receptor is activated by adenosine and inhibits the dopamine D2 receptor. Signal transduction of the body (Shook and Jackson, ACS Chemical Science, 2011, 2, 555-567).
- A2A receptor antagonists can enhance the downstream signal of D2 receptors as a drug for the treatment of Parkinson's disease.
- A2A receptor antagonists, as therapeutic drugs for Parkinson's disease can also reduce the side effects of dyskinesia induced by levodopa (L-DOPA).
- L-DOPA levodopa
- small molecule antagonists of A2A receptors such as ZM-241385, SCH58261, preladenant (SCH-420814), tozadenant (SYN-115), vipadenant (BIIB-014), etc. have been reported and used for treatment Research on Parkinson's disease (Pinna, CNS Drugs, 2014, 28, 455-474).
- Itratheline (istradefylline, KW-6002) was approved for marketing in Japan in 2013 and is used as an adjunct drug in combination with levodopa to treat Parkinson's disease. Although most A2A inhibitors are not effective as single agents in the clinical trials of Parkinson's disease, the potential of A2A receptor antagonists for the treatment of degenerative central nervous system diseases has been initially confirmed.
- Adenosine and adenosine A1, A2A, A2B and A3 receptors can activate the receptors and play different regulatory functions. Among them, A2A receptors play a major role in the tumor immunosuppression process.
- Adenosine and immune cell surface The binding of A2A receptor can suppress the immune function of these cells. Therefore, inhibiting the A2A receptor can significantly enhance the function of immune cells and promote the infiltration of immune cells into tumor tissue, which is beneficial to exert its anti-tumor effect.
- Some known A2A receptor antagonists such as vipadenant, CPI-444, PBF-509, and AZD4635 have entered clinical research as tumor immunotherapy drugs. Most of these drugs are used in combination with other tumor immune drugs or anti-tumor drugs.
- HDACs histone deacetylases
- HATs histone acetyltransferases
- HAT can catalyze the acetylation of lysine residues at the N-terminus of histones, leaving chromatin in a relatively loose and open state, which facilitates the transcription factor close to DNA and promotes the expression of specific genes; HDAC's function is to catalyze the removal of the histone The acetyl group on the lysine residue puts chromatin in a compact conformation, thereby blocking the transcription of DNA and the expression of specific genes (Kazantsev and Thompson, Nature Reviews Drug Discovery, 2008, 7,854-868). At present, there are 18 subtypes of human HDACs, which can be divided into four subfamilies of Class I-IV.
- Class I includes HDAC 1, 2, 3 and 8; Class II is divided into Class IIa (HDAC 4, 5, 7 and 9) and Class IIb (HDAC 6 and 10); Class IV has only one member, HDAC 11.
- the above three subfamilies are all Zn 2+ dependent HDACs, also known as classic HDAC.
- Class III also known as sirtuins, including SIRT 1-7, relies on NAD + to exert catalytic activity.
- HDAC anti-tumor
- Over-expression of HDAC will inhibit the expression of a series of tumor suppressor genes and promote the growth of tumor cells.
- abnormal HDAC function can lead to a decrease in the expression of the cell cycle inhibitor p21 and block the cell cycle; Acetylation blocks its binding to DNA and blocks the transcription of apoptotic genes.
- HDAC is also related to tumor blood vessel formation and regulating immune cell function (Falkenberg and Johnstone, Nature ReviewsDrug Discovery, 2014, 13,673-691).
- HDAC inhibitors in inhibiting tumor proliferation, their research and application as anti-tumor drugs have received extensive attention (Zagni et al., Medicinal Research Reviews, 2017, 37, 1373-1428),
- HDAC inhibitors vorinostat / SAHA, romidepsin / FK228, belinostat / PDX-101, panobinostat / LBH-589
- vorinostat / SAHA romidepsin / FK228, belinostat / PDX-101, panobinostat / LBH-589
- Another HDAC inhibitor Chidamid is also approved in China for the treatment of peripheral T-cell lymphoma.
- HDAC inhibitors such as abexinostat / PCI024781, givinostat / ITF2375, entinostat / MS-275, etc. which are in different stages of clinical research.
- HDAC2 can regulate brain function, nervous system development and deterioration; overexpression of HDAC2 can negatively regulate the plasticity and number of synapses and dendritic spine density, which in turn leads to the deterioration of learning and cognitive function , 2009,459,55-60).
- HDAC6 can regulate the phosphorylation level of tau protein, which in turn affects the development of tau protein-driven neurological diseases (Selenica et al., Alzheimer's Research & Therapy, 2014, 6, 12). HDAC6 can also regulate the degradation of misfolded proteins by regulating protein aggregation and HSP90 function, and the accumulation of misfolded proteins is a variety of neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease Pathological features. At present, there are literatures confirming that HDAC inhibitors can have a therapeutic effect on neurological diseases.
- SAHA can significantly improve cognition in animal models (Guan et al., Nature, 2009, 459, 55-60), LBH-589 in In animal models, the symptoms of Huntington's chorea can be reversed by inhibiting HDAC function (Siebzehnrübl et al., PNAS, 2018, doi / 10.1073 / pnas.1807962115).
- A2A receptors and HDAC are closely related to tumors and various central nervous system diseases, the synergistic use of the two is likely to play a more powerful therapeutic effect in the treatment of related diseases.
- dual-target small molecule drugs based on A2A receptor antagonists and HDAC inhibitors have been reported, for example, dual-target compounds of A2A receptor and dopamine D2 receptor et al., J Med Chem, 2015, 58, 718-738), dual target compounds of HDAC and cyclin-dependent kinase 4/9 (CDK4 / 9) (Li et al., J Med Chem, 2018, 61,3166- 3192), dual-target compounds of HDAC and nicotinamide phosphoribosyltransferase (NAMPT) (Dong et al., J Med Chem, 2017, 60, 7965-7983), but also dual-target small molecule compounds targeting HDAC and A2A receptor No reports.
- the technical problem to be solved by the present invention is to provide a triazolocyclic compound, its preparation method, intermediate and application.
- the triazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylation HDAC inhibitor. Further, the triazolocyclic compounds of the present invention can have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity, and thus can be used to treat tumors and central nervous system diseases and other related diseases.
- the present invention provides a compound represented by formula I or I ', pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, and solvates , Metabolites or prodrugs:
- R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
- R 3 is a substituted or unsubstituted C 6 -C 12 aryl group (such as phenyl) or a substituted or unsubstituted 5-12 membered heteroaryl group (such as 5, 6 or 7 membered heteroaryl group, such as furanyl, Again );
- the substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl means that it is substituted with one or more R 19 , each R 19 is independently halogen (for example, fluorine), C 1 -C 6 alkyl (such as C 1 -C 4 alkyl or methyl), C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
- X is N or CR 4 ;
- R 4 is hydrogen, fluorine or C 1 -C 3 alkyl
- Y is Or substituted or unsubstituted The nitrogen atom in Connected); said Is a 3-10 membered heterocycloalkylene (eg 3-8 membered heterocycloalkylene); the substituted Means it is replaced by one or more R 20 ;
- R 5 is hydrogen, C 1 -C 6 alkyl (such as C 1 -C 4 alkyl, such as methyl or ethyl), C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene )-(C 3 -C 6 cycloalkyl), C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
- Each L is independently the following case (i), (ii), (iii), (iv) or (v):
- L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene (for example, C 1 -C 7 alkylene Groups, such as C 5 alkylene, C 6 alkylene or C 7 alkylene), C 2 -C 10 alkenylene (eg C 2 -C 7 alkenylene, such as C 5 , C 6 or C 7 alkenylene), C 2 -C 10 alkynylene (e.g. C 5 -C 7 alkynylene), heteroalkylene having 2-10 chain atoms (e.g.
- heteroalkyl groups such as heteroalkylene groups having 5, 6 or 7 chain atoms
- heteroalkenylene groups having 2-10 chain atoms eg, heteroalkenylene groups having 2-7 chain atoms, and Such as heteroalkenylene having 5, 6 or 7 atoms) or heteroalkynylene having 3-10 chain atoms (eg heteroalkynylene having 5, 6 or 7 chain atoms);
- -M 1 -means that it is substituted by one or more R 21 ;
- L is substituted or unsubstituted -M 2 -M 3-
- M 2 is -NH-, -O-, -S-, single bond
- C 1 -C 6 alkylene eg C 1 -C 4 alkylene, such as methylene, ethylene or propylene
- heteroalkylene having 2-6 chain atoms eg heteroalkylene having 2 or 3 chain atoms, for example Another example E.g
- L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is -NH-, -O-, -S-, single bond, C 1 -C 6 alkylene (e.g.
- M 5 is a C 6 -C 12 arylene group (for example, phenylene, such as 1,4-phenylene) or a 5-12 membered heteroarylene group ( For example, 5, 6 or 7-membered heteroarylene, as in 1,4- (6-membered heteroarylene), and then );
- M 6 is C 1 -C 9 alkylene (eg C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or C 6 alkylene), having 2-9 Heteroalkylene groups of chain atoms (for example, heteroalkylene groups having 2, 3, 4, 5 or 6 atoms; another example is -U 1 -U 2 -where U 1 is -NH-, -O- or
- L is substituted or unsubstituted -M 7 -M 8 -M 9-
- M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene (eg methylene or Ethylene, such as ethylene) or a heteroalkylene group having 2-4 chain atoms (for example, a heteroalkylene group having 2 chain atoms)
- M 8 is C 3 -C 12 cycloalkylene ( For example, C 3 -C 8 cycloalkylene, like ) Or 3-12 membered heterocycloalkylene (eg 3-8 membered heterocycloalkylene )
- M 9 is C 6 -C 12 arylene (eg phenylene, such as 1,4-phenylene) or 5-12 membered heteroarylene (eg 5, 6 or 7 membered heteroarylene) , As in 1,4- (6-membered heteroarylene), as in );
- Each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 are independently halogen (for example fluorine or chlorine, such as fluorine), hydroxy, C 1 -C 6 alkyl (for example C 1 -C 3 alkyl) or C 1 -C 6 alkoxy (such as C 1 -C 3 alkoxy);
- halogen for example fluorine or chlorine, such as fluorine
- hydroxy for example C 1 -C 6 alkyl
- C 1 -C 3 alkyl for example C 1 -C 3 alkyl
- C 1 -C 6 alkoxy such as C 1 -C 3 alkoxy
- hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
- R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen (e.g. fluorine), C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl (eg 5, 6 or 7 membered heteroaryl, like thienyl, and then Thiophen-2-yl);
- halogen e.g. fluorine
- C 1 -C 6 alkyl C 1 -C 6 alkoxy
- C 1 -C 6 haloalkyl C 3 -C 6 cycloalkyl
- 3-6 membered heterocycloalkyl C 6 -C 12 aryl or 5-12 membered heteroaryl (eg 5, 6 or 7 membered heteroaryl, like thienyl, and then Thiophen-2
- hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
- the compound represented by Formula I or I 'as described above has the following structure:
- R 7 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(6-12 membered aryl) or-(C 1 -C 3 alkylene Radical)-(5-12 membered heteroaryl);
- R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
- X is N or CR 4 ;
- R 4 is hydrogen, fluorine or C 1 -C 3 alkyl
- Y is Or substituted or unsubstituted Said Is a 3-10 membered heterocycloalkylene; the substituted Means it is replaced by one or more R 20 ;
- R 5 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl,-(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), C 2 -C 6 Alkenyl or C 2 -C 6 alkynyl;
- L is the following case (i), (ii), (iii) or (iv):
- L is substituted or unsubstituted -M 1- , M 1 is -NH-, -O-, -S-, single bond, C 1 -C 10 alkylene, C 2 -C 10 alkenylene , C 2 -C 10 alkynylene, heteroalkylene having 2-10 chain atoms, heteroalkenylene having 2-10 chain atoms or heteroalkynylene having 3-10 chain atoms;
- the substituted -M 1 - refers to its substitution by one or more R 21 ;
- L is substituted or unsubstituted -M 2 -M 3-
- M 3 is C 6 -C 12 arylene or 5-12 membered heteroarylene; the substituted -M 2 -M 3 -means that it is replaced by one or more R 22 ;
- L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is -NH-, -O-, -S-, C 1 -C 4 alkylene or has 2-4 Heteroalkylene group of chain atom, M 8 is C 3 -C 12 cycloalkylene group or 3-12 membered heterocycloalkylene group, M 9 is C 6 -C 12 arylene group or 5-12 membered heteroarylene group Radical; the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
- Each R 20 , R 21 , R 22 , R 23 and R 24 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
- hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
- R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
- hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
- R 1 and R 2 are hydrogen.
- R 4 is hydrogen
- X is N or CH, preferably N.
- R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5 -12 membered heteroaryl; the substituent in the substituted C 6 -C 12 aryl or substituted 5-12 membered heteroaryl is independently C 1 -C 6 alkyl.
- R 3 is substituted or unsubstituted
- R 3 is substituted or unsubstituted phenyl or substituted or unsubstituted
- the substituents are independently C 1 -C 6 alkyl.
- R 3 is phenyl
- Y is R 5 is hydrogen or C 1 -C 6 alkyl.
- Y is R 5 is hydrogen, methyl or ethyl, for example hydrogen.
- ZBG is R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 6 -C 12 aryl or 5-12 membered heteroaryl.
- R 12 is halogen, such as fluorine.
- R 11 is a 5-12 membered heteroaryl, such as thiophen-2-yl.
- ZBG is E.g
- ZBG is
- ZBG is
- each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently C 1 -C 6 alkyl.
- the number of R 20 , R 21 , R 22 , R 23 , R 24 or R 25 may each be independently 1, 2, 3, 4, 5, 6, or 7, such as 1, 2, or 3, and then another one.
- M 1 is a C 1 -C 10 alkylene group or a heteroalkylene group having 2 to 10 chain atoms.
- M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene, or heteroalkylene having 5, 6 or 7 atoms.
- M 1 is C 5 alkylene, C 6 alkylene, or C 7 alkylene.
- M 2 is a C 1 -C 6 alkylene group or a heteroalkylene group having 2 to 6 chain atoms
- M 3 is a C 6 -C 12 subgroup Aryl or 5-12 membered heteroarylene.
- M 2 is methylene, ethylene, propylene, or a heteroalkylene group having 2 or 3 chain atoms
- M 3 is 1,4 -Phenylene or 1,4- (6-membered heteroarylene).
- M 2 is ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms
- M 3 is 1,4-phenylene .
- M 2 when Y is When L is substituted or unsubstituted -M 2 -M 3- , the definition of M 2 is as described in any of the aspects of the present invention, and M 3 is 1,4-phenylene.
- M 2 is methylene, ethylene, propylene or M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
- M 2 is ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms
- M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
- M 2 is ethylene and M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene);
- M 2 is propylene or a heteroalkylene group having 3 chain atoms
- M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
- M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms
- M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene
- M 6 is
- M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms
- M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene)
- M 6 is
- M 4 is as described in any scheme of the present invention.
- M 5 is 1,4-phenylene; M 6 is
- M 4 and M 6 are as described in any of the aspects of the present invention, and M 5 is 1,4-phenylene.
- M 4 is methylene or ethylene
- M 5 is 1,4-phenylene or 1,4- (6 membered heteroa Aryl)
- M 6 is
- M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms
- M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene
- M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene or has 2 , 3, 4, 5 or 6 chain atoms of heteroalkylene.
- M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms
- M 5 is 1,4-phenylene Radical or 1,4-6 membered heteroarylene
- M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene or “-U 1 -U 2- , wherein U 1 is -NH-, -O-, or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, or has 2 , A heteroalkylene group of 3, 4 or 5 chain atoms ".
- M 4 is methylene or ethylene
- M 5 is 1,4-phenylene or 1,4- (6 membered heteroa Aryl)
- M 6 is
- M 4 is C 1 -C 6 alkylene or heteroalkylene having 2-6 chain atoms
- M 5 is C 6- C 12 arylene or 5-12 membered heteroarylene
- M 4 is methylene, ethylene or a heteroalkylene group having 2 chain atoms
- M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene)
- M 6 is
- M 4 is ethylene and M 5 is 1,4-phenylene or 1,4- (6-membered heteroarylene); M 6 is
- M 7 is a C 1 -C 4 alkylene group or a heteroalkylene group having 2-4 chain atoms
- M 8 is M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
- M 7 is ethylene or heteroalkylene having two chain atoms
- M 8 is M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene).
- M 10 is ethylene
- Z 1 , Z 2 and Z 3 are CH.
- L is substituted or unsubstituted -M 1- , substituted or unsubstituted -M 2 -M 3- , substituted or unsubstituted -M 4 -M 5 -M 6- , substituted or unsubstituted- M 7 -M 8 -M 9 -or substituted or unsubstituted -M 10 -M 11- .
- R 1 and R 2 are hydrogen
- R 3 is a substituted or unsubstituted C 6 -C 12 aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the substituted C 6 -C 12 aryl group or a substituted 5-12 membered heteroaryl group Group means that it is substituted with one or more R 19 , each R 19 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3- C 6 cycloalkyl;
- X is N or CR 4 ;
- R 4 is hydrogen, fluorine or C 1 -C 3 alkyl
- Y is Or substituted or unsubstituted The substituted Means it is replaced by one or more R 20 ;
- R 5 is hydrogen or C 1 -C 6 alkyl
- Each L is independently the following case (i), (ii), (iii), (iv) or (v):
- L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms;
- the substituted -M 1 - refers to its substitution by one or more R 21 ;
- L is substituted or unsubstituted -M 2 -M 3- ;
- M 2 is ethylene, propylene, or a heteroalkylene group having 2 or 3 chain atoms (the heteroalkylene group is, for example, E.g And M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); alternatively, M 2 is ethylene, propylene or heteroalkylene having 2 or 3 chain atoms , And M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene), the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
- L is a substituted or unsubstituted -M 4 -M 5 -M 6- , is a methylene group, an ethylene group or a heteroalkylene group having 2 chain atoms, and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene), M 6 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, “-U 1 -U 2- , where U 1 is -NH-, -O- Or -S-, U 2 is C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene or heteroalkylene having 2, 3, 4 or 5 chain atoms ",
- the substituted -M 4 -M 5 -M 6 - refers to its substitution by one or more R 23 ;
- L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
- Each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently halogen, hydroxy, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
- hetero atoms in the heteroalkylene group, heteroalkenylene group, heteroalkynylene group, heterocycloalkylene group and heteroarylene group are each independently nitrogen, oxygen or sulfur, and the number of hetero atoms is independently 1, 2, 3 or 4;
- R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 6 ring Alkyl, 3-6 membered heterocycloalkyl, C 6 -C 12 aryl or 5-12 membered heteroaryl;
- hetero atoms in the heteroalkyl, heterocycloalkyl, and heteroaryl groups are each independently nitrogen, oxygen, or sulfur, and the number of hetero atoms is independently 1, 2, 3, or 4, respectively.
- the compound represented by Formula I is selected from any of the following structures:
- the compound represented by Formula I has any of the following structures:
- the compound represented by Formula I has any of the following structures:
- each L is independently the following case (i), (ii), (iii) or (iv):
- L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 chain atoms ;
- L is substituted or unsubstituted -M 2 -M 3-
- M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example or E.g ), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 2 -M 3 -means that it is substituted by one or more R 22 ;
- L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene, M 5 is 1,4-phenylene or 1,4- (6 member Heteroarylene), M 6 is Alternatively, M 4 is ethylene, M 5 is 1,4-phenylene or 1,4- (6-membered heteroarylene), M 6 is The substituted -M 4 -M 5 -M 6 -refers to its substitution by one or more R 23 ;
- L is substituted or unsubstituted -M 7 -M 8 -M 9- , M 7 is ethylene and M 8 is or M 9 is 1,4-phenylene or 1,4- (6-membered heteroarylene); the substituted -M 7 -M 8 -M 9 -means that it is substituted by one or more R 24 ;
- the compound represented by Formula I has any of the following structures:
- each L is independently the following situation (ii) or (iii):
- L is substituted or unsubstituted -M 2 -M 3-
- M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example or E.g )
- M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
- L is substituted or unsubstituted -M 4 -M 5 -M 6- , M 4 is methylene or ethylene (for example, M 4 is methylene), and M 5 is 1,4-phenylene Radical or 1,4- (6-membered heteroarylene) (eg M 5 is 1,4-phenylene), M 6 is The substituted -M 4 -M 5 -M 6 -refers to its substitution by one or more R 23 ;
- the compound represented by Formula I has the following structure:
- L is substituted or unsubstituted -M 2 -M 3- ; the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
- the compound represented by Formula I has the following structure:
- L is substituted or unsubstituted -M 2 -M 3- ; the substituted -M 2 -M 3 -means that it is substituted with one or more R 22 ;
- the compound represented by Formula I has any of the following structures:
- Each L is independently the following case (i) or (ii):
- L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms ( For example, M 1 is C 6 alkylene); the substituted -M 1 -means that it is substituted with one or more R 21 ;
- L is substituted or unsubstituted -M 2 -M 3-
- M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (all Heteroalkylene for example or E.g )
- M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
- the compound represented by Formula I ' has the following structure:
- L is substituted or unsubstituted -M 1- , M 1 is C 5 alkylene, C 6 alkylene, C 7 alkylene or heteroalkylene having 5, 6 or 7 atoms (eg M 1 Is C 6 alkylene); the substituted -M 1 -means that it is substituted with one or more R 21 ;
- the compound represented by Formula I ' has the following structure:
- L is substituted or unsubstituted -M 2 -M 3- , M 2 is M 2 is methylene, ethylene, propylene or a heteroalkylene group having 2 or 3 chain atoms (the Heteroalkyl for example or E.g ), M 3 is 1,4-phenylene or 1,4- (6-membered heteroarylene) (for example, M 3 is 1,4-phenylene); the substituted -M 2 -M 3 -Means it is replaced by one or more R 22 ;
- the compound represented by Formula I or I ' is selected from any of the following structures:
- the present invention also provides a method for preparing the compound shown in Formula I as described above, which is at least one of the following schemes:
- Scheme one includes the following steps: in an organic solvent (such as methanol), the compound shown in formula II and NH 2 -OH in the presence of a base (such as potassium hydroxide) in the presence of a substitution reaction to obtain formula I Is sufficient;
- ZBG is R 1, R 2, R 3 , X, Y and L are as defined above, R a is C 1 -C 6 alkyl (e.g. methyl or ethyl);
- Scheme two includes the following steps: In an organic solvent (such as DMF), the compound shown in formula III and The condensation reaction can be carried out in the presence of a condensing agent (such as HATU) and a base (such as DIPEA) to obtain the compound represented by Formula I; wherein, ZBG is R 1 , R 2 , R 3 , R 10 , R 11 , R 12 , R 13 , X, Y, and L are as defined above.
- a condensing agent such as HATU
- DIPEA a base
- the preparation method of the compound shown in formula III may include the following steps: In an organic solvent (such as a mixed solvent of tetrahydrofuran and water), the compound shown in formula II is present in a base (such as lithium hydroxide) The hydrolysis reaction is carried out under the conditions to obtain the compound represented by formula III; wherein, R 1 , R 2 , R 3 , X, Y and L are as defined above, and R a is C 1 -C 6 alkyl ( (Such as methyl or ethyl);
- the preparation method of the compound shown in Formula II may include the following steps: In an organic solvent (such as acetonitrile), the compound shown in Formula IV and the compound shown in Formula V are subjected to a condensation reaction to obtain a compound shown in Formula the compound represented by II; wherein, R 1, R 2, R 3, X, Y and L are as defined above, R a is C 1 -C 6 alkyl (e.g. methyl or ethyl), LG Is a leaving group (e.g. Where R 30 is C 1 -C 4 alkyl, such as methyl);
- the present invention also provides a compound, which has any of the following structures:
- R 1 , R 2 , R 3 , X, Y and L are as defined above, and R a is C 1 -C 6 alkyl (such as methyl or ethyl).
- the compound of formula II has any of the following structures:
- the compound of formula III has any of the following structures:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer Constructors, tautomers, solvates, metabolites or prodrugs, and at least one pharmaceutical excipient.
- the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
- a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
- the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation Structurants, solvates, metabolites or prodrugs, or the pharmaceutical composition is prepared for the treatment and / or prevention of diseases related to adenosine A2A receptor and / or histone deacetylase HDAC Application.
- the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
- a pharmaceutically acceptable salt thereof an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
- the use of structurants, solvates, metabolites or prodrugs, or said pharmaceutical composition in the preparation of a medicament for the treatment and / or prevention of cancer or diseases of the central nervous system.
- the compound represented by formula I or I ' its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites Or the dose of prodrug may be a therapeutically effective amount.
- the present invention also provides a method of treating and / or preventing "disease related to adenosine A2A receptor and / or histone deacetylase HDAC", which method comprises administering to a subject in need of such treatment effective Amount of a compound represented by formula I or I ', its pharmaceutically acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or Prodrugs.
- the present invention also provides a method of treating and / or preventing cancer or central nervous system diseases, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound represented by Formula I or I ', and its pharmacy Acceptable salts, isotopic derivatives, enantiomers, diastereomers, tautomers, solvates, metabolites or prodrugs.
- the "diseases associated with adenosine A2A receptor and / or histone deacetylase HDAC" as described above may be cancer or central nervous system diseases.
- Cancers as described above may be head and neck cancers (such as thyroid cancer, nasopharyngeal cancer, meningeal cancer, or intracranial metastases), cancers of the respiratory system (such as small cell lung cancer or non-small cell lung cancer), cancers of the digestive system (such as liver cancer , Gastric cancer, esophageal cancer, rectal cancer, colon cancer or pancreatic cancer), urinary system cancer (such as kidney cancer, bladder cancer, prostate cancer or testicular cancer), bone cancer, gynecological cancer (such as breast cancer, cervical cancer or ovarian cancer) , Hematological cancer (such as leukemia, lymphoma or myeloma or other types of cancer (such as melanoma, glioma or skin cancer).
- head and neck cancers such as thyroid cancer, nasopharyngeal cancer, meningeal cancer, or intracranial metastases
- cancers of the respiratory system such as small cell lung cancer or non-small cell lung cancer
- the central nervous system disease as described above may be Parkinson's disease, Alzheimer's disease, or Huntington's disease.
- the product or prodrug, or the pharmaceutical composition may also be used in any disease process characterized by abnormal cell proliferation, such as benign prostatic hyperplasia, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis , Glomerulonephritis, restenosis after angioplasty or vascular surgery, inflammatory bowel disease, transplant rejection, endotoxin shock and fungal infection.
- the present invention also provides a compound represented by formula I or I ′ as described above, a pharmaceutically acceptable salt thereof, an isotopic derivative, an enantiomer, a diastereomer, and a mutual variation
- a construct, solvate, metabolite, or prodrug, or the pharmaceutical composition described in the preparation of a product for modulating the activity of adenosine A2A receptor and / or histone deacetylase HDAC The use of a construct, solvate, metabolite, or prodrug, or the pharmaceutical composition described in the preparation of a product for modulating the activity of adenosine A2A receptor and / or histone deacetylase HDAC.
- the choice of the medicinal adjuvant varies according to the route of administration and the characteristics of the action, and can generally be conventional fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending aids Agent.
- the pharmaceutical composition can be administered by oral, injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, transbuccal, transrectal, transurethral, transvaginal, nasal, inhalation or topical routes. oral.
- substituted or “substituent” means that one or more hydrogen atoms are replaced with the specified group.
- substitution position is not specified, the substitution can be in any position, but only the formation of a stable or chemically feasible chemical substance is allowed.
- the term “optional” or “optionally” means that the subsequently described event or condition may, but need not necessarily occur, and the description includes the situation in which the event or condition occurs and the event or Situations where no situation occurs.
- the term “optionally substituted” means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis that they are chemically achievable.
- any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
- R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
- the group can be optionally substituted with up to two Rs, and R in each case has independent options.
- combinations of substituents and / or variants thereof are only allowed if such combinations will produce stable compounds.
- alkyl refers to a saturated monovalent hydrocarbon radical straight or branched chain having the indicated number of carbon atoms, for example C 1 -C 10 alkyl means an alkyl group having 1 to 10 carbon atoms, .
- alkyl groups include but are not limited to methyl (Me), ethyl (Et), propyl (such as n-propyl, isopropyl), butyl (such as n-butyl, isobutyl, s-butyl, t-butyl) and pentyl (eg n-pentyl, isopentyl, neopentyl).
- alkoxy refers to an alkyl group (as defined in the present invention) connected to the rest of the molecule through an oxygen bridge.
- alkenyl refers to a linear or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located at any position within the alkenyl group, for example C 2 -C 6 alkenyl refers to alkenyl groups having 2 to 6 carbon atoms.
- alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, and hexadienyl.
- alkynyl refers to a linear or branched monovalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located at any position within the alkynyl group, for example C 2 -C 6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms.
- alkynyl groups include, but are not limited to ethynyl and propynyl.
- alkylene refers to a saturated linear divalent hydrocarbon group having the specified number of carbon atoms.
- C 1 alkylene ie, methylene
- C 2 alkylene ie, ethylene
- C 3 alkylene refers to -CH 2- CH 2 -CH 2- .
- alkenylene refers to a linear divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, where the carbon-carbon double bond may be located at any position within the alkenylene group.
- C 2 alkenylene ie vinylene
- -CH 2 CH-CH 2 -CH 2-
- -CH 2 -CH-CH 2 CH 2- .
- alkynylene refers to a straight-chain divalent hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon triple bond, where the carbon-carbon triple bond may be located at any position within the alkynylene group.
- C 2 alkynylene (ethynylene) refers to C 3 alkynylene means
- heteroalkyl refers to a saturated linear or branched monovalent hydrocarbon group having the specified number of carbon atoms and at least one heteroatom selected from N, O, and S. Heteroalkyl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein.
- the heteroatom may be located at any internal position of the heteroalkyl group (including the position where the heteroalkyl group is connected to other parts of the molecule), that is, the heteroalkyl group does not include a hydroxyalkyl group (for example, -CH 2 OH, -CH (CH 3 ) OH) , Aminoalkyl (for example, -CH 2 NH 2 , -CH (CH 3 ) NH 2 ), etc.
- heteroalkyl groups include, but are not limited to, -O-CH 3 , -CH 2 -NH-CH 3 , -NH-CH (CH 3 ) -CH 3 , -CH 2 -O-CH 3, and -CH 2 -S -CH 3 .
- heteroalkylene refers to a saturated straight-chain divalent hydrocarbon group having a specified number of chain atoms, at least one of which is a hetero atom selected from N, O, and S, and the remaining chains The atom is carbon. Heteroalkylene groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein. Heteroalkylene groups having 2 chain atoms such as —O-CH 2 —, —NH—CH 2 —, etc.
- Heteroalkylene groups having 3 chain atoms such as —CH 2 —NH—CH 2 —, —O— CH 2 -CH 2- , -CH 2 -O-CH 2- , etc., a heteroalkylene group having 4 chain atoms such as -O-CH 2 -CH 2 -NH-.
- heteroalkenylene refers to a straight-chain divalent hydrocarbon group having a specified number of chain atoms and at least one double bond, wherein at least one chain atom is a hetero atom selected from N, O, and S .
- the heteroalkenylene group may be connected to other parts of the molecule through a hetero atom or a carbon atom therein.
- Heteroalkenylene having 2 chain atoms such as —N ⁇ CH 2 —, etc.
- Heteroalkenylene having 3 chain atoms such as —N ⁇ CH—CH 2 —, —CH ⁇ N-CH 2 —, etc.
- heteroalkynylene refers to a straight-chain divalent hydrocarbon group having a specified number of chain atoms and at least one triple bond, wherein at least one chain atom is a hetero atom selected from N, O, and S .
- the heteroalkynylene group may be connected to other parts of the molecule through a hetero atom or a carbon atom therein.
- Examples of heteroalkynylene include, but are not limited to (4 chain atoms) and (5 chain atoms).
- cycloalkyl refers to a non-aromatic saturated or partially unsaturated monovalent cyclic hydrocarbon group having a specified number of ring carbon atoms.
- the cycloalkyl group may be monocyclic or polycyclic (for example, bicyclic And tricyclic), can be a parallel ring, spiro ring and bridge ring structure.
- the cycloalkyl group optionally contains one or more double bonds or triple bonds.
- Monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-ene Group, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclo Nonyl, cyclodecyl, cycloundecyl and cyclododecyl.
- Cycloalkyl also includes polycyclic cycloalkyl structures, where the polycyclic structure optionally includes saturated or partially fused to saturated or partially unsaturated cycloalkyl or heterocyclic groups or aryl or heteroaryl rings Unsaturated cycloalkyl.
- Bicyclic carbocycles with 7 to 12 atoms can be arranged as, for example, bicyclic [4,5], [5,5], [5,6] or [6,6] systems, or as bridged ring systems such as bi [2.2 .1] Heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane.
- heterocycloalkyl refers to a non-aromatic saturation formed by replacing at least one ring carbon atom in a cycloalkyl group (as defined in the present invention) with a heteroatom selected from N, O and S Or a partially unsaturated monovalent cyclic hydrocarbon group.
- Heterocycloalkyl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms therein.
- heterocycloalkyl examples include, but are not limited to, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrothiophene -2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
- Bridged ring heterocycloalkyl for example
- cycloalkylene refers to a non-aromatic saturated or partially unsaturated divalent cyclic hydrocarbon group having the specified number of ring carbon atoms.
- the cycloalkylene group may be monocyclic or polycyclic, may For the ring, spiral ring and bridge ring structure.
- Examples of cycloalkylene include, but are not limited to (I.e. 1,3-cyclobutylene), (I.e. 1,3-cyclopentylene), (I.e. 1,4-cyclohexylene) or
- heterocycloalkylene refers to a non-aromatic group formed by replacing at least one ring carbon atom in a cycloalkylene group (as defined in the present invention) with a hetero atom selected from N, O, and S Group of saturated or partially unsaturated divalent cyclic hydrocarbon groups.
- Heterocycloalkylene can be connected to other parts of the molecule through heteroatoms or carbon atoms therein.
- Examples of heterocyclic heterocycloalkylene include, but are not limited to Bridged ring heterocycloalkylene groups include, but are not limited to Spirocyclic heterocycloalkylene groups include, but are not limited to with
- aryl refers to any stable monocyclic or polycyclic (eg bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, at least one of which is an aromatic ring.
- aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthrenyl, anthracenyl, or acenaphthyl. It can be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
- arylene refers to a divalent aryl group. 1,4-phenylene
- heteroaryl refers to a stable monocyclic or polycyclic (eg bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains at least one selected Heteroatoms from O, N and S. Heteroaryl groups can be attached to other parts of the molecule through heteroatoms or carbon atoms therein.
- heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinnoline, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl , Benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl (eg, pyrrole-1 -Base Pyrrol-2-yl ), Tetrahydroquinolinyl. It can be understood that in the case where the heteroaryl substituent is a bicyclic substituent, and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
- heteroarylene refers to a divalent heteroaryl group.
- the 6-membered heteroarylene group in 1,4- (6-membered heteroarylene) is monocyclic, where 1 and 4 do not refer to the original number of the ring atoms in the 6-membered heteroarylene group, but refer to the 6-membered subarylene group The relative position of the two connection sites of the heteroaryl group is para.
- 1,4- (6-membered heteroarylene) include but are not limited to
- the linking direction is connected in the same direction as the reading order from left to right.
- the linking group L 1 is -CD-, and then -CD- is connected to ring A and ring B in the same direction as the reading order from left to right
- the structure formed is Instead of when enumerating L is , The structure formed is Instead of
- halogen refers to F, Cl, Br, I.
- the term "pharmaceutically acceptable salt” means a salt formed of a suitable non-toxic organic acid, inorganic acid, organic base, or inorganic base and a compound represented by Formula I or I ', which retains the formula The biological activity of the compound represented by I or I '.
- the organic acid may be various organic acids that can form salts in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid , Propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalene sulfonic acid and one or more of salicylic acid.
- the inorganic acid may be various conventional inorganic acids capable of forming salts in the art, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
- the organic base may be a variety of conventional organic bases capable of forming salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines Species.
- the tertiary amine organic base is preferably triethylamine and / or N, N-diisopropylethylamine.
- the aniline organic base is preferably N, N-dimethylaniline.
- the pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine.
- the inorganic base may be various inorganic bases conventionally capable of forming salts in the art, preferably alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate , One or more of potassium bicarbonate and sodium bicarbonate.
- the alkali metal hydride is preferably sodium hydride and / or potassium hydride.
- the alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
- the alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium t-butoxide and sodium t-butoxide.
- the pharmaceutically acceptable salt is the hydrochloride salt.
- solvate means a substance formed by a compound represented by formula I or I 'and a suitable solvent.
- the solvent is preferably water or an organic solvent.
- the compounds of the present invention and their structures are also meant to include all isomers (e.g. enantiomers, diastereomers, geometric isomers and conformational isomers), which can be based on the absolute stereochemistry for amino acids Chemistry is defined as (R)-/ (S)-or (D)-/ (L)-or (R, R)-/ (R, S)-/ (S, S)-.
- the present invention includes all these possible isomers, as well as their racemic, enantiomerically enriched and optionally pure forms.
- Optical rotation (+) and (-), (R)-and (S)-and (R, R)-/ (R, S)-/ (S, S)-or (D)-and (L) -iso Constructs can be prepared using chiral synthesis, chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid phase (HPLC) using chiral columns.
- HPLC high performance liquid phase
- stereoisomer refers to a compound composed of the same atoms bonded with the same chemical bond but having different three-dimensional structures, and they are not interchangeable.
- the present invention covers various stereoisomers and mixtures thereof and includes “enantiomers” and “diastereomers”.
- Enantiomers refer to two stereoisomers whose molecules are non-overlapping mirror images of each other Conformator; diastereomer is a stereoisomer with two or more chiral centers and a non-mirror relationship between the molecules.
- tautomer refers to the movement of a proton from one atom of a molecule to another position of the same molecule.
- the invention includes tautomers of any of the compounds.
- the term "prodrug” refers to a derivative of a compound containing a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide The compound.
- the prodrug is inactive, or at least less active than the compound itself, so that the compound cannot exert its activity until it is cleaved from the bioreactive functional group.
- the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
- the prodrug may contain biohydrolyzable groups.
- biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable Acyl urea.
- the term "isotopic derivative” refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
- having the structure of the present invention in addition to replacing hydrogen with “deuterium” or “tritium”, or replacing fluorine with an 18 F-fluorine label ( 18 F isotope), or using 11 C-, 13 C-, or 14 C-rich Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present invention.
- Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
- Deuterated compounds can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased half-life in vivo or reduced dose requirements) ). Therefore, in the present invention, the isotopic derivative is preferably a deuterium.
- the term “therapeutically effective amount” refers to a sufficient amount of a drug or medicament that is non-toxic but achieves the desired effect.
- the “therapeutically effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
- the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine experiments.
- the reagents and raw materials used in the present invention are commercially available.
- the positive progress effect of the present invention is to provide a triazolocyclic compound, its preparation method, intermediate and application.
- the triazolocyclic compound of the present invention can be used as an adenosine A2A receptor antagonist or histone deacetylation HDAC inhibitor. Further, the triazolocyclic compounds of the present invention can have both adenosine A2A receptor antagonistic activity and histone deacetylase HDAC inhibitory activity, and thus can be used to treat tumors and central nervous system diseases and other related diseases.
- Step 1 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Preparation of amino) methyl) -N-hydroxybenzoic acid methyl ester (Intermediate Int-1)
- Step 2 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Amino) methyl) -N-hydroxybenzamide (Compound I-1)
- reaction solution was neutralized with 1,4-dioxane solution (4M) of hydrogen chloride to pH 7.4, the solvent was evaporated under reduced pressure, water was added to the solid residue, stirred at room temperature for 1 hour, and filtered to obtain white solid compound 1 (0.056g, 70% yield).
- Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with “Methyl 4- (3-aminopropyl) benzoate” (for the preparation method, see WO2012117421), the remaining required raw materials, reagents and preparation methods As in Example 1, a white solid compound (I-3) can be obtained.
- Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with “Methyl 4- (2-aminoethoxy) benzoate” (see WO2001000206 for the preparation method), the remaining required raw materials, reagents and preparation The method is the same as in Example 1, to obtain a white solid compound (I-4).
- Example 1 Replace "methyl 4-aminomethylbenzoate” in Example 1 with "(E) -3- (4- (aminomethyl) phenyl) acrylic acid methyl ester” (for the preparation method, see WO2011021209)
- the raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-5).
- Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with "(E) -3- (4- (2-aminoethyl) phenyl) acrylic acid methyl ester” (for preparation methods, see MedChemComm, 2013 , 4,1562-1570), the remaining required raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-6).
- Example 1 Replace “Methyl 4-aminomethylbenzoate” in Example 1 with “Methyl 4- (2- (methylamino) ethyl) benzoate” (see WO2008156820 for the preparation method), and the remaining required raw materials and reagents
- the preparation method is the same as that in Example 1, to obtain a white solid compound (I-7).
- Step 1 Preparation of methyl 4- (2- (ethylamino) ethyl) benzoate (intermediate Int-2)
- Methyl 4- (2-aminoethyl) benzoate (see WO2017133521 for preparation method) (0.50g, 2.78mmol), acetaldehyde (0.122g, 2.78mmol) and triethylamine (0.78mL) are dissolved in methanol (2.5 mL), add sodium borohydride acetate (0.91 g, 4.17 mmol), and stir at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography to obtain yellow solid intermediate Int-2 (0.43 g, yield 74%).
- HRMS (ESI) C 12 H 18 NO 2 + [M + H] + calculated value: 208.1332, found value: 208.1341.
- Step 2 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) (ethyl) amino) ethyl-N-hydroxybenzamide (Compound I-8)
- Example 1 The "methyl 4-aminomethylbenzoate" in Example 1 was replaced with the intermediate Int-2, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1, to obtain a white solid compound (I-8).
- Step 1 Preparation of methyl 4- (2-((tert-butoxycarbonyl) (methyl) amino) ethoxy) benzoate (intermediate Int-3)
- Step 2 Preparation of methyl 4- (2- (methylamino) ethoxy) benzoate (Intermediate Int-4)
- Step 3 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) (methyl) amino) ethoxy) -N-hydroxybenzamide (compound I-9)
- Example 1 Replace “Methyl 6-aminocaproate” in Example 1 with “Methyl 7-aminoheptanoate”, the remaining required raw materials, reagents and preparation methods are the same as in Example 1, to obtain a white solid compound (I-10) .
- Example 11-12 According to the listed methods provided in Example 1, the compounds listed in Examples 11-12 can be prepared in the same way by changing the corresponding raw materials, as shown in Table 1.
- Step 1 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) amino) amino) ethyl) -benzoic acid (Compound Int-5)
- ester intermediate 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl) amino) amino) ethyl) -benzoic acid methyl ester (0.19g, 0.50mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and water (2.5mL), Lithium hydroxide (0.060 g, 2.5 mmol) was added and stirred at room temperature overnight.
- reaction solution was neutralized to pH 7.4 with 1,4-dioxane solution (4M) of hydrogen chloride, and the solvent was evaporated under reduced pressure to obtain the crude product of the corresponding carboxylic acid intermediate Int-5, which was directly used in the next reaction.
- Step 2 4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine-5 -Yl) amino) amino) ethyl) -N- (2-aminophenyl) benzamide (Compound I-13)
- Example 13 According to the method provided in Example 13, by changing the corresponding raw materials, the compounds listed in Examples 15 and 16 can also be prepared by the same method, see Table 2 for details.
- Step 1 Preparation of 4- (4- (cyanomethyl) phenoxy) butyric acid methyl ester (Intermediate Int-6)
- Step 2 Preparation of methyl 4- (4- (2-aminoethyl) phenoxy) butanoate (Intermediate Int-7)
- the intermediate Int-6 (1.13g, 4.8mmol) was dissolved in a mixed solution of dichloromethane (20mL) and methanol (20mL), concentrated hydrochloric acid (1.5mL) and palladium / carbon (10% palladium, 500mg) were added, Stir at room temperature overnight under a hydrogen atmosphere. The solvent was distilled off under reduced pressure to obtain the hydrochloride salt of intermediate Int-7 (1.32 g, crude yield 100%).
- Step 3 4- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] tri Preparation of oxazin-5-yl) amino) ethyl) phenoxy) -N-hydroxybutyramide (Compound I-17)
- Example 1 The "methyl 6-aminocaproate" in Example 1 was replaced with the intermediate Int-7, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound (I-17).
- Step 1 Preparation of 8-((4- (cyanomethyl) phenyll) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-8)
- Step 2 Preparation of 8-((4- (2-aminoethyl) phenyl) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-9)
- Step 3 N 1- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] Preparation of triazin-5-yl) amino) ethyl) phenyl) -N 8 -hydroxy suberamide (Compound I-22)
- Example 1 The "methyl 6-aminocaproate" in Example 1 was replaced with the intermediate Int-9, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound (I-22).
- Example 22 According to the method provided in Example 22, by changing the corresponding raw materials, the compounds listed in Examples 23-25 can be prepared by the same method, see Table 3.
- Step 1 Preparation of 4- (4- (methoxycarbonyl) phenethyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate Int-10)
- Step 2 Preparation of methyl 4- (2- (piperazin-1-yl) ethyl) benzoate (Intermediate Int-11)
- Step 3 4- (2- (4- (2-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3, 5] Preparation of triazin-5-yl) piperazin-1-yl) ethyl) -N-hydroxybenzamide (compound I-26)
- Example 1 The methyl 6-aminocaproate in Example 1 was replaced with the intermediate Int-11, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1, to obtain a white solid compound (I-26).
- Example 26 by changing the corresponding raw materials, the compounds shown in Examples 27-29 can be prepared by the same method, see Table 4 for details.
- Example 1 According to the method described in Example 1, by changing the corresponding raw materials, the compounds listed in Examples 30-36 can be prepared in a similar manner, see Table 5 for details.
- Step 1 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Preparation of amino) methyl) benzoic acid (Intermediate Int-12)
- Step 2 4-(((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazin-5-yl ) Amino) methyl) -N- (2-aminophenyl) benzamide (Compound I-37)
- Example 38 4- (3-((7-amino-2- (furan-2-yl- [1,2,4] triazole [1,5-a] [1,3,5] triazine- Preparation of 5-yl) amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-38)
- Step 1 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) methyl benzoate (intermediate Int-13)
- reaction can also separate Int-14, another isomer of intermediate Int-13.
- the details will be described in Embodiment 41.
- Step 2 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of -7-yl) ethyl) benzoic acid (Intermediate Int-15)
- Step 3 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) -N- (2-aminophenyl) benzamide (Compound I-40)
- Step 1 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of methyl-8-yl) ethyl) benzoate (Intermediate Int-14)
- Step 2 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of -8-yl) ethyl) benzoic acid (Intermediate Int-16)
- Step 3 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) ethyl) -N- (2-aminophenyl) benzamide (compound I'-41)
- Step 1 (2- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] Pyrimidin-7-yl) ethyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-17)
- Example 40 Replace o-phenylenediamine in Step 3 of Example 40 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 40 to obtain a foamy intermediate (Int-17).
- Step 2 4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (compound I-42)
- Step 1 The intermediate Int-17 (0.06 g, 0.1 mmol) obtained in Step 1 was dissolved in methanol (5 mL), 4M hydrochloric acid dioxane solution (5 mL) was added, and the mixture was stirred overnight at room temperature.
- Step 1 (2- (4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] Pyrimidin-8-yl) ethyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-18)
- Example 41 Replace o-phenylenediamine in step 3 of Example 41 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 41 to obtain a foamy intermediate (Int-18).
- Step 2 4- (2- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) ethyl) -N- (2-amino-4-fluorophenyl) benzamide (compound I'-43)
- Step 1 The intermediate Int-18 (0.06 g, 0.1 mmol) obtained in Step 1 was dissolved in methanol (5 mL), 4M hydrochloric acid dioxane solution (5 mL) was added, and the mixture was stirred overnight at room temperature.
- Step 1 4-((5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7 -Yl) ethyl) methyl benzoate (intermediate Int-19)
- reaction can also separate Int-20, another isomer of intermediate Int-19. The details will be described in Example 46.
- Step 2 4-((5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7 -Yl) methyl) -N- (2-aminophenyl) benzamide (Compound I-45)
- Step 1 4-((5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8 -Yl) methyl) methyl benzoate (intermediate Int-20)
- Step 2 4-((5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8 -Yl) methyl) -N- (2-aminophenyl) benzamide (Compound I'-46)
- Example 48 4- (3- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) propyl) -N- (2-aminophenyl) benzamide (Compound I-48)
- Step 1 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of methyl -7-yl) propyl) benzoate (Intermediate Int-21)
- Step 2 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) propyl) -N- (2-aminophenyl) benzamide (Compound I-48)
- Step 1 4- (3- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine Preparation of Methyl-8-yl) propyl) benzoate (Intermediate Int-22)
- Step 2 4- (3- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -8-yl) propyl) -N- (2-aminophenyl) benzamide (compound I'-49)
- Example 50 4- (3- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-50)
- Step 1 (2- (4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) propyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-23)
- Example 48 Replace o-phenylenediamine in Step 2 of Example 48 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 48 to obtain a foamy intermediate (Int-23).
- Step 2 4- (3- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine -7-yl) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-50)
- Step 1 7- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7- Of methyl) heptanoate (intermediate Int-24)
- Step 1 of Example 40 Replace the methyl 4- (2-bromoethyl) benzoate in Step 1 of Example 40 with methyl 7-bromoheptanoate.
- the remaining required raw materials, reagents and preparation methods are the same as in Step 1 of Example 40 to obtain a white solid Intermediate (Int-24).
- reaction can also isolate Int-25, another isomer of intermediate Int-24. The details will be described in Example 52.
- Step 2 7- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-7- ) -N-hydroxyheptanamide (Compound I-51)
- Step 1 7- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8- Preparation of Methyl) heptanoate (Intermediate Int-25)
- Step 2 7- (5-Amino-2-((furan-2-yl) -8Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] pyrimidine-8- ) -N-hydroxyheptanamide (Compound I'-52)
- Step 1 Preparation of 6- (4- (2-hydroxyethyl) phenoxy) hexanoic acid methyl ester (Intermediate Int-26)
- Step 2 Preparation of 6- (4- (2-bromoethyl) phenoxy) hexanoic acid methyl ester (Intermediate Int-27)
- Step 3 6- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of methyl pyrimidin-7-yl) ethyl) phenoxy) hexanoate (intermediate Int-28)
- Step 1 of Example 40 Replace methyl 4- (2-bromoethyl) benzoate in step 1 of Example 40 with intermediate Int-27.
- the remaining required raw materials, reagents and preparation methods are the same as in Step 1 of Example 40 to obtain a white solid intermediate (Int-27).
- Step 4 6- (4- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of pyrimidin-7-yl) ethyl) phenoxy) -N-hydroxyhexanamide (compound I-53)
- Step 1 Preparation of 8-((4- (2-hydroxyethyl) phenyl) amino) -8-oxooctanoic acid methyl ester (Intermediate Int-29)
- Step 2 N 1- (4- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5 -c] pyrimidin-7-yl) ethyl) phenyl) -N 8 -hydroxyoctanediamide (Compound I-54)
- Step 1 4- (1- (2- (5-Amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of methyl pyrimidin-7-yl) ethyl) piperidin-4-yl) benzoate (intermediate Int-30)
- Step 2 4- (1- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5- c) Preparation of pyrimidin-7-yl) ethyl) piperidin-4-yl) -N-hydroxybenzamide (compound I-55)
- Example 56 2- (2- (5-amino-2-((furan-2-yl) -7Hpyrazole [4,3-e] [1,2,4triazole [1,5-c] Preparation of pyrimidin-7-yl) ethyl) -N-hydroxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (Compound I-56)
- Example 58 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-58)
- Step 1 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of Methyl Amino) propyl) benzoate (Intermediate Int-31)
- Step 2 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of Methyl Amino) propyl) benzoate (Intermediate Int-32)
- Step 3 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) propyl) -N- (2-aminophenyl) benzamide (Compound I-58)
- Example 60 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) amino) propane ) -N- (2-aminophenyl) benzamide (Compound I-60)
- Example 58 Replace methyl 4- (3- (methylamino) propyl) benzoate in step 1 of Example 58 with methyl 4- (3-aminopropyl) benzoate (for the preparation method, see WO2012117421)
- the raw materials, reagents and preparation methods are the same as in Example 58, to obtain a yellow solid compound (I-60).
- Example 61 4- (3-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-61)
- Step 1 (2- (4- (3-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) Preparation of (methyl) amino) propyl) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-33)
- Step 3 of Example 58 Replace o-phenylenediamine in Step 3 of Example 58 with tert-butyl (2-amino-5-fluorophenyl) carbamate, the remaining required raw materials, reagents and preparation methods are the same as Step 3 of Example 58 to obtain a foam Intermediate (Int-33).
- Step 2 4- (3-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) propyl) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-61)
- Example 62 4- (2-((5-amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl ) Amino) ethoxy) -N- (2-amino-4-fluorophenyl) benzamide (Compound I-62)
- Step 1 (2- (4- (2-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) Preparation of (methyl) amino) ethoxy) benzamide) -5-fluorophenyl) carbamic acid tert-butyl ester (intermediate Int-34)
- Example 59 Replace o-phenylenediamine in Example 59 with (2-amino-5-fluorophenyl) carbamic acid tert-butyl ester, the remaining required raw materials, reagents and preparation methods are the same as in Example 59 to obtain a foamy intermediate (Int -34).
- Step 2 4- (2-((5-Amino-2- (furan-2-yl)-[1,2,4] triazole [1,5-c] pyrimidin-7-yl) (methyl) Preparation of amino) ethoxy) -N- (2-amino-4-fluorophenyl) benzamide (compound I-62)
- Example 63 Determination of the inhibitory activity of the compound on histone deacetylase HDAC.
- the specific operation method is as follows:
- the compound to be tested is formulated into a corresponding DMSO solution at a concentration of 10 mM, and then diluted with DMSO to 1 mM, followed by a 3-fold gradient dilution at 10 concentration points;
- LGK (Ac) -AMC Gill Biochemical
- HDAC6 activity the final concentration of LGK (Ac) -AMC is 11 ⁇ M, and the final concentration of Trypsin is 0.01 ⁇ M;
- step (6) Add 15 ⁇ L of the enzyme solution prepared in step (4) to each well of the test 384-well plate, add 15 ⁇ L of the buffer in step (1) to the low control group, centrifuge at 1000 rpm for 1 minute, and then incubate at room temperature for 15 minutes;
- Example 64 Determination of the A2A receptor binding activity of the compounds of the invention.
- the compounds were tested for human A2A receptor binding activity using competitive binding experiments based on radioisotope ligands.
- the specific operation method is as follows:
- test compound is formulated into a DMSO solution with a corresponding concentration of 10 mM. Then dilute with buffer to 10 ⁇ M, then dilute with buffer 3 times, 10 concentration points;
- Example 65 Determination of the functional activity of the compounds of the invention on the A2A receptor.
- the activity of the compound on the human A2A receptor function test was measured using the cAMP test (Perkin Elmer) based on HTRF.
- the specific operation method is as follows:
- Example 66 Test of compounds of the present invention for inhibiting tumor cell proliferation activity.
- the compound's activity in inhibiting the proliferation of tumor cells was determined using HCT-116, HL-60, and B16F10 cells.
- HCT-116 and B16F10 cells were discarded from the culture medium and digested with trypsin. After digestion, they were neutralized with serum-containing medium, and the cells were pipetted to make the cells fall off. Pipette the cell suspension into a centrifuge tube and centrifuge at 800-1000rmp for 3-5 minutes. HL-60 cells were pipetted into the centrifuge tube, and centrifuged at 800-1000rmp for 3-5 minutes.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un composé à cycle triazolo, son procédé de préparation, des intermédiaires de celui-ci et une utilisation associée. En outre, le composé à cycle triazolo selon la présente invention peut avoir simultanément une activité antagoniste du récepteur de l'adénosine A2A et une activité inhibitrice de l'histone désacétylase (HDAC), et peut donc être utilisé pour traiter des maladies telles que des maladies tumorales et des maladies du système nerveux central.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811397796 | 2018-11-22 | ||
CN201811397796.3 | 2018-11-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020103939A1 true WO2020103939A1 (fr) | 2020-05-28 |
Family
ID=70773751
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/120284 WO2020103939A1 (fr) | 2018-11-22 | 2019-11-22 | Composé à cycle triazolo, son procédé de préparation, intermédiaires de celui-ci et utilisation associée |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN111205291B (fr) |
WO (1) | WO2020103939A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023191400A1 (fr) * | 2022-04-01 | 2023-10-05 | 에이치케이이노엔 주식회사 | Dérivés d'éthyl-pipéridine-triazolo-triazine, leur procédé de synthèse et composition pharmaceutique les contenant pour la prévention ou le traitement du cancer |
WO2023201267A1 (fr) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Polythérapie pour le traitement de cancers exprimant trop-2 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN117263936B (zh) * | 2023-11-21 | 2024-02-23 | 中国中医科学院医学实验中心 | 一种咪唑并[1, 2-a]吡啶衍生物及其制备方法和在中枢神经系统渗透性HDAC6抑制药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5356894A (en) * | 1990-05-29 | 1994-10-18 | Rodney Peter W | Morpholinyl substituted [1,2,4]-triazolo[1,5-a]triazine as antagonist |
WO2000015231A1 (fr) * | 1998-09-16 | 2000-03-23 | Medco Research Inc. | Modulateurs des recepteurs de l'adenosine a¿3? |
US7285550B2 (en) * | 2003-04-09 | 2007-10-23 | Biogen Idec Ma Inc. | Triazolotriazines and pyrazolotriazines and methods of making and using the same |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0459702A1 (fr) * | 1990-05-29 | 1991-12-04 | Zeneca Limited | Dérivés d'azoles |
US7122548B2 (en) * | 2003-07-02 | 2006-10-17 | Sugen, Inc. | Triazolotriazine compounds and uses thereof |
ES2603931T3 (es) * | 2012-11-07 | 2017-03-02 | F. Hoffmann-La Roche Ag | Compuestos de triazolo |
CN111164084B (zh) * | 2018-06-26 | 2023-05-23 | 浙江春禾医药科技有限公司 | 可用作a2a受体拮抗剂的三唑并三嗪衍生物 |
-
2019
- 2019-11-22 WO PCT/CN2019/120284 patent/WO2020103939A1/fr active Application Filing
- 2019-11-22 CN CN201911153069.7A patent/CN111205291B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5356894A (en) * | 1990-05-29 | 1994-10-18 | Rodney Peter W | Morpholinyl substituted [1,2,4]-triazolo[1,5-a]triazine as antagonist |
WO2000015231A1 (fr) * | 1998-09-16 | 2000-03-23 | Medco Research Inc. | Modulateurs des recepteurs de l'adenosine a¿3? |
US7285550B2 (en) * | 2003-04-09 | 2007-10-23 | Biogen Idec Ma Inc. | Triazolotriazines and pyrazolotriazines and methods of making and using the same |
Non-Patent Citations (2)
Title |
---|
MANUELA JOERG ET AL.: "Synthesis and Pharmacological Evaluation of Dual Acting Ligands Targeting the Adenosine A2A and Dopamine D2 Receptors for the Potential Treatment of Parkinson's Disease", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 2, 9 December 2014 (2014-12-09), pages 718 - 738, XP055709666 * |
STEPHANIE FEDERICO ET AL.: "Synthesis and Biological Evaluation of a New Series of 1, 2, 4- Triazolo[1, 5-a]-1, 3, 5-triazines as Human A2A Adenosine Receptor Antagonists with Improved Water Solubility", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 3, 7 January 2011 (2011-01-07), pages 877 - 889, XP055709658 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023191400A1 (fr) * | 2022-04-01 | 2023-10-05 | 에이치케이이노엔 주식회사 | Dérivés d'éthyl-pipéridine-triazolo-triazine, leur procédé de synthèse et composition pharmaceutique les contenant pour la prévention ou le traitement du cancer |
WO2023201267A1 (fr) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Polythérapie pour le traitement de cancers exprimant trop-2 |
Also Published As
Publication number | Publication date |
---|---|
CN111205291B (zh) | 2022-08-23 |
CN111205291A (zh) | 2020-05-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2997051C (fr) | Nouveau compose pyrrolo[3,4-d]pyrimidine ou sel correspondant | |
CA3119526A1 (fr) | Agents de degradations de petites molecules de helios et procedes d'utilisation | |
CN113387938B (zh) | 一种取代嘧啶类化合物、其制备方法、中间体及应用 | |
CA3133753A1 (fr) | Nouveaux inhibiteurs a petites molecules de facteurs de transcription tead | |
WO2020064002A1 (fr) | Composé d'isoindoline, procédé de préparation, composition pharmaceutique et utilisation associée | |
NL1026438C2 (nl) | Nieuwe verbindingen. | |
JP2016528197A (ja) | Ido阻害剤 | |
JP2016523974A (ja) | Ido阻害剤 | |
WO2020103939A1 (fr) | Composé à cycle triazolo, son procédé de préparation, intermédiaires de celui-ci et utilisation associée | |
TWI531573B (zh) | 新穎反轉模擬物之化合物及其用途 | |
EP3983384A1 (fr) | Dérivés de n-(phényl)-indole-3-sulfonamide et composés apparentés en tant que modulateurs de gpr17 pour le traitement de troubles du système nerveux central tels que la sclérose en plaques | |
CN102482283A (zh) | Raf抑制剂化合物及其使用方法 | |
BR112015017963A2 (pt) | composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto | |
JP2023036991A (ja) | Ehmt2阻害剤としてのアミン置換複素環化合物、その塩、及びそれらの合成方法 | |
JP2015527351A (ja) | Stat3阻害剤およびその抗癌的使用 | |
CA3064484A1 (fr) | Composes inhibiteurs des canaux ioniques pour le traitement du cancer | |
WO2020182159A1 (fr) | Inhibiteur de kinase jak, son procédé de préparation et ses applications dans le domaine de la médecine | |
WO2021052501A1 (fr) | Composé amide hétérocyclique, sel pharmaceutiquement acceptable de celui-ci, et son procédé de préparation et son utilisation | |
WO2023016540A1 (fr) | Inhibiteur de tyrosine kinase à plusieurs cibles d'urée et son utilisation médicale | |
KR20120099457A (ko) | 디아실글리세롤 아실트랜스퍼라제의 억제제 | |
KR20100135248A (ko) | 인돌리논 화합물 | |
CN116348468A (zh) | Cftr调节剂化合物、组合物及其用途 | |
AU2020255702B2 (en) | Quinolyl-containing compound and pharmaceutical composition, and use thereof | |
Sun et al. | Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists | |
CN111205244B (zh) | 噻唑并环类化合物、其制备方法、中间体和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19887014 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19887014 Country of ref document: EP Kind code of ref document: A1 |