CN111808079A - Indole ASK1 small molecule inhibitor and preparation method and application thereof - Google Patents
Indole ASK1 small molecule inhibitor and preparation method and application thereof Download PDFInfo
- Publication number
- CN111808079A CN111808079A CN202010777152.8A CN202010777152A CN111808079A CN 111808079 A CN111808079 A CN 111808079A CN 202010777152 A CN202010777152 A CN 202010777152A CN 111808079 A CN111808079 A CN 111808079A
- Authority
- CN
- China
- Prior art keywords
- indole
- isopropyl
- triazol
- carboxamide
- pyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 78
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 101001018196 Homo sapiens Mitogen-activated protein kinase kinase kinase 5 Proteins 0.000 title claims abstract description 46
- 102100033127 Mitogen-activated protein kinase kinase kinase 5 Human genes 0.000 title claims abstract description 46
- 239000003112 inhibitor Substances 0.000 title claims abstract description 35
- 150000003384 small molecules Chemical class 0.000 title claims abstract description 28
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 26
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 6
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract description 6
- -1 heterocyclic radical Chemical class 0.000 claims description 82
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 11
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- LYUQNMNUBOUCBX-UHFFFAOYSA-N 6-fluoro-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound FC1=CC=C2C=C(NC2=C1)C(=O)NC1=NC(=CC=C1)C1=NN=CN1C(C)C LYUQNMNUBOUCBX-UHFFFAOYSA-N 0.000 claims description 7
- WKEUSOIWGYPPHH-UHFFFAOYSA-N 7-acetamido-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound C(C)(=O)NC=1C=CC=C2C=C(NC=12)C(=O)NC1=NC(=CC=C1)C1=NN=CN1C(C)C WKEUSOIWGYPPHH-UHFFFAOYSA-N 0.000 claims description 7
- HWPIAYNLKGWDKU-UHFFFAOYSA-N 3-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=CC=CC=C2C=1C HWPIAYNLKGWDKU-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- LEERPYPMIWDZBT-UHFFFAOYSA-N N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-7-thiophen-3-yl-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=C(C=CC=C2C=1)C1=CSC=C1 LEERPYPMIWDZBT-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- TUWHHGVOZLPWQK-UHFFFAOYSA-N 1-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1N(C2=CC=CC=C2C=1)C TUWHHGVOZLPWQK-UHFFFAOYSA-N 0.000 claims description 5
- NOQMWRAHALCPKI-UHFFFAOYSA-N 4-(1-methylpyrazol-4-yl)-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=CC=CC(=C2C=1)C=1C=NN(C=1)C NOQMWRAHALCPKI-UHFFFAOYSA-N 0.000 claims description 5
- RYQBKOZDZJZMKR-UHFFFAOYSA-N 6-[1-(oxan-4-yl)pyrazol-4-yl]-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=CC(=CC=C2C=1)C=1C=NN(C=1)C1CCOCC1 RYQBKOZDZJZMKR-UHFFFAOYSA-N 0.000 claims description 5
- FITQULPYJHXHCX-UHFFFAOYSA-N 6-methoxy-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=CC(=CC=C2C=1)OC FITQULPYJHXHCX-UHFFFAOYSA-N 0.000 claims description 5
- WAMQLNJPCIOXDG-UHFFFAOYSA-N 7-chloro-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound ClC=1C=CC=C2C=C(NC=12)C(=O)NC1=NC(=CC=C1)C1=NN=CN1C(C)C WAMQLNJPCIOXDG-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- CCPVZOJLKCKCHU-UHFFFAOYSA-N N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-5-(1H-pyrazol-4-yl)-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=CC=C(C=C2C=1)C=1C=NNC=1 CCPVZOJLKCKCHU-UHFFFAOYSA-N 0.000 claims description 5
- KECOPANJJUYUCT-UHFFFAOYSA-N N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-6-(1H-pyrazol-4-yl)-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=CC(=CC=C2C=1)C=1C=NNC=1 KECOPANJJUYUCT-UHFFFAOYSA-N 0.000 claims description 5
- STCVPQXZSJQICF-UHFFFAOYSA-N N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-7-pyridin-4-yl-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=C(C=CC=C2C=1)C1=CC=NC=C1 STCVPQXZSJQICF-UHFFFAOYSA-N 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 5
- DBWSAOJEEJDSRA-UHFFFAOYSA-N 3-(furan-3-yl)-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound O1C=C(C=C1)C1=C(NC2=CC=CC=C12)C(=O)NC1=NC(=CC=C1)C1=NN=CN1C(C)C DBWSAOJEEJDSRA-UHFFFAOYSA-N 0.000 claims description 4
- HEURXYHRYWLVQH-UHFFFAOYSA-N 6-[1-(1-ethoxyethyl)pyrazol-4-yl]-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound C(C)OC(C)N1N=CC(=C1)C1=CC=C2C=C(NC2=C1)C(=O)NC1=NC(=CC=C1)C1=NN=CN1C(C)C HEURXYHRYWLVQH-UHFFFAOYSA-N 0.000 claims description 4
- 229940127254 ASK1 inhibitor Drugs 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- YAXPJVUJMIAASO-UHFFFAOYSA-N N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-7-(1H-pyrazol-4-yl)-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=C(C=CC=C2C=1)C=1C=NNC=1 YAXPJVUJMIAASO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- OHIHEJTUXNQOPM-UHFFFAOYSA-N methyl 6-aminopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(N)=N1 OHIHEJTUXNQOPM-UHFFFAOYSA-N 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- VZDNXXPBYLGWOS-UHFFFAOYSA-N methyl 3-aminobenzoate Chemical compound COC(=O)C1=CC=CC(N)=C1 VZDNXXPBYLGWOS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- KIWSYRHAAPLJFJ-DNZSEPECSA-N n-[(e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enyl]pyridine-3-carboxamide Chemical compound [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/CNC(=O)C1=CC=CN=C1 KIWSYRHAAPLJFJ-DNZSEPECSA-N 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229960004838 phosphoric acid Drugs 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229940032330 sulfuric acid Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 230000001476 alcoholic effect Effects 0.000 abstract 1
- 208000006454 hepatitis Diseases 0.000 abstract 1
- 231100000283 hepatitis Toxicity 0.000 abstract 1
- 230000001568 sexual effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 51
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 37
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 229910001868 water Inorganic materials 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 15
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 102100039019 Nuclear receptor subfamily 0 group B member 1 Human genes 0.000 description 12
- 210000001072 colon Anatomy 0.000 description 12
- 108091054455 MAP kinase family Proteins 0.000 description 10
- 102000043136 MAP kinase family Human genes 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 239000000872 buffer Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 239000012911 assay medium Substances 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 206010009887 colitis Diseases 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000010253 intravenous injection Methods 0.000 description 6
- GJUHMMVRWJIBNO-UHFFFAOYSA-N N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound C(C)(C)N1C(=NN=C1)C1=CC=CC(=N1)NC(=O)C=1NC2=CC=CC=C2C=1 GJUHMMVRWJIBNO-UHFFFAOYSA-N 0.000 description 5
- 210000001853 liver microsome Anatomy 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000012421 spiking Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108010075639 MAP Kinase Kinase Kinase 5 Proteins 0.000 description 3
- 102000011853 MAP Kinase Kinase Kinase 5 Human genes 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 210000001589 microsome Anatomy 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- WEVOQMNXVHCCOI-UHFFFAOYSA-N 3-bromo-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]-1H-indole-2-carboxamide Chemical compound BrC1=C(NC2=CC=CC=C12)C(=O)NC1=NC(=CC=C1)C1=NN=CN1C(C)C WEVOQMNXVHCCOI-UHFFFAOYSA-N 0.000 description 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 2
- MPBBJHFKDHDIRZ-UHFFFAOYSA-N 6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-amine Chemical compound CC(C)N1C=NN=C1C1=CC=CC(N)=N1 MPBBJHFKDHDIRZ-UHFFFAOYSA-N 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- DFDCWWITIDKOAX-UHFFFAOYSA-N ethyl 7-acetamido-1H-indole-2-carboxylate Chemical compound C1=CC(NC(C)=O)=C2NC(C(=O)OCC)=CC2=C1 DFDCWWITIDKOAX-UHFFFAOYSA-N 0.000 description 2
- CNBYMDSUCXNDIT-UHFFFAOYSA-N ethyl 7-amino-1h-indole-2-carboxylate Chemical compound C1=CC(N)=C2NC(C(=O)OCC)=CC2=C1 CNBYMDSUCXNDIT-UHFFFAOYSA-N 0.000 description 2
- GTZAIVBXGPLYGD-UHFFFAOYSA-N ethyl 7-nitro-1h-indole-2-carboxylate Chemical compound C1=CC([N+]([O-])=O)=C2NC(C(=O)OCC)=CC2=C1 GTZAIVBXGPLYGD-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- KTBLRYUFNBABGO-UHFFFAOYSA-N 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=COC=C1 KTBLRYUFNBABGO-UHFFFAOYSA-N 0.000 description 1
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 1
- NPJXLOSZPNYTSQ-UHFFFAOYSA-N 7-acetamido-1h-indole-2-carboxylic acid Chemical compound CC(=O)NC1=CC=CC2=C1NC(C(O)=O)=C2 NPJXLOSZPNYTSQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 101100455868 Arabidopsis thaliana MKK2 gene Proteins 0.000 description 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 102100023275 Dual specificity mitogen-activated protein kinase kinase 3 Human genes 0.000 description 1
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 1
- 101001115394 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 3 Proteins 0.000 description 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 238000013231 NASH rodent model Methods 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- JDDHUROHDHPVIO-UHFFFAOYSA-N Piperazine citrate Chemical compound C1CNCCN1.C1CNCCN1.C1CNCCN1.OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O JDDHUROHDHPVIO-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000008221 Superoxide Dismutase-1 Human genes 0.000 description 1
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001142 back Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- CFRRQTCJDBVMJF-UHFFFAOYSA-N ethyl 6-amino-1h-indole-2-carboxylate Chemical compound C1=C(N)C=C2NC(C(=O)OCC)=CC2=C1 CFRRQTCJDBVMJF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940117360 ethyl pyruvate Drugs 0.000 description 1
- 238000013210 evaluation model Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000009950 gastric cancer growth Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XCUBVSAYUSFHNN-UHFFFAOYSA-N hydron;(2-nitrophenyl)hydrazine;chloride Chemical compound [Cl-].[NH3+]NC1=CC=CC=C1[N+]([O-])=O XCUBVSAYUSFHNN-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- VBCVPMMZEGZULK-NRFANRHFSA-N indoxacarb Chemical compound C([C@@]1(OC2)C(=O)OC)C3=CC(Cl)=CC=C3C1=NN2C(=O)N(C(=O)OC)C1=CC=C(OC(F)(F)F)C=C1 VBCVPMMZEGZULK-NRFANRHFSA-N 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 1
- 229960005417 ketanserin Drugs 0.000 description 1
- 238000003674 kinase activity assay Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- IPISOFJLWYBCAV-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate Chemical compound C1=NN(C(=O)OC(C)(C)C)C=C1B1OC(C)(C)C(C)(C)O1 IPISOFJLWYBCAV-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses an indole ASK1 small molecule inhibitor and a preparation method and application thereof, wherein the inhibitor comprises a compound shown as a general formula (I) and a stereoisomer or pharmaceutically acceptable salt thereof. The experimental data prove that the inhibitor is used for non-alcoholic fatHas certain treatment effect on the sexual hepatitis and the ulcerative colitis and good application prospect.
Description
Technical Field
The invention mainly relates to a compound and a preparation method and application thereof, and particularly relates to an indole ASK1 small-molecule inhibitor and a preparation method and application thereof.
Background
Apoptosis signal-regulated kinase 1(ASK1) belongs to the family of cell mitogen-activated protein kinases (MAPK), and the MAPK signal pathway is one of the important signal transduction systems in organisms and participates in the physiological processes of cell proliferation, differentiation, apoptosis, inflammatory reaction and the like. The MAPK family includes extracellular signal-regulated kinase (ERK), P38MAPK and JNK three major subfamilies. The MAPK family contains tertiary kinases, the first of which is the activation of the cellular mitogen-activated protein kinase (MAP3K) by extracellular and intracellular stimuli, with activated MAP3K phosphorylation activating MAP2K, which in turn activates MAPK. ASK1 belongs to MAP3K5, at P38Upstream of the MAPK and JNK signaling pathways.
ASK1 is capable of being activated by a range of stress conditions, such as oxidative stress, endoplasmic reticulum stress, and calcium influx. Activated ASK1 activates MKK3/6 and MKK4/7 through phosphorylation to activate P38MAPK and JNK pathways. ASK1 plays an important role in regulating cell physiological processes such as apoptosis, cytokine response, cell differentiation, and innate immune response. The research shows that ASK1 has obvious effect on a plurality of diseasesAnd (4) correlation.
Relevant literature reports show that ASK1 small molecule inhibitors show therapeutic potential for various diseases. For example, GS-444217 has obvious effect in various animal experimental models of renal fibrosis and inflammation, and K811 and K812 have obvious effect in SOD1 of ALS (amyotrophic lateral sclerosis)G93AThe survival period of the mouse is prolonged in the transgenic mouse model, K811 inhibits the growth of gastric cancer cells in vitro and in vivo tests, and GS-4997 carries out clinical tests on pulmonary hypertension, diabetic nephropathy and the like. However, the structure type of the ASK1 small-molecule inhibitor is single at present, and further research is needed.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide an indole ASK1 small-molecule inhibitor which influences apoptosis signal regulation kinase 1 and thus shows therapeutic potential for various diseases. The invention also aims to disclose a preparation method of the inhibitor and application of the inhibitor in medicines for treating nonalcoholic steatohepatitis and ulcerative colitis.
The technical scheme is as follows: the indole ASK1 small molecule inhibitor comprises a compound shown as a general formula (I) and a stereoisomer or pharmaceutically acceptable salt thereof:
M1is selected from N or CH;
R1is the same or different and is independently selected from hydrogen atom, alkoxy, halogen, heterocyclic radical, aryl, heteroaryl, - (CH)2)nOR4、-(CH2)nNR5R6、-(CH2)nNR5C(O)R4N is 0, 1,2,3, 4 or 5; wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, and heterocyclyl;
R2the same or different, and each is independently selected from hydrogen atom, alkyl, halogen, aryl, heteroaryl;
R3selected from alkyl, hydroxyalkyl or heterocyclyl;
R4selected from alkyl groups;
R5and R6The same or different, and each is independently selected from hydrogen atom, heterocyclic radical;
x is selected from N (R)2)；
m is 0, 1,2,3 or 4;
p is 1 or 2.
The indole ASK1 small molecule inhibitor, M1Is N:
the indole ASK1 micromolecule inhibitor has the structure that X is imino and R is3Is isopropyl, and is specifically shown as a general formula (III):
the indole ASK1 small molecule inhibitor R1Selected from hydrogen atoms, C1-6Alkoxy, halogen, 6-membered heterocyclyl, 6-membered aryl, 5-6-membered heteroaryl, substituted 5-6-membered heteroaryl and- (CH)2)nNR5C(O)R4Preferably a hydrogen atom, C1-3Alkoxy, halogen, 6-membered heterocyclyl, 6-membered aryl, 5-6-membered heteroaryl, substituted 5-membered heteroaryl and- (CH)2)nNHC(O)R4More preferably a hydrogen atom, a methoxy group, a chlorine atom, a fluorine atom, a 3, 6-dihydro-2H-pyran-4-yl group, a 1,2,3, 6-tetrahydropyridin-4-yl group, a phenyl group, a pyrazolyl group, a thienyl group, a furyl group, a pyridyl group, a 1- (1-ethoxyethyl) -1H-pyrazol-4-yl group, a 1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl group, a 1-methyl-1H-pyrazol-4-yl group, an acetamido group; r2Selected from hydrogen atoms, C1-6Alkyl, 5-6 membered heteroaryl, halogen, preferably hydrogen atom, C1-3Alkyl, 5-membered heteroaryl and halogen, more preferably hydrogen atom, methyl, furyl; r3Is selected from C1-6Alkyl radical, C1-6Hydroxyalkyl, preferably C1-3Alkyl radical、C1-3Hydroxyalkyl, more preferably 1-hydroxyprop-2-yl, isopropyl; r4Is C1-6An alkyl group; r5Is a hydrogen atom; r6Is tetrahydro-2H-pyran-4-yl.
The indole ASK1 small molecule inhibitor is selected from the following compounds: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-1), 7-chloro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-2), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methoxy-1H-indole-2-carboxamide (I-3), 6-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-4), 5-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-5), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1H-indole-2-carboxamide (I-6), (R) -N- (6- (4- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-7), N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide (I-8), 6-fluoro-N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide (I-9), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-methyl-1H-indole-2-carboxamide (I-10), 3- (furan-3-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-11), 7-acetamido-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-12), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-13), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-14), 6- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-15), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-16), N- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) -4- (trifluoromethyl) benzamide (I-17), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-18), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-19), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (thiophen-3-yl) -1H-indole-2-carboxamide (I-20), 7- (furan-3-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-21), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-phenyl-1H-indole-2-carboxamide (I-22), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (pyridin-4-yl) -1H-indole-2-carboxamide (I-23), 7- (3, 6-dihydro-2H-pyran-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-24), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-indole-2-carboxamide (I-25), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxamide (I-26).
The structural formula of the specific compound is shown in the following table:
the indole ASK1 small molecule inhibitor, the pharmaceutically acceptable salt is a salt formed by the inhibitor and acid or base, and the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid; the base is an inorganic base containing a basic metal cation, an alkaline earth metal cation, or an ammonium cation salt.
The preparation method of the indole ASK1 small molecule inhibitor comprises the following steps:
(1) methyl 3-aminobenzoate or methyl 6-aminopyridine-2-carboxylate A is firstly converted into a hydrazide compound B;
(2) a compound C is obtained through ring closing reaction, and the compound C reacts with a carboxylic acid compound D to obtain a compound (I);
and (3) adding a corresponding acid or alkali solution into the solution of the compound (I) prepared by the method, and removing the solvent under reduced pressure after salt formation is completed to obtain the pharmaceutically acceptable salt of the ASK1 inhibitor.
A pharmaceutical composition comprising the indole ASK1 small molecule inhibitor of claim 1 and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The indole ASK1 small molecule inhibitor or the pharmaceutical composition is applied to preparation of ASK1 inhibitor drugs.
The indole ASK1 small molecule inhibitor or the pharmaceutical composition is applied to the preparation of drugs for treating inflammatory diseases and ASK1 related diseases; the inflammatory diseases are non-alcoholic steatohepatitis and ulcerative colitis.
Has the advantages that: compared with the prior art, the invention has the following remarkable characteristics: the indole ASK1 small molecule inhibitor shows good ASK1 kinase inhibition activity, is superior to AP1-HEK293 cell activity of GS-4996, the compound I-1 shows human liver microsome stability superior to GS-4997, and the compounds I-1 and I-4 show good in vivo pharmacokinetic properties. Experimental data prove that the compound I-4 has certain treatment effect on non-alcoholic steatohepatitis and ulcerative colitis.
Drawings
FIG. 1 is a graph showing the effect of compounds I-4 on colon length in mice with DSS-induced colitis;
FIG. 2 shows the effect of I-4 on colon histopathology in mice with DSS-induced colitis.
Detailed Description
The structure of the compound of the invention is hydrogen spectrum by nuclear magnetic resonance (1H-NMR) and Mass Spectrometry (MS). Purity of the compound is determined by High Performance Liquid Chromatography (HPLC)And (4) measuring.1The H-NMR was measured using Bruker Advance 300 and Bruker Advance400 NMR spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) And deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
Mass Spectrometry MS was performed using an Advion Mass expression CMS Mass spectrometer, and HPLC was performed using an Agilent1260Infinity liquid chromatography system.
Thin Layer Chromatography (TLC) adopts a thin layer chromatography silica gel plate (Nicotiana Yangtze friend silica gel development Co., Ltd.), a self-made silica gel thin layer plate adopts GF254 silica gel (Qingdao ocean chemical plant), and silica gel column chromatography generally adopts 200-plus 300-mesh silica gel (Qingdao ocean chemical plant).
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring, in dry nitrogen atmosphere, in dry solvent, at reaction temperature in degrees centigrade, unless otherwise specified.
Example 1
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-1)
First step preparation of 6-aminopyridine carbohydrazide
Methyl 6-aminopyridinecarboxylate (5.0g, 32.9mmol) was dissolved in MeOH and N was added2H4·H2O (3.22g, 65.8mmol), heating and refluxing the reaction liquid for 3 h; after cooling to room temperature, a solid precipitates out, the filter cake is washed with EA after suction filtration, and the target product (4.5g, 90%) is obtained after vacuum drying.
ESI-MS m/z:153.1[M+H]+.
Second step preparation of 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine
6-Aminopyridoformylhydrazine (4.5g, 29.61mmol) was dissolved with anhydrous Dioxane and triethyl orthoformate (5.92mL, 35.53mmol), N, was added2Reacting for 1h at 75 ℃ under protection. Addition of CH by syringe3COOH (5.08mL, 88.83mmol), cyclopropylamine (2.05mL, 29.61mmol), reacted at 110 ℃ for 4 h; TLC detection reaction is finished, reaction liquid is diluted by water, pH is adjusted to 10, extraction is carried out by EA, drying and spin-drying are carried out by EA, and silica gel column chromatography is carried out to obtain a target product (4.81g, 80%).
ESI-MS m/z:204.0[M+H]+.
Third step preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide
Dissolving 1H-indole-2-carboxylic acid (300mg, 1.86mmol) in 10mL DCM, adding 2 drops of DMF, adding oxalyl chloride (355mg, 2.79mmol) under ice bath condition, reacting for 2H after 10min by RT, and removing DCM to obtain acyl chloride for later use; dissolving 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (343mg, 1.68mmol) in DCM, adding DIEA (434mg, 3.36mmol), adding acyl chloride under ice bath condition, reacting for 4H after 10min by RT; TLC detected the reaction was complete, DCM removed and diluted with water, with DCM/MeOH 10: 1, extracting, drying organic phase, spin-drying, carrying out silica gel column chromatography, and purifying by a self-made silica gel large plate to obtain a target product (180mg, 31%).
1H NMR(300MHz,DMSO)11.89(s,1H),10.67(s,1H),8.90(s,1H),8.23(d,J＝8.2Hz,1H),8.04(t,J＝8.0Hz,1H),7.86(d,J＝7.5Hz,1H),7.71(d,J＝8.0Hz,1H),7.58(d,J＝1.4Hz,1H),7.50(d,J＝8.2Hz,1H),7.26(t,J＝7.2Hz,1H),7.10(t,J＝7.4Hz,1H),5.68-5.73(m,1H)，1.48(d,J＝6.7Hz,6H).
ESI-MS m/z:347.2[M+H]+.
Example 2
Preparation of 7-chloro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-2)
Preparation of 7-chloro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO-d6):12.06(s,1H),10.85(s,1H)，8.90(s,1H)，8.26(dd,J＝6.3,0.3Hz,1H),8.06(t,J＝8.7,1H),7.84(dd,J＝7.6,0.6Hz,1H)，7.68(d，J＝6.0Hz,1H),7.55(d,J＝2.1Hz,1H),7.37(dd,J＝5.7,0.6Hz,1H),7.12(t,J＝7.8Hz,1H),5.54-5.65(m,1H),1.48(d,J＝5.1Hz,6H).
ESI-MS m/z:381.1.[M+H]+.
Example 3
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methoxy-1H-indole-2-carboxamide (I-3)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methoxy-1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO)11.70(s,1H),10.56(s,1H),8.88(s，1H),8.23(d,J＝8.3Hz,1H)，8.02(t,J＝7.9Hz,1H),7.84(d，J＝7.5Hz,1H)，7.63–7.47(m,2H)，6.93(s,1H)，6.75(d,J＝8.7Hz,1H)，5.66-6.45(m,1H),3.80(s,3H),1.47(d，J＝6.5Hz,6H).
ESI-MS m/z:377.2[M+H]+.
Example 4
Preparation of 6-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-4)
Preparation of 6-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO-d6):11.95(s,1H)，10.72(s,1H)，8.88(s,1H)，8.21(d，J＝8.3Hz,1H),8.03(t,J＝7.9Hz,1H),7.85(d,J＝7.6Hz,1H),7.74(m,1H),7.59(s,1H),7.20(d,J＝9.9Hz,1H),6.97(t,J＝9.3Hz,1H),5.65-6.45(m,1H),1.47(d,J＝6.6Hz,6H).
ESI-MS m/z:365.1[M+H]+.
Example 5
Preparation of 5-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-5)
Preparation of 5-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 1.
ESI-MS m/z:365.1[M+H]+.
Example 6
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1H-indole-2-carboxamide (I-6)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1H-indole-2-carboxamide reference example 1.
1H NMR(400MHz,DMSO-d6):10.80(s,1H),8.88(s,1H),8.18(d,J＝8.2Hz,1H),8.03(t,J＝7.9Hz,1H),7.88(d,J＝7.5Hz,1H),7.73(d,J＝7.9Hz,1H),7.61(d,J＝8.4Hz,1H)，7.42(s,1H)，7.35(t,J＝7.6Hz,1H),7.16(t,J＝7.4Hz,1H),5.84–5.68(m,1H)，4.04(s,3H),1.45(d,J＝6.6Hz,6H).
ESI-MS m/z:361.2[M+H]+
Example 7
Preparation of (R) -N- (6- (4- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-7)
Preparation of (R) -N- (6- (4- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO-d6):11.89(s，1H)，10.65(s,1H),8.80(s，1H)，8.21(dd，J＝8.3，0.6Hz,1H),8.03(t,J＝8.0Hz,1H),7.84(dd,J＝7.6,0.3Hz,1H),7.71(d,J＝7.9Hz,1H),7.55(d,J＝1.5Hz,1H),7.49(d,J＝8.1Hz,1H),7.26(m,1H),7.09(m,1H),5.61(m,1H),4.99(t,J＝5.4Hz，1H),3.66(m，2H),1.48(d,J＝6.9Hz，3H).
ESI-MS m/z:363.1[M+H]+.
Example 8
Preparation of N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide (I-8)
Preparation of N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO-d6):11.81(s,1H),10.43(s,1H),8.89(s,1H),8.14(s,1H),7.98(d,J＝8.2Hz,1H)，7.70(d,J＝8.0Hz，1H)，7.57(t,J＝7.9Hz，1H)，7.48(d，J＝7.7Hz，2H)，7.35(d,J＝7.7Hz,1H),7.24(t，J＝7.6Hz,1H),7.08(t,J＝7.5Hz,1H),4.43-4.58(m,1H),1.46(d,J＝6.7Hz,6H).
ESI-MS m/z:346.2[M+H]+.
Example 9
Preparation of 6-fluoro-N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide (I-9)
Preparation of 6-fluoro-N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO-d6):11.90(s,1H),10.45(s,1H),8.89(s,1H),8.13(t,J＝1.6Hz,1H),7.99–7.93(m,1H),7.74(dd,J＝8.8,5.5Hz,1H),7.57(t,J＝7.9Hz,1H),7.49(d,J＝1.5Hz，1H)，7.35(d,J＝7.7Hz,1H),7.19(dd,J＝9.9,2.2Hz,1H),7.01–6.92(m,1H)，4.57–4.43(m，1H)，1.46(d,J＝6.7Hz，6H).
ESI-MS m/z:364.1[M+H]+
Example 10
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-methyl-1H-indole-2-carboxamide (I-10)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-methyl-1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO-d6):11.64(s,1H),10.22(s，1H),8.89(s,1H)，8.25(dd,J＝8.4,2.4Hz,1H),8.03(m,1H),7.84(dd,J＝7.5,2.4Hz,1H),7.68(d,J＝8.1Hz,1H),7.45(d,J＝8.4Hz,1H),7.30(m,1H),7.07(t,J＝7.8Hz,1H),5.55-5.74(m,1H),2.55(s,3H),1.47(d,J＝6.7Hz,6H)
ESI-MS m/z:361.2[M+H]+.
Example 11
Preparation of 3- (furan-3-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-11)
First step preparation of 3-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide
N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (200mg, 0.58mmol) was dissolved in THF and reacted with NBS at RT for 3H; TLC detection reaction was completed, THF was removed by rotation, diluted with water, extracted with DCM, dried and dried, and column-chromatographed on silica gel to give the desired product (199mg, 81%).
ESI-MS m/z:425.1[M+H]+.
Second step preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-methyl-1H-indole-2-carboxamide
3-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (100mg, 0.24mmol), Pd (dppf) Cl2(18mg,0.024mmol)、K2CO3(66mg,0.48mmol) and furan-3-boronic acid pinacol ester (70mg,0.36mmol) with dioxane/H2Dissolving O, and reacting for 6 hours at 100 ℃; TLC detection reaction is finished, the reaction solution is cooled to room temperature, diluted by water and extracted by EA, organic phase is dried and dried, and silica gel column chromatography is carried out to obtain a target product (69mg, 69%).
1H NMR(400MHz,DMSO)12.10(s,1H),9.56(s,1H),8.88(s,1H),8.31(d,J＝8.0Hz,1H)，8.18(s,1H)，8.04(t,J＝8.0Hz,1H),7.94(t,J＝1.6Hz,1H)，7.90(d,J＝7.5Hz,1H)，7.58(d,J＝8.1Hz,1H),7.53(d,J＝8.3Hz,1H),7.32(t,J＝7.3Hz,1H)，7.14(t,J＝7.5Hz,1H),6.86(d,J＝0.9Hz,1H),5.32-5.44(m,1H),1.43(d,J＝6.7Hz,6H).
ESI-MS m/z:413.2[M+H]+.
Example 12
Preparation of 7-acetamido-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-12)
First step preparation of ethyl (E) -2- (2- (2- (2-nitrophenyl) hydrazino) propionate
Dissolving o-nitrophenylhydrazine hydrochloride (1g, 6.53mmol) with EtOH, adding ethyl pyruvate (731mg,6.3mmol), and reacting for 12h by RT; the reaction was concentrated to give the product as a yellow solid (1.2g, 73%).
ESI-MS m/z:252.1[M+H]+.
Second step preparation of 7-nitro-1H-indole-2-carboxylic acid ethyl ester
Dissolving (E) -ethyl 2- (2- (2- (2-nitrophenyl) hydrazino) propionate (1.2g,4.78mmol) in polyphosphoric acid, reacting at 80 ℃ for 3h, detecting by TLC that the reaction is finished, cooling to RT, diluting the reaction solution with water, adjusting the pH to 8 with saturated NaOH, extracting the water phase with EA, washing the EA with water and saturated common salt, drying and spin-drying the EA, and carrying out silica gel column chromatography to obtain a target product (800mg, 71%).
ESI-MS m/z:235.1[M+H]+.
Third step preparation of 7-amino-1H-indole-2-carboxylic acid ethyl ester
Taking ethyl 7-nitro-1H-indole-2-carboxylate (800mg, 3.42mmol) and using EtOH/H2Dissolving O (6:1), adding Fe (957mg,17.0mmol) and NH4Cl (1.10g, 20.0mmol), reaction at 80 ℃ for 4 h; TLC detection reaction is finished, the solution is filtered while the solution is hot, the filtrate is extracted by DCM, dried and dried by DCM, and separated by silica gel column chromatography to obtain the target product (400mg, 57%).
ESI-MS m/z:205.1[M+H]+.
Fourth step preparation of ethyl 7-acetylamino-1H-indole-2-carboxylate
Dissolving 7-amino-1H-indole-2-carboxylic acid ethyl ester (200mg,0.98mmol) in DCM, adding DIEA (253mg,1.96mmol), adding acetyl chloride (115mg,1.47mmol), and reacting at RT for 3H; TLC detection reaction is finished, reaction liquid is concentrated and then diluted by adding water, EA is extracted, the EA layer is washed by water and saturated salt solution, EA is dried and dried, and the target product (150mg, 62%) is obtained by silica gel column chromatography.
ESI-MS m/z:247.1[M+H]+.
Fifth step preparation of 7-acetamido-1H-indole-2-carboxylic acid
Taking ethyl 7-acetylamino-1H-indole-2-carboxylate (150mg,0.61mmol) and reacting with THF/H2Dissolving O5:1, adding NaOH (253mg,1.96mmol), and reacting for 3h at RT; TLC detection reaction is finished, the reaction solution is extracted by EA, the pH of the water phase is adjusted to 2 by 2M HCl and then extracted by EA, EA is dried and dried, and the target product (100mg, 75%) is obtained by silica gel column chromatography.
ESI-MS m/z:219.1[M+H]+.
Sixth step preparation of 7-acetylamino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide
Preparation of 7-acetylamino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 1.
1H NMR(300MHz,DMSO-d6):11.82(s,1H),10.80(s,1H),9.94(s,1H),8.89(s,1H),8.22(d,J＝8.2Hz,1H),8.05(t,J＝7.9Hz，1H)，7.96(d，J＝7.5Hz，1H)，7.86(d,J＝7.4Hz,1H)，7.62(s，1H)，7.44(d,J＝7.8Hz,1H),7.05(t,J＝7.8Hz,1H),5.63–5.80(m,1H),2.18(s,3H),1.47(d,J＝6.5Hz,6H).
ESI-MS m/z:404.2[M+H]+.
Example 13
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-13)
First step preparation of 7-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide
Preparation of 7-acetylamino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 1 (third step).
ESI-MS m/z:425.1[M+H]+.
Second step preparation of 7-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide
Taking 7-bromo-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (100mg, 0.24mmol), Pd (dppf) Cl2(18mg,0.024mmol)、K3PO4(102mg,0.48mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (106mg,0.36mmol) with Dioxane/H2Dissolving O5:1, and reacting for 3h at 110 ℃; after the TLC detection reaction, the reaction solution was cooled to room temperature, diluted with water and extracted with EA, which was dried and then separated by silica gel column chromatography to obtain the desired product (50mg, 51%).
1H NMR(300MHz,DMSO-d6):13.14(s,1H),11.01(d,J＝47.6Hz,2H),8.89(s,1H),8.45–7.97(m,4H),7.82(d,J＝7.1Hz,1H),7.68–7.33(m,3H),7.15(s,1H),5.59(s,1H),1.47(d,J＝5.2Hz,6H).
ESI-MS m/z:413.2[M+H]+.
Example 14
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-14)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide reference was made to example 13.
1H NMR(300MHz,DMSO-d6):12.89(s，1H)，12.06(s,1H)，10.83(s，1H),8.89(s,1H)，8.22(d，J＝8.0Hz，1H)，8.04(t,J＝7.9Hz，3H)，7.90(s,1H),7.85(d，J＝7.3Hz，1H),7.50(q，J＝8.3Hz，3H)，5.81–5.66(m，1H)，1.47(d,J＝6.7Hz,6H).
ESI-MS m/z:413.2[M+H]+.
Example 15
Preparation of 6- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-15)
Preparation of 6- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) reference example 13.
1H NMR(400MHz,DMSO)12.01(s,1H),10.74(s,1H),8.90(s,1H),8.39(s,1H),8.23(d,J＝8.0Hz,1H),8.04(t,J＝8.0Hz,1H),7.94(s,1H),7.85(d,J＝7.5Hz,1H),7.70(d,J＝8.4Hz,1H)，7.64(s，1H)，7.54(s,1H),7.39(dd,J＝8.3,1.4Hz,1H)，5.73(dt,J＝13.3，6.6Hz,1H),5.58(q,J＝5.9Hz,1H),3.52–3.44(m,1H)，3.29–3.23(m,1H),1.66(d,J＝6.0Hz,3H),1.48(d,J＝6.7Hz,6H),1.06(t,J＝7.0Hz,3H).
ESI-MS m/z:485.2[M+H]+.
Example 16
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-16)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(300MHz，DMSO-d6):12.92(s,1H),11.88(s,1H),10.66(s,1H),8.89(s,1H),8.23(d,J＝8.2Hz,1H),8.04(t,J＝8.0Hz,2H),7.85(d,J＝7.6Hz,1H),7.68(d,J＝8.3Hz,1H),7.62(s,1H),7.54(s，1H),7.38(d，J＝8.3Hz，1H),5.62-5.73(m,1H),1.47(d,J＝6.6Hz,6H).
ESI-MS m/z:413.2[M+H]+.
Example 17
Preparation of N- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) -4- (trifluoromethyl) benzamide (I-17)
Preparation of N- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) -4- (trifluoromethyl) benzamide reference was made to example 13.
1H NMR(300MHz,DMSO-d6):12.07(s,1H),10.74(s,1H),8.93(s,1H),8.89(s,1H),8.58(d,J＝1.8Hz,1H),8.24(d,J＝8.1Hz,1H),8.13(d,J＝8.0Hz,1H),8.05(t,J＝7.9Hz,1H)，7.86(d，J＝1.8Hz,1H)，7.84(d,J＝2.7Hz,1H),7.76(s,1H)，7.63(d，J＝1.8Hz，1H)，7.54(m,1H)，7.46(d,J＝8.3Hz，1.2Hz,1H),5.77–5.66(m,1H)，1.48(d,J＝6.7Hz,6H).
ESI-MS m/z:424.2[M+H]+.
Example 18
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-18)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(400MHz,DMSO)11.87(s，1H)，10.64(s,1H)，8.90(s，1H)，8.27(s,1H)，8.23(d，J＝8.1Hz,1H)，8.04(t，J＝8.0Hz,1H)，7.89(s，1H)，7.85(d，J＝7.6Hz,1H)，7.69(d,J＝8.4Hz,1H),7.60(s,1H),7.55(d,J＝1.4Hz,1H)，7.36(dd,J＝8.4,1.3Hz,1H)，5.65-5.75(m，1H)，4.44(t，J＝7.6Hz，1H)，3.99(dd，J＝8.3，2.9Hz，2H)，3.49(td，J＝11.6,5.6Hz,2H),2.02(dt,J＝12.7，6.2Hz，4H),1.47(d,J＝6.7Hz,6H).
ESI-MS m/z:497.2[M+H]+.
Example 19
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-19)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(400MHz,DMSO-d6):12.00(s,1H),10.78(d,J＝7.1Hz,1H),8.89(s,1H),8.27(s,1H),8.22(d,J＝8.3Hz,1H),8.10–8.00(m,2H),7.96(s,1H),7.80(d,J＝7.6Hz,1H),7.39–7.33(m,1H),7.29–7.20(m,2H),5.46-5.65(m,1H),3.95(s,3H),1.46(d,J＝6.7Hz,6H).
ESI-MS m/z:427.2[M+H]+.
Example 20
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (thien-3-yl) -1H-indole-2-carboxamide (I-20)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (thiophen-3-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(300MHz,DMSO-d6):11.13(s,1H),10.90(s,1H),8.89(s,1H),8.26(d,J＝7.8Hz,1H),8.05(t,J＝8.0Hz,1H)，7.98(dd,J＝2.8,1.3Hz,1H)，7.82(d，J＝7.0Hz，1H),7.76(dd,J＝5.0,2.9Hz,1H),7.70(d,J＝7.8Hz,1H),7.59–7.52(m,2H),7.41(dd,J＝7.2,0.9Hz,1H)，7.24–7.15(m,1H)，5.65–5.49(m,1H)，1.46(d,J＝6.7Hz,6H).
ESI-MS m/z:429.1[M+H]+.
Example 21
Preparation of 7- (furan-3-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-21)
Preparation of 7- (furan-3-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(400MHz,DMSO)11.02(s，1H)，10.90(s，1H),8.89(s,1H)，8.41(s，1H)，8.27(d,J＝8.3Hz，1H)，8.05(t，J＝8.0Hz,1H),7.87(s,1H),7.82(d,J＝7.6Hz,1H),7.68(d,J＝7.9Hz,1H),7.53(d,J＝1.5Hz,1H),7.43(d,J＝7.1Hz,1H),7.18(t,J＝7.6Hz,1H),7.04(s，1H),5.59(m,5.52-5.65,1H),1.46(d，J＝6.7Hz,7H).
ESI-MS m/z:413.2[M+H]+.
Example 22
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-phenyl-1H-indole-2-carboxamide (I-22)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (thiophen-3-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(400MHz,DMSO)11.28(s,1H),10.87(s,1H),8.89(s,1H),8.25(d,J＝8.3Hz,1H),8.04(t,J＝8.0Hz,1H),7.83–7.78(m,1H),7.72(t,J＝7.8Hz,3H),7.59–7.52(m,3H),7.47(t,J＝7.4Hz，1H),7.29(dd,J＝7.2，1.0Hz,1H),7.22(t,J＝7.5Hz,1H),5.47-5.57(m,1H),1.46(d,J＝6.7Hz,6H).
ESI-MS m/z:423.2[M+H]+.
Example 23
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (pyridin-4-yl) -1H-indole-2-carboxamide (I-23)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (pyridin-4-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(300MHz,DMSO)11.59(s,1H),10.84(s,1H)，8.90(s，1H),8.74(s,2H),8.25(d，J＝8.3Hz,1H),8.05(t,J＝8.0Hz,1H),7.83(dd,J＝7.6,2.4Hz,2H),7.75(s,2H),7.60(d,J＝1.8Hz,1H),7.39(d,J＝6.3Hz,1H),7.32–7.20(m,1H),5.52-5.62(m,1H),1.45(t,J＝8.1Hz,6H).
ESI-MS m/z:424.2[M+H]+.
Example 24
Preparation of 7- (3, 6-dihydro-2H-pyran-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-24)
Preparation of 7- (3, 6-dihydro-2H-pyran-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(400MHz,DMSO)11.31(s,1H),10.79(s,1H),8.89(s,1H),8.25(t,J＝11.4Hz,1H),8.05(t,J＝7.1Hz,1H),7.83(d,J＝6.9Hz,1H),7.56(dt，J＝26.5，8.9Hz，3H)，7.22–7.01(m，1H),6.17(s，1H),5.81–5.47(m，1H),4.27(d，J＝31.8Hz，2H),3.97(d，J＝37.7Hz,2H)，2.13(d，J＝35.7Hz，2H),1.44(t,J＝18.2Hz,6H).
ESI-MS m/z:429.2[M+H]+.
Example 25
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-indole-2-carboxamide (I-25)
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-indole-2-carboxamide reference example 13.
1H NMR(300MHz,DMSO)11.38(s,1H),10.86–10.63(m,1H),8.88(d,J＝26.9Hz,1H),8.26(t,J＝12.3Hz,1H),8.13–7.95(m,1H),7.86(d，J＝7.5Hz，1H)，7.63(t，J＝9.9Hz，1H)，7.50(d，J＝19.8Hz，1H)，7.22–7.04(m,3H),6.08(s，1H)，5.68(dd，J＝13.0，6.5Hz,1H),4.10(s,3H),3.66(s,3H),1.51(s,6H).
ESI-MS m/z:428.2[M+H]+.
Example 26
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxamide (I-26)
First step preparation of ethyl 6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxylate
Ethyl 6-amino-1H-indole-2-carboxylate (500mg, 2.45mmol) was dissolved in DCM, DIEA (632mL, 4.9mmol) and tetrahydropyranone (370mg, 3.70mmol) were added, stirring was carried out at RT for 2H, sodium borohydride acetate (2.6g, 12.3mmol) was added, and reaction was carried out at RT for 2H. TLC detection reaction is finished, DCM is removed, residue is diluted by water and extracted by EA, EA is dried and dried, and silica gel column chromatography is carried out to obtain a target product (442mg, 60%).
ESI-MS m/z:289.1[M+H]+.
Second step preparation of 6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxylic acid
Ethyl 6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxylate (442mg, 1.47mmol) was taken in MeOH/H2O5:1, NaOH (118mg,2.94mmol) was added and the reaction was carried out at RT for 4 h. And (3) after TLC detection reaction is finished, adding a small amount of water into the reaction liquid, extracting with EA, adjusting the pH of the water phase to 2, extracting the water phase with EA, drying and spin-drying the EA to obtain the target product (300mg, 78%).
ESI-MS m/z:261.1[M+H]+.
Third step preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxamide
Preparation of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxamide reference is made to example 1.
1H NMR(400MHz,DMSO)11.85(s,1H),8.89(s,1H),8.29(d,J＝8.1Hz,1H),8.07(q,J＝8.2Hz，1H),7.91(dd，J＝7.7,0.8Hz，1H),7.85–7.78(m,2H),7.65(t，J＝8.9Hz,1H),7.51(t,J＝7.9Hz,1H),5.55-5.65(m,J,1H),4.87(s,1H),4.09–3.96(m,2H),3.57(t,J＝11.1Hz,2H),3.17(d,J＝5.3Hz，1H),2.71(dd,J＝15.4,7.8Hz,2H),1.69(d,J＝9.8Hz,2H)，1.48(t，J＝7.0Hz,6H).
ESI-MS m/z:446.2[M+H]+.
Biological activity assay
1. ASK1 protein kinase Activity assay
The test uses a homogeneous time-resolved fluorescence (HTRF) assay to test compounds for inhibitory activity against ASK1 kinase, in contrast to the positive compound GS-4997.
(1) Diluted compounds were added to 384-well plates, and AssayBuffer diluted DMSO was added to positive and negative control wells, respectively.
(2) The compound and positive control wells were loaded with STK-Substrate 3-biotin/ATP and ASK1(MAP3K5), and the negative control wells were loaded with STK-Substrate 3-biotin/ATP and Assay Buffer.
(3) After incubation for 2.0h at room temperature, STK S3 Antibody-Eu was added.
(4) Incubating at room temperature for 1.0h, measuring the fluorescence signal value of each plate hole by an enzyme-labeling instrument, and calculating the inhibition rate and IC according to the fluorescence signal value50Values were calculated by prism (graphpad software) fitting curves.
The ASK1 protein kinase activity of some of the compounds of the examples of the invention is shown in Table 1
TABLE 1 ASK1 protein kinase Activity of some of the compounds of the examples of the invention
| Compound numbering | ASK1 IC50 | Compound numbering | ASK1 IC50 |
| I-1 | 42nM | I-14 | 31.49nM |
| GS-4997 | 14nM | I-16 | 37.22nM |
| I-4 | 32.65nM | I-19 | 18.46nM |
| I-13 | 38.86nM | I-23 | 23.3nM |
The compounds of the above examples have strong ASK1 kinase inhibitory activity. As a powerful ASK1 small-molecule inhibitor, the compounds have great potential clinical application value aiming at the treatment of ASK1 related diseases.
2. AP1-HEK293 cell inhibitory Activity assay
The method utilizes AP1 Reporter-HEK293 recombinant cells to evaluate the influence of compounds on a downstream signal path of ASK1 at a cellular level.
(1) HEK293-AP1 cells were seeded into 96-well plates and 100uL Thaw Medium 1 was added.
(2) Exposing the cells to CO2Incubate overnight in the incubator.
(3) The medium was slowly poured out of the well plate, Assay medium was diluted with Assay medium and added to the wells, Assay medium dilutions of the same concentration of DMSO were added to the wells as controls, and Assay medium dilutions of the same concentration of DMSO were added to the wells without cells to remove background fluorescence signals.
(4) Incubate for 1 h.
(5) Background fluorescence signals were removed by adding dilutions of PMA Assay medium to the wells, 0.1% DMSO Assay medium to the wells as a control, and 0.1% DMSO Assay medium to the wells without cells.
(6) Using ONE-Step according to the operating specificationTMLuciferase assay system for luciferase assay: adding ONE-StepTMLuciferase reagent was added to the wells, shaken at room temperature for 15min, and the fluorescent signal was measured using a luminometer.
(7) And (3) data analysis: background fluorescence values were subtracted. ComputingInhibition per compound and IC was fitted from inhibition50The value is obtained.
The cell activity of the compound AP1-HEK293 of some examples of the invention is shown in Table 2
TABLE 2 AP1-HEK293 cell Activity of some of the compounds of the examples of the invention
The compound of some examples shows cell activity superior to that of the positive medicine GS-4997, and the compound has excellent physical and chemical properties and drug forming property.
3. Human liver microsome stability
The method preliminarily evaluates the in vitro metabolic stability of the compound through a human liver microsome stability experiment
The experimental steps are as follows:
(1) buffer A1.0L 0.1M Potassium dihydrogen phosphate buffer containing 1.0mM EDTA
Buffer B1.0L 0.1M dipotassium phosphate buffer containing 1.0mM EDTA
Buffer C0.1M potassium phosphate buffer, 1.0mM EDTA, pH7.4, 700mL of buffer B was titrated with buffer A while monitoring with a pH meter.
(2) Reference compound (Ketanserin) and test compound spiking solutions:
500 μ M spiking solution: mu.L of 10mM DMSO stock solution was added to 190. mu.L ACN.
Add 1.5. mu.M spiking solution (0.75mg/mL) to microsomes: mu.L of 500. mu.M spiking solution and 18.75. mu.L of 20mg/mL liver microsomes were added to 479.75. mu.L of buffer C on ice.
(3) An NADPH stock solution (6mM) was prepared by dissolving NADPH in buffer C.
(4) 30 μ L of 1.5 μ Mspiking solution containing 0.75mg/mL microsome solution was dispensed onto assay plates designated for different time points (0, 5, 15, 30, 45 minutes) on ice.
(5) For 0min, 135. mu.L of IS-containing ACN were added to the wells of the 0min plate, followed by 15. mu.L of NADPH stock solution (6 mM).
(6) All other plates were preincubated at 37 ℃ for 5 minutes.
(7) To the plate, 15. mu.L of NADPH stock solution (6mM) was added to start the reaction and timing.
(8) At 5min, 15min, 30 min and 45 min, 135. mu.L of IS-containing ACN was added to the wells of the respective plates to stop the reaction.
(9) After quenching, plates were shaken on a shaker (IKA, MTS 2/4) for 10 minutes (600 rpm) and then centrifuged at 5594g for 15 minutes (Thermo Multifuge. times.3R).
(10) From each well, 50 μ L of supernatant was transferred to a 96-well sample plate containing 50 μ L of ultrapure water (Millipore, ZMDS 50F01) for LC/MS analysis.
(11) And fitting a curve according to the peak areas of the compounds at different time points, and calculating the half-life and the clearance rate.
TABLE 3 hepatic microsome stability data for some of the compounds of the examples of the invention
| Compound numbering | T1/2(minute) | Clint(mL/min/kg) |
| GS-4997 | 212 | 8.21 |
| I-1 | 821.4 | 2.12 |
The I-1 compound shows in vitro human liver microsome metabolic stability superior to the positive drug GS-4997.
4. Rat in vivo PK
Experimental procedures
(1)6 male SD Rat,198-225g (JH Laboratory Animal Co. LTD), three intravenous injection groups, and 3 oral administration groups. The intravenous injection group is normally fed with food and water; oral groups were fasted overnight in advance and fed 4h after dosing. (2) Intravenous injection is carried out on the dorsum of foot at the concentration of 1mg/kg in an intravenous injection group, and oral gavage is carried out at the concentration of 10mg/kg in an oral group. (3) Animals were manually restrained at the indicated time points and approximately 150 μ L of blood samples were collected via the tail vein for serial infiltration into EDTA-K2 tubes. Blood samples were first stored in wet ice and centrifuged within 15 minutes after sampling to obtain plasma (2000g, 4 ℃, 5 minutes). The groups were given 0.083, 0.25, 0.5, 1,2,4, 8, 24h,8 time points for the group given intravenous injection, and 0.25, 0.5, 1,2,4, 8, and 24h, 7 time points for the group given oral administration. (4) Blood samples were stored at around-70 ℃ until analysis. (5) According to the blood concentration at each time point, the oral group calculates CL and Vss、AUClast、AUCINF、T1/2、MRTINF(ii) a Calculation of T by intravenous injection groupmax、Cmax、AUClast、AUCINF、T1/2、F。
TABLE 4 in vivo PK data in rats for I-1 Compounds
NA:Not available
TABLE 5 in vivo PK data in rats for I-4 Compounds
The I-1 and I-4 compounds show good in vivo pharmacokinetic properties, have conditions for carrying out in vivo pharmacodynamic experiments, and have excellent druggability.
5. CDAA (CDAA-induced nucleic acid sequence analysis) induced NASH (NASH) mouse pharmacodynamic model research
Purpose of the experiment: establishing a NASH (non-alcoholic steatohepatitis) in-vivo pharmacodynamic evaluation model, and carrying out pharmacodynamic study on the tested medicament in the NASH model.
Experimental materials: CDAA feed (Packo: Research Diets: A06071302), 10% neutral formaldehyde fixing solution (formalin, Chengdu Li Bio-technology Co., Ltd.), methylcellulose (MC, Shanghai Merlian Bio Co., Ltd.), Tween 80 (Shanghai Merlian Bio Co., Ltd.), C57BL/6J mouse (Beijing Wintoli laboratory animal technology Co., Ltd.), animal weighing scale (Shanghai Hua Chao electric appliances Co., Ltd.), microscope (MIC01964, Chuiss optical instrument), pipette (Eppendorf)
And (3) experimental operation:
(1) c57BL/6J mice were housed in SPF cell houses for at least one week of acclimation.
(2) The group was divided into a normal Control group (Control), a model group (Vehicle), and a compound of example 5 50mpk group by body weight and food intake. The other animals were fed CDAA feed except the normal control group. The molding time of CDAA was 12 weeks, and the administration was from week 5 to week 12. The administration route is intragastric administration, and the administration frequency is once a day. Performing cage-side observation every day, and measuring food intake and body weight once per week before administration; after administration, food intake and body weight were measured twice a week and once at 3-4 d.
(3) Fasting for more than 6 hours before dissection, anesthetizing by using 3% sodium pentobarbital, collecting blood by heart blood collection, centrifuging, taking supernatant, and sending the supernatant to a sample to detect blood biochemical indexes: ALP, TC, HDL, LDL.
(4) Experimental data for each group of animals are described as mean ± standard error (X ± SEM). The comparison between groups with uniform normal and variance adopts One-Way ANOVA (One-Way ANOVA), and the comparison between groups adopts LSD (least squares difference) method for inspection; p <0.05 is statistically significant for differences. All statistical analyses were done using Graphpad Prism 8.0 software.
The experimental results are as follows:
TABLE 6 Effect of I-4 Compounds in a mouse model of NASH
| Liver weight (g) | ALP(U/L) | HDL(mmol/L) | LDL/TC | |
| Control group | 1.097 | 116.8 | 2.553 | 0.06895 |
| Vehicle group | 1.534 | 196.9 | 1.276 | 0.1302 |
| EXAMPLE 4 group | 1.382 | 158.0 | 1.404 | 0.1225 |
Compared with Vehicle, the I-4 compound down-regulates the liver weight, down-regulates ALP, up-regulates HDL and down-regulates LDL/TC of NASH mice, and shows certain NASH treatment potential.
6. Research on drug effect model of DSS-induced acute colitis mouse
The experimental method comprises the following steps: (1) ICR mice, weight 18-22g, 6-8 weeks old, adaptive feeding 5 days later, randomly divided into 4 groups: control, DSS, GS-4997, example 4, 6 pieces per group. (2) Acute colitis was induced by 3% DSS, and the 3% DSS-containing aqueous solution was administered to the DSS, GS-4997, example 4 groups and allowed to drink freely. GS-4997 was administered at a dose of 25mg/kg, example 5 at a dose of 25mg/kg, and the Control (Control) was given normal drinking water for 7 consecutive days, with replacement every two days. During the molding period, the medicine is administered by means of intragastric administration, and the Control group and the DSS group are administered with the corresponding solvent CMC-Na once a day for 7 days continuously. (3) After 7 days, the mice were sacrificed by cervical dislocation, colon tissues were taken, the length of the colon was measured, 3 of each group were fixed in formalin solution for HE staining, and the remaining tissues were stored at-80 ℃.
The experimental results are as follows: the effect of the I-4 compounds on colon length in DSS-induced colitis mice is shown in FIG. 1.
The colon length was significantly shortened in DSS mice compared to Control mice: (###P<0.001). The colon length of the I-4 mice was significantly increased compared to the DSS group (. about.P)<0.05), while the colon length of the GS-4997 group mice is increased to a certain extent without significant difference. The effect of the I-4 compound on colon histopathology in DSS-induced colitis mice is shown in FIG. 2.
The colon tissue of the mice in the Control group is intact, and inflammatory cell infiltration phenomenon is not seen. DSS mice have severe damage to colon tissue and a large number of inflammatory cells infiltrate. The colon tissue of the mice in the I-4 compound administration group is relatively complete, and the inflammation is obviously reduced; the GS-4997 group mice had some reduction in tissue damage.
The results of two experiments of the I-4 compound in a mouse model of DSS-induced colitis show that the I-4 compound has a certain treatment effect on ulcerative colitis and is superior to the positive drug GS-4997.
Claims (10)
1. An indole ASK1 small molecule inhibitor, which is characterized by comprising a compound shown as a general formula (I) and a stereoisomer or pharmaceutically acceptable salt thereof:
M1is selected from N or CH;
R1is the same or different and is independently selected from hydrogen atom, alkoxy, halogen, heterocyclic radical, aryl, heteroaryl, - (CH)2)nOR4、-(CH2)nNR5R6、-(CH2)nNR5C(O)R4N is 0, 1,2,3, 4 or 5; wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, and heterocyclyl;
R2the same or different, and each is independently selected from hydrogen atom, alkyl, halogen, aryl, heteroaryl;
R3selected from alkyl, hydroxyalkyl or heterocyclyl;
R4selected from alkyl groups;
R5and R6The same or different, and each is independently selected from hydrogen atom, heterocyclic radical;
x is selected from N (R)2)；
m is 0, 1,2,3 or 4;
p is 1 or 2.
2. The indole ASK1 small-molecule inhibitor according to claim 1, wherein M is1Is N:
3. the indole ASK1 small-molecule inhibitor according to claim 2, wherein X is imino and R is R3Is isopropyl, and is specifically shown as a general formula (III):
4. the indole ASK1 small molecule inhibitor according to any one of claims 1-2, wherein R is1Selected from the group consisting of a hydrogen atom, a methoxy group, a chlorine atom, a fluorine atom, a 3, 6-dihydro-2H-pyran-4-yl group, a 1,2,3, 6-tetrahydropyridin-4-yl group, a phenyl group, a pyrazolyl group, a thienyl group, a furyl group, a pyridyl group, a 1- (1-ethoxyethyl) -1H-pyrazol-4-yl group, a 1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl group, a 1-methyl-1H-pyrazol-4-yl group, and an acetamido group; r2Selected from hydrogen atom, methyl, furyl; r3Selected from 1-hydroxypropan-2-yl, isopropyl; r4Is C1-6An alkyl group; r5Is a hydrogen atom; r6Is tetrahydro-2H-pyran-4-yl.
5. The indole ASK1 small molecule inhibitor according to claim 1, selected from the group consisting of: n- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-1), 7-chloro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-2), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methoxy-1H-indole-2-carboxamide (I-3), 6-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-4), 5-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-5), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-methyl-1H-indole-2-carboxamide (I-6), (R) -N- (6- (4- (4- (1-hydroxypropan-2-yl) -4H-1,2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-7), N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide (I-8), 6-fluoro-N- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1H-indole-2-carboxamide (I-9), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-methyl-1H-indole-2-carboxamide (I-10), 3- (furan-3-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-11), 7-acetamido-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-12), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-13), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-14), 6- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-15), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-16), N- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) -4- (trifluoromethyl) benzamide (I-17), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-18), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4- (1-methyl-1H-pyrazol-4-yl) -1H-indole-2-carboxamide (I-19), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (thiophen-3-yl) -1H-indole-2-carboxamide (I-20), 7- (furan-3-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-21), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-phenyl-1H-indole-2-carboxamide (I-22), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (pyridin-4-yl) -1H-indole-2-carboxamide (I-23), 7- (3, 6-dihydro-2H-pyran-4-yl) -N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1H-indole-2-carboxamide (I-24), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7- (1,2,3, 6-tetrahydropyridin-4-yl) -1H-indole-2-carboxamide (I-25), N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- ((tetrahydro-2H-pyran-4-yl) amino) -1H-indole-2-carboxamide (I-26).
6. The indole ASK1 small molecule inhibitor according to claim 1, wherein the pharmaceutically acceptable salt is a salt of the inhibitor with an acid or a base, the acid being hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, or mandelic acid; the base is an inorganic base containing a basic metal cation, an alkaline earth metal cation, or an ammonium cation salt.
7. The preparation method of the indole ASK1 small-molecule inhibitor as claimed in claim 1, comprising the following steps:
(1) methyl 3-aminobenzoate or methyl 6-aminopyridine-2-carboxylate A is firstly converted into a hydrazide compound B;
(2) a compound C is obtained through ring closing reaction, and the compound C reacts with a carboxylic acid compound D to obtain a compound (I);
and (3) adding a corresponding acid or alkali solution into the solution of the compound (I) prepared by the method, and removing the solvent under reduced pressure after salt formation is completed to obtain the pharmaceutically acceptable salt of the ASK1 inhibitor.
8. A pharmaceutical composition comprising the indole ASK1 small molecule inhibitor of claim 1 and one or more pharmaceutically acceptable carriers, diluents, or excipients.
9. The use of the indole ASK1 small molecule inhibitor of claim 1 or the pharmaceutical composition of claim 8 for the preparation of an ASK1 inhibitor medicament.
10. Use of the indole ASK1 small molecule inhibitor of claim 1 or the pharmaceutical composition of claim 8 for the preparation of a medicament for the treatment of inflammatory diseases and ASK 1-related diseases; the inflammatory diseases are non-alcoholic steatohepatitis and ulcerative colitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010777152.8A CN111808079A (en) | 2020-08-05 | 2020-08-05 | Indole ASK1 small molecule inhibitor and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010777152.8A CN111808079A (en) | 2020-08-05 | 2020-08-05 | Indole ASK1 small molecule inhibitor and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111808079A true CN111808079A (en) | 2020-10-23 |
Family
ID=72863886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010777152.8A Pending CN111808079A (en) | 2020-08-05 | 2020-08-05 | Indole ASK1 small molecule inhibitor and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111808079A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112300134A (en) * | 2020-10-30 | 2021-02-02 | 中国药科大学 | ASK1 inhibitor and derivative thereof, preparation method, pharmaceutical composition and application |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482257A (en) * | 2009-07-13 | 2012-05-30 | 吉利德科学股份有限公司 | Apoptosis signal-regulating kinase inhibitors |
| CN102834393A (en) * | 2010-02-03 | 2012-12-19 | 武田药品工业株式会社 | Apoptosis signal-regulating kinase 1 inhibitors |
| CN104080771A (en) * | 2012-01-27 | 2014-10-01 | 吉利德科学公司 | Apoptosis signal-regulating kinase inhibitor |
| CN105198789A (en) * | 2015-10-26 | 2015-12-30 | 山东大学 | Substituted3-indole Bcl-2 protein inhibitor and preparation method and application thereof |
| WO2018133865A1 (en) * | 2017-01-22 | 2018-07-26 | 福建广生堂药业股份有限公司 | Ask1 inhibitor and preparation method and use thereof |
| WO2018149284A1 (en) * | 2017-02-16 | 2018-08-23 | 四川科伦博泰生物医药股份有限公司 | Kinase inhibitor and preparation method therefor and use thereof |
| WO2018233553A1 (en) * | 2017-06-19 | 2018-12-27 | 广东东阳光药业有限公司 | Fused bicyclic compound and use thereof in medicine |
-
2020
- 2020-08-05 CN CN202010777152.8A patent/CN111808079A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482257A (en) * | 2009-07-13 | 2012-05-30 | 吉利德科学股份有限公司 | Apoptosis signal-regulating kinase inhibitors |
| CN102834393A (en) * | 2010-02-03 | 2012-12-19 | 武田药品工业株式会社 | Apoptosis signal-regulating kinase 1 inhibitors |
| CN104080771A (en) * | 2012-01-27 | 2014-10-01 | 吉利德科学公司 | Apoptosis signal-regulating kinase inhibitor |
| CN105198789A (en) * | 2015-10-26 | 2015-12-30 | 山东大学 | Substituted3-indole Bcl-2 protein inhibitor and preparation method and application thereof |
| WO2018133865A1 (en) * | 2017-01-22 | 2018-07-26 | 福建广生堂药业股份有限公司 | Ask1 inhibitor and preparation method and use thereof |
| WO2018149284A1 (en) * | 2017-02-16 | 2018-08-23 | 四川科伦博泰生物医药股份有限公司 | Kinase inhibitor and preparation method therefor and use thereof |
| CN109071498A (en) * | 2017-02-16 | 2018-12-21 | 四川科伦博泰生物医药股份有限公司 | Kinase inhibitor and its preparation method and application |
| WO2018233553A1 (en) * | 2017-06-19 | 2018-12-27 | 广东东阳光药业有限公司 | Fused bicyclic compound and use thereof in medicine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112300134A (en) * | 2020-10-30 | 2021-02-02 | 中国药科大学 | ASK1 inhibitor and derivative thereof, preparation method, pharmaceutical composition and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106928219B (en) | Nitrogen-containing fused heterocyclic compound, preparation method, intermediate, composition and application | |
| KR20070089201A (en) | Pyrrolopyrazines and pyrazolopyrazines useful as inhibitors of protein kinases | |
| AU2006210626A1 (en) | Raf inhibitor compounds and methods | |
| AU2006284751A1 (en) | Raf inhibitor compounds and methods of use thereof | |
| JPH10512896A (en) | Aryl and heteroaryl purine compounds | |
| JP2003513091A (en) | Pyrazolones substituted with heterocycles | |
| WO2014040549A1 (en) | Alkynyl heteroaromatic ring compound and application thereof | |
| WO2000023444A1 (en) | 5,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds | |
| AU2018248581B2 (en) | Heteroaromatic compounds useful in therapy | |
| CN109311891A (en) | The crystallization of Pyrrolopyrimidine compounds as JAK inhibitor | |
| CN111542522B (en) | Substituted pyrazolopyrimidines useful as kinase inhibitors | |
| KR20180066985A (en) | Thienopyrimidine derivative and use thereof | |
| CN116406271A (en) | Bicyclic compounds | |
| CA2508319A1 (en) | Jnk inhibitors | |
| JP2001520655A (en) | 5,7-Disubstituted 4-aminopyrido [2,3-D] pyrimidine compounds and their use as adenosine kinase inhibitors | |
| CA2602303A1 (en) | Tricyclic azole derivatives, their manufacture and use as pharmaceutical agents | |
| WO2020125513A1 (en) | Macrocyclic compound as cdk inhibitor, preparation method therefor, and use thereof in medicine | |
| CN111808079A (en) | Indole ASK1 small molecule inhibitor and preparation method and application thereof | |
| CN112513027A (en) | Indazole amine derivative, preparation method and medical application thereof | |
| CN113416181B (en) | Quinazoline derivative and application thereof | |
| CN116782903A (en) | Substituted pyridone compounds and uses thereof | |
| KR101546743B1 (en) | Indole derivatives, Abl kinase inhibiting composition and pharmaceutical compositions for prevention and treatment of abnormal cell growth diseases comprising the same | |
| CN112654604B (en) | 7-substituted indazole derivative, preparation method and medical application thereof | |
| CN114315837A (en) | Crystalline form of ERK inhibitor and preparation method thereof | |
| CN108752336B (en) | Imidazoquinoline derivatives and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20201023 |
|
| RJ01 | Rejection of invention patent application after publication |