CN111601790B - 作为蛋白激酶抑制剂的杂芳基化合物 - Google Patents
作为蛋白激酶抑制剂的杂芳基化合物 Download PDFInfo
- Publication number
- CN111601790B CN111601790B CN201980005170.XA CN201980005170A CN111601790B CN 111601790 B CN111601790 B CN 111601790B CN 201980005170 A CN201980005170 A CN 201980005170A CN 111601790 B CN111601790 B CN 111601790B
- Authority
- CN
- China
- Prior art keywords
- oxy
- amino
- phenyl
- ethyl
- chloropyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 125000001072 heteroaryl group Chemical group 0.000 title claims description 17
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
- 239000003909 protein kinase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- -1 Heterocycloalkyl radical Chemical class 0.000 claims description 345
- 125000000217 alkyl group Chemical group 0.000 claims description 101
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 85
- 229910052739 hydrogen Inorganic materials 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 76
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 55
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 24
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 21
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 claims description 11
- JWSNKXRQXLEKBI-UHFFFAOYSA-N 5-chloro-3-propan-2-yloxypyridin-2-amine Chemical compound NC1=NC=C(C=C1OC(C)C)Cl JWSNKXRQXLEKBI-UHFFFAOYSA-N 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 230000010261 cell growth Effects 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 230000002159 abnormal effect Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- XEXAJLKJFGBERQ-UHFFFAOYSA-N 5-chloro-3-[6-[(4-chlorophenyl)methoxy]-5-methoxypyridin-3-yl]oxypyridin-2-amine Chemical compound ClC=1C=C(C(=NC=1)N)OC=1C=NC(=C(C=1)OC)OCC1=CC=C(C=C1)Cl XEXAJLKJFGBERQ-UHFFFAOYSA-N 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- RQGFSHYQCLTEAK-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]-4-fluorophenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1F)NC(C1=CC(=CC=C1)OC)=O)Cl RQGFSHYQCLTEAK-UHFFFAOYSA-N 0.000 claims description 3
- NPJCOGXBFIATSP-UHFFFAOYSA-N N-[3-[1-(2-amino-5-chloropyridin-3-yl)oxycyclopropyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1OC1(CC1)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl NPJCOGXBFIATSP-UHFFFAOYSA-N 0.000 claims description 3
- KBFXFCDOUPTFEJ-UHFFFAOYSA-N N-[3-[2-(2-amino-5-chloropyridin-3-yl)cyclopropyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1C1C(C1)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl KBFXFCDOUPTFEJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 125000005504 styryl group Chemical group 0.000 claims description 3
- HUSYTLMIRXITQS-UHFFFAOYSA-N 1,3-benzodioxole-5-carboxamide Chemical compound NC(=O)C1=CC=C2OCOC2=C1 HUSYTLMIRXITQS-UHFFFAOYSA-N 0.000 claims description 2
- YESNROXZWJJKNA-UHFFFAOYSA-N 1-[3-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyphenyl]-3-(4-methylphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC=C(C=C1)C)C=1C=NN(C=1)C YESNROXZWJJKNA-UHFFFAOYSA-N 0.000 claims description 2
- FKRHPJQOJLVMLY-UHFFFAOYSA-N 1-[3-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyphenyl]-3-(4-methylsulfonylphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC=C(C=C1)S(=O)(=O)C)C=1C=NN(C=1)C FKRHPJQOJLVMLY-UHFFFAOYSA-N 0.000 claims description 2
- BOKLGANPDUMGKI-UHFFFAOYSA-N 1-[3-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyphenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)C=1C=NN(C=1)C BOKLGANPDUMGKI-UHFFFAOYSA-N 0.000 claims description 2
- PISQXVRWWPEFLB-UHFFFAOYSA-N 1-[4-(2-amino-5-chloropyridin-3-yl)oxy-2-methylphenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC1=CC(=C(C=C1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)C)Cl PISQXVRWWPEFLB-UHFFFAOYSA-N 0.000 claims description 2
- ZMDVJZMVVKPGGL-UHFFFAOYSA-N 1-[4-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxy-2-fluorophenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC1=CC(=C(C=C1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)F)C=1C=NN(C=1)C ZMDVJZMVVKPGGL-UHFFFAOYSA-N 0.000 claims description 2
- XJCVUWOLNKKPDW-UHFFFAOYSA-N 1-[4-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyphenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC1=CC=C(C=C1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)C=1C=NN(C=1)C XJCVUWOLNKKPDW-UHFFFAOYSA-N 0.000 claims description 2
- AVTKRDQDOBXORL-GFCCVEGCSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]-4-chlorophenyl]-2-chloro-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1Cl)NC(C1=C(C(=CC=C1)C)Cl)=O)Cl AVTKRDQDOBXORL-GFCCVEGCSA-N 0.000 claims description 2
- MBJVZBAHDZXJKT-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1,1-dioxo-1-benzothiophene-6-carboxamide Chemical compound S1(C2=C(C=C1)C=CC(=C2)C(=O)NC1=CC(=CC=C1)[C@@H](C)OC=1C(=NC=C(C=1)Cl)N)(=O)=O MBJVZBAHDZXJKT-CYBMUJFWSA-N 0.000 claims description 2
- UBYZRRXMXMJINC-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiophene-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC2=C(S(CC2)(=O)=O)C=C1)Cl UBYZRRXMXMJINC-CYBMUJFWSA-N 0.000 claims description 2
- NUTGTXVVLPLRSS-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiophene-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=CC2=C(S(CC2)(=O)=O)C=1)Cl NUTGTXVVLPLRSS-CYBMUJFWSA-N 0.000 claims description 2
- LDGJCEBWRFGVDC-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1,3-dihydro-2-benzofuran-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=C2COCC2=CC=1)Cl LDGJCEBWRFGVDC-CYBMUJFWSA-N 0.000 claims description 2
- ICSZJIZPSCQRKY-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-methyl-2,3-dihydroindole-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2CCN(C2=C1)C)Cl ICSZJIZPSCQRKY-CQSZACIVSA-N 0.000 claims description 2
- DRYGFIAOZFPAME-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-methyl-2-oxo-3H-indole-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2CC(N(C2=C1)C)=O)Cl DRYGFIAOZFPAME-CYBMUJFWSA-N 0.000 claims description 2
- LBWVNBKWUPTWDJ-OAHLLOKOSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-methyl-3,4-dihydro-2H-quinoline-7-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2CCCN(C2=C1)C)Cl LBWVNBKWUPTWDJ-OAHLLOKOSA-N 0.000 claims description 2
- HEDZCYSAPHBRST-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-methylindazole-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2C=NN(C2=C1)C)Cl HEDZCYSAPHBRST-CYBMUJFWSA-N 0.000 claims description 2
- JWGPLMYHTJNKNO-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-propan-2-ylpyrazole-4-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=NN(C=1)C(C)C)Cl JWGPLMYHTJNKNO-CYBMUJFWSA-N 0.000 claims description 2
- KJDJAPKMNLQDQA-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-tert-butylpyrazole-4-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=NN(C=1)C(C)(C)C)Cl KJDJAPKMNLQDQA-CYBMUJFWSA-N 0.000 claims description 2
- MMSDXQSCXYVZLP-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2,3-dihydro-1H-indene-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=C2CCCC2=CC=1)Cl MMSDXQSCXYVZLP-CQSZACIVSA-N 0.000 claims description 2
- FIYIMHXJNSOZGH-OAHLLOKOSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3,4-dimethylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)C)C)=O)Cl FIYIMHXJNSOZGH-OAHLLOKOSA-N 0.000 claims description 2
- OYGAGNRRSOUCHP-OAHLLOKOSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3,5-dimethylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC(=C1)C)C)=O)Cl OYGAGNRRSOUCHP-OAHLLOKOSA-N 0.000 claims description 2
- LDBLGZFDZQMPAR-OAHLLOKOSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-propan-2-yloxybenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)OC(C)C)=O)Cl LDBLGZFDZQMPAR-OAHLLOKOSA-N 0.000 claims description 2
- CSDLKXTZJBZZST-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-4-methylpyridine-2-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=NC=CC(=C1)C)=O)Cl CSDLKXTZJBZZST-CYBMUJFWSA-N 0.000 claims description 2
- KKNIVEGVGIMJHW-LLVKDONJSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-5-methyl-1,3-thiazole-2-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1SC(=CN=1)C)Cl KKNIVEGVGIMJHW-LLVKDONJSA-N 0.000 claims description 2
- ICRIMFYYSAGLRO-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-5-methylpyridine-2-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=NC=C(C=C1)C)=O)Cl ICRIMFYYSAGLRO-CYBMUJFWSA-N 0.000 claims description 2
- TVJPAMBZPCZGIG-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-1-methyl-2,3-dihydroindole-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2CCN(C2=C1)C)C=1C=NN(C=1)C TVJPAMBZPCZGIG-QGZVFWFLSA-N 0.000 claims description 2
- IBNSOOGWPRLVON-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-1-methylindole-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2C=CN(C2=C1)C)C=1C=NN(C=1)C IBNSOOGWPRLVON-QGZVFWFLSA-N 0.000 claims description 2
- FKGHLPXKWMMWDO-MRXNPFEDSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=CC2=C(CCO2)C=1)C=1C=NN(C=1)C FKGHLPXKWMMWDO-MRXNPFEDSA-N 0.000 claims description 2
- NSJUOFWRFCVECC-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-2,3-dihydro-1H-indene-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=C2CCCC2=CC=1)C=1C=NN(C=1)C NSJUOFWRFCVECC-QGZVFWFLSA-N 0.000 claims description 2
- GUXKGWRIURZIKV-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3,3-dimethyl-1H-2-benzofuran-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=C2C(OCC2=CC=1)(C)C)C=1C=NN(C=1)C GUXKGWRIURZIKV-QGZVFWFLSA-N 0.000 claims description 2
- WUVRCJGAPKKUMA-GOSISDBHSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3,5-dimethylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC(=C1)C)C)=O)C=1C=NN(C=1)C WUVRCJGAPKKUMA-GOSISDBHSA-N 0.000 claims description 2
- QCVJIQOKTYTFST-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3-cyclopropylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C1CC1)=O)C=1C=NN(C=1)C QCVJIQOKTYTFST-QGZVFWFLSA-N 0.000 claims description 2
- GAIIUAPRIJPBPS-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3-ethylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)CC)=O)C=1C=NN(C=1)C GAIIUAPRIJPBPS-QGZVFWFLSA-N 0.000 claims description 2
- ZBURWFORWNOPSS-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-5-propan-2-ylpyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CN=CC(=C1)C(C)C)=O)C=1C=NN(C=1)C ZBURWFORWNOPSS-QGZVFWFLSA-N 0.000 claims description 2
- KEEQRNSMFROTFS-QGZVFWFLSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]spiro[2H-1-benzofuran-3,1'-cyclopropane]-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=CC2=C(C=1)C1(CC1)CO2)C=1C=NN(C=1)C KEEQRNSMFROTFS-QGZVFWFLSA-N 0.000 claims description 2
- VPWRBMQMEAHGBM-UHFFFAOYSA-N NC1=NC=C(C=C1OC(C)C1=CC=CC=N1)Cl Chemical compound NC1=NC=C(C=C1OC(C)C1=CC=CC=N1)Cl VPWRBMQMEAHGBM-UHFFFAOYSA-N 0.000 claims description 2
- BLMYFOVRPAQMPC-UHFFFAOYSA-N n-(4-methylpiperazin-1-yl)benzamide Chemical compound C1CN(C)CCN1NC(=O)C1=CC=CC=C1 BLMYFOVRPAQMPC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 claims 1
- SIRXUSHVPXOANZ-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-ethynylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C#C)=O)Cl SIRXUSHVPXOANZ-CQSZACIVSA-N 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 150000003217 pyrazoles Chemical class 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 9
- 239000012453 solvate Substances 0.000 abstract description 3
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 abstract description 2
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 abstract description 2
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 73
- 238000006243 chemical reaction Methods 0.000 description 70
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 230000015572 biosynthetic process Effects 0.000 description 57
- 238000003786 synthesis reaction Methods 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 37
- 238000004440 column chromatography Methods 0.000 description 37
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- 125000001424 substituent group Chemical group 0.000 description 34
- 239000007787 solid Substances 0.000 description 33
- 229910052799 carbon Inorganic materials 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 22
- 239000012467 final product Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 19
- 238000001816 cooling Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 125000005843 halogen group Chemical group 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 16
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 13
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 108091000080 Phosphotransferase Proteins 0.000 description 12
- 102000020233 phosphotransferase Human genes 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 125000005842 heteroatom Chemical group 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 102000009465 Growth Factor Receptors Human genes 0.000 description 8
- 108010009202 Growth Factor Receptors Proteins 0.000 description 8
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 8
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000012224 working solution Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000005110 aryl thio group Chemical group 0.000 description 6
- 125000004104 aryloxy group Chemical group 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000004953 trihalomethyl group Chemical group 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 101150038994 PDGFRA gene Proteins 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 description 4
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- FUKOQNFWJNNEQO-UHFFFAOYSA-N 5-chloro-3-fluoro-2-nitropyridine Chemical compound [O-][N+](=O)C1=NC=C(Cl)C=C1F FUKOQNFWJNNEQO-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 3
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 3
- 102000003746 Insulin Receptor Human genes 0.000 description 3
- 108010001127 Insulin Receptor Proteins 0.000 description 3
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091008606 PDGF receptors Proteins 0.000 description 3
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 3
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 3
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 230000035935 pregnancy Effects 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 3
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 description 2
- KPPVNWGJXFMGAM-UUILKARUSA-N (e)-2-methyl-1-(6-methyl-3,4-dihydro-2h-quinolin-1-yl)but-2-en-1-one Chemical group CC1=CC=C2N(C(=O)C(/C)=C/C)CCCC2=C1 KPPVNWGJXFMGAM-UUILKARUSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BMRXXBXPVJOAMM-UHFFFAOYSA-N 2-amino-5-chloropyridin-3-ol Chemical compound NC1=NC=C(Cl)C=C1O BMRXXBXPVJOAMM-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 2
- HEXVDKYSYWTRJQ-UHFFFAOYSA-N 4-[[4-(2-amino-5-chloropyridin-3-yl)oxy-2-methoxyphenoxy]methyl]benzonitrile Chemical compound NC1=NC=C(C=C1OC1=CC(=C(OCC2=CC=C(C#N)C=C2)C=C1)OC)Cl HEXVDKYSYWTRJQ-UHFFFAOYSA-N 0.000 description 2
- CSYAYZQVCJIGPE-UHFFFAOYSA-N 4-[[5-(2-amino-5-chloropyridin-3-yl)oxy-3-methoxypyridin-2-yl]oxymethyl]benzonitrile Chemical compound NC1=NC=C(C=C1OC=1C=C(C(=NC=1)OCC1=CC=C(C#N)C=C1)OC)Cl CSYAYZQVCJIGPE-UHFFFAOYSA-N 0.000 description 2
- SKGGNNFXQPGCKF-UHFFFAOYSA-N 5-chloro-3-[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenoxy]piperazin-2-amine Chemical compound ClC1NC(C(NC1)N)OC1=CC(=C(C=C1)OCC1=CC=C(C=C1)OC)OC SKGGNNFXQPGCKF-UHFFFAOYSA-N 0.000 description 2
- RTQDGHHGNAZUNH-UHFFFAOYSA-N 5-chloro-3-[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenoxy]pyridin-2-amine Chemical compound ClC=1C=C(C(=NC=1)N)OC1=CC(=C(C=C1)OCC1=CC=C(C=C1)OC)OC RTQDGHHGNAZUNH-UHFFFAOYSA-N 0.000 description 2
- IGWPXYSUGKEAPQ-UHFFFAOYSA-N 5-chloro-3-[5-methoxy-6-[(4-methoxyphenyl)methoxy]pyridin-3-yl]oxypyridin-2-amine Chemical compound ClC=1C=C(C(=NC=1)N)OC=1C=NC(=C(C=1)OC)OCC1=CC=C(C=C1)OC IGWPXYSUGKEAPQ-UHFFFAOYSA-N 0.000 description 2
- USWHGMGMJPTWID-UHFFFAOYSA-N 5-chloro-3-[6-[[6-(trifluoromethyl)pyridin-3-yl]methylamino]pyridin-3-yl]oxypyridin-2-amine Chemical compound NC1=NC=C(C=C1OC=1C=CC(=NC=1)NCC=1C=NC(=CC=1)C(F)(F)F)Cl USWHGMGMJPTWID-UHFFFAOYSA-N 0.000 description 2
- HCWHCEAGCHAGBJ-UHFFFAOYSA-N 5-chloro-3-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methoxy]piperazin-2-amine Chemical compound ClC1NC(C(NC1)N)OCC1=CC(=C(C=C1)OCC1=CC=C(C=C1)OC)OC HCWHCEAGCHAGBJ-UHFFFAOYSA-N 0.000 description 2
- LIFWOSFCBCYIRU-UHFFFAOYSA-N 5-chloro-3-[[3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl]methoxy]pyridin-2-amine Chemical compound ClC=1C=C(C(=NC=1)N)OCC1=CC(=C(C=C1)OCC1=CC=C(C=C1)OC)OC LIFWOSFCBCYIRU-UHFFFAOYSA-N 0.000 description 2
- HBOBZADPNJESAU-UHFFFAOYSA-N 5-chloro-3-[[6-[(4-methoxyphenyl)methoxy]pyridin-3-yl]methoxy]pyridin-2-amine Chemical compound ClC=1C=C(C(=NC=1)N)OCC=1C=NC(=CC=1)OCC1=CC=C(C=C1)OC HBOBZADPNJESAU-UHFFFAOYSA-N 0.000 description 2
- FJLKSGVABQXSRT-UHFFFAOYSA-N 5-chloro-3-[[6-[[6-(trifluoromethyl)pyridin-3-yl]methylamino]pyridin-3-yl]methoxy]pyridin-2-amine Chemical compound NC1=NC=C(C=C1OCC=1C=CC(=NC=1)NCC=1C=NC(=CC=1)C(F)(F)F)Cl FJLKSGVABQXSRT-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102100039137 Insulin receptor-related protein Human genes 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- XEZAOVFWFYHQHU-OAHLLOKOSA-N N-[3-[(1R)-1-(5-chloropyridin-3-yl)oxyethyl]phenyl]-3-methylbenzamide Chemical compound ClC=1C=C(C=NC=1)O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O XEZAOVFWFYHQHU-OAHLLOKOSA-N 0.000 description 2
- HVNKELIZUNJOME-HXUWFJFHSA-N N-[3-[(1R)-1-[2-amino-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3-cyclopropylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C1CC1)=O)C=1C=NN(C=1)C1CCNCC1 HVNKELIZUNJOME-HXUWFJFHSA-N 0.000 description 2
- GEQJQIPVZIDZNF-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]-2-fluorophenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1OCC=1C(=C(C=CC=1)NC(C1=CC(=CC=C1)OC)=O)F)Cl GEQJQIPVZIDZNF-UHFFFAOYSA-N 0.000 description 2
- RDORNSDOEVKNOW-UHFFFAOYSA-N N-[3-[(2-aminopyridin-3-yl)oxymethyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=CC=C1OCC=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O RDORNSDOEVKNOW-UHFFFAOYSA-N 0.000 description 2
- GJEQMALXNGTKQK-UHFFFAOYSA-N N-[3-[(3-amino-6-chloropiperazin-2-yl)oxymethyl]phenyl]-3-methylbenzamide Chemical compound NC1C(NC(CN1)Cl)OCC=1C=C(C=CC1)NC(C1=CC(=CC=C1)C)=O GJEQMALXNGTKQK-UHFFFAOYSA-N 0.000 description 2
- URYYKVPBERHEAJ-UHFFFAOYSA-N N-[3-[1-(2-amino-5-chloropyridin-3-yl)oxycyclobutyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1OC1(CCC1)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl URYYKVPBERHEAJ-UHFFFAOYSA-N 0.000 description 2
- KSYFEZCTCGLZCM-UHFFFAOYSA-N N-[3-[1-(2-amino-5-chloropyridin-3-yl)oxycyclohexyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1OC1(CCCCC1)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl KSYFEZCTCGLZCM-UHFFFAOYSA-N 0.000 description 2
- OSPNDZHPCGZSHE-UHFFFAOYSA-N N-[3-[1-(2-amino-5-chloropyridin-3-yl)oxycyclopentyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1OC1(CCCC1)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl OSPNDZHPCGZSHE-UHFFFAOYSA-N 0.000 description 2
- YTUVYLXOKFEBSV-UHFFFAOYSA-N N-[3-[1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1OC(C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl YTUVYLXOKFEBSV-UHFFFAOYSA-N 0.000 description 2
- RFDCGDYUBFKAPR-UHFFFAOYSA-N N-[5-(2-amino-5-chloropyridin-3-yl)oxy-2-chlorophenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1OC=1C=CC(=C(C=1)NC(C1=CC(=CC=C1)OC)=O)Cl)Cl RFDCGDYUBFKAPR-UHFFFAOYSA-N 0.000 description 2
- MNMZOLKSUDKUAF-UHFFFAOYSA-N N-[5-(2-amino-5-chloropyridin-3-yl)oxy-2-fluorophenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1OC=1C=CC(=C(C=1)NC(C1=CC(=CC=C1)OC)=O)F)Cl MNMZOLKSUDKUAF-UHFFFAOYSA-N 0.000 description 2
- GFMOVEOPYVKJHH-UHFFFAOYSA-N N-[5-(2-amino-5-chloropyridin-3-yl)oxy-2-methylphenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1OC=1C=CC(=C(C=1)NC(C1=CC(=CC=C1)OC)=O)C)Cl GFMOVEOPYVKJHH-UHFFFAOYSA-N 0.000 description 2
- NGDNXRLYEXTTRO-UHFFFAOYSA-N N-[5-[1-(2-amino-5-chloropyridin-3-yl)oxyethyl]-2-fluorophenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1OC(C)C=1C=CC(=C(C=1)NC(C1=CC(=CC=C1)OC)=O)F)Cl NGDNXRLYEXTTRO-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 2
- 102000018967 Platelet-Derived Growth Factor beta Receptor Human genes 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000013078 crystal Chemical group 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 108010054372 insulin receptor-related receptor Proteins 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 102000027257 transmembrane receptors Human genes 0.000 description 2
- 108091008578 transmembrane receptors Proteins 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000004385 trihaloalkyl group Chemical group 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000004862 vasculogenesis Effects 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- OJZQOQNSUZLSMV-UHFFFAOYSA-N (3-aminophenyl)methanol Chemical compound NC1=CC=CC(CO)=C1 OJZQOQNSUZLSMV-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- VCINJRSLRABEQE-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(1-benzothiophen-5-yl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC2=C(SC=C2)C=C1)Cl VCINJRSLRABEQE-UHFFFAOYSA-N 0.000 description 1
- FEGDABGCFUGPKP-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(1-tert-butylpyrazol-4-yl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC=1C=NN(C=1)C(C)(C)C)Cl FEGDABGCFUGPKP-UHFFFAOYSA-N 0.000 description 1
- BETCPRYABOFIST-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(2,3-dihydro-1-benzothiophen-5-yl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC2=C(SCC2)C=C1)Cl BETCPRYABOFIST-UHFFFAOYSA-N 0.000 description 1
- WESCZLQGOVFAEB-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(3-methylphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC=1C=C(C=CC=1)C)Cl WESCZLQGOVFAEB-UHFFFAOYSA-N 0.000 description 1
- SPOSVCNVNPAGOY-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(4-methoxyphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC=C(C=C1)OC)Cl SPOSVCNVNPAGOY-UHFFFAOYSA-N 0.000 description 1
- KMJHZLHLZAOKNS-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(4-methylphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC=C(C=C1)C)Cl KMJHZLHLZAOKNS-UHFFFAOYSA-N 0.000 description 1
- AQEXCORLVDNZIU-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(4-methylsulfonylphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC=C(C=C1)S(=O)(=O)C)Cl AQEXCORLVDNZIU-UHFFFAOYSA-N 0.000 description 1
- NLZFVMXJPXXWBJ-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-[4-(dimethylamino)phenyl]urea Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(=O)NC1=CC=C(C=C1)N(C)C)Cl NLZFVMXJPXXWBJ-UHFFFAOYSA-N 0.000 description 1
- OUMTVCPFOOQBME-UHFFFAOYSA-N 1-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound Nc1ncc(Cl)cc1Oc1cccc(NC(=O)Nc2ccc(Cl)c(c2)C(F)(F)F)c1 OUMTVCPFOOQBME-UHFFFAOYSA-N 0.000 description 1
- IZMFMYDBVVFSRB-UHFFFAOYSA-N 1-[4-(2-amino-5-chloropyridin-3-yl)oxy-2-fluorophenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC1=CC(=C(C=C1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)F)Cl IZMFMYDBVVFSRB-UHFFFAOYSA-N 0.000 description 1
- JOYIFELCIRFFHI-UHFFFAOYSA-N 1-[4-(2-amino-5-chloropyridin-3-yl)oxy-3-fluorophenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC1=C(C=C(C=C1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)F)Cl JOYIFELCIRFFHI-UHFFFAOYSA-N 0.000 description 1
- XXRLBVQHSNGMHH-UHFFFAOYSA-N 1-[4-(2-amino-5-chloropyridin-3-yl)oxy-3-methylphenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC1=C(C=C(C=C1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)C)Cl XXRLBVQHSNGMHH-UHFFFAOYSA-N 0.000 description 1
- ZCSLBGQXLGXZFJ-UHFFFAOYSA-N 1-[4-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(3-methylphenyl)urea Chemical compound NC1=NC=C(C=C1OC1=CC=C(C=C1)NC(=O)NC=1C=C(C=CC=1)C)Cl ZCSLBGQXLGXZFJ-UHFFFAOYSA-N 0.000 description 1
- WTMKWQNSQNFIDW-UHFFFAOYSA-N 1-[4-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-(4-methylphenyl)urea Chemical compound NC1=NC=C(C=C1OC1=CC=C(C=C1)NC(=O)NC1=CC=C(C=C1)C)Cl WTMKWQNSQNFIDW-UHFFFAOYSA-N 0.000 description 1
- BVOAQXFXEGLNPF-UHFFFAOYSA-N 1-[4-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea Chemical compound NC1=NC=C(C=C1OC1=CC=C(C=C1)NC(=O)NC1=CC(=C(C=C1)Cl)C(F)(F)F)Cl BVOAQXFXEGLNPF-UHFFFAOYSA-N 0.000 description 1
- JFOQKVPNYUWDRC-UHFFFAOYSA-N 1-[5-(2-amino-5-chloropyridin-3-yl)oxy-2-chlorophenyl]-3-(4-methylphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=CC(=C(C=1)NC(=O)NC1=CC=C(C=C1)C)Cl)Cl JFOQKVPNYUWDRC-UHFFFAOYSA-N 0.000 description 1
- RDMUORWUEACLTN-UHFFFAOYSA-N 1-[5-(2-amino-5-chloropyridin-3-yl)oxy-2-methylphenyl]-3-(4-methylphenyl)urea Chemical compound NC1=NC=C(C=C1OC=1C=CC(=C(C=1)NC(=O)NC1=CC=C(C=C1)C)C)Cl RDMUORWUEACLTN-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- BMTSZVZQNMNPCT-UHFFFAOYSA-N 2-aminopyridin-3-ol Chemical compound NC1=NC=CC=C1O BMTSZVZQNMNPCT-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- CKQHAYFOPRIUOM-UHFFFAOYSA-N 3'-Aminoacetophenone Chemical compound CC(=O)C1=CC=CC(N)=C1 CKQHAYFOPRIUOM-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UWGGGYYCKDCTGN-UHFFFAOYSA-N 3-bromo-5-chloropyridin-2-amine Chemical compound NC1=NC=C(Cl)C=C1Br UWGGGYYCKDCTGN-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- GVCLNACSYKYUHP-UHFFFAOYSA-N 4-amino-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbothioamide Chemical compound C1=NC(N)=C2C(C(=S)N)=CN(COCCO)C2=N1 GVCLNACSYKYUHP-UHFFFAOYSA-N 0.000 description 1
- MGYGFNQQGAQEON-UHFFFAOYSA-N 4-tolyl isocyanate Chemical compound CC1=CC=C(N=C=O)C=C1 MGYGFNQQGAQEON-UHFFFAOYSA-N 0.000 description 1
- FPUPPVDVOFJSEP-UHFFFAOYSA-N 5-chloro-3-fluoropyridin-2-amine Chemical compound NC1=NC=C(Cl)C=C1F FPUPPVDVOFJSEP-UHFFFAOYSA-N 0.000 description 1
- ZWGWZXKNFDGBJP-UHFFFAOYSA-N 6-chloro-3h-[1,3]oxazolo[4,5-b]pyridin-2-one Chemical compound ClC1=CN=C2NC(=O)OC2=C1 ZWGWZXKNFDGBJP-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000714174 Feline sarcoma virus Species 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 238000003043 HTRF KinEASE-TK Methods 0.000 description 1
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 1
- CMKHPXJPRDBICF-UHFFFAOYSA-N N-[3-(2-amino-5-chloropyridin-3-yl)oxyphenyl]-3-cyclopropylbenzamide Chemical compound NC1=NC=C(C=C1OC=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C1CC1)=O)Cl CMKHPXJPRDBICF-UHFFFAOYSA-N 0.000 description 1
- AGOCTSWNXMNNFS-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1,1-dioxo-1-benzothiophene-5-carboxamide Chemical compound S1(C2=C(C=C1)C=C(C=C2)C(=O)NC1=CC(=CC=C1)[C@@H](C)OC=1C(=NC=C(C=1)Cl)N)(=O)=O AGOCTSWNXMNNFS-CYBMUJFWSA-N 0.000 description 1
- IGRVMELYLJYBIB-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiophene-4-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=CC=2S(CCC=21)(=O)=O)Cl IGRVMELYLJYBIB-CYBMUJFWSA-N 0.000 description 1
- KUJCEYWIOZANAD-GFCCVEGCSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1,5-dimethylpyrazole-3-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=NN(C(=C1)C)C)Cl KUJCEYWIOZANAD-GFCCVEGCSA-N 0.000 description 1
- LPADFMMQQLMEMX-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-benzofuran-6-carboxamide Chemical compound O1C=CC2=C1C=C(C=C2)C(=O)NC1=CC(=CC=C1)[C@@H](C)OC=1C(=NC=C(C=1)Cl)N LPADFMMQQLMEMX-CYBMUJFWSA-N 0.000 description 1
- DINIMPQPIPYRMX-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-methyl-2-oxo-3,4-dihydroquinoline-7-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2CCC(N(C2=C1)C)=O)Cl DINIMPQPIPYRMX-CQSZACIVSA-N 0.000 description 1
- FUZFABOAGZKTIJ-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-1-methylindole-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2C=CN(C2=C1)C)Cl FUZFABOAGZKTIJ-CQSZACIVSA-N 0.000 description 1
- MVTZZJJRASLGOV-LLVKDONJSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2,5-dichlorobenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)Cl)Cl)=O)Cl MVTZZJJRASLGOV-LLVKDONJSA-N 0.000 description 1
- KEJWHOSUQHWNSY-GFCCVEGCSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2-chloro-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=C(C(=CC=C1)OC)Cl)=O)Cl KEJWHOSUQHWNSY-GFCCVEGCSA-N 0.000 description 1
- BPCVWXSSDFXRCP-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2-chloro-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=C(C(=CC=C1)C)Cl)=O)Cl BPCVWXSSDFXRCP-CYBMUJFWSA-N 0.000 description 1
- DUPNCNLMOPNBEJ-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2-chloro-5-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)C)Cl)=O)Cl DUPNCNLMOPNBEJ-CYBMUJFWSA-N 0.000 description 1
- WHFMCGSJEJMPSW-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2-fluoro-5-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)C)F)=O)Cl WHFMCGSJEJMPSW-CYBMUJFWSA-N 0.000 description 1
- QIVACCOLJZPFMC-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-chloro-5-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC(=C1)C)Cl)=O)Cl QIVACCOLJZPFMC-CYBMUJFWSA-N 0.000 description 1
- UIWDYNUQMKXDAI-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-cyanobenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C#N)=O)Cl UIWDYNUQMKXDAI-CYBMUJFWSA-N 0.000 description 1
- DOJBEUZUMZTBHT-OAHLLOKOSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-cyclobutylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C1CCC1)=O)Cl DOJBEUZUMZTBHT-OAHLLOKOSA-N 0.000 description 1
- RYORRAAKRYRJII-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-cyclopropylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C1CC1)=O)Cl RYORRAAKRYRJII-CQSZACIVSA-N 0.000 description 1
- LXMDXXRVETXSGB-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-fluoro-5-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC(=C1)C)F)=O)Cl LXMDXXRVETXSGB-CYBMUJFWSA-N 0.000 description 1
- YWCIBALKLKFTEY-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)OC)=O)Cl YWCIBALKLKFTEY-CYBMUJFWSA-N 0.000 description 1
- YTUVYLXOKFEBSV-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl YTUVYLXOKFEBSV-CQSZACIVSA-N 0.000 description 1
- LEHNLCZEIFPVJJ-OAHLLOKOSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-propan-2-ylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C(C)C)=O)Cl LEHNLCZEIFPVJJ-OAHLLOKOSA-N 0.000 description 1
- QENYISHUCMDTBA-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-4-chloro-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)Cl)C)=O)Cl QENYISHUCMDTBA-CYBMUJFWSA-N 0.000 description 1
- OCZHQVUYNBRDLI-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-4-fluoro-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)F)C)=O)Cl OCZHQVUYNBRDLI-CYBMUJFWSA-N 0.000 description 1
- VPIBRQRJQJOLNY-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-4-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC=C(C=C1)C)=O)Cl VPIBRQRJQJOLNY-CQSZACIVSA-N 0.000 description 1
- CUMDGNFRRGGXCI-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-5-cyclopropylpyridine-2-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC1)NC(=O)C1=NC=C(C=C1)C1CC1)Cl CUMDGNFRRGGXCI-CYBMUJFWSA-N 0.000 description 1
- PYARAAMDFLMILZ-LLVKDONJSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-5-fluoropyridine-2-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=NC=C(C=C1)F)=O)Cl PYARAAMDFLMILZ-LLVKDONJSA-N 0.000 description 1
- XZCCVOAHZGQOMP-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-5-methylpyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CN=CC(=C1)C)=O)Cl XZCCVOAHZGQOMP-CYBMUJFWSA-N 0.000 description 1
- UPSHLBKQKXWTCA-CYBMUJFWSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-6-methylpyridine-2-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=NC(=CC=C1)C)=O)Cl UPSHLBKQKXWTCA-CYBMUJFWSA-N 0.000 description 1
- AGRLNTVYQJLVPE-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]isoquinoline-6-carboxamide Chemical compound C1=NC=CC2=CC(=CC=C12)C(=O)NC1=CC(=CC=C1)[C@@H](C)OC=1C(=NC=C(C=1)Cl)N AGRLNTVYQJLVPE-CQSZACIVSA-N 0.000 description 1
- SQIYGACOLJBEPR-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]quinoline-3-carboxamide Chemical compound N1=CC(=CC2=CC=CC=C12)C(=O)NC1=CC(=CC=C1)[C@@H](C)OC=1C(=NC=C(C=1)Cl)N SQIYGACOLJBEPR-CQSZACIVSA-N 0.000 description 1
- GHUUHRLWXPQNAH-CQSZACIVSA-N N-[3-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]quinoline-6-carboxamide Chemical compound N1=CC=CC2=CC(=CC=C12)C(=O)NC1=CC(=CC=C1)[C@@H](C)OC=1C(=NC=C(C=1)Cl)N GHUUHRLWXPQNAH-CQSZACIVSA-N 0.000 description 1
- ZUWODGUFVRQIKT-GOSISDBHSA-N N-[3-[(1R)-1-(2-amino-5-pyridin-3-ylpyridin-3-yl)oxyethyl]phenyl]-1-methyl-2,3-dihydroindole-6-carboxamide Chemical compound NC1=C(C=C(C=N1)C=1C=NC=CC=1)O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2CCN(C2=C1)C ZUWODGUFVRQIKT-GOSISDBHSA-N 0.000 description 1
- MQNFLUZLFBOTFM-LJQANCHMSA-N N-[3-[(1R)-1-(2-amino-5-pyridin-3-ylpyridin-3-yl)oxyethyl]phenyl]-3,4-dimethylbenzamide Chemical compound NC1=C(C=C(C=N1)C=1C=NC=CC=1)O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)C)C)=O MQNFLUZLFBOTFM-LJQANCHMSA-N 0.000 description 1
- SWAZFERQATUKLM-LJQANCHMSA-N N-[3-[(1R)-1-(2-amino-5-pyridin-3-ylpyridin-3-yl)oxyethyl]phenyl]-3,5-dimethylbenzamide Chemical compound NC1=C(C=C(C=N1)C=1C=NC=CC=1)O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC(=C1)C)C)=O SWAZFERQATUKLM-LJQANCHMSA-N 0.000 description 1
- XWQBHVIDMJWGJW-LJQANCHMSA-N N-[3-[(1R)-1-(2-amino-5-pyridin-3-ylpyridin-3-yl)oxyethyl]phenyl]-3-(dimethylamino)-4-methylbenzamide Chemical compound NC1=C(C=C(C=N1)C=1C=NC=CC=1)O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)C)N(C)C)=O XWQBHVIDMJWGJW-LJQANCHMSA-N 0.000 description 1
- JYSMBINPNBLKQZ-MRXNPFEDSA-N N-[3-[(1R)-1-(2-amino-5-pyridin-3-ylpyridin-3-yl)oxyethyl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound C[C@@H](OC1=C(N)N=CC(=C1)C1=CC=CN=C1)C1=CC=CC(NC(=O)C2=CC(=CC=C2)C(F)(F)F)=C1 JYSMBINPNBLKQZ-MRXNPFEDSA-N 0.000 description 1
- CULDHUGACBJHIO-GOSISDBHSA-N N-[3-[(1R)-1-(2-amino-5-pyridin-3-ylpyridin-3-yl)oxyethyl]phenyl]-3-cyclopropylbenzamide Chemical compound NC1=C(C=C(C=N1)C=1C=NC=CC=1)O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C1CC1)=O CULDHUGACBJHIO-GOSISDBHSA-N 0.000 description 1
- UBFXYJZWLZUHEB-GOSISDBHSA-N N-[3-[(1R)-1-(2-amino-5-pyridin-3-ylpyridin-3-yl)oxyethyl]phenyl]-3-methylbenzamide Chemical compound NC1=C(C=C(C=N1)C=1C=NC=CC=1)O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O UBFXYJZWLZUHEB-GOSISDBHSA-N 0.000 description 1
- GNDMAYJAVROQEY-MRXNPFEDSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiophene-6-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C=1C=CC2=C(S(CC2)(=O)=O)C=1)C=1C=NN(C=1)C GNDMAYJAVROQEY-MRXNPFEDSA-N 0.000 description 1
- CKYSOLJPTYEJAA-GOSISDBHSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3,4-dimethylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)C)C)=O)C=1C=NN(C=1)C CKYSOLJPTYEJAA-GOSISDBHSA-N 0.000 description 1
- OJSHPCFPPFVCAW-GOSISDBHSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3-(dimethylamino)-4-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)C)N(C)C)=O)C=1C=NN(C=1)C OJSHPCFPPFVCAW-GOSISDBHSA-N 0.000 description 1
- ZQKXYBSYDPUTFG-GOSISDBHSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3-propan-2-ylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C(C)C)=O)C=1C=NN(C=1)C ZQKXYBSYDPUTFG-GOSISDBHSA-N 0.000 description 1
- LCVJNSCTSNAEOX-GOSISDBHSA-N N-[3-[(1R)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]spiro[1,2-dihydroindene-3,1'-cyclopropane]-5-carboxamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=CC=1)NC(=O)C1=CC=C2CCC3(C2=C1)CC3)C=1C=NN(C=1)C LCVJNSCTSNAEOX-GOSISDBHSA-N 0.000 description 1
- OCUWGBXEFHWIPN-NSHDSACASA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2,3-dichlorobenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=C(C(=CC=C1)Cl)Cl)=O)Cl OCUWGBXEFHWIPN-NSHDSACASA-N 0.000 description 1
- MVTZZJJRASLGOV-NSHDSACASA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2,5-dichlorobenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)Cl)Cl)=O)Cl MVTZZJJRASLGOV-NSHDSACASA-N 0.000 description 1
- BPCVWXSSDFXRCP-ZDUSSCGKSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2-chloro-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=C(C(=CC=C1)C)Cl)=O)Cl BPCVWXSSDFXRCP-ZDUSSCGKSA-N 0.000 description 1
- DUPNCNLMOPNBEJ-ZDUSSCGKSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2-chloro-5-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)C)Cl)=O)Cl DUPNCNLMOPNBEJ-ZDUSSCGKSA-N 0.000 description 1
- WHFMCGSJEJMPSW-ZDUSSCGKSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-2-fluoro-5-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)C)F)=O)Cl WHFMCGSJEJMPSW-ZDUSSCGKSA-N 0.000 description 1
- VPFYDECQEBRARM-NSHDSACASA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3,4-dichlorobenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)Cl)Cl)=O)Cl VPFYDECQEBRARM-NSHDSACASA-N 0.000 description 1
- LZVGQKDXDRKTEN-LBPRGKRZSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-(trifluoromethoxy)benzamide Chemical compound C[C@H](OC1=CC(Cl)=CN=C1N)C1=CC=CC(NC(=O)C2=CC(OC(F)(F)F)=CC=C2)=C1 LZVGQKDXDRKTEN-LBPRGKRZSA-N 0.000 description 1
- WVDMEMBFPUCMNX-LBPRGKRZSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound C[C@H](OC1=CC(Cl)=CN=C1N)C1=CC=CC(NC(=O)C2=CC(=CC=C2)C(F)(F)F)=C1 WVDMEMBFPUCMNX-LBPRGKRZSA-N 0.000 description 1
- BUJGJDIAADKZIF-LBPRGKRZSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-bromobenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)Br)=O)Cl BUJGJDIAADKZIF-LBPRGKRZSA-N 0.000 description 1
- IOPSPVABRZEQDR-LBPRGKRZSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-chlorobenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)Cl)=O)Cl IOPSPVABRZEQDR-LBPRGKRZSA-N 0.000 description 1
- UIWDYNUQMKXDAI-ZDUSSCGKSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-cyanobenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C#N)=O)Cl UIWDYNUQMKXDAI-ZDUSSCGKSA-N 0.000 description 1
- RYORRAAKRYRJII-AWEZNQCLSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-cyclopropylbenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C1CC1)=O)Cl RYORRAAKRYRJII-AWEZNQCLSA-N 0.000 description 1
- YWCIBALKLKFTEY-ZDUSSCGKSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-methoxybenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)OC)=O)Cl YWCIBALKLKFTEY-ZDUSSCGKSA-N 0.000 description 1
- YTUVYLXOKFEBSV-AWEZNQCLSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=CC=C1)C)=O)Cl YTUVYLXOKFEBSV-AWEZNQCLSA-N 0.000 description 1
- ZQQLSBDXJGNBRG-NSHDSACASA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-5-chloropyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CN=CC(=C1)Cl)=O)Cl ZQQLSBDXJGNBRG-NSHDSACASA-N 0.000 description 1
- XZCCVOAHZGQOMP-ZDUSSCGKSA-N N-[3-[(1S)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]phenyl]-5-methylpyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CN=CC(=C1)C)=O)Cl XZCCVOAHZGQOMP-ZDUSSCGKSA-N 0.000 description 1
- OJSHPCFPPFVCAW-SFHVURJKSA-N N-[3-[(1S)-1-[2-amino-5-(1-methylpyrazol-4-yl)pyridin-3-yl]oxyethyl]phenyl]-3-(dimethylamino)-4-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@@H](C)C=1C=C(C=CC=1)NC(C1=CC(=C(C=C1)C)N(C)C)=O)C=1C=NN(C=1)C OJSHPCFPPFVCAW-SFHVURJKSA-N 0.000 description 1
- GPKJRABTZAWNAI-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-2-fluoro-5-methylbenzamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)C)F)=O)Cl GPKJRABTZAWNAI-UHFFFAOYSA-N 0.000 description 1
- KKQSGCNRYFIMTE-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-2-fluorobenzamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=C(C=CC=C1)F)=O)Cl KKQSGCNRYFIMTE-UHFFFAOYSA-N 0.000 description 1
- PXZCEBQZAXUMBZ-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-3-chlorobenzamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=CC(=CC=C1)Cl)=O)Cl PXZCEBQZAXUMBZ-UHFFFAOYSA-N 0.000 description 1
- AGHCKIGUTJNHEM-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-3-fluorobenzamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=CC(=CC=C1)F)=O)Cl AGHCKIGUTJNHEM-UHFFFAOYSA-N 0.000 description 1
- BNORAXLZBASGMO-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-5-chloropyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=CN=CC(=C1)Cl)=O)Cl BNORAXLZBASGMO-UHFFFAOYSA-N 0.000 description 1
- LLMRROHESXBOHB-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-5-fluoro-2-methylbenzamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=C(C=CC(=C1)F)C)=O)Cl LLMRROHESXBOHB-UHFFFAOYSA-N 0.000 description 1
- GPRFKVFMAPPIFM-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-5-fluoropyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=CN=CC(=C1)F)=O)Cl GPRFKVFMAPPIFM-UHFFFAOYSA-N 0.000 description 1
- KMLYSEBOMSITFT-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]-5-methylpyridine-3-carboxamide Chemical compound NC1=NC=C(C=C1OCC=1C=C(C=CC=1)NC(C1=CN=CC(=C1)C)=O)Cl KMLYSEBOMSITFT-UHFFFAOYSA-N 0.000 description 1
- UTGDSXPHSGODPJ-UHFFFAOYSA-N N-[3-[(2-amino-5-chloropyridin-3-yl)oxymethyl]phenyl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)NC1=CC(=CC=C1)COC=1C(=NC=C(C=1)Cl)N UTGDSXPHSGODPJ-UHFFFAOYSA-N 0.000 description 1
- RFYVFVYELFLFTP-CYBMUJFWSA-N N-[4-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]pyridin-2-yl]-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C1=CC(=NC=C1)NC(C1=CC(=CC=C1)C)=O)Cl RFYVFVYELFLFTP-CYBMUJFWSA-N 0.000 description 1
- SFHHXVSQGIFWLF-GFCCVEGCSA-N N-[5-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]-2-fluorophenyl]-2-chloro-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=CC(=C(C=1)NC(C1=C(C(=CC=C1)C)Cl)=O)F)Cl SFHHXVSQGIFWLF-GFCCVEGCSA-N 0.000 description 1
- BLYQMWVZASCSPU-GFCCVEGCSA-N N-[5-[(1R)-1-(2-amino-5-chloropyridin-3-yl)oxyethyl]pyridin-3-yl]-2-chloro-3-methylbenzamide Chemical compound NC1=NC=C(C=C1O[C@H](C)C=1C=C(C=NC=1)NC(C1=C(C(=CC=C1)C)Cl)=O)Cl BLYQMWVZASCSPU-GFCCVEGCSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- PEFASEPMJYRQBW-HKWQTAEVSA-N Robinin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(O[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)C=C3OC=2C=2C=CC(O)=CC=2)=O)O1 PEFASEPMJYRQBW-HKWQTAEVSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000016548 Vascular Endothelial Growth Factor Receptor-1 Human genes 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 125000005360 alkyl sulfoxide group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005362 aryl sulfone group Chemical group 0.000 description 1
- 125000005361 aryl sulfoxide group Chemical group 0.000 description 1
- 125000000461 aryl-fused-heterocycloalkyl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- OTKPPUXRIADSGD-PPRNARJGSA-N avoparcina Chemical compound O([C@@H]1C2=CC=C(C(=C2)Cl)OC=2C=C3C=C(C=2O[C@H]2C([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2O[C@@H](C)[C@H](O)[C@H](N)C2)OC2=CC=C(C=C2)[C@@H](O)[C@H](C(N[C@H](C(=O)N[C@H]3C(=O)N[C@H]2C(=O)N[C@@H]1C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)C=1C=CC(O)=CC=1)=O)NC(=O)[C@H](NC)C=1C=CC(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)=CC=1)[C@H]1C[C@@H](N)[C@@H](O)[C@H](C)O1 OTKPPUXRIADSGD-PPRNARJGSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- DFBKLUNHFCTMDC-GKRDHZSOSA-N endrin Chemical compound C([C@@H]1[C@H]2[C@@]3(Cl)C(Cl)=C([C@]([C@H]22)(Cl)C3(Cl)Cl)Cl)[C@@H]2[C@H]2[C@@H]1O2 DFBKLUNHFCTMDC-GKRDHZSOSA-N 0.000 description 1
- 230000008472 epithelial growth Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 108700024553 fms Genes Proteins 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 102000057421 human MET Human genes 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000008076 immune mechanism Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- DDELFAUOHDSZJL-UHFFFAOYSA-N kaempferol 3-O-rutinoside-7-O-rhamnoside Natural products OC1C(O)C(O)C(C)OC1OC1C(O)C(O)C(CO)OC1OC1=C(C=2C=CC(O)=CC=2)OC2=CC(OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C1=O DDELFAUOHDSZJL-UHFFFAOYSA-N 0.000 description 1
- PEFASEPMJYRQBW-UHFFFAOYSA-N kaempferol 7-O-alpha-L-rhamnopyradoside 3-O-beta-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(OC4C(C(O)C(O)C(C)O4)O)C=C3OC=2C=2C=CC(O)=CC=2)=O)O1 PEFASEPMJYRQBW-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- OVLXOTUWFLHWQT-UHFFFAOYSA-N oxazolo[4,5-b]pyridin-2(3H)-one Chemical compound C1=CC=C2OC(=O)NC2=N1 OVLXOTUWFLHWQT-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- PEFASEPMJYRQBW-XMWKPCQISA-N robinin Natural products O(C[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@H](OC2=C(c3ccc(O)cc3)Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@@H](O)[C@@H](C)O4)c3)C2=O)O1)[C@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 PEFASEPMJYRQBW-XMWKPCQISA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OPMWQSDBBSURGY-UHFFFAOYSA-N tert-butyl n-[3-(hydroxymethyl)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(CO)=C1 OPMWQSDBBSURGY-UHFFFAOYSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本文提供了对受体蛋白酪氨酸激酶具有活性的式(I)化合物,R1、R2、R3、A、Q、Z、X和W在本说明书中描述,以及其溶剂合物,水合物,互变异构体或其药学上可接受的盐。
Description
本申请对2018年3月15日提交的第201810212171.9号专利申请和2018年7月26日提交的第201810835038.9号专利申请提出优先权要求,两者全部通过引用并入本申请。
技术领域
本发明涉及一种具有激酶抑制活性的化合物,及其在医药领域中的应用。更具体地说,本发明提供了具有蛋白酪氨酸激酶活性的杂芳基化合物。所提供的信息仅意图于帮助读者进行理解。所提供的信息和所引用的参考文献都不是对本发明现有技术的承认。所引用的每一参考文献全部并入本文并用于任何目的。
背景技术
蛋白酪氨酸激酶(protein tyrosine kinase,PTK)能催化多种底物蛋白质酪氨酸残基磷酸化,在细胞生长、增殖、分化中具有重要的调控作用。异常的激酶活性与人类的许多疾病,包括癌症,自身免疫疾病和炎性疾病有关。由于蛋白质激酶属于细胞信号传导的关键调节剂,因此它们可以作为调节细胞功能的小分子激酶抑制剂的靶标,用于药物设计。
PTK活性的主要方面之一为其涉及生长因子受体。生长因子受体是细胞表面蛋白。当与生长因子配体结合时,生长因子受体被转化成与细胞膜内表面上的蛋白质发生相互作用的活性形式。这导致受体和其它蛋白质酪氨酸残基上发生磷酸化且在细胞内形成与各种胞质信号传导分子的复合物,而这些复合物随后影响大量细胞反应,诸如细胞分裂(增殖)、细胞分化、细胞生长、对胞外微环境的代谢作用的表达等。有关更完整的讨论参见Schiessinger和Ullrich《神经元》(Neuron)9:303-391(1992),将该文献,包括任何附图引入作为参考,其含义是将其全文引入本文。
具有PTK活性的生长因子受体称作受体酪氨酸激酶(“RTKs”)。它们包括具有不同生物活性的跨膜受体大家族。目前至少已经鉴定了19个不同的RTKs亚族。它们的实例为命名为″HER″RTK的亚族,包EGFR(上皮生长因子受体)、HER2、HER3和HER4。这些RTKs由胞外糖基化的配体结合域、跨膜结构域和可以使蛋白质上的酪氨酸残基磷酸化的催化结构域组成。
另一个RTK亚族由胰岛素受体(IR)、胰岛素样生长因子I受体(IGF-1R)和胰岛素受体相关受体(IRR)组成。IR和IGF-1R与胰岛素、IGF-I和IGF-II发生相互作用而形成两个完全胞外糖基化的α亚单位和两个通过细胞膜并含有酪氨酸激酶结构域的β亚单位组成的异四聚体。
第三个RTK亚族称作血小板衍生的生长因子受体(″PDGFR″)族,包括PDGFRα、PDGFRβ、Flt3、c-kit和c-fms。这些受体由糖基化胞外结构域组成,所述的结构域由可变数量的免疫球蛋白样环和胞内结构域组成,其中酪氨酸激酶结构域被无关氨基酸序列打断。
因与PDGFR亚族的相似性而有时被包含入该族的另一族为胎儿肝激酶(“flk”)受体亚族。认为该族由激酶插入结构域-受体胎儿肝激酶(KDRf/FLK-1)、flk-1R、flk-4和fms-样酪氨酸激酶(flt-1)构成。
酪氨酸激酶生长因子受体族中的另一个成员为成纤维细胞生长因子(″FGF″)受体亚组。该组由4种受体FGFR1-4和7种配体FGF1-7组成。尽管尚未充分定义,但是看起来这些受体由含有可变数量的免疫球蛋白样环和胞内结构域的糖基化胞外结构域组成,其中酪氨酸激酶序列被无关氨基酸序列区打断。
酪氨酸激酶生长因子受体族中的另一个成员为血管内皮生长因子(″VEGF″)受体亚组。VEGF是与PDGF类似、但具有不同生物功能和体内靶细胞特异性的二聚化糖蛋白。特别地,目前认为VEGF起的主要作用为血管发生(vasculogenesis)和血管发生(angiogenesis)。
酪氨酸激酶生长因子受体族中的另一个成员为MET,通常称作c-Met,也称作人肝细胞生长因子受体酪氨酸激酶(hHGFR)。认为c-Met在原发性肿瘤生长和转移中起作用。
更完整的已知RTK亚族目录描述在Plowman等的DN&P,7(6):334-339(1994)中,将该文献,包括任何附图引入作为参考,其含义是将其全文引入本文。
集落刺激因子1受体(CSF-1R),也称为巨噬细胞集落刺激因子受体(M-CSFR))和CD115(分化簇115),是在人体中由CSF-1R基因(也称为c-fms))编码的细胞表面蛋白。c-fms是调节控制细胞生长和增殖的关键信号转导级联反应的III型跨膜受体蛋白质酪氨酸激酶(receptor protein tyrosinekinases,RPTKs)。这种受体包括5个胞外免疫球蛋白(immunoglobulin,IG)结构域、1个跨膜结构域和由激酶插入部分隔开的分开的细胞质激酶结构域。
c-fms最初是从猫肉瘤病毒Susan McDonough株中分离的基因家族的成员。细胞原癌基因FMS(c-fms,cellular feline McDonoughsarcoma)编码巨噬细胞集落刺激因子(macrophage colony-stimulatingfactor,M-CSF)的受体。C-fms对于单核细胞-巨噬细胞系的生长和分化至关重要,并且M-CSF与c-fms的胞外结构域结合后,受体二聚化和跨膜自磷酸化胞质酪氨酸残基。
M-CSF最初由Robinsin及其同事描述(Blood.1969,33:396-9),是一种控制巨噬细胞产生、分化和行使功能的细胞因子。M-CSF刺激祖细胞分化成成熟的单核细胞,并延长单核细胞的存活。而且,M-CSF增强单核细胞和巨噬细胞中的细胞毒性、过氧化物产生、吞噬作用、趋化性和其它因子的二级细胞因子产生。这类其它因子的例子包括粒细胞集落刺激因子(G-CSF)、白细胞介素-6(IL-6)和白细胞介素-8(IL-8)。M-CSF刺激造血作用,促进破骨祖细胞的分化和增殖,并且对脂质代谢具有重要作用。而且,M-CSF在妊娠中是重要的。在生理上,胎盘中生成大量M-CSF,并且认为M-CSF在滋养层分化中起重要作用(Motoyoshi,hitJ.Hematol.1998,67:109-22)。早期妊娠时M-CSF血清水平升高可以参与负责维持妊娠的免疫机制(Flanagan&Lader,CurrOpin Hematol.1998,5:181-5)。
与c-fms和c-kit相关的是两种血小板衍生生长因子受体(platelet-derivedgrowth factor receptors),α(alpha)(即,pdgfra)和β(beta)(pdgfrb)(PDGF)。编码pdgfra的基因位于染色体4q11-q12上,与编码c-kit的癌基因位于4号染色体的同一区域。编码pdgfra和c-fms的基因似乎是通过基因复制从共同的祖先基因进化而来,因为这两种基因在5号染色体上串联连接。它们的方向是头对尾,c-fms基因的5’-端外显子仅位于编码pdgfra的基因的最后3’-端外显子500bp远。在炎症期间在组织中观察到主要的巨噬细胞生长因子M-CSF产生的增加,表明c-fms在疾病如,例如,炎性疾病中的作用。更具体地,由于在疾病状态下发现M-CSF水平增加,因此对c-fms活性的调节可以改善与M-CSF水平增加有关的疾病。
发明内容
本发明的目的是提供一种具有酪氨酸激酶抑制活性的化合物。
本发明所述的化合物至少含有一种通式(I)表示的化合物,
其中:
A选自N或CR2;
R1选自氢、C1-C5烷基、C3-C6环烷基、C(O)C1-C3烷基、S(O)2(C1-C3)烷基或S(O)2(C3-C6)环烷基;
R2选自氢、卤素、OH、NR5R6、氰基、C1-C5烷基;
R3选自氢、卤素、C6-C12芳基、5-12元杂芳基、羟基、硝基、氰基、O(C1-C5)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、(C1-C3)烷基(C3-C6)杂环烷基、C2-C5烯基、C2-C5炔基、C3-C7环烷基、C3-C6杂环烷基、NR5R6、C(O)R8、P(O)R8R9、S(O)n(C1-C3)烷基或S(O)n(C3-C6)环烷基,其中n=0,1,2;R3上的氢各自任选被1个或多个独立的R7取代,且相邻的R7可以形成4-12元环;
Q选自CHR5CHR6、O、OC(R5R6)、C(R5R6)、CO、NR5C(O)、NR5S(O)2、CH=CH、C≡C、S(O)n、S(O)n(C1-C3)烷基,其中n=0,1,2;
Z选自C6-C10芳基、5-10元杂芳基,其环上的氢可以被R4取代;
X选自O(C0-C3)烷基、NR5(C0-C3)烷基、NR5C(O)、NR5S(O)2、C(O)NR5、S(O)2NR5、N(R5)C(O)N(R6)、N(R5)C(S)N(R6);
W选自C6-C12芳基、5-12元杂芳基,其环上的氢可以被1个或多个独立的R7取代;
R4选自卤素、OH、氰基、O(C1-C5)烷基、C1-C5烷基;
R5和R6独立的选自氢、C1-C3烷基、C3-C6环烷基、C(O)C1-C3烷基、S(O)2(C1-C3)烷基或S(O)2(C3-C6)环烷基;或者R5和R6结合在一起形成3-6元环;或R1与R5或R6中的一个结合在一起形成5-7元环;
R7选自氢、卤素、C6-C12芳基、5-12元杂芳基、羟基、硝基、氰基、(C1-C5)烷基、O(C1-C6)烷基、(C1-C5)杂烷基、O(C3-C7)环烷基、O(C3-C6)杂环烷基、(C1-C3)烷基(C3-C6)杂环烷基、C2-C5烯基、C2-C5炔基、C3-C6环烷基、C3-C6杂环烷基、NR5R6、C(O)R8、P(O)R8R9、S(O)n(C1-C3)烷基或S(O)n(C3-C6)环烷基,其中n=0,1,2;且2个相邻的R7可以形成4-12元环。
R8和R9独立的选自C1-C3烷基、O(C1-C3)烷基、NR5R6。
在任意的和所有的实施方式中,取代基可以选自所列出的供选择项目的子集合。例如,在一些实施方式中,R3选自氢或卤素。
在一些实施方式中,R3选自氢或卤素;W选自苯环或5-10元杂芳基,其环上的氢可以被1个或多个独立的R7取代,且2个相邻的R7可以形成5-7元环;其中R7选自卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2。
在一些实施方式中,W选自苯环或5-10元杂芳基,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环;在进一步的实施方式中,W选自苯环,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环。
在一些实施方式中,W选自苯环或5-10元杂芳基,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环;R3选自苯基,5-10元杂芳基,其环的氢可以被卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2;R3上的氢各自任选被1个或多个独立的R7取代,且相邻的R7可以形成5-7元环;在进一步的实施方式中,W选自苯环或5-10元杂芳基,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环;R3选自苯基、吡唑、吡啶,其环上的氢可以被卤素、氰基、O(C1-C3)烷基、C1-C3烷基、C3-C6环烷基、(C1-C5)杂烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基取代;且R3上相邻的取代基可以形成5-7元环。
在一些实施方式中,W选自苯环,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环;R3选自苯基,5-10元杂芳基,其环的氢可以被卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2;R3上的氢各自任选被1个或多个独立的R7取代,且相邻的R7可以形成5-7元环;在进一步的实施方式中,W选自苯环,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环;R3选自苯基、吡唑、吡啶,其环上的氢可以被卤素、氰基、O(C1-C3)烷基、C1-C3烷基、C3-C6环烷基、(C1-C5)杂烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基取代;且R3上相邻的取代基可以形成5-7元环。
在一些实施方式中,A选自N;R3选自氢或卤素;W选自苯环或5-10元杂芳基,其环上的氢可以被1个或多个独立的R7取代,且2个相邻的R7可以形成5-7元环;其中R7选自卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2。
在一些实施方式中,A选自N;W选自苯环,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环;R3选自苯基,5-10元杂芳基,其环的氢可以被卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2;R3上的氢各自任选被1个或多个独立的R7取代,且相邻的R7可以形成5-7元环;在进一步的实施方式中,A选自N;W选自苯环,其环上的氢可以被1个或多个独立的R7取代,且取代基中的一个选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且2个相邻的R7可以形成5-7元环;R3选自苯基、吡唑、吡啶,其环上的氢可以被卤素、氰基、O(C1-C3)烷基、C1-C3烷基、C3-C6环烷基、(C1-C5)杂烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基取代;且R3上相邻的取代基可以形成5-7元环。
在上述所列的实施方式中的一个优选实施方案具有通式(Ia)表示的化合物,
其中:
R2选自氢、卤素、OH、NR5R6、氰基、C1-C5烷基;
Q选自CHR5CHR6、O、OC(R5R6)、C(R5R6)、CO、NR5C(O)、NR5S(O)2、CH=CH、C≡C、S(O)n、S(O)n(C1-C3)烷基,其中n=0,1,2;
Z选自苯环或吡啶,其环上的氢可以被R4取代;
X选自O(C0-C3)烷基、NR5(C0-C3)烷基、NR5C(O)、NR5S(O)2、C(O)NR5、S(O)2NR5、N(R5)C(O)N(R6)、N(R5)C(S)N(R6);
R4选自卤素、OH、氰基、O(C1-C5)烷基、C1-C5烷基;
R5和R6独立的选自氢、C1-C3烷基,或者R5和R6结合在一起形成3-6元环;
在此优选方案的一些实施方式中,R2选自氢;在进一步的一些实施方式中,R2选自氢;Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;
在此优选方案的一些实施方式中,Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基。在进一步的一些实施方式中,Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6独立的选自氢、C1-C3烷基,或者R5和R6结合在一起形成3-6元环;在再进一步的实施方式中,Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6中的一个为氢,另一个选自C1-C3烷基。
在此优选方案的一些实施方式中,R2选自氢;Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基。在进一步的一些实施方式中,R2选自氢;Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6独立的选自氢、C1-C3烷基,或者R5和R6结合在一起形成3-6元环;在再进一步的实施方式中,R2选自氢;Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6中的一个为氢,另一个选自C1-C3烷基。
在此优选方案的一些实施方式中,X选自OCH2、NHCH2、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH、NHC(O)NH、NHC(S)NH;在进一步的一些实施方式中,X选自NHC(O)、C(O)NH、NHC(O)NH、NHC(S)NH。
在此优选方案的一些实施方式中,Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;X选自OCH2、NHCH2、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH、NHC(O)NH、NHC(S)NH。在进一步的一些实施方式中,Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6独立的选自氢、C1-C3烷基,或者R5和R6结合在一起形成3-6元环;X选自OCH2、NHCH2、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH、NHC(O)NH、NHC(S)NH。在再进一步的实施方式中,Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6中的一个为氢,另一个选自C1-C3烷基;X选自OCH2、NHCH2、NHC(O)、NHS(O)2、C(O)NH、S(O)2NH、NHC(O)NH、NHC(S)NH。
在此优选方案的一些实施方式中,R2选自氢;Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;X选自NHC(O)、C(O)NH、NHC(O)NH、NHC(S)NH。在进一步的一些实施方式中,R2选自氢;Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6独立的选自氢、C1-C3烷基,或者R5和R6结合在一起形成3-6元环;X选自NHC(O)、C(O)NH、NHC(O)NH、NHC(S)NH。在再进一步的实施方式中,R2选自氢;Z选自苯环或吡啶,其环上的氢可以被1个或多个独立的R4取代,且R4选自卤素、OH、氰基、O(C1-C3)烷基、C1-C3烷基;Q选自OC(R5R6),其中R5和R6中的一个为氢,另一个选自C1-C3烷基;X选自NHC(O)、C(O)NH、NHC(O)NH、NHC(S)NH。
上述所述的化合物,进一步优选自通式(Ib)中的化合物:
R3选自氢、卤素、C6-C10芳基、5-10元杂芳基、C3-C6杂环烷基;R3上的氢各自任选被1个或多个独立的R7取代,且相邻的R7可以形成5-7元环;
W选自C6-C10芳基、5-10元杂芳基,其环上的氢可以被1个或多个独立的R7取代;
R7选自氢、卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、NR5R6、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2(C1-C3)烷基、SO2环丙基、S(C1-C3)烷基;且2个相邻的R7可以形成5-7元环;
R5和R6独立的选自氢、C1-C3烷基、C3-C6环烷基、C(O)C1-C3烷基、S(O)2(C1-C3)烷基或S(O)2(C3-C6)环烷基;或者R5和R6结合在一起形成3-6元环。
在一些实施方式中,通式(Ib)中的化合物R3选自氢、卤素;W选自苯环或5-10元杂芳基,其环上的氢可以被1个或多个独立的R7取代,且2个相邻的R7可以形成5-7元环;其中R7选自卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2。
在一些实施方式中,通式(Ib)中的化合物R3选自苯基、5-10元杂芳基、C3-C6杂环烷基,其环的氢可以被卤素、羟基、硝基、氰基、O(C1-C3)烷基、(C1-C5)杂烷基、O(C3-C6)环烷基、O(C3-C6)杂环烷基、C1-C5烷基、C=C、C≡C、C3-C6环烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基取代、SOn(C1-C3)烷基,其中n=0,1,2;W选自苯环或5-10元杂芳基,其环上的氢被1个或多个独立的R7取代,且取代基中的一个必须选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且R7或W上相邻的取代基可以形成5-7元环。在进一步的一些实施方式中,R3选自苯基、吡唑、吡啶,其环上的氢可以被卤素、氰基、O(C1-C3)烷基、C1-C3烷基、C3-C6环烷基、(C1-C5)杂烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基取代;且R3上相邻的取代基可以形成5-7元环。在再进一步的一些实施方式中,R3选自吡唑或吡啶,其环上的氢可以被卤素、氰基、C1-C3烷基、C3-C6环烷基、(C1-C5)杂烷基、C3-C6杂环烷基,且R3上相邻的取代基可以形成5-7元环。
在一些实施方式中,通式(Ib)中的化合物R3选自苯基、吡唑、吡啶,其环上的氢可以被卤素、氰基、O(C1-C3)烷基、C1-C3烷基、C3-C6环烷基、(C1-C5)杂烷基、C3-C6杂环烷基、N((C1-C2)烷基)2、NH(C1-C2)烷基取代;且R3上相邻的取代基可以形成5-7元环;W选自苯环,其环上的氢被1个或多个独立的R7取代,且取代基中的一个必须选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且W上相邻的取代基可以形成5-7元环。在进一步的一些实施方式中,R3选自吡唑或吡啶,其环上的氢可以被卤素、氰基、C1-C3烷基、C3-C6环烷基、(C1-C5)杂烷基、C3-C6杂环烷基,且R3上相邻的取代基可以形成5-7元环;W选自苯环,其环上的氢被1个或多个独立的R7取代,且取代基中的一个必须选自N((C1-C2)烷基)2、C(O)(C1-C2)烷基、C(O)O(C1-C2)烷基、P(O)(C1-C2烷基)2、SO2环丙基、S(O)n(C1-C3)烷基,其中n=0,1,2,且W上相邻的取代基可以形成5-7元环。
更具体地,本发明的优选化合物选自下列化合物中的任意一个:
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-3-甲基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-3-氟苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-3-氯苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-2-氟-5-甲基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-2-氟苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-氟-2-甲基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-甲基烟酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-氟烟酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-氯烟酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氟-5-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-5-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲氧基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-5-氯烟酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-5-甲基烟酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-氰基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-三氟甲氧基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-三氟甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-3-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2,3-二氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2,5-二氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3,4-二氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)苯并[d][1,3]二氧五环-5-苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-溴苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-环丙基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-C≡C苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲氧基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-氰基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2,5-二氯苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-C≡C苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(异丙磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(环丙磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(二甲膦酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(二甲胺基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-5-甲基烟酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氟-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-环丙基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-异丙基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-异丙氧基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(乙基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2-氯-3-甲氧基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-羟基环戊基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-羟基环丁基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-氯苯基)-2-氯-3-甲基苯甲酰胺
N-(3-((R)-1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-((2-羟基环己基)氨基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-氟苯基)-2-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-羟基环己基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-4-((4-甲基哌嗪-1-基)甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-((4-甲基哌嗪-1-基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2-甲氧基-5-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-((4-甲基哌嗪-1-基)甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(环丙基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(异丙基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(环戊基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)喹啉-3-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)异喹啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)喹啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(吡咯烷基-1-基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-环丙基吡啶甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)吡啶-3-基)-2-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-氰基环丙基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-环丁基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(吡咯烷基-1-基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-4-甲酰胺1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-5-甲酰胺1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-氟吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-甲基吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-甲基吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-(三氟甲基)吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-(三氟甲基)吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-6-(三氟甲基)吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-甲基-3-(甲磺酰基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-甲基苯基)-3-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(二氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-6-甲基吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-氟-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3,4-二甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢-1H-茚-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-6-甲酰胺1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-氟-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-氯-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3,5-二甲基苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-甲苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-氟苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-氯苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(6-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-吡啶)-2-基)-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-甲基苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-甲基苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(4-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)吡啶-2-基)-3-甲基苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-氯苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-氟苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-苯基)-3-(甲磺酰基)-4-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并[b]噻吩-5-甲酰胺1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并[b]噻吩-6-甲酰胺1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)-5-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3,4-二甲基-5-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1,5-二甲基-1H-吡唑-3-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-甲基噻唑-2-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-(叔丁基)-1H-吡唑-4-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-(异丙基)-1H-吡唑-4-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-1H-吲唑-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并呋喃-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-1H-吲哚-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-(叔丁基)异恶唑-3-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-2-氧-1,2,3,4-四氢喹啉-7-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-1,2,3,4-四氢喹啉-7-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-2-氧吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1,3-二氢异苯并呋喃-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,4-二甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,5-二甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-甲基l-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-6-甲酰胺1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-环丙基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)-4-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)-5-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,4-二甲基-5-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)-4-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-甲基-3-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2’,3’-二氢螺[环丙烷-1,1’-茚]-6’-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-1-甲基吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-氯-3-(二甲氨基)苯甲酰胺
甲基(R)-3-((3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)氨甲酰)苯甲酸酯
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-异丙基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2,3-二氢-1H-茚-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-乙基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-5-异丙基烟酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-1-甲基-1H-吲哚-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)苯并[b噻吩]-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,3-二甲基-1,3-二氢异苯并呋喃-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2H-螺[苯并呋喃-3,1’-环丙烷]-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并呋喃-5-甲酰胺
(R)-N-(3-(1-((6-氨基-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-环丙基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-三氟甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3,4-二甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3,5-二甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)-4-甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-1-甲基吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-环丙基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-环丙基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基哌啶-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(4-羟基-3-甲氧基苯基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((6-氨基-6’-(4-甲基哌嗪-1-基)-[3,3’-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,4'-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
N-(3-(((5-氯-2-(甲胺基)吡啶-3-基)氧基)甲基)苯)-3-甲基苯甲酰胺
N-(3-(((2-氨基吡啶-3-基)氧基)甲基)苯基)-3-甲基苯甲酰胺
5-(((2-氨基-5-氯吡啶-3-基)氧基)甲基)-N-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-2-胺
5-氯-3-((3-甲氧基-4-((4-甲氧基苄基)氧基)苄基)氧基)吡啶-2-胺
5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯氧基)吡啶-2-胺
N-(3-(((3-胺基-6-氯哌嗪-2-基)氧基)甲基)苯基)-3-甲基苯甲酰胺
5-氯-3-((3-甲氧基-4-((4-甲氧基苄基)氧基)苄基)氧基)哌嗪-2-胺
5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯氧基)哌嗪-2-胺
(S)-N-(3-(1-((3-氨基-6-氯哌嗪-2-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
5-氯-3-((6-((4-甲氧苄基)氧基)吡啶-3-基)甲氧基)吡啶-2-胺
(E)-5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯乙烯基)吡啶-2-胺
(E)-N-(3-(2-(2-氨基-5-氯吡啶-3-基)烯基)苯基)-3-甲基苯甲酰胺
N-(3-(2-(2-氨基-5-氯吡啶-3-基)环丙基)苯基)-3-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-3-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-2-氯-5-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-3-甲氧基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-2-氯-3-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-2,5-二氯苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环丙基)苯基)-3-甲基苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环丁基)苯基)-3-甲基苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环戊基)苯基)-3-甲基苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环己基)苯基)-3-甲基苯甲酰胺
5-氯-3-((5-甲氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)氧基)吡啶-2-胺
5-((2-氨基-5-氯吡啶-3-基)氧基)-N-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-2-胺
4-((4-((2-胺基-5-氯吡啶-3-基)氧基)-2-甲氧基苯氧基)甲基)苯甲腈
5-氯-3-(3-甲氧基-4-((4-三氟甲基)苄基)氧基)苯氧基)吡啶-2-胺
4-(((5-((2-胺基-5-氯吡啶-3-基)氧基)-3-甲氧基吡啶-2-基)氧基)甲基)苯甲腈
5-氯-3-((6-((4-氯苄基)氧基)-5-甲氧基吡啶-3-基)氧基)吡啶-2-胺
N-(4-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-甲氧基苯甲酰胺
N-(4-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-4-甲氧基苯甲酰胺
N-(4-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-4-氰基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-甲基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-甲氧基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-氯苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-三氟甲氧基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-4-甲基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-(甲磺酰基)苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(1-羟基环戊基)苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-环丙基苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(1-氰基环丙基)苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-甲基吡啶-1-基)苯甲酰胺
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-氟苯基)-3-甲氧基苯甲酰胺
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-氯苯基)-3-甲氧基苯甲酰胺
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-甲基苯基)-3-甲氧基苯甲酰胺
N-(5-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-2-氟苯基)-3-甲氧基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)-2-氟苯基)-3-甲氧基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)-4-氟苯基)-3-甲氧基苯甲酰胺
(R)-N-(3-(1-((5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺的合成
(R)-N-(3-(1-((6-氯吡嗪-2-基)氧基)乙基)苯基)-3-(三氟甲基)苯甲酰胺
(R)-1-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-(4-甲基苯基)脲
(R)-1-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-(3-甲基苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(间甲苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-甲苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-(甲磺酰基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(间甲苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-甲苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-2-甲基苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-3-甲基苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-3-氟苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-2-氟苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(5-((2-氨基-5-氯吡啶-3-基)氧)-2-甲基苯基)-3-(4-甲苯基)脲
1-(5-((2-氨基-5-氯吡啶-3-基)氧)-2-氯苯基)-3-(4-甲苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-(二甲氨基)苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-(甲氧基)苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(2,3-二氢苯[b]噻吩-5-基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(苯[b]噻吩-5-基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(1-(叔丁基)-1H-吡唑-4-基)脲
1-(3-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-甲苯基)脲
1-(3-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-(甲磺酰基)苯基)脲
1-(4-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)-2-氟苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-甲苯基)脲
1-(3-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-(甲磺酰基)苯基)脲
1-(4-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-5-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-环丙基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-氯-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-氟-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-氰基-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1,3-二甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-(2-(二甲胺基)-2-氧乙基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(3-甲基-1H-吡唑-5-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N1-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)间苯二甲酰胺
N-(3-((R)-1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲基亚磺酰基)苯甲酰胺
N-(3-((S)-1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲基亚磺酰基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)-4-甲基苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲硫基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-甲基-3-(甲硫基)苯甲酰胺
本发明的药物组合物含有至少一种有效治疗剂量的上述通式(I)化合物和至少一种药学上接受的辅料。
本发明的药物组合物可应用于制药中。
本发明用于治疗哺乳动物异常细胞生长的方法,包括对治疗对象施用治疗有效量的上述通式(I)化合物或其药物组合物,其中,异常细胞生长优选为癌症。
本发明用于治疗和预防CSF-1R激酶介导的黑色素瘤、卵巢癌、子宫癌、乳腺癌、结肠癌、胃癌、肝癌和非小细胞肺癌的方法,包括对治疗对象施用治疗有效量的通式(I)化合物或其药物组合物。
本发明的化合物和药物组合物用于制备治疗哺乳动物异常细胞生长的药物,其中异常细胞生长优选为癌症。
本发明的化合物和药物组合物用于制备治疗和预防CSF-1R激酶介导的癌症的药物。
本发明的化合物和药物组合物与化疗剂、放射、和/或癌症免疫疗法组合施用。
定义
除非另有述及,否则于本专利说明书与权利请求中使用的下述术语具有下文所讨论的意义。在本部分中定义的变量,例如A,R,X,Z等,仅供此部分内参考,并非意谓具有如可使用于此定义部分外的相同意义。再者,此处定义的许多基团可选择性地被取代。在此定义部分中典型取代基的清单是作为举例,并非意欲限制本专利说明书与权利要求书中别处所定义的取代基。
“Cm-Cn”是指所含的碳原子从m-n个。
“烷基”是指饱和脂族烃基团或连接臂,包括1至20个碳原子,优选为1至12个碳原子,更优选为1至8个碳原子,或1至6个碳原子,或1至4个碳原子的直链与支链基团。“低级烷基”特别指具有1至4个碳原子的烷基。烷基的实例包括-(CH2)3-,甲基、三氟甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基等。烷基可为被取代或未被取代。典型取代基包括环烷基、芳基、杂芳基、杂环烷基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳基硫基、氰基、卤代基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰胺基、C-羧基、O-羧基、硝基、硅烷基、氨基及-NRxRy,其中Rx与Ry独立选自包括氢、烷基、环烷基、芳基、羰基、乙酰基、磺酰基、三氟甲烷磺酰基及合并的5-或6-元杂环基环。
“杂烷基”是指烷基中一个或多个骨架链原子是杂原子,例如氧、氮、硫、硅、磷或它们的组合。所述杂原子(一个或多个)可以位于杂烷基内部的任意位置或在杂烷基与分子的其余部分相连的位置。实例包括但不限于-CH2-O-CH3,-CH2-CH2-O-CH3,-OCH2-,-CH2-NH-CH3,-CH2-CH2-NH-CH3,-CH2-N(CH3)-CH3,-NCH2CH2-,-CH2-CH2-NH-CH3,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH2-S(O)-CH3,-CH2-CH2-S(O)2-CH3。另外,可以至多两个杂原子可以是相连的,例如,举例说明,-CH2-NH-OCH3。
“环烷基”是指3至8元全碳单环状环,全碳5-元/6-元或6-元/6-元经稠合的双环状环,或多环状稠合环(“经稠合”环系统是指在此系统中的每一个环系与此系统中的其它环至少共有一个相邻碳原子)基团,其中一或多个环可含有一或多个双键,但这样的环均不具有完整的共轭π-电子系统,亦或双环通过共用一个碳形成螺环。环烷基的实例是(但不限于)环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己二烯、金刚烷、环庚烷、环庚三烯等。环烷基可为被取代或未被取代。典型取代基包括环烷基、芳基、杂芳基、杂环烷基、羚基、烷氧基、芳氧基、巯基、烷硫基、芳基硫基、氰基、卤代基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰胺基、C-羧基、O-羧基、硝基、硅烷基、氨基及-NRxRy,其中Rx与Ry系如上文定义。环烷基的说明性实例衍生自(但不限于)下列:
“环烷基烷基”是指本文定义的烷基被环烷基取代。非限制性的环烷基烷基包括环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基等。
“烯基”是指如本文中定义的烷基,包含至少两个碳原子及至少一个碳-碳双健。代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。
“芳基”是指6至12个碳原子的全碳单环状或稠合环多环基团,具有完整共扼π-电子系统。芳基的实例是但不限于苯基、萘基及蒽基。芳基可为被取代或未被取代。典型取代基包括卤代基、三卤代甲基、烷基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳基硫基、氰基、硝基、羰基、硫代羰基、C-羧基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰胺基、亚磺酰基、磺酰基、氨基及-NRxRy,其中Rx与Ry系如上文定义。芳基稠合杂环烷基可看作为芳基的特殊取代基,典型的实例包括但不限于:
“杂芳基”是指5至12个环原子的单环状或稠合环,含有一、二、三或四个选自N,O及S的环杂原子,其余环原子为C,且此外,具有完整共扼π-电子系统。未被取代杂芳基的实例是但不限于吡咯、呋喃、噻吩、咪唑、恶唑、噻唑、吡唑、吡啶、嘧啶、喹啉、异喹啉、嘌呤、四唑,三嗪及咔唑。杂芳基可为被取代或未被取代。典型取代基包括卤代基、三卤代甲基、烷基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳基硫基、氰基、硝基、羰基、硫代羰基、C-羧基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰胺基、亚磺酰基、磺酰基、氨基及-NRxRy,其中Rx与Ry系如上文定义。
药学上可接受的杂芳基是足够稳定以被连接至本发明的化合物被配制成药物组合物,及随后被施用有需要的病患者。
典型杂芳基的实例包括但不限于:
“杂环烷基”或“杂环”是指单环状或稠合环,亦或螺环,具有3至12个环原子在环中,其中一或两个环原子是选自N,O及S(O)n(其中n为0,1或2)的杂原子,其余环原子为C。这样的环亦可具有一或多个双健,也包括但不限于内酯或内酰胺。但是,这样的环并未具有完整共扼π一电子系统。适当饱和杂脂环基基团的实例包括但不限于:
杂环烷基团选择性地被一或多个取代基取代,取代基独立选自卤代基、低级烷基、被羧基取代的低级烷基、酯羟基或单或二烷氨基。
“羟基”是指-OH基团。
“烷氧基”是指-O-(烷基)或-O-(未被取代环烷基)两者。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷基或环烷基可为被取代或未被取代,典型的取代基包括卤代基等。代表性实例包括但不限于三氟甲氧基、二氟甲氧基等。
“芳氧基”是指如本文定义的-O-芳基或-O-杂芳基。代表性实例包括但不限于苯氧基、吡啶基氧基、呋喃基氧基、噻吩基氧基等,及其衍生物。
“巯基”是指-SH基团。
“烷硫基”是指-S-(烷基)或-S-(未取代环烷基)。代表性实例包括但不限于甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基、环己硫基等。
“芳基硫基”是指如本文定义的-S-芳基或-S-杂芳基。代表性实例包括但不限于苯硫基、吡啶基硫基、呋喃基硫基、噻吩基硫基、嘧啶基硫基等,及其衍生物。
“酰基”或”“羰基”是指-C(O)R"基团,其中R"选自包括氢、低级烷基、三卤代甲基、未被取代的环烷基,芳基,选择性地被一或多个,优选为一、二或三个取代基取代,取代基选自包括低级烷基、三卤代甲基、低级烷氧基、卤代基及-NRxRy基团,杂芳基(经过环碳结合),选择性地被一或多个,优选为一、二或三个取代基取代,取代基选自包括低级烷基、三卤代烷基、低级烷氧基、卤代基及-NRxRy基团,及杂脂环基(经过环碳结合),选择性地被一或多个,优选为一、二或三个取代基取代,取代基选自包括低级烷基、三卤代烷基、低级烷氧基、卤代基及-NRxRy基团。代表性酰基包括但不限于乙酸基、三氟乙酸基、苯甲酰基等。
“醛”是指酰基,其中R"为氢。
“硫酰基”或“硫代羰基”是指-C(S)R"基团,其中R"如上文定义。
“硫代羰基”是指-C(S)R"基团,其中R"如上文定义。
“C-羧基”是指-C(O)OR"基团,其中R"如上文定义。
“O-羧基”是指-OC(O)R"基团,其中R"如上文定义。
“酯”是指-C(O)OR"基团,其中R"如本文定义,但是R"不能为氢。
“乙酰基”是指-C(O)CH3基团。
“卤代基”是指氟、氯、溴或碘,优选为氟或氯。
“三卤甲基”是指含有三个卤代基的甲基,如三氟甲基。
“氰基”是指-C≡N基团。
“亚硫酰基”是指-S(O)R"基团,其中除了如上文定义以外,R"亦可为羟基。
“磺酰基”是指-S(O)2R"基团,其中除了如上文定义以外,R"亦可为羟基。
“膦酰基”是指-P(O)RxRy,其中Rx与Ry选自烷基或者烷氧基。
“S-磺酰氨基”是指-S(O)2NRxRy基团,其中Rx与Ry如上文定义。
“N-磺酰氨基”是指-NRxS(O)2Ry基团,其中Rx与Ry如上文定义。
“O-氨基甲酰基”是指-OC(O)NRxRy基团,其中Rx与Ry如上文定义。
“N-氨基甲酰基”是指RyOC(O)NRx-基团,其中Rx与Ry如上文定义。
“O-硫代氨基甲酰基”是指-OC(S)NRXRy基团,其中Rx与Ry如上文定义。
“N-硫代氨基甲酰基”是指RyOC(S)NRx一基团,其中Ry与Rx如上文定义。
“氨基”是指-NRxRy基团,其中Rx与Ry均为氢。
“C-酰氨基”是指-C(O)NRxRy基团,其中Rx与Ry如上文定义。
“N-酰胺基”是指RxC(O)NRy基团,其中Rx与Ry如上文定义。
“-酰氨基-”是指-C(O)NRy-基团,其中Rx与Ry如上文定义。
“硝基”是指-NO2基团。
“亚胺”是指-N=C-基团。
“卤代烷基”是指烷基,优选为低级烷基,它是被一或多个相同或不同卤代基原子取代,例如-CH2Cl、-CF3、-CH2CF3、-CH2CC13等。
“羟烷基”是指烷基,优选为低级烷基,它是被一、二或三个羟基取代;例如羟甲基、1或2-羟乙基、1,2-,1,3-或2,3-二羟基丙基等。
“芳烷基”是指烷基,优选为低级烷基,它是被如上文定义的芳基取代;例如-CH2苯基、-(CH2)2苯基、-(CH2)3苯基、CH 3CH(CH 3)CH2苯基等,及其衍生物。
“杂芳烷基”是指烷基,优选为低级烷基,它是被杂芳基取代;例如-CH2吡啶基、-(CH2)2嘧啶基、-(CH2)3咪唑基等,及其衍生物。
“单烷氨基”是指基团-NHR,其中R为烷基或未被取代的环烷基;例如甲氨基、(1-甲基乙基)氨基、环己氨基等。
“二烷氨基”是指基团-NRR,其中各R独立地为烷基或未被取代的环烷基;二甲氨基、二乙氨基、(1-甲基乙基)-乙氨基、环己基甲氨基、环戊基甲氨基等。
术语“杂原子”是指除了碳或氢以外的原子。杂原子通常独立地选自氧、硫、氮、硅和磷,但不限于这些原子。在其中存在两个或更多杂原子的实施方式中,所述两个或更多杂原子可以是彼此全都相同、或两个或多个杂原子的一些或全都可以是彼此不相同。
术语“任选取代的”或“取代的”是指所提及的基团可以被一个或多个基团取代,所述基团各自并且独立地选自烷基、杂烷基、环烷基、芳基、杂芳基、杂环烷基、羟基、烷氧基、芳氧基、烷硫基、芳硫基、烷基亚砜、芳基亚砜、烷基砜、芳基砜、氰基、卤素、羧基、硝基、卤代烷基、卤代烷基、氨基包括单氨基和二取代氨基和其被保护的衍生物。
“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,且该描述包括其中发生该事件或状况的情况,及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,且该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
本文使用的术语“可接受的”或“药物可接受的”,当涉及制剂、组合物或成分时,是指对被治疗的受治疗者的一般健康状况没有持久的不利影响或不损失化合物的生物活性或性质,并且相对无毒性。
上文所述“有效治疗剂量”是指一个化合物用于治疗对象时治疗并且预防和/或抑制一种疾病、病情、症状、适应症和/或不适的至少一种临床症状时,足以对这种疾病、病情、适应症、不适或症状的治疗产生一定效果的有效剂量。具体的“有效治疗剂量”可以根据化合物,用药途径,患者年龄,患者体重,所治疗的疾病或不适的类型、症状和严重程度等变化。在任意可能的情况下,一个合适的剂量对那些在本领域的专业人员可以是显而易见的,也可以是用常规实验方法确定的。
于本文中使用的“药学上可接受的盐”一词是指能保持母体化合物的生物有效性与性质的盐。此种盐包括:
(1)酸加成盐,其可通过母体化合物的游离碱,与无机酸类,例如盐酸、氢嗅酸、硝酸、磷酸、硫酸及过氯酸等,或与有机酸类,例如醋酸、草酸、(D)或(L)苹果酸、顺丁烯二酸、甲烷磺酸、乙烷磺酸、对一甲苯磺酸、水杨酸、酒石酸、柠檬酸、唬泊酸或丙二酸等的反应而获得;或
(2)当存在于母体化合物中的酸性质子,无论是被金属离子例如碱金属离子、碱土金属离子或铝离子置换;或与有机碱例如乙醇胺、二乙醇胺、三乙醇胺、丁三醇胺,N-甲基葡萄糖胺等配位时所形成的盐。
本文中,当一个化合物的化学结构式和化学名称有分歧或疑义时,以化学结构式确切定义此化合物。本文所描述的化合物有可能含有一个或多个手性中心,和/或者双键以及诸如此类的结构,也可能存在立体异构体,包括双键的异构体(比如几何异构体)、旋光对映异构体或者非对映异构体。相应的,在本文描述范围内的任意化学结构,无论是部分或整体结构中含有上述类似结构,都包括了此化合物的所有可能的对映异构体和非对映异构体,其中也包括了单纯的任一种立体异构体(如单纯的几何异构体、单纯的对映异构体或者单纯的非对映异构体)以及这些异构体的任意一种混合物。这些消旋异构体和立体异构体的混合物由本领域技术人员利用不同的分离技术或手性分子合成的方法也可进一步被拆分成其组成成分的对映异构体或立体异构体。
结构式I的化合物包含了,但并不仅限于,这些化合物的光学异构体、消旋体和/或其他的混合物。上述情况下,其中单一的对映异构体或非对映异构体,如有旋光的异构体,可以用不对称合成的方法或消旋体拆分的方法获得。消旋体的拆分可用不同的方法实现,如常规的用助拆分的试剂重结晶,或用色谱方法,如用手性高压液相色谱(HPLC)。另外,结构式I的化合物也包含了带双键的顺式和/或反式的异构体。结构式I所示的化合物中,存在互变异构体(tautomers)的,本发明也包含了这些化合物的所有互变异构体(tautomericforms)。
本发明所描述的化合物包含了,但并不仅限于,结构式I所示的化合物以及他们所有的在药学上可用的不同形式。这些化合物的药学上可用的不同形式包括各种可药用的盐、溶剂化物、晶型包括多种晶型和络合物、螯合物、非共价的复合物和基于上述物质基础上的药物前体,和以上所述的这些形式的任意混合物。本发明的某些实施中,本发明所描述的化合物以可药用的盐的形式存在。本文中“化合物”这个术语不仅包括了化合物本身,也包括了其所成的可药用的盐、溶剂化物、螯合物、非共价的复合物、基于上述化合物基础上的药物前体,和以上所述的这些形式的任意混合物。
式(I)化合物的“药物前体”也包含在所述化合物的范围内,例如相应化合物的酯或酰胺衍生物。本术语“药物前体”包括了任意在人体内能转化为式(I)化合物的化合物,比如通过药物前体的新陈代谢过程。该药物前体的范例包括,但并不仅限于,式(I)化合物上不同功能团(比如醇或氨基基团)的乙酰衍生物、甲酰衍生物、苯甲酰衍生物以及其他类似衍生物。
本发明化合物可以组合物的形式通过口服、鼻吸入、直肠或肠胃外给药的方式施用于需要治疗的患者。用于口服时,可将其制成常规的固体制剂如片剂、粉剂、颗粒剂、胶囊剂等,制成液体制剂如水或油悬浮剂或其他液体制剂如糖浆、CHI剂等;用于肠胃外给药时,可将其制成注射用的溶液、水、油性悬浮剂或冻干粉针等。优选的剂型是片剂、包衣片剂、胶囊、栓剂、鼻喷雾剂或注射剂,特别优选口服制剂。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如,将活性成分与一种或多种辅料混合,然后将其制成所需的剂型。
实施例
本发明用包括但并不仅限于以下实施例来进一步阐述本发明所描述的化合物的制备。
下述实施例仅用于说明本发明的具体实施方式,可以使本专业技术人员更加全面地理解本发明,但不以任何方式限制本发明。本发明的具体实施方式中,未作特别说明的技术手段或方法等为本技术领域的常规技术手段或方法等。
实施例1:
2-氨基-3-羟基-5-氯吡啶的合成
步骤1:往2-氨基-3羟基吡啶(19.8g,180.0mmol)的四氢呋喃(200ml)溶液中,加入N,N'-羰基二咪唑(43.8g,270.0mmol),升温至75℃回流搅拌16小时。反应结束后,柱层析提纯,得2,3-二氢吡啶并[2,3-d][1,3]唑-2-酮17.63g,收率:72%。
步骤2:0℃下,往2,3-二氢吡啶并[2,3-d][1,3]唑-2-酮(10.0g,73.5mmol)的DMF(90ml)溶液中滴加N-氯代丁二酰亚胺(12.3g,91.8mmol)的DMF(50ml)溶液,60min滴加完毕。升至室温反应3小时。加入150ml冰水,搅拌30min,过滤收集固体得到目标产物(12.0g)。
步骤3:往7.7g氢氧化钾的80ml冰水溶液中,加入6-氯恶唑并[4,5-B]吡啶-2(3H)-酮(11.0g,64.5mmol),回流16小时。降至室温后,在冰水浴中用浓盐酸调节PH至8,抽滤收集固体,并用水洗。烘干后得到2-氨基-3-羟基-5-氯吡啶5.1g,为黄色固体。
实施例2:
3-((3-氨基苄基)氧基)-5-氯吡啶-2-氨的合成
步骤1:往3-氨基苯甲醇(6.2g,50.0mmol),碳酸氢钠(6.3g,75.0mmol)的50ml乙腈溶液中滴加二碳酸二叔丁酯(13.1g,60.0mmol),30min内滴加完毕。室温反应16小时后,柱层析提纯,得到叔丁基(3-(羟甲基)苯基)氨基甲酸酯6为黄色油状物(11.8g)。
步骤2:-15℃下,氮气保护下,往6(5g,22.4mmol),三乙胺(12.54ml,89.6mmol)的二氯甲烷(100ml)溶液中滴加甲基磺酰氯(3.47ml,44.8mmol)的二氯甲烷(20ml)溶液,20min内滴加完毕。滴加完毕后升温至0℃反应16小时。反应液倒入到100ml水中,并搅拌5分钟。收集有机相,真空浓缩,柱层析法提纯得到产品7(1.86g,27.6%)。
步骤3:往丙酮(30ml)溶剂中加入7(1.86g,6.18mmol),4(896mg,6.18mmol)和碳酸铯(2.619g,8.03mmol)。混合物升至60℃回流反应16小时。反应液真空浓缩,柱层析法提纯,真空干燥,得到淡黄色固体8(810mg,37.5%)。
步骤4:往8(810mg,2.3mmol)的甲醇(10mL)溶液中,加入12N盐酸(0.5mL)。反应液50℃搅拌16小时,然后真空浓缩。残余物加入5ml甲苯混匀后再次真空浓缩至干,得到白色固体,为9的盐酸盐(650mg,98.3%),LC-MS[M+H]-m/z:250。
实施例3
化合物20-29的合成
一般反应步骤:
往反应瓶中依次加入9(57mg,0.2mmol),R-COOH(1.2eq,0.24mmol),EDCI(58mg,0.3mmol),和DMAP(5mg,0.04mmol)的DCM(5mL)溶液,搅拌下加入DIPEA(77mg,0.6mmol)。反应室温搅拌过夜,然后通过柱层析纯化得到产品。
表格一
实施例4
(S)-(3-(1-羟乙基)苯基)氨基甲酸叔丁酯的合成
氮气氛围下,往干燥的三口瓶中加入R-甲基-CBS-恶唑硼烷(0.2eq),硼烷二甲硫醚(10M,2.0eq),加入二氯甲烷稀释,于25℃下搅拌30min。降至-30℃,滴加(3-乙酰基苯基)氨基甲酸叔丁酯的二氯甲烷溶液,30min滴加完毕。继续于-30℃下搅拌3h。TCL小板监控原料基本反应完毕,于-30℃滴加甲醇淬灭,30min滴加完毕,升至80℃回流1h。浓缩反应液,柱层析提纯(石油醚:乙酸乙酯=3:1)真空干燥,得到目标产物,为无色透明油状物。LC-MS[M+Na]-m/z:260。
实施例5
化合物54-71的合成
步骤1:在搅拌条件下,将2-氨基-3-氟-5-氯吡啶(10g,68.2mmol)加入到将100ml冷却至-10℃的浓硫酸中,待溶解后继续于-10℃搅拌15min,然后缓慢滴加50ml30%过氧化氢水溶液,保持反应温度不高于0℃。混合物升至室温搅拌72h,在搅拌条件下将反应液缓慢倒入500ml 13%冰食盐水中,用200ml EA萃取,共三遍,合并有机相,用饱和碳酸氢钠水溶液洗涤至水相呈碱性。用无水硫酸钠干燥有机相并真空浓缩,残余物柱层析纯化得到产品2-硝基-3-氟-5-氯吡啶(2.8g,23.3%)。
步骤2:往31(1.0g,4.2mmol)干燥的四氢呋喃(10ml)溶液中,加入叔丁醇钾(517.0mg,4.6mmol),室温搅拌10min,加入2-硝基-3-氟-5-氯吡啶(741.0mg,4.6mmol),室温搅拌1h。向反应液中加入10g硅胶淬灭,柱层析分离得产品(1.50g,95%)。
步骤3:将34(1.50g,3.8mmol),无水三氯化铁(60mg,0.38mmol)和活性炭(200mg)的10ml甲醇的悬浮液回流15min,然后滴加水合肼(80%水溶液)(600mg,9.5mmol),回流1h。反应液倒入100ml 13%食盐水中,用50ml EA萃取三遍,合并有机相,用饱和食盐水洗涤三遍,无水硫酸钠干燥后真空浓缩得到的白色固体(1.0g,2.5mmol)。将固体重新溶于10ml甲醇中,加入1ml浓盐酸,升温至50℃搅拌3h;反应液冷却至室温,真空浓缩。剩余物倒入到100ml饱和碳酸氢钠水溶液中,用50ml EA萃取,共萃取三遍,合并有机相,用无水硫酸钠干燥并真空浓缩至干,得产品602.0mg,为黄色油状物。
步骤4:化合物54-71的合成同实施例3。
表格二
实施例6
化合物72-164的合成与化合物54-71的合成类似。
表格三
实施例7
化合物168-195的合成:
步骤1:将K3PO4(6.57g,30.0mmol)的水(10mL)溶液加入到165(2.64g,10.0mmol),166(3.12g,15.0mmol)和x-phos(954mg,2.0mmol)的二氧六环(100mL)溶液中,得到的混合物氮气置换三次,加入醋酸钯(225mg,1.0mmol),然后再次除气。反应液升至110℃回流24h。降至室温,将反应液倒入13%的食盐水中,乙酸乙酯萃取两遍,合并有机相,并用饱和食盐水洗一遍,干燥,过滤,浓缩。粗品柱层析纯化得棕色油状物。
步骤2:往167(62mg,0.2mmol),ArCOOH(1.2eq),HATU(1.5eq)DCM(2mL)溶液中加入TEA(3.0eq)。反应物室温搅拌16h,粗品通过柱层析或者PTLC纯化。
表格四
实施例8
199-208的合成与168-195的合成类似:
表格五
实施例9
(R)-N-(3-(1-((2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-环丙基苯甲酰胺的合成
步骤1:与实施例7步骤1的合成类似。
步骤2:往底物(0.2mmol)的甲醇溶液中,加入浓盐酸(1mL)。反应物50℃搅拌2h.。然后减压浓缩,剩余物乙醚打浆,固体过滤得产品。
实施例10
212-217的合成与168-195的合成类似:
表格六
实施例11
化合物222-226的合成
化合物222-226的合成方法与化合物54-71的合成类似
表格七
实施例12
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺的合成
步骤1:往3-氨基苯乙酮(5.0g,37mmol)的二氯甲烷(60mL)溶液中依次加入3-甲基苯甲酸(5.0g,37mmol),DMAP(0.9g,7.4mmol)和EDCI(10.6g,55.5mmol)。冷却下滴加DIPEA(14.3g,111mmol)。滴完升至室温反应过夜。反应液EA稀释,水洗一遍,稀盐酸洗三遍,然后再用饱和氯化钠洗一遍。有机层无水硫酸钠干燥,真空浓缩得白色固体(9.2g,98%)。
步骤2:在冰浴冷却下,往228(2.0g,7.9mmol)的甲醇(20mL)溶液中,小心加入硼氢化钠(320mg,8.4mmol)。反应室温搅拌1h,加水淬灭,乙酸乙酯萃取,合并的有机相无水硫酸钠干燥,减压浓缩,产品未进一步纯化,直接用于下一步反应。
步骤3:往229(100mg,0.39mmol)的干燥的四氢呋喃(10ml)中,加入叔丁醇钾(44mg,0.39mmol),室温搅拌10min,加入2-硝基-3-氟-5-氯吡啶(69mg,0.39mmol),室温继续搅拌1h。加入1g硅胶淬灭反应,柱层析纯化得产品(153mg,95%)。
步骤4:往230(153mg,0.37mmol)的甲醇(5ml)溶液中,加入无水三氯化铁(6mg),活性炭(20mg),混合物回流15min,然后向反应液中滴加水合肼(80%水溶液,0.1mL),回流1h。反应液倒入到20ml饱和食盐水中,用EA萃取三遍。合并的有机相用饱和食盐水洗,无水硫酸钠干燥后真空浓缩得产品(118mg,84%)。
实施例13
N-(3-(((5-氯-2-(甲胺基)吡啶-3-基)氧基)甲基)苯)-3-甲基苯甲酰胺的合成
步骤1:室温下,往3(853mg,5.0mmol)和K2CO3(1.037g,7.5mmol)的DMF(10mL)的混合物中加入碘甲烷(1.065g,7.5mmol)。反应室温过夜。反应液倒入饱和食盐水中,乙酸乙酯萃取。减压浓缩,粗品未进一步纯化直接用于下一步反应。
步骤2:往悬浮于水(20mL)中的步骤1的产物中加入KOH(1.4g,25mmol),反应物回流反应16h。冷至室温,稀盐酸调pH~6,乙酸乙酯萃取。合并的有机相干燥,真空浓缩。粗产品柱层析纯化,得白色固体(735mg,两步产率:93%)。
步骤3:往反应瓶中依次加入233(317mg,2.0mmol),碳酸铯(978mg,3.0mmol)和丙酮(20mL)。搅拌下,加入234(648mg,3.0mmol),然后回流3h。冷却,减压除去溶剂,然后加入水,乙酸乙酯萃取。合并的有机相无水硫酸钠干燥,真空浓缩,然后柱层析纯化(PE/EA=1:1),得白色固体(485mg,83%)。将固体重新溶于乙醇(20mL)中,加入氯化亚锡(1.86g,8.3mmol)和稀盐酸(0.5mL),反应回流3h。冷却,冰水稀释,用氢氧化钠调pH~14,乙酸乙酯萃取3遍。合并的有机相用饱和食盐水洗一遍,无水硫酸钠干燥,过滤,减压浓缩,粗品柱层析纯化(PE/EA=1:1),得白色固体(345mg,76%)。
步骤4:备过程与实施例3类似,得到的终产品,LC-MS[M+H]-m/z为398。
实施例14
N-(3-(((2-氨基吡啶-3-基)氧基)甲基)苯基)-3-甲基苯甲酰胺的合成
制备过程与实施例3类似,得到的终产品,LC-MS[M+H]-m/z为334。
实施例15
5-(((2-氨基-5-氯吡啶-3-基)氧基)甲基)-N-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-2-胺的合成
步骤1:往238(5.0g,26.2mmol)中小心加入二氯亚砜(10mL),混合物回流过夜。冷却,减压除去二氯亚砜,残留物的二氯亚砜用甲苯共沸除去。产品直接用于下一步反应。
步骤2:往冰浴冷却的240(4.0g,26.2mmol),三乙胺(5.3g,52.4mmol)的二氯甲烷(50mL)溶液中滴加239的二氯甲烷(20mL)溶液。由此产生的混合物升至室温过夜,然后水洗三遍,无水硫酸钠干燥,过滤,真空浓缩。残留物柱层析纯化(PE/EA=4:1),得白色固体(6.2g,73%)。
步骤3:于10℃,往四氢锂铝(1.9g,50mmol)的二氧六环(25mL)悬浮液中滴加241(1.63g,5.0mmol)的二氧六环(10mL)溶液。反应物回流过夜,然后冰浴冷却,小心滴加15%氢氧化钠水溶液(25mL)。由此得到的混合物升至室温搅拌1h,形成的固体滤掉,并用EA洗。有机溶液干燥,真空浓缩。残留物柱层析纯化,得粘稠状液体(327mg,23%)。
步骤4:制备过程与实施例12的步骤3和4类似,得到的终产品,LC-MS[M+H]-m/z为410。
实施例16
5-氯-3-((3-甲氧基-4-((4-甲氧基苄基)氧基)苄基)氧基)吡啶-2-胺的合成
步骤1:往244(5.0g,32.9mmol)的乙腈悬浮液中加入K2CO3(6.8g,49.4mmol)和4-甲氧基氯苄(7.7g,49.4mmol)。反应液回流过夜。冷却,倒入到水中,乙酸乙酯萃取。合并的有机相用水洗一遍,干燥,浓缩。粗品柱层析纯化,得白色固体(7.5g,83%)。
步骤2:往245(1.0g,3.7mmol)的甲醇(10mL)溶液中,加入硼氢化钠(141mg,3.7mmol),反应物搅拌0.5h,然后加水稀释,然后用乙酸乙酯萃取。合并的有机相无水硫酸钠干燥,减压浓缩。粗品未进一步纯化直接用于下一步反应。
步骤3和步骤4的合成与实施例2类似,得到的终产品,LC-MS[M+H]-m/z为401。
实施例17
5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯氧基)吡啶-2-胺的合成
步骤1:往245(1.0g,3.7mmol)的二氯甲烷(20mL)溶液中,加入间氯过氧苯甲酸(1.3g,7.4mmol),反应物搅拌过夜。滤去不溶物,滤液用碳酸钠水溶液洗两遍,干燥,浓缩,加入甲醇(20mL)和甲醇钠(500mg,9.3mmol),反应搅拌过夜。减压蒸除大多数溶剂,然后加入水,用稀盐酸调pH至4-5,乙酸乙酯萃取。合并的有机相干燥,浓缩,残留物柱层析纯化,得白色固体(547mg,57%)。
步骤2:制备过程与实施例12的步骤3和4类似,得到的终产品,LC-MS[M+H]-m/z为387。
实施例18
N-(3-(((3-胺基-6-氯哌嗪-2-基)氧基)甲基)苯基)-3-甲基苯甲酰胺的合成
化合物253的制备过程与实施例12的步骤1和3类似,得到的终产品,LC-MS[M+H]-m/z为369。
实施例19
5-氯-3-((3-甲氧基-4-((4-甲氧基苄基)氧基)苄基)氧基)哌嗪-2-胺的合成
化合物254的制备过程与实施例12的步骤3类似,得到的终产品,LC-MS[M+H]-m/z为402.
实施例20
5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯氧基)哌嗪-2-胺的合成
化合物255的制备过程与实施例12的步骤3类似,得到的终产品,LC-MS[M+H]-m/z为388.
实施例21
256-258制备过程与实施例18类似。
表格八
实施例22
5-氯-3-((6-((4-甲氧苄基)氧基)吡啶-3-基)甲氧基)吡啶-2-胺的合成
步骤1:往搅拌的4(1.45g,10.0mmol),碳酸铯(6.52g,20.0mmol)的丙酮(50mL)的溶液中加入259(3.24g,20.0mmol),得到的混合物升温回流过夜。冷却后,反应液倒入到饱和氯化钠溶液中,乙酸乙酯萃取。合并的有机相用无水硫酸钠干燥,真空浓缩。残留物柱层析纯化,得黄色固体(1.65g,61%)。
步骤2:冰浴冷却下,往4-甲氧基苄醇(2mL)中加入氢化钠(60%,200mg,5.0mmol),搅拌10min,然后加入260(135mg,0.5mmol)。100℃搅拌过夜。冷却至室温后,加入硅胶浓缩,残留物柱层析纯化,得白色固体(65mg,35%)。LC-MS[M+H]-m/z为372.
实施例23
(E)-5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯乙烯基)吡啶-2-胺的合成
步骤1:在氮气环境下,将甲基三苯基溴化膦(1.96g,5.5mmol)和氢化钠(60%,220mg,5.5mmol)加入到无水四氢呋喃中,混合物于25℃搅拌1小时,然后加入245(1.36g,5.0mmol),25℃搅拌16小时。反应加水淬灭,由此得到的化合物乙酸乙酯萃取,合并的有机相无水硫酸钠干燥,减压浓缩,粗产物用柱层析法提纯(石油醚:乙酸乙酯=20:1),得到白色固体1.22g,产率90%。
LC-MS[M+Na]-m/z为293。
步骤2:往水热釜中加入5-氯-3溴-2氨基吡啶(104mg,0.5mmol),263(203mg,0.75mmol)和DMF(5mL)。混合物搅拌,并氮气除气,5分钟后依次加入Pd(dppf)Cl2·CH2Cl2(41mg,0.05mmol),三乙胺(152mg,1.5mmol),将水热釜密封好,并在150℃加热过夜。冷却后,往反应液中加入饱和食盐水,用乙酸乙酯萃取。合并的有机相再用饱和食盐水洗两遍,干燥,浓缩。残留物柱层析提纯(石油醚:乙酸乙酯=2:1),得白色固体65mg,产率33%。
LC-MS[M+H]-m/z为397。
实施例24
(E)-N-(3-(2-(2-氨基-5-氯吡啶-3-基)烯基)苯基)-3-甲基苯甲酰胺的合成
步骤1:往化合物229(2.0g,7.8mmol)的二氯甲烷(40mL)溶液中,加入三乙胺(1.58g,15.6mmol),冰浴冷却下滴加甲磺酰氯(1.08g,9.4mmol)。由此得到的混合物升到室温反应过夜。反应液水洗一遍,再用饱和碳酸氢钠溶液洗两遍。有机层无水硫酸钠干燥,真空浓缩。冷却后,往残留物中加入DBU(10mL),50℃加热反应过夜。冷却后,加入水,乙酸乙酯萃取。合并的有机相用稀盐酸洗2遍,干燥,真空浓缩,残留物柱层析纯化,得白色固体(854mg,46%)。
步骤2:制备过程与实施例23的步骤2类似,得到的终产品,LC-MS[M+H]-m/z为364。
实施例25
N-(3-(2-(2-氨基-5-氯吡啶-3-基)环丙基)苯基)-3-甲基苯甲酰胺的合成
步骤1:往化合物267(200mg,0.55mmol)和DMAP(269mg,2.2mmol)的DMF(10mL)溶液中滴加Boc2O(480mg,2.2mmol)。反应液50℃搅拌20h。然后倒入到饱和氯化钠水溶液中,乙酸乙酯萃取。有机相再用饱和氯化钠水溶液洗三遍,干燥,浓缩,柱层析纯化,得黄色固体(157mg,43%)。
步骤2:室温氮气环境下,新鲜蒸馏的二氯甲烷(5.0mL)加入到schlenk管中,然后加入二乙基锌溶液(1.0mL,1.0mmol)(1.0M in hexane)。-40℃冷却10min后,二碘甲烷(540mg,2.0mmol)的二氯甲烷(5mL)溶液逐滴加入到schlenk管中。-40℃反应1h后,三氯乙酸(16mg,0.1mmol)和DME(45mg,0.5mmol)的二氯甲烷(1mL)溶液加入到反应液中,反应温度升到-15℃并在该温度下搅拌1h。在此温度下,将268(133mg,0.2mmol)的二氯甲烷(5mL)溶液逐滴加入到反应液中。然后升温至25℃,反应2h,用饱和碳酸氢钠溶液淬灭反应,室温搅拌20min,用水稀释后,二氯甲烷萃取两遍。合并的有机相依次用饱和氯化铵溶液、亚硫酸钠溶液、碳酸氢钠和饱和食盐水洗涤。有机相干燥,过滤,浓缩,柱层析纯化,得浅黄色固体(68mg,50%)。
步骤3:往化合物269(68mg,0.1mmol)的甲醇(5mL)溶液中,加入浓盐酸(0.2mL),由此得到的混合物于50℃反应4h。真空浓缩,残留物重新溶解于水中,并用碳酸氢钠调至碱性,EA萃取,有机层干燥,减压浓缩。粗品柱层析纯化,得白色固体(32mg,85%)。LC-MS[M+H]-m/z为378。
实施例26
化合物272-275的合成。
步骤1:氮气保护下,往已0℃搅拌0.5h的甲基氯化镁(3M乙醚溶液,2.0mL,6.0mmol)和甲基锂(3M乙醚溶液,2.0mL,6.0mmol)的干燥THF(30mL)溶液中加入228(507mg,2.0mmol)的THF(10mL)溶液。在0℃搅拌1h后,反应化合物升至室温搅拌过夜。然后混合物重新冷至0℃,饱和氯化铵水溶液淬灭反应,乙酸乙酯萃取。合并的有机相用无水硫酸钠干燥,过滤,浓缩。残留物柱层析纯化,得白色固体(404mg,75%)。
步骤2:0℃下,将271(135mg,0.5mmol)溶于干燥的THF(15mL)中,加入氢化钠(60%,24mg,0.6mmol),悬浮液搅拌10min,然后加入33(88mg,0.5mmol)。反应室温搅拌过夜。加入饱和氯化钠溶液,乙酸乙酯萃取。合并的有机相无水硫酸钠干燥,过滤,浓缩。残留物柱层析纯化,得浅黄色固体(100mg,47%)。
将所得固体(100mg,0.24mmol)重新溶于甲醇(10mL)中,加入无水三氯化铁(6mg),活性炭(20mg),混合物回流15min,然后滴加水合肼(80%水溶液)(0.1mL),并回流1h。反应液倒入饱和食盐水中,用EA萃取三遍,合并的有机相用饱和食盐水洗涤一遍,无水硫酸钠干燥,减压除去溶剂。粗产品柱层析纯化得白色固体(85mg,89%).
化合物273-276的合成与272类似:
表格九
实施例27
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环丙基)苯基)-3-甲基苯甲酰胺的合成
步骤1:往化合物277(2.0g,13.2mmol)和K2CO3(5.47g,39.6mmol)的乙腈(30mL)溶液中,加入BnBr(5.7g,33.0mmol)。反应室温搅拌过夜。反应化合物倒入饱和食盐水中,乙酸乙酯萃取。合并的有机相再用饱和食盐水洗,干燥,真空浓缩。残留物柱层析纯化,得产品(3.4g,78%)。
步骤2:0℃,氮气保护下,将乙基溴化镁(3M乙醚溶液,11.2mmol,3.7mL)的干燥的THF(10mL)溶液滴加到278(1.3g,4.0mmol)和四异丙醇钛(1.6g,6.4mmol)的THF(10mL)溶液中。反应化合物升至室温搅拌过夜。降至0℃,加入饱和氯化铵水溶液淬灭,乙酸乙酯萃取。合并的有机相依次用碳酸氢钠,水和饱和食盐水洗。由此得到的化合物柱层析纯化(PE/EA=5:1),得无色油状物(553mg,42%)。
将上述油状物(500mg,1.5mmol)溶于甲醇(20mL)中,然后加入10%Pd/C(50mg)。然后在氢气氛围下室温反应过夜。过滤,浓缩,残留物柱层析纯化(PE/EA=2:1),得黄色固体(21mg,9%)。
步骤3:同实施例3.
步骤4:同实施例26的步骤3。LC-MS[M+H]-m/z为394.
实施例28
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环丁基)苯基)-3-甲基苯甲酰胺的合成
步骤1:同实施例27的步骤1。
步骤2:氮气保护下,于-78℃将正丁基锂(1M正己烷溶液,5.2mmol)缓慢滴加到化合物283(1.4g,4.0mmol)的THF(20mL)中。该溶液于-78℃搅拌15分钟后,滴加环丁酮(280mg,4.0mmol),并将温度升高至-20℃搅拌1h。加入饱和氯化铵(50mL)淬灭反应,并以乙酸乙酯(50mL x 2)萃取。合并的有机相用饱和食盐水(50mL)洗涤两遍,以无水硫酸钠干燥,浓缩。浓缩物柱层析纯化,得产品(797mg,58%)。
步骤3:同实施例3.
步骤4:同实施例26的步骤3。LC-MS[M+H]-m/z为:408.
实施例29
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环戊基)苯基)-3-甲基苯甲酰胺的合成
化合物287的合成与实施例28类似。LC-MS[M+H]-m/z为:422.
实施例30
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环己基)苯基)-3-甲基苯甲酰胺的合成
化合物288的合成与实施例28类似。LC-MS[M+H]-m/z为:436.
实施例31
5-氯-3-((5-甲氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)氧基)吡啶-2-胺的合成
中间体292的合成参考文献[Meyers M J,Pelc M,Kamtekar S,et al.[J].Bioorganic&Medicinal Chemistry Letters,2010,20(5):1543-1547.]
步骤4:制备过程与实施例12的步骤3和4类似,得到的终产品,LC-MS[M+H]-m/z为388。
实施例32
5-((2-氨基-5-氯吡啶-3-基)氧基)-N-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-2-胺的合成
化合物297的制备与实施例31类似,得到的终产品,LC-MS[M+H]-m/z为396。
实施例33
4-((4-((2-胺基-5-氯吡啶-3-基)氧基)-2-甲氧基苯氧基)甲基)苯甲腈的合成
化合物298的制备与实施例13类似,得到的终产品,LC-MS[M+H]-m/z为382。
实施例34
5-氯-3-(3-甲氧基-4-((4-三氟甲基)苄基)氧基)苯氧基)吡啶-2-胺的合成
化合物299的制备与实施例17类似,得到的终产品,LC-MS[M+H]-m/z为425。
实施例35
4-(((5-((2-胺基-5-氯吡啶-3-基)氧基)-3-甲氧基吡啶-2-基)氧基)甲基)苯甲腈的合成
化合物300的制备与实施例31类似,得到的终产品,LC-MS[M+H]-m/z为383。
实施例36
5-氯-3-((6-((4-氯苄基)氧基)-5-甲氧基吡啶-3-基)氧基)吡啶-2-胺的合成
化合物301的制备与实施例31类似,得到的终产品,LC-MS[M+H]-m/z为392。
实施例37
化合物302-314的合成与实施例5类似:
表格十
实施例38
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-氟苯基)-3-甲氧基苯甲酰胺的合成
化合物315的制备与实施例5类似,得到的终产品,LC-MS[M+H]-m/z为388。
实施例39
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-氯苯基)-3-甲氧基苯甲酰胺的合成
化合物316的制备与实施例5类似,得到的终产品,LC-MS[M+H]-m/z为404。
实施例40
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-甲基苯基)-3-甲氧基苯甲酰胺的合成
化合物317的制备与实施例5类似,得到的终产品,LC-MS[M+H]-m/z为384。
实施例41
N-(5-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-2-氟苯基)-3-甲氧基苯甲酰胺的合成
化合物318的制备与实施例5类似,得到的终产品,LC-MS[M+H]-m/z为416。
实施例42
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)-2-氟苯基)-3-甲氧基苯甲酰胺的合成
化合物319的制备与实施例5类似,得到的终产品,LC-MS[M+H]-m/z为402。
实施例43
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)-4-氟苯基)-3-甲氧基苯甲酰胺的合成
化合物320的制备与实施例5类似,得到的终产品,LC-MS[M+H]-m/z为402。
实施例44
(R)-N-(3-(1-((5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺的合成
步骤1:中间体321的制备与实施例4类似。
步骤2:在0℃下,将DIAD(1.70g,8.0mmol)缓慢滴加到321(1.03g,4.0mmol),322(620mg,4.8mmol)和三苯基膦(2.10g,8.0mmol)的干燥的甲苯(50mL)溶液中,保持内温不超过5℃,滴加完毕后将反应液升至25℃搅拌过夜。反应完后,向反应液中加入10g硅胶,由此得到的混合物柱层析纯化,得淡黄色固体。LC-MS[M+H]-m/z为367。收率68.2%。
实施例45
(R)-N-(3-(1-((6-氯吡嗪-2-基)氧基)乙基)苯基)-3-(三氟甲基)苯甲酰胺
步骤1:中间体325的制备与实施例4类似。
步骤2:往室温下预搅拌5min的t-BuOK(448mg,4mmol)和325(1.23g,4.0mmol)的干燥四氢呋喃(2mL)溶液中,加入326(592mg,4.0mmol)。混合物50℃搅拌过夜。反应完向反应液中加入10g硅胶,由此得到的混合物柱层析纯化,得淡黄色油状物。LC-MS[M+H]-m/z为422。收率59.3%。
实施例46
(R)-1-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-(4-甲基苯基)脲的合成
往搅拌的165(132mg,0.5mmol)的丙酮(2mL)溶液中加入对甲苯异氰酸酯(80mg,0.6mmol)。反应液室温搅拌18h,反应完,滤去不溶物,滤液减压浓缩,残留物柱层析纯化,得白色固体。LC-MS[M+H]-m/z为397。
实施例47
(R)-1-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-(3-甲基苯基)脲的合成
化合物329的制备与实施例46类似,得到的终产品,LC-MS[M+H]-m/z为397。
实施例48
化合物330-347的合成路线如下:
表格十一
实施例49
化合物348-356的合成与实施例7的合成类似:
表格十二
实施例50
化合物357-366的合成与实施例7的合成类似:
表格十三
实施例51
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲基亚磺酰基)苯甲酰胺的合成
将化合物180(100mg,0.22mmol)加入到25mL的圆底烧瓶中,加入10mL乙醇和过氧化氢(30%,2mL),室温搅拌过夜。加入饱和食盐水,DCM萃取,合并的有机层干燥,真空浓缩,残留物柱层析纯化(DCM:MeOH=40:1),得白色固体。LC-MS[M+H]-m/z为476。
实施例52
化合物368-373的合成与实施例7的合成类似:
表格十四
实施例53:CSF-1R激酶的体外抑制活性
一.材料和仪器
OptiPlate-384,White Opaque 384-well MicroPlate(Cat.6007290,PerkinElmer)
HTRF kinEASE TK(Cat.62TKOPEC,Cisbio)
CSF-1R(Cat:PV3249,Invitrogen)
ATP 10mM(Cat.PV3227,Invitrogen)
DTT 1M(Cat.D5545,Sigma)
MgCl2 1M(Cat.M8266,Sigma)
MnCl2 1M(Cat.244589,Sigma)
二.实验步骤
1试剂配制
表十五激酶的反应体系各组分及浓度表
表十六1mL1×Kinase Buffer的组分(μL):
5×Substrate-TK和ATP工作液
Substrate-TK和ATP的具体浓度见表十五。
用1×Kinase Buffer稀释Substrate-TK和ATP至反应浓度的5倍。
5×Enzyme工作液
CSF-1R激酶的浓度见表十五。用1×kinase buffer配制5×酶工作液。
4×Sa-XL665工作液
Sa-XL665在反应中的浓度参见表十五。用Detection Buffer配制4×Sa-XL665工作液。
4×TK-Ab-cryptate工作液
用Detection Buffer将TK-Ab-Cryptate稀释100倍作为工作液。
2.实验流程
所有试剂按照上述方法配好后,除酶外,平衡到室温以后,开始进行加样。
a)首先使用配置好的1X kinase buffer分别配制2.5%的DMSO溶液(DMSO浓度过高会对反应产生影响,控制DMSO的终浓度为1%),然后用酶对应的2.5%的DMSO溶液稀释待测化合物,化合物的筛选浓度从1000nM开始4倍比梯度稀释,8个浓度。除对照孔外,向所用反应孔中加入4微升的稀释好的待测化合物溶液,向对照孔中加入4微升先前配制的CSF-1R激酶对应的2.5%的DMSO溶液。
b)向所有反应孔中加入2微升先前配制好的CSF-1R激酶对应底物浓度的TK-biotin substrate溶液。
c)向除阴性孔外的所有反应孔中加入2微升先前配制好的对应浓度的酶溶液,阴性孔用2微升酶对应1Xkinase buffer补足体积。用封板膜封板,混匀后室温孵育10分钟,让化合物和酶充分作用结合。
d)向所有反应孔中加入2微升激酶对应浓度的ATP溶液来启动激酶反应,酶反应时间为30分钟。
e)在激酶反应结束前5分钟开始配制检测液。使用试剂盒中的detection buffer分别配制两种酶对应浓度的Streptavidin-XL665和TK antibody europium cryptate(1:100)检测液。
f)待激酶反应结束后,向所有反应孔中加入5微升稀释好的的Streptavidin-XL665,混匀后立即加入稀释好的TK antibody europium cryptate检测液。
g)封板混匀,室温反应1h后,用ENVISION(Perkinelmer)仪器检测荧光信号(320nm激发,665nm,615nm发射)。通过全活性孔和背景信号孔计算出每个孔的抑制率,复孔取平均值,同时用专业的画图分析软件PRISM 5.0对每个待测化合物进行半数抑制活性(IC50)的拟合。
实验加样流程图如下:
表十七
3.数据分析
Emission Ratio(ER)=665nm Emission signal/615nm Emission signal
抑制率=(ERpositive-ERsample)/(ERpositive-ERnegative)*100%
使用Graphpad Prism 5和log(抑制剂)对归一化的响应拟合IC50曲线并计算IC50值。
代表性的实施例3-52中制备的化合物的半抑制浓度数据如下(表十八):
表十八
脚注:+++:≤50nM;++:51-500nM;+:≥500nM,但<10uM。
实施例54:NFS-60细胞实验
1.实验材料
1.1细胞株
鼠骨髓性白血病细胞(NFS-60)
1.2受试药物
临用前用DMSO溶解,用不含因子的全培养基配制所需应用浓度。
1.3主要试剂
培养基:RPMI Medium 1640 Gibco货号:31800-022
胎牛血清:PANSera ES货号:2602-P130707
双抗:TRANS
胰酶:Gibco货号:25300-062
PBS:Hyclone货号:SH30258.01
Mouse M-CSF/CSF-1 Protein:Sino Biological Inc.货号:51112-MNAH M-CSF:齐鲁制药有限公司
2.实验方法
取对数生长期的NFS-60细胞(培养基1640+10%FBS+40ng/mlM-CSF+双抗1%),离心(1000r/min),换成无因子的培养液37℃5%CO2下培养24h。离心(1000r/min),再换成含40ng/mL因子的培养基按照2×104个/mL,接种于96孔培养板,100μL/孔,16h后加入配置好的受试化合物10μL/孔,每个化合物设3个复孔,37℃5%CO2下继续培养72h后,每孔加入10μL CCK试剂,继续孵育4h后450nm波长测定每孔吸光度。
按公式:
抑制率(%)=(1-受试孔OD值/溶剂对照孔OD值)x 100%
3.实验结果
代表性的实施例3-52中制备的化合物0.5uM对NFS-60细胞增殖抑制作用实验结果如下表:
化合物 | 抑制率% | 化合物 | 抑制率% |
54 | ++ | 178 | +++ |
70 | +++ | 179 | +++ |
72 | +++ | 180 | +++ |
74 | +++ | 181 | +++ |
126 | +++ | 182 | +++ |
132 | +++ | 199 | +++ |
134 | +++ | 200 | +++ |
137 | +++ | 205 | +++ |
150 | +++ | 206 | +++ |
168 | +++ | 212 | +++ |
169 | +++ | 367 | +++ |
脚注:+++:≥50%;++:10%-50%;+:<10%
实施例55:动物药效学实验
本实验采用C57小鼠接种MC-38细胞株
实验动物:C57小鼠,雄性,5-6周龄(18-22g)
肿瘤株:MC38
接种:2×106/0.1mL,按3:1的比例加入Matrigel
PD1:InVivoMAb anti-mouse PD-1(CD279),BioXCell
分组给药:
接种第4天开始随机分组,共13组,分别为模型组,anti-PD1 2mg/kg组,anti-PD110mg/kg组,受试化合物单用组以及受试化合物与anti-PD1 10mg/kg联用组,化合物每天灌胃给药,给药剂量30mg/kg,anti-PD1每3天腹腔注射1次。连续给药2周。模型组每天灌胃80%的甘油+20%的0.5%CMC-Na。
实验结果:
代表性的实施例3-52中制备的化合物与anti-PD1联用对MC-38移植瘤肿瘤大小抑制作用的实验结果如下表:
组别 | 抑制率 | 组别 | 抑制率 |
anti-PD1-2mg/kg | + | ||
anti-PD1-10mg/kg | ++ | ||
72-30mg/kg | + | 72-30mg/kg+anti-PD1-10mg/kg | ++ |
78-30mg/kg | + | 78-30mg/kg+anti-PD1-10mg/kg | ++ |
83-30mg/kg | + | 83-30mg/kg+anti-PD1-10mg/kg | +++ |
85-30mg/kg | + | 85-30mg/kg+anti-PD1-10mg/kg | +++ |
86-30mg/kg | + | 86-30mg/kg+anti-PD1-10mg/kg | +++ |
178-30mg/kg | ++ | 178-30mg/kg+anti-PD1-10mg/kg | +++ |
179-30mg/kg | ++ | 179-30mg/kg+anti-PD1-10mg/kg | +++ |
182-30mg/kg | ++ | 182-30mg/kg+anti-PD1-10mg/kg | +++ |
脚注:+++:≥30%;++:10%~30%;+:<10%
上述实施例仅为充分说明本发明而列举的具体实施例,本发明的保护范围以权利要求书的内容为准,而不限于上述具体实施方式。说明书中公开的所有内容,包括摘要和附图,以及公开的所有方法和步骤,都可以任意组合,除非这些特征和/或步骤是相互排斥的组合。说明书中公开每一个技术特征,包括摘要和附图,除非另有说明,都可以被实现相同、等同或类似目的的技术特征所替换。因此,除非另有说明,本发明公开的每个技术特征仅是通常系列中的等同或类似的技术特征的一个实例。本领域的技术人员在本发明基础上所作的不脱离本发明实质内容的等同替代或变换,亦均在本发明的保护范围之内。而这样的修改亦均在本发明的保护范围之内。本申请引用的每个参考文献在此均引用其全文。
Claims (11)
2.权利要求1所述的化合物,其中W表示苯基、5-10元杂芳基,其环上的氢可以被1个或多个选自OH, CN, O(C1-C3)烷基, C1-C5 烷基,N((C1-C2)烷基)2, NH(C1-C2)烷基, S(O)n(C1-C3)烷基的取代基所取代, 其中, n=0, 1, or 2。
3.权利要求1所述的化合物,其中R3选自苯基、5-10元杂芳环,其环上的氢可以被1个或多个选自卤素、氰基、O(C1-C3)烷基、C1-C3烷基所取代。
4.权利要求1所述的化合物,其中R3选自吡唑或吡啶,其环上的氢可以被1个或多个选自卤素、羟基、硝基、氰基、O(C1-C3)烷基、C1-C3烷基的取代基所取代。
5.权利要求1所述的化合物,W选自苯环,其环上的氢被1个或多个选自卤素、羟基、硝基、氰基、O(C1-C3)烷基、N((C1-C2)烷基)2、S(O)n(C1-C3)烷基的取代基所取代,其中n=0, 1,2。
6.化合物选自:
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-3-甲基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-3-氟苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-3-氯苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-2-氟-5-甲基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-2-氟苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-氟-2-甲基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-甲基烟酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-氟烟酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)苯基)-5-氯烟酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氟-5-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-5-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲氧基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-5-氯烟酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-5-甲基烟酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-氰基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-三氟甲氧基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-三氟甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-3-甲基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2, 3-二氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2, 5-二氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3, 4-二氯苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)苯并[d][1,3]二氧五环-5-苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-溴苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-环丙基苯甲酰胺
(S)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-乙炔基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲氧基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-氰基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2, 5-二氯苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-乙炔基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(异丙磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(环丙磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(二甲膦酰基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-(二甲胺基)苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-5-甲基烟酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氟-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-2-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-环丙基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-异丙基苯甲酰胺
(R)-N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-异丙氧基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(乙基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2-氯-3-甲氧基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-羟基环戊基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-羟基环丁基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-氯苯基)-2-氯-3-甲基苯甲酰胺
N-(3-((R)-1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-((2-羟基环己基)氨基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-氟苯基)-2-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-羟基环己基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-4-((4-甲基哌嗪-1-基)甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-((4-甲基哌嗪-1-基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-4-(4-甲基哌嗪-1-基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2-甲氧基-5-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-((4-甲基哌嗪-1-基)甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(环丙基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(异丙基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(环戊基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)喹啉-3-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)异喹啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)喹啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(吡咯烷基-1-基磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-环丙基吡啶甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)吡啶-3-基)-2-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(1-氰基环丙基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-环丁基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(吡咯烷基-1-基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-4-甲酰胺 1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-5-甲酰胺 1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-氟吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-甲基吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-甲基吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-(三氟甲基)吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-(三氟甲基)吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-6-(三氟甲基)吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-甲基-3-(甲磺酰基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-甲基苯基)-3-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3-(二氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-6-甲基吡啶甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-氯-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-4-氟-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-3,4-二甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢-1H-茚-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-6-甲酰胺 1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基) 苯基)- 3-氟-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基) 苯基)- 3-氯-5-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基) 苯基)- 3,5-二甲基苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-甲苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-氟苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-氯苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(6-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-吡啶)-2-基)-3-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-4-甲基苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-甲基苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(4-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)吡啶-2-基)-3-甲基苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-氯苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-2-氟苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(5-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)-苯基)-3-(甲磺酰基)-4-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并[b]噻吩-5-甲酰胺 1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并[b]噻吩-6-甲酰胺 1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -3-(甲磺酰基)-5-(三氟甲基) 苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -3,4-二甲基-5-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -1,5-二甲基-1H-吡唑-3-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -5-甲基噻唑-2-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -1-(叔丁基)-1H-吡唑-4-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -1-(异丙基)-1H-吡唑-4-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -1-甲基-1H-吲唑-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)苯并呋喃-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基) -1-甲基-1H-吲哚-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-5-(叔丁基)异恶唑-3-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-2-氧-1,2,3,4-四氢喹啉-7-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-1,2,3,4-四氢喹啉-7-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1-甲基-2-氧吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-氯吡啶-3-基)氧)乙基)苯基)-1,3-二氢异苯并呋喃-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,4-二甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,5-二甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-甲基l-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并[b]噻吩-6-甲酰胺 1,1-二氧化物
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)- 3-环丙基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)-4-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)-5-(三氟甲基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,4-二甲基-5-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)- 3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)-4-甲基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)- 4-甲基-3-(甲硫基) 苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2’,3’-二氢螺[环丙烷-1,1’-茚]-6’-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-1-甲基吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-氯-3-(二甲氨基)苯甲酰胺
甲基(R)-3-((3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)氨甲酰)苯甲酸酯
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)- 3-异丙基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2,3-二氢-1H-茚-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)- 3-乙基苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-5-异丙基烟酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-1-甲基-1H-吲哚-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)苯并[b噻吩]-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3,3-二甲基-1,3-二氢异苯并呋喃-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2H-螺[苯并呋喃-3,1’-环丙烷]-5-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-2,3-二氢苯并呋喃-5-甲酰胺
(R)-N-(3-(1-((6-氨基-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-环丙基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-三氟甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3,4-二甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3,5-二甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)-4-甲基苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-3-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,3'-联吡啶]-5-基)氧)乙基)苯基)-1-甲基吲哚啉-6-甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-环丙基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-乙基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基哌啶-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(4-羟基-3-甲氧基苯基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((6-氨基-6’-(4-甲基哌嗪-1-基)-[3,3’-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((6-氨-[3,4'-联吡啶]-5-基)氧)乙基)苯基)-3-(二甲氨基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-3-基) 氧)乙基)苯基) -3-环丙基苯甲酰胺
(S)-3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-N-(3-甲基苯基)苯甲酰胺
(S)-3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-N-(3-甲氧基苯基)苯甲酰胺
(S)-3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-N-(3-氯苯基)苯甲酰胺
(S)-3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-N-(3-氰基苯基)苯甲酰胺
(S)-3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-N-(3-乙基苯基)苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
N-(3-(((5-氯-2-(甲胺基)吡啶-3-基)氧基)甲基)苯)-3-甲基苯甲酰胺
N-(3-(((2-氨基吡啶-3-基)氧基)甲基)苯基)-3-甲基苯甲酰胺
5-(((2-氨基-5-氯吡啶-3-基)氧基)甲基)-N-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-2-胺
5-氯-3-((3-甲氧基-4-((4-甲氧基苄基)氧基)苄基)氧基)吡啶-2-胺
5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯氧基)吡啶-2-胺
N-(3-(((3-胺基-6-氯哌嗪-2-基)氧基)甲基)苯基)-3-甲基苯甲酰胺
5-氯-3-((3-甲氧基-4-((4-甲氧基苄基)氧基)苄基)氧基)哌嗪-2-胺
5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯氧基)哌嗪-2-胺
(S)-N-(3-(1-((3-氨基-6-氯哌嗪-2-基)氧基)乙基)苯基)-3-甲基苯甲酰胺
5-氯-3-((6-((4-甲氧苄基)氧基)吡啶-3-基)甲氧基)吡啶-2-胺
(E)-5-氯-3-(3-甲氧基-4-((4-甲氧基苄基)氧基)苯乙烯基)吡啶-2-胺
(E)-N-(3-(2-(2-氨基-5-氯吡啶-3-基)烯基)苯基)-3-甲基苯甲酰胺
N-(3-(2-(2-氨基-5-氯吡啶-3-基)环丙基)苯基)-3-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-3-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-2-氯-5-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-3-甲氧基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-2-氯-3-甲基苯甲酰胺
N-(3-(2-((2-胺基-5-氯吡啶-3-基)氧基)丙烷)-2-基)苯基)-2, 5-二氯苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环丙基)苯基)-3-甲基苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环丁基)苯基)-3-甲基苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环戊基)苯基)-3-甲基苯甲酰胺
N-(3-(1-((2-胺基-5-氯吡啶-3-基)氧基)环己基)苯基)-3-甲基苯甲酰胺
5-氯-3-((5-甲氧基-6-((4-甲氧基苄基)氧基)吡啶-3-基)氧基)吡啶-2-胺
5-((2-氨基-5-氯吡啶-3-基)氧基)-N-((6-(三氟甲基)吡啶-3-基)甲基)吡啶-2-胺
4-((4-((2-胺基-5-氯吡啶-3-基)氧基)-2-甲氧基苯氧基)甲基)苯甲腈
5-氯-3-(3-甲氧基-4-((4-三氟甲基)苄基)氧基)苯氧基)吡啶-2-胺
4-(((5-((2-胺基-5-氯吡啶-3-基)氧基)-3-甲氧基吡啶-2-基)氧基)甲基)苯甲腈
5-氯-3-((6-((4-氯苄基)氧基)-5-甲氧基吡啶-3-基)氧基)吡啶-2-胺
N-(4-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-甲氧基苯甲酰胺
N-(4-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-4-甲氧基苯甲酰胺
N-(4-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-4-氰基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-甲基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-甲氧基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-氯苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-三氟甲氧基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-4-甲基苯甲酰胺
N-(3-((2-胺基-5-氯吡啶)-3-基)氧基)苯基)-3-(甲磺酰基)苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(1-羟基环戊基)苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-环丙基苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(1-氰基环丙基)苯甲酰胺
N-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-甲基吡啶-1-基)苯甲酰胺
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-氟苯基)-3-甲氧基苯甲酰胺
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-氯苯基)-3-甲氧基苯甲酰胺
N-(5-((2-胺基-5-氯吡啶-3-基)氧基)-2-甲基苯基)-3-甲氧基苯甲酰胺
N-(5-(1-((2-胺基-5-氯吡啶-3-基)氧基)乙基)-2-氟苯基)-3-甲氧基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)-2-氟苯基)-3-甲氧基苯甲酰胺
N-(3-(((2-胺基-5-氯吡啶-3-基)氧基)甲基)-4-氟苯基)-3-甲氧基苯甲酰胺
(R)-1-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-(4-甲基苯基)脲
(R)-1-(3-(1-((2-氨基-5-氯吡啶-3-基)基)乙基)苯基)-3-(3-甲基苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(间甲苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-甲苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-(甲磺酰基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(间甲苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-甲苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-2-甲基苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-3-甲基苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-3-氟苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-氯吡啶-3-基)氧)-2-氟苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(5-((2-氨基-5-氯吡啶-3-基)氧)-2-甲基苯基)-3-(4-甲苯基)脲
1-(5-((2-氨基-5-氯吡啶-3-基)氧)-2-氯苯基)-3-(4-甲苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-(二甲氨基)苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(4-(甲氧基)苯基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(2,3-二氢苯[b]噻吩-5-基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(苯[b]噻吩-5-基)脲
1-(3-((2-氨基-5-氯吡啶-3-基)氧)苯基)-3-(1-(叔丁基)-1H-吡唑-4-基)脲
1-(3-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-甲苯基)脲
1-(3-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-(甲磺酰基)苯基)脲
1-(4-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(4-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)-2-氟苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
1-(3-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-甲苯基)脲
1-(3-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-(甲磺酰基)苯基)脲
1-(4-((6-氨基-[3,3’-联吡啶-5-基)氧)苯基)-3-(4-氯-3-(三氟甲基)苯基)脲
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-5-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基) 苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-环丙基-1H-吡唑-4-基) 吡啶-3-基)氧)乙基)苯基)-4-(甲硫基) 苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-( 1H-吡唑-4-基) 吡啶-3-基)氧)乙基)苯基)-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-氯-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-氟-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-氰基-4-(甲硫基)苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-( 1,3-二甲基-1H-吡唑-4-基) 吡啶-3-基)氧)乙基)苯基)-4-(甲硫基) 苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-(2-(二甲胺基)-2-氧乙基-1H-吡唑-4-基) 吡啶-3-基)氧)乙基)苯基)-4-(甲硫基) 苯甲酰胺
(R)-N-(3-(1-((2-氨基-5-(3-甲基-1H-吡唑-5-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基) 苯甲酰胺
(R)-N1-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-4-(甲硫基) 间苯二甲酰胺
(R)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲基亚磺酰基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲基亚磺酰基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲磺酰基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)- 3-(二甲氨基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(二甲氨基)-4-甲基苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)-3-(甲硫基)苯甲酰胺
(S)-N-(3-(1-((2-氨基-5-(1-甲基-1H-吡唑-4-基)吡啶-3-基)氧)乙基)苯基)- 4-甲基-3-(甲硫基)苯甲酰胺。
7.一种药物组合物,其特征在于含有至少一种有效治疗剂量的权利要求1~6任一项所述的化合物和至少一种药学上接受的辅料。
8.权利要求7所述的药物组合物在制药中的应用。
9.权利要求1~6任一项所述的至少任意一种化合物或者权利要求7所述的药物组合物用于制备治疗哺乳动物异常细胞生长的药物。
10.权利要求1~6任一项所述的至少任意一种化合物或者权利要求7所述的药物组合物用于制备治疗癌症的药物。
11.权利要求1~6任一项所述的至少任意一种化合物或者权利要求7所述的药物组合物应用于制备治疗和预防CSF-1R激酶介导的癌症的药物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310197369.5A CN116715625A (zh) | 2018-03-15 | 2019-03-13 | 作为蛋白激酶抑制剂的杂芳基化合物 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018102121719 | 2018-03-15 | ||
CN201810212171 | 2018-03-15 | ||
CN2018108350389 | 2018-07-26 | ||
CN201810835038 | 2018-07-26 | ||
PCT/CN2019/078006 WO2019174601A1 (en) | 2018-03-15 | 2019-03-13 | Heteroaryl compounds as kinase inhibitor |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310197369.5A Division CN116715625A (zh) | 2018-03-15 | 2019-03-13 | 作为蛋白激酶抑制剂的杂芳基化合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111601790A CN111601790A (zh) | 2020-08-28 |
CN111601790B true CN111601790B (zh) | 2023-03-31 |
Family
ID=67908670
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980005170.XA Active CN111601790B (zh) | 2018-03-15 | 2019-03-13 | 作为蛋白激酶抑制剂的杂芳基化合物 |
CN202310197369.5A Pending CN116715625A (zh) | 2018-03-15 | 2019-03-13 | 作为蛋白激酶抑制剂的杂芳基化合物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310197369.5A Pending CN116715625A (zh) | 2018-03-15 | 2019-03-13 | 作为蛋白激酶抑制剂的杂芳基化合物 |
Country Status (16)
Country | Link |
---|---|
US (1) | US11767296B2 (zh) |
EP (1) | EP3749646B1 (zh) |
JP (1) | JP7034512B2 (zh) |
KR (1) | KR102556742B1 (zh) |
CN (2) | CN111601790B (zh) |
AU (1) | AU2019233207B2 (zh) |
CA (1) | CA3093138C (zh) |
DK (1) | DK3749646T3 (zh) |
ES (1) | ES2920702T3 (zh) |
HU (1) | HUE058998T2 (zh) |
LT (1) | LT3749646T (zh) |
PL (1) | PL3749646T3 (zh) |
PT (1) | PT3749646T (zh) |
SG (1) | SG11202008705TA (zh) |
SI (1) | SI3749646T1 (zh) |
WO (1) | WO2019174601A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102234399B1 (ko) * | 2018-05-23 | 2021-04-05 | 아주대학교산학협력단 | 톨-유사 수용체 3/7/8/9 억제 기능이 있는 길항성 소분자 화합물 tac5 시리즈 |
US20210147441A1 (en) * | 2019-09-26 | 2021-05-20 | Agency For Science, Technology And Research (A*Star) | Therapeutic compounds and methods of use thereof |
BR112023004719A2 (pt) * | 2020-09-21 | 2023-04-18 | Hutchison Medipharma Ltd | Compostos heteroaromáticos e usos dos mesmos |
CN115197130B (zh) * | 2022-07-27 | 2023-06-27 | 安徽医科大学 | 一种芳基脲类衍生物及其制备方法与应用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003078977A1 (en) * | 2002-03-19 | 2003-09-25 | Dicos Technologies Inc. | Metallic gas cells and method for manufacturing the same |
EP1545523A1 (en) * | 2002-07-03 | 2005-06-29 | Astex Technology Limited | 3-&-grave;(HETERO) ARYLMETHOXY ! PYRIDINES AND THEIR ANALOGUES ASP38 MAP KINASE INHIBITORS |
AP2114A (en) * | 2003-02-26 | 2010-03-04 | Sugen Inc | Aminoheteroaryl compounds as protein kinase inhibitors |
SI1603570T1 (sl) * | 2003-02-26 | 2013-03-29 | Sugen, Inc. | Spojine aminoheteroarila kot zaviralci proteinkinaze |
JP4333186B2 (ja) * | 2003-04-07 | 2009-09-16 | ソニー株式会社 | 通信システム及び通信照明装置 |
WO2005002673A1 (en) * | 2003-07-03 | 2005-01-13 | Astex Therapeutics Limited | Raf kinase inhibitors |
JP6200520B2 (ja) * | 2013-02-02 | 2017-09-20 | 正大天晴薬業集団股▲ふん▼有限公司 | 置換2−アミノピリジンプロテインキナーゼ阻害剤 |
-
2019
- 2019-03-13 SG SG11202008705TA patent/SG11202008705TA/en unknown
- 2019-03-13 EP EP19767545.7A patent/EP3749646B1/en active Active
- 2019-03-13 SI SI201930264T patent/SI3749646T1/sl unknown
- 2019-03-13 WO PCT/CN2019/078006 patent/WO2019174601A1/en unknown
- 2019-03-13 CN CN201980005170.XA patent/CN111601790B/zh active Active
- 2019-03-13 CA CA3093138A patent/CA3093138C/en active Active
- 2019-03-13 KR KR1020207026070A patent/KR102556742B1/ko active IP Right Grant
- 2019-03-13 ES ES19767545T patent/ES2920702T3/es active Active
- 2019-03-13 HU HUE19767545A patent/HUE058998T2/hu unknown
- 2019-03-13 CN CN202310197369.5A patent/CN116715625A/zh active Pending
- 2019-03-13 JP JP2020549595A patent/JP7034512B2/ja active Active
- 2019-03-13 LT LTEPPCT/CN2019/078006T patent/LT3749646T/lt unknown
- 2019-03-13 DK DK19767545.7T patent/DK3749646T3/da active
- 2019-03-13 AU AU2019233207A patent/AU2019233207B2/en active Active
- 2019-03-13 PT PT197675457T patent/PT3749646T/pt unknown
- 2019-03-13 PL PL19767545.7T patent/PL3749646T3/pl unknown
- 2019-03-13 US US16/979,195 patent/US11767296B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
PT3749646T (pt) | 2022-06-24 |
AU2019233207B2 (en) | 2021-05-27 |
US20220380312A1 (en) | 2022-12-01 |
EP3749646A1 (en) | 2020-12-16 |
KR20200119850A (ko) | 2020-10-20 |
SI3749646T1 (sl) | 2022-09-30 |
CA3093138C (en) | 2023-01-03 |
CA3093138A1 (en) | 2019-09-19 |
AU2019233207A1 (en) | 2020-10-01 |
CN116715625A (zh) | 2023-09-08 |
SG11202008705TA (en) | 2020-10-29 |
KR102556742B1 (ko) | 2023-07-18 |
EP3749646A4 (en) | 2020-12-23 |
PL3749646T3 (pl) | 2022-07-25 |
US11767296B2 (en) | 2023-09-26 |
JP7034512B2 (ja) | 2022-03-14 |
HUE058998T2 (hu) | 2022-09-28 |
EP3749646B1 (en) | 2022-04-06 |
WO2019174601A1 (en) | 2019-09-19 |
JP2021516250A (ja) | 2021-07-01 |
CN111601790A (zh) | 2020-08-28 |
LT3749646T (lt) | 2022-07-11 |
ES2920702T3 (es) | 2022-08-08 |
DK3749646T3 (da) | 2022-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111601790B (zh) | 作为蛋白激酶抑制剂的杂芳基化合物 | |
TWI772386B (zh) | 雜芳基并[4,3-c]嘧啶-5-胺類衍生物、其製備方法及其在醫藥上的使用 | |
KR102614872B1 (ko) | Hpk1 억제제 및 이의 사용 방법 | |
KR101749192B1 (ko) | 트리아진, 피리미딘 및 피리딘 유사체 및 이의 치료제 및 진단 프로브로의 용도 | |
KR101530117B1 (ko) | 야누스 키나제 억제제 화합물 및 방법 | |
KR20130129244A (ko) | 치환된 6,6-융합된 질소 헤테로환형 화합물 및 이의 용도 | |
KR20160039187A (ko) | Raf 키나아제 및/또는 raf 키나아제 이량체 저해제로서 융합 트리시클릭 우레아 화합물 | |
CN103254190A (zh) | 作为两面神激酶抑制剂的杂芳基取代的吡咯并[2,3-b]吡啶和吡咯并[2,3-b]嘧啶 | |
JP2008514628A (ja) | 蛋白質キナーゼ類のイミダゾ{4,5−b}ピラジノン阻害剤 | |
CA2673038A1 (en) | Substituted tricyclic heteroaryl compounds as janus kinase inhibitors | |
WO2005067546A2 (en) | Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases | |
JP2010514689A (ja) | 癌、炎症およびウイルス感染症の処置のためのcdk阻害剤としてのヘテロアリール−ヘテロアリール化合物 | |
CA2603115A1 (en) | 3-spirocyclopropyl2-oxindole kinase inhibitors | |
TWI530483B (zh) | 作為激酶抑制劑的吲哚啉酮化合物 | |
JP2021536436A (ja) | キノリン誘導体から調製される新規な阻害剤 | |
WO2011095045A1 (zh) | 吡啶酮酰胺类衍生物、其制备方法及其在医药上的应用 | |
EA037264B1 (ru) | Гетероциклическое сульфонамидное производное и содержащее его лекарственное средство | |
JP2023533349A (ja) | Btk阻害剤としての化合物およびその製造方法と応用 | |
KR20230035311A (ko) | Nek7 키나제의 억제제 | |
KR20220029719A (ko) | 에스트로겐-관련 수용체 알파 조절제 | |
TW202214634A (zh) | 雜環化合物及其衍生物 | |
KR20230107566A (ko) | 세로토닌 1b 수용체 조절제로서 효력있고 선택적인 화합물 | |
TW202140430A (zh) | 喹唑啉類化合物、製備方法及其應用 | |
TW201927785A (zh) | 治療或預防癌症的化合物 | |
TW201229047A (en) | Pyridone amide derivatives, preparation process and pharmaceutical use 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 | ||
CB02 | Change of applicant information |
Address after: The third and fourth floors of Block B, No. 177 Jinda Road, Jianxin Town, Cangshan District, Fuzhou City, Fujian Province, 350000 Applicant after: Fujian Haixi New Pharmaceutical Co.,Ltd. Address before: No.1 building, No.20 Jinzhou North Road, Jianxin Town, Cangshan District, Fuzhou City, Fujian Province 350028 Applicant before: FUJIAN HAIXI PHARMACEUTICALS Co.,Ltd. |
|
CB02 | Change of applicant information | ||
GR01 | Patent grant | ||
GR01 | Patent grant |