TWI785101B - 氮雜吲哚基吡啶酮及二氮雜吲哚基吡啶酮化合物 - Google Patents
氮雜吲哚基吡啶酮及二氮雜吲哚基吡啶酮化合物 Download PDFInfo
- Publication number
- TWI785101B TWI785101B TW107129491A TW107129491A TWI785101B TW I785101 B TWI785101 B TW I785101B TW 107129491 A TW107129491 A TW 107129491A TW 107129491 A TW107129491 A TW 107129491A TW I785101 B TWI785101 B TW I785101B
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- Taiwan
- Prior art keywords
- pyridin
- pyrrolo
- trifluoromethyl
- compound
- pharmaceutically acceptable
- Prior art date
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- SPZROILRMPRYER-UHFFFAOYSA-N 3-(2H-benzotriazol-4-yl)-1H-pyridin-2-one Chemical class N1N=NC2=C(C=CC=C12)C=1C(NC=CC=1)=O SPZROILRMPRYER-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 160
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 44
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 238000011282 treatment Methods 0.000 claims abstract description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 9
- 208000036142 Viral infection Diseases 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 230000009385 viral infection Effects 0.000 claims abstract description 7
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
- -1 cyano, phenyl Chemical group 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 206010021143 Hypoxia Diseases 0.000 claims description 13
- 230000001146 hypoxic effect Effects 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 10
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 208000032612 Glial tumor Diseases 0.000 claims description 6
- 206010018338 Glioma Diseases 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 201000010881 cervical cancer Diseases 0.000 claims description 6
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- 208000032839 leukemia Diseases 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- QVXZGMUKOWYSOX-UHFFFAOYSA-N 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6-[2-(trifluoromethyl)piperidin-1-yl]-1H-pyridin-2-one Chemical compound N1N=CC=2C1=NC=CC=2C1=CC(NC(=C1)N1C(CCCC1)C(F)(F)F)=O QVXZGMUKOWYSOX-UHFFFAOYSA-N 0.000 claims description 5
- JDKCFBIRILXMFJ-UHFFFAOYSA-N 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one Chemical compound N1C=CC=2C1=NC=CC=2C1=CC(NC(=C1)N1C(COCC1)C(F)(F)F)=O JDKCFBIRILXMFJ-UHFFFAOYSA-N 0.000 claims description 5
- SDFBGSCILLFDMY-UHFFFAOYSA-N 4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-morpholin-4-yl-1H-pyridin-2-one Chemical compound CC1=CC=2C(=NC=CC=2C2=CC(NC(=C2)N2CCOCC2)=O)N1 SDFBGSCILLFDMY-UHFFFAOYSA-N 0.000 claims description 5
- AINQHQYRXCJWMT-UHFFFAOYSA-N 4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-pyridin-3-yl-1H-pyridin-2-one Chemical compound CC1=CC=2C(=NC=CC=2C2=CC(NC(=C2)C=2C=NC=CC=2)=O)N1 AINQHQYRXCJWMT-UHFFFAOYSA-N 0.000 claims description 5
- PUNDGYRIKMMQHI-UHFFFAOYSA-N 6-(2-chlorophenyl)-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one Chemical compound ClC1=C(C=CC=C1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C PUNDGYRIKMMQHI-UHFFFAOYSA-N 0.000 claims description 5
- KUHXRVPOFWEIIL-UHFFFAOYSA-N 6-(2-chlorophenyl)-4-(2-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one Chemical compound ClC1=C(C=CC=C1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C=1C=NC=CC=1 KUHXRVPOFWEIIL-UHFFFAOYSA-N 0.000 claims description 5
- IBWQEYYDUJEVFR-UHFFFAOYSA-N 6-(2-chlorophenyl)-4-[2-(1,3-oxazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one Chemical compound ClC1=C(C=CC=C1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C1=CN=CO1 IBWQEYYDUJEVFR-UHFFFAOYSA-N 0.000 claims description 5
- SCKYJZZLWPCYAC-UHFFFAOYSA-N 6-[2-(trifluoromethyl)piperidin-1-yl]-4-[2-[6-(trifluoromethyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one Chemical compound FC(C1N(CCCC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C=1C=NC(=CC=1)C(F)(F)F)(F)F SCKYJZZLWPCYAC-UHFFFAOYSA-N 0.000 claims description 5
- VAWHMYMAEPEZTK-UHFFFAOYSA-N 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one Chemical compound C(C)S(=O)(=O)N1CC(N(CC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC=C2)C(F)(F)F VAWHMYMAEPEZTK-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 239000001301 oxygen Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- 229910052717 sulfur Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- DOJFVPVHXQICAN-UHFFFAOYSA-N 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)piperidin-1-yl]-1H-pyridin-2-one Chemical compound N1C=CC=2C1=NC=CC=2C1=CC(NC(=C1)N1C(CCCC1)C(F)(F)F)=O DOJFVPVHXQICAN-UHFFFAOYSA-N 0.000 claims description 4
- INUVCRPQYQBTTA-UHFFFAOYSA-N 4-[2-(5-methylthiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one Chemical compound CC1=CC=C(S1)C1=CC=2C(=NC=CC=2C2=CC(NC(=C2)N2C(COCC2)C(F)(F)F)=O)N1 INUVCRPQYQBTTA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- HUCPWIDCPVSLDW-UHFFFAOYSA-N 6-[2-(trifluoromethyl)piperidin-1-yl]-4-[2-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one Chemical compound FC(C1N(CCCC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C=1C=NC(=NC=1)C(F)(F)F)(F)F HUCPWIDCPVSLDW-UHFFFAOYSA-N 0.000 claims description 4
- LRTZISIKPSKAIP-UHFFFAOYSA-N 6-[2-(trifluoromethyl)piperidin-1-yl]-4-[2-[5-(trifluoromethyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one Chemical compound FC(C1N(CCCC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C=1C=NC=C(C=1)C(F)(F)F)(F)F LRTZISIKPSKAIP-UHFFFAOYSA-N 0.000 claims description 4
- LDLMFSXKVWKENB-UHFFFAOYSA-N 6-[3-(trifluoromethyl)morpholin-4-yl]-4-[2-[3-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one Chemical compound FC(C1N(CCOC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C1=CC(=CC=C1)C(F)(F)F)(F)F LDLMFSXKVWKENB-UHFFFAOYSA-N 0.000 claims description 4
- DNRNHHBDLRQHAU-UHFFFAOYSA-N 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one Chemical compound FC1=CC=C(C=C1)CS(=O)(=O)N1CC(N(CC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC=C2)C(F)(F)F DNRNHHBDLRQHAU-UHFFFAOYSA-N 0.000 claims description 4
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
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- CSXOYNVGINDZNB-UHFFFAOYSA-N 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one Chemical compound N1C=CC=2C1=NC=CC=2C1=CC(NC(=C1)C1=C(C=CC=C1)C(F)(F)F)=O CSXOYNVGINDZNB-UHFFFAOYSA-N 0.000 claims description 3
- UHLMTCFPIOAJRK-UHFFFAOYSA-N 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one Chemical compound C1(CC1)C1=CC=2C(=NC=CC=2C2=CC(NC(=C2)C2=C(C=CC=C2)C(F)(F)F)=O)N1 UHLMTCFPIOAJRK-UHFFFAOYSA-N 0.000 claims description 3
- CXYDPZLJNIQRAZ-UHFFFAOYSA-N 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one Chemical compound C1(CC1)C1=CC=2C(=NC=CC=2C2=CC(NC(=C2)N2C(CN(CC2)S(=O)(=O)CC)C(F)(F)F)=O)N1 CXYDPZLJNIQRAZ-UHFFFAOYSA-N 0.000 claims description 3
- FPZSPEGMNPCQHE-UHFFFAOYSA-N 6-(3-methylpyridin-4-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one Chemical compound CC=1C=NC=CC=1C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC=C2 FPZSPEGMNPCQHE-UHFFFAOYSA-N 0.000 claims description 3
- NCBUSDZFMYRPKX-UHFFFAOYSA-N 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one Chemical compound C(C)S(=O)(=O)N1CC(N(CC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NC(=C2)C)C(F)(F)F NCBUSDZFMYRPKX-UHFFFAOYSA-N 0.000 claims description 3
- GJZVFKVARNDTAZ-UHFFFAOYSA-N 6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyridin-2-one Chemical compound CS(=O)(=O)N1CC(N(CC1)C1=CC(=CC(N1)=O)C1=C2C(=NC=C1)NN=C2)C(F)(F)F GJZVFKVARNDTAZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
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- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- FOSUDXWCBCABNO-UHFFFAOYSA-N tert-butyl 4-(2,6-dichloropyridin-4-yl)indole-1-carboxylate Chemical compound ClC1=NC(=CC(=C1)C1=C2C=CN(C2=CC=C1)C(=O)OC(C)(C)C)Cl FOSUDXWCBCABNO-UHFFFAOYSA-N 0.000 description 1
- FGEIRKDVPVYBKL-UHFFFAOYSA-N tert-butyl 4-(2,6-dichloropyridin-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylate Chemical compound ClC1=NC(=CC(=C1)C1=C2C(=NC=C1)N(C=C2)C(=O)OC(C)(C)C)Cl FGEIRKDVPVYBKL-UHFFFAOYSA-N 0.000 description 1
- GHDNLFGEJLLKEC-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate Chemical compound C1=CN=C2N(C(=O)OC(C)(C)C)C=CC2=C1B1OC(C)(C)C(C)(C)O1 GHDNLFGEJLLKEC-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical group CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GOFOMJMAFIFSDO-UHFFFAOYSA-N tributyl-(5-methylthiophen-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=C(C)S1 GOFOMJMAFIFSDO-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical group CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 230000007332 vesicle formation Effects 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/45—Transferases (2)
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Abstract
Description
本發明是關於一種新穎的式(I)的氮雜吲哚基吡啶酮及二氮雜吲哚基吡啶酮化合物、含有這些化合物的醫藥組成物以及使用這些化合物治療疾病的方法,疾病包括癌症及第二型糖尿病。
屬於磷脂醯肌醇3-激酶(phosphatidylinositide 3-kinases,PI3K)家族的酶是幾種重要細胞事件的調節者。所述家族由第一型、第二型及第三型所組成,其中雖然第一型多年來一直是令人感興趣的藥物標靶,第二型及第三型則甚少被研究。PI3K第三型中的液泡分選蛋白34(Vps34,PIK3C3)與其調節亞基p150(Vps15)形成異二聚體,這種二聚體參與了幾種複雜的囊泡運輸調節事件,如自噬、胞吞作用、胞吐作用及微細胞泡飲作用(Amaravadi et al.Clin Cancer Res.2011,17:654-666;Carpentier et al.2013,Traffic)。所述酶負責將磷脂醯肌醇(PI)磷酸化為磷脂醯肌醇3-磷酸(PI3P)。與PX及FYVE結構域結合的配體造成這些效應蛋白的募集及離域,引發囊泡的形成、延伸及移動(Backer et al.J Biochem.2008,410:1-17)。
自噬是一種分解代謝過程,藉由將目標細胞成分包圍進雙層膜囊泡中以進行分解,雙層膜囊泡為與含有蛋白酶的溶體融合的自噬小體(auto-phagosome)。這是細胞處理受損胞器與錯誤折疊蛋白的方法,並藉此維持
細胞功能。此種途徑也是將細胞內容物再循環到新的構件中的一種方式(Boya et al,Nat Cell Biol 2013,15;713-720)。自噬是對壓力條件的細胞反應,如營養缺乏、酸中毒及缺氧,同時也包含藥物治療。
因此,自噬抑制是增強癌症藥物及使抗藥性腫瘤再敏化的方法(Nagelkerke et al,Semin Cancer Biol 2014,31;99-105)。大多數晚期腫瘤顯示出對自噬流(autophagic flux)的高度調節(Leone et al.Trends in Endocrin Metab 2013,24;209-217)。用於研究自噬流的已建立的標記是在自噬體上檢測脂質化LC3蛋白形式的自噬斑點(autophagic puncta)。藉由將LC3重新分佈到斑點中以測量因Vps 34的抑制導致自噬的抑制(Dowdle et al.,Nat Cell Biol 2014,16;1069-79)。
如最近所述,由於胰島素受體的內化減少,調節亞基p150的消除導致體內胰島素敏感性增加(Nemazanyy,Nature Commun.,2015,6:8283)。無激酶活性異質體的動物模型證實了這一結果,葡萄糖耐量增加,胰島素敏感性增加(WO2013076501)。
幾種疾病狀態可受益於Vps34抑制,包括癌症、發炎性疾病、自身免疫疾病、神經退行性病症、心血管病症、第二型糖尿病及病毒感染(回顧Rubinsztein et al,Nat Rev 2012,11;709-730)。受益於Vps34抑制的癌症形式包括但不限於乳癌,例如三陰性乳癌,膀胱癌、肝癌、子宮頸癌、胰腺癌、白血病、淋巴瘤、腎癌、大腸癌、神經膠質瘤、前列腺癌、卵巢癌、黑色素瘤及肺癌以及缺氧性腫瘤。因此,需要新穎與有效的Vps34抑制劑。
描述用於影響疾病的Vps34抑制劑的先前公開內容包括WO2015150555;WO2015150557;WO2015108861;WO2015108881;WO2012085815;WO2012085244;WO2013190510;Farkas,J.Biol.Chem.,2011 286(45)38904-12。
本發明的一個目的是提供新穎與有效的Vps34抑制劑。本發明的另一個目的是提供新穎與有效的Vps34抑制劑,其可用於治療癌症及其他疾病,例如第二型糖尿病。
根據本發明的一實施態樣,提供式(I)的化合物或藥學上可接受的鹽,或其藥學上可接受的鹽
其中X為N或CR1;R1選自H、C1-C3烷基、C1-C3鹵代烷基、C1-C3烷氧基C1-C3烷基、C3-C6環烷基、氰基、苯基、單環雜芳基、其中所述苯基及所述雜芳基任選地且獨立地被一個或多個選自下列的取代基取代:鹵代、N-C1-C3烷基胺基、N,N-二C1-C3烷基胺基、C3-C6環烷基、C1-C3烷氧基C1-C3烷基、C1-C3鹵代烷基、C1-C3鹵代烷氧基、C1-C3烷氧基及C1-C3烷基;R2選自氫、C1-C3鹵代烷基及C1-C3烷基;R3選自A、苯基及單環雜芳基,所述苯基及所述雜芳基任選地且獨立地被一個或多個R4取代;R4獨立地選自COR5、鹵素、C1-C6烷基、C1-C6烷氧基、C1-C6鹵代烷氧基、胺基、N-C1-C3烷基胺基、N,N-二C1-C3烷基胺基、1-吡咯啶基、1-哌啶基、
1-四氫吖唉基、NHSO2R6、SO2R7、羥基、C3-C6環烷基、C1-C3烷氧基C1-C3烷基、C1-C3氰基烷基及C1-C6鹵代烷基;R5選自C1-C3烷氧基、N-C1-C3烷基胺基、N,N-二C1-C3烷基胺基、1-吡咯啶基、1-哌啶基及1-四氫吖唉基;R6為C1-C3鹵代烷基或C1-C3烷基;R7選自R8、C1-C6烷基、N-C1-C3烷基胺基、N,N-二C1-C3烷基胺基及C1-C3烷氧基C1-C3烷基,所述C1-C6烷基及所述C1-C3烷氧基C1-C3烷基任選被一個R8及/或一個或多個鹵代取代;R8選自苯基、單環雜芳基、C3-C6環烷基、雜環基,各自任選地被一個或多個R9取代;R9選自鹵代、N-C1-C3烷基胺基、N,N-二C1-C3烷基胺基、C1-C3烷氧基C1-C3烷基、胺基、C1-C3鹵代烷基、C1-C3烷氧基、C1-C3鹵代烷氧基、C3-C6環烷基及C1-C3烷基;
A為;
R10選自氫、鹵素、COR11、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6環烷基、C1-C3氰基烷基、C1-C3鹵代烷基、苯基及雜芳基,其中所述苯基及所述雜芳基任選地且獨立地被一個或多個R12取代,並且當R10為苯基或雜芳基時,則X為N或CH;R11選自C1-C3烷氧基、N-C1-C3烷基胺基、N,N-二C1-C3烷基胺基、1-吡咯啶基、1-哌啶基及1-四氫吖唉基;Y為CH2、S、SO、SO2、NR13、NCOR7、NCOOR14、NSO2R7、NCOCH2R7、O或鍵;
R12選自C1-C6烷基、C3-C6環烷基、C1-C3烷氧基C1-C3烷基、C1-C3鹵代烷基、鹵素、N-C1-C3烷基胺基、N,N-二C1-C3烷基胺基、C1-C3鹵代烷氧基及C1-C3烷氧基;R13選自H、C1-C3鹵代烷基、C1-C3烷氧基C1-C3烷基、C1-C3烷基、C3-C6環烷基;R14選自R8、C1-C6烷基及C1-C3烷氧基C1-C3烷基,所述C1-C6烷基及所述C1-C3烷氧基C1-C3烷基任選地被一個R8及/或一個或多個鹵代取代。
根據本發明該實施態樣的一實施例,R2為氫或C1-C3烷基。
根據本發明該實施態樣的一實施例,R1選自H、C1-C3烷基、C1-C3鹵代烷基、C3-C6環烷基、氰基、苯基、雜芳基,其中所述苯基及所述雜芳基任選地且獨立地被一個或多個選自C1-C3鹵代烷基、鹵代、C3-C6環烷基及C1-C3烷基的取代基取代。
根據本發明該實施態樣的一實施例,R2為氫。
根據本發明該實施態樣的一實施例,R1中的所述雜芳基選自吡啶基、噁唑基、噻吩基及嘧啶基,各自任選地且獨立地被一個或多個選自鹵代、環丙基、C1-C3氟烷基及C1-C3烷基的取代基取代。
根據本發明該實施態樣的一實施例,R3選自A、苯基及單環雜芳基,所述單環雜芳基選自吡啶基、噻吩基、呋喃基、嘧啶基及吡唑基,其中所述苯基及所述雜芳基任選地及獨立地被一個或兩個R4取代。
根據本發明該實施態樣的一實施例,R3選自A、苯基及單環雜芳基,所述單環雜芳基選自吡啶基、噻吩基及吡唑基,其中所述苯基及所述雜芳基任選地及獨立地被一個或兩個R4取代。
根據本發明該實施態樣的一實施例,R3選自A、苯基及吡啶基,其中所述苯基及所述吡啶基任選地被一個R4取代。
根據本發明該實施態樣的一實施例,R3選自A、苯基及吡啶基,其中所述苯基及所述吡啶基任選地且獨立地被一個或兩個R4取代。
根據本發明該實施態樣的一實施例,R4選自氟、氯、C1-C3烷基、C3-C6環烷基、C1-C3氟烷基及SO2R7。
根據本發明該實施態樣的一實施例,R4選自氯、C1-C3烷基、C1-C3氟烷基及SO2R7。
根據本發明該實施態樣的一實施例,Y為CH2、NSO2R7、O或鍵。
根據本發明該實施態樣的一實施例,R10選自氫、C1-C3烷基、C3-C6環烷基、苯基、單環雜芳基及C1-C3鹵代烷基,其中所述苯基及所述雜芳基任選地且獨立地被一個R12取代;以及R12選自C1-C3烷基、環丙基、CF3、鹵素、C1-C3鹵代烷氧基及C1-C3烷氧基。
根據本發明該實施態樣的一實施例,R10選自氫、C1-C3烷基、苯基及C1-C3鹵代烷基。
根據本發明該實施態樣的一實施例,R7選自R8、N,N-二C1-C3烷基胺基、C1-C3烷基及甲氧基C1-C3烷基,所述C1-C3烷基任選被一個R8取代。
根據本發明該實施態樣的一實施例,R7選自C1-C3烷基及氟苯基。
根據本發明該實施態樣的一實施例,R7選自C1-C3烷基及氟苄基。
根據本發明該實施態樣的一實施例,R8選自苯基、吡啶基、咪唑基、異噁唑基、噁唑基、環丙基、環戊基、吡咯啶基、四氫呋喃基,各自任選地被一個或多個選自環丙基、甲基及氟的取代基取代。
根據本發明該實施態樣的一實施例,X為N。
根據本發明該實施態樣的一實施例,X為CR1。
根據本發明該實施態樣的一實施例,所述化合物如下:4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;6-(3-甲基-4-吡啶基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-苯基吡咯啶-1-基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-嗎啉代-1H-吡啶-2-酮;
6-(2-氯苯基)-4-(2-噁唑-5-基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-氯苯基)-4-[2-(3-吡啶基)-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-(2-氯苯基)-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;6-[3-(三氟甲基)嗎啉-4-基]-4-[2-[3-(三氟甲基)苯基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-[2-(5-甲基-2-噻吩基)-1H-吡咯並[2,3-b]吡啶-4-基]-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[2-(三氟甲基)嘧啶-5-基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[6-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[5-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;
6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-[2-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-6-氧代-1H-吡啶-4-基]-1H-吡咯並[2,3-b]吡啶-2-甲腈;4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;4-[2-氧代-6-[2-(三氟甲基)苯基]-1H-吡啶-4-基]-1H-吡咯並[2,3-b]吡啶-2-甲腈;4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;6-[4-甲磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡唑並[3,4-b]吡啶-4-基)-1H-吡啶-2-酮。
根據本發明該實施態樣的一實施例,所述化合物如下:4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;6-(3-甲基-4-吡啶基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-苯基吡咯啶-1-基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-嗎啉代-1H-吡啶-2-酮;6-(2-氯苯基)-4-(2-噁唑-5-基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-氯苯基)-4-[2-(3-吡啶基)-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-(2-氯苯基)-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;
6-[3-(三氟甲基)嗎啉-4-基]-4-[2-[3-(三氟甲基)苯基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-[2-(5-甲基-2-噻吩基)-1H-吡咯並[2,3-b]吡啶-4-基]-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[2-(三氟甲基)嘧啶-5-基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[6-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[5-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;或6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮。
在本發明的一實施態樣中,提供一種根據本發明的化合物,其用於治療或預防疾病。
在本發明的一實施態樣中,提供一種根據本發明的化合物,其用於治療癌症。一般而言,所述癌症選自乳癌,例如三陰性乳癌,膀胱癌、肝癌、子宮頸癌、胰腺癌、白血病、淋巴瘤、腎癌、大腸癌、神經膠質瘤、前列腺癌、卵巢癌、黑色素瘤及肺癌以及缺氧性腫瘤。
在本發明的一實施態樣中,提供一種根據本發明的化合物,其用於治療缺氧性腫瘤。
在本發明的一實施態樣中,提供一種根據本發明的化合物,其用於治療第二型糖尿病。
在本發明的一實施態樣中,提供一種根據本發明的化合物,其用於治療發炎性疾病、自身免疫疾病、神經退行性病症、心血管病症及病毒感染。
在本發明的一實施態樣中,提供一種根據本發明的化合物在製備用於治療癌症的藥物的用途。一般而言,所述癌症選自乳癌,例如三陰性乳癌,膀胱癌、肝癌、子宮頸癌、胰腺癌、白血病、淋巴瘤、腎癌、大腸癌、神經膠質瘤、前列腺癌、卵巢癌、黑色素瘤及肺癌以及缺氧性腫瘤。
在本發明的一實施態樣中,提供一種根據本發明的化合物在製備用於治療缺氧性腫瘤的藥物的用途。
在本發明的一實施態樣中,提供一種根據本發明的化合物在製備用於治療第二型糖尿病的藥物的用途。
在本發明的一實施態樣中,提供一種根據本發明的化合物在製備用於治療發炎性疾病、自身免疫疾病、神經退行性病症、心血管病症及病毒感染的藥物的用途。
在本發明的一實施態樣中,提供一種治療癌症的方法,包括將治療有效量的本發明化合物施用於有需要的患者。一般而言,所述癌症選自乳癌,例如三陰性乳癌,膀胱癌、肝癌、子宮頸癌、胰腺癌、白血病、淋巴瘤、腎癌、大腸癌、神經膠質瘤、前列腺癌、卵巢癌、黑色素瘤及肺癌以及缺氧性腫瘤。
在本發明的一實施態樣中,提供一種治療缺氧性腫瘤的方法,包括將治療有效量的本發明化合物施用於有需要的患者。
在本發明的一實施態樣中,提供一種根據本發明的化合物,其用於治療癌症,其中所述癌症治療還包括放射療法。
在本發明的一實施態樣中,提供一種治療癌症的方法,包括將治療有效量的本發明化合物與放射療法一起施用於有需要的患者。
本發明化合物還可以與放射療法及/或外科手術相結合用於癌症治療。一般而言,細胞毒性及/或細胞生長抑制劑與本發明的化合物或組成物的組合使用將用於:(1)與單獨施用任一種藥劑相比,產生更好的減少腫瘤生長或甚至消除腫瘤的功效,(2)提供較少量的施用化學治療劑的給藥,(3)提供使患者具有良好耐受性的化學治療,與單藥化學療法及某些其他聯合療法相比,觀察到的有害藥物並發症較少,(4)提供在哺乳動物,尤其是人類中治療更廣泛的不同癌症類型,(5)在受治療的患者中提供更高的緩解率,(6)與標準化學治療相比,治療患者的存活時間更長,(7)為腫瘤進程提供更長的時間,及/或(8)與其他癌症藥物組合產生拮抗作用的習知情況相比,產生的功效及耐受性至少與單獨使用的藥劑一樣好。
在本發明的一實施態樣中,提供一種治療缺氧性腫瘤的方法,包括對有需要的患者施用治療有效量的本發明化合物。
在本發明的一實施態樣中,提供一種治療第二型糖尿病的方法,包括對有需要的患者施用治療有效量的本發明化合物。
在本發明的一實施態樣中,提供一種治療選自發炎性疾病、自身免疫疾病、神經退行性病症及病毒感染的疾病的方法,包括對有需要的患者施用治療有效量的本發明化合物。
在本發明的一實施態樣中,提供一種醫藥組成物,包括根據本發明的化合物及藥學上可接受的稀釋劑、載體及/或賦形劑。
在本發明的一實施態樣中,提供一種醫藥組成物,包括根據本發明的化合物及另一種抗癌劑,其選自烷化劑、抗代謝物、抗癌喜樹鹼衍生物、植物源抗癌劑、抗生素、酶、鉑配位複合物、酪胺酸激酶抑制劑、激素、激素拮抗劑、單株抗體、干擾素及生物反應調節劑。
如本文所述,術語「C1-C6烷基」是指具有1至6個碳原子的直鏈及支鏈飽和烴基。C1-C6烷基的實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、4-甲基丁基、正己基、2-乙基丁基。在無支鏈的C1-C6烷基中,典型的是甲基、乙基、正丙基、正丁基、正戊基及正己基。在支鏈烷基中,可能提及的是異丙基、異丁基、二級丁基、三級丁基、4-甲基丁基及2-乙基丁基。
如本文所述,術語「C1-C3烷基」是指具有1至3個碳原子的直鏈及支鏈飽和烴基。C1-C3烷基的實例包括甲基、乙基、正丙基及異丙基。
如本文所述,術語「C1-C6烷氧基」是指O-C1-C6烷基基團,其中「C1-C6烷基」的定義如上所述。C1-C6烷氧基的實例包括但不限於甲氧基、乙氧基、異丙氧基、正丙氧基、正丁氧基、正己氧基、3-甲基丁氧基。
如本文所述,術語「C1-C3烷氧基」是指O-C1-C3烷基基團,其中「C1-C3烷基」的定義如上所述。C1-C3烷氧基的實例包括但不限於甲氧基、乙氧基、異丙氧基及正丙氧基。
如本文所述,術語「C1-C6鹵代烷基」是指具有1至6個碳原子且1個至所有氫被不同或相同類型的鹵素原子取代的直鏈及支鏈飽和烴基。C1-C6鹵代烷基的實例包括被1至3個鹵素原子取代的甲基、被1至5個鹵素原子取代的乙基、被1至7個鹵素原子取代的正丙基或異丙基、被1至9個鹵素原子取代的正丁基或異丁基以及被1至9個鹵素原子取代的二級丁基或三級丁基。
如本文所述,術語「C1-C3鹵代烷基」是指具有1至3個碳原子且1個至所有氫被不同或相同類型的鹵素原子取代的直鏈及支鏈飽和烴基。C1-C3鹵代烷基的實例包括被1至3個鹵素原子取代的甲基、被1至5個鹵素原子取代的乙基以及被1至7個鹵素原子取代的正丙基或異丙基。
如本文所述,術語「C1-C3鹵代烷氧基」是指具有1至3個碳原子且1個至所有氫被不同或相同類型的鹵素原子取代的直鏈及支鏈飽和烷氧基。C1-C3鹵代烷氧基的實例包括被1至3個鹵素原子取代的甲氧基、被1至5個鹵素原子取代的乙氧基以及被1至7個鹵素原子取代的正丙氧基或異丙氧基。
如本文所述,術語「C1-C3氟烷基」是指具有1至3個碳原子且1個至所有氫被氟原子取代的直鏈及支鏈飽和烴基。C1-C3氟烷基的實例包括被1至3個氟原子取代的甲基、被1至5個氟原子取代的乙基以及被1至7個氟原子取代的正丙基或異丙基。
如本文所述,術語「C1-C3氟烷氧基」是指具有1至3個碳原子且1個至所有氫被氟原子取代的直鏈及支鏈飽和烷氧基。C1-C3氟烷氧基的實例
包括被1至3個氟原子取代的甲氧基、被1至5個氟原子取代的乙氧基以及被1至7個氟原子取代的正丙氧基或異丙氧基。
如本文所述,術語「C3-C6環烷基」是指具有3至6個碳原子的環狀飽和烴基。C3-C6環烷基的實例包括環丙基、環丁基、環戊基及環己基。
如本文所述,術語「鹵素」是指氟、氯、溴或碘。如本文所述,術語「鹵代」是指氟基、氯基、溴基或碘基。
如本文所述,術語「芳基」是指單環芳族碳環基團。這類基團的實例包括苯基。
如本文所述,術語「單環芳基」是指單環芳族碳環基團。單環芳基的實例包括苯基。
如本文所述,術語「雜芳基」是指碳原子的單環或雙環芳族基團,其中1至3個碳原子被一個或多個獨立地選自氮、氧或硫的雜原子取代。在雙環芳基中,其中一個環可以是部分飽和的。這類基團的實例包括二氫吲哚基、二氫苯並呋喃及1,3-苯並二氧雜環戊烯基(1,3-benzodioxolyl)。
如本文所述,術語「單環雜芳基」是指碳原子的單環芳族基團,其中1至3個碳原子被一個或多個獨立地選自氮、氧或硫的雜原子取代。
單環雜芳基的實例包括但不限於呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、噁二唑基、噻二唑基、吡啶基、三唑基、三嗪基、噠嗪基、異噻唑基、異噁唑基、吡嗪基、吡唑基及嘧啶基。
雙環雜芳基的實例包括但不限於喹喔啉基、喹唑啉基、吡啶並吡嗪基、苯並噁唑基、苯並噻吩基、苯並咪唑基、萘啶基、喹啉基、苯並呋喃基、吲哚基、吲唑基、苯並噻唑基、吡啶並嘧啶基及異喹啉基。
如本文所述,術語「雜環基」是指碳原子的環狀基團,其中1至3個碳原子被一個或多個獨立地選自氮、氧或硫的雜原子取代。雜環基的實例包括但不限於四氫呋喃基、四氫吡喃基、吡咯啶基、哌啶基、哌嗪基、嗎啉基及二噁烷基。
取決於式(I)化合物中存在的取代基,化合物可以形成在本發明範圍內的鹽。適合用於醫藥的式(I)化合物的鹽是指其中相對離子(counterion)是藥學上可接受的鹽。
根據本發明的合適的鹽包括與有機或無機的酸或鹼形成的鹽。特別地,與酸形成的根據本發明的合適的鹽包括與無機酸形成的鹽、與強有機羧酸,如1至4個碳原子的烷基羧酸,其為未取代的或被例如鹵素取代的、
如飽和或不飽和二羧酸、如羥基羧酸、如胺基酸,形成的鹽或與有機磺酸,如未取代的或被例如鹵素取代的(C1-C4)烷基或芳基磺酸,形成的鹽。藥學上可接受的酸加成鹽包括由鹽酸、氫溴酸、硫酸、硝酸、檸檬酸、酒石酸、乙酸、磷酸、乳酸、丙酮酸、三氟乙酸、琥珀酸、高氯酸、富馬酸、馬來酸、乙醇酸、水楊酸、草醯乙酸、甲磺酸、乙磺酸、對甲苯磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸、羥乙磺酸、抗壞血酸、蘋果酸、鄰苯二甲酸、天門冬胺酸及谷胺酸、賴胺酸及精胺酸形成的鹽。
藥學上可接受的鹼鹽包括銨鹽、鹼金屬鹽(例如鉀鹽及鈉鹽)、鹼土金屬鹽(例如鈣鹽及鎂鹽)以及與有機鹼形成的鹽,例如二環己胺、N-甲基-D-葡萄糖胺、嗎啉、硫代嗎啉、哌啶、吡咯啶、單、二或三低級烷基胺(例如乙基、三級丁基、二乙基、二異丙基、三乙基、三丁基或二甲基丙胺)或單、二或三羥基低級烷基胺(例如單、二或三乙醇胺)。此外,可以形成相應的內鹽(internal salts)。
本發明化合物可以原樣用於預防及/或治療,或以醫藥組成物的形式使用。儘管活性成分可以單獨給藥,但它也可以存在於醫藥組成物中。因此,本發明提供一種醫藥組成物,其包含式(I)化合物及藥學上可接受的稀釋劑、賦形劑及/或載體。本發明的醫藥組成物可以採用如下所述的醫藥組成物的形式。
用於口服給藥的示例性組成物包括懸浮液,其可含有例如微晶纖維素,用於賦予鬆散劑、海藻酸或海藻酸鈉作為懸浮劑,甲基纖維素作為黏度增強劑,以及例如本領域習知的甜味劑或調味劑;以及速釋片劑,其可含有例如微晶纖維素、磷酸二鈣、澱粉、硬脂酸鎂、硫酸鈣、山梨糖醇、葡萄糖及/或乳糖及/或其它例如本領域習知的賦形劑、黏合劑、增量劑、崩解劑、稀釋劑及潤滑劑。合適的黏合劑包括澱粉、明膠、天然糖如葡萄糖
或β-乳糖、玉米甜味劑、天然及合成樹膠如阿拉伯膠、黃蓍膠或海藻酸鈉,羧甲基纖維素、聚乙二醇、蠟等。崩解劑包括但不限於澱粉、甲基纖維素、洋菜、膨潤土、黃原膠等。式(I)化合物還可以藉由舌下及/或口腔給藥通過口腔遞送。模製片劑、壓製片劑或凍乾片劑是可以使用的示例性形式。示例性組成物包括用快速溶解稀釋劑配製本發明化合物的組成物,稀釋劑例如為甘露醇、乳糖、蔗糖及/或環糊精。此類組成物中還包括高分子量賦形劑,例如纖維素(avicel)或聚乙二醇(PEG)。此類組成物還可包括有助於黏膜黏附的賦形劑,例如羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、羧甲基纖維素鈉(SCMC)、馬來酸酐共聚物(例如Gantrez)、以及控制釋放的試劑如聚丙烯酸共聚物(例如Carbopol 934)。還可以加入潤滑劑、助滑劑、調味劑、著色劑及穩定劑以便於製造及使用。這些劑型中使用的潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉等。對於液體形式的口服給藥,口服藥物組分可以與任何口服、無毒、藥學上可接受的惰性載體如乙醇、甘油、水等組合。
適於口服給藥的本發明組成物可以作為離散單元存在,例如膠囊、扁囊劑、丸劑或片劑,每個含有預定量的活性成分;作為粉末或顆粒;作為水性液體或非水性液體中的溶液或懸浮液,例如作為酏劑、酊劑、懸浮液或糖漿;或作為水包油液體乳液或油包水液體乳液。活性成分也可以以大丸劑、糖劑或糊劑形式存在。
片劑可以通過壓製或模塑製備,任選地含有一種或多種輔助成分。壓製片劑可以通過在合適的機器中壓製自由流動形式的活性成分如粉末或顆粒,任選地與黏合劑、潤滑劑、惰性稀釋劑、潤滑劑、表面活性劑或分散劑混合來製備。模製片劑可以通過在合適的機器中模塑用惰性液體稀釋劑潤濕的粉末化合物的混合物來製備。片劑可任選地包衣或刻痕,並可配
製成提供其中活性成分的緩慢或控制釋放。本發明化合物可以例如以適於立即釋放或延長釋放的形式給藥。立即釋放或延長釋放可以通過使用包含本發明化合物的合適醫藥組成物,或者特別是在延長釋放的情況下,通過使用諸如皮下植入物或滲透泵的裝置來實現。本發明化合物也可以脂質體給藥。
典型的單位劑量組成物為含有如上所述的有效劑量或其適當部分的活性成分。
除了上面特別提到的成分之外,應當理解本發明的組成物可以包括本領域習知的關於所討論的組成物類型的其他試劑,例如適合於口服給藥的組成物可以包括調味劑。
組成物可以以單位劑量的型式存在,並且可以通過藥學領域習知的任何方法製備。所述方法可包括使活性成分與構成一種或多種輔助成分的載體結合的步驟。組成物可以通過將活性成分與液體載體或細碎的固體載體或兩者均勻且緊密地結合在一起來製備,接著,依據需求將產物成形為所需的組合物。
本發明化合物還可以以脂質體遞送系統的形式給藥,例如小單層囊泡、大單層囊泡及多層囊泡。脂質體可由多種磷脂、1,2-二棕櫚醯磷脂醯膽鹼、磷脂醯乙醇胺(腦磷脂)、磷脂醯絲胺酸、磷脂醯肌醇、二磷脂醯甘油(心磷脂)或磷脂醯膽鹼(卵磷脂)形成。
用於腸胃外給藥的組成物包括水性及非水性無菌注射溶液,其可含有抗氧化劑、緩衝劑、抑菌劑及溶質,使組成物與預期接受者的血液等張;水性及非水性無菌懸浮液,其可含有懸浮劑及增稠劑。組成物可以單位劑量或多劑量容器存在,例如密封的安瓿及小瓶,並且可以在冷凍乾燥(凍乾)條件下儲存,僅需要在使用前立即加入無菌液體載體,例如鹽水
或注射用水。臨時注射溶液及懸浮液可以由前述類型的無菌粉末、顆粒及片劑製備。用於腸胃外給藥的示例性組成物包括可注射溶液或懸浮液,其可含有例如合適的無毒、腸胃外可接受的稀釋劑或溶劑,例如聚乙二醇、乙醇、1,3-丁二醇、水、林格氏溶液、等張氯化鈉溶液、或其他合適的分散或潤濕及懸浮劑,包括合成的甘油單酯或甘油二酯,以及脂肪酸,包括油酸或Cremaphor。
用於鼻、霧氣或吸入給藥的示例性組成物包括鹽水溶液,其可含有例如苯甲醇或其它合適的防腐劑,吸收促進劑以增強生物利用度,及/或其他例如本領域習知的助溶劑或分散劑。
用於直腸給藥的組成物可以作為栓劑存在,其具有常用的載體,例如可可脂、合成的甘油酯或聚乙二醇。這種載體在常溫下通常是固體,但在直腸腔中液化及/或溶解以釋放藥物。
用於口腔局部給藥的組合物,例如口腔或舌下給藥,包括含有調味基礎的活性成分的錠劑,所述活性成分例如蔗糖及阿拉伯膠或黃蓍膠,以及丸粒包含例如基於明膠及甘油或蔗糖及阿拉伯膠的活性成分。用於局部給藥的示例性組成物包括局部載體,例如Plastibase(用聚乙烯膠化的礦物油)。
式(I)化合物可以作為唯一的藥劑給藥或與一種或多種另外的治療劑組合給藥,其中所述組合不會引起不可接受的副作用。所述醫藥組成物包括給予單一藥物劑量組合物,其含有式(I)化合物及一種或多種另外的治療劑,以及在其自身單獨的藥物劑量組合物中給予式(I)化合物及每種另外的治療劑。例如,式(I)化合物及治療劑可以以單一口服劑量組合物(例如膠囊或片劑)一起給予患者,或者每種藥劑可以以具有單獨劑量的組成物給藥。
當使用單獨的劑量組合物時,式(I)化合物及一種或多種另外的治療劑可以在基本相同的時間(例如同時地)或在分開的交錯時間(例如有順序地)給藥。
當然,實現治療效果所需的活性成分的量將隨特定化合物、給藥途徑、治療對象的背景,包括類型、種類、年齡、體重、性別,治療對象的醫學狀況以及治療對象的腎及肝功能,與正在治療的特定疾病或病症,以及其嚴重程度而變化。通常熟練的醫生、獸醫或臨床醫生可以確實地決定與開出預防、抵抗或阻止病症進展所需的藥物的有效量。
當用於所示效果時,本發明的口服劑量對於成年人的範圍為約0.01mg/kg/天至約100mg/kg/天,較佳0.01mg/kg/天至10mg/kg/天,更佳0.1至5.0mg/kg/天。對於口服給藥,組合物可以以片劑或以含有0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100及500mg活性成分的離散單位的其他形式提供,以用於對欲治療患者的劑量的症狀調整。藥物通常含有約0.01mg至約500mg的活性成分,較佳約1mg至約100mg的活性成分。藥物通常含有約0.01mg至約500mg活性成分,優選約1mg至約100mg活性成分。靜脈內,在恆定速率輸注期間,更佳的劑量範圍為約0.1至約10mg/kg/分鐘。本發明化合物可以單日劑量給藥,或者每日總劑量可以每日兩次、三次或四次的分劑量給藥。此外,本發明化合物可以通過局部使用合適的鼻內載體以鼻內形式給藥,或通過經皮途徑,使用本領域普通技術人員熟知的那些經皮貼劑形式給藥。為了以經皮遞送系統的形式給藥,劑量給藥當然在整個給藥方案中是連續的而不是間歇的。
化合物製備
本發明化合物可通過下述方法製備成游離鹼或其藥學上可接受的鹽。以下對這些流程的描述中,應理解的是,在適當的情況下,會以有機
合成領域的技術人員容易理解的方式將合適的保護基添加到各種反應物及中間產物中,隨後從各種反應物及中間產物中除去。使用這種保護基的常規方法以及合適的保護基的實例例如描述於Protective Groups in Organic Synthesis by T.W.Greene,P.G.M Wutz,4th Edition,Wiley-Interscience,New York,2006。應理解的是微波可以替代地用於加熱反應混合物。
本發明的另一實施態樣提供製備式(I)化合物或其藥學上可接受的鹽的方法,其中除非另有說明,R2、R3及X如本文所定義。所述過程包括:
(i)形成相應的式(I)化合物
從例如式(II)的化合物開始,可以獲得式(I)的化合物(反應式1),其中RX可以是F、OCH3、OC(CH3)3或OSiR’R”R'''(其中R’、R”及R'''獨立地是芳基(如苯基)或烷基(如甲基或三級丁基))。如果RX是F,則轉化為(I)可以藉由例如使用HCl水溶液的酸性水解來進行。如果RX是OCH3,則轉化為(I)可以藉由在合適的溶劑例如氯仿中與例如三甲基甲矽基碘反應,或藉由在合適的溶劑例如乙酸中與HBr反應,或藉由在合適的溶劑例如二氯甲烷中與BBr3反應來進行。如果RX是OC(CH3)3,則轉化為(I)可以藉由在合適的溶劑如二氯甲烷中與例如三氟乙酸反應來進行。如果RX是OSiR’R”R''',則轉化為(I)可以藉由例如HCl在合適的溶劑如甲醇中或藉由
在四氫呋喃中使用四丁基氟化銨進行。如果在反應中使用純的鏡像或富含鏡像的化合物(II),則獲得純的鏡像或富含鏡像的化合物(I)。
式(II)化合物為可商購的化合物,或者為文獻中習知,或者它們可藉由本領域習知的標準方法製備。式(I)或(II)化合物可藉由本領域習知的標準方法,通過例如在掌性固定相上的層析分離成其鏡像異構物。
一般方法
使用的所有溶劑均為分析級,市售的無水溶劑通常用於反應。起始材料可從商業來源獲得,或根據文獻程序製備。室溫指+20-25℃。溶劑混合組成物以體積百分比或體積比表示。
微波加熱在產生2.45GHz的連續照射的Biotage Initiator微波空腔中進行。應理解微波可用於加熱反應混合物。
在Merck Silica gel 60(0.040-0.063mm)上手動進行直相層析,或使用所示溶劑系統的使用SiliaSep TM正相快速純化管柱的使用ISCO Combiflash®Companion TM系統自動進行。
在裝有適當構型的探針的400MHz(或更高磁場)NMR光譜儀上記錄NMR光譜。除非另有說明,否則在環境溫度下記錄光譜。化學位移從TMS(0.00ppm)的低磁場及高磁場的ppm表示。使用以下參考信號:DMSO-d 6 δ 2.5、CDCl3δ 7.26或Methanol-d 4 δ 3.31的殘留溶劑信號。共振多重性中,s、d、t、q、m及br分別表示單重態、雙重態、三重態、四重態、多重態及寬態。
高效能液相層析法(HPLC)係在反相柱上進行。使用例如流動相A(0.1%NH3水溶液或0.1%乙酸水溶液或0.1%甲酸水溶液)及B(乙腈或甲醇)施加線性梯度。使用電噴灑游離以正離子模式(ES+)進行質譜儀(MS)分析。
製備層析法在Gilson-PREP GX271或GX281上進行,使用Trilution 1c作為反相柱上的軟體。使用例如流動相A(0.1%NH3水溶液或0.1%乙酸水溶液或0.1%甲酸水溶液)及B(乙腈或甲醇)施加線性梯度。
用於分離鏡像異構物的製備掌性層析法在Thar SFC上在掌性固定相上使用超臨界流體層析法進行。使用流動相A(二氧化碳)及B(乙腈或甲醇或乙醇或2-丙醇或其任何混合物)施加線性梯度。可以使用添加劑(例如二乙胺或異丙胺或氨或甲酸或TFA)。
化合物已使用BIOVIA Draw 16.1命名。
縮寫
Amphos:(4-(N,N-二甲基胺基)苯基)二三級丁基膦
anh.:無水
aq.:水性
BuLi:丁基鋰
DCM:二氯甲烷
DMAc:N,N-二甲基乙醯胺
DME:1,2-二甲氧乙烷
DMF:N,N-二甲基甲醯胺
DMSO:二甲亞碸
EtOAc:乙酸乙酯
EtOH:乙醇
h:小時
HPLC:高效能液相層析法
KOtBu:叔丁醇鉀
LCMS:液相層析質譜法
MeCN:乙腈
2-MeTHF:2-甲基四氫呋喃
MeOH:甲醇
min.:分鐘
NMR:核磁共振
PEPPSI-iPr:[1,3-雙(2,6-二異丙基苯基)咪唑-2-亞基](3-氯吡啶基)二氯化鈀(II)
Pd(OAc)2:乙酸鈀(II)
PdCl2(dppf):[1,1'-雙(二苯基膦基)二茂鐵]-二氯化鈀(II)
quant.:定量
rt:室溫
sat.:飽和
S-Phos:2-二環己基膦基-2',6'-二甲氧基聯苯
TFA:三氟乙酸
THF:四氫呋喃
中間產物實施例1
4-(2,6-二氯-4-吡啶基)吡咯並[2,3-b]吡啶-1-羧酸叔丁酯
將4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡咯並[2,3-b]吡啶-1-羧酸叔丁酯(1.07g,3.1mmol)、2,6-二氯-4-碘-吡啶(850mg,3.1mmol),
PdCl2(PPh3)2(109mg,0.16mmol)及K2CO3(1.07g,7.76mmol)溶於DME:H2O:EtOH(6:3:1,8ml)中,並將所得混合物在70℃下攪拌過夜。當冷卻至室溫時,將混合物濃縮,將得到的殘餘物溶於DCM(10ml)中。過濾混合物,濾液在矽膠柱上純化,用0-40%EtOAc的庚烷溶液洗脫,得到固體產物(270mg,33%)。MS ES+ m/z 365[M+H]+。
中間產物實施例2
4-(2-三級丁氧基-6-氯-4-吡啶基)-1H-吡咯並[2,3-b]吡啶
將4-(2,6-二氯-4-吡啶基)吲哚-1-羧酸叔丁酯(500mg,1.37mmol)、KOtBu(462mg,4.12mmol)及甲苯(10ml)混合並在100℃下攪拌5小時。當冷卻至室溫時,將混合物用EtOAc(20ml)稀釋並加入1M HCl水溶液(10ml)。10分鐘後,用飽和NaHCO3將pH調整至7。分離有機層,水層用EtOAc(2×10ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾並濃縮,得到膠狀產物(460mg,定量)。MS ES+ m/z 302[M+H]+。
中間產物實施例3
4-[2-三級丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-1H-吡咯並[2,3-b]吡啶
將4-(2-三級丁氧基-6-氯-4-吡啶基)-1H-吡咯並[2,3-b]吡啶(220mg,0.73mmol)、[2-(三氟甲基)苯基]硼酸(190mg,1mmol)、PdCl2(dppf)(30mg,0.04mmol)及K2CO3(302mg,2.19mmol)溶於1,4-二噁烷:H2O:EtOH(6:3:1,4ml)中,並將所得混合物在80℃下攪拌過夜。當冷卻至室溫時,加入EtOAc(3ml)及鹽水(3ml),分離有機層。用EtOAc(2×3ml)萃取水層。將合併的有機物用Na2SO4乾燥,過濾並濃縮,得到產物(300mg,定量)。MS ES+ m/z 412[M+H]+。
實施例4
4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮
在室溫下將4-[2-三級丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-1H-吡咯並[2,3-b]吡啶(300mg,0.73mmol)溶於DCM(3ml)中。加入TFA(0.27ml,3.65mmol)並將所得混合物攪拌1小時。濃縮混合物,將得到的殘餘物溶於EtOAc(10ml)及飽和NaHCO3水溶液中。分離有機層,水層用EtOAc(2×10ml)萃取。將合併的有機物用Na2SO4乾燥,過濾,濃縮並通過製備型HPLC純化,得到固體產物(14mg,5%)。1H NMR(500MHz,DMSO-d 6)δ=12.10(br.s.,1 H),11.95(br.s.,1 H),8.30(d,1 H),7.89(d,1 H),7.83-7.76(m,1 H),7.75-7.65(m,2 H),7.61(t,1 H),7.24(d,1 H),6.75(br.s.,1 H),6.58(d,1 H).MS ES+ m/z 355[M+H]+。
中間產物實施例5
4-[2-三級丁氧基-6-(3-甲基-4-吡啶基)-4-吡啶基]-1H-吡咯並[2,3-b]吡啶
如中間產物實施例3所述製備標題化合物,使用(3-甲基-4-吡啶基)硼酸及Pd(amphos)Cl2,得到產物(125mg,53%)。MS ES+ m/z 359[M+H]+。
實施例6
6-(3-甲基-4-吡啶基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮
如實施例4所述製備標題化合物,使用4-[2-三級丁氧基-6-(3-甲基-4-吡啶基)-4-吡啶基]-1H-吡咯並[2,3-b]吡啶,得到產物(70mg,66%)。1H NMR(400MHz,DMSO-d 6)δ=11.94(br.s.,1 H),11.78(br.s.,1 H),8.57(s.,1 H),8.52(s.,1 H),8.31(s.,1 H),7.61(s.,1 H),7.47(s.,1 H),7.29(s.,1 H),6.77(s.,1 H),6.70(s.,1 H),6.63(s.,1 H),2.38(s.,3 H).MS ES+ m/z 303[M+H]+。
中間產物實施例7
4-[2-三級丁氧基-6-(2-苯基吡咯啶-1-基)-4-吡啶基]-1H-吡咯並[2,3-b]吡啶
將4-(2-三級丁氧基-6-氯-4-吡啶基)-1H-吡咯並[2,3-b]吡啶(134mg,0.44mmol)及2-苯基吡咯啶(131mg,0.89mmol)溶解於甲苯(5ml)。加入Pd2(dba)3(23mg,0.03mmol)、Xphos(23mg,0.05mmol)及KOtBu(160mg,1.43mmol),將懸浮液在100℃下攪拌2小時。加入鹽水及EtOAc,分離有機層,水相用EtOAc萃取。將合併的有機物用2M HCl水溶液、水、鹽水洗滌,經MgSO4乾燥,過濾並濃縮,得到產物(92mg,50%)。MS ES+ m/z 413[M+H]+。
實施例8
6-(2-苯基吡咯啶-1-基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮
如實施例4所述製備標題化合物,使用4-[2-三級丁氧基-6-(2-苯基吡咯啶-1-基)-4-吡啶基]-1H-吡咯並[2,3-b]吡啶,得到產物(6mg,8%)。1H NMR(400MHz,DMSO-d 6)δ ppm 1.84(br.s.,1 H)1.94(br.s.,2 H)2.35-2.45(m,1 H)3.66(d,1 H)3.86(br.s.,1 H)4.98(br.s.,1 H)5.72-6.01(m,2 H)7.02
(d,1 H)7.17-7.41(m,7 H)8.20(d,1 H)11.73(br.s.,1 H).MS ES+ m/z 357[M+H]+。
中間產物實施例9
2-甲氧基-6-(3-吡啶基)吡啶-4-胺
將2-氯-6-甲氧基-吡啶-4-胺(2g,12.61mmol)、3-吡啶基硼酸(1.55g,0.01mol)、Pd(amphos)Cl2(0.73g,0.63mmol)及K2CO3(3.49g,0.03mol)溶於MeCN(6ml)及水(2ml)中,並將混合物在微波反應器中於130℃加熱30分鐘。過濾混合物,蒸發有機層。將所得殘餘物溶於EtOAc中,用水、鹽水洗滌,經MgSO4乾燥並濃縮,得到固體產物(1.2g,47%)。MS ES+ m/z 202[M+H]+。
中間產物實施例10
4-氯-2-甲氧基-6-(3-吡啶基)吡啶
將2-甲氧基-6-(3-吡啶基)吡啶-4-胺(1g,4.92mmol)及氯化銅(779mg,7.87mmol)懸浮在乙腈(25ml)中並在冰浴中冷卻。加入亞硝酸異戊酯(1.06ml,7.87mmol),將混合物在室溫下攪拌過夜。加入水(60ml),用乙酸乙酯(2×20mL)萃取混合物。將合併的有機物用鹽水(20ml)
洗滌,經MgSO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-30% EtOAc的庚烷溶液洗脫,得到固體產物(403mg,37%)。MS ES+ m/z 222[M+H]+。
中間產物實施例11
1-(苯磺醯基)-4-[2-甲氧基-6-(3-吡啶基)-4-吡啶基]-2-甲基-吡咯並[2,3-b]吡啶
將4-氯-2-甲氧基-6-(3-吡啶基)吡啶(90mg,0.41mmol)、1-(苯磺醯基)-2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡咯並[2,3-b]吡啶(187mg,0.47mmol)、PdCl2(PPh3)2(14mg,0.02mmol)及K2CO3(141mg,1.02mmol)溶於MeCN(3ml)及水(0.5ml)中,並將得到的混合物在微波反應器中於140℃加熱15分鐘。加入更多的1-(苯磺醯基)-2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡咯並[2,3-b]吡啶(120mg,0.3mmol),將混合物再次在140℃加熱15分鐘。過濾混合物,濃縮濾液。將所得殘餘物溶於EtOAc(10ml)及水(10ml)中。分離有機層,水層用EtOAc(10ml)萃取。將合併的有機物用鹽水洗滌,經Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-80% EtOAc的庚烷溶液洗脫,得到產物(182mg,55%)。MS ES+ m/z 457[M+H]+。
實施例12
4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮
將1-(苯磺醯基)-4-[2-甲氧基-6-(3-吡啶基)-4-吡啶基]-2-甲基-吡咯並[2,3-b]吡啶(287mg,0.63mmol)溶於1,4-二噁烷(2ml)中,加入2M HCl水溶液(2ml)。將得到的混合物在微波反應器中在130℃下加熱1.5小時。加入濃縮HCl(0.5ml),將混合物再次在140℃加熱1小時。當冷卻至室溫時,使用2M NaOH水溶液將pH調節至>7,濾出形成的沉澱,用水、EtOAc洗滌並乾燥。將粗產物溶於MeOH(4ml)中並在微波反應器中於150℃加熱3分鐘。當冷卻至室溫時,濾出所得沉澱物,依次用MeOH、2-丙醇、戊烷洗滌並乾燥,得到固體產物(65mg,34%)。1H NMR(500MHz,DMSO-d 6)δ=12.03(br.s.,1 H),11.76(br.s.,1 H),9.11(br.s.,1 H),8.66(d,1 H),8.30(d,1 H),8.20(d,1 H),7.59-7.48(m,1 H),7.29(d,1 H),7.20(br.s.,1 H),6.80(br.s.,1 H),6.40(s,1 H),2.44(s,3 H).MS ES+ m/z 303[M+H]+。
中間產物實施例13
4-(6-氯-4-碘-2-吡啶基)嗎啉
將2,6-二氯-4-碘-吡啶(1.37g,5mmol)、嗎啉(0.56ml,6.5mmol)、L-脯胺酸(115mg,1mmol)、CuI(95mg,0.5mmol)及K2CO3(1.38g,10mmol)溶於DMSO(4ml)中,並將所得混合物在70℃下攪拌過夜。當
冷卻至室溫時,加入水(25ml)及EtOAc(10ml),分離有機層。用EtOAc(2×10ml)萃取水層。將合併的有機物用鹽水洗滌,經Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用20-50%EtOAc/庚烷洗脫,得到固體產物(865mg,53%)。MS ES+ m/z 325[M+H]+。
中間產物實施例14
4-[4-[1-(苯磺醯基)-2-甲基-吡咯並[2,3-b]吡啶-4-基]-6-氯-2-吡啶基]嗎啉
將1-(苯磺醯基)-2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡咯並[2,3-b]吡啶(518mg,1.3mmol)、4-(6-氯-4-碘-2-吡啶基)嗎啉(325mg,1mmol)、Pd(PPh3)4(58mg,0.05mmol)及K2CO3(415mg,3mmol)溶於1,4-二噁烷:H2O:EtOH(6:3:1,10ml)中,並將所得混合物在80℃下攪拌2小時。當冷卻至室溫時,加入EtOAc(5ml)及鹽水(5ml)。分離有機層,水層用EtOAc(5ml)萃取。將合併的有機物用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-50%EtOAc/庚烷洗脫,得到固體產物(470mg,定量)。MS ES+ m/z 470[M+H]+。
中間產物實施例15
4-[6-氯-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-2-吡啶基]嗎啉
將4-[4-[1-(苯磺醯基)-2-甲基-吡咯並[2,3-b]吡啶-4-基]-6-氯-2-吡啶基]嗎啉(335mg,0.71mmol)、(2,4-二甲氧基苯基)甲醇(144mg,0.86mmol)、KOtBu(400mg,3.57mmol)及甲苯(1ml)混合並在90℃下攪拌3小時。當冷卻至室溫EtOAc(10ml)時,加入水(5ml)及鹽水(5ml)。分離有機層,水層用EtOAc(2×5ml)萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾並濃縮,得到固體產物(300mg,64%)。MS ES+ m/z 330[M+H]+。
實施例16
4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-嗎啉代-1H-吡啶-2-酮
將4-[6-氯-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-2-吡啶基]嗎啉(300mg,0.46mmol)、Pd2(dba)3(21mg,0.02mmol)、XPhos(22mg,0.05mmol)、2M KOH水溶液(1ml)及1,4-二噁烷(2ml)混合並在微波反應器中在150℃下加熱30分鐘。當冷卻至室溫時,將混合物用EtOAc及水稀釋。分離有機層,水層用EtOAc萃取。將合併的有機物用鹽水洗滌,用Na2SO4乾燥,過濾並通過製備型HPLC純化,得到固體產物(4mg,3%)。1H NMR(500MHz,DMSO-d 6)δ=11.66(br.s.,1 H),10.43(br.s.,1 H),8.14(d,1 H),
7.13(d,1 H),6.38(br.s.,1 H),6.31(s,1 H),6.22(br.s.,1 H),3.75-3.66(m,4 H),3.43(br.s.,4 H),2.42(s,3 H).MS ES+ m/z 311[M+H]+。
中間產物實施例17
6-(2-氯苯基)-4-羥基-1H-吡啶-2-酮
在-78℃、氮氣氛下,將3-氧代丁酸乙酯(6.33ml,50mmol)逐滴加到60%NaH(1.92g,50mmol)的2-MeTHF(60ml)懸浮液中。5分鐘後,移去冷卻浴,將混合物在室溫下攪拌20分鐘。將混合物冷卻回-78℃並在20分鐘內緩慢加入1.6Mn-BuLi(31.25ml)。將所得溶液在-78℃下攪拌30分鐘。然後一次性加入固體的2-氯苄腈(6.88g,50mmol),將反應混合物在解凍冷卻浴上攪拌過夜。將混合物冷卻至0℃並緩慢加入MeOH(15ml)。移去冷卻浴,將混合物在室溫下攪拌30分鐘,然後再次冷卻至0℃。通過緩慢加入濃縮HCl中和混合物,濾出所得沉澱,用EtOH、戊烷洗滌並乾燥,得到固體產物(11.08g,87%)。MS ES+ m/z 222[M+H]+。
中間產物實施例18
2,4-二氯-6-(2-氯苯基)吡啶
將6-(2-氯苯基)-4-羥基-1H-吡啶-2-酮(5g,22.56mmol)溶於POCl3(40ml)中,並緩慢加入N,N-二甲基苯胺(5.5ml,43.4mmol)。將所得混合物回流過夜。當冷卻至室溫時,將混合物倒入冰(600ml)中並在室溫下攪拌30分鐘。濾出沉澱物並用水洗滌。將固體溶於EtOAc(100ml)中,用Na2SO4乾燥,過濾並濃縮,得到固體產物(7g,83%)。MS ES+ m/z 258[M+H]+。
中間產物實施例19
4-氯-6-(2-氯苯基)-1H-吡啶-2-酮
將2,4-二氯-6-(2-氯苯基)吡啶(5.7g,22.05mmol)及KOtBu(6.19g,55.12mmol)溶於甲苯(75ml)中,並將所得混合物在100℃下攪拌2小時。當冷卻至室溫時,加入水(40ml)並分離有機層。使用濃縮HCl使水層呈微酸性,並用EtOAc(2×40ml)萃取。將合併的有機物用鹽水(50ml)洗滌,用Na2SO4乾燥,過濾並濃縮。將所得殘餘物溶於DCM(30ml)中並加入TFA(5ml,67.3mmol)。將反應混合物在室溫下攪拌1小時,濃縮,將得到的殘餘物溶於MeOH(25ml)中。加入30% NH4OH(20ml)及水(20ml)並將混合物在室溫下攪拌過夜。濾出形成的沉澱,用水、EtOH、戊烷洗滌並乾燥,得到固體產物(4.13g,78%)。MS ES+ m/z 240[M+H]+。
中間產物實施例20
1-(苯磺醯基)-4-氯-吡咯並[2,3-b]吡啶-2-甲醛
在0℃下,將2.5M丁基鋰(2.8ml,7mmol)緩慢加入到N-異丙基丙-2-胺(1ml,7.14mmol)的2-MeTHF(15ml)溶液中。將所得混合物在0℃下攪拌5分鐘,然後冷卻至-78℃。逐滴加入1-(苯磺醯基)-4-氯-吡咯並[2,3-b]吡啶(1.5g,5.12mmol)的2-MeTHF(10ml)溶液。將所得混合物在-78℃下攪拌20分鐘,然後移去冷卻浴。將混合物在室溫下攪拌10分鐘,得到懸浮液,然後再次冷卻至-78℃。逐滴加入DMF(1.2ml,15.6mmol),將所得混合物在解凍冷卻浴上攪拌30分鐘,然後在室溫下攪拌30分鐘。加入飽和NH4Cl水溶液(12ml),分離有機層。水層用EtOAc(2×10ml)萃取,合併的有機物用0.5M HCl水溶液(20ml)、鹽水(15ml)洗滌,用Na2SO4乾燥,過濾並濃縮,得到膠狀產物(1.7g,定量)。MS ES+ m/z 321[M+H]+。
中間產物實施例21
5-(4-氯-1H-吡咯並[2,3-b]吡啶-2-基)噁唑
將1-(苯磺醯基)-4-氯-吡咯並[2,3-b]吡啶-2-甲醛(1g,3.12mmol)、TosMIC(609mg,3.12mmol)及K2CO3(431mg,3.12mmol)溶於MeOH(40ml)中,並將所得混合物在70℃下攪拌2小時。當冷卻至室溫時,將混
合物過濾並用MeOH洗滌沉澱物。濃縮濾液,將得到的殘餘物用EtOH重結晶,得到固體產物(120mg,18%)。MS ES+ m/z 220[M+H]+。
中間產物實施例22
5-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡咯並[2,3-b]吡啶-2-基]噁唑
將5-(4-氯-1H-吡咯並[2,3-b]吡啶-2-基)噁唑(120mg,0.55mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(208mg,0.82mmol)及KOAc(161mg,1.64mmol)溶於1,4-二噁烷(10ml)中,並將氮氣通入該混合物5分鐘。然後加入S-Phos(22mg,0.06mmol)及Pd(OAc)2(6mg,0.03mmol),將所得混合物在100℃下攪拌過夜。加入更多4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(208mg,0.82mmol)、KOAc(161mg,1.64mmol)、S-Phos(22mg,0.06mmol)及Pd(OAc)2(6mg,0.03mmol),並將所得混合物在100℃下攪拌過夜。加入Pd-118(25mg)並在100℃下繼續攪拌過夜。冷卻至室溫後,過濾混合物,向濾液中加入水(10ml)、鹽水(10ml)及EtOAc(10ml)。分離有機層,水層用EtOAc(2×10ml)萃取。將合併的有機物用Na2SO4乾燥,濃縮並在矽膠柱上純化,用0-10%MeOH的DCM溶液洗脫,得到固體產物(160mg,66%)。MS ES+ m/z 312[M+H]+。
實施例23
6-(2-氯苯基)-4-(2-噁唑-5-基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮
將5-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡咯並[2,3-b]吡啶-2-基]噁唑(160mg,0.36mmol)、4-氯-6-(2-氯苯基)-1H-吡啶-2-酮(75mg,0.31mmol)、PdCl2(PPh3)2(11mg,0.02mmol)及K2CO3(130mg,0.94mmol)溶於1,4-二噁烷:H2O:EtOH(6:3:1,3ml)中,並將所得混合物在微波反應器中於140℃加熱15分鐘。當冷卻至室溫時,加入水(2ml)並將混合物在室溫下攪拌15分鐘。濾出所得沉澱物,依次用水、1,4-二噁烷洗滌並乾燥。將粗產物懸浮在沸騰的2-丙醇(5ml)中。當冷卻至室溫時,濾出沉澱物並捨棄。濃縮濾液,將得到的殘餘物懸浮在少量EtOH中,過濾並濃縮,得到固體產物(11mg,9%)。MS ES+ m/z 389[M+H]+。
中間產物實施例24
1-(苯磺醯基)-4-氯-2-(3-吡啶基)吡咯並[2,3-b]吡啶
將1-(苯磺醯基)-4-氯-2-碘-吡咯並[2,3-b]吡啶(2.97g,7.09mmol)、3-吡啶基硼酸(0.87g,7.09mmol)、Pd(PPh3)4(0.41g,0.35mmol)及K2CO3(1.96g,14.2mmol)溶於MeCN(6ml)及水(2ml)中,並將混合物在微波反應器中於130℃加熱30分鐘。過濾混合物,蒸發有機層。將所得殘餘物溶於EtOAc中,用水、鹽水洗滌,經MgSO4乾燥,濃縮並在矽膠柱上純化,用50%EtOAc的庚烷溶液洗脫,得到固體產物(500mg,19%)。MS ES+ m/z 370[M+H]+。
中間產物實施例25
1-(苯磺醯基)-2-(3-吡啶基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡咯並[2,3-b]吡啶
如中間產物實施例22中所述製備標題化合物,使用1-(苯磺醯基)-4-氯-2-(3-吡啶基)吡咯並[2,3-b]吡啶代替5-(4-氯-1H-吡咯並[2,3-b]吡啶-2-基)噁唑,得到產物(100mg,16%)。MS ES+ m/z 462[M+H]+。
中間產物實施例26
4-[1-(苯磺醯基)-2-(3-吡啶基)吡咯並[2,3-b]吡啶-4-基]-6-(2-氯苯基)-1H-吡啶-2-酮
如實施例23所述製備標題化合物,使用1-(苯磺醯基)-2-(3-吡啶基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡咯並[2,3-b]吡啶代替5-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡咯並[2,3-b]吡啶-2-基]噁唑。在矽膠柱上純化,用0-10%MeOH的DCM溶液洗脫,得到固體產物(140mg,78%)。MS ES+ m/z 462[M+H]+。
實施例27
6-(2-氯苯基)-4-[2-(3-吡啶基)-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮
將4-[1-(苯磺醯基)-2-(3-吡啶基)吡咯並[2,3-b]吡啶-4-基]-6-(2-氯苯基)-1H-吡啶-2-酮(140mg,0.26mmol)溶於1,4-二噁烷(2ml)及2M HCl水溶液(1ml)中,並將所得混合物在微波反應器中於130℃加熱30分鐘。加入2M NaOH水溶液(1ml)及水(3ml),濾出所得沉澱物並用水洗滌。將粗產物溶於沸騰的2-丙醇(5ml)中,當冷卻至室溫時,濾出沉澱物並乾燥,得到固體產物(15mg,15%)。1H NMR(400MHz,DMSO-d 6)δ=12.59
(br.s.,1 H),9.27-9.19(m,1 H),8.56(d,1 H),8.41-8.30(m,2 H),7.72-7.58(m,2 H),7.57-7.43(m,4 H),7.35-7.24(m,2 H),6.81(d,1 H).MS ES+ m/z 399[M+H]+。
中間產物實施例28
4-[1-(苯磺醯基)-2-甲基-吡咯並[2,3-b]吡啶-4-基]-6-(2-氯苯基)-1H-吡啶-2-酮
如實施例23所述製備標題化合物,使用1-(苯磺醯基)-2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡咯並[2,3-b]吡啶代替5-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡咯並[2,3-b]吡啶-2-基]噁唑。在矽膠柱上純化,用50-100%EtOAc的庚烷溶液洗脫,得到固體產物(140mg,88%)。MS ES+ m/z 476[M+H]+。
實施例29
6-(2-氯苯基)-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮
如實施例27所述製備標題化合物,使用4-[1-(苯磺醯基)-2-甲基-吡咯並[2,3-b]吡啶-4-基]-6-(2-氯苯基)-1H-吡啶-2-酮代替4-[1-(苯磺醯基)-2-(3-吡啶基)吡咯並[2,3-b]吡啶-4-基]-6-(2-氯苯基)-1H-吡啶-2-酮,得到固體產物
(25mg,25%)。1H NMR(400MHz,DMSO-d 6)δ=12.03(br.s.,1 H),11.75(br.s.,1 H),8.18(d,1 H),7.65-7.58(m,2 H),7.54-7.42(m,3 H),7.20(d,1 H),6.71(br.s.,1 H),6.35(s,1 H),2.43(s,3 H).MS ES+ m/z 336[M+H]+。
中間產物實施例30
4-苄氧基-2,6-二氯-吡啶
在0℃下,將60%NaH(945mg,24.7mmol)分批加入到2,4,6-三氯吡啶(4.5g,24.7mmol)的DMF(25ml)溶液中。20分鐘後,逐滴加入苯基甲醇(2.7g,24.7mmol)並將混合物攪拌3小時。加入水(30ml),濾出沉澱物。將固體溶解在EtOAc中,經MgSO4乾燥,過濾並濃縮,得到固體產物(5g,80%)。MS ES+ m/z 254[M+H]+。
中間產物實施例31
4-苄氧基-2-三級丁氧基-6-氯-吡啶
將4-苄氧基-2,6-二氯-吡啶(5g,19.7mmol)及KOtBu(2.2g,19.7mmol)溶於2-MeTHF(25ml)中,並將混合物在70℃下攪拌2小時。當冷卻至室溫時,將混合物過濾,濃縮並在矽膠柱上純化,用30%EtOAc的庚烷溶液洗脫,得到產物(4g,70%)。MS ES+ m/z 292[M+H]+。
中間產物實施例32
4-苄氧基-2-三級丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶
將4-苄氧基-2-三級丁氧基-6-氯-吡啶(4g,13.7mmol)、2-(三氟甲基)哌啶(2.3g,15.1mmol)、PEPPSI-iPr(146mg,1.37mmol)及KOtBu(3.85g,34.3mmol)溶於1,4-二噁烷(30ml)中,並將混合物在90℃下攪拌2小時。當冷卻至室溫時,加入水及EtOAc,分離有機層,過濾,濃縮並在矽膠柱上純化,用30%EtOAc的庚烷溶液洗脫,得到產物(4.1g,73%)。MS ES+ m/z 409[M+H]+。
中間產物實施例33
2-三級丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶-4-醇
將4-苄氧基-2-三級丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶(3.5g,8.57mmol)及10%Pd/C(600mg,0.56mmol)在MeOH及EtOAc中的混合物在室溫下氫化(1.5巴)2小時。將混合物通過矽藻土過濾並濃縮,得到產物(2.7g,定量)。MS ES+ m/z 319[M+H]+。
中間產物實施例34
[2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]-4-吡啶基]三氟甲磺酸酯
在0℃下,將2-三級丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶-4-醇(2.7g,8.48mmol)及Et3N(1.66ml,11.9mmol)溶於DCM(20mL)中。在5分鐘內逐滴加入三氟甲磺醯三氟甲磺酸酯(2.54ml,11.9mmol)並攪拌1小時。將混合物用飽和NaHCO3水溶液(2×20mL)洗滌,濃縮並在矽膠柱上純化,用20%EtOAc的庚烷溶液洗脫,得到產物(3.5g,92%)。MS ES+ m/z 451[M+H]+。
中間產物實施例35
2-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-6-[2-(三氟甲基)-1-哌啶基]吡啶
將4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(2.96g,11.7mmol)、[2-三級丁氧基-6-[2-(三氟甲基)-1-哌啶基]-4-吡啶基]三氟甲磺酸酯(3.5g,7.77mmol)、KOAc(1.14g,11.7mmol)及PdCl2(dppf)(215mg,0.29mmol)溶於甲苯(10ml)
中並在90℃下攪拌5小時。當冷卻至室溫時,將混合物濃縮,將殘餘物溶解在EtOAc中,用水洗滌,濃縮並在矽膠柱上純化,用0-60%EtOAc的庚烷溶液洗脫,得到產物(2.15g,65%)。MS ES+ m/z 347[M+H]+。
實施例36
4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮
將2-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-6-[2-(三氟甲基)-1-哌啶基]吡啶(110毫克,0.26mmol)、4-氯-2-甲基-1H-吡咯並[2,3-b]吡啶(95mg,0.57mmol)、K2CO3(89mg,0.64mmol)及PdCl2(dppf)(14mg,0.02)溶於1,4-二噁烷及水中,並將混合物在90℃下攪拌2小時。當冷卻至室溫時,加入EtOAc並過濾混合物。分離有機層,用MgSO4乾燥並濃縮。將得到的殘餘物溶於DCM中,加入TFA(0.11ml,1.54mmol),將混合物在室溫下攪拌30分鐘,濃縮並通過製備型HPLC純化,得到固體產物(3.4mg,3%)。1H NMR(500MHz,METHANOL-d 4)δ ppm 1.62-1.70(m,1 H),1.76-1.94(m,4 H),2.07-2.16(m,1 H),2.51(d,3 H),3.19-3.28(m,1 H),3.85-4.06(m,1 H),5.37(br d,1 H),6.32(d,1 H),6.36(d,1 H),6.39-6.47(m,1 H),7.17(d,1 H),8.06-8.27(m,1 H).MS ES+ m/z 377[M+H]+。
實施例37
4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮
將4-氯-1H-吡咯並[2,3-b]吡啶(43mg,0.28mmol)、2-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-6-[2-(三氟甲基)-1-哌啶基]吡啶(100mg,0.23mmol)、K2CO3(81mg,0.58mmol)及PdCl2(dppf)(13mg,0.02mmol)溶於1,4-二噁烷及水中,並將混合物在微波反應器中在120℃下加熱1小時。當冷卻至室溫時,加入EtOAc並過濾混合物。分離有機層,經MgSO4乾燥,濃縮,並通過製備型HPLC純化,得到固體產物(3.4mg,4%)。1H NMR(500MHz,METHANOL-d 4)δ ppm 1.57-1.69(m,1 H),1.77-1.95(m,4 H),2.07-2.18(m,1 H),3.20-3.31(m,1 H),3.98(br d,1 H),5.27-5.57(m,1 H),6.34(d,1 H),6.46(s,1 H),6.67(d,1 H),7.28(s,1 H),7.49(d,1 H),8.15-8.39(m,1 H).MS ES+ m/z 363[M+H]+。
中間產物實施例38
4-(4-苄氧基-6-三級丁氧基-2-吡啶基)-3-(三氟甲基)嗎啉
如中間產物實施例32中所述製備標題化合物,使用3-(三氟甲基)嗎啉代替2-(三氟甲基)哌啶,得到油狀產物(1g,50%)。MS ES+ m/z 411[M+H]+。
中間產物實施例39
2-三級丁氧基-6-[3-(三氟甲基)嗎啉-4-基]吡啶-4-醇
如中間產物實施例33中所述製備標題化合物,得到產物(780mg,99%)。MS ES+ m/z 321[M+H]+。
中間產物實施例40
[2-三級丁氧基-6-[3-(三氟甲基)嗎啉-4-基]-4-吡啶基]三氟甲磺酸酯
如中間產物實施例34中所述製備標題化合物,得到油狀產物(800mg,81%)。MS ES+ m/z 453[M+H]+。
中間產物實施例41
4-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-3-(三氟甲基)嗎啉
如中間產物實施例35中所述製備標題化合物,得到產物(270mg,33%)。MS ES+ m/z 431[M+H]+。
實施例42
4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮
如實施例36所述製備標題化合物,使用4-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-3-(三氟甲基)嗎啉及4-氯-1H-吡咯並[2,3-b]吡啶,得到產物(20mg,22%)。1H NMR(500MHz,METHANOL-d 4)δ ppm 3.44-3.51(m,1 H),3.63(td,2.99Hz,1 H),3.72-3.83(m,2 H),3.99(dd,1 H),4.26(d,1 H),5.18(qd,1 H),6.35-6.39(m,1 H),6.37(s,1 H),6.41(s,1 H),6.65(d,1 H),7.20(d,1 H),7.43(d,1 H),8.23(d,1 H).MS ES+ m/z 365[M+H]+。
中間產物實施例43
1-(苯磺醯基)-4-氯-2-[3-(三氟甲基)苯基]吡咯並[2,3-b]吡啶
如中間產物實施例24所述,從[3-(三氟甲基)苯基]硼酸開始,製備標題化合物,得到產物(1.5g,29%)。MS ES+ m/z 437[M+H]+。
中間產物實施例44
4-氯-2-[3-(三氟甲基)苯基]-1H-吡咯並[2,3-b]吡啶
將5M NaOH的MeOH溶液(1.37ml,6.88mmol)加入到1-(苯磺醯基)-4-氯-2-[3-(三氟甲基)苯基]吡咯並[2,3-b]吡啶(1.5g,3.44mmol)的MeOH(10ml)溶液中,並將得到的混合物在室溫下攪拌1小時。加入水,混合物用EtOAc萃取。將合併的有機物用Na2SO4乾燥,過濾並在矽膠柱上純化,得到固體產物(510mg,50%)。MS ES+ m/z 297[M+H]+。
實施例45
6-[3-(三氟甲基)嗎啉-4-基]-4-[2-[3-(三氟甲基)苯基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮
如實施例36所述製備標題化合物,使用4-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-3-(三氟甲基)嗎啉及4-氯-2-[3-(三氟甲基)苯基]-1H-吡咯並[2,3-b]吡啶,得到產物(7mg,7%)。1H NMR(500MHz,METHANOL-d 4)δ ppm 3.46-3.53(m,1 H),3.67(td,3.00Hz,1 H),3.81-3.93(m,2 H),4.03(dd,1 H),4.30(d,1 H),5.21-5.28(m,1 H),6.46(d,1 H),6.54(s,1 H),7.14(s,1 H),7.28(d,1 H),7.66-7.70(m,2 H),8.14-8.18(m,1 H),8.21(s,1 H),8.31(d,1 H).MS ES+ m/z 509[M+H]+。
中間產物實施例46
1-(苯磺醯基)-4-氯-2-(5-甲基-2-噻吩基)吡咯並[2,3-b]吡啶
將三丁基-(5-甲基-2-噻吩基)錫烷(6g,15.46mmol)、1-(苯磺醯基)-4-氯-2-碘-吡咯並[2,3-b]吡啶(5.1g,將12.88mmol)、Pd(PPh3)4(1.7g,0.64mmol)及2M Na2CO3水溶液(12mL)的1,4-二噁烷(25mL)溶液的混合物用氬氣沖洗(purge)並在100℃下攪拌過夜。當冷卻至室溫時,將混
合物用EtOAc稀釋,用水、鹽水洗滌,經MgSO4乾燥,濃縮並在矽膠柱上純化,得到固體產物(2g,33%)。MS ES+ m/z 389[M+H]+。
中間產物實施例47
4-氯-2-(5-甲基-2-噻吩基)-1H-吡咯並[2,3-b]吡啶
如中間產物實施例44所述,從1-(苯磺醯基)-4-氯-2-(5-甲基-2-噻吩基)吡咯並[2,3-b]吡啶開始製備標題化合物,得到產物(835mg,59%)。MS ES+ m/z 249[M+H]+。
實施例48
4-[2-(5-甲基-2-噻吩基)-1H-吡咯並[2,3-b]吡啶-4-基]-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮
如實施例36所述製備標題化合物,使用4-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-3-(三氟甲基)嗎啉及4-氯-2-(5-甲基-2-噻吩基)-1H-吡咯並[2,3-b]吡啶,得到產物(5mg,5%)。1H NMR(500MHz,METHANOL-d 4)δ ppm 2.51(s,3 H),3.43-3.55(m,1 H),3.64(br d,1 H),3.73(br s,1 H),3.81(br d,1 H),4.02(br d,1 H),4.28(br d,1 H),5.11(br
s,1 H),6.40(br d,2 H),6.65-6.71(m,1 H),6.76(br s,1 H),7.12-7.16(m,1 H),7.25-7.31(m,1 H),8.17(br d,1 H).MS ES+ m/z 461[M+H]+。
實施例49
4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮
如實施例36所述,使用4-氯-1H-吡唑並[3,4-b]吡啶製備標題化合物,得到產物(6mg,7%)。1H NMR(500MHz,METHANOL-d 4)δ ppm 1.65(br d,1 H),1.78(br s,1 H),1.80-1.91(m,3 H),2.12(br d,1 H),3.24(br t,1 H),4.07(br d,1 H),5.47(br s,1 H),6.38(s,1 H),6.53(s,1 H),7.33-7.48(m,1 H),8.26(s,1 H),8.61(d,1 H).MS ES+ m/z 461[M+H]+。
中間產物實施例50
2-[[4-氯-2-[2-(三氟甲基)嘧啶-5-基]吡咯並[2,3-b]吡啶-1-基]甲氧基]乙基三甲基矽烷
將[4-氯-1-(2-三甲基矽基乙氧基甲基)吡咯並[2,3-b]吡啶-2-基]硼酸(2g,12.26mmol)、5-溴-2-(三氟甲基)嘧啶(2.6g,12.26mmol)、Pd(PPh3)4
(1.4g,1.22mmol)及2M Na2CO3水溶液(2mL)的1,4-二噁烷(30mL)溶液的混合物用氬氣沖洗,並在100℃下攪拌過夜。當冷卻至室溫時,將混合物濃縮並在矽膠柱上純化,得到產物(1.5g,28%)。MS ES+ m/z 429[M+H]+。
中間產物實施例51
4-氯-2-[2-(三氟甲基)嘧啶-5-基]-1H-吡咯並[2,3-b]吡啶
將1M TBAF的THF溶液(20.8ml,20.8mmol)加入到2-[[4-氯-2-[2-(三氟甲基)嘧啶-5-基]吡咯並[2,3-b]吡啶-1-基]甲氧基]乙基三甲基矽烷(2g,4.16mmol)的THF(10ml)溶液中,並將所得混合物回流過夜。當冷卻至室溫時,將混合物濃縮,在矽膠柱上純化,然後通過製備型HPLC純化,得到固體產物(530mg,43%)。MS ES+ m/z 299[M+H]+。
實施例52
6-[2-(三氟甲基)-1-哌啶基]-4-[2-[2-(三氟甲基)嘧啶-5-基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮
如實施例36所述,使用4-氯-2-[2-(三氟甲基)嘧啶-5-基]-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到產物(8mg,6%)。1H NMR(500MHz,
DMSO-d 6)δ ppm 1.46-1.60(m,1 H),1.70(br s,2 H),1.76(br d,2 H),2.02(br d,1 H),3.07(br s,1 H),4.15-4.30(m,1 H),5.50-5.68(m,1 H),6.34(s,1 H),6.62(br s,1 H),7.32(d,1 H),7.55(s,1 H),8.42(d,1 H),9.65(s,2 H),10.45(br s,1 H),12.78(br s,1 H).MS ES+ m/z 509[M+H]+。
中間產物實施例53
2-[[4-氯-2-[6-(三氟甲基)-3-吡啶基]吡咯並[2,3-b]吡啶-1-基]甲氧基]乙基三甲基矽烷
如中間產物實施例50所述,使用5-溴-2-(三氟甲基)吡啶製備標題化合物,得到產物(1.5g,79%)。MS ES+ m/z 428[M+H]+。
中間產物實施例54
4-氯-2-[6-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶
如中間產物實施例51中所述製備標題化合物,得到產物(520mg,50%)。MS ES+ m/z 298[M+H]+。
實施例55
6-[2-(三氟甲基)-1-哌啶基]-4-[2-[6-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮
如實施例36所述,使用4-氯-2-[6-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到產物(6mg,5%)。1H NMR(500MHz,DMSO-d 6)δ ppm 1.53(br d,1 H),1.69(br s,2 H),1.72-1.86(m,2 H),2.02(br d,1 H),3.07(br t,1 H),4.23(br d,1 H),5.58(br s,1 H),6.35(s,1 H),6.61(br s,1 H),7.30(d,1 H),7.40(s,1 H),8.02(d,1 H),8.39(d,1 H),8.64(dd,1 H),9.40(d,1 H),10.44(br s,1 H),12.68(br s,1 H).MS ES+ m/z 508[M+H]+。
中間產物實施例56
2-[[4-氯-2-[5-(三氟甲基)-3-吡啶基]吡咯並[2,3-b]吡啶-1-基]甲氧基]乙基三甲基矽烷
如中間產物實施例50所述,使用3-溴-5-(三氟甲基)吡啶製備標題化合物,得到產物(800mg,30%)。MS ES+ m/z 428[M+H]+。
中間產物實施例57
4-氯-2-[5-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶
如中間產物實施例51中所述製備標題化合物,得到產物(300mg,43%)。MS ES+ m/z 298[M+H]+。
實施例58
6-[2-(三氟甲基)-1-哌啶基]-4-[2-[5-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮
如實施例36所述,使用4-氯-2-[5-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到產物(7mg,6%)。1H NMR(500MHz,DMSO-d 6)δ ppm 1.47-1.63(m,1 H),1.69(br s,2 H),1.72-1.86(m,2 H),2.02(br d,1 H),3.06(br t,1 H),4.24(br d,1 H),5.58(br s,1 H),6.36(s,1 H),6.61(br s,1 H),7.29(d,1 H),7.46(s,1 H),8.38(d,1 H),8.82(s,1 H),8.93(d,1 H),9.52(d,1 H),10.43(br s,1 H),12.63(br s,1 H).MS ES+ m/z 508[M+H]+。
中間產物實施例59
1-[(4-氟苯基)甲磺醯基]-3-(三氟甲基)哌嗪
將2-(三氟甲基)-哌嗪(2g,13mmol)及TEA(2.17ml,15.6mmol)溶解在DCM(30ml)中。在0℃下分小份加入(4-氟苯基)甲磺醯氯(2.71g,13mmol)並將混合物在室溫下攪拌過夜。加入水(45ml),用DCM(2×80ml)萃取混合物。將合併的有機物用鹽水洗滌兩次,用Na2SO4乾燥,過濾並濃縮,得到固體產物(3.5g,83%)。MS ES+ m/z 327[M+H]+。
中間產物實施例60
1-(4-苄氧基-6-三級丁氧基-2-吡啶基)-4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪
將1-[(4-氟苯基)甲磺醯基]-3-(三氟甲基)哌嗪(1.2g,3.68mmol)、4-苄氧基-2-三級丁氧基-6-氯-吡啶(1.34g,4.6mmol)、Cs2CO3(2.4g,7.35mmol)、XantPhos(206mg,0.37mmol)及Pd(OAc)2(83mg,0.37mmol)在無水脫氣的1,4-二噁烷(50ml)中的混合物在氬氣下回流過夜。加入水,混合物用EtOAc萃取。將合併的有機物用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-100%EtOAc的庚烷溶液洗脫,得到產物(1.25g,58%)。MS ES+ m/z 582[M+H]+。
中間產物實施例61
2-三級丁氧基-6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]吡啶-4-醇
如中間產物實施例33中所述製備標題化合物,得到產物(1.22g,96%)。MS ES+ m/z 492[M+H]+。
中間產物實施例62
[2-三級丁氧基-6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]三氟甲磺酸酯
如中間產物實施例34中所述製備標題化合物,得到產物(700mg,45%)。MS ES+ m/z 624[M+H]+。
中間產物實施例63
1-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪
如中間產物實施例35中所述製備標題化合物,得到產物(490mg,73%)。MS ES+ m/z 602[M+H]+。
中間產物實施例64
4-[2-叔丁氧基-6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]-1H-吡咯並[2,3-B]吡啶
如中間產物實施例3中所述,從1-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪開始製備標題化合物,得到產物(70mg,49%)。MS ES+ m/z 592[M+H]+。
實施例65
6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮
如實施例4所述,使用4-[2-三級丁氧基-6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到產物(15mg,24%)。1H NMR(500MHz,DMSO-d 6)δ ppm 2.85-3.00(m,1 H),3.10-3.28(m,2 H),3.58-3.66(m,1 H),3.86-3.92(m,1 H),4.28-4.35(m,1 H),4.47-4.56(m,1 H),4.50-4.52(m,1 H),5.56(br s,1 H),6.33-6.40(m,1 H),6.54-6.60(m,1 H),6.61-6.66(m,1 H),7.16-7.26(m,3 H),7.45-7.51(m,2 H),7.55-7.61(m,1 H),8.27-8.32(m,1 H),10.61(br s,1 H),11.85(br s,1 H).MS ES+ m/z 536[M+H]+。
中間產物實施例66
1-乙磺醯基-3-(三氟甲基)哌嗪
如中間產物實施例59中所述,使用乙磺醯氯製備標題化合物,得到固體產物(3g,98%)。MS ES+ m/z 247[M+H]+。
中間產物實施例67
1-(4-苄氧基-6-三級丁氧基-2-吡啶基)-4-乙磺醯基-2-(三氟甲基)哌嗪
如實施例60中所述,使用1-乙磺醯基-3-(三氟甲基)哌嗪製備標題化合物,得到固體產物(2.53g,67%)。MS ES+ m/z 502[M+H]+。
中間產物實施例68
2-三級丁氧基-6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]吡啶-4-醇
如中間產物實施例33中所述製備標題化合物,得到產物(1.94g,85%)。MS ES+ m/z 412[M+H]+。
中間產物實施例69
[2-三級丁氧基-6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]三氟甲磺酸酯
如中間產物實施例34中所述製備標題化合物,得到產物(1.56g,62%)。MS ES+ m/z 544[M+H]+。
中間產物實施例70
1-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-4-乙磺醯基-2-(三氟甲基)哌嗪
如中間產物實施例35中所述製備標題化合物,得到產物(1.2g,86%)。MS ES+ m/z 440[M+H]+(硼酸)。
實施例71
6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮
如實施例36所述,使用1-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-4-乙磺醯基-2-(三氟甲基)哌嗪及4-氯-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到產物(6mg,7%)。1H NMR(500
MHz,DMSO-d 6 )δ ppm 1.23(t,3 H),2.97-3.05(m,1 H),3.13(q,2 H),3.22-3.30(m,2 H),3.66(br d,1 H),3.95(br d,1 H),4.34(br d,1 H),5.62(br s,1 H),6.37(s,1 H),6.59(dd,1 H),6.65(br s,1 H),7.24(d,1 H),7.58(s,1 H),8.30(d,1 H),10.58(br s,1 H),11.85(br s,1 H).MS ES+ m/z 456[M+H]+。
實施例72
4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮
如實施例36所述,使用1-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-4-乙磺醯基-2-(三氟甲基)哌嗪及4-氯-2-環丙基-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到產物(6mg,6%)。1H NMR(500MHz,METHANOL-d 4 )δ ppm 0.84-0.94(m,2 H),1.04-1.09(m,2 H),1.36(t,3 H),2.07-2.13(m,1 H),3.03-3.16(m,3 H),3.29(br s,1 H),3.45(br t,1 H),3.80(br d,1 H),4.10-4.21(m,2 H),5.57(br s,1 H),6.28(s,1 H),6.40(s,1 H),6.55(s,1 H),7.17(d,1 H),8.14(d,1 H).MS ES+ m/z 496[M+H]+。
實施例73
6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮
如實施例36所述,使用1-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-4-乙磺醯基-2-(三氟甲基)哌嗪及4-氯-2-甲基-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到固體產物(10mg,11%)。1H NMR(500MHz,DMSO-d 6)δ ppm 1.20-1.29(m,3 H),2.43(s,3 H),2.97-3.03(m,1 H),3.09-3.18(m,2 H),3.21-3.30(m,2 H),3.58-3.79(m,1 H),3.95(br d,1 H),4.32(br d,1 H),5.55-5.76(m,1 H),6.23-6.42(m,2 H),6.63(br s,1 H),7.17(d,1 H),8.17(d,1 H),10.54(br s,1 H),11.67(s,1 H).MS ES+ m/z 470[M+H]+。
實施例74
4-[2-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-6-氧代-1H-吡啶-4-基]-1H-吡咯並[2,3-b]吡啶-2-甲腈
如實施例36所述,使用1-[6-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2-吡啶基]-4-乙磺醯基-2-(三氟甲基)哌嗪及4-氯-1H-吡咯並[2,3-b]吡啶-2-甲腈製備標題化合物,得到固體產物(6mg,6%)。
1H NMR(500MHz,METHANOL-d 4)δ ppm 1.36(t,3 H),3.11(d,3 H),3.27-3.32(m,1 H),3.42-3.50(m,1 H),3.72-3.89(m,1 H),4.10-4.17(m,1 H),4.17-4.25(m,1 H),5.64(br d,1 H),6.39(d,1 H),6.57(s,1 H),7.36-7.42(m,2 H),8.51-8.56(m,1 H).MS ES+ m/z 481[M+H]+.
中間產物實施例75
4-苄氧基-2-三級丁氧基-6-[2-(三氟甲基)苯基]吡啶
將4-苄氧基-2-三級丁氧基-6-氯-吡啶(1.46g,5mmol)、[2-(三氟甲基)苯基]硼酸(950mg,5mmol)、K2CO3(1.73g,12.5mmol)及PdCl2(dppf)(366mg,0.5mmol)溶於1,4-二噁烷(25ml)及水(5ml)中,並將所得混合物在90℃下攪拌2小時。當冷卻至室溫時,將混合物用水及EtOAc稀釋。分離有機層,水層用EtOAc萃取。將合併的有機物通過矽藻土過濾,用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-80%EtOAc的庚烷溶液洗脫,得到固體產物(1.58g,79%)。MS ES+ m/z 402[M+H]+。
中間產物實施例76
2-三級丁氧基-6-[2-(三氟甲基)苯基]吡啶-4-醇
如中間產物實施例33中所述製備標題化合物,得到產物(948mg,72%)。MS ES+ m/z 312[M+H]+。
中間產物實施例77
[2-三級丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]三氟甲磺酸酯
如中間產物實施例34中所述製備標題化合物,得到產物(720mg,54%)。MS ES+ m/z 388[M-tBu]+。
中間產物實施例78
2-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-6-[2-(三氟甲基)苯基]吡啶
如中間產物實施例35中所述製備標題化合物,得到產物(450mg,76%)。MS ES+ m/z 340[M+H]+(硼酸)。
實施例79
4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮
如實施例36所述,使用2-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-6-[2-(三氟甲基)苯基]吡啶及4-氯-2-環丙基-1H-吡咯並[2,3-b]吡啶製備標題化合物,得到固體產物(10mg,10%)。1H NMR(500MHz,DMSO-d 6)δ ppm 0.84-0.91(m,2 H),0.98-1.05(m,2 H),2.04-2.12(m,1 H),6.23-6.29(m,1 H),6.44-6.65(m,1 H),6.69-6.78(m,1 H),7.12-7.17(m,1 H),7.66-7.70(m,1 H),7.71-7.76(m,1 H),7.78-7.83(m,1 H),7.88-7.92(m,1 H),8.13-8.19(m,1 H),11.74(br s,1 H),11.66-11.79(m,1 H).MS ES+ m/z 396[M+H]+。
實施例80
4-[2-氧代-6-[2-(三氟甲基)苯基]-1H-吡啶-4-基]-1H-吡咯並[2,3-b]吡啶-2-甲腈
如實施例36所述,使用2-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-6-[2-(三氟甲基)苯基]吡啶及4-氯-1H-吡咯並[2,3-b]吡
啶-2-甲腈製備標題化合物,並在加入TFA之前在短矽膠柱上純化中間產物,得到固體產物(5mg,3%)。1H NMR(500MHz,DMSO-d 6)δ ppm 6.44-6.69(m,1 H),6.74-6.82(m,1 H),7.38-7.44(m,1 H),7.46-7.52(m,1 H),7.68-7.76(m,2 H),7.76-7.83(m,1 H),7.86-7.91(m,1 H),8.54-8.59(m,1 H),11.34-12.51(m,1 H),12.64-13.76(m,1 H).MS ES+ m/z 381[M+H]+。
中間產物實施例81
4-[2-三級丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-1H-吡唑並[3,4-b]吡啶
將4-氯-1H-吡唑並[3,4-b]吡啶(61mg,0.4mmol)、2-三級丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-6-[2-(三氟甲基)苯基]吡啶(211mg,0.5mmol)、K2CO3(111mg,0.8mmol)及PdCl2(Amphos)(15mg,0.02mmol)在1,4-二噁烷(3ml)及水(0.75ml)中的混合物在90℃下攪拌2.5小時。當冷卻至室溫時,加入鹽水並將混合物用EtOAc萃取。將合併的有機物用Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-50%EtOAc的庚烷溶液洗脫,得到固體產物(52mg,32%)。MS ES+ m/z 413[M+H]+。
實施例82
4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮
在0℃下將TFA(0.66ml,8.83mmol)加入到4-[2-三級丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-1H-吡唑並[3,4-b]吡啶(52.0mg,0.13mmol)的DCM(6ml)溶液中,並將得到的混合物在室溫下攪拌1小時。濃縮混合物,用甲苯追踪並通過製備型HPLC純化,得到固體產物(28mg,62%)。1H NMR(500MHz,DMSO-d 6)δ ppm 6.67(br s,1 H),6.87(br s,1 H),7.43(d,1 H),7.69-7.77(m,2 H),7.79-7.83(m,1 H),7.90(d,1 H),8.27(s,1 H),8.62(d,1 H),11.61-12.46(m,1 H),13.95(br s,1 H).MS ES+ m/z 357[M+H]+。
中間產物實施例83
1-甲磺醯基-3-(三氟甲基)哌嗪
如中間產物實施例59中所述,使用甲磺醯氯製備標題化合物,得到固體產物(2.2g,97%)。1H NMR(500MHz,DMSO-d 6)δ ppm 2.66-2.74(m,1 H),2.76-2.85(m,2 H),2.93(s,3 H),2.96-3.02(m,2 H),3.28-3.34(m,2 H),3.45-3.52(m,2 H)。
中間產物實施例84
1-(4-苄氧基-6-三級丁氧基-2-吡啶基)-4-甲磺醯基-2-(三氟甲基)哌嗪
如中間產物實施例60所述,使用1-甲磺醯基-3-(三氟甲基)哌嗪製備標題化合物,得到固體產物(900mg,33%)。MS ES+ m/z 488[M+H]+。
中間產物實施例85
2-三級丁氧基-6-[4-甲磺醯基-2-(三氟甲基)哌嗪-1-基]吡啶-4-醇
如中間產物實施例33中所述製備標題化合物,用DMF作為共溶劑,得到產物(750mg,92%)。MS ES+ m/z 398[M+H]+。
中間產物實施例86
[2-三級丁氧基-6-[4-甲磺醯基-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]三氟甲磺酸酯
如中間產物實施例34中所述製備標題化合物,用三氟甲磺醯基三氟甲磺酸酯代替1,1,1-三氟-N-苯基-N-(三氟甲磺醯基)甲磺醯胺並在室溫下攪拌混合物過夜,得到固體產物(680mg,69%)。MS ES+ m/z 530[M+H]+。
中間產物實施例87
4-[2-三級丁氧基-6-[4-甲磺醯基-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]-1H-吡唑並[3,4-b]吡啶
在氬氣氛下,將[2-三級丁氧基-6-[4-甲基磺醯基-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]三氟甲磺酸酯(265mg,0.5mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(152mg,0.6mmol)、KOAc(98mg,1mmol)及PdCl2(dppf)(37mg,0.05mmol)在1,4-二噁烷(4ml)中的混合物加熱並在95℃下攪拌過夜。當冷卻至室溫時,加入4-溴-1H-吡唑並[3,4-b]吡啶(99mg,0.5mmol)、K2CO3(138mg,1mmol)、PdCl2(dppf)(18mg,0.03mmol)及水(1ml),並將所得混合物加熱並在95℃下攪拌3小時。當冷卻至室溫時,加入水及鹽水,並將混合物用EtOAc萃取。將合併的有機物用鹽水洗滌,經Na2SO4乾燥,過濾,濃縮並在矽膠柱上純化,用0-6%MeOH的DCM溶液洗脫,得到固體產物(210mg,84%)。MS ES+ m/z 499[M+H]+。
實施例88
6-[4-甲磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡唑並[3,4-b]吡啶-4-基)-1H-吡啶-2-酮
如實施例82所述製備標題化合物,得到固體產物(65mg,37%)。1H NMR(500MHz,DMSO-d 6)δ ppm 2.90-2.96(m,4 H),3.15-3.24(m,1 H),3.31-3.45(m,2 H),3.62(br d,1 H),3.89(br d,1 H),4.44(br d,1 H),5.70(br s,1 H),6.44(d,1 H),6.76(s,1 H),7.43(d,1 H),8.29(s,1 H),8.62(d,1 H),10.56-11.30(m,1 H).MS ES+ m/z 443[M+H]+。
實施例89
Vps34生化測定
稀釋系列的本發明化合物在DMSO中以最終測定濃度的100倍(n1=n0/3在10個點中)製備。將化合物進一步稀釋至測定緩衝液中的測定濃度的4倍(Life technologies buffer Q,PV5125,稀釋5倍,補充2mM DTT及2mM MnCl2)。將2.5μl稀釋的化合物加入到384孔測定板中,然後加入2.5μl的16.5nM Vps34酶(Life technologies,PV5126)。將酶及化合物在室溫下預反應15分鐘。然後將測定緩衝液中的含有20μM ATP(Life technologies,PV3227)及200μM PI:PS受質(Life technologies,PV5122)的5μl受質混合物加入到含有化合物及酶的孔中。通過移液幾次進行混合。將反應在室溫下進行1小時。然後加入如Adapta激酶測定試劑盒說明書(Life technologies,PV5099)中所述製備的5μl終止檢測混合物,其含有Adapta
Eu-anti-ADP抗體(2.3nM)、Alexa Fluor 647 ADP示蹤劑(9nM)及EDTA(30mM)在TR-FRET緩衝液中,以淬滅反應。通過移液幾次進行混合。然後將測定板在室溫下反應30分鐘並用Artemis微量板讀數器讀數。計算與DMSO處理的對照樣品相比化合物的抑制百分比。通過使用Dotmatics軟體,擬合化合物濃度與抑制百分比以產生IC50值。實施例化合物有效抑制Vps34,測定結果如表1所示(中位數IC50nM Adapta)。
實施例90
高含量篩選自噬測定
穩定表現經綠色螢光蛋白標記的LC3(GFP-LC3)的人骨肉瘤細胞(HOS)用於確定對專有化合物的自噬的抑制作用。為此目的,通過在5nM下在Bafilomycin A1(Sigma-Aldrich)存在下使用500nM的mTOR抑制劑KU-0063794活化自噬作用。不久,將細胞在DMEM-高度修飾培養基(Hi-Clone Cat # SH30285.01)中在透明底96孔板中鋪板過夜。在實驗開始時,除去培養基並用含有mTOR抑制劑、Bafilomycin A1及載體或是所示測試化合物的新鮮培養基替換。6小時後,除去培養基,用冰冷的磷酸鹽緩衝鹽水(PBS)洗滌細胞兩次,並在室溫下用4%聚甲醛固定20分鐘。然後用冰冷的PBS洗滌細胞兩次,然後在PBS中加入1μg/ml的Hoechst 33342進行核染色。在4℃反應過夜後,用PBS洗滌細胞一次以除去過量的染料,並向每個孔中加入100μl PBS。使用ImageXpress自動顯微鏡(Molecular Devices Inc.)以20x放大率,每孔6個圖像以獲得圖像,並用MetaXpress軟體分析以鑑定LC3-GFP病灶。每個細胞的病灶面積值用於產生劑量反應曲線,並且使用GraphPad Prism軟體中的非線性擬合分析計算IC50值。測試的實施例化合物有效抑制HOS細胞中的自噬。測定結果如表2所示(中位數IC50nM HOS-LC3)。
Claims (40)
- 一種式(I)化合物或其藥學上可接受的鹽
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中R2為氫或C1-C3烷基。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中R1選自H、C1-C3烷基、C1-C3鹵代烷基、C3-C6環烷基、氰基、苯基、雜芳基,其中所述苯基及所述雜芳基任選地且獨立地被一個或多個選自C1-C3鹵代烷基、鹵代、C3-C6環烷基及C1-C3烷基的取代基取代。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中R1中的所述雜芳基選自吡啶基、噁唑基、噻吩基及嘧啶基,各自任選地且獨立地被一個或多個選自鹵代、環丙基、C1-C3氟烷基及C1-C3烷基的取代基取代。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中R3選自A、苯基及單環雜芳基,所述單環雜芳基選自吡啶基、噻吩基、呋喃基、嘧啶基及吡唑基,其中所述苯基及所述雜芳基任選地及獨立地被一個或兩個R4取代。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中R3選自A、苯基及單環雜芳基,所述單環雜芳基選自吡啶基、噻吩基及吡唑基,其中所述苯基及所述雜芳基任選地及獨立地被一個或兩個R4取代。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中R3選自A、苯基及吡啶基,其中所述苯基及所述吡啶基任選地被一個或兩個R4取代。
- 如請求項1-9中任一項所述之化合物或其藥學上可接受的鹽,其中R4選自氟、氯、C1-C3烷基、C3-C6環烷基、C1-C3氟烷基及SO2R7。
- 如請求項1-9中任一項所述之化合物或其藥學上可接受的鹽,其中Y為CH2、NSO2R7、O或鍵。
- 如請求項1-9中任一項所述之化合物或其藥學上可接受的鹽,其中R10選自氫、C1-C3烷基、C3-C6環烷基、苯基、單環雜芳基及C1-C3鹵代烷基,其中所述苯基及所述雜芳基任選地且獨立地被一個R12取代;以及R12選自C1-C3烷基、環丙基、CF3、鹵素、C1-C3鹵代烷氧基及C1-C3烷氧基。
- 如請求項1-9中任一項所述之化合物或其藥學上可接受的鹽,其中R7選自R8、N,N-二C1-C3烷基胺基、C1-C3烷基及甲氧基C1-C3烷基,所述C1-C3烷基任選被一個R8取代。
- 如請求項1-9中任一項所述之化合物或其藥學上可接受的鹽,其中R7選自C1-C3烷基及氟苯基。
- 如請求項1-9中任一項所述之化合物或其藥學上可接受的鹽,其中R8選自苯基、吡啶基、咪唑基、異噁唑基、噁唑基、環丙基、環戊基、吡咯啶基、四氫呋喃基,各自任選地被一個或多個選自環丙基、甲基及氟的取代基取代。
- 如請求項1、2、7、8或9中任一項所述之化合物或其藥學上可接受的鹽,其中X為N。
- 如請求項1-9中任一項所述之化合物或其藥學上可接受的鹽,其中X為CR1。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中所述化合物如下:4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;6-(3-甲基-4-吡啶基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-苯基吡咯啶-1-基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-嗎啉代-1H-吡啶-2-酮;6-(2-氯苯基)-4-(2-噁唑-5-基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-氯苯基)-4-[2-(3-吡啶基)-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮; 6-(2-氯苯基)-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;6-[3-(三氟甲基)嗎啉-4-基]-4-[2-[3-(三氟甲基)苯基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-[2-(5-甲基-2-噻吩基)-1H-吡咯並[2,3-b]吡啶-4-基]-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[2-(三氟甲基)嘧啶-5-基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[6-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[5-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮; 6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-[2-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-6-氧代-1H-吡啶-4-基]-1H-吡咯並[2,3-b]吡啶-2-甲腈;4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;4-[2-氧代-6-[2-(三氟甲基)苯基]-1H-吡啶-4-基]-1H-吡咯並[2,3-b]吡啶-2-甲腈;4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;6-[4-甲磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡唑並[3,4-b]吡啶-4-基)-1H-吡啶-2-酮。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中所述化合物如下:4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;6-(3-甲基-4-吡啶基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-苯基吡咯啶-1-基)-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-嗎啉代-1H-吡啶-2-酮;6-(2-氯苯基)-4-(2-噁唑-5-基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-(2-氯苯基)-4-[2-(3-吡啶基)-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-(2-氯苯基)-4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮; 4-(2-甲基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;4-(1H-吡咯並[2,3-b]吡啶-4-基)-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;6-[3-(三氟甲基)嗎啉-4-基]-4-[2-[3-(三氟甲基)苯基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-[2-(5-甲基-2-噻吩基)-1H-吡咯並[2,3-b]吡啶-4-基]-6-[3-(三氟甲基)嗎啉-4-基]-1H-吡啶-2-酮;4-(1H-吡唑並[3,4-b]吡啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[2-(三氟甲基)嘧啶-5-基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[6-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;6-[2-(三氟甲基)-1-哌啶基]-4-[2-[5-(三氟甲基)-3-吡啶基]-1H-吡咯並[2,3-b]吡啶-4-基]-1H-吡啶-2-酮;4-(2-環丙基-1H-吡咯並[2,3-b]吡啶-4-基)-6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;6-[4-乙磺醯基-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮;6-[4-[(4-氟苯基)甲磺醯基]-2-(三氟甲基)哌嗪-1-基]-4-(1H-吡咯並[2,3-b]吡啶-4-基)-1H-吡啶-2-酮。
- 如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,其用於治療或預防一疾病。
- 如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,其用於治療癌症。
- 如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,其用於治療癌症,其中所述癌症選自乳癌、膀胱癌、肝癌、子宮頸癌、胰腺癌、白血病、淋巴瘤、腎癌、大腸癌、神經膠質瘤、前列腺癌、卵巢癌、黑色素瘤及肺癌以及缺氧性腫瘤。
- 如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,其用於治療缺氧性腫瘤。
- 如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,其用於治療癌症,其中所述癌症的治療還包括放射療法。
- 如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,其用於治療第二型糖尿病。
- 如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,其用於治療疾病,其中所述疾病選自發炎性疾病、自身免疫疾病、神經退行性病症、心血管病症及病毒感染。
- 一種如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽在製備用於治療癌症的藥物的用途。
- 一種如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽在製備用於治療癌症的藥物的用途,其中所述癌症選自乳癌、膀胱癌、 肝癌、子宮頸癌、胰腺癌、白血病、淋巴瘤、腎癌、大腸癌、神經膠質瘤、前列腺癌、卵巢癌、黑色素瘤及肺癌以及缺氧性腫瘤。
- 一種如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽在製備用於治療缺氧性腫瘤的藥物的用途。
- 一種如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽在製備用於治療第二型糖尿病的藥物的用途。
- 一種如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽在製備用於治療一疾病的藥物的用途,其中所述疾病選自發炎性疾病、自身免疫疾病、神經退行性病症、心血管病症及病毒感染。
- 一種醫藥組成物,包括如請求項1-9或22-26中任一項所述之化合物或其藥學上可接受的鹽,及一藥學上可接受的稀釋劑、載體及/或賦形劑。
- 一種醫藥組成物,包括治療有效量的如請求項1所述之化合物或其藥學上可接受的鹽,及另一抗癌劑,其中所述抗癌劑選自烷化劑、抗代謝物、抗癌喜樹鹼衍生物、植物源抗癌劑、抗生素、酶、鉑配位複合物、酪胺酸激酶抑制劑、激素、激素拮抗劑、單株抗體、干擾素及生物反應調節劑。
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WO2015108881A1 (en) * | 2014-01-14 | 2015-07-23 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
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