WO2022211812A1 - Composés hétérocycliques antiviraux - Google Patents
Composés hétérocycliques antiviraux Download PDFInfo
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- WO2022211812A1 WO2022211812A1 PCT/US2021/025358 US2021025358W WO2022211812A1 WO 2022211812 A1 WO2022211812 A1 WO 2022211812A1 US 2021025358 W US2021025358 W US 2021025358W WO 2022211812 A1 WO2022211812 A1 WO 2022211812A1
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- 230000000840 anti-viral effect Effects 0.000 title description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 661
- 238000000034 method Methods 0.000 claims abstract description 334
- 150000003839 salts Chemical class 0.000 claims abstract description 66
- 241000342334 Human metapneumovirus Species 0.000 claims abstract description 21
- 208000015181 infectious disease Diseases 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- -1 substituted Chemical class 0.000 claims description 193
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000003107 substituted aryl group Chemical group 0.000 claims description 17
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 206010022000 influenza Diseases 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 239000000651 prodrug Substances 0.000 abstract description 45
- 229940002612 prodrug Drugs 0.000 abstract description 45
- 150000002148 esters Chemical class 0.000 abstract description 44
- 241000711920 Human orthopneumovirus Species 0.000 abstract description 32
- 239000003112 inhibitor Substances 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 423
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 344
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 236
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 231
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 217
- 238000006243 chemical reaction Methods 0.000 description 193
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 193
- 239000007787 solid Substances 0.000 description 191
- 235000019439 ethyl acetate Nutrition 0.000 description 189
- 239000000203 mixture Substances 0.000 description 133
- 238000004440 column chromatography Methods 0.000 description 120
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 112
- 238000002953 preparative HPLC Methods 0.000 description 112
- 239000000741 silica gel Substances 0.000 description 105
- 229910002027 silica gel Inorganic materials 0.000 description 105
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 102
- 239000000243 solution Substances 0.000 description 88
- 239000000463 material Substances 0.000 description 80
- 239000002253 acid Substances 0.000 description 71
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 69
- 238000003756 stirring Methods 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 65
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 63
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 239000002243 precursor Substances 0.000 description 52
- 239000012071 phase Substances 0.000 description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
- 239000000047 product Substances 0.000 description 46
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- 150000001412 amines Chemical class 0.000 description 39
- 150000004702 methyl esters Chemical class 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
- 238000010931 ester hydrolysis Methods 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000013058 crude material Substances 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 230000002441 reversible effect Effects 0.000 description 26
- 150000001408 amides Chemical class 0.000 description 25
- 239000007821 HATU Substances 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 23
- 238000000605 extraction Methods 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- 238000001556 precipitation Methods 0.000 description 20
- 125000006239 protecting group Chemical group 0.000 description 20
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 19
- 238000010511 deprotection reaction Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 238000010168 coupling process Methods 0.000 description 18
- 238000000926 separation method Methods 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- 230000008878 coupling Effects 0.000 description 17
- 238000005859 coupling reaction Methods 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 16
- 239000012299 nitrogen atmosphere Substances 0.000 description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 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 13
- 229940079593 drug Drugs 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 125000000524 functional group Chemical group 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 238000010640 amide synthesis reaction Methods 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 9
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 241000725643 Respiratory syncytial virus Species 0.000 description 9
- 125000001931 aliphatic group Chemical group 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 125000002837 carbocyclic group Chemical group 0.000 description 9
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 9
- 239000007819 coupling partner Substances 0.000 description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
- UNWLRUADCZTRCF-UHFFFAOYSA-N methyl 8-hydroxyquinoline-6-carboxylate Chemical compound COC(=O)C1=CC2=CC=CN=C2C(O)=C1 UNWLRUADCZTRCF-UHFFFAOYSA-N 0.000 description 9
- 239000012453 solvate Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 8
- 239000007822 coupling agent Substances 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 7
- 229930006000 Sucrose Natural products 0.000 description 7
- 125000000304 alkynyl group Chemical group 0.000 description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 230000003000 nontoxic effect Effects 0.000 description 7
- 235000011181 potassium carbonates Nutrition 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 229960004793 sucrose Drugs 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- GQIRIWDEZSKOCN-UHFFFAOYSA-N 1-chloro-n,n,2-trimethylprop-1-en-1-amine Chemical compound CN(C)C(Cl)=C(C)C GQIRIWDEZSKOCN-UHFFFAOYSA-N 0.000 description 6
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 6
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000010443 alginic acid Nutrition 0.000 description 6
- 229920000615 alginic acid Polymers 0.000 description 6
- 150000005010 aminoquinolines Chemical class 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 6
- VYXZUOSQEKQOKI-UHFFFAOYSA-N methyl 8-aminoquinoline-6-carboxylate Chemical compound N1=CC=CC2=CC(C(=O)OC)=CC(N)=C21 VYXZUOSQEKQOKI-UHFFFAOYSA-N 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 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 6
- 150000001299 aldehydes Chemical class 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
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- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 4
- NFPYJDZQOKCYIE-UHFFFAOYSA-N 4-amino-3-hydroxybenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1O NFPYJDZQOKCYIE-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101001065501 Escherichia phage MS2 Lysis protein Proteins 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 206010057190 Respiratory tract infections Diseases 0.000 description 4
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- LZCVVMQABORALM-UHFFFAOYSA-N spiro[2.5]octyl Chemical group [CH]1CC11CCCCC1 LZCVVMQABORALM-UHFFFAOYSA-N 0.000 description 1
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- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- AOEDOXQZANMVHL-UHFFFAOYSA-N tert-butyl n-(2-iodoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCI AOEDOXQZANMVHL-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- PEHWWVVZOODHQY-UHFFFAOYSA-N tert-butyl-(2-chloroethoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCl PEHWWVVZOODHQY-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
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- 230000013715 transcription antitermination Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates generally to compounds and pharmaceutical compositions useful as Respiratory Syncytial Virus (RSV) inhibitors and Human Metapneumovirus (HMPV) inhibitors.
- RSV Respiratory Syncytial Virus
- HMPV Human Metapneumovirus
- HRSV Human respiratory syncytial virus
- HRSV contains 10 genes that encode for 11 proteins.
- RNP ribonucleoprotein
- F fusion protein
- HRSV acute lower respiratory infections
- patient populations at high risk during HRSV infections include the elderly, immunocompromised, children up to the age of two and patients with chronic obstructive pulmonary disorder (COPD) or chronic heart failure (CHF).
- COPD chronic obstructive pulmonary disorder
- CHF chronic heart failure
- HRSV was found over four years to cause 177,500 hospital admissions and 14,000 deaths in the U.S. elderly population. It is well-known that almost all children will be infected with HRSV in the first 3 years after birth and HRSV infection is more severe in premature infants. In fact, HRSV is the most common cause of bronchiolitis and pneumonia in infants under the age of one in the U.S.
- HRSV has been associated with more deaths of infants below one year old and more infant hospitalizations than influenza. HRSV infection can also affect healthy individuals and repeated HRSV infections even over the course of two months can occur. Symptoms are similar to colds in healthy individuals, however fever, wheezing, rapid and difficult breathing, and cyanosis occur in more severe cases.
- Palivizumab is a monoclonal antibody that is approved for prophylactic use, but its use is limited due to its high price.
- Palivizumab is generally only used for high risk infants, such as premature infants or those with cardiac/lung disease, but has been only 60% effective in reducing hospitalizations.
- Ribavirin is approved as an inhalation treatment option, but its effectiveness is limited and there are safety concerns associated with it. Taking into account the treatment options, and the consistent seasonality of the HRSV epidemic, the development of new therapeutic agents for the treatment of HRSV is desirable.
- RSV fusion inhibitors that have been disclosed in the following publications: WO2010/103306, WO2012/068622, WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334, WO 2013/186332, WO 2012080451, WO 2012/080450, WO2012/080449, WO 2012/080447, WO 2012/080446, WO 2015/110446, WO 2017/009316, J. Med. Chem.2015, 58, 1630-1643, Bioorg. Med. Chem. Lett., 2015, 25, 976-981 and Nat. Commun., 2017, 8, 167.
- N-protein inhibitors for treatment of HRSV have been disclosed in the following publications: WO 2004/026843, J. Med. Chem.2006, 49, 2311-2319, and J. Med. Chem.2007, 50, 1685-1692.
- L-protein inhibitors for HRSV have been disclosed in the following publications: WO 2011/005842, WO 2005/042530, Antiviral Res.2005, 65, 125-131, and Bioorg. Med. Chem. Lett.2013, 23, 6789-6793.
- HMPV human metapneumovirus
- ARTIs acute lower respiratory tract infections
- HMPV infection is responsible for 6% of total respiratory infections in lung transplants and 3% of lower respiratory infections associated with stem cell transplant. HMPV infection is also thought to be associated with acute graft rejection.
- HMPV L protein sequence is homologous to HRSV L protein.
- HMPV infection is the second most common cause of lower respiratory tract infection in children (behind HRSV) and also problematic for the elderly population.
- the present invention has identified compounds that are heterocyclic molecules that are potent against HRSV-A/B and HMPV.
- the invention includes methods to prepare these molecules, methods for the RSV cell-based assay, the HMPV-GFP cell-based assay and small-molecules that have potential to treat HRSV/HMPV infection.
- the present invention provides compounds represented by Formula (I), and pharmaceutically acceptable salts, esters and prodrugs thereof that can be used to treat or prevent viral (particularly HRSV or HMPV) infection: wherein: A is selected from the group consisting of: 1) optionally substituted aryl; and 2) optionally substituted heteroaryl; R1 and R2 are each independently selected from the group consisting of: 3) optionally substituted –C 1 -C 6 alkyl; alternatively, R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6- membered ring; Z is selected from the group consisting of: 1) hydrogen; 2) halogen; 5) nitro; 6) optionally substituted –C 1 -C 6 alkoxy; and 7) optionally substituted –C 1 -C 6 alkyl; W is selected from the group consisting of: 1) hydrogen; 2) halogen; 3) optionally substituted –C 1 -C 6 alkoxy; 4)
- DETAILED DESCRIPTION O is a compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof.
- B is O.
- Y is O.
- Y is O, and n is 1 or
- R 1 is hydrogen or F.
- R 2 is hydrogen or F.
- Z is hydrogen, Cl or F.
- R1 is hydrogen, R2 is hydrogen, and Z is hydrogen.
- W is optionally substituted methyl, optionally substituted ethyl, or optionally substituted cyclopropyl. In certain embodiments of the compounds of Formula (I), W is -CH 3 or -CF 3 . In certain embodiments of the compounds of Formula (I), W is halogen, preferably chlorine or fluorine, and more preferably fluorine. In certain embodiments of the compounds of Formula (I), R 3 is -OH. In certain embodiments of the compounds of Formula (I), R 4 is optionally substituted methyl. In certain embodiments of the compounds of Formula (I), R 3 is OH, and R 4 is CF 3 .
- R 1 is hydrogen
- R 2 is hydrogen
- R 3 is OH
- R 4 is CF 3 .
- G is optionally substituted –C(O)NR 11 R 12 . 2NHR 13 , –
- A is selected from one of the following by removal of a hydrogen atom: wherein each of these groups is optionally substituted. In certain embodiments of the compounds of Formula (I), A is selected from the
- A is C(O)R 11 , -C(O)OR 11 , -C(O)NR 11 R 12 , optionally substituted –C 1 -C 6 alkyl, optionally substituted – C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;
- Rb and Rb’ are each independently selected from hydrogen, halogen, -OR 11 , -NR 11 R 12 , optionally substituted –C 1 -C 6 -alkyl, optionally substituted –C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
- Rb and Rb’ are taken together with the carbon atoms to which they are attached to form a 4- to 7- membered ring fused with the phenyl ring.
- E is optionally substituted aryl, preferably optionally substituted phenyl.
- E is selected from one of the following by removal of a hydrogen atom: wherein each of these groups is optionally substituted.
- E is selected from the groups set forth below.
- the compound of Formula (I) is represented by Formula (Ia) or Formula (Ib), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein A, B, R1, R2, Z, W, G, n, Y, E, R 3 , and R 4 are as previously defined.
- the compound of Formula (I) has the stereochemistry shown in Formula (Ib).
- the compound of Formula (I) is represented by Formula (IIa) or Formula (IIb), or a pharmaceutically acceptable salt, ester or wherein A, R1, R2, W, G, n, Y, E, R 3 , and R 4 are as previously defined.
- the compound of Formula (I) is represented by Formula (IIIa) or Formula (IIIb), or a pharmaceutically acceptable salt, ester wherein A, W, G, n, Y, E, n, R 3 , and R4 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (IVa) ⁇ (IVd), or a pharmaceutically acceptable salt, ester or
- the compound of Formula (I) is represented by one of Formulae (Va) ⁇ (Vd), or a pharmaceutically acceptable salt, ester or rodru thereof: wherein A, W, G, E, R 14 , R 3 , and R 4 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (VIa) ⁇ (VId), or a pharmaceutically acceptable salt, ester or rodru thereof:
- W is optionally substituted methyl or halogen; more preferably, W is -CH 3 , -CF 3 or fluorine.
- the compound of Formula (I) is represented by one of Formulae (VII-1) ⁇ (VII-12), or a pharmaceutically acceptable salt, ester or prodrug thereof:
- W is optionally substituted methyl or halogen; more preferably, W is -CH 3 , -CF 3 or fluorine.
- the compound of Formula (I) is represented by one of Formulae (VII-1a) ⁇ (VII-12a), or a pharmaceutically acceptable salt, ester or prodrug thereof:
- W is optionally substituted methyl or halogen; more preferably, W is -CH 3 , -CF 3 or fluorine.
- the compound of Formula (I) is represented by one of Formulae (VIIIa) ⁇ (VIIId), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein each R 21 is independently optionally substituted methyl, halo, -CN, -OR 11 , or - NR 11 R 12 ; m is 0, 1, 2, 3, 4 or 5; A, W, G, R 11 , R 12 , R 14 , R 3 , and R 4 are as previously defined.
- each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2.
- each R 21 is independently -F, -Cl, -CN, -CF 3 , -CH 2 F or -CHF 2 , and m is 1 or
- the compound of Formula (I) is represented by one of Formulae (VIIIe) ⁇ (VIIIh), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein R 21 , m, A, W, G, R 14 , R 3 , and R 4 are as previously defined.
- each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2.
- the compound of Formula (I) is represented by one of Formulae (IXa) ⁇ (IXd), or a pharmaceutically acceptable salt, ester, wherein R 21 , m, R 3 , R 4 , A, W, R 11 , R 12 , and R 14 are as previously defined.
- each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2.
- the compound of Formula (I) is represented by one of Formulae (IXe) ⁇ (IXh), or a pharmaceutically acceptable salt, ester or wherein R 21 , m, R 3 , R 4 , A, W, R 11 , R 12 , and R 14 are as previously defined.
- R 21 is halo or optionally substituted methyl, and m is 1 or 2.
- the compound of Formula (I) is represented by one of Formulae (X-1) ⁇ (X-6), or a pharmaceutically acceptable salt, ester or wherein m is 0, 1 or 2; R 21 , A, W, R 11 , R 12 , and R 13 are as previously defined.
- m is 0, 1 or 2;
- m In one embodiment of the present invention, the compound of Formula (I) is represented by one of Formulae (X-1a) ⁇ (X-6a), or a pharmaceutically acceptable salt, ester, or prodrug thereof:
- R21, m ’ , A, W, R11, R12, and R13 are as previously defined.
- m ’ is 2.
- the compound of Formula (I) is represented by one of Formulae (XI-1) ⁇ (XI-12), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein R 21 , m ’ , A, R 11 , R 12 , and R 13 are as previously defined.
- m ’ is 2.
- the compound of Formula (I) is represented by one of Formulae (XI-1a) ⁇ (XI-12a), or a pharmaceutically acceptable salt, ester or prodrug thereof:
- the compound of Formula (I) is represented by one of Formulae (XIVa) ⁇ (XIVd), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein W, R21, m ’ , R11, and R12 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (XIVe) ⁇ (XIVh), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein W, R 21 , m ’ , R 11 , and R 12 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (XVa) ⁇ (XVd), or a pharmaceutically acceptable salt, ester
- the compound of Formula (I) is represented by one of Formulae (XVe) ⁇ (XVh), or a pharmaceutically acceptable salt, ester or prodrug thereof:
- W, m ’ , R 3 , R 4, R 21 , R 31 , R 11 , and R 12 are as previously defined.
- two adjacent R 31 groups are taken together with the carbon atoms to which they are attached to form a 4- to 12- membered carbocyclic or heterocyclic ring, and which said 4- to 12- membered carbocyclic or heterocyclic is fused with the phenyl or quinolinyl.
- the compound of Formula (I) is represented by one of Formulae (XVa) ⁇ (XVh), or a pharmaceutically acceptable salt, ester or prodrug thereof, R 3 is -OH, and R 4 is -CH 3 , -CF 3 , or cyclopropyl.
- the compound of Formula (I) is represented by one of Formulae (XVa-1) ⁇ (XVb-1), Formulae (XVc-1) ⁇ (XVc-4), Formulae (XVd-1) ⁇ (XVd-4), or a pharmaceutically acceptable salt, ester or prodrug thereof:
- each R 32 is independently halogen, -OR 11 ; -NR 11 R 12 , optionally substituted –C 1 - C 6 -alkyl; optionally substituted –C 3 -C 8 -cycloalkyl; optionally substituted 3- to 8- membered heterocyclic; optionally substituted aryl; or optionally substituted heteroaryl; W, m ’ , R 3 , R 4 , R 21 , R 31 , R 11 , and R 12 are as previously defined.
- two adjacent R32 groups are taken together with the carbon atoms to which they are attached to form a 4- to 12- membered carbocyclic or heterocyclic ring, and which said 4- to 12- membered carbocyclic or heterocyclic is fused with the phenyl or quinolinyl.
- the compound of Formula (I) is represented by one of Formulae (XVa-1) ⁇ (XVb-1), Formulae (XVc-1) ⁇ (XVc-4), Formulae (XVd-1) ⁇ (XVd-4), or a pharmaceutically acceptable salt, ester or prodrug thereof, R 3 is - OH, and R 4 is -CH 3 , -CF 3 , or cyclopropyl.
- the compound of Formula (I) is represented by one of Formulae (XVe-1) - (XVf-1), Formulae (XVg-1) ⁇ (XVg-4), Formulae (XVh-1) ⁇ (XVh-4), or a pharmaceutically acceptable salt, ester or prodrug thereof:
- R 32 groups are taken together with the carbon atoms to which they are attached to form a 4- to 12- membered carbocyclic or heterocyclic ring, and which said 4- to 12- membered carbocyclic or heterocyclic is fused with the phenyl or quinolinyl.
- the compound of Formula (I) is represented by one of Formulae (XVe-1) ⁇ (XVf-1), Formulae (XVg-1) ⁇ (XVg-4), Formulae (XVh-1) ⁇ (XVh-4), or a pharmaceutically acceptable salt, ester or prodrug thereof, R 3 is - OH, and R 4 is -CH 3 , -CF 3 , or cyclopropyl.
- the compound of Formula (I) is represented by one of Formulae (XVIa) ⁇ (XVIh), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein R22 is hydrogen, halogen, -OR 11 ; -NR 11 R 12 , optionally substituted –C 1 -C 6 -alkyl; optionally substituted –C 3 -C 8 -cycloalkyl; optionally substituted 3- to 8-membered heterocyclic; optionally substituted aryl; or optionally substituted heteroaryl; and W, R 31 , R 21 , m ’ , R 3 , R 4 , R 11 , and R 12 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (XVIa) ⁇ (XVIh), or a pharmaceutically acceptable salt, ester or prodrug thereof, R 3 is -OH, and R 4 is -CH 3 , -CF 3 , or cyclopropyl.
- the compound of Formula (I) is represented by one of Formulae (XVIIa) ⁇ (XVIIh), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein W, R21, R22, R31, m ’ , R3, R4, R11, and R12 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (XVIIa) ⁇ (XVIIh), or a pharmaceutically acceptable salt, ester or prodrug thereof, R 3 is -OH, and R 4 is -CH 3 , -CF 3 , or cyclopropyl.
- the compound of Formula (I) is represented by one of Formulae (XVIIIa) ⁇ (XVIIId), or a pharmaceutically acceptable salt, ester or prodrug thereof:
- R 23 is hydrogen, optionally substituted –C 1 -C 6 -alkyl; optionally substituted –C 3 - C 8 -cycloalkyl; optionally substituted 3- to 8-membered heterocyclic; optionally substituted aryl; or optionally substituted heteroaryl; R3, R4, A, W, R11, R12, and R14 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (XVIIIe) ⁇ (XVIIIh), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein R23, R3, R4, A, W, R11, R12, and R14 are as previously defined.
- the compound of Formula (I) is represented by one of Formulae (XVIIIa) ⁇ (XVIIIh), or a pharmaceutically acceptable salt, ester or prodrug thereof, R 3 is -OH, and R 4 is -CH 3 , -CF 3 , or cyclopropyl.
- R 3 is -OH
- R 4 is -CH 3 , -CF 3 , or cyclopropyl.
- the definition of any substituent or variable e.g., R 1 , R 2 , etc.
- the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
- the present invention provides a method for the prevention or treatment of RSV activities and for treating RSV infection in a subject in need thereof.
- the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).
- the present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of RSV.
- a compound of formula (I), or pharmaceutically acceptable salt thereof is combined with a steroid anti-inflammatory compound, for example budesonide or fluticasone.
- the steroid is administered in low doses to minimize immuno- suppressant effects.
- a compound of formula (I), or a pharmaceutically acceptable salt thereof is combined with a non-steroid anti-inflammatory compound, for example leukotriene antagonists such as Singulair (Merck) or Accolate (Astra Zeneca), phosphodiesterase 4 inhibitors such as roflumilast (Altana), TNF alpha inhibitors such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbott) or CDP870 (Celltech) or NSAIDS.
- a compound of formula (I) is combined with interleukin 8 or interleukin 9 inhibitors.
- the present invention thus also relates to a product containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-inflammatory compound for simultaneous, separate or sequential use in the treatment of RSV.
- the present invention also relates to a combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, with an anti-influenza compound and the use of such a combination in the treatment of concomitant RSV and influenza infections.
- the present invention thus also relates to a product containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-influenza compound for simultaneous, separate or sequential use in the treatment of concomitant RSV and influenza infections.
- the compounds of the invention may be administered in a variety of dosage forms.
- the compounds of the invention can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
- the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
- the compounds may also be administered as suppositories.
- the compounds of the invention are administered by intranasal or intrabronchial administration.
- the present invention also provides an inhaler or nebulizer containing a medicament which comprises (a) a derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or diluent.
- the present invention also provides a pharmaceutical composition containing such a benzodiazepine derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
- the compounds of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
- solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g.
- disaggregating agents e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, nontoxic and pharmacologically inactive substances used in pharmaceutical formulations.
- Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
- Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
- the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
- Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
- the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
- Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
- the present invention also relates to the novel compounds, as defined above; or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body.
- the present invention also relates to a pharmaceutical composition comprising a novel compound as defined above and a pharmaceutically acceptable diluant or carrier.
- the pharmaceutical composition comprises a pharmaceutically acceptable salt of a novel compound as defined above.
- a pharmaceutically acceptable salt is as defined above.
- the novel compounds of the invention are typically administered in the manner defined above and the compounds are typically formulated for administration in the manner defined above.
- the pharmaceutical compositions comprise optically active isomers of the novel compounds of the invention.
- preferred novel compounds of the invention containing only one chiral center include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
- pharmaceutical contains a compound of the invention which is a substantially pure optical isomer.
- the novel compounds of the invention can, if desired, be used in the form of solvates.
- Yet a further aspect of the present invention is a process of making any of the compounds delineated herein employing any of the synthetic means delineated herein.
- aryl refers to a mono-, bi-, or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
- a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
- Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
- heteroaryl refers to a mono-, bi-, or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
- Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
- a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. In accordance with the invention, aromatic groups can be substituted or unsubstituted.
- alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
- C1-C3 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
- C1-C3 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
- C1-C3 alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
- C1-C3 alkyl C 1 -C 6 alkyl
- C1-C10 alkyl C2-C4 alkyl
- C3-C6 alkyl refer to alkyl groups containing from one to three, one to six, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively.
- C 1 -C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
- alkenyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
- C2-C10 alkenyl refers to alkenyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively.
- Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
- alkynyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
- C2-C10 alkynyl refers to alkynyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively.
- Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
- cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
- Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C 3 -C 8 cycloalkyl and C 4 -C 7 cycloalkyl.
- C 3 -C 12 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3- methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.
- cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
- Preferred cycloalkenyl groups include C 3 -C 12 cycloalkenyl, C 3 -C 8 cycloalkenyl or C 5 -C 7 cycloalkenyl groups.
- C3-C12 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept- 2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl, and the like.
- arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl.
- substituted arylalkyl means an arylalkyl functional group in which the aryl group is substituted.
- heteroarylalkyl means a functional group wherein an alkylene chain is attached to a heteroaryl group.
- substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
- alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
- Preferred alkoxy are (C1-C3) alkoxy. It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
- An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
- aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2, C(O)NHS(O)2NH or C(O)NHS(O)2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
- functional groups such as alkyl, alkenyl, alkynyl, O, OH,
- Carbon atoms of an aliphatic group can be optionally oxo-substituted.
- An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
- aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
- Carbocycle or “carbocyclic” refers to a saturated, partially unsaturated or aromatic cyclic group in which each atom within the ring is carbon.
- cabocyclics include cycloalkyl, cycloalkenyl and aryl groups.
- heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
- heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5- azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl.
- heterocyclic groups may be further substituted.
- Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible). It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
- One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
- substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, -C1-C12-alkyl; -C2-C12-alkenyl, -C2-C12-alkynyl, -C3-C12-cycloalkyl, protected hydroxy, -NO 2 , -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH-C 1 -C 12 -alkyl, -NH-C 2 -C 8 - alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH- heterocycloalkyl, -dial
- the substituents are independently selected from halo, preferably Cl and F; C 1- C 4 -alkyl, preferably methyl and ethyl; halo-C 1- C 4 -alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6- cycloalkyl, such as cyclopropyl; C1-C4-alkoxy, such as methoxy and ethoxy; halo-C1-C4- alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy, -CN; -OH; NH2; C1- C 4 -alkylamino; di(C 1- C 4 -alkyl)amino; and NO 2 .
- each substituent in a substituted moiety is additionally optionally substituted when possible with one or more groups, each group being independently selected from C 1- C 4 -alkyl; -CF 3 , -OCH 3 , -OCF 3 , -F, -Cl, -Br, -I, - OH, -NO 2 , -CN, and -NH 2 .
- a substituted alkyl, alkenyl or alkoxy group is substituted with one or more halogen atoms, preferably fluorine or chlorine atoms.
- substituted alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
- substituted alkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy.
- halo or halogen alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
- optionally substituted means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted.
- the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
- hydrogen includes hydrogen and deuterium.
- the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
- the compounds of each formula herein are defined to include isotopically labelled compounds.
- An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope.
- one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%.
- a deuterated compound may, for example, be metabolized more slowly than its non- deuterated analog, and therefore exhibit a longer half-life when administered to a subject.
- Such compounds can synthesize using methods known in the art, for example by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable.
- hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
- hydroxyl activating group include, but are not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like.
- activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate groups, for example.
- hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
- hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy- carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl- methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)- ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
- protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
- hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B.
- amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
- amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
- Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl- methoxycarbonyl, benzyloxycarbonyl, and the like.
- protected amino refers to an amino group protected with an amino protecting group as defined above.
- leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
- representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
- aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
- Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
- hydrocarbons such as hexane and toluene
- halogenated hydrocarbons such as, for example, methylene chloride, ethylene chloride, chloroform, and the like
- heterocyclic compounds such as, for example, tetrahydrofuran and N-methylpyrrolidinone
- ethers such as diethyl ether, bis-methoxymethyl ether.
- protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
- solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
- stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
- the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
- Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2 nd Ed. Wiley-VCH (1999); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
- subject refers to an animal.
- the animal is a mammal. More preferably, the mammal is a human.
- a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
- the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
- the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
- the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
- Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
- any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
- Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
- the present invention includes each conformational isomer of these compounds and mixtures thereof.
- the term "pharmaceutically acceptable salt,” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
- the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
- nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
- alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
- Pharmaceutically acceptable salts can also be prepared by deprotonation of the parent compound with a suitable base, thereby forming the anionic conjugate base of the parent compound. In such salts the counter ion is a cation.
- Suitable cations include ammonium and metal cations, such as alkali metal cations, including Li + , Na + , K + and Cs + , and alkaline earth metal cations, such as Mg 2+ and Ca 2+ .
- pharmaceutically acceptable ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
- Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
- esters include, but are not limited to, esters of C 1 -C 6 -alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.
- the invention provides pharmaceutically acceptable prodrugs of the compounds disclosed herein.
- prodrugs refers to those prodrugs of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
- Prodrug as used herein means a compound, which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant invention.
- prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol.4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
- prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002). Additional types of prodrugs are also encompassed.
- free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, ethyl succinate, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
- Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
- Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
- Prodrugs of this type are described in J. Med. Chem.1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides.
- prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
- a compound of the invention can incorporate two or more groups that are metabolically removed in vivo to yield the active parent compound.
- treating means relieving, lessening, reducing, eliminating, modulating, or ameliorating, i.e. causing regression of the disease state or condition. Treating can also include inhibiting, i.e. arresting the development, of an existing disease state or condition, and relieving or ameliorating, i.e. causing regression of an existing disease state or condition, for example when the disease state or condition may already be present.
- preventing means, to completely or almost completely stop a disease state or condition, from occurring in a patient or subject, especially when the patient or subject is predisposed to such or at risk of contracting a disease state or condition.
- the compounds of the present invention for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
- Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
- Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
- “Solvates” means solvent addition forms that contain either stoichiometric or nonstoichiometric amounts of solvent.
- Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.
- the solvent is water
- the solvate formed is a hydrate
- the solvent is alcohol
- the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
- the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
- an analog is a compound that is similar to or comparable in function and appearance to the reference compound.
- Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.
- stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
- the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
- Synthetic chemistry transformations and protecting group methodologies useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.
- compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
- the term "pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
- materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen
- compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
- the pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
- the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
- Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite
- the dosage form may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
- the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
- Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
- dosage forms can be made by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin.
- the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- ACN for acetonitrile
- AD-mix- ⁇ for (9S)-(9''S)-9,9''-[1,4-Phthalazinediylbis(oxy)]bis[10,11-dihydro-6'- methoxycinchonan]
- Bn for benzyl
- BOP for (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
- BzCl for benzoyl chloride
- mCPBA for meta-chloroperbenzoic acid
- Cbz for benzyloxycarbonyl
- CDI for carbonyldiimidazole
- DAST for diethylaminosulfur trifluoride
- DBU for 1, 8-Diazabicycloundec-7-ene
- DCE for dichloroethane
- DCM dichloromethane
- epoxide 4 Alkylation of the hydroxy pyridine 1 with hydroxy epoxide using Mitsunobu reaction conditions affords epoxide 4.
- hydroxy epoxide is converted to 3 which has a leaving group such as but not limited to, tosyl and methanlsulfonyl followed by alkylation in the presence of base such as but not limited to, K 2 CO 3 and Cs 2 CO 3, provides 4.
- Intramolecular epoxide opening mediated by base such as but not limited to, LDA, produces compound 5.
- Hydroxy group compound 5 is protected with proper protecting group such as but not limited to, TBDPS and TBS, affords compound 6.
- Trifluomethyl ketone 7 is obtained from iodine-magnesium exchange of compound 6 followed by addition of ester such as but not limited to, ethyl 2,2,2-trifluoroacetate. Trifluoromethyl ketone 7 in cross-coupled with various metal coupling partners 8, but not limited to, boronic acids, boronic esters, organotin reagents, organozinc reagents, organomagnesium reagents, organo silicon reagents or the like catalyzed by appropriate Pd, Ni, Cu or the like catalyst to afford compound 9. Nitromethane addition in the presence of base such as but not limited to, K 2 CO 3 and Cs 2 CO 3, to compound 9 affords compound 10.
- Compound 14-1 is further transformed to acetamide 19 in the presence of a catalyst such as, but not limited to, Parkin’s catalyst.
- a catalyst such as, but not limited to, Parkin’s catalyst.
- Scheme 2 As seen in scheme 3, wherein Ar1 is A; Ar is E; R is R11; and A, E, R11 are as previously defined.
- An aldehyde 16 is converted to the benzyl protected amine through reductive amination. Hydrogenolysis affords the free amine 20.
- displacement with a variety of electrophiles gives N-substituted compounds 21.
- Ketone 9 is converted to compound of formula 26 via olefination.
- 26 is obtained from; 1) 6 via cross-coupling with metal coupling partner 6-1, which can be, but is not limited to, a boronic acid, a boronic ester, an organotin reagent, an organozinc reagent, an organomagnesium reagent, an organosilicon reagent or the like catalyzed by appropriate Pd, Ni, Cu or the like catalyst to afford compound 25; 2) compound 25 is converted to compound 26 as previously described method in scheme 1.
- Compounds of formula 27 are prepared by dihydroxylation followed by epoxide formation.
- Epoxide opening of compound 27 with amine equivalent such as but not limited to, NH 4 OH and NH 3 provides compounds of formula 11.
- Scheme 5 illustrates another method to prepare a compound of formula 23, wherein Ar1 is A; Ar is E; R’ is –C 1 -C 6 alkyl, –C3-C6 cycloalkyl, aryl, or heteroaryl; n is 1, 2 or 3; and A, and E are as previously defined.
- Amine 11 is protected with a protecting group such as but not limited to, Boc and Cbz. After deprotection of hydroxy protecting group, subsequent oxidations provide acid 30.
- Compound 30 is coupled with various amines to provide amide 31.
- step b ped with a stir bar was added to the compound from step a (11.77 g, 31.8 mmol). The flask was purged with nitrogen, and the solid dissolved in THF (80 mL, 0.3 M). At 0oC, an LDA solution (35.0 mmol, 17.5 mL 2.0 M LDA in 26 mL THF) was slowly added (fast, dropwise pace) over 10 minutes. The reaction was stirred at 0oC and monitored by LCMS (5- and 6-membered rings have different retention times). If not complete, the flask was warmed to room temperature until complete.
- step c To a 500-mL round bottom flask containing the compound from step b (11.77 g, 31.8 mmol, mixture) was added a stir bar. The residue was dissolved in DMF (64 mL, 0.5 M), and imidazole (4.76 g, 70.0 mmol) was added.
- step d To a 250-mL round bottom flask containing the compound from step c (7.87 g, 12.94 mmol) was added a stir bar, and the flask purged with nitrogen. The flask was cooled to -40oC and ethyl trifluoroacetate (2.317 ml, 19.40 mmol) was added. Isopropylmagnesium chloride (7.76 ml, 15.52 mmol) was then slowly added and the reaction stirred for 10 minutes. The flask was then warmed to 0oC and monitored by LCMS. (1 hr: the reaction can be warmed to room temperature).
- Example 1 step e To a 250-mL round bottom flask containing the compound from step d (7.27 g, 12.57 mmol) was added a stir bar. The residue was dissolved in 1,4-dioxane (50 mL, 0.2 M), and potassium carbonate (3.91 g, 28.3 mmol) was added. PdCl2(dppf) (0.460 g, 0.628 mmol) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.35 g, 15.08 mmol) were added and the flask purged with nitrogen. Water (12 mL, sparged with nitrogen for 15 minutes) was then added.
- the flask was then quickly equipped with a condenser and heated to 90oC for 14 hrs under flow of nitrogen. Reaction conversion monitored by LCMS. The reaction was diluted with EtOAc and quenched with saturated ammonium chloride. An EtOAc extraction was carried out and the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give a mixture of product and hydrate. The product was dissolved in 20 mL toluene, and MgSO 4 was added to form a suspension and stirred vigorously for 1.5 hr to dehydrate. Dehydration was monitored by HNMR aliquots. The MgSO4 was filtered off and rinsed with DCM and concentrated.
- step f To a 250-mL round bottom flask containing the compound from step e (6.33 g, 10.02 mmol) was added a stir bar. Nitromethane (40 mL, 0.25 M) was added followed by potassium carbonate (4.16 g, 30.1 mmol). The flask was stirred at room temperature and the progress was monitored by LCMS (2.5 hrs). The reaction was diluted with EtOAc and quenched with water and saturated ammonium chloride.
- Zinc (6.01 g, 92 mmol) was added, the reaction warmed to room temperature and monitored by LCMS (2 hrs). The reaction was diluted with EtOAc and the zinc removed by filtering over a pad of celite. The celite was rinsed with EtOAc and MeOH. The combined organics were concentrated under reduced pressure to remove most of the acetic acid. The crude residue was dissolved in EtOAc and water was added. The pH was brought about 8-9 with saturated sodium bicarbonate and stirring. The aqueous was extracted with EtOAc (4 times) and concentrated under reduced pressure.
- Example 2 To a 40-mL flask equipped with a stir bar was added to the compound from Example 1, step g (1.00 g, 1.601 mmol). The flask was purged with nitrogen, and the solid dissolved in THF (5 mL, 0.33 M). At 0oC, TBAF (3.20 ml, 3.20 mmol) was slowly added.
- step c To a 20-mL vial equipped with a stir bar was added to the compound from step b (575 mg, 0.828 mmol). The solid was dissolved in DCM (2.5 mL, 0.33 M) and the vial cooled to 0oC. Dess-Martin Periodinane (386 mg, 0.91 mmol) was added, the vial purged with nitrogen and stirred for 10 minutes.
- the solid was disso lved in DCE (0.2 mL, 0.33 M) and cyclopropylamine was added (solution of DCE, 3.3 mg, 0.058 mmol).
- Sodium triacetoxyborohydride (18.36 mg, 0.087 mmol) was added in one portion, the vial purged with nitrogen and stirred at room temperature.
- the reaction was monitored by LCMS (4 hrs), diluted with DCM and quenched with water.
- the aqueous was brought to pH around 8-9 with saturated sodium bicarbonate.
- a DCM extraction was carried out with a phase separator cartridge, residue concentrated. The crude residue was carried forward to the TBS deprotection seen below in Method D.
- step d (42.4 mg, 0.058 mmol) was added a stir bar, and the solid dissolved in DCM (0.39 mL, 0.15 M). HCl in dioxane (4M, 0.19 mL, 0.74 mmol) was added and the reaction stirred at room temperature. Upon completion by LCMS (2 hrs), the reaction was diluted with DCM and quenched with saturated sodium bicarbonate until pH about 8-9. A DCM extraction was carried out with a phase separator cartridge and the organics concentrated. The mixture of diastereomers was analyzed on HPLC to check separation.
- Example 7 The title compound was synthesized similarly to the phenyl carbamate formation above (Example 6) using 30 mg of the compound from example 2, step b, however using cyclopropyl isocyanate (CAUTION, volatile).
- ESI-MS m/z: 778.5 [M+H] + (TBS alcohol).
- TBS group was deprotected as explained in Method D.
- the mixture of diastereomers was analyzed on HPLC to check separation.
- the mixture was purified by prep-HPLC (20- 90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (4 mg, 15%) ESI-MS m/z: 664.5 [M+H] + .
- the title compound was synthesized according to Method C utilizing 137 mg of the compound from example 2, step c, benzyl amine (30.0 ⁇ l, 0.27 mmol, 1.7 equiv.) and 1.7 equiv. of sodium triacetoxyborohydride.
- step b To a 20-mL vial containing the compound from step a (100 mg, 0.128 mmol) was added a stir bar. The solid was dissolved in anhydrous MeOH (0.85 mL, 0.15 M) and Pd-C (33.9 mg, 0.032 mmol) was added.
- step c To a 2-dram vial equipped with a stir bar was added the compound from step b (28.65 mg, 0.041 mmol). The vial was purged with nitrogen and the solid dissolved in DCM (0.21 mL, 0.20 M).
- Example 9 The title compound was synthesized according to Method E using 30 mg of the compound from example 8, step b and cyclopropanecarbonyl chloride. The crude residue was analyzed by HNMR to observed shifting of the primary amine alpha-protons. The crude residue was carried forward to the TBS deprotection as described in Method D. The mixture of diastereomers was analyzed on HPLC to check separation.
- step b In a 2-dram vial equipped with a stir bar was added the compound from step a (52 mg, 0.073 mmol).
- Example 12 The title compound was synthesized according to Method G using 50 mg of the compound from Example 10, step a, cyclopropylsulfonamide (26 mg, 0.212 mmol, 3.0 equiv.), 3.0 equiv Hunig’s base and 1.5 equiv HATU. ESI-MS m/z: 812.4 [M+H] + (TBS alcohol).
- Example 14 To a 40 mL vial equipped with a stir bar was added 4-cyclopropoxy-3-methoxybenzoic acid (100 mg, 0.480 mmol), and the vial was purged with nitrogen. DCM (3.20 mL, 0.15 M) was added, and then Ghosez’s reagent (127 ⁇ l, 0.960 mmol) was slowly added.
- Example 16 The title compound was synthesized according to Method B using 195 mg of the compound from Example 15 and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give a the title compound as white, foamy solid (155 mg, 80%, mixture of diastereomers).
- Example 17 The title compound was synthesized according to Method C using 50 mg of the compound from Example 16. The mixture of diastereomers was analyzed on HPLC and by TLC to check separation.
- the title compound was synthesized according to Method C using 50 mg of the compound from Example 16 and cyclopropylmethylamine. The mixture of diastereomers was analyzed on HPLC and by TLC to check separation. The mixture was purified by prep-HPLC (20- 90%, 25 min) and lyophilized to the give the title compound as a white, fluffy solid (13 mg, 29%).
- ESI-MS m/z: 572.2 [M+H] + The title compound was synthesized according to Method B using 282 mg of the compound from example 21 and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes, then 0-25% methanol in dichloromethane) to give a the title compound as a white, foamy solid (260 mg, 93%, mixture of diastereomers). ESI-MS m/z: 570.2 [M+H] + .
- Example 23 The title compound was synthesized according to Method C using 50 mg of the compound from example 22. 1.50 equiv. of each amine and borohydride were used, and the reaction stirred overnight.
- Example 24 The title compound was synthesized according to Method C using 50 mg of the compound from example 22. 1.50 equiv. of each (S)-1-cyclopropylethylamine and sodium triacetoxyborohydride were used, and the reaction stirred overnight. The mixture of diastereomers was analyzed on HPLC and by TLC to check separation.
- Example 25 The title compound was synthesized according to Method C using 50 mg of the compound from example 22. 1.50 equiv. of each cyclopropylmethylamine and sodimu triacethoxyborohydride were used, and the reaction stirred overnight. The mixture of diastereomers was analyzed on HPLC and by TLC to check separation.
- the mixture was purified by prep-HPLC (20-90%, 25 min, 0.01% TFA), washed with saturated sodium bicarbonate, and lyophilized to give a white, fluffy solid (31.4 mg, 64%, mixture of +).
- the title compound was synthesized according to Method F using 100 mg of the compound from example 22, dried on high vacuum overnight, and carried forward crude to the next step.
- the title compound was synthesized according to Method G using 50 mg of the compound from example 26.
- the mixture of diastereomers was analyzed on HPLC and by TLC to check separation.
- Example 28 The title compound was synthesized according to Method G using 56 mg of the compound from example 26, ammonium chloride (20.46 mg, 0.383 mmol, 4.0 equiv), 5.0 equiv Hunig’s base and BOP (50.8 mg, 0.115 mmol, 1.2 equiv.) as the coupling agent.
- Example 29 step d The title compounds were synthesized according the procedure in Example 1, step e using of the compounds from step c (P1: 132 mg, and P2: 144 mg, respectively). The residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give sticky residues as single diastereomers. The residues were dehydrated by azeotroping/triturating 3x with 2 mL of toluene (P1: 101 mg, 73%, P2: 141 mg, 80%, respectively).
- step e The title compounds were synthesized according the procedure in Example 1, step f using of the compound from step d (P1: 101 mg and P2:141 mg, respectively). The crude residues were dried on high vacuum to give the title compounds as white solids (P1: 97 mg, 84%, P2: 113 mg, 85%). The crude material was carried forward to the next step without further purification.
- Example 33 The title compound was synthesized according to Method B using 472 mg of the compound (P1) from example 32, step b. The crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford the title compound as a white, foamy solid (387 mg, 82%, single diastereomer). ESI-MS m/z: 485.0 [M+H] + .
- Example 33 step b The title compound was synthesized according to Method C using 200 mg of the compound from step a, but with 5.0 equiv of cyclopropylmethylamine and 5.0 equiv hydride for 14 hours. The crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford the title compound as a white, foamy solid (163 mg, 73%). ESI-MS m/z: 540.2 [M+H] + .
- Example 33 step c To a 20 mL scintillation vial containing the compound from step b (193 mg, 0.358 mmol) was added a stir bar.
- the title compound was synthesized according to Method G using 15 mg of the compound from step c and 1.0 equiv of the respective acid for 2 hrs.
- the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to afford the title compound as white, fluffy solid (12.8 mg, 55%).
- Exam le 34 The title compound was synthesized according to Method G using 15 mg of the compound from step c and 1.0 equiv of the respective acid for 2 hrs.
- Example 35 The title compound was synthesized according to Method G using 15 mg of the compound from step c and 1.0 equiv of the respective acid for 2 hrs. The crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to afford a white, fluffy solid (10.2 mg, 43%). ESI-MS m/z: 614.2 [M+H] + .
- the title compound was synthesized according to Method G using 15 mg of the compound from step c, 1.0 equiv of the respective acid and PyBOP (21 mg, 1.2 equiv) as the coupling agent for 2 hrs.
- the crude residue was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to afford a white, fluffy solid (9 mg,
- the title compound was synthesized according to Method G using 15 mg of the compound from step c, 1.0 equiv of the respective acid and PyBOP (21 mg, 1.2 equiv) as the coupling agent for 2 hrs.
- Example 38 The title compound was synthesized according to Method G using 15 mg of the compound from step c, 1.0 equiv of the respective acid and PyBOP (21 mg, 1.2 equiv) as the coupling agent for 2 hrs.
- the crude residue was purified by automated column chromatography (silica gel, 0-50% ethyl acetate in hexanes to 0-20% methanol in dichloromethane) and lyophilized to afford a white, fluffy solid (16.2 mg, 79%).
- Example 40 The title compound was synthesized according to Method G using 15 mg of the compound from step c, 1.0 equiv of the respective acid and PyBOP (21 mg, 1.2 equiv) as the coupling agent for 2 hrs. The crude residue was purified by automated column chromatography (silica gel, 0-50% ethyl acetate in hexanes to 0-20% methanol in dichloromethane) and lyophilized to afford a white, fluffy solid (12 mg, 59%). ESI-MS m/z: 600.2 [M+H] + .
- Example 41 The title compound was synthesized according to Method G using 16 mg of example 33, step c, 1.0 equiv of the respective acid and PyBOP (23 mg, 1.2 equiv) as the coupling agent for 2 hrs.
- the crude residue was purified by automated column chromatography (silica gel, 0- 100% ethyl acetate in hexanes) and lyophilized to afford a white, fluffy solid (16.6 mg, 71%).
- the title compound was synthesized according to Method G using 16 mg of example 33, step c, 1.0 equiv of the respective acid and PyBOP (23 mg, 1.2 equiv) as the coupling agent for 2 hrs.
- step d the compound from Example 1, step d (1g, 1.644 mmol), 4,4,6-trimethyl-2-(3,3,3- trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (438 mg, 1.972 mmol), Pd(dppf)Cl 2 ⁇ DCM (81 mg, 0.099 mmol), and K2CO3 (681 mg, 4.93 mmol) were dissolved in 1,4-dioxane (7.40 ml) and water (0.822 ml). The reaction was sparged with N2 and sealed. The reaction was heated at 90°C for 2hr and cooled to room temperature and water was added. The aqueous layer was washed with EtOAc.
- Example 43 step b In a vial, the product from Example 43 step a (686 mg, 1.190 mmol), (4-fluorophenyl)boronic acid (200 mg, 1.428 mmol), PdCl 2 (dppf) (43.5 mg, 0.059 mmol), and K 2 CO 3 (370 mg, 2.68 mmol) were dissolved in dioxane (4.76 ml) and water (1.190 ml). The reaction was sparged with N2 and sealed. The vial was heated at 90°C for 2 hr. The reaction was monitored by LCMS. Vial cooled to RT and water added.
- Example 44 The title compound was synthesized according to Method C using 20 mg of the compound from example 22 (as a single diastereomer). 3.0 equiv. of amine HCl salt.3.0 equiv borohydride, 4.0 equiv. TEA were used, and the reaction stirred overnight. The crude reaction was purified by prep-HPLC (20-90%, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.0 mg, 27%). ESI-MS m/z: 625.2 [M+H] + .
- the title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 4.0 equiv of amine HCl salt, and 5.0 equiv. of DIPEA.
- the crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (9.1 mg, 33%).
- the title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 12.0 equiv of amine, and 5.0 equiv. of DIPEA for 48 hrs.
- Example 47 The title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 14.0 equiv of amine, and 4.0 equiv. of DIPEA. The crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (4.5 mg, 16%).
- Example 48 The title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 8.0 equiv of amine, 4.0 equiv. of DIPEA, and the adding 4.0 equiv more of HATU after 2 hrs. The crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (5.3 mg, The title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 10.0 equiv of amine, 4.0 equiv. of DIPEA for 14 hrs.
- the crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a + Example 51
- the title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 5.0 equiv of amine HCl salt, 6.0 equiv. of DIPEA for 3 hrs, then 5 equiv. amine/DIPEA and 4.0 equiv HATU for 2 hrs.
- the crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (8.4 mg, 28%).
- the title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 4.0 equiv of amine, 4.0 equiv. of DIPEA for 4 hrs, then 10 equiv. amine/DIPEA and 4.0 equiv HATU for 18 hrs.
- the crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (11.5 mg, 42%).
- Example 53 The title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 4.0 equiv of amine HCl salt, 5.0 equiv. of DIPEA for 4 hrs, then 10 equiv. amine/DIPEA and 4.0 equiv HATU for 18 hrs.
- the crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (12.0 mg, 39%).
- Example 54 The title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 4.0 equiv of amine HCl salt, 5.0 equiv. of DIPEA for 14 hrs.
- the crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (8.6 mg, 31%).
- the title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 4.0 equiv of amine HCl salt, 5.0 equiv. of DIPEA for 14 hrs.
- Example 56 The title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 10.0 equiv of amine, 5.0 equiv. of DIPEA for 14 hrs. The crude reaction was purified by automated column chromatography (0-10% methanol in dichloromethane), and lyophilized to give the title compound as a white, fluffy solid (15.0 mg, 57%).
- Example 57 The title compound was synthesized according to Method G using 25 mg of the compound from example 26 (as a single diastereomer), 4.0 equiv of amine HCl salt, 5.0 equiv. of DIPEA for 14 hrs. The crude reaction was purified by prep-HPLC (20-90%, 25 min), and lyophilized to give the title compound as a white, fluffy solid (8.0 mg, 29%). ESI-MS m/z: 655.0 [M+H] + .
- Example 59 Example 59 step a The title compound was synthesized according to Method F using 380 mg of the aldehyde (as a single diastereomer).
- the crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (354 mg, 90%, ESI-MS m/z: 444.9 [M+H] + .
- the title compound was synthesized according to Method G using 354 mg of the acid from step a.
- the crude residue was purified using automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (266 mg, 57%), ESI-MS m/z: 443.9 [M+H] + .
- the title compound was synthesized according to the deprotection procedure in example 33, step c, using 120 mg of the amide from step b.
- the crude residue was triturated with dichloromethane/hexanes, to afford a light yellow solid (95 mg, 99%), ESI-MS m/z: 400.0 [M+H] + .
- the title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs.
- the crude reaction was purified by automated column chromatography (silica gel, 0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (6.7 mg, 24%).
- Example 60 The title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs. The crude reaction was purified by automated column chromatography (silica gel, 0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy The title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs.
- the crude reaction was purified by automated column chromatography (silica gel, 0-20% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (20.9 mg, 76%).
- the title compound was synthesized according to Method G using 23 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs.
- the crude reaction was purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) and lyophilized to give the title compound as a white, fluffy solid (16.0 mg, 52%).
- Example 63 The title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv of respective acid for 1.5 hrs. The crude reaction was purified by automated column chromatography (silica gel, 0-10% methanol in dichloromethane) and lyophilized to give the title compound as a white, fluffy solid (10.5 mg 41%). ESI-MS m/z: 572.9 [M+H] + .
- the title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv of respective acid for 1.5 hrs.
- the crude reaction was purified by prep-HPLC (20-90% MeCN/H 2 O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (6.3 mg, 22%).
- Example 65 The title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv of respective acid for 1.5 hrs.
- Example 66 The title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs. The crude reaction was purified by prep-HPLC (20-90% MeCN/H 2 O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (9.3 mg, 35%). ESI-MS m/z: 583.9 [M+H] + .
- the title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs.
- the crude reaction was purified by prep-HPLC (20-90% MeCN/H2O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (11.3 mg, 34%).
- Example 68 The title compound was synthesized according to Method G using 25 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs.
- Example 69 The title compound was synthesized according to Method G using 25 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs. The crude reaction was purified by prep-HPLC (20-90% MeCN/H 2 O, 25 min) and lyophilized to give the title compound as a white, fluffy solid (10.0 mg, 31%). ESI-MS m/z: 584.1 [M+H] + .
- the title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs.
- the crude reaction was purified by automated column chromatography (silica gel) and lyophilized to give the title compound as a white, fluffy solid (10.5 mg, 31%).
- the title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs.
- ESI-MS m/z: 578.3 The title compound was synthesized according to Method G using 20 mg of the compound from example 59 step c above, (1.0 equiv) and 1.0 equiv. of respective acid for 1.5 hrs. The crude reaction was purified by automated column chromatography and lyophilized to give the title compound as a white, fluffy solid (8.6 mg, 25%). ESI-MS m/z: 615.2 [M+H] + .
- example 21 (as a single diastereomer) (200 mg, 0.35 mmol) in DMF (4 mL), then 4-methylbenzenesulfonyl chloride (70.0 mg, 0.37 mmol), N,N- dimethylpyridin-4-amine (42.8 mg, 0.35 mmol) and triethylamine (0.15 mL, 1.05 mmol) were slowly added. After the resulting mixture was stirred at room temperature for 20 hrs, it was diluted with DCM (50 mL). The mixture was washed with brine, dried and purified by automated column chromatography (silica gel, 0-3% methanol in dichloromethane) to afford the title compound (87 mg, 34%).
- Example 77 was prepared using a procedure similar to that used to prepare example 59 from the corresponding acid in step d.
- Example 78 was prepared using a procedure similar to that used to prepare example 59 from the corresponding acid in step d. ESI-MS m/z: 638.2 [M+H] + .
- Table 1 The following examples in Table 1 were made in an analogous fashion to Example 59 with the corresponding intermediates.
- Example 98 step a (Method K) The following example was made in analogous fashion to Method I step a with 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine and methyl 3-bromo-4- cyclopropoxybenzoate.
- Example 100 steps a and b (Method M) A solution of the methyl 3-bromo-4-cyclopropoxybenzoate (300 mg, 1.11 mmol), 2- (tributylstannyl)pyrazine (615 mg, 1.66 mmol) and Pd(PPh 3 ) 2 Cl 2 (68 mg, 0.09 mmol) in DMF (3 mL) was stirred for 2 hours at 90oC under N2 atmosphere. The resulting solution was purified by silica gel column chromatography (EtOAc in hexanes) to afford desired product as a white solid. ESI-MS m/z: 271.00 [M+H] +.
- Example 101 steps a and b (Method N) A solution of the 3-bromo-4-cyclopropoxybenzoic acid (1 g, 3.9 mmol), bis(pinacolato)diboron (2 g, 7.78 mmol), KOAc (1.2 g, 11.67 mmol) and Pd(dppf)Cl 2 (DCM) (635 mg, 0.78 mmol) in dioxane (6 mL) was stirred for 2 hours at 90oC. ESI-MS m/z: 223.05 [M+H] + .
- Example 102 step a (Method O) A solution of methyl 4-hydroxy-3-methoxybenzoate (3 g, 16.47 mmol), K 2 CO 3 (6.8 g, 49.57 mmol), 1,2-dibromoethane (15.5 g, 82.34 mmol) in DMF (30 mL) was stirred for 2 hours at 45oC. The resulting solution was quenched with water and extracted with EtOAc. The combined organics were dried, concentrated and purified by reverse phase C18 column chromatography (MeCN/H 2 O) to afford desired product as a light-yellow solid (3 g, 61%).
- Example 102 step b (Method O) A solution of the compound from step a (1 g.3.64 mmol), morpholine (0.6 g, 6.88 mmol) and K2CO3 (1 g, 6.95 mmol) in DMF was stirred for 2 hours at 50 oC. The reaction was quenched with water and extracted with EtOAc. The combined organics were dried, concentrated and the crude product purified by reverse phase C18 column chromatography (MeCN/H 2 O) to afford desired product (1 g, 93%). ESI-MS m/z: 296.05 [M+H] + .
- Example 196 step a Into a 40-mL vial were added methyl 4-bromo-3 cyclopropoxybenzoate(1 g, 3.69 mmol), tributyl(1-ethoxy-ethenyl)stannane (1.6 g, 4.426 mmol), Pd(dppf)Cl2(DCM) (0.6 g, 0.74 mmol) and DMF (15 mL) at room temperature.
- Example 196 step b Into a 100 mL round-bottom flask were added the compound from step a (450 mg, 1.91 mmol), NBS (373 mg, 2.1 mmol), THF (10 mL) and H 2 O (3 mL) at room temperature.
- Example 196 step e The title compound was prepared in an analogous fashion to Method J with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (11 mg, 23%). ESI-MS m/z: 641.10 [M+H] + .
- Example 197 The title compound was prepared in an analogous fashion to Example 196 above with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (30.6 mg, 65%). ESI-MS m/z: 615.18 [M+H] + .
- Example 198 steps a and b A solution of bromide from Example 196 step b (187 mg, 0.60 mmol), HCONH2 (158 mg, 3.5 mmol) and formic acid (5mL) was stirred at 100oC under nitrogen atmosphere. The resulting mixture was concentrated under vacuum and by reverse phase chromatography (C18 silica gel; 10-70%, 25 min. MeCN/H2O) to afford the title compound (60 mg, 33%). ESI-MS m/z: 260.08 [M+H] + .
- Example 198 step c The title compound was prepared in an analogous fashion to Method J with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (36.7 mg, 74%). ESI-MS m/z: 627.25 [M+H] + .
- Example 199 The title compound was prepared in an analogous sequence to Example 198 above with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (27.2 mg, 60%). ESI-MS m/z: 601.16 [M+H] + .
- Example 200 Example 200 step a A solution of methyl 4-bromo-3-methoxybenzoate (4 g, 16.32 mmol), Pd(OAc) 2 , (733 mg, 3.26 mmol) and dppp (1.3 g, 3.26 mmol) in DMF:H2O:TEA (4:4:1, 20 mL) was stirred for 6 hours at 100oC under CO atmosphere. The resulting solution was extracted with EtOAc, the organic layer dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN/H2O) to afford desired product (1.8 g, 52%). ESI-MS m/z: 211.10 [M+H] + .
- Example 200 steps b and c A solution of the compound from step a (1.7 g, 8.08 mmol),HATU (4.6 g, 12.12 mmol), DIPEA (2 g, 16.17 mmol) and Boc-hydrazine (1.4 g, 12.12 mmol) in DMF (10 mL) was stirred for 2 hours at room temperature. The reaction was quenched with water, extracted with EtOAc, and combined organics were dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN/H 2 O) to afford desired product (2.1g, 80%). ESI-MS m/z 269.10 [M+H-56] + .
- Example 200 step f The title compound was prepared in an analogous fashion to Method J with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (36.5 mg, 74%). ESI-MS m/z: 602.05 [M+H] + .
- Example 201 step a A solution of Example 200 step b (above) (300 mg, 1.34 mmol) and formic acid (924 mg, 20.07 mmol) in toluene (5 mL) was stirred for 4 hours at 120oC. The reaction was quenched with water, extracted with EtOAc, and combined organics were dried and concentrated.
- Example 202 step a LDA was added to acetone (691 mg, 11.89 mmol) in THF (10 mL) at -78°C. The resulting solution was stirred for 0.5 hour at -78°C.
- a solution of 2-methoxy-4- (methoxycarbonyl)benzoic acid (500 mg, 2.38 mmol) and (1-chloro-2-methylprop-1-en-1- yl)dimethylamine (1.6 g, 12.03 mmol) in DCM (10 mL) was stirred for 0.5 hour at room temperature. The resulting mixture was concentrated under vacuum. The LDA reaction mixture was added and stirred for 30 minutes at room temperature.
- Example 202 step d The title compound was prepared in an analogous fashion to Method J with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (30.8 mg, 67%).
- Example 203 step a In a vial, methyl (R)-3-bromo-4-(2-hydroxypropoxy)benzoate (100 mg, 0.346 mmol), PdCl 2 (dppf) (25.3 mg, 0.035 mmol), K 2 CO 3 (120 mg, 0.865 mmol), and pyrimidin-5- ylboronic acid (64.3 mg, 0.519 mmol) were dissolved in Dioxane (1.383 ml) and Water (0.346 ml). The reaction weas heated to 85°C overnight. The reaction was cooled to RT and water was added. The aqueous layer was washed with EtOAc and the combined organic layer was dried over MgSO 4 .
- Example 203 step b In a vial, methyl methyl (R)-4-(2-hydroxypropoxy)-3-(pyrimidin-5-yl)benzoate (54 mg, 0.187 mmol) and lithium hydroxide (22.43 mg, 0.937 mmol) were dissolved in THF (0.3 ml), MeOH (0.3 ml), and Water (0.3 ml). The reaction was allowed to stir overnight. Water was added and 1M aq. HCl was added to pH 2-3.
- Example 204 The title compound was prepared in an analogous fashion using Example 203 above and Method J with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (1.2 mg, 3%). ESI-MS m/z: 655.18 [M+H] + .
- Example 205 step a Into a 100 mL round-bottom flask were added Example 1, step b (3.80 g, 10.27 mmol), acetone (100 mL), the solution was cooled to 0oC, and then Jones reagent (1.9 ⁇ 2.2 M, 10 mL) was added dropwise (with internal temperature monitoring).
- Example 205 step b Into a 100 mL round-bottom flask were added the compound from step a (3.95 g, 10.28 mmol), NH 4 Cl (1.10 g, 20.57 mmol) and the solids dissolved in DMF (20 mL).
- Example 205 step c Into a 100 mL round-bottom flask were added the compound from step b (3.00 g, 7.83 mmol), 3,3,3-trifluoroprop-1-en-2-ylboronic acid (2.19 g, 15.65 mmol), Pd(dppf)Cl2 (1.15 g, 1.56 mmol), and the material dissolved in dioxane (40 mL) and H2O (5 mL). K2CO3 (3.25 g, 23.50 mmol) was then added and the resulting mixture was stirred for 1 h at 90oC under nitrogen atmosphere. The mixture was cooled to room temperature, poured into water, extracted with EtOAc and the combined organics were concentrated under reduced pressure.
- step d To a stirred solution of step c (5.00 g, 14.24 mmol) and 3-chloro-4-fluorophenylboronic acid (3.72 g, 21.33 mmol) in THF (80 mL) were added Na2CO3 (3.32 g, 31.33 mmol), H2O (20 mL) and Pd(PPh3)2Cl2 (1.00 g, 1.42 mmol) .
- Example 205 step e To a 500 mL round-bottom flask equipped with a stir bar was added AD-mix- ⁇ (33.82 g, 43.41 mmol) and methanesulfonamide (1.38 g, 14.47 mmol). The solids were dissolved in tBuOH (60 mL) and H 2 O (100 mL), and the flask cooled to 0oC and the compound from step d (5.80 g, 14.47 mmol) was added slowly as a solution of tBuOH (40 mL). The reaction was allowed to warm to room temperature naturally and stirred for 16 hrs.
- Example 205 step f Into a 250 mL round-bottom flask were added the compound from step e (4.70 g, 10.81 mmol) and DCM (80 mL) at room temperature. The solution was cooled to 0oC, and DMAP (264 mg, 2.16 mmol), TEA (3.28 g, 32.43 mmol and TsCl (2.47 g, 12.97 mmol) were then sequentially added. The resulting mixture was stirred for 1 h at 0oC. The mixture was acidified to pH 4 with 2 M HCl, and the aqueous extracted with DCM.
- Example 205 step g Into a 100 mL round-bottom flask was added NH 3 in MeOH (35 mL) at room temperature, and the compound from step g (6.20 g, 10.52 mmol) was slowly added. The resulting mixture was stirred at room temperature and monitored by LCMS (5 hr). The mixture was dissolved in EtOAc, washed with sat. sodium bicarbonate 3x, brine, dried, and concentrated to afford the title compound (2.93 g, 64%).
- Example 206 Example 206 step a To a 100-mL round bottom flask containing the compound from (R)-7-bromo-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine (4.32 g, 8.94 mmol) was added a stir bar, N-methoxy-N-methylacetamide (1.43 mL, 13.4 mmol) and THF (45 ml).
- Example 206 step b To a 250-mL round bottom flask containing methyltriphenylphosphonium bromide (5.34 g, 15.0 mmol), was added THF (42 mL), the mixture was cooled to 0 °C and potassium tert- butoxide (1.60 g, 14.2 mmol) was added slowly as a solution in THF (14 mL). The yellow suspension was stirred for 30 min at 0 °C, then step a (4.327 g, 8.94 mmol) was added as a solution in THF (33 mL).
- Example 206 step c The title compound was synthesized according the procedure in Example 205, step d using 1.2 eq. of (4-fluorophenyl)boronic acid, and the compound from step b (2.13 g 5.36 mmol). The residue was purified by automated silica gel chromatography (0-5% EtOAc/hexanes) to give the title compound as a colorless oil. (2.19 g, 99%.) ESI-MS m/z: 414.8 [M+H] + .
- Example 206 step d A suspension of AD-mix- ⁇ (8.26 g, 10.6 mmol) and methanesulfonamide (0.504 g, 5.30 mmol) in water (26.5 mL) and tBuOH (2 mL) was cooled to 0 oC then was added the compound from step c (2.19 g, 5.30 mmol) as a solution in tBuOH (24.5 ml). The reaction was allowed to warm to room temperature with stirring for 16 h and was then quenched with the addition of sodium sulfite (2.00 g, 15.9 mmol), diluted with water and EtOAc. The layers were separated, and the aqueous layer was washed with EtOAc.
- step e To a solution of the compound from step d (2.30 g, 5.13 mmol) was added triethylamine (2.1 mL, 15 mmol) and DMAP (627 mg, 5.13 mmol), the mixture was cooled in an ice bath, then TsCl (1.1 eq) was added slowly as a solid.
- Example 206 step g The title compound was synthesized according to the procedure in Example 32, step a using the compound from step f (3.09 g, 6.92 mmol) and 1.1 equiv of Boc-anhydride. The reaction mixture was purified by automated silica gel chromatography (0-15% EtOAc/hexanes) to afford the title compound (3.39 g, 90% over two steps) as a yellow oil. ESI-MS m/z: 547.7 [M+H] + .
- Example 206 step i To a suspension of P1 from step h (220 mg, 0.508 mmol) in aqueous sodium hydroxide (1.2 mL, 5 wt%, 1.5 mmol), was added dropwise potassium permanganate (281 mg 0.778 mmol) as a solution in water (5.6 mL). The reaction was monitored by LCMS until complete (42 h), and was then cooled to 0 oC, and quenched with the dropwise addition of sodium sulfite (640 mg, 5.08 mmol) as a solution in water (6.4 mL). The mixture was then acidified to pH 1-3 with the addition of 1 M HCl.
- Example 206 step j The title compound was synthesized according to Example 205 step b using 137 mg of the compound from step i and 10 equiv of NH4Cl. The compound was purified by automated silica gel chromatography (0-100% EtOAc/hexanes) to afford the title compound (86 mg, 63%) as a white solid. ESI-MS m/z: 446.4 [M+H] + . .
- Example 206 step k A suspension of the compound from step j (259 mg, 0.580 mmol) in DCM (7.3 mL) was cooled to 0 oC and HCl in water (1.5 mL, 4 N, 5.8 mmol) was added. The reaction was monitored by TLC and LCMS until complete (2 h,) at which time diethyl ether (20 mL) was added, and the mixture stirred for 1 h, as white solids precipitated. The solids were collected by filtration to afford the title compound (184 mg, 83%) as a white solid. ESI-MS m/z: 346.3 [M+H] + .
- Example 207 This intermediate was used for the synthesis of a wide variety of analogs in an analogous sequence to Examples 205 and 206.
- This example was prepared in an analogous sequence to Example 206, instead using N- methoxy-N-methylcyclopropanecarboxamide.
- the residue was purified by silica gel column chromatography (10% EtOAc/hexanes) to afford the desired product as a yellow-green oil.
- Example 208 step a A solution of methyl 3-hydroxy-4-methoxybenzoate (20 g, 0.11 mol), vinyl acetate (19 g, 0.22 mol), [Ir(cod)Cl]2 (62.4 mg, 0.11 mol) and NaHCO3 (18.44 g, 0.22 mol) in toluene (500 mL) was stirred for 3h at 110oC under a N2 atmosphere. The resulting mixture was concentrated under vacuum and the residue purified by silica gel column chromatography (20% EtOAc in hexanes, 30 min) to the desired compound as a yellow oil (10.4 g, 45%). ESI- MS m/z: 209.10 [M+H] + .
- Example 208 steps b and c To a stirred solution of the compound step a (10.4 g, 47.84 mmol) in DCE (200 mL) were added CH2I2 (25.65 g, 95.69 mmol) and Et2Zn (1 M, 96 mL, 96 mmol) in portions at 0oC under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 0oC under nitrogen atmosphere. The reaction was quenched by the addition of water DCM and the combined organics were washed with brine, dried and concentrated. The crude material was purified by reverse phase C18 column chromatography (MeCN/H2O) to give the desired compound as a yellow solid (7.8 g, 70%).
- Example 208 step d A solution of the compound from step c (4.6 g, 23.59 mmol) in MeOH (40 mL) and H2O (3 mL) was stirred for 3 hr at 80oC under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (20% EtOAc in hexanes, 30 min) to afford the desired compound as a yellow oil (4.7 g, 95.91%).
- Example 208 steps e and f To a stirred solution of methyl 3-cyclopropoxy-4-hydroxybenzoate (4.0 g, 20 mmol) and (+)- propylene oxide (3.43 g, 60 mmol) in DMF (50 mL) were added K2CO3 (5.4 g, 40 mmol), and the resulting mixture was stirred for 16 hr at 80oC. The reaction was quenched with water at 0oC, and the resulting mixture was extracted with EtOAc. The combined organics were washed with brine, dried and concentrated. The crude material was purified by silica gel column chromatography (0-75% EtOAc in hexanes) to afford the product (3g, 58%).
- Example 210 A solution of 4-amino-3-hydroxybenzoic acid (600 mg, 3.91 mmol) and crotonaldehyde (824 mg, 11.75 mmol) in AcOH:HCl (2:3, 10 mL) was stirred for 1 hour at 100oC under N2 atmosphere. The resulting solution was concentrated, and the crude material was purified by reverse phase C18 column chromatography (MeCN/H2O) to afford desired product (600 mg, 75%).
- Example 212 The title compound was synthesized according to Method P using 493 mg 4-amino-3- hydroxybenzoic acid and 533 ⁇ l methacrolein. Solids were collected by filtration to afford the title compound (195 mg, 30%) as a yellow solid. ESI-MS m/z: 203.9 [M+H] + .
- Example 213 The title compound was synthesized according to Method P using 5.00 g 4-amino-3- methoxybenzoic acid and 5.0 ml methacrolein.
- Example 214 The title compound was synthesized according to Method P using 2.00 g 4-amino-3- hydroxybenzoic acid and 1.82 g 2-methylenebutanal. The aqueous layer was washed with EtOAc (4 x 5 mL), solids had then precipitated in the aqueous layer, these were collected by filtration to afford the title compound (70 mg, 3%) as a yellow solid.
- Example 215 The title compound was synthesized according to Method P using 2.98 g 4-amino-3- methoxybenzoic acid and 3.00 g 2-methylenebutanal. The aqueous layer was washed with EtOAc (4 x 5 mL), solids had then precipitated in the aqueous layer, these were collected by filtration to afford the title compound (811 mg, 20%) as a yellow solid. ESI-MS m/z: 232.1 [M+H] + .
- Example 216 step a To a solution of methyl 3-fluoro-4-nitrobenzoate (5.66 g, 28.4 mmol) in DMF (56 mL) was added Cs2CO3 (13.89 g, 42.6 mmol) and cyclopropanol (2.7 ml, 42.6 mmol). The mixture was heated to 75°C for 16 h, then cooled to room temperature and diluted with H 2 O (30 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic phase was washed with water (2 x 5 mL) then saturated aqueous NaCl (5 mL) and dried over Na2SO4. The crude material was carried forward to the next step directly.
- Example 216 step d This example was prepared by Method P using the compound from step c and methacrolein. After the reaction was complete the aqueous layer was washed with EtOAc (3 x 15 mL), the aqueous layer was then concentrated to dryness, the resulting solids were washed with MeOH (3 mL) and collected to afford desired product as yellow solids (160 mg, 14% over two steps). ESI-MS m/z: 244.0 [M+H] + .
- Example 217 steps a and b To a 50 mL round-bottom flask equipped with a stir bar was added methyl 8- hydroxyquinoline-6-carboxylate (500 mg, 2.461 mmol), 2-bromoacetamide (509 mg, 3.69 mmol) and potassium carbonate (850 mg, 6.15 mmol). The solids were dissolved in DMF (0.5 M), the reaction stirred at 40oC and monitored by LCMS (3 hrs). The reaction was cooled to room temperature, diluted with EtOAc and quenched with water. Solid precipitated (quinoline products have solubility issues). Added DCM and hexanes to further precipitate. Stirred vigorously.
- Example 218 Method 1 Example 218 Method 1 step a The vinyl ether was synthesized in an analogous fashion to Example 208 step a utilizing methyl 8-hydroxyquinoline-6-carboxylate (5 g, 24.6 mmol). The material was purified by automated column chromatography to afford the title compound (1.97 g, 35%).
- Example 218 Method 1 steps b and c The cyclopropanation was carried out according to Example 208 step b using step a. The material was purified by automated column chromatography to afford the title compound (1.67 g, 80%). ESI-MS m/z: 243.08 [M+H] + . The methyl ester was hydrolyzed in a similar manner to Method O, and the material was purified by reverse phase prep-HPLC (MeCN/H2O) to give the desired compound as a white solid (1.50 g, 95%). ESI-MS m/z: 230.05 [M+H] + .
- Example 218 Method 2 steps a, b, c Cyclization precursor was synthesized in an analogous fashion to Example 216 steps a, b and c above.
- ESI-MS m/z 194.0 [M+H] + .
- Example 218 Method 2 step d The following example was prepared according to Method P using acrolein (1.5 eq) and step c to afford the title compound as a light, brown solid (5.2 g, 74%).
- Method 3 Example 218 Method 3 step a To a 250-mL tank equipped with a stir bar was added to 6-bromoquinolin-8-ol (10 g, 44.64 mmol).
- step b To a stirred solution of step a (4.50 g, 17.03 mmol) in MeOH (50 mL) was added TEA (5.17 g, 51.11 mmol) and Pd(dppf)Cl2 (1.25 g, 1.70 mmol). The resulting mixture was stirred for 4 hr at 100oC under a CO atmosphere (10 atm). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc/hexanes) to afford the title compound (2.9 g, 70 %) as a light-yellow solid.
- Example 218 Method 3 step c The methyl ester was hydrolyzed in a similar manner to Method O, and the material was purified by reverse phase flash chromatography (MeCN/H2O) to give the desired compound as a white solid (1.30 g, 48%). ESI-MS m/z: 230.15 [M+H] + .
- Method 4 Example 218 Method 4 step a The following example was prepared according to Method P using acrolein (2.0 eq) to afford the title compound as a yellow solid (9.0 g, 36%). ESI-MS m/z: 208.0 [M+H] + .
- Example 218 Method 4 step b A solution of step a (9.00 g, 47.57 mmol) in 98% H2SO4 (8 mL) and MeOH (100 mL) was stirred for 2h at 80oC. The resulting mixture was concentrated under reduced pressure. The crude material was diluted with EtOAc, washed with water and saturated NaHCO 3 and concentrated to afford the title compound (8.9 g, 91%) as a yellow solid. ESI-MS m/z: 204.05 [M+H] + .
- Example 218 Method 4 steps c and d The bromocyclopropane alkylation was carried out using step b in an analogous fashion to Example 218, Method 3 step a.
- Example 218 Method 3 step c.
- the following examples in Table 3 were prepared using the corresponding intermediates from Examples 205-207, or derivatives thereof.
- the target compounds were made according to Method J with PyBOP (and in some cases HATU) using either amine or amine HCl salt.
- the crude material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) in most cases.
- the aryl acid coupling partners were made according to Examples 208-218, and if not specifically listed, they were synthesized in an analogous manner. Table 3
- Table 4 contains examples that were prepared according to Method J (PyBOP or HATU) with commercially available aryl acid coupling partners. The majority of compounds were purified by Gilson prep-HPLC, and some were purified by automated column chromatography (silica gel).
- Table 4 Example 335 step a (Method S) A suspension of methyl 8-hydroxyquinoline-6-carboxylate (3.00 g, 14.76 mmol) and Hunig's base (5.16 ml, 29.5 mmol) in DCM (59.1 ml) was cooled to 0°C and treated with triflic anhydride (2.74 ml, 16.24 mmol). The suspension immediately became homogeneous and was warmed to room temperature and monitored by LC-MS.
- Example 335 step b (Method S) A mixture of pyridin-4-amine (0.047 g, 0.500 mmol), step a (0.168 g, 0.500 mmol), t- BuBrettPhos Pd G3 (0.021 g, 0.025 mmol), and potassium carbonate (0.097 g, 0.700 mmol) in t-BuOH (2.0 mL) was heated to 90°C. After stirring overnight, the reaction was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated.
- step b A solution of step b (0.140 g, 0.500 mmol) and potassium trimethylsilanolate (0.192 g, 1.500 mmol) in THF (5 mL) was stirred at room temperature overnight.
- Example 350 steps a and b A 20 mL vial was charged a magnetic stir-bar, pyridin-3-ylboronic acid (0.160 g, 1.300 mmol), Example 335 step a (Method S) (0.335 g, 1.00 mmol), and potassium carbonate (0.415 g, 3.00 mmol). THF (8 mL) and water (2 mL) were added and the reaction mixture was sparged with nitrogen and treated with bis(triphenylphosphine)palladium(II) chloride (0.070 g, 0.100 mmol). The reaction was heated to 70°C and monitored by LC-MS (1 hr).
- Example 350 step c The following example was prepared using amine HCl salt (96 mg, 0.240 mmol) according to Method J (HATU). The crude material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (36 mg, 24%). ESI-MS m/z: 632.3 [M+H] + .
- Example 351 The following example was prepared in an analogous fashion to Example 350 using amine HCl salt (35 mg, 0.08 mmol), and the crude material was purified by Gilson prep-HPLC (20- 90%, MeCN/Water, 25 min) to afford the title compound (24 mg, 48%). ESI-MS m/z: 632.3 [M+H] + .
- Example 352 The following example was prepared in an analogous fashion to Example 350 using amine HCl salt (33 mg, 0.075 mmol), and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (0.5 mg, 1%). ESI-MS m/z: 648.3 [M+H] + .
- Example 353 The following example was prepared in an analogous fashion to Example 350 using amine (52 mg, 0.120 mmol), and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (6.4 mg, 9%). ESI-MS m/z: 632.2 [M+H] + .
- Example 354 The following example was prepared in an analogous fashion to Example 350 using amine (78 mg, 0.179 mmol), and the crude material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (82 mg, 72%).
- Example 355 Example 355 steps a and b A mixture of methyl 8-hydroxyquinoline-6-carboxylate (1.00 g, 4.92 mmol), tert-butyl (2- iodoethyl)carbamate (2.00 g, 7.38 mmol), and cesium carbonate (3.21 g, 9.84 mmol) in DMF (20 mL) was stirred at room temperature for 24 hr. The reaction mixture was poured into brine and extracted thrice with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated.
- Example 355 step c The following example was prepared according to Method J (HATU) with amine HCl salt (204 mg, 0.511 mmol), and the crude material was purified by automated column chromatography to afford the title compound (262 mg, 72%). ESI-MS m/z: 714.3 [M+H] + .
- Example 356 The following example was prepared according to Example 355 step b and Method J (HATU) with amine HCl salt (17 mg, 0.511 mmol) and Boc-acid (14 mg). The crude material was dissolved in ⁇ 1.5 mL DCM and treated with 0.25 mL TFA at room temperature.
- Example 357 step a A solution of Example 355 step a (1.00 g, 2.89 mmol) in DCM (9 mL) was treated with TFA (1.80 mL) at room temperature. Upon complete consumption of SM (14 hr, LCMS), the reaction was concentrated and partitioned between DCM/MeOH (9:1) and sat'd aq. NaHCO 3 .
- Example 357 step d The following example was prepared according to Method J (HATU) with amine HCl salt (50 mg, 0.125 mmol). The crude material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (52 mg, 63%). ESI-MS m/z: 656.2 [M+H] + .
- Example 358 The aryl acid coupling partner was prepared using Example 357 step a (amine above) and mesyl-chloride over the same sequence to afford the title compound. ESI-MS m/z: 231.0 [M+H] + .
- Example 360 steps a and b A mixture of methyl 8-hydroxyquinoline-6-carboxylate (1.00 g, 4.92 mmol), tert-butyl(2- chloroethoxy)dimethylsilane (1.43 g, 7.38 mmol), and cesium carbonate (3.21 g, 9.84 mmol) in DMF (10 mL) was stirred at 50°C for 24 hr. The reaction mixture was poured into brine and extracted thrice with EtOAc. The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated.
- Example 361 Example 361 steps a and b A solution of 6-bromo-8-methoxyisoquinoline (400 mg, 1.7 mmol), TEA (510 mg, 5.0 mmol) and Pd(dppf)Cl 2 (246 mg, 0.3 mmol) in MeOH (20 mL) was stirred for 3 h at 100oC under a CO atmosphere (10 atm). The mixture was filtered, concentrated and purified by silica gel column chromatography (EtOAc/hexanes) to afford the desired compound as a light-yellow solid (300 mg, 82%). ESI-MS m/z: 218.05 [M+H] + .
- Example 362 step a In a vial, 1-chloroisoquinoline-6-carboxylic acid (100 mg, 0.482 mmol) and sodium methoxide (771 ⁇ l, 3.37 mmol) (25% in MeOH) were stirred at reflux overnight. The reaction was concentrated, and water added. The aqueous layer acidified with 1M aq. HCl and washed with EtOAc. Combined organics dried over MgSO4 and concentrated to give 1- methoxyisoquinoline-6-carboxylic acid (85 mg, 87%). ESI-MS m/z: 203.93 [M+H] + .
- Example 362 step b The title compound was prepared in an analogous fashion using Method J with amine (30 mg, 0.075 mmol), and the material was purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (13 mg, 30%). ESI-MS m/z: 585.10 [M+H] + .
- Example 363 The following example was prepared using the same procedures as Method J (PyBOP) with the corresponding acid and amine HCl salt (200 mg) coupling partners, and purified by automated column chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford the title compound 195 mg (68%).
- Example 364 To a 2-dram vial containing a stir bar was added Example 363 (25 mg, 0.044 mmol), 2- bromoacetamide (7.25 mg, 0.053 mmol) and potassium carbonate (12.11 mg, 0.088 mmol). The solids were dissolved in DMF (0.15 M), the reaction stirred at room temperature and monitored by LCMS. Another equiv. of bromoacetamide was added after 2 hours to push conversion. The reaction was diluted with EtOAc and quenched with water. The aqueous was extracted with EtOAc, with a phase separator cartridge, and the combined organics were concentrated.
- Example 365 This example was prepared in an analogous fashion as Example 364 with 4 eq of 2-bromo- 2,2-difluoroacetamide at 60oC for 16 hrs. The material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (8.1 mg, 23%). ESI-MS m/z: 664.1 [M+H] + .
- Example 366 The starting material was prepared with Example 212 analogously to Example 363 to afford the hydroxyquinoline precursor (53 mg, 61%). ESI-MS m/z: 585.2 [M+H] + .
- Example 366 was prepared in an analogous fashion as example 364 with 1.5 eq 2- bromoacetamide for 3 hr (added 1.2 eq more after 2 hr). The material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (25.0 mg, 43%). ESI-MS m/z: 642.1 [M+H] + .
- Example 367 The starting material was prepared with Example 212 analogously to Example 363 to afford the hydroxyquinoline precursor (62 mg, 67%).
- Example 367 was prepared in an analogous fashion as example 364. The material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (30.0 mg, 44%). ESI-MS m/z: 676.1 [M+H] + .
- Example 368 The starting material was prepared with Example 214 analogously to Example 363 to afford the hydroxyquinoline precursor (58 mg, 65%). ESI-MS m/z: 599.1 [M+H] + .
- Example 368 was prepared in an analogous fashion as example 364 with 1.5 eq 2- bromoacetamide for 3 hr (added 1.2 eq more after 2 hr). The material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (31.5 mg, 50%). ESI-MS m/z: 656.2 [M+H] + .
- Example 369 The starting material was prepared with Example 214 analogously to Example 363 to afford the hydroxyquinoline precursor (63 mg, 66%). ESI-MS m/z: 635.3 [M+H] + .
- Example 369 was prepared in an analogous fashion as Example 364.
- Example 370 step b (Method T) OH O N O OMe O
- a stir bar a stir bar
- TFA 4.69 ml, 60.8 mmol
- the reaction was stirred for 10 minutes, warmed to room temperature and monitored by LCMS (added 5.0 eq. more TFA after 3 hr, 5.5 hr total).
- the mixture was quenched with water and diluted with DCM. Solid precipitates. Further diluted with DCM and stirred vigorously for 10 minutes.
- step b H N O N O OMe O
- DIPEA 407 ⁇ l, 2.332 mmol
- 1-methylcyclopropan-1-amine hydrochloride 124 mg, 1.148 mmol
- Example 370 step d (Method T) H N O N O OH O
- General hydrolysis notes In some cases, the reaction was heated to 45oC to force material into solution and accelerate hydrolysis. After hydrolysis, the product was isolated by precipitation. If no precipitate, the product was either extracted, or the aqueous concentrated (material dried and used crude). The major MS + m/z for all these compounds is C-C cleavage: ESI-MS m/z: 202.0 [M+H] + .
- Example 370 step c 9 mg, 0.312 mmol was added a stir bar. The compound was dissolved in MeOH, THF and Water (0.2 M, 2:1:1).
- Lithium hydroxide hydrate (62 mg, 1.56 mmol) was added, the reaction stirred at room temperature and monitored by LCMS. The stir bar was removed, and the vial cooled to 0oC. The reaction was acidified with 2 M HCl, and the pH brought to around 4-5 (used 1M NaOH if too acidic). The product was extracted 3x with 10% MeOH/DCM with a phase separator and concentrated. Dried on high vacuum to afford the title compound (45 mg, 50%). ESI-MS m/z: 202.0 [M+H] + .
- Example 370 step e H N O N O F H F 3 C OH N N O O H 2 N O The following example was prepared using the same procedures as Method J (PyBOP) with the corresponding acid from step d and amine HCl salt (25 mg) coupling partners. The residue was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (8 mg, 20%) ESI-MS m/z: 682.2
- Example 371 H N O Ph N O F H F 3 C OH N N O O H 2 N O The following example was prepared using analogous procedures as Method J (PyBOP). The acid precursor was prepared according to Method T and isolated by extraction (32 mg, 50%).
- Example 374 H N O N O F H F 3 C OH N N O O H 2 N O
- the following example was prepared using analogous procedures as Method J (PyBOP).
- the acid precursor was prepared according to Method T and isolated by extraction (41 mg, 69%), and 25 mg amine HCl salt used for the final amide coupling. The residue was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (18.8 mg, 49%) ESI-MS m/z: 670.3 [M+H] + .
- Example 375 H N O OMe N O F H F 3 C OH N N O O H 2 N O
- the following example was prepared using analogous procedures as Method J (PyBOP).
- the acid precursor was prepared according to Method T and isolated by precipitation (42 mg, 70%), and 25 mg amine HCl salt used for the final amide coupling.
- the residue was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (13.4 mg, 35%) ESI-MS m/z: 686.3 [M+H] + .
- Example 376 H N O N O F H F 3 C OH N N O O H 2 N O The following example was prepared using analogous procedures as Method J (PyBOP).
- the acid precursor was prepared according to Method T and isolated by aqueous precipitation (used crude), and 25 mg amine HCl salt used for the final amide coupling.
- Example 380 NH O 2 N O F H F 3 C OH N N O O H 2 N O
- the methyl ester was prepared using analogous procedures as Method R with 2.5 eq. K 2 CO 3 and 1.5 eq.2-bromo-2-methylpropionamide at 80oC for 16 hrs.
- Example 381 NH O 2 N O F H F 3 C OH N N O O H 2 N O
- Example 381 step a Br O t Bu O N O OMe O The following example was prepared according to Method T, step a with 2.5 eq. K 2 CO 3 and 1.2 eq. tert-butyl 2,4-dibromobutanoate at 40oC for 4 hr (Added 1.0 eq. more bromide after 3 hr).
- step b O t Bu O N O OMe O
- step a 1.236 g, 2.91 mmol
- THF 0.1 M
- Example 382 NH O 2 Cl N O F H F 3 C OH N N O O H 2 N O
- the acid precursor was used from Method R and 20 mg of amine HCl salt precursor was used according to Method J (PyBOP), and the material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (12.4 mg, 41%).
- Example 383 NH O 2 N O F H F 3 C OH N N O O H 2 N O
- the methyl ester precursor was prepared in analogously to Method R with 1.5 eq. ( ⁇ )-2- bromopropanamide at 40oC for 16 hr (109 mg, 32%).
- the methyl ester hydrolysis was carried out in an analogous fashion to Method R, and isolated by precipitation (50 mg, 48%).
- Example 383 was prepared with 60 mg of amine HCl salt precursor was according to Method J (PyBOP), and the material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound as a mixture of diastereomers (34.3 mg, 38%).
- Example 384 NH HN 2 N O F H F 3 C OH N N O O H 2 N O
- the methyl ester was prepared in an analogous fashion as Method R with methyl-8- aminoquinoline 6-carboxylate (200 mg), 4.0 eq.2-bromoacetamide at 40oC for 16 hr (78 mg, 30%).
- the methyl ester hydrolysis was carried out in an analogous fashion to Method T, step d and isolated by precipitation (38 mg, 52%).
- Example 384 was prepared with 25 mg of amine HCl salt and the material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (14.0 mg, 39%).
- Example 385 HN N F H F 3 C OH N N O O H 2 N O The methyl ester was prepared in an analogous fashion as Method R with methyl-8- aminoquinoline 6-carboxylate (300 mg), 1.2 eq. iodomethane at r.t. for 48 hrs (150 mg, 47%).
- Example 386 O N N F H F 3C OH N N O O H 2 N O
- Example 386 steps a and b O N N OH O To a 20 mL vial equipped with a stir bar and pressure relief septa was added methyl 8- hydroxyquinoline-6-carboxylate (116 mg, 0.570 mmol), picolinic acid (11.69 mg, 0.095 mmol), potassium phosphate tribasic (202 mg, 0.949 mmol) and copper(I) iodide (9.04 mg, 0.047 mmol). The solids were dissolved in DMSO (0.33M), and 2-bromopyridine (45.3 ⁇ l, 0.475 mmol) was added.
- Example 386 step c O N N F H F 3 C OH N N O O H 2 N O This example was prepared according to Method J (PyBOP with 10 mg of amine HCl salt precursor. The material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (1.6 mg, 11%). ESI-MS m/z: 648.2 [M+H] + .
- Example 387 N O N N F H F 3 C OH N N O O H 2 N O This example was prepared in an analogous sequence to Example 386. 2-bromopyrazine Ullman coupling (32 mg, 25%). ESI-MS m/z: 282.0 [M+H] + .
- Example 388 steps a and b N O N OH O In a 20 mL vial equipped with a stir bar was added methyl 8-hydroxyquinoline-6-carboxylate (100 mg, 0.492 mmol), cesium carbonate (481 mg, 1.476 mmol) and 4-fluoropyridine HCl (526 mg, 3.94 mmol). The solids were dissolved in DMA (0.4 M), and DIPEA (688 ⁇ l, 3.94 mmol) was added. The reaction was stirred for 30 minutes at room temperature and heated to 100oC for 22 hrs. The reaction was quenched with sat.
- Example 388 step c N O N F H F 3 C OH N N O O H 2 N O This example was prepared according to Method J (PyBOP) with 15 mg of amine HCl salt precursor, and the material purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (1.5 mg, 7%). ESI-MS m/z: 649.1 [M+H] + .
- Example 389 N O O N F H F 3 C OH N N O O H 2 N O This example was prepared in an analogous sequence to Example 388. The SNAr was carried out with 3 eq of 2-bromooxazole in DMF (0.33 M) and no DIPEA at 60oC (57 mg, 29%).
- the acid precursor was prepared according to Method T and was isolated by precipitation (16 mg, 30%).
- Example 389 was prepared with 20 mg of amine HCl salt according to Method J (PyBOP), and the material purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (12 mg, 40%).
- Example 390 steps a and b O N N N O OH O To a 2-dram vial equipped with a stir bar was added oxazol-2-ylmethanol (58.5 mg, 0.591 mmol), and the oil was dissolved in THF. methyl 8-hydroxyquinoline-6-carboxylate (100 mg, 0.492 mmol) and 2-pyridyldiphenylphospine (155 mg, 0.591 mmol) were then added, and the vial cooled to 0oC.
- Example 390 step c N O N O F H F 3C OH N N O O H 2 N O This example was prepared according to Method J (PyBOP) with 25 mg of amine HCl salt precursor. The material was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (15.7 mg, 41%). ESI-MS m/z: 652.2 [M+H] + .
- Example 391 N O N O F H F 3C OH N N O O H 2 N O This example was prepared in an analogous sequence to Example 390. Mitsunobu reaction (162 mg, 110%, impure).
- Example 391 was prepared with 25 mg of amine HCl salt precursor was used according to Method J (PyBOP), and the material purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (13.8 mg, 36%).
- Example 392 O HN N F H F 3C OH N N O O H 2 N O
- Example 392 steps a and b O HN N OH O To a 40 mL vial equipped with a stir bar was added methyl 8-aminoquinoline-6-carboxylate (100 mg, 0.495 mmol). The solid was dissolved in DCM (0.2 M) and cooled to 0C. DIPEA (216 ⁇ l, 1.236 mmol) was added followed by cyclopropanecarbonyl chloride (49.4 ⁇ l, 0.544 mmol). The reaction was allowed to warm naturally to room temperature and monitored by LCMS (1 hr). The reaction was diluted with DCM and quenched with water and sat. sodium bicarbonate.
- Example 392 step c O HN N F H F 3C OH N N O O H 2 N O This example was prepared according to Method J (PyBOP) with 25 mg of amine HCl salt precursor, and the material purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (22.2 mg, 60%). ESI-MS m/z: 628.2 [M+H] + .
- Example 393 O HN N F H F 3 C OH N N O O H 2 N O This example was prepared in an analogous sequence to Example 392. Aminoquinoline acylation (99 mg, 82%). ESI-MS m/z: 245.1 [M+H] + .
- the acid precursor was prepared according to Method T, step d and isolated by precipitation (51 mg, 55%).
- Example 395 O O S HN N F H F 3 C OH N N O O H 2 N O This example was prepared in an analogous sequence to Example 392.
- 2,2-difluoroacetic acid (46.7 ⁇ l, 0.742 mmol) was then added after to be buffered, and the vial was cooled to 0oC.
- PyBOP (290 mg, 0.556 mmol) was then added, the reaction stirred for 10 minutes, warmed to room temperature and monitored by LCMS (16 hr).
- the reaction was diluted with DCM and quenched with water and sat. sodium bicarbonate. Aqueous was extracted with 10% MeOH/DCM with a phase separator cartridge and concentrated. The material was purified by automated column chromatography (silica gel, 0-50% EtOAc in hexanes) to afford the title compound (37 mg, 36%).
- ESI-MS m/z 648.1 [M+H] + .
- Example 397 O N HN N O F H F C OH N 3 N O O H 2 N O The acid precursor was prepared in an analogous sequence to Method U. Aminoquinoline amide formation (19 mg, 17%). ESI-MS m/z: 312.0 [M+H] + . The methyl ester was hydrolyzed according to Method t, step d (heated to 45oC) and isolated by aqueous concentration (used crude). ESI-MS m/z: 298.0 [M+H] + .
- Example 398 step c O N HN N O F H F3C OH N N O O H 2 N O This example was prepared according to Method J (PyBOP) with 20 mg of amine HCl salt precursor, and the material purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (12.0 mg, 35%). ESI-MS m/z: 665.1 [M+H] + .
- Example 399 O HN NH N F H F3C OH N N O O H 2 N O
- Example 399 steps a and b O HN NBoc N OH O The acid intermediate was prepared according to Method V. Ghosez coupling carried out for 14 hrs (134 mg, 94%).
- step c 753.2 [M+H] + .
- step c 65 mg, 0.086 mmol
- TFA 66.5 ⁇ l, 0.864 mmol
- the reaction was stirred for 10 minutes, warmed to room temperature and monitored by LCMS (3 hr).
- Example 402 O H N HN N N F H F C OH N 3 N O O H 2 N O
- Example 402 steps a and b O SEM N HO N
- ethyl 2-methyl-1H-imidazole-4- carboxylate 500 mg, 3.24 mmol
- the vial was cooled to 0C, and NaH (136 mg, 5.68 mmol) was added in one portion.
- the reaction was allowed to stir for 30 minutes at r.t.
- the vial was then cooled to 0oC, and (2- (chloromethoxy)ethyl)trimethylsilane (861 ⁇ l, 4.86 mmol) was slowly added.
- Example 402 steps c and d O SEM HN N N N N OH O
- the following example was prepared according to Method V: SEM-imidazole aminoquinoline Ghosez coupling (81 mg, 50%).
- Methyl ester hydrolysis according to Method T, step d was isolated by precipitation (25 mg, 31%).
- Example 402 steps e and f O H N HN N N F H F3C OH N N O O H 2 N O SEM-imidazole amide formation with according to Method J (PyBOP) with 25 mg amine HCl salt precursor, purified by automated column chromatography (silica gel, 0-100% EtOAc/hexanes) to afford the title compound (50 mg, 100%).
- Example 405 O H O O N F H F 3 C OH N N O O H 2 N O
- Example 405 steps a and b O Cl N OEt O To a 50 mL round-bottom flask equipped with a stir bar was added ethyl 8- cyclopropoxyquinoline-6-carboxylate (10.29 g, 40.0 mmol), and the solid was dissolved in CHCl3 (0.33 M). The flask was cooled to 0oC and mCPBA (19.72 g, 80 mmol) was added portionwise over 5-10 minutes (monitoring internal temperature at 3oC). The reaction was stirred for 10 minutes and warmed to room temperature over 20 minutes.
- Example 406 O H O N F H F 3 C OH N N O O H 2 N O
- Example 406 step a O I N OEt O
- ethyl 2-chloro-8- cyclopropoxyquinoline-6-carboxylate 300 mg, 1.028 mmol
- ACN 0.5 M
- Sodium iodide 231 mg, 1.543 mmol
- acetyl chloride 146 ⁇ l, 2.057 mmol
- the reaction was stirred for 5 minutes (turn cloudy and orange), heated to 100oC and monitored by LCMS (4 hrs, 80% conv).
- the flask was cooled to r.t.
- step a 100 mg, 0.261 mmol
- step b 100 mg, 0.261 mmol
- step a 100 mg, 0.261 mmol
- step b 100 mg, 0.261 mmol
- step b 100 mg, 0.261 mmol
- step a isopropylmagnesium chloride (261 ⁇ l, 0.522 mmol) was added.
- the reaction was stirred for 30 minutes, then N,N-dimethylformamide (404 ⁇ l, 5.22 mmol) was added.
- the reaction was allowed to warm to 0oC and stirred for 1 hr longer.
- the reaction was diluted with EtOAc and quenched with water and sat. ammonium chloride.
- step b To a 20 mL vial containing ethyl 8-cyclopropoxy-2-formylquinoline-6-carboxylate, step b (26 mg, 0.091 mmol) was added a stir bar and the solid was dissolved in EtOH (0.2 M). The reaction was cooled to 0oC, and NaBH 4 (5.17 mg, 0.137 mmol) was added.
- Example 406 step e O H O N F H F 3 C OH N N O O H 2 N O
- This example was prepared according to Method J (PyBOP) with step d and 30 mg of amine HCl salt precursor, and the material purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound. (15.0 mg, 33%).
- Example 407 O H O N F H F 3 C OH N N O O H 2 N O
- the following example was prepared analogously to Example 406 steps b and d (Grignard exchange and addition).
- Example 408 step c O HN NH 2 N F H F 3 C OH N N O O H 2 N O
- This example was prepared according to Method J (PyBOP) with 25 mg of amine HCl salt precursor, and the material purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (21.8 mg, 61%).
- the acid precursor was prepared following example was prepared according to Method W.
- Example 410 O HN N N F H F 3 C OH N N O O H 2 N O
- the acid precursor was prepared following example was prepared according to Method W. Urea formation extracted and used crude (91 mg, 100%).
- the methyl ester hydrolysis was carried out according to Method T, step d and isolated by precipitation (60 mg, 69%).
- Example 416 steps b and c NH 2 N OEt O To a 20 mL vial containing 3-methyl-8-nitroquinoline-6-carboxylic acid (357 mg, 1.538 mmol) was added a stir bar and the solid was dissolved in DMF. Potassium carbonate (531 mg, 3.84 mmol) was added followed by iodoethane (373 ⁇ l, 4.61 mmol). The reaction was stirred for 14 hr at room temperature. The reaction was diluted with EtOAC and quenched with water and sat. sodium ammonium chloride. The aqueous was extracted with EtOAc and DCM/MeOH with a phase separator cartridge, and concentrated (168 mg, 42%).
- the acid precursor was prepared following example was prepared according to Method W with 3-methylquinoline analog from Example 416 step c. Urea formation extracted and used crude (54 mg, 99%).
- the crude reaction mixture was purified by silica gel column chromatography (0-60% EtOAc/Hexanes) to furnish the title compound (250 mg, 97%).
- compound from step a 250 mg, 0.999 mmol
- lithium hydroxide (239 mg, 10 equiv) were dissolved in THF (2.335 ml), MeOH (0.259 ml), and Water (0.259 ml).
- the reaction was heated to 40oC for 4 hours.
- the reaction was diluted with water and the pH adjusted to 3-4 with 1M aq. HCl.
- Example 421 steps a and b F N H 2 N S OH O To methyl 4-amino-3-fluorobenzoate (45g, 266 mmol) and sodium thiocyanate (86 g, 1064 mmol) in acetic acid (350 ml) at 0 °C was added bromine (13.57 ml, 263 mmol) in AcOH (100 ml) via additional funnel over 1h, and the mixture was warmed up to RT and stirred for 2 days. The mixture was filtered, and the precipitate was washed with water and dried under vacuum to the title compound and taken forward as a crude mixture.
- the reaction mixture was heated to 60 oC and stirred for 4 hr, cooled to RT, and then concentrated under reduced pressure.
- the pH was adjusted to 5 with 3M HCl and 3% citric acid. The pale-yellow solid was precipitated and collected by filtration, washed with water, dried.
- Example 423 step a OH N O S O O In a vial, methyl 4-isopropoxy-2-methoxybenzo[d]thiazole-6-carboxylate (180 mg, 0.640 mmol) was dissolved in DCM (8 mL) and the solution was cooled to 0°C. Boron trichloride (2559 ⁇ l, 2.56 mmol) was added slowly and the reaction was allowed to warm to RT and stir for 2 hr. The reaction was quenched upon addition of 1N HCl. The aqueous layer washed with DCM and combined organic layer dried over MgSO 4 and concentrated.
- step a 150 mg, 0.627 mmol was dissolved in THF (4.18 mL) and MeOH (2.090 mL). The solution was cooled to 0 °C and trimethylsilyldiazomethane (940 ⁇ l, 1.881 mmol) was added slowly and the reaction was allowed to warm to room temperature.
- Example 449 O N F H F 3 C OH N N O O HO O
- the Example 449 was prepared diastereomerically pure using the methods described in Example 206 (with CF 3 olefin and TBS-alcohol). The TBS-alcohol was converted into the acid according to Methods A, B and F. (1.34 g, 58%). ESI-MS m/z: 612.17 [M+H] + .
- Table 7 contains examples that were synthesized using Example 449 (or methoxy analog) and Method J (PyBOP). The compounds were either purified by automated column chromatography or Gilson prep-HPLC (20-90%, MeCN/Water, 25 min). Table 7
- Example 495 F F 3 C OH H 2 N N O HO N O H
- Example 495 step a F F 3 C OH BocHN N O HO N O H
- Compound from Example 59 step a 400 mg, 0.80 mmol
- 1-amino-2-methylpropan-2-ol 142 mg, 1.60 mmol
- Hunig's base 698 ⁇ l, 4.00 mmol
- PyBOP 832 mg, 1.60 mmol
- step b F F 3 C OH H 3 N N Cl O HO N O H
- Compound from step a 360 mg, 0.63 mmol was dissolved in DCM (2 mL), then 4N HCl in 1,4-dioxane (2 mL) was slowly added. After stirred at rt for 2 hrs, reaction was completed. After evaporated the solvent and dried in vacuo, the desired compound (310 mg, 97%) was obtained as a HCl salt.
- ESI-MS m/z 472.20 [M+H] + .
- Table 8 contains examples that were synthesized according to Method J (PyBOP). The majority of compounds were purified by Gilson prep-HPLC, and some were purified by automated column chromatography (silica gel). Table 8
- Example 508 O O F H F 3 C OH N N O O H 2N O
- Example 508 step a O O OMe O
- the crude product was purified by reverse phase chromatography (MeCN/H 2 O, 0% to 100%, 30 min) to give the desired compound as a yellow oil (2.3 g, 95%).
- Example 508 step b O HO OMe O A solution of the compound from step a (2.3 g, 10.08 mmol) in NMP (10 mL), was stirred for 16 hrs at 200oC. The crude product was purified by reverse phase chromatography (MeCN/H 2 O, 0% to 100%, 30 min ) to give the desired compound as a yellow oil (2.0 g, 87%). ESI-MS m/z: 223.10 [M+H] + .
- Example 508 step c O HO HO OMe O To a stirred solution of the compound step b (2.0 g, 9 mmol) in THF (20 mL) were added H2O2 (30%) (2.00 mL) and BH3 ⁇ THF (1 N) (1.7 mL, 18 mmol) in portions at 0oC under nitrogen atmosphere and the reaction was stirred for 1 hr. The reaction was quenched by the addition of NaOH (0.02 M) and warmed to room temperature. The resulting mixture was extracted with DCM and the combined organics washed with brine, dried and concentrated. The crude product mixture was used in the next step directly without further purification. ESI-MS m/z: 241.10 [M+H] + .
- Example 508 steps d and e O O OMe O To a stirred mixture of the compound step c (1.8 g, 7.3 mmol) and PPh 3 (2.9 g, 11 mmol) in THF (30 mL) was added DIAD (2.95 g, 15 mmol) in portions at 0oC. The resulting mixture was stirred 16 hr at room temperature. The reaction was quenched with water/ice at 0oC. and extracted with DCM. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The material was purified by reverse phase column chromatography to afford the desired product as a white solid (1.4g, 86%). ESI-MS m/z: 223.09 [M+H] + .
- Example 509 O O H F 3 C OH N N O O H 2 N O
- Example 509 step a F N Br 3C O TBSO This example was prepared in an analogous procedure to Example 205, with the TBS-alcohol precursor used instead. The material was prepared using 3.05 g of (R)-7-bromo-3-(((tert- butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-2,3-dihydrofuro[2,3-c]pyridine for the cross-coupling to afford the title compound as a clear, yellow oil. (2.37 g, 83%). ESI-MS m/z: 452.0/454.0 [M+H] + .
- step b N Br F 3 C O HO O
- acetone 105 ml
- Jones reagent 2M in aq H2SO4, 13.12 ml, 26.2 mmol
- the reaction was allowed to slowly warm to room temperature and stirred overnight.
- the reaction was quenched with isopropanol and the majority of acetone was removed by rotary evaporation.
- the remaining material was taken up in water and extracted with EtOAc. The combined organic extracts were washed with brine, dried, filtered, and concentrated.
- step c F C N Br 3 O H 2 N O This example was prepared according to the procedure of Example 97 step b (New route) with step b (3.024 g) and the material was purified by automated column chromatography (silica gel, 0-100% EtOAc) to afford the title compound as a clear yellow oil (2.97 g, 98%). ESI-MS m/z: 352.8 [M+H] + .
- Example 509 step d N F 3 C O H 2 N O A 500 mL round-bottom flask charged with step c (2.87 g, 8.17 mmol) was added a magnetic stir-bar, bis(triphenylphosphine)palladium(II) chloride (0.287 g, 0.409 mmol), and copper(I) iodide (0.078 g, 0.409 mmol). The flask was evacuated and backfilled with nitrogen 3 times and dry diisopropylamine (40.9 ml) was added by syringe. The resulting mixture was treated with ethynyltrimethylsilane (2.83 ml, 20.43 mmol) at room temperature.
- Example 509 step g F 3 C OH H 2 N N O H 2 N O The above compound was prepared according to the procedure in Example 205 step g with step f (0.712 g). The crude material was dissolved in EtOAc and washed with sat. sodium bicarbonate three times to afford the title compound white foam which was used without further purification. ESI-MS m/z: 330.1 [M+H] + .
- Example 510 O F O H F 3 C OH N N O O H 2 N O A 1-dram vial was charged a stir-bar, Example 509 step h (0.025 g, 0.048 mmol), 1-fluoro-4- iodobenzene (0.014 ml, 0.120 mmol), bis(triphenylphosphine)palladium(II) chloride (6.76 mg, 9.63 ⁇ mol), and copper(I) iodide (1.833 mg, 9.63 ⁇ mol).
- Example 511 F O F O H F C OH N 3 N F O O H 2 N O The Example 511 was prepared according to the procedure in Example 510.
- Example 512 O F O H F 3 C OH N N Cl O O H 2 N O Example 512 was prepared according to the procedure in Example 510. The crude material was purified by flash column chromatography on silica gel and further purified by prep- HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (3 mg, 10%) as a white solid. ESI-MS m/z: 648.2 [M+H] + .
- Example 513 O O H F 3 C OH N N Cl F O O H 2 N O
- the Example 513 was prepared according to the procedure in Example 510.
- the crude material was purified by flash column chromatography on silica gel and further purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (3 mg, 10%) as a white solid.
- Example 514 O Cl O H F 3C OH N N F O O H 2 N O
- the Example 514 was prepared according to the procedure in Example 510.
- Example 515 O O H F 3 C OH N N O O H 2 N O The Example 515 was prepared according to the procedure in Example 510. The crude material was purified by flash column chromatography on silica gel and further purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (6 mg, 21%) as a white solid. ESI-MS m/z: 596.2 [M+H] + .
- Example 516 O O H F 3 C OH F N N O O H 2 N O
- the Example 516 was prepared according to the procedure in Example 510.
- the crude material was purified by flash column chromatography on silica gel and further purified by prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (2 mg, 7%) as a white solid.
- Example 517 O O H F 3 C OH N N N N N N F O O H 2 N O
- the reaction was monitored by LC- MS; after 2 h an additional portion of 1-azido-4-fluorobenzene (0.193 ml, 0.096 mmol) was added and the reaction was stirred at room temperature overnight.
- Example 545 (in table) O N F H F N N O O H 2 N O
- Example 545 step a F HO TsO N O H 2 N O
- the title compound was prepared in an analogous sequence to Example 205. The residue was concentrated under reduced pressure to afford the crude product as a brown solid.
- Example 545 step b F HO Br N O H 2 N O A mixture of the compound from step a (1.30 g, 2.59 mmol) and LiBr (676 mg) in acetone (50 mL) was stirred for 3 days at 60 o C. The resulting mixture was concentrated under reduced pressure.
- step c F F Br N O H 2 N O Into a 100 mL round-bottom flask were added the compound from step b (620 mg, 1.51 mmol) and DCM (15 mL) at room temperature. The mixture was cooled to 0 o C, DAST (488 mg, 3.03 mmol) was added and the reaction stirred for 30 min at the same temperature. The reaction was allowed to stirred for 5 min at room temperature and quenched with a cold aq. NaHCO 3 solution.
- step d F F N 3 N O H 2 N O A mixture of the compound from step c (545 mg, 1.32 mmol), NaN 3 (1.39 g, 21.38 mmol) and TBAI (244 mg, 0.66 mmol) in DMSO (25 mL) was stirred for 4 h at 100 o C.
- step e F F H 2 N N O H 2 N O A mixture of the compound from step d (370 mg, 0.99 mmol), PPh 3 (2.60 g, 9.91 mmol), THF (20 mL) and H2O (2 mL) was stirred for 1 h at 70 o C under nitrogen atmosphere.
- step b O N S n O (n-Bu)3 O A solution of the compound from step a (1.00 g, 3.38 mmol), Pd(PPh 3 ) 4 (585 mg, 0.51 mmol) and Sn2(nBu)6 (3.92 g, 6.76 mmol) in dioxane (20.00 mL) was stirred for 8 hr at 100 o C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum.
- Example 566 steps a and b O N OH O A solution of Example 565 step a (300 mg, 1.01 mmol), cyclopropylboronic acid (261 mg, 3.04 mmol), PCy 3 (284 mg, 1.01 mmol), tricyclohexylphosphine (9 mg, 0.03 mmol) and K3PO4 (645 mg, 3.04 mmol) in Toluene/H2O (6 mL, 5:1) was stirred for 2 hours at 100 o C under nitrogen atmosphere. The resulting solution was diluted with water, extracted with EtOAc, and the organic layer dried and concentrated.
- 2-chloroacrolein was prepared according to the literature (Eur. J. Org. Chem.2018, 45, 6256) in two steps from 2,3-dichloropropene. The resulting solution was purified by reverse phase C18 column chromatography (CH 3 CN/H 2 O) to afford desired product (300 mg, 23%) as a yellow solid. ESI-MS m/z: 238.15 [M+H] + .
- Example 568 O N OH Cl O The title compound was prepared in a similar fashion to Example 567 to afford the desired product (350 mg, 27%) as a white solid. ESI-MS m/z: 264.00 [M+H] + .
- Example 569 steps a and b O N F OH 3C O A solution of methyl 3-iodo-8-methoxyquinoline-6-carboxylate (400 mg, 1.16 mmol),CuI (444 mg, 2.33 mmol), KF (135 mg, 2.33 mmol), and methyl 2,2-difluoro-2-sulfoacetate (1.1 g, 5.83 mmol) in NMP (3 mL) was stirred for 4 hours at 120 o C under nitrogen atmosphere. The resulting solution was diluted with water, extracted with EtOAc and the organic layer was dried and concentrated. The resulting solution was purified by reverse phase C18 column chromatography (CH3CN/H2O) to afford desired product (200 mg, 60%) as a light yellow solid.
- NMP 3 mL
- the ester hydrolysis was carried out in a similar manner to Method T (step d).
- the resulting solution was purified by reverse phase C18 column chromatography (CH 3 CN/H 2 O) to afford desired product (120 mg crude) as a light yellow solid.
- the title compound was prepared in a similar fashion to Example 210 and Method P with 2- methyl-2-butenal (commercially available).
- Example 571 I N OH O
- the title compound was prepared in a similar fashion to Example 210 and Method P with methacrolein and methyl 4-amino-3-iodobenzoate.
- the crude product was re-crystallized from EA/H 2 O to afford the desired product (7 g, 62%) as a yellow solid.
- Example 572 step a I N OBn O A solution of the crude from Example 571 above, benzyl bromide (6.56 g, 38.35 mmol) and DIEA (0.50 mg, 2.87 mmol) in DMSO (20 mL) was stirred for 6 hours at room temperature.
- Example 575 step a O H O N OMe O
- a solution of methyl 4-amino-3-methoxybenzoate (2.00 g, 11.1 mmol) and 2- chlorocyclohex-1-enecarbaldehyde (4.32 g, 0.1 mmol) in toluene were added BINAP (1.37 g, 2.2 mmol), Pd(OAc)2 (495 mg, 2.2 mmol) and Cs2CO3 (10.79 g, 33.1 mmol) dropwise at 90oC under nitrogen atmosphere for 3 hrs.
- the resulting solution was extracted with EtOAc, the organic layer was dried and concentrated.
- step d The ester hydrolysis was carried out in a similar manner to Method T (step d).
- the resulting solution was purified by reverse phase C18 column chromatography (CH 3 CN/H 2 O) to afford desired product (106 mg, 40%) as a yellow solid.
- step a F O F O 2 N O O
- methyl 4-amino-3-hydroxybenzoate 5 g, 30 mmol
- methyl 2-chloro-2,2-difluoroacetate 6.5 g, 45 mmol
- K 2 CO 3 (8.3 g, 60 mmol
- DMF (30 mL) at room temperature.
- Example 576 step b F O F H 2 N O O Into a 250 mL round-bottom flask were added the compound from step a (1.7 g, 6.9mmol), Fe (3.07 g, 55.03 mmol), NH4Cl (2.94 g, 55.03 mmol), EtOH (30 mL) and H2O (30 mL) at room temperature. The resulting m o ixture was stirred overnight at 80 C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOH and the filtrate was concentrated under reduced pressure.
- Example 577 step a O H 2 N O O Into a 100 mL round-bottom flask were added methyl 4-amino-3-hydroxybenzoate (2 g, 11.96 mmol), 2-iodopropane (3.05 g, 17.95 mmol), Cs 2 CO 3 (7.8 g, 23.93 mmol) and acetone (20 mL) at room temperature. The resulting mixture was stirred for 2 hr at 60 o C under nitrogen atmosphere. The aqueous layer was extracted with CH2Cl2 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in hexanes) to give the desired compound (2.54 g, 100%).
- Example 578 step a O N Br S OMe O
- a solution methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate (2 g), CuBr 2 (3.7 g, 16.78 mmol) and t-BuNO2 (1.7 g, 16.77 mmol) in CH3CN was stirred for 16 hours at room temperature under N 2 atmosphere.
- the resulting solution was diluted with water, extracted with EtOAc and the organic layer was dried, concentrated.
- the resulting solution was purified by silica gel column chromatography (EtOAc in hexanes) to afford desired product (1.6 g, 63%) as orange solid.
- Example 578 steps b and c O N S OH O
- a solution of the compound from step a (1.6 g), Pd(dppf)Cl2.CH2Cl2 (0.9 g, 1.06 mmol), Na 2 CO 3 (1.7 g, 23.50 mmol), H 2 O (1 mL) and methylboronic acid (0.48 g, 7.94 mmol) in dioxane (30 mL) was stirred for 3 hours at 100 o C under N2 atmosphere.
- the resulting solution was diluted with water, extracted with EtOAc and the organic layer was dried, concentrated.
- Example 579 steps a and b OCF 3 N H 2 N S OH O The title compound was synthesized in a similar manner to Example 421 using methyl 4- amino-3-(trifluoromethoxy)benzoate (1.50 g, 6.4 mmol). The ester hydrolysis was carried out in a similar manner to Method T (step d). The title compound was isolated by precipitation, and the solids were washed with MeCN to afford the desired product (370 mg, 74.74%) as a white solid. ESI-MS m/z: 279.05 [M+H] + .
- Example 580 steps a and b N HN S OH O O
- methyl 2-aminobenzo[d]thiazole-6-carboxylate 350 mg, 1.681 mmol
- DCM dimethylethyl sulfoxide
- Cyclopropanecarbonyl chloride 183 ⁇ l, 2.017 mmol
- pyridine 408 ⁇ l, 5.04 mmol
- the reaction was allowed to stir overnight. Water was added and the aqueous layer was washed with DCM. Combined organic layer dried over MgSO4 and concentrated under reduced pressure.
- Example 581 step a N N N I OMe O To a stirred solution of methyl 4-amino-3-iodobenzoate (2.7 g, 10 mmol) in HCl (6 mL) were added NaNO 2 (0.7 g in 5 mL water) dropwise at 5oC for 1 hr. To the above mixture was added piperidine (1 mL) dropwise at 5oC. The resulting mixture was stirred for additional 1 hr at room temperature. The resulting mixture was extracted with EA and the combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 .
- Example 581 step c N N OMe B r O A solution of the compound from step b (1.5 g, 5.26 mmol,) and HBr in water (850 mg, 10.51 mmol) in acetone (10 mL) was stirred for 2 hr at room temperature. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and dried over anhydrous Na 2 SO 4 . The residue was purified by silica gel column chromatography (EtOAc in hexanes) to afford the desired product (900 mg, 61%) as a yellow solid. ESI-MS m/z: 281.00 [M+H] + .
- Example 581 step d H HN N OMe O A solution of the compound from step c (900 mg, 3.2 mmol) and Pd/C (681 mg, 6.40 mmol) in MeOH (20 mL) was stirred for 2 hr at room temperature under H 2 atmosphere. The resulting mixture was filtered and the solution was concentrated to use directly for next step. ESI-MS m/z: 205.00 [M+H] + .
- Example 581 steps e and f N N OH O A solution of compound from step d and MnO 2 (1.5 g, 17.67 mmol) in THF (20 mL) was stirred for 2 hr at room temperature.
- Example 584 H OO N F H F 3 C OH N N O O H 2 N O
- Example 584 steps a and b H O O N OH O To a vial containing N-oxide Example 405 step a (100 mg) was added Water (3.7 mL, 0.1 M), and Ms-Cl (0.057 mL, 0.732 mmol) was slowly added. The reaction was stirred at room temperature and monitored by LCMS. The reaction was diluted with DCM and quenched with sat. sodium bicarbonate. The aqueous was extracted with DCM/MeOH with a phase separator cartridge.
- Table 11 contains examples that were prepared according to Method J (PyBOP or HATU). The majority of compounds were purified by Gilson prep-HPLC, and some were purified by automated column chromatography (silica gel). The aryl acid coupling partners were prepared according to Methods S, U, V, W or previously described methods. Table 11
- Table 12 contains examples that were prepared according to Method J (PyBOP or HATU). The majority of compounds were purified by Gilson prep-HPLC, and some were purified by automated column chromatography (silica gel). The aryl acid coupling partners were prepared according the previously described procedures.
- step b O S O N F H HO CF 3 N N O O H 2 N O
- the title compound was prepared according to Method J with step a (25 mg) and PyBOP.
- the crude material was purified by Shimadzu prep-HPLC (20-95%, MeCN/Water, 0.1% formic acid, 25 min) to afford the title compound as a white solid (23 mg, 38%) as a white solid.
- Example 649 step a (Method X) O N O OH S O O
- step b O N F H HO CF 3 O N N S O O O H 2 N O
- the title compound was prepared according to Method J with step a (16 mg) and PyBOP.
- Example 650 O 15 F HO O H F 3C OH N N O NH HO
- Example 650 step a I N Cl N HBn To a 50-mL round bottom flask equipped with a stir bar was charged 2,6-dichloropyridin-3- amine (0.489 g, 3 mmol) and benzaldehyde (0.350 g, 3.30 mmol) followed by ethyl acetate (6 mL).
- step b I N Cl N B n O To a 50-mL round bottom flask containing the compound from step a (3600 mg, 10.45 mmol in DMF (10 mL) was added a stir bar. The flask was cooled to 0 o C and added sodium hydride (627 mg, 15.67 mmol) in 2 min.
- Example 650 step c I N Cl NBn HO To a 100-mL round bottom flask containing the compound from step b (1130 mg, 2.73 mmol) in THF (27.3 ml) was added a stir bar, and the flask was purged with nitrogen. The flask was cooled at 0 o C and added LDA (1998 ⁇ l, 3.00 mmol) dropwise. The reaction was stirred at 0 o C for 5 min then stirred at 35 o C for 4 hr. The reaction was quenched with EtOAc/water and extracted with EtOAc.
- step e F C N Cl 3 NBn TBDPSO To a 30 mL microwave vial containing the compound from step d (817 mg, 1.25 mmol) was added a stir bar. The residue was dissolved in DME/water (12.5 mL, 4:1), and cesium carbonate (812 mg, 2.50 mmol), PdCl 2 (dppf) (92 mg, 0.125 mmol) were added followed by 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (557 mg, 2.50 mmol).
- Example 650 step f F 3 C OH HO N Cl NBn TBDPSO To a 50-mL round bottom flask containing the compound from step e (400 mg, 0.644 mmol) was added a stir bar. The residue was dissolved in t-Butanol (5.37 ml) and Water (5.37 ml) at room temperature. Methanesulfonamide (61.2 mg, 0.644 mmol) was added followed AD- mix beta (1003 mg, 1.288 mmol). The mixture was stirred at room temperature for 48 hours (LC-MS showed >50% conversion ) The reaction was quenched with sat. aqueous Na 2 SO 3 solution and extracted with EtOAc.
- Example 650 step j O TBSO O F HF 3 C OH N N O NBn TBDPSO
- a stir bar containing the compound from step i (57 mg, 0.059 mmol) was added a stir bar.
- the residue was dissolved in 1,4-dioxane/water (9:1, 0.8 mL) and the vial was added (4-fluorophenyl)boronic acid (41 mg, 0.390 mmol), cesium carbonate (39 mg, 0.156 mmol) followed by PdCl2(dppf) (6 mg, 0.01 mmol).
- the mixture was degassed for 5 min using nitrogen.
- the vial was then sealed and heated at 130 o C for 2 hours.
- Example 663 I N Br O F H 2 N O Example 663 step a I N Br O F O O
- N-fluoro-N-(phenylsulfonyl) benzenesulfonamide 963 mg, 3.05 mmol
- methyl 7-bromo-5-iodo-2,3-dihydrofuro[2,3- c]pyridine-3-carboxylate 586 mg, 1.526 mmol
- the vial was cooled to -78oC, and LDA (916 ⁇ l, 1.831 mmol) was slowly added.
- reaction was stirred at -78C for 1 hr. After 1 hr at -78oC, reaction gelled up. The reaction was warmed to rt and stirred and monitored by LCMS. The reaction was diluted with EtOAc and quenched with water and sat. ammonium chloride. EtOAc and DCM/MeOH 1x each extraction with a phase separator cartridge. Concentrated. The material was purified by automated column chromatography (0-1900% EtOAc/cHex) to afford the title compound (483 mg, 71%). ESI-MS m/z: 401.86/403.86 [M+H] + .
- Example 663 step c I N Br O F H 2 N O The above compound was prepared in an analogous fashion to Intermediate 36 step b. The crude material was purified by automated column chromatography (silica gel, 0-100% EtOAc/cHex) to afford the title compound as an orange oil (243 mg, 43%) ESI-MS m/z: 386.33 [M+H] + .
- Example 664 F F 3 C OH H 2 N N O F H 2 N O The above example was prepared in an analogous sequence to Intermediate 36as a mixture of diastereomers to afford the desired amino alcohol (42 mg).
- ASSAYS Methods for RSV-A assay Hep-2 cells, (originally derived from tumors grown in irradiated-cortisonised weanling rats that had been injected with epidermoid carcinoma tissue from a 56 year old male’s larynx, but later found to be indistinguishable from HeLa cells by PCR DNA analysis), were used for the culturing of genotype A, “Long” strain RSV. Flasks were inoculated with RSV and viral stocks were collected once cytopathic effect (CPE) was greater than 90%. Viral stocks in 25% sucrose media were snap frozen using liquid nitrogen to increase viral stability.
- CPE cytopathic effect
- Viral stock titers were quantified by tissue culture infectious dose 50% (TCID 50 ) using 8,000 cells per well and 3-fold viral dilutions across a 96-well plate, cultured for 4 days. Viral stock titers were also quantified by a plaque forming unit assay, as described elsewhere.
- Hep-2 cells are seeded into the inner 60 wells of a 96-well plate at 8,000 cells per well in a volume of 50 ⁇ L using Growth Media (DMEM without phenol red, 1% L-Glut, 1% Penn/Strep, 1% nonessential amino acids, 10% heat-inactivated FBS).2-fold serial dilutions of control and test compounds are added to the wells in duplicate in a total volume of 25 ⁇ L. Viral stock is then added to the wells at a multiplicity of infection (MOI) of 0.1 in a volume of 25 ⁇ L, bringing the total volume of each well to 100 ⁇ L.
- MOI multiplicity of infection
- Each 96-well plate has a control column of 6 wells with cells and virus but no compound (negative control, max CPE), a column with cells but no compound or virus (positive control, minimum CPE), and a column with no cells or virus or compound (background plate/reagent control).
- the control wells with cells but no virus are given an additional 25 ⁇ L of growth media containing an equal quantity of sucrose as those wells receiving the viral stock in order to keep consistent in media and volume conditions.
- the outer wells of the plate are filled with 125 ⁇ L of moat media (DMEM, 1% Penn/Strep) to act as a thermal and evaporative moat around the test wells.
- DMEM moat media
- EC 50 each compound (Table 17). EC 50 ranges are as follows: A ⁇ 0.2 ⁇ M; B > 0.2 ⁇ M. Table 17 Summary of Activities for RSV-A Methods for HMPV antiviral assay HMPV antiviral activity was evaluated using a recombinant version of HMPV CAN97-83 engineered to contain the coding sequence for enhanced green fluorescence protein (eGFP) in the 3’ end of the virus genome (MPV-GFP1, ViraTree).
- eGFP enhanced green fluorescence protein
- Vero E6 cells (ATCC # CCL-7) were seeded at a density of 12,000 cells/100 ⁇ L/well into 96-well cell plates one day prior to the assay. On the day of screening, the cell culture medium was aspirated from the wells and cells were washed twice with serum-free Eagle’s Modified Essential Medium (EMEM, ATCC #) containing 1% penicillin-streptomycin (Invitrogen) (SF-EMEM). Cell washes were performed by dispensing 100 ⁇ L SF-EMEM per well and immediately aspirating the wash medium from the well.
- EMEM serum-free Eagle’s Modified Essential Medium
- SF-EMEMEM penicillin-streptomycin
- SF-OptiMEM serum-free OptiMEM
- VENDOR serum-free OptiMEM
- VENDOR TPCK-Trypsin
- penicillin-streptomycin was added to the cells at 50 ⁇ L/well.
- Compounds were added into the 96-well plates using a JANUS automated liquid handling system (VENDOR).
- VENDOR JANUS automated liquid handling system
- Compounds were initially diluted 1:50 into an intermediate 96-well plate containing SF- OptiMEM prior to transfer to the assay plate (25 ⁇ L/well).
- test compounds were tested in duplicate wells at final concentrations starting from 8 ⁇ M or 2 ⁇ M using 1 ⁇ 2 stepwise dilutions for a total of 8 points.
- Virus infection was performed by preparing a working stock of MPV-GFP1 at a multiplicity of infection (MOI) equal to 0.05/25 ⁇ L and aliquoting 25 ⁇ L of virus inoculum to the compound and positive control wells.
- MOI multiplicity of infection
- SF-OptiMEM was added (25 ⁇ L/well) to the appropriate wells to serve as a virus-free negative control for the assay.
- the final DMSO concentration of all wells is 0.5%. Plates were incubated at 32°C, 5% CO 2 for 5 days.
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Abstract
La présente invention concerne des composés de formule (I), ou leurs sels, esters ou promédicaments pharmaceutiquement acceptables : ceux-ci inhibent le virus respiratoire syncytial humain (VRSH) ou les inhibiteurs du métapneumovirus humain (MPVH). La présente invention concerne en outre des compositions pharmaceutiques comprenant les composés susmentionnés pour une administration à un sujet atteint d'une infection à VRSH ou MPVH. L'invention concerne également des procédés de traitement d'une infection à VHRS ou VHMP chez un sujet par l'administration d'une composition pharmaceutique comprenant les composés de la présente invention.
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WO2015026792A1 (fr) * | 2013-08-21 | 2015-02-26 | Alios Biopharma, Inc. | Composés antiviraux |
US20160244460A1 (en) * | 2015-02-25 | 2016-08-25 | Alios Biopharma, Inc. | Antiviral compounds |
WO2021066922A1 (fr) * | 2019-10-04 | 2021-04-08 | Enanta Pharmaceuticals, Inc. | Composés hétérocycliques antiviraux |
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WO2015026792A1 (fr) * | 2013-08-21 | 2015-02-26 | Alios Biopharma, Inc. | Composés antiviraux |
US20160244460A1 (en) * | 2015-02-25 | 2016-08-25 | Alios Biopharma, Inc. | Antiviral compounds |
WO2021066922A1 (fr) * | 2019-10-04 | 2021-04-08 | Enanta Pharmaceuticals, Inc. | Composés hétérocycliques antiviraux |
Non-Patent Citations (2)
Title |
---|
DATABASE Pubchem compound ANONYMOUS : "N-[(2R)-2-[(3S)-3-amino-7-(3-chloro-4-fluorophenyl)-3-methyl-2H-furo[2,3-c]pyridin-5-yl]-3,3,3-trifluoro-2-hydroxypropyl]-4-ethoxy-3-methoxybenzamide", XP055976868, retrieved from NCBI Database accession no. 117923975 * |
DATABASE Pubchem compound ANONYMOUS : "N-[2-[8-[4-fluoro-3-(1-fluoroethyl)phenyl]-4-iodo-4-methyl-2,3-dihydropyrano[2,3-c]pyridin-6-yl]-2-oxoethyl]-3-methoxy-4-[2-[(4-methoxyphenyl)methoxy]ethoxy]benzamide ", XP055977128, retrieved from NCBI Database accession no. 117924454 * |
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