CN113874380A - 具有对抗rsv活性的其他杂芳香族化合物 - Google Patents
具有对抗rsv活性的其他杂芳香族化合物 Download PDFInfo
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- CN113874380A CN113874380A CN202080037990.XA CN202080037990A CN113874380A CN 113874380 A CN113874380 A CN 113874380A CN 202080037990 A CN202080037990 A CN 202080037990A CN 113874380 A CN113874380 A CN 113874380A
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- mixture
- etoac
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- 230000000694 effects Effects 0.000 title description 3
- 150000002390 heteroarenes Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 claims abstract description 8
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
- 208000030925 respiratory syncytial virus infectious disease Diseases 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- -1 hydroxy, hydroxycarbonyl Chemical group 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 7
- 238000004519 manufacturing process Methods 0.000 claims 1
- 241000725643 Respiratory syncytial virus Species 0.000 abstract description 21
- 230000000840 anti-viral effect Effects 0.000 abstract description 13
- 230000010076 replication Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 383
- 239000000543 intermediate Substances 0.000 description 311
- 239000000203 mixture Substances 0.000 description 225
- 235000019439 ethyl acetate Nutrition 0.000 description 190
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 113
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 112
- 229910001868 water Inorganic materials 0.000 description 109
- 239000011541 reaction mixture Substances 0.000 description 107
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 106
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 104
- 239000007787 solid Substances 0.000 description 104
- 239000010410 layer Substances 0.000 description 103
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 93
- 239000012071 phase Substances 0.000 description 93
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 65
- 239000012044 organic layer Substances 0.000 description 64
- 239000012267 brine Substances 0.000 description 63
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 63
- 239000000047 product Substances 0.000 description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 49
- 230000001788 irregular Effects 0.000 description 43
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- 229910020175 SiOH Inorganic materials 0.000 description 29
- 239000007864 aqueous solution Substances 0.000 description 27
- 239000000284 extract Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 238000010926 purge Methods 0.000 description 25
- 239000008346 aqueous phase Substances 0.000 description 24
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000007821 HATU Substances 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 229910000024 caesium carbonate Inorganic materials 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 238000000746 purification Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 13
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 13
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 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 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- QPILYVQSKNWRDD-MRVPVSSYSA-N (1r)-1-methyl-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2[C@@H](C)NCCC2=C1 QPILYVQSKNWRDD-MRVPVSSYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 238000007865 diluting Methods 0.000 description 10
- 239000001301 oxygen Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 9
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
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- 238000011068 loading method Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
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- 239000003921 oil Substances 0.000 description 7
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- 238000003756 stirring Methods 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 229910002666 PdCl2 Inorganic materials 0.000 description 6
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- 125000004429 atom Chemical group 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- VVBSXSVVMNGQIN-JEDNCBNOSA-N methyl (3s)-pyrrolidine-3-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@H]1CCNC1 VVBSXSVVMNGQIN-JEDNCBNOSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 5
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 5
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- 229940126543 compound 14 Drugs 0.000 description 5
- 229940126086 compound 21 Drugs 0.000 description 5
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- 235000003599 food sweetener Nutrition 0.000 description 5
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- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
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- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 5
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 5
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
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- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
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- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 4
- UPCARQPLANFGQJ-UHFFFAOYSA-N 4-bromo-2-fluorobenzaldehyde Chemical compound FC1=CC(Br)=CC=C1C=O UPCARQPLANFGQJ-UHFFFAOYSA-N 0.000 description 4
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 4
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
本发明涉及具有抗病毒活性的、特别是对呼吸道合胞病毒(RSV)的复制具有抑制活性的具有式(I)的化合物。本发明进一步涉及包含这些化合物的药物组合物以及将这些化合物用于在呼吸道合胞病毒感染的治疗中使用。
Description
技术领域
本发明涉及具有抗病毒活性的、特别是对呼吸道合胞病毒(RSV)的复制具有抑制活性的化合物。本发明进一步涉及包含这些化合物的药物组合物以及将这些化合物用于在呼吸道合胞病毒感染的治疗中使用。
背景技术
人RSV或呼吸道合胞病毒是一种大的RNA病毒,连同牛RSV病毒一起是肺病毒科(Pneumoviridae)、正肺病毒属(Orthopneumovirus)的成员。人RSV是造成全世界所有年龄的人群中一系列呼吸道疾病的原因。它是婴儿期和儿童期下呼吸道疾病的主要原因。超过一半的婴儿在他们出生后第一年遭遇RSV,并且几乎所有婴儿在他们出生后头两年内遭遇RSV。在幼儿中的感染可以引起持续多年的肺损害,并且在以后的生活中可以引起慢性肺疾病(慢性喘息、哮喘)。大龄儿童和成人在RSV感染时经常患有(重)普通感冒。在晚年,易感性再次增加,并且RSV已经在老年人中牵连了许多肺炎的爆发,导致显著的死亡率。
被来自给定亚群的病毒感染并不会在下一个冬季中保护免于随后被来自相同亚群的RSV分离株所感染。因此尽管仅存在两种亚型(A和B),但是再次感染RSV是常见的。
当今仅有两种药物被批准用于对抗RSV感染。第一种是利巴韦林(一种核苷类似物),它提供用于住院儿童严重RSV感染的气溶胶治疗。气溶胶施用途径、毒性(致畸性风险)、成本和高度可变的效力限制了它的用途。(帕利珠单抗(一种单克隆抗体))用于被动免疫预防。尽管的益处已被证实,但治疗费用昂贵,需要肠胃外施用,并且仅限于有发生严重病理的风险的儿童。
清楚地,对针对RSV复制有效无毒并且易于施用的药物存在需求。特别优选的是提供对抗RSV复制的、可以口服施用的药物。
展现出抗RSV活性的化合物披露于WO-2016/174079中。
具体实施方式
本发明涉及具有式(I)的化合物,
包括其任何立体化学异构形式,其中
X1、X2、X3和X4各自独立地选自C、CH、N、NR5、O或S,条件是X1、X2、X3和X4都不是C或CH;
Y1和Y2各自独立地选自CH、CF和N;
R1是CH3或CH2CH3;
R2是氢、卤代或C1-4烷基;
R3是卤代;
R4是C1-6烷基;C3-6环烷基;二(C1-4烷基)氨基;吡咯烷基;苯基;吡啶;或被1、2或3个取代基取代的苯基或吡啶,这些取代基各自单独地选自卤代、羟基、氰基、C1-4烷基、多卤代C1-4烷基、和C1-4烷氧基;
R5是氢或C1-4烷基;
R6是NH2或选自取代基(a)或(b)的取代基;其中
(a)是-NR7-(CO)-杂环,其中所述杂环被一个、两个或三个取代基取代,这些取代基各自独立地选自卤代、羟基、C1-4烷氧基的C1-4烷基;或
(b)是C3-6环烷基或杂环,其中所述C3-6环烷基和杂环被一个、两个或三个取代基取代,这些取代基各自独立地选自
C1-6烷基;
被一个、两个或三个取代基取代的C1-6烷基,这些取代基各自独立地选自卤代、羟基、羟基羰基、和氨基羰基;
羟基;
卤代;
-(CO)-OH;
-(CO)-NR10R11;
-(CO)-NR8-SO2-R9;
-NR8R9;
-NR8-(CO)-C1-4烷基;
-NR8-(CO)-C3-6环烷基;
-NR8-SO2-R9;
-SO2-NR10R11;或
-SO2-NR8-(CO)-R9;
其中
R7是氢或C1-4烷基;
每个R8独立地选自氢、C1-4烷基、或羟基C1-4烷基;
R9是C1-4烷基、多卤代C1-4烷基或C3-6环烷基;
R10和R11各自独立地选自氢;C1-4烷基;多卤代C1-4烷基;C3-6环烷基;被C1-4烷基取代的C3-6环烷基;或被羟基或氰基取代的C1-4烷基;
杂环是氮杂环丁烷基、吡咯烷基、哌啶基、或高哌啶基;
或其药学上可接受的酸加成盐。
如在前述的定义中使用的:
-卤代是氟、氯、溴和碘的通称;
-C1-4烷基定义了具有1个至4个碳原子的直链和支链的饱和烃基,例如像甲基、乙基、丙基、丁基、1-甲基乙基、2-甲基-丙基等;
-C1-6烷基意在包括C1-4烷基及其具有5个或6个碳原子的更高级同系物,例如像2甲基丁基、戊基、己基等;
-C3-6环烷基是环丙基、环丁基、环戊基和环己基的通称;
-多卤代C1-4烷基被定义为多卤代取代的C1-4烷基,特别是被2至6个卤素原子取代的C1-4烷基(如上文所定义的),例如二氟甲基、三氟甲基、三氟乙基等;
--(CO)-或(CO)意指羰基。
如本文使用的术语“本发明的化合物”意在包括具有式(I)的化合物及其盐和溶剂化物。
如本文使用的,任何具有仅显示为实线并且不显示为实楔形键或虚楔形键的键的化学式,或者另外表示为围绕一个或多个原子具有特殊构型(例如R,S)的化学式,考虑每种可能的立体异构体,或者两种或更多种立体异构体的混合物。
在上文和下文中,术语“具有式(I)的化合物”和“式(I)的合成的中间体”意指包括其立体异构体及其互变异构形式。
术语“立体异构体”、“立体异构形式”或“立体化学异构形式”在上文或下文中可互换地使用。
本发明包括本发明的化合物呈纯立体异构体形式或呈两种或更多种立体异构体的混合物形式的所有立体异构体。对映异构体为彼此不可重叠的镜像的立体异构体。对映异构体对的1:1混合物是外消旋体或外消旋混合物。非对映体(或非对映异构体)为非对映体的立体异构体,即它们并非为镜像关系。如果化合物含有双键,则这些取代基可以呈E或Z构型。二价环状(部分地)饱和基上的取代基可以具有顺式构型或反式构型;例如,如果化合物含有二取代的环烷基基团,则这些取代基可以呈顺式构型或反式构型。
术语“立体异构体”还包括任何旋转异构体,也称作构象异构体,具有式(I)的化合物可以形成。
因此,只要化学上可能,本发明包括对映异构体、非对映体、外消旋体、E异构体、Z异构体、顺式异构体、反式异构体、旋转异构体及其混合物。
所有那些术语(即,对映异构体、非对映体、外消旋体、E异构体、Z异构体、顺式异构体、反式异构体及其混合物)的含义是本领域技术人员已知的。
绝对构型是根据卡恩-英戈尔德-普雷洛格(Cahn-Ingold-Prelog)系统指定的。不对称原子处的构型是由R或S规定的。绝对构型未知的经过拆分的立体异构体可以根据它们旋转平面偏振光的方向而由(+)或(-)指定。例如,绝对构型未知的已拆分的对映异构体可以根据它们旋转平面偏振光的方向而由(+)或(-)指定。
当鉴定具体的立体异构体时,这意指所述立体异构体基本上不含其他立体异构体,即与少于50%、优选地少于20%、更优选地少于10%、甚至更优选地少于5%,特别是少于2%并且最优选地少于1%的其他立体异构体相关联。因此,当具有式(I)的化合物例如被指定为(R)时,这意指该化合物基本上不含(S)异构体;当具有式(I)的化合物例如被指定为E时,这意指该化合物基本上不含Z异构体;当具有式(I)的化合物例如被指定为顺式时,这意指该化合物基本上不含反式异构体。
一些根据式(I)的化合物还能以它们的互变异构形式存在。尽管在以上式(I)中未明确指示,但是这类形式在它们可能存在的情况下旨在包括在本发明的范围内。
由此得出,单一化合物可以按立体异构和互变异构形式存在。
阻转异构体(atropisomer)(或限制构型异构体(atropoisomer))是具有特定空间构型的立体异构体,该特定空间构型由大空间位阻所致的围绕单键受限制的旋转所产生。具有式(I)的化合物的所有阻转异构形式旨在包括在本发明的范围内。
如上文所提及的药学上可接受的酸加成盐意指包括具有式(I)的化合物所能形成的有治疗活性的无毒酸加成盐形式。这些药学上可接受的酸加成盐可以方便地通过用这种适当的酸来处理碱形式来获得。适当的酸包括例如,无机酸,如氢卤酸(例如盐酸或氢溴酸)、硫酸、硝酸、磷酸以及类似酸;或有机酸,例如像乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸(即乙二酸)、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己氨磺酸、水杨酸、对氨基水杨酸、双羟萘酸以及类似酸。
相反地,可以通过用适当的碱处理将所述盐形式转化为游离碱形式。
具有式(I)的化合物可以按未溶解形式和溶解形式存在。本文所使用的术语“溶剂化物”描述了包括本发明的化合物以及一种或多种药学上可接受的溶剂分子的(如水或乙醇)的分子缔合物。当所述溶剂是水时,使用术语‘水合物’。
为了避免疑义,具有式(I)的化合物可以包括其天然或非天然同位素的任何形式的阐述的原子。在这方面,可被提及的本发明的实施例包括那些实施例,其中(a)具有式(I)的化合物对于该化合物的任何原子不是同位素富集的或不是标记的;和(b)具有式(I)的化合物对于该化合物的一个或多个原子是同位素富集的或是标记的。同位素富集的或被一个或多个稳定同位素标记的具有式(I)的化合物包括,例如同位素富集的或被一个或多个原子(例如氘、13C、14C、14N、15O等)标记的具有式(I)的化合物。
第一组化合物是具有式(I)的化合物,其中X1、X2、X3和X4选自
X<sub>1</sub> | X<sub>2</sub> | X<sub>3</sub> | X<sub>4</sub> | |
CH | C | NR<sup>5</sup> | CH | (b-1) |
N | C | NR<sup>5</sup> | CH | (b-2) |
N | C | NR<sup>5</sup> | N | (b-3) |
NR<sup>5</sup> | C | N | N | (b-4) |
CH | N | N | CH | (b-5) |
N | N | CH | CH | (b-6) |
N | C | O | CH | (b-7) |
N | N | CH | N | (b-8) |
N | C | S | CH | (b-9) |
O | C | CH | N | (b-10) |
N | C | O | N | (b-11) |
O | C | CH | CH | (b-12) |
CH | C | S | N | (b-13) |
S | C | N | N | (b-14)。 |
第二组化合物是具有式(I)的化合物,其中基团A具有式(a-1)。
第三组化合物是具有式(I)的化合物,其中R6是取代基(a)。
第四组化合物是具有式(I)的化合物,其中R6是取代基(b)。
第五组化合物是具有式(I)的化合物,其中Y1和Y2各自独立地选自CH。
感兴趣的具有式(I)的化合物是适用一个或多个下述限制的那些具有式(I)的化合物:
a)A是具有式(a-1)的基团,其中R1是CH3;或
b)R2是氢;或
c)R3是氟;或
d)R4是C3-6环烷基,特别是环丙基;或
e)R4是C1-4烷基,特别是乙基;或
f)R4是苯基;或
g)R6是具有式-NR7-(CO)-杂环的取代基(a),其中所述杂环是被羟基取代的吡咯烷基;或
h)R6是取代基(b)且取代基(b)是被一个或两个取代基取代的C3-6环烷基,这些取代基各自独立地选自-(CO)-OH或-(CO)-NR10R11,其中R10和R11各自是氢;以及
i)R6是取代基(b)且取代基(b)是杂环,其中所述杂环是被一个或两个取代基取代的吡咯烷基,这些取代基各自独立地选自羟基、-(CO)-OH或-(CO)-NR10R11,其中R10和R11各自是氢。
在一个实施例中,本发明涉及具有式(I)的化合物
包括其任何立体化学异构形式,其中
X1、X2、X3和X4选自
Y1和Y2各自独立地选自CH;
R1是CH3;
R2是氢;
R3是卤代;
R4是C1-6烷基、C3-6环烷基或苯基;
R5是氢或C1-4烷基;
R6是NH2或选自取代基(a)或(b)的取代基;其中
(a)是-NR7-(CO)-杂环,其中所述杂环被羟基取代,且R7是氢;或
(b)是C3-6环烷基或杂环,其中所述C3-6环烷基和杂环被一个或两个取代基取代,这些取代基各自独立地选自羟基、-(CO)-OH或-(CO)-NR10R11,其中R10和R11各自是氢;
并且
杂环是吡咯烷基;
或其药学上可接受的酸加成盐。
通常,具有式(I)的化合物可以通过以下方式制备:使具有式(II)的中间体与具有式(III)的烷基硼酸酯中间体在至少一种反应惰性溶剂中并且任选地在至少一种过渡金属偶联试剂和/或至少一种适合的配体的存在下反应,所述方法进一步任选地包括将具有式(I)的化合物转化为其加成盐。用于此反应的适合的金属偶联试剂和/或适合的配体是例如钯化合物,如四(三苯基膦)钯、三(二亚苄基-丙酮)二钯、2,2’-双(二苯基膦)-1,1’-联萘等。
一般也可以通过在反应惰性溶剂(例如二氯甲烷或DMF)中,在合适的试剂(例如HATU(1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]-吡啶鎓3-氧化物六氟磷酸酯))和碱(例如三乙胺)的存在下,使具有式(IV)的中间体与具有式(V)的中间体进行反应来制备具有式(I)的化合物。
也可以通过在反应惰性溶剂中和任选地在至少一种过渡金属偶联试剂和/或至少一种合适的配体的存在下,使具有式(VI)的中间体与具有式(VII)的中间体反应来制备具有式(I)的化合物。
用于制备具有式(I)的化合物的其他合成途径已经描述于
作为一般制备方法的实验部分和具体工作实例中。
具有式(I)的化合物可以进一步按照本领域已知的基团转化反应通过将具有式(I)的化合物相互转化而制备。
这些起始材料以及一些中间体是熟知的化合物并且是可商购得或是可以根据本领域中通常已知的常规反应程序制备的。
如上文所述的方法制备的具有式(I)的化合物可合成为对映异构体的外消旋混合物形式,这些对映异构体可依照本领域已知的拆分程序彼此分离。那些以外消旋形式获得的具有式(I)的化合物可以通过与合适的手性酸发生反应而转化成相应的非对映异构体盐形式。所述非对映异构盐形式接着例如通过选择性或分步结晶而分离,并且对映异构体通过碱由其释放。分离具有式(I)的化合物的对映异构形式的替代方式涉及使用手性固定相的液相色谱法。所述纯立体化学异构形式还可以来源于适当原材料的相应的纯立体化学异构形式,条件是反应立体定向地发生。优选地,如果一种具体的立体异构体是所希望的,那么所述化合物将通过立体专一的制备方法得以合成。这些方法将有利地采用对映异构体纯的原材料。
具有式(I)的化合物显示抗病毒特性。使用本发明的化合物和方法可治疗的病毒感染包括那些由正粘病毒和副粘病毒并且特别是由人类和牛呼吸道合胞病毒(RSV)引起的感染。并且本发明的多个化合物针对RSV突变株是有活性的。另外,本发明的许多化合物显示了良好的药物代谢动力学曲线并且在生物可利用度(包括可接受的半衰期、AUC和峰值)以及没有不利现象(例如作用不够快以及组织保留不充分)方面具有引人注目的特性。
如在说明书实验部分所述的测试中对本发明化合物针对RSV的体外抗病毒活性进行测试,并且还可以在病毒产率减少测定中对其进行证明。如Wyde等人在AntiviralResearch[抗病毒研究],38,第31-42页(1998)中描述的那样,可以在使用棉鼠的测试模型中证明本发明化合物的针对RSV的体内抗病毒活性。
此外,本发明提供了以下药物组合物,这些药物组合物包含至少一种药学上可接受的载体以及治疗有效量的具有式(I)的化合物。还提供了以下药物组合物,这些药物组合物包含药学上可接受的载体、治疗有效量的具有式(I)的化合物以及另一种抗病毒剂,尤其是抑制RSV的化合物。
为了制备本发明的药物组合物,将有效量的呈碱或酸加成盐形式的特定化合物(作为活性成分)与至少一种药学上可接受的载体紧密混合,所述载体依照施用所需的制剂形式可采用广泛的各种形式。这些药物组合物希望是处于单位剂型,优选适用于口服施用、直肠施用、经皮施用或肠胃外注射。
例如,在制备处于口服剂型的组合物中,可以使用任何常见液体药物载体,在口服液体制剂(例如悬浮液、糖浆剂、酏剂以及溶液)的情况下,例如像水、二醇类、油类、醇类等;或在粉剂、丸剂、胶囊和片剂的情况下,固体药物载体例如淀粉、糖、高岭土、润滑剂、粘合剂、崩解剂等。片剂和胶囊由于其易于施用而代表最有利的口服剂量单位形式,在此情况下,显然使用固体药物载体。对于肠胃外注射组合物,药物载体将主要包括无菌水,但可以包括其他成分来用于改进活性成分的溶解性。可注射溶液可以例如通过使用包括盐溶液、葡萄糖溶液或两者的混合物的药物载体来制备。也可通过使用适当的液体载体、悬浮剂等制备可注射悬浮液。在适用于经皮施用的组合物中,药物载体可以任选地包括渗透增强剂和/或合适的润湿剂,任选地与小比例的不会对皮肤造成显著有害影响的合适的添加剂组合。可以选择所述添加剂以便促进活性成分的皮肤施用和/或有助于制备所希望的组合物。这些局部用组合物可以按多种方式施用,例如作为透皮贴剂,点涂剂(spot-on)或软膏剂。由于具有式(I)的化合物的加成盐与相应的碱形式相比有增加的水溶性,显然更适合用在水性组合物的制备中。
这点对于配制处于易于施用和剂量均匀的剂量单位形式的本发明的药物组合物是尤其有利的。如本文使用的“剂量单位形式”是指适合作为单位剂量的物理离散单位,各单位包含预定量的活性成分,该预定量的活性成分经计算以与所要求药物载体相结合而产生所希望的治疗效果。此类剂量单位形式的实例是片剂(包括刻痕或包衣片剂)、胶囊剂、丸剂、散剂包、糯米纸囊剂、可注射溶液剂或混悬剂、一茶匙的量、一汤匙的量等,以及分离的多个这些剂量单位形式。
对于口服施用,本发明的药物组合物可以采取固体剂型的形式,例如片剂(可吞咽及可咀嚼的形式)、胶囊或软胶囊,它们是由常规手段采用药学上可接受的赋形剂和载体制得的,这些赋形剂和载体如结合剂(例如预胶化玉米淀粉、聚乙烯吡咯烷酮、羟丙基甲基纤维素等)、填充剂(例如乳糖、微晶纤维素、磷酸钙等)、润滑剂(例如硬脂酸镁、滑石粉、二氧化硅等)、崩解剂(例如马铃薯淀粉、淀粉乙醇酸钠等)、润湿剂(例如十二烷基硫酸钠)等。此类片剂还可通过本领域熟知的方法来进行包衣。
用于口服施用的液体制剂可以采取例如溶液、糖浆或悬浮液的形式,或其可以被配制成一种在使用前与水和/或其他合适的液体载体混合的干产品。这样的液体制剂可通过常规的方法,任选地用其他药学上可接受的添加剂例如助悬剂(例如山梨糖醇糖浆、甲基纤维素、羟丙基甲基纤维素或氢化食用油)、乳化剂(例如卵磷脂或阿拉伯胶)、非水性载体(例如杏仁油、油酯或乙醇)、甜味剂、调味剂、掩蔽剂和防腐剂(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)来制备。
在本发明的药物组合物中有用的药学上可接受的甜味剂优选地包括至少一种强力甜味剂,例如阿斯巴甜、乙酰磺胺酸钾、环拉酸钠、阿力甜、双氢查耳酮甜味剂、莫内林、甜菊苷、三氯蔗糖(4,1',6'-三氯-4,1',6'-三脱氧半乳蔗糖)或优选糖精、糖精钠或糖精钙,以及任选地至少一种填充型甜味剂,例如山梨糖醇、甘露糖醇、果糖、蔗糖、麦芽糖、异麦芽酮糖醇、葡萄糖、氢化的葡萄糖浆、木糖醇、焦糖或蜂蜜。强力甜味剂方便地以低浓度使用。例如,在糖精钠的情况下,所述浓度的范围可以是从最终配制品的约0.04%至0.1%(重量/体积)。填充型甜味剂可以在较大的以下浓度范围内有效地使用:从约10%至约35%,优选从约10%至15%(重量/体积)。
可以掩盖低剂量配制品中的苦味成分的药学上可接受的调味剂优选是果味调味剂,如樱桃、覆盆子、黑醋栗或草莓调味剂。两种调味剂的组合可以产生非常好的效果。在高剂量配制品中,可能需要较强的药学上可接受的调味剂,如焦糖巧克力、冰薄荷、迷幻剂(Fantasy)等。每种调味剂可以按范围为从约0.05%至1%(重量/体积)的浓度存在于最终组合物中。可有利地使用所述强调味剂的组合。优选地,使用在配制品的环境下不会出现任何味道和/或颜色的改变或丢失的调味剂。
可以将具有式(I)的化合物配制成用于通过注射(方便地在静脉内、肌内或皮下注射)的肠胃外施用,例如通过静脉快速推注或连续静脉输注。用于注射的配制品能以单位剂型存在,例如以安瓿或包括添加的防腐剂的多剂量容器存在。它们可采用在油性或水性媒介中的悬浮液、溶液或乳液形式,并可含有配制剂例如等渗剂、助悬剂、稳定剂和/或分散剂。可替代地,活性成分能以粉末的形式存在,以在使用前与合适的媒介(例如无菌无热源水)混合。
这些具有式(I)的化合物还可以配制成直肠组合物(例如栓剂或保留灌肠剂),例如包含常规的栓剂基质(例如可可油和/或其他甘油酯)。
通常,应考虑到抗病毒有效的日用量将是从0.01mg/kg至500mg/kg体重,更优选从0.1mg/kg至50mg/kg体重。可以适当地将所需剂量在全天中以适当的时间间隔作为两个、三个、四个或更多个分剂量施用。所述分剂量可被配制成单位剂型,例如每单位剂型含有1至1000mg,且具体来说5至200mg的活性成分。
如本领域的技术人员所熟知的,施用的确切剂量和频率取决于所使用的具有式(I)的特定化合物,所治疗的特定病症,所治疗的病症的严重程度,特定患者的年龄、体重、性别、障碍程度以及总体身体健康状况,连同个体可以服用的其他药物。此外,显而易见的是,所述有效日用量可以降低或提高,这取决于所治疗的受试者的应答和/或取决于给出本发明的化合物处方的医生的评估。因此,上文提及的有效日用量范围仅具有指导意义。
还有,另一种抗病毒剂和具有式(I)的化合物的组合可以用作药物。因此,本发明还涉及包含(a)具有式(I)的化合物,以及(b)另一种抗病毒化合物的产品,该产品作为组合的制剂用于在抗病毒治疗中同时、分开或相继的使用。不同的药物可以连同药学上可接受的载体组合为单个制剂。例如,本发明的化合物可以与干扰素-β或肿瘤坏死因子-α组合以治疗或预防RSV感染。与具有式(I)的化合物组合用于RSV治疗的其他抗病毒化合物(b)是RSV融合抑制剂或RSV聚合酶抑制剂。与在RSV的治疗中有用的任一种具有式(I)的化合物组合的具体抗病毒化合物是选自以下的抑制RSV的化合物:利巴韦林、卢米西他滨(lumicitabine)、普列沙托韦(presatovir)、ALX-0171、MDT-637、BTA-9881、BMS-433771、YM-543403、A-60444、TMC-353121、RFI-641、CL-387626、MBX-300、西那托韦(sisunatovir)、齐拉索韦(ziresovir)、3-({5-氯-1-[3-(甲基-磺酰基)丙基]-1H-苯并咪唑-2-基}甲基)-1-环丙基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮、3-[[7-氯-3-(2-乙基磺酰基-乙基)咪唑并[1,2-a]吡啶-2-基]甲基]-1-环丙基-咪唑并[4,5-c]吡啶-2-酮、和3-({5-氯-1-[3-(甲基-磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮。
实验部分
A.缩写
对于一些化合物,尽管化合物本身已经作为单一的立体异构体被分离并且是对映异构体纯的,但是当绝对立体化学未确定时(即使这些键被立体定向地绘制出),已经将立体化学构型指定为R*或S*(或*R或*S)。这意指由*表示的该立体中心的绝对立体构型是未确定的(即使这些键被立体定向地绘制出),尽管该化合物在指定中心处是对映异构体纯的。
B.化合物合成
1.噁唑并吡啶的合成
1.1化合物1的合成
中间体A1
2,6-二氯-4-乙基-3-硝基吡啶
将在甲苯中的二乙基锌15%(4.4mL,4.9mmol)添加至4-溴-2,6-二氯-3-硝基吡啶(1.33g,4.89mmol)在THF(30mL)中的溶液中。将混合物用N2吹扫。添加PdCl2(PPh3)2(343mg,0.489mmol)。将混合物用N2吹扫并在室温下搅拌4h。用EtOAc和水进行萃取。将有机层用盐水洗涤,经MgSO4干燥,蒸发至干燥。将残余物通过制备型LC(不规则SiOH 15-40μm,40g流动相梯度:从庚烷/EtOAc 99/1至50/50)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体A1(922mg,85%)。
中间体A2
2,6-二氯-4-乙基吡啶-3-胺
在密封管中,将中间体A1(922mg,4.17mmol)、铁(1.17g,20.9mmol)、氯化铵(2.23g,41.8mmol)在THF(13mL)、MeOH(13mL)和H2O(6.6mL)中的溶液在80℃下加热18h。将混合物冷却至室温,然后在EtOAc和水中稀释。将各层分离并将有机层用盐水洗涤,经MgSO4干燥,过滤并蒸发以给出棕色油状物,将其通过制备型LC(不规则SiOH,15-40μm,40g,流动相梯度:从庚烷/EtOAc 99/01至50/50)纯化。将含有产物的级分合并并在真空下蒸发以给出呈无色油状物的中间体A2(538mg,68%)。
中间体A3
N-(2,6-二氯-4-乙基吡啶-3-基)-2-氟-4-硝基苯甲酰胺
在0℃下,将2-氟-4-硝基苯甲酰氯(688mg,3.38mmol)添加至中间体A2(497mg,2.60mmol)和TEA(0.542mL,3.90mmol)在DCE(17mL)中的溶液的混合物中。将所得混合物在室温下搅拌18h。在真空下除去溶剂并将残余物用DCM吸收,将固体将玻璃料过滤以给出呈黄色固体状的中间体A3(777mg,83%)。
中间体A4
4-氨基-N-(2,6-二氯-4-乙基吡啶-3-基)-2-氟苯甲酰胺
在密封管中,将中间体A3(308mg,0.86mmol)、铁(0.24g,4.3mmol)、氯化铵(0.461g,8.61mmol)在THF(2.7mL)、MeOH(2.7mL)和H2O(1.4mL)中的溶液在80℃下加热18h。将混合物冷却至室温,然后在EtOAc和水中稀释。将各层分离并将有机层用盐水洗涤,经MgSO4干燥,过滤并蒸发以给出呈白色固体状的中间体A4(285mg,定量)。
中间体A5
4-(5-氯-7-乙基噁唑并[5,4-b]吡啶-2-基)-3-氟苯胺
中间体A4(555mg,1.69mmol)和K2CO3(701mg,5.07mmol)在甲苯(13.5mL)中的混合物。将混合物用N2吹扫。然后添加DMEDA(218μL,2.03mmol)和CuI(354mg,1.86mmol)并将反应混合物在110℃下搅拌18h。将混合物冷却至室温,然后经过滤并将滤液蒸发至干燥。将残余物通过制备型LC(不规则SiOH 15-40μm,24g流动相:从庚烷/EtOAc 70/30至20/80)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体A5(356mg,72%)。
中间体A6
苯基(4-(5-氯-7-乙基噁唑并[5,4-b]吡啶-2-基)-3-氟苯基)氨基甲酸酯
在中间体A5(356mg,1.22mmol)和K2CO3(388mg,2.81mmol)在THF(15mL)中的混合物中添加氯甲酸苯酯(0.153mL,1.22mmol)。将混合物在室温下搅拌18h。添加水和EtOAc并用EtOAc进行萃取(两次)。将合并的有机层经MgSO4干燥,过滤并在真空中浓缩以给出中间体A6(499mg,99%)。
中间体A7
(R)-N-(4-(5-氯-7-乙基噁唑并[5,4-b]吡啶-2-基)-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
向中间体A6(475mg,1.15mmol)和(R)-(+)-3-吡咯烷醇(151mg,1.73mmol)在DMF(26mL)中的搅拌混合物中添加DIPEA(994μL,5.77mmol)。将反应混合物在室温下搅拌2h。在真空下除去溶剂。添加水和EtOAc。将水层用EtOAc萃取(两次),将合并的有机层经MgSO4干燥、过滤并在真空中浓缩。将残余物通过制备型LC(不规则SiOH 15-40μm,24g流动相梯度:从DCM/MeOH99/1至90/10)纯化。将含有产物的级分合并并在真空下蒸发以给出呈白色固体状的中间体A7(420mg,90%)。
中间体A8
乙基(R)-7-乙基-2-(2-氟-4-(3-羟基吡咯烷-1-甲酰胺基)苯基)噁唑并[5,4-b]吡啶-5-甲酸酯
在压力容器反应器中,向中间体A7(0.42g,1.04mmol)和乙酸钠(170mg,2.08mmol)在EtOH(6.2mL)和DMF(2.7mL)中的脱气混合物中添加PdCl2(dppf)(78mg,0.10mmol),然后将所得混合物在7巴的CO下搅拌。将所得混合物在70℃下加热16h。将混合物冷却至室温,然后添加水和EtOAc。将各层分离并且将水层用EtOAc萃取(一次)。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并且在真空中除去溶剂。将残余物通过制备型LC(不规则SiOH,15-40μm,24g,流动相梯度:从DCM/MeOH 99/1至90/10)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体A8(272mg,59%)。
中间体A9
钾(R)-7-乙基-2-(2-氟-4-(3-羟基吡咯烷-1-甲酰胺基)苯基)噁唑并[5,4-b]吡啶-5-甲酸酯
将中间体A8(272mg,0.615mmol)和氢氧化钾(76mg,1.3mmol)在EtOH(5.3mL)中的混合物在室温下搅拌16h。将沉淀物过滤并经玻璃料干燥以给出呈钾盐的中间体A9(168mg,60%)。
化合物1
(R)-N-(4-(7-乙基-5-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)噁唑并[5,4-b]吡啶-2-基)-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
将中间体A9(149mg,0.329mmol)、R-(1)-甲基-(1,2,3,4)-四氢异喹啉(163mg,0.428mmol)、DIPEA(0.17mL,0.99mmol)和HATU(58mg,0.40mmol)在DMF(1.9mL)中的混合物在室温下搅拌18h。将水和EtOAc添加至反应混合物中。将各层分离。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤(4次),经MgSO4干燥并在真空中蒸发以给出吸收在MeCN中的褐色固体。将获得的沉淀物过滤并在50℃下真空干燥6h。将固体通过制备型LC(球形C1825μm,40g YMC-ODS-25,流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从75:25至25:75)纯化。将含有产物的级分合并并蒸发,然后将所得固体吸收在MeCN中。将获得的沉淀物过滤并在50℃下真空干燥6h以给出呈白色固体状的化合物1(82mg,46%)。
1.2化合物2的合成
中间体B1
2,6-二溴-4-环丙基吡啶-3-胺
在室温下,将NBS(0.558g,3.13mmol)添加至3-氨基-4-环丙基吡啶(200mg,1.49mmol)在DMSO(3mL)和H2O(75μL)中的混合物中。将所得混合物在室温下搅拌3h,添加水和EtOAc。将各层分离。将水层用EtOAc/庚烷萃取。将合并的有机层用水,然后用NaHCO3饱和水溶液洗涤(一次),经MgSO4干燥,过滤并在真空中除去溶剂以给出中间体B1(342mg,79%)。
中间体B2
N-(2,6-二溴-4-环丙基吡啶-3-基)-2-氟-N-(2-氟-4-硝基苯甲酰基)-4-硝基苯甲酰胺
在0℃下,将2-氟-4-硝基苯甲酰氯(663mg,3.26mmol)添加至中间体B1(732mg,2.51mmol)和TEA(0.523mL,3.76mmol)在DCE(17mL)中的混合物中。将所得混合物在室温下搅拌18h。添加额外量的2-氟-4-硝基苯甲酰氯(337mg,1.66mmol),并将混合物在室温下搅拌18h。在真空下除去溶剂,并将残余物通过制备型LC(规则SiOH 40μm,40g流动相梯度:从庚烷/EtOAc 90/10至40/60)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体B2(1.15g,73%)。
中间体B3
5-溴-7-环丙基-2-(2-氟-4-硝基苯基)噁唑并[5,4-b]吡啶
中间体B2(1.15g,1.84mmol)和碳酸钾(0.76g,5.5mmol)在甲苯(15mL)中的混合物。将混合物用N2吹扫。然后添加DMEDA(237μL,2.20mmol)和CuI(385mg,2.02mmol)并将反应混合物在110℃搅拌18h。将混合物冷却至室温,然后经过滤并蒸发至干燥。将残余物通过制备型LC(不规则SiOH 40μm,40g流动相:从庚烷/EtOAc 90/10至40/60)纯化。收集纯的级分并蒸发至干燥以给出中间体B3(363mg,52%)。
中间体B5
(R)-(2-(4-氨基-2-氟苯基)-7-环丙基噁唑并[5,4-b]吡啶-5-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体B3(520mg,1.38mmol)和K2CO3(228mg,1.65mmol)在NMP(14mL)和H2O(1.0mL,55mmol)中的脱气混合物在3巴下用Pd(OAc)2(31mg,0.14mmol)和A(99mg,0.28mmol)作为催化剂进行羰基化。将所得混合物在130℃下搅拌18h。将混合物冷却至室温,然后将反应混合物经二氧化硅过滤并与甲苯共蒸发三次以给出粗中间体B4在NMP中的溶液。向此溶液中添加在DMF(7.9mL)中的HATU(680mg,1.79mmol)、DIPEA(711μL,4.13mmol)和(1R)-甲基-(1,2,3,4)-四氢异喹啉(243mg,1.65mmol)。将所得混合物在室温下搅拌18h。将水和EtOAc添加至反应混合物中。将各层分离。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤,经MgSO4干燥,并在真空中蒸发。将残余物通过制备型LC(规则SiOH,40μm,40g流动相梯度:从庚烷/EtOAc 80/20至20/80)纯化。将含有产物的级分合并并在真空下蒸发以给出呈白色固体状的中间体B5(200mg,33%,经过2个步骤)。
中间体B6
(R)-(2-(4-溴-2-氟苯基)-7-环丙基噁唑并[5,4-b]吡啶-5-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
向中间体B5(200mg,0.452mmol)在MeCN(1.5mL)中的溶液中逐滴添加亚硝酸异戊酯(91μL,0.68mmol),然后在35℃下升温并搅拌20分钟。
然后允许反应混合物冷却至室温并用N2吹扫。一次性添加CuBr2(76mg,0.34mmol)。将反应混合物再次用N2吹扫,升温至35℃并搅拌1小时。添加额外的CuBr2(15mg,0.068mmol),将反应混合物再次用氮气吹扫,升温至35℃并搅拌1小时。将混合物冷却至室温,然后添加水和EtOAc并将各层分离。将水层用EtOAc萃取(一次)。将合并的有机层经MgSO4干燥,过滤并且在真空中除去溶剂。将残余物通过制备型LC(规则SiOH 40μm,24gBuchi,流动相梯度:从庚烷/EtOAc,从90/10至30/70)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体B6(161mg,70%)。
化合物2
(7-环丙基-2-(4-((3S,4S)-3,4-二羟基吡咯烷-1-基)-2-氟苯基)噁唑并[5,4-b]吡啶-5-基)((R)-1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
在密封管中,将中间体B6(128mg,253μmol)、(3S,4S)-吡咯烷-3,4-二醇(26mg,0.25mmol)和K2CO3(122mg,0.885mmol)在THF(3.0mL)中的混合物用N2脱气10min。添加DavePhos(20mg,51μmol)和Pd2(dba)3(23mg,25μmol)并将混合物用N2进行吹扫。将混合物在75℃下加热18h。将混合物冷却至室温,然后添加EtOAc和水并将各层分离。将水层用EtOAc萃取。将合并的有机层用盐水洗涤,经MgSO4干燥并浓缩。将残余物通过制备型LC(规则SiOH40μm,24g流动相梯度:从DCM/iPrOH 99/1至84/16)纯化。将含有产物的级分合并并在真空下蒸发。将残余物通过制备型LC(球形C18 25μm,40g YMC-ODS-25,干法加载流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从70:30至30:70)纯化。将含有产物的级分合并并冷冻干燥以给出呈白色固体状的化合物2(56mg,42%)。
苯并呋喃的合成
1.3化合物3的合成
中间体C1
钾3-乙酰基-4-羟基苯甲酸酯
将甲基3-乙酰基-4-羟基苯甲酸酯(1.68g,8.65mmol)和氢氧化钾(933mg,16.6mmol)在EtOH(31mL)和H2O(1mL)中的混合物在60℃下搅拌16h。将混合物冷却至室温,然后将固体过滤并经玻璃料干燥以给出中间体C1(1.9g,定量)。
中间体C2
(R)-1-(2-羟基-5-(1-甲基-1,2,3,4-四氢异喹啉-2-羰基)苯基)乙烷-1-酮
将中间体C1(1.8g,8.2mmol)、(1R)-甲基-(1,2,3,4)-四氢异喹啉(1.46g,9.90mmol)、(8.83g,20.6mmol)和DIPEA(4.4mL,26mmol)在DMF(48mL)中的混合物在室温下搅拌18h。将反应混合物在乙酸乙酯中稀释,用NaHCO3饱和水溶液、盐水洗涤,经MgSO4干燥并在真空中蒸发以给出残余物,将残余物通过制备型LC(规则SiOH 40μm,40g流动相梯度:从庚烷/EtOAc 90:10至70:30)纯化。将含有产物的级分合并并在真空下蒸发以给出呈黄色油状物的中间体C2(187mg,7%)。
中间体C3
(R)-(3-乙基-4-羟基苯基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
在高压釜中,在室温下、H2气氛(15巴)下,用活性碳(湿的(5%))上的钯(386mg,0.181mmol)作为催化剂,将中间体C2(187mg,0.604mmol)和乙酸(1.1mL)搅拌18h。将混合物经过滤并蒸发至干燥。将残余物通过制备型LC(规则SiOH,40μm,24g,流动相梯度:从庚烷/EtOAc 90:10至20:80)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体C3(122mg,68%)。
中间体C4
(R)-(3-乙基-4-羟基-5-碘苯基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
在室温下,将NIS(85mg,0.38mmol)分批添加至中间体C3(102mg,0.345mmol)在乙酸(1.0mL)中的搅拌悬浮液中。将混合物在室温下搅拌1h。在真空下除去溶剂,然后将残余物通过制备型LC(规则SiOH,40μm,12g,流动相梯度:从庚烷/AcOEt 90:10至20:80)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体C4(103mg,71%)。
中间体C5
(R)-(2-(4-溴-2-氟苯基)-7-乙基苯并呋喃-5-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体C4(122mg,0.290mmol)、4-溴-1-乙炔基-2-氟苯(75mg,0.38mmol)、TEA(121μL,0.869mmol)和THF(2.4mL)的混合物用N2吹扫。添加PdCl2(PPh3)2(61mg,0.087mmol)和CuI(55mg,0.29mmol)并将混合物用N2吹扫。将混合物在85℃下加热18h。将混合物冷却至室温,然后添加水和EtOAc并进行萃取。将水层用EtOAc萃取。将有机层合并,用盐水洗涤,干燥(MgSO4),过滤,蒸发并通过制备型LC(规则SiOH,40μm,24g,流动相梯度:从庚烷/EtOAc 90:10至40:60)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体C5(81mg,57%)。
化合物3
(2-(4-((3S,4S)-3,4-二羟基吡咯烷-1-基)-2-氟苯基)-7-乙基苯并呋喃-5-基)((R)-1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
在密封管中,将中间体C5(81.0mg,165μmol)、(3S,4S)-吡咯烷-3,4-二醇(17mg、0.17mmol)和K2CO3(80mg,0.58mmol)在THF(1.9mL)中的混合物用N2脱气10min。添加DavePhos(13mg,33μmol)和Pd2(dba)3(15mg,16μmol)并将混合物用N2吹扫。将混合物在85℃下加热18h。将混合物冷却至室温,然后添加EtOAc和水。将水层用EtOAc萃取。将合并的有机层用盐水洗涤,经MgSO4干燥并浓缩。将残余物通过制备型LC(规则SiOH,40μm,24g Buchi,流动相梯度:从庚烷/EtOAc 50:50至à:100)纯化。将含有产物的级分合并并在真空下蒸发以给出褐色固体,将其通过制备型LC(球形C18 25μm,40g YMC-ODS-25,干法加载(Celite),流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从65:35至25:75)纯化。将含有产物的级分合并并冷冻干燥以给出呈白色固体状的化合物3(35mg,41%)。
2.噻吩并吡啶的合成
2.1化合物4的合成
中间体D1
2-(三甲基甲硅烷基)乙基5-氨基噻吩-2-甲酸酯
将5-氨基噻吩-2-甲酸甲酯(1.58g,10.1mmol)、2-三甲基-甲硅烷基乙醇(7.2mL,50.3mmol)、Ti(OiPr)4(3mL,10.1mmol)和甲苯(36ml)的混合物使用具有MS 迪安-斯达克分水器在回流下搅拌6h。将混合物冷却至室温,蒸发然后通过制备型LC(不规则SiOH15-40μm,80g流动相梯度:从庚烷/EtOAc 100:0至50:50)纯化。将含有产物的级分合并并在真空下蒸发以给出呈黑色油状物的中间体D1(1.26g纯度为83%,43%)。
中间体D2
6-乙基2-(2-(三甲基甲硅烷基)乙基)4-环丙基噻吩并[2,3-b]吡啶-2,6-二甲酸酯
将中间体D1(1.26g,4.30mmol,纯度83%)、(3E)-4-环丙基-2-氧代-3-丁烯酸乙酯(705mg,4.96mmol)和乙酸(8mL)的混合物在80℃下搅拌18h。将混合物冷却至室温然后将固体过滤。将滤液蒸发并通过制备型LC(球形C18 25μm,40g YMC-ODS-25,流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从50:50至0:100)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体D2(449mg,27%)。
中间体D3
4-环丙基-6-(乙氧基羰基)噻吩并[2,3-b]吡啶-2-甲酸
将中间体D2(449mg,1.15mmol)、THF中的TBAF 1M(1.17mL,1.17mmol)和THF(3mL)的混合物在室温下搅拌2h。添加10%KHSO4水溶液和EtOAc。分离各层并且用EtOAc萃取水层。将合并的有机层经MgSO4干燥,过滤并蒸发以给出中间体D3(390mg纯度为85%,定量)。
中间体D4
乙基2-(4-溴-2-氟苯基)-4-环丙基噻吩并[2,3-b]吡啶-6-甲酸酯
中间体D3(390mg,1.14mmol,纯度为85%)、1-溴-3-氟-4-碘苯(342mg,1.14mmol)、Ag2CO3(941mg,3.41mmol)在DMA(15mL)中的混合物用N2吹扫。添加PdCl2(20mg,0.114mmol)和CyJohnPhos(80mg,0.228mmol)。将混合物用N2吹扫然后在150℃下搅拌2h。将混合物冷却至室温,然后添加水和EtOAc并将各层分离。将水层用EtOAc萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤,蒸发并通过制备型LC(不规则SiOH 15-40μm,24g流动相梯度:从庚烷/EtOAc 100:0至0:100)纯化。将含有产物的级分合并并在真空下蒸发,然后将残余物再次通过反相(球形C18 25μm,40g YMC-ODS-25,流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从50:50至0:100)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体D4(46mg,10%)。
中间体D5
2-(4-溴-2-氟苯基)-4-环丙基噻吩并[2,3-b]吡啶-6-甲酸
将中间体D4(76mg,0.181mmol)和氢氧化锂一水合物(15mg,0.362mmol)在THF(4.1mL)和H2O(0.33mL)中的混合物在室温下搅拌2h。向混合物中添加EtOAc和10%KHSO4水溶液。分离各层并且用EtOAc萃取水层。将有机层合并,用盐水洗涤,经MgSO4干燥,过滤并蒸发以给出呈黄色固体状的中间体D5(67mg,定量)。
中间体D6
(R)-(2-(4-溴-2-氟苯基)-4-环丙基噻吩并[2,3-b]吡啶-6-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体D5(67mg,0.171mmol)、(1R)-甲基-(1,2,3,4)-四氢-异喹啉(28mg,0.188mmol)、HATU(97mg,0.256mmol)和DIPEA(90μL,0.512mmol)在DMF(1.2mL)中的混合物在室温下搅拌4h。将水和EtOAc添加至反应混合物中。将各层分离。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤(3次),经MgSO4干燥,过滤,蒸发并通过制备型LC(不规则SiOH 15-40μm,40g 流动相梯度:从庚烷/EtOAc 75:25至0:100)纯化。将含有产物的级分合并并在真空下蒸发以给出呈白色固体状的中间体D6(86mg,97%)。
化合物4
(4-环丙基-2-(4-((3S,4S)-3,4-二羟基吡咯烷-1-基)-2-氟苯基)噻吩并[2,3-b]吡啶-6-基)((R)-1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
在N2下,将中间体D6(76mg,0.146mmol)、(3S,4S)-吡咯烷-3,4-二醇(18mg,0.175mmol)和K2CO3(60mg,0.437mmol)在THF(1.4mL)中的混合物用N2脱气10min。添加DavePhos(23mg,0.0583mmol)和Pd2(dba)3(13mg,0.0146mmol)并将反应混合物用N2吹扫。将混合物在80℃下加热18h。将混合物冷却至室温,然后添加水和EtOAc。将水层用EtOAc萃取,将合并的有机层经MgSO4干燥,过滤,在真空中浓缩并通过制备型LC(规则SiOH 40μm,40g流动相梯度:从DCM/MeOH 100:0至90:10)纯化。将含有产物的级分合并并在真空下蒸发。将残余物用MeCN/水溶解并冻干以给出呈黄色固体状的化合物4(57mg,72%)。
3.噻唑并吡啶的合成
3.1化合物5的合成
中间体E1
乙基2-(4-溴-2-氟苯基)-7-环丙基噻唑并[4,5-b]吡啶-5-甲酸酯
将2-(4-溴-2-氟苯基)-4-噻唑胺(174mg,0.637mmol)、(3E)-4-环丙基-2-氧代-3-丁烯酸乙酯(107mg,0.637mmol)和乙酸(2.5mL)的混合物在80℃下搅拌18h。将混合物冷却至室温,蒸发,然后通过制备型LC(不规则SiOH 15-40μm,40g流动相梯度:从庚烷/EtOAc 100:0至50:50)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体E1(142mg,53%)。
中间体E2
2-(4-溴-2-氟苯基)-7-环丙基噻唑并[4,5-b]吡啶-5-甲酸
将中间体E1(142mg,0.337mmol)和氢氧化锂一水合物(28mg,0.674mmol)在THF(7.6mL)和H2O(0.6mL)中的混合物在室温下搅拌2h。向混合物中添加EtOAc和10%KHSO4水溶液。将各层分离并用EtOAc萃取水层(两次)。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并蒸发以给出呈黄色固体状的中间体E2(116mg,88%)。
中间体E3
(R)-(2-(4-溴-2-氟苯基)-7-环丙基噻唑并[4,5-b]吡啶-5-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体E2(116mg,0.295mmol)、(1R)-甲基-(1,2,3,4)-四氢-异喹啉(48mg,0.324mmol)、HATU(168mg,0.442mmol)和DIPEA(155μL,0.885mmol)在DMF(2mL)中的混合物在室温下搅拌18h。将水和EtOAc添加至反应混合物中。将各层分离。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤(3次),经MgSO4干燥,过滤,蒸发并通过制备型LC(不规则SiOH 15-40μm,40g流动相梯度:从庚烷/EtOAc 75:25至0:100)纯化。将含有产物的级分合并并在真空下蒸发以给出呈黄色固体状的中间体E3(100mg,65%)。
化合物5
(7-环丙基-2-(4-((3S,4S)-3,4-二羟基吡咯烷-1-基)-2-氟苯基)噻唑并[4,5-b]吡啶-5-基)((R)-1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
在N2下,将中间体E3(90mg,0.172mmol)、(3S,4S)-吡咯烷-3,4-二醇(21mg,0.207mmol)和K2CO3(71mg,0.517mmol)在THF(1.6mL)中的混合物用N2脱气。添加DavePhos(27mg,0.0689mmol)和Pd2(dba)3(16mg,0.0172mmol)并将反应混合物用N2吹扫。将混合物在80℃下加热18h。将反应冷却至室温,然后添加水和EtOAc。将各层分离并用EtOAc萃取水层(两次)。将合并的有机层经MgSO4干燥,过滤,在真空中浓缩并通过制备型LC(规则SiOH 40μm,40g流动相梯度:从DCM/MeOH 100:0至88:12)纯化。将含有产物的级分在真空下蒸发,然后用MeCN/水溶解并冻干以给出呈黄色固体状的化合物5(21mg,22%)。
4.呋喃并吡啶的合成
4.1化合物6的合成
中间体F1
甲基2-(4-溴-2-氟苯基)呋喃并[3,2-b]吡啶-5-甲酸酯
甲基5-羟基-6-碘吡啶-2-甲酸酯(4.8g,15.5mmol)、4-溴-1-乙炔基-2-氟苯(4.0g,20mmol)、TEA(4.8mL,34.6mmol)和THF(28mL)的混合物用N2吹扫。添加PdCl2(PPh3)2(1.2g,1.7mmol)和CuI(680mg,3.58mmol)并将混合物用N2吹扫。使用具有输出功率从0至400W范围的单模微波(Biotage Initiator EXP 60),将混合物在100℃下加热30min[固定的保持时间]。将混合物冷却至室温,然后添加水和EtOAc。将各层分离并将水层用EtAOc萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤,蒸发并通过制备型LC(不规则SiOH15-40μm,120g流动相梯度:庚烷/EtOAc从100:0至25:75)纯化。将含有产物的级分合并并在真空下蒸发。将残余物通过制备型LC(球形C18 25μm,300g YMC-ODS-25,干法加载流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从60:40至0:100)纯化。将含有产物的级分浓缩然后添加DCM和水。分离各层并且用DCM萃取水层。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并蒸发以给出呈灰白色固体状的中间体F1(2.02g,25%)。
中间体F2
2-(4-溴-2-氟苯基)-5-(甲氧基羰基)呋喃并[3,2-b]吡啶4-氧化物
将中间体F1(2.02g,5.77mmol)、mCPBA(4g,23.2mmol)和DCM(26mL)的混合物在室温下搅拌18h。用NaHCO3水溶液和DCM进行萃取,将有机层用盐水洗涤,经MgSO4干燥并蒸发以给出呈黄色固体状的中间体F2(2.4g纯度为88%,定量)。
中间体F3
甲基2-(4-溴-2-氟苯基)-7-氯呋喃并[3,2-b]吡啶-5-甲酸酯
将中间体F2(2.4g,5.77mmol,88%纯度)、POCl3(2.7mL,28.8mmol)和DCM(35mL)中的混合物在100℃下搅拌2h。将混合物冷却至室温,然后缓慢添加NaHCO3水溶液并将各层分离。将水层用EtOAc萃取(一次)。将合并的有机层经MgSO4干燥,过滤并蒸发。将残余物通过制备型LC(不规则SiOH 15-40μm,120g流动相梯度:庚烷/EtOAc从100:0至50:50)纯化。将含有产物的级分合并并在真空下蒸发以给出呈白色固体状的中间体F3(1.08g,49%)。
中间体F4
甲基(R)-7-氯-2-(2-氟-4-(3-羟基吡咯烷-1-甲酰胺基)苯基)呋喃并[3,2-b]吡啶-5-甲酸酯
将中间体F3(1.08g,2.81mmol)、(3R)-3-羟基-1-吡咯烷甲酰胺(393mg,2.81mmol)和Cs2CO3(2.75g,8.43mmol)的混合物装入密封管中并用N2吹扫。添加1,4二噁烷(59mL)并将混合物用N2脱气,然后添加Pd(OAc)2(63mg,0.281mmol)和Xantphos(162mg,0.281mmol)。将反应混合物用N2吹扫,然后搅拌并在100℃下加热18h。将混合物冷却至室温,然后添加EtOAc和水,并将混合物经过滤。将各层分离并且将水层用EtOAc萃取(一次)。将合并的有机层用盐水洗涤,经MgSO4干燥,蒸发并通过制备型LC(不规则SiOH 15-40μm,80g流动相梯度:DCM/MeOH从100:0至95:5)纯化。将含有产物的级分合并并在真空下蒸发以给出呈淡黄色固体状的中间体F4(259mg,21%)。
中间体F5
甲基(R)-7-乙基-2-(2-氟-4-(3-羟基吡咯烷-1-甲酰胺基)苯基)呋喃并[3,2-b]-吡啶-5-甲酸酯
将中间体F4(259mg,597μmol)、THF中的三乙基硼烷1M(1.8mL,1.79mmol)、Cs2CO3(973mg,2.99mmol)和DMF(10mL)的混合物用N2吹扫。添加PdCl2dppf(52mg,70μmol),将混合物在70℃下搅拌18h。将混合物冷却至室温。将溶剂蒸发,然后将残余物通过制备型LC(球形C18 25μm,40g YMC-ODS-25,干法加载流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从95:05至50:50)纯化。将含有产物的级分冻干以给出呈白色固体状的F5(100mg,39%)。
化合物6
(R)-N-(4-(7-乙基-5-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)呋喃并[3,2-b]吡啶-2-基)-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
将中间体F5(100mg,0.234mmol)和氢氧化钾(26mg,0.468mmol)在EtOH(2mL)和H2O(162μL)中的混合物在室温下搅拌4h。将混合物在真空下蒸发并与THF共蒸发(3次)。将残余物溶解在DMF(2mL)中,然后添加(1R)-甲基-(1,2,3,4)-四氢异喹啉(41mg,0.279mmol)、HATU(133mg,0.349mmol)和DIPEA(122μL,0.698mmol)。将所得混合物在室温下搅拌18h。添加EtOAc和水。将有机层分离,用盐水洗涤,经MgSO4干燥,过滤并通过制备型LC(不规则SiOH15-40μm,24g流动相梯度:DCM/MeOH从100:0至90:10)纯化。将含有产物的级分合并并在真空下蒸发。将残余物通过制备型LC(球形C18 25μm,40gYMC-ODS-25,流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从90:10至10:90)纯化。将含有产物的级分冻干以给出呈白色固体状的化合物6(55mg,44%)。
5.氮杂吲唑的合成
5.1化合物7的合成
中间体G1
7-溴-5-氯-2-(2-氟-4-硝基苯基)-2H-吡唑并[4,3-b]吡啶
将在MeCN(36mL)中的7-溴-5-氯-1H-吡唑并[4,3-b]吡啶(1.12g,4.72mmol)、3,4-二氟硝基苯(575μL,5.19mmol)、K2CO3(1.96g,14.2mmol)在80℃下搅拌18h。将混合物冷却至室温,然后添加水和EtOAc。分离各层并且用EtOAc萃取水层。将合并的有机层经MgSO4干燥,过滤并且在真空中浓缩。将残余物通过制备型LC(不规则SiOH 15-40μm,40g干法加载流动相梯度:从庚烷/EtOAc 100:0至50:50并用DCM/MeOH 100:00至90:10洗涤)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体G1(1.1g,63%)。
中间体G2
5-氯-7-环丙基-2-(2-氟-4-硝基苯基)-2H-吡唑并[4,3-b]吡啶
向中间体G1(1.1g,2.9mmol)、cPrB(OH)2(349mg,4.07mmol)和Cs2CO3(4.0g,12mmol)在二噁烷(8.7mL)和H2O(87mL)中的脱气混合物中添加PdCl2dppf(303mg,0.414mmol),并将所得混合物在100℃下搅拌18h。将混合物冷却至室温,然后添加EtOAc和水。将各层分离并将水层用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤并且在真空中除去溶剂。将残余物通过制备型LC(不规则SiOH 15-40μm,80g干法加载流动相梯度:从庚烷/EtOAc 100:0至50:50)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体G2(520mg,53%)。
中间体G3
4-(5-氯-7-环丙基-2H-吡唑并[4,3-b]吡啶-2-基)-3-氟苯胺
将中间体G2(590mg,1.77mmol)、铁(495mg,8.87mmol)和氯化铵(950mg,17.8mmol)在THF(5.6mL)、MeOH(5.6mL)和H2O(2.8mL)中的混合物在70℃下搅拌3h。将混合物冷却至室温并通过垫过滤。添加DCM和水,将各层分离,并将有机层经MgSO4干燥,过滤并在真空中浓缩以给出中间体G3(520mg,96%)。
中间体G4
甲基2-(4-氨基-2-氟苯基)-7-环丙基-2H-吡唑并[4,3-b]吡啶-5-甲酸酯
向中间体G3(520mg,1.72mmol)和TEA(597μL,4.29mmol)在MeOH(11.8mL)中的脱气混合物中添加PdCl2dppf(88mg,0.12mmol)。将所得混合物在3巴的CO下、在80℃下搅拌2h。将混合物冷却至室温并蒸发至干燥。添加DCM和水,将各层分离,并将有机层经MgSO4干燥、过滤并在真空中浓缩。将残余物通过制备型LC(不规则SiOH 15-40μm,25g干法加载流动相梯度:从DCM/MeOH 100:0至98:2)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体G4(420mg,75%)。
中间体G5
2-(4-氨基-2-氟苯基)-7-环丙基-2H-吡唑并[4,3-b]吡啶-5-甲酸
将中间体G4(420mg,1.29mmol)和氢氧化钾(144mg,2.57mmol)在EtOH(19mL)和H2O(1.9mL)中的混合物在室温下搅拌3h。添加10%KHSO4水溶液直至pH=1,并将水层用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤并在真空中浓缩以给出中间体G5(390mg,95%)。
中间体G6
(R)-(2-(4-氨基-2-氟苯基)-7-环丙基-2H-吡唑并[4,3-b]吡啶-5-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体G5(96mg,0.29mmol)、(1R)-甲基-(1,2,3,4)-四氢异喹啉(86mg,0.58mmol)、HATU(167mg,0.438mmol)和DIPEA(153μL,0.876mmol)在DMF(2.0mL)中的混合物在室温下搅拌20h。将盐水和EtOAc添加至反应混合物中。将各层分离。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤(3次),经MgSO4干燥,过滤并蒸发。将残余物通过制备型LC(不规则SiOH 15-40μm,12g干法加载流动相梯度:从DCM/MeOH100:0至98:2)纯化。将含有产物的级分合并并在真空下蒸发。将残余物通过制备型LC(不规则SiOH 15-40μm,12g干法加载流动相梯度:从庚烷/EtOAc 100/00至50/50)纯化。将含有产物的级分合并并在真空下蒸发以给出中间体G6(82mg,76%)。
中间体G7
苯基(R)-(4-(7-环丙基-5-(1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-2H-吡唑并[4,3-b]吡啶-2-基)-3-氟苯基)氨基甲酸酯
在中间体G6(23mg,0.052mmol)和K2CO3(17mg,0.12mmol)在THF(648μL)中的混合物中添加氯甲酸苯酯(6.5μL)。将混合物在室温下搅拌3h。添加水和EtOAc并且将各层分离。将水层用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤并在真空中浓缩以给出中间体G7(21mg,72%)。
化合物7
(R)-N-(4-(7-环丙基-5-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-2H-吡唑并[4,3-b]吡啶-2-基)-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
向中间体G7(39.5mg,0.0703mmol)和(R)-(+)-3-吡咯烷醇(9.2mg,0.11mmol)在DMF(1.6mL)中的搅拌混合物中添加DIPEA(61μL,0.35mmol)。将反应混合物在室温下搅拌2h。添加水和EtOAc,然后将各层分离。将水层用EtOAc萃取。将合并的有机层用盐水进行洗涤,经MgSO4进行干燥,过滤并在真空中浓缩。将残余物通过制备型LC(不规则SiOH 15-40μm,4g干法加载流动相梯度:从DCM/MeOH 100/00至90/10)纯化。将含有产物的级分合并并在真空下蒸发。将残余物溶解在MeCN(2mL)中,用水(10mL)扩展并冻干以给出呈白色蓬松固体状的化合物7(19mg,51%)。
6.吲哚的合成
6.1化合物8的合成
中间体H0
乙基(1S,2S)-2-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)环丙烷-1-甲酸酯
在N2下,在密封管中,将B2Pin2(10g,39.4mmol)和乙酸钾(6.8g,69.3mmol)添加至(1S,2S)-2-(4-溴-3-氟苯基)-环丙烷甲酸乙酯(10g,34.8mmol)在二噁烷(170mL)中的溶液中。将溶液用氮气吹扫并用PdCl2dppf·DCM(2.8g,3.42mmol)填充。将所得溶液再次用氮气吹扫并在100℃下搅拌18h。添加EtOAc并将有机层用水和盐水洗涤,经MgSO4干燥,浓缩并通过制备型LC(不规则SiOH,15-40μm,400g,流动相梯度:从庚烷/EtOAc 100/0至75/25)纯化。将含有产物的级分合并并在真空下蒸发以给出呈无色油状物的中间体H0(9.26g,80%)。
中间体H1
甲基3-环丙基-4-氟-5-硝基苯甲酸酯
向3-溴-4-氟-5-硝基-苯甲酸甲酯(960mg,3.45mmol)在甲苯(20mL)中的溶液中添加环丙基硼酸(593mg,6.91mmol)、K3PO4(1.83g,8.63mol)、三环己基膦(290mg,1.04mmol)和H2O(4mL)。将圆底烧瓶用N2吹扫(3次)并添加Pd(OAc)2(116mg,518μmol)。将反应混合物在95℃下加热18h。将混合物冷却至室温,然后将EtOAc和水添加至混合物中。分离各层并且用EtOAc萃取水层。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。将残余物通过制备型LC(不规则SiOH 15-40μm,120g流动相梯度:从庚烷/EtOAc从100:0至85:15)纯化。将纯的级分合并并在真空下蒸发以给出呈黄色固体状的中间体H1(460mg,56%)。
中间体H2
二甲基2-(2-环丙基-4-(甲氧基羰基)-6-硝基苯基)丙二酸酯
将NaH 60%的矿物油(223mg,5.58mmol)在DMSO(8mL)中的溶液中在室温下搅拌,然后逐滴添加二甲基丙二酸酯(352μL,3.08mmol)。添加完成后,将反应在100℃下搅拌1h。将混合物在室温下冷却并添加中间体H1(460mg,1.92mmol)。将反应在室温下搅拌30min,然后在100℃下搅拌1h。将EtOAc和NH4Cl的饱和水溶液添加至混合物。将水层用EtOAc萃取。将有机层经MgSO4干燥,过滤并且蒸发。将残余物通过制备型LC(不规则SiOH 15-40μm,80g流动相梯度:从庚烷/EtOEc 100/0至70/30)纯化。将纯的级分合并并在真空下蒸发以给出呈白色固体状的中间体H2(470mg,70%)。
中间体H3
甲基4-环丙基-2-氧代吲哚啉-6-甲酸酯
将铁(148mg,2.65mmol)缓慢添加至中间体H2(310mg,882μmol)在乙酸(16mL)中的混合物,然后在120℃下搅拌1h。将反应混合物冷却至室温并通过垫过滤,并在真空中除去溶剂。将所得固体溶解于EtOAc和水中。将各层分离并将有机层用盐水洗涤,经MgSO4干燥,蒸发并通过制备型LC(不规则SiOH,15-40μm,40g流动相梯度:从庚烷/EtOAc 75/25至50/50)纯化。将纯的级分合并并在真空下蒸发以给出呈白色固体状的中间体H3(130mg,64%)。
中间体H4
甲基2-溴-4-环丙基-1H-吲哚-6-甲酸酯
向中间体H3(53mg,0.23mmol)在DCE(1.5mL)中的溶液中逐滴添加POBr3(94mg,0.33mmol)在DCE(1.5mL)中的溶液。将反应混合物在80℃下搅拌1h。添加POBr3(94mg,0.33mmol)并将反应在80℃下搅拌2h。将混合物冷却至室温,然后通过添加NaHCO3饱和水溶液将pH调整至7-8。将各层分离并将有机层用盐水洗涤,经MgSO4干燥,蒸发。将残余物通过制备型LC(不规则SiOH,15-40μm,24g流动相梯度:从庚烷/EtOAc 100/0至50/50)纯化。将纯的级分合并并在真空下蒸发以给出呈白色固体状的中间体H4(34mg,50%)。
中间体H5
1-(叔丁基)6-甲基2-溴-4-环丙基-1H-吲哚-1,6-二甲酸酯
将DMAP(28mg,0.23mmol)和Boc2O(50mg,0.23mmol)添加至A(64mg,0.22mmol)在DCM(2mL)中的溶液中。将反应在室温下搅拌4h。将DCM和水添加至混合物。然后添加HCl 1N的水溶液并将各层分离。将有机层用盐水洗涤,经MgSO4干燥并蒸发。将残余物通过制备型LC(不规则SiOH,15-40μm,12g流动相梯度:从庚烷/EtOAc 100:0至90:10)纯化。将纯的级分合并并在真空下蒸发以给出呈白色固体状的中间体H5(68mg,79%)。
中间体H6
2-溴-4-环丙基-1H-吲哚-6-甲酸
将氢氧化钾(34mg,0.51mmol)添加至中间体H5(68mg,0.17mmol)在EtOH(1.5mL)中的溶液中,并将反应混合物在80℃下加热18h。添加EtOAc和HCl 1N水溶液。将各层分离并将水层用EtOAc萃取。将有机层用盐水洗涤,经MgSO4干燥,蒸发以给出呈黄色油状物的中间体H6(40mg,83%)。
中间体H7
(R)-(2-溴-4-环丙基-1H-吲哚-6-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体H6(40mg,0.14mmol)、(1R)-甲基-(1,2,3,4)-四氢异喹啉(25mg,0.17mmol)、HATU(72mg,0.19mmol)和DIPEA(72μL,0.42mmol)在DMF(2mL)中的混合物在室温下搅拌20h。将混合物在乙酸乙酯中稀释,用NaHCO3饱和水溶液、盐水洗涤,经MgSO4干燥,过滤和蒸发。将残余物通过制备型LC(不规则SiOH 15-40μm,12g流动相梯度:从庚烷/EtOAc从100:0至50:50)纯化以给出呈白色固体状的中间体H7(39mg,67%)。
中间体H8
乙基(1S,2S)-2-(4-(4-环丙基-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-1H-吲哚-2-基)-3-氟苯基)环丙烷-1-甲酸酯
向中间体H7(39mg,95μmol)在二噁烷中的溶液中添加中间体H0(32mg,95μmol)、H2O(0.43mL)和K3PO4(69mg,0.32mmol)。将反应混合物用N2吹扫并添加Pd118(7.1mg,11μmol)随后用N2吹扫。使用具有输出功率从0至400W范围的单模微波(Biotage InitiatorEXP 60),将密封罐在80℃下加热30min[固定的保持时间]。将EtOAc添加至溶液中并将各层分离。将有机层用盐水洗涤,经MgSO4干燥,过滤,浓缩并通过制备型LC(不规则SiOH 15-40μm,12g流动相:庚烷/EtOAc 100:0至50:50)纯化。收集纯的级分并在真空中除去溶剂以给出呈黄色固体状的中间体H8(27mg,53%)。
化合物8
(1S,2S)-2-(4-(4-环丙基-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-1H-吲哚-2-基)-3-氟苯基)环丙烷-1-甲酸
将氢氧化锂一水合物(12mg,277μmol)添加至中间体H8(27mg,50.3μmol)在THF(1.5mL)和H2O(0.5mL)中的溶液中,并将反应混合物在室温下搅拌18h。添加10%KHSO4水溶液直至pH=6,并将水层用EtOAc萃取。将有机层用水洗涤,经MgSO4干燥,过滤,蒸发并通过制备型LC(球形C18 25μm,40g YMC-ODS-25,流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从85:15至45:55)纯化。将含有产物的级分合并并冻干以给出呈白色固体状的化合物8(19mg,74%)。
6.2化合物9的合成
中间体I1
甲基2-溴-4-环丙基-1-甲基-1H-吲哚-6-甲酸酯
将甲基碘(165μL,2.66mmol)添加至中间体H4(521mg,1.77mmol)和K2CO3(367mg,2.66mmol)在DMF(12mL)中的溶液中,并将反应混合物在室温下搅拌3h。将甲基碘(28μL,0.44mmol)添加至混合物中,并将反应搅拌2h。添加EtOAc和水,并将各层分离。将有机层用盐水洗涤,经MgSO4干燥,蒸发并通过制备型LC(不规则SiOH 15-40μm,80g流动相梯度:从庚烷/EtOAc100/0至90/10)纯化。将含有产物的级分合并并冻干以给出呈无色油状物的中间体I1(170mg,86%)。
中间体I2
2-溴-4-环丙基-1-甲基-1H-吲哚-6-甲酸
将氢氧化钾(300mg,4.55mmol)添加至中间体I1(470mg,1.53mmol)在EtOH(13mL)中的溶液中,并将反应混合物在80℃加热5h。添加EtOAc和HCl 1N水溶液。将各层分离并将有机层用盐水洗涤,经MgSO4干燥,过滤并蒸发以给出呈白色固体状的中间体I2(432mg,96%)。
中间体I3
(R)-(2-溴-4-环丙基-1-甲基-1H-吲哚-6-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体I3(432mg,1.47mmol)、(1R)-甲基-(1,2,3,4)-四氢异喹啉(259mg,1.76mmol)、HATU(737mg,1.94mmol)和DIPEA(0.74mL,4.27mmol)在DMF(21mL)中的混合物在室温下搅拌5h。将混合物在EtOAc中稀释,用NaHCO3饱和水溶液(两次)、盐水洗涤,经MgSO4干燥,蒸发并通过制备型LC(不规则SiOH 15-40μm,50g Merck,流动相梯度:从庚烷/EtOAc从100:0至50:50)纯化。将含有产物的级分合并并冻干以给出呈白色泡沫状的中间体I3(612mg,98%)。
中间体I4
乙基(1S,2S)-2-(4-(4-环丙基-1-甲基-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-1H-吲哚-2-基)-3-氟苯基)环丙烷-1-甲酸酯
向中间体I3(300mg,0.71mmol)在二噁烷(13mL)中的溶液中添加中间体H0(237mg,0.71mmol)、H2O(3mL)和K3PO4(511mg,2.41mmol)。将反应混合物用N2吹扫并添加Pd118(53mg,81μmol),随后用N2吹扫。使用具有输出功率从0至400W范围的单模微波(BiotageInitiator EXP 60),将密封罐在80℃下加热30min[固定的保持时间]。将EtOAc添加至溶液中,并将有机层用盐水洗涤,经MgSO4干燥,过滤,浓缩并通过制备型LC(不规则SiOH 15-40μm,50g Merck,流动相:庚烷/EtOAc 100:0至50:50)纯化。收集纯的级分并在真空中除去溶剂以给出呈黄色固体状的中间体I4(303mg,78%)。
化合物9
(1S,2S)-2-(4-(4-环丙基-1-甲基-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-1H-吲哚-2-基)-3-氟苯基)环丙烷-1-甲酸
将氢氧化锂一水合物(127mg,3.03mmol)添加至中间体I4(303mg,0.55mmol)在THF(16mL)和H2O(4mL)中的溶液中,并将反应混合物在室温下搅拌18h。添加10%KHSO4水溶液直至pH=6,并将水层用EtOAc萃取。将有机层用水洗涤,经MgSO4干燥,过滤,蒸发并通过制备型LC(球形C18 25μm,40g YMC-ODS-25,固体加载(Celite),流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从85:15至45:55)纯化。将含有产物的级分用10%KHSO4酸化直至pH=6并将水层用EtOAc萃取。将有机层水洗涤,经MgSO4干燥,过滤并蒸发以给出呈黄色固体状的化合物9(212mg,74%)。
6.3化合物10的合成
化合物10
(R)-1-(4-(4-环丙基-1-甲基-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-1H-吲哚-2-基)-3-氟苯基)吡咯烷-3-甲酸
在密封管中,将中间体I3(230mg,0.543mmol)、(3S)-1-[3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]-3-吡咯烷甲酸甲酯(228mg,0.652mmol)和K3PO4(346mg,1.63mmol)在二噁烷(8mL)和H2O(1.5mL)中的溶液用N2吹扫。添加Pd118(36mg,55μmol),将混合物再次用N2吹扫并且使用具有输出功率从0至400W范围的单模微波(BiotageInitiator EXP 60)在80℃下加热30分钟[固定的保持时间]。添加氢氧化锂一水合物(228mg,5.43mmol)并将反应在50℃下搅拌18h。将溶液冷却至室温,然后添加EtOAc和HCl水溶液(1N)并将水层用EtOAc萃取。将有机层用水洗涤,经MgSO4干燥,过滤,蒸发,并将残余物通过制备型LC(不规则SiOH15-40μm,50g Merck,流动相:DCM/(DCM/MeOH/AcOH 80:18:2)从100:0至90:10)纯化。将含有产物的级分合并并在真空下蒸发。将残余物通过制备型LC(球形C18 25μm,40g YMC-ODS-25,干法加载流动相梯度0.2%NH4 +HCO3 -/MeCN水溶液从75:25至35:65)纯化。将含有产物的级分冻干以给出呈白色固体状的化合物10(32mg,11%)。
7.氮杂苯并咪唑的合成
7.1化合物11的合成
中间体J1
4-环丙基-3-硝基吡啶-2-胺
将4-氯-3-硝基-2-吡啶胺[6980-08-1](95.0g,547mmol)、环丙基三氟硼酸钾[1065010-87-8](162g,1.09mol)、乙酸钯(2.46g,11.0mmol)、碳酸铯(535g,1.64mol)和A(5.89g,16.4mmol)在H2O(250mL)和甲苯(2.5L)中的混合物在100℃下搅拌12h。将反应混合物通过垫过滤并将滤饼用EtOAc洗涤。将各层分离并将水相用EtOAc(3x500mL)萃取。将合并的有机萃取物在真空中浓缩。将粗混合物通过柱色谱法(SiO2,流动相梯度:石油醚/EtOAc从20:1至3:1)纯化以得到呈黄色固体状的中间体J1(70g,71%)。
中间体J2
4-环丙基吡啶-2,3-二胺
向中间体J1(77.0g,429.7mmol)在HCl(80mL)和EtOH(1L)中的溶液中分批添加铁粉(132g,2.36mol)。将反应混合物在80℃下搅拌2h。将反应混合物通过垫过滤并将滤饼用DCM洗涤。将滤液在真空中浓缩以得到呈浅黄色固体状的中间体J2(60g,94%),将其不经进一步纯化而用于下一步中。
中间体J3
2-(4-溴-2-氟苯基)-7-环丙基-3H-咪唑并[4,5-b]吡啶
将中间体J2(53.0g,355mmol)和4-溴-2-氟-5-甲基苯甲醛[57848-46-1](86.5g,426mmol)在DMSO(530mL)中的混合物在80℃下搅拌2h。将反应混合物倒入水(6L)中。将沉淀物滤出并将固体用H2O(3x200mL)洗涤。将粗产物在DCM(2x100mL)中研磨以得到呈淡黄色固体状的中间体J3(85g,72%)。
中间体J4
2-(4-溴-2-氟苯基)-7-环丙基-3H-咪唑并[4,5-b]吡啶-4-鎓-4-醇盐
向中间体J3(20.0g,60.2mmol)在DCM(100mL)中的溶液中添加m-CPBA(12.2g,60.2mmol)。将反应混合物在室温下搅拌12h。将反应混合物用Na2S2O3水溶液(2x100mL)和NaHCO3水溶液(3x100mL)洗涤,经Na2SO4干燥,过滤并在真空中浓缩以得到呈浅黄色固体状的中间体J4(15g,70%)。
中间体J5
2-(4-溴-2-氟苯基)-7-环丙基-3H-咪唑并[4,5-b]吡啶-5-甲腈
将中间体J4(14.0g,40.2mmol)、TMSCN(23.9g,241.3mmol)和Et3N(16.3g,160.8mmol)在MeCN(75mL)中的混合物在110℃下搅拌10h。将溶剂在真空中蒸发。将粗混合物通过柱色谱法(SiO2,流动相梯度:DCM/MeOH从1:0至99.5:0.5)纯化以得到呈浅黄色固体状的中间体J5(11g,73%,95%纯度)。
中间体J6
乙基2-(4-溴-2-氟苯基)-7-环丙基-3H-咪唑并[4,5-b]吡啶-5-甲酸酯
将中间体J5(15.0g,42.0mmol)在EtOH中的HCl(4.0M,100mL)中的混合物在80℃下搅拌2h。将溶剂在真空中蒸发。将粗混合物通过制备型HPLC(柱:Phenomenex luna C18250*50mm*10um,流动相梯度:H2O(+0.1%TFA)/MeCN从70:30至35:65)纯化。将残余物用NaHCO3水溶液碱化直至pH 7-8。将各层分离并将有机相经Na2SO4干燥、过滤并在真空中浓缩以得到呈浅黄色固体的中间体J6(8g,45%,95%纯度)。
中间体J7和J7’的合成
将硫酸二甲酯(737μL,7.79mmol)添加至中间体J6(3.0g,7.4mmol)和氢氧化钾(437mg,7.79mmol)在丙酮(42mL)中的混合物中。将反应混合物在室温下搅拌20h。将反应混合物蒸发。将水和DCM添加至残余物。将水层用DCM萃取。将合并的有机层经MgSO4干燥,过滤并在真空中蒸发。将残余物通过制备型LC(不规则SiOH,15-40μm,330g流动相梯度:从庚烷/EtOAc90/10至40/60)纯化。将含有中间体J7和中间体J7’的级分分别蒸发以给出2个级分。含有呈黄色固体状的中间体J7’的第一级分(477mg,15%)以及吸收在MeCN中并蒸发以给出呈无色胶状的中间体J7(静置后结晶)的第二级分(1.74g,56%)。
中间体J8
钾2-(4-溴-2-氟苯基)-7-环丙基-3-甲基-3H-咪唑并[4,5-b]吡啶-5-甲酸酯
将中间体J7(1.74g,4.16mmol)和氢氧化钾(467mg,8.32mmol)在EtOH(55mL)中的混合物在室温下搅拌16h。将反应混合物经玻璃料过滤。将固体用Et2O洗涤并在高真空下、在50℃下干燥2h,以得到呈白色固体状的中间体J8(1.48g,91%)。
中间体J9
(1R)-2-[2-(4-溴-2-氟苯基)-7-环丙基-3-甲基-3H-咪唑并[4,5-b]吡啶-5-羰基]-1-甲基-1,2,3,4-四氢异喹啉
向中间体J8(1.48g,3.79mmol)、(R)-1-甲基-1,2,3,4-四氢-异喹啉[84010-66-2](838mg,5.69mmol)和DIPEA(1.67mL,9.70mmol)在DMF(20mL)中的混合物中添加HATU(2.60g,6.83mmol)。将反应混合物在室温下搅拌16h。将反应混合物用H2O稀释并用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并将溶剂在真空中蒸发。将粗混合物通过制备型LC(规则SiOH,15-40μm,80g,流动相梯度:庚烷/EtOAc从90:10至50:50)纯化以得到呈白色固体状的中间体J9(1.84g,88%)。
中间体J10
乙基反式2-(4-{7-环丙基-3-甲基-5-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-3H-咪唑并[4,5-b]吡啶-2-基}-3-氟苯基)环丙烷-1-甲酸酯
在氮气气氛下,向中间体J9(200mg,362μmol,94%纯度)[1612792-88-7](顺式:反式14:86)(159mg,724μmol)和碳酸铯(354mg,1.09mmol)在甲苯(4mL)和H2O(0.4mL)中的混合物中添加A(31.1mg,86.9μmol)和乙酸钯(13.0mg,57.9μmol)。将反应混合物用氮气吹扫并在100℃下搅拌18h。将反应混合物用水和EtOAc稀释。分离各层并将水相用EtOAc萃取(两次)。将合并的有机萃取物经MgSO4干燥,过滤并在真空中浓缩。将粗混合物通过制备型LC(不规则SiOH,15-40μm,40g流动相梯度:庚烷/EtOAc从90:10至40:60)纯化以得到呈灰白色固体状的中间体J10(154mg,77%)。
化合物11(反式)
反式2-(4-{7-环丙基-3-甲基-5-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-3H-咪唑并[4,5-b]吡啶-2-基}-3-氟苯基)环丙烷-1-甲酸
将氢氧化锂一水合物(35.1mg,0.84mmol)添加至中间体J10(154mg,279μmol)在THF(2.3mL)和H2O(0.9mL)中的溶液中。将反应混合物在室温下搅拌16h。将反应混合物用盐水稀释并添加10%KHSO4水溶液。将水相用EtOAc萃取。将合并的有机萃取物用H2O洗涤,经MgSO4干燥,过滤并在真空中浓缩。将粗混合物吸收在MeOH中并在真空中浓缩。将残余物在Et2O中研磨。将固体滤出并在高真空下、在50℃下干燥20h,以给出呈白色固体状的化合物11(92mg,63%)。
7.2化合物12的合成
中间体J11
甲基(3S)-1-(4-{7-环丙基-3-甲基-5-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-3H-咪唑并[4,5-b]吡啶-2-基}-3-氟苯基)吡咯烷-3-甲酸酯
将密封管用中间体J9(165mg,318μmol)、(S)-甲基吡咯烷-3-甲酸酯盐酸盐[1099646-61-3](63.1mg,381μmol)、碳酸铯(311mg,0.95mmol)和XantPhos(18.4mg,31.8μmol)填充并用氮气吹扫。添加1,4-二噁烷(5mL)并将混合物再次用氮气吹扫。添加乙酸钯(7.13mg,31.8μmol)。将反应混合物用氮气吹扫并且在100℃下搅拌17h。将反应混合物用EtOAc和H2O稀释。分离各层并将水相用EtOAc萃取(两次)。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并将溶剂在真空中蒸发。将粗混合物通过制备型LC(不规则SiOH,15-40μm,40g流动相梯度:庚烷/EtOAc从90:10至40:60)纯化以得到呈黄色泡沫的中间体J11(131mg,70%,96%纯度)。
化合物12
甲基(3S)-1-(4-{7-环丙基-3-甲基-5-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-3H-咪唑并[4,5-b]吡啶-2-基}-3-氟苯基)吡咯烷-3-甲酸
将氢氧化锂一水合物(29.1mg,0.69mmol)添加至中间体J11(131mg,231μmol)在THF(1.9mL)和H2O(0.7mL)中的溶液中。将反应混合物在室温下搅拌16h。将反应混合物用盐水稀释并添加10%KHSO4水溶液。将水相用EtOAc萃取。将合并的有机萃取物用H2O洗涤,经MgSO4干燥,过滤并在真空中浓缩。将粗混合物吸收在MeCN中并在真空中浓缩。将残余物在Et2O中研磨。将固体滤出并在高真空下、在50℃下干燥20h,以给出呈淡黄色固体状的化合物12(89mg,70%)。
7.3化合物13的合成
中间体J12
2-(4-溴-2-氟苯基)-7-环丙基-1-甲基-1H-咪唑并[4,5-b]吡啶-5-甲酸
将中间体J7’(477mg,1.14mmol)和氢氧化钾(128mg,2.28mmol)在EtOH(15mL)中的混合物在室温下搅拌16h。将混合物在真空中蒸发,将残余物吸收在水中并用HCl水溶液(1N)酸化混合物。将水层用DCM萃取,以给出呈黄色胶状物的中间体J12(200mg,45%)。
中间体J13
(R)-(2-(4-溴-2-氟苯基)-7-环丙基-1-甲基-1H-咪唑并[4,5-b]吡啶-5-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
在室温下,向中间体J12(200mg,0.513mmol)和(1R)-甲基-(1,2,3,4)-四氢异喹啉(113mg,0.769mmol)和DIPEA(226μL,1.31mmol)在DMF(3mL)中的混合物中添加HATU(351mg,0.923mmol)。将所得混合物在室温下搅拌16h。向混合物中添加水并用EtOAc萃取产物。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并且在真空中除去溶剂。将残余物通过制备型LC(规则SiOH,15-40μm,12g,流动相梯度:从庚烷/EtOAc 90/10至70/30)纯化。将含有产物的级分合并并在真空中蒸发以给出呈白色泡沫的中间体J13(281mg,不纯的,按原样用于下一步)。
中间体J14(反式)
乙基(反式)-2-(4-(7-环丙基-1-甲基-5-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-1H-咪唑并[4,5-b]吡啶-2-基)-3-氟苯基)环丙烷-1-甲酸酯
在氮气气氛下,向中间体J13(139mg,0.268mmol)、(T-4)-硼酸酯(1-)[rel-(1R,2R)-2-(乙氧基羰基)环丙基]三氟-、钾(1:1)(1612792-88-7)(118mg,0.535mmol)和Cs2CO3(262mg,0.803mmol)在甲苯(3mL)和H2O(0.3mL)中的混合物中添加A(23mg,0.064mmol)和Pd(OAc)2(10mg,0.043mmol)。将混合物用氮气吹扫并在100℃下搅拌18h。添加水和EtOAc。分离各层并且用EtOAc萃取水层。将合并的有机层经MgSO4干燥、过滤、蒸发。将残余物通过制备型LC(不规则SiOH,15-40μm,12g,流动相梯度:从DCM/EtOAc 100/0至70/30)纯化。将含有产物的级分合并并在真空中蒸发以给出呈无色胶状物的中间体J14(58mg,39%)。
化合物13
(反式)-2-(4-(7-环丙基-1-甲基-5-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)-1H-咪唑并[4,5-b]吡啶-2-基)-3-氟苯基)环丙烷-1-甲酸
将氢氧化锂一水合物(13mg,0.32mmol)添加至中间体J14(58mg,0.11mmol)在THF(0.9mL)和H2O(0.3mL)中的溶液中,并将反应混合物在室温下搅拌18h。添加CPME中的HCl3M(0.120mL,0.357mmol),将混合物在室温下搅拌30min并在真空中蒸发。将残余物通过反相(固定相:YMC-actus Triart C18 10μm 30*150mm,流动相:梯度从65%TFA水溶液0.1%pH=2.5,35%MeCN至25%TFA水溶液pH=2.5,75%MeCN)纯化。将含有产物的级分合并并在真空中蒸发。将所得无色胶状物吸收在THF(1mL)中。然后添加CPME中的HCl 3M(0.5mL),并将溶液在室温下搅拌1h。将溶液在真空中蒸发。将残余物在Et2O中研磨,过滤并干燥以给出呈白色固体状的化合物13(34mg,58%)。
8.苯并咪唑的合成
8.1中间体K1的合成
中间体K1
(3R)-3-羟基吡咯烷-1-甲酰胺
将异氰酸三甲基甲硅烷基酯[1118-02-1](8.0mL,64.3mmol)逐滴添加至(R)-3-羟基吡咯烷[104706-47-0](4.00g,45.9mmol)在i-PrOH(110mL)中的溶液中。将反应混合物在室温下搅拌16h。将混合物在真空中浓缩直至观察到沉淀(约溶剂的一半)。将固体滤出,用i-PrOH洗涤并干燥,以得到呈白色固体状的中间体K1(4.6g,77%)。
8.2化合物14的合成
中间体K2
乙基4-氨基-3-溴-5-硝基苯甲酸酯
向乙基4-氨基-3-硝基苯甲酸酯[76918-64-4](55.0g,261mmol)在DCM(2L)中的溶液中逐滴添加溴(62.7g,392mmol)。将反应混合物在40℃下搅拌4h。在搅拌下,将反应混合物倒入Na2SO3的饱和水溶液(2L)中。将各层分离并将水相用DCM(2x1L)萃取。将合并的有机萃取物用NaHCO3的水溶液(1L)洗涤,经Na2SO4干燥,过滤并在真空中浓缩。将残余物溶解于DCM(1.5L)中。将悬浮液通过垫过滤。将滤液在真空中浓缩以得到呈黄色固体状的中间体K2(76g,定量)。
中间体K3
乙基4-氨基-3-环丙基-5-硝基苯甲酸酯
向碳酸铯(103g,316mmol)在H2O(760mL)中的溶液中添加中间体K2(76g,263mmol)在甲苯(760mL)中的溶液。将混合物用氮气吹扫30min。添加环丙基硼酸[411235-57-9](45.2g,526mmol)和[1,1’-双(二苯基-膦基)二茂铁]二氯化钯(II)(19.2g,26.3mmol)。将反应混合物在氮气气氛下、在100℃下搅拌16h。将反应混合物通过垫过滤并将滤饼用DCM(1.5L)洗涤。将滤液用H2O稀释。将各层分离并将水相用DCM(2x1L)萃取。将合并的有机萃取物用H2O(1L)洗涤,经Na2SO4干燥,过滤并在真空中蒸发溶剂。将残余物溶解于DCM(1.5L)中。将悬浮液通过垫过滤。将滤液在真空中浓缩以得到呈黄色固体状的中间体K3(68g,粗品)。
中间体K4
乙基3,4-二氨基-5-环丙基苯甲酸酯
向中间体K3(68.0g,272mmol)在EtOH(800mL)中的溶液中添加Pd/C(10wt.%10.0g,9.39mmol)。将反应混合物在H2气氛下、在室温下搅拌24h。将反应混合物通过垫过滤并将滤饼用EtOH(1.5L)洗涤。将滤液在真空中浓缩以得到呈黑色固体状的中间体K4(50.0g,84%,经过2个步骤),将其不经进一步纯化而用于下一步中。
中间体K5
乙基2-(4-溴-2-氟苯基)-4-环丙基-1H-1,3-苯并二唑-6-甲酸酯
将中间体K4(45g,204mmol)和4-溴-2-氟苯甲醛[57848-46-1](46.0g,227mmol)在DMSO(450mL)中的溶液在80℃下搅拌8h。添加另外的量的4-溴-2-氟苯甲醛(5.00g,24.6mmol)并将反应混合物在80℃下再搅拌3h。在搅拌下,将反应混合物倒入水(3L)中。将水相用EtOAc(3x1.5L)萃取。将合并的有机萃取物用H2O(2x1L)洗涤,经Na2SO4干燥,过滤并在真空中蒸发。将粗混合物通过从EtOAc(1L)中重结晶以得到呈棕色固体的中间体K5(36g,44%)。
中间体K6
乙基2-(4-溴-2-氟苯基)-4-环丙基-1-甲基-1H-1,3-苯并二唑-6-甲酸酯
向中间体K5(500mg,1.24mmol)和碳酸铯(1.41g,4.34mmol)在DMF(2.5mL)中的混合物中逐滴添加甲基碘(116μL,1.86mmol)。将反应混合物在室温下搅拌1h。将反应混合物用H2O和EtOAc稀释。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash40g,30μm,流动相梯度:庚烷/EtOAc从100:0至80:20)纯化以得到呈白色固体状的中间体K6(0.36g,70%)。
中间体K7
钾2-(4-溴-2-氟苯基)-4-环丙基-1-甲基-1H-1,3-苯并二唑-6-甲酸酯
将中间体K6(2.26g,5.42mmol)和氢氧化钾(912mg,16.3mmol)在EtOH(70mL)中的混合物在回流下搅拌5h。将反应混合物冷却至0℃,并用3N HCl水溶液酸化。将沉淀物滤出并真空干燥以得到呈米色固体状的中间体K7(1g,43%)。
中间体K8
(1R)-2-[2-(4-溴-2-氟苯基)-4-环丙基-1-甲基-1H-1,3-苯并二唑-6-羰基]-1-甲基-1,2,3,4-四氢异喹啉
向中间体K7(0.61g,1.43mmol)和(R)-1-甲基-1,2,3,4-四氢异喹啉[84010-66-2](252mg,1.71mmol)在DMF(18mL)中的溶液中添加DIPEA(0.74mL,4.28mmol)和HATU(0.71g,1.86mmol)。将反应混合物在室温下搅拌2h。将反应混合物缓慢倒入水中并用EtOAc萃取。将合并的有机萃取物用H2O和盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash40g,30μm,流动相梯度:庚烷/EtOAc从100:0至60:40)纯化以得到呈米色固体状的中间体K8(416mg,56%)。
中间体K9
乙基顺式-2-(4-{4-环丙基-1-甲基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1H-1,3-苯并二唑-2-基}-3-氟苯基)环丙烷-1-甲酸酯
将中间体K8(0.25g,482μmol)、(T-4)-硼酸酯(1-)[rel-(1R,2R)-2-(乙氧基羰基)环丙基]三氟-、钾(1:1)(1612792-88-7)(顺式:反式86:14)(256mg,1.21mmol)和碳酸铯(0.47g,1.45mmol)在甲苯(5.2mL)和水(0.53mL)中的混合物用氮气吹扫10min。添加A(41.5mg,116μmol)和乙酸钯(17.3mg,77.2μmol)。将反应混合物用氮气吹扫5min并在100℃下搅拌15h。将反应混合物用H2O和EtOAc稀释。将混合物通过垫过滤并用EtOAc洗涤。将各层分离并将有机相用H2O和盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash80g,30μm,流动相梯度:庚烷/DCM,从100:0至40:60)纯化以得到呈米色固体状的中间体K9(0.2g,75%)。
化合物14
反式-2-(4-{4-环丙基-1-甲基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1H-1,3-苯并二唑-2-基}-3-氟苯基)环丙烷-1-甲酸
将中间体K9(0.19g,0.34mmol)和氢氧化锂一水合物(0.10g,2.41mmol)在THF(8.5mL)和水(2mL)中的混合物在回流下搅拌15h。添加柠檬酸水溶液(463mg在5mL H2O中)。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥以给出呈米色固体状的化合物14(0.18g,定量)。
8.3化合物15的合成
化合物15
顺式-2-(4-{4-环丙基-1-甲基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1H-1,3-苯并二唑-2-基}-3-氟苯基)环丙烷-1-甲酰胺
将化合物14(0.14g,0.27mmol)、HATU(122mg,0.32mmol)和DIPEA(0.18mL,1.07mmol)在DMF(5.5mL)中的混合物在室温下搅拌15min。添加氨(30%在H2O中,0.11mL,1.60mmol)并将反应混合物在室温下搅拌1h。将反应混合物用EtOAc和H2O稀释。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用水和盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash25g,30μm,流动相梯度:DCM/MeOH从100:0至97:3)纯化。通过非手性SFC(固定相:AMINO 5μm 150*30mm,流动相:75%CO2,25%MeOH)进行第二次纯化。将残余物(78mg)吸收在Et2O中。将固体滤出并真空干燥以给出呈白色固体状的化合物15(65mg,47%)。
8.4化合物16和17的合成
中间体K10
甲基(3S)-1-(4-{4-环丙基-1-甲基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1H-1,3-苯并二唑-2-基}-3-氟苯基)吡咯烷-3-甲酸酯
将中间体K8(0.41g,0.79mmol)、(S)-甲基吡咯烷-3-甲酸酯盐酸盐[1099646-61-3](144mg,0.87mmol)、碳酸铯(1.03g,3.16mmol)和XantPhos(45.8mg,79.1μmol)在1,4-二噁烷(7mL)中的混合物用氮气吹扫。添加乙酸钯(17.8mg,79.1μmol)。将反应混合物再次用氮气吹扫并在100℃下搅拌5h。将反应混合物用EtOAc和H2O稀释。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并将溶剂在真空中蒸发。将粗混合物通过硅胶快速色谱法(Puriflash40g,30μm,流动相梯度:DCM/MeOH从100:0至97:3)纯化以得到呈白色固体状的中间体K10(334mg,74%)。
化合物16
(3S)-1-(4-{4-环丙基-1-甲基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1H-1,3-苯并二唑-2-基}-3-氟苯基)吡咯烷-3-甲酸
将中间体K10(0.33g,582μmol)和氢氧化锂一水合物(147mg,3.49mmol)在THF(15mL)和H2O(3mL)中的混合物在室温下搅拌过夜。添加柠檬酸水溶液(671mg在12mL H2O中)。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将残余物(0.31g)吸收在Et2O中。将固体滤出并真空干燥以给出呈米色固体状的化合物16(0.24g,74%)。
化合物17
(3S)-1-(4-{4-环丙基-1-甲基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1H-1,3-苯并二唑-2-基}-3-氟苯基)吡咯烷-3-甲酰胺
将化合物16(0.10g,0.18mmol)、HATU(103mg,0.27mmol)和DIPEA(94μL,0.54mmol)在DMF(4mL)中的混合物在室温下搅拌15min。添加氨(30%在H2O中,73μL,1.09mmol)并将反应混合物在室温下搅拌2h。将反应混合物用EtOAc和H2O稀释。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用H2O(3次)和盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥以给出呈白色固体状的化合物17(75mg,75%)。
8.5化合物18的合成
化合物18
(3R)-N-(4-{4-环丙基-1-甲基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1H-1,3-苯并二唑-2-基}-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
将中间体K8(0.20g,0.39mmol)、中间体K1(75.3mg,0.58mmol)、碳酸铯(0.63g,1.93mmol)和XantPhos(22.3mg,38.6μmol)在1,4-二噁烷(8mL)中的混合物在氮气下吹扫。添加乙酸钯(8.66mg,38.6μmol)并将反应混合物再次用氮气吹扫。将反应混合物在100℃下搅拌3h。将反应混合物用EtOAc和H2O稀释。将各层分离。将水相用EtOAc萃取。将合并的有机萃取物用H2O洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash25g,30μm,流动相梯度:DCM/MeOH从100:0至96:4)纯化。将残余物吸收在Et2O中。将固体滤出并真空干燥以给出呈米色固体状的化合物18(0.12g,55%)。
9.吲唑的合成
9.1化合物19的合成
中间体L1
甲基7-溴-2-(2-氟-4-硝基苯基)-2H-吲唑-5-甲酸酯
将甲基7-溴-1H-吲唑-5-甲酸酯[1427460-96-5](50.0mg,196μmol)、3,4-二氟硝基苯[369-34-6](23.9μL,216μmol)和碳酸钾(81.3mg,0.59mmol)在MeCN(1.5mL)中的混合物在80℃下搅拌18h。将反应混合物用H2O和EtOAc稀释。分离各层并将水相用EtOAc萃取。将合并的有机萃取物经MgSO4干燥,过滤并在真空中浓缩以得到中间体L1(50mg,65%)。
中间体L2
甲基7-环丙基-2-(2-氟-4-硝基苯基)-2H-吲唑-5-甲酸酯
向中间体L1(1.27,3.22mmol)、环丙基-三氟硼酸钾[1065010-87-8](1.19,8.04mmol)和碳酸铯(3.14g,9.65mmol)在H2O(2.4mL)和甲苯(12mL)中的脱气混合物中添加A(231mg,643μmol)和乙酸钯(72.2mg,0.32mmol)。将反应混合物在110℃下搅拌24h。将混合物用H2O和EtOAc稀释。分离各层并将水相用EtOAc萃取(两次)。将合并的有机萃取物经MgSO4干燥,过滤并将溶剂在真空中蒸发。将粗混合物通过制备型LC(不规则SiOH,15-40μm,80g GraceResolvTM,干法加载流动相梯度:庚烷/EtOAc从95:5至70:30)纯化以给出呈黄色固体状的中间体L2(400mg,35%)。
中间体L3
7-环丙基-2-(2-氟-4-硝基苯基)-2H-吲唑-5-甲酸
将氢氧化锂一水合物(267mg,6.35mmol)添加至中间体L2(410mg,1.15mmol)在THF(34mL)和H2O(8.4mL)中的溶液中。将反应混合物在50℃下搅拌18h。添加10%KHSO4水溶液直至pH 6,并且将水相用EtOAc萃取。将合并的有机萃取物用H2O洗涤,经MgSO4干燥,过滤并在真空中蒸发以得到中间体L3(315mg,78%)。
中间体L4
(1R)-2-[7-环丙基-2-(2-氟-4-硝基苯基)-2H-吲唑-5-羰基]-1-甲基-1,2,3,4-四氢异喹啉
将中间体L3(277mg,0.79mmol)、(R)-1-甲基-1,2,3,4-四氢异喹啉[84010-66-2](135mg,917μmol)和DIPEA(675μL,3.92mmol)在DCM(2mL)中的混合物在0℃下搅拌。缓慢添加PPACA(50wt.%在EtOAc中,1.20mL,2.00mmol)。将反应混合物在0℃下搅拌10min并在室温下搅拌18h。将反应混合物用H2O和EtOAc稀释。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并在真空中蒸发。将粗混合物通过制备型LC(不规则SiOH,15-40μm,24g GraceResolvTM,流动相梯度:庚烷/EtOAc从90:10至50:50)纯化。将残余物吸收在MeCN中,并且在真空中蒸发以给出中间体L4(291mg,78%)。
化合物19
4-{7-环丙基-5-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-2H-吲唑-2-基}-3-氟苯胺
向中间体L4(440mg,935μmol)在MeOH(9.4mL)中的溶液中添加氯化铵(350mg,6.55mmol)和锌粉(917mg,14.0mmol)。将反应混合物在室温下搅拌18h。将反应混合物通过垫过滤。将滤液在真空中浓缩并用DCM和H2O稀释。将各层分离并将有机相经MgSO4干燥,过滤并在真空中蒸发以给出化合物19(362mg,88%)。
9.2化合物20的合成
化合物20
(3S)-N-(4-{7-环丙基-5-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-2H-吲唑-2-基}-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
将CDI(73.6mg,454μmol)添加至化合物19(100mg,227μmol)在THF(850μL)中的溶液中。将反应混合物在室温下搅拌3h。添加(S)-3-羟基吡咯烷[100243-39-8](23.7mg,272μmol)并将反应混合物在室温下再搅拌2h。将反应混合物用EtOAc稀释。将有机相用NH4Cl水溶液洗涤,经MgSO4干燥,过滤并浓缩至干燥。将粗混合物与另一批次(20.0mg,45.4μmol)合并,并通过制备型LC(球形C1825μm,40g YMC-ODS-25,干法加载流动相梯度:0.2%NH4HCO3/MeCN水溶液从75:25至35:65)纯化。将残余物(50mg)在MTBE中研磨。将固体滤出并在高真空下、在50℃下干燥过夜以给出呈白色固体状的化合物20(40mg,32%)。
苯并噁唑的合成
9.3化合物21的合成
中间体M1
甲基4-溴-2-(4-溴-2-氟苯基)-1,3-苯并噁唑-6-甲酸酯
在0℃下,向甲基4-氨基-3-溴-5-羟基苯甲酸酯[1246759-65-8](1.30g,5.28mmol)、4-溴-2-氟苯甲酸[112704-79-7](1.74g,7.93mmol)和三苯基膦(4.16g,15.9mmol)在MeCN(14mL)中的混合物中逐滴添加三氯乙腈(1.06mL,10.6mmol)。使用具有输出功率从0至850W范围的单模微波(Anton Paar Monowave 300),将反应混合物在150℃下加热15min。将反应混合物用冰浴冷却。将沉淀物滤出并真空干燥以得到呈米色固体状的中间体M1(1.68g,74%)。
中间体M2
4-溴-2-(4-溴-2-氟苯基)-1,3-苯并噁唑-6-甲酸
将中间体M1(1.00g,2.33mmol)和氢氧化锂一水合物(0.44g,10.5mmol)在THF(23mL)和H2O(6mL)中的混合物在室温下搅拌过夜。添加柠檬酸水溶液(2.0g在20mL H2O中)。将沉淀物滤出,用H2O和Et2O洗涤,并真空干燥以得到呈黄色固体状的中间体M2(0.75g,按原样用于下一步)。
中间体M3
(1R)-2-[4-溴-2-(4-溴-2-氟苯基)-1,3-苯并噁唑-6-羰基]-1-甲基-1,2,3,4-四氢异喹啉
向中间体M2(0.75g,1.82mmol)、(1R)-1-甲基-1,2,3,4-四氢异喹啉[84010-66-2](321mg,2.18mmol)和DIPEA(1.27mL,7.27mmol)在DMF(30mL)中的混合物中添加HATU(829mg,2.18mmol)。将反应混合物在室温下搅拌2h。将混合物缓慢倒入水中并将水相用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash40g,30μm,流动相梯度:庚烷/EtOAc从100:0至70:30)纯化以得到呈白色固体状的中间体M3(0.49g,39%,经过2个步骤)。
中间体M4
甲基(3S)-1-(4-{4-溴-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1,3-苯并噁唑-2-基}-3-氟苯基)吡咯烷-3-甲酸酯
将中间体M3(0.49g,0.90mmol)、(S)-甲基吡咯烷-3-甲酸酯盐酸盐[1099646-61-3](149mg,0.90mmol)、碳酸铯(0.88g,2.70mmol)和XantPhos(52.1mg,0.09mmol)在1,4-二噁烷(11.5mL)中的混合物用氮气吹扫。添加乙酸钯(20.2mg,0.09mmol)。将反应混合物再次用氮气吹扫并在100℃下搅拌4h。将反应混合物用EtOAc和H2O稀释。分离各层并将水相用EtOAc萃取(两次)。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并将溶剂在真空中蒸发。将粗混合物通过硅胶快速色谱法(Puriflash40g,30μm,流动相梯度:庚烷/EtOAc从100:0至60:40)纯化以得到呈米色固体状的中间体M4(0.26g,79%)。
中间体M5
甲基(3S)-1-(4-{4-环丙基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1,3-苯并噁唑-2-基}-3-氟苯基)吡咯烷-3-甲酸酯
将中间体M4(0.52g,0.88mmol)、环丙基硼酸[411235-57-9](113mg,1.32mmol)和碳酸钾(607mg,4.39mmol)在THF(10mL)中的混合物用氮气吹扫5min。添加PdCl2(dppf).DCM(71.7mg,87.8μmol)并将混合物再次用氮气吹扫2min。使用具有输出功率从0至850W范围的单模微波(Anton Paar Monowave 300),将反应混合物在120℃下加热20min。将反应混合物用H2O和EtOAc稀释。将混合物通过垫过滤并用EtOAc洗涤。分离各层并将有机相用H2O、盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash25g,30μm,流动相梯度:庚烷/EtOAc从100:0至60:40)纯化以得到呈米色固体状的中间体M5(0.44g,91%)。
化合物21
(3S)-1-(4-{4-环丙基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1,3-苯并噁唑-2-基}-3-氟苯基)吡咯烷-3-甲酸
将中间体M5(0.43g,0.78mmol)和氢氧化锂一水合物(147mg,3.50mmol)在THF(7mL)和H2O(2mL)中的混合物在室温下搅拌过夜。添加柠檬酸水溶液(0.67g在5mL H2O中)。将沉淀物滤出,用H2O洗涤并真空干燥。将残余物(0.39g)吸收在Et2O中。将固体滤出并真空干燥以给出呈米色固体状的化合物21(0.37g,88%)。
9.4化合物22的合成
化合物22
(3S)-1-(4-{4-环丙基-6-[(1R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基]-1,3-苯并噁唑-2-基}-3-氟苯基)吡咯烷-3-甲酰胺
将化合物21(0.25g,0.46mmol)、HATU(247mg,0.65mmol)和DIPEA(0.32mL,1.85mmol)在DMF(10mL)中的混合物在室温下搅拌15min。添加氨(30%在H2O中,0.19mL,2.78mmol)。将反应混合物在室温下搅拌1h。将反应混合物用EtOAc和H2O稀释。分离各层并将水相用EtOAc萃取。将合并的有机萃取物用H2O和盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash25g,30μm,流动相梯度:DCM/MeOH从100:0至98:2)纯化以给出呈米色固体状的化合物22(140mg,56%)。
9.5化合物23的合成
中间体M6
(R)-N-(4-(4-溴-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)苯并[d]噁唑-2-基)-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
将中间体M3(0.30g,0.55mmol)、中间体K1(72mg,0.55mmol)、碳酸铯(720mg,2.2mmol)和XantPhos(32mg,0.055mmol)在1,4-二噁烷(9mL)中的混合物用氮气吹扫。添加乙酸钯(12mg,0.055mmol)。将反应混合物再次用氮气吹扫并在100℃下搅拌4h。将反应混合物用EtOAc和H2O稀释。分离各层并将水相用EtOAc萃取(两次)。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并将溶剂在真空中蒸发。将粗混合物通过硅胶快速色谱法(Puriflash40g,30μm,流动相梯度:DCM/MeOH从100:0至97:3)纯化以得到呈黄色固体状中间体M6(0.10g,30%)。
化合物23
(R)-N-(4-(4-环丙基-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)苯并[d]噁唑-2-基)-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
将中间体M6(85mg,0.14mmol)、环丙基硼酸[411235-57-9](18mg,0.22mmol)和碳酸钾(99mg,0.72mmol)在THF(1.8mL)中的混合物用氮气吹扫5min。添加PdCl2(dppf).DCM(12mg,14μmol)并将混合物再次用氮气吹扫2min。使用具有输出功率从0至850W范围的单模微波(Anton Paar Monowave 300),将反应混合物在120℃下加热20min。将反应混合物用H2O和EtOAc稀释。将混合物通过垫过滤并用EtOAc洗涤。分离各层并将有机相用H2O、盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash12g,30μm,流动相梯度:DCM/MeOH从100:0至98:2)纯化,以在蒸发纯的级分后得到残余物,将其在Et2O中研磨以在过滤后给出呈米色固体状的化合物23(52mg,65%)。
10.苯并噻唑的合成
10.1化合物24的合成
中间体N1
甲基4-氨基-3-环丙基苯甲酸酯
向4-氨基-3-溴苯甲酸甲酯(1.0g,4.4mmol)在甲苯(15mL)中的溶液中添加环丙基硼酸(0.56g,6.5mmol)、K3PO4(2.8g,13mol)、三环己基膦(0.12g,0.44mmol)和H2O(2mL)。将反应混合物再次用氮气吹扫2min,然后使用具有输出功率从0至850W范围的单模微波(Anton Paar Monowave 300)在120℃下加热45min。将反应混合物通过垫过滤并用EtOAc和H2O洗涤。将获得的滤液用EtOAc萃取,并将有机层用盐水洗涤,经MgSO4干燥,过滤并且蒸发直至干燥。将残余物通过制备型LC(规则SiOH 30μm,40g流动相梯度:从庚烷/EtOAc从100:0至70:30)纯化。将纯的级分合并并在真空下蒸发以给出呈黄色油状物的中间体N1(0.77g,93%)。
中间体N2
甲基2-氨基-4-环丙基苯并[d]噻唑-6-甲酸酯
在0℃下,向硫氰酸钠(1.3g,16mmol)在HOAc(15mL)中的混合物中逐滴添加中间体N1(0.77g,4.0mmol)在HOAc(15mL)中的溶液,然后逐滴添加溴(0.25mL,4.83mmol)。将反应混合物在室温下搅拌过夜。添加水(50mL)并在室温下搅拌2h。将黄色沉淀物过滤。将获得的固体在DCM/MeOH(9/1)中稀释并用NH3水溶液碱化直至pH 8。将所得混合物通过短垫过滤。将有机层蒸发直至干燥并将残余物吸收在MeOH中并在室温下搅拌过夜。将固体过滤,用水MeOH冲洗并在真空中干燥以给出呈黄色固体状的中间体N2(0.55g,55%)。
中间体N3
甲基2-溴-4-环丙基苯并[d]噻唑-6-甲酸酯
在N2和冰浴冷却下,向亚硝酸异戊酯(0.43mL,3.06mmol)和CuBr2(0.55g,2.45mmol)在ACN(8mL)中的溶液中逐滴添加中间体N2(0.55g,2.04mmol)在ACN(2.1mL)中的溶液。将反应混合物在室温下搅拌1h。添加H2O和HCl(1N)。将混合物用DCM萃取两次。将有机层经MgSO4干燥,过滤并蒸发直至干燥。将残余物通过硅胶快速色谱法(Puriflash40g,30μm,干法加载流动相梯度:庚烷/EtOAc从100/0至80/20)纯化。将纯的级分收集并蒸发至干燥以给出白色粉末状的中间体N3(0.41g,64%)。
中间体N4
甲基(R)-4-环丙基-2-(2-氟-4-(3-羟基吡咯烷-1-甲酰胺基)苯基)苯并[d]噻唑-6-甲酸酯
将中间体N3(0.30g,0.96mmol)、(R)-N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-3-羟基吡咯烷-1-甲酰胺(1.0g,1.15mmol)和水中的K2CO3 2M(1.44mL,2.88mmol)在THF(9.6mL)中的溶液用N2吹扫5min,然后向此溶液中添加PdCl2dppf·DCM(79mg,0.10mmol)。将反应混合物再次用氮气吹扫2min,然后使用具有输出功率从0至850W范围的单模微波(Anton Paar Monowave 300)在120℃下加热35min。添加H2O和EtOAc并分离。将水层用EtOAc萃取,将合并的有机层用H2O、盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗品通过硅胶快速色谱法(Puriflash25g,30μm,干法加载流动相梯度:庚烷/EtOAc,从80/20至0/100)纯化。将纯的级分收集并蒸发至干燥以给出呈米色固体状的中间体N4(0.17g,34%)。
中间体N5
(R)-4-环丙基-2-(2-氟-4-(3-羟基吡咯烷-1-甲酰胺基)苯基)苯并[d]-噻唑-6-甲酸
将中间体N4(0.17g,0.29mmol)和LiOH.H20(86mg,2.04mmol)在THF(7mL)和水(1.5mL)中的混合物搅拌并回流5h。添加柠檬酸水溶液(390mg在10mL H2O中)。将混合物用EtOAc萃取,用盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥以得到呈黄色固体状的中间体N5(0.14g,定量)。
化合物24
(R)-N-(4-(4-环丙基-6-((R)-1-甲基-1,2,3,4-四氢异喹啉-2-羰基)苯并[d]噻唑-2-基)-3-氟苯基)-3-羟基吡咯烷-1-甲酰胺
向中间体N5(0.14g,0.30mmol)、(1R)-1-甲基-1,2,3,4-四氢-异喹啉[84010-66-2](56mg,0.38mmol)和DIPEA(0.16mL,0.89mmol)在DMF(3.7mL)中的混合物中添加HATU(0.12g,0.32mmol)。将反应混合物在室温下搅拌2h。将混合物缓慢倒入水中并将水相用EtOAc萃取。将合并的有机萃取物用盐水洗涤,经MgSO4干燥,过滤并蒸发至干燥。将粗混合物通过硅胶快速色谱法(Puriflash25g,30μm,流动相梯度:DCM/MeOH从100:0至98:2)纯化,以在Et2O中研磨并过滤后得到呈米色固体状的化合物24(90mg,53%)。
11.吲唑的合成
11.1化合物25的合成
中间体O1
甲基4-苯基-1H-吲唑-6-甲酸酯
将甲基4-溴-1H-吲唑-6-甲酸酯(1g,3.92mmol)、苯基硼酸(1.2g,5.88mmol)和Cs2CO3(3.8g,11.8mmol)在H2O(5mL)和二噁烷(15mL)中的混合物用N2吹扫,然后添加Pd118(256mg,0.392mmol)并将混合物再次用N2吹扫。将所得混合物在80℃下搅拌2h。将混合物冷却至室温,然后添加EtOAc和水。将有机层用盐水(一次)洗涤,经MgSO4干燥,过滤,蒸发并通过制备型LC(不规则SiOH,15-40μm,120g流动相梯度:从DCM/MeOH 100/0至95/5)纯化。将含有产物的级分蒸发以给出中间体O1(830mg,84%)。
中间体O2
甲基2-(2-氟-4-硝基苯基)-4-苯基-2H-吲唑-6-甲酸酯
将在MeCN(19mL)中的中间体O1(630mg,2.50mmol)、3.4-二氟硝基苯(304μL,2.75mmol)、K2CO3(1.04g,7.49mmol)在80℃下搅拌18h。将混合物冷却至室温,然后将水和EtOAc添加至反应混合物中。将各层分离。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤,蒸发并经过制备型LC(不规则SiOH 15-40μm,12g流动相:DCM 100%)纯化。将含有产物的级分蒸发以给出呈黄色泡沫的中间体O2(150mg,15%)。
中间体O3
甲基2-(4-氨基-2-氟苯基)-4-苯基-2H-吲唑-6-甲酸酯
将中间体O2(140mg,0.358mmol)、MeOH(3.5mL)、锌粉(351mg,5.37mmol)和NH4Cl(134mg,2.50mmol)的混合物在室温下搅拌18h。添加锌粉(351mg,5.37mmol)和NH4Cl(134mg,2.50mmol)并将混合物在室温下搅拌24h。将混合物在垫上过滤,添加DCM和NaHCO3饱和水溶液。将混合物在室温下搅拌2h。将层分离。将有机层经MgSO4干燥,过滤并蒸发以给出呈黄色固体状的中间体O3(129mg,定量)。
中间体O4
甲基2-(4-溴-2-氟苯基)-4-苯基-2H-吲唑-6-甲酸酯
向中间体O3(129mg,0.357mmol)在MeCN(2.2mL)中的溶液中逐滴添加亚硝酸异戊酯(72μL,0.54mmol)然后在35℃下升温并搅拌30分钟。然后允许反应混合物冷却至室温并用氮气吹扫。一次性添加CuBr2(100mg,0.446mmol)。将反应混合物再次用氮气吹扫,升温至35℃并搅拌1小时。将反应混合物冷却至室温,用EtOAc和水稀释。将有机层分离,用水洗涤,然后用盐水洗涤,经MgSO4干燥,过滤,蒸发并通过制备型LC(规则SiOH 40μm,24g流动相梯度:从庚烷/EtOAc 100:0至20:80)纯化。将含有产物的级分合并并在真空下蒸发以给出呈白色固体状的中间体O4(26mg,17%)。
中间体O5
2-(4-溴-2-氟苯基)-4-苯基-2H-吲唑-6-甲酸
将中间体O4(26mg;0.061mmol)和氢氧化锂一水合物(5mg;0.12mmol)在THF(1.4mL)和H2O(0.1mL)中的混合物在室温下搅拌18h。将EtOAc和10%KHSO4水溶液添加至混合物并进行萃取。将水层用EtOAc萃取。将有机层合并,用盐水洗涤,经MgSO4干燥,过滤并蒸发以给出呈白色固体状的中间体O5(26mg,定量)。
中间体O6
(R)-(2-(4-溴-2-氟苯基)-4-苯基-2H-吲唑-6-基)(1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体O5(26mg,0.0632mmol)、(1R)-甲基-(1,2,3,4)-四氢-异喹啉(10mg,0.0695mmol)、HATU(36mg,0.0948mmol)和DIPEA(33μL,0.190mmol)在DMF(0.5mL)中的混合物在室温下搅拌4h。将水和EtOAc添加至反应混合物中。将各层分离。将水层用EtOAc萃取两次。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤,蒸发并通过制备型LC(不规则SiOH15-40μm,12g流动相梯度:从庚烷/EtOAc 75/25至0/100)纯化。将含有产物的级分蒸发以给出呈白色固体状的中间体O6(23mg,67%)。
化合物25
(2-(4-((3S,4S)-3,4-二羟基吡咯烷-1-基)-2-氟苯基)-4-苯基-2H-吲唑-6-基)((R)-1-甲基-3,4-二氢异喹啉-2(1H)-基)甲酮
将中间体O6(23mg,0.0426mmol)、(3S,4S)-吡咯烷-3,4-二醇(5mg,0.051mmol)和Cs2CO3(69mg,0.21mmol)的混合物装入密封管中并用N2吹扫。添加二噁烷(0.5mL)并将混合物用N2脱气,然后添加XPhos(4mg,8.51μmol)和Pd2(dba)3(2.0mg,2.1μmol)。将反应混合物用N2吹扫,然后搅拌并在100℃下加热18h。将混合物冷却至室温,然后添加水和EtOAc。将水层用EtOAc萃取,将合并的有机层经MgSO4干燥,过滤,在真空中浓缩并通过制备型LC(不规则SiOH 15-40μm,40g流动相梯度:从DCM/MeOH 100:0至88:12)纯化。将含有产物的级分蒸发然后通过制备型LC(球形C18 25μm,40g YMC-ODS-25,流动相梯度0.2%NH4+HCO3-/MeCN水溶液从75:25至0:100)纯化。将含有产物的级分冻干以给出呈淡黄色固体状的化合物25(9mg,38%)。
C.化合物鉴定
1H-NMR
在使用内部氘锁且配备有具有z梯度的反向双共振(1H,13C,SEI)探头并且在针对质子的400MHz和针对碳的100MHz下操作的Bruker Avance DRX 400光谱仪上,以及在配备有具有z梯度的Bruker5mm BBFO探头并且在针对质子的500MHz和针对碳的125MHz下操作的Bruker Avance 500MHz光谱仪上记录1H-NMR光谱。
除非另有说明,否则在环境温度下记录NMR谱。
数据报告如下:在积分、多重性(s=单峰、d=二重峰、t=三重峰、q=四重峰、quin=五重峰、sex=六重峰、m=多重峰、b=宽峰或它们的组合)方面,化学位移相对于TMS(δ=0ppm)(用作内部标准)以百万分率(ppm)为单位,偶联常数J以赫兹(Hz)为单位。
化合物1
主要旋转异构体(65%)1H NMR(500MHz,DMSO-d6)δppm 8.79(s,1H),8.13(t,J=8.5Hz,1H),7.83(br d,J=13.2Hz,1H),7.52-7.62(m,2H),7.03-7.34(m,4H),5.56-5.64(m,1H),4.93-5.02(m,1H),4.32(br s,1H),3.86(br d,J=10.1Hz,1H),3.31-3.55(m,5H),2.81-3.22(m,3H),2.74(br d,J=16.1Hz,1H),1.95(br dd,J=8.4,4.3Hz,1H),1.84(brs,1H),1.49-1.60(m,3H),1.30-1.42(m,3H)。
次要旋转异构体(35%)1H NMR(500MHz,DMSO-d6)δppm 8.79(s,1H),8.13(t,J=8.5Hz,1H),7.83(br d,J=13.2Hz,1H),7.52-7.62(m,2H),7.03-7.34(m,4H),4.93-5.02(m,2H),4.58(br dd,J=13.1,4.6Hz,1H),4.32(br s,1H),3.31-3.55(m,5H),2.81-3.22(m,4H),1.95(br dd,J=8.4,4.3Hz,1H),1.84(br s,1H),1.49-1.60(m,3H),1.30-1.42(m,3H)。
化合物2:
主要旋转异构体(65%)1H NMR(500MHz,DMSO-d6)δppm 7.99(t,J=8.7Hz,1H),7.04-7.32(m,5H),6.58(br d,J=8.8Hz,1H),6.51(br d,J=14.8Hz,1H),5.59(q,J=6.8Hz,1H),5.22(d,J=2.5Hz,2H),4.09(br s,2H),3.83(br dd,J=13.4,3.9Hz,1H),3.58(dd,J=10.7,3.5Hz,2H),3.37-3.51(m,1H),3.22-3.27(m,2H),2.80-3.07(m,1H),2.64-2.77(m,1H),2.37-2.47(m,1H),1.48-1.58(m,3H),1.19-1.31(m,4H)。
次要旋转异构体(35%)1H NMR(500MHz,DMSO-d6)δppm 7.99(t,J=8.7Hz,1H),7.04-7.32(m,5H),6.58(br d,J=8.8Hz,1H),6.51(br d,J=14.8Hz,1H),5.22(d,J=2.5Hz,2H),4.97(br d,J=6.6Hz,1H),4.56(br dd,J=12.8,5.2Hz,1H),4.09(br s,2H),3.58(dd,J=10.7,3.5Hz,2H),3.22-3.27(m,3H),2.80-3.07(m,2H),2.37-2.47(m,1H),1.48-1.58(m,3H),1.19-1.31(m,4H)。
化合物3:
1H NMR(500MHz,DMSO-d6,77℃)δppm 7.75(t,J=8.8Hz,1H),7.45(s,1H),7.13-7.25(m,4H),7.10(s,1H),6.97(d,J=3.2Hz,1H),6.50(dd,J=8.7,2.4Hz,1H),6.44(dd,J=14.7,2.0Hz,1H),5.24-5.48(m,1H),4.89-5.01(m,2H),4.09(br s,2H),3.99(br s,1H),3.56(dd,J=10.6,3.9Hz,2H),3.37(br t,J=11.2Hz,1H),3.18(d,J=10.4Hz,2H),2.91-3.01(m,3H),2.75(br d,J=16.7Hz,1H),1.50(d,J=6.9Hz,3H),1.36(t,J=7.6Hz,3H)。
化合物4:
主要旋转异构体(65%)1H NMR(400MHz,DMSO-d6)δppm 7.87-7.98(m,1H)7.68-7.80(m,1H)6.99-7.37(m,5H)6.41-6.57(m,2H)5.59(q,J=6.8Hz,1H)5.21(d,J=3.3Hz,2H)4.07(br s,2H)3.72-3.83(m,1H)3.54(dd,J=10.5,3.5Hz,2H)3.39-3.49(m,1H)3.18(d,J=10.8Hz,2H)2.67-3.09(m,3H)1.49-1.60(m,3H)1.13-1.26(m,2H)0.93-1.04(m,2H)。
次要旋转异构体(35%)1H NMR(400MHz,DMSO-d6)δppm 7.87-7.98(m,1H)7.68-7.80(m,1H)6.99-7.37(m,5H)6.41-6.57(m,2H)5.21(d,J=3.3Hz,2H)4.84-5.00(m,1H)4.51-4.62(m,1H)4.07(br s,2H)3.54(dd,J=10.5,3.5Hz,2H)3.23-3.29(m,1H)3.18(d,J=10.8Hz,2H)2.67-3.09(m,3H)1.49-1.60(m,3H)1.13-1.26(m,2H)0.93-1.04(m,2H)。
化合物5:
主要旋转异构体(65%)1H NMR(400MHz,DMSO-d6)δppm 8.06-8.22(m,1H)6.94-7.35(m,5H)6.43-6.64(m,2H)5.57(q,J=6.8Hz,1H)5.19(d,J=3.1Hz,2H)3.96-4.12(m,2H)3.72(br dd,J=13.4,4.0Hz,1H)3.47-3.60(m,2H)3.35-3.45(m,1H)3.18(br d,J=11.2Hz,2H)2.64-3.03(m,2H)2.05-2.18(m,1H)1.42-1.56(m,3H)1.08-1.24(m,2H)0.95-1.08(m,2H)。
次要旋转异构体(35%)1H NMR(400MHz,DMSO-d6)δppm 8.06-8.22(m,1H)6.94-7.35(m,5H)6.43-6.64(m,2H)5.19(d,J=3.1Hz,2H)4.82-4.94(m,1H)4.48-4.61(m,1H)3.96-4.12(m,2H)3.47-3.60(m,2H)3.35-3.45(m,1H)3.18(br d,J=11.2Hz,2H)2.64-3.03(m,2H)2.05-2.18(m,1H)1.42-1.56(m,3H)1.08-1.24(m,2H)0.95-1.08(m,2H)。
化合物6:
主要旋转异构体(65%)1H NMR(400MHz,DMSO-d6)δppm 8.67(s,1H)7.95(t,J=8.8Hz,1H)7.80(br d,J=14.8Hz,1H)7.54(br d,J=8.8Hz,1H)7.44(s,1H)6.98-7.37(m,5H)5.53-5.68(m,1H)4.91-5.06(m,1H)4.32(br s,1H)3.82(br dd,J=13.1,3.7Hz,1H)3.34-3.58(m,5H)2.69-3.12(m,4H)1.77-2.03(m,2H)1.50-1.61(m,3H)1.33-1.45(m,3H)。
次要旋转异构体(35%)1H NMR(400MHz,DMSO-d6)δppm 8.67(s,1H)7.95(t,J=8.8Hz,1H)7.80(br d,J=14.8Hz,1H)7.54(br d,J=8.8Hz,1H)7.39(s,1H)6.98-7.37(m,5H)4.91-5.06(m,2H)4.55-4.68(m,1H)4.32(br s,1H)3.34-3.58(m,4H)3.22-3.28(m,1H)2.69-3.12(m,4H)1.77-2.03(m,2H)1.50-1.61(m,3H)1.33-1.45(m,3H)。
化合物7:
主要旋转异构体(65%)1H NMR(400MHz,DMSO-d6)δppm 8.98-9.10(m,1H)8.66(s,1H)7.75-7.93(m,2H)7.56(br d,J=8.9Hz,1H)7.02-7.38(m,5H)5.57-5.68(m,1H)4.95-5.07(m,1H)4.32(br s,1H)3.83(br dd,J=13.4,3.8Hz,1H)3.34-3.57(m,5H)2.68-3.11(m,2H)2.42-2.48(m,1H)1.89-2.03(m,1H)1.83(m,1.7Hz,1H)1.53(d,J=6.7Hz,3H)1.29-1.37(m,2H)1.14-1.22(m,2H)。
次要旋转异构体(35%)1H NMR(400MHz,DMSO-d6)δppm 8.98-9.10(m,1H)8.66(s,1H)7.75-7.93(m,2H)7.56(br d,J=8.9Hz,1H)7.02-7.38(m,5H)4.95-5.07(m,2H)4.55-4.65(m,1H)4.32(br s,1H)3.34-3.57(m,4H)3.20-3.29(m,1H)2.68-3.11(m,2H)2.42-2.48(m,1H)1.89-2.03(m,1H)1.83(m,1.7Hz,1H)1.53(d,J=6.7Hz,3H)1.29-1.37(m,2H)1.14-1.22(m,2H)。
化合物8:
主要旋转异构体(70%)1H NMR(500MHz,DMSO-d6)δppm11.61(s,1H),7.83(t,J=8.2Hz,1H),7.07-7.29(m,8H),6.59(br s,1H),5.56(br s,1H),3.78(br s,1H),3.17-3.52(m,2H),2.87-3.03(m,1H),2.68-2.84(m,1H),2.24-2.33(m,1H),1.88-1.96(m,1H),1.50(d,J=6.9Hz,3H),1.37-1.53(m,3H),0.98-1.07(m,2H),0.80(br s,2H)。
次要旋转异构体(30%)1H NMR(500MHz,DMSO-d6)δppm11.61(s,1H),7.83(t,J=8.2Hz,1H),7.07-7.29(m,8H),6.59(br s,1H),4.91(br s,1H),4.52(br s,1H),3.17-3.52(m,2H),2.87-3.03(m,1H),2.68-2.84(m,1H),2.24-2.33(m,1H),1.88-1.96(m,1H),1.50(d,J=6.9Hz,3H),1.37-1.53(m,3H),0.98-1.07(m,2H),0.80(br s,2H)。
化合物9:
主要旋转异构体(70%)1H NMR(500MHz,DMSO-d6)δppm12.42(br s,1H),7.13-7.51(m,8H),6.76(s,1H),6.64(br s,1H),5.58(br s,1H),3.76(br s,1H),3.62(s,3H),3.19-3.46(m,2H),2.92-3.04(m,1H),2.74(br s,1H),2.24-2.33(m,1H),1.92-2.00(m,1H),1.52(d,J=6.6Hz,3H),1.43-1.54(m,2H),0.98-1.06(m,2H),0.81(br s,2H)。
次要旋转异构体(30%)1H NMR(500MHz,DMSO-d6)δppm12.42(br s,1H),7.13-7.51(m,8H),6.76(s,1H),6.64(br s,1H),4.87(br s,1H),4.54(br s,1H),3.62(s,3H),3.19-3.46(m,2H),2.92-3.04(m,1H),2.74(br s,1H),2.24-2.33(m,1H),1.92-2.00(m,1H),1.52(d,J=6.6Hz,3H),1.43-1.54(m,2H),0.98-1.06(m,2H),0.81(br s,2H)。
化合物10:
主要旋转异构体(70%)1H NMR(500MHz,DMSO-d6)δppm 6.95-7.38(m,6H),6.64(s,1H),6.62(br s,1H),6.48-6.54(m,2H),5.57(br s,1H),3.77(br s,1H),3.61(br s,3H),3.35-3.55(m,5H)3.16-3.23(m,2H),2.93-3.05(m,1H),2.66-2.83(m,1H),2.13-2.32(m,3H),1.51(d,J=6.9Hz,3H),0.98-1.05(m,2H),0.80(br s,2H)。
次要旋转异构体(30%)1H NMR(500MHz,DMSO-d6)δppm 6.95-7.38(m,6H),6.64(s,1H),6.62(br s,1H),6.48-6.54(m,2H),4.88(br s,1H),4.53(br s,1H),3.61(br s,3H),3.35-3.55(m,5H),3.16-3.23(m,2H),2.93-3.05(m,1H),2.66-2.83(m,1H),2.13-2.32(m,3H),1.51(d,J=6.9Hz,3H),0.98-1.05(m,2H),0.80(br s,2H)。
化合物11:
主要旋转异构体(65%)1H NMR(500MHz,DMSO-d6)δppm12.45(br s,1H),7.66(t,J=7.9Hz,1H),7.35(br d,J=11.7Hz,1H),7.32(br d,J=7.6Hz,1H),7.29(br d,J=8.2Hz,1H),7.05-7.25(m,4H),5.59(q,J=6.8Hz,1H),3.87(br dd,J=13.2,4.1Hz,1H),3.71(s,3H),3.24-3.45(m,1H),3.11-3.20(m,1H),2.73(br d,J=15.8Hz,1H),2.55-2.60(m,2H),2.01(dt,J=8.4,4.5Hz,1H),1.53(br d,J=6.9Hz,3H),1.47-1.53(m,2H),1.22-1.30(m,2H),1.13-1.22(m,2H)。
次要旋转异构体(35%)1H NMR(500MHz,DMSO-d6)δppm12.45(br s,1H),7.66(t,J=7.9Hz,1H),7.35(br d,J=11.7Hz,1H),7.29(br d,J=8.2Hz,1H),7.05-7.25(m,5H),5.05(q,J=6.6Hz,1H),4.57(br dd,J=13.1,4.9Hz,1H),3.71(s,3H),3.24-3.45(m,1H),2.89-2.98(m,1H),2.82-2.89(m,1H),2.55-2.60(m,2H),2.01(dt,J=8.4,4.5Hz,1H),1.65(d,J=6.6Hz,3H),1.47-1.53(m,2H),1.22-1.30(m,2H),1.13-1.22(m,2H)。
化合物12:
主要旋转异构体(60%)1H NMR(400MHz,DMSO-d6)δppm12.57(br s,1H),7.54(t,J=8.8Hz,1H),7.32(d,J=7.6Hz,1H),7.04-7.25(m,4H),6.52-6.62(m,2H),5.58(q,J=7.1Hz,1H),3.89(br dd,J=13.6,3.5Hz,1H),3.71(s,3H),3.48-3.62(m,3H),3.34-3.46(m,3H),3.21-3.30(m,1H),3.10-3.21(m,1H),2.73(br d,J=16.2Hz,1H),2.14-2.31(m,2H),1.53(d,J=6.6Hz,3H),1.13-1.30(m,4H)。
次要旋转异构体(40%)1H NMR(400MHz,DMSO-d6)δppm12.57(br s,1H),7.54(t,J=8.8Hz,1H),7.04-7.25(m,5H),6.52-6.62(m,2H),5.06(q,J=7.1Hz,1H),4.56(br dd,J=12.6,3.5Hz,1H),3.71(s,3H),3.48-3.62(m,3H),3.34-3.46(m,3H),3.21-3.30(m,1H),2.89-2.99(m,1H),2.80-2.88(m,1H),2.14-2.31(m,2H),1.65(d,J=6.6Hz,3H),1.13-1.30(m,4H)。
化合物13:
反式主要旋转异构体(55%)1H NMR(500MHz,DMSO-d6)δppm12.50(br s,1H),8.12-8.25(m,1H),6.94-7.58(m,7H),5.60(q,J=6.6Hz,1H),3.48-4.64(m,5H),2.67-3.17(m,3H),2.55-2.61(m,1H),1.99-2.09(m,1H),1.23-1.70(m,9H)。
反式次要旋转异构体(20%)1H NMR(500MHz,DMSO-d6)δppm12.50(br s,1H),8.12-8.25(m,1H),6.94-7.58(m,7H),4.73(q,J=6.9Hz,1H),3.48-4.64(m,5H),2.67-3.17(m,3H),2.55-2.61(m,1H),1.99-2.09(m,1H),1.23-1.70(m,9H)。
顺式主要旋转异构体(20%)1H NMR(500MHz,DMSO-d6)δppm12.50(br s,1H),8.12-8.25(m,1H),6.94-7.58(m,7H),5.69(q,J=6.6Hz,1H),3.48-4.64(m,5H),2.67-3.17(m,3H),2.55-2.61(m,1H),1.99-2.09(m,1H),1.23-1.70(m,9H)。
顺式次要旋转异构体(5%)1H NMR(500MHz,DMSO-d6)δppm12.50(br s,1H),8.12-8.25(m,1H),6.94-7.58(m,7H),4.83-4.91(m,1H),3.48-4.64(m,5H),2.67-3.17(m,3H),2.55-2.61(m,1H),1.99-2.09(m,1H),1.23-1.70(m,9H)。
化合物14:
主要旋转异构体(70%)1H NMR(500MHz,DMSO-d6)δppm12.08(br s,1H),7.61(t,J=7.9Hz,1H),7.47(br s,1H),7.25-7.37(m,3H),7.12-7.25(m,3H),6.83(br s,1H),5.60(br s,1H),3.69(br s,3H),3.41(br s,1H),2.93-3.03(m,1H),2.61-2.85(m,3H),2.52-2.56(m,1H),2.13(q,J=7.6Hz,1H),1.63(q,J=6.0Hz,1H),1.52(br d,J=6.6Hz,3H),1.40(td,J=8.0,5.0Hz,1H),0.97-1.12(m,4H)。
次要旋转异构体(30%)1H NMR(500MHz,DMSO-d6)δppm12.08(br s,1H),7.61(t,J=7.9Hz,1H),7.47(br s,1H),7.25-7.37(m,3H),7.12-7.25(m,3H),6.83(br s,1H),4.83(br s,1H),4.56(br s,1H),3.69(br s,3H),2.93-3.03(m,1H),2.61-2.85(m,3H),2.52-2.56(m,1H),2.13(q,J=7.6Hz,1H),1.63(q,J=6.0Hz,1H),1.52(br d,J=6.6Hz,3H),1.40(td,J=8.0,5.0Hz,1H),0.97-1.12(m,4H)。
化合物15:
主要旋转异构体(70%)1H NMR(500MHz,DMSO-d6)δppm 7.56(t,J=7.9Hz,1H),7.50(br s,1H),7.46(br s,1H),7.06-7.35(m,6H),6.83(br s,1H),6.71(br s,1H),5.60(br s,1H),3.69(br s,4H),3.16-3.49(m,2H),2.91-3.06(m,1H),2.65-2.85(m,1H),2.52-2.57(m,1H),2.11(q,J=7.4Hz,1H),1.56(q,J=5.6Hz,1H),1.52(br d,J=6.6Hz,3H),1.27(td,J=8.1,4.6Hz,1H),0.98-1.13(m,4H)。
次要旋转异构体(30%)1H NMR(500MHz,DMSO-d6)δppm 7.56(t,J=7.9Hz,1H),7.50(br s,1H),7.46(br s,1H),7.06-7.35(m,6H),6.83(br s,1H),6.71(br s,1H),4.85(br s,1H),4.56(br s,1H),3.69(br s,3H),3.16-3.49(m,2H),2.91-3.06(m,1H),2.65-2.85(m,1H),2.52-2.57(m,1H),2.11(q,J=7.4Hz,1H),1.56(q,J=5.6Hz,1H),1.52(br d,J=6.6Hz,3H),1.27(td,J=8.1,4.6Hz,1H),0.98-1.13(m,4H)。
化合物16:
主要旋转异构体(65%)1H NMR(500MHz,DMSO-d6)δppm12.55(br s,1H),7.49(t,J=8.5Hz,1H),7.45(br s,1H),7.31(br s,1H),7.22(br s,1H),7.17(br s,2H),6.81(brs,1H),6.50-6.61(m,2H),5.59(br s,1H),3.69(br s,4H),3.48-3.59(m,2H),3.30-3.47(m,3H),3.25(br quin,J=6.9Hz,1H),2.92-3.05(m,1H),2.67-2.88(m,1H),2.52-2.60(m,1H),2.15-2.31(m,2H),1.52(br d,J=6.6Hz,3H),0.96-1.07(m,4H)。
次要旋转异构体(35%)1H NMR(500MHz,DMSO-d6)δppm12.55(br s,1H),7.49(t,J=8.5Hz,1H),7.45(br s,1H),7.17(br s,2H),6.97-7.13(m,2H),6.81(br s,1H),6.50-6.61(m,2H),4.84(br s,1H),4.55(br s,1H),3.69(br s,3H),3.48-3.59(m,2H),3.30-3.47(m,3H),3.25(br quin,J=6.9Hz,1H),2.92-3.05(m,1H),2.67-2.88(m,1H),2.52-2.60(m,1H),2.15-2.31(m,2H),1.52(br d,J=6.6Hz,3H),0.96-1.07(m,4H)。
化合物17:
1H NMR(500MHz,DMSO-d6,77℃)δppm 7.45(t,J=8.7Hz,1H),7.35(s,1H),7.21-7.32(br s,1H),7.13-7.21(m,4H),6.79(s,1H),6.64-6.76(br s,1H),6.54(dd,J=8.7,2.0Hz,1H),6.47(dd,J=13.7,1.7Hz,1H),5.36(br s,1H),4.01(br s,1H),3.66(d,J=1.3Hz,3H),3.53(t,J=8.8Hz,1H),3.41-3.47(m,2H),3.31-3.41(m,2H),3.12(quin,J=7.5Hz,1H),2.92-3.01(m,1H),2.74(br d,J=15.8Hz,1H),2.50-2.56(m,1H),2.10-2.26(m,2H),1.51(d,J=6.6Hz,3H),0.99-1.08(m,4H)。
化合物18:
主要旋转异构体(70%)1H NMR(500MHz,DMSO-d6)δppm 8.62(s,1H),7.77(dd,J=13.4,1.7Hz,1H),7.51-7.60(m,2H),7.45(br s,1H),7.09-7.34(m,4H),6.81(br s,1H),5.59(br s,1H),4.99(d,J=3.8Hz,1H),4.33(br s,1H),3.70(br s,3H),3.45-3.54(m,3H),3.41(br s,1H),3.35(br d,J=10.7Hz,1H),2.94-3.04(m,1H),2.67-2.80(m,1H),2.51-2.57(m,1H),1.91-1.98(m,1H),1.80-1.87(m,1H),1.52(d,J=6.9Hz,3H),0.99-1.11(m,4H)。
次要旋转异构体(30%)1H NMR(500MHz,DMSO-d6)δppm 8.62(s,1H),7.77(dd,J=13.4,1.7Hz,1H),7.51-7.60(m,2H),7.45(br s,1H),7.09-7.34(m,4H),6.81(br s,1H),4.99(d,J=3.8Hz,1H),4.84(br s,1H),4.55(br s,1H),4.33(br s,1H),3.70(br s,3H),3.45-3.54(m,3H),3.35(br d,J=10.7Hz,1H),2.94-3.04(m,1H),2.67-2.80(m,1H),2.51-2.57(m,1H),1.91-1.98(m,1H),1.80-1.87(m,1H),1.52(d,J=6.9Hz,3H),0.99-1.11(m,4H)。
化合物19:
主要旋转异构体(70%)1H NMR(400MHz,DMSO-d6)δppm 8.63(d,J=2.1Hz,1H),7.60(s,1H),7.52(t,J=8.9Hz,1H),7.29(br s,1H),7.11-7.25(br s,3H),6.84(br s,1H),6.55-6.58(m,1H),6.54(s,1H),5.86(s,2H),5.57(br s,1H),3.76(br s,1H),3.35-3.49(m,1H),2.90-3.03(m,1H),2.70-2.81(m,1H),2.39-2.47(m,1H),1.50(d,J=6.7Hz,3H),0.98-1.13(m,4H)。
次要旋转异构体(30%)1H NMR(400MHz,DMSO-d6)δppm 8.63(d,J=2.1Hz,1H),7.60(s,1H),7.52(t,J=8.9Hz,1H),7.29(br s,1H),7.11-7.25(br s,3H),6.84(br s,1H),6.55-6.58(m,1H),6.54(s,1H),5.86(s,2H),4.80-4.99(m,1H),4.44-4.64(m,1H),3.35-3.49(m,1H),2.90-3.03(m,1H),2.70-2.81(m,1H),2.39-2.47(m,1H),1.50(d,J=6.7Hz,3H),0.98-1.13(m,4H)。
化合物20:
主要旋转异构体(70%)1H NMR(400MHz,DMSO-d6)δppm 8.79(d,J=2.2Hz,1H),8.64(s,1H),7.78-7.90(m,2H),7.64(br s,1H),7.54(dd,J=9.0,1.4Hz,1H),7.02-7.40(m,4H),6.88(br s,1H),5.58(br s,1H),5.02(d,J=3.3Hz,1H),4.33(br s,1H),3.76(brs,1H),3.43-3.55(m,3H),3.35(br s,1H),2.91-3.03(m,1H),2.70-2.84(m,1H),2.40-2.47(m,1H),1.90-2.01(m,1H),1.78-1.88(m,1H),1.51(d,J=6.6Hz,3H),1.00-1.14(m,4H)。
次要旋转异构体(30%)1H NMR(400MHz,DMSO-d6)δppm 8.79(d,J=2.2Hz,1H),8.64(s,1H),7.78-7.90(m,2H),7.64(br s,1H),7.54(dd,J=9.0,1.4Hz,1H),7.02-7.25(m,4H),6.88(br s,1H),5.02(d,J=3.3Hz,1H),4.82-4.95(br s,1H),4.46-4.63(br s,1H),4.33(br s,1H),3.43-3.55(m,3H),3.35(br s,1H),2.91-3.03(m,1H),2.70-2.84(m,1H),2.40-2.47(m,1H),1.90-2.01(m,1H),1.78-1.88(m,1H),1.51(d,J=6.6Hz,3H),1.00-1.14(m,4H)。
化合物21:
主要旋转异构体(75%)1H NMR(500MHz,DMSO-d6,38℃)δppm 12.45(br s,1H),7.98(t,J=8.7Hz,1H),7.51(br s,1H),7.05-7.36(m,4H),6.95(s,1H),6.59(br d,J=8.8Hz,1H),6.52(br d,J=14.2Hz,1H),5.58(br s,1H),3.63-3.76(m,1H),3.50-3.62(m,2H),3.31-3.49(m,3H),2.89-3.05(m,1H),2.68-2.85(m,1H),2.38-2.47(m,2H),2.15-2.32(m,2H),1.50(br d,J=6.3Hz,3H),1.04-1.15(m,4H)。
次要旋转异构体(25%)1H NMR(500MHz,DMSO-d6,38℃)δppm 12.45(br s,1H),7.98(t,J=8.7Hz,1H),7.51(br s,1H),7.05-7.36(m,4H),6.95(s,1H),6.59(br d,J=8.8Hz,1H),6.52(br d,J=14.2Hz,1H),4.80(br s,1H),4.53(br,1H),3.50-3.62(m,2H),3.31-3.49(m,3H),2.89-3.05(m,1H),2.68-2.85(m,1H),2.38-2.47(m,2H),2.15-2.32(m,2H),1.50(br d,J=6.3Hz,3H),1.04-1.15(m,4H)。
化合物22:
主要旋转异构体(70%)1H NMR(500MHz,DMSO-d6,35℃)δppm 7.98(br t,J=8.7Hz,1H),7.52(br s,1H),7.47(br s,1H),7.29(br s,1H),7.10-7.23(m,3H),6.96(brs,2H),6.57(br d,J=8.8Hz,1H),6.50(br d,J=14.5Hz,1H),5.58(br s,1H),3.67(br s,1H),3.55(br t,J=9.0Hz,1H),3.32-3.51(m,4H),3.11(quin,J=7.3Hz,1H),2.91-3.03(m,1H),2.74(br s,1H),2.39-2.48(m,1H),2.18-2.27(m,1H),2.07-2.18(m,1H),1.51(brd,J=6.0Hz,3H),1.04-1.15(m,4H)。
次要旋转异构体(30%)1H NMR(500MHz,DMSO-d6,35℃)δppm 7.98(br t,J=8.7Hz,1H),7.52(br s,1H),7.47(br s,1H),7.29(br s,1H),7.10-7.23(m,3H),6.96(brs,2H),6.57(br d,J=8.8Hz,1H),6.50(br d,J=14.5Hz,1H),4.80(br s,1H),4.55(br s,1H),3.55(br t,J=9.0Hz,1H),3.32-3.51(m,4H),3.11(quin,J=7.3Hz,1H),2.91-3.03(m,1H),2.74(br s,1H),2.39-2.48(m,1H),2.18-2.27(m,1H),2.07-2.18(m,1H),1.51(brd,J=6.0Hz,3H),1.04-1.15(m,4H)。
化合物23:
1H NMR(500MHz,DMSO-d6)δppm 8.76(s,1H),8.08(t,J=8.5Hz,1H),7.81(dd,J=14.5,1.9Hz,1H),7.49-7.66(m,2H),6.93-7.26(m,5H),5.34-5.70(m,0.7H),4.99(d,J=3.5Hz,1H),4.68-4.89(m,0.3H),4.45-4.63(m,0.3H),4.32(br s,1H),3.32-3.77(m,5.7H),2.91-3.02(m,1H),2.65-2.89(m,1H),2.42-2.47(m,1H),1.89-2.03(m,1H),1.79-1.90(m,1H),1.51(br d,J=5.7Hz,3H),1.12(br d,J=5.0Hz,4H)。
化合物24:
1H NMR(500MHz,DMSO-d6)δppm 8.73(s,1H),8.27(t,J=8.83Hz,1H),7.98(br s,1H),7.84(dd,J=15.1,1.9Hz,1H),7.56(dd,J=8.8,1.9Hz,1H),6.92-7.26(m,5H),5.51-5.65(m,0.70H),4.98(d,J=3.5Hz,1H),4.69-4.84(m,0.3H),4.50-4.67(m,0.3H),4.26-4.38(m,1H),3.32-3.72(m,5.7H),2.92-3.05(m,1H),2.88(br qt,J=5.0Hz,1H),2.66-2.80(m,1H)1.90-2.01(m,1H),1.78-1.89(m,1H),1.40-1.65(m,3H),1.11-1.19(m,2H),0.96-1.08(m,2H)。
化合物25:
主要旋转异构体(65%)1H NMR(400MHz,DMSO-d6)δppm 8.80(s,1H)7.67-7.94(m,4H)7.43-7.63(m,3H)7.04-7.39(m,5H)6.45-6.69(m,2H)5.63-5.73(m,1H)5.24(d,J=3.2Hz,2H)4.10(br s,2H)3.77-3.94(m,1H)3.44-3.63(m,3H)3.20(br d,J=10.5Hz,2H)2.72-3.12(m,2H)1.57(t,J=6.7Hz,3H)
次要旋转异构体(35%)1H NMR(400MHz,DMSO-d6)δppm 8.80(s,1H)7.67-7.94(m,4H)7.43-7.63(m,3H)7.04-7.39(m,5H)6.45-6.69(m,2H)5.24(d,J=3.2Hz,2H)4.90-5.11(m,1H)5.55-5.73(m,1H)4.10(br s,2H)3.44-3.63(m,3H)3.20(br d,J=10.5Hz,2H)2.72-3.12(m,2H)1.57(t,J=6.7Hz,3H)
LC-MS数据
使用LC泵、二极管阵列(DAD)或UV检测器以及如在对应的方法中所指定的柱进行高效液相色谱法(HPLC)测量。如果必要的话,包括其他检测器(参见下文的方法表格)。
将来自柱的流带至配置有大气压离子源的质谱仪(MS)。设置调谐参数(例如扫描范围、停留时间等)以便获得允许鉴定化合物的标称单一同位素分子量(MW)的离子在技术人员的知识内。利用适当的软件进行数据采集。
通过其实验保留时间(Rt)和离子描述化合物。如果未在数据表中不同地指定,那么报道的分子离子对应于[M+H]+(质子化的分子)和/或[M-H]-(去质子的分子)。在该化合物不是直接可电离的情况下,指定加合物类型(即[M+NH4]+、[M+HCOO]-等)。对于具有多种同位素模式的分子(Br、Cl等)来说,报道的值是针对最低同位素质量获得的值。获得的所有结果具有通常与所使用的方法相关的实验不确定性。
在下文中,“SQD”意指单四极检测器,“RT”室温,“BEH”桥连的乙基硅氧烷/二氧化硅杂合体,“HSS”高强度二氧化硅,“DAD”二极管阵列检测器。
表:LCMS方法代码(以mL/min表示流量;以℃表示柱温度(T);以分钟表示运行时间)。
旋光度
使用具有在钠的D-线波长(589nm)处的光的旋光计,在20℃的温度下,在作为溶剂的DMF中,来测量旋光度。在20℃下,在436nm处在作为溶剂的DMF中,来测量化合物(1)、(3)和(10)的比旋光度。
化合物编号 | OR |
1 | +67.96°(436nm,c 0.309w/v%,DMF,20℃) |
2 | +50.69°(589nm,c 0.29w/v%,DMF,20℃) |
3 | +5.68°(436nm,c 0.25w/v%,DMF,20℃) |
4 | +5.56°(589nm,c 0.27w/v%,DMF,20℃) |
5 | +6.67°(589nm,c 0.27w/v%,DMF,20℃) |
6 | -21.29°(589nm,c 0.31w/v%,DMF,20℃) |
7 | -25.33°(589nm,c 0.3w/v%,DMF,20℃) |
8 | +93.13°(589nm,c 0.2212w/v%,DMF,20℃) |
9 | +163°(589nm,c 0.3w/v%,DMF,20℃) |
10 | +14.62°(436nm,c 0.26w/v%,DMF,20℃) |
11 | +17.86°(589nm,c 0.28w/v%,DMF,20℃) |
12 | +57.69°(589nm,c 0.26w/v%,DMF,20℃) |
16 | +7.93°(589nm,c 0.2522w/v%,DMF,20℃) |
17 | -28.37°(589nm,c 0.208w/v%,DMF,20℃) |
18 | -27.67°(589nm,c 0.3w/v%,DMF,20℃) |
20 | -24.69°(589nm,c 0.32w/v%,DMF,20℃) |
21 | -23.4°(589nm,c 0.282w/v%,DMF,20℃) |
22 | -24.03°(589nm,c 0.258w/v%,DMF,20℃) |
23 | -26.29°(589nm,c 0.232w/v%,DMF,20℃) |
24 | -27.85°(589nm,c 0.219w/v%,DMF,20℃) |
E.药理学实例
E.1抗病毒活性
将黑色384孔透明底微量滴定板(康宁公司(Corning),阿姆斯特丹,荷兰)经由声滴喷射(acoustic drop ejection)使用回声液体处理器(Labcyte公司,森尼维尔市,加利福尼亚)进行填装。将200nL的化合物储备溶液(100%DMSO)转移到测定板上。使化合物进行9次连续4倍稀释,每象限(quadrant)产生相同的化合物浓度。通过向每个孔里添加10μL的培养基(不含酚红的RPMI基质,10%FBS-热灭活,0.04%庆大霉素(50mg/mL))来起始测定。所有添加步骤通过使用多支路分液器(赛默科技公司(Thermo Scientific),埃伦博德海姆(Erembodegem),比利时)来完成。接下来,将在培养基中稀释的rgRSV224病毒(MOI=1)添加至这些板中。rgRSV224病毒是一种工程化病毒,其包含另外的GFP基因(Hallak LK,Spillmann D,Collins PL,Peeples ME.Glycosaminoglycan sulfation requirementsfor respiratory syncytial virus infection[呼吸道合胞病毒感染的糖胺聚糖硫酸化要求];Journal of virology[病毒学杂志](2000),74(22),10508-13)并且是从NIH(贝塞斯达,马里兰州,美国)得到授权。最后,将20μL的海拉(HeLa)细胞悬浮液(3,000个细胞/孔)进行铺板。每个测试中包括培养基、病毒感染的和假感染的对照。这些孔每体积含有0.05%DMSO。将细胞在5%CO2气氛中在37℃下进行孵育。病毒暴露三天后,通过内部开发的MSM激光显微镜(蒂博泰克公司(Tibotec),贝尔塞,比利时)测量细胞中的GFP表达而对病毒复制进行定量。EC50被定义为针对GFP表达的50%抑制浓度。平行地,将化合物在一组白色384孔微量滴定板(康宁公司)中孵育三天,并且通过根据制造商的说明书使用ATPlite试剂盒(铂金埃尔默公司(Perkin Elmer),扎芬特姆(Zaventem),比利时)测量海拉细胞的ATP含量而确定这些细胞中的化合物的细胞毒性。CC50被定义为针对细胞毒性的50%浓度。
表:抗病毒数据(几次重复试验的平均数据)
F.预示的成分实例
如在通篇的这些实例中使用的“活性成分”涉及具有式(I)的最终化合物、其药学上可接受的盐、其溶剂化物及其立体化学异构形式和互变异构体。
用于本发明的配制品的配方的典型实例如下:
F.1.片剂
在此实例中,可以将活性成分替换为相同量的根据本发明的任何化合物,尤其是相同量的任何示例性化合物。
F.2.悬浮液
制备水性悬浮液用于口服施用,这样使得每1毫升含有1mg至5mg的这些活性化合物之一、50mg的羧甲基纤维素钠、1mg的苯甲酸钠、500mg的山梨糖醇以及水(补足到1ml)。
F.3.注射剂
通过搅拌在按体积计在水中的10%丙二醇中的按重量计1.5%的本发明的活性成分来制备肠胃外组合物。
F.4.软膏剂
在此实例中,可以将活性成分替换为相同量的根据本发明的任何化合物,尤其是相同量的任何示例性化合物。
Claims (10)
1.一种具有式(I)的化合物
包括其任何立体化学异构形式,其中
X1、X2、X3和X4各自独立地选自C、CH、N、NR5、O或S,条件是X1、X2、X3和X4都不是C或CH;
Y1和Y2各自独立地选自CH、CF和N;
R1是CH3或CH2CH3;
R2是氢、卤代或C1-4烷基;
R3是卤代;
R4是C1-6烷基;C3-6环烷基;二(C1-4烷基)氨基;吡咯烷基;苯基;吡啶;或被1、2或3个取代基取代的苯基或吡啶,这些取代基各自单独地选自卤代、羟基、氰基、C1-4烷基、多卤代C1-4烷基、和C1-4烷氧基;
R5是氢或C1-4烷基;
R6是NH2或选自取代基(a)或(b)的取代基;其中
(a)是-NR7-(CO)-杂环,其中所述杂环被一个、两个或三个取代基取代,这些取代基各自独立地选自卤代、羟基、C1-4烷氧基的C1-4烷基;或
(b)是C3-6环烷基或杂环,其中所述C3-6环烷基和杂环被一个、两个或三个取代基取代,这些取代基各自独立地选自
C1-6烷基;
被一个、两个或三个取代基取代的C1-6烷基,这些取代基各自独立地选自卤代、羟基、羟基羰基、和氨基羰基;
羟基;
卤代;
-(CO)-OH;
-(CO)-NR10R11;
-(CO)-NR8-SO2-R9;
-NR8R9;
-NR8-(CO)-C1-4烷基;
-NR8-(CO)-C3-6环烷基;
-NR8-SO2-R9;
-SO2-NR10R11;或
-SO2-NR8-(CO)-R9;
其中
R7是氢或C1-4烷基;
每个R8独立地选自氢、C1-4烷基、或羟基C1-4烷基;
R9是C1-4烷基、多卤代C1-4烷基或C3-6环烷基;
R10和R11各自独立地选自氢;C1-4烷基;多卤代C1-4烷基;C3-6环烷基;被C1-4烷基取代的C3-6环烷基;或被羟基或氰基取代的C1-4烷基;
杂环是氮杂环丁烷基、吡咯烷基、哌啶基、或高哌啶基;
或其药学上可接受的酸加成盐。
3.如权利要求1所述的化合物,其中
基团A是(a-1);
Y1和Y2各自独立地选自CH;
R1是CH3;
R2是氢;
R3是卤代;
R4是C1-6烷基、C3-6环烷基或苯基;
R5是氢或C1-4烷基;
R6是NH2或选自取代基(a)或(b)的取代基;其中
(a)是-NR7-(CO)-杂环,其中所述杂环被羟基取代,且R7是氢;或
(b)是C3-6环烷基或杂环,其中所述C3-6环烷基和杂环被一个或两个取代基取代,这些取代基各自独立地选自羟基、-(CO)-OH或-(CO)-NR10R11,其中R10和R11各自是氢;
并且
杂环是吡咯烷基。
4.如权利要求2所述的化合物,其中
基团A是(a-1);
Y1和Y2各自独立地选自CH;
R1是CH3;
R2是氢;
R3是卤代;
R4是C1-6烷基、C3-6环烷基或苯基;
R5是氢或C1-4烷基;
R6是NH2或选自取代基(a)或(b)的取代基;其中
(a)是-NR7-(CO)-杂环,其中所述杂环被羟基取代;或
(b)是C3-6环烷基或杂环,其中所述C3-6环烷基和杂环被一个或两个取代基取代,这些取代基各自独立地选自羟基、-(CO)-OH或-(CO)-NR10R11,其中R10和R11各自是氢;
并且
杂环是吡咯烷基。
5.一种药物组合物,该药物组合物包含药学上可接受的载体和治疗有效量的如权利要求1至4中任一项所述的化合物。
6.如权利要求5所述的药物组合物,该药物组合物进一步包含另一种抗病毒剂。
7.如权利要求6所述的药物组合物,其中该另一种抗病毒剂是抑制RSV的化合物。
8.一种用于制备如权利要求5至7中任一项所述的药物组合物的方法,其中将治疗有效量的如权利要求1至4中任一项所述的化合物与药学上可接受的载体紧密混合。
9.如权利要求1至4中任一项所述的化合物,用作药物。
10.如权利要求1至4中任一项所述的化合物、或如权利要求5至7中任一项所述的药物组合物,用于在呼吸道合胞病毒感染的治疗中使用。
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