CN110627770A - 作为bet溴域抑制剂的四氢喹啉组成物 - Google Patents
作为bet溴域抑制剂的四氢喹啉组成物 Download PDFInfo
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- CN110627770A CN110627770A CN201910939773.9A CN201910939773A CN110627770A CN 110627770 A CN110627770 A CN 110627770A CN 201910939773 A CN201910939773 A CN 201910939773A CN 110627770 A CN110627770 A CN 110627770A
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- China
- Prior art keywords
- methyl
- tetrahydroquinoline
- pyrazol
- tetrahydroquinolin
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 102000001805 Bromodomains Human genes 0.000 title claims abstract description 82
- 108050009021 Bromodomains Proteins 0.000 title claims abstract description 80
- 239000003112 inhibitor Substances 0.000 title abstract description 29
- 239000000203 mixture Substances 0.000 title description 111
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 title description 23
- 150000001875 compounds Chemical class 0.000 claims description 206
- -1 (1- { 2-methyl-octahydrocyclopenta [ c ] pyrrol-5-yl } -1H-pyrazol-4-yl) -1,2,3, 4-tetrahydroquinoline-1-carboxylic acid methyl ester Chemical compound 0.000 claims description 137
- 150000003839 salts Chemical class 0.000 claims description 53
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 239000003937 drug carrier Substances 0.000 claims description 25
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 24
- 230000002401 inhibitory effect Effects 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- YJWBLUNCDGLWIF-AWEZNQCLSA-N 1-[(2S)-2-methyl-6-(5-methylsulfonylpyridin-2-yl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)C=1C=CC(=NC1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC YJWBLUNCDGLWIF-AWEZNQCLSA-N 0.000 claims description 6
- FYKRSWDVFVZSHA-UHFFFAOYSA-N 1-[2-methyl-6-(4-methylsulfonylphenyl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)C1=CC=C(C=C1)C=1C(=C2CCC(N(C2=CC1)C(C)=O)C)OC1=CC=CC=C1 FYKRSWDVFVZSHA-UHFFFAOYSA-N 0.000 claims description 6
- FHPPCNHAICXZHK-UHFFFAOYSA-N 1-(2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl)ethanone Chemical compound CC1N(C2=CC=CC(=C2CC1)OC1=CC=CC=C1)C(C)=O FHPPCNHAICXZHK-UHFFFAOYSA-N 0.000 claims description 5
- HLOPTEVMYKPJHD-LBPRGKRZSA-N 1-[(2S)-5-cyclobutyloxy-6-(1-cyclopropylpyrazol-4-yl)-7,8-difluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C(=C1C=1C=NN(C1)C1CC1)F)F)C(C)=O)C HLOPTEVMYKPJHD-LBPRGKRZSA-N 0.000 claims description 5
- ROVUUBNJOXIYGB-AWEZNQCLSA-N 1-[(2S)-5-cyclobutyloxy-7,8-difluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C(=C1C=1C=NN(C1)C1CCNCC1)F)F)C(C)=O)C ROVUUBNJOXIYGB-AWEZNQCLSA-N 0.000 claims description 5
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 5
- QBRZZPGDGJGWSO-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CCNCC1)F)C(=O)OC)C QBRZZPGDGJGWSO-HNNXBMFYSA-N 0.000 claims description 5
- WZXCEJABKMVOIB-HNNXBMFYSA-N 1-[(2S)-2-methyl-5-propoxy-6-pyrazolo[1,5-a]pyridin-2-yl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1=NN2C(C=CC=C2)=C1)C(C)=O WZXCEJABKMVOIB-HNNXBMFYSA-N 0.000 claims description 4
- GJSIDODCRAYPJG-ZDUSSCGKSA-N 1-[(2S)-5-cyclobutyloxy-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CC1)F)C(C)=O)C GJSIDODCRAYPJG-ZDUSSCGKSA-N 0.000 claims description 4
- KLXUJHWSHXGDHK-NSHDSACASA-N 1-[(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1N=NN(C1)C)F)C(C)=O)C KLXUJHWSHXGDHK-NSHDSACASA-N 0.000 claims description 4
- USMORCGYHHJWCN-HNNXBMFYSA-N 1-[(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CCNCC1)F)C(C)=O)C USMORCGYHHJWCN-HNNXBMFYSA-N 0.000 claims description 4
- XYBQHAOYYVXKGC-NSHDSACASA-N 1-[(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NNC1)F)C(C)=O)C XYBQHAOYYVXKGC-NSHDSACASA-N 0.000 claims description 4
- KORXZGOBIABHPB-HNNXBMFYSA-N 1-[(2S)-6-imidazo[1,2-a]pyridin-2-yl-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound N=1C(=CN2C1C=CC=C2)C=2C(=C1CC[C@@H](N(C1=CC2)C(C)=O)C)OCCC KORXZGOBIABHPB-HNNXBMFYSA-N 0.000 claims description 4
- YVYCCJQRTYINPK-AWEZNQCLSA-N 2-[[(2S)-1-acetyl-2-methyl-6-(5-methylsulfonylpyridin-2-yl)-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=NC=C(C=C1)S(=O)(=O)C)OCC(=O)N(C)C)C YVYCCJQRTYINPK-AWEZNQCLSA-N 0.000 claims description 4
- BIIDBUHYULVVIZ-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1,2-oxazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NOC1)C(=O)C1CC1)C BIIDBUHYULVVIZ-ZDUSSCGKSA-N 0.000 claims description 4
- YITSGRKDCGVZMF-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-methylimidazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=CN(C1)C)C(=O)C1CC1)C YITSGRKDCGVZMF-AWEZNQCLSA-N 0.000 claims description 4
- XUCHRPWHTOGIOB-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=NN(C1)C)C(=O)C1CC1)C XUCHRPWHTOGIOB-ZDUSSCGKSA-N 0.000 claims description 4
- VWQNDJADSJOLOJ-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1H-pyrazol-5-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=CC=NN1)C(=O)C1CC1)C VWQNDJADSJOLOJ-ZDUSSCGKSA-N 0.000 claims description 4
- SVQPQQLNAXYEIO-LBPRGKRZSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1SC(=NN1)C)C(=O)C1CC1)C SVQPQQLNAXYEIO-LBPRGKRZSA-N 0.000 claims description 4
- MDBGQOVYYAVSMJ-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CC1)F)C(=O)C1CC1)C MDBGQOVYYAVSMJ-AWEZNQCLSA-N 0.000 claims description 4
- QKTUWYNLUPWFSH-LBPRGKRZSA-N [(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1N=NN(C1)C)F)C(=O)C1CC1)C QKTUWYNLUPWFSH-LBPRGKRZSA-N 0.000 claims description 4
- LEQDGABIQOLUTE-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CCNCC1)F)C(=O)C1CC1)C LEQDGABIQOLUTE-INIZCTEOSA-N 0.000 claims description 4
- XJLNSJPUSIWMKZ-LBPRGKRZSA-N [(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NNC1)F)C(=O)C1CC1)C XJLNSJPUSIWMKZ-LBPRGKRZSA-N 0.000 claims description 4
- LLLUZKVTAMUNSJ-ZDUSSCGKSA-N methyl (2S)-5-cyclobutyloxy-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CC1)F)C(=O)OC)C LLLUZKVTAMUNSJ-ZDUSSCGKSA-N 0.000 claims description 4
- XLOUWFKVTYUTRQ-NSHDSACASA-N methyl (2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1N=NN(C1)C)F)C(=O)OC)C XLOUWFKVTYUTRQ-NSHDSACASA-N 0.000 claims description 4
- WXMPJWLOUXYXDP-NSHDSACASA-N methyl (2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NNC1)F)C(=O)OC)C WXMPJWLOUXYXDP-NSHDSACASA-N 0.000 claims description 4
- ZPVVDHQMDNLPMV-KRWDZBQOSA-N tert-butyl 4-[(2S)-1-acetyl-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1CCN(CC1)C(=O)OC(C)(C)C)OCCC)C ZPVVDHQMDNLPMV-KRWDZBQOSA-N 0.000 claims description 4
- HNHSNVXCOUGUTN-NSHDSACASA-N [(2S)-6-(5-amino-1,3,4-thiadiazol-2-yl)-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=NN=C(S1)N)C(=O)C1CC1)C HNHSNVXCOUGUTN-NSHDSACASA-N 0.000 claims description 3
- AHFVLWDAXQXZOP-INIZCTEOSA-N cyclopropyl-[(2S)-2-methyl-6-(1-methylimidazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=CN(C1)C)OC1=CC=CC=C1)C AHFVLWDAXQXZOP-INIZCTEOSA-N 0.000 claims description 3
- AVALAFKCUACXBX-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC=CC=C1)C AVALAFKCUACXBX-HNNXBMFYSA-N 0.000 claims description 3
- WYWYLOKEHCZWRJ-SFHVURJKSA-N cyclopropyl-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NN(C1)C1CCNCC1)OC1=CC=CC=C1)C WYWYLOKEHCZWRJ-SFHVURJKSA-N 0.000 claims description 3
- OLJKLNDGYFXLCY-KRWDZBQOSA-N methyl (2S)-8-fluoro-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(=O)OC)C)OC1=CC=CC=C1)C=1C=NN(C1)C1CCNCC1 OLJKLNDGYFXLCY-KRWDZBQOSA-N 0.000 claims description 3
- UPCYLWBKVSCKIX-AWEZNQCLSA-N (2S)-1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-6-carbonitrile Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C#N)OC1=CC=CC=C1)C UPCYLWBKVSCKIX-AWEZNQCLSA-N 0.000 claims description 2
- FBBKDIBVHQAGDS-NSHDSACASA-N 1-[(2S)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=CC(=C2CC1)OCCC)C(C)=O FBBKDIBVHQAGDS-NSHDSACASA-N 0.000 claims description 2
- HFEJIPGFSAJUMK-INIZCTEOSA-N 1-[(2S)-2-methyl-6-(1-methylsulfonyl-2,3-dihydroindol-5-yl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)N1CCC2=CC(=CC=C12)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC HFEJIPGFSAJUMK-INIZCTEOSA-N 0.000 claims description 2
- PMDLIKFTDZRJNX-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-(1-methylsulfonylpiperidin-4-yl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1CCN(CC1)S(=O)(=O)C)C(C)=O PMDLIKFTDZRJNX-HNNXBMFYSA-N 0.000 claims description 2
- MZIVMRRAEYOKJC-AWEZNQCLSA-N 1-[(2S)-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)C=1N=NN(C1)C)C(C)=O MZIVMRRAEYOKJC-AWEZNQCLSA-N 0.000 claims description 2
- KUSFFMFFJOZKME-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-(3-methylsulfonylphenyl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)C=1C=C(C=CC1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC KUSFFMFFJOZKME-HNNXBMFYSA-N 0.000 claims description 2
- QFRWALIQWBOCIR-SFHVURJKSA-N 1-[(2S)-2-methyl-6-[3-(morpholine-4-carbonyl)phenyl]-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1=CC(=CC=C1)C(=O)N1CCOCC1)C(C)=O QFRWALIQWBOCIR-SFHVURJKSA-N 0.000 claims description 2
- COEZUQIGNOQHJV-SFHVURJKSA-N 1-[(2S)-2-methyl-6-[4-(morpholine-4-carbonyl)phenyl]-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1=CC=C(C=C1)C(=O)N1CCOCC1)C(C)=O COEZUQIGNOQHJV-SFHVURJKSA-N 0.000 claims description 2
- TVBDWGYLBWHCJB-AWEZNQCLSA-N 1-[(2S)-2-methyl-6-piperidin-4-yl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1CCNCC1)C(C)=O TVBDWGYLBWHCJB-AWEZNQCLSA-N 0.000 claims description 2
- QKDFYRKODQLZIE-HNNXBMFYSA-N 1-[(2S)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-6-(1-methylsulfonyl-2,3-dihydroindol-5-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=C2CCN(C2=CC1)S(=O)(=O)C)C(C)=O)C QKDFYRKODQLZIE-HNNXBMFYSA-N 0.000 claims description 2
- DSPRCEMNSXRYLE-AWEZNQCLSA-N 1-[(2S)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-6-(4-methylsulfonylphenyl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=CC=C(C=C1)S(=O)(=O)C)C(C)=O)C DSPRCEMNSXRYLE-AWEZNQCLSA-N 0.000 claims description 2
- VLMBHXZMUPRNLP-ZDUSSCGKSA-N 1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1)C(C)=O)C VLMBHXZMUPRNLP-ZDUSSCGKSA-N 0.000 claims description 2
- IQPJOPZMWVPXGD-LXKVQUBZSA-N 1-[(2S)-5-[(E)-2-chloroethenoxy]-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound Cl/C=C/OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C IQPJOPZMWVPXGD-LXKVQUBZSA-N 0.000 claims description 2
- NUNROUNVEBUEKZ-SFHVURJKSA-N 1-[(2S)-5-anilino-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)NC1=CC=CC=C1)C=1C=NN(C1)C1CCNCC1)C(C)=O NUNROUNVEBUEKZ-SFHVURJKSA-N 0.000 claims description 2
- WYRLFWQPXSEHLL-AWEZNQCLSA-N 1-[(2S)-6-(1,3-benzothiazol-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound S1C(=NC2=C1C=CC=C2)C=2C(=C1CC[C@@H](N(C1=CC2)C(C)=O)C)OCCC WYRLFWQPXSEHLL-AWEZNQCLSA-N 0.000 claims description 2
- IIUMBFRJKJGOBU-AWEZNQCLSA-N 1-[(2S)-6-(1,3-benzoxazol-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound O1C(=NC2=C1C=CC=C2)C=2C(=C1CC[C@@H](N(C1=CC2)C(C)=O)C)OCCC IIUMBFRJKJGOBU-AWEZNQCLSA-N 0.000 claims description 2
- FCQVCLDTDNDINU-HNNXBMFYSA-N 1-[(2S)-6-(1-benzofuran-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound O1C(=CC2=C1C=CC=C2)C=2C(=C1CC[C@@H](N(C1=CC2)C(C)=O)C)OCCC FCQVCLDTDNDINU-HNNXBMFYSA-N 0.000 claims description 2
- BWSLNVFQPLKPPB-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=C(C1)F)C(C)=O)C)OC1=CC=CC=C1 BWSLNVFQPLKPPB-HNNXBMFYSA-N 0.000 claims description 2
- IHMGKKFPFYXZDD-INIZCTEOSA-N 1-[(2S)-6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C(C)N1CCC(CC1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC IHMGKKFPFYXZDD-INIZCTEOSA-N 0.000 claims description 2
- CNBICKCYAMPLMG-AWEZNQCLSA-N 1-[(2S)-6-(1H-benzimidazol-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound N1C(=NC2=C1C=CC=C2)C=2C(=C1CC[C@@H](N(C1=CC2)C(C)=O)C)OCCC CNBICKCYAMPLMG-AWEZNQCLSA-N 0.000 claims description 2
- VQTCVIROKDTIQB-HNNXBMFYSA-N 1-[(2S)-6-(1H-indol-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound N1C(=CC2=CC=CC=C12)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC VQTCVIROKDTIQB-HNNXBMFYSA-N 0.000 claims description 2
- QMFHTBFSXPWNHN-INIZCTEOSA-N 1-[(2S)-6-(4-ethylsulfonylphenyl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C(C)S(=O)(=O)C1=CC=C(C=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC QMFHTBFSXPWNHN-INIZCTEOSA-N 0.000 claims description 2
- XXUZWVAQEYVSQG-SFHVURJKSA-N 1-[(2S)-6-[4-[2-(dimethylamino)ethoxy]phenyl]-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CN(CCOC1=CC=C(C=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC)C XXUZWVAQEYVSQG-SFHVURJKSA-N 0.000 claims description 2
- KHUSFTUVXQSMBE-ZDUSSCGKSA-N 1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(C)=O)C)OC1=CC=CC=C1)C=1C=NNC1 KHUSFTUVXQSMBE-ZDUSSCGKSA-N 0.000 claims description 2
- OPQIGPTVHCKZIU-ZDUSSCGKSA-N 1-[(2S)-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(C)=O)C)OC1=CC=CC=C1)C=1N=NN(C1)C OPQIGPTVHCKZIU-ZDUSSCGKSA-N 0.000 claims description 2
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- GIWFCZVBUXYRLG-HNNXBMFYSA-N 2-[[(2S)-1-acetyl-2-methyl-6-(3-methylsulfonylphenyl)-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC(=CC=C1)S(=O)(=O)C)OCC(=O)N(C)C)C GIWFCZVBUXYRLG-HNNXBMFYSA-N 0.000 claims description 2
- FHBNBLUFURXLBV-HNNXBMFYSA-N 2-[[(2S)-1-acetyl-2-methyl-6-(4-methylsulfonylphenyl)-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=C(C=C1)S(=O)(=O)C)OCC(=O)N(C)C)C FHBNBLUFURXLBV-HNNXBMFYSA-N 0.000 claims description 2
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- KUBVSYZZPPFKAD-INIZCTEOSA-N 2-[[(2S)-1-acetyl-2-methyl-6-[4-[methyl(methylsulfonyl)amino]phenyl]-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=C(C=C1)N(S(=O)(=O)C)C)OCC(=O)N(C)C)C KUBVSYZZPPFKAD-INIZCTEOSA-N 0.000 claims description 2
- SNNCDXXWPFRRHH-INIZCTEOSA-N 2-[[(2S)-1-acetyl-6-(4-ethylsulfonylphenyl)-2-methyl-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=C(C=C1)S(=O)(=O)CC)OCC(=O)N(C)C)C SNNCDXXWPFRRHH-INIZCTEOSA-N 0.000 claims description 2
- ZSXMYTPJGWKWLR-HNNXBMFYSA-N 2-[[(2S)-1-acetyl-6-[3-(methanesulfonamido)phenyl]-2-methyl-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC(=CC=C1)NS(=O)(=O)C)OCC(=O)N(C)C)C ZSXMYTPJGWKWLR-HNNXBMFYSA-N 0.000 claims description 2
- ZQKNMLNZUGUIRQ-HNNXBMFYSA-N 2-[[(2S)-1-acetyl-6-[4-(methanesulfonamido)phenyl]-2-methyl-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=C(C=C1)NS(=O)(=O)C)OCC(=O)N(C)C)C ZQKNMLNZUGUIRQ-HNNXBMFYSA-N 0.000 claims description 2
- OCCXNFQMLTVMSJ-SFHVURJKSA-N 2-[[(2S)-1-acetyl-6-[4-[2-(dimethylamino)ethoxy]phenyl]-2-methyl-3,4-dihydro-2H-quinolin-5-yl]oxy]-N,N-dimethylacetamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=C(C=C1)OCCN(C)C)OCC(=O)N(C)C)C OCCXNFQMLTVMSJ-SFHVURJKSA-N 0.000 claims description 2
- BWJUBYZOWZBKQZ-INIZCTEOSA-N 4-[(2S)-1-acetyl-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-6-yl]-N-ethylpiperidine-1-carboxamide Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1CCN(CC1)C(=O)NCC)OCCC)C BWJUBYZOWZBKQZ-INIZCTEOSA-N 0.000 claims description 2
- AVBOMLHAAZPIFO-HNNXBMFYSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-methylsulfonyl-2,3-dihydroimidazo[1,2-b]pyrazol-7-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN2C1N(CC2)S(=O)(=O)C)C(=O)C2CC2)C AVBOMLHAAZPIFO-HNNXBMFYSA-N 0.000 claims description 2
- PFFSTKHUWPNLIG-KRWDZBQOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-piperidin-4-ylpyrazol-3-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=NN(C=C1)C1CCNCC1)C(=O)C1CC1)C PFFSTKHUWPNLIG-KRWDZBQOSA-N 0.000 claims description 2
- GDCFAPBNSIQTAA-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-piperidin-4-yltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=NN(C1)C1CCNCC1)C(=O)C1CC1)C GDCFAPBNSIQTAA-INIZCTEOSA-N 0.000 claims description 2
- QYYOXQRTBWZVJA-KRWDZBQOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(2-piperidin-4-ylpyrazol-3-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=CC=NN1C1CCNCC1)C(=O)C1CC1)C QYYOXQRTBWZVJA-KRWDZBQOSA-N 0.000 claims description 2
- YPVWYUYDYGSQRR-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(2-piperidin-4-yltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=NN(N=C1)C1CCNCC1)C(=O)C1CC1)C YPVWYUYDYGSQRR-INIZCTEOSA-N 0.000 claims description 2
- KLSGBMSNZZCPRP-LBPRGKRZSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(2H-triazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=NNC1)C(=O)C1CC1)C KLSGBMSNZZCPRP-LBPRGKRZSA-N 0.000 claims description 2
- BISLDUGWGNTUSM-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(5-piperidin-4-yl-1H-imidazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1NC(=CN1)C1CCNCC1)C(=O)C1CC1)C BISLDUGWGNTUSM-INIZCTEOSA-N 0.000 claims description 2
- VOTDBTSNDCQSQA-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(triazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1N1N=CC=N1)C(=O)C1CC1)C VOTDBTSNDCQSQA-ZDUSSCGKSA-N 0.000 claims description 2
- JHOWLTMTDSTDPM-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-pyrazol-1-yl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1N1N=CC=C1)C(=O)C1CC1)C JHOWLTMTDSTDPM-AWEZNQCLSA-N 0.000 claims description 2
- ISLBCWHIRDCQIS-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-6-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN2C1NCC2)C(=O)C2CC2)C ISLBCWHIRDCQIS-AWEZNQCLSA-N 0.000 claims description 2
- ZGQPEJSJOXVJHP-ZDUSSCGKSA-N [(2S)-6-(5-amino-1,3,4-thiadiazol-2-yl)-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=NN=C(S1)N)OC1=CC=CC=C1)C ZGQPEJSJOXVJHP-ZDUSSCGKSA-N 0.000 claims description 2
- STBYXWBVTUGCDB-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-3-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=NN(C=C1)C1CCNCC1)OC1=CC=CC=C1)C STBYXWBVTUGCDB-IBGZPJMESA-N 0.000 claims description 2
- SAZMZAKOKFOIOJ-SFHVURJKSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(1-piperidin-4-yltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C1CCNCC1)OC1=CC=CC=C1)C SAZMZAKOKFOIOJ-SFHVURJKSA-N 0.000 claims description 2
- RFOCINPYVFGAPE-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(1H-pyrazol-5-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=NN1)OC1=CC=CC=C1)C RFOCINPYVFGAPE-HNNXBMFYSA-N 0.000 claims description 2
- YBITYTLUKLYJDE-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(2-piperidin-4-ylpyrazol-3-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=NN1C1CCNCC1)OC1=CC=CC=C1)C YBITYTLUKLYJDE-IBGZPJMESA-N 0.000 claims description 2
- LIGDASUINQIVIE-SFHVURJKSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(2-piperidin-4-yltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=NN(N=C1)C1CCNCC1)OC1=CC=CC=C1)C LIGDASUINQIVIE-SFHVURJKSA-N 0.000 claims description 2
- XQZOBJQIAOZYCD-AWEZNQCLSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(2H-triazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NNC1)OC1=CC=CC=C1)C XQZOBJQIAOZYCD-AWEZNQCLSA-N 0.000 claims description 2
- ZFGPVOPEPHKOLL-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(4-piperazin-1-ylpyrazol-1-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC(=C1)N1CCNCC1)OC1=CC=CC=C1)C ZFGPVOPEPHKOLL-IBGZPJMESA-N 0.000 claims description 2
- FLNSAANKOCGWEX-SFHVURJKSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(5-piperidin-4-yl-1H-imidazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1NC(=CN1)C1CCNCC1)OC1=CC=CC=C1)C FLNSAANKOCGWEX-SFHVURJKSA-N 0.000 claims description 2
- UJSNYIXIDZMVMO-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(triazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC=N1)OC1=CC=CC=C1)C UJSNYIXIDZMVMO-HNNXBMFYSA-N 0.000 claims description 2
- VYLDWPJEORIWPH-INIZCTEOSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-prop-1-ynyl-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C#CC)OC1=CC=CC=C1)C VYLDWPJEORIWPH-INIZCTEOSA-N 0.000 claims description 2
- GBZZKMFTUFISMS-INIZCTEOSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-pyrazol-1-yl-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC=C1)OC1=CC=CC=C1)C GBZZKMFTUFISMS-INIZCTEOSA-N 0.000 claims description 2
- DKILLVRXOWPPJS-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-6-(1,2-oxazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NOC1)OC1=CC=CC=C1)C DKILLVRXOWPPJS-HNNXBMFYSA-N 0.000 claims description 2
- LZRAONNKSBDXGD-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-6-(4-morpholin-4-ylpyrazol-1-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC(=C1)N1CCOCC1)OC1=CC=CC=C1)C LZRAONNKSBDXGD-IBGZPJMESA-N 0.000 claims description 2
- GUNJVTAVGFLBLO-AWEZNQCLSA-N cyclopropyl-[(2S)-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1SC(=NN1)C)OC1=CC=CC=C1)C GUNJVTAVGFLBLO-AWEZNQCLSA-N 0.000 claims description 2
- YDSNWUIMAAKNGD-ZDUSSCGKSA-N cyclopropyl-[(2S)-5-(2,5-difluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=C(C=CC(=C1)F)F)C YDSNWUIMAAKNGD-ZDUSSCGKSA-N 0.000 claims description 2
- QYDUCSHUSJAWAI-AWEZNQCLSA-N cyclopropyl-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=C(C=CC=C1)F)C QYDUCSHUSJAWAI-AWEZNQCLSA-N 0.000 claims description 2
- UAPRHDLSCMAUPJ-ZDUSSCGKSA-N cyclopropyl-[(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC(=C(C=C1)F)F)C UAPRHDLSCMAUPJ-ZDUSSCGKSA-N 0.000 claims description 2
- UIASWGHAJXNAIU-AWEZNQCLSA-N cyclopropyl-[(2S)-5-(3-fluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC(=CC=C1)F)C UIASWGHAJXNAIU-AWEZNQCLSA-N 0.000 claims description 2
- KCWUSQKVZBOMSC-HNNXBMFYSA-N cyclopropyl-[(2S)-5-(3-methoxyphenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC(=CC=C1)OC)C KCWUSQKVZBOMSC-HNNXBMFYSA-N 0.000 claims description 2
- PEYGWWFDSQICEG-AWEZNQCLSA-N cyclopropyl-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC=C(C=C1)F)C PEYGWWFDSQICEG-AWEZNQCLSA-N 0.000 claims description 2
- ODPGKYVCCDPOOD-INIZCTEOSA-N cyclopropyl-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NN(C1)C1CC1)OC1=CC=CC=C1)C ODPGKYVCCDPOOD-INIZCTEOSA-N 0.000 claims description 2
- MQODKXWHJDFRDL-HNNXBMFYSA-N cyclopropyl-[(2S)-6-cyclopropyl-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1CC1)OC1=CC=CC=C1)C MQODKXWHJDFRDL-HNNXBMFYSA-N 0.000 claims description 2
- QEAFUMSIOGSHSS-HNNXBMFYSA-N cyclopropyl-[(2S)-6-ethynyl-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C#C)OC1=CC=CC=C1)C QEAFUMSIOGSHSS-HNNXBMFYSA-N 0.000 claims description 2
- NDSWOYYTVOZYEH-AWEZNQCLSA-N cyclopropyl-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NNC1)OC1=CC=CC=C1)C NDSWOYYTVOZYEH-AWEZNQCLSA-N 0.000 claims description 2
- CPWOBDURELDNNC-AWEZNQCLSA-N cyclopropyl-[(2S)-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1N=NN(C1)C)OC1=CC=CC=C1)C CPWOBDURELDNNC-AWEZNQCLSA-N 0.000 claims description 2
- VHVMGVCBNABLSJ-SFHVURJKSA-N cyclopropyl-[(2S)-8-fluoro-5-(3-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NN(C1)C1CCNCC1)OC1=CC(=CC=C1)OC)C VHVMGVCBNABLSJ-SFHVURJKSA-N 0.000 claims description 2
- ZFSANWVXGOXOEE-SFHVURJKSA-N methyl (2S)-2-methyl-5-phenoxy-6-(4-piperazin-1-ylpyrazol-1-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)N1N=CC(=C1)N1CCNCC1)C(=O)OC ZFSANWVXGOXOEE-SFHVURJKSA-N 0.000 claims description 2
- OUSVOXRCQUSQRN-AWEZNQCLSA-N methyl (2S)-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)C=1N=NN(C1)C)C(=O)OC OUSVOXRCQUSQRN-AWEZNQCLSA-N 0.000 claims description 2
- XVOINJTYRNIAPF-SFHVURJKSA-N methyl (2S)-2-methyl-6-(4-morpholin-4-ylpyrazol-1-yl)-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)N1N=CC(=C1)N1CCOCC1)C(=O)OC XVOINJTYRNIAPF-SFHVURJKSA-N 0.000 claims description 2
- CMXRILIORBROOC-SFHVURJKSA-N methyl (2S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=CC(=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCN(CC2)C)C(=O)OC)C)C=C1)C#N CMXRILIORBROOC-SFHVURJKSA-N 0.000 claims description 2
- UXUUIAWEWZVOJO-INIZCTEOSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CN(C2)C)C(=O)OC)C)C=C1 UXUUIAWEWZVOJO-INIZCTEOSA-N 0.000 claims description 2
- JKFQZZBMVYZXQS-SFHVURJKSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCN(CC2)C)C(=O)OC)C)C=C1 JKFQZZBMVYZXQS-SFHVURJKSA-N 0.000 claims description 2
- HRVXKZCYAZCCIB-DIMJTDRSSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylpyrrolidin-3-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CN(CC2)C)C(=O)OC)C)C=C1 HRVXKZCYAZCCIB-DIMJTDRSSA-N 0.000 claims description 2
- NOBCDXXBHQGQPM-UCFFOFKASA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(2-oxopiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC(NCC2)=O)C(=O)OC)C)C=C1 NOBCDXXBHQGQPM-UCFFOFKASA-N 0.000 claims description 2
- SVTUQICDHSQQRH-XCUTYXLRSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-[(2S)-2-methylazetidin-3-yl]pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2[C@@H](NC2)C)C(=O)OC)C)C=C1 SVTUQICDHSQQRH-XCUTYXLRSA-N 0.000 claims description 2
- UOBQCJGAKCYHID-XFXRKFMASA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-(3-methoxy-1-methylpiperidin-4-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2C(CN(CC2)C)OC)C(=O)OC)C)C=C1 UOBQCJGAKCYHID-XFXRKFMASA-N 0.000 claims description 2
- HUBOGKWCWRLYSY-HHDZUXODSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-(3-methoxypiperidin-4-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2C(CNCC2)OC)C(=O)OC)C)C=C1 HUBOGKWCWRLYSY-HHDZUXODSA-N 0.000 claims description 2
- DGMVPOAXOWHHSV-INIZCTEOSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(1-methyl-2-piperazin-1-ylimidazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(N(C1)C)N1CCNCC1)C(=O)OC)C DGMVPOAXOWHHSV-INIZCTEOSA-N 0.000 claims description 2
- LHJAQGIVKJQOHV-INIZCTEOSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(1-methyl-2-piperidin-4-ylimidazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(N(C1)C)C1CCNCC1)C(=O)OC)C LHJAQGIVKJQOHV-INIZCTEOSA-N 0.000 claims description 2
- QWQCGYMXXFHKGO-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(2-piperazin-1-yl-1,3-thiazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)N1CCNCC1)C(=O)OC)C QWQCGYMXXFHKGO-HNNXBMFYSA-N 0.000 claims description 2
- ZDGAPQWSCPZGLE-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(2-piperidin-4-yl-1H-imidazol-5-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(NC1)C1CCNCC1)C(=O)OC)C ZDGAPQWSCPZGLE-HNNXBMFYSA-N 0.000 claims description 2
- JRABXTMGSKWHOL-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CN(C1)C)C(=O)OC)C JRABXTMGSKWHOL-HNNXBMFYSA-N 0.000 claims description 2
- IXZDHAJIGPSGHY-KRWDZBQOSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCN(CC1)C)C(=O)OC)C IXZDHAJIGPSGHY-KRWDZBQOSA-N 0.000 claims description 2
- JWAFUHKUTMCGTJ-ATNAJCNCSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(1-methylpyrrolidin-3-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CN(CC1)C)C(=O)OC)C JWAFUHKUTMCGTJ-ATNAJCNCSA-N 0.000 claims description 2
- WHCYONWUXBGTDX-GGQJKKPXSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC2C(CN(C2)C)C1)C(=O)OC)C WHCYONWUXBGTDX-GGQJKKPXSA-N 0.000 claims description 2
- MYUSUBPPYGBQQI-MYJWUSKBSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(2-oxopiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC(NCC1)=O)C(=O)OC)C MYUSUBPPYGBQQI-MYJWUSKBSA-N 0.000 claims description 2
- UMRNEJKPOLVZOP-CJUKTHODSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-[(2S)-2-methylazetidin-3-yl]pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1[C@@H](NC1)C)C(=O)OC)C UMRNEJKPOLVZOP-CJUKTHODSA-N 0.000 claims description 2
- WHYNWXATOAHSRR-LBPRGKRZSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[2-(methylcarbamoyl)-1,3-thiazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C(NC)=O)C(=O)OC)C WHYNWXATOAHSRR-LBPRGKRZSA-N 0.000 claims description 2
- YWQWJWHPOUQRAQ-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-6-(5-fluoro-1-piperidin-4-ylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1F)C1CCNCC1)C(=O)OC)C YWQWJWHPOUQRAQ-HNNXBMFYSA-N 0.000 claims description 2
- HRNDKKDCJPPIAV-OOHWJJMZSA-N methyl (2S)-5-cyclobutyloxy-6-[1-(3-hydroxycyclobutyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC(C1)O)C(=O)OC)C HRNDKKDCJPPIAV-OOHWJJMZSA-N 0.000 claims description 2
- CKHGTCKQFMDPRV-XWFFHEKESA-N methyl (2S)-5-cyclobutyloxy-6-[1-(3-methoxy-1-methylpiperidin-4-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1C(CN(CC1)C)OC)C(=O)OC)C CKHGTCKQFMDPRV-XWFFHEKESA-N 0.000 claims description 2
- FECFXOORCLGJMD-BPURVQTLSA-N methyl (2S)-5-cyclobutyloxy-6-[1-(3-methoxypiperidin-4-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1C(CNCC1)OC)C(=O)OC)C FECFXOORCLGJMD-BPURVQTLSA-N 0.000 claims description 2
- DBMGIUFETYDSPO-ZDUSSCGKSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(3-fluoroazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CNC1)F)C(=O)OC)C DBMGIUFETYDSPO-ZDUSSCGKSA-N 0.000 claims description 2
- DPCOFTYQCFKCJC-ZDUSSCGKSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(3-hydroxyazetidin-1-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)N1CC(C1)O)C(=O)OC)C DPCOFTYQCFKCJC-ZDUSSCGKSA-N 0.000 claims description 2
- GJXLRMCHGJLIOF-ZDUSSCGKSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(3-hydroxyazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CNC1)O)C(=O)OC)C GJXLRMCHGJLIOF-ZDUSSCGKSA-N 0.000 claims description 2
- FXYYNBFXKFVCJE-AWEZNQCLSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(3-methoxyazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CNC1)OC)C(=O)OC)C FXYYNBFXKFVCJE-AWEZNQCLSA-N 0.000 claims description 2
- SWHIXTNQWFMWBE-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(4-fluoropiperidin-4-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CCNCC1)F)C(=O)OC)C SWHIXTNQWFMWBE-HNNXBMFYSA-N 0.000 claims description 2
- APXPYZBGCWNWTK-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(4-hydroxypiperidin-4-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CCNCC1)O)C(=O)OC)C APXPYZBGCWNWTK-HNNXBMFYSA-N 0.000 claims description 2
- XZLJCXSMPIMBHH-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=C(C1)F)C(=O)OC)C)OC1=CC=CC=C1 XZLJCXSMPIMBHH-HNNXBMFYSA-N 0.000 claims description 2
- XCFWGMQFWWSDSQ-LBPRGKRZSA-N methyl (2S)-6-(2-acetamido-1,3-thiazol-4-yl)-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)NC(C)=O)C(=O)OC)C XCFWGMQFWWSDSQ-LBPRGKRZSA-N 0.000 claims description 2
- HCALQDMVHUZFPT-NSHDSACASA-N methyl (2S)-6-(2-carbamoyl-1,3-thiazol-4-yl)-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C=1SC=C(N1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1CCC1 HCALQDMVHUZFPT-NSHDSACASA-N 0.000 claims description 2
- FPJHFFHZHQKJOK-ZDUSSCGKSA-N methyl (2S)-6-[2-(azetidin-3-yl)-1,3-thiazol-4-yl]-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)C=1SC=C(N1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1CCC1 FPJHFFHZHQKJOK-ZDUSSCGKSA-N 0.000 claims description 2
- PPKNUWOYANVMPR-ZDUSSCGKSA-N methyl (2S)-6-cyano-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=CC=C1 PPKNUWOYANVMPR-ZDUSSCGKSA-N 0.000 claims description 2
- JVWTTXSDOCKREN-AWEZNQCLSA-N methyl (2S)-6-cyclopropyl-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=CC=C1 JVWTTXSDOCKREN-AWEZNQCLSA-N 0.000 claims description 2
- CMMCNCHORZHNMV-AWEZNQCLSA-N methyl (2S)-6-ethynyl-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#C)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=CC=C1 CMMCNCHORZHNMV-AWEZNQCLSA-N 0.000 claims description 2
- BZQPKAMWHPKYRS-ZDUSSCGKSA-N methyl (2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(=O)OC)C)OC1=CC=CC=C1)C=1C=NNC1 BZQPKAMWHPKYRS-ZDUSSCGKSA-N 0.000 claims description 2
- NDUMJKSEQMSGCF-ZDUSSCGKSA-N methyl (2S)-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(=O)OC)C)OC1=CC=CC=C1)C=1N=NN(C1)C NDUMJKSEQMSGCF-ZDUSSCGKSA-N 0.000 claims description 2
- JZTPZZPAIKCNDK-HNNXBMFYSA-N methyl 4-[(2S)-1-acetyl-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-6-yl]piperidine-1-carboxylate Chemical compound C(C)(=O)N1[C@H](CCC2=C(C(=CC=C12)C1CCN(CC1)C(=O)OC)OCCC)C JZTPZZPAIKCNDK-HNNXBMFYSA-N 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 21
- 201000011510 cancer Diseases 0.000 abstract description 14
- 208000008589 Obesity Diseases 0.000 abstract description 8
- 235000020824 obesity Nutrition 0.000 abstract description 8
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 abstract description 6
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 188
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- DMQLCGUTBZIOEE-KRWDZBQOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-pyridin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC=C1)C=1C=NN(C1)C1CCNCC1)C(=O)OC DMQLCGUTBZIOEE-KRWDZBQOSA-N 0.000 description 3
- SNJKTIMGCXGSPW-IBGZPJMESA-N methyl (2S)-2-methyl-6-[1-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]pyrazol-4-yl]-5-propoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC SNJKTIMGCXGSPW-IBGZPJMESA-N 0.000 description 3
- NJPDUMHRMYGUSX-ZDUSSCGKSA-N methyl (2S)-5-(1-amino-2-methyl-1-oxopropan-2-yl)oxy-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C(C)(OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C)C NJPDUMHRMYGUSX-ZDUSSCGKSA-N 0.000 description 3
- BLUDKZNKVWCUKX-NSHDSACASA-N methyl (2S)-5-(2-amino-1,1-difluoro-2-oxoethoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C(OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C)(F)F BLUDKZNKVWCUKX-NSHDSACASA-N 0.000 description 3
- AQNOXIQFFQEXJG-AWEZNQCLSA-N methyl (2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C AQNOXIQFFQEXJG-AWEZNQCLSA-N 0.000 description 3
- FZXUDDAQTSTLND-VOJFVSQTSA-N methyl (2S)-5-[(1R)-2-amino-1-fluoro-2-oxoethoxy]-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)[C@H](OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C)F FZXUDDAQTSTLND-VOJFVSQTSA-N 0.000 description 3
- FZXUDDAQTSTLND-BBATYDOGSA-N methyl (2S)-5-[(1S)-2-amino-1-fluoro-2-oxoethoxy]-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)[C@@H](OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C)F FZXUDDAQTSTLND-BBATYDOGSA-N 0.000 description 3
- QYODKKNUZPIIBA-HNNXBMFYSA-N methyl (2S)-5-[2-(azetidin-1-yl)-2-oxoethoxy]-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1(CCC1)C(COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C)=O QYODKKNUZPIIBA-HNNXBMFYSA-N 0.000 description 3
- KLOZTGGTPYMVOH-AWEZNQCLSA-N methyl (2S)-5-[2-(dimethylamino)-2-oxoethoxy]-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CN(C(=O)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C)C KLOZTGGTPYMVOH-AWEZNQCLSA-N 0.000 description 3
- HWLXFEXZHRLMIH-HNNXBMFYSA-N methyl (2S)-5-[2-[cyclopropyl(methyl)amino]-2-oxoethoxy]-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N(C(=O)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C)C HWLXFEXZHRLMIH-HNNXBMFYSA-N 0.000 description 3
- GQXXLAFSZYIHNN-LBPRGKRZSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(F)(F)F GQXXLAFSZYIHNN-LBPRGKRZSA-N 0.000 description 3
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- QTKLLGURCIHWHA-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[2-(oxetan-3-yl)ethoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC1COC1 QTKLLGURCIHWHA-HNNXBMFYSA-N 0.000 description 3
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- VRUNSBGXRXNTHO-IBGZPJMESA-N methyl (2S)-2-methyl-5-(6-morpholin-4-ylpyrimidin-4-yl)oxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=NC(=C1)N1CCOCC1)C=1C=NN(C1)C1CCNCC1)C(=O)OC VRUNSBGXRXNTHO-IBGZPJMESA-N 0.000 description 1
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- JDAWHGDFNPUKBU-KRWDZBQOSA-N methyl (2S)-2-methyl-5-[2-[methyl(methylsulfonyl)amino]ethoxy]-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCN(S(=O)(=O)C)C)C=1C=NN(C1)C1CCNCC1)C(=O)OC JDAWHGDFNPUKBU-KRWDZBQOSA-N 0.000 description 1
- XKNOLOXQEAWICY-INIZCTEOSA-N methyl (2S)-2-methyl-5-[2-[methyl(methylsulfonyl)amino]ethoxy]-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCN(S(=O)(=O)C)C XKNOLOXQEAWICY-INIZCTEOSA-N 0.000 description 1
- JAAPBMJMUHPXKJ-FUHWJXTLSA-N methyl (2S)-2-methyl-5-[[(2R)-5-oxopyrrolidin-2-yl]methoxy]-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC[C@@H]1NC(CC1)=O)C=1C=NN(C1)C1CCNCC1)C(=O)OC JAAPBMJMUHPXKJ-FUHWJXTLSA-N 0.000 description 1
- XGCGINYPXGMPDS-HNNXBMFYSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[2-(trifluoromethyl)pyrimidin-4-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC(=NC=C1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC XGCGINYPXGMPDS-HNNXBMFYSA-N 0.000 description 1
- DSJZRASWLTULJM-INIZCTEOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC=C1C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC DSJZRASWLTULJM-INIZCTEOSA-N 0.000 description 1
- VBESJGVEDCOYOB-HNNXBMFYSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[4-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC(=N1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC VBESJGVEDCOYOB-HNNXBMFYSA-N 0.000 description 1
- BVTVGYKADOZPAO-INIZCTEOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=C(C=C1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC BVTVGYKADOZPAO-INIZCTEOSA-N 0.000 description 1
- OZSZZCZBEWKVBZ-HNNXBMFYSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=C(C=N1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC OZSZZCZBEWKVBZ-HNNXBMFYSA-N 0.000 description 1
- QBGBWPYIAUZDIK-ROUUACIJSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC[C@@H]1CNCC1)C=1C=NN(C1)C1CCNCC1)C(=O)OC QBGBWPYIAUZDIK-ROUUACIJSA-N 0.000 description 1
- XPVOYJPSRUJAPC-INIZCTEOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CN=C1)C=1C=NN(C1)C1CCNCC1)C(=O)OC XPVOYJPSRUJAPC-INIZCTEOSA-N 0.000 description 1
- VZAXJRVNHTZNNQ-INIZCTEOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-pyrimidin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC=N1)C=1C=NN(C1)C1CCNCC1)C(=O)OC VZAXJRVNHTZNNQ-INIZCTEOSA-N 0.000 description 1
- HCKXUJOAEAXNSS-KRWDZBQOSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(N1CCCC1)=O HCKXUJOAEAXNSS-KRWDZBQOSA-N 0.000 description 1
- XLVRGOGBMXFGBO-KRWDZBQOSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-(oxan-4-ylmethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC1CCOCC1 XLVRGOGBMXFGBO-KRWDZBQOSA-N 0.000 description 1
- CHMCQYHGEXFAGS-HNNXBMFYSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CC=C1C(F)(F)F CHMCQYHGEXFAGS-HNNXBMFYSA-N 0.000 description 1
- SEICFVOAUGADIY-HNNXBMFYSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1)C(F)(F)F SEICFVOAUGADIY-HNNXBMFYSA-N 0.000 description 1
- YLYFDISIHVJCOV-AWEZNQCLSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C(F)(F)F YLYFDISIHVJCOV-AWEZNQCLSA-N 0.000 description 1
- IFUSCYHONWYUSR-DOTOQJQBSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[[(2R)-5-oxopyrrolidin-2-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1NC(CC1)=O IFUSCYHONWYUSR-DOTOQJQBSA-N 0.000 description 1
- YCRGOGKEZSKOMU-IRXDYDNUSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1CNCC1 YCRGOGKEZSKOMU-IRXDYDNUSA-N 0.000 description 1
- MOOCCEDMGTWABG-HNNXBMFYSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-propoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC MOOCCEDMGTWABG-HNNXBMFYSA-N 0.000 description 1
- LTSNWQKGIMBOBN-HNNXBMFYSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CN=C1 LTSNWQKGIMBOBN-HNNXBMFYSA-N 0.000 description 1
- RRHSAYKFLZSURU-INIZCTEOSA-N methyl (2S)-5-(2,3-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC=C1F RRHSAYKFLZSURU-INIZCTEOSA-N 0.000 description 1
- CUPVKTDAEOEELG-INIZCTEOSA-N methyl (2S)-5-(2,4-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC(=C1)F CUPVKTDAEOEELG-INIZCTEOSA-N 0.000 description 1
- YIGGUSCGDJSARZ-INIZCTEOSA-N methyl (2S)-5-(2,5-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C(C=C1)F YIGGUSCGDJSARZ-INIZCTEOSA-N 0.000 description 1
- YLPGFIAZJPHQOX-KRWDZBQOSA-N methyl (2S)-5-(2-chloro-4-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC(=C1)C#N YLPGFIAZJPHQOX-KRWDZBQOSA-N 0.000 description 1
- KGWUUPAANRZEGI-KRWDZBQOSA-N methyl (2S)-5-(2-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC=C1 KGWUUPAANRZEGI-KRWDZBQOSA-N 0.000 description 1
- WPYQALSRTIVPJC-HNNXBMFYSA-N methyl (2S)-5-(2-chlorophenoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC2)C(=O)OC)C)C=CC=C1 WPYQALSRTIVPJC-HNNXBMFYSA-N 0.000 description 1
- IVCPIKZUMHJTFW-KRWDZBQOSA-N methyl (2S)-5-(2-cyano-4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC(=C1)F IVCPIKZUMHJTFW-KRWDZBQOSA-N 0.000 description 1
- BQMSNUBCGGPJIB-SFHVURJKSA-N methyl (2S)-5-(2-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC=C1 BQMSNUBCGGPJIB-SFHVURJKSA-N 0.000 description 1
- LRECQERUFXDBHJ-KRWDZBQOSA-N methyl (2S)-5-(2-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC=C1 LRECQERUFXDBHJ-KRWDZBQOSA-N 0.000 description 1
- AANWXWLKOVHZFM-HNNXBMFYSA-N methyl (2S)-5-(3-carbamoylpyridin-2-yl)oxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C AANWXWLKOVHZFM-HNNXBMFYSA-N 0.000 description 1
- ADTDFIGJYUXGKQ-AWEZNQCLSA-N methyl (2S)-5-(3-carbamoylpyridin-2-yl)oxy-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C ADTDFIGJYUXGKQ-AWEZNQCLSA-N 0.000 description 1
- PCKGJVFGASZHDH-KRWDZBQOSA-N methyl (2S)-5-(3-chloro-2-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC=1C(=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1)C#N PCKGJVFGASZHDH-KRWDZBQOSA-N 0.000 description 1
- VTHVYYMEDOOPNK-KRWDZBQOSA-N methyl (2S)-5-(3-cyano-4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1F VTHVYYMEDOOPNK-KRWDZBQOSA-N 0.000 description 1
- GMWKSKZQMPKPPL-KRWDZBQOSA-N methyl (2S)-5-(3-cyanopyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C GMWKSKZQMPKPPL-KRWDZBQOSA-N 0.000 description 1
- VWSDHENGRCTOMI-INIZCTEOSA-N methyl (2S)-5-(3-cyanopyridin-2-yl)oxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C VWSDHENGRCTOMI-INIZCTEOSA-N 0.000 description 1
- XULDDQZZWNVTLS-HNNXBMFYSA-N methyl (2S)-5-(3-cyanopyridin-2-yl)oxy-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C XULDDQZZWNVTLS-HNNXBMFYSA-N 0.000 description 1
- SCDACDYMFHBSJB-INIZCTEOSA-N methyl (2S)-5-(3-cyanopyridin-2-yl)oxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C SCDACDYMFHBSJB-INIZCTEOSA-N 0.000 description 1
- WTLZIWGOOFAYIF-HNNXBMFYSA-N methyl (2S)-5-(3-cyanopyridin-2-yl)oxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C WTLZIWGOOFAYIF-HNNXBMFYSA-N 0.000 description 1
- LLVYCUYGFFQABD-KRWDZBQOSA-N methyl (2S)-5-(4-carbamoylphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1 LLVYCUYGFFQABD-KRWDZBQOSA-N 0.000 description 1
- HVLOEVMWPJELJP-HNNXBMFYSA-N methyl (2S)-5-(4-carbamoylphenoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC2)C(=O)OC)C)C=C1 HVLOEVMWPJELJP-HNNXBMFYSA-N 0.000 description 1
- AZFPZKNRNNQNEF-KRWDZBQOSA-N methyl (2S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=CC(=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1)C#N AZFPZKNRNNQNEF-KRWDZBQOSA-N 0.000 description 1
- JGVUJYJCSXZKJT-KRWDZBQOSA-N methyl (2S)-5-(4-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1 JGVUJYJCSXZKJT-KRWDZBQOSA-N 0.000 description 1
- DQKDGZHMAZOYBV-HNNXBMFYSA-N methyl (2S)-5-(4-chlorophenoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC2)C(=O)OC)C)C=C1 DQKDGZHMAZOYBV-HNNXBMFYSA-N 0.000 description 1
- YHALVBHSAVYQSX-KRWDZBQOSA-N methyl (2S)-5-(4-cyano-2-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=CC(=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1)F YHALVBHSAVYQSX-KRWDZBQOSA-N 0.000 description 1
- UHYUGSKLLATOIM-SFHVURJKSA-N methyl (2S)-5-(4-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1 UHYUGSKLLATOIM-SFHVURJKSA-N 0.000 description 1
- SOLFFSWFCCKGII-INIZCTEOSA-N methyl (2S)-5-(4-cyanophenoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC2)C(=O)OC)C)C=C1 SOLFFSWFCCKGII-INIZCTEOSA-N 0.000 description 1
- PIJNGDIQIFLMCI-UCFFOFKASA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-pyrrolidin-3-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CNCC2)C(=O)OC)C)C=C1 PIJNGDIQIFLMCI-UCFFOFKASA-N 0.000 description 1
- FTYUMYQBFGNMTI-VJWVULDSSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC3C(CN(C3)C)C2)C(=O)OC)C)C=C1 FTYUMYQBFGNMTI-VJWVULDSSA-N 0.000 description 1
- LRXMWXNPBAELIF-KRWDZBQOSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(oxan-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCOCC2)C(=O)OC)C)C=C1 LRXMWXNPBAELIF-KRWDZBQOSA-N 0.000 description 1
- AXLJVHWCUNJUHM-XTZPKPCCSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-[(3R,4R)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)[C@H]2[C@@H](CNCC2)F)C(=O)OC)C)C=C1 AXLJVHWCUNJUHM-XTZPKPCCSA-N 0.000 description 1
- AXLJVHWCUNJUHM-IGUJJWBZSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-[(3R,4S)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)[C@@H]2[C@@H](CNCC2)F)C(=O)OC)C)C=C1 AXLJVHWCUNJUHM-IGUJJWBZSA-N 0.000 description 1
- AXLJVHWCUNJUHM-UIDQEFQQSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-[(3S,4R)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)[C@H]2[C@H](CNCC2)F)C(=O)OC)C)C=C1 AXLJVHWCUNJUHM-UIDQEFQQSA-N 0.000 description 1
- AXLJVHWCUNJUHM-DQLWACAZSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-[(3S,4S)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)[C@@H]2[C@H](CNCC2)F)C(=O)OC)C)C=C1 AXLJVHWCUNJUHM-DQLWACAZSA-N 0.000 description 1
- MILSQULUHYXSTP-INIZCTEOSA-N methyl (2S)-5-(5-carbamoylpyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(N)(=O)C=1C=CC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C MILSQULUHYXSTP-INIZCTEOSA-N 0.000 description 1
- UARQZJKFXMXSCO-KRWDZBQOSA-N methyl (2S)-5-(5-cyclopropylpyrimidin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)C=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C UARQZJKFXMXSCO-KRWDZBQOSA-N 0.000 description 1
- KINJTVLREVSOHN-INIZCTEOSA-N methyl (2S)-5-(5-cyclopropylpyrimidin-2-yl)oxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)C=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C KINJTVLREVSOHN-INIZCTEOSA-N 0.000 description 1
- VNMQQWPAJSWGEH-INIZCTEOSA-N methyl (2S)-5-(5-cyclopropylpyrimidin-2-yl)oxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)C=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C VNMQQWPAJSWGEH-INIZCTEOSA-N 0.000 description 1
- IUUJKMSUSUNNJF-HNNXBMFYSA-N methyl (2S)-5-(5-cyclopropylpyrimidin-2-yl)oxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)C=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C IUUJKMSUSUNNJF-HNNXBMFYSA-N 0.000 description 1
- DZYXHDSZIYXNJQ-HNNXBMFYSA-N methyl (2S)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C DZYXHDSZIYXNJQ-HNNXBMFYSA-N 0.000 description 1
- QOBMYCSXXLKSDA-AWEZNQCLSA-N methyl (2S)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C QOBMYCSXXLKSDA-AWEZNQCLSA-N 0.000 description 1
- UWSBQWOHTZOJSA-AWEZNQCLSA-N methyl (2S)-5-(5-fluoropyrimidin-2-yl)oxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C UWSBQWOHTZOJSA-AWEZNQCLSA-N 0.000 description 1
- ODFANPLALYWVKF-ZDUSSCGKSA-N methyl (2S)-5-(5-fluoropyrimidin-2-yl)oxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C ODFANPLALYWVKF-ZDUSSCGKSA-N 0.000 description 1
- FVGODSHCEARRCG-KRWDZBQOSA-N methyl (2S)-5-(5-methoxycarbonylpyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound COC(=O)C=1C=CC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C FVGODSHCEARRCG-KRWDZBQOSA-N 0.000 description 1
- OUEHWSGWXGNTJN-KRWDZBQOSA-N methyl (2S)-5-(6-cyclopropylpyrimidin-4-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)C1=CC(=NC=N1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C OUEHWSGWXGNTJN-KRWDZBQOSA-N 0.000 description 1
- RHIMOWXVUNHGQC-KRWDZBQOSA-N methyl (2S)-5-(6-methoxypyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound COC1=CC=CC(=N1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C RHIMOWXVUNHGQC-KRWDZBQOSA-N 0.000 description 1
- STODOJZJIXRDTC-SFHVURJKSA-N methyl (2S)-5-(cyclopentylmethoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C STODOJZJIXRDTC-SFHVURJKSA-N 0.000 description 1
- CVWUGSPNZAWNHR-KRWDZBQOSA-N methyl (2S)-5-(cyclopentylmethoxy)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C CVWUGSPNZAWNHR-KRWDZBQOSA-N 0.000 description 1
- COWFTWBCAALKLH-KRWDZBQOSA-N methyl (2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C COWFTWBCAALKLH-KRWDZBQOSA-N 0.000 description 1
- ADVNSCXXJFQVTE-INIZCTEOSA-N methyl (2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C ADVNSCXXJFQVTE-INIZCTEOSA-N 0.000 description 1
- XMLGGVDPYKCFIV-INIZCTEOSA-N methyl (2S)-5-[2-(dimethylamino)-2-oxoethoxy]-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CN(C(=O)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C)C XMLGGVDPYKCFIV-INIZCTEOSA-N 0.000 description 1
- GCQVWUKOCUWTDO-HNNXBMFYSA-N methyl (2S)-5-[2-(dimethylamino)-2-oxoethoxy]-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CN(C(=O)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C)C GCQVWUKOCUWTDO-HNNXBMFYSA-N 0.000 description 1
- UGUMNPCLOJQRDS-HNNXBMFYSA-N methyl (2S)-5-[2-(dimethylamino)-2-oxoethoxy]-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CN(C(=O)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C)C UGUMNPCLOJQRDS-HNNXBMFYSA-N 0.000 description 1
- DSVWTEUSCWEDIG-HNNXBMFYSA-N methyl (2S)-5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C(=NC=C(C1)C(F)(F)F)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C DSVWTEUSCWEDIG-HNNXBMFYSA-N 0.000 description 1
- RBIUUZKKJHNEHD-AWEZNQCLSA-N methyl (2S)-5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C(=NC=C(C1)C(F)(F)F)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C RBIUUZKKJHNEHD-AWEZNQCLSA-N 0.000 description 1
- DVIJRZVCENWJRB-AWEZNQCLSA-N methyl (2S)-5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C(=NC=C(C1)C(F)(F)F)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C DVIJRZVCENWJRB-AWEZNQCLSA-N 0.000 description 1
- PJPCQWXJFCPKDV-ZDUSSCGKSA-N methyl (2S)-5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C(=NC=C(C1)C(F)(F)F)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C PJPCQWXJFCPKDV-ZDUSSCGKSA-N 0.000 description 1
- NWLUPWWSZWSZLW-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C NWLUPWWSZWSZLW-HNNXBMFYSA-N 0.000 description 1
- IMHQXKIZOLOLFU-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C IMHQXKIZOLOLFU-HNNXBMFYSA-N 0.000 description 1
- DOOJHPDXDXOTAS-AWEZNQCLSA-N methyl (2S)-5-cyclobutyloxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C DOOJHPDXDXOTAS-AWEZNQCLSA-N 0.000 description 1
- IGEPYXYBHMRMID-ZAOYMGCJSA-N methyl (2S)-5-cyclobutyloxy-6-[1-[(3R,4R)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)[C@H]1[C@@H](CNCC1)F)C(=O)OC)C IGEPYXYBHMRMID-ZAOYMGCJSA-N 0.000 description 1
- IGEPYXYBHMRMID-GNSUPJDDSA-N methyl (2S)-5-cyclobutyloxy-6-[1-[(3R,4S)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)[C@@H]1[C@@H](CNCC1)F)C(=O)OC)C IGEPYXYBHMRMID-GNSUPJDDSA-N 0.000 description 1
- RJUDCTXBIPHZCI-ONTRVFCTSA-N methyl (2S)-5-cyclobutyloxy-6-[1-[(3R,4S)-4-fluoropyrrolidin-3-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)[C@@H]1CNC[C@@H]1F)C(=O)OC)C RJUDCTXBIPHZCI-ONTRVFCTSA-N 0.000 description 1
- IGEPYXYBHMRMID-LVWPNOBMSA-N methyl (2S)-5-cyclobutyloxy-6-[1-[(3S,4S)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)[C@@H]1[C@H](CNCC1)F)C(=O)OC)C IGEPYXYBHMRMID-LVWPNOBMSA-N 0.000 description 1
- MACMCDJVWABJMX-INIZCTEOSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(1-propan-2-ylazetidin-3-yl)oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound COC(=O)N1[C@@H](C)CCC2=C1C=CC(C1=CN(N=C1)C1CC1)=C2OC1CN(C1)C(C)C MACMCDJVWABJMX-INIZCTEOSA-N 0.000 description 1
- ZGSCAGKCPWYLCN-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(5-methylpyrimidin-2-yl)oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C ZGSCAGKCPWYLCN-HNNXBMFYSA-N 0.000 description 1
- GKTGJMVMKBVMIK-AWEZNQCLSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CC=C1C(F)(F)F GKTGJMVMKBVMIK-AWEZNQCLSA-N 0.000 description 1
- GPWVBDVMNGAODI-AWEZNQCLSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1)C(F)(F)F GPWVBDVMNGAODI-AWEZNQCLSA-N 0.000 description 1
- XRPSXNKWWDWTDO-ZDUSSCGKSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C(F)(F)F XRPSXNKWWDWTDO-ZDUSSCGKSA-N 0.000 description 1
- XCBLPDQEVUAOAM-AWEZNQCLSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CN=C1 XCBLPDQEVUAOAM-AWEZNQCLSA-N 0.000 description 1
- GEBDNIHVGHMSKF-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(1-ethylazetidin-3-yl)oxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1CN(C1)CC GEBDNIHVGHMSKF-HNNXBMFYSA-N 0.000 description 1
- PAQWVQGTXDTEJP-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=C(C=CC=C1)F PAQWVQGTXDTEJP-HNNXBMFYSA-N 0.000 description 1
- RIHNPVSHKSDELO-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=C(C=C1)F RIHNPVSHKSDELO-HNNXBMFYSA-N 0.000 description 1
- JNERBYHSESJCEM-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(5-cyclopropylpyrimidin-2-yl)oxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C1CC1 JNERBYHSESJCEM-HNNXBMFYSA-N 0.000 description 1
- XZTVHSWKRZWDMP-ZDUSSCGKSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)F XZTVHSWKRZWDMP-ZDUSSCGKSA-N 0.000 description 1
- PAHHACYBHFXKOB-ZDUSSCGKSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1F)C(F)(F)F PAHHACYBHFXKOB-ZDUSSCGKSA-N 0.000 description 1
- WFRSYACDPIBNCN-OLYSNNBPSA-N methyl (2S)-6-[1-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC3C(CNC3)C2)C(=O)OC)C)C=C1 WFRSYACDPIBNCN-OLYSNNBPSA-N 0.000 description 1
- MENJVDZGKKMBNV-INIZCTEOSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(C)C)(C)C MENJVDZGKKMBNV-INIZCTEOSA-N 0.000 description 1
- MGWUDHBOZTXGBY-KRWDZBQOSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(N1CCCC1)=O)(C)C MGWUDHBOZTXGBY-KRWDZBQOSA-N 0.000 description 1
- RHDRFPNPXWRPFZ-INIZCTEOSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-(5-methylpyrimidin-2-yl)oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C)(C)C RHDRFPNPXWRPFZ-INIZCTEOSA-N 0.000 description 1
- CRGUXKOPWRJECW-KRWDZBQOSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC1CCOCC1)(C)C CRGUXKOPWRJECW-KRWDZBQOSA-N 0.000 description 1
- ULEACNCGPRCMEF-INIZCTEOSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[2-[methyl(methylsulfonyl)amino]ethoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCN(S(=O)(=O)C)C)(C)C ULEACNCGPRCMEF-INIZCTEOSA-N 0.000 description 1
- LBAYNPPFSHJSIN-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CC=C1C(F)(F)F)(C)C LBAYNPPFSHJSIN-HNNXBMFYSA-N 0.000 description 1
- ZAGONFXELSNOKP-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1)C(F)(F)F)(C)C ZAGONFXELSNOKP-HNNXBMFYSA-N 0.000 description 1
- BSFJYPUNSPVJKC-AWEZNQCLSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C(F)(F)F)(C)C BSFJYPUNSPVJKC-AWEZNQCLSA-N 0.000 description 1
- ITINIWCXTCKCCZ-DOTOQJQBSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[[(2R)-5-oxopyrrolidin-2-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1NC(CC1)=O)(C)C ITINIWCXTCKCCZ-DOTOQJQBSA-N 0.000 description 1
- UKWJPEZRUGBRAK-IRXDYDNUSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1CNCC1)(C)C UKWJPEZRUGBRAK-IRXDYDNUSA-N 0.000 description 1
- DGLLKZWLXSWOJA-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-propoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC)(C)C DGLLKZWLXSWOJA-HNNXBMFYSA-N 0.000 description 1
- GXNDGIHQAINLMJ-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CN=C1)(C)C GXNDGIHQAINLMJ-HNNXBMFYSA-N 0.000 description 1
- FHGWNUSCMPQQMR-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(C)C FHGWNUSCMPQQMR-HNNXBMFYSA-N 0.000 description 1
- RVFCJSQQTMYUMM-INIZCTEOSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(N1CCCC1)=O RVFCJSQQTMYUMM-INIZCTEOSA-N 0.000 description 1
- OELCSWNVKXQQEP-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-(5-methylpyrimidin-2-yl)oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C OELCSWNVKXQQEP-HNNXBMFYSA-N 0.000 description 1
- ZHFLWLNHFMMXLH-INIZCTEOSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-(oxan-4-ylmethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC1CCOCC1 ZHFLWLNHFMMXLH-INIZCTEOSA-N 0.000 description 1
- SJIWDCRHEXFYTJ-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[2-[methyl(methylsulfonyl)amino]ethoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCN(S(=O)(=O)C)C SJIWDCRHEXFYTJ-HNNXBMFYSA-N 0.000 description 1
- RBDSWTBQOBSAMJ-AWEZNQCLSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CC=C1C(F)(F)F RBDSWTBQOBSAMJ-AWEZNQCLSA-N 0.000 description 1
- BWRDDXFROXRDFG-AWEZNQCLSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1)C(F)(F)F BWRDDXFROXRDFG-AWEZNQCLSA-N 0.000 description 1
- DZXYELYSWMFYQS-ZDUSSCGKSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C(F)(F)F DZXYELYSWMFYQS-ZDUSSCGKSA-N 0.000 description 1
- WSBSAIKZXOMGKV-GOEBONIOSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[[(2R)-5-oxopyrrolidin-2-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1NC(CC1)=O WSBSAIKZXOMGKV-GOEBONIOSA-N 0.000 description 1
- FAUWOUSJWPFHHJ-HOTGVXAUSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1CNCC1 FAUWOUSJWPFHHJ-HOTGVXAUSA-N 0.000 description 1
- RRHJNKNWTXBXCT-AWEZNQCLSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-propoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC RRHJNKNWTXBXCT-AWEZNQCLSA-N 0.000 description 1
- KXORCPUVRIGISK-AWEZNQCLSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CN=C1 KXORCPUVRIGISK-AWEZNQCLSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
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Abstract
本发明关于适用于治疗癌症、发炎性疾病、糖尿病和肥胖症的溴(bromo)和外端(BET)溴域的抑制剂,其具有式(I),其中W、X、Y、Z、R1、R2、R5和R8如本文所述。
Description
本申请是申请日为2014年11月18日、发明名称为“作为BET溴域抑制剂的四氢喹啉组成物”的中国专利申请No.201480073069.5的分案申请。
相关申请案
本申请案要求2013年11月18日申请的美国临时专利申请案第61/905,639号和2014年9月24日申请的美国临时专利申请案第62/054,811号的权益和优先权。所述申请案的全部内容借此以全文引用的方式并入。
技术领域
本发明针对溴域的溴和外端(BET)家族的抑制剂,其适用于治疗与调节溴域的溴和外端(BET)家族相关的疾病或病症。具体来说,本发明涉及用于抑制溴域的溴和外端(BET)家族的化合物和组成物,治疗、预防或改善与抑制溴域的溴和外端(BET)家族相关的疾病或病症的方法,以及合成这些化合物的方法。
背景技术
哺乳动物中的溴和外端(BET)家族蛋白质含有四个成员,BRD2、BRD3、BRD4和BRDT,其中这些成员中的每一个含有两个溴域(BRD):保守N端溴域(溴域1[BD1])和C端溴域(溴域2[BD2])。BET家族蛋白质已显示在细胞增殖和细胞周期进程中具有关键作用。
已知含溴域蛋白质参与转录调控。一般来说,溴域存在于调控染色质结构和基因表达的蛋白质中。这些蛋白质的存在为各种生长和抗凋亡基因的全身表达所需。另外,这些蛋白质在普遍存在的细胞周期进程中起作用,这是因为许多核蛋白具有与染色质相互作用的溴域,例如组蛋白乙酰转移酶。含溴域蛋白质的功能不良与许多疾病的发展、尤其与癌症的发展相关联(Muller,S.Filippakopoulos,P.Knapp,S.(2011),作为治疗目标的溴域(Bromodomains as therapeutic targets).《分子医学的专业评论(ExpertRev.Mol.Med.)》13:e29)。溴域还牵涉于发炎过程中(Nicodeme等人,《自然(Nature)》,2010,第468卷,第1119页)。
作为基因产物的BRD4蛋白含有1362个氨基酸。BRD4 BD1为约75-147;BRD4 BD2为约368-440;由此每一个的长度为73个残基。出于生物化学筛选、生物物理学或X射线结晶学的目的,表达并使用具有经添加用于两个溴域的其它N端和C端残基的各种蛋白质构筑体。另外,还已经使用具有表达于同一蛋白质内的两个溴域的蛋白质构筑体(总共约400aa残基)。
蛋白质包含四个α螺旋,全部左旋定向,这与蛋白质的高度多样化序列性质成鲜明对比。螺旋(αZ、αA、αC和αB)以Z与A螺旋相互作用形成长“ZA环”且C与B螺旋相互作用形成短“BC环”的方式排列(Dhalluin C.,Carlson J.E.,Zeng L.,He C.,Aggarwal A.K.,ZhouM.M.(1999),组蛋白乙酰转移酶溴域的结构和配位体(Structure and ligand of ahistone acetyltransferase bromodomain).《自然》.399,491-6)。这些环形成蛋白质中的疏水袋,在此处蛋白质与乙酰化赖氨酸残基相互作用。突变诱发研究表明,两个螺旋间环之间的疏水残基和芳香族残基当中的三级接触直接促成蛋白质的结构稳定性(Dhalluin C.,Carlson J.E.,Zeng L.,He C.,Aggarwal A.K.,Zhou M.M.(1999),组蛋白乙酰转移酶溴域的结构和配位体.《自然》.399,491-6)。
长久以来已表明,溴域在染色质重塑中起重要作用。近年来,双溴域家族的某些蛋白质,包括BRD2、BRD3、BRD4和BRDT,已经鉴别为人类癌症中的主要表观遗传调控子。因而,这些双溴域看起来在人类癌症增生和分化中起到尤其重要的作用。举例来说,BRD4影响乳癌微环境和存活率(Crawford,N.P,Alsarraj,J.,Lukes,L.,Walker,R.C.,Officewala,J.S.,Yang,H.H.,Lee,M.P.,Ozato,K.,Hunter,K.W.(2008),溴域4活化预测乳癌存活率(Bromodomain 4Activation Predicts Breast Cancer Survival).《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》.105(17):6380-6385)。BRD4也在卡波西氏肉瘤(Kaposi′ssarcoma)中起作用且BRD2为一些混合谱系白血病中的因子(Guo,N.,Faller,D.V.,Denis,G.V.,活化诱发的RING3核转运(Activation-Induced Nuclear Translocation of RING3)(2001),《细胞科学杂志(J.Cell Sci.)》113(17):3085-3091)。另外,由RNAi进行基因敲除或细胞暴露于BET抑制剂已引起MYC(许多癌症中所见的突变型式)的显著转录下调(Delmore J.E.,Issa G.C.,Lemieux M.E.,Rahl,P.B.,Shi J.,Jacobs H.M.(2011),作为目标c-Myc的治疗策略的BET溴域抑制(BET Bromodomain Inhibition as a TherapeuticStrategy to Target c-Myc).《细胞(Cell)》.146:904-17)。因此,抑制这些相互作用和细胞暴露于BET抑制剂引起显著转录下调。这又为医疗团体提供用于治疗癌症的新颖药理学策略。
溴域的高度分化的序列性质已成为发现强力且有效的溴域抑制剂的严重阻碍(Dawson,M.A,Prinjha,R.K.,Dittman,A.Giotopoulos,G.Bantcheff,M.,Chan,W-I.,Robson,S.C.,Chung,C.,Hopf,C.,Savitski,M.M.,Hutmacher,C.,Gudgin,E.,Lugo,D.,Beinke,S.,Chapman.T.D.,Roberts,E.J.,Soden.P.E.,Auger,K.R.,Mirguet,O.,Doehner,K.,Delwel,R.,Burnett,A.K.,Jeffrey,P.,Drewes,G.,Lee,K.,Huntly,B.J.P.和Kouzarides,T.(2011),抑制核染色质的BET募集为MLL融合白血病的有效治疗(Inhibitionof BET recruitment of chromatin as an effective treatment of MLL-fusionleukemia).《自然》.0:1-5;Picaud,S.,Da Costa,D.Thanasopoulou,A.,Filippakopoulos,P.,Fish,P.,Philpott,M.,Federov,O.Brennan,P.,Bunnage,M.E.,Owen,D.R.,Bradner,J.E.,Taniere,P.,O′Sullivan,B.,Muller,S,Schwaller,J.,Stankovic,T.,Knapp,S.,PFI-1-一种靶向BET溴域的高度选择性蛋白质相互作用抑制剂(PFI-1-Ahighly SelectiveProtein Interaction Inhibitor Targeting BET Bromodomains),《癌症研究(CancerRes.)》,73(11),2013,3336-3346)。因此,当前不存在可用于市面上的经批准的溴域抑制剂,尽管其具有作为抗癌治疗剂的公认潜力。出于这些原因,对BET溴域的新颖且强力的小分子调节剂仍有相当大的需要。
发明内容
本发明的一个方面关于式I化合物:
和其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物和互变异构物,
其中:
W为O、S、C(O)或CHR3;
X为N或CR4;
Y为N或CR6;
Z为N或CR7;
R1为氢、C1-C6烷基或C1-C6卤代烷基;
R2为氢或NRaRb;
R3为氢、卤素、羟基、C1-C6烷基或C1-C6卤代烷基;
R4为氢、-(CH2)nRd、-O(CH2)nRd、-N(CH2)nRd、-O(CH2)nC(O)Rd或-O(CH2)nS(O)2Rd;
R5和R6各自独立地为氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C3-C8环烷基、杂环烷基、环烯基、杂环烯基、芳基、杂芳基、-(C1-C6)-亚烷基-芳基、-(C1-C6)-亚烷基-杂芳基、-(C1-C6)-亚烷基-杂环烷基、-(CRaRb)nORc、-(CRaRb)nRc、-O(CRaRb)nNRaRb、-NRaRb、-NRaC(O)Rb、-NRaS(O)2Rb或Rc,其中所述烷基、烯基、炔基、环烷基、杂环烷基、环烯基、杂环烯基、芳基和杂芳基任选经一个或多个独立地选自Ra、Rb和Rc的取代基取代;
R7为氢或卤素;
R8为Ra、-ORa、-NRa或杂环烷基;
Ra和Rb各自独立地为氢、卤素、C1-C6烷基、环烷基或杂环烷基;其中C1-C6烷基、环烷基或杂环烷基任选经一个或多个Re取代;
Rc为-NH2、OH、-NH(C1-C6烷基)、-O(CH2)nNRaRb、-NH(C1-C6烷氧基)、-(CH2)nRa、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-(CH2)nS(O)2CH3、-S(O)2Ra、-S(O)2NRaRb、-NRa-S(O)2Rb、-NHC(O)Ra、C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、芳基、杂芳基、环烷基、杂环烷基、卤基、氰基或氧代基;其中C1-C6烷基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、芳基、杂芳基、环烷基以及杂环烷基任选经一个或多个Re取代;
或两个相邻Rc可与其所连接的碳原子组合形成碳环或杂环;
Rd为氢、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C1-C6烷基、环烷基、杂环烷基、芳基或杂芳基,其中所述烷基、环烷基、杂环烷基、芳基和杂芳基任选经一个或多个独立地选自Ra、Rb和Rc的取代基取代;
Re为氢、卤素、OH、C1-C6烷基、环烷基、杂环烷基、氧代基、C1-C6卤代烷基、C1-C6卤代烷氧基、C1-C6烷氧基或S(O)2(C1-C6烷基);以及
n为0、1或2。
本发明的另一方面关于一种医药组成物,其包含式I化合物,或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物,和药学上可接受的载剂。
另一方面,本发明关于一种调节BET家族溴域中的一个或多个的方法。所述方法包括向有需要的患者投予治疗有效量的式I化合物,或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物。
本发明的另一方面关于一种抑制BET家族溴域中的一个或多个的方法。所述方法包括向有需要的患者投予治疗有效量的式I化合物,或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物。
另一方面,本发明关于一种抑制BET家族溴域中的一个或多个的方法。所述方法包括向有需要的患者投予治疗有效量的式I的医药组成物。
本发明的另一方面关于一种治疗、预防、抑制或消除患者的与抑制BET家族溴域中的一个或多个相关的疾病或病症的方法。所述方法包括向有需要的患者投予治疗有效量的本文所述的式I化合物,其中所述疾病或病症选自由以下组成的群组:癌症、发炎性病症、大肠激躁综合症、发炎性肠病、类风湿性关节炎、肥胖症和糖尿病。
另一方面,本发明关于一种男性避孕药,其包含治疗有效量的本文所述的式I化合物。
本发明提供BET域的抑制剂,其为治疗例如癌症、发炎、代谢和神经病症和感染性疾病的治疗剂。
具体实施方式
本发明关于能够调节BET家族溴域,例如BRD2、BRD3、BRD4和BRDT溴域的活性的化合物和组成物。本发明特征在于治疗、预防或改善与BET溴域相关的疾病或病症的方法,这是通过向有需要的患者投予治疗有效量的式(I)、(II)、(III)或(IV)的化合物,或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物来达成。本发明的方法可用于通过抑制BET溴域的活性来治疗多种BET溴域依赖性疾病和病症。BET溴域的抑制提供一种用以治疗、预防或改善包括(但不限于)癌症、发炎性疾病、糖尿病和肥胖症的疾病,和研发男性避孕药的新颖方法。
本发明的一个方面关于式I化合物
和其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物,其中W、X、Y、Z、R1、R2、R3、R4、R5、R6、R7、R8、Ra、Rb、Rc、Rd和n如上文所述。
本发明的细节阐述于下文的随附描述中。尽管类似或等效于本文所述的那些的方法和材料可用于实施或测试本发明,但现描述说明性方法和材料。本发明的其它特征、目的和优点将从描述和从权利要求书显而易知。在说明书和所附权利要求书中,除非本文另有明确指示,否则单数形式还包括复数。除非另有规定,否则本文所用的所有技术和科学术语具有与一般技术人员通常所理解的含义相同的含义。本说明书中所引用的所有专利和公开案以全文引用的方式并入本文中。
定义
如上文所用且在本发明通篇中,除非另有指示,否则以下术语应理解为具有以下含义。如果缺少定义,那么以如所属领域技术人员已知的惯用定义为准。
如本文所用的术语“包括”、“含有”和“包含”以其开放式、非限制性含义使用。
冠词“一(a和an)”在本发明中用于指冠词的一个或超过一个(即至少一个)语法对象。举例来说,“一个要素”意思是一个要素或超过一个要素。
除非另有指示,否则本发明中所用的术语“和/或”意思是“和”或“或”。
为提供更简明的描述,本文所给出的一些定量表述不用术语“约”修饰。应了解,无论术语“约”是否明确使用,本文所给出的每个量打算指实际给定值,并且还打算指将基于一般技术人员的合理推断所述给定值的近似值,包括由于实验和/或测量条件产生的所述给定值的等效值和近似值。在产率以百分比给出的任何情况下,所述产率指的是给出产率的实体的质量相对于在特定化学计量条件下可获得的相同实体的最大量。除非有不同指示,否则以百分比给出的浓度指的是质量比。
“患者”为哺乳动物,例如人类、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪,或非人类灵长类动物,例如猴、黑猩猩、狒狒或恒河猴。“患者”包括人类与动物两个。
术语“抑制剂”指的是阻断或以其它方式干扰特定生物活性的分子,例如化合物、药物、酶或激素。
术语“溴域抑制剂”表示抑制溴域与其同源乙酰化蛋白质结合的化合物。在一个实施例中,溴域抑制剂为抑制溴域中的任一个或其组合与乙酰化赖氨酸残基结合的化合物。在另一实施例中,溴域抑制剂为抑制溴域与组蛋白、尤其组蛋白H3和H4上的乙酰化赖氨酸残基结合的化合物。
术语“BET家族溴域抑制剂”或“BET家族蛋白质的溴域的抑制剂”意思是抑制BET(溴和外端)溴域BRD2 BD1、BRD2 BD2、BRD3 BD1、BRD3 BD2、BRD4 BD1、BRD4 BD2、BRDT BD1或BRDT BD2的结合的化合物。在一个实施例中,BET家族溴域抑制剂为式I-IV的化合物。根据另一实施例,BET家族溴域抑制剂为选自表1的化合物。
术语“有效量”或“治疗有效量”当与化合物联合使用时指的是足以提供所需生物结果的化合物的量。所述结果可以是疾病的征象、症状或病因的减少和/或减轻,或生物系统的任何其它所需改变。举例来说,用于治疗用途的“有效量”为提供疾病的临床显著减退所需的包含如本文所披露的化合物的组成物的量。在任何个别情况下的适当“有效量”可由一般技术人员使用常规实验来确定。因此,表述“有效量”一般指的是具有治疗效果的活性物质的量。在本发明情况下,活性物质为BET蛋白质的溴域的抑制剂。
如本文所用的术语“治疗(treat/treatment)”与术语“预防”同义,且打算指示延缓疾病的发展,预防疾病的发展,和/或降低将会发展或预期会发展的所述症状的严重性。因此,这些术语包括改善现有疾病症状,预防其它症状,改善或预防症状的潜在病因,抑制病症或疾病,例如遏止病症或疾病的发展,减轻病症或疾病,引起病症或疾病的衰退,减轻由疾病或病症引起的病状,或终止或减轻疾病或病症的症状。
除非另有指示,否则本发明中所用的术语“病症”意思是术语疾病、病状或疾患,并且可与所述术语互换使用。
使用术语“药学上可接受”或“药理学上可接受”意思是生物学上或其它方面合乎需要的物质-可将所述物质投予受检者而不引起任何实质上不合需要的生物作用或以有害方式与含有其的组成物的任何组分相互作用。
如本发明中所用的术语“载剂”涵盖载剂、赋形剂和稀释剂并且意思是将医药剂从受检者的身体的一个器官或部分载运或转运到身体的另一器官或部分所涉及的物质、组成物或媒剂,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封物质。赋形剂应基于所需剂型的相容性和释放型态特性来选择。示范性载剂物质包括例如粘合剂、悬浮剂、崩解剂、填充剂、表面活性剂、增溶剂、稳定剂、润滑剂、湿润剂、稀释剂等。
“药学上相容的载剂物质”可包含例如阿拉伯胶、明胶、胶态二氧化硅、甘油磷酸钙、乳酸钙、麦芽糊精、甘油、硅酸镁、酪蛋白酸钠、大豆卵磷脂、氯化钠、磷酸三钙、磷酸二钾、硬脂酰乳酸钠、角叉菜胶、单酸甘油酯、二酸甘油酯、预胶凝化淀粉等。参见例如Hoover,John E.,《雷明顿药学大全(Remington′s Pharmaceutical Sciences)》,Mack PublishingCo.,Easton,Pa.1975。
如本文所用的术语“受检者”涵盖哺乳动物和非哺乳动物。哺乳动物的实例包括(但不限于)哺乳纲的任何成员:人类、非人类灵长类动物,例如黑猩猩,和其它猿和猴物种;农畜,例如牛、马、绵羊、山羊、猪;家畜,例如兔、狗和猫;实验动物,包括啮齿动物,例如大鼠、小鼠和豚鼠等。非哺乳动物的实例包括(但不限于)鸟、鱼等。在本发明的一个实施例中,哺乳动物为人类。
本发明还包括本发明化合物的“前药”。术语“前药”意思是在体内由代谢方式(例如通过水解)可转化成所披露的化合物或活性成分的化合物。前药可通过所属领域技术人员已知的技术来制备。这些技术一般对给定化合物中的适当官能团(例如羟基、氨基、羧基等基团)进行改性。然而,这些经改性官能团通过常规操作或在体内重新产生原始官能团。前药的实例包括(但不限于)本发明化合物中的羟基或氨基官能团的酯(例如乙酸酯、甲酸酯和苯甲酸酯衍生物)、氨基甲酸酯(例如N,N-二甲基氨基羰基)、酰胺(例如三氟乙酰基氨基、乙酰基氨基等)等。由于已知前药增强医药品的众多所需质量(例如溶解度、生物可用性、制造、运输、药效学等),因此本发明化合物可依前药形式传递。前药例如可通过经口投予而具生物可用性,甚至在母体药物不可这样时。因此,本发明打算涵盖本发明所主张的化合物的前药、其传递方法和含有其的组成物。一般来说,前药为在投予之后转化或代谢成生理活性物质的药物本身的衍生物。转化可为自发的,例如在生理环境中水解,或可经酶催化。前药包括可经氧化、还原、氨化、脱氨化、羟基化、脱羟基化、水解、酯化、烷基化、脱烷基化、酰化、脱酰化、磷酸化和/或脱磷酸化以产生活性化合物的化合物。
如本文所用的术语“IC50”指的是例如肿瘤细胞的细胞的可测量活性、表型或反应(例如生长或增殖)被抑制50%的浓度。IC50值可以从适当剂量反应曲线估算,例如用眼睛或通过使用适当曲线拟合或统计软件。更确切来说,IC50值可使用非线性回归分析来确定。
如本发明中所用的术语“投予(administered,administration或administering)”指的是将所披露的化合物或所披露的化合物的药学上可接受的盐或组成物直接投予受检者,或将化合物或化合物的药学上可接受的盐的前药衍生物或类似物或组成物投予受检者,这可以通过使所述受检者与所述化合物接触或以其它方式使所述受检者暴露于所述化合物而在需要治疗的受检者(包括动物)体内形成等效量的活性化合物。
如本文所用的“烷基”意思是具有1到10个碳原子的直链或分支链饱和链。代表性饱和烷基包括(但不限于)甲基、乙基、正丙基、异丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基等,以及更长烷基,例如庚基以及辛基等。烷基可未经取代或经取代。含有三个或更多个碳原子的烷基可为直链或分支链。如本文所用的“低碳烷基”意思是具有1到6个碳原子的烷基。
如本文所用的“烯基”包括含有2-12个碳原子的未分支或分支烃链。“烯基”含有至少一个双键。烯基的双键可未结合或结合到另一不饱和基团。烯基的实例包括(但不限于)乙烯基(ethylenyl、vinyl)、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基、4-(2-甲基-3-丁烯)-戊烯基等。烯基可未经取代或经取代。如本文所定义的烯基还可为分支链或直链。
如本文所用的“炔基”包括含有2-12个碳原子的未分支或分支链不饱和烃链。“炔基”基团含有至少一个三键。炔基的三键可未结合或与另一不饱和基团结合。炔基的实例包括(但不限于)乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基、4-甲基-1-丁炔基、4-丙基-2-戊炔基、4-丁基-2-己炔基等。炔基可未经取代或经取代。
术语“亚烷基(alkylene或alkylenyl)”指的是二价烷基。上文所提到的单价烷基中的任一个可通过从烷基除去第二氢原子而成为亚烷基。如本文所定义的亚烷基还可以是C1-C6亚烷基。亚烷基可进一步为C1-C4亚烷基。典型亚烷基包括(但不限于)-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。
术语“三氟甲基”、“磺酰基”和“羧基”分别指的是CF3、S(O)2和C(O)OH。
术语“羟基(hydroxyl或hydroxy)”意思是OH基团。
术语“羟烷基”意思是如上文所定义的烷基,其中所述烷基经一个或多个OH基团取代。羟烷基的实例包括HO-CH2-、HO-CH2-CH2-和CH3-CH(OH)-。
如本文所用的术语“烷氧基”指的是含有1-12个碳原子且在链中含有末端“O”的直链或分支链饱和烃,即-O(烷基)。烷氧基的实例包括(但不限于)甲氧基、乙氧基、丙氧基、丁氧基、叔丁氧基或戊氧基。
“芳烷基”或“芳基烷基”意思是经每个环含有3到24个环原子的芳基环取代的如上文所定义的C1-C6烷基。举例来说,本文所述的芳基烷基可具有下式:其中n为1到6的整数。适合芳烷基的非限制性实例包括苯甲基、2-苯乙基和萘基甲基。与母体部分的键结是经烷基。
“环烷基烷基”意思是含有3-18个碳原子且进一步经C1-C6烷基取代的单环饱和碳环。一般来说,本文所述的环烷基烷基展示下式:其中m为1到6的整数且n为1到16的整数。
“杂环烷基-烷基”意思是经每个环含有3到24个环原子的杂环烷基环取代的如上文所定义的C1-C6烷基。举例来说,杂环烷基-烷基可具有以下结构:其中n为1到6的整数。与母体部分的键结是经烷基。
“杂芳基烷基”意思是经每个环含有5到24个环原子的杂芳基环取代的如上文所定义的C1-C6烷基。举例来说,杂芳基烷基可具有以下结构:其中n为1到6的整数。与母体部分的键结是经烷基。
还应注意,假定在本文中的正文、流程、实例和表格中具有不饱和价数的任何碳以及杂原子具有足以使价数饱和的数目的氢原子。
如本文所用,必要时,提到氢还可指氘取代。如本文所用的术语“氘”意思是具有奇数个质子和中子的稳定氢同位素。
术语“卤基”或“卤素”指的是氟、氯、溴或碘。
如本文所用的术语“卤代烷基”指的是经一个或多个卤素取代的如本文所定义的烷基。卤代烷基的实例包括(但不限于)三氟甲基、二氟甲基、五氟乙基、三氯甲基等。
如本文所用的术语“卤代烷氧基”指的是经一个或多个卤素取代的如本文所定义的烷氧基。卤代烷基的实例包括(但不限于)三氟甲氧基、二氟甲氧基、五氟乙氧基、三氯甲氧基等。
如本文所用的术语“氰基”意思是碳原子经三键连接到氮原子的取代基,即
如本文所用的术语“胺”指的是伯(R-NH2,R≠H)、仲(R2-NH,R2≠H)和叔(R3-N,R≠H)胺。经取代的胺的意思打算是至少一个氢原子已经取代基置换的胺。
如本文所用的术语“氨基”意思是含有至少一个氮原子的取代基。具体来说,NH2、-NH(烷基)或烷基氨基、-N(烷基)2或二烷基氨基、酰胺-、碳酰胺-、脲和硫酰胺取代基包括于术语“氨基”中。
如本文所用的术语“(氨基)烷氧基”或“氨基烷氧基”意思是如上文所定义的烷氧基,其中所述烷氧基的直链或分支链饱和烃经一个或多个氨基取代。
如本文所用的术语“氨基烷基”或“氨基(烷基)”指的是经一个或多个氨基取代一次或多次的如本文所定义的烷基。
如本文所用的术语“烷基氨基”指的是一个氢已经如上文所定义的烷基置换的氨基或NH2基团,即-NH-烷基。烷基氨基的实例包括(但不限于)甲基氨基(即-NHCH3)、乙基氨基、丙基氨基、异丙基氨基、正丁基氨基、仲丁基氨基和叔丁基氨基。
如本文所用的术语“二烷基氨基”指的是两个氢已经如上文所定义的烷基置换的氨基或NH2基团,即-N(烷基)2。氨基上的烷基可为相同或不同烷基。烷基氨基的实例包括(但不限于)二甲基氨基(即-N(CH3)2)、二乙基氨基、二丙基氨基、二异丙基氨基、二正丁基氨基、二仲丁基氨基、二叔丁基氨基、甲基(乙基)氨基、甲基(丁基氨基)等。
术语“芳氧基”指的是含有末端“O”的如本文所定义的芳基环,即Ar-O-,其中Ar为芳基。芳氧基的实例包括(但不限于)苯氧基、联苯氧基和萘氧基。
如本文所用的术语“亚甲二氧基”意思是具有结构式-O-CH2-O-的官能团,其通过两个化学键经氧连接到分子。
如本文所用的“烷氧基烷基”意思是进一步经一个或多个如本文所定义的烷氧基取代的如本文所定义的烷基,即烷基-O-烷基-。
如本文所用的术语“(烷氧基烷基)氨基”意思是具有至少一个如上文所定义的烷氧基烷基和至少一个如上文所定义的氨基的氨基取代基。
除非另有特别规定,否则术语“芳基”指的是具有1到3个芳香族环的环状、芳香族烃基,包括单环或双环基团,例如苯基、联苯基或萘基。在含有两个芳香族环(双环等)的情况下,芳基的芳香族环可在单一点处连接(例如联苯基),或稠合(例如萘基)。芳基可在任何连接点处任选经一个或多个取代基,例如1到5个取代基取代。取代基本身可任选经取代。此外,当含有两个稠合环时,本文所定义的芳基可具有与完全饱和环稠合的不饱和或部分饱和环。这些芳基的示范性环系统包括(但不限于)苯基、联苯基、萘基、蒽基、萉基、菲基、二氢茚基、茚基、四氢萘基、四氢苯并轮烯基等。
除非另有特别规定,否则“杂芳基”意思是5到18个环原子的单价单环芳香族基团、或多环芳香族基团,其含有一个或多个选自N、O或S的环杂原子,其余环原子为C。如本文所定义的杂芳基意思还是双环杂芳香族基团,其中杂原子选自N、O或S。芳香族基团任选独立地经一个或多个本文所述的取代基取代。取代基本身可任选经取代。实例包括(但不限于)苯并噻吩、呋喃基、噻吩基、吡咯基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基、咪唑基、异噁唑基、噁唑基、噁二唑基、吡嗪基、吲哚基、噻吩-2-基、喹啉基、苯并吡喃基、异噻唑基、噻唑基、噻二唑基、噻吩并[3,2-b]噻吩、三唑基、三嗪基、咪唑并[1,2-b]吡唑基、呋喃并[2,3-c]吡啶基、咪唑并[1,2-a]吡啶基、吲唑基、吡咯并[2,3-c]吡啶基、吡咯并[3,2-c]吡啶基、吡唑并[3,4-c]吡啶基、苯并咪唑基、噻吩并[3,2-c]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[2,3-b]吡啶基、苯并噻唑基、吲哚基、吲哚啉基、吲哚啉酮基、二氢苯并噻吩基、二氢苯并呋喃基、苯并呋喃、色满基、硫代色满基、四氢喹啉基、二氢苯并噻嗪、二氢苯并噁烷基、喹啉基、异喹啉基、1,6-萘啶基、苯并[de]异喹啉基、吡啶并[4,3-b][1,6]萘啶基、噻吩并[2,3-b]吡嗪基、喹唑啉基、四唑并[1,5-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、异吲哚基、吡咯并[2,3-b]吡啶基、吡咯并[3,4-b]吡啶基、吡咯并[3,2-b]吡啶基、咪唑并[5,4-b]吡啶基、吡咯并[1,2-a]嘧啶基、四氢吡咯并[1,2-a]嘧啶基、3,4-二氢-2H-1λ2-吡咯并[2,1-b]嘧啶、二苯并[b,d]噻吩、吡啶-2-酮、呋喃并[3,2-c]吡啶基、呋喃并[2,3-c]吡啶基、1H-吡啶并[3,4-b][1,4]噻嗪基、苯并噁唑基、苯并异噁唑基、呋喃并[2,3-b]吡啶基、苯并噻吩基、1,5-萘啶基、呋喃并[3,2-b]吡啶、[1,2,4]三唑并[1,5-a]吡啶基、苯并[1,2,3]三唑基、咪唑并[1,2-a]嘧啶基、[1,2,4]三唑并[4,3-b]哒嗪基、苯并[c][1,2,5]噻二唑基、苯并[c][1,2,5]噁二唑、1,3-二氢-2H-苯并[d]咪唑-2-酮、3,4-二氢-2H-吡唑并[1,5-b][1,2]噁嗪基、4,5,6,7-四氢吡唑并[1,5-a]吡啶基、噻唑并[5,4-d]噻唑基、咪唑并[2,1-b][1,3,4]噻二唑基、噻吩并[2,3-b]吡咯基、3H-吲哚基和其衍生物。此外,当含有两个稠合环时,本文所定义的杂芳基可具有与完全饱和环稠合的不饱和或部分饱和环。
如本文所用的术语“环烷基”指的是每个环具有3到18个碳原子的饱和或部分饱和、单环、稠合或螺式多环碳环。环烷基环或碳环可在任何连接点处任选经一个或多个取代基,例如1到5个取代基取代。取代基本身可任选经取代。环烷基的实例包括(但不限于)环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片基、降冰片烯基、双环[2.2.2]辛基、双环[2.2.2]辛烯基、十氢萘基、八氢-1H-茚基、环戊烯基、环己烯基、环己-1,4-二烯基、环己-1,3-二烯基、1,2,3,4-四氢萘基、八氢并环戊二烯基、3a,4,5,6,7,7a-六氢-1H-茚基、1,2,3,3a-四氢并环戊二烯基、双环[3.1.0]己基、双环[2.1.0]戊基、螺[3.3]庚基、双环[2.2.1]庚基、双环[2.2.1]庚-2-烯基、双环[2.2.2]辛基、6-甲基双环[3.1.1]庚基、2,6,6-三甲基双环[3.1.1]庚基和其衍生物。
如本文所用的术语“杂环烷基”指的是饱和或部分饱和单环或稠合或螺式多环环结构,其含有碳和获自氧、氮或硫的杂原子且其中不存在环碳或杂原子之间共用的非定域π电子(芳香族性)。杂环烷基环结构可经一个或多个取代基取代。取代基本身可任选经取代。杂环基环的实例包括(但不限于)氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡咯烷基、噁唑啉基、噁唑啶基、噻唑啉基、四氢噻唑基、吡喃基、硫代吡喃基、四氢吡喃基、二氧杂环戊烷基、哌啶基、吗啉基、硫代吗啉基、硫代吗啉基S-氧化物、硫代吗啉基S-二氧化物、哌嗪基、氮呯基、氧呯基、二氮呯基、托烷基、高托烷基、二氢噻吩-2(3H)-酮基、四氢噻吩1,1-二氧化物、2,5-二氢-1H-吡咯基、咪唑啶-2-酮、吡咯烷-2-酮、二氢呋喃-2(3H)-酮、1,3-二氧杂环戊烷-2-酮、异四氢噻唑1,1-二氧化物、4,5-二氢-1H-咪唑基、4,5-二氢噁唑基、环氧乙烷基、吡唑烷基、4H-1,4-噻嗪基、硫代吗啉基、1,2,3,4-四氢吡啶基、1,2,3,4-四氢吡嗪基、1,3-噁嗪烷-2-酮、四氢-2H-硫代吡喃1,1-二氧化物、7-氧杂双环[2.2.1]庚基、1,2-硫氮杂环庚烷1,1-二氧化物、八氢-2H-喹嗪基、1,3-二氮杂双环[2.2.2]辛基、2,3-二氢苯并[b][1,4]二氧杂环己烷、3-氮杂双环[3.2.1]辛基、8-氮杂螺[4.5]癸烷、8-氧杂-3-氮杂双环[3.2.1]辛基、2-氮杂双环[2.2.1]庚烷、2,8-二氮杂螺[5.5]十一烷基、2-氮杂螺[5.5]十一烷基、3-氮杂螺[5.5]十一烷基、十氢异喹啉基、1-氧杂-8-氮杂螺[4.5]癸基、8-氮杂双环[3.2.1]辛基、1,4′-联哌啶基、氮杂环庚烷基、8-氧杂-3-氮杂双环[3.2.1]辛基、3,4-二氢-2H-苯并[b][1,4]噁嗪基、5,6,7,8-四氢咪唑并[1,2-a]吡啶基、1,4-二氮杂环庚烷基、啡噁噻基、苯并[d][1,3]二氧杂环戊烯基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、4-(哌啶-4-基)吗啉基、3-氮杂螺[5.5]十一烷基、十氢喹啉基、哌嗪-2-酮、1-(吡咯烷-2-基甲基)吡咯烷基、1,3'-联吡咯烷基和6,7,8,9-四氢-1H,5H-吡唑并[1,2-a][1,2]二氮呯基。
如本文所用的数值范围打算包括顺序的整数。举例来说,表示为“0到4”的范围将包括0、1、2、3和4。
如本文所用的术语“经取代”意思是指定基团或部分带有一个或多个适合的取代基,其中所述取代基可在一个或多个位置处连接到指定基团或部分。举例来说,经环烷基取代的芳基可指示环烷基以一键或通过与芳基稠合且共用两个或更多个共有原子而连接到芳基的一个原子。
如本文所用的术语“未经取代”意思是指定基团不带有取代基。
术语“任选经取代”应理解为意思是给定化学部分(例如烷基)可能(但不需要)键结其它取代基(例如杂原子)。举例来说,任选经取代的烷基可为完全饱和的烷基链(即纯烃)。或者,上述任选经取代的烷基可具有不同于氢的取代基。举例来说,其可在沿着链的任何点处结合到卤素原子、羟基或本文所述的任何其它取代基。因此,术语“任选经取代”意思是给定化学部分具有含其它官能团的潜力,但不一定具有任何其它官能团。在所述基团的任选取代中所用的适合取代基包括(但不限于)氧代基、-卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、-OC1-C6烯基、-OC1-C6炔基、-C1-C6烯基、-C1-C6炔基、-OH、CN(氰基)、-CH2CN、-OP(O)(OH)2、-C(O)OH、-OC(O)C1-C6烷基、-C(O)C1-C6烷基、-C(O)-C0-C6亚烷基-环烷基、-C(O)-C0-C6亚烷基-杂环烷基、-C(O)-C0-C6亚烷基-芳基、-C(O)-C0-C6亚烷基-杂芳基、-OC(O)OC1-C6烷基、NH2、NH(C1-C6烷基)、N(C1-C6烷基)2、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-C(O)NH环烷基、-C(O)N(C1-C6烷基)环烷基、-C(O)NH杂环烷基、-C(O)N(C1-C6烷基)杂环烷基、-C(O)NH芳基、-C(O)N(C1-C6烷基)芳基、-C(O)NH杂芳基、-C(O)N(C1-C6烷基)杂芳基、-S(O)2-C1-C6烷基、-S(O)2-C1-C6卤代烷基、-S(O)2-环烷基、-S(O)2-杂环烷基、-S(O)2-芳基、-S(O)2-杂芳基、-C0-C6亚烷基-S(O)2NH2、-S(O)2NHC1-C6烷基、-S(O)2N(C1-C6烷基)2、-S(O)2NH环烷基、-S(O)2NH杂环烷基、-S(O)2NH芳基、-S(O)2NH杂芳基、-NHS(O)2C1-C6烷基、-N(C1-C6烷基)S(O)2(C1-C6烷基)、-NHS(O)2芳基、-N(C1-C6烷基)S(O)2芳基、-NHS(O)2杂芳基、-N(C1-C6烷基)S(O)2杂芳基、-NHS(O)2环烷基、-N(C1-C6烷基)S(O)2环烷基、-NHS(O)2杂环烷基、-N(C1-C6烷基)S(O)2杂环烷基、-N(C1-C6烷基)S(O)2芳基、-C0-C6亚烷基-芳基、-C0-C6亚烷基-杂芳基、-C0-C6亚烷基-环烷基、-C0-C6亚烷基-杂环烷基、-O-芳基、-NH-芳基和N(C1-C6烷基)芳基。取代基本身可任选经取代。当展示多官能部分时,与核心的连接点由线指示,例如,(环烷氧基)烷基-指的是烷基为与核心的连接点,而环烷基经氧基连接到烷基。“任选经取代”还指“经取代”或“未经取代”,其含义描述于上文。
如本文所用的术语“氧基”指的是“-O-”基团。
如本文所用的术语“氧代基”指的是“=O”基团。
术语“溶剂合物”指的是由溶质和溶剂形成的可变化学计量的复合物。用于本发明目的的所述溶剂可能不干扰溶质的生物活性。适合溶剂的实例包括(但不限于)水、MeOH、EtOH和AcOH。水为溶剂分子的溶剂合物典型地称作水合物。水合物包括含有化学计量量的水的组成物,以及含有可变量的水的组成物。
术语“异构物”指的是具有相同组成和分子量,但物理和/或化学特性不同的化合物。结构差异可在构造方面(几何异构物)或在使偏振光的平面旋转的能力方面(立体异构物)。关于立体异构物,式(I)、(II)、(III)或(IV)的化合物可具有一个或多个不对称碳原子且可依外消旋物、外消旋混合物形式和个别对映异构物或非对映异构物形式出现。
如本文所用的术语“盐”表示与无机和/或有机酸形成的酸性盐,以及与无机和/或有机碱形成的碱性盐。另外,当化学式的化合物含有例如(但不限于)吡啶或咪唑的碱性部分与例如(但不限于)羧酸的酸性部分时,可形成两性离子(“内盐”)且其包括于如本文所用的术语“盐”内。优选是药学上可接受(即无毒、生理学上可接受)的盐,不过其它盐也适用。化学式的化合物的盐可例如通过使化学式的化合物与一定量(例如当量)的酸或碱在例如盐于其中沉淀的介质中或在水性介质中反应继而冻干来形成。
在本发明的另一实施例中,式(I)-(IV)的化合物为对映异构物。在一些实施例中,化合物为(S)-对映异构物。在其它实施例中,化合物为(R)-对映异构物。在其它实施例中,式(I)、(II)、(III)或(IV)的化合物可为(+)或(-)对映异构物。
应了解,所有异构形式都包括于本发明内,包括其混合物。如果化合物含有双键,那么取代基可呈E或Z构型。如果化合物含有经二取代的环烷基,那么环烷基取代基可具有顺式或反式构型。所有互变异构形式也打算包括在内。
各种化学式的化合物和其盐、溶剂合物、酯和前药可依其互变异构形式(例如酰胺或亚胺基醚形式)存在。所用所述互变异构形式作为本发明的一部分涵盖于本文中。
各种化学式的化合物可含有不对称或对掌性中心,且因此以不同立体异构形式存在。各种化学式的化合物的所有立体异构形式以及其混合物(包括外消旋混合物)打算构成本发明的一部分。另外,本发明包涵所有几何和位置异构物。举例来说,如果各种化学式的化合物并有双键或稠合环,那么顺式与反式形式以及混合物包涵于本发明的范围内。本文所披露的各化合物包括符合化合物的通式结构的所有对映异构物。化合物可呈外消旋或对映异构纯的形式,或依据立体化学的任何其它形式。分析结果可反映外消旋形式、对映异构纯的形式或依据立体化学的任何其它形式所收集的数据。
非对映异构物混合物可基于其物理化学差异通过所属领域技术人员众所周知的方法,例如通过色谱和/或分步结晶而分离成其个别非对映异构物。对映异构物可通过使对映异构物混合物经与适当光学活性化合物(例如对掌性助剂,例如对掌性醇或莫舍氏酸氯化物(Mosher′s acid chloride))反应而转化成非对映异构物混合物,分离非对映异构物且使个别非对映异构物转化(例如水解)成相应纯对映异构物来分离。此外,各种化学式的化合物中的一些化合物可为滞转异构物(例如经取代的联芳基化物)且视为本发明的一部分。对映异构物还可通过使用对掌性HPLC柱来分离。
各种化学式的化合物还可能以不同互变异构形式存在,且所有所述形式都包涵于本发明的范围内。此外,举例来说,化合物的所有酮-烯醇和亚胺-烯胺形式包括于本发明中。
本发明化合物(包括化合物的盐、溶剂合物、酯和前药以及前药的盐、溶剂合物和酯)的所有立体异构物(例如几何异构物、光学异构物等),例如由于各种取代基上的不对称碳而可存在的立体异构物,包括对映异构形式(其甚至在不存在不对称碳的情况下也可存在)、旋转异构形式、滞转异构物和非对映异构形式,涵盖于本发明的范围内,位置异构物(例如4-吡啶基和3-吡啶基)同样如此。(举例来说,如果各种化学式的化合物并有双键或稠合环,那么顺式与反式形式以及混合物包涵于本发明的范围内。此外,举例来说,化合物的所有酮-烯醇和亚胺-烯胺形式包括于本发明中。)本发明化合物的个别立体异构物可例如实质上无其它异构物,或可例如以外消旋物形式混合,或与所有其它或其它所选立体异构物混合。本发明的对掌性中心可具有如由IUPAC 1974Recommendations定义的S或R构型。术语“盐”、“溶剂合物”、“酯”、“前药”等的使用打算同等地适用于本发明化合物的对映异构物、立体异构物、旋转异构物、互变异构物、位置异构物、外消旋物或前药的盐、溶剂合物、酯和前药。
本发明还包涵经同位素标记的本发明化合物,其与本文所述的化合物相同,但一个或多个原子经原子质量或质量数不同于自然界中通常所见的原子质量或质量数的原子置换。可并入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别为例如2H(或D)、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。
某些经同位素标记的各种化学式的化合物(例如经3H和14C标记的化合物)适用于化合物和/或基质组织分布分析。氚化(即3H)和碳-14(即14C)同位素因其制备简易性和可检测性而尤其优选。此外,经例如氘(即2H)的较重同位素取代可得到由较高代谢稳定性而产生的某些治疗优势(例如增加的体内半衰期或降低的剂量需求)且因此在一些情况下可能优选。经同位素标记的各种化学式的化合物一般可通过遵循与下文的流程中和/或实例中所披露的程序类似的程序,通过用适当经同位素标记的试剂取代未经同位素标记的试剂来制备。
式I到IV的化合物可形成盐,所述盐也处于本发明的范围内。除非另有指示,否则在本文中提到化学式的化合物应理解为包括提到其盐。
本发明关于作为BET家族的一个或多个溴域的调节剂的化合物。在一个实施例中,本发明化合物为BET家族的一个或多个溴域的抑制剂。
本发明针对如本文所述的化合物和其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物,和包含如本文所述的一种或多种化合物或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物的医药组成物。
本发明化合物
本发明关于能够调节BET家族溴域,包括BRD2、BRD3、BRD4和BRDT的化合物或其药学上可接受的盐或异构物,其适用于治疗与调节BET家族溴域相关的疾病和病症。本发明进一步关于适用于抑制BET家族溴域的化合物或其药学上可接受的盐或异构物。
本发明的另一方面提供医药组成物,其包含治疗有效量的至少一种具有式I、II、III或IV的化合物。
本发明的一个方面关于式I化合物
和其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物和互变异构物,其中W、X、Y、Z、R1、R2、R3、R4、R5、R6、R7、R8、Ra、Rb、Rc、Rd和n如上文所述。
本发明的一个实施例关于式II化合物
和其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物和互变异构物,
其中:
W为O、C(O)或CHR3;
Ar为芳基或杂芳基;
R2为氢或NRaRb;
R3为氢、羟基或卤基;
R4为氢、-O(CH2)nRd、-O(CH2)nC(O)Rd、-O(CH2)nS(O)2Rd或-N(CH2)nRd;
R7为氢或卤基;
R8为Ra、-ORa或杂环烷基;
Ra和Rb各自独立地为氢、C1-C6烷基、环烷基或杂环烷基;
Rc为Ra、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-S(O)2Ra、卤基或氧代基;以及
n为0、1或2;
Rd为氢、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6烷基、环烷基、杂环烷基、芳基或杂芳基,其中所述烷基、环烷基、杂环烷基、芳基和杂芳基任选经一个或多个独立地选自Ra、Rb和Rc的取代基取代;
且n为0、1或2。
本发明的另一实施例关于式III化合物
和其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物和互变异构物,
其中:
Ar为吡唑基或苯基;
R4为氢、-O(CH2)nRd、-O(CH2)nC(O)Rd或-O(CH2)nS(O)2Rd;
R8为甲基、甲氧基或环丙基;
Ra和Rb各自独立地为氢或C1-C6烷基;
Rc为-(CH2)nRa、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-(CH2)nS(O)2CH3、-S(O)2Ra、-S(O)2NRaRb、C1-C6卤代烷基、C1-C6卤代烷氧基、环烷基、杂环烷基、卤基、氰基或氧代基;
Rd为氢、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6烷基、环烷基、杂环烷基、芳基或杂芳基,其中所述烷基、环烷基、杂环烷基、芳基和杂芳基任选经一个或多个独立地选自Ra、Rb和Rc的取代基取代;且n为0、1或2。
本发明的另一实施例关于式IV化合物
和其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物和互变异构物,
其中:
R4为-O(CH2)nRd、-O(CH2)nC(O)Rd或-O(CH2)nS(O)2Rd;
R8为烷基、环烷基、O-烷基或O-环烷基;
Ra和Rb各自独立地为氢或C1-C6烷基;
Rc为-(CH2)nRa、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-S(O)2Ra、-S(O)2NRaRb、C1-C6卤代烷基、C1-C6卤代烷氧基、芳基、杂芳基、环烷基、杂环烷基、卤基、氰基或氧代基;
Rd为氢、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6烷基、环烷基、杂环烷基、芳基或杂芳基,其中所述烷基、环烷基、杂环烷基、芳基和杂芳基任选经一个或多个独立地选自Ra、Rb和Rc的取代基取代;以及
n为0、1或2。
本发明的一方面涉及作为或可为BET家族的一个或多个溴域的抑制剂的化合物。
本发明的一方面涉及BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除肿瘤的药剂的用途。
本发明的一方面涉及BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除癌症的药剂的用途。
本发明的一方面涉及BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除与慢性自体免疫和发炎性病状相关的疾病的药剂的用途。
本发明的一方面涉及BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除与急性发炎性病状相关的疾病的药剂的用途。
本发明的一方面涉及BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除与全身发炎反应综合症相关的疾病的药剂的用途。
本发明的一方面涉及BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除与病毒、细菌或真菌感染相关的疾病或病症的药剂的用途。
本发明的一方面涉及BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除糖尿病或肥胖症的药剂的用途。
本发明的一方面涉及BET家族溴域的抑制剂用于制备男性避孕药的用途。
本发明的一个实施例关于式I化合物,其中X为CR4且Y和Z为CH。
本发明的另一实施例关于式I化合物,其中W为CHR3。
本发明的另一实施例关于式II化合物,其中W为CHR3。
本发明的另一实施例关于式II化合物,其中Ar为吡唑或苯基。
本发明的另一实施例关于式III化合物,其中Ar为吡唑且Rc为环烷基或杂环烷基。
本发明的另一方面关于式III化合物,其中Rc为环丙基。
本发明的又一实施例针对式III化合物,其中Ar为苯基,Rc为-(CH2)nS(O)2CH3。
本发明的另一实施例针对式IV化合物,其中Rc为环烷基或杂环烷基。
本发明的另一实施例针对式IV化合物,其中R4为-O(CH2)nRc。
本发明的另一实施例针对式IV化合物,其中Rc为芳基、杂芳基或环烷基。
在本发明的一些实施例中,W为CH。在另一实施例中,W为CH。在又一实施例中,W为CH且X为CR4。在另一实施例中,W为CH,X为CR4且Y为CH。在又一实施例中,W为CH,X为CR4,Y为CH,且Z为CR7。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CR7,且R1为C1-C6烷基。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CR7,R1为C1-C6烷基且R2为H。在又一实施例中,W为CH,X为CR4,Y为CH,Z为CR7,R1为C1-C6烷基,R2为H,且R8为Ra或ORa。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CR7,R1为C1-C6烷基,R2为H,R8为Ra或ORa,且Ra为C1-C6烷基或环烷基。在又一实施例中,W为CH,X为CR4,Y为CH,Z为CR7,R1为C1-C6烷基,R2为H,R8为Ra或ORa,Ra为C1-C6烷基或环烷基,且R4为ORd。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CR7,R1为C1-C6烷基,R2为H,R8为Ra或ORa,Ra为C1-C6烷基或环烷基,R4为ORd,且Rd为任选经一个或多个优选取代基取代的C1-C6烷基、C1-C6卤代烷基、环烷基、芳基或杂芳基。在又一实施例中,W为CH,X为CR4,Y为CH,Z为CR7,R1为C1-C6烷基,R2为H,R8为Ra或ORa,Ra为C1-C6烷基或环烷基,R4为ORd,Rd为任选经一个或多个优选取代基取代的C1-C6烷基、C1-C6卤代烷基、环烷基、芳基或杂芳基,且R5为任选经一个或多个优选取代基取代的杂芳基。
在本发明的一些实施例中,W为CH。在另一实施例中,W为CH。在又一实施例中,W为CH且X为CR4。在另一实施例中,W为CH,X为CR4且Y为CH。在又一实施例中,W为CH,X为CR4,Y为CH,且Z为CH或CF。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CH或CF,且R1为甲基。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CH或CF,R1为甲基且R2为H。在又一实施例中,W为CH,X为CR4,Y为CH,Z为CH或CF,R1为甲基,R2为H,且R8为Ra或ORa。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CH或CF,R1为甲基,R2为H,R8为Ra或ORa,且Ra为C1-C6烷基或环烷基。在又一实施例中,W为CH,X为CR4,Y为CH,Z为CH或CF,R1为甲基,R2为H,R8为Ra或ORa,Ra为C1-C6烷基或环烷基,且R4为ORd。在另一实施例中,W为CH,X为CR4,Y为CH,Z为CH或CF,R1为甲基,R2为H,R8为Ra或ORa,Ra为C1-C6烷基或环烷基,R4为ORd,且Rd为任选经一个或多个优选取代基取代的C1-C6烷基、C1-C6卤代烷基、环烷基、芳基或杂芳基。在又一实施例中,W为CH,X为CR4,Y为CH,Z为CH或CF,R1为甲基,R2为H,R8为Ra或ORa,Ra为C1-C6烷基或环烷基,R4为ORd,Rd为任选经一个或多个优选取代基取代的C1-C6烷基、C1-C6卤代烷基、环烷基、芳基或杂芳基,且R5为任选经一个或多个优选取代基取代的杂芳基。
本发明的另一方面为一种包含式I化合物和药学上可接受的载剂的医药组成物。
本发明的另一方面为一种包含式I化合物和药学上可接受的载剂的医药组成物,其包含治疗有效量的一种或多种其它治疗剂。
在本发明的一些实施例中,本发明关于一种包含式I化合物和药学上可接受的载剂的医药组成物,其包含治疗有效量的一种或多种其它治疗剂,其中所述其它治疗剂选自由以下组成的群组:细胞毒性剂、顺铂(cisplatin)、小红莓(doxorubicin)、克癌易(taxotere)、紫杉醇(taxol)、依托泊苷(etoposide)、伊立替康(irinotecan)、开普拓(camptostar)、拓扑替康(topotecan)、太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)、埃博霉素(epothilone)、他莫昔芬(tamoxifen)、5-氟尿嘧啶、氨甲喋呤(methotrexate)、替莫唑胺(temozolomide)、环磷酰胺、SCH 66336、替吡法尼(tipifarnib)、R115777、L778,123、BMS 214662、C225、芳香酶组合、ara-C、阿霉素(adriamycin)、癌得星(cytoxan)、吉西他滨(gemcitabine)、尿嘧啶芥(Uracil mustard)、氮芥(Chlormethine)、异环磷酰胺(Ifosfamide)、美法仑(Melphalan)、苯丁酸氮芥(Chlorambucil)、哌泊溴烷(Pipobroman)、三亚乙基三聚氰胺(Triethylenemelamine)、三亚乙基硫代磷酰胺(Triethylenethiophosphoramine)、白消安(Busulfan)、卡莫司汀(Carmustine)、洛莫司汀(Lomustine)、链脲菌素(Streptozocin)、达卡巴嗪(Dacarbazine)、氟尿苷(Floxuridine)、阿糖胞苷(Cytarabine)、6-巯基嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨(Fludarabinephosphate)、甲酰四氢叶酸(leucovirin)、奥沙利铂(oxaliplatin;)、喷司他丁(Pentostatine)、长春碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)、博莱霉素(Bleomycin)、放线菌素D(Dactinomycin)、道诺霉素(Daunorubicin)、表柔比星(Epirubicin)、伊达比星(Idarubicin)、MithramycinTM、去氧助间型霉素(Deoxycoformycin)、丝裂霉素C(Mitomycin-C)、L-天冬酰胺酶、替尼泊苷(Teniposide)、17α-乙炔雌二醇(17α-Ethinylestradiol)、己烯雌酚(Diethylstilbestrol)、睪固酮(Testosterone)、泼尼松(Prednisone)、氟甲睪固酮(Fluoxymesterone)、丙酸屈他雄酮(Dromostanolone propionate)、睪内酯(Testolactone)、乙酸甲地孕酮(Megestrol acetate)、甲基泼尼松龙(Methylprednisolone)、甲基睪固酮(Methyltestosterone)、泼尼松龙(Prednisolone)、曲安西龙(Triamcinolone)、氯烯雌醚(Chlorotrianisene)、羟孕酮(Hydroxyprogesterone)、氨鲁米特(Aminoglutethimide)、雌莫司汀(Estramustine)、乙酸甲羟孕酮(Medroxyprogesteroneacetate)、亮丙瑞林(Leuprolide)、氟他胺(Flutamide)、托瑞米芬(Toremifene)、戈舍瑞林(goserelin)、卡铂(Carboplatin)、羟基脲、安吖啶(Amsacrine)、丙卡巴肼(Procarbazine)、米托坦(Mitotane)、米托蒽醌(Mitoxantrone)、左旋咪唑(Levamisole)、诺维本(Navelbene)、阿那曲唑(Anastrazole)、利妥唑(Letrazole)、卡培他滨(Capecitabine)、雷洛昔芬(Reloxafine)、屈洛昔芬(Droloxafine)、六甲三聚氰胺(Hexamethylmelamine)、癌思停(Avastin)、贺癌平(herceptin)、百克沙(Bexxar)、万珂(Velcade)、泽瓦灵(Zevalin)、三氧化二砷(Trisenox)、截瘤达(Xeloda)、长春瑞滨(Vinorelbine)、卟吩姆(Porfimer)、尔必得舒(Erbitux)、微脂体(Liposomal)、沙奥特帕(Thiotepa)、六甲蜜胺(Altretamine)、美法仑、曲妥珠单抗(Trastuzumab)、利妥唑(Lerozole)、氟维司群(Fulvestrant)、依西美坦(Exemestane)、利妥昔单抗(Rituximab)、C225、坎帕斯(Campath)、甲酰四氢叶酸、地塞米松(dexamethasone)、比卡鲁胺(bicalutamide)、卡铂、苯丁酸氮芥、顺铂、利妥唑、甲地孕酮(megestrol)和戊柔比星(valrubicin)。
本发明的另一方面针对一种抑制患者的BET家族溴域中的一个或多个的方法,其包括向有需要的患者投予有效量的式I化合物。
本发明的另一方面针对一种抑制患者的BET家族溴域中的一个或多个的方法,其包括向有需要的患者投予有效量的包含式I化合物和药学上可接受的载剂的医药组成物。
本发明的另一方面针对一种治疗、预防、抑制或消除患者的与一个或多个BET家族溴域的活性相关的疾病或病症的方法,其包括向所述有需要的患者投予治疗有效量的式I化合物。
本发明的一个实施例关于一种治疗、预防、抑制或消除患者的与一个或多个BET家族溴域的活性相关的疾病或病症的方法,其包括向所述有需要的患者投予治疗有效量的式I化合物,且进一步包括向所述有需要的患者投予治疗有效量的另一治疗剂。
本发明的另一实施例关于一种治疗、预防、抑制或消除患者的与一个或多个BET家族溴域的活性相关的疾病或病症的方法,其包括向所述有需要的患者投予治疗有效量的式I化合物,其中所述疾病或病症选自由以下组成的群组:癌症、发炎性病症、大肠激躁综合症、发炎性肠病、类风湿性关节炎、肥胖症和糖尿病。
本发明的另一方面为一种男性避孕药,其包含治疗有效量的至少一种式I化合物。
本发明的另一方面为一种男性避孕药,其包含治疗有效量的至少一种表1的化合物。
本发明是由表1中所示的化合物与所述化合物的IUPAC命名和结构来进一步说明。所述表格还提供对用以制造如下文实例中所述的各化合物的方法的参考。
在另一实施例中,本发明的说明性化合物包括:
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-{[3-(羟甲基)氧杂环丁烷-3-基]甲氧基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-{八氢环戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(3,3-二氟环丁氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-(氮杂环丁烷-3-基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(3-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(1,3-二氟丙-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(3-羟基-2,2-二甲基丙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-2-甲基丙酰胺;
(2S)-1-环丙烷羰基-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
1-(2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙基)吡咯烷-2-酮;
(2S)-1-环丙烷羰基-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-1-(吗啉-4-基)乙-1-酮;
(2S)-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-(2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙基)-1λ6,2-噻唑烷-1,1-二酮;
(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}甲烷磺酰胺;
(2S)-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基甲烷磺酰胺;
(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[2-(氧杂环丁烷-3-基)乙氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(2,2-二氟环丙基)甲氧基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
3-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-{[3-(羟甲基)氧杂环丁烷-3-基]甲氧基}-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(3-氟氧杂环丁烷-3-基)甲氧基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(3,3-二氟环丁氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(氮杂环丁烷-3-基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1H-吡唑-5-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-({1-[(叔丁氧基)羰基]氮杂环丁烷-3-基}氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-6-[1-(1,1-二氧代基-1λ6-硫杂环丁烷-3-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[1-(1,1-二氧代基-1λ6-硫杂环己烷-3-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2R)-2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-2-氟乙酰胺;
(2S)-2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-2-氟乙酰胺;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(3-氟氧杂环丁烷-3-基)甲氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-2,2-二氟乙酰胺;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-2-甲基-6-[1-(氧杂环己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
(2S)-5-[(二甲基氨甲酰基)甲氧基]-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N-乙基乙酰胺;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N-环丙基-N-甲基乙酰胺;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-1-(氮杂环丁烷-1-基)乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-1-(哌啶-1-基)乙-1-酮;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(氨甲酰基二氟甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(1,3-二氟丙-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(3-羟基-2,2-二甲基丙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(1-氨甲酰基-1-甲基乙氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(R)-氨甲酰基(氟)甲氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(S)-氨甲酰基(氟)甲氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(乙基氨甲酰基)甲氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-{[环丙基(甲基)氨甲酰基]甲氧基}-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[2-(氮杂环丁烷-1-基)-2-氧代基乙氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[2-氧代基-2-(哌啶-1-基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[2-(2-氧代基吡咯烷-1-基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[2-(吗啉-4-基)-2-氧代基乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[2-(1,1-二氧代基-1λ6,2-噻唑烷-2-基)乙氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(氨磺酰基甲氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(二甲基氨磺酰基)甲氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[2-(氧杂环丁烷-3-基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(2,2-二氟环丙基)甲氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(喹唑啉-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(1,3-苯并噁唑-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(1,3-苯并噁唑-2-基氧基)-2-甲基-6-[1-(氧杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-(嘧啶-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}吡啶-3-甲酰胺;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{1H-吡唑并[3,4-d]嘧啶-6-基氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1,3-噻唑-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}吡啶-3-甲腈;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(3-氯吡啶-2-基)氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(4,6-二甲基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
6-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}哒嗪-3-甲腈;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(吡咯烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-(1-{八氢环戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[6-(4-甲烷磺酰基苯基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-(2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基)乙-1-酮;
1-[(2S)-5-环丙氧基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(5-甲烷磺酰基吡啶-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
N-{6-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]吡啶-3-基}甲烷磺酰胺;
2-{[(2S)-1-乙酰基-6-(5-甲烷磺酰基吡啶-2-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(1,3-苯并噁唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-丙氧基-6-{吡唑并[1,5-a]吡啶-2-基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-{咪唑并[1,2-a]吡啶-2-基}-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1,3-苯并噻唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1H-1,3-苯并二唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-1,2,3,4-四氢喹啉;
5-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1,3,4-噻二唑-2-胺;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(2-氰基-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(2-氯-4-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氰基-2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-5-(2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(2-氰基苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(2-氰基-3-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
4-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(3-氯吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}吡啶-3-甲腈;
1-[(2S)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡嗪-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(4-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(3-氰基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(2-氰基-3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氯-2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
2-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}-6-氟苯甲腈;
4-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}-3-氟苯甲腈;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯-4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
4-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲酰胺;
1-[(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氨甲酰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氰基-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氯-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-(2-氯苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-(4-氯苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
4-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-(3-氯-4-氟苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(3-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯苯氧基)-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-(3-氯苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(3,5-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
5-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1,3,4-噻二唑-2-胺;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(吡咯烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
4-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}苯甲酰胺;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-5-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-6-[1-(1,1-二氧代基-1λ6-硫杂环己烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(1,1-二氧代基-1λ6-硫杂环丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(4-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
3-{4-[(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环丁烷-1,1-二酮;
3-{4-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环丁烷-1,1-二酮;
1-[(2S)-5-(2-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氰基苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(2-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氨甲酰基苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
4-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[1-(丙-2-基)氮杂环丁烷-3-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-5-环丁氧基-2-甲基-6-[1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-(1-{2-甲基-八氢环戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-{2-甲基-八氢环戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(1-乙基氮杂环丁烷-3-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[1-(丙-2-基)氮杂环丁烷-3-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(1-乙基氮杂环丁烷-3-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(异喹啉-1-基氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(2,4-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(2,3-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(2,3-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-(2,3-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(2,3-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
1-[(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮
1-[(2S)-5-{[(E)-2-氯乙烯基]氧基}-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-{1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-甲烷磺酰基-1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-6-[2-(4-羟基哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(4-氟哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(3-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氯吡啶-2-基)氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(7H-嘌呤-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
3-{4-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮;
3-{4-[(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮;
(2S)-5-环丁氧基-2-甲基-6-[1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-{1-[(2S)-2-甲基氮杂环丁烷-3-基]-1H-吡唑-4-基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-{1-[(2S)-2-甲基氮杂环丁烷-3-基]-1H-吡唑-4-基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
N-{4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1-环丙基-1H-吡唑-5-基}甲烷磺酰胺;
N-{4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1-环丙基-1H-吡唑-5-基}乙酰胺;
(2S)-5-环丁氧基-6-[1-(3-羟基环丁基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-甲基-2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(氧杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}-N-甲基乙酰胺;
1-[(2S)-2-甲基-5-(1,2-噁唑-5-基甲氧基)-6-[1-(氧杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
N-(2-{[(2S)-1-乙酰基-2-甲基-6-[1-(氧杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}乙基)甲烷磺酰胺;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1,2-噁唑-5-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
N-(2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙基)甲烷磺酰胺;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N-甲基乙酰胺;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(氧杂环丁烷-3-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(环戊基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[2-(二甲基氨基)乙氧基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(丙-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(环丙基甲氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙酰胺;
1-[(2S)-5-(环丁基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(苯甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(3-甲基氧杂环丁烷-3-基)甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(环戊氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙腈;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-甲氧基乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-3-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(氧杂环己烷-4-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-5-(环己基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-2-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(1-甲基-1H-吡唑-3-基)甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1,3-噻唑-5-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-(氧杂环己烷-4-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(氧杂环己烷-4-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-(氧杂环己烷-4-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-(氧杂环己烷-4-基甲氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
2-{[(2S)-1-乙酰基-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-(2-甲基丙氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(环戊基甲氧基)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(环戊基甲氧基)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(环戊基甲氧基)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(环戊基甲氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-1-(吡咯烷-1-基)乙-1-酮;
2-{[(2S)-1-乙酰基-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-1-(吡咯烷-1-基)乙-1-酮;
2-{[(2S)-1-乙酰基-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-1-(吡咯烷-1-基)乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}-1-(吡咯烷-1-基)乙-1-酮;
(5R)-5-({[(2S)-1-乙酰基-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}甲基)吡咯烷-2-酮;
(5R)-5-({[(2S)-1-乙酰基-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}甲基)吡咯烷-2-酮;
(5R)-5-({[(2S)-1-乙酰基-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}甲基)吡咯烷-2-酮;
(5R)-5-({[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}甲基)吡咯烷-2-酮;
N-(2-{[(2S)-1-乙酰基-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙基)-N-甲基甲烷磺酰胺;
N-(2-{[(2S)-1-乙酰基-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙基)-N-甲基甲烷磺酰胺;
N-(2-{[(2S)-1-乙酰基-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙基)-N-甲基甲烷磺酰胺;
N-(2-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}乙基)-N-甲基甲烷磺酰胺;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-(氧杂环己烷-4-基甲氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(氧杂环己烷-4-基甲氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-(氧杂环己烷-4-基甲氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-(氧杂环己烷-4-基甲氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(二甲基氨甲酰基)甲氧基]-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(二甲基氨甲酰基)甲氧基]-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(二甲基氨甲酰基)甲氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-(2-甲基丙氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(环戊基甲氧基)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(环戊基甲氧基)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(环戊基甲氧基)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(环戊基甲氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-[2-氧代基-2-(吡咯烷-1-基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[2-氧代基-2-(吡咯烷-1-基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-[2-氧代基-2-(吡咯烷-1-基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-[2-氧代基-2-(吡咯烷-1-基)乙氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-氧代基吡咯烷-2-基]甲氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-氧代基吡咯烷-2-基]甲氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-氧代基吡咯烷-2-基]甲氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-{[(2R)-5-氧代基吡咯烷-2-基]甲氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺酰胺基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺酰胺基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺酰胺基)乙氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-[2-(N-甲基甲烷磺酰胺基)乙氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基-1,3-噁唑-2-基)甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-4-基甲氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(1,3-苯并噁唑-2-基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(4-甲烷磺酰基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(4-甲烷磺酰基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-[4-(乙烷磺酰基)苯基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-[4-(乙烷磺酰基)苯基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-{4-[2-(二甲基氨基)乙氧基]苯基}-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-{4-[2-(二甲基氨基)乙氧基]苯基}-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-2-甲基-6-[3-(吗啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[3-(吗啉-4-羰基)苯基]-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
N-{3-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}甲烷磺酰胺;
2-{[(2S)-1-乙酰基-6-(3-甲烷磺酰胺基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(3-甲烷磺酰基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(3-甲烷磺酰基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
N-{4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}甲烷磺酰胺;
2-{[(2S)-1-乙酰基-6-(4-甲烷磺酰胺基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-2-甲基-6-[4-(吗啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[4-(吗啉-4-羰基)苯基]-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
2-{4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}-1λ6,2-噻唑烷-1,1-二酮;
2-{[(2S)-1-乙酰基-6-[4-(1,1-二氧代基-1λ6,2-噻唑烷-2-基)苯基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(1-甲烷磺酰基-2,3-二氢-1H-吲哚-5-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-甲烷磺酰基-2,3-二氢-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
N-{4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}-N-甲基甲烷磺酰胺;
2-{[(2S)-1-乙酰基-2-甲基-6-[4-(N-甲基甲烷磺酰胺基)苯基]-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(1-苯并呋喃-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1H-吲哚-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(氧杂环己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
3-{4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮;
3-{4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环丁烷-1,1-二酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(嘧啶-2-基氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-{[6-(吗啉-4-基)嘧啶-4-基]氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(6-环丙基嘧啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-环丙基嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}吡啶-3-甲酰胺;
1-[(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
6-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}吡啶-3-甲酸甲酯;
6-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}吡啶-3-甲酰胺;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(嘧啶-2-基氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡嗪-2-基氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-{[6-(吗啉-4-基)嘧啶-4-基]氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(6-环丙基嘧啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-环丙基嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-{[5-(甲氧基羰基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-氨甲酰基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉;
2-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}吡啶-3-甲腈;
(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(4,6-二甲基嘧啶-2-基)氧基]-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(丙-2-基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-5-[(5-甲氧基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-环丙基嘧啶-2-基)氧基]-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(1-甲烷磺酰基-2,3-二氢-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(4-甲烷磺酰基苯基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(1-羟基-2-甲基丙-2-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{4-[(2S)-1-乙酰基-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-6-基]苯基}-1λ6,2-噻唑烷-1,1-二酮;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-环丙基嘧啶-2-基)氧基]-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-环丙基嘧啶-2-基)氧基]-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-环丙基嘧啶-2-基)氧基]-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(5-环丙基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(3-氨甲酰基吡啶-2-基)氧基]-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-[(3-氨甲酰基吡啶-2-基)氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-甲烷磺酰基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-羟乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(氧杂环己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
4-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基苯甲酰胺;
(2S)-5-(3-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-环丙烷羰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-2-甲基-6-[1-(氧杂环丁烷-3-基)-1H-吡唑-4-基]-5-[(3R)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-6-[1-(氧杂环丁烷-3-基)-1H-吡唑-4-基]-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(3R)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-羟基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯烷-3-基甲氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-5-(环戊基甲氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1E)-丙-1-烯-1-基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1Z)-丙-1-烯-1-基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-2-甲基-6-[1-甲基-2-(哌嗪-1-基)-1H-咪唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[2-(哌嗪-1-基)-1,3-噻唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-羟基氮杂环丁烷-1-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-5-环丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-7,8-二氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1H-吡唑-1-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-3-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-3-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-5-环丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-[(2,6-二甲基吡啶-3-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-[(2,6-二甲基吡啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-[(6-氯吡啶-2-基)氧基]-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-[(6-氟吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-2-甲基-6-[4-(吗啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌啶-4-基)-1H-吡唑-1-基]-1,2,3,4-四氢喹啉;
(2S)-2-甲基-6-[4-(吗啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-甲腈;
(2S)-1-环丙烷羰基-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(丙-1-炔-1-基)-1,2,3,4-四氢喹啉;
(2S)-6-氰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[2-(氮杂环丁烷-3-基)-1,3-噻唑-4-基]-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-氟氮杂环丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-羟基氮杂环丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-甲氧基氮杂环丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(2-氨甲酰基-1,3-噻唑-4-基)-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[2-(甲基氨甲酰基)-1,3-噻唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-(2-乙酰胺基-1,3-噻唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-6-环丙基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-6-环丙基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-8-氟-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
2-{[(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-1-环丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-6-[1-(1,1-二氧代基-1λ6-硫杂环己烷-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
4-{4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮;
1-[(2S)-6-(1-乙酰基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-甲烷磺酰基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]-1,2,3,6-四氢吡啶-1-甲酸叔丁酯;
1-[(2S)-2-甲基-6-(哌啶-4-基)-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]-N-乙基哌啶-1-甲酰胺;
4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]哌啶-1-甲酸甲酯;
1-[(2S)-6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-(苯基氨基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(2-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(2-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-6-[5-氟-1-(哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-{1-[(3R*,4S*)-4-氟吡咯烷-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;和
(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-[(3R*,4S*)-4-氟哌啶-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉。
在另一实施例中,本发明的适合化合物包括:
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
1-[(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
1-[(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氯吡啶-2-基)氧基]-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(2-氰基-3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氯-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(氧杂环己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-(4-氯苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
4-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
2-{[(2S)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-6-[1-(1,1-二氧代基-1l6-硫杂环丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(3-氯-4-氟苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-6-[1-(氮杂环丁烷-3-基)-1H-吡唑-4-基]-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-(2-氯苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-5-(3-氯苯氧基)-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
3-{4-[(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1l6-硫杂环丁烷-1,1-二酮;
3-{4-[(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1l6-硫杂环己烷-1,1-二酮;
(2S)-1-环丙烷羰基-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;和
1-[(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮。
合成化合物的方法
本发明化合物可通过包括标准化学法的多种方法制得。适合的合成途径描绘于下文所给出的流程中。
本发明化合物,即式(I)-(IV)的化合物,或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物,可通过如部分地由以下合成流程所阐述的在有机合成技术中已知的方法来制备。在下文所述的流程中,应充分了解,根据一般原则或化学性在必要时采用针对敏感性或反应性基团的保护基。根据有机合成的标准方法操作保护基(T.W.Greene和P.G.M.Wuts,“有机合成中的保护基(Protective Groups in OrganicSynthesis)”,第三版,Wiley,New York 1999)。在化合物合成的适宜阶段使用所属领域技术人员显而易知的方法去除这些基团。选择过程以及反应条件和其执行次序应与式(I)-(IV)的化合物的制备一致。
所属领域技术人员将辨别式(I)-(IV)的化合物中是否存在立体中心。因此,本发明包括可能的立体异构物(除非合成中有规定),且不仅包括外消旋化合物,而且同样包括个别对映异构物和/或非对映异构物。当化合物需要为单一对映异构物或非对映异构物时,其可通过立体特异性合成或通过解析最终产物或任何适宜中间物来获得。最终产物、中间物或起始物质的解析可通过所属领域中已知的任何适合方法来实现。参见例如E.L.Eliel,S.H.Wilen和L.N.Mander的“有机化合物的立体化学性(Stereochemistry of OrganicCompounds)”(Wiley-lnterscience,1994)。
本文所述的化合物可以从市售起始物质制得或使用已知的有机、无机和/或酶促法来合成。
化合物的制备
本发明化合物可依有机合成技术的技术人员众所周知的许多方式来制备。举例来说,本发明化合物可使用下文所述的方法,连同合成有机化学技术中已知的合成方法,或如所属领域技术人员所了解的对其作出的变化来合成。说明性方法包括(但不限于)下文所述的那些方法。本发明化合物可通过遵循一般流程1和2中所概述的步骤来合成,所述流程包含装配中间物的不同顺序。起始物质可购得或通过所报告的文献中的已知程序或如说明来制得。
流程1
其中R5和R8如上文所定义。
本文所述的经取代的四氢喹啉(10)可根据流程1中所概述的一般程序来制备。使用氯醌作为氧化剂对2-氯-5-甲氧基苯胺和丁烯醛进行氧化环化,得到呈其盐酸盐形式的甲氧基喹啉2。在碱存在下催化氢化以还原方式去除氯,得到良好产率的3。在高压下用对掌性钌(II)络合物对3进行催化不对称氢化,得到极佳产率的所需四氢喹啉4。或者,可经使用对掌性铑(II)错合物对3进行不对称转移氢化来获得四氢喹啉4。可经两种途径中的一种使4转化成酚7。用酸氯化物或氯甲酸酯使4酰化且用三溴化硼脱甲基,得到7。还可通过用氢溴酸脱甲基,继而用酸氯化物或氯甲酸酯酰化来获得酚7。用N-溴代丁二酰亚胺对7进行区域选择性溴化,得到作为主要产物的8。分别用适当芳基或烷基卤化物进行亲核芳香族取代或烷基化,得到9。可经使用适当硼酸或酯进行钯催化的铃木(Suzuki)交叉偶合使芳基溴化物9转化成所需四氢喹啉10。或者,可经用双(频哪醇根基)二硼进行钯催化的交叉偶合使芳基溴化物9转化成硼酸酯11。随后用适当芳基卤化物进行钯催化的铃木交叉偶合,得到所需四氢喹啉10。
流程2
其中R5和R8如上文所定义。
或者,四氢喹啉(10)可根据流程2中所概述的程序来制备。可通过在硫酸存在下用硝酸钠对2-氨基-3-硝基苯酚(12)进行重氮化,继而添加碘化钾来获得碘苯酚13。用甲氧基甲基氯保护苯酚,得到中间物14,其可与(R)-丁-3-炔-2-醇进行钯催化的薗头(Sonagashira)偶合,得到16。对16中的三键进行钯催化的氢化,得到17,其可用适当酸氯化物、酸酐或氯甲酸酯酰化,得到18。用甲烷磺酰氯处理18,继而与氢化钠反应引起分子内环化,得到四氢喹啉20。去除甲氧基甲基得到酚7,其可经用N-溴代丁二酰亚胺进行区域选择性溴化而转化成中间物8。分别用适当芳基或烷基卤化物进行亲核芳香族取代或烷基化,得到9。可经使用适当硼酸或酯进行钯催化的铃木交叉偶合使芳基溴化物9转化成所需四氢喹啉10。或者,可经用双(频哪醇根基)二硼进行钯催化的交叉偶合使芳基溴化物9转化成硼酸酯11。随后用适当芳基卤化物进行钯催化的铃木交叉偶合,得到所需四氢喹啉10。
使用所披露的化合物的方法
本发明的一个方面关于一种调节BET家族溴域中的一个或多个的方法,其包括向有需要的患者投予治疗有效量的式(I)、(II)、(III)或(IV)的化合物。
本发明的另一方面关于一种抑制BET家族溴域中的一个或多个的方法,其包括向有需要的患者投予治疗有效量的式(I)、(II)、(III)或(IV)的化合物。
另一方面,本发明关于一种抑制BET家族溴域中的一个或多个的方法,其包括向有需要的患者投予治疗有效量的式(I)、(II)、(III)或(IV)的医药组成物。
本发明的另一方面关于一种治疗、预防、抑制或消除患者的与抑制BET家族溴域中的一个或多个相关的疾病或病症的方法,所述方法包括投予治疗有效量的式(I)、(II)、(III)或(IV)的化合物。在一个实施例中,疾病或病症选自由以下组成的群组:癌症、发炎性病症、大肠激躁综合症、发炎性肠病、类风湿性关节炎、肥胖症和糖尿病。
本发明还关于BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除由BET家族溴域介导的疾病或病症的药剂的用途,其中所述药剂包含式(I)、(II)、(III)或(IV)的化合物。
另一方面,本发明关于一种制造用以治疗、预防、抑制或消除由BET家族溴域介导的疾病或病症的药剂的方法,其中所述药剂包含式(I)、(II)、(III)或(IV)的化合物。
本发明的另一方面关于一种用于治疗由BET家族溴域介导的疾病或病症的方法中的医药组成物,其中所述医药组成物包含式(I)、(II)、(III)或(IV)的化合物。
另一方面,本发明关于一种用于治疗由BET家族溴域介导的疾病或病症的方法中的化合物,其中所述化合物包含式(I)、(II)、(III)或(IV)的化合物。
本发明还关于BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除肿瘤的药剂的用途,其中所述药剂包含式(I)、(II)、(III)或(IV)的化合物。
本发明进一步关于BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除癌症的药剂的用途,其中所述药剂包含式(I)、(II)、(III)或(IV)的化合物。
在一个实施例中,本发明关于BET家族溴域的抑制剂用于制备用以治疗、预防、抑制或消除与慢性自体免疫发炎性病状、急性发炎性病状、全身发炎反应综合症、病毒、细菌或真菌感染、糖尿病和/或肥胖症相关的疾病的药剂的用途。在一个实施例中,所制备的药剂包含式(I)、(II)、(III)或(IV)的化合物,或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物。在另一实施例中,本发明关于BET家族溴域的抑制剂用于制备男性避孕药的用途,其中所述抑制剂包含式(I)、(II)、(III)或(IV)的化合物。
本发明的另一实施例关于式(I)、(II)、(III)或(IV)的化合物,或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物,或包含本发明化合物或其药学上可接受的盐、对映异构物、水合物、溶剂合物、前药、异构物或互变异构物和药学上可接受的载剂的医药组成物,其在投予人类后提供肿瘤负荷和/或转移的减少。医药组成物可由经口方式或其它适合方式投予。
在另一实施例中,本发明关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗癌症,包括(但不限于)子宫颈癌、结肠癌、乳癌、肺癌和胃癌;血液癌,例如(但不限于)白血病、淋巴瘤和多发性骨髓瘤;中线癌、间叶肿瘤、肝肿瘤、肾肿瘤和神经肿瘤;和黑素瘤、鳞状细胞癌和皮肤T细胞淋巴瘤。
在另一实施例中,本发明关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗与全身或组织发炎、对感染或低氧的发炎反应、细胞活化和增殖、脂质代谢、纤维化有关的多种疾病或病症,和预防和治疗病毒感染。在一个实施例中,使用医药组成物。
本发明的另一实施例关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗多种慢性和发炎性病状,包括(但不限于)类风湿性关节炎、骨关节炎、急性痛风、牛皮癣、全身性红斑狼疮、多发性硬化、克罗恩氏病(Crohn′s disease)、溃疡性结肠炎、哮喘、慢性阻塞性气道疾病、肺炎、心肌炎、心包炎、肌炎、湿疹、皮炎、秃头症、白癜风、大疱性皮肤病、肾炎、血管炎、动脉粥样硬化、阿兹海默氏病(Alzheimer′s disease)、抑郁症、修格连氏综合症(Sjogren′s syndrome)、涎腺炎、视网膜中央静脉阻塞、视网膜分支静脉阻塞、伊尔文-盖斯综合症(Irvine-Gass syndrome)、旁中心凹毛细血管扩张症、色素性视网膜炎、睫状体平坦部炎、鸟枪弹丸样视网膜脉络膜病变、视网膜前膜、囊样黄斑水肿、黄斑病变、玻璃体黄斑牵引综合症、视网膜脱离、神经视网膜炎、特发性黄斑水肿、视网膜炎、干眼病、春季角膜结膜炎、异位性角膜结膜炎、前葡萄膜炎、全葡萄膜炎、后葡萄膜炎、葡萄膜炎相关的黄斑水肿、巩膜炎、糖尿病性视网膜病变、糖尿病性黄斑水肿、年龄相关的黄斑营养不良、肝炎、胰腺炎、原发性胆汁性肝硬化、硬化性胆管炎、艾迪森氏病(Addison′s disease)、垂体炎、甲状腺炎、I型糖尿病和移植生物体的急性排斥反应。
在另一实施例中,本发明关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗多种急性发炎性病状,例如急性痛风、巨细胞动脉炎、包括狼疮肾炎的肾炎、伴有器官累及的血管炎(例如肾小球肾炎)、包括巨细胞动脉炎的血管炎、韦格纳氏肉芽肿病(Wegner′s granulomatosis)、结节性多动脉炎、白塞氏病(Becet′s disease)、川崎病(Kawasaki disease)、高安氏动脉炎(Takayasu′sarteritis)、坏疽性脓皮病、伴有器官累及的血管炎和移植器官的急性排斥反应。
本发明的另一实施例关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗涉及对细菌、病毒、真菌、寄生虫或其毒素感染的发炎反应的多种疾病或病症,例如(但不限于)败血症、败血综合症、败血性休克、内毒素血症、全身发炎反应综合症、多器官功能障碍综合症、中毒性休克综合症、急性肺损伤、急性呼吸窘迫综合症、急性肾衰竭、暴发型肝炎、烧伤、急性胰腺炎、术后综合症、肉状瘤病、赫氏反应(Herxheimer reaction)、脑炎、脊髓炎、脑膜炎、疟疾、与例如(但不限于)流感、带状疱疹、单纯疮疹和冠状病毒的病毒感染相关的全身发炎反应。
在另一实施例中,本发明关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗与缺血再灌注损伤相关的多种病状,例如心肌梗塞、脑血管缺血、急性冠状动脉综合症、肾再灌注损伤、器官移植、冠状动脉绕道手术、心、肺和绕道手术、肺、肾、肝、胃肠或外周肢栓塞。
本发明的另一实施例关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗多种脂质代谢病症,例如高胆固醇血症、动脉粥样硬化和阿兹海默氏病。
在另一实施例中,本发明关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗多种纤维化病状,例如(但不限于)特发性肺纤维化、肾纤维化、术后结构、瘢瘤性疤痕形成、硬结病和心纤维化。
本发明的另一实施例关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物的医药组成物,其用于治疗多种病毒感染,一般来说,例如(但不限于)疱疹病毒、人乳头状瘤病毒、腺病毒、痘病毒和DNA病毒。
在另一实施例中,本发明关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗多种病状,例如非恶性黑素瘤、光化性角化病、基底细胞黑素瘤、原位黑素瘤、鳞状细胞癌和皮肤T细胞淋巴瘤。
本发明的另一实施例关于式(I)、(II)、(III)或(IV)的化合物或包含本发明化合物和药学上可接受的载剂的医药组成物,其用于治疗肥胖症。
在另一实施例中,本发明关于式(I)、(II)、(III)或(IV)的化合物或包含药学上可接受的本发明化合物和药学上可接受的载剂的医药组成物,其用于男性避孕药。
本发明的另一实施例关于一种治疗与全身发炎反应综合症相关的疾病的方法,所述疾病例如(但不限于)败血症、烧伤、胰腺炎、严重创伤、出血和缺血,所述方法包括投予式(I)、(II)、(III)或(IV)的化合物。
在另一实施例中,本发明关于一种在诊断时通过投予式(I)、(II)、(III)或(IV)的化合物来降低SIRS、休克发作、多器官功能障碍综合症、急性肺损伤、急性肾、肝、心和胃肠损伤的发病率的方法。
本发明的另一实施例关于一种在具有高败血症风险的手术或任何程序之前降低败血症、出血、组织损伤和多器官功能障碍的发病率的方法,所述方法包括投予式(I)、(II)、(III)或(IV)的化合物。
所披露的本发明化合物可按有效量投予以治疗或预防受检者的病症和/或防止其发展。
本发明还关于一种医药组成物,其包含式(I)、(II)、(III)或(IV)的化合物和药学上可接受的载剂。药学上可接受的载剂可进一步包括赋形剂、稀释剂、添加剂或表面活性剂。
本发明的化合物或医药组成物可经针对治疗剂的任何投予模式来投予。这些模式包括全身或局部投予,例如经口、经鼻、非经肠、经皮、皮下、经阴道、经颊、经直肠或表面投予模式。
视预期投予模式而定,所披露的化合物或组成物可呈固体、半固体或液体剂型,例如可注射剂、锭剂、栓剂、丸剂、定时释放胶囊、酏剂、酊剂、乳液、糖浆、散剂、液体、悬浮液等,有时呈单位剂量且与惯用医药实践一致。同样地,其还可依静脉内(推注与输注)、腹膜内、皮下或肌肉内形式和医药技术人员众所周知的所有使用形式来投予。
组成物可分别根据惯用混合、粒化或包衣方法制备,且本发明医药组成物可含有以重量或体积计约0.1%到约99%、约5%到约90%或约1%到约20%的所披露化合物。
在一个实施例中,本发明关于一种制备本发明的医药组成物的方法,这是通过混合至少一种药学上可接受的本发明化合物,和任选一种或多种药学上可接受的载剂、添加剂或赋形剂来达成。
在另一实施例中,本发明关于一种制备本发明的医药组成物的方法,这是通过混合至少一种药学上可接受的本发明化合物和一种或多种其它治疗剂来达成。
根据本发明的一个实施例,其它治疗剂可选自由以下组成的群组:细胞毒性剂、顺铂、小红莓、克癌易、紫杉醇、依托泊苷、伊立替康、开普拓、拓扑替康、太平洋紫杉醇、多烯紫杉醇、埃博霉素、他莫昔芬、5-氟尿嘧啶、氨甲喋呤、替莫唑胺、环磷酰胺、SCH 66336、替吡法尼R115777、L778,123、BMS 214662、C225、芳香酶组合、ara-C、阿霉素、癌得星、吉西他滨、尿嘧啶芥、氮芥、异环磷酰胺、美法仑、苯丁酸氮芥、哌泊溴烷、三亚乙基三聚氰胺、三亚乙基硫代磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲菌素、达卡巴嗪、氟尿苷、阿糖胞苷、6-巯基嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、甲酰四氢叶酸、奥沙利铂喷司他丁、长春碱、长春新碱、长春地辛、博莱霉素、放线菌素D、道诺霉素、表柔比星、伊达比星、MithramycinTM、去氧助间型霉素、丝裂霉素C、L-天冬酰胺酶、替尼泊苷、17α-乙炔雌二醇、己烯雌酚、睪固酮、泼尼松、氟甲睪固酮、丙酸屈他雄酮、睪内酯、乙酸甲地孕酮、甲基泼尼松龙、甲基睪固酮、泼尼松龙、曲安西龙、氯烯雌醚、羟孕酮、氨鲁米特、雌莫司汀、乙酸甲羟孕酮、亮丙瑞林、氟他胺、托瑞米芬、戈舍瑞林、卡铂、羟基脲、安吖啶、丙卡巴肼、米托坦、米托蒽醌、左旋咪唑、诺维本、阿那曲唑、利妥唑、卡培他滨、雷洛昔芬、屈洛昔芬、六甲三聚氰胺、癌思停、贺癌平、百克沙、万珂、泽瓦灵、三氧化二砷、截瘤达、长春瑞滨、卟吩姆、尔必得舒、微脂体、沙奥特帕、六甲蜜胺、美法仑、曲妥珠单抗、利妥唑、氟维司群、依西美坦、利妥昔单抗、C225、坎帕斯、甲酰四氢叶酸、地塞米松、比卡鲁胺、卡铂、利妥唑、甲地孕酮和戊柔比星。
本发明的剂型可含有一种或多种本发明化合物的混合物,且可包括所属领域技术人员已知作为医药赋形剂的其它物质。稳定添加剂可并入传递剂溶液中。关于一些药物,所述添加剂的存在促进溶液中药剂的稳定剂和可分散性。稳定添加剂可按约0.1%和5%(W/V)范围内的浓度采用,优选为约0.5%(W/V)。稳定添加剂的适合但非限制性实例包括阿拉伯胶、明胶、甲基纤维素、聚乙二醇、羧酸和其盐,和聚赖氨酸。在一个实施例中,稳定添加剂为阿拉伯胶、明胶和甲基纤维素。
医药赋形剂和添加剂的实例包括(但不限于):酸化剂(乙酸、冰乙酸、柠檬酸、反丁烯二酸、盐酸、稀盐酸、苹果酸、硝酸、磷酸、稀磷酸、硫酸、酒石酸);气雾剂推进剂(丁烷、二氯二氟-甲烷、二氯四氟乙烷、异丁烷、丙烷、三氯单氟甲烷);空气置换物(二氧化碳、氮气);醇变性剂(苯甲地那铵(denatonium benzoate)、甲基异丁基酮、蔗糖八乙酸酯);碱化剂(浓氨溶液、碳酸铵、二乙醇胺、二异丙醇胺、氢氧化钾、碳酸氢钠、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺(trolamine));防结块剂(参见助流剂);消泡剂(二甲硅油(dimethicone)、西甲硅油(simethicone));抗微生物防腐剂(氯化苯甲烃铵(benzalkonium chloride)、氯化苯甲烃铵溶液、氯化苯铵松宁(benzethonium chloride)、苯甲酸、苯甲醇、对羟基苯甲酸丁酯、氯化鲸蜡基吡啶嗡、氯丁醇、氯甲酚、甲酚、脱氢乙酸、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、对羟基苯甲酸甲酯钠、苯酚、苯基乙醇、乙酸苯汞、硝酸苯汞、苯甲酸钾、山梨酸钾、对羟基苯甲酸丙酯、对羟基苯甲酸丙酯钠、苯甲酸钠、脱氢乙酸钠、丙酸钠、山梨酸、硫柳汞(thimerosal)、百里酚);抗氧化剂(抗坏血酸、抗坏血酸棕榈酸酯、丁基化羟基苯甲醚、丁基化羟基甲苯、次磷酸、单硫代甘油、没食子酸丙酯、甲醛次硫酸钠、焦亚硫酸钠、硫代硫酸钠、二氧化硫、生育酚、生育酚赋形剂);缓冲剂(乙酸、碳酸铵、磷酸铵、硼酸、柠檬酸、乳酸、磷酸、柠檬酸钾、偏磷酸钾、磷酸二氢钾、乙酸钠、柠檬酸钠、乳酸钠溶液、磷酸氢二钠、磷酸二氢钠);胶囊润滑剂(参见锭剂和胶囊润滑剂);螯合剂(依地酸二钠(edetate disodium)、乙二胺四乙酸和盐、依地酸(edetic acid));包衣剂(羧甲基纤维素钠、乙酸纤维素、邻苯二甲酸乙酸纤维素、乙基纤维素、明胶、药用釉料、羟丙基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、甲基丙烯酸共聚物、甲基纤维素、聚乙二醇、邻苯二甲酸聚乙酸乙烯酯、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、玉米蛋白);着色剂(糖色、红色、黄色、黑色或掺合物、氧化铁);错合剂(乙二胺四乙酸和盐(EDTA)、依地酸、龙胆酸乙醇酰胺、硫酸羟喹啉);干燥剂(氯化钙、硫酸钙、二氧化硅);乳化剂和/或增溶剂(阿拉伯胶、胆固醇、二乙醇胺(佐剂)、单硬脂酸甘油酯、羊毛脂醇、卵磷脂、单酸甘油酯和二酸甘油酯、单乙醇胺(佐剂)、油酸(佐剂)、油醇(稳定剂)、泊洛沙姆(poloxamer)、聚氧乙烯50硬脂酸酯、聚氧乙烯35蓖麻油、聚氧乙烯40氢化蓖麻油、聚氧乙烯10油醚、聚氧乙烯20鲸蜡硬脂醚、聚氧乙烯40硬脂酸酯、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、丙二醇二乙酸酯、丙二醇单硬脂酸酯、月桂基硫酸钠、硬脂酸钠、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯、硬脂酸、三乙醇胺、乳化蜡);助滤剂(粉状纤维素、纯化硅藻土);调味剂和香料(茴香脑、苯甲醛、乙基香草醛、薄荷醇、水杨酸甲酯、谷氨酸单钠、橙花油、薄荷、薄荷油、欧薄荷醑、玫瑰油、浓玫瑰水、百里酚、吐鲁香脂酊、香草、香草酊、香草醛);助流剂和/或防结块剂(硅酸钙、硅酸镁、胶态二氧化硅、滑石);保湿剂(甘油、己二醇、丙二醇、山梨糖醇);增塑剂(蓖麻油、二乙酰化单酸甘油酯、邻苯二甲酸二乙酯、甘油、单乙酰化和二乙酰化单酸甘油酯、聚乙二醇、丙二醇、三醋精、柠檬酸三乙酯);聚合物(例如乙酸纤维素、烷基纤维素、羟烷基纤维素、丙烯酸聚合物和共聚物);溶剂(丙酮、乙醇、稀乙醇、水合戊烯、苯甲酸苯甲酯、丁醇、四氯化碳、氯仿、玉米油、棉籽油、乙酸乙酯、甘油、己二醇、异丙醇、甲醇、亚甲基氯、甲基异丁基酮、矿物油、花生油、聚乙二醇、碳酸伸丙酯、丙二醇、芝麻油、注射用水、无菌注射用水、无菌冲洗用水、纯化水);吸附剂(粉状纤维素、木炭、纯化硅藻土);二氧化碳吸附剂(氢氧化钡石灰、碱石灰);硬化剂(氢化蓖麻油、鲸蜡硬脂醇、鲸蜡醇、鲸蜡酯蜡、硬脂、石蜡、聚乙烯赋形剂、硬脂醇、乳化蜡、白蜡、黄蜡);悬浮剂和/或增粘剂(阿拉伯胶、琼脂、海藻酸、单硬脂酸铝、膨润土、纯化膨润土、岩浆膨润土、卡波姆934p(carbomer 934p)、羧甲基纤维素钙、羧甲基纤维素钠、羧甲基纤维素钠12、角叉菜胶、微晶和羧甲基纤维素钠纤维素、糊精、明胶、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、硅酸镁铝、甲基纤维素、果胶、聚氧化乙烯、聚乙烯醇、聚维酮(povidone)、丙二醇海藻酸酯、二氧化硅、胶态二氧化硅、海藻酸钠、黄蓍胶、三仙胶);甜味剂(阿斯巴甜糖、葡萄糖结合剂(dextrate)、右旋糖、右旋糖赋形剂、果糖、甘露糖醇、糖精、糖精钙、糖精钠、山梨糖醇、山梨糖醇溶液、蔗糖、可压缩糖、糖粉、糖浆);锭剂粘合剂(阿拉伯胶、海藻酸、羧甲基纤维素钠、微晶纤维素、糊精、乙基纤维素、明胶、液体葡萄糖、瓜尔胶、羟丙基甲基纤维素、甲基纤维素、聚氧化乙烯、聚维酮、预胶凝化淀粉、糖浆);锭剂和/或胶囊稀释剂(碳酸钙、磷酸氢钙、磷酸三钙、硫酸钙、微晶纤维素、粉状纤维素、葡萄糖结合剂、糊精、右旋糖赋形剂、果糖、高岭土、乳糖、甘露糖醇、山梨糖醇、淀粉、预胶凝化淀粉、蔗糖、可压缩糖、糖粉);锭剂崩解剂(海藻酸、微晶纤维素、交联羧甲基纤维素钠(croscarmellose sodium)、交联聚维酮(crospovidone)、波拉克林钾(polacrilin potassium)、羧基乙酸淀粉钠、预胶凝化淀粉);锭剂和/或胶囊润滑剂(硬脂酸钙、山嵛酸甘油酯、硬脂酸镁、轻质矿物油、聚乙二醇、硬脂酰反丁烯二酸钠、硬脂酸、纯化硬脂酸、滑石、氢化植物油、硬脂酸锌);张力剂(右旋糖、甘油、甘露糖醇、氯化钾、氯化钠);媒剂:调味和/或加甜(芳香酏、复方苯甲醛酏、等醇酏、薄荷水、山梨糖醇溶液、糖浆、吐鲁香脂糖浆);媒剂:油性(杏仁油、玉米油、棉籽油、油酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、矿物油、轻质矿物油、肉豆寇醇、辛基十二烷醇、橄榄油、花生油、桃仁油、芝麻油、大豆油、角鲨烷);媒剂:固体载剂(糖丸);媒剂:无菌(抑菌注射用水、抑菌氯化钠注射剂);增粘剂(参见悬浮剂);拒水剂(环甲硅油(cyclomethicone)、二甲硅油、西甲硅油);和湿润剂和/或增溶剂(氯化苯甲烃铵、氯化苯铵松宁、氯化鲸蜡基吡啶嗡、多库酯钠(docusate sodium)、壬苯聚醇9(nonoxynol 9)、壬苯聚醇10(nonoxynol 10)、辛苯聚醇9(octoxynol 9)、泊洛沙姆、聚氧乙烯35蓖麻油、聚氧乙烯40、氢化蓖麻油、聚氧乙烯50硬脂酸酯、聚氧乙烯10油醚、聚氧乙烯20、鲸蜡硬脂醚、聚氧乙烯40硬脂酸酯、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、月桂基硫酸钠、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯、泰洛沙泊(tyloxapol))可用作赋形剂。这一清单不打算为排他性的,而是仅代表可用于本发明的剂型中的赋形剂种类和特定赋形剂。
说明性医药组成物为锭剂和明胶胶囊,其包含本发明化合物和药学上可接受的载剂,例如a)稀释剂,例如纯化水、三酸甘油酯油(例如氢化或部分氢化植物油,或其混合物)、玉米油、橄榄油、向日葵油、红花油、鱼油(例如EPA或DHA,或其酯或三酸甘油酯或其混合物)、ω-3脂肪酸或其衍生物、乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纤维素、钠、糖精、葡萄糖和/或甘氨酸;b)润滑剂,例如二氧化硅、滑石、硬脂酸、其镁或钙盐、油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠和/或聚乙二醇;对于锭剂来说,还存在c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、碳酸镁、天然糖(例如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成胶(例如阿拉伯胶、黄蓍胶或海藻酸钠)、蜡和/或聚乙烯吡咯烷酮(必要时);d)崩解剂,例如淀粉、琼脂、甲基纤维素、膨润土、三仙胶、海藻酸或其钠盐,或泡腾混合物;e)吸收剂、着色剂、调味剂和甜味剂;f)乳化剂或分散剂,例如吐温80(Tween 80)、辛酸癸酸聚乙二醇甘油酯(Labrasol)、HPMC、DOSS、丙二醇单辛酸酯909(caproyl 909)、丙二醇双癸酸酯(labrafac)、油酸聚乙二醇甘油酯(labrafil)、单油酸甘油酯(peceol)、二乙二醇单乙基醚(transcutol)、中链脂肪酸甘油酯MCM(capmul MCM)、中链脂肪酸甘油酯PG-12(capmul PG-12)、中链三酸甘油酯355(captex 355)、单硬脂酸甘油酯(gelucire)、维生素ETGPS或其它可接受的乳化剂;和/或g)增强化合物吸收的试剂,例如环糊精、羟丙基-环糊精、PEG400、PEG200。
对于从本发明所述的化合物制备医药组成物,药学上可接受的惰性载剂可为固体或液体。固体形式制剂包括散剂、锭剂、可分散颗粒、胶囊、扁囊剂和栓剂。散剂和锭剂可包含约5%到约95%的活性成分。适合的固体载剂在所属领域中为已知的,例如碳酸镁、硬脂酸镁、滑石、糖或乳糖。锭剂、散剂、扁囊剂和胶囊可用作适合于经口投予的固体剂型。药学上可接受的载剂的实例和制造各种组成物的方法可见于A.Gennaro(编),《雷明顿药学大全》,第18版,(1990),Mack Publishing Co.,Easton,Pa中。
液体形式制剂包括溶液、悬浮液和乳液。举例来说,水或水-丙二醇溶液用于非经肠注射或添加甜味剂和遮光剂用于口服溶液、悬浮液和乳液。液体形式制剂还可包括供鼻内投予的溶液。
液体、尤其可注射组成物可例如通过溶解、分散等来制备。举例来说,将所披露的化合物溶解于药学上可接受的溶剂中或与药学上可接受的溶剂混合,所述溶剂为例如水、盐水、右旋糖水溶液、甘油、乙醇等,以借此形成可注射等渗溶液或悬浮液。例如白蛋白、乳糜微粒粒子或血清蛋白的蛋白质可用于溶解所披露的化合物。
非经肠可注射剂投予一般用于皮下、肌肉内或静脉内注射和输注。可注射剂可依惯用形式,作为液体溶液或悬浮液或适合于在注射前溶解于液体中的固体形式制备。
适合于吸入的气雾剂制剂可包括溶液和呈粉末形式的固体,其可与药学上可接受的载剂,例如惰性压缩气体,例如氮气组合。
还包括固体形式制剂,其打算在即将使用前转变成液体形式制剂以供经口或非经肠投予。所述液体形式包括溶液、悬浮液和乳液。
本发明化合物也可经皮传递。经皮组成物可采用乳膏、洗剂、气雾剂和/或乳液的形式,且可包括于如所属领域中惯用于所述目的的基质或储集型经皮贴片中。
所披露的化合物也可调配成栓剂,其可以从脂肪乳液或悬浮液制备;使用聚烷二醇(例如丙二醇)作为载剂。
所披露的化合物也可依脂质体传递系统的形式投予,例如小单层囊泡、大单层囊泡和多层囊泡。脂质体可以从多种磷脂形成,其含有胆固醇、硬脂胺或磷脂酰胆碱。在一些实施例中,液体组分的膜与药物的水溶液水合以形成囊封药物的脂质层,如美国专利第5,262,564号中所述。
所披露的化合物也可通过使用单株抗体作为所披露的化合物偶合的个别载体来传递。所披露的化合物还可与作为可靶向药物载体的可溶性聚合物偶合。所述聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚,或经棕榈酰基残基取代的聚氧化乙烯聚赖氨酸。此外,所披露的化合物可偶合到一类适用于达成药物的控制释放的可生物降解聚合物,例如聚乳酸、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯,和水凝胶的交联或两亲性嵌段共聚物。在一个实施例中,所披露的化合物并不共价结合于聚合物,例如聚羧酸聚合物或聚丙烯酸酯。
如果调配成固定剂量,那么所述组合产品采用在本文所述或如所属领域技术人员已知的剂量范围内的本发明化合物。
由于本发明化合物打算用于医药组成物中,因此所属领域技术人员应了解,其可依实质上纯的形式提供,例如至少60%纯、更适宜至少75%纯、优选至少85%纯且最优选至少98%纯(w/w)。
医药制剂可呈单位剂型。在所述形式中,制剂细分成适当大小的单位剂量,其含有适量(例如有效量)的活性组分以达成所需目的。
制剂的单位剂量中活性化合物的量可根据特定应用在约1mg到约1000mg、约1mg到约500mg、约1mg到约250mg或约1mg到约25mg之间变化或调整。
利用所披露的化合物的剂量方案根据多种因素来选择,包括患者的类型、物种、年龄、体重、性别和医学状况;所治疗病状的严重程度;投予途径;患者的肾或肝功能;和所采用的特定披露的化合物。一般技术的医师或兽医容易确定和开立预防、对抗或遏止病状进展所需的药物的有效量。
所采用的实际剂量可视患者的需求和所治疗病状的严重程度而变化。针对特定情况的适当给药方案的确定处于所属领域的技能范围内。为方便起见,需要时,可分割总日剂量且在一天当中分数份投予。
本发明化合物和/或其药学上可接受的盐的投予量和频率将根据主治临床医师的判断考虑以下因素来调节:例如患者的年龄、状况和体型以及所治疗症状的严重程度。所披露的化合物的有效剂量当用于指定作用时在如治疗病状所需的约0.5mg到约5000mg所披露的化合物的范围内。供体内或体外使用的组成物可含有约0.5、5、20、50、75、100、150、250、500、750、1000、1250、2500、3500或5000mg所披露的化合物,或在剂量清单中的一个量到另一个量的范围内。供经口投予的典型推荐日剂量方案可在约1毫克/天到约500毫克/天或1毫克/天到200毫克/天的范围内,分两个到四个分次剂量。
式I到IV的化合物可形成盐,它也处于本发明的范围内。除非另有指示,否则在本文中提到化学式的化合物应理解为包括提到其盐。
示范性酸加成盐包括乙酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、反丁烯二酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳酸盐、顺丁烯二酸盐、甲烷磺酸盐、萘磺酸盐、硝酸盐、草酸盐、磷酸盐、丙酸盐、水杨酸盐、丁二酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(还称为甲苯磺酸盐(tosylate))等。另外,一般视为适于从碱性医药化合物形成药学上适用的盐的酸例如由以下论述:P.Stahl等人,Camille G.(编)药用盐手册.特性,选择和使用(Handbook ofPharmaceutical Salts.Properties,Selection and Use).(2002)Zurich:Wiley-VCH;S.Berge等人,《药学科学杂志(Journal of Pharmaceutical Sciences)》(1977)66(1)1-19;P.Gould,《药学国际杂志(International J.of Pharmaceutics)》(1986)33201-217;Anderson等人,《医药化学实践(The Practice of Medicinal Chemistry)》(1996),Academic Press,New York;和橘皮书(The Orange Book)(食品药品监督管理局(Food&Drug Administration),Washington,D.C.在其网站上)。这些披露内容以引用的方式并入本文中。
示范性碱性盐包括铵盐;碱金属盐,例如钠、锂和钾盐;碱土金属盐,例如钙和镁盐;与有机碱(例如有机胺)的盐,所述有机碱为例如二环己胺、叔丁胺;和与氨基酸的盐,所述氨基酸为例如精氨酸、赖氨酸等。碱性含氮基团可用以下试剂进行四级铵化:例如低碳烷基卤化物(例如甲基、乙基和丁基氯化物、溴化物和碘化物)、硫酸二烷酯(例如硫酸二甲酯、硫酸二乙酯和硫酸二丁酯)、长链卤化物(例如癸基、月桂基和硬脂基氯化物、溴化物和碘化物)、芳烷基卤化物(例如苯甲基溴和苯乙基溴)等。
出于本发明的目的,所有所述酸盐和碱盐打算为处于本发明范围内的药学上可接受的盐且所有酸盐和碱盐视为等效于相应化合物的游离形式。
实例
本发明由以下实例和合成流程进一步说明,其不应解释为将本发明的范围或精神限于本文所述的特定程序。应了解,提供实例以说明某些实施例且借此不打算对本发明的范围作限制。应进一步了解,在不脱离本发明的精神和/或所附权利要求书的范围的情况下可采用本身可为所属领域技术人员所想到的各种其它实施例、修改以及其等效物。
呈现用于合成本文所披露的某些化合物的合成流程。还描述测试BET家族溴域抑制和对癌细胞系增殖的影响的分析的过程和结果。
以下流程和本文别处所用的定义为:
材料
除非另有注释,否则所有材料都获自商业供应商且未经进一步纯化即使用。无水溶剂获自Sigma-Aldrich(Milwaukee,WI)且直接使用。涉及空气或水分敏感性试剂的所有反应都在氮气气氛下进行。
除非另有注释,否则质量触发式HPLC纯化和/或纯度和低解析度质谱数据使用以下测量:(1)使用220nm下的UV检测和低共振电喷雾正离子模式(ESI)的Waters Acquity超高效液相色谱(UPLC)系统(具有样品组织器和Waters Micromass ZQ质谱仪的WatersAcquity UPLC)(柱:Acquity UPLC BEH C18 1.7μm 2.1×50mm;梯度:含5-100%溶剂B(95/5/0.09%:乙腈/水/甲酸)的溶剂A(95/5/0.1%:10mM甲酸铵/乙腈/甲酸)维持2.2分钟,接着含100-5%溶剂B的溶剂A维持0.01分钟,接着保持含5%溶剂B的溶剂A维持0.29分钟);或(2)使用220nm和254nm下的UV检测和低共振电喷雾电离(正/负)模式(ESI)的WatersHT2790Alliance高效液相色谱(HPLC)系统(Waters 996PDA和Waters ZQ单四极杆质谱仪)(柱:XBridge Phenyl或C18,5μm 4.6×50mm;梯度:含5-95%溶剂B(95%甲醇/5%水,含0.1%甲酸)的溶剂A(95%水/5%甲醇,含0.1%甲酸)维持2.5分钟,接着保持含95%溶剂B的溶剂A维持1分钟)(仅纯度和低解析度MS)。
实例1:中间物1--(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉.
步骤1. 8-氯-5-甲氧基-2-甲基喹啉盐酸盐
向1000-mL 3颈圆底烧瓶中装入2-氯-5-甲氧基苯胺(50g,317mmol)、正丁醇(120mL)、浓盐酸(37%,90mL)和氯醌(四氯-1,4-苯醌)(78g,317mmol)。在100℃下于油浴中搅拌所得溶液1小时。经1小时逐滴添加(E)-丁烯醛(28.9mL,349mmol)于正丁醇(50mL)中的溶液。在100℃下于油浴中搅拌所得溶液1小时,接着冷却到70℃。添加四氢呋喃(650mL),且在70℃下搅拌反应混合物1小时,接着冷却到0℃。使所得沉淀物在0-5℃下保持1小时。过滤混合物,用冷(约0℃)THF(2×350mL)洗涤固体,接着在烘箱中干燥,得到呈黄色固体状的8-氯-5-甲氧基-2-甲基喹啉盐酸盐(83.0g,74%)。MS(ES,m/z):208[M+H]+
步骤2. 5-甲氧基-2-甲基喹啉
向1000-mL圆底烧瓶中装入8-氯-5-甲氧基-2-甲基喹啉盐酸盐(50.0g,204.8mmol)、甲醇(300mL)、氢氧化钠水溶液(3M,205mL)和10%钯/活性碳(25g)。用氢气净化系统,且在室温下于氢气气氛下搅拌所得混合物3小时。经硅藻土衬垫过滤反应混合物,且在真空下浓缩以去除大部分甲醇。用乙酸乙酯(2×2000mL)萃取所得溶液。合并有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以0-20%乙酸乙酯/石油醚进行梯度洗提)纯化残余物,得到呈黄色固体状的5-甲氧基-2-甲基喹啉(36g,63%)。MS(ES,m/z):174[M+H]+
步骤3.(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(中间物1)
向具有磁性搅拌棒的30-mL玻璃衬里不锈钢反应器中装入5-甲氧基-2-甲基喹啉(4.0g,23.1mmol)、Ru(OTf)(η6-六甲基苯)((S,S)-TsDPEN)([N-[(1S,2S)-2-(氨基-κN)-1,2-二苯基乙基]-4-甲基苯磺酰胺根合-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-六甲基苯](1,1,1-三氟甲烷磺酸根合-κO)-钌,根据《美国化学会志(J.Am.Chem.Soc.)》2011,133,9878-9891中的程序制备)(0.100g,0.13mmol)和甲醇(10mL)。将反应器封闭,且最初在50atm的压力下引入氢气,随后降到1atm。重复这一程序三次之后,用氢气将反应器加压到50atm。在室温下于这一氢气压力下搅拌所得混合物24小时。小心释放氢气之后,在真空下浓缩反应混合物。经硅胶柱色谱(以0-20%乙酸乙酯/石油醚进行梯度洗提)纯化残余物,得到呈黄色油状的(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(4.0g,98%,>99%ee)。MS(ES,m/z):178[M+H]+
实例2:中间物1--盐酸盐.(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉盐酸盐
步骤1.(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉
向配备有顶置式搅拌器、热电偶和氮气入口的三颈2-L圆底烧瓶中装入甲醇(1350mL)和甲酸(51.8mL,1350mmol)。使烧瓶下降到冰-水浴中,且当内部温度达到13℃时,缓慢添加三乙胺(75mL,540mmol),使得内部温度升到21℃。接着,一次性添加5-甲氧基-2-甲基喹啉(58.47g,338mmol),且冷却所得溶液到0℃。最后,一次性添加Cp*RhCl[(S,S)-TsDPEN]([N-[(1S,2S)-2-(氨基-κN)-1,2-二苯基乙基]-4-甲基苯磺酰胺根合-κN]氯[(1,2,3,4,5-η)-1,2,3,4,5-五甲基-2,4-环戊二烯-1-基]铑,根据《有机化学通讯(Org.Lett.)》1999,1,841中的程序制备)(2.157g,3.38mmol)。将冰浴保留于原处且缓慢终止。22小时(内部温度=17℃)后,再添加甲酸(12.95mL,338mmol)到反应混合物中。在室温下搅拌深色溶液4天。总共5天后,在减压下浓缩溶液。将经浓缩的反应混合物再溶解于乙酸乙酯(约750mL)中,且用饱和碳酸氢钠水溶液(250mL、接着100mL)洗涤两次,且最后用5%氯化钠水溶液(100mL)洗涤。接着在减压下浓缩乙酸乙酯萃取物,得到64.7g深色糊浆。对掌性HPLC分析显示物质具有97.2:2.8e.r.的对映物纯度(94.4%ee)。(对掌性HPLC方法:柱:ODH;方法:ODH 98%己烷/2%IPA;UV:254,流量:0.5mL/min)。粗(S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(59.8g,338mmol,100%产率)未经进一步纯化即用于盐形成(假定100%产率)。MS(ES,m/z):178[M+H]+
步骤2.(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉盐酸盐(中间物1-盐酸盐)
向配备有磁性搅拌棒和热电偶的三颈500-mL圆底烧瓶中装入乙醇(160mL),且冷却溶液到0℃。经45分钟缓慢添加乙酰氯(26.4mL,372mmol),同时维持内部温度低于8℃。去除冰浴,且使HCl溶液(约2M)升温约30分钟(内部温度=15℃)。
向配备有顶置式搅拌器、热电偶和氮气入口的三颈1-L圆底烧瓶中装入粗(S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(59.9g,338mmol)于乙酸乙酯(600mL)中的溶液。接着,在17℃下向这一溶液中添加新鲜制备的HCl溶液(约2M,于乙醇中,86mL,372mmol)。在添加HCl溶液时,混合物最初变混浊,但接着在完全添加后变成澄清溶液。内部温度升到26℃。在周围温度下搅拌澄清溶液,且在10-15分钟后,形成粒状沉淀物。在周围温度下搅拌浆液4.5小时,接着在600-mL玻璃布氏漏斗(Buchner funnel)上过滤。用新鲜乙酸乙酯冲洗烧瓶和固体,过滤,且在抽吸和氮气正压下在过滤器上干燥,得到呈乳白色自由流动粒状固体状的(S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉盐酸盐(64.43g,89%)。对掌性HPLC分析显示盐具有98.9:1.1e.r.的对映物纯度(97.8%ee)。(对掌性HPLC方法:柱:ODH;方法:ODH 98%己烷/2%IPA;UV:254,流量:0.5mL/min)。MS(ES,m/z):178[M+H]+
实例3:中间物2--(2S)-6-溴-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇
步骤1a.(2S)-1-环丙烷羰基-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉
向1000-mL 3颈圆底烧瓶中装入(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(47.41g,267.5mmol)、二氯甲烷(500mL)和吡啶(38mL)。在0℃下于搅拌下逐滴添加环丙烷羰基氯(28.4g,271.7mmol),且在0℃下搅拌所得溶液3小时。将反应混合物倒入400mL水/冰中,接着用2N盐酸(1×100mL)和盐水(3×300mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以0-15%乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色固体状的(2S)-1-环丙烷羰基-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(64.6g,98%)。MS(ES,m/z):246[M+H]+
步骤2a.(2S)-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇
向1000-mL圆底烧瓶中装入(2S)-1-环丙烷羰基-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(15.0g,61.2mmol)和二氯甲烷(300mL)。在0℃下逐滴添加三溴化硼溶液(1M,于二氯甲烷中,308mL,308mmol),且在0℃下搅拌所得溶液1小时。接着将反应混合物倒入500mL水/冰中,且用二氯甲烷(2×500mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以0-80%乙酸乙酯/石油醚洗提)纯化残余物,得到呈灰白色固体状的(2S)-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇(9.4g,66%)。MS(ES,m/z):232[M+H]+
步骤1b.(S)-2-甲基-1,2,3,4-四氢喹啉-5-醇氢溴酸盐
向配备有加热罩和顶置式搅拌器的500-mL圆底烧瓶中装入(S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉盐酸盐(20g,94mmol),继而装入氢溴酸(48%,154mL,1361mmol)。加热混合物到100℃,且反应容易地进行,同时损失的溴甲烷通过未冷却的回流冷凝器。1小时后,固体从溶液中沉淀。在100℃下10小时后反应完成,且使其冷却到周围温度,同时搅拌隔夜。将反应混合物置于冰浴中,且在0-5℃下搅拌2小时。过滤所得白色浆液,且用20mL冰冷水洗涤罐和固体。在氮气覆盖层下于布氏漏斗上干燥滤饼,得到呈白色粉末状的(S)-2-甲基-1,2,3,4-四氢喹啉-5-醇氢溴酸盐(21.71g,95%)。MS(ES,m/z):164[M+H]+
步骤2b.(2S)-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇
向配备有氮气入口、顶置式搅拌器、加料漏斗和热电偶的1000-mL圆底烧瓶中装入(S)-2-甲基-1,2,3,4-四氢喹啉-5-醇氢溴酸盐(20g,82mmol),继而装入无水DMF(109mL)和吡啶(19.8mL,246mmol)。经30分钟逐滴添加环丙烷羰基氯(7.43mL,82mmol),同时用冷水浴保持温度低于20℃。添加完成之后,在周围温度下搅拌反应混合物1.5小时。将罐在冰浴中冷却到0℃,且经15分钟逐滴添加0.29M HCl水溶液(315mL)。在冰浴中搅拌浆液90分钟,随后过滤。用25mL冰水洗涤罐和滤饼。在氮气下于布氏漏斗上干燥滤饼,得到呈灰白色粉末状的(2S)-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇
(17.16g,91%)。MS(ES,m/z):232[M+H]+
步骤3.(2S)-6-溴-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇(中间物2).
向用惰性氮气气氛净化并维持的1000-mL 3颈圆底烧瓶中置放含(2S)-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇(4.0g,17.3mmol)的乙腈(600mL)和二氯甲烷(150mL)。冷却溶液到-10℃,且经3小时逐滴添加N-溴代丁二酰亚胺(3.08g,17.3mmol)于乙腈(50mL)中的溶液。在-10℃下搅拌所得溶液30分钟,接着在真空下浓缩。经硅胶柱色谱(以0-20%乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色固体状的(2S)-6-溴-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇(3.6g,68%)。MS:(ES,m/z):310,312[M+H]+
实例4:中间物3.(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
步骤1. 2-碘-3-硝基苯酚
向配备有顶置式搅拌器、热电偶和氮气入口的1-L三颈圆底烧瓶中装入2-氨基-3-硝基苯酚(17.5g,114mmol)、DMSO(280mL)和30%硫酸(280mL,1575mmol)。加热深红色-橙色溶液到50℃。45分钟后,停止加热,且冷却溶液到3℃(一旦溶液达到13℃,即形成沉淀物)。接着,将亚硝酸钠(10.97g,159mmol)于水(35mL)中的溶液缓慢添加到浆液中,同时维持内部温度低于5℃;添加耗时约5-7分钟。在0℃下搅拌溶液。1小时后,经5分钟的时段缓慢添加碘化钾(52.8g,318mmol)于水(105mL)中的溶液。1小时后,去除冰浴,且使反应混合物升温到室温且搅拌20小时。接着用甲基叔丁基醚(1×800mL和1×400mL)萃取反应混合物。用20%硫代硫酸钠水溶液(2×200mL)、继而用5%氯化钠水溶液(2×200mL)洗涤经合并的甲基叔丁基醚萃取物。在减压下浓缩有机萃取物。添加甲苯(200mL),接着在减压下去除,得到呈棕色粉末状的2-碘-3-硝基苯酚(30.2g,100%)。1H NMR(400MHz,CDCl3):δ7.44(dd,J=8.0,1.5Hz,1H),7.37(t,J=8.0Hz,1H),7.24(dd,J=8.0,1.5Hz,1H),5.97(br,1H)ppm。
步骤2. 2-碘-1-(甲氧基甲氧基)-3-硝基苯
向配备有磁性搅拌棒的200-mL圆底烧瓶中装入乙酸乙酯(37mL)、二甲氧基甲烷(12.25mL,137mmol)和乙酸锌(2.51mg,0.014mmol)。接着,经20分钟的时段缓慢添加乙酰氯(9.73mL,137mmol)。在室温下搅拌溶液2小时。接着将这一氯甲基甲基醚溶液添加到2-碘-3-硝基苯酚(30.2g,114mmol)于N,N-二甲基甲酰胺(170mL)中的溶液中。冷却所得溶液到0℃,且经20分钟的时段用二异丙基乙胺(49.8mL,285mmol)缓慢处理。将冰浴保留于原处,且在冰浴缓慢终止时搅拌反应混合物隔夜。接着用乙酸乙酯稀释反应混合物,且分配于水(340mL)与乙酸乙酯(500mL)之间。分离有机层,且用半饱和碳酸氢钠水溶液(1×340mL)和5%氯化钠水溶液(1×340mL、接着1×200mL)洗涤。接着在减压下浓缩有机层,得到深棕色糊浆(33.6g),其在静置时结晶。将粗产物溶解于少量二氯甲烷中,且通过经硅胶衬垫(14cm(d)×6cm(h),以3:2己烷-二氯甲烷洗提)过滤来纯化,得到呈浅黄色固体状的2-碘-1-(甲氧基甲氧基)-3-硝基苯(30.2g,86%)。1H NMR(400MHz,CDCl3):δ7.39(t,J=8.1Hz,1H),7.34(dd,J=8.0,1.6Hz,1H),7.25(dd,J=8.1,1.6Hz,1H),5.30(s,2H),3.52(s,3H)ppm。
步骤3.(R)-4-(2-(甲氧基甲氧基)-6-硝基苯基)丁-3-炔-2-醇
向配备有磁性搅拌棒的两颈100-mL圆底烧瓶中装入2-碘-1-(甲氧基甲氧基)-3-硝基苯(5.0g,16.18mmol)、碘化铜(I)(0.154g,0.809mmol)、氯化双(三苯基膦)钯(II)(0.284g,0.404mmol)、N,N-二甲基乙酰胺(25mL)和三乙胺(9.02mL,64.7mmol)。使氮气鼓泡通过深橙色溶液持续数分钟,接着添加(R)-丁-3-炔-2-醇(1.33mL,17.0mmol),这使得溶液颜色明显变淡。接着加热溶液到70℃维持10小时,届时停止加热且使反应混合物冷却到室温。在室温下搅拌10小时后,用乙酸异丙酯稀释反应混合物,且用水(50mL)、饱和氯化铵水溶液(50mL)和5%氯化钠水溶液(2×50mL)洗涤。在减压下浓缩有机层,得到深棕色糊浆(4.7g)。通过硅胶急骤色谱(以2:1己烷-乙酸乙酯、接着3:2己烷-乙酸乙酯和最后1:1己烷-乙酸乙酯洗提)纯化粗产物,得到(R)-4-(2-(甲氧基甲氧基)-6-硝基苯基)丁-3-炔-2-醇(2.1g,52%)。MS(ESI,正离子)m/z 274[M+23]+。
步骤4.(R)-4-(2-氨基-6-(甲氧基甲氧基)苯基)丁-2-醇
将装有(R)-4-(2-(甲氧基甲氧基)-6-硝基苯基)丁-3-炔-2-醇(2.9g,11.54mmol)、甲醇(58mL)和10%钯/碳(50%水,1.228g,0.577mmol)的400-mL帕尔瓶(Parrbottle)用氢气加压到39psig,接着震荡。快速消耗氢气,且在15分钟内,压力已降到0psig。将瓶再加压到39psig,且继续震荡。压力经下一个15分钟降到约20psig且稳定。将瓶再加压到34psig,且在继续震荡下保持2小时。用氮气吹洗混合物,接着经硅藻土衬垫过滤。用甲醇冲洗瓶和催化剂,且在减压下浓缩滤液。添加甲苯且浓缩混合物,得到呈深黄色糊浆状的(R)-4-(2-氨基-6-(甲氧基甲氧基)苯基)丁-2-醇(2.60g,100%),其未经进一步纯化即使用。MS(ESI,正离子)m/z 248[M+23]+。
步骤5.(R)-N-(2-(3-羟丁基)-3-(甲氧基甲氧基)苯基)乙酰胺
将粗(R)-4-(2-氨基-6-(甲氧基甲氧基)苯基)丁-2-醇(2.60g,11.54mmol)和吡啶(2.80mL,34.6mmol)于二氯甲烷(52mL)中的溶液冷却到0℃,且用乙酸酐(1.14mL,12.1mmol)处理。去除冰浴,且在室温下搅拌反应混合物。45分钟后,用5%氯化钠水溶液(2×20mL)洗涤溶液,接着在减压下浓缩。添加甲苯(约100mL)且浓缩混合物。通过硅胶柱色谱(以25-100%乙酸乙酯-己烷进行梯度洗提)纯化残余物,得到呈浅黄色糊浆状的(R)-N-(2-(3-羟丁基)-3-(甲氧基甲氧基)苯基)乙酰胺(2.7g,88%)。MS(ESI,正离子)m/z 290[M+23]+。
步骤6.甲烷磺酸(R)-4-(2-乙酰胺基-6-(甲氧基甲氧基)苯基)丁-2-基酯
用三乙胺(3.13mL,22.44mmol)处理(R)-N-(2-(3-羟丁基)-3-(甲氧基甲氧基)苯基)乙酰胺(4.0g,14.96mmol)于乙腈(40mL)中的溶液,且冷却到0℃。缓慢添加甲烷磺酰氯(1.46mL,18.7mmol),且立即形成沉淀物。在0℃下搅拌浆液。3小时后,用乙酸乙酯稀释反应混合物,且倒入5%氯化钠水溶液(50mL)中。分离各层,且再用5%氯化钠水溶液(40mL)洗涤有机层。用乙酸乙酯萃取经合并的水层,且在减压下浓缩经合并的有机层。将残余物溶解于甲苯(50-75mL)中,接着在减压下去除,得到呈琥珀色糊浆状的甲烷磺酸(R)-4-(2-乙酰胺基-6-(甲氧基甲氧基)苯基)丁-2-基酯(5.17g,100%)。粗物质未经进一步纯化即使用。MS(ESI,正离子)m/z 250[M-95]·+。
步骤7.(S)-1-(5-(甲氧基甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
将甲烷磺酸(R)-4-(2-乙酰胺基-6-(甲氧基甲氧基)苯基)丁-2-基酯(3.39g,9.8mmol)溶解于N,N-二甲基甲酰胺(34mL)中。冷却溶液到0℃,且一次性添加氢化钠(60%,于矿物油中,0.510g,12.74mmol)。去除冰浴,且在室温下搅拌反应混合物。2小时后,用冰浴冷却反应混合物到0℃,且用水(40mL)缓慢稀释。用乙酸乙酯萃取混合物。分离有机层,且用5%氯化钠水溶液(2×40mL)洗涤。用乙酸乙酯萃取经合并的水层,且在减压下浓缩经合并的有机萃取物,得到深琥珀色糊浆(3.9g)。经硅胶柱色谱(以2:1己烷-乙酸乙酯、继而3:2己烷-乙酸乙酯洗提)纯化粗产物,得到呈深黄色-橙色糊浆状的(S)-1-(5-(甲氧基甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(1.74g,71%)。MS(ESI,正离子)m/z 250[M+1]+。
步骤8.(S)-1-(5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
在室温下,用浓盐酸(1.0mL,12.8mmol)处理(S)-1-(5-(甲氧基甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(1.6g,6.42mmol)于甲醇(16mL)中的溶液。加热溶液到50℃维持90分钟。停止加热,且使溶液缓慢冷却到室温隔夜。在减压下去除甲醇,且将残余物分配于二氯甲烷与水之间。分离水层,且用二氯甲烷萃取。在减压下浓缩经合并的有机萃取物。将残余物溶解于乙腈(约20-30mL)中,接着在减压下浓缩,得到呈灰白色到褐色固体状的(S)-1-(5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(1.23g,93%)。MS(ESI,正离子)m/z 206[M+1]+。
步骤9.(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(中间物3).
将(S)-1-(5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(1.2g,5.85mmol)于乙腈(24mL)中的溶液冷却到0℃,且用N-溴代丁二酰亚胺(1.041g,5.85mmol)一次性处理。溶液颜色最初变成深黄色-橙色,接着经下一个10-15分钟变淡到浅橙色。30分钟后,在减压下浓缩溶液。通过硅胶柱色谱(以8:1二氯甲烷-乙酸乙酯、继而7:1二氯甲烷-乙酸乙酯洗提)纯化粗产物,得到(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(1.37g,82%)。MS(ESI,正离子)m/z 284,286[M+1]+。
还可遵循用于合成(2S)-6-溴-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇的程序,用乙酰氯替代环丙烷羰基氯,从(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉合成中间物3。MS:(ES,m/z):284,286[M+H]+
实例5:中间物4.(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯遵循用于(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮的程序,用氯甲酸甲酯替代步骤5中的乙酰氯合成,或遵循用于合成(2S)-6-溴-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇的程序,用氯甲酸甲酯替代环丙烷羰基氯,从(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉合成。MS:(ES,m/z):300,302[M+H]+
实例6:中间物5和6.外消旋-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(5)和外消旋-6-溴-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(6)
步骤1. 3-氨基-4-氯苯酚
向配备有磁性搅拌棒的100-mL圆底烧瓶中装入4-氯-3-硝基苯酚(6.0g,34.6mmol)和乙酸(60mL)。添加铁粉(325目)(19.31g,346mmol),且在100℃下加热混合物30分钟。冷却混合物到室温,且用水(40mL)稀释。接着经硅藻土衬垫过滤混合物,且用水冲洗。接着用乙酸乙酯萃取滤液,且在减压下浓缩经合并的萃取物。将庚烷(约100mL)添加到滤液中,接着在减压下去除以去除残余乙酸和水。重复这一过程。将残余物溶解于乙腈中,且在减压下浓缩。使所得固体悬浮于庚烷中且在减压下浓缩,得到呈浅紫色/琥珀色固体状的3-氨基-4-氯苯酚(4.38g,88%)。MS(ESI,正离子)m/z 144[M+1]。
步骤2. 2-氯-5-苯氧基苯胺
向配备有磁性搅拌棒的经加热枪干燥的100-mL圆底烧瓶中装入磷酸钾(5.91g,27.9mmol)、吡啶甲酸(0.171g,1.393mmol)、碘化铜(I)(0.133g,0.697mmol)、3-氨基-4-氯苯酚(2.0g,13.93mmol)、二甲亚砜(27.9mL)和碘苯(3.41g,16.72mmol)。加热所得混合物到80℃。15小时后,对反应混合物进行水性处理,得到粗产物,接着通过急骤色谱来纯化,得到纯2-氯-5-苯氧基苯胺(2.61g,85%)。MS(ESI,正离子)m/z 220[M+1]。
步骤3. 8-氯-2-甲基-5-苯氧基喹啉
向配备有磁性搅拌棒的50-mL圆底烧瓶中装入2-氯-5-苯氧基苯胺(1.25g,5.69mmol)、氯醌(1.399g,5.69mmol)、正丁醇(5mL)和浓盐酸(1.61mL,19.3mmol)。加热混合物到100℃,接着经5分钟缓慢添加(E)-丁-2-烯醛(0.566mL,6.83mmol)于正丁醇(2mL)中的溶液。混合物变成深琥珀色/棕色溶液。45分钟后,停止加热。冷却后,用THF(30mL)稀释溶液。接着在减压下浓缩溶液以去除THF。添加乙酸乙酯且形成沉淀物。搅拌浆液15分钟,接着过滤。用乙酸乙酯冲洗固体且干燥,得到1.9g深黄色-棕色固体。使这一物质悬浮于25mL 1N氢氧化钠水溶液中,且快速搅拌浆液30分钟,接着过滤。用水彻底冲洗固体且干燥,得到呈灰白色固体状的8-氯-2-甲基-5-苯氧基喹啉(0.95g,62%)。MS(ESI,正离子)m/z 270[M+1]。
步骤4. 2-甲基-5-苯氧基喹啉
向帕尔瓶中装入8-氯-2-甲基-5-苯氧基喹啉(0.93g,3.45mmol)、甲醇(20mL)和3M氢氧化钠水溶液(3.79mL,11.38mmol)。用氮气吹洗所述瓶,且添加10%钯/碳(0.5g,0.470mmol)。接着在氢气气氛(30psig)下震荡混合物。4.5小时后,经硅藻土衬垫过滤混合物。用甲醇冲洗瓶和过滤衬垫。在减压下浓缩滤液。接着将残余物分配于乙酸乙酯与5%氯化钠水溶液(25mL)之间。分离各层,且再次用5%氯化钠水溶液(25mL)洗涤有机层。用乙酸乙酯萃取水性洗涤物一次,且浓缩经合并的萃取物,得到呈浅黄色-橙色糊浆状的粗2-甲基-5-苯氧基喹啉(0.82g,101%),其未经进一步纯化即使用。MS(ESI,正离子)m/z 236[M+1]。
步骤5.外消旋-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(中间物5)
向配备有磁性搅拌棒的玻璃螺旋盖小瓶中装入2-甲基-5-苯氧基喹啉(0.05g,0.213mmol)、甲醇(1mL)和氯化镍(II)(4.96mg,0.038mmol)。在室温下经30秒逐份添加硼氢化钠(0.032g,0.850mmol)。反应混合物变成深紫色(接近黑色),且观测到放热。10分钟后,在氮气流下浓缩反应混合物。接着用1N氢氧化钠水溶液(1mL)和二氯甲烷(2-3mL)处理残余物。经硅藻土衬垫过滤所得乳液,且用乙酸乙酯洗涤。浓缩滤液,得到呈浅黄色糊浆状的外消旋-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(0.051g)。粗产物未经进一步纯化即继续使用。MS(ESI,正离子)m/z 240[M+1]。
步骤6.外消旋-6-溴-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(中间物6)
向配备有磁性搅拌棒和热电偶的50-mL圆底烧瓶中装入外消旋-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(0.574g,2.399mmol)和乙腈(11.5mL)。冷却溶液到0℃,且一次性添加N-溴代丁二酰亚胺(0.427g,2.399mmol)。溶液变成黄色,且内部温度升到5℃,随后下降返回到0℃。10分钟后,添加N-溴代丁二酰亚胺(0.021g,0.120mmol)。再经10分钟后,自冰浴去除反应混合物且在减压下浓缩。接着将残余物分配于乙酸乙酯与10%碳酸钠水溶液之间。分离各层,且用5%氯化钠水溶液(10mL)洗涤乙酸乙酯层且浓缩成黄色油状物(0.81g)。通过硅胶柱色谱(以12:1己烷-乙酸乙酯、继而10:1己烷-乙酸乙酯洗提)纯化粗产物,得到呈无色糊浆状的外消旋-6-溴-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(0.60,79%)。MS(ESI,正离子)m/z 318,320[M+1]。
实例7:中间物7--3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)硫杂环丁烷1,1-二氧化物
向100-mL圆底烧瓶中装入4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.942g,4.85mmol)、N,N-二甲基甲酰胺(20mL)和碳酸铯(3.16g,9.71mmol)。添加3-溴硫杂环丁烷1,1-二氧化物(0.925g,5.00mmol),且在60℃下搅拌反应物隔夜。冷却反应混合物到室温,接着分配于乙酸乙酯与水之间。分离水相,且用乙酸乙酯萃取。用水和盐水洗涤经合并的有机相且浓缩,得到油状物。经硅胶柱色谱(以1:5乙酸乙酯-己烷洗提)纯化这一物质,得到呈白色固体状的3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)硫杂环丁烷1,1-二氧化物(0.172g,12%产率)。MS(ESI,正离子)m/z 299[M+H]+。
实例8:中间物8--3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)四氢-2H-硫代吡喃1,1-二氧化物
根据上文针对3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)硫杂环丁烷1,1-二氧化物(中间物7)所概述的程序,自4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑和4-溴四氢-2H-硫代吡喃1,1-二氧化物合成3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)四氢-2H-硫代吡喃1,1-二氧化物。13C NMR(400MHz,CDCl3)δppm 20.85(s,1C),24.75(s,1C),24.77(s,4C),31.38(s,1C),50.50(s,1C),56.62(s,1C),57.33(s,1C),83.50(s,2C),134.95(s,1C),146.21(s,1C)。MS(ESI,正离子)m/z 327[M+H]+。
实例9:中间物9--8-氟-5-甲氧基-2-甲基喹啉
根据上文针对8-氯-5-甲氧基-2-甲基喹啉盐酸盐(中间物1,步骤1)所述的程序,自2-氟-5-甲氧基苯胺(30.0g,213mmol)合成8-氟-5-甲氧基-2-甲基喹啉,作出以下改变:将盐酸盐溶解于二氯甲烷(400mL)中,且用饱和碳酸钾水溶液将所得溶液的pH值调整到8-9。用二氯甲烷萃取所得混合物,且经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以20%乙酸乙酯-石油醚洗提)纯化残余物,得到呈黄色固体状的8-氟-5-甲氧基-2-甲基喹啉(25.2g,62%)。MS(ESI,正离子)m/z 192[M+H]+。
实例10:中间物10--(S)-8-氟-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉
根据上文针对(2S)-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉(中间物1)所述的程序,自8-氟-5-甲氧基-2-甲基喹啉合成(S)-8-氟-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉。MS(ESI,正离子)m/z 196[M+H]+。
实例11:中间物11--(S)-(6-溴-8-氟-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
根据上文针对(2S)-6-溴-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇(中间物2,步骤1a、2a和3)所述的程序,自(S)-8-氟-5-甲氧基-2-甲基-1,2,3,4-四氢喹啉合成(S)-(6-溴-8-氟-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮。MS(ESI,正离子)m/z 328,330[M+H]+。
根据上文针对中间物11所述的程序制备以下中间物:
实例12:中间物12--(S)-1-(6-溴-8-氟-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
MS(ESI,正离子)m/z 302,304[M+H]+。
实例13:中间物13--(S)-6-溴-8-氟-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
MS(ESI,正离子)m/z 318,320[M+H]+。
实例14:中间物14--(S)-1-(6-溴-5-环丁氧基-7,8-二氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
步骤1.(3,4-二氟苯氧基)三异丙基硅烷
将氯化三异丙基硅烷(166mL,961.5mmol)缓慢添加到3,4-二氟苯酚(125g,961.5mmol)和咪唑(65.4g,961.5mmol)于N,N-二甲基甲酰胺(500mL)中的混合物中,且在室温下搅拌所得溶液隔夜。用水(1500mL)稀释反应混合物,且用二氯甲烷(3×300mL)萃取。用水(3×200mL)和盐水(2×200mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以石油醚洗提)纯化残余物,得到呈无色油状的(3,4-二氟苯氧基)三异丙基硅烷(220g,80%)。
步骤2. 2,3-二氟-5-(三异丙基硅烷氧基)苯甲酸
将N,N,N′,N″,N″-五甲基二亚乙基三胺(60.4g,349.1mmol)于四氢呋喃(480mL)中的溶液冷却到-70℃,且经10分钟添加仲丁基锂(1.25M,于环己烷中,335mL,419mmol)。经1小时逐滴添加(3,4-二氟苯氧基)三异丙基硅烷(99.85g,349.1mmol),且在-70℃下搅拌所得混合物2小时。将二氧化碳鼓入溶液中,且在-70℃下搅拌所得混合物5小时,接着在室温下搅拌2小时。接着将反应混合物倒入水(200mL)中,且用2N盐酸将pH值调整到5。用乙酸乙酯(3×500mL)萃取所得混合物,且用盐水(200mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤且浓缩,得到呈淡黄色固体状的2,3-二氟-5-(三异丙基硅烷氧基)苯甲酸(99.1g,86%)。MS(ESI,负离子)m/z 329[M-H]-。
步骤3. 2,3-二氟-5-羟基苯甲酸
将三水合氟化四丁基铵(191g,731.8mmol)分数份添加到2,3-二氟-5-(三异丙基硅烷氧基)苯甲酸(99.13g,300.0mmol)于四氢呋喃(500mL)中的溶液中,且在室温下搅拌所得混合物隔夜。将反应混合物倒入水(1000mL)中,且用乙酸乙酯(2×500mL)萃取。用盐水(2×500mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩,得到呈淡黄色固体状的2,3-二氟-5-羟基苯甲酸(50g,95%)。MS(ESI,负离子)m/z 173[M-H]-。
步骤4. 5-环丁氧基-2,3-二氟苯甲酸环丁酯
将溴环丁烷(150g,1.12mol)添加到2,3-二氟-5-羟基苯甲酸(50g,287mmol)和碳酸钾(230g,1.67mol)于乙腈(1500mL)中的混合物中,且在90℃下搅拌所得混合物隔夜。冷却反应混合物到室温,过滤,且在真空下浓缩。经硅胶柱色谱(以石油醚洗提)纯化残余物,得到呈黄绿色固体状的5-环丁氧基-2,3-二氟苯甲酸环丁酯(49g,60%)。MS(ESI,正离子)m/z 283[M+H]+。
步骤5. 5-环丁氧基-2,3-二氟苯甲酸
将5-环丁氧基-2,3-二氟苯甲酸环丁酯(49g,174mmol)、乙醇(300mL)、氢氧化钠(20g,500mmol)和水(300mL)的混合物在60℃下搅拌隔夜。冷却混合物到室温,且用石油醚(2×100mL)萃取。用6M盐酸将水层的pH值调整到5,接着将其用乙酸乙酯(3×300mL)萃取。用盐水洗涤经合并的乙酸乙酯层,经无水硫酸钠干燥,过滤且浓缩,得到呈白色固体状的5-环丁氧基-2,3-二氟苯甲酸(38g,96%)。MS(ESI,负离子)m/z 227[M-H]-。
步骤6. 5-环丁氧基-2,3-二氟苯基氨基甲酸叔丁酯
将5-环丁氧基-2,3-二氟苯甲酸(38g,148mmol)、叔丁醇(280mL)、三乙胺(21.4mL,154mmol)和二苯基磷酰基叠氮化物(33.2mL,154mmol)的溶液在90℃下搅拌隔夜。冷却反应混合物到室温且浓缩。将残余物溶解于二氯甲烷(200mL)中,用1M氢氧化钠(2×100mL)和盐水(2×50mL)洗涤,经无水硫酸钠干燥,过滤且浓缩。经硅胶柱色谱(以5%乙酸乙酯/石油醚洗提)纯化残余物,得到呈白色固体状的5-环丁氧基-2,3-二氟苯基氨基甲酸叔丁酯(32g,76%)。MS(ESI,正离子)m/z 230[M+H]+。
步骤7. 5-环丁氧基-2,3-二氟苯胺盐酸盐
将三氟乙酸(70mL)添加到5-环丁氧基-2,3-二氟苯基氨基甲酸叔丁酯(32g,107mmol)于二氯甲烷(320mL)中的溶液中,且在室温下搅拌所得溶液隔夜。浓缩反应溶液,且将残余物溶解于二氯甲烷(500mL)中。在搅拌下缓慢添加HCl溶液(4M,于1,4-二噁烷中,120mL)。浓缩所得混合物,且倒入乙醚(480mL)中。过滤所得沉淀物,且在减压下干燥滤饼,得到呈淡黄色固体状的5-环丁氧基-2,3-二氟苯胺盐酸盐(21g,89%)。MS(ESI,正离子)m/z200[M+H]+。
步骤8. 5-环丁氧基-7,8-二氟-2-甲基喹啉盐酸盐
将5-环丁氧基-2,3-二氟苯胺盐酸盐(9.9g,42.1mmol)、浓盐酸(36mL)、氯醌(12.32g,49.8mmol)于正丁醇(60mL)中的混合物在100℃下搅拌1小时。逐滴添加(E)-丁烯醛(19.8mL,239mmol),且在100℃下搅拌所得溶液1小时,接着冷却到70℃。添加四氢呋喃(600mL),且在70℃下再搅拌混合物30分钟。冷却反应混合物到室温,且在真空下浓缩。将残余物倒入水(300mL)中,且用饱和碳酸钾水溶液将混合物的pH值调整到7-8。用乙酸乙酯(3×300mL)萃取所得混合物,且经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以25%乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色固体状的5-环丁氧基-7,8-二氟-2-甲基喹啉盐酸盐(6g,57%)。MS(ESI,正离子)m/z 250[M+H]+。
步骤9.(S)-5-环丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉
向30-mL玻璃衬里不锈钢反应器中装入5-环丁氧基-7,8-二氟-2-甲基喹啉(4.2g,16.9mmol)、Cp*Ru(OTf)[(S,S)-TsDPEN](0.100g,0.13mmol)和甲醇(10mL)。将反应器封闭,且在50atm的压力下引入氢气,随后降到1atm。重复这一程序三次之后,用氢气将反应器加压到50atm。在室温下于这一氢气压力下搅拌所得混合物24小时。小心释放氢气之后,在真空下浓缩反应混合物。经硅胶柱色谱(以25%乙酸乙酯/石油醚洗提)纯化残余物,得到呈无色油状的(S)-5-环丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉(1.4g,33%,87%ee)。
MS(ESI,正离子)m/z 254[M+H]+。
步骤10.(S)-6-溴-5-环丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉
将N-溴代丁二酰亚胺(0.703g,3.95mmol)于乙腈(10mL)中的溶液逐滴添加到(S)-5-环丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉(1.0g,3.95mmol)于乙腈(80mL)和二氯甲烷(15mL)中的-5℃溶液中,且在-5℃下搅拌所得溶液4小时。在真空下浓缩反应混合物。经硅胶柱色谱(以50%乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色固体状的(S)-6-溴-5-环丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉(1.05g,81%)。MS(ESI,正离子)m/z332,334[M+H]+。
步骤11.(S)-1-(6-溴-5-环丁氧基-7,8-二氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
将乙酰氯(0.21mL,3.02mmol)逐滴添加到(S)-6-溴-5-环丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉(1.0g,3.02mmol)于二氯甲烷(20mL)和吡啶(0.6mL)中的0℃溶液中,且搅拌所得溶液且升温到室温隔夜。用二氯甲烷(40mL)稀释反应混合物,用1N盐酸(40mL)和盐水(40mL)洗涤,经无水硫酸钠干燥,过滤且浓缩,得到呈黄色油状的(S)-1-(6-溴-5-环丁氧基-7,8-二氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(1.19g,99%)。MS(ESI,正离子)m/z 374,376[M+H]+。
实例15:中间物15--4-(4-溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯
步骤1. 4-(1H-咪唑-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯
将2-溴-1H-咪唑(1.2g,8.16mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(3.0g,9.70mmol)、碳酸钠(2.1g,19.8mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.120g,0.16mmol)于1,4-二噁烷(30mL)和水(10mL)中的混合物在100℃下搅拌隔夜。冷却反应混合物到室温,倒入乙酸乙酯(100mL)中,用水(30mL)和盐水(30mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以25%乙酸乙酯-石油醚洗提)纯化残余物,得到呈淡黄色固体状的4-(1H-咪唑-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(0.300g,15%)。MS(ESI,正离子)m/z 250[M+H]+。
步骤2. 4-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯
将钯/碳(10wt%,0.100g)添加到4-(1H-咪唑-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(0.300g,1.20mmol)于乙醇(20mL)中的溶液中,且在室温下于氢气气氛下搅拌混合物2小时。过滤反应混合物,且在真空下浓缩滤液,得到呈灰白色固体状的4-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(0.300g,99%)。MS(ESI,正离子)m/z 252[M+H]+。
步骤3. 4-(4-溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯
向100-mL圆底烧瓶中装入4-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(0.300g,1.19mmol)和四氢呋喃(10mL),且冷却溶液到-78。添加N-溴代丁二酰亚胺(0.185g,1.04mmol),且在-78℃下搅拌所得溶液2小时。将反应混合物倒入水(10mL)中,且用乙酸乙酯(3×20mL)萃取。用盐水(10mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以2:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈白色固体状的4-(4-溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(0.26g,66%)。MS(ESI,正离子)m/z 330,332[M+H]+。
实例16:中间物16--4-(4-溴-1-甲基-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯
根据上文针对4-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(中间物15)所述的程序,用2-溴-1-甲基-1H-咪唑替代步骤1中的2-溴-1H-咪唑来合成4-(4-溴-1-甲基-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯。MS(ESI,正离子)m/z 264[M+H]+。
实例17:中间物17和18--4-(3-溴-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(中间物17)和4-(5-溴-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(中间物18)
步骤1. 4-(甲基磺酰氧基)哌啶-1-甲酸叔丁酯
将甲烷磺酰氯(2.90mL,37.6mmol)添加到4-羟基哌啶-1-甲酸叔丁酯(5.00g,24.8mmol)和三乙胺(10.4mL,74.65mmol)于二氯甲烷(50mL)中的0℃溶液中,且在室温下搅拌所得溶液1小时。用二氯甲烷(200mL)稀释反应混合物,用水(2×50mL)洗涤,经无水硫酸钠干燥,过滤且浓缩,得到呈黄色固体状的4-(甲基磺酰氧基)哌啶-1-甲酸叔丁酯(7.00g,99%)。MS(ESI,正离子)m/z 280[M+H]+。
步骤2. 4-(3-溴-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(中间物17)和4-(5-溴-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(中间物18)
将4-(甲基磺酰氧基)哌啶-1-甲酸叔丁酯(0.837g,3.00mmol)、3-溴-1H-吡唑(0.441g,3.02mmol)和碳酸铯(2.94g,9.02mmol)于DMF(10mL)中的混合物在100℃下搅拌5小时。冷却反应混合物到室温,且倒入乙酸乙酯(50mL)中。用水(3×10mL)洗涤混合物,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以10%二氯甲烷/甲醇洗提)纯化残余物,得到呈白色固体状的4-(3-溴-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.25g,25%)。MS(ESI,正离子)m/z 330,332[M+H]+。
还获得呈白色固体状的4-(5-溴-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.150g,15%)。MS(ESI,正离子)m/z 330,332[M+H]+。
实例18:中间物19和20--4-(4-溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸叔丁酯(中间物19)和4-(4-溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸叔丁酯(中间物20)
步骤1. 4,5-二溴-2H-1,2,3-三唑
将溴(11.59g,73.35mmol)逐滴添加到2H-1,2,3-三唑(5.00g,72.46mmol)于水(50mL)中的0℃溶液中,且使所得溶液升温到室温且搅拌隔夜。通过过滤收集沉淀物且干燥,得到呈白色固体状的4,5-二溴-2H-1,2,3-三唑(8.00g,49%)。MS(ESI,正离子)m/z228,226,230[M+H]+。
步骤2. 4-(4,5-二溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸叔丁酯和4-(4,5-二溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸叔丁酯
将4,5-二溴-2H-1,2,3-三唑(2.27g,10.08mmol)、4-(甲基磺酰氧基)哌啶-1-甲酸叔丁酯(2.79g,10.00mmol)和碳酸铯(9.75g,29.91mmol)于N,N-二甲基甲酰胺(50mL)中的混合物在100℃下搅拌隔夜。冷却反应混合物到室温,倒入水(100mL)中,且用乙酸乙酯(2×100mL)萃取。用盐水(100mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤且浓缩,得到呈黄色油状的4-(4,5-二溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸叔丁酯与4-(4,5-二溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸叔丁酯的混合物(4.00g,97%)。MS(ESI,正离子)m/z411,409,413[M+H]+。
步骤3. 4-(4-溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸叔丁酯(中间物19)和4-(4-溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸叔丁酯(中间物20)
将正丁基锂(2.5M,于己烷中,2.92mL,7.30mmol)逐滴添加到含有4-(4,5-二溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸叔丁酯和4-(4,5-二溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸叔丁酯的混合物(3.00g,7.35mmol)于四氢呋喃(20mL)中的-78℃溶液中。在-78℃下搅拌所得溶液1小时,接着将反应混合物倒入饱和氯化铵水溶液(20mL)中。分离水相且用乙酸乙酯(3×20mL)萃取,且经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以2:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈无色油状的4-(4-溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸叔丁酯(0.800g,33%)。MS(ESI,正离子)m/z 331,333[M+H]+。
还获得呈无色油状的4-(4-溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸叔丁酯(0.500g,20%)。MS(ESI,正离子)m/z 331,333[M+H]+。
实例19:中间物21--3-(4-溴噻唑-2-基)氮杂环丁烷-1-甲酸叔丁酯
将1,2-二溴乙烷(0.084mL,0.97mmol)添加到锌粉(0.520g,8.13mmol)于四氢呋喃(2mL)中的混合物中,且在80℃下搅拌所得混合物10分钟,接着冷却到室温。在搅拌下逐滴添加氯三甲基硅烷(0.115mL,1.22mmol)于四氢呋喃(1mL)中的溶液,且在室温下搅拌所得混合物45分钟。添加3-碘氮杂环丁烷-1-甲酸叔丁酯(1.74g,6.15mmol)于四氢呋喃(2mL)中的溶液,且在室温下搅拌所得混合物2小时。添加2,4-二溴噻唑(0.744g,3.09mmol)于四氢呋喃(1mL)中的溶液和四(三苯基膦)钯(0)(0.354g,0.31mmol),且在室温下搅拌所得混合物隔夜。将反应混合物倒入水(10mL)中,且用乙酸乙酯(3×10mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以1:2乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的3-(4-溴噻唑-2-基)氮杂环丁烷-1-甲酸叔丁酯(0.151g,8%)。MS(ESI,正离子)m/z 319,321[M+H]+。
实例20:中间物22--3-(4-溴噻唑-2-基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯
将正丁基锂(1.6M,于THF中,6.3mL,10.1mmol)逐滴添加到2,4-二溴噻唑(2.00g,8.30mmol)于四氢呋喃(50mL)中的-78℃溶液中,且在-78℃下搅拌混合物1小时。添加3-氧代基氮杂环丁烷-1-甲酸叔丁酯(2.83g,16.55mmol)于四氢呋喃(5mL)中的溶液,且在室温下搅拌所得混合物1小时。将反应混合物倒入饱和氯化铵水溶液(50mL)中,且用二氯甲烷(3×50mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以20%乙酸乙酯/石油醚洗提)纯化残余物,得到呈白色固体状的3-(4-溴噻唑-2-基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯(0.890g,32%)。MS(ESI,正离子)m/z 335,337[M+H]+。
实例21:中间物23--N-(4-溴噻唑-2-基)乙酰胺
使4-溴噻唑-2-胺(0.500g,2.81mmol)、乙酸酐(0.43mL,4.50mmol)和乙酸(5mL)的溶液回流2小时。冷却反应混合物到室温,且在真空下浓缩。经硅胶柱色谱(以25%乙酸乙酯-石油醚洗提)纯化残余物,得到呈白色固体状的N-(4-溴噻唑-2-基)乙酰胺(0.300g,49%)。MS(ESI,正离子)m/z 221,223[M+H]+。
实例22:中间物24--N-(4-溴噻唑-2-基)乙酰胺
向100-mL圆底烧瓶中置放4-溴噻唑-2-甲酸(800mg,3.86mmol,1.00当量)、DIEA(1.03g,7.92mmol,2.00当量)、四氢呋喃(50mL)、NH4Cl(424mg,8.00mmol,2.07当量)和HATU(1.82g,4.80mmol,1.24当量)。在25℃下搅拌所得混合物24小时。在真空下浓缩反应混合物,溶解于25mL乙酸乙酯中,用3×5mL水、5mL盐水洗涤,经无水硫酸钠干燥,且在真空下浓缩。将残余物施加到具有乙酸乙酯/石油醚(1/1)的硅胶柱上。这得到500mg(63%)呈白色固体状的4-溴噻唑-2-甲酰胺。MS(ESI,正离子)m/z207,209[M+H]+。
实例23:中间物25--4-溴-N-甲基噻唑-2-甲酰胺
根据上文针对N-(4-溴噻唑-2-基)乙酰胺(中间物24)所述的程序,用甲胺替代氯化铵来合成4-溴-N-甲基噻唑-2-甲酰胺。MS(ESI,正离子)m/z 221,223[M+H]+。
实例24:(S)-1-(6-(1-(2-羟乙基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-1)
步骤1.(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮
在80℃下加热(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.150g,0.528mmol)、1-溴丙烷(0.24mL,2.64mmol)和叔丁醇钾(0.296g,2.64mmol)于N,N-二甲基甲酰胺(3.0mL)中的混合物。24小时后,添加第二份1-溴丙烷(0.24mL,2.64mmol)和叔丁醇钾(0.296g,2.64mmol),且在100℃下加热混合物24小时。冷却反应混合物到室温,且添加水。用二氯甲烷萃取混合物,且用水和盐水洗涤经合并的有机相,经无水硫酸钠干燥,过滤且浓缩,得到黄色油状物。经硅胶柱色谱(Biotage 25g柱,以50-100%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色油状的(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.100g,58%)。MS(ESI,正离子)m/z 326,328[M+H]+。
步骤2.(S)-1-(6-(1-(2-羟乙基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮
将(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.050g,0.153mmol)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)乙醇(0.055g,0.230mmol)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)(2′-氨基-1,1′-联苯-2-基)钯(II)(XPhos第2代预催化剂)(0.012g,0.015mmol)和碳酸铯(0.150g,0.460mmol)于1,4-二噁烷(2.0mL)和水(0.40mL)中的混合物在100℃下于微波中加热2.5小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage 25g柱,以50-100%乙酸乙酯-己烷、继而10%甲醇-乙酸乙酯进行梯度洗提)纯化这一物质,得到呈灰白色固体状的(S)-1-(6-(1-(2-羟乙基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.047g,86%)。1H NMR(300MHz,DMSO-d6)δppm 0.97(t,J=7.48Hz,3H),1.03(d,J=6.45Hz,3H),1.23(m,1H),1.64-1.80(m,2H),2.07(s,3H),2.18-2.38(m,2H),2.75-2.90(m,1H),3.50-3.65(m,2H),3.68-3.80(m,2H),4.17(t,J=5.57Hz,2H),4.62(m,1H),4.84-4.94(m,1H),7.12(br d,J=8.21Hz,1H),7.38(d,J=8.50Hz,1H),7.85(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z 358[M+H]+。
根据针对实例24所概述的程序制得以下实例:
(S)-2-(1-乙酰基-6-(1-(2-羟乙基)-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-N,N-二甲基乙酰胺(I-2)
1H NMR(300MHz,DMSO-d6)δppm 0.98-1.09(m,3H),1.29(m,1H),2.08(s,3H),2.18-2.40(m,1H),2.75-2.90(m,2H),2.81(s,3H),2.84(s,3H),3.63-3.78(m,2H),4.05-4.18(m,2H),4.22-4.48(m,2H),4.61(m,1H),4.82-4.95(m,1H),7.15(br d,J=8.50Hz,1H),7.43(d,J=8.50Hz,1H),7.93(s,1H),8.21(s,1H)。MS(ESI,正离子)m/z 401[M+H]+。
(S)-5-(2-(二甲基氨基)-2-氧代基乙氧基)-6-(1-(2-羟乙基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-3)
1H NMR(300MHz,DMSO-d6)δppm 1.03-1.12(m,3H),1.48(td,J=13.12,6.89Hz,1H),2.09(td,J=13.63,5.28Hz,1H),2.70-2.82(m,2H),2.80(s,3H),2.84(s,3H),3.67(s,3H),3.72(q,J=5.77Hz,2H),4.11(t,J=5.57Hz,2H),4.35(q,J=13.88Hz,2H),4.42-4.56(m,1H),4.88(t,J=5.28Hz,1H),7.23-7.34(m,1H),7.35-7.45(m,1H),7.90(s,1H),8.18(s,1H)。MS(ESI,正离子)m/z 417[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-N-乙基乙酰胺(I-4)
1H NMR(300MHz,CD3OD)δppm 1.01-1.15(m,7H),1.22(t,J=7.20Hz,3H),1.29-1.42(m,1H),2.17(s,3H),2.31-2.45(m,2H),2.91-3.01(m,1H),3.35-3.43(m,3H),3.65-3.72(m,1H),4.07(d,J=14.40Hz,1H),4.15(d,J=14.40Hz,1H),4.71-4.81(m,1H),7.08-7.15(m,1H),7.43(d,J=8.40Hz,1H),7.89(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 397[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-5)
1H NMR(300MHz,CD3OD)δppm 1.01-1.15(m,7H),1.21-1.39(m,1H),2.15(s,3H),2.22-2.43(m,2H),2.95-2.07(m,1H),3.63-3.71(m,1H),3.81-4.01(m,2H),4.50-4.62(m,1H),4.67-4.78(m,2H),7.02-7.13(m,1H),7.45(d,J=8.40Hz,1H),7.89(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 358[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-N-环丙基-N-甲基乙酰胺(I-6)
1H NMR(400MHz,CD3OD)δppm 0.55-0.65(m,2H),0.72-0.78(m,2H),1.05-1.15(m,7H),1.23-1.41(m,1H),2.19(s,3H),2.30-2.42(m,2H),2.51-2.59(m,1H),2.98(s,3H),2.95-3.08(m,1H),3.65-3.72(m,1H),4.55(d,J=14.80Hz,1H),4.64(d,J=14.80Hz,1H),4.71-4.83(m,1H),7.05-7.20(m,1H),7.47(d,J=8.40Hz,1H),7.91(s,1H),8.21(s,1H)。MS(ESI,正离子)m/z 423[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-1-(氮杂环丁烷-1-基)乙酮(I-7)
1H NMR(300MHz,CD3OD)δppm 1.02-1.15(m,7H),1.24-1.43(m,1H),2.16(s,3H),2.24-2.43(m,4H),2.90-3.05(m,1H),3.65-3.75(m,1H),4.01-4.25(m,6H),4.65-4.82(m,1H),7.05-7.15(m,1H),7.45(d,J=8.10Hz,1H),7.89(s,1H),8.19(s,1H)。MS(ESI,正离子)m/z 409[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-1-(哌啶-1-基)乙酮(I-8)
1H NMR(300MHz,CD3OD)δppm 1.01-1.18(m,7H),1.21-1.53(m,3H),1.55-1.73(m,4H),2.18(s,3H),2.30-2.47(m,2H),2.94-3.05(m,1H),3.21-3.38(m,2H),3.58-3.65(m,2H),3.66-3.74(m,1H),4.39(d,J=14.10Hz,1H),4.50(d,J=14.10Hz,1H),4.73-4.85(m,1H),7.09-7.17(m,1H),7.48(d,J=8.40Hz,1H),7.92(s,1H),8.21(s,1H)。MS(ESI,正离子)m/z 437[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-9)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.49-1.68(m,1H),2.14-2.28(m,1H),2.50-2.63(m,1H),2.87-3.01(m,1H),3.65-3.78(m,1H),3.78(s,3H),4.01-4.18(m,2H),4.55-4.68(m,1H),7.37(q,d=8.70Hz,2H),7.83(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 410[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-10)
1H NMR(400MHz,CD3OD)δppm 1.01-1.20(m,7H),1.50-1.62(m,1H),2.20-2.28(m,1H),2.49-2.59(m,1H),2.91-3.01(m,1H),3.67-3.72(m,1H),3.79(s,3H),3.79-3.91(m,2H),4.55-4.62(m,1H),6.10(tt,J=54.80,3.60Hz,1H),7.37(s,2H),7.86(s,1H),8.04(s,1H)。MS(ESI,正离子)m/z 392[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-11)
1H NMR(400MHz,CD3OD)δppm 1.01-1.15(m,4H),1.18(d,J=6.80Hz,3H),1.47-1.58(m,1H),2.18-2.25(m,1H),2.48-2.58(m,1H),2.90-2.99(m,1H),3.63-3.71(m,1H),3.78(s,3H),3.81-3.87(m,1H),3.90-3.94(m,1H 0),4.51-4.62(m,2H),4.68-4.73(m,1H),7.33(d,J=8.40Hz,1H),7.38(d,J=8.80Hz,1H),7.88(s,1H),8.11(s,1H)。MS(ESI,正离子)m/z 374[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-12)
1H NMR(300MHz,CD3OD)δppm 1.02-1.19(m,7H),1.51-1.62(m,1H),1.77(t,J=18.90Hz,3H),2.15-2.25(m,1H),2.51-2.68(m,1H),2.89-3.01(m,1H),3.65-3.71(m,1H),3.75-3.85(m,5H),4.55-4.65(m,1H),7.36-7.37(m,2H),7.86(s,1H),8.06(s,1H)。MS(ESI,正离子)m/z 406[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-13)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.48-1.61(m,1H),2.15-2.27(m,1H),2.48-2.72(m,3H),2.85-2.95(m,1H),3.65-3.72(m,1H),3.72-3.83(m,5H),4.58-4.62(m,1H),7.28-7.34(m,2H),7.82(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z424[M+H]+。
(S)-5-(2-氨基-1,1-二氟-2-氧代基乙氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-14)
1H NMR(300MHz,CD3OD)δppm 0.98-1.21(m,7H),1.25-1.39(m,1H),2.21-2.45(m,2H),2.91-3.04(m,1H),3.61-3.68(m,1H),3.77(s,3H),4.41-4.52(m,1H),7.37-7.41(m,2H),7.79(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 421[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(1,3-二氟丙-2-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-15)
1H NMR(300MHz,CD3OD)δppm 0.98-1.15(m,4H),1.18(d,J=6.60Hz,3H),1.35-1.45(m,1H),2.20-2.31(m,1H),2.35-2.47(m,1H),2.95-3.03(m,1H),3.62-3.69(m,1H),3.69(s,3H),4.05-4.25(m,1H),4.29-4.33(m,1H),4.45-4.52(m,3H),4.61-4.63(m,1H),7.31(s,2H),7.78(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 406[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-16)
1H NMR(300MHz,CD3OD)δppm 0.98-1.18(m,7H),1.37-1.62(m,7H),2.11-2.23(m,1H),2.48-2.59(m,1H),2.87-2.99(m,1H),3.57(s,1H),3.58-3.71(m,2H),3.77(s,3H),4.52-4.62(m,1H),7.28-7.29(m,2H),7.86(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z 402[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(3-羟基-2,2-二甲基丙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-17)
1H NMR(300MHz,CD3OD)δppm 0.99(s,6H),1.01-1.18(m,7H),1.45-1.61(m,1H),2.17-2.23(m,1H),2.47-2.57(m,1H),2.91-3.01(m,1H),3.30-3.45(m,4H),3.60-3.71(m,1H),3.77(s,3H),4.51-4.62(m,1H),7.19-7.30(m,2H),7.76(s,1H),7.98(s,1H)。MS(ESI,正离子)m/z 414[M+H]+。
(S)-5-(1-氨基-2-甲基-1-氧代基丙-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-18)
1H NMR(300MHz,CD3OD)δppm 0.98-1.38(m,14H),2.20-2.39(m,2H),2.92-3.03(m,1H),3.63-3.72(m,1H),3.77(s,3H),4.38-4.52(m,1H),7.18-7.28(m,2H),7.72(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 413[M+H]+。
(S)-5-((R)-2-氨基-1-氟-2-氧代基乙氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-19)
1H NMR(300MHz,CD3OD)δppm 1.01-1.34(m,7H),1.42-1.58(m,1H),2.15-2.29(m,1H),2.48-2.62(m,1H),2.95-3.09(m,1H),3.59-3.71(m,1H),3.79(s,3H),4.52-4.63(m,1H),5.41(d,J=61.20Hz,1H),7.38(d,J=8.70Hz,1H),7.45(d,J=8.70Hz,1H),7.83(s,1H),8.08(s,1H)。MS(ESI,正离子)m/z 403[M+H]+。以试验方式指定氟的立体化学性。
(S)-5-((S)-2-氨基-1-氟-2-氧代基乙氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-20)
1H NMR(300MHz,CD3OD)δppm 1.03-1.1.35(m,7H),1.45-1.55(m,1H),2.17-2.24(m,1H),2.49-2.72(m,1H),3.01-3.12(m,1H),3.68-3.73(m,1H),3.80(s,3H),4.55-4.65(m,1H),5.49(d,J=61.50Hz,1H),7.41(d,J=8.40Hz,1H),7.47(d,J=8.70Hz,1H),7.84(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z 403[M+H]+。以试验方式指定氟的立体化学性。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-(乙基氨基)-2-氧代基乙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-21)
1H NMR(300MHz,CD3OD)δppm 1.01-1.27(m,10H),1.55-1.65(m,1H),2.15-2.23(m,1H),2.58-2.68(m,1H),2.83-2.93(m,1H),3.29-3.38(m,2H),3.65-3.71(m,1H),3.78(s,3H),4.08(s,2H),4.55-4.65(m,1H),7.35-7.42(m,2H),7.86(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z 413[M+H]+。
(S)-5-(2-(环丙基(甲基)氨基)-2-氧代基乙氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-22)
1H NMR(300MHz,CD3OD)δppm 0.48-0.62(m,2H),0.65-0.83(m,2H),1.01-1.09(m,4H),1.17(d,J=6.30Hz,3H),1.48-1.62(m,1H),2.15-2.25(m,1H),2.28-2.63(m,2H),2.78-3.01(m,4H),3.65-3.72(m,1H),3.77(s,3H),4.049-4.63(m,3H),7.31-7.41(m,2H),7.87(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 439[M+H]+。
(S)-5-(2-(氮杂环丁烷-1-基)-2-氧代基乙氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-23)
1H NMR(300MHz,CD3OD)δppm 0.99-1.19(m,7H),1.49-1.62(m,1H),2.15-2.35(m,3H),2.49-2.63(m,1H),2.87-2.9 8(m,1H),3.76-3.82(m,1H),3.76(s,3H),4.01-4.20(m,6H),4.58-4.65(m,1H),7.36(s,2H),7.86(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 425[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2-氧代基-2-(哌啶-1-基)乙氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-24)
1H NMR(300MHz,CD3OD)δppm 0.99-1.12(m,4H),1.17(d,J=6.60Hz,3H),1.38-1.72(m,7H),2.10-2.23(m,1H),2.49-2.62(m,1H),2.85-2.99(m,1H),3.17-3.21(m,2H),3.55-3.60(m,2H),3.61-3.68(m,1H),3.76(s,3H),4.38(q,J=14.10Hz,2H),4.51-4.62(m,1H),7.36(s,2H),7.86(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 453[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2-(2-氧代基吡咯烷-1-基)乙氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-25)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.48-1.62(m,1H),2.03-2.25(m,3H),2.40-2.58(m,3H),2.80-2.91(m,1H),3.50-3.61(m,4H),3.68-3.79(m,6H),4.55-4.65(m,1H),7.25-7.32(m,2H),7.80(s,1H),8.03(s,1H)。MS(ESI,正离子)m/z439[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2-吗啉基-2-氧代基乙氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-26)
1H NMR(300MHz,CD3OD)δppm 1.01-1.12(m,4H),1.18(d,J=6.40Hz,3H),1.52-1.63(m,1H),2.17-2.23(m,1H),2.50-2.65(m,1H),2.89-3.01(m,1H),3.53-3.73(m,7H),3.78(s,3H),4.31-4.45(m,2H),4.58-4.63(m,1H),7.30-7.38(m,2H),7.88(s,1H),8.15(s,1H)。MS(ESI,正离子)m/z 455[M+H]+。
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-[2-(1,1-二氧代基-1λ6,2-噻唑烷-2-基)乙氧基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-27)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.48-1.49(m,1H),2.15-2.23(m,1H),2.30-2.41(m,2H),2.48-2.58(m,1H),2.89-3.01(m,1H),3.18-3.22(m,2H),3.35-3.41(m,4H),3.63-3.79(m,6H),4.52-4.62(m,1H),7.32(s,2H),7.87(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z 475[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(氨磺酰基甲氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-28)
1H NMR(300MHz,CD3OD)δppm 0.99-1.09(m,2H),1.11-1.19(m,5H),1.49-1.62(m,1H),2.15-2.25(m,1H),2.52-2.68(m,1H),2.99-2.3.12(m,1H),3.61-3.70(m,1H),3.78(s,3H),4.50-4.63(m,3H),7.39(s,2H),7.89(s,1H),8.20(s,1H)。MS(ESI,正离子)m/z 421[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-((N,N-二甲基氨磺酰基)甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-29)
1H NMR(300MHz,CD3OD)δppm 0.98-1.19(m,7H),1.52-1.63(m,1H),2.15-2.25(m,1H),2.55-2.73(m,1H),2.88-3.02(m,7H),3.60-3.72(m,1H),3.77(s,3H),4.50-4.67(m,3H),7.34(d,J=8.70Hz,1H),7.41(d,J=8.70Hz,1H),7.85(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 449[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2-(氧杂环丁烷-3-基)乙氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-30)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.45-1.69(m,1H),2.03-2.21(m,3H),2.38-2.53(m,1H),2.75-2.89(m,1H),3.15-3.20(m,1H),3.47-3.58(m,2H),3.65-3.73(m,1H),3.76(s,3H),4.40-4.48(m,2H),4.49-4.62(m,1H),4.78-4.83(m,2H),7.21-7.31(m,2H),7.80(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 412[M+H]+。
(2S)-6-(1-环丙基-1H-吡唑-4-基)-5-((2,2-二氟环丙基)甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-31)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,8H),1.45-1.58(m,2H),1.90-2.05(m,1H),2.18-2.25(m,1H),2.45-2.55(m,1H),2.88-2.99(m,1H),3.57-3.71(m,2H),3.77(s,3H),3.78-3.83(m,1H),4.50-4.61(m,1H),7.32(s,2H),7.84(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 418[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-((3-(羟甲基)氧杂环丁烷-3-基)甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-32)
1H NMR(300MHz,CD3OD)δppm 1.01-1.17(m,7H),1.45-1.55(m,1H),2.15-2.25(m,1H),2.48-2.62(m,1H),2.88-2.99(m,1H),3.67-3.72(m,1H),3.75-3.85(m,7H),4.45-4.63(m,5H),7.25(d,J=8.40Hz,1H),7.33(d,J=8.70Hz,1H),7.73(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z 428[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(3,3-二氟环丁氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-33)
1H NMR(400MHz,CD3OD)δppm 1.02-1.19(m,7H),1.38-1.48(m,1H),2.25-2.31(m,1H),2.39-2.48(m,1H),2.53-2.82(m,4H),2.89-2.95(m,1H),3.68-3.73(m,1H),3.78(s,3H),4.21-4.30(m,1H),4.48-4.58(m,1H),7.30(s,2H),7.79(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 418[M+H]+。
(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(I-34)
1H NMR(300MHz,DMSO-d6)δppm 0.94(t,3H),1.00(d,3H),1.20-1.30(m,2H),1.40(s,9H),1.59-1.69(m,2H),2.05(s,3H),2.16-2.32(m,2H),2.36-2.44(m,2H),2.70-2.81(m,1H),3.49(d,2H),3.53-3.67(m,2H),3.94(t,2H),5.82(m,1H),6.98(d,1H),7.07(d,1H)。MS(ESI,正离子)m/z 429[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-35)
1H NMR(300MHz,CD3OD)δppm 1.01-1.18(m,7H),1.21-1.42(m,1H),2.16(s,3H),2.28-2.32(m,2H),2.95-3.05(m,1H),3.65-3.75(m,1H),4.01-4.21(m,2H),4.68-4.83(m,1H),7.10-7.20(m,1H),7.43(d,J=8.10Hz,1H),7.85(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 394[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-36)
1H NMR(300MHz,CD3OD)δppm 1.01-1.20(m,7H),1.28-1.43(m,1H),2.18(s,3H),2.28-2.35(m,2H),2.95-3.05(m,1H),3.65-3.75(m,1H),3.85-4.01(m,2H),4.61(s,1H),4.69-4.82(m,1H),6.13(tt,J=54.60,3.30Hz,1H),7.05-7.15(m,1H),7.46(d,J=8.40Hz,1H),7.90(s,1H),8.11(s,1H)。MS(ESI,正离子)m/z 376[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-37)
1H NMR(400MHz,CD3OD)δppm 1.01-1.18(m,7H),1.25-1.40(m,1H),1.77(t,J=18.80Hz,3H),2.18(s,3H),2.30-2.42(m,2H),2.95-3.05(m,1H),3.68-3.89(m,3H),4.70-4.82(m,1H),7.05-7.18(m,1H),7.44(d,J=8.40Hz,1H),7.88(s,1H),8.10(s,1H)。MS(ESI,正离子)m/z 390[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(1,3-二氟丙-2-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-38)
1H NMR(300MHz,CD3OD)δppm 0.98-1.30(m,8H),2.15(s,3H),2.25-2.49(m,2H),3.05-3.12(m,1H),3.65-3.72(m,1H),4.10-4.32(m,2H),4.47-4.54(m,2H),4.65-4.80(m,2H),7.05-7.15(m,1H),7.40(d,J=8.10Hz,1H),7.92(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 390[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(3-羟基-2,2-二甲基丙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-39)
1H NMR(400MHz,CD3OD)δppm 0.99(s,6H),1.05-1.25(m,7H),1.23-1.35(m,1H),2.17(s,3H),2.23-2.38(m,2H),3.01-3.13(m,1H),3.40-3.48(m,4H),3.65-3.75(m,1H),4.70-4.83(m,1H),7.01-7.09(m,1H),7.35(d,J=8.00Hz,1H),7.81(s,1H),8.04(s,1H)。MS(ESI,正离子)m/z 398[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-2-甲基丙酰胺(I-40)
1H NMR(300MHz,CD3OD)δppm 0.98-1.20(m,11H),1.30(s,3H),2.05-2.30(m,4H),2.33-2.45(m,1H),3.01-3.12(m,1H),3.65-3.72(m,1H),4.60-4.72(m,1H),7.05-7.12(m,1H),7.33(d,J=8.10Hz,1H),7.77(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 397[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-41)
1H NMR(400MHz,CDCl3)δppm 1.07-1.18(m,7H),1.31-1.37(m,1H),2.18(s,2H),2.38-2.41(m,2H),2.61-2.72(m,2H),2.97-3.02(m,1H),3.69-3.75(m,1H),3.82-3.92(m,2H),4.78(s,1H),7.14(s,1H),7.41(d,J=8.00Hz,1H),7.87(s,1H),8.10(s,1H)。MS(ESI,正离子)m/z 408[M+H]+。
(S)-1-(2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)乙基)吡咯烷-2-酮(I-42)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.25-1.39(m,1H),2.01-2.19(m,5H),2.27-2.48(m,4H),2.85-2.95(m,1H),3.55-3.68(m,4H),3.59-3.84(m,3H),4.65-4.78(m,1H),7.01-7.12(m,1H),7.37(d,J=8.40Hz,1H),7.83(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z 423[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-1-吗啉基乙酮(I-43)
1H NMR(300MHz,CD3OD)δppm 1.01-1.15(m,7H),1.15-1.45(m,1H),2.16(s,3H),2.30-2.43(m,2H),2.90-3.05(m,1H),3.50-3.80(m,7H),4.35-4.55(m,2H),4.68-4.84(m,1H),7.05-7.15(m,1H),7.46(d,J=8.40Hz,1H),7.90(s,1H),8.19(s,1H)。MS(ESI,正离子)m/z 439[M+H]+。
2-(2-{[(2S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}乙基)-1λ6,2-噻唑烷-1,1-二酮(I-44)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.25-1.35(m,1H),2.16(s,3H),2.28-2.45(m,4H),2.98-3.05(m,1H),3.22(t,J=7.80Hz,2H),3.28-3.42(m,4H),3.68-3.86(m,3H),4.70-4.83(m,1H),7.05-7.12(m,1H),7.41(d,J=8.40Hz,1H),7.91(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 459[M+H]+。
(S)-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)甲烷磺酰胺(I-45)
1H NMR(400MHz,CD3OD)δppm 1.01-1.25(m,7H),1.30-1.45(m,1H),2.18(s,3H),2.30-2.45(m,2H),3.10-3.20(m,1H),3.68-3.72(m,1H),4.58-4.68(m,2H),4.70-4.85(m,1H),7.10-7.20(m,1H),7.47(d,J=8.40Hz,1H),7.93(s,1H),8.21(s,1H)。MS(ESI,正离子)m/z 405[M+H]+。
(S)-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-N,N-二甲基甲烷磺酰胺(I-46)
1H NMR(400MHz,CD3OD)δppm 1.03-1.23(m,7H),1.34-1.52(m,1H),2.18(s,3H),2.30-2.52(m,2H),3.00(s,6H),3.05-3.15(m,1H),3.68-3.74(m,1H),4.67(d,J=10.80Hz,1H),4.72-4.79(m,2H),7.10-7.20(m,1H),7.45(d,J=8.40Hz,1H),7.91(s,1H),8.22(s,1H)。MS(ESI,正离子)m/z 433[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2-(氧杂环丁烷-3-基)乙氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-47)
1H NMR(300MHz,CD3OD)δppm 1.05-1.15(m,7H),1.21-1.37(m,1H),2.05-2.15(m,5H),2.25-2.42(m,2H),2.82-2.95(m,1H),3.18-3.30(m,1H),3.55-3.78(m,3H),4.46(t,J=6.30Hz,2H),4.65-4.83(m,2H),4.83-4.89(m,1H),7.01-7.11(m,1H),7.37(d,J=8.40Hz,1H),7.84(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 396[M+H]+。
1-((S)-6-(1-环丙基-1H-吡唑-4-基)-5-((2,2-二氟环丙基)甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-48)
1H NMR(400MHz,CD3OD)δppm 1.01-1.15(m,8H),1.21-1.35(m,1H),1.45-1.55(m,1H),1.90-2.05(m,1H),2.16(s,3H),2.25-2.45(m,2H),2.95-3.05(m,1H),3.58-3.75(m,2H),3.85-3.99(m,1H),4.67-4.82(m,1H),7.05-7.12(m,1H),7.42(d,J=8.40Hz,1H),7.89(s,1H),8.10(s,1H)。MS(ESI,正离子)m/z 402[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-((3-(羟甲基)氧杂环丁烷-3-基)甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-49)
1H NMR(300MHz,CD3OD)δppm 1.01-1.19(m,7H),1.15-1.42(m,1H),2.17(s,3H),2.28-2.45(m,2H),2.95-3.05(m,1H),3.68-3.75(m,1H),3.79-3.95(m,4H),4.45-4.57(m,4H),4.68-4.82(m,1H),7.05-7.12(m,1H),7.35(d,J=8.40Hz,1H),7.77(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 412[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-((3-氟氧杂环丁烷-3-基)甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-50)
1H NMR(300MHz,CD3OD)δppm 0.99-1.15(m,7H),1.25-1.41(m,1H),2.16(s,3H),2.28-2.45(m,2H),2.95-3.05(m,1H),3.65-3.75(m,1H),3.99-4.25(m,2H),4.55-4.85(m,5H),7.05-7.15(m,1H),7.41(d,J=8.70Hz,1H),7.84(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 400[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(3,3-二氟环丁氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-51)
1H NMR(300MHz,CD3OD)δppm 1.01-1.15(m,7H),1.15-1.25(m,1H),2.15(s,3H),2.20-2.48(m,2H),2.55-2.89(m,4H),2.91-3.01(m,1H),3.68-3.75(m,1H),4.25-4.35(m,1H),4.65-4.80(m,1H),7.05-7.11(m,1H),7.38(d,J=8.40Hz,1H),7.82(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 402[M+H]+。
(S)-1-(5-(氮杂环丁烷-3-基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-52)
1H NMR(300MHz,CD3OD)δppm 1.00-1.15(m,7H),1.21-1.39(m,1H),2.16(s,3H),2.25-2.45(m,2H),2.75-3.10(m,3H),3.48-3.65(m,2H),3.70-3.95(m,4H),4.69-4.85(m,1H),7.05-7.11(m,1H),7.37(d,J=8.40Hz,1H),7.82(s,1H),8.03(s,1H)。MS(ESI,正离子)m/z 381[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-53)
1H NMR(300MHz,CDCl3)δppm 0.65-0.67(m,1H),0.81-0.92(m,1H),0.93-1.03(m,1H),1.13(d,J=6.60Hz,3H),1.23-1.32(m,1H),1.33-1.42(m,1H),1.60-1.70(m,1H),1.83-1.87(m,2H),2.03-2.26(m,4H),2.27-2.44(m,2H),2.91-3.07(m,1H),4.05-4.28(m,4H),4.68-4.82(m,1H),7.15-7.28(m,1H),7.92-8.08(m,2H)。MS(ESI,正离子)m/z367[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-54)
1H NMR(300MHz,CD3OD)δppm 0.55-0.65(m,1H),0.72-0.89(m,2H),1.13(d,J=6.60Hz,4H),1.13-1.40(m,2H),1.41-1.70(m,1H),1.71-1.90(m,1H),1.90-1.93(m,4H),2.14-2.39(m,2H),2.90-3.02(m,1H),3.99-4.16(m,1H),4.55-4.65(m,1H),7.05(d,J=8.10Hz,1H),7.31(d,J=8.10Hz,1H),7.88(s,1H)。MS(ESI,正离子)m/z 352[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-55)
1H NMR(300MHz,CD3OD)δppm 0.65-0.79(m,1H),0.85-1.01(m,2H),1.13(d,J=6.60Hz,4H),1.25-1.51(m,2H),1.51-1.76(m,1H),1.85-2.01(m,1H),2.01-2.57(m,6H),2.99-3.15(m,1H),3.85-3.04(m,3H),4.12-4.31(m,1H),4.61-4.79(m,1H),7.15(d,J=8.10Hz,1H),7.39(d,J=8.10Hz,1H),7.86(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z367[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(1H-吡唑-5-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-56)
1H NMR(300MHz,CD3OD)δppm 0.61-0.85(m,1H),0.85-1.03(m,2H),1.15(d,J=6.60Hz,4H),1.25-1.51(m,2H),1.51-1.80(m,1H),1.81-2.28(m,5H),2.29-2.60(m,2H),2.99-3.20(m,1H),4.06-4.29(m,1H),4.68-4.82(m,1H),7.15(br s,1H),7.04-7.32(m,1H),7.61(br s,2H)。MS(ESI,正离子)m/z 352[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-57)
1H NMR(400MHz,CD3OD)δppm 0.63-0.78(m,1H),0.87-0.98(m,2H),1.29(d,J=13.20Hz,4H),1.25-1.36(m,1H),1.37-1.51(m,1H),1.61-1.77(m,1H),1.84-1.96(m,1H),2.05-2.49(m,6H),2.99-3.13(m,1H),3.81(s,3H),4.13-4.35(m,1H),4.62-4.77(m,1H),7.17(d,J=8.40Hz,1H),7.70(s,1H),7.64-7.76(m,2H)。MS(ESI,正离子)m/z 366[M+H]+。
(S)-5-(1-(叔丁氧基羰基)氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-58)
1H NMR(300MHz,CD3OD)δppm 1.05-1.21(m,7H),1.39-1.55(m,10H),2.18-2.28(m,1H),2.40-2.53(m,1H),2.85-2.95(m,1H),3.68-3.75(m,1H),3.79(s,3H),3.78-4.05(m,4H),4.50-4.65(m,2H),7.28-7.30(m,2H),7.80(s,1H),8.03(s,1H)。MS(ESI,正离子)m/z483[M+H]+。
(S)-5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-59)
根据实例5-1步骤3中所概述的程序,通过用三氟乙酸处理(S)-5-(1-(叔丁氧基羰基)氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯于二氯甲烷中的溶液来制备(S)-5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3OD)δppm 1.01-1.15(m,7H),1.40-1.58(m,1H),2.15-2.25(m,1H),2.35-2.50(m,1H),2.80-2.92(m,1H),3.40-3.59(m,2H),3.60-3.81(m,6H),4.43-4.62(m,2H),7.21-7.32(m,2H),7.75(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z 383[M+H]+。
(S)-1-(5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-60)
如上文针对实例1-58和1-59所概述,自(S)-3-((1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基)氧基)氮杂环丁烷-1-甲酸叔丁酯制备(S)-1-(5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮。1HNMR(400MHz,CD3OD)δppm 0.85-1.05(m,7H),1.10-1.25(m,1H),2.04(s,3H),2.05-2.35(m,2H),2.78-2.88(m,1H),3.34-3.48(m,2H),3.55-3.75(m,3H),4.35-4.45(m,1H),4.55-4.65(m,1H),6.85-7.05(m,1H),7.25(d,J=8.40Hz,1H),7.69(s,1H),7.97(s,1H)。MS(ESI,正离子)m/z 367[M+H]+。
(S)-5-环丁氧基-6-(1-(1,1-二氧离子基硫杂环丁烷-3-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-61)
MS(ESI,正离子)m/z 446[M+H]+。
(2S)-5-环丁氧基-6-(1-(1,1-二氧离子基四氢-2H-硫代吡喃-3-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-62)
MS(ESI,正离子)m/z 474[M+H]+。
(R)-2-((S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-2-氟乙酰胺(I-63)
1H NMR(300MHz,CD3OD)δppm 1.03-1.30(m,7H),1.32-1.38(m,2H),2.17(s,3H),2.35-2.42(m,2H),3.08-3.17(m,1H),3.65-3.72(m,1H),4.75-4.77(m,1H),5.42-5.63(m,1H),7.22-7.24(m,1H),7.47-7.50(m,1H),7.86(s,1H),8.15(s,1H)。MS(ESI,正离子)m/z387[M+H]+。任意指定立体化学性。
2-((S)-1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-2-氟乙酰胺(I-64)
1H NMR(300MHz,CD3OD)δppm 1.00-1.21(m,7H),1.21-1.40(m,2H),2.17(s,3H),2.25-2.45(m,2H),3.03-3.19(m,1H),3.65-3.72(m,1H),4.68-4.84(m,1H),5.53(d,J=61.20Hz,1H),7.15-7.25(m,1H),7.49(d,J=8.40Hz,1H),7.86(s,1H),8.11(s,1H)。MS(ESI,正离子)m/z 387[M+H]+。任意指定立体化学性。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-((3-氟氧杂环丁烷-3-基)甲氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-65)
1H NMR(300MHz,CD3OD)δppm 1.05-1.23(m,7H),1.41-1.71(m,1H),2.12-2.38(m,1H),2.47-2.70(m,1H),2.81-3.05(m,1H),3.65-3.73(m,1H),3.78(s,3H),3.96-4.19(m,2H),4.55-4.83(m,5H),7.28-7.41(m,2H),7.82(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z416[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)-2,2-二氟乙酰胺(I-66)
1H NMR(400MHz,CDCl3)δppm 0.93-1.19(m,8H),2.06(s,3H),2.16-2.22(m,1H),2.30-2.37(m,1H),2.95-2.98(m,1H),3.55-3.61(m,1H),4.61-4.77(m,1H),7.18(s,1H),7.41(d,J=8.00Hz,1H),7.74(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 405[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-67)
1H NMR(300MHz,CDCl3)δppm 1.04-1.17(m,7H),1.24-1.53(m,7H),2.17(s,3H),2.21-2.35(m,2H),2.96-3.01(m,1H),3.57-3.64(m,3H),4.75-4.85(m,1H),6.91-6.98(m,1H),7.30-7.33(m,1H),7.81(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 386[M+H]+。
(S)-5-环丁氧基-2-甲基-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-68)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.30Hz,3H),1.25-1.50(m,2H),1.55-1.67(m,1H),2.05-2.21(m,8H),2.22-2.29(m,1H),2.35-2.49(m,1H),2.91-3.01(m,1H),3.52-3.66(m,2H),3.77(s,3H),4.05-4.21(m,3H),4.42-4.61(m,2H),7.25-7.36(m,2H),7.84(s,1H),8.07(s,1H)。MS(ESI,正离子)m/z 426[M+H]+。
(S)-(5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-69)
1H NMR(400MHz,CD3OD)δppm 0.62-0.71(m,1H),0.85-1.03(m,3H),1.08-1.20(m,8H),1.37-1.48(m,1H),1.59-1.71(m,2H),2.10-2.31(m,5H),2.41-2.51(m,1H),3.07-3.13(m,1H),3.69-3.78(m,1H),4.10-4.22(m,1H),4.68-4.75(m,1H),7.28(d,J=10.80Hz,1H),7.90(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 410[M+H]+。
(S)-(5-环丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-70)
1H NMR(400MHz,DMSO-d6)δppm 0.55-0.89(m,4H),0.99-1.18(m,4H),1.26-1.35(m,1H),1.48-1.61(m,2H),1.99-2.41(m,6H),2.90-3.01(m,1H),4.09-4.13(m,1H),4.55-4.65(m,1H),7.43(d,J=10.80Hz,1H),7.92-8.21(m,2H)。MS(ESI,正离子)m/z370[M+H]+。
(S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-71)
1H NMR(400MHz,CD3OD)δppm 1.08-1.20(m,7H),1.22-1.41(m,2H),1.60-1.71(m,1H),2.05-2.20(m,4H),2.25-2.42(m,2H),2.96-3.05(m,1H),3.67-3.80(m,4H),4.11-4.19(m,1H),4.38-4.49(m,1H),7.14(d,J=11.20Hz,1H),7.85(s,1H),8.06(s,1H)。MS(ESI,正离子)m/z 400[M+H]+。
(S)-5-环丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-72)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.30Hz,3H),1.25-1.35(m,2H),1.55-1.65(m,1H),2.01-2.18(m,4H),2.23-2.41(m,2H),2.95-3.07(m,1H),3.74(s,3H),4.07-4.15(m,1H),4.39-4.45(m,1H),7.15(d,J=14.40Hz,1H),8.00(s,2H)。MS(ESI,正离子)m/z360[M+H]+。
(S)-1-(5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-73)
1H NMR(400MHz,CD3OD)δppm 1.10-1.18(m,8H),1.35-1.45(m,1H),1.59-1.70(m,1H),1.95-2.25(m,8H),2.42-2.51(m,1H),3.05-3.11(m,1H),3.70-3.78(m,1H),4.15-4.20(m,1H),4.70-4.80(m,1H),7.29(d,J=11.20Hz,1H),7.90(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 384[M+H]+。
(S)-1-(5-环丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-74)
1H NMR(400MHz,CD3OD)δppm 1.10-1.18(m,4H),1.35-1.45(m,1H),1.59-1.70(m,1H),2.05-2.25(m,8H),2.42-2.51(m,1H),3.05-3.11(m,1H),4.15-4.20(m,1H),4.70-4.80(m,1H),7.31(d,J=11.20Hz,1H),8.05(br s,2H)。MS(ESI,正离子)m/z 344[M+H]+。
(S)-1-(5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-7,8-二氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-75)
根据上文合成(S)-1-(6-(1-(2-羟乙基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(实例24)的步骤2中所述的程序,自(S)-1-(6-溴-5-环丁氧基-7,8-二氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮合成(S)-1-(5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-7,8-二氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮。1H NMR(300MHz,CD3OD)δppm1.11-1.18(m,9H),1.56-1.68(m,1H),1.98-2.47(m,9H),2.94-3.08(m,1H),3.70-3.81(m,1H),4.09-4.20(m,1H),4.73-4.81(m,1H),7.86(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z402[M+H]+。
(S)-5-(氮杂环丁烷-3-基甲氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-76)
1H NMR(300MHz,CD3OD)δppm 1.01-1.21(m,6H),1.48-1.68(m,1H),2.18-2.28(m,1H),2.48-2.63(m,1H),2.83-2.99(m,1H),3.65-3.99(m,9H),4.55-4.68(m,1H),7.25-7.35(m,2H),7.81(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 397[M+H]+。
实例25:(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮.(I-77)
步骤1.(S)-1-(6-溴-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮
将(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.025g,0.088mmol)、2-氯喹唑啉(0.017g,0.106mmol)和碳酸钾(0.024g,0.176mmol)于N,N-二甲基甲酰胺(1.0mL)中的混合物在100℃下于微波中搅拌4小时。冷却反应混合物到室温,且添加水。用二氯甲烷萃取混合物,且用水和盐水洗涤经合并的有机相,经无水硫酸钠干燥,过滤且浓缩,得到黄色油状物。经硅胶柱色谱(Biotage 10g柱,以50-100%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到(S)-1-(6-溴-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.023g,63%)。MS(ESI,正离子)m/z 412,414[M+H]+。
步骤2.(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮
将(S)-1-(6-溴-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.025g,0.061mmol)、1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.017g,0.073mmol)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)(2′-氨基-1,1′-联苯-2-基)钯(II)(XPhos第2代预催化剂)(2.4mg,0.003mmol)和碳酸铯(0.059g,0.182mmol)于1,4-二噁烷(2.0mL)和水(0.40mL)中的混合物在100℃下加热2小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage 25g柱,以25-100%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈白色固体状的(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.012g,45%)。MS(ESI,正离子)m/z 440。1H NMR(300MHz,DMSO-d6)δppm 0.81-0.91(m,5H),1.07(d,J=6.74Hz,3H),1.47(m,1H),2.03(br dd,J=13.34,6.89Hz,1H),2.18(s,3H),2.44(m,1H),3.55-3.67(m,1H),4.63(m,1H),7.41(br s,1H),7.51-7.70(m,3H),7.72(s,1H),7.91(ddd,J=8.50,7.04,1.47Hz,1H),8.06(s,1H),8.10(d,J=8.21Hz,1H),9.54(s,1H)。MS(ESI,正离子)m/z 440[M+H]+。
根据上文针对实例25所述的程序制得以下实例:
(S)-1-(5-(苯并[d]噁唑-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-78)
MS(ESI,正离子)m/z 429[M+H]+。
(S)-1-(5-(苯并[d]噁唑-2-基氧基)-2-甲基-6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-79)
MS(ESI,正离子)m/z 445[M+H]+。
(S)-1-(6-(1-(2-羟乙基)-1H-吡唑-4-基)-2-甲基-5-(嘧啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-80)
1H NMR(300MHz,DMSO-d6)δppm 1.04(d,J=6.45Hz,3H),1.42(m,1H),1.93-2.10(m,1H),2.16(s,3H),2.28(m,1H),2.40(br t,J=7.18Hz,1H),3.64(q,J=5.47Hz,2H),4.05(t,J=5.72Hz,2H),4.64(m,1H),4.83(t,J=5.28Hz,1H),7.21(t,J=4.84Hz,1H),7.38(br s,1H),7.52(d,J=8.50Hz,1H),7.70(s,1H),7.94(s,1H),8.60(d,J=4.69Hz,2H)。MS(ESI,正离子)m/z 394[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)烟碱酰胺(I-81)
1H NMR(400MHz,CD3OD)δppm 0.91-1.01(m,4H),1.16(d,J=6.40Hz,3H),1.35-1.55(m,1H),2.05-2.35(m,4H),2.37-2.55(m,1H),2.70-2.85(m,1H),3.51-3.59(m,1H),4.70-4.85(m,1H),7.11-7.18(m,1H),7.20-7.35(m,1H),7.53(d,J=8.40Hz,1H),7.32(s,1H),7.96(s,1H),8.01-8.09(m,1H),8.35-8.39(m,1H)。MS(ESI,正离子)m/z432[M+H]+。
(S)-1-(5-(1H-吡唑并[3,4-d]嘧啶-6-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-82)
1H NMR(400MHz,CD3OD)δppm 0.90-1.01(m,4H),1.18(d,J=6.40Hz,3H),1.35-1.52(m,1H),2.15-2.45(m,5H),2.60-2.72(m,1H),3.52-3.59(m,1H),4.73-4.85(m,1H),7.25-7.35(m,1H),7.57(d,J=8.40Hz,1H),7.78(s,1H),7.99(s,1H),8.19(s,1H),9.05(s,1H)。MS(ESI,正离子)m/z 430[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(噻唑-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-83)
1H NMR(300MHz,CD3OD)δppm 0.98-1.05(m,4H),1.15(d,J=6.60Hz,3H),1.39-1.53(m,1H),2.15-2.45(m,5H),2.70-2.82(m,1H),3.58-3.65(m,1H),4.70-4.85(m,1H),6.95(d,J=4.20Hz,1H),7.18(d,J=4.20Hz,1H),7.30-7.45(m,1H),7.60(d,J=8.40Hz,1H),7.79(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 395[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)烟碱腈(I-84)
1H NMR(300MHz,CD3OD)δppm 0.95-1.02(m,4H),1.15(d,J=6.60Hz,3H),1.35-1.52(m,1H),2.15-2.38(m,5H),2.51-2.63(m,1H),3.53-3.63(m,1H),4.70-4.85(m,1H),7.15-7.19(m,1H),7.25-7.35(m,1H),7.51(d,J=8.40Hz,1H),7.70(s,1H),7.92(s,1H),8.15-8.25(m,2H)。MS(ESI,正离子)m/z 414[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(4-(三氟甲基)嘧啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-85)
1H NMR(300MHz,CD3OD)δppm 0.95-1.05(m,4H),1.16(d,J=6.60Hz,3H),1.40-1.58(m,1H),2.15-2.45(m,5H),2.55-2.65(m,1H),3.55-3.65(m,1H),4.70-4.85(m,1H),7.25-7.35(m,1H),7.53-7.60(m,2H),7.76(s,1H),7.99(s,1H),8.85(d,J=5.10Hz,1H)。MS(ESI,正离子)m/z 458[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3-(三氟甲基)吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-86)
1H NMR(300MHz,CD3OD)δppm 0.89-1.01(m,4H),1.05-1.15(m,3H),1.20-1.45(m,1H),1.95-2.25(m,5H),2.75-2.89(m,1H),3.49-3.60(m,1H),4.70-4.85(m,1H),7.11-7.19(m,1H),7.20-7.35(m,1H),7.54(d,J=8.40Hz,1H),7.68(s,1H),7.84(s,1H),8.09-8.19(m,2H)。MS(ESI,正离子)m/z 457[M+H]+。
(S)-1-(5-(3-氯吡啶-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-87)
1H NMR(300MHz,CD3OD)δppm 0.95-1.05(m,4H),1.16(d,J=6.60Hz,3H),1.35-1.60(m,1H),2.10-2.30(m,5H),2.50-2.63(m,1H),3.55-3.60(m,1H),4.70-4.89(m,1H),6.95-7.09(m,1H),7.25-7.35(m,1H),7.54(d,J=8.40Hz,1H),7.78(s,1H),7.82-7.89(m,1H),7.91-7.99(m,2H)。MS(ESI,正离子)m/z 423[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡嗪-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-88)
1H NMR(300MHz,CD3OD)δppm 0.95-1.01(m,4H),1.14(d,J=5.40Hz,3H),1.30-1.48(m,1H),2.10-2.40(m,5H),2.55-2.68(m,1H),3.50-3.65(m,1H),4.68-4.85(m,1H),7.20-7.35(m,1H),7.52(d,J=8.40Hz,1H),7.69(s,1H),7.92(s,1H),7.99-8.03(m,1H),8.22(d,J=2.70Hz,1H),8.50(d,J=1.20Hz,1H)。MS(ESI,正离子)m/z 390[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-89)
1H NMR(300MHz,CD3OD)δppm 0.95-1.05(m,4H),1.16(d,J=6.60Hz,3H),1.32-1.50(m,1H),2.10-2.32(m,5H),2.55-2.72(m,1H),3.55-3.65(m,1H),4.72-4.90(m,1H),6.94(d,J=8.10Hz,1H),7.02-7.10(m,1H),7.32(br s,1H),7.58(d,J=8.40Hz,1H),7.74(s,1H),7.75-7.85(m,1H),7.93(s,1H),8.05-8.09(m,1H)。MS(ESI,正离子)m/z389[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(4,6-二甲基嘧啶-2-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-90)
1H NMR(300MHz,CD3OD)δppm 0.95-1.01(m,4H),1.14(d,J=6.30Hz,3H),1.30-1.49(m,1H),2.10-2.35(m,11H),2.52-2.65(m,1H),3.55-3.65(m,1H),4.70-4.85(m,1H),6.93(s,1H),7.20-7.35(m,1H),7.54(d,J=8.10Hz,1H),7.75(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 418[M+H]+。
(S)-6-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)哒嗪-3-甲腈(I-91)
1H NMR(300MHz,CD3OD)δppm 0.95-1.01(m,4H),1.15(d,J=6.60Hz,3H),1.45(brs,1H),2.15-2.32(m,5H),2.55-2.72(m,1H),3.52-3.69(m,1H),4.75-4.90(m,1H),7.39(brs,1H),7.54(d,J=8.10Hz,1H),7.62-7.69(m,2H),7.92(s,1H),8.12(d,J=9.30Hz,1H)。MS(ESI,正离子)m/z 415[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(5-甲基嘧啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-92)
1H NMR(400MHz,CDCl3)δppm 0.90-0.92(m,4H),1.04(d,J=6.40Hz,3H),1.35(m,1H),2.07-2.14(m,8H),2.49-2.55(m,1H),3.45-3.51(m,1H),4.68(m,1H),7.19(m,1H),7.44(d,J=8.40Hz,1H),7.64(s,1H),7.84(s,1H),8.27(d,J=4.80Hz,2H)。MS(ESI,正离子)m/z 404[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(2-(三氟甲基)嘧啶-4-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-93)
1H NMR(400MHz,CD3OD)δppm 1.02(s,4H),1.15(s,3H),1.49(s,1H),2.19-2.38(m,5H),2.52-2.63(m,1H),3.55-3.63(m,1H),4.76-4.82(m,1H),7.29-7.49(m,2H),7.56(d,J=8.40Hz,1H),7.70(s,1H),7.94(s,1H),8.78(s,1H)。MS(ESI,正离子)m/z 458[M+H]+。
根据上文针对实例25所述的程序制得以下实例,作出以下改变:(1)在步骤2中,使用4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯替代1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑;(2)根据下文实例27的步骤3中所述的程序去除Boc基团。
(S)-(5-(6-氯吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-94)
1H NMR(300MHz,CD3OD)δppm 0.73-0.82(m,1H),0.91-1.02(m,2H),1.12-1.21(m,4H),1.45-1.53(m,1H),1.85-2.00(m,2H),2.00(s,3H),2.22-2.41(m,2H),2.63-2.71(m,1H),2.72-2.82(m,2H),3.16-3.24(m,2H),4.22-4.31(m,1H),4.71-4.85(m,1H),6.87(d,J=8.10Hz,1H),7.07(d,J=7.50Hz,1H),7.39(d,J=8.40Hz,1H),7.57(d,J=8.40Hz,1H),7.73-7.77(m,2H),7.96(s,1H)。MS(ESI,正离子)m/z 492[M+H]+。
(S)-环丙基(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-(吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-95)
1H NMR(300MHz,CD3OD)δppm 0.73-0.82(m,1H),0.89-1.01(m,2H),1.12-1.24(m,4H),1.41-1.51(m,1H),2.05-2.37(m,7H),2.62-2.71(m,1H),3.14-3.22(m,2H),3.50-3.64(m,2H),4.45-4.55(m,1H),4.78-4.85(m,1H),6.92(d,J=8.40Hz,1H),7.04-7.09(m,1H),7.39(d,J=8.40Hz,1H),7.59(d,J=8.40Hz,1H),7.77-7.81(m,2H),7.96(s,1H),8.05(t,J=3.60Hz,1H)。MS(ESI,正离子)m/z 458[M+H]+。
(S)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-(吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-96)
1H NMR(300MHz,CD3OD)δppm 1.16(d,J=6.90Hz,3H),1.25-1.33(m,1H),1.54-1.64(m,1H),1.73-1.90(m,2H),1.95-2.15(m,3H),2.40-2.50(m,1H),2.53-2.76(m,3H),3.09-3.16(m,2H),3.81(s,3H),4.15-4.24(m,1H),4.60-4.71(m,1H),6.83(d,J=8.40Hz,1H),7.01-7.09(m,1H),7.47-7.61(m,2H),7.70-7.80(m,2H),7.89(s,1H),8.06(m,1H)。MS(ESI,正离子)m/z 448[M+H]+。
(S)-环丙基(5-(6-氟吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-97)
1H NMR(400MHz,CD3OD)δppm 0.67-0.74(m,1H),0.81-0.92(m,2H),1.02-1.08(m,4H),1.42-1.49(m,1H),1.62-1.71(m,2H),1.82-1.95(m,3H),2.05-2.16(m,1H),2.05-2.16(m,1H),2.27-2.34(m,1H),2.46-2.58(m,3H),2.95-3.05(m,2H),4.05-4.16(m,1H),4.66-4.74(m,1H),6.78-6.81(m,1H),6.95-7.00(m,1H),7.33-7.37(m,1H),7.66(s,1H),7.96-8.05(m,2H)。MS(ESI,正离子)m/z 476[M+H]+。
实例26:(S)-环丙基(5-(6-甲氧基吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-98)
将(S)-环丙基(5-(6-氟吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.024g,0.05mmol)和甲醇钠(0.015g,0.28mmol)于N,N-二甲基甲酰胺(1mL)中的混合物在80℃下搅拌隔夜。冷却反应混合物到室温,用乙酸乙酯(15mL)稀释,用盐水(2×5mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,SunFirePrep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内16%到34%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈白色固体状的(S)-环丙基(5-(6-甲氧基吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.0033g,13%)。1HNMR(400MHz,CD3OD)δppm 0.79-0.87(m,1H),0.91-1.00(m,2H),1.10-1.18(m,4H),1.39-1.49(m,1H),1.79-1.84(m,2H),1.97-2.09(m,3H),2.18-2.41(m,2H),2.62-2.79(m,3H),3.12-3.19(m,2H),3.62(s,3H),4.15-4.27(m,1H),4.72-4.89(m,1H),6.41(t,J=8.00Hz,2H),7.36(d,J=8.40Hz,1H),7.55-7.65(m,2H),7.79(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 488[M+H]+。
实例27:(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉(I-99)
步骤1.(2S)-6-溴-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉
向250-mL圆底烧瓶中装入(2S)-6-溴-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-5-醇(2.00g,6.45mmol)、溴环丁烷(1.81mL,2.60g,19.3mmol)、碳酸铯(6.3g,19.34mmol)和乙腈(100mL)。在80℃下搅拌所得混合物6小时。经硅藻土衬垫过滤反应混合物,且在真空下浓缩。经硅胶柱色谱(以0-10%乙酸乙酯-石油醚进行梯度洗提)纯化残余物,得到呈无色油状的(2S)-6-溴-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉(2.00g,85%)。MS(ES,m/z):364,366[M+H]+。
步骤2.(S)-4-(4-(5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
用惰性氮气气氛净化并维持250-mL圆底烧瓶,且装入(2S)-6-溴-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉(2.0g,5.5mmol)、4-[4-(四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(2.5g,6.63mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.45g,0.55mmol)、碳酸钾(2.3g,16.64mmol)、1,4-二噁烷(50mL)和水(5mL)。在100℃下搅拌所得混合物隔夜。冷却反应混合物到室温,接着经硅藻土衬垫过滤。浓缩滤液,且经硅胶柱色谱(以0-30%乙酸乙酯-石油醚进行梯度洗提)纯化残余物,得到呈淡黄色固体状的(S)-4-(4-(5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(2.2g,75%)。MS(ES,m/z):535[M+H]+
步骤3.(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉
将三氟乙酸(0.5mL,6.49mmol)添加到(S)-4-(4-(5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.032g,0.060mmol)于二氯甲烷(2.0mL)中的0℃溶液中。去除冰浴,且在室温下搅拌混合物1.5小时。浓缩反应混合物,且将残余物分配于二氯甲烷与饱和碳酸氢钠水溶液之间。分离各层,且用盐水洗涤有机相,经无水硫酸钠干燥,过滤且浓缩,得到呈灰白色固体状的(S)-(5-环丁氧基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.022g,85%)。1H NMR(300MHz,氯仿-d)δppm 0.57-0.71(m,1H),0.78-0.91(m,1H),0.92-1.04(m,1H),1.13(d,J=6.45Hz,3H),1.19-1.45(m,3H),1.53-1.71(m,2H),1.79-2.42(m,11H),2.74-2.92(m,2H),2.94-3.09(m,1H),3.30(br d,J=12.61Hz,2H),4.04-4.21(m,1H),4.28(ddt,J=11.43,7.62,3.96,3.96Hz,1H),4.66-4.84(m,1H),7.12(d,J=8.21Hz,1H),7.28(d,J=8.21Hz,1H),7.81(s,1H),7.88(s,1H)。MS(ESI,正离子)m/z 435[M+H]+。
根据针对实例27所概述的程序制得以下实例:
(S)-环丙基(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-100)
1H NMR(300MHz,CD3OD)δppm 0.65-0.778(m,1H),0.85-0.99(m,2H),1.01-1.19(m,7H),1.25-1.42(m,1H),1.70-1.82(m,2H),1.85-2.05(m,3H),2.10-2.21(m,2H),2.30-2.49(m,2H),2.75-2.89(m,2H),2.95-3.07(m,1H),3.17-3.20(m,2H),3.58-3.72(m,2H),4.28-4.42(m,1H),4.70-4.83(m,1H),7.19(d,J=8.10Hz,1H),7.44(d,J=8.10Hz,1H),7.93(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 423[M+H]+
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-101)
1H NMR(300MHz,CD3OD)0.65-0.75(m,1H),0.85-0.95(m,2H),1.05-1.15(m,4H),1.20-1.40(m,2H),1.50-1.70(m,1H),1.80-1.95(m,1H),2.01-2.45(m,6H),2.95-3.05(m,1H),3.92-4.01(m,2H),4.10-4.25(m,3H),4.65-4.75(m,1H),5.25-5.40(m,1H),7.15(d,J=8.10Hz,1H),7.40(d,J=8.70Hz,1H),7.96(s,1H),8.14(s,1H)。MS(ESI,正离子)m/z 407[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-102)
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-102)
1H NMR(300MHz,CD3OD)δppm 0.60-0.75(m,1H),0.85-0.95(m,2H),1.00-1.08(m,3H),1.10-1.18(m,4H),1.25-1.38(m,1H),1.70-1.80(m,2H),1.85-1.95(m,1H),2.30-2.45(m,2H),2.90-3.05(m,1H),3.55-2.75(m,2H),3.95-4.05(m,2H),4.15-4.25(m,2H),4.65-4.75(m,1H),5.28-5.38(m,1H),7.17(d,J=8.40Hz,1H),7.43(d,J=8.40Hz,1H),8.00(s,1H),8.15(s,1H)。MS(ESI,正离子)m/z 395[M+H]+。
(S)-(5-环丁氧基-8-氟-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-103)
1H NMR(400MHz,DMSO-d6)δppm 0.56-0.90(m,4H),0.99-1.17(m,4H),1.25-1.34(m,1H),1.47-1.59(m,2H),1.74-1.81(m,2H),1.95-2.28(m,7H),2.31-2.41(m,1H),2.55-2.61(m,2H),2.85-2.93(m,1H),3.02-3.09(m,2H),4.05-4.24(m,2H),4.56-4.67(m,1H),7.42(d,J=10.0Hz,1H),7.90(s,1H),8.18(s,1H)。MS(ESI,正离子)m/z 453[M+H]+。
实例28:(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-104)
步骤1.(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮
在80℃下加热(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.150g,0.528mmol)、1-溴丙烷(0.240mL,2.64mmol)和叔丁醇钾(0.296g,2.64mmol)于DMF(3.0mL)中的混合物。24小时后,再添加1-溴丙烷(0.240mL,2.64mmol),且在70℃下搅拌混合物16小时。反应未完成,因此添加1-溴丙烷(0.240mL,2.64mmol)和叔丁醇钾(0.296g,2.64mmol),且在100℃下搅拌混合物。24小时后,冷却反应混合物到室温,且添加水。用二氯甲烷萃取混合物,且用水和盐水洗涤经合并的有机相,经无水硫酸钠干燥,过滤且浓缩,得到黄色油状物。经硅胶柱色谱(Biotage 25g柱,以50-100%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色油状的(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.100g,58%)。MS(ESI,正离子)m/z 326,328[M+H]+
步骤2.(S)-4-(4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
将(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.050g,0.153mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.058g,0.153mmol)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)(2′-氨基-1,1′-联苯-2-基)钯(II)(XPhos第2代预催化剂)(0.012g,0.015mmol)和碳酸铯(0.150g,0.460mmol)于1,4-二噁烷(2.0mL)和水(0.40mL)中的混合物在100℃下于微波中加热2.5小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage25g柱,以50-100%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈灰白色固体状的(S)-4-(4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.063g,83%)。MS(ESI,正离子)m/z 497[M+H]+
步骤3.(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮
将三氟乙酸(0.5mL,6.49mmol)添加到(S)-4-(4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.063g,0.127mmol)于二氯甲烷(2.0mL)中的溶液中,且在室温下搅拌反应混合物1.5小时。浓缩反应混合物,且将残余物分配于二氯甲烷与饱和碳酸氢钠水溶液之间。分离有机相,经无水硫酸钠干燥,过滤且浓缩,得到呈褐色固体状的(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.045g,89%)。1H NMR(300MHz,DMSO-d6)δppm 0.91-1.12(m,6H),1.18-1.37(m,1H),1.57-1.88(m,5H),1.97(br d,J=10.26Hz,2H),2.07(s,3H),2.16-2.40(m,2H),2.53-2.66(m,2H),2.73-2.89(m,1H),3.03(br d,J=12.61Hz,2H),3.46-3.65(m,2H),4.09-4.30(m,1H),4.62(br d,J=5.86Hz,1H),7.11(br d,J=8.21Hz,1H),7.38(d,J=8.21Hz,1H),7.84(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z 397[M+H]+。
根据针对实例28所概述的程序制得以下实例:
(S)-1-(5-环丁氧基-8-氟-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-105)
1H NMR(400MHz,CD3OD)δppm 0.93-1.17(m,4H),1.27-1.41(m,1H),1.55-1.68(m,1H),1.92-2.48(m,13H),2.70-2.83(m,2H),3.02-3.10(m,1H),3.10-3.22(m,2H),4.05-4.18(m,1H),4.25-4.43(m,1H),4.70-4.88(m,1H),7.15-7.35(m,1H),7.90(s,1H),8.13(s,1H)。MS(ESI,正离子)m/z 427[M+H]+。
(S)-1-(5-环丁氧基-7,8-二氟-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-106)
根据上文合成(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(实例4-1)的步骤2和3中所述的程序,自(S)-1-(6-溴-5-环丁氧基-7,8-二氟-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮合成(S)-1-(5-环丁氧基-7,8-二氟-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮。1H NMR(300MHz,CD3OD)δppm1.12-1.28(m,4H),1.30-1.41(m,1H),1.56-1.68(m,1H),1.98-2.20(m,11H),2.32-2.49(m,2H),2.75-2.88(m,2H),2.99-3.10(m,1H),3.21-3.25(m,2H),4.17-4.20(m,1H),4.35-4.45(m,1H),4.75-4.82(m,1H),7.91(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z445[M+H]+。
实例29:(S)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-107)
步骤1.(S)-6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯
在100℃下于密封管中加热(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.110g,0.366mmol)、1-溴丙烷(0.166mL,1.832mmol)和叔丁醇钾(0.103g,0.916mmol)于DMF(3.0mL)中的混合物。24小时后,再添加1-溴丙烷(0.166mL,1.832mmol)和叔丁醇钾(0.103g,0.916mmol),且在100℃下于密封管中加热混合物24小时。冷却反应混合物到室温,且添加水。用二氯甲烷萃取混合物,且用水和盐水洗涤经合并的有机相,经无水硫酸钠干燥,过滤且浓缩,得到黄色油状物。经硅胶柱色谱(Biotage 25g柱,以0-25%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色油状的(S)-6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.120g,96%)。MS(ESI,正离子)m/z 342,344[M+H]+。
步骤2.(S)-6-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.060g,0.175mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.066g,0.175mmol)、氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)(2′-氨基-1,1′-联苯-2-基)钯(II)(XPhos第2代预催化剂)(0.014g,0.018mmol)和碳酸铯(0.171g,0.526mmol)于1,4-二噁烷(2.0mL)和水(0.40mL)中的混合物在100℃下于微波中加热5小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage25g柱,以0-50%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色油状的(S)-6-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.090g,100%)。MS(ESI,正离子)m/z 513[M+H]+。
步骤3.(S)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟乙酸(0.5mL,6.49mmol)添加到(S)-6-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.090g,0.176mmol)于二氯甲烷(2.0mL)中的溶液中,且在室温下搅拌反应混合物1小时。浓缩反应混合物,且将残余物分配于二氯甲烷与饱和碳酸氢钠水溶液之间。分离有机相,经无水硫酸钠干燥,过滤且浓缩,得到呈灰白色固体状的(S)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.070g,97%)。1H NMR(300MHz,DMSO-d6)δppm 0.97(t,J=7.48Hz,3H),1.05-1.13(m,3H),1.48(dq,J=13.05,6.50Hz,1H),1.63-1.87(m,5H),1.88-2.03(m,2H),2.05-2.19(m,2H),2.53-2.66(m,2H),2.72-2.90(m,1H),3.04(br d,J=12.61Hz,2H),3.54(br t,J=6.60Hz,2H),3.67(s,3H),4.11-4.32(m,1H),4.37-4.57(m,1H),7.21-7.31(m,1H),7.31-7.40(m,1H),7.81(s,1H),8.06(s,1H)。MS(ESI,正离子)m/z413[M+H]+。MS(ESI,正离子)m/z 413[M+H]+。
实例30:(2S)-5-环丁氧基-2-甲基-6-(1-(吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-108)
步骤1.(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
向100-mL圆底烧瓶中装入(2S)-6-溴-5-羟基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(600mg,2.00mmol)、溴环丁烷(807mg,5.98mmol)、乙腈(30mL)和碳酸铯(1.96g,6.00mmol)。在80℃下于油浴中搅拌混合物6小时。冷却到室温后,将反应混合物倒入10mL水中,且分离各层。用乙酸乙酯(3×15mL)萃取水层。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以8:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈无色油状的(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.67g,95%)。MS(ESI,正离子)m/z 354,356[M+H]+。
步骤2.(2S)-5-环丁氧基-2-甲基-6-(1-(吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
根据上文实例29的步骤2和3中所概述的程序,自(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸酯和3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)吡咯烷-1-甲酸叔丁酯合成(2S)-5-环丁氧基-2-甲基-6-(1-(吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δppm 1.17(d,J=6.40Hz,3H),1.25-1.65(m,3H),1.98-2.30(m,6H),2.31-2.45(m,2H),2.85-3.08(m,2H),3.20-3.35(m,3H),3.79(s,3H),4.10-4.15(m,1H),4.49-4.55(m,1H),4.90-5.05(m,1H),7.20-7.32(m,2H),7.86(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 411[M+H]+。
根据针对实例30所概述的程序制得以下实例:
(2S)-5-环丁氧基-2-甲基-6-(1-(八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-109)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.30Hz,3H),1.20-1.52(m,2H),1.55-1.75(m,1H),1.95-2.30(m,7H),2.35-2.50(m,3H),2.85-3.00(m,1H),3.05-3.20(m,4H),3.50-3.62(m,2H),3.77(s,1H),4.05-4.15(m,1H),4.45-4.55(m,1H),4.85-5.00(m,1H),7.20-7.30(m,2H),7.85(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 451[M+H]+。
(S)-5-环丁氧基-8-氟-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-110)
1H NMR(300MHz,CD3OD)δppm 1.14(d,J=6.60Hz,3H),1.21-1.38(m,2H),1.55-1.61(m,1H),1.90-2.16(m,8H),2.35-2.40(m,2H),2.71-2.79(m,2H),2.95-3.15(m,1H),3.15-3.22(m,2H),3.71(s,3H),4.05-4.16(m,1H),4.25-4.43(m,2H),7.11(d,J=11.40Hz,1H),7.83(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 443[M+H]+。
实例31:外消旋-1-(2-甲基-6-(4-(甲基磺酰基)苯基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-111)
步骤1.外消旋-1-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮
将外消旋-6-溴-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(0.022g,0.069mmol)于二氯甲烷(1mL)和吡啶(0.017mL,0.207mmol)中的溶液冷却到0℃,且用乙酰氯(5.41μL,0.076mmol)处理。接着在室温下搅拌反应混合物。10分钟后,再添加乙酰氯(3.93μL,0.055mmol),且在室温下继续搅拌。75分钟后,用二氯甲烷稀释反应混合物,且用1N盐酸水溶液(2×0.5mL)和5%氯化钠水溶液(0.5mL)洗涤。浓缩二氯甲烷层,得到呈几乎无色胶状的粗外消旋-1-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.024g,96%),其在静置时凝固。粗产物未经进一步纯化即使用。MS(ESI,正离子)m/z 360,362[M+H]+。
步骤2.外消旋-1-(2-甲基-6-(4-(甲基磺酰基)苯基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮
向配备有磁性搅拌棒的螺旋盖小瓶中装入外消旋-1-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.024g,0.067mmol)、4-(甲基磺酰基)苯基硼酸(0.020g,0.100mmol)、1,4-二噁烷(0.67mL)、1.0M碳酸氢钠水溶液(0.200mL,0.200mmol)和氯化双(三苯基膦)钯(II)(4.7mg,6.7μmol)。用氮气吹洗小瓶,接着封盖。接着加热反应混合物到80℃维持3小时,接着冷却到室温。用5%氯化钠水溶液(0.5mL)和乙酸乙酯稀释反应混合物。分离各层,且用乙酸乙酯萃取水层。在减压下浓缩经合并的萃取物,得到深棕色残余物,接着通过制备型薄层色谱(1×1000微米板;以3:2乙酸乙酯-己烷洗提)纯化。分离主要色带(26mg)且通过制备型HPLC进一步纯化,得到外消旋-1-(2-甲基-6-(4-(甲基磺酰基)苯基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮。1H NMR(400MHz,CDCl3)δppm1.17(d,J=6.60Hz,3H),1.45(br s,1H),2.07-2.24(m,1H),2.27(s,3H),2.29-2.37(m,1H),2.71(dt,J=16.13,6.42Hz,1H),3.01(s,3H),4.79(br s,1H),6.59-6.69(m,2H),6.82-6.95(m,1H),7.15(t,J=7.70Hz,2H),7.32(br d,J=7.33Hz,2H),7.65(d,J=8.43Hz,2H),7.84(d,J=8.43Hz,2H)。MS(ESI,正离子)m/z 436[M+H]+。
实例32:外消旋-1-(2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-112)
向配备有磁性搅拌棒的玻璃螺旋盖小瓶中装入外消旋-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(0.050g,0.21mmol)于二氯甲烷(1mL)和吡啶(0.051mL,0.630mmol)中的溶液。冷却溶液到0℃,且添加乙酰氯(0.015mL,0.210mmol)。去除冰浴,且在室温下搅拌反应混合物。10分钟后,用二氯甲烷稀释反应混合物,且用1N盐酸水溶液(2×1mL)、继而用5%氯化钠水溶液(1mL)洗涤。将有机层浓缩成黄色油状物,其在静置时结晶。通过制备型薄层色谱(1×1000微米板,以2:1己烷-乙酸乙酯洗提)纯化粗产物,得到呈几乎无色油状的1-(2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.0189g,32%)。1H NMR(400MHz,CDCl3)δppm1.13(d,J=6.60Hz,3H),1.36-1.55(m,1H),2.11-2.27(m,4H),2.36(br s,1H),2.85(dt,J=16.04,6.09Hz,1H),4.88(br s,1H),6.76(d,J=8.80Hz,1H),6.89-6.96(m,2H),6.96-7.04(m,1H),7.04-7.11(m,1H),7.12-7.19(m,1H),7.29-7.37(m,2H)。MS(ESI,正离子)m/z282[M+H]+。
实例33:(S)-1-(5-环丙氧基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-113)
步骤1.(S)-1-(6-溴-5-环丙氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
将(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(17.05mg,0.06mmol)于DMF(500μL)中的溶液添加到配备有磁性搅拌棒的微波反应小瓶中。接着添加溴环丙烷(150μL,1.87mmol)、碘化钠(8.99mg,0.060mmol)和碳酸铯(98mg,0.300mmol),且密封反应物。在180℃下于微波中加热反应物6小时。用乙酸乙酯稀释混合物,且用盐水洗涤。经无水硫酸钠干燥有机层,过滤且浓缩,得到(S)-1-(6-溴-5-环丙氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.019g,100%),其未经进一步纯化即使用。MS(ESI,正离子)m/z324,326[M+H]+。
步骤2.(S)-1-(5-环丙氧基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
向1.5mL反应小瓶中装入(S)-1-(6-溴-5-环丙氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.019g,0.06mmol)和1,4-二噁烷(50μL)。添加1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.2M溶液,于1,4-二噁烷中,540μL,0.108mmol)和碳酸钾(1M溶液,于水中,180μL,0.18mmol),且用氮气净化反应混合物。添加[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.02M溶液,于1,2-二氯乙烷中,300μL,0.006mmol),且用氮气净化反应物,且在加热震荡器上加热到80℃隔夜。用乙酸乙酯稀释反应物,且用1N氢氧化钠水溶液洗涤。分离水层且用乙酸乙酯洗涤,且在氮气流下浓缩经合并的有机层。通过质量触发式制备型HPLC纯化粗产物。合并含产物的洗提份且在Genevac中浓缩,得到(S)-1-(5-环丙氧基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.0039g,19%)。MS(ESI,正离子)m/z 352[M+H]+。
实例34:(S)-1-(2-甲基-6-(5-(甲基磺酰基)吡啶-2-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-114)
步骤1.(S)-1-(2-甲基-5-丙氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)乙酮
在80℃下加热(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.127g,0.389mmol)、双(频哪醇根基)二硼(0.109g,0.428mmol)、乙酸钾(0.096g,0.973mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的复合物(0.028g,0.039mmol)于1,4-二噁烷(3.0mL)中的混合物。24小时后,添加更多份[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的复合物(0.028g,0.039mmol)、双(频哪醇根基)二硼(0.109g,0.428mmol)和乙酸钾(0.096g,0.973mmol),且在100℃下加热混合物4小时。冷却反应混合物到室温且经硅藻土过滤,得到深棕色油状物。经硅胶柱色谱(Biotage 25g柱,以25-50%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色油状的(S)-1-(2-甲基-5-丙氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.110g,76%)。MS(ESI,正离子)m/z 374[M+H]+。
步骤2.(S)-1-(2-甲基-6-(5-(甲基磺酰基)吡啶-2-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮
将(S)-1-(2-甲基-5-丙氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.055g,0.147mmol)、2-溴-5-(甲基磺酰基)吡啶(0.037g,0.155mmol)、XPhos第2代预催化剂(0.012g,0.015mmol)和碳酸铯(0.144g,0.442mmol)于1,4-二噁烷(2.0mL)和水(0.40mL)中的混合物在100℃下于微波中加热1.5小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage 25g柱,以25-100%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈褐色固体状的(S)-1-(2-甲基-6-(5-(甲基磺酰基)吡啶-2-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(0.016g,27%)。1H NMR(300MHz,DMSO-d6)δppm 0.85(t,J=7.33Hz,3H),1.07(d,J=6.45Hz,3H),1.32-1.50(m,2H),1.56(dt,J=14.07,7.04Hz,2H),2.14(s,3H),2.19-2.33(m,1H),2.79-2.94(m,1H),3.37(s,3H),3.50(td,J=6.30,2.64Hz,2H),4.51-4.75(m,1H),7.33(br d,J=8.50Hz,1H),7.64(d,J=8.50Hz,1H),8.08-8.21(m,1H),8.36(dd,J=8.50,2.35Hz,1H),9.14(d,J=2.05Hz,1H)。MS(ESI,正离子)m/z 403[M+H]+。
实例35:(S)-N-(6-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)吡啶-3-基)甲烷磺酰胺(I-115)
步骤1.N-(6-碘吡啶-3-基)甲烷磺酰胺
将N,N-二异丙基乙胺(0.992mL,5.68mmol)添加到6-碘吡啶-3-胺(0.500g,2.273mmol)和甲烷磺酰氯(0.186mL,2.386mmol)于1,2-二氯乙烷(10.0mL)中的溶液中,且在50℃下搅拌混合物2.5小时。浓缩反应混合物,得到棕色油状物,将其溶解于1,4-二噁烷(5.0mL)和水(1.0mL)中。添加氢氧化钾(0.128g,2.273mmol),且在80℃下搅拌混合物4小时。冷却反应混合物到室温,接着分配于二氯甲烷与水之间。分离水相,且用二氯甲烷萃取。用盐水洗涤经合并的有机相,经无水硫酸钠干燥,过滤且浓缩,得到棕色油状物。经硅胶柱色谱(Biotage 25g柱,以0-50%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈褐色固体状的N-(6-碘吡啶-3-基)甲烷磺酰胺(0.537g,79%)。MS(ESI,正离子)m/z 299[M+H]+。
步骤2.(S)-N-(6-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)吡啶-3-基)甲烷磺酰胺
将(S)-1-(2-甲基-5-丙氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.055g,0.147mmol)、N-(6-碘吡啶-3-基)甲烷磺酰胺(0.046g,0.155mmol)、XPhos第2代预催化剂(0.012g,0.015mmol)和碳酸铯(0.144g,0.442mmol)于1,4-二噁烷(2.0mL)和水(0.40mL)中的混合物在100℃下于微波中加热1.5小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage 25g柱,以25-100%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈灰白色固体状的(S)-N-(6-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)吡啶-3-基)甲烷磺酰胺(0.007g,11%)。1H NMR(300MHz,CDCl3)δppm 0.79-0.85(m,3H),1.08(d,J=6.45Hz,3H),1.17-1.55(m,3H),2.12(s,3H),2.20-2.41(m,2H),2.82-3.01(m,1H),3.04(s,3H),3.28-3.59(m,2H),4.76(br s,1H),6.64-6.86(m,1H),6.98(br s,1H),7.52(d,J=8.21Hz,1H),7.68(dd,J=8.79,2.64Hz,1H),7.87(d,J=8.50Hz,1H),8.47(d,J=2.64Hz,1H)。MS(ESI,正离子)m/z418[M+H]+。
根据针对实例34所概述的程序制得以下实例:
(S)-2-(1-乙酰基-2-甲基-6-(5-(甲基磺酰基)吡啶-2-基)-1,2,3,4-四氢喹啉-5-基氧基)-N,N-二甲基乙酰胺(I-116)
1H NMR(300MHz,CDCl3)δppm 1.09(d,J=6.74Hz,3H),2.07-2.20(m,3H),2.20-2.42(m,2H),2.73(s,3H),2.83-2.94(m,3H),2.94-3.07(m,1H),3.11(s,3H),4.03(dt,J=19.35,6.89Hz,1H),4.20-4.30(m,2H),4.61-4.82(m,1H),7.00-7.17(m,1H),7.63(d,J=8.50Hz,1H),8.15-8.20(m,2H),9.06-9.22(m,1H)。MS(ESI,正离子)m/z 446[M+H]+。
(S)-1-(6-(苯并[d]噁唑-2-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-117)
1H NMR(300MHz,DMSO-d6)δppm 1.01(t,J=7.48Hz,3H),1.08(d,J=6.45Hz,3H),1.38-1.58(m,2H),1.79(dq,J=14.14,7.01Hz,2H),2.17(s,3H),2.20-2.32(m,1H),2.77-3.01(m,1H),3.84(t,J=6.30Hz,2H),4.52-4.74(m,1H),7.36-7.45(m,3H),7.71-7.85(m,2H),7.92(d,J=8.50Hz,1H)。MS(ESI,正离子)m/z 365[M+H]+。
(S)-1-(2-甲基-5-丙氧基-6-(吡唑并[1,5-a]吡啶-2-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-118)
1H NMR(300MHz,DMSO-d6)δppm 0.73(t,J=7.33Hz,3H),1.03-1.10(m,6H),1.32-1.51(m,3H),2.12(s,3H),2.20-2.45(m,2H),2.89(dt,J=15.32,5.09Hz,1H),3.36-3.43(m,1H),3.94(s,1H),4.55-4.72(m,1H),6.93(t,J=6.89Hz,1H),7.18-7.30(m,2H),7.33(d,J=8.21Hz,1H),7.73(d,J=8.79Hz,1H),8.24(s,1H),8.71(dd,J=7.04,0.88Hz,1H)。MS(ESI,正离子)m/z 364[M+H]+。
(S)-1-(6-(咪唑并[1,2-a]吡啶-2-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-119)
1H NMR(300MHz,DMSO-d6)δppm 0.98-1.08(m,6H),1.21-1.56(m,1H),1.78-
96(m,2H),2.10(s,3H),2.21-2.44(m,2H),2.79-3.00(m,1H),3.60-3.78(m,2H),4.44-4.76(m,1H),6.88(t,J=6.74Hz,1H),7.16-7.30(m,2H),7.56(d,J=9.09Hz,1H),8.04(d,J=8.50Hz,1H),8.35(s,1H),8.65(d,J=6.74Hz,1H)。MS(ESI,正离子)m/z 364[M+H]+。
(S)-1-(6-(苯并[d]噻唑-2-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-120)
1H NMR(300MHz,DMSO-d6)δppm 1.01-1.15(m,6H),1.43(m,2H),1.82-2.04(m,2H),2.15(s,3H),2.29(br dd,J=12.46,6.01Hz,1H),2.82-2.98(m,1H),3.84(br t,J=6.45Hz,2H),4.53-4.70(m,1H),7.31-7.49(m,2H),7.49-7.61(m,1H),8.05(d,J=7.92Hz,1H),8.16(t,J=9.09Hz,2H)。MS(ESI,正离子)m/z 381[M+H]+。
(S)-1-(6-(1H-苯并[d]咪唑-2-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-121)
1H NMR(300MHz,DMSO-d6)δppm 0.88(t,J=7.33Hz,3H),1.07(d,J=6.45Hz,3H),1.36-1.52(m,2H),1.57-1.79(m,2H),2.15(s,3H),2.22-2.38(m,1H),2.90(dt,J=15.83,5.86Hz,1H),3.50-3.72(m,2H),4.52-4.78(m,1H),7.10-7.25(m,2H),7.33(br d,J=8.21Hz,1H),7.51-7.60(m,1H),7.61-7.70(m,1H),7.83(d,J=8.50Hz,1H),12.30(s,1H)。MS(ESI,正离子)m/z 364[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-122)
1H NMR(400MHz,CD3OD)δppm 0.65-0.83(m,1H),0.85-1.06(m,2H),1.11-1.22(m,4H),1.23-1.38(m,1H),1.41-1.53(m,1H),1.53-1.69(m,1H),1.81-1.94(m,1H),2.15-2.51(m,6H),2.84(s,3H),2.95-2.13(m,1H),4.32-4.51(m,1H),4.60-4.79(m,1H),7.33(d,J=8.40Hz,1H),7.85-8.12(m,1H)。MS(ESI,正离子)m/z 384[M+H]+。
(S)-(5-环丁氧基-6-(异噁唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-123)
1H NMR(400MHz,CD3OD)δppm 0.66-0.72(m,1H),0.76-0.71(m,2H),0.98-1.08(m,4H),1.15-1.33(m,2H),1.50-1.58(m,1H),1.74-1.81(m,1H),1.96-2.03(m,2H),2.03-2.14(m,2H),2.14-2.33(m,2H),2.89-2.94(m,1H),4.10-4.16(m,1H),4.52-4.63(m,1H),7.11(d,J=8.40Hz,1H),7.35(d,J=8.40Hz,1H),8.73(s,1H),8.96(s,1H)。MS(ESI,正离子)m/z353[M+H]+。
(S)-(5-环丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-124)
1H NMR(400MHz,CD3OD)δppm 0.76-0.85(m,1H),0.91-1.03(m,3H),1.04-1.30(m,4H),1.35-1.47(m,1H),1.61-1.72(m,2H),2.13-2.36(m,5H),2.46-2.55(m,1H),3.05-3.13(m,2H),4.20-4.27(m,4H),4.69-4.78(m,1H),7.69(d,J=8.40Hz,1H),8.38(s,1H)。MS(ESI,正离子)m/z 385[M+H]+。
(S)-5-环丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-125)
1H NMR(400MHz,CDCl3)δppm 1.21-1.25(m,3H),1.25-1.34(m,4H),1.60-1.70(m,1H),2.05-2.20(m,4H),2.26-2.41(m,1H),3.79(s,3H),4.13-4.14(m,1H),4.17(s,3H),4.42-4.53(m,1H),7.8(s,1H),8.0(s,1H)。MS(ESI,正离子)m/z 375[M+H]+。
(S)-1-(5-环丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-126)
1H NMR(300MHz,CD3OD)δppm 1.11-1.25(m,4H),1.31-1.45(m,1H),1.55-1.71(m,1H),1.98-2.55(m,9H),2.97-3.10(m,1H),4.20-4.37(m,4H),4.71-4.83(m,1H),7.69(d,J=11.10Hz,1H),8.37(s,1H)。MS(ESI,正离子)m/z 359[M+H]+。
(S)-(6-(5-氨基-1,3,4-噻二唑-2-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-127)
对于(S)-(6-(5-氨基-1,3,4-噻二唑-2-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮,使用(5-溴-1,3,4-噻二唑-2-基)氨基甲酸叔丁酯作为芳基溴化物来源。如实例29步骤3中所概述去除Boc基团。1H NMR(400MHz,CD3OD)δppm 0.65-0.80(m,1H),0.87-1.01(m,2H),1.09-1.19(m,4H),1.21-1.39(m,1H),1.42-1.59(m,1H),1.68-1.79(m,1H),1.82-1.96(m,1H),2.15-2.53(m,6H),2.97-3.10(m,1H),4.32-4.54(m,1H),4.60-4.75(m,1H),7.27(d,J=8.40Hz,1H),7.82-7.94(m,1H)。MS(ESI,正离子)m/z 385[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-128)
对于(S)-(5-环丁氧基-2-甲基-6-(1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮,使用1-苯甲基-4-溴-1H-1,2,3-三唑作为芳基溴化物来源。使用上文针对中间物1步骤2所概述的氢化条件去除苯甲基。1H NMR(300MHz,CD3OD)δppm 0.65-0.80(m,1H),0.87-0.99(m,2H),1.13(d,J=6.60Hz,4H),1.27-1.39(m,2H),1.53-1.73(m,1H),1.82-1.97(m,1H),2.01-2.23(m,4H),2.27-2.44(m,2H),2.99-3.16(m,1H),4.05-4.28(m,4H),4.65-4.81(m,1H),7.24(d,J=7.80Hz,1H),7.72(d,J=8.40Hz,1H),8.15(s,1H)。MS(ESI,正离子)m/z 353[M+H]+。
(S)-6-(2-氨甲酰基噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-129)
1H NMR(300MHz,CDCl3)δppm 1.19(d,J=6.60Hz,3H),1.21-1.32(m,2H),1.46-1.56(m,1H),2.01-2.16(m,4H),2.18-2.27(m,1H),2.86-3.00(m,1H),3.80(s,3H),4.05-4.13(m,1H),4.55-4.63(m,1H),5.58-5.63(m,1H),7.41(d,J=8.70Hz,1H),7.74(d,J=8.70Hz,1H),8.03(s,1H)。MS(ESI,正离子)m/z 402[M+H]+。
(S)-5-环丁氧基-2-甲基-6-(2-(甲基氨甲酰基)噻唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-130)
1H NMR(300MHz,CDCl3)δppm 1.16-1.31(m,5H),1.45-1.59(m,2H),1.98-2.11(m,4H),2.15-2.28(m,1H),2.45-2.55(m,1H),2.90-2.99(m,1H),3.06(d,J=5.40Hz,3H),3.80(s,3H),4.05-4.14(m,1H),4.55-4.65(m,1H),7.41(d,J=8.70Hz,1H),7.72(d,J=8.70Hz,1H),7.96(s,1H)。MS(ESI,正离子)m/z 416[M+H]+。
(S)-6-(2-乙酰胺基噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-131)
1H NMR(400MHz,CDCl3)δppm 1.17(d,J=6.40Hz,3H),1.25-1.36(m,1H),1.45-1.66(m,1H),1.67-1.75(m,1H),1.92-1.95(m 3H),1.97-2.13(m,4H),2.16-2.26(m,1H),2.45-2.51(m,1H),2.90-3.00(m,1H),3.79(s,3H),4.13-4.15(m,1H),4.55-4.62(m,1H),7.31-7.37(m,2H),7.54-7.57(m,1H),11.6(br s,1H)。MS(ESI,正离子)m/z 416[M+H]+。
实例36:(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-132)
步骤1.(S)-6-溴-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.050g,0.167mmol)、5-氯-2-氟苯甲腈(0.065g,0.416mmol)和碳酸铯(0.136g,0.416mmol)于DMF(2.0mL)中的混合物在100℃下加热16小时。冷却反应混合物到室温,且添加水。将混合物分配于乙酸乙酯与水之间。分离水相,且用乙酸乙酯萃取。用盐水洗涤经合并的有机相,经无水硫酸钠干燥,过滤且浓缩,得到棕色油状物。经硅胶柱色谱(Biotage 25g柱,以0-25%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈灰白色固体状的(S)-6-溴-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.068g,94%)。MS(ESI,正离子)m/z435,437[M+H]+。
步骤2.(S)-6-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-溴-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.068g,0.156mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.065g,0.172mmol)、XPhos第2代预催化剂(0.012g,0.016mmol)和碳酸铯(0.153g,0.468mmol)于二噁烷(2.0mL)和水(0.400mL)中的混合物在100℃下于微波中加热2小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage25g柱,以25-50%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈灰白色固体状的(S)-6-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.057g,60%)。MS(ESI,正离子)m/z 606[M+H]+。
步骤3.(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟乙酸(0.5mL,6.49mmol)添加到(S)-6-(1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.057g,0.094mmol)于二氯甲烷(2.0mL)中的溶液中,且在室温下搅拌反应混合物1.5小时。浓缩反应混合物,且将残余物分配于二氯甲烷与饱和碳酸氢钠水溶液之间。分离有机相,经无水硫酸钠干燥,过滤且浓缩,得到呈灰白色固体状的(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.041g,86%)。1H NMR(300MHz,DMSO-d6)δppm 1.01-1.09(m,4H),1.49-1.79(m,4H),1.80-2.07(m,4H),2.52-2.63(m,2H),2.99(br d,J=12.31Hz,2H),3.72(s,3H),4.03-4.23(m,1H),4.45-4.70(m,1H),6.44(br d,J=9.09Hz,1H),7.47-7.64(m,3H),7.67(s,1H),7.95(s,1H),8.10(d,J=2.35Hz,1H)。MS(ESI,正离子)m/z 506[M+H]+。
根据针对实例36所概述的程序制得以下实例:
(S)-5-(2-氰基-4-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-133)
1H NMR(300MHz,DMSO-d6)δppm 1.00-1.12(m,4H),1.48-1.79(m,4H),1.79-2.05(m,4H),2.51-2.61(m,2H),2.98(br d,J=12.31Hz,2H),3.72(s,3H),3.99-4.23(m,1H),4.38-4.67(m,1H),6.43(br d,J=5.28Hz,1H),7.37(td,J=8.79,3.22Hz,1H),7.54-7.70(m,3H),7.89-7.98(m,2H)。MS(ESI,正离子)m/z 490[M+H]+。
(S)-5-(2-氯-4-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-134)
1H NMR(300MHz,DMSO-d6)δppm 1.06(br d,J=1.76Hz,4H),1.43-1.75(m,4H),1.77-2.08(m,4H),2.52-2.68(m,2H),2.98(br d,J=12.02Hz,2H),3.72(s,3H),4.09(brt,J=12.02Hz,1H),4.44-4.73(m,1H),6.27-6.66(m,1H),7.50-7.65(m,3H),7.67(s,1H),7.95(s,1H),8.22(s,1H)。MS(ESI,正离子)m/z 506[M+H]+。
(S)-5-(4-氰基-2-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-135)
1H NMR(300MHz,DMSO-d6)δppm 1.00-1.12(m,4H),1.50-1.76(m,4H),1.79-2.09(m,4H),2.47-2.64(m,2H),2.99(br d,J=12.61Hz,2H),3.72(s,3H),4.01-4.21(m,1H),4.44-4.70(m,1H),6.52(br t,J=8.65Hz,1H),7.37-7.71(m,4H),7.94(s,1H),8.05(br d,J=11.14Hz,1H)。MS(ESI,正离子)m/z 490[M+H]+。
(S)-2-(1-乙酰基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-136)
1H NMR(300MHz,CD3OD)δppm 1.16(d,J=6.60Hz,3H),1.47(br s,1H),1.78-1.93(m,2H),2.01-2.09(m,2H),2.15-2.35(m,5H),2.55-2.83(m,3H),3.10-3.21(m,2H),4.18-4.32(m,1H),4.78(br s,1H),6.50(d,J=8.10Hz,1H),7.11(t,J=7.80Hz,1H),7.35-7.50(m,2H),7.61(d,J=8.40Hz,1H),7.71-7.79(m,2H),7.99(s,1H)。MS(ESI,正离子)m/z 456[M+H]+。
(S)-5-(2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-137)
1H NMR(400MHz,CD3OD)δppm 1.06(d,J=6.40Hz,3H),1.48-1.55(m,1H),1.65-1.74(m,1H),1.85-2.05(m,3H),2.20-2.85(m,4H),2.95-3.05(m,2H),3.72(s,3H),4.05-4.15(m,1H),4.50-4.60(m,1H),6.30-6.40(m,1H),6.93-6.99(m,1H),7.23-7.30(m,1H),7.43(d,J=8.80Hz,1H),7.50-7.60(m,1H),7.59-7.65(m,2H),7.79(s,1H)。MS(ESI,正离子)m/z 472[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2-氰基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-138)
1H NMR(300MHz,DMSO-d6)δppm 1.00(br d,J=6.45Hz,3H),1.39-1.62(m,2H),1.83-2.00(m,2H),3.29-3.51(m,2H),3.55-3.63(m,1H),3.66(s,3H),3.70-3.82(m,1H),4.52(m,1H),4.80(br d,J=7.04Hz,1H),4.95-5.16(m,1H),6.37(br d,J=8.50Hz,1H),6.94-7.20(m,1H),7.42(q,J=7.52Hz,1H),7.55(m,2H),7.65-7.75(m,1H),7.75-7.90(m,1H),7.93-8.12(m,1H)。MS(ESI,正离子)m/z 444[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2-氰基-3-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-139)
1H NMR(300MHz,DMSO-d6)δppm 1.00(br d,J=5.86Hz,3H),1.45-1.67(m,2H),1.81-1.99(m,2H),3.29-3.51(m,2H),3.66(s,3H),3.73-4.02(m,2H),4.40-4.65(m,1H),4.82(m,1H),4.98-5.27(m,1H),6.25(br d,J=7.33Hz,1H),7.08(br t,J=8.79Hz,1H),7.38-7.64(m,3H),7.72(br d,J=6.16Hz,1H),7.89-8.10(m,1H)。MS(ESI,正离子)m/z 462[M+H]+。
(S)-4-(1-乙酰基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-140)
1H NMR(300MHz,CD3OD)δppm 1.15(d,J=6.60Hz,3H),1.20-1.45(m,1H),1.80-1.95(m,2H),1.97-2.05(m,2H),2.10-2.25(m,5H),2.52-2.69(m,1H),2.72-2.82(m,2H),3.20(d,J=12.90Hz,2H),4.15-4.25(m,1H),4.65-4.82(m,1H),6.93(d,J=8.70Hz,2H),7.38(br s,1H),7.62(t,J=9.00Hz,3H),7.75(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z456[M+H]+。
(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-(3-(三氟甲基)吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-141)
1H NMR(400MHz,CD3OD)δppm 1.15(s,3H),1.20-1.50(m,1H),1.72-1.87(m,2H),1.95-2.05(m,2H),2.07-2.45(m,6H),2.65-2.75(m,2H),3.05-3.15(m,2H),4.10-4.22(m,1H),4.79(br s,1H),7.15-7.37(m,2H),7.56(d,J=8.40Hz,1H),7.71(s,1H),7.86(s,1H),8.12-8.19(m,2H)。MS(ESI,正离子)m/z 500[M+H]+。
(S)-1-(5-(3-氯吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-142)
1H NMR(300MHz,CD3OD)δppm 1.16(d,J=6.60Hz,3H),1.45(br s,1H),1.75-1.92(m,2H),1.97-2.10(m,2H),2.15-2.32(m,5H),2.50-2.70(m,1H),2.69-2.78(m,2H),3.08-3.15(m,2H),4.08-4.21(m,1H),4.72-4.91(m,1H),6.95-7.05(m,1H),7.25-7.35(m,1H),7.55(d,J=8.10Hz,1H),7.77(s,1H),7.85-7.95(m,2H),7,96(s,1H)。MS(ESI,正离子)m/z466[M+H]+。
(S)-2-(1-乙酰基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)烟碱腈(I-143)
1H NMR(400MHz,CD3OD)δppm 1.17(d,J=6.80Hz,3H),1.38-1.55(m,1H),1.79-1.92(m,2H),1.98-2.09(m,2H),2.15-2.41(m,5H),2.52-2.70(m,1H),2.70-2.79(m,2H),3.10-3.18(m,2H),4.18-4.28(m,1H),4.70-4.85(m,1H),7.12-7.18(m,1H),7.20-7.39(m,1H),7.53(d,J=8.40Hz,1H),7.74(s,1H),7.95(s,1H),8.11-8.22(m,2H)。MS(ESI,正离子)m/z 457[M+H]+。
(S)-1-(2-甲基-5-(5-甲基嘧啶-2-基氧基)-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-144)
1H NMR(400MHz,CD3OD)δppm 1.02(d,J=6.80Hz,3H),1.25-1.35(m,1H),1.65-1.78(m,2H),1.85-95(m,2H),2.01-2.21(m,8H),2.45-2.65(m,3H),2.98-3.059(m,2H),4.05-4.12(m,1H),4.58-4.75(m,1H),7.05-7.20(m,1H),7.43(d,J=8.40Hz,1H),7.66(s,1H),7.87(s,1H),8.27(s,2H)。MS(ESI,正离子)m/z 447[M+H]+。
(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-(吡嗪-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-145)
1H NMR(400MHz,CD3OD)δppm 1.05(d,J=6.40Hz,3H),1.20-1.45(m,1H),1.65-1.80(m,2H),1.82-1.89(m,2H),2.05-2.25(m,5H),2.48-2.65(m,3H),2.95-3.05(m,2H),4.05-4.15(m,1H),4.60-4.78(m,1H),7.10-7.25(m,1H),7.43(d,J=8.40Hz,1H),7.61(s,1H),7.84(s,1H),7.92(s,1H),8.10(d,J=2.80Hz,1H),8.38(s,1H)。MS(ESI,正离子)m/z433[M+H]+。
(S)-5-(4-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-146)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.30Hz,3H),1.52-1.65(m,1H),1.75-1.95(m,2H),1.97-2.15(m,3H),2.38-2.48(m,1H),2.55-2.78(m,3H),3.08-3.15(m,2H),3.83(s,1H),4.15-4.29(m,1H),4.65-4.72(m,1H),6.89-6.99(m,2H),7.53-7.70(m,5H),7.92(s,1H)。MS(ESI,正离子)m/z 472[M+H]+。
(S)-5-(3-氰基吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-147)
1H NMR(400MHz,CD3OD)δppm 1.18(d,J=6.80Hz,3H),1.59-1.68(m,1H),1.80-1.95(m,2H),1.99-2.15(m,3H),2.30-2.70(br m,2H),2.70-2.80(m,2H),3.10-3.19(m,2H),3.83(s,3H),4.15-4.25(m,1H),4.65-4.71(m,1H),7.11-7.15(m,1H),7.45(d,J=8.80Hz,1H),7.61(d,J=8.80Hz,1H),7.71(s,1H),7.91(s,1H),8.12-8.21(m,2H)。MS(ESI,正离子)m/z 473[M+H]+。
(S)-5-(2-氰基-3-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-148)
1H NMR(300MHz,CD3OD)δppm 1.19(d,J=6.60Hz,3H),1.58-1.72(m,1H),1.78-1.99(m,2H),1.98-2.15(m,3H),2.68-2.82(m,2H),3.07-3.19(m,2H),4.20-4.30(m,1H),4.60-4.75(m,1H),6.25-6.35(m,1H),6.96(t,J=8.40Hz,1H),7.39-7.55(m,2H),7.65-7.71(m,1H),7.76(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z 490[M+H]+。
(S)-5-(3-氯-2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-149)
1H NMR(300MHz,CD3OD)δppm 1.05-1.20(m,3H),1.58-1.72(m,1H),1.79-1.95(m,2H),1.98-2.15(m,3H),2.20-2.70(br s,1H),2.65-2.80(m,3H),3.05-3.15(m,2H),3.82(s,3H),4.15-4.25(m,1H),4.60-4.75(m,1H),6.30-6.50(m,1H),7.20(d,J=8.10Hz,1H),7.38(t,J=8.40Hz,1H),7.52(d,J=8.70Hz,1H),7.60-7.75(m,2H),7.93(s,1H)。MS(ESI,正离子)m/z 506[M+H]+。
(S)-2-(1-(环丙烷羰基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-150)
1H NMR(300MHz,CD3OD)δppm 0.75-0.90(m,1H),0.95-1.05(m,2H),1.15-1.30(m,4H),1.45-1.65(m,1H),1.81-1.99(m,2H),2.01-2.13(m,3H),2.20-2.60(m,2H),2.65-2.82(m,3H),3.10-3.21(m,2H),4.20-4.35(m,1H),4.80-4.95(m,1H),6.50-6.64(m,1H),7.18(t,J=7.50Hz,1H),7.45-7.55(m,2H),7.67(d,J=8.40Hz,1H),7.78-7.82(m,2H),8.03(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(S)-2-(1-(环丙烷羰基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)-6-氟苯甲腈(I-151)
1H NMR(400MHz,CD3OD)δppm 0.75-0.82(m,1H),0.85-1.01(m,2H),1.10-1.21(m,4H),1.45-1.60(m,1H),1.79-1.92(m,2H),1.95-2.10(m,3H),2.15-2.30(m,1H),2.30-2.50(m,1H),2.65-2.79(m,3H),3.08-3.19(m,2H),4.15-4.30(m,1H),4.78-4.90(m,1H),6.30-6.40(m,1H),6.90-7.00(m,1H),7.40-7.50(m,2H),7.62(d,J=8.40Hz,1H),7.78(s,1H),7.98(s,1H)。MS(ESI,正离子)m/z 500[M+H]+。
(S)-4-(1-(环丙烷羰基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)-3-氟苯甲腈(I-152)
1H NMR(400MHz,CD3OD)δppm 0.65-0.70(m,1H),0.78-0.92(m,2H),0.99-1.11(m,4H),1.30-1.42(m,1H),1.65-1.80(m,2H),1.85-1.95(m,3H),2.08-2.19(m,1H),2.20-2.30(m,1H),2.50-2.65(m,3H),2.95-3.05(m,2H),4.05-4.15(m,1H),4.65-4.75(m,1H),6.51(t,J=8.40Hz,1H),7.24(d,J=8.80Hz,1H),7.36(d,J=8.40Hz,1H),7.51(d,J=8.40Hz,1H),7.60-7.70(m,2H),7.80(s,1H)。MS(ESI,正离子)m/z 500[M+H]+。
(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-153)
根据上文针对实例36所述的程序合成(S)-2-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈,作出以下改变:(1)在步骤2中,使用1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑替代4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯;(3)去除步骤3(去除Boc保护基)。1HNMR(300MHz,CD3OD)δppm 0.92-1.05(m,4H),1.16(d,J=6.30Hz,3H),1.35-1.52(m,1H),2.10-2.40(m,5H),2.58-2.80(m,1H),3.55-3.65(m,1H),4.68-4.89(m,1H),6.40-6.55(m,1H),7.05-7.15(m,1H),7.30-7.52(m,2H),7.55-7.65(m,1H),7.70-7.80(m,2H),7.96(s,1H)。MS(ESI,正离子)m/z 413[M+H]+。
实例37:(S)-2-(1-(环丙烷羰基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-154)
步骤1.(S)-2-(1-(环丙烷羰基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈
将(S)-2-(6-溴-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(0.70g,0.17mmol,1.00当量)、双(频哪醇根基)二硼(0.216g,0.85mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.015g,0.02mmol)、乙酸钾(0.042g,0.43mmol)于1,4-二噁烷(10mL)中的混合物在90℃下搅拌隔夜。冷却混合物到室温,用乙酸乙酯(50mL)稀释,用水(20mL)和盐水(20mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以25%乙酸乙酯-石油醚洗提)纯化残余物,得到呈黄色油状的(S)-2-(1-(环丙烷羰基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(0.050g,64%)。MS(ESI,正离子)m/z 459[M+H]+。
步骤2.(S)-2-(1-(环丙烷羰基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈
将(S)-2-(1-(环丙烷羰基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(0.050g,0.11mmol)、4-溴-1-甲基-1H-1,2,3-三唑(0.025g,0.15mmol)、碳酸铯(0.110g,0.34mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.10g,0.01mmol)于1,4-二噁烷(10mL)和水(3mL)中的混合物在80℃下搅拌隔夜。冷却反应混合物到室温,且经短硅藻土衬垫过滤。浓缩滤液,且经制备型薄层色谱(以25%乙酸乙酯-石油醚洗提)纯化,得到呈白色固体状的(S)-2-(1-(环丙烷羰基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(0.006g,13%)。MS(ESI,正离子)m/z 414[M+H]+。1H NMR(400MHz,CD3OD)δppm 0.75-0.82(m,1H),0.88-1.05(m,2H),1.15-1.25(m,3H),1.28-1.35(m,1H),1.45-1.55(m,1H),1.97-2.05(m,1H),2.15-2.25(m,1H),2.27-2.45(m,1H),2.60-2.75(m,1H),4.09(s,3H),4.75-4.85(m,1H),6.58(d,J=8.40Hz,1H),7.17(t,J=8.00Hz,1H),7.45-7.51(m,1H),7.57(d,J=8.40Hz,1H),7.78(d,J=1.20Hz,1H),8.03-8.07(m,2H)。MS(ESI,正离子)m/z 414[M+H]+。
实例38:(S)-4-(1-乙酰基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺(I-155)
步骤1. 4-[[(2S)-1-乙酰基-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基]苯甲酰胺
向配备有经空气填充的气球的100-mL圆底烧瓶中装入1-[(2S)-6-溴-5-羟基-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(0.300g,1.06mmol)、(4-氨甲酰基苯基)硼酸(0.437g,2.65mmol)、乙酸铜(0.386g,2.12mmol)、吡啶(1mL)、二氯甲烷(40mL)和分子筛(4.0g)。在室温下搅拌所得混合物3天。经硅藻土衬垫过滤反应混合物,且在真空下浓缩滤液。通过制备型薄层色谱(以20-25%乙酸乙酯-石油醚洗提)纯化残余物,得到呈黄色油状的4-[[(2S)-1-乙酰基-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基]苯甲酰胺(0.148g,35%)。MS(ESI,正离子)m/z 403,405[M+H]+。
步骤2. 4-[4-[(2S)-1-乙酰基-5-(4-氨甲酰基苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯
将4-[[(2S)-1-乙酰基-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基]苯甲酰胺(0.080g,0.20mmol)、4-[4-(四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(0.090g,0.24mmol)、碳酸钾(0.082g,0.59mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.016g,0.02mmol)于1,4-二噁烷(20mL)和水(2mL)中的混合物在100℃下搅拌隔夜。冷却反应混合物到室温,经硅藻土衬垫过滤,且在真空下浓缩。经制备型薄层色谱(以50%乙酸乙酯-石油醚洗提)纯化残余物,得到呈黄色油状的4-[4-[(2S)-1-乙酰基-5-(4-氨甲酰基苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(0.080g,70%)。MS(ESI,正离子)m/z 574[M+H]+。
步骤3.(S)-4-(1-乙酰基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺
将三氟乙酸(3.5mL)添加到4-[4-[(2S)-1-乙酰基-5-(4-氨甲酰基苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(0.080g,0.14mmol)于二氯甲烷(30mL)中的溶液中。在室温下搅拌反应混合物2小时,接着在真空下浓缩。将残余物溶解于二氯甲烷(50mL)中,用饱和碳酸钾水溶液(3×20mL)和盐水(20mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。通过制备型HPLC使用以下条件(制备型HPLC-12)纯化残余物:柱,XBridge Prep C18OBD柱,19×150mm 5μm 13nm;移动相:水(0.05%碳酸氢铵)和乙腈(在18分钟内20%到95%乙腈,流动速率:20mL/min);检测器,UV 254/220nm。这得到呈灰白色固体状的4-[[(2S)-1-乙酰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基]苯甲酰胺(0.033g,50%)。1H NMR(300MHz,CD3OD)δppm 1.15(d,J=6.60Hz,3H),1.25-1.45(m,1H),1.72-1.92(m,2H),1.95-2.05(m,2H),2.15-2.40(m,5H),2.60-2.80(m,3H),3.05-3.15(m,2H),4.15-4.25(m,1H),4.79(br s,1H),6.87(d,J=8.70Hz,2H),7.38(br s,1H),7.64(d,J=8.70Hz,1H),7.75-7.89(m,3H),7.96(s,1H)。MS(ESI,正离子)m/z 474[M+H]+。
根据针对实例38所概述的程序制得以下实例:
(S)-1-(5-(3-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-156)
1H NMR(300MHz,CD3OD)δppm 1.11(d,J=6.60Hz,3H),1.22-1.42(m,1H),1.75-1.89(m,2H),1.98-2.08(m,2H),2.23(s,3H),2.14-2.35(m,2H),2.64-2.79(m,3H),3.09-3.18(m,2H),3.72(s,3H),4.15-4.25(m,1H),4.68-4.83(m,1H),6.28-35(m,2H),6.52-6.57(m,1H),7.14(t,J=8.10Hz,1H),7.20-7.35(m,1H),7.61(d,J=8.40Hz,1H),7.80(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 461[M+H]+。
(S)-1-(5-(2-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-157)
1H NMR(400MHz,CD3OD)δppm 1.16(d,J=6.80Hz,3H),1.30-1.45(m,1H),1.75-1.89(m,2H),1.95-2.05(m,2H),2.15-2.35(m,5H),2.55-2.79(m,3H),3.09-3.15(m,2H),4.12-4.22(m,1H),4.78(br s,1H),6.30-6.35(m,1H),6.89-6.97(m,1H),6.99-7.05(m,1H),7.37(br s,1H),7.42-7.49(m,1H),7.64(d,J=8.40Hz,1H),7.83(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-158)
1H NMR(300MHz,CD3OD)δppm 1.14(d,J=6.60Hz,3H),1.48-1.62(m,1H),1.75-1.91(m,2H),1.95-2.15(m,3H),2.35-2.45(m,1H),2.55-2.78(m,3H),3.09-3.18(m,2H),4.15-4.25(m,1H),4.55-4.68(m,1H),6.68-6.78(m,2H),6.91-7.02(m,2H),7.49-7.52(m,2H),7.76(s,1H),7.92(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-5-(4-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-159)
1H NMR(300MHz,CD3OD)δppm 1.15(d,J=6.60Hz,3H),1.50-1.62(m,1H),1.75-1.92(m,2H),1.97-2.15(m,3H),2.35-2.48(m,1H),2.52-2.82(m,3H),3.09-3.18(m,2H),4.15-4.25(m,1H),4.55-4.72(m,1H),6.77(d,J=8.70Hz,2H),7.24(d,J=9.00Hz,2H),7.45-7.55(m,2H),7.77(s,1H),7.92(s,1H)。MS(ESI,正离子)m/z 481[M+H]+。
(S)-5-(2-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-160)
1H NMR(300MHz,CD3OD)δppm 1.15(d,J=6.60Hz,3H),1.52-1.68(m,1H),1.72-1.92(m,2H),1.95-2.15(m,4H),2.65-2.80(m,3H),3.05-3.18(m,2H),3.81(s,3H),4.12-4.25(m,1H),4.55-4.75(m,1H),6.28-6.35(m,1H),6.85-6.95(m,1H),6.95-7.05(m,1H),7.42-7.65(m,3H),7.79(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 481[M+H]+。
(S)-5-(4-氨甲酰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-161)
1H NMR(400MHz,CD3OD)δppm 1.16(d,J=6.40Hz,3H),1.52-1.62(m,1H),1.83-1.95(m,2H),1.99-2.13(m,3H),2.42-2.49(m,1H),2.55-2.65(m,1H),2.78-2.85(m,2H),3.15-3.22(m,2H),3.83(s,3H),4.19-4.25(m,1H),4.62-4.65(m,1H),6.84(d,J=8.80Hz,2H),7.50-7.60(m,2H),7.75-7.82(m,3H),7.91(s,1H)。MS(ESI,正离子)m/z 490[M+H]+。
(S)-5-(3-氰基-4-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-162)
1H NMR(400MHz,CD3OD)δppm 1.16(d,J=6.80Hz,3H),1.55-1.65(m,1H),1.80-1.98(m,2H),1.99-2.12(m,3H),2.39-2.48(m,1H),2.60-2.80(m,3H),3.10-3.20(m,2H),3.82(s,3H),4.19-4.30(m,1H),4.60-4.70(m,1H),7.05-7.22(m,3H),7.50-7.62(m,2H),7.75(s,1H),7.94(s,1H)。MS(ESI,正离子)m/z 490[M+H]+。
(S)-5-(3-氯-4-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-163)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.60Hz,3H),1.52-1.65(m,1H),1.78-1.95(m,2H),1.97-2.15(m,3H),2.38-2.45(m,1H),2.58-2.79(m,3H),3.09-3.15(m,2H),3.83(s,3H),4.15-4.30(m,1H),4.60-4.72(m,1H),6.68-6.72(m,1H),6.85-6.89(m,1H),7.13(t,J=9.00Hz,1H),7.52-7.63(m,2H),7.76(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z499[M+H]+。
(S)-环丙基(5-(4-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-164)
1H NMR(400MHz,CD3OD)δppm 0.65-0.82(m,1H),0.85-1.01(m,2H),1.01-1.19(m,4H),1.30-1.45(m,1H),1.75-1.90(m,2H),1.90-2.05(m,3H),2.09-2.35(m,2H),2.60-2.80(m,3H),3.05-3.20(m,2H),4.11-4.28(m,1H),4.70-4.82(m,1H),6.79(s,1H),6.90-7.03(m,2H),7.39(d,J=8.00Hz,1H),7.62(d,J=8.00Hz,1H),7.79(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 475[M+H]+。
(S)-(5-(2-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-165)
1H NMR(400MHz,CD3OD)δppm 0.72-0.82(m,1H),0.90-1.05(m,2H),1.10-1.25(m,4H),1.40-1.50(m,1H),1.78-1.95(m,2H),1.95-2.10(m,3H),2.20-2.40(m,2H),2.70-2.90(m,3H),3.10-3.18(m,2H),4.15-4.25(m,1H),4.75-4.85(m,1H),6.35-6.42(m,1H),6.90-6.98(m,1H),7.01-7.09(m,1H),7.40-7.50(m,2H),7.65(d,J=8.40Hz,1H),7.84(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 491[M+H]+。
(S)-(5-(4-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-166)
1H NMR(400MHz,CD3OD)δppm 0.72-0.80(m,1H),0.85-1.05(m,2H),1.10-1.19(m,4H),1.35-1.45(m,1H),1.75-1.90(m,2H),1.95-2.05(m,3H),2.15-2.35(m,2H),2.65-2.79(m,3H),3.10-3.20(m,2H),4.15-4.30(m,1H),4.75-4.85(m,1H),6.80(dd,J=10.80,2.00Hz,2H),7.26(dd,J=10.80,2.00Hz,2H),7.40(d,J=8.40Hz,1H),7.63(d,J=8.40Hz,1H),7.79(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 491[M+H]+。
(S)-4-(1-(环丙烷羰基)-2-甲基-6-1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-167)
1H NMR(300MHz,CD3OD)δppm 0.69-0.80(m,1H),0.83-1.01(m,2H),1.09-1.22(m,4H),1.30-1.50(m,1H),1.70-1.90(m,2H),1.90-2.01(m,3H),2.11-2.35(m,2H),2.60-2.75(m,3H),3.03-3.12(m,2H),4.10-4.25(m,1H),4.70-4.85(m,1H),6.95(d,J=8.70Hz,2H),7.41(d,J=8.40Hz,2H),7.55-7.68(m,3H),7.73(s,1H),7.92(s,1H)。MS(ESI,正离子)m/z491[M+H]+。
(S)-环丙基(2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-168)
1H NMR(400MHz,CD3OD)δppm 0.75-0.80(m,1H),0.90-1.01(m,2H),1.10-1.20(m,4H),1.32-1.45(m,1H),1.75-1.92(m,2H),1.95-2.05(m,3H),2.15-2.35(m,2H),2.65-2.75(m,3H),3.05-3.15(m,2H),4.10-4.25(m,1H),4.70-4.82(m,1H),6.80(d,J=8.00Hz,2H),6.98(t,J=7.20Hz,1H),7.28(t,J=8.00Hz,2H),7.39(d,J=8.40Hz,1H),7.80(s,1H),7.98(s,1H)。MS(ESI,正离子)m/z 457[M+H]+。
(S)-(5-(3-氯-4-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-169)
1H NMR(400MHz,CD3OD)δppm 0.62-0.72(m,1H),0.78-0.90(m,2H),0.98-1.10(m,4H),1.25-1.35(m,1H),1.68-1.80(m,2H),1.85-1.95(m,3H),2.09-2.25(m,2H),2.55-2.70(m,3H),2.95-3.05(m,2H),4.05-4.15(m,1H),4.65-4.75(m,1H),6.55-6.65(m,1H),6.75-6.85(m,1H),7.03(t,J=8.80Hz,1H),7.31(d,J=8.40Hz,1H),7.51(d,J=8.40Hz,1H),7.67(s,1H),7.83(s,1H)。MS(ESI,正离子)m/z 509[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-170)
1H NMR(400MHz,CD3OD)δppm 0.58-0.70(m,1H),0.78-0.92(m,2H),0.95-1.10(m,4H),1.20-1.30(m,1H),1.80-1.90(m,1H),2.05-2.18(m,2H),2.55-2.65(m,1H),3.75-3.85(m,2H),3.88-3.95(m,2H),4.60-4.70(m,1H),5.01-5.12(m,1H),6.65-6.70(m,2H),6.85-6.90(m,2H),7.28(d,J=8.40Hz,1H),7.51(d,J=8.40Hz,1H),7.77(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z 447[M+H]+。
(S)-环丙基(5-(3-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-171)
1H NMR(400MHz,CD3OD)δppm 0.62-0.72(m,1H),0.78-0.90(m,2H),0.95-1.10(m,4H),1.20-1.35(m,1H),1.68-1.80(m,2H),1.85-1.95(m,3H),2.05-2.25(m,2H),2.55-2.70(m,3H),2.95-3.10(m,2H),4.05-4.15(m,1H),4.65-4.70(m,1H),6.40-6.52(m,2H),6.55-6.65(m,1H),7.10-7.15(m,1H),7.30(d,J=8.40Hz,1H),7.52(d,J=8.40Hz,1H),7.69(s,1H),7.85(s,1H)。MS(ESI,正离子)m/z 475[M+H]+。
(S)-环丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-172)
1H NMR(400MHz,CD3OD)δppm 0.65-0.70(m,1H),0.75-0.90(m,2H),0.95-1.10(m,4H),1.25-1.35(m,1H),1.65-1.80(m,2H),1.85-1.95(m,3H),2.05-2.25(m,2H),2.55-2.65(m,3H),2.95-3.05(m,2H),4.05-4.18(m,1H),4.65-4.75(m,1H),6.40-6.50(m,1H),6.55-6.70(m,1H),6.95-7.10(m,1H),7.30(d,J=8.40Hz,1H),7.51(d,J=8.40Hz,1H),7.68(s,1H),7.86(s,1H)。MS(ESI,正离子)m/z 493[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-173)
1H NMR(400MHz,CD3OD)δppm 0.65-0.72(m,1H),0.75-0.90(m,2H),0.95-1.10(m,4H),1.20-1.35(m,1H),1.85-1.95(m,1H),2.05-2.25(m,2H),2.55-2.65(m,1H),3.55-3.70(m,1H),3.75-3.85(m,1H),3.90-3.98(m,1H),4.65-4.72(m,1H),5.05-5.12(m,1H),6.40-6.50(m,2H),6.55-6.70(m,1H),7.05-7.15(m,1H),7.25-7.30(m,1H),7.53(d,J=8.40Hz,1H),7.70-7.79(m,1H),7.90-8.00(m,1H)。MS(ESI,正离子)m/z 447[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-174)
1H NMR(400MHz,CD3OD)δppm 0.60-0.70(m,1H),0.75-0.90(m,2H),0.95-1.10(m,4H),1.20-1.35(m,1H),1.85-1.90(m,1H),2.05-2.22(m,2H),2.55-2.62(m,1H),3.75-3.85(m,2H),3.92-3.98(m,2H),4.65-4.70(m,1H),5.05-5.15(m,1H),6.40-6.50(m,1H),6.60-6.68(m,1H),6.95-7.05(m,1H),7.30(d,J=8.40Hz,1H),7.52(d,J=8.00Hz,1H),7.77(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-175)
1H NMR(400MHz,CD3OD)δppm 0.75-0.80(m,1H),0.85-1.02(m,2H),1.10-1.20(m,4H),1.30-1.40(m,1H),1.92-2.02(m,1H),2.12-2.32(m,2H),2.65-2.75(m,1H),4.48(d,J=7.60,4H),4.75-4.81(m,1H),5.30-41(m,1H),6.75-6.82(m,2H),6.95-7.01(m,1H),7.23-7.29(m,2H),7.40(d,J=8.40Hz,1H),7.64(d,J=8.40Hz,1H),7.98(s,1H),8.03(s,1H)。MS(ESI,正离子)m/z 429[M+H]+。
(S)-5-(3,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-176)
1H NMR(400MHz,CD3OD)δppm 1.04(d,J=6.40Hz,3H),1.45-1.52(m,1H),1.68-1.82(m,2H),1.87-2.02(m,3H),2.25-2.35(m,1H),2.45-2.70(m,3H),3.00-3.10(m,2H),3.70(s,3H),4.05-4.15(m,1H),4.48-4.55(m,1H),6.35-6.42(m,1H),6.55-6.65(m,1H),6.95-7.05(m,1H),7.45-7.55(m,2H),7.65(s,1H),7.80(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3-氯苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-177)
1H NMR(300MHz,DMSO-d6)δppm 1.06(d,J=6.60Hz,3H),1.46-1.67(m,1H),1.89-2.09(m,1H),2.37-2.48(m,2H),3.60-3.90(m,7H),4.45-4.70(m,1H),5.03-5.20(m,1H),6.59-6.64(m,1H),6.86(s,1H),6.95-7.11(m,1H),7.21-7.33(m,1H),7.58(s,2H),7.78(s,1H),8.14(s,1H)。MS(ESI,正离子)m/z 453[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3-氯苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-178)
1H NMR(400MHz,CD3OD)δppm 0.59-0.75(m,1H),0.76-0.99(m,2H),0.99-1.14(m,4H),1.14-1.41(m,1H),1.80-1.99(m,1H),2.02-2.31(m,2H),2.58-2.69(m,1H),3.48-3.71(m,1H),3.77-3.98(m,1H),3.98-4.07(m,1H),4.58-4.71(m,1H),4.82-4.90(m,1H),5.00-5.22(m,1H),6.55-6.67(m,1H),6.67-6.80(m,1H),6.80-6.97(m,1H),7.13-7.22(m,1H),7.23-7.39(m,1H),7.42-7.49(m,1H),7.53-7.62(m,1H),7.62-7.80(m,1H),7.85-8.08(m,1H)。MS(ESI,正离子)m/z 463[M+H]+。
(S)-(5-(3-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-179)
1H NMR(400MHz,CD3OD)δppm 0.69-0.84(m,1H),0.90-1.09(m,2H),1.10-1.26(m,4H),1.37-1.52(m,1H),1.80-1.95(m,2H),1.98-2.11(m,3H),2.18-2.39(m,1H),2.39-2.43(m,1H),2.68-2.84(m,3H),3.17-3.22(m,2H),4.14-4.34(m,1H),4.70-4.89(m,1H),6.62-6.78(m,1H),6.80-6.85(m,1H),6.93-7.07(m,1H),7.14-7.30(m,1H),7.34-7.46(m,1H),7.55-7.66(m,1H),7.79(s,1H),8.00(s,1H)。MS(ESI,正离子)m/z491[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-180)
1H NMR(300MHz,CD3OD)δppm 1.16(d,J=6.30Hz,3H),1.55-1.69(m,1H),2.06-2.18(m,1H),2.41-2.55(m,1H),2.62-2.75(m,1H),3.82(s,3H),3.90-4.01(m,2H),4.01-4.15(m,1H),4.64-4.75(m,1H),5.21-5.31(m,1H),6.39(d,J=8.40Hz,2H),6.54-6.63(m,1H),7.55-7.65(m,2H),7.86(s,1H),8.04(s,1H)。MS(ESI,正离子)m/z455[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-181)
1H NMR(400MHz,CD3OD)δppm 0.78-0.81(m,1H),0.95-1.00(m,2H),1.13-1.20(m,4H),1.40-1.53(m,1H),2.01-2.08(m,1H),2.22-2.27(m,1H),2.29-2.38(m,1H),2.69-2.74(m,1H),3.85-3.94(m,2H),4.04-4.08(m,2H),4.75-4.84(m,1H),5.22-5.28(m,1H),6.41-6.48(m,2H),6.53-6.63(m,1H),7.44(d,J=8.40Hz,1H),7.63(d,J=8.40Hz,1H),7.88(s,1H),8.07(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-5-(3,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-182)
1H NMR(400MHz,CD3OD)δppm 1.17(m,3H),1.56-1.67(m,1H),185-1.97(m,2H),2.01-2.11(m,2H),2.11-2.18(m,1H),2.43-2.52(m,1H),2.62-2.69(m,1H),2.71-2.82(m,2H),3.14-3.12(m,2H),3.83(s,3H),4.22-4.33(m,1H),4.75-4.84(m,1H),6.41-6.48(m,2H),6.53-6.63(m,1H),7.54-7.57(m,1H),7.63-7.65(m,1H),7.77(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(S)-环丙基(5-(3,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-183)
1H NMR(300MHz,CD3OD)δppm 0.76-7.84(m,1H),0.91-1.03(m,2H),1.11-1.21(m,4H),1.41-1.52(m,1H),1.87-2.11(m,5H),2.22-2.41(m,2H),3.20-3.28(m,2H),6.39-6.46(m,2H),6.53-6.63(m,1H),7.43(d,J=8.40Hz,1H),7.63(d,J=8.70Hz,1H),7.80(s,1H),8.00(s,1H)。MS(ESI,正离子)m/z 493[M+H]+。
(S)-(6-(5-氨基-1,3,4-噻二唑-2-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-184)
1H NMR(400MHz,CD3OD)δppm 0.79-0.88(m,1H),0.92-1.09(m,2H),1.11-1.25(m,4H),1.38-1.49(m,1H),1.96-2.08(m,1H),2.14-2.24(m,1H),2.24-2.35(m,1H),2.62-2.73(m,1H),4.73-4.82(m,1H),6.75-6.89(m,2H),6.97-7.12(m,1H),7.20-7.37(m,2H),7.42-7.53(m,1H),8.08-8.19(m,1H)。MS(ESI,正离子)m/z 407[M+H]+。
(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-185)
1H NMR(400MHz,CD3OD)δppm 1.15(d,J=6.40Hz,3H),1.48-1.52(m,1H),2.01-2.11(m,2H),2.20-2.30(m,1H),2.38-2.45(m,1H),2.55-2.70(m,1H),2.90-3.01(m,1H),3.02-3.25(m,3H),3.82(s,3H),4.60-4.70(m,1H),4.80-4.95(m,1H),6.68-6.75(m,2H),6.91-7.00(m,2H),7.50-7.58(m,2H),7.78(s,1H),7.92(s,1H)。MS(ESI,正离子)m/z 451[M+H]+。
(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-186)
1H NMR(300MHz,CD3OD)δppm 1.14(d,J=6.60Hz,3H),1.48-1.62(m,1H),1.79-1.90(m,2H),1.98-2.10(m,1H),2.15-2.25(m,2H),2.35-2.45(m,1H),2.58-2.70(m,5H),2.95-3.05(m,2H),3.80(s,3H),4.58-4.80(m,2H),6.68-6.72(m,2H),6.93-7.02(m,2H),7.50-7.60(m,2H),7.76(s,1H),7.89(s,1H)。MS(ESI,正离子)m/z 491[M+H]+。
(S)-环丙基(2-甲基-5-苯氧基-6-(1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-187)
对于(S)-环丙基(2-甲基-5-苯氧基-6-(1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮,使用1-苯甲基-4-溴-1H-1,2,3-三唑作为芳基溴化物来源。使用上文针对中间物1步骤2所概述的氢化条件去除苯甲基。1H NMR(400MHz,CD3OD)δppm 0.75-0.87(m,1H),0.91-1.03(m,2H),1.11-1.22(m,4H),1.39-1.52(m,1H),1.95-2.08(m,1H),2.17-2.29(m,1H),2.29-2.38(m,1H),2.66-2.82(m,1H),4.73-4.88(m,1H),6.71-6.89(m,2H),6.96-7.22(m,1H),7.21-7.38(m,2H),7.44-7.53(m,1H),8.03(s,1H),8.03-8.14(m,1H)。MS(ESI,正离子)m/z 375[M+H]+。
(S)-5-(3-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-188)
MS(ESI,正离子)m/z 465[M+H]+。
(S)-5-(3-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-189)
MS(ESI,正离子)m/z 481[M+H]+。
(S)-1-(5-(4-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-190)
1H NMR(300MHz,CD3OD)δppm 1.10-1.15(m,3H),1.30-1.43(m,1H),1.76-1.86(m,2H),1.94-2.10(m,2H),2.20-2.35(m,5H),2.63-2.76(m,3H),3.06-3.18(m,2H),4.15-4.26(m,1H),4.69-4.81(m,1H),6.70-6.78(m,2H),6.97-7.03(m,2H),7.30(br s,1H),7.61(d,J=8.40Hz,1H),7.78(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z 449[M+H]+。
(S)-1-(5-(4-氯苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-191)
1H NMR(300MHz,CD3OD)δppm 1.13(d,J=6.30Hz,3H),1.35-1.51(m,1H),1.75-1.90(m,2H),1.95-2.10(m,2H),2.15-2.33(m,5H),2.63-2.77(m,3H),3.08-3.15(m,2H),4.15-4.27(m,1H),4.68-4.81(m,1H),6.73-6.80(m,2H),7.20-7.39(m,3H),7.59-7.63(m,1H),7.78(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-192)
1H NMR(400MHz,CD3OD)δppm 1.04(d,J=6.80Hz,3H),1.41-1.48(m,1H),1.93-2.02(m,1H),2.29-2.36(m,1H),2.51-2.57(m,1H),3.70(s,3H),3.77-3.82(m,2H),3.93-3.99(m,2H),4.50-4.60(m,1H),5.08-5.16(m,1H),6.40-6.45(m,1H),6.55-6.64(m,1H),6.95-7.07(m,1H),7.40-7.51(m,2H),7.74(s,1H),7.91(s,1H)。MS(ESI,正离子)m/z 455[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-193)
1H NMR(400MHz,CD3OD)δppm 1.03(d,J=6.80Hz,3H),1.38-1.48(m,1H),1.91-2.01(m,1H),2.35-2.48(m,1H),2.49-2.58(m,1H),3.70(s,3H),3.73-3.82(m,2H),2.85-2.95(m,2H),4.43-4.53(m,1H),5.05-5.13(m,1H),6.65(d,J=8.80Hz,2H),6.84-6.89(m,1H),7.12-7.18(m,2H),7.47(s,1H),7.91(s,1H),7.74(s,1H)。MS(ESI,正离子)m/z 419[M+H]+。
(S)-环丙基(5-(2-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-194)
1H NMR(400MHz,CD3OD)δppm 0.75-0.81(m,1H),0.92-1.02(m,2H),1.14-1.22(m,4H),1.39-1.49(m,1H),1.77-1.88(m,2H),2.01-2.09(m,3H),2.21-2.35(m,2H),2.69-2.79(m,3H),3.14-3.19(m,2H),4.02(s,3H),4.15-4.25(m,1H),4.75-4.84(m,1H),6.30(d,J=3.60Hz,1H),6.69-6.73(m,1H),6.94-6.98(m,1H),7.11-7.15(m,1H),7.38(d,J=6.30Hz,1H),7.65(d,J=6.30Hz,1H),7.86(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 487[M+H]+。
(S)-环丙基(5-(3-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-195)
1H NMR(400MHz,CD3OD)δppm 0.78-0.85(m,1H),0.83-1.01(m,2H),1.12-1.21(m,4H),1.38-1.46(m,1H),1.85-1.95(m,2H),1.97-2.09(m,3H),2.20-2.47(m,2H),2.69-2.81(m,3H),3.15-3.20(m,2H),3.74(s,3H),4.21-4.31(m,1H),4.75-4.85(m,1H),6.33-6.38(m,2H),6.55-6.58(m,1H),7.15-7.19(m,1H),7.37-7.41(m,1H),7.64-7.68(m,1H),7.81(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 487[M+H]+。
(S)-环丙基(5-(4-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-196)
1H NMR(400MHz,CD3OD)δppm 0.63-0.71(m,1H),0.83-0.91(m,2H),0.96-1.11(m,4H),1.25-1.31(m,1H),1.66-1.78(m,2H),1.85-1.95(m,3H),2.10-2.21(m,2H),2.57-2.69(m,3H),3.02-3.08(m,2H),3.61(s,3H),4.09-4.19(m,1H),4.63-4.69(m,1H),6.57-6.61(m,2H),6.70-6.73(m,2H),7.24(d,J=8.40Hz,1H),7.51(d,J=8.40Hz,1H),7.69(s,1H),7.81(s,1H)。MS(ESI,正离子)m/z 487[M+H]+。
(S)-5-(2-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-197)
1H NMR(400MHz,CD3OD)δppm 1.04(d,J=6.40Hz,3H),1.42-1.49(m,1H),1.69-1.78(m,2H),1.90-1.99(m,3H),2.31-2.39(m,1H),2.52-2.59(m,1H),2.61-2.68(m,2H),3.05-3.11(m,2H),3.70(s,3H),3.89(s,3H),4.05-4.15(m,1H),4.46-4.58(m,1H),6.15-6.17(m,1H),6.52-6.58(m,1H),6.75-6.81(m,1H),6.96-9.99(m,1H),7.44(s,1H),7.71(s,1H),7.90(s,1H)。MS(ESI,正离子)m/z 477[M+H]+。
(S)-5-(3-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-198)
1H NMR(400MHz,CD3OD)δppm 1.15(d,J=6.40Hz,3H),1.42-1.49(m,1H),1.78-1.91(m,2H),2.01-2.13(m,3H),2.41-2.48(m,1H),7.26-2.78(m,3H),3.12-3.20(m,2H),3.7 2(s,3H),3.82(s,3H),4.18-4.28(m,1H),4.63-4.72(m,1H),6.29-6.36(m,1H),6.53-6.58(m,1H),7.10-7.17(m,1H),7.55(s,1H),7.77(s,1H),7.91(s,1H)。MS(ESI,正离子)m/z477[M+H]+。
(S)-5-(4-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-199)
1H NMR(400MHz,CD3OD)δppm 1.15(d,J=6.40Hz,3H),1.42-1.49(m,1H),1.80-1.91(m,2H),2.01-2.13(m,3H),2.41-2.48(m,1H),2.63-2.79(m,3H),3.12-3.20(m,2H),3.72(s,3H),3.81(s,3H),4.18-4.28(m,1H),4.63-4.69(m,1H),6.68-6.70(m,2H),6.80-6.80(m,2H),7.53(s,2H),7.53(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z 477[M+H]+。
(S)-2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-200)
1H NMR(300MHz,CDCl3)δppm 1.10-1.15(m,3H),1.48-1.59(m,1H),1.75-1.95(m,2H),1.96-2.12(m,3H),2.40-2.50(m,1H),2.56-2.81(m,3H),3.16-3.37(m,2H),3.81(s,3H),4.08-4.20(m,1H),4.61-4.72(m,1H),6.71-6.79(m,2H),6.89-6.95(m,1H),7.21-7.26(m,2H),7.45-7.48(m,1H),7.63-7.68(m,2H),7.72(s,1H)。MS(ESI,正离子)m/z 447[M+H]+。
(S)-1-(2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-201)
1H NMR(300MHz,CD3OD)δppm 1.14(d,J=6.60Hz,3H),1.30-1.43(m,1H),1.76-1.90(m,2H),1.97-2.11(m,2H),2.21-2.32((m,5H),2.65-2.80(m,3H),3.10-3.21(m,2H),4.15-4.29(m,1H),4.71-4.84(m,1H),6.75-6.81(m,2H),6.98(d,J=7.20Hz,1H),7.25-7.34(m,3H),7.62(d,J=6.60Hz,1H),7.80(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z 431[M+H]+。
(S)-3-(1-(环丙烷羰基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-202)
1H NMR(400MHz,CD3OD)δppm 0.76-0.83(m,1H),1.13-1.22(m,4H),1.29-1.38(m,1H),1.81-1.94(m,2H),1.96-2.10(m,3H),2.22-2.38(m,2H),2.36-2.78(m,3H),3.15-3.21(m,2H),4.24-4.31(m,1H),4.80-4.85(m,1H),7.78(s,1H),7.89(s,1H)。MS(ESI,正离子)m/z 482[M+H]+。
(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-(吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-203)
1H NMR(300MHz,CD3OD)δppm 1.11(d,J=6.60Hz,3H),1.29-1.49(m,1H),1.75-1.90(m,2H),1.92-2.01(m,2H),2.18(s,5H),2.59-2.69(m,1H),2.70-2.80(m,2H),4.15-4.26(m,1H),4.68-4.81(m,1H),6.85-6.91(m,1H),6.95-7.04(m,1H),7.21-7.33(m,1H),7.55-7.58(m,1H),7.71-7.79(m,2H),7.89(s,1H),7.97-8.04(m,1H)。MS(ESI,正离子)m/z432[M+H]+。
(S)-环丙基(8-氟-2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-204)
1H NMR(400MHz,DMSO-d6)δppm 0.63-0.95(m,4H),1.04-1.31(m,4H),1.60-1.71(m,3H),1.82-1.91(m,2H),2.11-2.23(m,2H),2.54-2.57(m,2H),2.95-3.05(m,1H),3.27-3.40(m,1H),4.60-4.71(m,1H),6.81(d,J=8.00Hz,2H),6.95-7.01(m,1H),7.25-7.32(m,2H),7.64-7.70(m,1H),7.80(s,1H),8.10(s,1H)。MS(ESI,正离子)m/z475[M+H]+。
(S)-8-氟-2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-205)
1H NMR(400MHz,CD3OD)δppm 1.18(d,J=6.40Hz,3H),1.35-1.46(m 1H),1.76-1.84(m,2H),1.96-2.05(m,2H),2.20-2.32(m,2H),2.68-2.73(m,3H),3.15-3.20(m,2H),3.79(s,3H),4.17-4.22(m,1H),4.43-4.53(m,1H),6.75-6.78(m,2H),6.95-7.00(m,1H),7.25-7.31(m,2H),7.45-7.52(m,1H),7.79(s,1H),7.97(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-1-(8-氟-2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-206)
1H NMR(400MHz,CD3OD)δppm 1.10-1.25(m,4H),1.78-1.91(m,2H),1.96-2.07(m,2H),2.10-2.20(m,3H),2.25-2.37(m,2H),2.67-2.79(m,3H),3.10-3.18(m,2H),4.18-4.18(m 1H),4.77-4.83(m,1H),6.79-6.82(m,2H),6.95-7.03(m,1H),7.25-7.30(m,2H),7.55-7.59(m,1H),7.83(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 449[M+H]+。
(S)-环丙基(8-氟-5-(3-甲氧基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-207)
1H NMR(400MHz,CD3OD)δppm 0.61-0.85(m,4H),1.02-1.11(m,4H),1.60(m,1H),2.04-2.20(m,6H),2.62-2.66(m,1H),3.03-3.10(m,2H),3.39-3.42(m,2H),3.63(s,3H),4.37-4.42(m,1H),4.60-4.67(m,1H),6.23-6.28(m,2H),6.46-6.48(m,1H),7.03-7.08(m,1H),7.40-7.42(m,1H),7.78(s,1H),7.90(s,1H)。MS(ESI,正离子)m/z 505[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3-氯-4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-208)
1H NMR(300MHz,DMSO-d6)δppm 0.99(d,J=6.45Hz,3H),1.33-1.56(m,2H),1.80-2.02(m,2H),2.22-2.40(m,2H),3.34-3.48(m,1H),3.55-3.64(m,1H),3.65(s,3H),3.69-3.84(m,1H),4.36-4.61(m,1H),4.70-4.93(m,1H),6.52-6.70(m,1H),6.87-7.04(m,1H),7.12-7.31(m,1H),7.52(s,2H),7.69-7.79(m,1H),8.06(br d,J=13.49Hz,1H)。MS(ESI,正离子)m/z 471[M+H]+。
实例39:(S)-4-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺(I-209)
步骤1.(S)-4-(1-乙酰基-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺
向配备有经空气填充的气球的100-mL圆底烧瓶中装入(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.300g,1.06mmol)、4-氨甲酰基苯基硼酸(0.437g,2.65mmol)、吡啶(1mL)、二氯甲烷(40mL)、乙酸铜(II)(0.580g,3.20mmol)和分子筛(4.0g)。在室温下搅拌所得混合物3天。过滤反应混合物,且在真空下浓缩滤液。通过制备型薄层色谱(以3:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-4-(1-乙酰基-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺(0.148g,35%)。MS(ESI,正离子)m/z403,405[M+H]+。
步骤2.(S)-4-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺
向50-mL圆底烧瓶中装入(S)-4-(1-乙酰基-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺(0.068g,0.17mmol)、1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.059g,0.25mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的复合物(0.014g,0.02mmol)、碳酸钾(0.070g,0.50mmol)、1,4-二噁烷(20mL)和水(2mL)。在100℃下搅拌所得混合物隔夜。冷却到室温后,使反应混合物通过短硅藻土衬垫,且在真空下浓缩滤液。通过制备型薄层色谱(以1:1乙酸乙酯/石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,XBridge Prep C18OBD柱,19×150mm 5μm 13nm;移动相,水(0.05%碳酸氢铵)和乙腈(在12分钟内15.0%到95%乙腈;流动速率:20mL/min);检测器,UV 254/220nm。这得到呈灰白色固体状的(S)-4-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲酰胺(0.029g,40%)。1H NMR(300MHz,CD3OD)δppm 0.93-1.03(m,4H),1.15(d,J=6.60Hz,3H,1.19-1.42(m,1H),2.18-2.27(m,5H),2.67-2.75(m,1H),3.56-3.63(m,1H),4.77-4.79(m,1H),6.85-6.88(m,2H),7.37(m,1H),7.63(d,J=8.40Hz,1H),7.77(s,1H),7.81-7.85(m,2H),7.94(s,1H)。MS(ESI,正离子)m/z 431[M+H]+。
根据上文针对实例39所概述的程序合成以下化合物:
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-210)
1H NMR(300MHz,CD3OD)δppm 0.95-1.02(m,4H),1.16(d,J=6.60Hz,3H),1.30-1.48(m,1H),2.15-2.40(m,5H),2.65-2.80(m,1H),3.55-3.65(m,1H),4.70-4.89(m,1H),6.35-6.45(m,1H),6.95-7.00(m,2H),7.15-7.25(m,1H),7.29-7.38(m,1H),7.61(d,J=8.40Hz,1H),7.79(s,1H),7.97(s,1H)。MS(ESI,正离子)m/z 406[M+H]+。
(S)-1-(5-(2-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-211)
1H NMR(400MHz,CD3OD)δppm 0.89-1.01(m,4H),1.15(d,J=6.80Hz,3H),1.30-1.45(m,1H),2.05-2.34(m,5H),2.55-2.78(m,1H),3.55-3.65(m,1H),4.68-4.88(m,1H),6.31-6.38(m,1H),6.97(t,J=7.20Hz,1H),7.07(t,J=7.20Hz,1H),7.25-7.40(m,1H),7.45-7.50(m,1H),7.58-7.65(m,1H),7.81(s,1H),7.98(s,1H)。MS(ESI,正离子)m/z 422[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-212)
1H NMR(400MHz,CD3OD)δppm 0.95-1.01(m,4H),1.13(d,J=6.80Hz,3H),1.51-1.65(m,1H),2.01-2.10(m,1H),2.35-2.45(m,1H),2.58-2.71(m,1H),3.55-3.60(m,1H),3.81(s,3H),4.58-4.62(m,1H),6.69-6.75(m,2H),6.91-7.01(m,2H),7.49-7.59(m,2H),7.74(s,1H),7.89(s,1H)。MS(ESI,正离子)m/z 422[M+H]+。
实例13-5.(S)-5-(4-氰基苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-213)
1H NMR(300MHz,CD3OD)δppm 0.97-1.01(m,4H),1.15(d,J=6.60Hz,3H),1.55-1.65(m,1H),1.98-2.15(m,1H),2.35-2.45(m,1H),2.55-2.68(m,1H),3.50-3.60(m,1H),3.83(s,3H),4.61-4.72(m,1H),6.90-6.98(m,2H),7.51-7.71(m,5H),7.89(s,1H)。MS(ESI,正离子)m/z 429[M+H]+。
(S)-5-(4-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-214)
1H NMR(300MHz,CD3OD)δppm 0.97-1.01(m,4H),1.16(d,J=6.60Hz,3H),1.50-1.68(m,1H),1.99-2.15(m,1H),2.35-2.48(m,1H),2.55-2.75(m,1H),3.52-3.62(m,1H),3.82(s,3H),4.58-4.70(m,1H),6.75-6.81(m,2H),7.20-7.28(m,2H),7.48-7.60(m,2H),7.73(s,1H),7.89(s,1H)。MS(ESI,正离子)m/z 438[M+H]+。
(S)-5-(2-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-215)
1H NMR(300MHz,CD3OD)δppm 0.90-1.01(m,4H),1.15(d,J=6.60Hz,3H),1.52-1.65(m,1H),1.99-2.10(m,1H),2.10-2.90(br m,2H),3.50-3.60(m,1H),3.81(s,3H),4.61-4.71(m,1H),6.29-6.38(m,1H),6.85-6.95(m,1H),6.98-7.05(m,1H),7.45-7.62(m,3H),7.76(s,1H),7.92(s,1H)。MS(ESI,正离子)m/z 438[M+H]+。
(S)-5-(4-氨甲酰基苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-216)
1H NMR(300MHz,CD3OD)δppm 0.89-1.05(m,4H),1.16(d,J=6.60Hz,3H),1.55-1.65(m,1H),1.98-2.15(m,1H),2.38-2.48(m,1H),2.55-2.75(m,1H),3.50-3.60(m,1H),3.83(s,3H),4.60-4.75(m,1H),6.85(d,J=8.70Hz,2H),7.50-7.62(m,2H),7.70-7.92(m,4H)。MS(ESI,正离子)m/z 447[M+H]+。
(S)-4-(1-乙酰基-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-5-基氧基)苯甲腈(I-217)
1H NMR(300MHz,CD3OD)δppm 0.93-0.99(m,4H),1.12(d,J=6.60Hz,3H),1.30-1.45(m,1H),2.10-2.30(m,5H),2.55-2.70(m,1H),3.50-3.60(m,1H),4.65-4.83(m,1H),6.93(d,J=9.00Hz,2H),7.28-7.35(m,1H),7.55-7.68(m,3H),7.71(s,1H),7.90(s,1H)。MS(ESI,正离子)m/z 413[M+H]+。
(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-5-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-218)
1H NMR(400MHz,CD3OD)δppm 0.72-0.87(m,1H),0.95-1.08(m,2H),1.11-1.22(m,4H),1.35-1.51(m,1H),1.95-2.08(m,1H),2.18-2.28(m,1H),2.29-2.39(m,1H),2.69-2.79(m,1H),4.72-4.84(m,1H),6.51-6.69(m,2H),6.71-6.82(m,2H),6.89-7.02(m,1H),7.12-7.37(m,2H),7.39-8.00(m,3H)。MS(ESI,正离子)m/z 374[M+H]+。
(S)-环丙基(2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-219)
1H NMR(300MHz,CD3OD)δppm 0.63-99(m,3H),1.03(d,J=9.90Hz,4H),1.30-1.50(m,1H),1.88-2.01(m,1H),2.01-2.18(m,1H),2.20-2.39(m,1H),2.53-2.62(m,1H),4.00(s,3H),4.58-4.79(m,1H),6.74-6.89(m,2H),6.90-7.09(m,1H),7.19-7.37(m,2H),7.42-7.54(m,1H),8.03-8.15(m,2H)。MS(ESI,正离子)m/z 389[M+H]+。
(S)-环丙基(2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-220)
1H NMR(300MHz,CD3OD)δppm 0.72-0.89(m,1H),0.92-1.09(m,2H),1.11-1.29(m,4H),1.35-1.52(m,1H),1.88-2.07(m,1H),2.08-2.27(m,1H),2.27-2.46(m,1H),2.62-2.81(m,4H),4.74-4.83(m,1H),6.71-6.98(m,2H),6.89-7.19(m,1H),7.28-7.39(m,2H),7.39-7.69(m,1H),8.21-8.39(m,1H)。MS(ESI,正离子)m/z 406[M+H]+。
(S)-环丙基(2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-221)
1H NMR(300MHz,CD3OD)δppm 0.72-0.84(m,1H),0.91-1.03(m,2H),1.08-1.19(m,4H),1.29-1.44(m,1H),1.88-2.07(m,1H),2.13-2.33(m,2H),2.62-2.76(m,1H),3.64(s,3H),4.76-4.83(m,1H),6.74-6.79(m,2H),6.86-7.06(m,1H),7.20-7.37(m,3H),7.38-7.47(m,1H),7.61(s,1H),7.76-8.02(m,1H)。MS(ESI,正离子)m/z 388[M+H]+。
(2S)-6-(1-(1,1-二氧离子基四氢-2H-硫代吡喃-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-222)
MS(ESI,正离子)m/z 514[M+H]+。
(S)-6-(1-(1,1-二氧离子基硫杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-223)
MS(ESI,正离子)m/z 486[M+H]+。
(S)-环丙基(2-甲基-6-(1-甲基-1H-吡唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-224)
1H NMR(400MHz,CDCl3)δppm 0.75-0.88(m,1H),0.93-1.04(m,2H),1.11-1.23(m,4H),1.38-1.52(m,1H),1.95-2.08(m,1H),2.17-2.29(m,1H),2.29-2.38(m,1H),2.66-2.81(m,1H),4.72-4.86(m,1H),6.69-6.89(m,2H),6.96-7.12(m,1H),7.22-7.37(m,2H),7.45-7.54(m,1H),8.03(s,1H),8.00-8.14(m,1H)。MS(ESI,正离子)m/z 388[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-225)
1H NMR(300MHz,CD3OD)δppm 1.00-1.03(m,4H),1.14(d,J=6.30Hz,3H),1.36-1.38(m,1H),2.19-2.24(m,5H),2.66-2.76(m,1H),3.57-3.64(m,1H),4.77(m,1H),6.75-6.81(m,2H),6.97-7.04(m,2H),7.32(m,1H),7.61(d,J=8.40Hz,1H),7.75(s,1H),7.91(s,1H)。MS(ESI,正离子)m/z 406[M+H]+。
(S)-1-(5-(4-氯苯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-226)
1H NMR(300MHz,CD3OD)δ0.89-0.94(m,4H),1.15(d,J=6.60Hz,3H),1.34-1.44(m,1H),2.26-2.34(m,5H),2.60-2.65(m,1H),4.70(m,1H),6.75(d,J=8.40Hz,2H),7.35(m,1H),7.60(d,J=8.40Hz,1H),7.75(s,1H),7.91(s,1H)。MS(ESI,正离子)m/z422[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-227)
1H NMR(300MHz,CD3OD)δppm 0.73-0.82(m,1H),0.90-1.01(m,2H),1.11-1.21(m,4H),1.25-1.31(m,1H),1.31-1.44(m,1H),1.93-2.09(m,1H),2.13-2.45(m,2H),2.68-2.77(m,1H),4.73-4.81(m,1H),6.79(d,J=7.80Hz,2H),6.95-7.02(m,1H),7.28-7.33(m,2H),7.39(d,J=8.40Hz,1H),7.66(d,J=8.40Hz,1H),7.91(s,2H)。MS(ESI,正离子)m/z 374[M+H]+。
3-[4-[(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]-1λ6-硫杂环丁烷-1,1-二酮(I-229)
1H NMR(400MHz,CD3OD)δppm 0.92-1.01(m,2H),1.12-1.23(m,4H),1.37-1.46(m,1H),1.96-2.05(m,1H),2.11-2.36(m,2H),2.65-2.78(m,1H),4.56-4.79(m,4H),4.73-4.83(m,1H),5.22-5.34(m,1H),6.75-6.81(m,2H),6.95-7.06(m,2H),7.40(d,J=8.40Hz,1H),7.63(d,J=8.80Hz,1H),7.92(s,1H),8.12(s,1H)。MS(ESI,正离子)m/z 524[M+H]+。
3-[4-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]-1λ6-硫杂环丁烷-1,1-二酮(I-230)
1H NMR(300MHz,CD3OD)δppm 0.64-0.81(m,1H),0.89-1.02(m,2H),1.12-1.22(m,4H),1.33-1.45(m,1H),1.92-2.05(m,1H),2.15-4.41(m,2H),2.63-2.77(m,1H),4.54-4.63(m,4H),4.75-4.79(m,1H),5.25-5.34(m,1H),6.79(d,J=7.80Hz,2H),6.95-7.04(m,1H),7.25-7.29(m,2H),7.35-7.42(m,1H),7.63(d,J=8.40Hz,1H),7.90(s,1H),8.11(s,1H)。MS(ESI,正离子)m/z 478[M+H]+。
(S)-环丙基(6-(异噁唑-4-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-231)
1H NMR(400MHz,CD3OD)δppm 0.75-0.82(m,1H),0.85-1.14(m,2H),1.11-1.25(m,4H),1.40-1.49(m,1H),1.95-2.08(m,1H),2.15-2.34(m,2H),2.67-2.76(m,1H),4.77-4.85(m,1H),6.78-6.81(m,2H),6.99-7.04(m,1H),7.25-7.35(m,2H),7.45-7.53(m,1H),7.66-7.71(m,1H),8.78(s,1H),8.88(s,1H)。MS(ESI,正离子)m/z 375[M+H]+。
(S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-232)
1H NMR(400MHz,CD3OD)δppm 1.04(d,J=6.40Hz,3H),1.39-1.43(m,1H),1.81-2.02(m,1H),2.25-2.42(m,1H),2.45-2.62(m,1H),3.71(s,1H),3.92(s,2H),4.42-4.65(m,1H),6.68(d,J=8.00Hz,2H),6.88(t,J=7.20Hz,1H),7.16-7.13(m,2H),7.55(d,J=8.80Hz,1H),7.88(t,J=6.40Hz,2H)。MS(ESI,正离子)m/z 379[M+H]+。
(S)-1-(2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-233)
1H NMR(300MHz,CD3OD)δppm 1.16(d,J=6.60Hz,3H),1.30-1.40(m,1H),2.15-2.26(m,5H),2.64-2.74(m,1H),4.04(s,3H),4.76-4.80(m,1H),6.80-6.83(m,2H),6.99-7.02(m,1H),7.24-7.30(m,2H),7.41-7.43(m,1H),8.01(s,1H),8.08(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z 363[M+H]+。
(S)-环丙基(5-(3-甲氧基苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-234)
1H NMR(400MHz,CD3OD)δppm 0.70-0.80(m,1H),0.89-1.02(m,2H),1.13-1.20(m,4H),1.30-1.45(m,1H),1.98-2.05(m,1H),2.15-2.35(m,2H),2.70-2.75(m,1H),3.75(s,3H),4.06(s,3H),4.79-4.83(m,1H),6.33-6.37(m,1H),6.41-6.43(m,1H),6.57-6.61(m,1H),7.14-7.19(m,1H),7.48(d,J=8.40Hz,1H),8.00(s,1H),8.07(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z 419[M+H]+。
(S)-环丙基(5-(3-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-235)
1H NMR(400MHz,CD3OD)δppm 0.75-0.83(m,1H),0.89-1.05(m,2H),1.10-1.25(m,4H),1.35-1.45(m,1H),1.95-2.05(m,1H),2.15-2.48(m,2H),2.65-2.75(m,1H),4.06(s,3H),4.75-4.85(m,1H),6.55-6.67(m,2H),6.69-6.77(m,1H),7.09-7.27(m,1H),7.51(d,J=8.70Hz,1H),8.04(s,1H),8.07(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z 407[M+H]+。
(S)-环丙基(5-(4-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-236)
1H NMR(300MHz,CD3OD)δppm 0.72-0.82(m,1H),0.87-1.02(m,2H),1.08-1.21(m,4H),1.37-1.48(m,1H),1.95-2.05(m,1H),2.15-2.36(m,2H),2.65-2.78(m,1H),4.71-4.85(m,1H),6.75-6.83(m,2H),6.95-7.05(m,2H),7.48(d,J=8.40Hz,1H),8.03(s,1H),8.07(d,J=8.70Hz,1H)。MS(ESI,正离子)m/z 407[M+H]+。
(S)-环丙基(6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-237)
1H NMR(300MHz,DMSO-d6)δppm 0.63-0.72(m,1H),0.83-0.99(m,5H),1.04-1.31(m,4H),1.60-1.71(m,3H),2.11-2.33(m,2H),2.68-2.77(m,1H),3.52-3.59(m,1H),4.71-4.78(m,1H),6.73-6.78(m,2H),6.95-7.01(m,1H),7.25-7.32(m,2H),7.45-7.55(m,1H),7.75(s,1H),7.92(s,1H)。MS(ESI,正离子)m/z 432[M+H]+。
(S)-环丙基(8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-238)
1H NMR(300MHz,DMSO-d6)δppm 0.69-0.80(m,1H),0.91-1.08(m,3H),1.10-1.36(m,4H),1.70-1.80(m,1H),2.11-2.33(m,2H),2.71-2.79(m,1H),4.73-4.80(m,1H),6.76-6.82(m,2H),6.95-7.03(m,1H),7.25-7.32(m,2H),7.51-7.62(m,1H),7.93(s,1H)。MS(ESI,正离子)m/z 392[M+H]+。
(S)-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-239)
1H NMR(400MHz,CD3OD)δppm 0.95-1.01(m,4H),1.18(d,J=6.40Hz,3H),1.35-1.46(m 1H),2.20-2.32(m,2H),2.68-2.73(m,1H),3.55-3.62(m,1H),3.79(s,3H),4.43-4.53(m,1H),6.75-6.78(m,2H),6.95-7.02(m,1H),7.25-7.29(m,2H),7.41-7.45(m,1H),7.77(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z 422[M+H]+。
(S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-240)
1H NMR(400MHz,CD3OD)δppm 1.19(d,J=6.40Hz,3H),1.35-1.46(m 1H),2.20-2.32(m,2H),2.68-2.73(m,1H),3.79(s,3H),4.46-4.53(m,1H),6.77-6.79(m,2H),6.95-7.02(m,1H),7.25-7.29(m,2H),7.42-7.45(m,1H),7.91(br s,2H)。MS(ESI,正离子)m/z382[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-241)
1H NMR(300MHz,CD3OD)δppm 0.95-1.02(m,4H),1.10-1.23(m,4H),2.16-2.15(m,3H),2.24-2.37(m,2H),2.68-2.80(m,1H),3.55-3.64(m,1H),4.76-4.85(m,1H),6.77-6.82(m,2H),6.95-7.03(m,1H),7.25-7.33(m,2H),7.49-7.54(m,1H),7.81(s,1H),7.98(s,1H)。MS(ESI,正离子)m/z 406[M+H]+。
(S)-1-(8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-242)
1H NMR(300MHz,CD3OD)δppm 1.09-1.30(m,4H),2.11-2.37(m,5H),2.71-2.81(m,1H),4.75-4.85(m,1H),6.81(d,J=7.80Hz,2H),7.00(t,J=7.20Hz,1H),7.29(t,J=8.10Hz,2H),7.57(d,J=10.80Hz,2H),7.95(s,2H)。MS(ESI,正离子)m/z 366[M+H]+。
(S)-环丙基(6-环丙基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-243)
1H NMR(300MHz,CDCl3)δppm 0.57-0.72(m,3H),0.79-0.91(m,3H),1.91-2.03(m,1H),1.09(d,J=6.60Hz,3H),1.25-1.31(m,1H),1.32-1.34(m,1H),1.84-1.91(m,2H),2.13-2.21(m,1H),2.25-2.37(m,1H),2.66-2.75(m,1H),4.78-4.65(m,1H),6.73-6.81(m,3H),6.95-7.04(m,1H),7.19(d,J=7.80Hz,1H),7.26-7.33(m,2H)。MS(ESI,正离子)m/z348[M+H]+。
(S)-6-环丙基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-244)
1H NMR(400MHz,CD3OD)δppm 0.55-0.60(m,2H),0.62-0.77(m,2H),1.11(d,J=6.60Hz,3H),1.49-1.59(m,1H),1.82-1.88(m,1H),2.00-2.07(m,1H),2.39-2.49(m,1H),2.58-2.67(m,1H),3.79(s,3H),4.62-4.68(m,1H),6.73-6.80(m,3H),6.95-7.00(m,1H),7.23-7.26(m,1H),7.25-7.27(m,1H),7.43(d,J=8.70Hz,1H)。MS(ESI,正离子)m/z338[M+H]+。
实例40:(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-245)
将甲醛(37%水溶液,0.015mL,0.198mmol)添加到(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.010g,0.020mmol)于甲醇(1.0mL)中的溶液中,且搅拌反应混合物2小时。冷却混合物到0℃,且添加三乙酰氧基硼氢化钠(8.4mg,0.040mmol)。在0℃下搅拌反应混合物,且使其升温到室温隔夜。将反应混合物分配于乙酸乙酯与水之间。用乙酸乙酯萃取水相,且用盐水洗涤经合并的有机相,经无水硫酸钠干燥,过滤且浓缩,得到呈白色固体状的(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.0095g,92%)。1H NMR(300MHz,DMSO-d6)δppm 1.06(br d,J=6.74Hz,3H),1.47-1.69(m,4H),1.71-2.13(m,4H),2.19(s,3H),2.71-2.90(m,2H),3.72(s,3H),3.93-4.13(m,1H),4.32-4.45(m,1H),4.50-4.65(m,1H),6.35-6.54(m,1H),7.45-7.65(m,4H),7.65-7.72(m,1H),7.97(s,1H),8.11(d,J=2.64Hz,1H)。MS(ESI,正离子)m/z521[M+H]+。
实例41:(S)-2-((1-乙酰基-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基)氧基)苯甲腈(I-246)
将(S)-2-((1-乙酰基-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-基)氧基)苯甲腈(0.017g,0.044mmol)、1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶(0.030g,0.101mmol)、XPhos第2代预催化剂(3.47mg,4.41μmol)和碳酸铯(0.058g,0.177mmol)于二噁烷(2.0mL)和水(0.400mL)中的混合物在100℃下加热16小时。经硅藻土过滤反应混合物且浓缩,得到橙色油状物。经硅胶柱色谱(Biotage 25g柱,以0-50%(90:10:1二氯甲烷/甲醇/氢氧化铵)-二氯甲烷进行梯度洗提)纯化这一物质,得到呈白色固体状的(S)-2-((1-乙酰基-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-5-基)氧基)苯甲腈(0.017g,82%)。1H NMR(300MHz,DMSO-d6)δppm 1.04(d,J=7.04Hz,3H),1.27-1.58(m,2H),1.77-1.97(m,4H),1.97-2.14(m,4H),2.17(s,3H),2.19(s,3H),2.81(br d,J=11.43Hz,2H),3.90-4.17(m,1H),4.62(br s,1H),6.48(br s,1H),7.14(t,J=7.62Hz,1H),7.39-7.56(m,2H),7.61(d,J=8.50Hz,1H),7.72(s,1H),7.89(dd,J=7.77,1.61Hz,1H),8.01(s,1H)。MS(ESI,正离子)m/z 470[M+H]+。
实例42:(2S)-5-环丁氧基-2-甲基-6-(1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-247)
根据上文针对实例40所概述的程序,自(2S)-5-环丁氧基-2-甲基-6-(1-(吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯合成(2S)-5-环丁氧基-2-甲基-6-(1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δppm 1.17(d,J=6.40Hz,3H),1.25-1.48(m,2H),1.55-1.65(m,1H),1.99-2.20(m,4H),2.21-2.28(m,1H),2.30-2.50(m,2H),2.75-2.99(m,2H),3.01-3.20(m,3H),3.30-3.40(m,1H),3.55-3.72(m,1H),3.78(s,3H),3.90-4.05(m,2H),4.10-4.25(m,1H),4.48-4.60(m,1H),7.20-7.30(m,2H),7.95(s,1H),8.09(s,1H)。MS(ESI,正离子)m/z425[M+H]+。
实例43:(2S)-5-环丁氧基-2-甲基-6-(1-(2-甲基-八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-248)
根据上文针对实例40所概述的程序,自(2S)-5-环丁氧基-2-甲基-6-(1-(八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯合成(2S)-5-环丁氧基-2-甲基-6-(1-(2-甲基-八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯。1HNMR(400MHz,CD3OD)1.17(d,J=6.40Hz,3H),1.28-1.48(m,2H),1.55-1.70(m,1H),1.99-2.20(m,6H),2.21-2.50(m,9H),2.79-2.98(m,5H),3.78(s,3H),4.05-4.15(m,1H),4.45-4.55(m,1H),4.85-4.95(m,1H),7.20-7.30(m,2H),7.83(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
实例44:(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-249)
根据上文针对实例40所概述的程序,自(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯合成(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯。1HNMR(400MHz,CD3OD)δppm 1.15(d,J=6.40Hz,3H),1.48-1.65(m,1H),2.01-2.10(m,1H),2.12-2.23(m,1H),2.38-2.45(m,1H),2.55-2.85(m,2H),2.92-3.05(m,3H),3.20-3.30(m,1H),3.40-4.60(m,1H),3.82(s,3H),3.89-3.95(m,2H),4.58-4.65(m,1H),5.15-5.25(m,1H),6.68-6.74(m,2H),6.95-7.02(m,2H),7.48-6.60(m,2H),7.89(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 465[M+H]+。
实例45:(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-甲基-八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-250)
根据上文针对实例40所概述的程序,自(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯合成(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-甲基-八氢环戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3OD)δppm 1.14(d,J=6.60Hz,3H),1.50-1.62(m,1H),1.85-1.99(m,2H),2.01-2.20(m,3H),2.25-2.45(m,6H),2.55-2.75(m,5H),4.55-4.70(m,1H),4.70-4.82(m,1H),6.65-6.75(m,2H),6.90-7.02(m,2H),7.48-7.52(m,2H),7.75(s,1H),7.89(s,1H)。MS(ESI,正离子)m/z 505[M+H]+。
实例46:(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(1-乙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-251)
根据上文针对实例40所概述的程序,自(S)-5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯和乙醛合成(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(1-乙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δppm 0.96(t,J=7.20Hz,3H),1.05-1.20(m,7H),1.42-1.55(m,1H),2.15-2.25(m,1H),2.40-2.52(m,3H),2.81-2.95(m,1H),3.01-3.15(m,2H),3.41-3.52(m,2H),3.68-3.71(m,1H),3.78(s,3H),4.21-4.28(m,1H),4.51-4.61(m,1H),7.20-7.32(m,2H),7.76(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 411[M+H]+。
实例47:(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(1-异丙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-252)
根据上文针对实例40所概述的程序,自(S)-5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯和丙酮合成(S)-6-(1-环丙基-1H-吡唑-4-基)-5-(1-异丙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1HNMR(400MHz,CD3OD)δppm 0.85-0.95(m,6H),1.05-1.15(m,7H),1.45-1.55(m,1H),2.15-2.52(m,3H),2.80-2.90(m,1H),3.01-3.11(m,2H),3.40-3.50(m,2H),3.67-3.71(m,1H),3.78(s,3H),4.15-4.25(m,1H),4.51-4.62(m,1H),7.20-7.35(m,2H),7.76(s,1H),7.97(s,1H)。MS(ESI,正离子)m/z 425[M+H]+。
实例48:(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(1-乙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-253)
根据上文针对实例40所概述的程序,自(S)-1-(5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮和乙醛合成(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(1-乙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮。1H NMR(400MHz,CD3OD)δppm 0.97(t,J=7.20Hz,3H),1.05-1.18(m,7H),1.10-1.35(m,1H),2.16(s,3H),2.20-2.40(m,2H),2.51(q,J=7.20Hz,2H),2.88-2.98(m,1H),3.07(t,J=7.20Hz,1H),3.15(t,J=7.20Hz,1H),3.41-3.55(m,2H),3.68-3.75(m,1H),4.25-4.32(m,1H),4.65-4.80(m,1H),7.01-7.12(m,1H),7.37(d,J=8.00Hz,1H),7.81(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 395[M+H]+。
实例49:(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(1-异丙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-254)
根据上文针对实例40所概述的程序,自(S)-1-(5-(氮杂环丁烷-3-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮和丙酮合成(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(1-异丙基氮杂环丁烷-3-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮。1HNMR(400MHz,CD3OD)δppm 0.89-1.01(m,6H),1.01-1.15(m,7H),1.21-1.35(m,1H),2.16(s,3H),2.25-2.45(m,3H),2.85-2.95(m,1H),3.06(t,J=7.20Hz,1H),3.15(t,J=7.20Hz,1H),3.41-3.55(m,2H),3.68-3.73(m,1H),4.21-4.29(m,1H),4.65-4.81(m,1H),7.01-7.12(m,1H),7.36(d,J=8.00Hz,1H),7.81(s,1H),8.03(s,1H)。MS(ESI,正离子)m/z 409[M+H]+。
实例50:1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮(I-255)
步骤1. 1-[(2S)-6-溴-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮
向20-mL微波管中装入1-[(2S)-6-溴-5-羟基-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(200mg,0.70mmol)、2-氯-4-甲基吡啶(180mg,1.41mmol)、N,N-二甲基甲酰胺(15mL)、碘化铜(I)(133mg,0.70mmol)和碳酸铯(700mg,2.10mmol)。在120℃下于微波辐射下加热反应混合物8小时。冷却到室温后,用乙酸乙酯(50mL)稀释所得混合物,用水(3×15mL)和盐水(15mL)洗涤,经无水硫酸钠干燥,过滤且浓缩。经硅胶柱色谱(以2:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色固体状的1-[(2S)-6-溴-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮(111mg,42%)。MS(ESI,正离子)m/z 375,377[M+H]+。
步骤2. 1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮
用惰性氮气气氛净化并维持50-mL圆底烧瓶,且装入1-[(2S)-6-溴-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮(111mg,0.30mmol)、1,4-二噁烷(15mL)、1-环丙基-4-(四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(139mg,0.59mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(30mg,0.04mmol)、碳酸钾(124mg,0.90mmol)和水(5mL)。在100℃下搅拌所得混合物隔夜。冷却到室温后,用乙酸乙酯(10mL)稀释溶液。分离水层,且用乙酸乙酯(2×20mL)萃取。用盐水洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1:1乙酸乙酯/石油醚洗提)纯化残余物。合并所收集的洗提份,且在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)进一步纯化粗产物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在7分钟内65%到85%乙腈,流动速率20mL/min);检测器,UV 220和254nm。这得到呈灰白色固体状的1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮(63.6mg,53%)。1H NMR(300MHz,CD3OD)δppm 0.95-1.01(m,4H),1.14(d,J=6.30Hz,3H),1.30-1.45(m,1H),2.10-2.30(m,5H),2.34(s,3H),2.55-2.70(m,1H),3.55-3.65(m,1H),4.68-4.85(m,1H),6.75(s,1H),6.85-6.95(m,1H),7.20-7.32(m,1H),7.55-7.58(m,1H),7.72(s,1H),7.89-7.93(m,2H)。MS(ESI,正离子)m/z 403[M+H]+。
根据针对实例50所概述的程序制得以下实例:
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(6-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-256)
1H NMR(300MHz,CD3OD)δppm 0.91-0.99(m,4H),1.12(d,J=6.60Hz,3H),1.25-1.45(m,1H),2.10-2.30(m,5H),2.37(s,3H),2.55-2.68(m,1H),3.55-3.62(m,1H),4.65-4.83(m,1H),6.45(d,J=8.40Hz,1H),6.89(d,J=7.50Hz,1H),7.20-7.35(m,1H),7.50-7.62(m,2H),7.73(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z 403[M+H]+。
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-5-(异喹啉-1-基氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-257)
1H NMR(300MHz,CD3OD)δppm 0.68-0.71(m,2H),0.83-0.90(m,2H),1.19(d,J=6.60Hz,3H),1.46(m,1H),2.18-2.31(m,5H),2.67(m,1H),3.43-3.48(m,1H),4.75-4.80(m,1H),7.36-7.44(m,1H),7.57(d,J=4.80Hz,1H),7.60-7.67(m,1H),7.74(s,1H),7.76-7.79(m,1H),7.89(m,3H),7.91-7.98(m,1H),8.61(d,J=8.10Hz,1H)。MS(ESI,正离子)m/z 439[M+H]+。
实例51:(S)-1-(5-(2-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-258)
步骤1. 1-[(2S)-6-溴-5-(2-氟-4-硝基苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮
用惰性氮气气氛净化并维持50-mL圆底烧瓶,且装入1-[(2S)-6-溴-5-羟基-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(350mg,1.23mmol)、N,N-二甲基甲酰胺(10mL)、1,2-二氟-4-硝基苯(415mg,2.61mmol)和碳酸铯(1.3g,3.99mmol)。在110℃下搅拌所得混合物3小时。冷却到室温后,将反应混合物倒入二氯甲烷(50mL)中,用水(10mL)和盐水(10mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以5:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的1-[(2S)-6-溴-5-(2-氟-4-硝基苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(450mg,86%)。MS(ESI,负离子)m/z 421,423[M-H]。
步骤2. 1-[(2S)-5-(4-氨基-2-氟苯氧基)-6-溴-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮
用惰性氮气气氛净化并维持100-mL圆底烧瓶,且装入1-[(2S)-6-溴-5-(2-氟-4-硝基苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(500mg,1.18mmol)、铁粉(331mg,5.91mmol)、氯化铵(128mg,2.37mmol)、四氢呋喃(9mL)、乙醇(3mL)和水(9mL)。在80℃下搅拌所得混合物12小时,接着过滤。浓缩滤液,且用乙酸乙酯稀释残余物,用水洗涤,经无水硫酸钠干燥,过滤且浓缩,得到呈淡棕色固体状的1-[(2S)-5-(4-氨基-2-氟苯氧基)-6-溴-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(370mg,80%)。MS(ESI,正离子)m/z393,395[M+H]+。
步骤3. 1-[(2S)-6-溴-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮
向100-mL圆底烧瓶中装入1-[(2S)-5-(4-氨基-2-氟苯氧基)-6-溴-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(370mg,0.92mmol)和乙酸(5mL)。分数份添加亚硝酸钠(1.3g,18.8mmol),且在室温下搅拌混合物30分钟。添加亚硫酸氢钠(2.0g,18.8mmol)和乙醇(5mL),且在室温下搅拌所得混合物12小时。在真空下浓缩反应混合物,用二氯甲烷稀释,用水和盐水洗涤,经无水硫酸钠干燥,过滤且浓缩。经硅胶柱色谱(以5:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的1-[(2S)-6-溴-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(300mg,86%)。MS(ESI,正离子)m/z 378,380[M+H]+。
步骤4.(S)-4-(4-(1-乙酰基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
用惰性氮气气氛净化并维持100-mL圆底烧瓶,且装入1-[(2S)-6-溴-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(300mg,0.79mmol)、1,4-二噁烷(18mL)、水(3mL)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(65mg,0.08mmol)、碳酸铯(776mg,2.37mmol)和4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(378mg,1.00mmol)。在80℃下搅拌所得混合物12小时。冷却到室温后,使反应混合物通过短硅藻土衬垫,且在真空下浓缩。经硅胶柱色谱(以5:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-4-(4-(1-乙酰基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(370mg,85%)。MS(ESI,正离子)m/z 549[M+H]+。
步骤5.(S)-1-(5-(2-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮
向100-mL圆底烧瓶中装入(S)-4-(4-(1-乙酰基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(370mg,0.67mmol)、二氯甲烷(10mL)和三氟乙酸(4mL)。在室温下搅拌所得溶液2小时。用饱和碳酸钾水溶液将溶液的pH值调整到8。用乙酸乙酯萃取所得混合物。合并有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以5:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈白色固体状的(S)-1-(5-(2-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(141mg,47%)。1H NMR(300MHz,CD3OD)δppm 1.15(d,J=6.60Hz,3H),1.25-1.45(m,1H),1.75-1.95(m,2H),1.97-2.08(m,2H),2.15-2.35(m,5H),2.65-2.89(m,3H),3.09-3.20(m,2H),4.15-4.29(m,1H),4.65-4.85(m,1H),6.35-6.48(m,1H),6.85-6.98(m,2H),7.13-7.22(m,1H),7.27-7.42(m,1H),7.61(d,J=8.40Hz,1H),7.81(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z 449[M+H]+。
根据针对实例51所概述的程序制得以下实例:
(S)-5-(2-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-259)
1H NMR(400MHz,CD3OD)δppm 1.17(d,J=6.80Hz,3H),1.55-1.68(m,1H),1.78-1.92(m,2H),1.97-2.13(m,3H),2.45-2.55(m,1H),2.60-2.79(m,3H),3.11-3.18(m,2H),4.18-4.25(m,1H),4.62-4.70(m,1H),6.38-6.42(m,1H),6.85-6.95(m,2H),7.15-7.25(m,1H),7.50-7.62(m,2H),7.78(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z465[M+H]+。
(S)-环丙基(5-(2-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-260)
1H NMR(400MHz,CD3OD)δppm 0.75-0.85(m,1H),8.87-1.01(m,2H),1.10-1.20(m,4H),1.39-1.50(m,1H),1.78-1.90(m,2H),1.95-2.09(m,3H),2.15-2.38(m,2H),2.65-2.80(m,3H),3.11-3.19(m,2H),4.18-4.28(m,1H),4.75-4.85(m,1H),6.41-6.48(m,1H),6.85-6.99(m,2H),7.18-7.28(m,1H),7.42(d,J=8.40Hz,1H),7.63(d,J=8.80Hz,1H),7.81(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 475[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-261)
1H NMR(400MHz,CD3OD)δppm 1.16(d,J=6.40Hz,3H),1.55-1.64(m,1H),2.05-2.14(m,1H),2.45-2.52(m,1H),2.63-2.72(m,1H),3.82(s,3H),3.90-3.98(m,2H),4.03-4.11(m,2H),4.63-4.73(m,1H),5.19-5.29(m,1H),6.35-6.42(m,1H),6.83-6.95(m,2H),7.17-7.25(m,1H),7.20-7.25(m,1H),7.53-7.62(m,2H),7.65-7.70(m,1H),8.03(s,1H)。MS(ESI,正离子)m/z 437[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-262)
1H NMR(400MHz,CD3OD)δppm 0.60-0.70(m,1H),0.75-0.90(m,2H),1.00-1.10(m,4H),1.20-1.30(m,1H),1.80-1.92(m,1H),2.05-2.25(m,2H),2.55-2.65(m,1H),3.72-3.80(m,2H),3.85-3.95(m,2H),4.65-4.75(m,1H),5.05-5.15(m,1H),6.25-6.35(m,1H),6.70-6.90(m,2H),7.05-7.15(m,1H),7.30(d,J=8.40Hz,1H),7.51(d,J=8.40Hz,1H),7.78(s,1H),7.95(s,1H)。MS(ESI,正离子)m/z 447[M+H]+。
根据上文针对实例51所概述的程序制得以下实例,对步骤1作出以下改变:(1)使用1,2,5-三氟-3-硝基苯替代1,2-二氟-4-硝基苯;(2)使用叔丁醇钾替代碳酸铯;(3)使用四氢呋喃作为溶剂替代DMF;(4)与在110℃下3小时相对比,反应在0℃下进行1小时。
(S)-5-(2,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-263)
1H NMR(400MHz,CDCl3)δppm 1.15(d,J=6.80Hz,3H),1.55-1.65(m,1H),1.80-1.95(m,2H),2.01-2.15(m,3H),2.35-2.45(m,1H),2.60-2.80(m,3H),3.20-3.30(m,2H),4.08-4.20(m,1H),4.60-4.70(m,1H),6.30-6.40(m,1H),6.50-6.60(m,1H),6.85-6.95(m,1H),7.41(d,J=8.80Hz,1H),7.60(d,J=8.40Hz,1H),7.69-7.62(m,2H)。MS(ESI,正离子)m/z 483[M+H]+。
(S)-环丙基(5-(2,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-264)
1H NMR(400MHz,CD3OD)δppm 0.70-0.80(m,1H),0.89-1.03(m,2H),1.09-1.20(m,4H),1.35-1.45(m,1H),1.80-2.10(m,5H),2.15-2.40(m,2H),2.68-2.80(m,3H),3.10-3.20(m,2H),4.20-4.30(m,1H),4.75-4.85(m,1H),6.40-6.50(m,1H),6.70-6.80(m,1H),7.05-7.12(m,1H),7.42(d,J=8.40Hz,1H),7.61(d,J=8.80Hz,1H),7.80(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 493[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-265)
1H NMR(400MHz,CD3OD)δppm 0.70-0.82(m,1H),0.89-1.02(m,2H),1.10-1.22(m,3H),1.40-1.52(m,1H),1.95-2.05(m,1H),2.15-2.42(m,2H),2.68-2.80(m,1H),3.65-3.85(m,2H),4.10-4.30(m,2H),4.75-4.85(m,1H),4.90-5.05(m,1H),6.40-6.50(m,1H),6.65-6.75(m,1H),7.05-7.15(m,1H),7.43(d,J=8.40Hz,1H),7.55-7.65(m,1H),7.80-8.10(m,2H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-266)
1H NMR(400MHz,CD3OD)δppm 1.17(d,J=6.40Hz,3H),1.56-1.66(m,1H),2.07-2.15(m,1H),2.45-2.51(m,1H),2.63-2.71(m,1H),3.82(s,3H),3.92-3.97(m,2H),4.06-4.12(m,2H),4.65-4.71(m,1H),7.51-7.56(m,1H),7.57-7.64(m,1H),7.85(m,1H),8.05(s,1H)。MS(ESI,正离子)m/z 455[M+H]+。
根据上文针对实例51所概述的程序制得以下实例,对步骤1作出以下改变:(1)使用1,2,3-三氟-4-硝基苯替代1,2-二氟-4-硝基苯;(2)使用叔丁醇钾替代碳酸铯;(3)使用四氢呋喃作为溶剂替代DMF;(4)与在110℃下3小时相对比,反应在0℃下进行1小时。
(S)-环丙基(5-(2,3-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-267)
1H NMR(400MHz,CD3OD)δppm 0.75-0.80(m,1H),0.85-1.01(m,2H),1.10-1.21(m,4H),1.40-1.50(m,1H),1.80-2.10(m,5H),2.15-2.40(m,2H),2.68-2.82(m,3H),3.10-3.25(m,2H),4.20-4.34(m,1H),4.75-4.85(m,1H),6.20-6.30(m,1H),6.80-6.95(m,2H),7.44(d,J=8.40Hz,1H),7.62(d,J=8.40Hz,1H),7.79(s,1H),7.99(s,1H)。MS(ESI,正离子)m/z493[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2,3-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-268)
1H NMR(400MHz,CD3OD)δppm 0.72-0.80(m,1H),0.85-1.01(m,2H),1.10-1.20(m,4H),1.40-1.52(m,1H),1.95-2.05(m,1H),2.15-2.45(m,2H),2.65-2.80(m,1H),3.60-3.82(m,1H),3.85-4.12(m,3H),4.75-4.85(m,1H),5.15-5.30(m,1H),6.20-6.30(m,1H),6.82-6.95(m,2H),7.44(d,J=8.80Hz,1H),7.62(d,J=8.40Hz,1H),7.80-7.90(m,1H),8.02-8.12(m,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-5-(2,3-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-269)
1H NMR(400MHz,CD3OD)1.05(d,J=6.80Hz,3H),1.55-1.65(m,1H),1.65-1.80(m,2H),1.85-2.05(m,3H),2.30-2.42(m,1H),2.50-2.65(m,3H),3.01-3.10(m,2H),3.71(s,1H),4.05-4.15(m,1H),4.52-4.62(m,1H),6.05-6.15(M,1H),6.68-6.78(m,2H),7.41(d,J=8.80Hz,1H),7.51(d,J=8.80Hz,1H),7.64(s,1H),7.83(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2,3-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-270)
1H NMR(400MHz,CD3OD)δppm 1.09(d,J=6.40Hz,3H),1.60-1.66(m,1H),2.08-2.13(m,1H),2.46-2.52(m,1H),2.63-2.71(m,1H),3.82(s,3H),3.92-3.98(m,2H),4.06-4.13(m,2H),4.64-4.71(m,1H),5.21-5.28(m,1H),6.21-6.28(m,1H),6.84-6.91(m,2H),7.54(d,J=8.80Hz,1H),7.63(d,J=8.40Hz,1H),7.85(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 455[M+H]+。
根据上文针对实例51所概述的程序制得以下实例,对步骤1作出以下改变:(1)使用1,2,4-三氟-5-硝基苯替代1,2-二氟-4-硝基苯;(2)使用叔丁醇钾替代碳酸铯;(3)使用四氢呋喃作为溶剂替代DMF;(4)与在110℃下3小时相对比,反应在0℃下进行1小时。
(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-271)
1H NMR(300MHz,DMSO-d6)δppm 0.98-1.16(m,3H),1.49-1.55(m,1H),1.95-2.06(m,1H),2.36-2.44(m,2H),3.61-3.68(m,2H),3.69-3.75(m 3H),3.77-3.85(m,2H),4.46(m,1H),5.02-5.20(m,1H),6.35-6.61(m,1H),6.85-7.11(m,1H),7.18-7.43(m,1H),7.58(s,2H),7.79(s,1H),8.13(s,1H)。MS(ESI,正离子)m/z 455[M+H]+。
(S)-(6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-272)
1H NMR(400MHz,CD3OD)δppm 0.59-0.72(m,1H),0.82-0.93(m,2H),1.02-1.09(m,4H),1.30-1.43(m,1H),1.88-1.95(m,1H),2.13-2.23(m,1H),2.60-2.70(m,1H),3.53-3.69(m,1H),3.82-4.05(m,3H),4.69-4.74(m,1H),5.13-5.19(m,1H),6.03-6.11(m,1H),7.08-7.19(m,1H),7.34-7.38(m,1H),7.50-7.55(m,1H),7.73-7.77(m,1H),7.93-7.99(m,1H)。MS(ESI,正离子)m/z 465[M+H]+。
(S)-5-(2,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-273)
1H NMR(400MHz,CD3OD)δppm 1.18(d,J=6.80Hz,3H),1.50-1.59(m,1H),2.11-2.22(m,5H),2.45-2.54(m,1H),2.63-2.72(m,1H),3.04-3.11(m,2H),3.39-3.46(m,2H),3.83(m,3H),4.49-4.59(m,1H),4.66-4.71(m,1H),6.08-6.16(m,1H),6.62-6.74(m,1H),7.18-7.27(m,1H),7.56(d,J=8.40Hz,1H),7.65(d,J=8.40Hz,1H),7.82(s,1H),7.96(s,1H),8.57(br s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(S)-环丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-274)
1H NMR(400MHz,CD3OD)δppm 0.75-0.82(m,1H),0.91-1.02(m,2H),1.11-1.22(m,4H),1.41-1.52(m,1H),1.80-1.91(m,2H),1.98-2.07(m,3H),2.21-2.32(m,1H),2.33-2.41(m,1H),2.64-2.79(m,3H),3.11-3.15(m,2H),4.18-4.29(m,1H),4.71-4.83(m,1H),6.12-6.21(m,1H),6.63-6.74(m,1H),7.22-7.29(m,1H),7.45(d,J=8.40Hz,1H),7.63(d,J=8.40Hz,1H),7.80(m,1H)。MS(ESI,正离子)m/z 493[M+H]+。
实例52:(S)-1-(5-(3,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-275)
和(S)-1-(5-(2,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-276)
步骤1.(S)-(6-溴-5-(2,5-二氟-4-硝基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮和(S)-(6-溴-5-(4,5-二氟-2-硝基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
向100-mL 3颈圆底烧瓶中装入(S)-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(2.00g,6.45mmol)于四氢呋喃(20mL)中的溶液。在0℃下分数份添加叔丁醇钾(0.797g,7.10mmol),且搅拌混合物5分钟。接着添加1,2,4-三氟-5-硝基苯(1.72g,9.71mmol),且在0℃下搅拌所得混合物3小时。添加盐酸(1N水溶液,10mL),且分离水相,且用乙酸乙酯(2×15mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以1:10乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-(6-溴-5-(2,5-二氟-4-硝基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮与(S)-(6-溴-5-(4,5-二氟-2-硝基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮的混合物(2.1g,70%)。MS(ESI,正离子)m/z 467,469[M+H]+。
步骤2.(S)-(5-(4-氨基-2,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮和(S)-(5-(2-氨基-4,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
向100-mL圆底烧瓶中装入(S)-(6-溴-5-(2,5-二氟-4-硝基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮与(S)-(6-溴-5-(4,5-二氟-2-硝基苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮的混合物(2.1g,4.49mmol)、铁粉(1.26g,22.5mmol)、氯化铵(0.476g,8.90mmol)、四氢呋喃(10mL)、乙醇(10mL)和水(3mL)。在80℃下搅拌所得混合物隔夜。冷却到室温后,过滤反应混合物,且用乙酸乙酯(2×15mL)萃取滤液。在真空下浓缩经合并的有机层,得到呈棕色油状的(S)-(5-(4-氨基-2,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮与(S)-(5-(2-氨基-4,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮的混合物(1.8g,96%),其未经进一步纯化即直接用于下一步骤中。MS(ESI,正离子)m/z 437,439[M+H]+。
步骤3.(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮和(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
向100-mL圆底烧瓶中装入(S)-(5-(2-氨基-4,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮与(S)-(5-(4-氨基-2,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮的混合物(1.8g,4.12mmol)和N,N-二甲基甲酰胺(10mL)。逐滴添加亚硝酸叔丁酯(1.2g,11.64mmol)于N,N-二甲基甲酰胺(10mL)中的溶液,且在50℃下搅拌所得溶液4小时。冷却到室温后,用乙酸乙酯(100mL)稀释反应混合物。用水(3×20mL)和盐水(20mL)洗涤有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1:10乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮与(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮的混合物(0.600g,35%)。MS(ESI,正离子)m/z 422,424[M+H]+。
步骤4. 4-[4-[(2S)-1-乙酰基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯和4-[4-[(2S)-1-乙酰基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯
向100-mL圆底烧瓶中装入(S)-1-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮与(S)-1-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮的混合物(0.130g,0.33mmol)、4-[3-(四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯(0.149mg,0.39mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.027g,0.03mmol)、碳酸钾(0.137mg,0.99mmol)、1,4-二噁烷(15mL)和水(3mL)。在100℃下搅拌所得混合物隔夜。冷却到室温后,使反应混合物通过短硅藻土衬垫,且在真空下浓缩滤液。经制备型薄层色谱(以1:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的4-[4-[(2S)-1-乙酰基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯与4-[4-[(2S)-1-乙酰基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸叔丁酯的混合物(0.160g,86%)。MS(ESI,正离子)m/z 567[M+H]+。
步骤5.(S)-1-(5-(3,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮和(S)-1-(5-(2,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮
向100-mL圆底烧瓶中装入(S)-4-(4-(1-乙酰基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯与(S)-4-(4-(1-乙酰基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯的混合物(0.160g,0.28mmol)、二氯甲烷(9mL)和三氟乙酸(3mL)。在室温下搅拌所得溶液2小时。用饱和碳酸钾水溶液将溶液的pH值调整到7-8。分离水层,且用二氯甲烷(3×10mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱:XBridge RP C18,19×150mm,5μm;移动相:水(0.05%碳酸氢铵)和乙腈(在7.0分钟内5%到60%乙腈,流动速率:20mL/min);检测器,UV 254和220nm。这得到:
呈淡黄色固体状的(S)-1-(5-(3,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.031g,24%)。1H NMR(300MHz,CD3OD)δppm1.10(d,J=6.60Hz,3H),1.18-1.41(m,1H),1.72-1.89(m,2H),1.92-2.01(m,2H),2.10-2.31(m,2H),2.16(s,3H),2.58-2.74(m,3H),3.08-3.12(m,2H),4.10-4.23(m,1H),4.63-4.83(m,1H),6.45-6.52(m,1H),6.60-6.73(m,1H),7.11(q,J=9.30Hz,1H),7.20-7.33(m,1H),7.57(d,J=8.40Hz,1H),7.74(s,1H),7.92(s,1H)。MS(ESI,正离子)m/z 467[M+H]+。
和
呈淡黄色固体状的(S)-1-(5-(2,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.006g,5%)。1H NMR(300MHz,CD3OD)δppm1.11(d,J=6.60Hz,3H),1.25-1.49(m,1H),1.71-1.87(m,2H),1.92-2.05(m,2H),2.19(s,3H),2.15-2.38(m,2H),2.59-2.73(m,3H),3.11(d,J=12.60Hz,2H),4.10-4.22(m,1H),4.65-4.85(m,1H),6.05-6.15(m,1H),6.57-6.71(m,1H),7.13-7.21(m,1H),7.22-7.39(m,1H),7.58(d,J=8.40Hz,1H),7.75(s,1H),7.93(s,1H)。MS(ESI,正离子)m/z 467[M+H]+。
实例53:(S,E)-1-(5-(2-氯乙烯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-277)
步骤1. 1-[(2S)-6-溴-5-(2,2-二氯乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮
向40-mL可再密封管中装入1-[(2S)-6-溴-5-羟基-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(90mg,0.32mmol)、甲烷磺酸2,2-二氯乙酯(82mg,0.42mmol)、碳酸钾(135mg,0.96mmol)和N,N-二甲基甲酰胺(10mL)。在110℃下搅拌所得混合物48小时。冷却到室温后,过滤反应混合物且在减压下浓缩。通过制备型薄层色谱(以石油醚/乙酸乙酯洗提,10:1、接着1:2)纯化残余物,得到呈淡黄色油状的1-[(2S)-6-溴-5-(2,2-二氯乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(56mg,46%)。MS(ESI,正离子)m/z 31,383[M+H]+。
步骤2.(S,E)-1-(5-(2-氯乙烯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
用惰性氮气气氛净化并维持50-mL圆底烧瓶,且装入1-[(2S)-6-溴-5-(2,2-二氯乙氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(43mg,0.11mmol)、1-环丙基-4-(四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(40mg,0.17mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(8mg,0.01mmol)、碳酸钾(31mg,0.22mmol)、1,4-二噁烷(24mL)和水(4mL)。在100℃下于油浴中搅拌所得混合物15小时。冷却到室温后,使反应混合物通过短硅藻土衬垫,且在真空下浓缩。通过制备型薄层色谱(以二氯甲烷/甲醇洗提,50:1、接着20:1)纯化残余物,得到呈白色固体状的(S,E)-1-(5-(2-氯乙烯氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(12mg,26%)。1H NMR(300MHz,CD3OD)δppm 1.05-1.15(m,7H),1.35-1.58(m,1H),2.21(s,3H),2.25-2.50(m,2H),2.80-2.93(m,1H),3.65-3.75(m,1H),4.61(s,1H),4.70-4.85(m,1H),5.52(d,J=4.20Hz,1H),6.52(d,J=4.20Hz,1H),7.15-7.25(m,1H),7.54(d,J=8.40Hz,1H),7.89(s,1H),8.07(s,1H)。MS(ESI,正离子)m/z372[M+H]+。
实例54:((2S)-5-环丁氧基-6-(2,3-二氢-1H-吡唑并[1,5-a]咪唑-7-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-278)
步骤1. 5-氨基-1-(2-羟乙基)-1H-吡唑-4-甲腈.
向100-mL圆底烧瓶中装入2-(乙氧基亚甲基)丙二腈(4.88g,39.96mmol)、乙醇(50mL)和2-肼基乙-1-醇(4.4g,57.82mmol)。在95℃下搅拌所得溶液10小时。冷却到室温后,在真空下浓缩反应混合物。经硅胶柱色谱(以9:1二氯甲烷/甲醇洗提)纯化残余物,得到呈黄色固体状的5-氨基-1-(2-羟乙基)-1H-吡唑-4-甲腈(3.9g,63%)。MS(ESI,正离子)m/z153[M+H]+。
步骤2. 2,3-二氢-1H-咪唑并[1,2-b]吡唑.
向250-mL 3颈圆底烧瓶中装入5-氨基-1-(2-羟乙基)-1H-吡唑-4-甲腈(6.00g,39.4mmol)和浓硫酸(80mL)。在170℃下搅拌所得溶液隔夜。用冰/水浴冷却到0℃之后,用氢氧化钠将溶液的pH值调整到8。用氯仿(4×500mL)萃取所得溶液。合并有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1:4乙酸乙酯/石油醚洗提)纯化残余物。通过用乙醚再结晶进一步纯化粗产物,得到呈黄色固体状的2,3-二氢-1H-咪唑并[1,2-b]吡唑(2.0g,46%)。MS(ESI,正离子)m/z 110[M+H]+。
步骤3. 7-溴-2,3-二氢-1H-咪唑并[1,2-b]吡唑氢溴酸盐.
向100-mL圆底烧瓶中装入2,3-二氢-1H-咪唑并[1,2-b]吡唑(1.7g,15.6mmol)和乙酸(5mL)。接着缓慢添加溴(7.39g,46.2mmol)于乙酸(47mL)中的溶液。在室温下搅拌所得溶液3小时。过滤反应混合物且在真空下浓缩滤液,得到呈黄色固体状的7-溴-2,3-二氢-1H-咪唑并[1,2-b]吡唑氢溴酸盐(3.0g,72%)。MS(ESI,正离子)m/z 188,190[M+H]+。
步骤4. 7-溴-2,3-二氢-1H-咪唑并[1,2-b]吡唑-1-甲酸叔丁酯.
向50-mL圆底烧瓶中装入7-溴-2,3-二氢-1H-咪唑并[1,2-b]吡唑氢溴酸盐(100mg,0.53mmol)于二氯甲烷(5mL)中的溶液。添加氢化钠(30mg,1.20mmol),且在室温下搅拌反应混合物15分钟。添加二碳酸二叔丁酯(232mg,1.06mmol)和4-二甲基氨基吡啶(6.5mg,0.05mmol),且在室温下搅拌所得混合物3.5小时。将反应混合物倒入10mL水中,且分离各层。用乙酸乙酯(3×50mL)萃取水层。合并有机层,用盐水(3×20mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以35%乙酸乙酯-石油醚洗提)纯化残余物,得到呈白色固体状的7-溴-2,3-二氢-1H-咪唑并[1,2-b]吡唑-1-甲酸叔丁酯(100mg,65%)。MS(ESI,正离子)m/z 288,290[M+H]+。
步骤5.(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,4-四氢喹啉.
向100-mL圆底烧瓶中装入(2S)-6-溴-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉(1.54g,4.25mmol)、双(频哪醇根基)二硼(3.22g,12.68mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(347mg,0.04mmol)、乙酸钾(1.04g,10.60mmol)和1,4-二噁烷(15mL)。在80℃下搅拌所得混合物隔夜。冷却到室温后,将反应混合物倒入50mL水中,且分离各层。用乙酸乙酯(3×100mL)萃取水层。合并有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以9%乙酸乙酯-石油醚洗提)纯化残余物,得到呈黄色油状的(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,4-四氢喹啉(0.9g,55%)。MS(ESI,正离子)m/z 386[M+H]+。
步骤6. 7-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-2,3-二氢咪唑并[1,2-b]吡唑-1-甲酸叔丁酯.
向8-mL可再密封管中装入(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,4-四氢喹啉(60mg,0.15mmol)、7-溴-2,3-二氢-1H-咪唑并[1,2-b]吡唑-1-甲酸叔丁酯(45mg,0.16mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(11mg,0.02mmol)、碳酸钠(30mg,0.28mmol)、1,4-二噁烷(1.5mL)和水(0.5mL)。在80℃下搅拌所得混合物隔夜。冷却到室温后,将反应混合物倒入20mL乙酸乙酯中。分离有机层,且用水和盐水洗涤,经无水硫酸钠干燥,过滤且在真空下浓缩。经硅胶柱色谱(以40%乙酸乙酯-石油醚洗提)纯化残余物,得到呈黑色固体状的7-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-2,3-二氢咪唑并[1,2-b]吡唑-1-甲酸叔丁酯(50mg,69%)。MS(ESI,正离子)m/z 493[M+H]+。
步骤7.((2S)-5-环丁氧基-6-(2,3-二氢-1H-咪唑并[1,2-b]吡唑-7-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮.
向8-mL小瓶中装入7-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-2,3-二氢咪唑并[1,2-b]吡唑-1-甲酸叔丁酯(50mg,0.10mmol)、二氯甲烷(3mL)和三氟乙酸(1mL)。在室温下搅拌所得溶液4小时。在真空下浓缩反应混合物。经制备型薄层色谱(以30%乙酸乙酯-石油醚洗提)纯化残余物,得到呈白色固体状的((2S)-5-环丁氧基-6-(2,3-二氢-1H-咪唑并[1,2-b]吡唑-7-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(11.7mg,20%)。1H NMR(400MHz,CD3OD)δppm 0.65-0.75(m,1H),0.85-0.95(m,2H),1.05-1.15(m,4H),1.20-1.45(m,2H),1.58-1.72(m,1H),1.85-1.95(m,1H),1.98-2.45(m,6H),3.01-3.09(m,1H),3.99-4.09(m,2H),4.10-4.22(m,3H),4.65-4.75(m,1H),7.14(d,J=8.00Hz,1H),7.30(d,J=8.00Hz,1H),7.65(s,1H)。MS(ESI,正离子)m/z 393[M+H]+。
实例55:((2S)-5-环丁氧基-2-甲基-6-(1-(甲基磺酰基)-2,3-二氢-1H-吡唑并[1,5-a]咪唑-7-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-279)
根据上文针对(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,4-四氢喹啉(实例54)所概述的程序制备((2S)-5-环丁氧基-2-甲基-6-(1-(甲基磺酰基)-2,3-二氢-1H-吡唑并[1,5-a]咪唑-7-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮,作出以下改变:(1)在步骤4中,使用三乙胺作为碱以替代氢化钠,甲烷磺酰氯替代二碳酸二叔丁酯,且不添加DMAP;(2)去除步骤7(Boc脱保护)。1H NMR(400MHz,CD3OD)δppm0.72(d,J=7.60Hz,1H),0.85-0.96(m,2H),1.14(d,J=7.60Hz,4H),1.28-1.46(m,2H),1.55-1.60(m,1H),1.88-2.21(m,5H),2.21-2.33(m,2H),2.95-3.05(m,1H),3.08(s,3H),4.05-4.18(m,1H),4.26-4.51(m,2H),4.51-4.69(m,2H),4.70-4.80(m,1H),7.13(d,J=8.40Hz,1H),7.24(d,J=8.00Hz,1H),7.59(s,1H)。MS(ESI,正离子)m/z 471[M+H]+。
实例56:(S)-5-环丁氧基-6-(2-(4-羟基哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-280)
步骤1. 4-(4-溴噻唑-2-基)-4-羟基哌啶-1-甲酸叔丁酯
将正丁基锂(1.6M,于己烷中,1.48mL,2.37mmol)逐滴添加到2,4-二溴噻唑(0.524g,2.16mmol)于二氯甲烷(11mL)中的-78℃溶液中。在-78℃下搅拌混合物20分钟,接着分8份添加4-氧代基哌啶-1-甲酸叔丁酯(0.516g,2.59mmol)。在-78℃下搅拌反应混合物10分钟。去除冷却浴,且经1小时使反应物升温到室温。冷却反应混合物到-30℃,接着通过添加饱和氯化铵水溶液淬灭。分离水相且用二氯甲烷萃取,且经无水硫酸钠干燥经合并的有机相,过滤且浓缩。经硅胶柱色谱(Biotage 50g柱,以5-60%乙酸乙酯-己烷进行梯度洗提)纯化残余物,得到4-(4-溴噻唑-2-基)-4-羟基哌啶-1-甲酸叔丁酯(0.744g,95%)。MS(ESI,正离子)m/z 363,365[M+H]+。
步骤2.(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-溴-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.534g,1.51mmol)、双(频哪醇根基)二硼(0.421g,1.66mmol)、乙酸钾(0.370g,3.77mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.123g,0.151mmol)于1,4-二噁烷(5.0mL)中的混合物在80℃下加热隔夜。冷却反应混合物到室温,经硅藻土衬垫过滤,且浓缩。经硅胶柱色谱(Biotage 25g柱,以5-10%乙酸乙酯-己烷进行梯度洗提)纯化残余物,得到呈无色油状的(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.217g,36%)。MS(ESI,正离子)m/z 402[M+H]+。
步骤3.(S)-6-(2-(1-(叔丁氧基羰基)-4-羟基哌啶-4-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.109g,0.273mmol)、4-(4-溴噻唑-2-基)-4-羟基哌啶-1-甲酸叔丁酯(0.090g,0.248mmol)、XPhos第2代预催化剂(0.019g,0.025mmol)和碳酸铯(0.242g,0.743mmol)于1,4-二噁烷(1.0mL)和水(0.2mL)中的混合物在100℃下加热2.5小时。冷却反应混合物到室温,经硅藻土衬垫过滤,且浓缩。经硅胶柱色谱(Biotage 25g柱,以5-50%乙酸乙酯-己烷进行梯度洗提)纯化残余物,得到(S)-6-(2-(1-(叔丁氧基羰基)-4-羟基哌啶-4-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.128g,93%)。MS(ESI,正离子)m/z 558[M+H]+。
步骤4.(S)-5-环丁氧基-6-(2-(4-羟基哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将HCl(4M,于1,4-二噁烷中,0.58mL,2.30mmol)添加到(S)-6-(2-(1-(叔丁氧基羰基)-4-羟基哌啶-4-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.128g,0.230mmol)于1,4-二噁烷(1.0mL)中的溶液中,且在室温下搅拌反应混合物1小时。浓缩反应混合物,且将残余物分配于乙酸乙酯与饱和碳酸氢钠水溶液之间。分离水相,且用乙酸乙酯萃取。经无水硫酸钠干燥经合并的有机相,过滤且浓缩。将残余物溶解于二氯甲烷中,接着经硅胶栓塞(以10%乙醇-乙酸乙酯洗提)过滤。浓缩滤液,得到(S)-5-环丁氧基-6-(2-(4-羟基哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(62mg,59%)。1H NMR(300MHz,DMSO-d6)δppm 1.11(d,J=6.45Hz,3H),1.22-1.72(m,6H),1.93-2.24(m,7H),2.39-2.49(m,2H),2.71-2.96(m,4H),3.69(s,3H),4.05-4.20(m,1H),4.47(dq,J=13.05,6.50Hz,1H),5.88(s,1H),7.33(d,J=8.79Hz,1H),7.69(d,J=8.50Hz,1H),7.77(s,1H)。MS(ESI,正离子)m/z 458[M+H]+。
实例57:(S)-5-环丁氧基-6-(2-(4-氟哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-281)
步骤1. 4-(4-溴噻唑-2-基)-4-氟哌啶-1-甲酸叔丁酯
将三氟化二乙基氨基硫(DAST)(0.083mL,0.627mmol)添加到4-(4-溴噻唑-2-基)-4-羟基哌啶-1-甲酸叔丁酯(0.207g,0.570mmol)于二氯甲烷(2.8mL)中的0℃溶液中。5分钟后,去除冷却浴,且在室温下搅拌反应混合物隔夜。添加饱和碳酸氢钠水溶液,且分离水相,且用二氯甲烷萃取。经无水硫酸钠干燥经合并的有机相,过滤且浓缩。经硅胶柱色谱(Biotage 25g柱,以5-50%乙酸乙酯-己烷进行梯度洗提)纯化残余物,得到呈无色蜡状固体状的4-(4-溴噻唑-2-基)-4-氟哌啶-1-甲酸叔丁酯(0.163g,78%)。MS(ESI,正离子)m/z387,389[M+Na]+。
步骤2.(S)-6-(2-(1-(叔丁氧基羰基)-4-氟哌啶-4-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.099g,0.247mmol)、4-(4-溴噻唑-2-基)-4-氟哌啶-1-甲酸叔丁酯(0.082g,0.224mmol)、XPhos第2代预催化剂(0.018g,0.022mmol)和碳酸铯(0.219g,0.673mmol)于1,4-二噁烷(1.0mL)和水(0.2mL)中的混合物在100℃下加热2小时。冷却反应混合物到室温,经硅藻土衬垫过滤,且浓缩。经硅胶柱色谱(Biotage 25g柱,以25-50%乙酸乙酯-己烷进行梯度洗提)纯化残余物,得到(S)-6-(2-(1-(叔丁氧基羰基)-4-氟哌啶-4-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.072g,57%)。MS(ESI,正离子)m/z 558[M+H]+。
步骤3.(S)-5-环丁氧基-6-(2-(4-羟基哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将HCl(4M,于1,4-二噁烷中,0.32mL,1.28mmol)添加到(S)-6-(2-(1-(叔丁氧基羰基)-4-氟哌啶-4-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.072g,0.128mmol)于1,4-二噁烷(0.5mL)中的溶液中,且在室温下搅拌反应混合物1小时。浓缩反应混合物,且通过质量触发式制备型HPLC纯化残余物。合并含产物的洗提份且在Genevac中浓缩,得到(S)-5-环丁氧基-6-(2-(4-羟基哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。MS(ESI,正离子)m/z 460[M+H]+。
实例58:(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-282)
步骤1.(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(2.00g,6.66mmol)、(4-氟苯基)硼酸(1.865g,13.33mmol)、乙酸铜(II)(1.33g,7.33mmol)、分子筛(1g)、三乙胺(0.93mL,6.66mmol)和吡啶(1.08mL,13.33mmol)于二氯甲烷(30mL)中的混合物在室温下在对空气敞开下搅拌两天。经硅藻土过滤反应混合物且浓缩滤液,得到棕色油状物。经硅胶柱色谱(Biotage 25g柱,以0-10%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色膜状的(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(1.81g,69%)。MS(ESI,正离子)m/z 394,396[M+H]+。
步骤2.(S)-6-(1-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.100g,0.254mmol)、3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-甲酸叔丁酯(0.106g,0.304mmol)、XPhos第2代预催化剂(0.004g,0.005mmol)和碳酸铯(0.246g,0.761mmol)于1,4-二噁烷(2.0mL)和水(0.40mL)中的混合物在100℃下加热16小时。经硅藻土过滤反应混合物且浓缩,得到绿色油状物。经硅胶柱色谱(Biotage 10g柱,以25-50%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色油状的(S)-6-(1-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.098g,72%)。MS(ESI,正离子)m/z 537[M+H]+。
步骤3.(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟乙酸(1.0mL,6.49mmol)添加到(S)-6-(1-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3-氯-4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.098g,0.033mmol)于二氯甲烷(1.0mL)中的溶液中,且在室温下搅拌反应混合物2小时。接着浓缩混合物,且将残余物分配于二氯甲烷与饱和碳酸氢钠水溶液之间。分离有机相,经无水硫酸钠干燥,过滤且浓缩,得到呈灰白色固体状的(S)-6-(1-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.105g,100%)。MS(ESI,正离子)m/z 437[M+H]+。
步骤4.(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(105mg,0.241mmol)溶解于甲醇中,且添加甲醛(179μL,2.41mmol)。在周围温度下搅拌反应物4小时,接着冷却到0℃。添加三乙酰氧基硼氢化钠(0.102g,0.481mmol),且使反应物缓慢升温到周围温度。16小时后,反应完成,且将反应混合物分配于乙酸乙酯与水之间。分离水相且用乙酸乙酯萃取,且用盐水洗涤经合并的有机层,经无水硫酸钠干燥,过滤且浓缩,得到呈浅橙色油状的(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.086g,79%)。1H NMR(300MHz,CDCl3)δppm 1.13(d,J=6.45Hz,3H)1.18-1.20(m,1H)1.20-1.33(m,1H)1.55(br dd,J=13.34,5.42Hz,1H)1.94-2.18(m,4H)2.22-2.49(m,1H)2.49-2.69(m,1H)3.81(s,3H)4.26(br s,1H)4.61-4.89(m,2H)5.13-5.32(m,1H)6.63-6.82(m,2H)6.83-7.01(m,2H)7.40(d,J=8.79Hz,1H)7.54-7.67(m,2H)7.79-8.02(m,1H)。MS(ESI,正离子)m/z 451[M+H]+。
实例59:(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-283)
根据上文针对实例58所概述的程序,自(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯和4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯合成(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CDCl3)δppm 0.74-1.01(m,1H),1.14(d,J=6.74Hz,3H),1.47-1.82(m,2H),1.99-2.07(m,1H),2.31(br s,1H),2.44(dt,J=17.00,5.72Hz,1H),2.52-2.72(m,1H),2.77(s,3H),3.16(br s,1H),3.27-3.62(m,2H),3.82(s,3H),4.43(br s,1H),4.57-4.84(m,2H),4.85-5.10(m,1H),6.68-6.75(m,2H),6.86-6.98(m,2H),7.27(s,1H),7.41(d,J=8.50Hz,1H),7.57-7.78(m,2H)。MS(ESI,正离子)m/z 479[M+H]+。
实例60:(S)-5-环丁氧基-2-甲基-6-(1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-284)
步骤1.(S)-6-(1-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
用氮气净化(S)-6-溴-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.096g,0.254mmol)、3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)氮杂环丁烷-1-甲酸叔丁酯(0.113g,0.325mmol)和碳酸铯(0.264g,0.811mmol)于二噁烷(2.0mL)和水(0.40mL)中的混合物以去除任何氧气。添加XPhos第2代预催化剂(0.020g,0.027mmol),且用氮气净化反应物,接着在100℃下加热16小时。浓缩反应混合物,且将残余物分配于乙酸乙酯与饱和碳酸氢钠水溶液之间。分离水相且用乙酸乙酯萃取,且浓缩经合并的有机相,得到油状物。经硅胶柱色谱(Biotage 10g柱,以25-50%乙酸乙酯-己烷进行梯度洗提)纯化这一物质,得到呈无色油状的(S)-6-(1-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.132g,98%)。MS(ESI,正离子)m/z 497[M+H]+。
步骤2.(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟乙酸(1.0mL,6.49mmol)添加到(S)-6-(1-(1-(叔丁氧基羰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(3-氯-4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.132g,0.265mmol)于二氯甲烷(1.0mL)中的溶液中,且在室温下搅拌反应混合物2小时。浓缩反应混合物,且将残余物分配于二氯甲烷与饱和碳酸氢钠水溶液之间。分离有机相,经无水硫酸钠干燥,过滤且浓缩,得到呈灰白色固体状的(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.115g,88%)。MS(ESI,正离子)m/z 396[M+H]+。
步骤3.(S)-5-环丁氧基-2-甲基-6-(1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-6-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸酯(0.115g,0.290mmol)溶解于甲醇(3.6mL)中,且添加甲醛(216μL,2.90mmol)。在周围温度下搅拌反应物4小时且冷却到0℃。添加三乙酰氧基硼氢化钠(0.123g,0.58mmol),且使反应物缓慢升温到周围温度。16小时后,将反应物分配于乙酸乙酯与水之间。分离水相且用乙酸乙酯萃取,且用盐水洗涤经合并的有机相,且经无水硫酸钠干燥,过滤且浓缩,得到呈浅橙色油状的(S)-5-环丁氧基-2-甲基-6-(1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.115g,97%)。1H NMR(300MHz,CDCl3)δppm 1.16-1.33(m,4H),1.33-1.41(m,1H),1.41-1.54(m,1H),1.55-1.68(m,1H),1.95-2.30(m,4H),2.34-2.67(m,1H),2.92(dt,J=15.68,6.08Hz,1H),3.06(s,2H),3.22(br d,J=15.54Hz,1H),3.33-3.64(m,2H),3.69-3.89(m,3H),4.33(brs,2H),4.54(dq,J=13.34,6.69Hz,1H),4.78-4.97(m,1H),5.32(五重峰,J=7.40Hz,1H),7.08-7.43(m,2H),7.68-7.87(m,1H),7.96(s,1H)。MS(ESI,正离子)m/z 411[M+H]+。
实例61:(S)-5-环丁氧基-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-285)
根据上文针对实例60所概述的程序,自(S)-6-溴-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯和4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯合成(S)-5-环丁氧基-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CDCl3)δppm 0.64-0.99(m,1H),1.12-1.26(m,4H),1.39-1.52(m,1H),1.55-1.67(m,1H),1.97-2.14(m,5H),2.14-2.27(m,1H),2.30-2.58(m,2H),2.63(br s,1H),2.73-2.78(m,1H),2.79(s,3H),2.84-3.09(m,1H),3.15(br s,1H),3.37-3.63(m,4H),3.64-3.92(m,3H),4.54(s,1H),7.14-7.39(m,2H),7.81(d,J=8.21Hz,2H)。MS(ESI,正离子)m/z 439[M+H]+。
实例62:(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-286)
步骤1. 3-甲基吡啶-2-基硼酸
向100-mL 3颈圆底烧瓶中装入2-溴-3-甲基吡啶(1.00g,5.81mmol)和乙醚(30mL)。在0℃下于搅拌下逐滴添加氯化异丙基镁溶液(2M,于THF中,8.0mL,16.0mmol),且在0℃下搅拌所得溶液3小时。添加硼酸三异丙酯(2.6g,13.8mmol),且在室温下搅拌溶液1小时。接着通过添加饱和氯化铵水溶液(10mL)淬灭反应物。分离水层,且用乙酸乙酯(2×10mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩,得到呈淡黄色油状的3-甲基吡啶-2-基硼酸(0.730g,92%)。MS(ESI,正离子)m/z 138[M+H]+。
步骤2.(S)-1-(6-溴-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮
向配备有经空气填充的气球的100-mL圆底烧瓶中装入(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.200g,0.70mmol)、吡啶(1mL)、乙酸铜(II)(0.382g,2.10mmol)、3-甲基吡啶-2-基硼酸(0.190g,1.39mmol)和N,N-二甲基甲酰胺(8mL)。在90℃下搅拌所得混合物隔夜。冷却到室温后,过滤反应混合物,且在真空下浓缩滤液。通过硅胶柱色谱(以1:8乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-1-(6-溴-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.129g,49%)。MS(ESI,正离子)m/z 375,377[M+H]+。
步骤3.(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮
向100-mL圆底烧瓶中装入(S)-1-(6-溴-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.129g,0.34mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(0.025g,0.03mmol)、碳酸钾(0.142g,1.03mmol)、1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.243g,1.04mmol)、1.4-二噁烷(10mL)和水(2mL)。在100℃下搅拌所得混合物隔夜。冷却到室温后,使反应混合物通过短硅藻土衬垫,且在真空下浓缩滤液。通过制备型薄层色谱(以50%乙酸乙酯-石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,SunFire Prep C18,19×150mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内54%到80%乙腈,流动速率:20mL/min);检测器,UV220和254nm。这得到呈灰白色固体状的(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.0285g,21%)。1H NMR(300MHz,CD3OD)δppm 1.00-1.03(m,4H),1.16(d,J=6.60Hz,3H),1.32-1.42(m,1H),2.20-2.28(m,5H),2.48(s,3H),2.54-2.59(m,1H),3.57-3.64(m,1H),4.75-4.80(m,1H),6.95-7.00(m,1H),7.22-7.27(m,1H),7.54(d,J=8.40Hz,1H),7.63(s,1H),7.72-7.77(m,2H),7.80(s,1H)。MS(ESI,正离子)m/z 403[M+H]+。
根据针对实例62所概述的程序制得以下实例:
(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(5-甲基吡啶-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-287)
1H NMR(300MHz,CD3OD)δppm 1.01-1.04(m,4H),1.16(d,J=6.60Hz,3H),1.30-1.40(m,1H),2.06-2.27(m,8H),2.63-2.68(m,1H),3.57-3.62(m,1H),4.80(m,1H),6.80(d,J=8.40Hz,1H),7.31-7.32(m,1H),7.56-7.66(m,2H),7.74(s,1H),7.88-7.92(m,2H)。MS(ESI,正离子)m/z 403[M+H]+。
(S)-1-(5-(5-氯吡啶-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-288)
1H NMR(300MHz,CD3OD)0.90-1.02(m,4H),1.14(d,J=6.30Hz,3H),1.42(br s,1H),2.10-2.32(m,5H),2.55-2.69(m,1H),3.52-3.69(m,1H),4.65-4.90(m,1H),7.00(d,J=8.70Hz,1H),7.30(br s,1H),7.53(d,J=8.70Hz,1H),7.70(s,1H),7.75-7.85(m,1H),7.90(s,1H),8.00(d,J=2.70Hz,1H)。MS(ESI,正离子)m/z 423[M+H]+。
实例63:(S)-1-(5-(7H-嘌呤-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(I-289)
步骤1. 2-氯-7-(四氢-2H-吡喃-2-基)-7H-嘌呤
向100-mL圆底烧瓶中装入2-氯-7H-嘌呤(0.200g,1.29mmol)、甲苯(20mL)、对甲苯磺酸(0.011g,0.06mmol)、3,4-二氢-2H-吡喃(0.328g,3.90mmol),且在80℃下搅拌所得溶液2小时。冷却到室温后,在真空下浓缩反应混合物。通过硅胶柱色谱(以1:5乙酸乙酯/石油醚洗提)纯化残余物,得到呈棕色油状的2-氯-7-(四氢-2H-吡喃-2-基)-7H-嘌呤(0.245g,79%)。MS(ESI,正离子)m/z 239[M+H]+。
步骤2. 1-((S)-6-溴-2-甲基-5-(7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮
向100-mL圆底烧瓶中装入(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.170g,0.60mmol)、2-氯-7-(四氢-2H-吡喃-2-基)-7H-嘌呤(0.200g,0.84mmol)、碳酸钾(0.247g,1.79mmol)和N,N-二甲基甲酰胺(6mL)。在110℃下搅拌所得混合物隔夜。冷却到室温后,过滤反应混合物,且在真空下浓缩滤液。通过制备型薄层色谱(以1:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的1-((S)-6-溴-2-甲基-5-(7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.200g,69%)。MS(ESI,正离子)m/z 486,488[M+H]+。
步骤3. 1-((S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮
向100-mL圆底烧瓶中装入1-((S)-6-溴-2-甲基-5-(7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.200g,0.41mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(0.030g,0.04mmol)、碳酸钾(0.170g,1.23mmol)、1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.288g,1.23mmol)、1,4-二噁烷(20mL)和水(2mL)。在100℃下搅拌所得混合物隔夜。冷却到室温后,使反应混合物通过短硅藻土衬垫,且在真空下浓缩滤液。通过制备型薄层色谱(以1:2乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色油状的1-((S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.150g,71%)。MS(ESI,正离子)m/z 514[M+H]+。
步骤4.(S)-1-(5-(7H-嘌呤-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮
向100-mL圆底烧瓶中装入1-((S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(7-(四氢-2H-吡喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(0.150g,0.29mmol)、HCl(6M水溶液,3mL)和甲醇(20mL)。在40℃下搅拌所得溶液隔夜。冷却到室温后,用饱和碳酸钠水溶液将反应混合物的pH值调整到7-8。浓缩所得混合物以去除甲醇,且添加乙酸乙酯。分离水层,且用乙酸乙酯(3×20mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤且浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,SunFirePrepC18,19×150mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内37%到58%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈黄色固体状的(S)-1-(5-(7H-嘌呤-2-基氧基)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.030g,24%)。1H NMR(300MHz,CD3OD)δppm 0.86-1.00(m,4H),1.16(d,J=6.30Hz,3H),1.21-1.49(m,1H),2.18-2.47(m,5H),2.63-2.72(m,1H),3.52-3.59(m,1H),4.72-4.80(m,1H),7.19-7.30(m,1H),7.56(d,J=8.40Hz,1H),7.60(s,1H),7.99(s,1H),8.41(s,1H),8.79(s,1H)。MS(ESI,正离子)m/z 430[M+H]+。
实例64:(2S)-5-环丁氧基-6-(1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-290)
步骤1.(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
向100-mL圆底烧瓶中装入4-(四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-甲酸叔丁酯(250mg,0.85mmol)、(S)-6-溴-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(317mg,0.89mmol)、碳酸钠(150mg,1.42mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)(58mg,0.18mmol)、1,4-二噁烷(10mL)和水(2mL)。在100℃下于油浴中搅拌所得混合物隔夜。冷却到室温后,将反应混合物倒入10mL水中,且分离各层。用乙酸乙酯(3×10mL)萃取水层。合并有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以5:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(200mg,52%)。MS(ESI,正离子)m/z 342[M+H]+。
步骤2.(2S)-6-(1-[1-[(叔丁氧基)羰基]-3-羟基哌啶-4-基]-1H-吡唑-4-基)-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯
向100-mL圆底烧瓶中装入(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(200mg,0.59mmol)和N,N-二甲基甲酰胺(10mL)。添加氢化钠(47mg,1.96mmol),且在室温下搅拌混合物30分钟。添加7-氧杂-3-氮杂双环[4.1.0]庚烷-3-甲酸叔丁酯(995mg,4.99mmol),且在80℃下于油浴中搅拌所得溶液隔夜。冷却到室温后,将反应混合物倒入乙酸乙酯(50mL)中,用水(3×10mL)和盐水(10mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以10:1二氯甲烷/甲醇洗提)纯化残余物,得到呈黄色油状的(2S)-6-(1-[1-[(叔丁氧基)羰基]-3-羟基哌啶-4-基]-1H-吡唑-4-基)-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(250mg,78%)。MS(ESI,正离子)m/z 541[M+H]+。
步骤3.(2S)-6-(1-(1-(叔丁氧基羰基)-3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
向50-mL圆底烧瓶中装入(2S)-6-(1-[1-[(叔丁氧基)羰基]-3-羟基哌啶-4-基]-1H-吡唑-4-基)-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(250mg,0.46mmol)和N,N-二甲基甲酰胺(5mL)。添加氢化钠(78mg,3.25mmol),且在室温下搅拌混合物30分钟。添加碘甲烷(0.079mL,1.28mmol),且在室温下搅拌所得溶液4小时。接着将反应混合物倒入20mL水中,且用乙酸乙酯(3×20mL)萃取。合并有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1:5乙酸乙酯/石油醚洗提)纯化残余物,得到呈无色油状的(2S)-6-(1-(1-(叔丁氧基羰基)-3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(80mg,31%)。MS(ESI,正离子)m/z 555[M+H]+。
步骤4.(2S)-5-环丁氧基-6-(1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
向25-mL圆底烧瓶中装入(2S)-6-(1-(1-(叔丁氧基羰基)-3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(40mg,0.07mmol)、二氯甲烷(3mL)和三氟乙酸(1mL)。在室温下搅拌所得溶液1小时。在真空下浓缩反应混合物。通过制备型HPLC使用以下条件纯化残余物:柱:Xbridge RP C18,19×150mm,5μm;移动相:水(0.05%三氟乙酸)、乙腈(在9分钟内15%到43%乙腈,流动速率:20mL/min);检测器,254/220nm。合并洗提份且在真空下浓缩,且经逆相色谱(乙腈/水(0.05%碳酸氢铵)=5/95-95/5)进一纯化残余物。合并洗提份,浓缩且冻干,得到呈灰白色固体状的(2S)-5-环丁氧基-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(14mg,43%)。1H NMR(300MHz,CD3OD)δppm 1.10-1.20(m,3H),1.25-1.50(m,2H),1.50-1.70(m,1H),1.95-2.52(m,8H),2.80-3.10(m,2H),3.10-3.35(m,4H),3.55-3.90(m,6H),4.05-3.15(m,1H),4.40-4.65(m,2H),7.18-7.35(m,2H),7.93(s,1H),8.01-8.12(m,2H)。MS(ESI,正离子)m/z 455[M+H]+。
实例65:(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-291)
根据针对实例52所概述的程序,自(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯合成(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δppm 1.16(d,J=6.40Hz,3H),1.55-1.65(m,1H),2.01-2.12(m,1H),2.20-2.50(m,3H),2.60-2.72(m,1H),2.90-3.01(m,3H),3.08-3.15(m,2H),3.45-3.75(m,3H),3.82(s,3H),4.25-4.35(m,1H),4.60-4.70(m,1H),6.65-4.75(m,2H),6.90-7.00(m,2H),7.50-7.60(m,2H),7.82-8.01(m,2H)。MS(ESI,正离子)m/z 495[M+H]+。
实例69:(2S)-5-环丁氧基-6-(1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-292)
根据上文针对实例40所概述的程序,自(2S)-6-(1-(1-(叔丁氧基羰基)-3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯和甲醛合成(2S)-5-环丁氧基-6-(1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3OD)δppm 1.19(d,J=6.00Hz,3H),1.20-1.50(m,2H),1.55-1.85(m,1H),2.01-2.22(m,4H),2.22-2.68(m,4H),2.88-3.08(m,5H),3.10-3.22(m,2H),3.50-3.60(m,1H),3.80(s,3H),3.81-4.01(m,1H),4.05-4.25(m,1H),4.30-4.45(m,1H),4.48-4.70(m,1H),7.20-7.40(m,2H),7.85-8.10(m,2H)。MS(ESI,正离子)m/z 469[M+H]+。
实例70:(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-293)
根据上文针对实例40所概述的程序,自(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯和甲醛合成(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δppm 1.16(d,J=6.80Hz,3H),1.50-1.65(m,1H),1.98-2.11(m,1H),2.15-2.22(m,1H),2.40-2.70(m,3H),2.78-3.01(m,5H),3.02-3.18(m,1H),3.42-3.85(m,8H),4.15-4.25(m,1H),4.55-4.72(m,1H),6.72-6.80(m,2H),6.90-7.01(m,2H),7.50-7.62(m,2H),7.80-8.10(m,2H)。MS(ESI,正离子)m/z 509[M+H]+。
实例71:3-{4-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮(I-294)
步骤1.(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
向配备有经空气填充的气球的100-mL圆底烧瓶中装入(S)-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.800g,2.58mmol)、苯基硼酸(0.937g,7.68mmol)、吡啶(0.83mL,10.30mmol)、二氯甲烷(50mL)和乙酸铜(II)(0.934g,5.14mmol)。在40℃下搅拌所得混合物1天。冷却混合物到室温且过滤。在真空下浓缩滤液,且经硅胶柱色谱(以5-10%乙酸乙酯/石油醚进行梯度洗提)纯化残余物,得到呈白色固体状的(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.700g,70%)。MS(ESI,正离子)m/z 386,388[M+H]+。
步骤2.(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮
向100-mL圆底烧瓶中装入(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.400g,1.04mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.083g,0.10mmol)、碳酸铯(0.985g,3.02mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-甲酸叔丁酯(0.343g,1.17mmol)、1,4-二噁烷(10mL)和水(3mL)。在100℃下搅拌所得混合物隔夜且冷却到室温。使反应混合物通过短硅藻土衬垫,且在真空下浓缩滤液。经硅胶柱色谱(以10-25%乙酸乙酯/石油醚进行梯度洗提)纯化残余物,得到呈淡黄色固体状的(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.200g,52%)。MS(ESI,正离子)m/z 374[M+H]+。
步骤3. 3-{4-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮
向100-mL圆底烧瓶中装入(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.200g,0.56mmol)、碳酸铯(0.114g,0.35mmol)、N,N-二甲基甲酰胺(5mL)和4-溴-1λ6-硫杂环己烷-1,1-二酮(0.114g,0.53mmol)。在100℃下搅拌所得混合物4小时,接着冷却到室温。用乙酸乙酯(50mL)稀释反应混合物且用水(3×10mL)洗涤。经无水硫酸钠干燥有机相,过滤,且在真空下浓缩。经硅胶柱色谱(以25-50%乙酸乙酯/石油进行梯度洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水和乙腈(在7分钟内55%到75%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈白色固体状的3-{4-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮(0.122g,43%)。1H NMR(400MHz,CD3OD)δppm0.76-0.82(m,1H),0.92-1.02(m,2H),1.13-1.22(m,4H),1.42-1.50(m,1H),1.95-2.08(m,3H),2.08-2.13(m,1H),2.14-2.37(m,3H),2.68-2.77(m,1H),3.11-3.19(m,2H),3.37(s,1H),3.53-3.60(m,1H),4.66-4.72(m,1H),4.74-4.81(m,1H),6.79(d,J=8.00Hz,2H),6.98(t,J=7.60Hz,1H),7.23(t,J=7.60Hz,2H),7.62(d,J=8.40Hz,1H),7.83(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 506[M+H]+。
根据针对实例71所概述的程序制得以下实例:
3-{4-[(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫杂环己烷-1,1-二酮(I-295)
1H NMR(300MHz,CD3OD)δppm 0.73-0.81(m,1H),0.91-1.01(m,2H),1.13(d,J=6.30Hz,4H),1.32-147(m,1H),1.94-2.15(m,5H),2.16-2.34(m,3H),2.78-2.87(m,1H),3.13-3.19(m,2H),3.53-3.62(m,1H),4.65-4.79(m,2H),6.74-6.79(m,2H),6.93-7.02(m,2H),7.38(d,J=8.70Hz,1H),7.60(d,J=8.40Hz,1H),8.02(s,1H)。MS(ESI,正离子)m/z524[M+H]+。
实例72:(2S)-5-环丁氧基-2-甲基-6-(1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-296)
步骤1. 4-(甲基磺酰氧基)-2-氧代基哌啶-1-甲酸叔丁酯
向100-mL圆底烧瓶中装入4-羟基-2-氧代基哌啶-1-甲酸叔丁酯(1.00g,4.65mmol)于二氯甲烷(30mL)中的溶液。添加三乙胺(1.03mL,7.42mmol)和4-二甲基氨基吡啶(0.057g,0.47mmol),且冷却混合物到0℃。逐滴添加甲烷磺酰氯(0.47mL,6.05mmol),且在室温下搅拌所得溶液1小时。用水(2×10mL)和0.1M HCl水溶液(2×10mL)洗涤反应混合物,经无水硫酸钠干燥,过滤,且在真空下浓缩,得到呈棕色固体状的4-(甲基磺酰氧基)-2-氧代基哌啶-1-甲酸叔丁酯(0.900g,66%)。MS(ESI,正离子)m/z 294[M+H]+。
步骤2.(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
向100-mL圆底烧瓶中装入4-(四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-甲酸叔丁酯(0.250g,0.85mmol)、(S)-6-溴-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.317g,0.89mmol)、碳酸钠(0.150g,1.42mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.070g,0.085mmol)、1,4-二噁烷(10mL)和水(2mL)。在100℃下搅拌所得混合物隔夜,冷却到室温,且添加水(10mL)。分离水层,且用乙酸乙酯(3×10mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以5:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.200g,52%)。MS(ESI,正离子)m/z 342[M+H]+。
步骤3.(2S)-5-环丁氧基-2-甲基-6-(1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
向8-mL可再密封管中装入(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.050g,0.15mmol)和N,N-二甲基甲酰胺(2mL)。添加氢化钠(60%分散液,于矿物油中,0.012g,0.50mmol),且在室温下搅拌所得混合物15分钟。添加4-(甲基磺酰氧基)-2-氧代基哌啶-1-甲酸叔丁酯(0.141g,0.48mmol),且在50℃下搅拌所得混合物隔夜。冷却反应混合物到室温,且添加水(10mL)。分离水相,且用乙酸乙酯(3×10mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,Xbridge RPC18,19×150mm,5μm;移动相,水(0.05%碳酸氢铵)和乙腈(在8分钟内13%到60%乙腈;流动速率:20mL/min);检测器,UV254和220。这得到呈白色固体状的(2S)-5-环丁氧基-2-甲基-6-(1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.0091mg,14%)。1H NMR(400MHz,CD3OD)δppm 1.17-1.20(m,3H),1.29-1.40(m,1H),1.40-1.51(m,1H),1.58-1.68(m,1H),2.03-2.19(m,4H),2.22-2.35(m,3H),2.41-2.49(m,1H),2.92-2.99(m,1H),3.32-3.48(m,2H),3.78(s,3H),4.12-4.22(m,1H),4.50-4.60(m,1H),4.78-4.88(m,1H),7.25-7.33(m,2H),7.87(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 439[M+H]+。
根据针对实例72所概述的程序制得以下实例:
(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-297)
1H NMR(400MHz,CD3OD)δppm 1.17-1.20(m,3H),1.54-1.62(m,1H),2.13-2.20(m,3H),2.41-2.50(m,1H),2.60-2.71(m,1H),2.75-2.81(m,2H),6.72-6.79(m,2H),2.92-2.99(m,1H),3.32-3.48(m,2H),3.78(s,3H),4.62-4.75(m,1H),6.72-6.79(m,2H),6.95-7.02(m,2H),7.52-7.61(m,2H),7.81(s,1H),7.94(s,1H)。MS(ESI,正离子)m/z479[M+H]+。
实例73:(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-298)
步骤1. 2-(溴甲基)-3-甲基环氧乙烷
向2000-mL圆底烧瓶中装入(E)-1-溴丁-2-烯(50.0g,370.4mmol)和二氯甲烷(1000mL)。经1.5小时分数份添加3-氯过氧苯甲酸(75wt%,94g,407mmol),且在室温下搅拌所得混合物隔夜。用饱和碳酸氢钠水溶液(3×200mL)和盐水(2×200mL)洗涤反应混合物,经无水硫酸钠干燥,过滤且浓缩,得到呈淡黄色油状的2-(溴甲基)-3-甲基环氧乙烷(42.4g,84%)。MS(ESI,正离子)m/z 192,194[M+H+MeCN]+。
步骤2. 1-二苯甲基-2-甲基氮杂环丁烷-3-醇
向500-mL圆底烧瓶中装入2-(溴甲基)-3-甲基环氧乙烷(42.4g,280mmol)、甲醇(120mL)和二苯基甲胺(44mL,260mmol),且在80℃下搅拌所得溶液隔夜。冷却反应混合物到室温且浓缩。经硅胶柱色谱(以50:1二氯甲烷/甲醇洗提)纯化残余物,得到呈白色固体状的1-二苯甲基-2-甲基氮杂环丁烷-3-醇(25g,35%)。MS(ESI,正离子)m/z 254[M+H]+。
步骤3.甲烷磺酸1-二苯甲基-2-甲基氮杂环丁烷-3-基酯
向500-mL圆底烧瓶中装入1-二苯甲基-2-甲基氮杂环丁烷-3-醇(15.0g,59.2mmol)、二氯甲烷(30mL)和N,N-二异丙胺(21mL,160mmol),且冷却溶液到0℃。添加甲烷磺酰氯(6.2mL,77mmol)于二氯甲烷(10mL)中的溶液,且在室温下搅拌所得溶液隔夜。将反应混合物倒入200mL水中,且分离水相,且用二氯甲烷(2×100mL)萃取。用盐水(2×100mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以20:1二氯甲烷/乙酸乙酯洗提)纯化残余物。通过自己烷中再结晶进一步纯化产物,得到呈白色固体状的甲烷磺酸1-二苯甲基-2-甲基氮杂环丁烷-3-基酯(5.6g,29%)。MS(ESI,正离子)m/z332[M+H]+。
步骤4.(2S)-6-(1-(1-二苯甲基-2-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
向100-mL圆底烧瓶中装入(S)-5-(4-氟苯氧基)-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.300g,0.79mmol)和N,N-二甲基甲酰胺(10mL),且冷却溶液到0℃。添加氢化钠(60%分散液,于矿物油中,0.047g,1.17mmol),且在室温下搅拌所得混合物30分钟。添加甲烷磺酸1-二苯甲基-2-甲基氮杂环丁烷-3-基酯(0.286g,0.86mmol),且在50℃下搅拌所得混合物隔夜。冷却反应混合物到室温,且倒入水(30mL)中。分离水相,且用乙酸乙酯(3×20mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以25%乙酸乙酯-石油醚洗提)纯化残余物,得到呈黄色油状的(2S)-6-(1-(1-二苯甲基-2-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.100g,21%)。MS(ESI,正离子)m/z 617[M+H]+。
步骤5.(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
向50-mL圆底烧瓶中装入(2S)-6-(1-(1-二苯甲基-2-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.020g,0.03mmol)、1,2-二氯乙烷(5mL)和氯甲酸1-氯乙酯(1mL),且在80℃下搅拌所得溶液3小时。冷却反应混合物到室温,接着用乙酸乙酯(20mL)稀释。分离有机相且用水(10mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以25%乙酸乙酯-石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,Xbridge RP C18,19×150mm,5μm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内20%到80%乙腈;流动速率:20mL/min);检测器,UV254和220。这得到呈白色固体状的(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.0021g,14%)。1H NMR(300MHz,CD3OD)δppm 0.75(d,J=6.40Hz,3H),0.85-0.97(m,1H),1.10-1.18(m,3H),1.29-1.39(m,3H),1.52-1.65(m,1H),1.99-2.25(m,2H),2.41-2.75(m,2H),3.82(s,3H),4.05-4.17(m,2H),4.26-4.35(m,1H),4.62-4.73(m,1H),5.16-5.23(m,1H),6.73-6.81(m,2H),6.93-6.99(m,2H),7.51-7.62(m,2H),7.85(s,1H),8.05(s,1H)。MS(ESI,正离子)m/z 451[M+H]+。
根据针对实例73所概述的程序制得以下实例:
(2S)-5-环丁氧基-2-甲基-6-(1-(2-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-299)
1H NMR(300MHz,CD3OD)δppm 0.85-0.92(m,1H),1.17-1.19(m,6H),1.25-1.51(m,11H),1.52-1.70(m,2H),1.99-2.32(m,7H),2.38-2.48(m,1H),2.90-3.01(m,1H),3.77(s,1H),4.14-4.19(m,1H),4.49-4.68(m,2H),4.72-4.82(m,1H),4.92-5.10(m,1H),5.31-5.45(m,1H),7.26-7.33(m,2H),8.03(s,2H)。MS(ESI,正离子)m/z 411[M+H]+。
实例74:N-(4-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-环丙基-1H-吡唑-5-基)甲烷磺酰胺(I-300)
步骤1. 1-环丙基-1H-吡唑-5-胺
向100-mL圆底烧瓶中装入3,3-二乙氧基丙腈(0.600g,4.19mmol)、环丙基肼二盐酸盐(0.610g,4.21mmol)和乙醇(20mL),且在80℃下搅拌所得溶液18小时。冷却反应混合物到室温,且在真空下浓缩。经硅胶柱色谱(以10:1二氯甲烷/甲醇洗提)纯化残余物,得到呈淡黄色油状的1-环丙基-1H-吡唑-5-胺(0.206g,36%)。MS(ESI,正离子)m/z 124[M+H]+。
步骤2. 1-环丙基-4-碘-1H-吡唑-5-胺
向100-mL圆底烧瓶中装入1-环丙基-1H-吡唑-5-胺(0.410g,3.33mmol)和N,N-二甲基甲酰胺(10mL)。添加N-碘代丁二酰亚胺(0.820g,3.64mmol),且在室温下搅拌所得溶液18小时。将反应混合物倒入饱和亚硫酸氢钠水溶液(50mL)中,且用乙酸乙酯(3×20mL)萃取。用盐水(10mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色油状的1-环丙基-4-碘-1H-吡唑-5-胺(0.440g,48%)。MS(ESI,正离子)m/z 250[M+H]+。
步骤3.((2S)-6-(5-氨基-1-环丙基-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
向50-mL圆底烧瓶中装入(S)-(5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.140g,0.34mmol)、1-环丙基-4-碘-1H-吡唑-5-胺(0.071g,0.29mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(23.2mg,0.03mmol,0.10当量)、碳酸钠(0.061g,0.58mmol)、1,4-二噁烷(10mL)和水(3mL)。在80℃下搅拌所得混合物18小时,接着冷却到室温。经短硅藻土衬垫过滤反应混合物,且在真空下浓缩滤液。经硅胶柱色谱(以1:5乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色油状的((2S)-6-(5-氨基-1-环丙基-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.025g,20%)。MS(ESI,正离子)m/z 407[M+H]+。
步骤4.N-(4-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-环丙基-1H-吡唑-5-基)甲烷磺酰胺
向8-mL圆底烧瓶中装入((2S)-6-(5-氨基-1-环丙基-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.020g,0.05mmol)、1,4-二噁烷(1mL)和4M氢氧化钠水溶液(1mL)。添加甲烷磺酰氯(0.028g,0.019mL,0.24mmol),且在室温下搅拌所得溶液隔夜。用1N HCl水溶液将反应混合物的pH值调整到7,且用乙酸乙酯(3×5mL)萃取混合物。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内20%到80%乙腈,流动速率:20mL/min);检测器,UV220和254nm。这得到呈黄色油状的N-(4-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-环丙基-1H-吡唑-5-基)甲烷磺酰胺(0.010g,42%)。1H NMR(300MHz,CD3OD)δppm 0.63-0.75(m,1H),0.80-1.00(m,2H),1.00-1.18(m,8H),1.25-1.34(m,2H),1.51-1.68(m,1H),1.85-2.11(m,5H),2.25-2.42(m,2H),2.99-3.08(m,1H),3.13(s,3H),3.65-3.75(m,1H),3.96-4.17(m,1H),4.66-4.74(m,1H),7.15(d,J=8.10Hz,1H),7.38(d,J=8.40Hz,1H),7.82(s,1H)。MS(ESI,正离子)m/z 485[M+H]+。
实例75:N-(4-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-环丙基-1H-吡唑-5-基)乙酰胺(I-301)
步骤1.N-(1-环丙基-4-碘-1H-吡唑-5-基)乙酰胺
向100-mL圆底烧瓶中装入1-环丙基-4-碘-1H-吡唑-5-胺(0.250g,1.00mmol)、N,N-二异丙胺(0.52mL,2.99mmol)和二氯甲烷(8mL),且冷却溶液到0℃。逐滴添加乙酰氯(0.085mL,1.19mmol)于二氯甲烷(2mL)中的溶液,且在0℃下搅拌所得溶液1小时。在真空下浓缩反应混合物,且经硅胶柱色谱(以0.5-50%乙酸乙酯/石油醚进行梯度洗提)纯化残余物,得到呈黄色油状的N-(1-环丙基-4-碘-1H-吡唑-5-基)乙酰胺(0.300g,92%)。MS(ESI,正离子)m/z 292[M+H]+。
步骤2.N-(4-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-环丙基-1H-吡唑-5-基)乙酰胺
向25-mL圆底烧瓶中装入N-(1-环丙基-4-碘-1H-吡唑-5-基)乙酰胺(0.067g,0.23mmol)、(S)-(5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.103g,0.25mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.019mg,0.02mmol)、碳酸钠(0.048g,0.45mmol)、1,4-二噁烷(10mL)和水(3mL)。在80℃下搅拌所得混合物18小时且冷却到室温。经短硅藻土衬垫过滤反应混合物,且在真空下浓缩滤液。经硅胶柱色谱(以0.5-50%乙酸乙酯/石油醚进行梯度洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,XBridgeRPC18OBD柱,5μm,19×150mm;移动相,水(0.03%氨水)和乙腈(在10分钟内16%到34%乙腈,流动速率:20mL/min);检测器,UV254和220nm。这得到23mg(22%)呈白色固体状的N-(4-((2S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-环丙基-1H-吡唑-5-基)乙酰胺。1H NMR(400MHz,CD3OD)δppm 0.68-0.80(m,1H),0.91-0.99(m,2H),1.06-1.19(m,8H),1.28-1.45(m,3H),1.55-1.68(m,1H),1.90-2.11(m,8H),2.29-2.48(m,2H),2.94-3.15(m,1H),3.62-3.78(m,1H),4.00-4.20(m,1H),4.67-4.83(m,1H),7.14(d,J=8.00Hz,1H),7.21(d,J=8.40Hz,1H),7.83(s,1H)。MS(ESI,正离子)m/z 449[M+H]+。
实例76:(S)-5-环丁氧基-6-(1-(3-羟基环丁基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-302)
步骤1. 3-(苯甲氧基)环丁醇
向100-mL圆底烧瓶中装入3-(苯甲氧基)环丁酮(2.00g,11.4mmol)、四氢呋喃(20mL)和甲醇(1mL),且冷却溶液到0℃。逐份添加硼氢化钠(0.475g,12.5mmol),且在室温下搅拌所得混合物30分钟。将反应混合物倒入水(30mL)中,且用乙酸乙酯(2×30mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤且浓缩,得到呈黄色油状的3-(苯甲氧基)环丁醇(1.83g,90%)。MS(ESI,正离子)m/z 179[M+H]+。
步骤2.甲烷磺酸3-(苯甲氧基)环丁酯
向100-mL圆底烧瓶中装入3-(苯甲氧基)环丁醇(1.83g,10.3mmol)、二氯甲烷(20mL)和三乙胺(2.15mL,15.4mmol),且冷却溶液到0℃。逐滴添加甲烷磺酰氯(1.20mL,1.77g,15.4mmol),且在0℃下搅拌所得溶液30分钟。将反应混合物倒入水(30mL)中,且用二氯甲烷(2×30mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤且浓缩,得到呈淡黄色固体状的甲烷磺酸3-(苯甲氧基)环丁酯(2.60g,99%)。MS(ESI,正离子)m/z 257[M+H]+。
步骤3. 1-(3-(苯甲氧基)环丁基)-4-碘-1H-吡唑
向250-mL圆底烧瓶中装入4-碘-1H-吡唑(1.97g,10.2mmol)、N,N-二甲基甲酰胺(20mL)、甲烷磺酸3-(苯甲氧基)环丁酯(2.60g,10.2mmol)和碳酸铯(9.75g,29.9mmol),且在80℃下搅拌所得混合物隔夜。冷却反应混合物到室温,倒入水(50mL)中,且用乙酸乙酯(3×50mL)萃取。用盐水(50mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤且浓缩,得到呈黄色油状的1-(3-(苯甲氧基)环丁基)-4-碘-1H-吡唑(3.00g,83%)。MS(ESI,正离子)m/z355[M+H]+。
步骤4.(S)-6-(1-(3-(苯甲氧基)环丁基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
向25-mL圆底烧瓶中装入(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.100g,0.25mmol)、1-(3-(苯甲氧基)环丁基)-4-碘-1H-吡唑(0.106g,0.30mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.020g,0.02mmol)、碳酸钠(0.053g,0.50mmol)、1,4-二噁烷(10mL)和水(3mL)。在80℃下搅拌所得混合物隔夜,接着冷却到室温。用乙酸乙酯(20mL)稀释反应混合物,用水(10mL)和盐水(10mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1-10%乙酸乙酯/石油醚进行梯度洗提)纯化残余物,得到呈黄色固体状的(S)-6-(1-(3-(苯甲氧基)环丁基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.060g,48%)。MS(ESI,正离子)m/z 502[M+H]+。
步骤5.(S)-5-环丁氧基-6-(1-(3-羟基环丁基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将钯/碳(10wt%,0.060g)添加到(S)-6-(1-(3-(苯甲氧基)环丁基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.060g,0.12mmol)于甲醇(10mL)中的溶液中,且在室温下于氢气气氛下搅拌所得混合物16小时。过滤反应混合物,且在真空下浓缩滤液。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,XBridgePrepShield RP18OBD柱,19×150mm,5μm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内30%到50%乙腈,流动速率:20mL/min);检测器,UV254和220nm。这得到呈白色固体状的(S)-5-环丁氧基-6-(1-(3-羟基环丁基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.031g,63%)。1H NMR(300MHz,CD3OD)δppm 1.16(d,J=6.30Hz,3H),1.32-1.51(m,2H),1.55-1.68(m,1H),2.00-2.33(m,5H),2.33-2.58(m,3H),2.76-2.84(m,2H),2.93-3.01(m,1H),3.77(s,3H),4.12-4.19(m,1H),4.51-4.64(m,2H),4.99-5.08(m,1H),7.24-7.35(m,2H),7.86(s,1H),8.04(s,1H)。MS(ESI,正离子)m/z 412[M+H]+。
实例77:(S)-5-环丁氧基-2-甲基-6-(2-(哌啶-4-基)-1H-咪唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-303)
步骤1.(S)-6-(2-(1-(叔丁氧基羰基)哌啶-4-基)-1H-咪唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.080g,0.20mmol)、4-(4-溴-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(0.200g,0.61mmol)、碳酸钠(0.45g,0.42mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.010g,0.01mmol)于1,4-二噁烷(10mL)和水(3mL)中的混合物在90℃下搅拌隔夜。冷却反应混合物到室温,经短硅藻土衬垫过滤,且在真空下浓缩。经制备型薄层色谱(以1:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色固体状的(S)-6-(2-(1-(叔丁氧基羰基)哌啶-4-基)-1H-咪唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.050g,48%)。MS(ESI,正离子)m/z 525[M+H]+。
步骤2.(S)-5-环丁氧基-2-甲基-6-(2-(哌啶-4-基)-1H-咪唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯将三氟乙酸(3mL)添加到(S)-6-(2-(1-(叔丁氧基羰基)哌啶-4-基)-1H-咪唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.050g,0.09mmol)于二氯甲烷(6mL)中的溶液中,且在室温下搅拌反应混合物3小时。在真空下浓缩反应混合物,且经制备型HPLC(Waters I)纯化残余物:柱:Waters HSS C18,2.1×50mm,1.8μm;移动相:水(0.05%碳酸氢铵)和乙腈(在10分钟内5%到95%乙腈,流动速率:20mL/min);检测器:UV254和220nm。这得到呈灰白色固体状的(S)-5-环丁氧基-2-甲基-6-(2-(哌啶-4-基)-1H-咪唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.0039g,10%)。1H NMR(300MHz,CD3OD)δppm 1.15-1.26(m,2H),1.32-1.68(m,3H),1.95-2.55(m,8H),2.97-3.19(m,3H),3.40-3.47(m,2H),3.77-3.82(m,2H),4.13-4.25(m,1H),4.51-4.71(m,3H),7.28-7.47(m,2H),8.55-8.61(m,1H)。MS(ESI,正离子)m/z 425[M+H]+。
根据上文针对实例77所概述的程序制得以下实例:
(S)-5-环丁氧基-2-甲基-6-(1-甲基-2-(哌啶-4-基)-1H-咪唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-304)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.30Hz,3H),1.25-1.33(m,1H),1.85-1.99(m,8H),2.18-2.27(m,1H),2.50-2.61(m,1H),2.81-2.95(m,3H),3.01-3.15(m,1H),3.21-3.26(m,2H),3.47(s,3H),3.79(s,3H),3.93-3.99(m,1H),6.86(s,1H),7.08(d,J=8.70Hz,1H),7.37(d,J=8.70Hz,1H)。MS(ESI,正离子)m/z 439[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-3-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-305)
1H NMR(400MHz,DMSO-d6)δppm 0.63-0.68(m,1H),0.75-0.80(m,1H),0.80-0.85(m,1H),0.95-1.01(m,1H),1.05(d,J=6.40Hz,3H),1.22-1.35(m,2H),1.52-1.61(m,1H),1.75-1.87(m,3H),1.93-2.12(m,5H),2.27-2.33(m,2H),2.55-2.61(m,2H),2.89-2.95(m,1H),3.01-3.07(m,2H),4.15-4.28(m,2H),4.59-4.68(m,1H),6.64(s,1H),7.13(d,J=8.40Hz,1H),7.64(d,J=8.40Hz,1H),7.79(s,1H)。MS(ESI,正离子)m/z 435[M+H]+。
((2S)-5-环丁氧基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-5-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-306)
1H NMR(400MHz,DMSO-d6)δppm 0.67-0.75(m,1H),0.75-0.85(m,1H),0.85-0.89(m,1H),0.99-1.05(m,1H),1.07(d,J=6.40Hz,3H),1.17-1.23(m,1H),1.41-1.51(m,2H),1.67-1.78(m,3H),1.78-1.99(m,6H),2.22-2.29(m,1H),2.31-2.49(m,3H),2.83-2.91(m,1H),2.92-3.01(m,2H),3.85-3.96(m,2H),4.86-4.78(m,1H),6.24(s,1H),7.11(d,J=8.40Hz,1H),7.23(d,J=8.40Hz,1H),7.53(s,1H)。MS(ESI,正离子)m/z 435[M+H]+。
(S)-环丙基(2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-3-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-307)
1H NMR(400MHz,DMSO-d6)δppm 0.68-0.75(m,1H),0.81-0.89(m,1H),0.90-0.97(m,1H),1.01-1.08(m,4H),1.31-1.42(m,1H),1.69-1.79(m,2H),1.81-1.98(m,3H),2.05-2.15(m,1H),2.21-2.32(m,1H),2.51-2.60(m,3H),2.99-3.05(m,2H),4.11-4.19(m,1H),4.65-4.77(m,1H),6.42(s,1H),6.76-6.82(m,2H),6.96-7.01(m,1H),7.28-7.33(m,2H),7.36-7.41(m,1H),7.66(s,1H),7.93(m,1H)。MS(ESI,正离子)m/z 457[M+H]+。
环丙基((2S)-2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-吡唑-5-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-308)
1H NMR(400MHz,DMSO-d6)δppm 0.72-0.88(m,2H),0.90-0.97(m,1H),1.01-1.08(m,4H),1.45-1.51(m,2H),1.55-1.62(m,1H),1.77-1.95(m,2H),1.97-2.03(m,1H),2.05-2.14(m,1H),2.32-2.41(m,3H),2.53-2.59(m,1H),2.91-2.99(m,2H),3.89-3.95(m,1H),4.73-4.81(m,1H),6.08(s,1H),6.62-6.67(m,2H),6.91-6.96(m,1H),7.20-7.40(m,3H),7.36(s,1H),7.47(m,1H)。MS(ESI,正离子)m/z 457[M+H]+。
(S)-(5-环丁氧基-2-甲基-6-(2-(哌啶-4-基)-2H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(3929975)(I-309)
1H NMR(300MHz,CD3OD)δppm 0.68-0.77(m,1H),0.89-0.99(m,2H),1.13(d,J=6.60Hz,4H),1.25-1.42(m,2H),1.61-1.72(m,1H),1.85-1.96(m,1H),2.05-2.26(m,9H),2.29-2.56(m,2H),2.75-2.88(m,2H),3.02-3.11(m,1H),3.19-3.28(m,2H),4.17-4.19(m,1H),4.63-4.74(m,2H),7.22(d,J=8.40Hz,1H),7.72(d,J=8.40Hz,1H),8.05(s,1H)。MS(ESI,正离子)m/z 436[M+H]+。三唑区位化学试验性地指定。
(S)-(5-环丁氧基-2-甲基-6-(1-(哌啶-4-基)-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-310)
1H NMR(300MHz,CD3OD)δppm 0.68-0.77(m,1H),0.89-0.99(m,2H),1.13(d,J=6.60Hz,4H),1.25-1.47(m,2H),1.61-1.69(m,1H),1.85-1.96(m,1H),2.05-2.48(m,10H),2.82-3.11(m,3H),3.23-3.28(m,2H),4.17-4.26(m,1H),4.70-4.81(m,2H),7.25(d,J=8.40Hz,1H),7.82(d,J=8.40Hz,1H),8.35(s,1H)。MS(ESI,正离子)m/z 436[M+H]+。三唑区位化学试验性地指定。
(S)-环丙基(2-甲基-5-苯氧基-6-(2-(哌啶-4-基)-2H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-311)
1H NMR(300MHz,CD3OD)δppm 0.75-0.87(m,1H),0.90-1.07(m,2H),1.12-1.23(m,4H),1.31-1.49(m,1H),1.95-2.40(m,7H),2.69-2.83(m,3H),3.11-3.19(m,2H),3.34(s,1H),4.53-4.66(m,1H),4.80-4.85(m,1H),6.78-6.83(m,2H),6.95-7.03(m,1H),7.24-7.30(m,2H),7.43-7.59(m,1H),7.78(s,1H),7.98(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z 458[M+H]+。三唑区位化学试验性地指定。
(S)-环丙基(2-甲基-5-苯氧基-6-(1-(哌啶-4-基)-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-312)
1H NMR(300MHz,CD3OD)δppm 0.73-0.83(m,1H),0.90-1.05(m,2H),1.11-1.22(m,4H),1.35-1.47(m,1H),1.83-2.10(m,5H),2.17-2.41(m,2H),2.69-2.80(m,3H),3.10-3.20(m,2H),4.51-4.62(m,1H),4.75-4.83(m,1H),6.78-6.82(m,2H),6.93-7.01(m,1H),7.23-7.30(m,2H),7.45-7.51(m,1H),8.04-8.09(m,2H)。MS(ESI,正离子)m/z 458[M+H]+。三唑区位化学试验性地指定。
(S)-6-(2-(氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-313)
1H NMR(300MHz,CD3OD)δppm 1.13-1.21(m,3H),1.23-1.41(m,1H),1.45-1.64(m,2H),1.95-2.14(m,4H),2.18-2.31(m,1H),2.45-4.53(m,1H),2.91-3.02(m,1H),3.78(s,3H),4.01-4.19(m,5H),4.33-4.48(m,1H),4.51-4.65(m,1H),7.34(d,J=8.70Hz,1H),7.69(d,J=8.40Hz,1H),7.76(s,1H)。MS(ESI,正离子)m/z 414[M+H]+。
(S)-甲基-5-环丁氧基-6-(2-(3-羟基氮杂环丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-314)
1H NMR(400MHz,CD3OD)δppm 1.08(d,J=6.40Hz,3H),1.16-1.25(m,1H),1.33-1.45(m,1H),1.46-1.52(m,1H),1.90-2.09(m,4H),2.12-2.21(m,1H),2.35-2.42(m,1H),2.83-2.92(m,1H),3.68(s,3H),3.76-3.78(m,2H),3.80-3.86(m,1H),4.03-4.12(m,3H),4.45-4.51(m,1H),7.24-7.27(m,1H),7.67-7.73(m,2H)。MS(ESI,正离子)m/z 430[M+H]+。
实例78:(S)-5-环丁氧基-2-甲基-6-(1-甲基-2-(哌嗪-1-基)-1H-咪唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-315)
步骤1. 1-(4-溴-1-甲基-1H-咪唑-2-基)哌嗪
向20-mL可再密封管中装入2,4-二溴-1-甲基-1H-咪唑(0.480g,2.00mmol)和哌嗪(3.4g,39.5mmol),且在130℃下搅拌所得混合物3小时。冷却反应混合物到室温,用二氯甲烷(20mL)稀释,用水(2×10mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以10:1二氯甲烷/甲醇洗提)纯化残余物,得到呈淡黄色固体状的1-(4-溴-1-甲基-1H-咪唑-2-基)哌嗪(0.300g,61%)。MS(ESI,正离子)m/z 245,247[M+H]+。
步骤2.(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
向100-mL圆底烧瓶中装入(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.580g,1.47mmol)、1-(4-溴-1-甲基-1H-咪唑-2-基)哌嗪(0.300g,1.22mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.100g,0.12mmol)、碳酸钠(0.260g,2.45mmol)、1,4-二噁烷(9mL)和水(3mL)。在80℃下搅拌所得混合物18小时。冷却反应混合物到室温,经短硅藻土衬垫过滤,且在真空下浓缩滤液。经硅胶柱色谱(以10:1二氯甲烷/甲醇洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,XBridge Prep C18OBD柱,5μm,19×150mm;移动相,水(0.03%氨水)和乙腈(在10分钟内16.0%到34.0%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈淡黄色固体状的(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.015g,6%)。1H NMR(400MHz,CD3OD)δppm 1.17(d,J=4.80Hz,3H),1.25-1.33(m,1H),1.34-1.49(m,2H),1.57-1.68(m,1H),2.03-2.28(m,5H),2.39-2.49(m,1H),2.93-2.99(m,1H),2.99-3.02(m,4H),3.09-3.13(m,4H),3.59(s,3H),3.77(s,3H),4.18-4.23(m,1H),4.51-4.53(m,1H),7.18-7.29(m,2H),7.53-7.57(m,1H)。MS(ESI,正离子)m/z 440[M+H]+。
实例79:(S)-5-环丁氧基-2-甲基-6-(2-(哌嗪-1-基)噻唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-316)
步骤1. 4-(4-溴噻唑-2-基)哌嗪-1-甲酸叔丁酯
向100-mL圆底烧瓶中装入2,4-二溴噻唑(1.00g,4.12mmol)、哌嗪-1-甲酸叔丁酯(0.918g,4.93mmol)、三乙胺(1.72mL,12.35mmol)和N,N-二甲基甲酰胺(20mL)。在120℃下搅拌所得溶液18小时。冷却反应混合物到室温,倒入水(50mL)中,且用乙酸乙酯(3×20mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以10:1二氯甲烷/甲醇洗提)纯化残余物,得到呈棕色油状的4-(4-溴噻唑-2-基)哌嗪-1-甲酸叔丁酯(0.350g,23%)。MS(ESI,正离子)m/z 348,350[M+H]+。
步骤2.(S)-6-(2-(4-(叔丁氧基羰基)哌嗪-1-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
向50-mL圆底烧瓶中装入(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.080g,0.20mmol)、4-(4-溴噻唑-2-基)哌嗪-1-甲酸叔丁酯(0.083g,0.24mmol)、碳酸钠(0.042g,0.40mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.081g,0.10mmol)、1,4-二噁烷(10mL)和水(3mL)。在80℃下搅拌所得混合物4小时。冷却反应混合物到室温,经短硅藻土衬垫过滤,且在真空下浓缩滤液。经制备型薄层色谱(以10:1二氯甲烷/甲醇洗提)纯化残余物,得到呈淡黄色固体状的(S)-6-(2-(4-(叔丁氧基羰基)哌嗪-1-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.070g,64%)。MS(ESI,正离子)m/z 543[M+H]+。
步骤3.(S)-5-环丁氧基-2-甲基-6-(2-(哌嗪-1-基)噻唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟乙酸(1mL)添加到(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.070g,0.13mmol)于二氯甲烷(3mL)中的溶液中,且在室温下搅拌所得溶液2小时。在真空下浓缩反应溶液,且通过制备型HPLC使用以下条件(Waters 1)纯化残余物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在7分钟内55%到75%乙腈,流动速率:20mL/min);检测器,UV220和254nm。这得到呈白色固体状的(S)-5-环丁氧基-2-甲基-6-(2-(哌嗪-1-基)噻唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.010mg,9%)。1H NMR(300MHz,DMSO-d6)δppm1.19(d,J=6.30Hz,3H),1.20-1.45(m,3H),1.45-1.52(m,1H),2.03-2.21(m,5H),2.80-2.86(m,4H),3.33-3.42(m,5H),3.68(s,3H),4.15-4.22(m,1H),4.40-4.50(m,1H),7.15(s,1H),7.27(d,J=8.70Hz,1H),7.67(d,J=8.70Hz,1H)。MS(ESI,正离子)m/z 443[M+H]+。
实例80:(S)-5-环丁氧基-6-(2-(3-羟基氮杂环丁烷-1-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-317)
步骤1. 1-(4-溴噻唑-2-基)氮杂环丁烷-3-醇
将2,4-二溴噻唑(1.00g,4.12mmol)、氮杂环丁烷-3-醇盐酸盐(0.543g,4.96mmol)和碳酸铯(4.03g,12.37mmol)于乙腈(30mL)中的混合物在70℃下搅拌18小时。冷却反应混合物到室温且过滤。在真空下浓缩滤液,且经硅胶柱色谱(以10:1二氯甲烷/甲醇洗提)纯化残余物,得到呈淡黄色固体状的1-(4-溴噻唑-2-基)氮杂环丁烷-3-醇(0.535g,53%)。MS(ESI,正离子)m/z 235,237[M+H]+。
步骤2.(S)-5-环丁氧基-6-(2-(3-羟基氮杂环丁烷-1-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.080g,0.20mmol)、1-(4-溴噻唑-2-基)氮杂环丁烷-3-醇(0.056g,0.24mmol)、碳酸钠(0.042g,0.40mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.081g,0.10mmol)于1,4-二噁烷(10mL)和水(3mL)中的混合物在80℃下搅拌4小时。冷却反应混合物到室温,且经短硅藻土衬垫过滤。在真空下浓缩滤液,且经硅胶柱色谱(以2:1乙酸乙酯/石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(WatersI)进一步纯化产物:柱,XBridge Prep C18OBD柱,5μm,19×150mm;移动相,水(0.03%氨水)和乙腈(在10分钟内16.0%到34.0%乙腈,流动速率:20mL/min);检测器:UV254和220nm。这得到呈白色固体状的(S)-5-环丁氧基-6-(2-(3-羟基氮杂环丁烷-1-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.030g,34%)。1H NMR(400MHz,CD3OD)δppm 1.17(d,J=6.40Hz,3H),1.32-1.41(m,1H),1.42-1.54(m,1H),1.55-1.67(m,1H),2.04-2.18(m,4H),2.21-2.29(m,1H),2.45-2.55(m,1H),2.91-3.00(m,1H),3.78(s,3H),3.90-3.96(m,2H),4.15-4.21(m,1H),4.32-4.39(m,2H),4.53-4.59(m,1H),4.73-4.80(m,1H),6.99(s,1H),7.28-7.30(m,1H),7.53-7.55(m,1H)。MS(ESI,正离子)m/z 430[M+H]+。
实例81:(S)-环丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-318)和(S)-环丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-319)
步骤1.(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮和(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
根据上文针对(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮和(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(实例52,步骤1-3)所述的程序,自(S)-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮和1,2,4-三氟-5-硝基苯制备(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮和(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮。MS(ESI,正离子)m/z 422,424[M+H]+。
步骤2.(S)-环丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮和(S)-环丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将含(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮与(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮的混合物(0.100g,0.24mmol)、双(频哪醇根基)二硼(0.600g,2.37mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.019g,0.02mmol)和乙酸钾(0.046mg,0.47mmol)的1,4-二噁烷(10mL)在80℃下搅拌隔夜。冷却反应混合物到室温,用乙酸乙酯(50mL)稀释,用水(20mL)和盐水(20mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。通过制备型薄层色谱(以1:5乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-环丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮与(S)-环丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮的混合物(0.080g,72%)。MS(ESI,正离子)m/z470[M+H]+。
步骤3.(S)-环丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮和(S)-环丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将含(S)-环丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮与(S)-环丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮的混合物(0.080g,0.09mmol)、4-溴-1-甲基-1H-1,2,3-三唑(0.062g,0.38mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.021g,0.03mmol)和碳酸铯(0.167g,0.51mmol)的1,4-二噁烷(10mL)和水(3mL)在90℃下搅拌隔夜。冷却反应混合物到室温,用乙酸乙酯(50mL)稀释,用水(20mL)和盐水(20mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1:5乙酸乙酯/石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,Xbridge Prep C18OBD柱,5μm,19×150mm;移动相,水(0.03%氢氧化铵)和乙腈(在10分钟内16%到34%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到:
呈白色固体状的(S)-环丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.0083g,23%)(I-318)。1H NMR(300MHz,CD3OD)δppm 0.75-0.82(m,1H),0.85-1.05(m,2H),1.10-1.23(m,4H),1.38-1.52(m,1H),1.95-2.05(m,1H),2.17-2.42(m,2H),2.65-2.79(m,1H),4.08(s,3H),4.75-4.88(m,1H),6.18-6.28(m,1H),6.67-6.78(m,1H),7.23-7.31(m,1H),7.54(d,J=8.40Hz,1H),8.01-8.10(m,2H)。MS(ESI,正离子)m/z 425[M+H]+。
和
呈白色固体状的(S)-环丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.0053g,15%)(I-319)。1H NMR(300MHz,CD3OD)δppm 0.72-0.83(m,1H),0.89-1.02(m,2H),1.11-1.22(m,4H),1.35-1.49(m,1H),1.96-2.05(m,1H),2.18-2.39(m,2H),2.67-2.75(m,1H),4.07(s,3H),4.75-4.88(m,1H),6.51-6.62(m,1H),6.78-6.89(m,1H),7.13(d,J=9.00Hz,1H),7.20(d,J=9.00Hz,1H),7.51(d,J=8.40Hz,1H),8.03-8.09(m,2H)。MS(ESI,正离子)m/z 425[M+H]+。
实例82:(S)-环丙基(5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-320)
步骤1.(S)-环丙基(5-(2-氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将(S)-(6-溴-5-(2-氟苯氧基)-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(根据针对1-[(2S)-6-溴-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮(实例51,步骤1-3)所述的程序制备,0.270g,0.67mmol)、双(频哪醇根基)二硼(3.30g,13.00mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(50mg,0.07mmol)和乙酸钾(0.170g,1.73mmol)于1,4-二噁烷(10mL)中的混合物在80℃下搅拌隔夜。冷却反应混合物到室温,用乙酸乙酯(920mL)稀释,用水(2×10mL)和盐水(10mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以5-10%乙酸乙酯-石油醚洗提)纯化残余物,得到呈淡黄色固体状的(S)-环丙基(5-(2-氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.140g,46%)。MS(ESI,正离子)m/z 452[M+H]+。
步骤2.(S)-环丙基(5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将(S)-环丙基(5-(2-氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.140g,0.31mmol)、4-溴-1-甲基-1H-1,2,3-三唑(0.050g,0.31mmol)、碳酸钠(0.090g,0.85mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.010g,0.01mmol)于1,4-二噁烷(10mL)和水(3mL)中的混合物在80℃下搅拌隔夜。冷却反应混合物到室温,经短硅藻土衬垫过滤,且在真空下浓缩。经制备型薄层色谱(以2:1石油醚-乙酸乙酯洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,XBridge C18,19×150mm,5μm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内35%到65%乙腈,流动速率:20mL/min);检测器:UV254和220nm。这得到呈白色固体状的(S)-环丙基(5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.033g,26%)。1H NMR(400MHz,CD3OD)δppm0.74-0.81(m,1H),0.89-1.03(m,2H),1.11-1.21(m,4H),1.35-1.47(m,1H),1.95-2.05(m,1H),2.17-2.40(m,2H),2.65-2.78(m,1H),4.07(s,3H),4.75-4.81(m,1H),6.40-6.49(m,1H),6.89-6.97(m,2H),7.21-7.27(m,1H),7.51(d,J=8.40Hz,1H),8.03(s,1H),8.08(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z 407[M+H]+。
根据上文针对实例82所述的程序制得以下实例:
(S)-环丙基(8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-321)
1H NMR(400MHz,CD3OD)δppm 0.64-0.87(m,1H),0.92-1.10(m,3H),1.10-1.35(m,4H),1.65-1.80(m,1H),2.10-2.41(m,2H),2.68-2.79(m,1H),4.05(s,3H),4.70-4.89(m,1H),6.85(d,J=8.00Hz,2H),7.03(t,J=7.60Hz,1H),7.31(t,J=8.00Hz,2H),7.93-7.97(m,1H),8.06(s,1H)。MS(ESI,正离子)m/z 407[M+H]+。
(S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-322)
1H NMR(300MHz,DMSO-d6)δppm 1.11(d,J=6.60,3H),1.21-1.36(m,2H),2.05-2.15(m,1H),2.17-2.30(m,1H),3.70(s,3H),4.40(d,J=6.60Hz,3H),4.35-4.45(m,1H),6.81(d,J=7.80Hz,2H),7.01(t,J=7.50Hz,1H),7.28-7.34(m,2H),7.84(d,J=11.4Hz,1H),8.11(s,1H)。MS(ESI,正离子)m/z 397[M+H]+。
(S)-1-(8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)乙酮(I-323)
1H NMR(300MHz,CD3OD)δppm 1.05-1.31(m,4H),2.10-2.44(m,5H),2.61-2.80(m,1H),4.05(s,3H),4.70-4.90(m,1H),6.78-6.90(m,2H),6.95-7.10(m,1H),7.25-7.40(m,2H),7.90-8.10(m,2H)。MS(ESI,正离子)m/z 381[M+H]+。
实例83:(S)-(5-环丁氧基-2-甲基-6-(1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-324)
将(S)-(6-溴-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.182g,0.50mmol)、1H-吡唑(0.340g,5.00mmol)、碘化铜(I)(0.038g,0.20mmol)、(1R,2R)-N1,N2-二甲基环己-1,2-二胺(0.57g,0.40mmol)和碳酸钾(0.276g,2.00mmol)于1,4-二噁烷(10mL)中的混合物在120℃下搅拌18小时。冷却反应混合物到室温,且倒入乙酸乙酯(50mL)中。用水(3×10mL)洗涤混合物,经无水硫酸钠干燥,过滤,且在真空下浓缩。通过制备型薄层色谱(以1:2乙酸乙酯/石油醚洗提)纯化残余物,得到呈白色固体状的(S)-(5-环丁氧基-2-甲基-6-(1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.023g,13%)。1HNMR(300MHz,DMSO-d6)δppm 0.63-0.72(m,1H),0.77-0.91(m,2H),0.99-1.10(m,4H),1.15-1.19(m,1H),1.30-1.53(m,2H),1.72-1.95(m,5H),2.22-2.43(m,2H),2.95-2.96(m,1H),3.88-3.95(m,1H),4.63-4.71(m,1H),6.51(s,1H),7.24(d,J=8.70Hz,1H),7.41(d,J=8.70Hz,1H),7.73(s,1H),8.08(s,1H)。MS(ESI,正离子)m/z 352[M+H]+。
根据上文针对实例83所述的程序制备以下实例:
(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-325)
1H NMR(300MHz,DMSO-d6)δppm 0.65-0.99(m,3H),0.95-1.11(m,4H),1.35-1.50(m,1H),1.85-2.00(m,1H),2.02-2.15(m,1H),2.23-2.42(m,1H),2.50-2.65(m,1H),4.65-4.75(m,1H),6.31-6.35(m,1H),6.71-6.78(m,2H),6.90-7.01(m,1H),7.18-7.30(m,2H),7.45-7.50(m,1H),7.58-7.68(m,2H),8.02(s,1H)。MS(ESI,正离子)m/z 374[M+H]+。
实例84:(S)-(5-环丁氧基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-326)
步骤1.(S)-环丙基(5-羟基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将(S)-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(1.20g,3.87mmol)、2H-1,2,3-三唑(0.258g,3.74mmol)、碘化铜(I)(0.030g,0.16mmol)、(1R,2R)-N1,N2-二甲基环己-1,2-二胺(0.044g,0.31mmol)和碳酸钾(1.60g,11.61mmol)于N,N-二甲基甲酰胺(20mL)中的混合物在120℃下搅拌24小时。冷却反应混合物到室温,且倒入乙酸乙酯(100mL)中。用水(3×20mL)洗涤混合物,经无水硫酸钠干燥,过滤,且在真空下浓缩。通过硅胶柱色谱(以1:3乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色油状的(S)-环丙基(5-羟基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.150g,13%)。MS(ESI,正离子)m/z 299[M+H]+。
步骤2.(S)-(5-环丁氧基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
将(S)-环丙基(5-羟基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.055g,0.18mmol)、溴环丁烷(0.050g,0.37mmol)和碳酸铯(0.150g,0.46mmol)于乙腈(5mL)中的混合物在80℃下搅拌18小时。冷却反应混合物到室温且过滤,且在真空下浓缩滤液。通过制备型HPLC使用以下条件(Waters 1)纯化残余物:柱,XBridge PrepC18OBD柱,5μm,19×150mm;移动相,水(0.03%氨水)和乙腈(在10分钟内16%到34%乙腈,流动速率:20mL/min);检测器:UV 220和254nm。这得到呈白色固体状的(S)-(5-环丁氧基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.030g,45%)。1H NMR(300MHz,CD3OD)δppm 0.67-0.75(m,1H),0.85-0.95(m,2H),1.11-1.17(m,4H),1.22-1.55(m,3H),1.74-2.01(m,5H),2.31-2.46(m,2H),2.95-3.07(m,1H),3.88-3.94(m,1H),4.72-4.82(m,1H),7.28(d,J=8.40Hz,1H),7.37(d,J=8.40Hz,1H),7.99(s,2H)。MS(ESI,正离子)m/z 353[M+H]+。
实例85:(S)-环丙基(2-甲基-5-苯氧基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-327)
向配备有空气气球的50-mL圆底烧瓶中装入(S)-环丙基(5-羟基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.150g,0.50mmol)、苯基硼酸(0.185g,1.52mmol)、乙酸铜(II)(0.228g,1.26mmol)、吡啶(0.12mL,1.49mmol)、三乙胺(0.10mL,0.75mmol)和二氯甲烷(4mL),且在40℃下搅拌所得混合物18小时。冷却反应混合物到室温且过滤,且在真空下浓缩滤液。经硅胶柱色谱(以5%二氯甲烷/甲醇洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在7分钟内55%到75%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈白色固体状的(S)-环丙基(2-甲基-5-苯氧基-6-(2H-1,2,3-三唑-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.025g,14%)。1HNMR(300MHz,CD3OD)δppm 0.76-0.84(m,1H),0.91-1.06(m,2H),1.15-1.23(m,4H),1.43-1.52(m,1H),1.94-2.04(m,1H),2.21-2.49(m,2H),2.75-2.88(m,1H),4.75-4.83(m,1H),6.65-6.74(m,2H),6.92(d,J=7.20Hz,1H),7.17(t,J=7.50Hz,2H),7.52(d,J=8.70Hz,1H),7.62(d,J=8.70Hz,1H),7.75(s,2H)。MS(ESI,正离子)m/z 375[M+H]+。
实例86:(S)-(5-环丁氧基-2-甲基-6-(5-(哌啶-4-基)-1H-咪唑-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(I-328)
步骤1. 2,5-二溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑
将氢化钠(60%分散液,于矿物油中,0.212g,5.30mmol)分数份添加到2,5-二溴-1H-咪唑(0.600g,2.67mmol)于N,N-二甲基甲酰胺(4mL)中的0℃溶液中,且在0℃下搅拌所得混合物30分钟。在0℃下添加2-(三甲基硅烷基)乙氧基甲基氯(0.665g,4.01mmol)于N,N-二甲基甲酰胺(0.5mL)中的溶液,且在室温下再搅拌所得溶液2.5小时。将反应混合物倒入乙酸乙酯(20mL)中,用盐水(3×5mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以10:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色油状的2,5-二溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑(0.390g,41%)。MS(ESI,正离子)m/z 357,355,359[M+H]+。
步骤2.((S)-6-(5-溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-2-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
将(S)-(5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.200g,0.49mmol)、2,5-二溴-1-[[2-(三甲基硅烷基)乙氧基]甲基]-1H-咪唑(0.178g,0.50mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.046g,0.06mmol)和碳酸铯(0.549g,1.68mmol)于水(3mL)和1,4-二噁烷(10mL)中的混合物在80℃下搅拌隔夜。冷却反应混合物到室温且经短硅藻土衬垫过滤,且在真空下浓缩滤液。通过制备型薄层色谱(以50%乙酸乙酯/石油醚洗提)纯化残余物,得到呈白色固体状的((S)-6-(5-溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-2-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.091g,32%)。MS(ESI,正离子)m/z 560,562[M+H]+。
步骤3. 4-(2-((S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-5-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯
将((S)-6-(5-溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-2-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.091g,0.16mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(0.050g,0.16mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.013g,0.02mmol)和碳酸铯(0.159g,0.49mmol)于水(3mL)和1,4-二噁烷(10mL)中的混合物在80℃下搅拌隔夜。冷却反应混合物到室温且经短硅藻土衬垫过滤,且在真空下浓缩滤液。通过制备型薄层色谱(以1:2乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色固体状的4-(2-((S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-5-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(0.094g,87%)。MS(ESI,正离子)m/z663[M+H]+。
步骤4. 4-(2-((S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-5-基)哌啶-1-甲酸叔丁酯
将4-[2-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1-[[2-(三甲基硅烷基)乙氧基]甲基]-1H-咪唑-5-基]-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(0.094g,0.14mmol)和钯/碳(10wt%,0.047g)于甲醇(4mL)中的混合物在室温下于氢气气氛下搅拌30分钟。过滤反应混合物,且在真空下浓缩滤液,得到呈淡黄色固体状的4-(2-((S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-5-基)哌啶-1-甲酸叔丁酯(0.094g,100%)。MS(ESI,正离子)m/z 665[M+H]+。
步骤5.(S)-(5-环丁氧基-2-甲基-6-(5-(哌啶-4-基)-1H-咪唑-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
将氯化氢(气体)鼓入4-(2-((S)-5-环丁氧基-1-(环丙烷羰基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-咪唑-5-基)哌啶-1-甲酸叔丁酯(0.094g,0.14mmol)于二氯甲烷(4mL)和四氢呋喃(1mL)中的溶液中,且在室温下搅拌所得溶液1.5小时。在真空下浓缩反应混合物,且将残余物溶解于甲醇(5mL)中。用饱和碳酸钠水溶液将溶液的pH值调整到8,且用乙酸乙酯(3×10mL)萃取所得溶液。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在7分钟内55%到75%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈白色固体状的(S)-(5-环丁氧基-2-甲基-6-(5-(哌啶-4-基)-1H-咪唑-2-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.0018g,3%)。1H NMR(400MHz,CD3OD)δppm 0.71-0.78(m,1H),0.82-0.99(m,2H),1.13-1.18(m,4H),1.21-1.41(m,5H),1.55-1.65(m,1H),1.75-2.21(m,9H),2.32-2.48(m,2H),2.89-3.11(m,4H),3.31-3.34(m,1H),4.16-4.21(m,1H),4.70-4.81(m,1H),6.97(s,1H),7.26(d,J=8.40Hz,1H),7.65(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z435[M+H]+。
根据上文针对实例86所述的程序制备以下实例:
(S)-环丙基(2-甲基-5-苯氧基-6-(5-(哌啶-4-基)-1H-咪唑-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-329)
1H NMR(400MHz,CD3OD)δppm 0.75-0.83(m,1H),0.85-1.01(m,4H),1.14-1.18(m,3H),1.18-1.21(m,1H),1.25-1.40(m,2H),1.42-1.51(m,1H),1.52-1.77(m,3H),1.93-2.14(m,4H),2.18-2.22(m,2H),2.31-2.42(m,2H),2.72-2.89(m,2H),2.89-2.99(m,2H),3.20-3.31(m,2H),4.75(s,1H),4.81-4.86(m,1H),6.72-6.82(m,3H),6.92-6.99(m,1H),7.20-7.25(m,2H),7.48(d,J=8.40Hz,1H),7.83(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z 457[M+H]+。
实例87:(S)-环丙基(5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-330)
步骤1.(S)-4-(4-(1-(环丙烷羰基)-5-羟基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
将(S)-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(1.00g,3.24mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(2.40g,6.37mmol)、碳酸钠(0.686g,6.47mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.263g,0.32mmol)、1,4-二噁烷(15mL)和水(5mL)的混合物在80℃下搅拌隔夜。冷却反应混合物到室温,倒入水(20mL)中,且用乙酸乙酯(3×20mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以70%乙酸乙酯/石油醚洗提)纯化残余物,得到呈深红色固体状的(S)-4-(4-(1-(环丙烷羰基)-5-羟基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.400g,26%)。MS(ESI,正离子)m/z 481[M+H]+。
步骤2.(S)-4-(4-(1-(环丙烷羰基)-5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
将(S)-4-(4-(1-(环丙烷羰基)-5-羟基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.100g,0.21mmol)、4-溴-2,6-二甲基吡啶(0.077g,0.42mmol)、碘化铜(I)(0.004g,0.02mmol)、吡啶甲酸(0.013g,0.10mmol)和磷酸钾(0.133g,0.63mmol)于DMSO(2mL)中的混合物在90℃下搅拌隔夜。冷却反应混合物到室温,倒入水(5mL)中,且用乙酸乙酯(3×5mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经硅胶柱色谱(以1:2乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-4-(4-(1-(环丙烷羰基)-5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.030g,25%)。MS(ESI,正离子)m/z 586[M+H]+。
步骤3.(S)-环丙基(5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将三氟乙酸(1mL)添加到(S)-4-(4-(1-(环丙烷羰基)-5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.030g,0.05mmol)于二氯甲烷(3mL)中的溶液中,且在室温下搅拌所得溶液1小时。在真空下浓缩反应混合物,且经硅胶柱色谱(以1:2乙酸乙酯/石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化粗产物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在7分钟内65%到85%乙腈,流动速率:20mL/min);检测器,UV 220/254nm。这得到呈白色粉末状的(S)-环丙基(5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.003g,12%)。1HNMR(400MHz,CD3OD)δppm 0.73-0.84(m,1H),0.92-1.03(m,2H),1.12-1.21(m,4H),1.42-1.51(m,1H),1.99-2.20(m,5H),2.20-2.29(m,2H),2.29-2.41(m,6H),2.63-2.72(m,1H),2.95-3.04(m,2H),3.31-3.41(m,2H),4.35-4.45(m,1H),4.79-4.90(m,1H),6.53(s,2H),7.45(d,J=8.40Hz,1H),7.63(d,J=8.80Hz,1H),7.79(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 486[M+H]+。
根据上文针对实例87所述的程序制得以下实例:
(S)-环丙基(2-甲基-5-(6-甲基吡啶-2-基氧基)-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-331)
1H NMR(400MHz,CD3OD)δppm 0.62-0.71(m,1H),0.80-0.90(m,2H),1.03-1.10(m,4H),1.31-1.38(m,1H),1.70-1.81(m,2H),1.89-1.97(m,3H),2.11-2.27(m,2H),2.26(s,3H),2.55-2.69(m,3H),3.03-3.09(m,2H),4.05-4.16(m,1H),4.68-4.73(m,1H),6.39(d,J=8.40Hz,1H),6.80(d,J=8.40Hz,1H),7.28(d,J=8.40Hz,1H),7.46-7.51(m,2H),7.67(s,1H),7.86(s,1H)。MS(ESI,正离子)m/z 472[M+H]+。
(S)-环丙基(5-(2,6-二甲基吡啶-3-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-332)
1H NMR(300MHz,CD3OD)δppm 0.73-0.84(m,1H),0.88-1.01(m,2H),1.11-1.23(m,4H),1.25-1.33(m,1H),1.36-1.43(m,1H),1.91-2.11(m,5H),2.19-2.37(m,2H),2.40(s,3H),2.53-2.71((m,4H),2.80-2.92(m,2H),3.22-3.27(m,1H),4.28-4.37(m,1H),4.76-4.85(m,1H),6.58(d,J=8.40Hz,1H),6.88(d,J=8.40Hz,1H),7.38-7.41(m,1H),7.55-7.61(m,1H),7.71(s,1H),7.86(s,1H)。MS(ESI,正离子)m/z 486[M+H]+。
(S)-2-甲基-5-(6-甲基吡啶-2-基氧基)-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-333)
1H NMR(300MHz,CD3OD)δppm 1.13-1.19(m,3H),1.54-1.64(m,1H),1.88-1.99(m,2H),2.00-2.14(m,3H),2.41(s,4H),2.54-2.67(m,1H),2.69-2.79(m,2H),3.14-3.22(m,2H),3.82(s,3H),4.18-4.41(m,1H),4.65-4.73(m,1H),6.41(d,J=8.10Hz,1H),6.91(d,J=7.50Hz,1H),7.50-7.62(m,3H),7.76(s,1H),7.94(s,1H)。MS(ESI,正离子)m/z462[M+H]+。
(S)-1-(2-甲基-5-(6-甲基吡啶-2-基氧基)-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-334)
1H NMR(300MHz,CD3OD)δppm 1.09-1.21(m,3H),1.35-1.51(m,1H),1.81-1.95(m,2H),1.96-2.10(m,2H),2.16-2.31(m,5H),2.38(s,3H),2.61-2.81(m,3H),3.13-3.21(m,2H),4.19-4.29(m,1H),4.72-4.83(m,1H),6.49(d,J=8.70Hz,1H),6.90(d,J=7.20Hz,1H),7.32(br s,1H),7.55-7.63(m,2H),7.78(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 446[M+H]+。
(S)-5-(6-甲氧基吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-335)
1H NMR(300MHz,CD3OD)δppm 1.15(d,J=6.60Hz,3H),1.55-1.69(m,1H),1.75-1.91(m,2H),1.95-2.15(m,3H),2.40-2.79(m,4H),3.07-3.18(m,2H),3.66(s,3H),3.80(s,3H),4.15-4.22(m,1H),4.60-4.75(m,1H),6.30(d,J=7.80Hz,1H),6.38(d,J=7.80Hz,1H),7.48-7.61(m,3H),7.74(s,1H)。7.92(s,1H)。MS(ESI,正离子)m/z 478[M+H]+。
(S)-1-(5-(6-甲氧基吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-336)
1H NMR(300MHz,CD3OD)δppm 1.11(d,J=6.60Hz,3H),1.31-1.48(m,1H),1.78-1.94(m,2H),1.95-2.08(m,2H),2.18-2.39(m,2H),2.22(s,3H),2.60-2.82(m,3H),3.09-3.18(m,2H),3.60(s,3H),4.15-4.28(m,1H),4.70-4.88(m,1H),6.36-6.42(m,2H),7.18-7.34(m,1H),7.55-7.65(m,2H),7.77(s,1H),7.20(s,1H)。MS(ESI,正离子)m/z462[M+H]+。
实例88:(S)-环丙基(2-甲基-5-苯氧基-6-(4-(哌嗪-1-基)-1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-337)
步骤1.(S)-环丙基(2-甲基-6-(4-硝基-1H-吡唑-1-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮
向配备有经空气填充的气球的100-mL圆底烧瓶中装入(S)-环丙基(2-甲基-5-苯氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.240g,0.55mmol)、4-硝基-1H-吡唑(0.188g,1.66mmol)、乙酸铜(II)(0.301g,1.66mmol)、吡啶(0.2mL)和N,N-二甲基甲酰胺(5mL),且在90℃下搅拌所得混合物隔夜。冷却反应混合物到室温,且经硅藻土衬垫过滤。浓缩滤液,且通过制备型薄层色谱(以1:3乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-环丙基(2-甲基-6-(4-硝基-1H-吡唑-1-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(0.060g,26%)。MS(ESI,正离子)m/z419[M+H]+。
步骤2.(S)-(6-(4-氨基-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
将(S)-环丙基(2-甲基-6-(4-硝基-1H-吡唑-1-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(0.060g,0.15mmol)、铁粉(0.040g,0.72mmol)、氯化铵(0.023g,0.43mmol)、四氢呋喃(4mL)、乙醇(4mL)和水(1mL)的混合物在80℃下搅拌隔夜。冷却反应混合物到室温且过滤。在真空下浓缩滤液,且通过制备型薄层色谱(以1:1乙酸乙酯/石油醚洗提)纯化残余物,得到呈棕色固体状的(S)-(6-(4-氨基-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.045g,81%)。MS(ESI,正离子)m/z 389[M+H]+。
步骤3.(S)-环丙基(2-甲基-5-苯氧基-6-(4-(哌嗪-1-基)-1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将(S)-(6-(4-氨基-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.020g,0.05mmol)、双(2-溴乙基)胺(0.020g,0.09mmol)、碘化钠(0.003g,0.02mmol)和碳酸铯(0.084g,0.26mmol)于乙腈(2mL)中的混合物在85℃下搅拌隔夜。冷却反应混合物到室温且过滤。在真空下浓缩滤液,且通过制备型薄层色谱(以10%甲醇/二氯甲烷洗提)纯化残余物。通过制备型HPLC使用以下条件进一步纯化产物:柱:XBridgeRPC18,19×150mm,5μm;移动相:水(0.05%碳酸氢铵)和乙腈(在7.0分钟内5%到60%乙腈,流动速率:20mL/min);检测器:UV220和254nm。这得到呈淡黄色固体状的(S)-环丙基(2-甲基-5-苯氧基-6-(4-(哌嗪-1-基)-1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.0011g,5%)。1H NMR(300MHz,CD3OD)δppm 0.96-0.82(m,1H),0.91-1.06(m,2H),1.15-1.22(m,3H),1.31-1.38(m,2H),1.42-1.51(m,1H),1.95-2.07(m,1H),2.21-2.32(m,1H),2.33-2.45(m,1H),2.73-2.92(m,9H),4.55-4.65(m,1H),6.71-6.79(m,2H),6.93-7.01(m,1H),7.19-7.26(m,2H),7.40(s,1H),7.45-7.50(m,1H),7.54-7.63(m,2H)。MS(ESI,正离子)m/z 458[M+H]+。
根据上文针对实例88所述的程序制得以下实例:
(S)-环丙基(2-甲基-6-(4-吗啉基-1H-吡唑-1-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-338)
1H NMR(300MHz,CD3OD)δppm 0.74-0.86(m,1H),0.89-1.03(m,2H),1.13-1.24(m,4H),1.42-1.51(m,1H),1.93-2.07(m,1H),2.21-2.33(m,1H),2.33-2.47(m,1H),2.78-2.88(m,5H),3.70-3.80(m,4H),4.78-4.81(m,1H),6.74-6.78(m,2H),6.93-7.01(m,1H),7.18-7.24(m,2H),7.40-7.51(m,2H),7.55-7.63(m,2H)。MS(ESI,正离子)m/z 459[M+H]+。
(S)-2-甲基-6-(4-吗啉基-1H-吡唑-1-基)-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-339)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.60Hz,3H),1.55-1.64(m,1H),2.05-2.18(m,1H),2.49-2.58(m,1H),2.67-2.80(m,1H),2.80-2.86(m,4H),3.72-3.80(m,4H),3.84(s,3H),4.65-4.74(m,1H),6.68-6.73(m,2H),6.93-7.01(m,1H),7.16-7.23(m,2H),7.37(s,1H),7.49-7.55(m,2H),7.65-7.71(m,1H)。MS(ESI,正离子)m/z 449[M+H]+。
(S)-2-甲基-5-苯氧基-6-(4-(哌嗪-1-基)-1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-340)
1H NMR(300MHz,CD3OD)δppm 1.17(d,J=6.30Hz,3H),1.29-1.34(m,1H),1.56-1.65(m,1H),2.05-2.13(m,1H),2.50-2.59(m,1H),2.65-2.78(m,1H),2.82-2.91(m,4H),2.92-2.97(m,4H),3.82(s,3H),4.64-4.72(m,1H),6.68-6.74(m,2H),6.91-6.99(m,1H),7.15-7.24(m,2H),7.39(s,1H),7.50-7.54(m,2H),7.64-7.70(m,1H)。MS(ESI,正离子)m/z448[M+H]+。
实例89:(2S)-5-环丁氧基-6-[1-(1,1-二氧代基-1λ6-硫杂环己烷-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-341)
步骤1.甲烷磺酸1,1-二氧离子基四氢-2H-硫代吡喃-4-基酯
将三乙胺(7.80mL,55.9mmol)添加到4-羟基四氢-2H-硫代吡喃1,1-二氧化物(3.5g,23.3mmol)于二氯甲烷(35.0mL)中的溶液中。冷却反应溶液到0℃,且添加甲烷磺酰氯(3.25ml,41.9mmol)。10分钟后,使反应溶液升温到室温且搅拌3小时。经添加饱和氯化铵水溶液(15mL)淬灭反应物。分离有机层,且用饱和碳酸氢钠水溶液(15mL)和盐水(15mL)洗涤,经无水硫酸钠干燥,过滤且在真空中浓缩,得到灰白色固体。使固体残余物悬浮于乙酸乙酯(20mL)中且过滤。接着收集经过滤的固体且在真空中干燥,得到呈白色固体状的甲烷磺酸1,1-二氧离子基四氢-2H-硫代吡喃-4-基酯(5.1g,95%)。1H NMR(400MHz,CDCl3)δppm2.38-2.56(m,4H)2.94-3.06(m,2H)3.10(s,3H)3.23-3.39(m,2H)5.03(tt,J=4.74,2.49Hz,1H)。
步骤2.(2S)-5-环丁氧基-6-[1-(1,1-二氧代基-1λ6-硫杂环己烷-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯
将(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.160g,0.47mmol)、甲烷磺酸1,1-二氧离子基四氢-2H-硫代吡喃-4-基酯(0.320g,1.40mmol)和碳酸铯(0.457g,1.40mmol)于N,N-二甲基甲酰胺(5mL)中的混合物在110℃下搅拌隔夜。冷却反应混合物到室温,用水(20mL)稀释,且用乙酸乙酯(3×10mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。通过制备型薄层色谱(以50%乙酸乙酯/石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,Xbridge RP18 5μm,19×150mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内40%到80%乙腈;流动速率:20mL/min);检测器,UV 220和254nm。这得到呈白色固体状的(2S)-5-环丁氧基-6-[1-(1,1-二氧代基-1λ6-硫杂环己烷-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(0.040g,18%)。1H NMR(400MHz,CD3OD)δppm 1.18(d,J=6.40Hz,3H),1.29-1.31(m,1H),1.47-1.49(m,1H),1.60-1.62(m,1H),2.01-2.08(m,4H),2.11-2.24(m,1H),2.45-2.47(m,1H),2.63-2.68(m,4H),2.90-2.94(m,1H),3.10-3.17(m,2H),3.45-3.47(m,2H),3.78(s,3H),4.06-1.10(m,1H),4.45-4.58(m,2H),7.22(d,J=8.40Hz,1H),7.31(d,J=8.40Hz,1H),7.81(s,2H)。MS(ESI,正离子)m/z 474[M+H]+。
根据上文针对实例89所述的程序制得以下实例:
4-[4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1H-吡唑-1-基]-1λ6-硫杂环己烷-1,1-二酮(I-342)
1H NMR(400MHz,CD3OD)δppm 0.64-0.66(m,1H),0.83-0.85(m,1H),0.98-0.99(m,1H),1.13(d,J=6.40Hz,3H),1.24-1.37(m,3H),1.58-1.65(m,1H),1.82-1.85(m,1H),2.05-2.17(m,4H),2.32-2.36(m,2H),2.65-2.68(m,4H),2.92-2.99(m,1H),3.01-3.17(m,2H),3.45-3.46(m,2H),4.11-4.15(m,1H),4.50-4.58(m,1H),4.75-4.77(m,1H),7.14(d,J=8.00Hz,1H),7.26(d,J=8.00Hz,1H),7.85(s,1H),7.96(s,1H)。MS(ESI,正离子)m/z 484[M+H]+。
实例90:(S)-1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-甲腈(I-343)
将(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.100g,0.26mmol)、四(三苯基膦)钯(0)(0.30g,0.03mmol)和氰化锌(0.036g,0.31mmol)于N,N-二甲基甲酰胺(2mL)中的混合物在160℃下于微波照射下加热30分钟。冷却反应混合物到室温,倒入乙酸乙酯(10mL)中,用水(3×2mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经硅胶柱色谱(以1:8乙酸乙酯/石油醚洗提)纯化残余物,得到呈无色油状的(S)-1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-甲腈(0.27g,32%)。1H NMR(300MHz,CDCl3)δppm 0.74-0.82(m,1H),0.90-1.10(m,2H),1.10-1.18(m,3H),1.28-1.39(m,1H),1.49-1.61(m,1H),1.80-1.91(m,1H),2.10-2.22(m,1H),2.39-2.51(m,1H),2.67-2.80(m,1H),4.71-4.89(m,1H),6.85(d,J=8.10Hz,2H),7.08(t,J=7.50Hz,1H),7.28-7.38(m,2H),7.40-7.47(m,1H),7.49-7.55(m,1H)。MS(ESI,正离子)m/z 333[M+H]+。
(S)-6-氰基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-344)
根据上文针对(S)-1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-甲腈(实例90)所概述的程序合成(S)-6-氰基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1HNMR(300MHz,CD3Cl)δppm 1.12(d,J=6.60Hz,3H),1.52-1.70(m,1H),1.88-2.10(m,1H),2.42-2.72(m,2H),3.84(s,3H),4.62-4.80(m,1H),6.82(d,J=8.10Hz,2H),7.06(t,J=7.50Hz,1H),7.20-7.35(m,2H),7.48(d,J=8.70Hz,1H),7.75(d,J=8.70Hz,1H)。MS(ESI,正离子)m/z 323[M+H]+。
实例91:(S)-环丙基(6-乙炔基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(I-345)
将(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.030g,0.08mmol)、三丁基(乙炔基)锡烷(0.030g,0.09mmol)和四(三苯基膦)钯(0)(0.037g,0.03mmol)于N,N-二甲基甲酰胺(1.5mL)中的混合物在120℃下搅拌隔夜。冷却反应混合物到室温,倒入乙酸乙酯(15mL)中,用水(2×5mL)和盐水(5mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经制备型薄层色谱(以1:5乙酸乙酯/石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters III)进一步纯化产物:柱,Xbridge RP C18,19×150mm,5μm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内50%到100%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈棕色半固体状的(S)-环丙基(6-乙炔基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(0.004g,16%)。1H NMR(300MHz,CD3OD)δppm 0.65-0.85(m,1H),0.87-1.04(m,2H),1.05-1.25(m,4H),1.38-1.52(m,1H),1.85-2.02(m,1H),2.11-2.47(m,2H),2.62-2.85(m,1H),3.47(m,1H),4.75-4.82(m,1H),6.79(d,J=8.10Hz,2H),6.95-7.05(m,1H),7.19-7.39(m,3H),7.45(d,J=8.40Hz,1H)。MS(ESI,正离子)m/z 332[M+H]+。
实例92:(S)-6-乙炔基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-346)
根据上文针对(S)-环丙基(6-乙炔基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)甲酮(实例91)所概述的程序合成(S)-6-乙炔基-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-甲酸甲酯。1HNMR(300MHz,CD3OD)δppm 1.06(d,J=6.60Hz,3H),1.49-1.71(m,1H),1.85-2.06(m,1H),2.33-2.49(m,2H),3.73(s,3H),4.07(s,1H),4.54-4.60(m,1H),6.76(d,J=7.80Hz,2H),7.01(t,J=7.50Hz,1H),7.45-7.21(m,3H),7.57(d,J=8.70Hz,1H)。MS(ESI,正离子)m/z 322[M+H]+。
实例93:(S)-环丙基(2-甲基-5-苯氧基-6-(丙-1-炔基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-347)
将(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.050g,0.13mmol)、RuPhos第3代预催化剂(甲烷磺酸(2-二环己基膦基-2′,6′-二异丙氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II))(0.011g,0.01mmol)、氟化铯(0.099g,0.65mmol)和三丁基(丙-1-炔基)锡烷(0.107g,0.32mmol)于1,4-二噁烷(4mL)中的混合物在160℃下于微波照射下加热1小时。冷却反应混合物到室温,通过短硅藻土衬垫,且在真空下浓缩。经制备型薄层色谱(以1:5乙酸乙酯/石油醚洗提)纯化残余物。通过制备型HPLC使用以下条件(Waters I)进一步纯化产物:柱,SunFire Prep C18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内50%到100%乙腈,流动速率:20mL/min);检测器:UV 220和254nm。这得到呈淡棕色半固体状的(S)-环丙基(2-甲基-5-苯氧基-6-(丙-1-炔基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.011g,26%)。1H NMR(400MHz,CD3OD)δppm0.65-0.85(m,1H),1.02-0.87(m,2H),1.03-1.22(m,4H),1.37-1.51(m,1H),1.82(s,3H),1.88-2.03(m,1H),2.07-2.42(m,2H),2.58-2.82(m,1H),4.85-4.72(m,1H),6.78(d,J=7.80Hz,2H)7.00(t,J=7.50Hz,1H),7.25-7.31(m,4H)。MS(ESI,正离子)m/z 346[M+H]+。
实例94:(S)-环丙基(2-甲基-5-苯氧基-6-(4-(哌啶-4-基)-1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮(I-348)
步骤1.(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.300g,0.78mmol)、1H-吡唑(0.053g,0.78mmol)、氧化铜(I)(0.056g,0.39mmol)、碳酸铯(0.508g,1.56mmol)于N,N-二甲基甲酰胺(5mL)中的混合物在100℃下搅拌18小时。冷却所得混合物到室温,用水(20mL)稀释,且用乙酸乙酯(3×20mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经制备型薄层色谱(以1:10乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色固体状的(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.050g,17%)。MS(ESI,正离子)m/z 374[M+H]+。
步骤2.(S)-(6-(4-溴-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮
将N-溴代丁二酰亚胺(0.025g,0.15mmol)添加到(S)-环丙基(2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.050g,0.13mmol)于N,N-二甲基甲酰胺(2mL)中的溶液中,且在室温下搅拌所得溶液隔夜。用水(5mL)稀释反应混合物,且用乙酸乙酯(3×10mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经制备型薄层色谱(以1:10乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的(S)-(6-(4-溴-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.055g,91%)。MS(ESI,正离子)m/z 452,454[M+H]+。
步骤3.(S)-4-(1-(1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-4-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯
将(S)-(6-(4-溴-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮(0.060g,0.14mmol)、4-(四甲基-1,3,2-二氧硼戊环-2-基)-1,2,3,6-四氢吡啶-1-甲酸叔丁酯(0.049g,0.16mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.011g,0.01mmol)和碳酸铯(0.085g,0.26mmol)于1,4-二噁烷(8mL)和水(2mL)中的混合物在80℃下搅拌隔夜。冷却反应混合物到室温,通过短硅藻土衬垫,且在真空下浓缩。经制备型薄层色谱(以50%乙酸乙酯/石油醚洗提)纯化残余物,得到呈白色固体状的(S)-4-(1-(1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-4-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(0.050g,68%)。MS(ESI,正离子)m/z 555[M+H]+。
步骤4.(S)-4-(1-(1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-4-基)哌啶-1-甲酸叔丁酯
将(S)-4-(1-(1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-4-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(0.050g,0.09mmol)和钯/木炭(10%wt%,0.040g)于甲醇(15mL)中的混合物在室温下于氢气气氛下搅拌20分钟。过滤反应混合物且在真空下浓缩,得到呈白色固体状的(S)-4-(1-(1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(0.048g,99%)。MS(ESI,正离子)m/z 557[M+H]+。
步骤5.(S)-环丙基(2-甲基-5-苯氧基-6-(4-(哌啶-4-基)-1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮
将三氟乙酸(3mL)添加到(S)-4-(1-(1-(环丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-4-基)哌啶-1-甲酸叔丁酯(0.048g,0.09mmol)于二氯甲烷(10mL)中的溶液中,且在室温下搅拌所得溶液20分钟。用饱和碳酸钾水溶液将溶液的pH值调整到8,且用二氯甲烷(2×10mL)萃取所得溶液。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,SunFirePrepC18,5μm,19×100mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内20%到50%乙腈,流动速率:20mL/min);检测器,UV 220和254nm。这得到呈淡黄色固体状的(S)-环丙基(2-甲基-5-苯氧基-6-(4-(哌啶-4-基)-1H-吡唑-1-基)-3,4-二氢喹啉-1(2H)-基)甲酮(0.0095g,24%)。1H NMR(400MHz,CDCl3)δppm 0.65-0.78(m,1H),0.89-0.99(m,2H),1.03-1.16(m,4H),1.28-1.45(m,3H),1.61-1.82(m,2H),1.83-2.02(m,1H),2.18-2.22(m,1H),2.24-2.38(m,1H),2.45-2.62(m,3H),2.68-2.82(m,1H),2.88-3.01(m,2H),4.69-4.78(m,1H),6.64(d,J=8.80Hz,2H),6.84(t,J=7.60Hz,1H),7.08-7.11(m,2H),7.42-7.28(m,2H),7.38(d,J=8.80Hz,1H),7.48(s,1H)。MS(ESI,正离子)m/z 457[M+H]+。
实例95:(S)-5-环丁氧基-6-(2-(3-氟氮杂环丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-349)
步骤1.(S)-6-(2-(1-(叔丁氧基羰基)-3-羟基氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.400g,1.00mmol)、3-(4-溴噻唑-2-基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯(0.367g,1.10mmol)、碳酸钠(0.212g,2.00mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.082g,0.10mmol)于1,4-二噁烷(10mL)和水(3mL)中的溶液在80℃下搅拌隔夜。冷却反应混合物到室温,经硅藻土衬垫过滤,且在真空下浓缩。经硅胶柱色谱(以30%乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色固体状的(S)-6-(2-(1-(叔丁氧基羰基)-3-羟基氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.366g,69%)。MS(ESI,正离子)m/z 530[M+H]+。
步骤2.(S)-6-(2-(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟化(二乙基氨基)硫(DAST)(0.152g,0.94mmol)添加到(S)-6-(2-(1-(叔丁氧基羰基)-3-羟基氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.100g,0.19mmol)于二氯甲烷(4mL)中的-78℃溶液中,且在-78℃下搅拌所得溶液2小时。将反应混合物倒入饱和碳酸氢钠水溶液(20mL)中,且用二氯甲烷(3×20mL)萃取。经无水硫酸钠干燥经合并的有机层,过滤,且在真空下浓缩。经制备型薄层色谱(以30%乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色固体状的(S)-6-(2-(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.059g,59%)。MS(ESI,正离子)m/z 532[M+H]+。
步骤3.(S)-5-环丁氧基-6-(2-(3-氟氮杂环丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟乙酸(1mL)添加到(S)-6-(2-(1-(叔丁氧基羰基)-3-氟氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.059g,0.11mmol)于二氯甲烷(3mL)中的溶液中,且在室温下搅拌所得溶液2小时,接着在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,XBridge C18,19×150mm,5μm;移动相:水(0.05%碳酸氢铵)和乙腈(在8分钟内5%到95%乙腈;流动速率:20mL/min);检测器,UV220和254nm。这得到呈白色固体状的(S)-5-环丁氧基-6-(2-(3-氟氮杂环丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.025g,53%)。1H NMR(400MHz,CD3OD)δppm1.20(d,J=6.40Hz,3H),1.31-1.40(m,1H),1.45-1.55(m,1H),1.55-1.66(m,1H),2.02-2.18(m,4H),2.22-2.31(m,1H),2.49-2.55(m,1H),2.95-3.06(m,1H),3.80(s,3H),4.08-4.20(m,3H),4.28-4.36(m,2H),4.56-4.64(m,1H),7.24-7.27(m,1H),7.67-7.73(m,2H)。MS(ESI,正离子)m/z 432[M+H]+。
实例96:(S)-5-环丁氧基-6-(2-(3-甲氧基氮杂环丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-350)
步骤1.(S)-6-(2-(1-(叔丁氧基羰基)-3-甲氧基氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将氢化钠(60%分散液,于矿物油中,0.012g,0.30mmol)添加到(S)-6-(2-(1-(叔丁氧基羰基)-3-羟基氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.100g,0.19mmol)于N,N-二甲基甲酰胺(2mL)中的溶液中,且在室温下搅拌所得混合物30分钟。添加碘甲烷(0.014mL,0.23mmol),且在室温下搅拌所得混合物隔夜。将反应混合物倒入10mL水中,用3×10mL乙酸乙酯萃取。合并有机层,经无水硫酸钠干燥,且在真空下浓缩。通过制备型TLC使用乙酸乙酯/石油醚(1/3)纯化残余物。这得到70mg(68%)呈无色油状的(S)-6-(2-(1-(叔丁氧基羰基)-3-甲氧基氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯。MS(ESI,正离子)m/z 544[M+H]+。
步骤2.(S)-5-环丁氧基-6-(2-(3-甲氧基氮杂环丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将三氟乙酸(1mL)添加到(S)-6-(2-(1-(叔丁氧基羰基)-3-甲氧基氮杂环丁烷-3-基)噻唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.070g,0.13mmol)于二氯甲烷(3mL)中的溶液中,且在室温下搅拌所得溶液2小时。在真空下浓缩反应混合物,且通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,Xbridge C18,5μm,19×150nm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内25%到65%乙腈;流动速率:20mL/min);检测器,220和254nm。这得到呈灰白色固体状的(S)-5-环丁氧基-6-(2-(3-甲氧基氮杂环丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(0.037g,65%)。1HNMR(400MHz,CD3OD)1.20(d,J=6.80Hz,3H),1.25-65(m,3H),1.95-2.20(m,4H),2.20-2.31(m,1H),2.45-2.55(m,1H),2.90-3.01(m,1H),3.30(s,3H),3.80(s,3H),3.92-3.98(m,2H),4.10-4.22(m,3H),4.55-4.62(m,1H),7.36(d,J=8.40Hz,1H),7.82(d,J=8.40Hz,1H),7.95(s,1H)。MS(ESI,正离子)m/z 444[M+H]+。
实例97:(S,E)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-351)
和(S,Z)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(I-352)
步骤1. 1-烯丙基-2-溴-1H-苯并[d]咪唑
将2-溴-1H-苯并[d]咪唑(0.400g,2.04mmol)、烯丙基溴(0.35mL,4.08mmol)、1,4-二噁烷(15mL)和2M氢氧化钠水溶液(15mL,3.00mmol)的混合物在100℃下搅拌2小时。冷却反应混合物到室温,且用乙酸乙酯(50mL)稀释。分离有机相,且用盐水(30mL)洗涤,经无水硫酸钠干燥,过滤,且在真空下浓缩。经制备型薄层色谱(以20%乙酸乙酯/石油醚洗提)纯化残余物,得到呈黄色油状的1-烯丙基-2-溴-1H-苯并[d]咪唑(0.251g,52%)。MS(ESI,正离子)m/z 237,239[M+H]+。
步骤2.(S)-5-(1-烯丙基-1H-苯并[d]咪唑-2-基氧基)-6-溴-2-甲基-1,2,3,4-四氢喹啉
将(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.200g,0.71mmol)、1-烯丙基-2-溴-1H-苯并[d]咪唑(0.340g,1.44mmol)和碳酸钾(0.293g,2.12mmol)于N,N-二甲基乙酰胺(10mL)中的混合物在200℃下于微波中加热2小时。冷却反应混合物到室温,过滤,且在真空下浓缩。经制备型薄层色谱(以20%乙酸乙酯/石油醚洗提)纯化残余物,得到呈淡黄色固体状的(S)-5-(1-烯丙基-1H-苯并[d]咪唑-2-基氧基)-6-溴-2-甲基-1,2,3,4-四氢喹啉(0.115g,41%)。MS(ESI,正离子)m/z 398,400[M+H]+。
步骤3.(E/Z)-(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-((1-(丙-1-烯-1-基)-1H-苯并[d]咪唑-2-基)氧基)-1,2,3,4-四氢喹啉
将(S)-5-(1-烯丙基-1H-苯并[d]咪唑-2-基氧基)-6-溴-2-甲基-1,2,3,4-四氢喹啉(0.115g,0.29mmol)、1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.269g,1.15mmol)、碳酸钾(0.118g,0.85mmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.023g,0.03mmol)于1,4-二噁烷(10mL)和水(3mL)中的混合物在100℃下搅拌3小时。冷却反应混合物到室温,经短硅藻土衬垫过滤,且在真空下浓缩。经制备型薄层色谱(以1:2乙酸乙酯/石油醚洗提)纯化残余物,得到呈红色油状的(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-((1-(丙-1-烯-1-基)-1H-苯并[d]咪唑-2-基)氧基)-1,2,3,4-四氢喹啉(0.106g,86%),其为E与Z异构物的混合物。MS(ESI,正离子)m/z 426[M+H]+。
步骤4.E-和Z-(S)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮
将乙酰氯(0.035mL,0.49mmol)逐滴添加到E-和Z-(S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-1,2,3,4-四氢喹啉(0.070g,0.16mmol)和吡啶(0.029mL,0.36mmol)于二氯甲烷(20mL)中的0℃溶液中。在室温下使所得溶液保持2小时,接着在真空下浓缩。通过制备型HPLC使用以下条件(Waters I)纯化残余物:柱,Xbridge Prep C18,19×150mm;移动相,水(0.05%碳酸氢铵)和乙腈(在10分钟内37%到56%乙腈,流动速率:20mL/min);检测器,UV220和254nm。这得到呈淡黄色固体状的(S,E)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(2.6mg,3%)。(I-351)1H NMR(300MHz,CD3OD)δppm0.92-1.00(m,4H),1.19(d,J=6.60Hz,3H),1.51(br s,1H),1.71-1.80(m,3H),2.15-2.30(m,4H),2.31-2.45(m,1H),2.67-2.81(m,1H),3.51-3.65(m,1H),4.70-4.92(m,1H),6.11-6.25(m,1H),6.70-6.79(m,1H),7.10-7.25(m,3H),7.29-7.45(m,2H),7.54(d,J=8.40Hz,1H),7.66(s,1H),7.86(s,1H)。MS(ESI,正离子)m/z 468[M+H]+。E-丙烯立体化学试验性地指定。
还获得呈淡黄色固体状的(S,Z)-1-(6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-3,4-二氢喹啉-1(2H)-基)乙酮(2.4mg,3%)。(I-352)1H NMR(300MHz,CD3OD)δppm 0.88-1.00(m,4H),1.18(d,J=6.60Hz,3H),1.50(brs,1H),2.01-2.05(m,3H),2.15-2.30(m,4H),2.31-2.45(m,1H),2.65-2.82(m,1H),3.48-3.62(m,1H),4.72-4.92(m,1H),6.25-6.42(m,1H),7.05-7.35(m,4H),7.36-7.45(m,1H),7.48-7.58(m,2H),7.65(s,1H),7.84(s,1H)。MS(ESI,正离子)m/z 468[M+H]+。Z-丙烯立体化学试验性地指定。
实例98:(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮(I-353)
步骤1.(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)哌啶-1-甲酸叔丁酯
将经氢气加压的气球装入含有(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(500mg,1.17mmol)和20%氢氧化钯/碳(30mg,0.21mmol)于甲醇(10mL)中的悬浮液的圆底烧瓶中。在气球压力下搅拌反应物2小时。使反应物与氮气相通,且经硅藻土衬垫过滤。在真空中浓缩经过滤的溶液,且经硅胶柱色谱(Biotage 25g柱,以20-40%乙酸乙酯-己烷进行梯度洗提)纯化,得到呈无色油状的(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)哌啶-1-甲酸叔丁酯(500mg,100%)。MS(ESI,正离子)m/z 432[M+H]+。
步骤2.(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮
将氯化氢溶液(4.0N,于1,4-二噁烷中,1.4mL,5.6mmol)添加到(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)哌啶-1-甲酸叔丁酯(480mg,1.1mmol)于1,4-二噁烷(3mL)中的溶液中。搅拌反应物3小时,产生白色沉淀物。用乙醚(10mL)稀释反应溶液,且通过过滤收集沉淀物。再用乙醚(10mL)洗涤滤液,收集且在真空中干燥,得到呈白色粉末状的标题化合物的盐酸盐。经在乙酸乙酯中用饱和碳酸钠水溶液中和直到达到pH=7.5使盐呈游离碱形式。经无水硫酸钠干燥有机层,过滤且在真空中浓缩,得到呈无色固体状的(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮(356mg,97%)。1H NMR(300MHz,DMSO-d6)δppm 0.96-1.06(m,6H),1.11-1.26(m,1H),1.38-1.61(m,4H),1.66-1.89(m,2H),2.20(s,3H),2.16-2.28(m,2H),2.52(m,2H),2.67-2.80(m,2H),2.83-2.94(m,1H),2.99(br d,J=12.02Hz,2H),3.58-3.72(m,2H),4.40-4.63(br d,J=6.75Hz,1H),7.03(br s,2H)。MS(ESI,正离子)m/z 331[M+H]+。
实例99:(S)-1-(4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)哌啶-1-基)乙-1-酮(I-354)
将乙酰氯(6μL,0.08mmol)添加到(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(26.1mg,0.07mmol)和三乙胺(0.03mL,0.21mmol)于二氯甲烷(1.0mL)中的溶液中,且在室温下搅拌反应物隔夜。经硅胶柱色谱(Biotage 10g柱,以含10-20%甲醇的乙酸乙酯进行梯度洗提)直接纯化反应溶液,得到呈灰白色固体状的(S)-1-(4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)哌啶-1-基)乙-1-酮(19mg,71%)。1HNMR(300MHz,DMSO-d6)δppm 0.98-1.05(m,6H),1.17-1.29(m,1H),1.38-1.47(m,1H),1.54-1.59(m,1H),1.65-1.81(m,5H),2.01(s,6H),2.16-2.35(m,2H),2.48-2.59(m,1H),2.71-2.78(m,1H),3.01-3.03(m,2H),3.55-3.76(m,2H),3.90(br d,J=14.66Hz,1H),4.52(brd,J=13.20Hz,1H),7.04(br s,2H)。MS(ESI,正离子)m/z 373[M+H]+。
实例100:(S)-1-(2-甲基-6-(1-(甲基磺酰基)哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮(I-355)
将甲烷磺酰氯(4μL,0.05mmol)添加到(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(17.0mg,0.05mmol)和三乙胺(0.02mL,0.14mmol)于二氯甲烷(1.0mL)中的溶液中,且在室温下搅拌反应物隔夜。经硅胶柱色谱(Biotage 10g柱,以含10-0%己烷的乙酸乙酯进行梯度洗提)直接纯化反应溶液,得到呈白色固体状的(S)-1-(2-甲基-6-(1-(甲基磺酰基)哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮(14mg,72%)。1HNMR(300MHz,DMSO-d6)δppm 0.98-1.04(m,6H),1.19-1.26(m,1H),1.58-1.81(m,6H),2.02(s,3H),2.17-2.30(m,2H),2.68-2.85(m,3H),2.89(s,3H),2.89-2.99(m,1H),3.60-3.76(m,4H),4.57(br d,J=6.45Hz,1H),7.09(br s,2H)。MS(ESI,正离子)m/z409[M+H]+。
实例101:(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)-N-乙基哌啶-1-甲酰胺(I-356)
将三乙胺(0.05mL,0.35mmol)添加到(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(20.0mg,0.06mmol)于二氯甲烷(5mL)中的溶液中。冷却反应物到0℃,且添加溶解于二氯甲烷(3mL)中的三光气(6.3mg,0.02mmol)。使反应混合物升温到室温且搅拌3小时。接着按顺序添加吡啶(3μL,0.03mmol)和乙胺(2.7mg,0.06mmol),且搅拌溶液隔夜。经添加水(5mL)和1M柠檬酸(1mL)淬灭反应物。收集有机层且再用水(5mL)和盐水(5mL)洗涤。经无水硫酸钠干燥有机层,过滤且在真空中浓缩。经硅胶柱色谱(Biotage10g柱,以含0-5%甲醇的乙酸乙酯进行梯度洗提)纯化残余物,得到呈无色油状的(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)-N-乙基哌啶-1-甲酰胺(15mg,61%)。1H NMR(300MHz,DMSO-d6)δppm 0.97-1.05(m,6H),1.15(t,J=7.04Hz,3H),1.18-1.27(m,1H),1.37-1.53(m,2H),1.63(br d,J=11.73Hz,2H),1.69-1.78(m,2H),2.02(s,3H),2.15-2.30(m,2H),2.63-2.79(m,3H),2.90-3.07(m,3H),3.60-3.75(m,2H),4.07(brd,J=16.12Hz,2H),4.50-4.62(m,1H),6.45(br t,J=5.42Hz,1H),7.03(br s,2H)。MS(ESI,正离子)m/z 402[M+H]+。
实例102:(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)哌啶-1-甲酸甲酯(I-357)
将氯甲酸甲酯(5μL,0.06mmol)添加到(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(20mg,0.05mmol)和三乙胺(0.04mL,0.27mmol)于二氯甲烷(0.5mL)中的溶液中,且在室温下搅拌反应物隔夜。经添加水(5mL)淬灭反应物。收集有机层且再用水(5mL)和盐水(5mL)洗涤。经无水硫酸钠干燥有机层,过滤且在真空中浓缩。经硅胶柱色谱(Biotage 10g柱,以含10-20%甲醇的乙酸乙酯进行梯度洗提)纯化残余物,得到呈无色油状的(S)-4-(1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基)哌啶-1-甲酸甲酯(19mg,89%)。1H NMR(300MHz,DMSO-d6)δppm 0.94-1.07(m,6H),1.17-1.26(m,1H),1.43-1.57(m,2H),1.60-1.79(m,4H),2.01(s,3H),2.16-2.31(m,2H),2.68-2.91(m,3H),2.95-3.03(m,1H),3.58(s,3H),3.61-3.73(m,2H),4.04-4.15(m,2H),4.56(br d,J=6.45Hz,1H),7.05(br s,2H)。MS(ESI,正离子)m/z 389[M+H]+。
实例103:(S)-1-(6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮(I-358)
将碘乙烷(5μl,0.06mmol)添加到(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙酮(20mg,0.06mmol)和碳酸钾(38mg,0.27mmol)于DMF(1.0mL)中的溶液中,且在室温下搅拌反应物隔夜。经添加水(5mL)淬灭反应物,且用乙酸乙酯(2×10mL)萃取。收集有机层且再用水(5mL)和盐水(5mL)洗涤,经无水硫酸钠干燥,过滤,且在真空中浓缩。经硅胶柱色谱(Biotage 10g柱,以含50-80%甲醇的乙酸乙酯进行梯度洗提)纯化残余物,得到呈淡黄色油状的(S)-1-(6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮(10mg,51%)。1H NMR(300MHz,DMSO-d6)δppm 0.96-1.06(m,6H),1.15(t,J=7.04Hz,3H),1.15-1.26(m,1H),1.38-1.61(m,4H),1.66-1.89(m,2H),2.20(s,3H),2.16-2.28(m,2H),2.52(m,2H),2.67-2.80(m,2H),2.83-2.94(m,1H),2.92-3.07(m,3H),3.58-3.72(m,2H),4.40-4.63(br d,J=6.75Hz,1H),7.03(br s,2H)。MS(ESI,正离子)m/z359[M+H]+。
实例104:(S)-1-(2-甲基-5-(苯基氨基)-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)乙-1-酮(I-359)
步骤1.(S)-4-(4-(1-乙酰基-5-羟基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
将XPhos第2代预催化剂(0.186g,0.24mmol)添加到(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.672g,2.36mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(0.892g,2.36mmol)和磷酸钾(2.51g,11.8mmol)于1,4-二噁烷(4.0mL)和水(0.8mL)中的经氮气净化溶液中,且在100℃下加热反应混合物隔夜。经硅胶柱色谱(Biotage 25g柱,以含30-10%己烷的乙酸乙酯进行梯度洗提)直接纯化粗反应混合物,得到呈白色松散粉末状的(S)-4-(4-(1-乙酰基-5-羟基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(225mg,21%)。MS(ESI,正离子)m/z 455[M+H]+。
步骤2.(S)-4-(4-(1-乙酰基-2-甲基-5-(((三氟甲基)磺酰基)氧基)-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
将三乙胺(0.07mL,0.54mmol)和N,N-二甲基吡啶-4-胺(6.1mg,0.049mmol)添加到(S)-4-(4-(1-乙酰基-5-羟基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(225mg,0.495mmol)于二氯甲烷(4.5mL)中的溶液中。冷却反应溶液到0℃,且逐滴添加N-(5-氯吡啶-2-基)-1,1,1-三氟-N-((三氟甲基)磺酰基)甲烷磺酰胺(214mg,0.544mmol)(澄清溶液变成淡黄橙色)。接着使反应混合物缓慢升温返回到室温,且搅拌2小时。经硅胶柱色谱(Biotage 25g柱,以含0-4%MeOH的二氯甲烷进行梯度洗提)直接纯化反应溶液,得到呈白色固体状的(S)-4-(4-(1-乙酰基-2-甲基-5-(((三氟甲基)磺酰基)氧基)-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(290mg,100%)。MS(ESI,正离子)m/z 587[M+H]+。
步骤3.(S)-4-(4-(1-乙酰基-2-甲基-5-(苯基氨基)-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
将XPhos第2代预催化剂(10.7mg,0.014mmol)添加到(S)-4-(4-(1-乙酰基-2-甲基-5-(((三氟甲基)磺酰基)氧基)-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(40mg,0.068mmol)、苯胺(7μL,0.075mmol)和磷酸钾(43.4mg,0.20mmol)于1,4-二噁烷(0.5mL)中的经氮气净化溶液中,且在100℃下加热反应混合物隔夜。经硅胶柱色谱(Biotage 25g柱,以含25-40%乙酸乙酯的己烷进行梯度洗提)直接纯化粗反应混合物,得到呈淡黄色油状的(S)-4-(4-(1-乙酰基-2-甲基-5-(苯基氨基)-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯与(S)-4-(4-(1-乙酰基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯的混合物(31mg)。MS(ESI,正离子)m/z 530[M+H]+和438[M+H]+。
步骤4.(S)-4-(4-(1-乙酰基-5-((叔丁氧基羰基)(苯基)氨基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯
将二碳酸二叔丁酯(0.02mL,0.088mmol)添加到含有(S)-4-(4-(1-乙酰基-2-甲基-5-(苯基氨基)-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯与(S)-4-(4-(1-乙酰基-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯的混合物(31mg,0.059mmol)和DMAP(7.2mg,0.059mmol)于THF(1.0mL)中的0℃溶液中。使反应混合物升温到室温且搅拌3小时。在真空中浓缩反应溶液,且经硅胶柱色谱(Biotage 25g柱,以含40-50%乙酸乙酯的己烷进行梯度洗提)直接纯化粗产物,得到呈白色固体状的(S)-4-(4-(1-乙酰基-5-((叔丁氧基羰基)(苯基)氨基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(29.5mg,80%)。MS(ESI,正离子)m/z 630[M+H]+。
步骤5.(S)-1-(6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮
将氯化氢(4N,于1,4-二噁烷中,0.024mL,0.095mmol)添加到(S)-4-(4-(1-乙酰基-5-((叔丁氧基羰基)(苯基)氨基)-2-甲基-1,2,3,4-四氢喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(12mg,0.019mmol)于二噁烷(1.0mL)中的溶液中。在室温下搅拌反应溶液1小时,产生白色沉淀物。在氮气流下浓缩反应溶液,添加乙醚(1mL),且经添加饱和碳酸氢钠水溶液(1mL)中和产物。收集有机层,经无水硫酸钠干燥,过滤,且在真空中浓缩,得到呈淡黄色蜡状固体状的(S)-1-(6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-3,4-二氢喹啉-1(2H)-基)乙-1-酮(5.1mg,62%)。1H NMR(300MHz,DMSO-d6)δppm 1.03(d,J=6.74Hz,3H),1.11-1.25(m,2H),1.35-1.52(m,1H),1.61-1.69(m,1H),1.76-1.90(m,2H),1.97-2.10(m,2H),2.15(s,3H),2.19-2.30(m,1H),2.36-2.44(m,1H),2.91-3.01(m,2H),3.98-4.16(m,1H),4.53-4.68(m,1H),6.84-7.04(m,2H),7.04-7.11(m,1H),7.12-7.19(m,1H),7.29-7.37(m,3H),7.83(s,1H),8.11(s,1H),10.02(br s,1H)。MS(ESI,正离子)m/z 430[M+H]+。
实例105:(S)-5-环丁氧基-6-(5-氟-1-(哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-360)
步骤1. 1-苯甲基-4-(4-溴-1H-吡唑-1-基)哌啶
将苯甲基溴(0.42mL,3.56mmol)和碳酸钾(670mg,4.85mmol)添加到4-(4-溴-1H-吡唑-1-基)哌啶(743.7mg,3.23mmol)于DMF(10mL)中的溶液中,且在室温下搅拌反应物隔夜。通过添加水(50mL)淬灭反应物,且用乙酸乙酯(3×50mL)萃取。合并有机萃取物,且用水(2×50mL)和盐水(30mL)洗涤,经无水硫酸钠干燥,过滤且在真空中浓缩。经硅胶柱色谱(Biotage 25g柱,以含20-30%乙酸乙酯的己烷进行梯度洗提)直接纯化粗产物,得到呈淡黄色油状的1-苯甲基-4-(4-溴-1H-吡唑-1-基)哌啶(673mg,65%)。MS(ESI,正离子)m/z321[M+H]+。
步骤2. 1-苯甲基-4-(4-溴-5-氟-1H-吡唑-1-基)哌啶
将二异丙基胺化锂溶液(1.0M,于THF/己烷中)(1.25mL,1.25mmol)缓慢添加到1-苯甲基-4-(4-溴-1H-吡唑-1-基)哌啶(200mg,0.625mmol)于THF(2.0mL)中的-78℃溶液中,且在-78℃下搅拌反应物1小时。添加N-氟-N-(苯基磺酰基)苯磺酰胺(295mg,0.937mmol),且在-78℃下再搅拌反应物1小时。经添加饱和氯化铵水溶液(5mL)淬灭反应物。使反应物升温到室温,且在真空中浓缩。添加乙酸乙酯(25mL),且用水(2×10mL)和盐水(10mL)洗涤有机溶液。经无水硫酸钠干燥有机层,过滤,且在真空中浓缩。经硅胶柱色谱(Biotage 25g柱,以含20-30%乙酸乙酯的己烷进行梯度洗提)直接纯化粗产物,得到呈淡黄色油状的1-苯甲基-4-(4-溴-5-氟-1H-吡唑-1-基)哌啶(53mg,25%)。MS(ESI,正离子)m/z 339[M+H]+。
步骤3.(S)-6-(1-(1-苯甲基哌啶-4-基)-5-氟-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将XPhos第2代预催化剂(6.0mg,0.008mmol)添加到(S)-5-环丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(30.8mg,0.077mmol)、1-苯甲基-4-(4-溴-5-氟-1H-吡唑-1-基)哌啶(26.0mg,0.077mmol)和磷酸钾(81mg,0.384mmol)于1,4-二噁烷(1.00mL)和水(0.20mL)中的经氮气净化溶液中,且在100℃下加热反应混合物隔夜。经硅胶柱色谱(Biotage 25g柱,以含10-20%乙酸乙酯的己烷进行梯度洗提)直接纯化粗反应混合物,得到呈白色固体状的(S)-6-(1-(1-苯甲基哌啶-4-基)-5-氟-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(16mg,39%)。MS(ESI,正离子)m/z 533[M+H]+。
步骤4.(S)-5-环丁氧基-6-(5-氟-1-(哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将填充氢气的气球装入(S)-6-(1-(1-苯甲基哌啶-4-基)-5-氟-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(15.0mg,0.028mmol)和20%氢氧化钯/碳(40mg,0.285mmol)于甲醇(10mL)中的经氮气净化悬浮液中。用氢气回填反应烧瓶3次。接着在氢气气氛下搅拌反应溶液2小时。用氮气净化烧瓶,且经硅藻土过滤反应混合物,且用乙酸乙酯(10mL)洗涤硅藻土床。接着在真空中浓缩经过滤的溶剂。将粗产物直接添加到硅胶栓塞中且用含30%乙酸乙酯的甲醇洗提,得到呈灰白色固体状的(S)-5-环丁氧基-6-(5-氟-1-(哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(7.2mg,58%)。1H NMR(300MHz,DMSO-d6)δppm 1.09(d,J=6.45Hz,3H),1.21-1.30(m,2H),1.42-1.57(m,1H),1.76-1.88(m,3H),1.89-2.01(m,5H),2.34-2.43(m,2H),2.53-2.61(m,1H),2.71-2.85(m,2H),3.03(br d,J=12.31Hz,1H),3.13-3.21(m,1H),3.68(s,3H),3.95-4.05(m,1H),4.15-4.30(m,1H),4.41-4.52(m,1H),7.14(d,J=8.15Hz,1H),7.29(d,J=8.79Hz,1H),7.61(s,1H)。MS(ESI,正离子)m/z 443[M+H]+。
实例106:(S)-5-环丁氧基-6-(1-((3S,4R)-3-氟哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-361)
步骤1.(3S,4S)-3-氟-4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯
将三乙胺(0.95mL,6.8mmol)添加到(3S,4S)-3-氟-4-羟基哌啶-1-甲酸叔丁酯(500.0mg,2.28mmol)和甲烷磺酰氯(0.27mL,3.4mmol)于二氯甲烷(9mL)中的0℃溶液中,且使所得混合物升温到室温且搅拌隔夜。用饱和碳酸氢钠水溶液(10mL)淬灭反应物。再添加二氯甲烷(10mL),且分离各层。用1M柠檬酸水溶液(10mL)和盐水(10mL)洗涤有机层,经无水硫酸钠干燥,过滤且在真空中浓缩。经硅胶柱色谱(Biotage 50g柱,以含20-30%乙酸乙酯的己烷进行梯度洗提)直接纯化粗产物,得到呈无色油状的(3S,4S)-3-氟-4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯(629mg,93%),其在静置时凝固成白色固体。1H NMR(300MHz,CDCl3)δppm 1.46(s,9H),1.73-1.87(m,1H),2.15-2.25(m,1H),2.97-3.12(m,2H),3.08(s,3H),3.85-3.95(m,1H),4.39-4.46(m,1H),4.55-4.62(m,1H),4.65-4.78(m,1H)。
步骤2.(S)-6-(1-((3S,4R)-1-(叔丁氧基羰基)-3-氟哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(3S,4S)-3-氟-4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯(96mg,0.322mmol)添加到(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(100mg,0.293mmol)和碳酸铯(153mg,0.469mmol)于DMF(1.0mL)中的溶液中,且在100℃下加热反应混合物1小时。冷却反应溶液到室温,用水稀释,且用乙酸乙酯(3×50mL)萃取。用水(2×25mL)和盐水(25mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空中浓缩。经硅胶柱色谱(Biotage 25g柱,以含20-30%乙酸乙酯的己烷进行梯度洗提)纯化粗产物,得到呈无色油状的(S)-6-(1-((3S,4R)-1-(叔丁氧基羰基)-3-氟哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(89mg,56%)。MS(ESI,正离子)m/z 543[M+H]+。
步骤3.(S)-5-环丁氧基-6-(1-((3S,4R)-3-氟哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将氯化氢(4.0N,于1,4-二噁烷中,0.23mL,0.931mmol)添加到(S)-6-(1-((3S,4R)-1-(叔丁氧基羰基)-3-氟哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(101mg,0.186mmol)于1,4-二噁烷(1.0mL)中的溶液中,且在室温下搅拌反应混合物3小时。在氮气流下浓缩反应溶液,用饱和碳酸氢钠水溶液(1mL)稀释,且用乙酸乙酯(3×1mL)萃取。将经合并的有机层直接添加到硅胶栓塞中且用含30%乙酸乙酯的甲醇洗提,得到呈白色固体状的(S)-5-环丁氧基-6-(1-((3S,4R)-3-氟哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯(38mg,47%)。1H NMR(300MHz,DMSO-d6)δppm 1.07(d,J=6.45Hz,3H),1.19-1.39(m,2H),1.47-1.58(m,1H),1.96-2.18(m,8H),2.34-2.43(m,2H),2.55-2.72(m,1H),2.77-2.89(m,2H),3.00-3.13(m,1H),3.14(br d,J=4.98Hz,1H),3.65(s,3H),4.02-4.12(m,1H),4.37-4.49(m,1H),4.78-4.94(m,1H),7.21(d,J=8.50Hz,1H),7.32(d,J=8.79Hz,1H),7.83(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z443[M+H]+。
根据上文针对实例106所述的程序制得以下实例:
(2S)-5-环丁氧基-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-362)
1H NMR(300MHz,DMSO-d6)δppm 1.07(d,J=6.45Hz,3H),1.19-1.39(m,2H),1.47-1.58(m,1H),1.96-2.18(m,8H),2.34-2.43(m,2H),2.55-2.72(m,1H),2.77-2.89(m,2H),3.00-3.13(m,1H),3.14(br d,J=4.98Hz,1H),3.65(s,3H),4.02-4.12(m,1H),4.31-4.49(m,1H),4.72-4.94(m,1H),7.21(d,J=8.50Hz,1H),7.32(d,J=8.79Hz,1H),7.83(s,1H),8.00(s,1H)。MS(ESI,正离子)m/z 443[M+H]+。
(2S)-5-环丁氧基-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-363)
1H NMR(300MHz,DMSO-d6)δppm 1.06(d,J=6.45Hz,3H),1.19-1.39(m,2H),1.47-1.58(m,1H),1.89-2.18(m,8H),2.34-2.43(m,2H),2.55-2.72(m,1H),2.77-2.87(m,2H),2.88-2.95(m,1H),3.65(s,3H),4.01-4.11(m,1H),4.31-4.45(m,1H),4.60-4.84(m,1H),7.21(d,J=8.50Hz,1H),7.28(d,J=8.79Hz,1H),7.82(s,1H),8.08(s,1H)。MS(ESI,正离子)m/z 443[M+H]+。
(2S)-5-(4-氟苯氧基)-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-364)
1H NMR(300MHz,DMSO-d6)δppm 1.04(d,J=6.74Hz,3H),1.51(dd,J=13.34,5.72Hz,1H),1.79-1.98(m,4H),2.34-2.46(m,4H),2.87(br d,J=9.09,1H),3.19-3.29(m,1H),3.70(s,3H),4.17-4.35(m,1H),4.50-4.77(m,2H),6.73-6.77(m,2H),7.06-7.12(m,2H),7.54(d,J=2.93Hz,2H),7.76(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(2S)-5-(4-氟苯氧基)-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-365)
1H NMR(300MHz,DMSO-d6)δppm 1.04(d,J=6.74Hz,3H),1.51(dd,J=13.92,4.84Hz,1H),1.71-1.80(m,1H),1.90-2.04(m,3H),2.34-2.46(m,4H),2.93-3.10(m,1H),3.11-3.19(m,1H),3.70(s,3H),4.27-4.42(m,1H),4.48-4.57(m,1H),4.65-4.84(m,1H),6.72-6.76(m,2H),7.06-7.12(m,2H),7.51-7.61(m,2H),7.76(s,1H),7.94(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-366)
1H NMR(300MHz,DMSO-d6)δppm 1.04(d,J=6.74Hz,3H),1.51(dd,J=13.92,4.84Hz,1H),1.71-1.80(m,1H),1.90-2.04(m,3H),2.34-2.46(m,4H),2.93-3.10(m,1H),3.11-3.19(m,1H),3.70(s,3H),4.27-4.42(m,1H),4.48-4.57(m,1H),4.63-4.85(m,1H),6.72-6.76(m,2H),7.06-7.12(m,2H),7.51-7.61(m,2H),7.76(s,1H),7.94(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(2S)-5-环丁氧基-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-367)
1H NMR(300MHz,DMSO-d6)δppm 1.06(d,J=6.45Hz,3H),1.17-1.28(m,1H),1.29-1.42(m,1H),1.47-1.56(m,1H),1.86-2.17(m,8H),2.34-2.43(m,2H),2.55-2.72(m,1H),2.77-2.87(m,2H),2.88-2.95(m,1H),3.65(s,3H),4.01-4.11(m,1H),4.31-4.45(m,1H),4.60-4.84(m,1H),7.21(d,J=8.50Hz,1H),7.28(d,J=8.79Hz,1H),7.82(s,1H),8.08(s,1H)。MS(ESI,正离子)m/z 443[M+H]+。
(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-368)
1H NMR(300MHz,DMSO-d6)δppm 1.04(d,J=6.74Hz,3H),1.51(dd,J=13.92,4.84Hz,1H),1.71-1.84(m,2H),1.90-2.04(m,3H),2.67-2.73(m,1H),2.81-2.93(m,2H),3.11-3.19(m,1H),3.70(s,3H),4.23-4.36(m,1H),4.50-4.60(m,1H),4.63-4.83(m,1H),6.72-6.76(m,2H),7.06-7.12(m,2H),7.54(d,J=2.93Hz,2H),7.76(s,1H),8.02(s,1H)。MS(ESI,正离子)m/z 483[M+H]+。
(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉(I-369)
1H NMR(300MHz,DMSO-d6)δppm 0.59-0.68(m,1H),0.73-0.87(m,2H),0.91-0.98(m,1H),1.01(d,J=6.45Hz,3H),1.17-1.31(m,2H),1.49-1.59(m,1H),1.73-1.93(m,2H),1.96-2.17(m,6H),2.23-2.33(m,2H),2.60-2.77(m,1H),2.86-2.95(m,2H),4.05-4.18(m,1H),4.29-4.39(m,1H),4.43-4.62(m,2H),4.74-4.97(m,1H),7.08(d,J=8.50Hz,1H),7.42(d,J=8.50Hz,1H),7.87(s,1H),8.07(s,1H)。MS(ESI,正离子)m/z453[M+H]+。
(2S)-5-环丁氧基-6-{1-[(3R,4S)-4-氟吡咯烷-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-370)和(2S)-5-环丁氧基-6-{1-[(3S,4R)-4-氟吡咯烷-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯(I-371)
异构物的2:1混合物。主要异构物:1H NMR(300MHz,DMSO-d6)δppm 1.09(d,J=6.45Hz,3H),1.19-1.43(m,2H),1.49-1.60(m,1H),1.99-2.22(m,4H),2.35-2.43(m,1H),2.79-3.11(m,4H),3.68(s,3H),4.07-4.15(m,1H),4.40-4.47(m,1H),4.69-4.85(m,1H),5.01-5.18(m,2H),5.26-5.37(m,1H),7.23(d,J=8.50Hz,1H),7.33(d,J=8.79Hz,1H),7.84(s,1H),8.10(s,1H)。MS(ESI,正离子)m/z 429[M+H]+。
(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-[(3R,4S)-4-氟哌啶-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉(I-372)和(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-[(3S,4R)-4-氟哌啶-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氢喹啉(I-373)
异构物的1:1混合物。1H NMR(300MHz,CDCl3)δppm 0.51-0.62(m,1H),0.73-0.83(m,2H),0.87-0.95(m,1H),1.06(d,J=6.45Hz,3H),1.12-1.30(m,4H),1.50-1.63(m,1H),1.73-1.82(m,1H),1.90-2.15(m,7H),2.23-2.33(m,2H),2.88-2.98(m,1H),3.05-3.32(m,1H),3.41-3.62(m,1H),4.00-4.11(m,1H),4.60-4.73(m,1H),4.96-5.29(m,1H),7.06(d,J=8.21Hz,1H),7.19(m,1H),7.78(s,1H),7.89(s,1H)。MS(ESI,正离子)m/z 453[M+H]+。
实例107:(S)-5-环丁氧基-2-甲基-6-(1-((2S,4R)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-374)和(S)-5-环丁氧基-2-甲基-6-(1-((2R,4S)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-375)
步骤1. 2-甲基-4-氧代基哌啶-1-甲酸叔丁酯
将二碳酸二叔丁酯(1.09g,5.01mmol)添加到2-甲基哌啶-4-酮盐酸盐(异构物的1:1混合物,0.500g,3.34mmol)和DMAP(0.817g,6.68mmol)于无水THF(10mL)中的0℃溶液中,且在0℃下搅拌所得混合物2小时。通过添加饱和氯化铵水溶液(50mL)淬灭反应物,且添加乙酸乙酯(70mL)。分离水相,且用乙酸乙酯(2×50mL)萃取。用盐水(50mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空中浓缩。经硅胶柱色谱(Biotage50g柱,以含25-35%乙酸乙酯的己烷进行梯度洗提)纯化残余物,得到呈白色固体状的2-甲基-4-氧代基哌啶-1-甲酸叔丁酯(0.660g,93%)。1H NMR(300MHz,DMSO-d6)δppm1.06(d,J=6.74Hz,3H),1.40(s,9H),2.11-2.25(m,2H),2.36-2.45(m,1H),2.68(dd,J=14.51,6.6Hz,1H),3.25-3.36(m,1H),3.93-4.06(m,1H),4.42-4.48(m,1H)。
步骤2.(外消旋)-(顺)-4-羟基-2-甲基哌啶-1-甲酸叔丁酯和(外消旋)-(反)-4-羟基-2-甲基哌啶-1-甲酸叔丁酯
遵循见于Plettenburg,Oliver等人(PCT国际申请案2007012421)中的程序,将硼氢化钠(213mg,5.6mmol)逐份添加到2-甲基-4-氧代基哌啶-1-甲酸叔丁酯(1.0g,4.7mmol)于乙醇(10mL)中的溶液中。在室温下搅拌混合物2小时。在真空中浓缩溶液,接着分配于水(40mL)与乙酸乙酯(40mL)之间。用乙酸乙酯(40mL)萃取水层两次。用盐水(20mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空中浓缩。经硅胶柱色谱(Biotage50g柱,以含40-50%乙酸乙酯的己烷进行梯度洗提)纯化残余物,得到呈白色固体状的(外消旋)-(顺)-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(367mg,36%)和(外消旋)-(反)-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(205mg,20%)。
步骤3.(外消旋)-(顺)-2-甲基-4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯
将三乙胺(0.49mL,3.49mmol)添加到(外消旋)-(顺)-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(250mg,1.16mmol)和甲烷磺酰氯(0.14mL,1.74mmol)于二氯甲烷(4.5mL)中的0℃溶液中。使所得混合物升温到室温且搅拌隔夜。通过添加饱和碳酸氢钠水溶液(10mL)淬灭反应物,且添加二氯甲烷(10mL)。分离有机层,且用1M柠檬酸水溶液(10mL)和盐水(10mL)洗涤,经无水硫酸钠干燥,过滤,且在真空中浓缩。经硅胶柱色谱(Biotage 50g柱,以含20-30%乙酸乙酯的己烷进行梯度洗提)纯化残余物,得到呈无色油状的(外消旋)-(顺)-2-甲基-4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯(315mg,92%),其在静置时缓慢凝固成白色固体。1H NMR(300MHz,DMSO-d6)δppm 1.17(d,J=7.04Hz,3H),1.38(s,9H),1.63-1.76(m,1H),1.85-1.90(m,3H),2.96-3.06(m,1H),3.18(s,3H),3.72-3.78(m,1H),4.16-4.24(m,1H),4.93-4.98(m,1H)。
步骤4.(S)-6-(1-((2S,4R)-1-(叔丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯和(S)-6-(1-((2R,4S)-1-(叔丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯
将(外消旋)-(顺)-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(55.9mg,0.190mmol)添加到(S)-5-环丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(50.0mg,0.146mmol)和碳酸铯(76mg,0.234mmol)于DMF(1.0mL)中的溶液中,且加热反应混合物到100℃,且搅拌隔夜。冷却混合物到室温,用水稀释,且用乙酸乙酯(3×50mL)萃取。用水(2×25mL)和盐水(25mL)洗涤经合并的有机层,经无水硫酸钠干燥,过滤,且在真空中浓缩。经硅胶柱色谱(Biotage 25g柱,以含20-30%乙酸乙酯的己烷进行梯度洗提)纯化残余物,得到呈无色油状的(S)-6-(1-((2S,4R)-1-(叔丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯与(S)-6-(1-((2R,4S)-1-(叔丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯的1:1混合物(54.2mg,69%)。MS(ESI,正离子)m/z 539[M+H]+。
步骤5.(S)-5-环丁氧基-2-甲基-6-(1-((2S,4R)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯和(S)-5-环丁氧基-2-甲基-6-(1-((2R,4S)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯
将氯化氢(4.0N,于1,4-二噁烷中,0.126mL,0.503mmol)添加到含有(S)-6-(1-((2S,4R)-1-(叔丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯与(S)-6-(1-((2R,4S)-1-(叔丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-环丁氧基-2-甲基-3,4-二氢喹啉-1(2H)-甲酸甲酯的1:1混合物(54.2mg,0.101mmol)于1,4-二噁烷(1.0mL)中的溶液中,且在室温下搅拌反应混合物3小时。在氮气流下浓缩溶液,用饱和碳酸氢钠水溶液(1.0mL)稀释,且用乙酸乙酯(3×1.0mL)萃取。将经合并的有机层直接添加到硅胶栓塞中,且用含30%乙酸乙酯的甲醇洗提产物,得到呈白色固体状的(S)-5-环丁氧基-2-甲基-6-(1-((2S,4R)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯与(S)-5-环丁氧基-2-甲基-6-(1-((2R,4S)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯的1:1混合物(18.1mg,41%)。1HNMR(300MHz,DMSO-d6)δppm 0.81(d,J=6.74Hz,3H),1.05(d,J=6.74Hz,3H),1.22-1.43(m,3H),1.48-1.65(m,2H),1.81-2.22(m,8H),2.34-2.43(m,1H),2.72-2.87(m,2H),2.90-3.00(m,1H),3.10-3.17(m,1H),3.66(s,3H),4.05-4.12(m,1H),4.40-4.52(m,1H),7.21(d,J=8.79Hz,1H),7.30(d,J=9.38Hz,1H),7.78(s,1H),8.08(s,1H)。MS(ESI,正离子)m/z439[M+H]+。
根据上文针对实例107所述的程序制得以下实例:
(S)-5-环丁氧基-2-甲基-6-(1-((2S,4S)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-376)和(S)-5-环丁氧基-2-甲基-6-(1-((2R,4R)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-甲酸甲酯(I-377)
1H NMR(300MHz,DMSO-d6)δppm 0.80(d,J=6.45Hz,3H),1.05(d,J=6.74Hz,3H),1.22-1.43(m,3H),1.48-1.75(m,2H),1.90-2.13(m,8H),2.34-2.45(m,1H),2.58-2.70(m,2H),2.76-2.86(m,1H),2.99-3.05(m,1H),3.66(s,3H),4.02-4.12(m,1H),4.15-4.264.36-4.48(m,1H),7.20(d,J=8.79Hz,1H),7.29(d,J=9.38Hz,1H),7.76(s,1H),8.01(s,1H)。MS(ESI,正离子)m/z 439[M+H]+。
实例108:文库方案A
向半打兰小瓶中装入(S)-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-醇A(0.2M,于N,N-二甲基乙酰胺中,150μL,30μmol)和叔丁醇钾(1M,于THF中,36μL,36μmol),且震荡混合物5秒。添加烷基卤化物B(0.2M,于N,N-二甲基乙酰胺中,180μL,36μmol),且密封系统,且在80℃下震荡14小时。添加乙酸乙酯(0.7mL)和含1N氢氧化钠的盐水(0.5mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(100μL)中。添加芳基硼酸酯C(0.2M,于1,4-二噁烷中,270μL,54μmol)、碳酸钾(1M水溶液,90μL,90μmol)和[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.02M,于1,2-二氯乙烷中,150μL,3μmol),且密封混合物,且在80℃下震荡14小时。添加乙酸乙酯(0.5mL)和含1N氢氧化钠的盐水(0.4mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,得到粗产物。通过质量触发式制备型HPLC纯化这一物质。合并含产物的洗提份且在Genevac中浓缩,得到所需产物。
根据上述方案合成表1中的下列化合物:
表1
实例109:文库方案B
向半打兰小瓶中装入(S)-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-醇A(0.2M,于乙腈中,200μL,40μmol)和芳基卤化物B(0.4M,于乙腈中,200μL,80μmol)。添加碳酸铯(66mg,200μmol),且密封系统,且在80℃下震荡14小时。添加乙酸乙酯(0.7mL)和含1N氢氧化钠的盐水(0.5mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(100μL)中。添加吡唑硼酸酯C(0.2M,于1,4-二噁烷中,360μL,72μmol)和碳酸钾(1M水溶液,120μL,120μmol),且将反应物移到手套箱中。在氮气气氛下添加[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.02M,于1,2-二氯乙烷中,200μL,4μmol),且密封混合物,且在80℃下震荡14小时。添加乙酸乙酯(0.5mL)和含1N氢氧化钠的盐水(0.4mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(200μL)中。添加HCl(4M,于1,4-二噁烷中,100μL),且密封系统,且在50℃下震荡2小时。浓缩混合物,且溶解于乙酸乙酯(500μL)中。将溶液转移到基于二氧化硅的阳离子交换柱(SCX 0.5g),且用乙酸乙酯/甲醇(3:1,3mL)(以洗提废物)、继而用氨(2M,于甲醇中,3mL)(以洗提产物)洗涤。浓缩氨溶液,得到粗产物。通过质量触发式制备型HPLC纯化这一物质。合并含产物的洗提份且在Genevac中浓缩,得到所需产物。
根据上述方案合成表2中的下列化合物:
表2
实例110:文库方案C
向半打兰小瓶中装入(S)-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-醇A(0.2M,于乙腈中,150μL,30μmol)和芳基卤化物B(0.4M,于乙腈中,150μL,60μmol)。添加碳酸铯(50mg,150μmol),且密封系统,且在80℃下震荡14小时。添加乙酸乙酯(0.7mL)和含1N氢氧化钠的盐水(0.5mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(100μL)中。添加芳基硼酸酯C(0.2M,于1,4-二噁烷中,270μL,54μmol)和碳酸钾(1M水溶液,90μL,90μmol),且将反应物转移到手套箱中。接着在氮气气氛下添加[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.02M,于1,2-二氯乙烷中,150μL,3μmol),且密封混合物,且在80℃下震荡14小时。添加乙酸乙酯(0.5mL)和盐水(0.5mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,且通过质量触发式制备型HPLC纯化残余物。合并含产物的洗提份且在Genevac中浓缩,得到所需产物。
根据上述方案合成表3中的下列化合物:
表3
实例111:文库方案D
向半打兰小瓶中装入芳基硼酸B(0.2M,于1,4-二噁烷中,500μL,100μmol)和乙酸铜(II)(0.2M,于水中,260μL,52μmol)。浓缩混合物,且添加分子筛(50mg)。添加(S)-6-溴-2-甲基-1,2,3,4-四氢喹啉-5-醇A(0.2M,于1,2-二氯乙烷中,200μL,40μmol)和吡啶(0.5M,于1,2-二氯乙烷中,400μL,200μmol),且密封系统,且在80℃下震荡14小时。添加乙酸乙酯(0.7mL)和饱和氯化铵水溶液(0.5mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(100μL)中。添加吡唑硼酸酯C(0.2M,于1,4-二噁烷中,400μL,80μmol)和碳酸钾(1M水溶液,120μL,120μmol),且将反应物转移到手套箱中。接着在氮气气氛下添加[1,1-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.02M,于1,2-二氯乙烷中,200μL,4μmol),且密封混合物,且在80℃下震荡14小时。添加乙酸乙酯(0.5mL)和含1N氢氧化钠的盐水(0.4mL),且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(200μL)中。(注意:对于缺乏经Boc保护的中间物的实例,省略以下酸水解步骤和SCX纯化)。添加HCl(4M,于1,4-二噁烷中,100μL),且密封系统,且在50℃下震荡2小时。浓缩混合物,且溶解于乙酸乙酯(500μL)中。将溶液转移到基于二氧化硅的阳离子交换柱(SCX0.5g),且用乙酸乙酯/甲醇(3:1,3mL)(以洗提废物)、继而用氨(2M,于甲醇中,3mL)(以洗提产物)洗涤。浓缩氨溶液,得到粗产物。通过质量触发式制备型HPLC纯化这一物质。合并含产物的洗提份且在Genevac中浓缩,得到所需产物。
根据上述方案合成表4中的下列化合物:
表4
实例112:文库方案E
向反应小瓶中装入6-溴-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉(0.2M,于1,2-二氯乙烷中,0.10mL,0.02mmol)、N,N-二异丙基乙胺(10.5μL,0.06mmol)和酸氯化物或氯甲酸酯(A)(0.5M,于1,2-二氯乙烷中,0.05mL,0.025mmol),且在50℃下震荡混合物2小时。添加乙酸乙酯和水,且震荡混合物。分离有机层,且用乙酸乙酯萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(100μL)中。添加1-环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1H-吡唑(0.2M,于1,4-二噁烷中,0.10mL,0.02mmol)和碳酸氢钠(1M水溶液,0.06mL,0.06mmol),且将反应物转移到手套箱中。接着在氮气气氛下添加[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.02M,于1,2-二氯乙烷中,0.05mL,0.001mmol),且密封混合物,且在80℃下震荡18小时。添加乙酸乙酯和水,且震荡混合物。分离有机层,且用乙酸乙酯萃取水相。浓缩经合并的有机相,得到粗产物。通过质量触发式制备型HPLC纯化这一物质。合并含产物的洗提份且在Genevac中浓缩,得到所需产物。
根据上述方案合成表5中的下列化合物:
表5
实例113:文库方案F
向反应小瓶中装入(S)-1-(6-溴-5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.2M,于N,N-二甲基乙酰胺中,0.100mL,0.02mmol)和(R)-或(S)-3-(溴甲基)吡咯烷-1-甲酸叔丁酯A(0.2M,于N,N-二甲基乙酰胺中,0.12mL,0.024mmol)。添加叔丁醇钾(1M,于THF中,0.024mL,0.024mmol),且密封系统,且在80℃下震荡隔夜。添加乙酸乙酯和含1N氢氧化钠的盐水,且震荡混合物。分离有机层,且用乙酸乙酯萃取水相。浓缩经合并的有机相,且将残余物溶解于无水1,4-二噁烷(100μL)中。添加吡唑硼酸酯B(0.2M,于1,4-二噁烷中,0.15mL,0.030mmol)和碳酸钾(1M水溶液,0.060mL,0.060mmol),且将反应物转移到手套箱中。接着在氮气气氛下添加[1,1′-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷加合物(0.02M,于1,2-二氯乙烷中,0.10mL,2.0μmol),且密封混合物,且在80℃下震荡4小时。添加乙酸乙酯和含1N氢氧化钠的盐水,且震荡混合物。分离有机层,且用乙酸乙酯(1.0mL)萃取水相。浓缩经合并的有机相,得到粗产物。将残余物溶解于1,2-二氯乙烷(0.1mL)中,添加三氟乙酸(0.1mL,1.3mmol),且在室温下搅拌混合物2小时。浓缩反应混合物,且将残余物分配于乙酸乙酯与饱和碳酸氢钠水溶液之间。分离水层且用乙酸乙酯萃取,且在氮气流和真空下浓缩经合并的有机层。通过质量触发式制备型HPLC纯化粗产物。合并含产物的洗提份且在Genevac中浓缩,得到所需产物。
根据上述方案合成表6中的下列化合物:
表6
实例114:文库方案G
向1.5-mL反应小瓶中装入(S)-1-(5-羟基-2-甲基-3,4-二氢喹啉-1(2H)-基)乙酮(0.2M溶液,于N,N-二甲基乙酰胺中,0.1mL,0.02mmol)和叔丁醇钾(1M,于THF中,0.024mL,0.024mmol)。接着添加芳基卤化物(A)(0.2M溶液,于N,N-二甲基乙酰胺中,0.12mL,0.024mmol),且在加热震荡器上加热反应物到80℃隔夜。用乙酸乙酯稀释反应物,且用1N氢氧化钠水溶液洗涤。分离水层且用乙酸乙酯洗涤,且在氮气流和真空下浓缩经合并的有机层。通过质量触发式制备型HPLC纯化粗产物。合并含产物的洗提份且在Genevac中浓缩,得到所需产物。
根据上述方案制得表7中的下列实例:
表7
实例119:AlphaScreen结合分析
使用384孔AlphaScreen分析技术评估实例化合物与BRD4溴域1和BRD4溴域2的结合。将经His表位标记的BRD4 BD144-168和BRD4 BD2333-460克隆,表达,并且纯化到均质。通过使用AlphaScreen技术(PerkinElmer)监测经生物素标记的组蛋白H4(1-21)K5/8/12/16四乙酰基化肽与标靶的接合来评估BRD4 BD1和BRD4 BD2结合和抑制。具体来说,在384孔黑色或白色平底盘中,在50mM HEPES(pH 7.3)、100mM NaCl、0.1%(w/v)BSA和0.01%(w/v)Triton X-100中于DMSO(最终1.25%DMSO)或含化合物连续稀释液的DMSO存在下将BRD4BD1(最终50nM)或BRD4 BD2(最终100nM)与肽(对于BD1最终50nM或对于BD2最终100nM)组合。添加α抗生蛋白链菌素供体珠粒和镍螯合物接受体珠粒,各自达到10μg/ml的最终浓度。最少平衡1小时之后,在BMGPHERAstar FS多标记读取器(BMG LabTech)上读取盘。使用具有四参数逻辑曲线拟合的IDBS Activity Base软件由等式y=A+((B-A)/(1+((C/x)^D)))计算半最大抑制浓度(IC50)值,其中A表示曲线的底部平台,B表示曲线的顶部平台,C表示曲线中间的x值,D表示斜率因子,x表示原始已知x值,且y表示原始已知y值。使用莱文贝格-马夸特演算法(Levenburg Marquardt algorithm)对数据进行拟合。
下表8根据BRD4 BD1的抑制提供代表性化合物的活性。化合物分为四个类别:在<0.1μM的浓度下抑制;在介于0.1μM与1μM之间的浓度下抑制;在介于1μM与10μM之间的浓度下抑制;在>10μM的浓度下抑制。
表8.根据BRD4 BD1的抑制排列的示范性化合物.
*指的是对映异构物的
外消旋混合物
表9提供根据BRD4 BD2的抑制排列的化合物。
化合物分为三个组:IC50<0.05μM;0.05≥IC50≤0.5μM;和IC50>0.5μM。
表9根据BRD4 BD2的抑制排列的示范性化合物
实例120:肿瘤学细胞生长分析
在3天增殖分析中使用急性髓细胞白血病(AML)细胞系MV4-11(ATCC)确定实例化合物对癌细胞增殖的影响。在37℃和5%CO2气氛下将MV4-11细胞维持于补充有10%FBS的RPMI 1640培养基中。对于化合物测试,在384孔白色平底盘中于DMSO中经自2mM到0.001mM的3倍连续稀释来制备化合物连续稀释液。孔中的最终化合物浓度为10、3.3、1.1、0.37、0.12、0.041、0.013和0.0045μM。将MV4-11细胞以3000个细胞/孔的密度涂铺于50μl最终体积的培养基中,且培育72小时。根据制造商建议的方案使用CellTiter-Glo发光细胞存活力分析套组(Promega)测定活细胞的量。在EnVision多标记盘读取器(PerkinElmer)上读取来自CellTiter-Glo分析的发光信号。使用具有四参数逻辑曲线拟合的IDBS Activity Base软件由等式y=A+((B-A)/(1+((C/x)^D)))确定在DMSO对照与背景对照(无细胞)之间使细胞生长抑制50%的值(gIC50),其中A表示曲线的底部平台,B表示曲线的顶部平台,C表示曲线中间的x值,D表示斜率因子,x表示原始已知x值,且y表示原始已知y值。使用莱文贝格-马夸特演算法对数据进行拟合。
表10提供根据MV411细胞系增殖的抑制排列的化合物。化合物分为三个组:IC50<0.5μM;0.5μM≥IC50≤1.0μM;和IC50>1.0μM。
表10.根据MV411的抑制排列的示范性化合物
*指的是对映异构物的
外消旋混合物
在文献中预期且指示,所有BET家族抑制剂对所有BET溴域都具有一定活性。
等效物
尽管已结合上文所阐述的特定实施例描述本发明,但其许多替代、修改和其它变化将为普通技术人员显而易知。所有所述替代、修改和变化打算处于本发明的精神和范围内。
Claims (3)
1.一种化合物,或其药学上可接受的盐,其选自:
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1H-吡唑-5-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-1,2,3,4-四氢喹啉;
1-[6-(4-甲烷磺酰基苯基)-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-(2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基)乙-1-酮;
1-[(2S)-6-(5-甲烷磺酰基吡啶-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
N-{6-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]吡啶-3-基}甲烷磺酰胺;
2-{[(2S)-1-乙酰基-6-(5-甲烷磺酰基吡啶-2-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(1,3-苯并噁唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-丙氧基-6-{吡唑并[1,5-a]吡啶-2-基}-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-{咪唑并[1,2-a]吡啶-2-基}-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1,3-苯并噻唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1H-1,3-苯并二唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-1,2,3,4-四氢喹啉;
5-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1,3,4-噻二唑-2-胺;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
5-[(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-基]-1,3,4-噻二唑-2-胺;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-5-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
2-{[(2S)-1-乙酰基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-5-环丁氧基-2-甲基-6-[1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-(1-{2-甲基-八氢环戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-{2-甲基-八氢环戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-5-{[(E)-2-氯乙烯基]氧基}-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-{1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-6-{1-甲烷磺酰基-1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-6-[2-(4-羟基哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(4-氟哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(1-甲基氮杂环丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(2-氧代基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-(4-氟苯氧基)-2-甲基-6-{1-[(2S)-2-甲基氮杂环丁烷-3-基]-1H-吡唑-4-基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-{1-[(2S)-2-甲基氮杂环丁烷-3-基]-1H-吡唑-4-基}-1,2,3,4-四氢喹啉-1-甲酸甲酯;
N-{4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1-环丙基-1H-吡唑-5-基}甲烷磺酰胺;
N-{4-[(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-1,2,3,4-四氢喹啉-6-基]-1-环丙基-1H-吡唑-5-基}乙酰胺;
(2S)-5-环丁氧基-6-[1-(3-羟基环丁基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[1-甲基-2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-6-(4-甲烷磺酰基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(4-甲烷磺酰基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-[4-(乙烷磺酰基)苯基]-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-[4-(乙烷磺酰基)苯基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-{4-[2-(二甲基氨基)乙氧基]苯基}-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-{4-[2-(二甲基氨基)乙氧基]苯基}-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-2-甲基-6-[3-(吗啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[3-(吗啉-4-羰基)苯基]-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
N-{3-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}甲烷磺酰胺;
2-{[(2S)-1-乙酰基-6-(3-甲烷磺酰胺基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(3-甲烷磺酰基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(3-甲烷磺酰基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
N-{4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}甲烷磺酰胺;
2-{[(2S)-1-乙酰基-6-(4-甲烷磺酰胺基苯基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-2-甲基-6-[4-(吗啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-6-[4-(吗啉-4-羰基)苯基]-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
2-{4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}-1λ6,2-噻唑烷-1,1-二酮;
2-{[(2S)-1-乙酰基-6-[4-(1,1-二氧代基-1λ6,2-噻唑烷-2-基)苯基]-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(1-甲烷磺酰基-2,3-二氢-1H-吲哚-5-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-6-(1-甲烷磺酰基-2,3-二氢-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
N-{4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]苯基}-N-甲基甲烷磺酰胺;
2-{[(2S)-1-乙酰基-2-甲基-6-[4-(N-甲基甲烷磺酰胺基)苯基]-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-6-(1-苯并呋喃-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1H-吲哚-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(1-甲烷磺酰基-2,3-二氢-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(4-甲烷磺酰基苯基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{4-[(2S)-1-乙酰基-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氢喹啉-6-基]苯基}-1λ6,2-噻唑烷-1,1-二酮;
1-[(2S)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
2-{[(2S)-1-乙酰基-2-甲基-1,2,3,4-四氢喹啉-5-基]氧基}-N,N-二甲基乙酰胺;
1-[(2S)-5-(环戊基甲氧基)-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1E)-丙-1-烯-1-基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1Z)-丙-1-烯-1-基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-2-甲基-6-[1-甲基-2-(哌嗪-1-基)-1H-咪唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[2-(哌嗪-1-基)-1,3-噻唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-羟基氮杂环丁烷-1-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-5-环丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-环丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-7,8-二氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-5-环丁氧基-6-(1-环丙基-1H-吡唑-4-基)-7,8-二氟-2-甲基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(1H-吡唑-1-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-3-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-2-甲基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-3-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-1,2,3-三唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-1-环丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-5-环丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-5-环丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-2-甲基-6-[4-(吗啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌啶-4-基)-1H-吡唑-1-基]-1,2,3,4-四氢喹啉;
(2S)-2-甲基-6-[4-(吗啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-6-甲腈;
(2S)-1-环丙烷羰基-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-2-甲基-5-苯氧基-6-(丙-1-炔-1-基)-1,2,3,4-四氢喹啉;
(2S)-6-氰基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-[2-(氮杂环丁烷-3-基)-1,3-噻唑-4-基]-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-氟氮杂环丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-羟基氮杂环丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-[2-(3-甲氧基氮杂环丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-6-(2-氨甲酰基-1,3-噻唑-4-基)-5-环丁氧基-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-2-甲基-6-[2-(甲基氨甲酰基)-1,3-噻唑-4-基]-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-5-环丁氧基-6-(2-乙酰胺基-1,3-噻唑-4-基)-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-6-环丙基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉;
(2S)-6-环丙基-2-甲基-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
(2S)-1-环丙烷羰基-8-氟-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉;
(2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-甲酸甲酯;
1-[(2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
(2S)-1-环丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
2-{[(2S)-1-环丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉-5-基]氧基}苯甲腈;
(2S)-1-环丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
(2S)-1-环丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氢喹啉;
1-[(2S)-6-(1-乙酰基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-甲烷磺酰基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]-1,2,3,6-四氢吡啶-1-甲酸叔丁酯;
1-[(2S)-2-甲基-6-(哌啶-4-基)-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]-N-乙基哌啶-1-甲酰胺;
4-[(2S)-1-乙酰基-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-6-基]哌啶-1-甲酸甲酯;
1-[(2S)-6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氢喹啉-1-基]乙-1-酮;
1-[(2S)-2-甲基-5-(苯基氨基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氢喹啉-1-基]乙-1-酮;和
(2S)-5-环丁氧基-6-[5-氟-1-(哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氢喹啉-1-甲酸甲酯。
2.一种医药组成物,其包含根据权利要求1所述的化合物和药学上可接受的载剂。
3.根据权利要求2所述的医药组成物,其用于抑制有需要的患者中的一个或多个BET家族溴域,其中将以治疗有效量向所述患者投予所述医药组成物。
Applications Claiming Priority (5)
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